APPLICATION OF CHIRAL BORATES IN ASYMMETRIC CATALYSIS AND CHIRAL
RESOLUTION
By
Xiaopeng Yin

A DISSERTATION
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of
Chemistry – Doctor of Philosophy
2018

ABSTRACT
APPLICATION OF CHIRAL BORATES IN ASYMMETRIC CATALYSIS AND CHIRAL
RESOLUTION
By
Xiaopeng Yin
A highly diastereoselective and enantioselective epoxidation of aldehydes with
diazoacetamides has been developed with mesoborate ester catalyst of VANOL. A wide
range of aromatic and aliphatic aldehydes could be employed in this method to afford the
cis-3,4-epoxy amides with good to excellent ee (67 to >99% ee) in good to excellent yield
(47 to 99%). The synthetic application was demonstrated by the synthesis of the sidechain of taxol (6 steps, 63% overall yield). Based on the non-linear effect studies, the
mesoborate catalyst was proposed to consist of two VANOL ligands in contrast to one for
boroxinate catalyst, which was also effective for the same reaction. The mode of
activation for aldehydes was proposed to be via a Lewis acid catalysis mechanism,
supported by NMR studies. The mesoborate catalysts were found to be also effective in
hetero-Diels-Alder reaction of aldehydes with Danishefsky’s diene, aziridination reaction
of imines and ethyl diazoacetate and three-component Passerini reaction of aldehydes.
A simple and efficient chiral resolution of VANOL/BINOL/VAPOL and their
derivatives via the spiroborate formation with quinine/quinidine has been developed. This
method can be applied to 18 different ligands, including 9 new ligands such as 5,5’-, 3,3’and 7,7’-substituted VANOLs. Optically pure ligands could be obtained in up to 47% yield
(50% maximum). These ligands are thought to be useful in optimization and mechanistic
investigation of various asymmetric reactions.

Copyright by
XIAOPENG YIN
2018

This thesis is dedicated to my mother Lihua Chen and my father Dechun Yin who
always supported me, whatever path I chose to take.

iv

ACKNOWLEDGMENTS
Dr Wulff
First and foremost, I would like to thank Dr Wulff for guiding me through the entire
journey with patience and warmth. You really inspire me with your extensive knowledge,
great passion and remarkable work ethic. You are my scientist role model to look up to in
my career. Thank you for showing me what it takes to be a good synthetic chemist in
Saturday meeting; for making literature reading delightful and fruitful in Friday group
meeting; for teaching me how to enjoy life and sharing those fantastic stories in the postgroup meetings and summer/birthday parties. It was privileged to work for you and to
have become a PhD under your supervision, for which I am forever indebted to you.
Babak
I would like to thank Professor Borhan for being second reader of my thesis. I had
the privilege of attending your CEM 845 course, and I must say that is the most
memorable course I ever had. I really appreciate all the advice you have given me during
my time at MSU, especially on choosing my postdoctoral research areas.
Ned and Mitch
I would like to thank both Professor Jackson and Professor Smith for taking your
time to serve on my dissertation committee. I was also fortunate to have taken CEM 956
Computational Organic Chemistry by Ned and the CEM 820 Organometallic Chemistry
by Mitch. The knowledge I learned from these two courses and the perspective you
brought played key roles in my graduate work.

v

The Wulff Lab
Dr Anil Gupta, thanks for your mentorship in my first few months in the lab. Thank
you for teaching me how to set up and run reactions properly. I really appreciate the
advice on research and life you gave me along the way. Dr Hong Ren and Professor
Mathew Vetticatt, working with you has been quite a ride. Both of you had a huge
influence on the way I think about organic chemistry. I thank Mathew for teaching me
summit DFT jobs for Gaussian calculation and all the hard work you put in for the KIE
studies for my second-year oral exam. Dr Yong Guan, Dr Wenjun Zhao and Dr Xin Zhang,
thank you guys for teaching me both chemistry and how to survive the second-year
seminar. Without you guys, I would definitely be much more frustrated. Dr Yubai Zhou, it
has been a pleasure to start my journey in the Wulff Lab with you. I am really glad that
we had so many good and bad memories together. I hope that your research at
Northwestern goes well and that you finally get the job you desired. Yijing, you were a
truly nice labmate and I am wishing you all the best for the job search. I am sure you will
do great in whatever path you choose. Ali, I had a great time collaborating with you on
the Chameleon project. You taught me a lot with your excellent skills in growing crystals.
You truly are a very motivated and intelligent individual. I have a feeling you will achieve
a lot in the Wulff Lab. Li, one of a few “real labmates” in lab room 532, I really enjoyed
your company. You are the friend that felt like I have known for a long time. You are
capable of doing great things inside or outside chemistry. Thanks for all the sense of
humor you brought to room 532 and the assistance that I really need in the last few
months. I have also been fortunate to mentor and work with several undergraduates in

vi

the lab, Kelsee, Robert and Benjamin. Thank you for your hard work and upbeat attitude.
And I would like to express my sincere gratitude to Ken Wilson and Yu Zhang, former
member of the Wulff lab, for the encouraging and supporting in my searching for the new
position.
Friends outside the Wulff Lab
Hadi, Bardia, Aritra, Jun, Kumar, Arvind, Dan, Saeedeh, Debarshi and many others
from the Borhan lab, you are great group of chemists and friends. I am going to miss all
the fun and laughter we had in the lab and the campsite. Dr Yinan Shu, I had a great time
having Starbucks coffee or dinner with you in the first 3 years. I have learned a lot about
chemistry and gossip in the department from you and I have no doubt that you are going
to be an excellent professor. Dr Peng Zhang, former member of our lunch club and current
members, Wei Sheng, Xinliang Ding and Shuang Gao, and our hot pot buddies, Peng
Wang and Jun Zhang I already miss the interesting talks we had during our lunches in
the study room at the 5th floor and in the hot pot parties. I can’t imagine how I can survive
my PhD without you guys.
Mentors before graduate school
I would like to thank a handful of people who have had a profound impact on the
path I have taken. First, I thank Mr Xu, my high school chemistry teacher, for being an
inspirational instructor with patient and great organizational skills. Dr Hao Sun, my
undergraduate mentor at Nanjing University, I owe most of what I know about column
chromatography, hard effort in the lab, and value of clean, organized bench to you.
Finally, I have to thank Professor William Reusch, for creating the Virtuall Textbook of

vii

Organic Chemistry, which I came across when I took organic chemistry course in my
sophomore year. It was this book that make me appreciate the mechanism, and enjoy the
logic and reasoning in organic chemistry. And that was my first encounter with Michigan
State University.
Faculty and Staff in Department of Chemistry at MSU
It has been an absolute pleasure to work with Professor Frost, Professor Geiger,
Dr Azadnia, Dr Vasileiou and Dr Pollock as TA for various courses in Chemistry. You all
have been nice and kind to me even though you have quite different personalities. I have
learned a lot about teaching chemistry from you. Thank you for giving me the opportunities
to interact with many undergraduate students with talent and enthusiasm in chemistry. I
would like to thank Dr Holmes and Dr Li for their time in my NMR training and DOSY
studies. I thank Dr Staples for his efforts in selecting samples from many of my attempts,
solving the X-ray structures of several compounds of mine and teaching me growing
single crystals patiently. I also thank Professor Jones, Dr Chen and Dr Schilmiller for their
assistance at Mass Spectrometry Facility at MSU. In addition, I thank Joni, Marvey, Heidi
Eric, Tom, Bob, Bill and many other staff in the department for being friendly and helpful
all the time.
Athletics in MSU
One of the reasons that there isn’t another institute I would rather finish a PhD than
Michigan State University is the sport here. I have been really fortunate to witness the
golden era of Spartan sports during my time. I would like to give a special shout-out to
Coach Dantonio and Coach Izzo not only for building two successful sport teams I really

viii

enjoy watching and cheering for, but also for being two classy and well-respected
individuals.
Yi Yi
It is so amazing to have you by my side. Thank you for your crucial support through
the journey. Without you, I would be 99% less happy during my time here. I am happy
that things have led us to exactly where we are now, and I look forward to our next chapter
in life.

ix

TABLE OF CONTENTS

LIST OF TABLES .......................................................................................................... xiii
LIST OF FIGURES ......................................................................................................... xv
LIST OF SCHEMES ...................................................................................................... xvi
CHAPTER ONE VANOL MESOBORATE CATALYSIS –– ASYMMETRIC
EPOXIDATION OF ALDEHYDES AND DIAZOACETAMIDES ........................................ 1
1.1 Asymmetric epoxidation ...................................................................................... 1
1.2 Boron catalysts in asymmetric catalysis .............................................................. 6
1.3 Optimization and KIE study of epoxidation catalyzed by VANOL-boroxinate ... 20
1.4 Screening of aniline as base additive ................................................................ 27
1.5 Discovery of VANOL meso-borate catalyst ....................................................... 29
1.6 Ligand comparison and a distinction between two catalysts ............................. 34
1.7 Reaction scope ................................................................................................. 39
1.8 Gram-scale reaction and synthesis of Taxol-side chain .................................... 44
1.9 NMR studies and DFT calculations ................................................................... 47
1.10 Hetero Diels-Alder reactions (HDA) catalyzed by VANOL mesoborates ........ 57
1.11 Passerini reaction and aziridination reaction ................................................... 64
1.12 Asymmetric aziridination and future work ....................................................... 73
REFERENCES ............................................................................................................... 79
CHAPTER TWO CHIRAL RESOLUTION OF VANOL/VAPOL DERIVATIVES ............. 90
2.1 Strategies in optical resolution .......................................................................... 90
2.2 Resolution of Bi-2-naphthol (BINOL) ................................................................. 93
2.3 VANOL/VAPOL derivatives and deracemization .............................................. 98
2.4 Discovery of resolution system for tBuVANOL by trial and error .................... 102
2.5 Condition optimization and scale up ............................................................... 111
2.6 Synthesis and resolution of VANOL derivatives .............................................. 116
2.6.1 Synthesis of 5,5’-disubstituted VANOL derivatives .................................. 117
2.6.2 Synthesis of 3,3’-disubstituted VANOL derivatives .................................. 122
2.6.3 Synthesis of 7,7’-disubstituted VANOL ..................................................... 122
2.6.4 Synthesis of 7,7’-Ad2VANOL .................................................................... 124
2.6.5 Resolution scope with quinine .................................................................. 128
2.6.6 Resolution scope with quinidine ............................................................... 130
2.7 Stability of 5,5’-substituted VANOL derivatives ............................................... 132
2.8 Crystallization-induced dynamic resolution ..................................................... 135
2.9 Computational Model ...................................................................................... 138
2.10 Conclusion and outlook ................................................................................. 142
REFERENCES ............................................................................................................. 143

x

CHAPTER THREE DEVELOPMENT OF OTHER STRATEGIES FOR THE
SYNTHESIS OF VANOL MONOMER ...................................................................... 152
3.1 Strategies of 1-naphthol synthesis .................................................................. 152
3.2 Syntheses of 3-phenyl-1-naphthol .................................................................. 159
3.3 Syntheses of 3,3’-dialkyl-VANOL .................................................................... 177
REFERENCES ............................................................................................................. 184
CHAPTER FOUR EXPERIMENTAL SECTION ........................................................... 188
4.1 General Experimental ..................................................................................... 188
4.2 Experimental for Chapter One ........................................................................ 191
4.2.1 Preparations of diazo compounds ............................................................ 191
4.2.2 General Procedure B for symmetric epoxidation catalyzed
by Boroxinate I-103a (Table 1.2) -- illustrated for benzaldehyde
I-51a and N-butyl-2-diazoacetamide I-23a ............................................... 203
4.2.3 Protonation/nucleophilic addition to I-23b ................................................ 210
4.2.4 Optimization of asymmetric epoxidation using N-phenyl diazoacetamide
I-107b (Table 1.3) -- illustrated by entry 16 .............................................. 210
4.2.5 KIE samples preparation (Table 1.4) -- illustrated by set 2 ...................... 212
4.2.6 Epoxidation catalyzed by boroxinate with aniline (Table 1.5) -- illustrated
by entry 16 ............................................................................................... 214
4.2.7 Evolution of catalyst (Table 1.6) -- illustrated by entry 3 ........................... 216
4.2.8 Optimization of condition for epoxidation catalyzed by
mesoborate I-118 (Table 1.7) -- illustrated by entry 9 .............................. 218
4.2.9 Catalyst loading and stability study (Table 1.8 & 1.9) -- illustrated by
entry 3 for both ........................................................................................ 220
4.2.10 Ligand effect in epoxidation catalyzed by mesoborate I-118
(Table 1.10) -- illustrated by entry 6 ........................................................ 223
4.2.11 PhOH additive studies (Table 1.11) -- illustrated by entry 3 ................... 226
4.2.12 Nonlinear effect study on two catalytic systems (Table 1.12) -- illustrated
by entry 7 ................................................................................................ 228
4.2.13 General Procedure C for substrate scope study with respect to aldehydes
(Scheme 1.14) -- illustrated for I-111a .................................................... 231
4.2.14 Substrate scope with respect to diazoacetamides (Scheme 1.15) ......... 265
4.2.15 Gram-scale synthesis of cis-epoxide I-108a (Scheme 1.16) .................. 272
4.2.16 Synthesis of Taxol-side chain I-146 (Scheme 1.18) ............................... 274
4.2.17 NMR studies and DFT calculations ........................................................ 281
4.2.18 Synthesis of Danishefsky’s diene I-56a and related
compound I-56b-d (Scheme 1.21) .......................................................... 289
4.2.19 General procedure E for HDA reactions catalyzed by
mesoborate I-118 (Table 1.13) -- illustrated for the reaction of 4bromobenzaldehyde I-51f and Danishefsky’s diene I-56a with VANOL
ligand ...................................................................................................... 292
4.2.20 General procedure F for 3C Passerini reaction catalyzed by VANOL
mesoborate I-118 (Scheme 1.23) -- illustrated for the reaction with 4-

xi

bromobenzaldehyde I-51f, and tbutyl isocyanide I-101 with benzoic acid I174a ........................................................................................................ 294
4.2.21 General procedure G for aziridination reaction of benzhydryl imine
I-176 and ethyl diazoacetate I-94 (Table 1.22) -- illustrated by using
VANOL boroxinate catalyst I-90b ........................................................... 301
4.3 Experimental for Chapter Two ........................................................................ 304
4.3.1 Synthesis of (Âą)-tBuVANOL II-46b (Scheme 2.10) ................................... 304
4.3.2 Resolution of tBuVANOL and recovery of quinine (Scheme 2.18) ........... 309
4.3.3 Synthesis of 5,5’-R2VANOL (Table 2.2).................................................... 312
4.3.4 Synthesis of 5,5’-tBu2VANOL (Scheme 2.23)........................................... 320
4.3.5 Synthesis of 5,5’-CN2VANOL (Scheme 2.24) ........................................... 325
4.3.6 Synthesis of 3,3’-R2-phenyl VANOL (Table 2.3) ....................................... 326
4.3.7 Synthesis of 7,7’-R2VANOL (Scheme 2.25) ............................................. 331
4.3.8 Synthesis of 7,7’-Ad2VANOL (Scheme 2.27)............................................ 339
4.3.9 General Procedure M for chiral resolution of VANOL derivatives with
quinine borates (Table 2.4) -- illustrated for resolution of
(±)-5,5’-Br2VANOL rac-II-46c .................................................................. 344
4.3.10 General Procedure N for chiral resolution of VANOL derivatives with
quinidine borates (Table 2.5) -- illustrated for resolution of
(±)-5,5’-Br2VANOL rac-II-46c ................................................................. 359
4.3.11 Crystallization-induced dynamic resolution of VANOL (Table 2.7) ......... 369
4.3.12 Computational Model of VANOL borates with quinine/quinidine ........... 371
4.4 Experimental for Chapter Three ...................................................................... 383
4.4.1 Synthesis of 2'-iodoacetophenone III-28 (Scheme 3.7) ............................ 383
4.4.2 CuCl2-catalyzed arylation/cycloaromatization reaction ............................. 384
4.4.3 Syntheses of o-alkynylacetophenone III-74 (Scheme 3.14) ..................... 388
4.4.4 Base-promoted cycloaromatization (Scheme 3.15) .................................. 392
4.4.5 Syntheses of 3,3’-dialkylVANOL (Scheme 3.15) ...................................... 396
4.4.6 General Procedure S for deracemization of 3,3’-dialkylVANOL
(Scheme 3.16) -- illustrated for 3,3’-Cy2VANOL III-76a ........................... 399
4.4.7 Aziridination catalyzed by boroxinate of
3,3’-dialkylVANOL (Scheme 3.17) ........................................................... 401
REFERENCES ............................................................................................................. 403

xii

LIST OF TABLES

Table 1.1 Scope of boroxinate catalyzed asymmetric epoxidation ................................ 20
Table 1.2 Boroxinate catalyzed asymmetric epoxidation ............................................... 22
Table 1.3 Optimization of asymmetric epoxidation using N-phenyl diazoacetamide	I107b ............................................................................................................... 24
Table 1.4 KIE samples preparation ................................................................................ 25
Table 1.5 Epoxidation catalyzed by boroxinate with various anilines as
base additive .................................................................................................. 28
Table 1.6 Evolution of catalyst ....................................................................................... 30
Table 1.7 Optimization of condition for epoxidation catalyzed by mesoborate I-118 ..... 31
Table 1.8 Catalyst loading study .................................................................................... 33
Table 1.9 Catalyst stability study ................................................................................... 34
Table 1.10 Ligand effect in epoxidation catalyzed by mesoborate I-118 ....................... 36
Table 1.11 Effect of PhOH in epoxidation catalyzed by mesoborate I-118 .................... 36
Table 1.12 Nonlinear effect study on two catalytic systems .......................................... 38
Table 1.13 Temperature and ligand screening for HDA reaction ................................... 60
Table 1.14 Studies of time and temperature for HDA reaction ...................................... 61
Table 1.15 Solvent screening for HDA reaction ............................................................. 62
Table 1.16 Additive studies for HDA reaction ................................................................ 63
Table 1.17 Early attempts of asymmetric 3-component Passerini reaction ................... 68
Table 1.18 Temperature screening of the Passerini reaction catalyzed by
mesoborate I-118 ........................................................................................ 69

xiii

Table 1.19 Solvent screening of Passerini reaction catalyzed by mesoborate I-118 ..... 70
Table 1.20 Ligand screening of Passerini reaction catalyzed by mesoborate I-118 ...... 70
Table 1.21 Effect of DMSO in Passerini reaction catalyzed by mesoborate I-118 ........ 71
Table 1.22 Asymmetric aziridination of imine I-176 with EDA I-94 catalyzed by
spiroborate I-118b and boroxinate I-90b ..................................................... 74
Table 2.1 Optimization of the Resolution of tBuVANOL .............................................. 111
Table 2.2 Synthesis of 5,5’-R2VANOL ......................................................................... 118
Table 2.3 Synthesis of 3,3’-R2VANOL ......................................................................... 122
Table 2.4 Scope of resolution of VANOL derivatives with quinine borates .................. 130
Table 2.5 Scope of resolution of VANOL derivatives with quinidine borates ............... 132
Table 2.6 Racemization experiments with 5,5’-R2VANOL ........................................... 133
Table 2.7 Crystallization-induced dynamic resolution of VANOL ................................. 136
Table 2.8 Structural properties of optimized DFT structures of quinine/quinidine borates
with VANOL derivatives ............................................................................... 141
Table 3.1 Initial optimization of the arylation/cycloaromatization reaction ................... 165
Table 3.2 Additive effect study of the arylation/cycloaromatization reaction ................ 167
Table 3.3 Optimization of CuCl2-catalyzed arylation/cycloaromatization reaction ....... 168
Table 3.4 Further optimization of CuCl2-catalyzed arylation/cycloaromatization
reaction ....................................................................................................... 170
Table 3.5 Optimization of conditions for CuCl2-catalyzed arylation/cycloaromatization
reaction ........................................................................................................ 173
Table 3.6 Further optimazation of conditions for CuCl2-catalyzed
arylation/cycloaromatization reaction ........................................................... 174
Table 3.7 Optimization of base-promoted cycloaromatization ..................................... 180

xiv

LIST OF FIGURES

Figure 1.1 X-ray Structure of boroxinate-imine complex ............................................... 15
Figure 1.2 Experimental 13C KIE for the reaction of N-phenyl diazoacetamide I-107b . 26
Figure 1.3 Yield of epoxide I-129a for non-linear studies .............................................. 39
Figure 1.4 Non-linear effect studies on two catalysts .................................................... 39
Figure 1.5 11B NMR spectra of mesoborate I-118 and DMSO titration studies ............. 49
Figure 1.6 13C NMR spectra of mesoborate I-118 and DMSO titration studies ............. 50
Figure 1.7 11B NMR spectra of mesoborate I-118 with benzaldehyde .......................... 51
Figure 1.8 1H NMR spectra of mesoborate I-118 with benzaldehyde............................ 52
Figure 1.9 11B NMR spectra of mesoborate I-118 with 10 equiv benzaldehyde ............ 53
Figure 1.10 11B NMR spectra of mesoborate I-118 with additives................................. 54
Figure 1.11 Lowest-energy ground-state structure of mesoborate I-118 at the
B3LYP/6-31G(d) level ................................................................................ 55
Figure 1.12 Lowest-energy ground-state structure of mesoborate I-118 bound to DMSO
at the B3LYP/6-31G(d) level ..................................................................... 55
Figure 1.13 Proposed role of DMSO ............................................................................. 56
Figure 2.1 a) Sorting (R)-tBuVANOL crystals by tweezers; b) One (R)-tBuVANOL
crystal ......................................................................................................... 115
Figure 2.2 spiroBorate ester of (S)-VANOL with quinine II-102 ................................... 138
Figure 2.3 Possible geometries of VANOL quinine borates at the
B3LYP/6-31G(d) level................................................................................ 139
Figure 4.1 Home-made 50 mL Schlenk flask .............................................................. 190
Figure 4.2 Geometries of 2:1 mesoborate catalyst at the B3LYP/6-31G(d) level ........ 281
Figure 4.3 Geometries of DMSO-mesoborate complex at the B3LYP/6-31G(d) level 281

xv

LIST OF SCHEMES

Scheme 1.1 Catalytic Asymmetric Alkene Epoxidation ................................................... 2
Scheme 1.2 Asymmetric Corey-Chaykovsky Reaction ................................................... 3
Scheme 1.3 Asymmetric Darzens Reaction .................................................................... 4
Scheme 1.4 Asymmetric Epoxidation of Aldehydes with Diazoacetamides .................... 4
Scheme 1.5 Asymmetric Epoxidation of Electron-Deficient Alkenes ............................... 5
Scheme 1.6 Historical perspective of boron catalysts in organic chemistry
before 1990 ................................................................................................. 7
Scheme 1.7 Kaufmann’s propeller catalyzed ADA reaction ............................................ 8
Scheme 1.8 Proposed mechanism for the CBS reduction .............................................. 9
Scheme 1.9 Borate catalysts by Yamamoto .................................................................. 10
Scheme 1.10 Activated oxazaborolidine catalysts ........................................................ 14
Scheme 1.11 Boroxinate catalysts by Wulff ................................................................. 18
Scheme 1.12 Syntheses of diazoacetamide I-23 .......................................................... 21
Scheme 1.13 Protonation/nucleophilic addition to I-23b ............................................... 22
Scheme 1.14 Substrate scope of asymmetric epoxidation with mesoborate catalyst
I-118: variation of aldehydes ................................................................... 41
Scheme 1.15 Substrate scope of asymmetric epoxidation with mesoborate catalyst
I-118: variation of diazo compounds........................................................ 43
Scheme 1.16 Gram-scale synthesis of cis-epoxide I-108a ........................................... 44
Scheme 1.17 Synthetic strategies of taxol and the taxol side chain I-146 .................... 46
Scheme 1.18 Synthesis of the taxol side chain I-146 .................................................... 47

xvi

Scheme 1.19 Hetero Diels-Alder reaction of Danishefsky’s diene I-57a
with aldehydes ......................................................................................... 58
Scheme 1.20 HDA reaction of Danishefsky’s diene I-56a with aldehydes catalyzed
by boroxinate catalyst ............................................................................. 59
Scheme 1.21 HDA reaction of Danishefsky’s diene I-56 with different silyl group ........ 64
Scheme 1.22 Enantioselective Passerini reaction ......................................................... 66
Scheme 1.23 Screening of acid component for 3C Passerini reaction catalyzed by
spiroborate I-118 ..................................................................................... 73
Scheme 1.24 Potential applications of asymmetric epoxidation in total synthesis ........ 76
Scheme 2.1 General scheme of classical resolution ..................................................... 90
Scheme 2.2 Commonly used resolving agents ............................................................. 92
Scheme 2.3 Resolution of BINOL (1) ............................................................................ 94
Scheme 2.4 Resolution of BINOL (2) ............................................................................ 95
Scheme 2.5 Resolution of BINOL (3) ............................................................................ 96
Scheme 2.6 Resolution of BINOL (4) ............................................................................ 97
Scheme 2.7 Application of tBuVANOL and VAPOL derivatives .................................. 100
Scheme 2.8 Most commonly used route to BINOL and VANOL derivatives ............... 101
Scheme 2.9 Deracemization of tBuVANOL II-46b ....................................................... 101
Scheme 2.10 Synthesis of (Âą)-tBuVANOL	II-46b ........................................................ 103
Scheme 2.11 Resolution of VANOL with (–)-brucine and 1st attempt with
tBuVANOL ........................................................................................... 104
Scheme 2.12 Resolution of VANOL via Camphorsulfonate and 2nd attempt with
tBuVANOL ............................................................................................. 105
Scheme 2.13 Resolution of BINOL via inclusion complex formation and 3rd and 4th
attempt with tBuVANOL ........................................................................ 107
Scheme 2.14 5th resolution attempt via Boc-tryptophan ester .................................... 108

xvii

Scheme 2.15 Resolution of BINOL via cyclic borate ester with quinine and 7th
attempt with tBuVANOL ........................................................................ 109
Scheme 2.16 Resolution of BINOL via spiroborate ester with quinine and 8th attempt
with tBuVANOL ..................................................................................... 110
Scheme 2.17 Recovery of quinine .............................................................................. 112
Scheme 2.18 Attempted resolution to get access to (R)-tBuVANOL ........................... 113
Scheme 2.19 Enantiomeric excess enhancement by recrystallization ....................... 114
Scheme 2.20 Enantiomeric excess enhancement by hexanes wash .......................... 115
Scheme 2.21 Resolution of tBuVANOL ....................................................................... 116
Scheme 2.22 Application of selected 7,7’-disubstituted VANOL derivatives ............... 117
Scheme 2.23 Synthesis of 5,5’-tBu2VANOL ................................................................ 119
Scheme 2.24 Synthesis of 5,5’-CN2VANOL ................................................................ 121
Scheme 2.25 Synthesis of 7,7’-R2VANOL .................................................................. 123
Scheme 2.26 Ligands/catalysts containing adamantyl group and their applications ... 126
Scheme 2.27 Synthesis of 7,7’-Ad2VANOL ................................................................. 128
Scheme 2.28 Racemization of 5,5’-(CF3)2VANOL ....................................................... 133
Scheme 2.29 Proposed pathway for racemization BINOL and VANOL ...................... 135
Scheme 3.1 Benzannulation via a vinylketene intermediate ....................................... 154
Scheme 3.2 Synthesis of 1-naphthols via addition/condensation cascade ................. 156
Scheme 3.3 Acid/base-promoted cycloaromatization .................................................. 157
Scheme 3.4 Synthesis of 1-naphthols via Diels Alder [4+2] cycloaddition .................. 158
Scheme 3.5 Synthesis of 1-naphthols via ring expansion ........................................... 159
Scheme 3.6 Synthesis of VANOL monomer III-30 ...................................................... 160
Scheme 3.7 Synthesis of 2'-iodoacetophenone III-28 ................................................. 162
xviii

Scheme 3.8 Copper-catalyzed coupling/cycloaromatization reaction ......................... 163
Scheme 3.9 Base-promoted arylation of acetophenone III-29 with iodobenzene ....... 163
Scheme 3.10 CuCl2-catalyzed arylation/cycloaromatization reaction with other ohaloacetophenone substrates .............................................................. 171
Scheme 3.11 1H NMR analysis of the mixtures of 3-aryl-1-naphthols ......................... 172
Scheme 3.12 Proposed mechanism for CuCl2-catalyzed
arylation/cycloaromatization reaction .................................................... 176
Scheme 3.13 Synthesis of 3-(4-(trifluoromethyl)phenyl)-1-naphthol ........................... 177
Scheme 3.14 Syntheses of o-alkynylacetophenones III-74 via the Sonogashira
Coupling ................................................................................................ 178
Scheme 3.15 Syntheses of 3,3’-dialkylVANOL ............................................................ 181
Scheme 3.16 Deracemization of 3,3’-dialkylVANOL ................................................... 182
Scheme 3.17 Aziridination catalyzed by boroxinate of 3,3’-dialkylVANOL .................. 183

xix

CHAPTER ONE
VANOL MESOBORATE CATALYSIS –– ASYMMETRIC EPOXIDATION
OF ALDEHYDES AND DIAZOACETAMIDES

“Everything should be made as simple as possible, but no simpler.”
– Albert Einstein

1.1 Asymmetric epoxidation
Chiral epoxides are important building blocks and widely used in asymmetric
synthesis of complex molecules because of the versatility in their ring opening by
nucleophiles. Asymmetric epoxidation has been extensively studied for over 30 years.
Most of the efforts have been focused on asymmetric alkene epoxidation, of which three
successful examples are shown in (Scheme 1.1). The Sharpless epoxidation1-2 is one of
the most widely used methods in asymmetric oxidation and earned him a share of the
2001 Noble Price in chemistry. The reaction is limited to allylic alcohols but proceeds in
high enantioselectivity with virtually any substitution pattern on the alkenes. Katsuki3 and
Jacobsen4 pioneered the asymmetric epoxidation of unfunctionalized olefins catalyzed by
Mn(salen) catalyst. The Jacobsen-Katsuki epoxidation can be applied to mono-, di-, tri-,
and tetrasubstituted aryl olefins. However, trans-alkenes and cis-dialkyl alkenes are
generally poor substrates (slow and low ee) for Mn(salen) and related systems5. Another
efficient asymmetric epoxidation with a wide scope substrates was pioneered by Shi6-7.
The reaction is mediated by dioxiranes, which are generated in situ from fructose-derived
ketone catalysts I-8 and Oxone as an oxidant. By carefully tuning the ketone catalysts,

1

this methodology displays a broad generality for alkene with different substitution
patterns. The major drawbacks include difficult set up (slow addition of Oxone, careful
control of pH to ensure consistent result) and the unequal accessibility of the enantiomeric
catalyst.
Scheme 1.1 Catalytic Asymmetric Alkene Epoxidation
Sharpless Epoxidation2 (1980)
5-10 mol% Ti(Oi-Pr)4,
6-12 mol% (+)-dialkyl tartrate
I-2a or I-2b

R3
R1

OH
R2
I-1

R1

O

OH

R3
OH

R2 I-3
excellent enantioselectivity

tBuOOH, 3Å or 4Å MS
DCM, –20 ºC

R

O

O

O

R

O
OH
R = Et, (+)-DET I-2a
R = iPr, (+)-DIPT I-2b

Jacobsen Epoxidation4 (1990)
2-8 mol% (S,S)-Mn(salen) I-5
20 mol% NMO

R3
R1

R4

mCPBA/NaOCl
DCM

R2
I-4

R1

O

R3

H

H
N

R4
R2

I-6
excellent enantioselectivity
with cyclic alkenes

Mn
O Cl O

I-5

Shi Epoxidation7 (1996)

R1

R3
R2
I-7

N

20-30 mol% ketone I-8,
oxone

R1
R2

pH 10.5, base,
H2O, CH3CN

O

O

R3

I-9

excellent enantioselectivity
with trans-di- and trisubstituted alkenes

O

O
O

O
O
I-8a

A complementary approach to chiral epoxides from alkenes is the addition of either
an ylide, a Darzens reagent or a carbene to an aldehyde (Scheme 1.2-4). The
enantioselective Corey-Chaykovsky reaction was developed by many groups since its
first report8 by Furukawa et al in 1989 (a, Scheme 1.2).

2

Scheme 1.2 Asymmetric Corey-Chaykovsky Reaction
a) Furukawa et al.8
O
H

+

Br

1.0 equiv I-12
KOH, CH3CN, rt, 36 h

I-11
2.2 equiv

I-10
1.9 equiv

O
Ph

Ph

I-13
100%, 47% ee

OH
SMe
I-12

b) Aggarwal, McGarrigle, et al.9

O

+
S
R1

OTf

R2

O

KOH, CH3CN/H2O (9:1),
H

0 ÂşC, 12-24 h

R1

R2
I-16

28 examples,
75:25 - 99:1 dr
up to >99% ee

I-15
I-14
1
2
R = aryl, alkenyl; R = aryl, alkenyl, alkyl

The lack of synthetic applications of this methodology in the literature can be attributed to
1) limited substrate scope with excellent (>90%) ees; 2) stoichiometric amount of chiral
sulfide is used to ensure high yield and enantioselectivity. Aggarwal and coworkers
demonstrated9 a practical process using a cheap sulfide to prepare chiral trans-epoxides
in moderate to good yields and up to >99% ees (b, Scheme 1.2). The first catalytic
asymmetric Darzens reaction was reported10 by Arai and Shioiri in 1998 (a, Scheme 1.3).
The desired product was afforded using 10 mol% phase transfer catalyst (PTC) I-18a in
moderate to high yield with up to 79% ee. In 2011, Deng and coworkers reported11 a
synthetically useful procedure using their modified PTC I-18b, with a phenanthracenyl
group in the 9-position and a hydroxyl group in the 6’-position (b, Scheme 1.3). The
reaction gave excellent yield with good to excellent enantioselectivity. Feng et al
reported12 a Co-catalyzed Darzens reaction of isatins with phenacyl bromides (c, Scheme
1.3). A wide range of optically active products were obtained in moderate to good yields
and enantioselectivities.

3

Scheme 1.3 Asymmetric Darzens Reaction
a) Arai and Shioiri10
10 mol% PTC I-18a,

O
RCHO +
I-15
R = aryl, alkyl

Cl

Ph
I-17a

LiOH•H2O,
n-Bu2O, 4 ÂşC

O

O

R

Ph
I-19a

9 examples,
32-83% yield
42-79% ee

N

R2 O

Ar

R1

Br

b) Deng et al.11
N
5 mol% PTC I-18b,

O
RCHO

Cl

Ar
I-17b

I-15
R = aryl, alkyl

LiOH•H2O,
DCM, 0 ÂşC, 24 h

O
R

R1 =

O

Ar
I-19b

H,

R2

= H, Ar = 4-CF3C6H5,
PTC I-18a;

R1 = OH, R2 = 9-phenanthracenyl,
Ar = 3,4,5,-F3C6H2, PTC I-18b

10 examples,
90-96% yield
81-99% ee

c) Feng et al.12
O
O
O +

R1

Br

N
PG

R2
I-17c

I-20

O

1.1 mol% Co(acac)2
10 mol% I-21
[K3PO4]/[K2PO4] (10/1)
THF/acetone (3:1),
5A MS, –30 ºC

R1

O

N
O

R2

N
PG
I-22

O

34 examples,
35-99% yield
51-95% ee

N
O

N H
H N
I-21
Ar
Ar

O

Ar = 2,4,6-iPr3C6H2

Scheme 1.4 Asymmetric Epoxidation of Aldehydes with Diazoacetamides
O

O
+
R

H

N2

I-15

O

O
+
R

N
H
I-23b

H

I-15

N2

N
H
I-23b

10 mol% (R)-BINOL/Ti(OiPr)4
CH2Cl2, 4A MS, 0 ÂşC, 1 h

O
R

CONHPh

28 examples
52-95% yield
87-99% ee

(S,S)-I-26
10 mol% (R)-3,3’-I2BINOL/Zr(OnBu)4
3A MS, CHCl3, rt

O
R

CONHPh

26 examples
73-97% yield
91-99% ee

(R,R)-I-26

In 2009, Gong and co-workers reported13 a breakthrough, where they reacted
aldehydes with diazoacetamides I-23b catalyzed by a Ti/BINOL complex to prepare
epoxides with excellent yields and ees. They later reported14 excellent results could also
be obtained with a Zr/3,3’-I2BINOL system (Scheme 1.4).

4

Scheme 1.5 Asymmetric Epoxidation of Electron-Deficient Alkenes
a)

b)

[O]

O
R

EWG

low dr/ee

[O]

O

EWG
R

R

R

EWG

N

O

EWG

high yield
excellent dr/ee

O

CO2Et

N

(2R,3R)-I-25
91%, 97% ee

N

CO2Et

OTf
Fe

2 mol% I-26, H2O2 (1.6 equiv),
3 mol% S-Ibuprofen, CH3CN, –30
ÂşC, 30 min

N

(2S,3R)-I-25
73%, 96% ee

OTf

N

O

O
O

AcO
OAc

20 mol% I-8b, Oxone (5.0 equiv),
6 mol% BuNHSO4, CH3CN
NaHCO3 (14.4 euqiv), 0 ÂşC, 24 h

Fe(PDP) I-26 N

O

O

I-8b

O

OH

O
I-27
80%, 96% ee

CO2Et

O

OH
OH

10 mol% Yb-I-28,
TBHP (3 equiv),
THF, 4A MS, rt, 127 h

(2R,3S)-I-25
89%, 99% ee
2 mol% Y-I-29-Ph3P=O (1:1:1)
TBHP (1.2 equiv), THF, 4A MS, rt

I-28

OH
OH

O
O

I-29

One of the key aspects of this transformation is that cis-epoxide products are
difficult to synthesize from the cis-ι,β-unsaturated carbonyl compounds. In contrast to
trans-epoxides, which can be obtained by epoxidation of trans-ι,β-unsaturated carbonyl
compounds with excellent ees using a variety of methodologies15, such as Shi
epoxidation16 and the nucleophilic epoxidation method developed17 by Shibasaki (b,
Scheme 1.5). The cis-substrates under the same conditions usually gave mixture of cisand trans-epoxides with moderate ees. Only two catalytic systems provide the cisepoxides

from

electron-deficient

cis-alkene

with

both

high

diastereo-

and

enantioselectivities (a, Scheme 1.5). Costas reported18 a highly enantioselective
Fe(PDP)19 catalyst I-26 for asymmetric epoxidation with H2O2. Excellent ee could be
obtained by the use of a catalytic amount of a carboxylic acid additive. They also
obtained20 I-25 with slightly higher enantioselectivity (98% ee) but in lower yield (77%)

5

using Mn(PDP) catalyst. However, the substrate scope of their methodologies was limited
to aryl alkenes. Shibasaki reported21 asymmetric epoxidation of cis-enones catalyzed by
Yb-I-28, the reaction with alkyl olefins gave rise to cis-epoxides with excellent drs and
ees. Only a 2:1 dr was achieved with aryl alkenes.
1.2 Boron catalysts in asymmetric catalysis
It is well known22 that boron compounds are Lewis acids because there is an
unfilled p-orbital on boron (Scheme 1.6). Applications of BF3 as a catalyst in a number of
organic reactions has been well documented23-26 by Nieuwland dating back to the early
1930. In 1933, Meerwein found27 that BF3 reacts with water to give a stable complex
which can act as a Brønsted acid. The ability of borate esters to form Lewis acid-base
complex also has been documented28 in 1952 by Schäfer and Braun. It was not until 1969
that the capability of using borate esters to catalyze a reaction was reported. Wolf and
Barnes described29 the epoxidation of olefins with tetralin hydroperoxide induced by 1
equiv of tricyclohexylboroxine. Since the early 1970, a large number of research groups
have been interested in developing asymmetric catalysts for the Diels-Alder reaction and
for ketone reductions. There has been remarkable progress in the area of asymmetric
catalysis employing chiral boron Lewis acids.

6

Scheme 1.6 Historical perspective of boron catalysts in organic chemistry before 1990
H
H
N
BH3

BF3 as Lewis acid
to activate alkynes
Nieuwland et al.
(1930)

Ph
Ph

N
O
H 3B B
Asymmetric ketone reduction
H
BF3 catalyzed
by desoxyephedrine-BH3 Asymmetric ketone reduction
Fridel-Crafts alkylation
complex (5% ee)
Corey, Bakshi, Shibata (1987)
Nieuwland et al. (1935) Fiaud and Kagan (1969)
O
COOHO
R

1930

1950

1970

1990

O

O
O B
R
ADA catalyzed by acyloxyborane
Yamamoto et al. (1988)

ADA catalyzed by
epoxidation of alkenes
BF3•menthylOEt (3% ee)
induced by
O O
Mamedov et al. (1976)
Cy
O
Cy
O
O
B
B
B
O B
ADA
of
juglone
borate Lewis acid-base
O
O
O O
borate reagent
B
complex obtained
*
Kelly
et
al.
(1986)
Schäfer and Braun (1952)
Cy
Yamamoto et al. (1986) ADA catalyzed by
Wolf and Barnes (1969)
O
O
BINOL borate propeller
B
Kaufmann (1990)
O O
*
O O
B
O O

*

*

Mamedov and coworkers reported30 the first example of an asymmetric Diels-Alder
reaction (ADA) with BF3•menthylOEt as chiral catalyst in 1976. Although the
enantioselectivity of this method is far from satisfactory (3.3% ee), it laid the foundation
for the significant discovery31 in 1979 by Koga and coworkers where they achieved up to
72% ee with (menthyloxy)aluminum dichloride. Borate complexes of naphthoquinone
(juglone) and 3,3’-Ph2BINOL was prepared by Kelly and coworkers32. These complexes
promote the ADA reaction with various dienes in high yields and excellent
enantioselectivities. The BINOL ligand could be recovered quantitatively. Yamamoto
reported33 a similar reaction using tartrate derivatives as the ligand. The first ADA induced
by catalytic amounts of borates was reported34 by Kaufmann and Boese in 1990. They
unexpectedly discovered a propeller compound I-30 by reacting BINOL with H2BBr•Me2S.
This catalyst gave excellent results for the ADA reaction of cyclopentadiene I-31 and
methacrolein I-32 (Scheme 1.7).
7

Scheme 1.7 Kaufmann’s propeller catalyzed ADA reaction

2 equiv H2BBr•SMe2

OH
OH

(S)-BINOL
3 equiv

I-30

CHO
+

3 mol% I-30
–78 ºC

I-31

O
O B O
B
O O O

I-32

CHO
CH3
(S)-I-33
85%
97:3 exo/endo
99% ee

The asymmetric reduction of ketones employing chiral borane reagents was first
reported35 by Fiaud and Kagan in 1969 with poor asymmetric induction (less than 5% ee).
A major improvement36 in the evolution of chiral borane reagents was made by Itsuno
and coworkers in 1981. Propiophenone can be reduced with up to 60% ee using the
borane complex of an ι,β-amino alcohol. Intrigued by the work of Itsuno and others,
Corey’s group began detailed mechanism studies of this reaction and their efforts led to
the discovery37 of a highly enantioselective catalytic reduction of ketones by an isolable
and structurally defined oxazaborolidine catalyst (CBS reduction). The catalytic cycle
including the six-membered transition state I-37 were proposed38 and is shown in Scheme
1.8. The coordination of borane to the nitrogen atom of oxazaborolidine I-34 not only
activates the reducing power, but also strongly enhances the Lewis acidity of the
endocyclic boron atom. This was one of the earliest examples of Lewis acid assisted

8

Lewis acid catalysis (LLA), the concept Yamamoto came up with39 in 1998. The high
enantioselectivity can be explained by favorable coordination of the less sterically
hindered lone pair of the carbonyl and face-selective hydride transfer via a six-membered
transition state. The catalyst turnover may be achieved by two pathways: 1) the alkoxide
coordinated to the endocyclic boron reacts with the exocyclic boron through a 4membered ring transition state I-38 to generate borinate I-40 and oxazaborolidine I-34; or
2) reacts with another BH3 molecule via a 6-membered ring transition state I-39 to
produce borinate I-40 and complex I-35. Applying a similar strategy, Brown and
coworkers reported40 the asymmetric addition of organozinc reagents to aldehydes using
an oxazaborolidine catalyst to produce chiral alcohols with 52-95% ees.
Scheme 1.8 Proposed mechanism for the CBS reduction
HPh Ph
O
N B
I-34 R

RS

O
N B
H 3B R
I-35

I-40
Ph

H2BO
I-40 H RL

O R
RS
B
Ph
N
O
H 2B
H RL
B
H
H
H
I-39
Ph

HCl, MeOH
RS
HO
H RL
I-41

HPh Ph

BH3•THF

Ph
Ph

O R
RS
B
N
O
B
H RL
H2

Ph

O
RL

O R
B
N
O
H 2B H
I-37

I-38

9

RS
I-36

RS
RL

Scheme 1.9 Borate catalysts by Yamamoto
OiPr O

O

O

H
O

O

O

H O
O B O
O

B O
O

B R
O

OiPr O
CAB I-42, R = H
CAB I-43, R = 3,5-(CF3)2C6H3
CAB I-44, R = 2-MeOC6H4

I-45

I-46

imine-H

catalyst
CHO

+
4 equiv
I-31
catalyst
10 mol% CAB I-43
10 mol% BLA I-47
10 mol% I-48
5 mol% BLA I-49
5 mol% BLA I-50

I-32

O

OTMS
H

+

I-51a

CHO

–78 ºC
I-33

I-46b
85%, 89:11 exo/endo, 96% ee (R)
>99%, >99:1 exo/endo, 99% ee (R)
97:3 exo/endo, 65% ee (S)
96%, >99:1 exo/endo, 99% ee (S)
>95%, 94:6 exo/endo, 86% ee (R)
O

20 mol% CAB I-42

I-52

Ph

H

TMS

+

I-51a

OH

EtCN, –88 ºC, 4.5 h

20 mol% CAB I-44
+

I-51a

O
B
H
O
O

O

EtCN, –78 ºC

Ph

I-56b
Bn

OMe
+
OTMS
I-56a

I-58a

O

Bn

BLA I-49

N

DCM, 4A MS
Ph
O
–78 ºC, 12 h
I-59
catalyst
BLA I-45
75%, 82% ee
BLA I-46
78%, 86% ee

F3C

CF3

(5)
O
H
O

Ph

OTMS
+

OtBu
I-60

1 equiv catalyst

HN

Ph
CO2tBu

DCM, 4A MS
Ph
–78 ºC, 12 h
I-61
catalyst
BLA I-45 59%, 92% ee
BLA I-46 65%, >99% ee

10

CF3

(4)

I-57
86%, 97% ee
1 equiv catalyst

H

I-58b

CF3

I-55
94%, 91% ee

OTMS

H

(3)

OMe
H

N

BLA I-47, R = H
I-48, R = Bn

Ph

I-54

O

N

(2)

I-53
96%, 94:6 syn/anti
96% ee
20 mol% CAB I-43

O O
B
R
O
O

OH

EtCN, –78 ºC, 2 h

O

O
O
B
O
O

(1)

B
H
O

(6)
Ph
BLA I-50

CF
3

CF3
Ph

Yamamoto’s group was the major player in the field of asymmetric borate catalysis.
In 1988, they reported41 the ADA reaction of acrylic acid and cyclopentadiene catalyzed
by 10 mol% of a chiral acyloxyborane (CAB) catalyst I-43 derived from tartaric acid (eq 1,
Scheme 1.9). They later successfully applied CAB I-42 to I-44 to the ADA reaction of Îą,
β-unsaturated aldehydes with dienes42-43, the aldol reactions of silyl ketene acetals with
aldehydes (eq 2, Scheme 1.9)44, the allylation of aldehydes (eq 3, Scheme 1.9)45 and the
asymmetric hetero Diels-Alder reaction (AHDA) of aldehydes with Danishefsky diene I56b (eq 4, Scheme 1.9)46. The activation of CAB was later proposed47 to be a Brønsted
acid assisted chiral Lewis acid catalysis (BLA). In 1992, another boron catalyst I-45 was
prepared48 from optically pure BINOL and triphenyl borate in a 1:1 ratio. The proposed
mixed borate I-45 was not isolated or spectroscopically characterized. It was employed
as a stoichiometric chiral Lewis acid for AHDA of imines I-58a with Danishefsky diene I56a (eq 5, Scheme 1.9)48-50 and aldol reactions of aldimines I-58b (eq 6, Scheme 1.9)5152

. By changing the ratio of BINOL and B(OMe)3 to 2:1, the borate I-46 was generated

and the structure of its complex with an imine was determined by X-ray diffraction53. The
complex I-46 can promote the same reaction with higher efficiency in general (eq 5 and
6, Scheme 1.9). The structure of I-45 was called into question by other researchers54 due
to the fact that many attempts to prepare it gave Kaufmann’s propeller I-30 instead of the
mixed borate I-45. Moreover, involvement of I-46 was indicated by a nonlinear effects
study55 on the AHDA catalyzed by a presumed catalyst with the structure I-45. The mode
of activation of the imine by the catalyst was misinterpreted56 as a BLA catalyst I-46 in
Yamamoto’s paper: the X-ray structure clearly suggested it to be a Brønsted acid catalyst.

11

Therefore, this would be one of the earliest examples57 of asymmetric counteraniondirected catalysis (ACDC), a concept first described58 in 2006 by List. The concept and
designed of BLA was first introduced in the report59 of ADA of ι,β-enals and dienes by
Yamamoto and coworkers in 1994. Excellent enantioselectivity and exo/endo selectivity
were obtained in the presence of 10 mol% catalyst I-47. The control catalyst I-48 lacking
the 4th hydroxyl group gave the opposite ee of the desired product I-33 with low
selectivity. This result provided strong evidence for the combined acid catalysis47. They
subsequently introduced60-61 new BLA catalysts I-49 and I-50 generated from a boronic
acid and a chiral triol. These catalysts provide excellent enantio- and exo/endo selectivity
for ADA reaction (eq 1, Scheme 1.9) and gave better results for intramolecular ADA than
the CAB catalyst I-42. In 2007 and 2008, Nakagawa and coworkers reported62-63 the
enantioselective Pictet-Spengler reaction promoted by 2 equivalents of BLA I-46. High
yields (39-94%) and moderate enantioselectivities (15-91%) were achieved for 6
examples.
The activation mode of the acid activated chiral oxazaborolidine was revisited64 by
Corey and coworkers, who reported the highly enantioselective ADA reaction of ι,β-enals
catalyzed by I-62 and I-63 (eq 1, Scheme 1.10). The same type of catalyst was
subsequently employed in the ADA reaction of other ι,β-unsaturated carbonyl
compounds65-68, enantioselective cyanosilylation of aldehydes69 and ketones70 (eq 2,
Scheme 1.10), and asymmetric [3+2] cycloaddition of 1,4-benzoquinones I-72 and 2,3dihydrofuran I-7371 (eq 3, Scheme 1.10). The ADA reactions catalyzed by chiral
oxazaborolidine I-62-64 were applied in multiple total synthesis72-75. Yamamoto and

12

coworkers extended their concept of LLA catalysis to oxazaborolidine catalyst I-68 by
employing Lewis acid SnCl4 instead of Brønsted acid as an activator. They successfully
applied this moisture-tolerant I-68 in the ADA reaction of dienes with ι,β-unsaturated
carbonyl compounds (eq 1, Scheme 1.10)76 and ι-halo-ι,β-unsaturated ketones (eq 4,
Scheme 1.10)77. Corey and coworkers also demonstrated that oxazaborolidine I-69
activated by Lewis acid AlBr3 were effective in catalyzing the ADA reactions (eq 1,
Scheme 1.10)78-79 and [2+2] cycloadditon reaction of trifluoroehtyl acrylate I-77 to enol
ethers (eq 5, Scheme 1.10)80. Ryu and coworkers reported81-82 an asymmetric threecomponent coupling reaction catalyzed by oxazaborolidine catalyst I-63. The chiral βiodo Morita-Baylis-Hillman product I-81 can be prepared in up to 99% yield and excellent
asymmetric induction (62-94% ee) (eq 6, Scheme 1.10). Subsequently they reported a
variety of enantioselective reactions involving diazoesters catalyzed by acid activated
oxazaborolidine catalyst I-65-6783-85. Cyclopropanation of substituted acroleins afforded
the chiral trans-cyclopropane I-84 in excellent yield and ee (eq 7, Scheme 1.10).
Interestingly, a similar reaction in DCM catalyzed by I-66 gave 1,3-dipolar adducts with
high to excellent ees (not shown)86. An asymmetric Roskamp reaction87-90 of diazo
compounds with aldehydes catalyzed by I-66 produced chiral β-keto carbonyl compounds
in high yields and excellent enantioselectivities (eq 8, Scheme 1.10). When they switched
solvent from toluene to propionitrile, the same insertion intermediate underwent 1,2-aryl
migration instead of 1,2-hydride migration to yield the formal aryl-CHO bond insertion
product (not shown)91. A highly enantioselective formal Csp2-H insertion of diazo esters to
cyclic enones has been developed92 (eq 9, Scheme 1.10).

13

Scheme 1.10 Activated oxazaborolidine catalysts
O
H
I-31
5 equiv

(S)-I-33

H OTMS

10 mol% I-64

TMSCN

I-51a
O

20 mol% I-65

O

O
I-72

+

O

F

HO

I-73

OEt +

TMSI

I-79

+

Br

CHO

N2
Bn

EtO2C

OCH2CF3
I-78
87%, 99% ee
>99:1 exo:endo

Ph

OEt

(6)

I-81 I
95%, 94% ee,
99:1 Z/E

I-62, Ar = 2-methylphenyl,
X = OTf, R = H
I-63, Ar = 2-methylphenyl,
X = OTf, R = Me
I-64, Ar = 2-methylphenyl,
X = NTf2, R = H
I-65, Ar = 1-naphthyl,
X = OTf, R = Me
I-66, Ar = 2,4-dimethylphenyl,
X = NTf2, R = H
I-67, Ar = 1-naphthyl,
X = NTf2, R = Me

H
O
N B
Ph
SnCl4

CHO

20 mol% I-65
EtCN, –78 ºC, 2 h tBuO2C

Br

(7)

I-84
80%, 95% ee,
91:9 trans/cis

20 mol% I-66

EtO2C

I-68

COPh
(8)

Bn
I-86
92%, 95% ee

I-51a

H
N B
Br3Al

O

O

N2
tBuO2C

PhCHO

(5)

OH O

20 mol% I-63

5 mol% I-67

Me
I-87

+

CO2tBu

DCM, –20 ºC
I-88

I-89 Me
95%, 90% ee

14

R

X

O

toluene, –78 ºC, 2 h

I-85

(4)

O

I-80

I-83

+

O
N B
H Ar

I-76
75%, 94% ee
83:17 exo/endo
10 mol% I-69

R
H

Bu

DCM, –78 ºC, 2 h

H
tBuO2C
I-82

R

(3)

O

O

N2

99%, 93% ee
92:8 exo/endo

I-74
63%, 91% ee

I-77

I-51a

4 mol% I-69
–78 ºC, 2 h

R
O

OCH2CF3 DCM, –78 ºC, 3 h

PhCHO +

97%, 96% ee
91:9 exo/endo
99%, 95% ee
68:32 exo/endo

F

O

(S)-I-33

1 mol% I-68
DCM, –78 ºC, 2 h

O H

10 mol% I-68

I-75

+

6 mol% I-63
–95 ºC, 1 h

H

Bu DCM, –78 ºC, 6 h

I-31

O

CN
I-71
94%, 95% ee

DCM: CH3CN (1:1),
–95 ºC, 2 h then,
–78 ºC to 23 ºC, 5 h

I-73

(2)

Ph

Ph3PO, toluene
0 ÂşC, 40 h

I-70

+

(1)

conditions

I-32

PhCHO +

catalyst/condition for eq 1

CHO

catalyst

+

(9)

I-69

O

Figure 1.1 X-ray Structure of boroxinate-imine complex
Another important boron catalyst in asymmetric catalysis has been contributed by
the Wulff group (Scheme 1.11). In 1999, Wulff and Antilla reported93 the asymmetric
aziridination (AA) reaction of imines with ethyl diazoacetate I-94 (EDA) catalyzed by a
VAPOL-boron species. The catalyst was generated by reacting 1 equiv of VAPOL with 3
equiv BH3•THF and was thought to be functioning as a Lewis acid catalyst. Understanding
of the nature of the catalyst increased along with the evolution94-95 of the preparation
method for the catalyst. Nonlinear studies95 with the ligands revealed a linear relationship
between the ee of the ligands and product, suggesting that one molecule of the ligand
most likely was involved in the active catalyst. Mechanistic investigations96-97 by 11B and
1

H NMR, together with crystal structures of the precatalyst-iminium complex (Figure 1.1)

provide strong evidence that the reaction of imines is catalyzed by a Brønsted acid

15

mechanism. Natural abundance

13

C KIE studies98 showing unity for the iminium carbon

in contrast to a large KIE for the Îą-carbon of the EDA suggested that aziridine formation
is a two-step process with the ring closure step to be the first irreversible step. This
aziridination of imines was extensively studied by Wulff and coworkers (eq 1, Scheme
1.11). Benzhydryl imines I-93a prepared from aromatic and aliphatic aldehydes can be
aziridinated with EDA in high yield and excellent asymmetric induction. By introducing
electron-donating groups into the phenyl group of the benzhydryl imine99-101 (DAM I-93b,
MEDAM I-93c, BUDAM I-93d), both the yields and stereoselectivities of the cis-aziridines
were generally improved. In terms of the scope of the diazo compounds, diazomethyl
ketones bearing alkene, alkyne, ester, amide, acetal and bromo group, prepared either
from diazo transfer reaction of methyl ketone with 4-dodecylbenzenesulfonyl azides102, or
by reacting acid chlorides with TMSCHN2103, were compatible with the reaction condition,
giving cis-aziridines with high yields and excellent ees. Trisubstituted aziridines can also
be obtained104 with good yields (30-85%) and excellent ees (83-98%) by employing Îąalkyl-diazo-N-acyloxazolidinone with the more reactive N-Boc aryl imines. More recently,
a multi-component AA of aldehydes with amines and EDA was developed105-106. This
method enables the preparation of unbranched aliphatic substituted aziridines since their
imines were difficult to obtained in high purity. A systematic study107 of structure-activity
relationship on the VANOL ligand for the cis-aziridination identified the optimal VANOL
ligand as 7,7’-tBu2VANOL. The synthetic utility of cis-aziridination has been illustrated by
the synthesis of (–)-Chloroamphenicol108, BIRT-377109 and most recently, two
stereoisomers of sphinganine110 via a multicomponent AA. By simply changing the ethyl

16

diazo acetate (EDA) to diazoacetamide I-23b, trans-aziridines could be prepared111 in
good (7:1 to 36:1) trans/cis ratios and excellent (82-99%) ees (eq 2, Scheme 1.11). The
reason for the reversal in diastereoselectivity has been identified112 by DFT calculation to
be associated with a H-bonding between the amidic hydrogen and an oxygen atom of the
boroxinate catalyst. The synthetic application of the trans AA was demonstrated in the
syntheses of all four stereoisomers of sphinganine110. Hetero ADA of imines I-93a with
Danishefsky diene I-56a was developed113 by Wulff and coworkers (eq 3, Scheme 1.11).
Interestingly, it was found that an excess of triphenylborate could help with the turnover
with sub-stoichiometric amount of chiral boron catalyst. The catalyst was proposed to be
a Lewis acid in the original report but now it is thought that a boroxinate is involved56, 114.
In 2011, Wulff and Ren reported114 the aza-Cope rearrangement of imines I-98 catalyzed
by a boroxinate catalyst in the presence of benzoic acid (eq 4, Scheme 1.11). Chiral
homoallylic amines I-99 could be prepared with excellent optically purities (80-96%) via a
simple process. The usefulness of this method has also been demonstrated115 in the total
synthesis of (+)-sedridine and (+)-allosedridine. Wulff and coworkers reported116 that the
asymmetric catalytic three-component Ugi reaction could be possible by using a
boroxinate catalyst (eq 5, Scheme 1.11). The optimal catalyst I-92 was identified by
screening 13 ligands, 12 amines and 47 alcohols or phenols.

17

Scheme 1.11 Boroxinate catalysts by Wulff

3 equiv BH3•Me2S,
2 equiv PhOH,
3 equiv H2O,
Base

OH
OH

Ph
Ph

toluene, 100 ÂşC, 1 h
then 0.5 mm Hg,
100 ÂşC, 0.5 h

OAr
O
B
O

Ph
Ph

O
O B
O
H-Base
B
O
O O B
O

O B
O

Ar3

OAr

Ar3

O B

H-Base
VANOL Boroxinate catalyst I-90
VAPOL Boroxinate catalyst I-91

(S)-VANOL/VAPOL

I-92
tBu

OMe
Ar1 =

R

N

O
N2

I-93

I-94

trans-Aziridination
Base = imine I-93c or I-93d

R

N

NHPh
5 mol% (S)-I-90

O

Ar
Ar

+
N2

Ar

Ar

Ar
N

R

N

OTMS
Ph

+

(3)

R = aryl, 2Âş-alkyl,
10 examples,
45-85%, 73-93% ee

Ph

5-10 mol% (S)-I-90
1 equiv B(OPh)3
OMe

N

Ph
R

O

I-97

I-56a

I-93a

R = aryl, 1Âş-, 2Âş-, 3Âş-alkyl;
Ar = Ar1, Ar2,
13 examples,
64-90%, 82-99% ee

I-96

Heteroatom Diels-Alder
Base = imine I-93a
Ph

(2)
CONHPh

R

I-23b

I-93c or I-93d

Ar3 =

R = aryl, 1Âş-, 2Âş-, 3Âş-alkyl;
I-93a, Ar = Ph, 15 examples, 54-91%, 90-98% ee
1
(1) I-93b, Ar = Ar2, 10 examples, 14-95%, 52-98% ee
N
I-93c, Ar = Ar , 10 examples, 67-98%, 90-99% ee
R
COOEt I-93d, Ar = Ar3, 11 examples, 57-99%, 78-99% ee
I-95
R = alkynyl,
I-93d, 6 examples, 24-86%, 53-97% ee

Ar
OEt 2-10 mol%
(S)-I-90 or I-91

+

Ar

Ar2 =

tBu

cis-Aziridination
Base = imine I-93a-I-93d
Ar

OMe

OMe

aza-Cope rearrangement
Base = imine I-98

R

N

5 mol% (R)-I-90
Ar
Ar 5 mol% benzoic acid

Ar =

2 N HCl

I-98
in situ generated

R

(4)

NH2•HCl
I-99

R = aryl, 1Âş-, 2Âş-, 3Âş-alkyl;
18 examples,
57-99%, 80-96% ee

Three-Component Asymmetric Catalytic Ugi Reaction
Base = iminium generated from I-15 and I-100
Bn

O

R

H

0.5 mmol
I-15

+

Bn

N
H

Bn

2.0 mmol
I-100

20 mol% (R)-I-92

+

R

CN

N

Bn
H
N
O

1.5 mmol
I-101

I-102

18

(5)

R = aryl
16 examples,
51-87%, 56-90% ee

While developing the trans-aziridination of imines with diazoacetamides with
boroxinate catalyst, Desai and Wulff found117 that cis-epoxides could be formed from
aldehydes and diazoacetamides, although in low yields. Gupta and Wulff went on to
further develop this reactions118 and found that the cis-epoxide can be obtained in 62%
yield by reacting benzaldehyde and phenyl diazoacetamide in the presence of 20 mol%
B(OPh)3. And gratifyingly, chiral cis-epoxides could be obtained in the presence of 10
mol% of boroxinate catalyst albeit with rather low yields and asymmetric inductions.
Gupta also found that DMSO was the optimal base for generation of the boroxinate
catalyst (an aldehyde is not basic enough to induce boroxinate formation). After further
optimization by screening different diazoacetamides, concentration, solvent and
temperature, the optimal condition for boroxinate-catalyzed epoxidation was established
by Gupta (Table 1.1). Excellent yields and ees were observed for aromatic aldehydes
with substitutions in the m- or p-positions. o-Substituted aromatic aldehydes and aliphatic
aldehydes only gave moderate to good results. The goal of further studies would focus
on improving asymmetric inductions for these substrates. The strategy of optimization
would be similar to that used for Ugi reaction development which led to the first highly
enantioselective Ugi reaction116.

19

Table 1.1 Scope of boroxinate catalyzed asymmetric epoxidation118

10 mol%
(R)-VANOL

10 mol% DMSO

toluene, 100 ÂşC, 1 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

toluene, rt, 1 h,
then cool to –60 ºC

DMSO-H

O

O
R

30 mol% BH3•Me2S
20 mol% PhOH
30 mol% H2O

+
H

I-15

N2

O

10 mol% I-103

N
H
I-23a

toluene, –60 ºC,
24 h, 0.05 M

OPh
O B
O
O
* O B
O B
OPh
Boroxinate catalyst I-103a

R

CONHBu

I-104

14 examples
78 to 99% ee
60 to 97% yield

OMe
NO2
88%, 99% ee

97%, 92% ee

92%, 98% ee

60%, 80% ee

Br
70%, 80% ee

CN

80%, 99% ee

80%, 90% ee

70%, 92% ee

Br
Br
88%, 99% ee

88%, 96% ee

84%, 96% ee

5

OAc
82%, 97% ee 65%, 78% ee

84%, 90% ee

1.3 Optimization and KIE study of epoxidation catalyzed by VANOL-boroxinate
We started the investigation by preparing the diazo acetamide by a modified
procedure from literature119 (Scheme 1.12). Succinimidyl diazoacetate I-110 could be
obtained in good yield from gram scale preparation and is stable in crystalline form at
room temperature under nitrogen for months. The N-alkyl diazoacetamide I-23a and I23c can be prepared in excellent yield in a single step under mild conditions from I-110.
However, the reaction of I-110 with aniline is quite slow. Therefore, the preparation of the
N-aryl diazoacetamide I-23b was achieved by reaction of I-108 with aniline and then
elimination of the tosyl group in the presence of DBU.

20

Scheme 1.12 Syntheses of diazoacetamide I-23

H 2N

H
N

O
+

p-Ts

HO

OH

p-Ts

H 2O

OH
I-106

I-105

O

2.5 M HCl
0.5 mol

N
H

N

O

2 equiv SOCl2
OH

I-107
86%

p-Ts

benzene, reflux
210 mmol

O
p-Ts

N
H

N

I-108

Cl

50 mmol

N

OH
O I-109

Na2CO3 , CH2Cl2
0 °C to rt, 6 h
50 mmol

O
N2

2.0 equiv
R NH2

O
O

N

THF, rt, 1 h
O

40 mmol

O
N2

N
H

R

I-23a, R = Bu, 90%
I-23c, R = Bn, 92%

I-110
60%

Cl

I-108
70%

O
1.2 equiv

N
H

N

1.1 equiv aniline
2 equiv. DBU
CH2Cl2,
0 ÂşC to rt, 2 h
O

N2

N
H
I-23b
63%

With the diazoacetamides in hand, attention was next turned to testing the
epoxidation of benzaldehyde with N-butyl diazoacetamide I-23a following the procedures
by Gupta (Table 1.2). It was found that the results of reactive aromatic aldehydes could
be reproduced (entry 1 and 2, Table 1.2). The results from reactions with less reactive
substrates were rather hit and miss (entry 3-5, Table 1.2). It was also noticed that the
yields and asymmetric inductions of the reaction were very sensitive to temperature (entry
4 vs 6, Table 1.2). When the addition of aldehydes was carried out as a solution at –60
ÂşC instead of neat at rt, the reduced temperature fluctuations improved the ees of the
epoxides. To increase the reproducibility, we made a few modifications to the procedure:
1) increased the scale of the reaction from 0.2 to 0.5 mmol; 2) the aldehydes were cooled
to the reaction temperature before addition.

21

Table 1.2 Boroxinate catalyzed asymmetric epoxidation

10 mol%
(R)-VANOL

30 mol% BH3•Me2S
20 mol% PhOH
30 mol% H2O

toluene, rt, 1 h,
then cool to –60 ºC

O
+
H

I-51
1.1 equiv

N2

OPh
O B
O
O
* O B
O B
OPh
Boroxinate catalyst I-103a

10 mol% DMSO

toluene, 100 ÂşC, 1 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

O
R

DMSO-H

O

10 mol% I-103a

N
H
I-23a

toluene, –60 ºC,
24 h, 0.05 M

R

CONHBu

I-111a

entry

aldehyde

R

%conversionc
(I-23a)

%yieldd
(I-111a)

%eee
(I-111a)

1a
2a
3a
4b
5b
6bf

I-51a
I-51b
I-51c
I-51d
I-51e
I-51d

Ph
4-MeC6H4
2-MeC6H4
cyclohexyl
nonyl
cyclohexyl

> 99
> 99
84
93
ND
93

88
81
53
54
81
55

> 99
99
79
67
79
84

aThe

reaction was carried out on a 0.2 mmol scale. bThe reaction was carried out on
a 0.5 mmol scale. cDetermined by 1H NMR analysis of crude product using Ph3CH
as an internal standard. dIsolated yield after chromatography on silica gel. eAs
judged by chiral HPLC. fAldehyde was added as a toluene solution precooled to
–60ºC.

Scheme 1.13 Protonation/nucleophilic addition to I-23b
O
N2

N
H
I-23b

SO3H

+

CDCl3, 0.1 M
rt, 3 h

I-112

O

TsO

N
H
I-113
74%

In order to have a good comparison, it was decided to use N-phenyl
diazoacetamide I-23b as the substrate for 13C KIE study because the same substrate has
been employed in the KIE studies for trans-120 and alkynyl cis-aziridination121. Epoxidation
of benzaldehyde I-51a with I-23b was chosen as the model epoxidation and further
optimized (Table 1.3). The reaction is very sluggish at room temperature giving low yield
and racemic product (entry 1 and 2, Table 1.3). Presumably this was due to the side
22

reaction between diazoacetamide with boroxinate catalysts or ligands at room
temperature106. Indeed, treatment of diazoacetamide I-23b with 1 equiv TsOH at room
temperature gave rise to I-113 in 74% yield (Scheme 1.13). The same reaction at –60 ºC
only gave 25% of the O-H insertion product. In terms of ligands, VANOL is superior to
VAPOL, which gave almost racemic epoxide at –40 ºC either with or without DMSO (entry
4 & 6 vs 3 & 5, Table 1.3). The enantioselectivity of epoxidation was improved in the
presence of weak basic additives (entry 4,7,8 vs 6, Table 1.3). Whereas, stronger amine
base shut down the reaction completely (entry 9 & 10, Table 1.3). Among the bases we
screened, DMSO gave best result in terms of yield. Surprisingly the reaction gave
comparable result with aniline given that there is the significant pKa difference between
protonated aniline and aldehyde (pKa = 4.6 vs pKa = –7). Unlike N-butyl diazoacetamide
I-23a, switching the solvent from chloroform to toluene resulted in lower conversion and
lower ee (entry 11 & 12 vs 4 & 14, Table 1.3). This might be explained by the huge
solubility difference of these two diazoacetamides in toluene. Enantioselectivity was
indicated to be dependent on concentration. Lowering the concentration resulted in higher
ee but gave a slower reaction (entry 13 & 15 vs 12 & 14, Table 1.3). Further experiments
using different addition techniques indicated that the local warming effect seems to play
a role (entry 17 & 18 vs 14, Table 1.3). A higher yield and enantioselectivity was observed
when boron source was changed from triphenylborate to borane dimethyl sulfide complex
(entry 16 vs 14, Table 1.3). It is worth noting that in the epoxidation reaction catalyzed by
boroxinate, the major side product we observed in 5-15% NMR yield is the Roskamp
product β-ketoamide I-114b.

23

Table 1.3 Optimization of asymmetric epoxidation using N-phenyl diazoacetamide	I-107b

10 mol%
(R)-VANOL
or VAPOL

10 mol% base

toluene, 80 ÂşC, 1 h,
then 0.5 mm Hg, 80 ÂşC, 0.5 h

toluene, rt, 1 h,
then cool to –60 ºC

O
H

+

N2

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16b
17c
18d

10 mol% I-103

N
H
I-23b

conc.
[M]

VAPOL
DMSO
CHCl3
VANOL
DMSO
CHCl3
VAPOL
DMSO
CHCl3
VANOL
DMSO
CHCl3
VAPOL
none
CHCl3
VANOL
none
CHCl3
VANOL
PhNH2
CHCl3
VANOL acetanilide CHCl3
VANOL
DMAP
CHCl3
VANOL
Et3N
CHCl3
VANOL
DMSO
toluene
VANOL
DMSO
toluene
VANOL
DMSO
toluene
VANOL
DMSO
CHCl3
VANOL
DMSO
CHCl3
VANOL
DMSO
CHCl3
VANOL
DMSO
CHCl3
VANOL
DMSO
CHCl3

0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.05
0.5
0.05
0.5
0.5
0.4

aGeneral

CONHPh
+

I-111b

temperature %conversiond
[Âş C]
(I-23b)
25
25
–40
–40
–40
–40
–40
–40
–40
–40
–40
–60
–60
–60
–60
–60
–60
–60

O
CONHPh

solvent, temperature,
24 h

solvent

base

OPh
O B
O
O
* O B
O B
OPh
Boroxinate catalyst I-103

O

O

I-51a
1.1 equiv
entrya ligand

base-H

30 mol% B(OPh)3
30 mol% H2O

99
99
99
99
99
99
98
99
ND
ND
99
99
ND
95
87
99
99
99

I-114b
5-15%
%yielde
(I-111b)

cis/transd
(I-111b)

%eef
(I-111b)

26
25
47
64
48
53
51
51
<1
<1
60
44
29
60
53
70
69
58

8.8:1
11:1
25:1
49:1
26:1
35:1
> 50:1
24:1
—
—
26:1
29:1
32:1
> 50:1
> 50:1
> 50:1
> 50:1
> 50:1

7
0
–5
62
5
36
64
51
—
—
41
51
82
61
92
67
70
76

procedure: Reaction was performed in a Schlenk flask. Benzaldehyde was added using a syringe at rt. bBH3•Me2S
and PhOH were used instead of B(OPh)3. cBenzaldehyde was precooled and added using canula. dReaction was
performed in a RBF; catalyst was precooled and added using syringe. dDetermined by 1H NMR analysis of crude product
using Ph3CH as an internal standard. dIsolated yield after chromatography on silica gel. eAs judged by chiral HPLC.
fAldehyde was added as a precooled toluene solution.

24

Table 1.4 KIE samples preparation
30 mol% BH3•Me2S
20 mol% PhOH
30 mol% H2O

10 mol%
(S)-VANOL

DMSO-H

toluene, 100 ÂşC, 1 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

30 mol% BH3•Me2S
20 mol% PhOH
30 mol% H2O

10 mol%
(S)-VANOL

base-H

O
+

H

N2

OPh
O B
O
O
* O B
O B
OPh
boroxinate catalyst B

cool to –60 ºC

O

10 mol% A or B
N
H

I-51a

toluene, rt, 1 h,
then cool to –60 ºC

100 mol% I-23b

toluene, 100 ÂşC, 1 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

O

OPh
O B
O
O
* O B
O B
OPh
boroxinate catalyst A

10 mol% DMSO

CONHPh

CHCl3, 0.2 M, –60 ºC,
24 h

I-23b

I-111b

Set

Catalyst

I-51a
[mmol]

I-23b
[mmol]

%yielda
(I-111b)

%eeb
(I-111b)

1

A
A
A
A
B
B
B
B

2
10
2.4
12
2.4
12
2.4
12

10
2
12
2.4
12
2.4
12
2.4

57
37
80
67
65
45
65
60

91
82
90
93
60
58
61
58

2
3
4
aIsolated

yield after chromatography on silica gel. bAs judged by chiral HPLC.

Entry 16 in Table 1.3 was chosen as the condition for KIE sample preparation with
0.2 M as the concentration to ensure 100% conversion of the limiting reagent. Under the
optimized reaction conditions, 4 sets of modified procedures122 to measure KIE were
performed (Table 1.4). Two sets were with DMSO as an additive while the other two were
without DMSO to explore the possibility of a different mechanism. In each set of

25

experiments, there were two reactions: reaction #1 with 0.2 equivalent aldehyde and 1.0
equiv of diazoacetamide and the reverse stoichiometry for reaction #2. One reactant is
excess and reacts with low conversion in reaction #1, while it is the limiting reagent in
reaction #2, where the product serves as the 100%-reaction standard. Interestingly, in 4
sets of experiments, those with excess diazoacetamide gave higher yields than those
with excess aldehyde. In agreement with the optimization studies, the samples obtained
from the reactions with DMSO were determined to have higher ees (entry 1&2 vs 3&4,
Table 1.4).
without DMSO
1.054(7)

with DMSO
1.022 (3)
1.023 (2)

with DMSO
0.993 (3) without DMSO
0.999 (8)
0.996 (4)
O
CONHPh
I-111b
PhCHO
boroxinate cat

N
1.022 (5)
1.019 (4)

1.002 (2)
1.001 (3)
MEDAM
N

Ph

MEDAM

O

N2

N
Ph
H
I-23b
boroxinate cat
boroxinate cat

N

MEDAM

1.031 (5)
1.027 (7)

1.003 (6)
1.004 (6)
MEDAM
N
CONHPh

CONHPh

Ph

I-115

I-116

Figure 1.2 Experimental 13C KIE for the reaction of N-phenyl diazoacetamide I-107b
The

13

C KIEs for both substrates in this reaction were determined by the

methodology123 for high-precision determination of small KIEs at natural abundance
developed by Singleton and coworkers. The data was collected and processed by Dr.
Mathew Vetticatt. The KIE values obtained from three independent experiments are
shown in Figure 1.2, together with the KIE data124 of trans-aziridination and alkynyl cis-

26

aziridination. In contrast to the KIE results from cis-aziridination98 where a large

13

C KIE

of ~5% was observed for the Îą-carbon of EDA, moderate 13C KIEs (2-3%) were observed
for the Îą-carbon of the imine or of the aldehyde for the three reactions with N-phenyl
diazoacetamide I-107b. This suggest that the first irreversible step would be the addition
of the diazoacetamide to imine/aldehyde carbons to form the diazonium ion intermediate.
The disparity of KIE between epoxidation reactions with and without DMSO indicated the
mechanism is different for two conditions.
1.4 Screening of aniline as base additive
During the optimization of the epoxidation reaction, it was found that addition of
aniline gave comparable result to DMSO. Examining variations of aniline might be
worthwhile for further optimization and a mechanistic study. A variety of aniline derivatives
I-117a-j was tested under the optimized condition (Table 1.5).
The weakest base in the bunch, diphenylamine I-117b, gave a result that is close
to DMSO and better than aniline. Interestingly, the highest ee was observed when 2aminophenol I-117j was used, a base that is slightly stronger than aniline. All the other
anilines with either an electron donating group (I-117i) or withdrawing groups (I-117c-e,
I-117f-h) gave slightly worse results than aniline. Another observation is that when the
reaction is more enantioselective, the yield of the side product I-114b was subdued.
However, the real role of 2-aminophenol is not clear. Because not only can I-117j function
as a base, but it also can switch with the phenol in the boroxinate and become incorporate
into the catalyst.

27

Table 1.5 Epoxidation catalyzed by boroxinate with various anilines as base additive

10 mol%
(R)-VANOL

30 mol% BH3•Me2S
20 mol% PhOH
30 mol% H2O
toluene, 100 ÂşC, 1 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

H

10 mol% I-103b

N2

+

I-51a

CHCl3, rt, 1 h,
then cool to –60 ºC
O

O

O

OPh
O B
O
O
* O B
O B
OPh
Boroxinate catalyst I-103b

[I-117-H]
10 mol% aniline I-117

N
H

CONHPh

CONHPh +

CHCl3, 0.5 M, –60 ºC,
24 h

I-23b

I-114b

I-111b

NH2

NH2

O

H
N

Br

NH2
Br

I-117a

I-117b

Br
I-117c

NH2

NH2

NH2

Br

NH2

Br
Cl
I-117d

NH2

Cl
I-117e

NH2
OH

Cl

NO2

Cl
I-117f

Cl
I-117h

I-117g

I-117i

I-117j

entry

base

%conversiona
(I-23b)

%yielda
(I-114)

%yieldb
(I-111b)

cis/transb
(I-111b)

%eec
(I-111b)

1
2
3
4
5
6
7
8
9
10
11
12

none
DMSO
I-117a
I-117b
I-117c
I-117d
I-117e
I-117f
I-117g
I-117h
I-117i
I-117j

95
99
92
96
99
97
94
95
93
95
ND
99

9
6
9
5
9
7
16
16
14
10
6
5

56
59
47
65
48
64
28
33
42
42
44
55

37:1
> 50:1
> 50:1
> 50:1
45:1
45:1
18:1
29:1
40:1
> 50:1
> 50:1
28:1

70
79
76
81
70
73
71
75
74
71
72
87

by 1H NMR analysis of crude product using Ph3CH as an internal standard.
yield after chromatography on silica gel. cAs judged by chiral HPLC.

aDetermined
bIsolated

28

1.5 Discovery of VANOL meso-borate catalyst
We attempted to optimize the boroxinate catalyst by varying the phenol/alcohol
component. We start off the screening by setting up a control experiment without the
phenol, where a negative result was expected. Surprisingly, the reaction gave an equally
great yield and excellent ee (entry 3 vs 1, Table 1.6). For the reaction without DMSO, the
control (without phenol) experiment gave higher yield than the experiment with phenol
with a comparable ee (entry 4 vs 2, Table 1.6). In the absence of phenol, it is still possible
that a boroxinate forms from water molecule to give a catalyst where the phenols are
replaced by hydroxides. Therefore, both phenol and water were left out of the recipe for
the precatalyst. It was shocking to find that the results are as good as, if not better than,
those from original conditions (entry 5 & 6 vs 1 & 2, Table 1.6). The boroxinate catalyst I103a can’t be the catalytic species under these new conditions. After reviewing the types
of chiral borate catalysts known in the literature, it was suspected that the active catalyst
might be a mesoborate BLA53 or a propeller borate34. The stoichiometry of BH3•Me2S was
readjusted to such that the VANOL/borane ratio was 2:1 based on a mesoborate
structure. We were delighted to obtain the cis-epoxide I-111a in 98.6% yield and >99%
ee after 5 hours (entry 7, Table 1.6). The reaction that was catalyzed by a precatalyst
generated with a ligand/boron ratio of 2:1 proceeded faster and gave higher
enantioselectivity at –40 ºC (entry 8 vs 9, Table 1.6). A control experiment showed that
the boron is essential for the catalytic reaction (entry 10, Table 1.6). Modifications such
as decreasing the catalyst loading, and precatalyst formation by heating DMSO with

29

VANOL and borane, have negative effects on the yield of the reaction (entry 11 & 12,
Table 1.6).
Table 1.6 Evolution of catalyst
“boroxinate conditon”

10 mol%
(R)-VANOL

10 mol% DMSO

toluene, 100 ÂşC, 1 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

toluene, rt, 1 h,
then cool to –60 ºC

O

O
Ph

30 mol% BH3•Me2S
20 mol% PhOH
30 mol% H2O

+
H

I-51a
1.1 equiv

N2

Bu

N
H
I-23a
0.50 mmol

DMSO-H

10 mol% I-103a
toluene, –60 ºC,
time, 0.10 M

entry

variation from “boroxinate conditon”

1
2
3
4
5
6
7
8
9
10
11
12

none
w/o DMSO
w/o phenol
w/o phenol and DMSO
w/o phenol and H2O
w/o phenol, H2O and DMSO
entry 4, 5 mol% BH3•Me2S
entry 7, –40 ºC
–40 ºC
entry 7, w/o BH3•Me2S
entry 7, half the catalyst loading
entry 7, heating with DMSO

O
Ph

CONHBu

OPh
O B
O
O
* O B
O B
OPh
Boroxinate catalyst I-103a
O

+
Ph

I-111a
cis/trans > 50 : 1

CONHBu

I-114a

time (h) %yielda (I-111a) %eeb (I-111a) %yieldc (I-114a)
24
24
24
24
8
24
5
1
24
24
24
24

88
79
92
90
92
90
99
97
90
0
69
36

99
90
99
89
99
96
99
99
98
—
—
—

<1
5
<1
<1
<1
<1
<1
<1
<1
—
18
18

yield after chromatography on silica gel. bAs judged by chiral HPLC. cDetermined by 1H NMR analysis
of crude product using Ph3CH as an internal standard.
aIsolated

30

Table 1.7 Optimization of condition for epoxidation catalyzed by mesoborate I-118
“mesoborate conditon”

H O

10 mol%
(R)-VANOL

+

H

I-51a
1.1 equiv
entry

10 mol% DMSO

toluene, 100 ÂşC, 1 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

toluene, rt, 1 h,
then cool to –40 ºC

O

O
Ph

5 mol% BH3•Me2S

N2

N
H

Bu

10 mol% I-118

O

toluene, –40 ºC,
1 h, 0.10 M

I-23a
0.50 mmol

Ph

CONHBu

*

*
O
B O
O
O S

mesoborate catalyst I-118

O

+

Ph

I-111a
cis/trans > 50 : 1

CONHBu

I-114a

%yielda (I-111a) %eeb (I-111a) %yieldc (I-114a)

variation from “boroxinate conditon”

none
1
4
Å
MS,
–60 ºC
2
w/o 0.5 mm Hg, –60 ºC
3
w/o 0.5 mm Hg
4
w/o 0.5 mm Hg, –20 ºC
5
w/o 0.5 mm Hg, 0 ÂşC
6
w/o 0.5 mm Hg, w/o DMSO, 4 Å MS
7
w/o DMSO, 4 Å MS
8
9 heating for 0.5 h, skip 1h after addition of DMSO, 4 Å MS
entry 9, 0 ºC, w/o 4 Å MS
10
entry 9, w/o 4 Å MS, 10 mol% H2O at –40 ºC
11
entry 9, w/o 4 Å MS, 10 mol% H2O at rt
12
entry 9, B(OPh)3 instead of BH3•Me2S
13
entry 9, B(OPh)3 instead of BH3•Me2S, no heating
14

97
99
99
97
42
16
34
86
97
94
99
8
99
45

99
99
99
99
—
—
—
87
99
96
99
—
99
—

<1
<1
<1
<1
31
38
1
1
<1
<1
<1
—
<1
2

aIsolated yield after chromatography on silica gel. bAs judged by chiral HPLC. cDetermined by 1H NMR analysis of crude
product using Ph3CH as an internal standard.

It was decided to further optimize the mesoborate system. Removing solvents after
the precatalyst formation will presumably get rid of the unreacted borane and Me2S
molecules. This step proved to be worthwhile at higher temperature where the catalyst
becomes less efficient (entry 6 vs 10, 7 vs 8, Table 1.7). The incorporation of 4 Å
molecular sieves was thought to help increase the stability of the borate catalyst but it
turned out to be unnecessary and even detrimental in many reactions. As shown in control
experiments, the catalyst is sensitive to water but tolerant of water at low temperature

31

(entry 11 and 12, Table 1.7). These findings prompted us to omit the 4 Å MS from the
optimal conditions and use a simple round bottom flask to run the reactions rather than in
a Schlenck flask. The 30 min heating time for precatalyst formation was proved to be
enough and no induction time was needed for DMSO to engage in the system (entry 9,
Table 1.7). These procedural adjustments decreased the set-up time for the reaction
significantly from 3 h to 1 h. Finally, triphenyl borate can be used as an alternative boron
source. However, in contrast to boroxinate formation, heating is required for effective 2:1
mesoborate catalyst generation (entry 13 and 14, Table 1.7).
Next experiments were carried out to figure out the limit of catalyst loading (Table
1.8). When the concentration of the catalyst was kept constant, the reaction was equally
effective in the presence of 2.5 mol% catalyst. When 2.0 mol% catalyst loading was
employed, the epoxide was obtained with excellent enantioselectivity, albeit in slightly
lower yield. (entry 1-3, Table 1.8). Further decreasing the loading was impractical and
caused a considerable loss in yield (entry 4-5, Table 1.8).

32

Table 1.8 Catalyst loading study
H O

2 equiv
(S)-VANOL

1 equiv BH3•Me2S

2 equiv DMSO

toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

toluene, rt, 1 h,
then cool to –40 ºC

Ph

mesoborate catalyst I-118

O

O

+

N2

H

I-51a
1.2 equiv

entry

mmol
(I-51a)

1
2
3
4
5

0.5
0.5
0.5
1.0
1.0

N
H
I-23a

Bu

*

*
O
B O
O
O S

I-118

O

toluene, –40 ºC,
1 h, concentration

Ph

CONHBu

I-111a
cis/trans > 50 : 1

concentration mol% %yielda %eeb
of I-51a (M) ( I-118) (I-111a) (I-111a)
5
2.5
2.0
1.0
0.5

0.1
0.2
0.25
0.25
0.25

94
99
88
(48)
(5)

99
99
99
—
—

aIsolated

yield after chromatography on silica gel. Yields in
parentheses are determined by 1H NMR analysis using Ph3CH as
an internal standard. bAs judged by chiral HPLC. ccis/trans = 27:1

To test the idea of whether the reaction can be run with catalyst prepared in
advance as a stock solution to avoid preparation of the catalyst each time before every
reaction, a stability study was conducted (Table 1.9). The mesoborate catalyst I-118 was
generated and stored in a Shlenk Flask under nitrogen atmosphere on the benchtop. The
results showed that the catalyst is relatively stable under moisture-free conditions and
maintained its catalytic ability over 5 weeks.

33

Table 1.9 Catalyst stability study
H O

10 mol%
(S)-VANOL

O
+

I-51f
1.2 equiv

10 mol% DMSO

toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

toluene, rt,
then cool to –40 ºC
time

O
H

Br

5 mol% BH3•Me2S

N2

N
H

Bu

I-23a
0.50 mmol

O

10 mol% I-118
toluene, –40 ºC,
time, 0.10 M Br

CONHBu

I-129a
cis/trans > 50 : 1

*

*
O
B O
O
O S

mesoborate catalyst I-118
stock solution under N2

entry days time %yielda %eeb
(min) (I-129a) (I-129a)
1
2
3

0
8
37

10
30
30

99
98
97

99
99
99

aIsolated

yield after chromatography on
silica gel. bAs judged by chiral HPLC.

1.6 Ligand comparison and a distinction between two catalysts
The ligand effect was investigated with the 2:1 mesoborate catalyst (Table 1.10).
It was surprising to observe a dramatic decrease in yield when BINOL and VAPOL were
used as ligands under the optimal condition (entry 1-3 vs 4, Table 1.10). It was decided
to increase the reaction temperature in order to elevate their reactivity to produce a better
comparison between the ligands. The reactions performed at 0 ÂşC indicated that catalysts
generated from VANOL are superior to BINOL and VAPOL in terms of yield and ee no
matter whether DMSO is added or not. Oddly, BINOL and VAPOL catalyst performed
better in the absence of DMSO (entry 5 vs 6 and 7 vs 8, Table 1.10). Moderate yield and
ee of the epoxide was observed for BINOL catalyst while almost racemic epoxide was
produced with the VAPOL catalyst (entry 5-8 vs 9-10, Table 1.10). The notable difference
in performance of the 2:1 catalyst in the epoxidation might be explained by their inherent
structural characteristics. First, the BINOL mesoborate should have a wider crevice in the
chiral pocket since the fused benzene rings are located distal to the phenol hydroxyl

34

groups. This would decrease the energy difference of the transition states leading to the
major and minor enantiomers. Second, BINOL is reported to react with BH3 generate
mesoborates53 or propeller borates34. Under the conditions for the preparation of the 2:1
catalyst, the propeller borate could be generated as a byproduct. Both propeller borate
and mesoborate of BINOL could catalyze the epoxidation of aldehydes. It is likely that the
propeller borate would be a less enantioselective catalyst than mesoborate which causes
the decrease in ee. On the other hand, VAPOL is more sterically hindered than VANOL
in its chiral pocket. This might result in a lower conversion into mesoborate. It would also
be difficult for the aldehyde substrate to bind to the active catalytic site. Both factors might
cause the lower conversion and enantioselectivity of VAPOL mesoborate catalyst.
The question remains whether the active catalysts generated from 1:3 boroxinate
or 2:1 mesoborate conditions are distinct species or not. Although the epoxidation
reactions under mesoborate conditions were faster and more enantioselective for many
substrates, it might be explained by a situation where the active catalyst is the same but
generated in a more efficient manner under the 2:1 conditions. Indeed, the
enantioselectivity can be hampered by adding 20 mol% phenol or by recombining the
missing components from the boroxinate conditions (Table 1.11).

35

Table 1.10 Ligand effect in epoxidation catalyzed by mesoborate I-118
H O

10 mol%
(R)-Ligand

5 mol% BH3•Me2S

10 mol% DMSO

toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

toluene, rt,
then cool to –40 ºC

O

O

+

N2

N
H

H

Ph

I-51a
1.2 equiv

*

mesoborate catalyst I-118

10 mol% I-118

Bu

I-23a
0.50 mmol

*
O
B O
O
O S

O

toluene,
temperature
time, 0.10 M

Ph

%yieldb (I-111a) %eec (I-111a)

CONHBu

I-111a

entry

ligand

DMSO

temperature

time (h)

%conva (I-23a)

1
2
3
4
5
6
7
8
9
10

BINOL
BINOL
VAPOL
VANOL
BINOL
BINOL
VAPOL
VAPOL
VANOL
VANOL

yes
no
yes
yes
yes
no
yes
no
yes
no

–40 ºC
–40 ºC
–40 ºC
–40 ºC
0 ÂşC
0 ÂşC
0 ÂşC
0 ÂşC
0 ÂşC
0 ÂşC

24
22
24
1
12
0.5
24
24
0.5
0.5

47
66
73
100
51
100
79
91
100
100

—
—
—
99
—
62
—
6
96
88

(3)
(12)
(13)
97
(5)
62
(23)
43
94
84

by 1H NMR analysis of crude product using Ph3CH as an internal standard. bIsolated yield after
chromatography on silica gel. Yields in parentheses are determined by 1H NMR analysis. cAs judged by chiral
HPLC.
aDetermined

Table 1.11 Effect of PhOH in epoxidation catalyzed by mesoborate I-118
H O
10 mol%
(R)-VANOL

5 mol% BH3•Me2S

10 mol% DMSO

toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

toluene, rt,
then cool to –40 ºC

25 mol% BH3•Me2S
20 mol% PhOH,
30 mol% H2O,
O

O
H +
7

I-51g
1.2 equiv

N2

N
H

Ph

I-23b
0.50 mmol

toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

O

10 mol% I-118
toluene, –40 ºC,
24 h, 0.10 M

*

O
B O
O
O S

mesoborate catalyst I-118

“complement” to boroxinate
entry

variation

1
2
3

none
+ 20 mol% PhOH
+ “complement”

CONHPh
7

I-137b
cis/trans > 50 : 1

aIsolated
bAs

36

%yielda %eeb
(I-137b) (I-137b)
88
72
92

89
63
83

yield after chromatography on silica gel.
judged by chiral HPLC.

To resolve this issue, it was decided to perform nonlinear effect (NLE) studies to
investigate the nature of these two catalyst systems. Nonlinear studies have been
employed to probe boron-catalyzed reactions, such as Yamamoto’s BINOL-BLA
catalyzed AHDA by James and Bull55, boroxinate catalyzed aziridination by Wulff95 and
3-borono-BINOL catalyzed aza-Michael additions by Maruoka125.
The results of the experiment are shown below (Table 1.11, Figure 1.3, Figure 1.4).
A large difference between these two catalysts in the epoxidation can be observed from
the data and the graph. For the boroxinate catalyst, the yields of epoxide remain
consistent when varying the enantiopurity of VANOL. And in support the proposed
boroxinate catalyst, no nonlinear effect was observed in the graph, which is in agreement
of the NLE studies in aziridination95 and consistent with the structure A that a single
molecule of the ligand in the catalyst. In contrast, the yields and rates of epoxidation
increase as the enantiopurity of the VANOL in the mesoborate catalyst increases. A
significant (+)-NLE was revealed, providing strong experimental evidence that the active
catalyst responsible for asymmetric induction under the 2:1 conditions contains more than
1 equivalent of VANOL.
Therefore, the catalysts generated from these two conditions are distinct boron
catalysts. Both catalysts are effective in catalyzing epoxidation of aldehydes with
diazoacetamides. But the mesoborate has the edge over the boroxinate with regards to
rate and enantioselectivity of reactions at higher temperatures.

37

Table 1.12 Nonlinear effect study on two catalytic systems

10 mol%
(R)-VANOL
of various ee

30 mol% BH3•Me2S
20 mol% PhOH
30 mol% H2O

DMSO-H

OPh
O B
O
O
* O B
O B
OPh
boroxinate catalyst A

10 mol% DMSO
toluene, rt, 1 h,
then cool to –40 ºC

toluene, 100 ÂşC, 1 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

H O
10 mol%
(R)-VANOL
of various ee

5 mol% BH3•Me2S

10 mol% DMSO

O
B O
O
O S

*

toluene, rt,
then cool to –40 ºC

toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

mesoborate catalyst B
O
H +

O
N2

Br
I-51f
1.2 equiv

N
H

O

10 mol% catalyst

Bu

I-23a
0.50 mmol

catalsyt A
entry

%ee of
VANOL

%yielda
(I-129a)

%eeb
(I-129a)

1
2
3
4
5
6
7
8
9
10
11

0
10
19
32
39
50
57
69
79
93
>99

68
69
67
67
69
68
68
68
73
61
77

0
11
21
33
43
51
58
69
74
84
88

aIsolated

CONHBu

toluene, –40 ºC, 0.10 M
2-12 h for A
Br
time for B,

I-129a

catalsyt B
time %yielda %eeb
(min) (I-129a) (I-129a)
30
30
30
30
30
10
20
10
10
10
10

55
52
56
75
91
70
86
93
96
88
99

0
23
57
69
82
85
95
97
98
98
99

yield after chromatography on silica gel. bAs judged by chiral HPLC.

38

100

yield of epoxide (%)

80
60
40
20
0

catalyst A
catalyst B

0

20

40

60

80

100

ee of VANOL (%)

Figure 1.3 Yield of epoxide I-129a for non-linear studies

100

ee of epoxide (%)

80
60
40
20
catalyst A
catalyst B

0

0

20

40

60

80

100

ee of VANOL (%)

Figure 1.4 Non-linear effect studies on two catalysts
1.7 Reaction scope
Having identified the optimal conditions for the asymmetric epoxidation catalyzed
by the mesoborate catalyst, attention was next turned to the evaluation of the scope of
this reaction for the aldehyde component. As shown in Scheme 1,14, a wide variety of
39

aryl aldehydes were first investigated. In general, electronically varied benzaldehyde
derivatives (I-111-142) underwent the epoxidation reaction in excellent yield with
excellent asymmetric inductions. The reaction tolerates various functional groups
including alkyl (I-119-120), methoxy (I-123-124), ester (I-125), halogen (I-127-132), nitrile
(I-133), and nitro (I-134-135) moieties. The reactions of aryl aldehydes with substituents
at o-position were slower and gave the epoxide with slightly lower ee (I-119, 121, 123,
127). In addition, the substrates with electron withdrawing group on the phenyl ring
underwent the reaction slower and gave lower asymmetric inductions (I-133-135).
Epoxidation of 5-bromo-2-fluorobenzaldehyde gave I-132 in 82% yield and with moderate
induction after 24 h. The reaction of 4-methoxybenzaldehyde was sluggish even when 10
mol% of catalyst was employed. This might be due to the instability of the resulting
epoxide under these conditions and the resulting ring-opened product might bind to the
catalyst and cause inhibition. Subsequently, aliphatic aldehydes were examined. It was
delightful to find that the epoxidation could be extended to both unbranched and Îąbranched aliphatic aldehydes with excellent asymmetric inductions (I-136c-138c). It was
found that the N-benzyl diazoacetamide I-23c was more suitable for aliphatic substrates.
Alkyl substituted cis-epoxides were obtained with almost perfect ees, although the
reactions were slower and this is thought to be due to the lower solubility of I-23c.
Reaction of Îą, Îą -bis-branched alkyl aldehyde was substantially slower and only gave
moderate yield when 10 mol% catalyst was used (I-139). Reaction with an alkenyl
aldehyde was unfruitful (I-140). However, alkynyl aldehdyes were well-tolerated, albeit
giving only moderate yields (I-141-142).

40

Scheme 1.14 Substrate scope of asymmetric epoxidation with mesoborate catalyst I-118:
variation of aldehydesa
H O

10 mol%
(R)-VANOL

5 mol% BH3•Me2S

10 mol% DMSO

toluene, 100 ÂşC, 1 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

toluene, rt,
then cool to –40 ºC

*

*
O
B O
O
O S

mesoborate catalyst I-118
O

O
H
R
1.2 equiv.

+

N2

R1
N
H
0.5 mmol
I-23a, R1 = Bu
I-23b, R1 = Ph
I-23c, R1 = Bn

O

5 mol% I-118,
(or without DMSO)b
toluene, –40 ºC
time, 0.1 M

R

CONHR1

cis : trans > 50 : 1

O

O

O

CONHBu

CONHBu

I-119, 2 h, 89%, 97% ee

I-120, 0.17 h, 94%, 99% ee

CONHR1

R1 =

I-111a,
Bu, 0.17 h, 99%, >99% ee
(2 h, 86%, 93% ee)
I-111b, R1 = Ph, 12 h, 93%, 98% ee
I-111c, R1 = Bn, 1 h, 88%, >99% ee
(3 h, 98%, 97% ee)

O

O

I-121, 1 h, 88%, 97% ee
OMe

CONHBu

CONHBu

I-122, 0.25 h, 91%, >99% ee
O

O

O
CONHBu

MeO

CONHBu

CONHBu

MeO

I-123, 0.17 h, 92%, 94% ee

I-125, 24 hc, 19%d, —

I-124, 0.17 h, 92%, 97% ee

O

Br

O

O

CONHBu

CONHBu

Br

CONHBu

AcO

I-126, 0.25 h, 92%, >99% ee

I-127, 0.5 h, 94%, 90% ee

O

O

O
CONHBu

Cl

CONHBu

Cl

CONHBu

Cl

Br

I-129a, 0.17 h, 99%, >99% ee
(2 h, 72%, 90% ee)

I-130, 0.17 h, 93%, 98% ee

CONHBu

CONHBu

F
I-132, 24 h, 82%, 63% ee

NC
I-133, 0.25 h, 98%, 96% ee

41

I-131, 0.25 h, 96%, 99% ee

O

O

O

Br

I-128, 0.17 h, 96%, 98% ee

CONHBu

O2N
I-134, 3 h, 87%, 94% ee

Scheme 1.14 (cont’d)
O

O

O2N

CONHR1

CONHBu

I-136a, R1 = Bu, 0.25 h, 87%, 96% ee
I-136b, R1 = Ph, 12 h, 94%, 90% ee
I-136c, R1 = Bn, 12 h, 93%, >99% ee

Cl

I-135, 1 h, 98%, 89% ee
O

O
6

I-137b, R1 = Ph, 12 h, 88%, 89% ee
I-137c, R1 = Bn, 12 h, 93%, >99% ee
(12 h, 82%, >99% ee)

O
CONHBn

CONHR1

I-138b, R1 = Ph, 12 h, 99%, 98% ee
I-138c, R1 = Bn, 2 h, 92%, >99% ee
(1 h, 93%, >99% ee)

CONHR1

I-139b, R1 = Ph, 36 h, 70%, 92% ee
I-139c, R1 = Bn, 24 hc, 47%e, >99% ee

O

O

O
CONHR1

CONHBn
12

I-140, 24 h, <5%, –

CONHBu

Ph

I-141a, R1 = Bu, 24 h, 63%, 91% ee
I-141c, R1 = Bn, 24 h, 63%, >99% ee
(1 h, 79%, 93% ee)

I-142, 4 h, 53%f, 93% ee

aReported

are Isolated yields after chromatography on silica gel and ees judged by chiral HPLC. bResults of reaction without
DMSO are shown in parentheses. c10 mol% catalyst was used d65% conversion. e78% conversion. fcis : trans = 26 : 1

The scope of various N-substituted diazoacetamide or diazo esters with 4bromobenzaldehyde I-51f was evaluated. The diazo acetamides 23c-o were synthesized
by the aforementioned procedure (Scheme 1.12). Pleasingly, the N-substituted
diazoacetamides bearing phenyl, 2Âş and 3Âş alkyl, alkene, alkyne, ester and ether
functional groups performed well in the reaction to afford the epoxides in moderate to
good yields with excellent ees (I-129c-129j). Contrastingly, reactions with the Nsubstituted diazoacetamides bearing free hydroxyl, indole N-H, acidic sensitive Boc and
acetal groups were sluggish and failed to go to completion. Our attempts to applied N,Ndisubstituted acetamide I-129o and diazo esters I-129p-q were unsuccessful. These
results suggested the important role of the amide group and amidic N-H in this epoxidation
reaction.

42

Scheme 1.15 Substrate scope of asymmetric epoxidation with mesoborate catalyst I-118:
variation of diazo compoundsa

10 mol%
(R)-VANOL

H O

5 mol% BH3•Me2S

10 mol% DMSO

*

toluene, rt,
then cool to –40 ºC

toluene, 100 ÂşC, 1 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

mesoborate catalyst I-118

O
O

H

+

Br

R

O

H
N

OH

I-129k, 17 h, (9%)

O
Boc
N

HN

O

H
N

OEt

O

Br
Br

H
N
O

Br

I-129j, 1.0 h, 93%, 99% ee

O
HN

I-129h, 15 h, 97%, 94% ee

OMe

O

Br

O

O

H
N

OEt

H
N

Br

I-129g, 12 h, 47%, 99% ee

I-129i, 24 h, 90%, 99% ee
O

O

H
N

O

O

O

I-129e, 1.0 h, 91%, 99% ee

O

O

H
N

Br

O

Br

H
N

O

I-129d, 3.0 h, 88%, 99% ee

I-129f, 1.0 h, 87%, 99% ee
O

I-129
cis : trans > 50 : 1

O

H
N
O

Br

Br

H
N

Br

O

CONHR1

toluene, –40 ºC
time, 0.1 M
O

I-129c, 3.0 h, 90%, 99% ee

Br

O
5 mol% I-118,

H
N
O

Br

N2

I-23c-q
0.5 mmol

I-51f
1.2 equiv.
O

O
B O
O
O S

OEt

Br
I-129l, 17 h, (35%)

I-129m, 17 h, (24%)

O

O

O

O
I-129o, 24 h, 0%

O
O

OEt

N
Br

I-129n, 17 h, (30%)

O

Br
I-129p, 24 h, 0%

aReported

Br

O

N

O

I-129q, 24 h, 0%

are Isolated yields after chromatography on silica gel and ees judged by chiral HPLC. Yield in parentheses are
determined by 1H NMR analysis. c10 mol% catalyst was used d65% conversion. e78% conversion. fcis : trans = 26 : 1

43

1.8 Gram-scale reaction and synthesis of Taxol-side chain
The asymmetric epoxidation of benzaldehyde with N-butyl diazoacetamide I-23a
catalyzed by mesoborate catalyst I-118 could be easily scaled up 10-fold to afford 1.25 g
of I-111a with >99%ee in 20 min. Pleasingly, we could recover 98.6% of VANOL ligand
from the reaction mixture by chromatography. The gram-scale reaction was much slower
in the presence of 4 Å MS. After 17 h only a 54% yield of I-111a was obtained with 92%
ee and it delivered I-111a of 97% ee in 86% yield after 80 h.
Scheme 1.16 Gram-scale synthesis of cis-epoxide I-108a
O

O
H

+

N2
I-51a
1.2 equiv

N
H

I-23a
6 mmol

Bu

5 mol% I-118
toluene, –40 ºC
0.5 h

O
CONHBu
I-111a
1.254 g, 95% yield, 99% ee
98% of VANOL was recovered

The synthetic usefulness of this methodology was demonstrated in the synthesis
of taxol side-chain I-146. Taxol I-145, whose structure first elucidated126 by Wani and
coworkers in 1971, is one of the best-selling cancer drugs ever manufactured. Due of the
limited amount of taxol that can be isolated from the yew tree (0.02%), organic chemists
have been interested in the synthesis of taxol to meet its increasing demand. The first
total synthesis of taxol was achieved127-128 by Holton and coworkers in Dec 9th, 1993.
However, the synthesis was not commercially viable due to the low yield and complexity.
The large-scale production of taxol was made possible from a semisynthesis from 10deacetyl-baccatin III I-143, which can be extracted from leaves of yew tree (0.1%). This
process was first addressed129 by Potier and developed by Holton. The key step is

44

installing the C-13 side chain by Ojima’s lactam130 I-144 (a. Scheme 1.17). Therefore, the
enantioselective synthesis of the taxol side chain has attracted the attention of many
synthetic chemists. The first asymmetric synthesis of the taxol side chain was reported131132

by Greene et al. They used the Sharpless asymmetric epoxidation for the introduction

of two chiral centers. The desired ester was isolated in 23% overall yield but
recrystallization was needed to enrich the ee to >95%. Multiple pathways to the taxol side
chain were developed by many other groups, including Ojima133, Jacobsen134,
Yamamoto135, Sharpless136 and Shibasaki137 etc., using different strategies (b. Scheme
1.17).
The synthesis of the taxol side chain begins with epoxide I-111a which was
prepared by asymmetric epoxidation of benzaldehyde described in this chapter. Amide I111a was first converted to ester I-25 in 78% yield, a common intermediate in the
synthesis by Greene131 and Jacobsen134. The ethyl glycidate I-25 was then reacted with
TMSN3 in the presence of ZnCl2 to afford azido alcohol I-153 in 96% yield. Benzoylation
of followed by CuCl-catalyzed azide reduction138 gave the desired ester I-146 in 90%
yield. In this way, the taxol side chain was isolated after 5 steps in 63% overall yield
without erosion of ee.

45

Scheme 1.17 Synthetic strategies of taxol and the taxol side chain I-146
a. Semisynthesis of taxol

O

Ph

OH
O

N
OH

HO

Et3SiO
I-144

HO
O
O O

O

Ph
O

O

NH

O

O

O

OH

O
O

OH

4 steps, 80%

O

HO
O
O O
I-145

I-143

O
O

b. Strategies in asymmetric syntheses of taxol side chain

O
NMe2

Ph
I-152

asymmetric
epoxidation

Ph

OCH3
I-151

OH
I-147

Sharpless epoxidation

Sharpless (1994)
R = H, 7 steps, 99% ee,
23% overall yield

O

Ph

Greene (1986)
Shibasaki (2005)
R = Me, 5 steps, >95% ee,
R = Me, 7 steps, 99% ee,
23% overall yield
58% overall yield
36% overall yield (1990)

Sharpless dihydroxylation

Ojima (1991)
R = H, 4 steps, >99% ee,
58% overall yield

NH

O

O

OTIPS
*RO

chiral auxiliary

OLi
I-148

OR
OH
I-146

Jacobsen (1992)
R = H, 5 steps, 95-97% ee
25% overall yield

Yamamoto (1993)
R = H, 3 steps, 95-97% ee
65% overall yield
chiral boron promoted
Manich reaction

Ph

N

Jacobsen
epoxidation

OTBS

Ph
+

I-58b

R* = (–)-trans-2-phenylcyclohexanol

Ph

CO2Et
I-149

OMe
TBSO
I-150

46

Scheme 1.18 Synthesis of the taxol side chain I-146
O

1) BuLi, THF,
-78 ÂşC, 30 min
2) Boc2O, –78 ºC, 2 h
then -45 ÂşC, 2 h
CONHBu

I-111a
99% ee

OEt
O

3) EtONa, EtOH,
0 ÂşC to rt, 30 min

BzCl, Et3N
0.05 equiv DMAP

O

O

78%

I-25

O
N3

OBz

CH2Cl2, rt, 1 h

1) 0.1 equiv ZnCl2,
TMSN3, 70 ÂşC, 24 h

MeCN, rt, overnight

OEt
OH

2) HCl, HOAc, THF,
rt, 1 h

0.2 equiv CuCl
aq. (NH4)2S

OEt

N3

I-153
96%
O

BzHN

OEt
OH

I-146 (R = Et)
taxol side-chain
90%, 99% ee

I-154
99%

1.9 NMR studies and DFT calculations
For a better understanding the mechanism of the mesoborate-catalyzed
epoxidation of aldehydes with diazoacetamides and the role of DMSO, NMR studies were
conducted by preparing a mesoborate sample by the general procedure which was then
subjected to 11B NMR, 1H NMR and 13C NMR analysis.
In the DMSO titration studies, the

11

B NMR spectra clearly showed that the peak

of mesoborate at ~20 ppm shifts upfield to ~7.0 ppm gradually (a-f, Figure 1.5). The most
upfield peak (6.7 ppm) results from 1.0 equiv DMSO. These observations suggest that
the formation of a 1:1 complex with DMSO coordinating to the boron of the mesoborate.
In support of the coordination of DMSO, 13C NMR spectra from the same studies showed
that the change of chemical shift (40.9 ppm for e vs 35.3 ppm for b) and peak broadening
of the methyl carbon signal of DMSO (b-d vs e, Figure 1.6). Addition of 1 equiv of
benzaldehyde to the mesoborate catalyst barely changed the characteristic tricoodinated
boron peak of ~20 ppm in the

11

B NMR (b vs a, Figure 1.7). In contrast, in the presence

47

of 1 equiv DMSO, a distinctive shoulder peak at ~15 ppm could be observed (c, Figure
1.7). Obviously, the coordination of the mesoborate with DMSO is more favorable than
with benzaldehyde. Compared with the 1H NMR spectrum of mesoborate with 1 equiv
benzaldehyde, the spectrum with an additional 1 equiv DMSO showed a notable increase
in the intensity of a peak at 7.8 ppm and line broadening for most peaks in the aromatic
region in the 1H NMR spectrum (c vs b, Figure 1.8). In comparison, addition of 10 equiv
of aldehyde to mesoborate I-118 revealed a peak at 6.1 ppm in the

11

B NMR, which

suggested the coordination of aldehyde to boron of mesoborate catalyst in the reaction
conditions. Finally, the additive studies showed the different borate species resulting from
addition of different additives with various pKas. For benzhydryl aldimine I-176 (pKa = ~7)
and 2-Aminophenol I-117j (pKa = 4.84), the mesoborate was deprotonated to form an
ionic spiroborate complex (~10 ppm sharp peak in 11B NMR) with protonated imine/aniline
(b & c, Figure 1.9). Benzaldehyde I-52a (pKa = –7), diazo acetamide I-23a (pKa = ~0)
and DMSO (pKa = –2) were too weak to deprotonate the mesoborate (d-f, Figure 1.9).
Thus, the interaction was likely to be coordination to boron. The fact that the weaker base
DMSO coordinates better than the diazoacetamide I-23a could be explained by the steric
effect: DMSO is small enough to bind to the boron in the chiral pocket of the mesoborate
catalyst.

48

H O
2 equiv
(S)-VANOL
0.1 mmol

1 equiv BH3•Me2S
toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

O
B O
O I-118
mesoborate catalyst
*

0.7 mL CDCl3

x equiv
DMSO

11B

NMR

a. mesoborate I-118

b. mesoborate I-118 + 0.25 equiv DMSO

c. mesoborate I-118 + 0.50 equiv DMSO

d. mesoborate I-118 + 0.75 equiv DMSO

e. mesoborate I-118 + 1.0 equiv DMSO

f. mesoborate I-118 + 2.0 equiv DMSO

Figure 1.5 11B NMR spectra of mesoborate I-118 and DMSO titration studies
49

H O
2 equiv
(S)-VANOL
0.1 mmol

1 equiv BH3•Me2S
toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

O
* O B O
I-118
mesoborate catalyst

0.7 mL CDCl3

x equiv
DMSO

13C

a. mesoborate I-118

b. mesoborate I-118 + 0.5 equiv DMSO

c. mesoborate I-118 + 1.0 equiv DMSO

d. mesoborate I-118 + 2.0 equiv DMSO

e. DMSO

Figure 1.6 13C NMR spectra of mesoborate I-118 and DMSO titration studies
50

NMR

H O
2 equiv
(S)-VANOL
0.1 mmol

1 equiv BH3•Me2S
toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

O
* O B O
I-118
mesoborate catalyst

0.7 mL CDCl3

additive

a. mesoborate I-118

b. mesoborate I-118 + 1.0 equiv PhCHO I-51a

c. mesoborate I-118 + 1.0 equiv DMSO + 1.0 equiv PhCHO I-51a

Figure 1.7 11B NMR spectra of mesoborate I-118 with benzaldehyde

51

11B

NMR

H O
2 equiv
(S)-VANOL
0.1 mmol

1 equiv BH3•Me2S
toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

O
* O B O
I-118
mesoborate catalyst

0.7 mL CDCl3

additive

a. mesoborate I-118

b. mesoborate I-118 + 1.0 equiv PhCHO I-51a

c. mesoborate I-118 + 1.0 equiv DMSO + 1.0 equiv PhCHO I-51a

Figure 1.8 1H NMR spectra of mesoborate I-118 with benzaldehyde

52

1H

NMR

H O

2 equiv
(S)-VANOL
0.1 mmol

0.7 mL CDCl3
O
B
O
*
O I-118
x equiv PhCHO
mesoborate catalyst

1 equiv BH3•Me2S
toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

11B

a. mesoborate I-118

b. mesoborate I-118 + 1.0 equiv PhCHO I-51a

c. mesoborate I-118 + 10.0 equiv PhCHO I-51a

Figure 1.9 11B NMR spectra of mesoborate I-118 with 10 equiv benzaldehyde

53

NMR

H O
2 equiv
(S)-VANOL
0.1 mmol

1 equiv BH3•Me2S
toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

O
* O B O
I-118
mesoborate catalyst

0.7 mL CDCl3

additive

11B

NMR

a. mesoborate I-118

b. mesoborate I-118 + 1.0 equiv imine I-176

c. mesoborate I-118 + 1.0 equiv aniline I-117j

d. mesoborate I-118 + 1.0 equiv diazoacetamide I-23a

e. mesoborate I-118 + 1.0 equiv benzaldehdye I-51a

f. mesoborate I-118 + 1.0 equiv DMSO

Figure 1.10 11B NMR spectra of mesoborate I-118 with additives
Computational modeling of the VANOL mesoborate catalyst using density
functional theory (DFT) revealed a minimum energy structure in which the boron is
tricoordinated with three phenol hydroxyl group with the free hydroxyl H-bonding (2.07 Å)
to an O of the other molecule of the ligand (Figure 1.10). Modeling the DMSO with
different coordination patterns result in the lowest-energy structure where the oxygen of
DMSO is bound to the boron from the same side of boron as where the H-bonding occurs

54

(Figure 1.11). The shorter distance of the H-bonding (1.73 Å) indicates the synergetic
effect of the hydroxyl group (BLA).

Figure 1.11 Lowest-energy ground-state structure of mesoborate I-118 at the B3LYP/631G(d) level

Figure 1.12 Lowest-energy ground-state structure of mesoborate I-118 bound to DMSO
at the B3LYP/6-31G(d) level

55

The role of DMSO in improving the yields and ees for the epoxidation reactions is
still not clear at this point. It would be reasonable to hypothesize that the DMSO molecule
functions as a “recruiter”. Because an electrophilic sulfur atom that results upon
coordination of the oxygen of the DMSO to the mesoborate is more accessible than the
boron in the mesoborate, which is deep down in the chiral pocket. The DMSO could be
replaced via a ligand exchange process to give structure B, where the aldehyde is
activated by boron coordination (Lewis acid activation). Alternatively, the aldehyde can
be activated by coordination to sulfur as shown in the structure A. On the other hand,
DMSO molecule assembles the mesoborate catalyst from various possible species of
three-coordinated borate ester. Thus, this recruiting effect increases the rates of the
reactions.
Meanwhile, the coordination of DMSO decreases the Brønsted acidity of the
mesoborate, which could possibly make the reaction more enantioselective if there is a
less enantioselective Brønsted acid catalysis pathway that is operational.
naphthyl groups of the ligand
are not shown for clarity

H O

H O
O
* O B O
I-118
mesoborate catalyst

DMSO
aldehdye

O S
O B
O
O O
A

– DMSO

H
R

diazo acetamide
epoxides

Figure 1.13 Proposed role of DMSO

56

H O

O
O B
O
O
B

diazo acetamide
epoxides

R

1.10 Hetero Diels-Alder reactions (HDA) catalyzed by VANOL mesoborates
With the successful application of mesoborate catalyst on asymmetric epoxidation
of aldehydes, an attempt was made to extend this catalyst to other reactions with
aldehydes. The catalytic asymmetric HDA reaction has been intensively explored139 since
Danishefsky et al reported140 the first HDA with aldehydes catalyzed by ZnCl2 in 1982. A
wide variety of chiral Lewis acids have been developed for the HDA reaction of
Danishefsky’s diene with aldehydes (Scheme 1.19). Yamamoto and coworkers
reported141 the first efficient asymmetric HDA catalyzed by chiral aluminum catalyst I-156.
Corey and coworkers employed142 the chiral oxazaborolidine I-157 to catalyze the
formation of Mukaiyama aldol products. Subsequent acid treatment of the aldol products
gave the formal HDA adducts I-155 with high enantioselectivities. Chiral Cr(III) complex
I-158 was applied143 by Jacobsen in HDA with various aldehydes to give I-155 and
derivatives with high enantioselectivities. Several highly efficient Lewis acid catalysts,
including aluminum144, titanium145, zinc146, magnesium147 and zirconium148 complexes
generated from BINOL derivatives I-159-162 were developed by Jørgensen, Ding and
Kobayashi. In 2012, List and coworker reported149 a highly enantioselective HDA reaction
of aldehydes with I-56a and related catalyzed by chiral disulfonimide I-163. The HDA
reaction was performed at –78 ºC for 4 days to afford a number of 2,6-disubstituted and
2,5,6-trisubstituted dihydropyrones in high yields (up to 97%) and excellent ees (up to
98%).

57

Scheme 1.19 Hetero Diels-Alder reaction of Danishefsky’s diene I-57a with aldehydes
OMe

O
+

1) catalyst

H

TMSO
I-56a

2)

O
Ph

“H+”

O

I-51a

H
I-155a

Danishefsky et al138 (1982) Yamamoto et al139 (1988)

Corey et al140 (1992)

Jacobsen et al141 (1998)

0.5 equiv ZnCl2
rt, 1-2 days

10 mol% I-156
toluene, –20 ºC, hours

20 mol% I-157
EtCN, –78 ºC, 14 h

2 mol% I-158
tBuOMe, –30 ºC,

65%

71%, 67% ee (R)

100%, 82% ee (R)

85%, 87% ee (R)

Ding et al143 (2002)

Jørgensen et al142 (2000)

10 mol% I-159/AlMe3 0.05 mol% Ti(OiPr)4/ I-160 1:2
neat, rt,
tBuOMe, –38 ºC,
99%, 99% ee (R)

97%, >99% ee (R)

Ding et al144 (2002)

Ding et al145 (2008)

5 mol% I-161/Et2Zn
toluene, –25 ºC,

10 mol% I-160/MgBu2 1:1.5
toluten, rt,

99%, 97% ee (R)

99%, 99% ee (S)

OCy

H
N

SiPh3

O

O
Al Me
O

O
B
N
Bu
Ts

SiPh3

OCy
OH
OH
OCy

I-157

F3C CF
3
F

I-156
I-159
H

CF3
F
CF3

OCy

H
SO2
NH
SO2

Cr
O

O
BF4

F

I-158

CF3
CF3

I-163
Br
OH
OH

I-160

I

C2F5

Br

F

CF3

OH
OH

OH
OH

I-161

F3C

I

C2F5
I-162

During the development of aza-Diels-Alder reaction of in situ generated imines,
Newman and Wulff attempted the HDA reaction of benzaldehyde with I-56a catalyzed by

58

VAPOL/B(OPh)3 1:3 catalyst. The desired dihydropyrone was isolated in 67% yield with
28% ee. We then tested the same reaction with the VANOL boroxinate catalyst with
DMSO under the same condition. The reaction gave low conversion (<20%) and the
product was not isolated (Scheme 1.20).
Scheme 1.20 HDA reaction of Danishefsky’s diene I-56a with aldehydes catalyzed by
boroxinate catalyst
OMe

O
+

H

TMSO
I-56a
2.0 equiv

toluene, –45 ºC,
48 h

I-51a

OMe

O
+

TMSO
I-56a

30 mol% B(OPh)3
(S)-VAPOL

O
H
O

Ph

I-155a
67%, 28% ee

10 mol% (S)-VANOL boroxinate
10 mol% DMSO,

O
H

H

toluene, –45 ºC, 48 h
I-51a

O

Ph

I-155a
<20% conversion

2.0 equiv

It was pleasing to find that the HDA reaction of 4-bromobenzaldehyde with
Danishefsky’s diene catalyzed by VANOL mesoborate catalyst gave I-155b in 84% yield
and 40% ee at rt. In contrast to the epoxidation reaction, the enantioselectivity increase
to 62% ee when DMSO was not added (entry 2 vs 1, Table 1.13). Decreasing the reaction
temperature for the reactions with 20 mol% DMSO did not improve the ee but slowed
down the rate significantly (entry 3 & 4 vs 1, Table 1.13). Attention was then turned to the
study of the ligand effect (entry 5-7 & 1, Table 1.13). The reaction with BINOL mesoborate
gave a better result (94%, 83% ee) than VANOL. Compared with VANOL, the reaction
catalyzed by tBuVANOL mesoborate afforded I-155b in higher yield with comparable ee,
while the reaction with VAPOL mesoborate did not yield the desired product. This is quite

59

surprising because the steric hindrance of VAPOL and tBuVANOL are similar. It was
delightful to see that lowering the reaction temperature to –40 ºC in the absence of DMSO
had positive effects for both VANOL and BINOL. The dihydropyrone I-155b could be
isolated in 89% with 83% ee for VANOL mesoborate catalyst, and 96% with 91% ee for
BINOL mesoborate catalyst (entry 8 & 9, Table 1.13).
Table 1.13 Temperature and ligand screening for HDA reaction
H O
20 mol%
(S)-ligand

10 mol% BH3•Me2S
toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

OMe

O
+

O
B O
O

mesoborate catalyst

10 mol% mesoborate

H

TMSO
I-56a

*

I-51f

Br

toluene, temp,
24 h

O
O

Br

H
I-155b

2.0 equiv
entry

ligand

DMSO

1
VANOL 20 mol%
2
—
VANOL
3
VANOL 20 mol%
4
VANOL 20 mol%
5
—
BINOL
6
VAPOL
—
7 tBuVANOL —
8
VANOL
—
9
BINOL
—

temperature %yielda (I-155b) %eeb (I-155b)
rt
rt
0 ÂşC
–40 ºC
rt
rt
rt
–40 ºC
–40 ºC

84
79
82
40
94
0
90
89
96

40
62
25
37
83
—
64
83
91

aIsolated
bAs

yield after chromatography on silica gel.
judged by chiral HPLC.

The reaction time was optimized. The reactions were completed within 1 h at rt
and at –40 ºC (entry 1 vs 2, 3 vs 4, Table 1.14). However, a further decrease the reaction
temperature to –78 ºC in an effort to increase the enantioselectivity proved to be fruitless.
The reaction became very sluggish and did not go to completion for a longer period of

60

time (entry 5, 7-8, Table 1.14). As with the reaction with VANOL, the reaction with BINOL
mesoborate at –78 ºC was also affected, and to a greater extent. Both the yield and ee
of the adduct were reduced substantially compared with that at –40 ºC (96%, 91% ee)
(entry 6, Table 1.14). It is noteworthy that contrary to most of the HDA reactions in the
literature, the VANOL mesoborate catalyzed HDA did not require a treatment of acid to
yield the cyclized product. This observation suggests that the reaction might proceed
through a concerted [4+2] mechanism rather than the widely accepted142, 149 stepwise
pathway (Mukaiyama aldol then cyclization). Mechanistic investigations in this regard
were not carried out.
Table 1.14 Studies of time and temperature for HDA reaction
OMe

O
+

H

TMSO
I-56a
2.0 equiv

I-51f

entry temperature
1c
2c
3c
4d
5e
6ef
7e
8e
9g

rt
rt
–40 ºC
–40 ºC
–78 ºC
–78 ºC
–78 ºC
–78 ºC
–60 ºC

aIsolated

10 mol% (S)-VANOL
mesoborate

Br

toluene, temp,
time

O
O

Br

H
I-155b

%yielda (I-155b) %eeb (I-155b)

time
24 h
1h
24 h
1h
1h
1h
2h
4h
1.5 h

79
83
89
92
49
16
56
57
61

62
59
83
84
83
71
79
90
87

yield after chromatography on silica gel. bAs judged by chiral

by 1 M aq. HCl. dQuenched by TFA. eQuenched
by Et3N. fBINOL was used instead of VANOL. gQuenched by
EtOH/H2O
HPLC.

cQuenched

Next, the solvent effect was investigated for HDA reaction catalyzed by the VANOL
mesoborate at rt. Toluene appeared to be superior to the more polar solvents, such as
61

DCM and THF (entry 2 & 3 vs 1, Table 1.15). The optimal solvent system for aza-HDA
reaction113 delivered the product with higher yield, albeit slightly lower ee (entry 4, Table
1.15). The attempts to search for a better solvent for the mesoborate catalyzed HDA
reaction at –40 ºC were unsuccessful (entry 5-10, Table 1.15). The reaction in the polar
solvent chloroform and the coordinating solvent Et2O gave I-155b in low to moderate
yield. In other aromatic solvents, including benzene, mesitylene and m-xylene, the
reaction was much slower and gave similar enantioselectivity.
Table 1.15 Solvent screening for HDA reaction
OMe

O
+

H

TMSO
I-56a

10 mol% (S)-VANOL
mesoborate

I-51f

Br

solvent, temp,
24 h

O
O

Br

H
I-155b

2.0 equiv
entry

solvent

toluene
1
DCM
2
THF
3
4 DCM/toluene (1:1)
toluene
5c
CHCl3
6c
c
benzene
7
Et2O
8c
c
mesitylene
9
m-xylene
10c
aIsolated

c

temperature %yielda (I-155b) %eeb (I-155b)
rt
rt
rt
rt
–40 ºC
–40 ºC
–40 ºC
–40 ºC
–40 ºC
–40 ºC

79
65
56
88
79
13
31
49
9
16

62
54
48
59
81
—
—
79
76
—

yield after chromatography on silica gel. bAs judged by chiral HPLC.

Quenched after 1 h

It was reasoned that the low reactivity in xylene and mesitylene could be caused
by the water residue. In an attempt to improve the efficiency of the mesoborate, effects
of additives were investigated. The reaction gave comparable results in the presence of
4 Å MS or Na2CO3 (entry 2 & 3 vs 1, Table 1.16). The fact that the inorganic base Na2CO3

62

did not inhibit the reaction may be due to its low solubility in toluene at –40 ºC. In
agreement with the reaction at rt (entry 2 vs 1, Table 1.13) DMSO was detrimental to the
catalyzed reaction (entry 4 vs 1, Table 1.16). Addition of 20 mol% benzoic acid also had
an adverse effect on the results, probably due to the formation of acyloxy borate (entry 5
vs 1, Table 1.16). Lastly, Et3N shut down the reaction at –40 ºC as expected (entry 6,
Table 1.16).
Table 1.16 Additive studies for HDA reaction
OMe

10 mol% (S)-VANOL
mesoborate

O
+

H

TMSO
I-56a

Br

I-51f

toluene, –40 ºC,
1h

O
O

Br

H
I-155b

2.0 equiv

entry

additive

1
2
3
4
5
6

none
4 Å MS
20 mol% Na2CO3
20 mol% DMSO
20 mol% PhCOOH
20 mol% Et3N

%yielda (I-155b) %eeb (I-155b)
92
91
91
17
47
NR

84
83
83
—
74
—

aIsolated
bAs

yield after chromatography on silica gel.
judged by chiral HPLC.

To investigate the effect of different silyl groups in the Danishefsky’s diene, 3 other
dienes I-56b-d was prepared by a modified procedure150 in quantitative yields. It was a
disappointment that employing the dienes with bulky silyl group such as TES, TIPS and
TBS, slowed down the HDA reaction significantly with both VANOL and BINOL
mesoborate catalysts.

63

Scheme 1.21 HDA reaction of Danishefsky’s diene I-56 with different silyl group
2.7 equiv Et3N
1.1 equiv R3SiOTf

O
MeO

OR’

Et2O, –20 ºC to 0 ºC, 2 h

MeO

quant
I-56b, R’ = TES
I-56c, R’ = TIPS
I-56d, R’ = TBS

I-164
OMe

10 mol% (S)-VANOL
mesoborate

O
+

H

’RO
I-56a-d

I-51f

OMe
H

’RO

Br

I-56a-d

toluene, –40 ºC,
1h

O

H

I-155b
92%, 84% ee for I-56a
no reaction for I-56b-d

10 mol% (S)-BINOL
mesoborate

O
+

Br

Br

O

toluene, –40 ºC,
1h

Br

O
O

H
I-155b

I-51f

96%, 91% ee for I-56a
no reaction for I-56b
15% for I-56c
24% for I-56d

In

summary,

HDA

reaction

of

Danishefsky’s

diene

I-56a

with

4-

bromobenzaldehyde I-51f catalyzed by mesoborate has been developed. By
investigating the effect of temperature, time, ligand, solvent, additive and silyl group, the
reaction under optimal condition afforded 89% dihydropyrone I-155b with 83% ee for
VANOL mesoborate, and 96% yield with 91% ee for BINOL mesoborate.
1.11 Passerini reaction and aziridination reaction
Another reaction of interest to test our mesoborate catalyst on is the Passerini
reaction. The Passerini reaction is a three-component (3C) reaction involving an
isocyanide, an aldehyde (or ketone) and a carboxylic acid to afford an Îą-acyloxyamide
with a chiral center. Although this reaction was discovered151 about a century ago, only
limited success has been achieved on a catalytic enantioselective version, since first of

64

which began to appear 14 years ago. Denmark and Fan reported152 an asymmetric
Passerini-type reaction without the carboxylic acid component catalyzed by a Lewis base
catalyst, the chiral bisphosphoramide I-165. After aqueous workup, the reaction yielded
Îą-hydroxyamides with high to excellent enantioselectivities for aromatic aldehydes but
only moderate to high enantioselectivities was achieved for aliphatic or alkynyl aldehydes
(eq 1, Scheme 1.22). The classic 3C Passerini reaction was first reported153 in an
asymmetric catalytic version by DĂśmling and coworkers by massive screening of
hundreds of Lewis acid/ligand combinations. However, under the optimal conditions, the
reaction promoted by complex Ti(OiPr)4-taddol I-166 only afforded Îą-acyloxyamides with
low enantioselectivities in low to moderate yields (eq 2, Scheme 1.22). Shreiber and
coworkers developed154 a Passerini 3C reaction catalyzed by the indan-pybox-Cu(II)
complex I-167. High enantioselectivity was only observed when a chelating aldehyde was
used (eq 3, Scheme 1.22). Zhu, Wang and coworkers demonstrated155 that a chiral Alsalen I-168 complex could catalyze the Passerini 3C reaction to afford moderate to good
yield and good to excellent enantioselectivities only for a variety of aliphatic aldehydes
(eq 4, Scheme 1.22). In 2015, Tan, Liu and coworkers achieved156 a highly efficient
asymmetric 3C Passerini reaction with a broad substrate scope by using the BINOL
derived phosphoric acid I-169. Good yields and high to excellent ees were observed for
the reaction with both aromatic and aliphatic aldehydes (eq 5, Scheme 1.22). The
proposed transition state I-170 involves activation of both aldehyde and isocyanide
though hydrogen-bonding and ion pair interactions.

65

Scheme 1.22 Enantioselective Passerini reaction

O
N
O
P
N
N

N
O
P
5N N

HO

O
N

OH

I-166

OTf–

O H O
O
P
O
O H O

*

O
O P
O
OH

I-168

N

I-167

H

OH HO

O

N
Cu

OTf–

I-165

H

O

O
R2

I-169

H

C

R3

N

R1

I-170

Denmark (2003): Psserini-type Reaction
NC

O

+

+
R

I-101

SiCl4

H

I-15

5 mol% I-165

OH

aq. NaHCO3

NHtBu

R

–74 ºC

(1)

12 examples,
R = aryl or alkenyl,
81-93%, 84-99% ee
R = alkyl or alkynyl,
53-92%, 35-74% ee

(2)

6 examples,
12-48%, 32-42% ee

(3)

16 examples,
75-98%, 60-98% ee

(4)

16 examples,
51-70%, 63-99% ee

(5)

35 examples,
41-99%, 84-99% ee

I-172 O

I-171

DĂśmling (2003):
NC

O

+

COOH I-166/Ti(iOPr)4

+

H

–78 ºC, 24 h
I-173a

I-51h

Schreiber (2004):
R1 NC

+

H

O
I-175a

20 mol% I-167
+

O

N
H

I-174a

O

R2

O

R3 COOH

O
R3

DCM, 0 ÂşC, MS

O
R2

O

I-15
I-173
I-174
R1 = alkyl; R2 = alkyl, aryl with O or S groups; R3 = Ph or Bn

N
H

R1

I-175

Zhu and Wang (2008):
10 mol%
I-168/Et2AlCl

O
R1 NC

+

R2

H

+ R3 COOH

O
R3

–40 ºC, 48 h

O
O

I-173
I-15
I-174
R1 = aryl, alkyl; R2 = alkyl; R3 = aryl, alkyl

R2
I-175

N
H

R1

Tan and Liu (2015):
O

O
R1 NC

+

R2

10 mol% 5
H

+ R3 COOH

I-15
I-173
R1 = alkyl; R2, R3 = aryl, alkyl

I-174

CHCl3, –20 ºC or rt,
24-36 h

66

R3

O
O

R2
I-175

N
H

R1

Gupta and Wulff attempted118 the Passerini 3C reaction of benzaldehyde, benzoic
acid and tbutyl isocyanide catalyzed by VANOL phosphoric acid (PA) in toluene at 80 ÂşC
to afford the desired Îą-acyloxyamide with 6% ee in only 35% yield. In this work, the
Passerini 3C reaction was examined with the mesoborate catalyst described above which
was effective for the epoxidations and AHDA reactions of aldehydes.
4-Bromobenzaldehyde was chosen instead of benzaldehyde for the model
reaction since it is easier to handle and is relatively stable. The fact that the control
reaction at rt without any catalyst gave a 49% yield of the desired product I-175b indicated
a severe background reaction (entry 1, Table 1.17). Consistent with the result from the
VAPOL PA catalyzed reaction, VANOL PA catalyzed the reaction at rt to afford 58% of I175b with only –8% ee (entry 2, Table 1.17). The reaction catalyzed by either the
mesoborate or boroxinate catalyst gave a higher yield than the background reaction and
both gave rise to the I-175b in 14% ee (entry 3 & 4, Table 1.17). Other Lewis acid systems
that were effective in catalyzing reaction with imines157 were also attempted. A Ti-VANOL
complex was less effective. The Zr-VANOL157 did not accelerate the Passerini reaction
either with or without N-methyl imidazole (NMI) (entry 6 & 7, Table 1.17).

67

Table 1.17 Early attempts of asymmetric 3-component Passerini reaction
Br
O

O
NC

+

H

+

I-101

O

toluene, rt, 24 h, 0.25 M

Br
0.5 mmol

catalyst

OH

0.5 mmol

0.5 mmol

I-51f

I-174a

O

H
N

O
I-175b

entry

catalyst

1
2
3
4
5
6
7

none
10% (S)-VANOL PA
10 mol% (S)-VANOL mesoborate
20 mol% (S)-VANOL boroxinate
10 mol% (S)-VANOL/Tic
10 mol% (S)-VANOL/Zrd
10 mol% (S)-VANOL/Zr/NMIe

%yielda (I-175b) %eeb (I-175b)
49
58
68
74
56
46
45

—
–8
14
14
–10
–10
–6

aIsolated

yield after chromatography on silica gel.
judged by chiral HPLC. Absolute stereochemistry was not established.
cCatalyst was prepared by heating 20 mol% VANOL and 10 mol%
Zr(OiPr)4•(HOiPr) at 100 ºC for 0.5 h, then pumping for 0.5 h
dCatalyst was prepared by heating 20 mol% VANOL and 10 mol% Ti(OiPr) at
4
100 ÂşC for 0.5 h, then pumping for 0.5 h
e10 mol% NMI was added to catalyst of entry 6
bAs

It was decided to further optimize the mesoborate catalyst even though boroxinate
gave slightly higher yield. Running the reaction at 0 ÂşC increased the enantioselectivity
while the yield dropped to 52% (entry 2 vs 1, Table 1.18). Adding 4 Å MS did not have a
positive effect on the outcome (entry 4 vs 2, Table 1.18). A control reaction at 0 ÂşC showed
that the background reaction seriously competes with the catalyzed reaction (entry 3,
Table 1.18). Further decreasing the temperature to –20 ºC was not too rewarding. The
ee of I-175b increased 5% but the loss in yield was 14% yield.

68

Table 1.18 Temperature screening of the Passerini reaction catalyzed by mesoborate I118
H O
20 mol%
(S)-ligand

“standard” condition

NC

10 mol% BH3•Me2S
toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

O

O

+

+

H

OH

0.5 mmol
I-51f

mesoborate catalyst

0.5 mmol

O

H
N

O
I-175b

I-174a

none
0 ÂşC
0 ÂşC, w/o catalyst
0 ºC, 4 Å MS
–20 ºC

Br

O

toluene, rt,
24 h, 0.25 M

entry variation from “standard”

1
2
3
4
5

O
B O
O

10 mol% (S)-VANOL
mesoborate

Br
0.5 mmol
I-101

*

%conv.a %yieldb %eec
(I-51f) (I-175b) (I-175b)
91
81
87
60
67

68
52
54
56
38

14
35
—
34
40

by 1H NMR analysis of crude product using Ph3CH as an
internal standard. bIsolated yield after chromatography on silica gel.
cAs judged by chiral HPLC. Absolute stereochemistry was not established.
aDetermined

Next, the effect of solvent and ligand was investigated on the mesoborate
catalyzed Passerini reaction at 0 ÂşC. Other common solvents including DCM, chloroform,
THF and acetonitrile were screened (Table 1.19). Toluene gave the lowest yield of the
product but with highest enantioselectivity among 5 solvents screened (entry 1, Table
1.19). Reaction in DCM afford I-175b in the highest yield of 71%, albeit with lower ee. The
coordinating solvent THF gave the product with the lowest ee as expected (entry 4, Table
1.19). Toluene was used as the solvent for ligand screening. In contrary to the results
from the AHDA reaction, BINOL mesoborate was less effective than the corresponding
VANOL/VAPOL catalysts (entry 2, Table 1.20). VANOL was superior ligand in terms of
yield and ee of the product (entry 1, Table 1.20). Interestingly, same atropisomer of
69

VAPOL induced the opposite enantioselectivity for the reaction with VANOL and
tBuVANOL mesoborate catalyst (entry 3 & 4, Table 1.20).
Table 1.19 Solvent screening of Passerini reaction catalyzed by mesoborate I-118
Br
O

O
NC

+

H

+

OH

0.5 mmol
I-51f

0.5 mmol
I-174a
entry

1
2
3
4
5

O

solvent, 0 ÂşC,
24 h, 0.25 M

Br
0.5 mmol
I-101

10 mol% (S)-VANOL
mesoborate

H
N

O
I-175b

O

solvent %conv.a %yieldb %eec
(I-51f) (I-175b) (I-175b)
81
86
79
70
68

toluene
DCM
CHCl3
THF
MeCN

52
71
58
60
58

35
27
29
15
29

by 1H NMR analysis of crude
product using Ph3CH as an internal standard.
bIsolated yield after chromatography on silica gel.
cAs judged by chiral HPLC. Absolute
stereochemistry was not established.
aDetermined

Table 1.20 Ligand screening of Passerini reaction catalyzed by mesoborate I-118
Br
O

O
NC

+

H

+

OH

toluene, 0 ÂşC,
24 h, 0.25 M

Br
0.5 mmol

0.5 mmol

0.5 mmol

I-101

I-51f

I-174a
entry

ligand

1
2
3
4

VANOL
BINOL
VAPOL
tBuVANOL

10 mol% (S)-ligand
mesoborate

O

I-175b
%conv.a %yieldb %eec
(I-51f) (I-175b) (I-175b)
81
78
75
78

52
26
49
21

35
–2
–23
24

by 1H NMR analysis of crude
product using Ph3CH as an internal standard.
bIsolated yield after chromatography on silica gel.
cAs judged by chiral HPLC. Absolute
stereochemistry was not established.
aDetermined

70

H
N

O
O

Notably, in the presence of 20 mol% DMSO, the Passerini reaction catalyzed by
mesoborate afforded I-175b in higher yield but with slightly lower ee (entry 2 vs 1, 6 vs 5,
Table 1.21). Control experiments revealed that the uncatalyzed reactions were not
significantly affected either at rt or 0 ÂşC (entry 3 vs 4, 7 vs 8, Table 1.21). This might have
suggested that DMSO was somehow engaged in the mesoborate catalyst, which was
helpful with the catalytic turnover.
Table 1.21 Effect of DMSO in Passerini reaction catalyzed by mesoborate I-118
Br
O

O
NC

+

H

+

10 mol% (S)-VANOL
mesoborate

OH

toluene, temp,
24 h, 0.25 M

Br
0.5 mmol
I-101

0.5 mmol

0.5 mmol

I-51f

O
O

H
N

O
I-175b

I-174a
entry

catalyst

temp

DMSO

1
2
3
4
5
6
7
8

yes
yes
no
no
yes
yes
no
no

rt
rt
rt
rt
0 ÂşC
0 ÂşC
0 ÂşC
0 ÂşC

0
20 mol%
20 mol%
0
0
20 mol%
20 mol%
0

%yielda %eeb
(I-175b) (I-175b)
68
79
45
49
52
94
64
56

14
9
—
—
35
34
—
—

aIsolated

yield after chromatography on silica gel. bAs judged by
chiral HPLC. Absolute stereochemistry was not established.

The enantioselectivity of the mesoborate catalyzed Passerini reaction was
hampered by competition with the uncatalyzed reaction. It was reasoned that by varying
the acid component, it might be possible to slow down the background reaction, thus to
increase the asymmetric induction of the reaction (Scheme 1.23).

71

With a more steric hindered 1-naphthoic acid, the reaction afforded I-175b in lower
yield with minimal increase in ee. An aliphatic carboxylic acid was compatible in the
reaction but did not improve the enantioselectivity (I-175c). The reaction with 4substituted benzoic acids without DMSO was sluggish. Gratifyingly, in the presence of
DMSO, the reaction of 4-methoxybenzoic acid afforded 50% of I-175d with 49% ee, while
the 4-nitrobenzoic acid gave only 32% nearly racemic I-175e. This result was in
agreement of our hypothesis that use of a weaker acid would slow down the background,
thus increasing the ee of the product. However, the reaction with 3,4,5-trimethoxybenzoic
acid did not afford I-175f with better ee, probably because of it’s lower capability to donate
a H-bond to the mesoborate catalyst.
In summary, mesoborate catalyst could be extended to 3C Passerini reaction to
afford Îą-acyloxyamides with low to moderate enantioselectivities. In order to optimize it
into a highly enantioselective reaction, one would need to develop a more reactive
catalyst that can outcompete the uncatalyzed reaction. Perhaps this could be achieved
by screening mesoborates generated from a variety of VANOL derivatives.

72

Scheme 1.23 Screening of acid component for 3C Passerini reaction catalyzed by
spiroborate I-118
Br
O
NC

+

H

+
R

Br

0.5 mmol
I-101

10 mol% (S)-VANOL
mesoborate

O

0.5 mmol
I-51f

O

OH

toluene, 0 ÂşC,
24 h, 0.25 M

0.5 mmol
I-174

R

H
N

O
I-175 O

Br
Br

Br
O

O

H
N

O

H
N

O

O

O

O
I-175a
81% conv.a, 52%b, 35% eec

I-175b
69% conv.a, 43%b, 37% eec

O

O

I-175d
55% conv.a, 14% NMR yielda
(66% conv.a, 50%b, 49% eec)d

Br

O

H
N

O
MeO

O
I-175c
72% conv.a, 40%b, 35% eec

Br

Br

H
N

O
O

O2N

H
N

O

I-175e
62% conv.a, 12% NMR yielda
(66% conv.a, 32%b, 3% eec)d

O
MeO
MeO

H
N

O
O

OMe I-175f
(32%b, 37% eec)e
(rt, 92%b, 24% eec)d

by 1H NMR analysis of aldehyde using Ph3CH as an internal standard. bIsolated yield after chromatography
on silica gel. cAs judged by chiral HPLC. Absolute stereochemistry was not established. dWith 20 mol% DMSO. eB(OPh)3
was used for spiroborate formation instead of BH3•Me2S.
aDetermined

1.11

Asymmetric aziridination and future work
Asymmetric aziridination reactions catalyzed by BINOL spiroborate catalysts has

been studied56. It was found that the BINOL spiroborate can catalyze the aziridination
reaction of imine I-176 and EDA I-94 to afford the cis-aziridine I-177 with the opposite ee
compared to that with the BINOL boroxinate catalyst (entry 1 vs 2, Table 1.22).
Furthermore, the BINOL spiroborate is formed alongside the boroxinate catalyst as a
mixure under the 1:3 BINOL to boron conditions. Therefore, only low optical purity (1320% ee) could be achieved by the boroxinate conditions (entry 2, Table 1.22).
73

Table 1.22 Asymmetric aziridination of imine I-176 with EDA I-94 catalyzed by spiroborate
I-118b and boroxinate I-90b
I-176–H

OPh
O B
O
O
* O B
O B
I-90b OPh
boroxinate catalyst

I-176–H

O

*

O
B
*
O O

I-118b
spiroborate catalyst

Ph
+
N

O

OEt

catalyst

N

solvent, 0.5 M, rt, 24 h

N2

I-176
0.5 mmol

Ph

COOEt

I-94
1.2 equiv

I-177
methoda

entry

catalyst

1
2
3
4

10 mol% BINOL-I-118b
10 mol% BINOL-I-118b/I-90be
5 mol% VANOL-I-118b
10 mol% VANOL-I-90b

solvent cis:transb %yieldc %eed
(I-177) (I-177)
(I-177)
DCM
DCM
toluene
toluene

A
B
C
D

8:1
18:1
30:1
>50:1

44
58
82
84

–26
24
52
93

aA:

precatalyst prepared by reaction of (S)-BINOL with 3 equiv of B(OPh)3 in CH2Cl2 at
55 °C for 1 h and then removal of volatiles. B: reaction performed by adding 12 equiv
of I-94 to a CH2Cl2 solution of a (2:1:10) mixture of BINOL, B(OPh)3, and imine I-176.
C: precatalyst prepared by reaction of the 10 mol% (S)-VANOL and 5 mol% BH3¡Me2S
in toluene at 100 °C for 1 h and then removal of the volatiles. D: precatalyst prepared
by reaction of the 10 mol% (S)-VANOL, BH3¡Me2S, PhOH, and H2O (1:3:2:3) in toluene
at 100 °C for 1 h and then removal of the volatiles. bAs judged by 1H NMR crude.
cIsolated yield after chromatography on silica gel. dAs judged by chiral HPLC. eThe
mixure of I-118b/I-90b was determined to be 5:2 by 11B NMR.

It would be interesting to evaluate the VANOL spiroborate catalyst I-118 in the
aziridination of aldimines with EDA. The spiroborate precatalyst of VANOL was prepared
by the general conditions and then was added imine I-176. EDA I-94 was added after 5
min and the mixture was stirred at rt for 24 h. The reaction afforded the desired cisaziridine in 82% yield with 52% ee. It was found that VANOL spiroborate gave better
stereoselectivity than its BINOL analog (entry 3 vs 1, Table 1.22). In addition, VANOL

74

spiroborate gave the same enantiomer ((2R,3R)-I-177) as the VANOL boroxinate
catalyst, albeit with much lower enantioselectivity (entry 3 vs 4, Table 1.22).
It was pleasing to find that by optimization of the protecting group in the imine and
optimizing the ligand in the catalyst, a highly enantioselective aziridination has been
developed158. The mechanism of this reaction is proposed to be a Brønsted acid
catalyzed pathway. Deprotonation by imine to give a spiroborate precatalyst was
supported by

11

B NMR studies and X-ray crystallography158. In addition, a Hammett plot

study158 with catalysts prepared from VANOLs having substituents with varying electronic
properties in the 5,5’-postions was conducted. Preliminary results are in agreement with
a Brønsted acid catalysis mechanism. It would be also worthwhile to investigate the
mechanism of the mesoborate-catalyzed epoxidation by a Hammett study and a KIE
study. If the experimental evidence supports the Lewis acid pathway, these borate
catalysts would be one of the rare cases of the “chameleon catalysts”, which could
catalyze different reactions by two distinct pathways (Brønsted vs Lewis acid catalysis)
depending on the substrates.

75

Scheme 1.24 Potential applications of asymmetric epoxidation in total synthesis
O

O

O
N
N
H

O

O

I-178a
(–)-tedanalactam
H

O

O

O

O

NH2

VANOL
mesoborate

O

N
O
H
I-178a
(–)-tedanalactam

1. VANOL
mesoborate
2. protection

O
N2

N

O

O

NH

I-23t

I-23a

H
R
O

H

O

H
NH2

I-182
R = alkyl

NH2

R
O

O

O
I-182

H

O

O
H

N
I-182
O

H

ozonolysis

O

N

H

I-183

I-23u

O

H
R

3. oxidation
4. Boc2O

O

H
N

N2

1. VANOL
mesoborate
2. deprotection

N
Boc

NH2

H

H

O

H
N

N2

N2

I-181

O

I-23s

H

deprotection

OH
+

O

ozonolysis

N2
O

Regitz diazo
transfer

H

I-23r
oxidation

O

I-179c
(+)-epogymnolactam

H
N

O

O

O

NH2

O

2. lactamization

I-180

N3

H

I-179b
(+)-tetrahydrocerulenin

O

H

H

O

H

1. Staudinger
BocN

I-178c
(+)-piplaroxide
H

O

O

O

I-178b
(+)-kaousine

I-179a
(+)-cerulenin

N3

N

O

O
OPG
I-182

O

+

NH
N2
I-23a

Also in the future work, the asymmetric epoxidation could be applied in the total
synthesis of natural products containing a 3,4-epoxy amide motif, such as (–)tedanalactam I-178a, (+)-cerulenin I-179a and related compounds (Scheme 1.24). The
enantioselective total synthesis of (–)-tedanalactam has been reported on three

76

occasions159-161. The source of chirality is produced by the Sharpless asymmetric
dihydroxylation159, from the chiral pool160 and by a classical resolution161. Our approach
is to introduce chirality by epoxidation of the azide containing aldehyde I-181 with
diazoacetamide I-23a, followed by Staudinger reaction and lactamization to finish the
synthesis. Alternatively, a more challenging intramolecular epoxidation of I-23r could be
employed as th last step to construct the cis-epoxide group asymmetrically. However, the
synthesis of a diazo compound that contains an aldehyde functional group has not been
reported. The synthesis of diazo compound I-23s containing a hydroxyl group and I-23t
containing a diethyl acetal group was carried out (see Chapter 4 section 4.21) using
general procedure and went well. But the attempts to oxidize the hydroxyl group into
aldehydes using DMP, Swern oxidation and PCC oxidation failed to give I-23r due to the
sensitivity of diazo group under those conditions. Deprotection of I-23t by a mild
I2/acetone condition also failed due to the decomposition of the diazo compound. Other
protecting groups for aldehyde such as silyl cyanohydrin acetals would be worth trying.
Alternatively, I-23r could be prepared by Regiz diazo transfer reaction from I-182 or by
ozonolysis of compound I-23u if the diazo group can survive the ozonolysis process.
Another interesting compound cerulenin I-179a, an antifungal antibiotic that has
been the target of several racemic162-165 and enantioselective166-168 total syntheses.
Natural (+)-cerulenin and related compounds have been synthesized from chiral synthon
166
, D-tartaric
D-glucose

acid167 and using the Sharpless asymmetric epoxidation168. The

shortest synthesis168 was reported by Mani and Townsend, with the longest linear
sequence of 8 steps and 26% overall yield. Our approach is straight forward: the

77

epoxidation of racemic protected Îą-hydroxy aldehyde I-182 with diazo acetamide I-23a
would afford the epoxide with the correct stereochemistry. Hopefully, the asymmetric
epoxidation would display a high catalyst-controlled rather than control by the
stereocenter of the hydroxyl group in the aldehyde substrates. After several steps of
functional group manipulation, the natural product (+)-cerulenin I-179a could hopefully be
accessed.

The

related

compound

(+)-tetrahydrocerulenin

I-179b

epogymnolactam I-179c could also be synthesized in the similar manner.

78

and

(+)-

REFERENCES

79

REFERENCES

1.
Katsuki, T.; Martin, V., Asymmetric Epoxidation of Allylic Alcohols: the Katsuki–
Sharpless Epoxidation Reaction. In Organic Reactions, John Wiley & Sons, Inc.: 2004.
2.

Katsuki, T.; Sharpless, K. B., J. Am. Chem. Soc. 1980, 102 (18), 5974-5976.

3.
Irie, R.; Noda, K.; Ito, Y.; Matsumoto, N.; Katsuki, T., Tetrahedron Lett. 1990, 31
(50), 7345-7348.
4.
Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N., J. Am. Chem. Soc.
1990, 112 (7), 2801-2803.
5.

McGarrigle, E. M.; Gilheany, D. G., Chem. Rev. 2005, 105 (5), 1563-1602.

6.

Wong, O. A.; Shi, Y., Chem. Rev. 2008, 108 (9), 3958-3987.

7.

Tu, Y.; Wang, Z.-X.; Shi, Y., J. Am. Chem. Soc. 1996, 118 (40), 9806-9807.

8.

Furukawa, N.; Sugihara, Y.; Fujihara, H., J. Org. Chem. 1989, 54 (17), 4222-4224.

9.
Illa, O.; Namutebi, M.; Saha, C.; Ostovar, M.; Chen, C. C.; Haddow, M. F.;
Nocquet-Thibault, S.; Lusi, M.; McGarrigle, E. M.; Aggarwal, V. K., J. Am. Chem. Soc.
2013, 135 (32), 11951-11966.
10.

Arai, S.; Shioiri, T., Tetrahedron Lett. 1998, 39 (15), 2145-2148.

11.
Liu, Y.; Provencher, B. A.; Bartelson, K. J.; Deng, L., Chemical Science 2011, 2
(7), 1301-1304.
12.
Kuang, Y.; Lu, Y.; Tang, Y.; Liu, X.; Lin, L.; Feng, X., Org. Lett. 2014, 16 (16), 42444247.
13.

Liu, W.-J.; Lv, B.-D.; Gong, L.-Z., Angew. Chem. Int. Ed. 2009, 48 (35), 6503-6506.

14.
He, L.; Liu, W.-J.; Ren, L.; Lei, T.; Gong, L.-Z., Adv. Synth. Catal. 2010, 352 (7),
1123-1127.
15.
Porter, M. J.; Skidmore, J., Asymmetric Epoxidation of Electron-Deficient Alkenes.
In Organic Reactions, John Wiley & Sons, Inc.: 2004.
16.

Wu, X.-Y.; She, X.; Shi, Y., J. Am. Chem. Soc. 2002, 124 (30), 8792-8793.

17.
Kakei, H.; Tsuji, R.; Ohshima, T.; Shibasaki, M., J. Am. Chem. Soc. 2005, 127 (25),
8962-8963.

80

18.
CussĂł, O.; Garcia-Bosch, I.; Ribas, X.; Lloret-Fillol, J.; Costas, M., J. Am. Chem.
Soc. 2013, 135 (39), 14871-14878.
19.

Chen, M. S.; White, M. C., Science 2007, 318 (5851), 783.

20.
CussĂł, O.; Garcia-Bosch, I.; Font, D.; Ribas, X.; Lloret-Fillol, J.; Costas, M., Org.
Lett. 2013, 15 (24), 6158-6161.
21.
Watanabe, S.; Arai, T.; Sasai, H.; Bougauchi, M.; Shibasaki, M., J. Org. Chem.
1998, 63 (23), 8090-8091.
22.
Ishihara, K., Achiral B(III) Lewis Acids. In Lewis Acids in Organic Synthesis, WileyVCH Verlag GmbH: 2008; pp 89-133.
23.
Nieuwland, J. A.; Vogt, R. R.; Foohey, W. L., J. Am. Chem. Soc. 1930, 52 (3),
1018-1024.
24.

Bowlus, H.; Nieuwland, J. A., J. Am. Chem. Soc. 1931, 53 (10), 3835-3840.

25.
Slanina, S. J.; Sowa, F. J.; Nieuwland, J. A., J. Am. Chem. Soc. 1935, 57 (9), 15471549.
26.

Lappert, M. F., Chem. Rev. 1956, 56 (5), 959-1064.

27.
Meerwein, H., Berichte der deutschen chemischen Gesellschaft (A and B Series)
1933, 66 (3), 411-414.
28.

Schäfer, H.; Braun, O., Naturwissenschaften 1952, 39 (12), 280-281.

29.

Wolf, P. F.; Barnes, R. K., J. Org. Chem. 1969, 34 (11), 3441-3445.

30.
Guseinov, M. M., Akhmedov, I.M., and Mamedov, E.G., Azerb. Khim. Zh. 1976,
46-48.
31.
Hashimoto, S.-i.; Komeshima, N.; Koga, K., J. Chem. Soc., Chem. Commun. 1979,
(10), 437-438.
32.
Kelly, T. R.; Whiting, A.; Chandrakumar, N. S., J. Am. Chem. Soc. 1986, 108 (12),
3510-3512.
33.
Maruoka, K.; Sakurai, M.; Fujiwara, J.; Yamamoto, H., Tetrahedron Lett. 1986, 27
(40), 4895-4898.
34.
Kaufmann, D.; Boese, R., Angewandte Chemie International Edition in English
1990, 29 (5), 545-546.
35.

Fiaud, J. C.; Kagan, H. B., Bull. Soc. Chim. Fr. 1969, 2742-2743.

81

36.
Hirao, A.; Itsuno, S.; Nakahama, S.; Yamazaki, N., J. Chem. Soc., Chem.
Commun. 1981, (7), 315-317.
37.
Corey, E. J.; Bakshi, R. K.; Shibata, S., J. Am. Chem. Soc. 1987, 109 (18), 55515553.
38.

Corey, E. J.; Helal, C. J., Angew. Chem. Int. Ed. 1998, 37 (15), 1986-2012.

39.
Oishi, M.; Aratake, S.; Yamamoto, H., J. Am. Chem. Soc. 1998, 120 (32), 82718272.
40.
Joshi, N. N.; Srebnik, M.; Brown, H. C., Tetrahedron Lett. 1989, 30 (41), 55515554.
41.
Furuta, K.; Miwa, Y.; Iwanaga, K.; Yamamoto, H., J. Am. Chem. Soc. 1988, 110
(18), 6254-6255.
42.
Furuta, K.; Shimizu, S.; Miwa, Y.; Yamamoto, H., J. Org. Chem. 1989, 54 (7), 14811483.
43.

Ishihara, K.; Gao, Q.; Yamamoto, H., J. Org. Chem. 1993, 58 (24), 6917-6919.

44.

Furuta, K.; Maruyama, T.; Yamamoto, H., Synlett 1991, 1991 (06), 439-440.

45.

Furuta, K.; Mouri, M.; Yamamoto, H., Synlett 1991, 1991 (08), 561-562.

46.
Gao, Q.; Maruyama, T.; Mouri, M.; Yamamoto, H., J. Org. Chem. 1992, 57 (7),
1951-1952.
47.

Yamamoto, H.; Futatsugi, K., Angew. Chem. Int. Ed. 2005, 44 (13), 1924-1942.

48.

Hattori, K.; Yamamoto, H., J. Org. Chem. 1992, 57 (12), 3264-3265.

49.

Hattori, K.; Yamamoto, H., Synlett 1993, 1993 (02), 129-130.

50.

Hattori, K.; Yamamoto, H., Tetrahedron 1993, 49 (9), 1749-1760.

51.

Hattori, K.; Yamamoto, H., Synlett 1993, 1993 (03), 239-240.

52.

Hattori, K.; Yamamoto, H., Tetrahedron 1994, 50 (9), 2785-2792.

53.
Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.; Yamamoto, H., J. Am. Chem. Soc.
1994, 116 (23), 10520-10524.
54.

Chong, J. M.; Shen, L.; Taylor, N. J., J. Am. Chem. Soc. 2000, 122 (8), 1822-1823.

55.
Cros, J. P.; PĂŠrez-Fuertes, Y.; Thatcher, M. J.; Arimori, S.; Bull, S. D.; James, T.
D., Tetrahedron: Asymmetry 2003, 14 (14), 1965-1968.
82

56.
Hu, G.; Gupta, A. K.; Huang, L.; Zhao, W.; Yin, X.; Osminski, W. E. G.; Huang, R.
H.; Wulff, W. D.; Izzo, J. A.; Vetticatt, M. J., J. Am. Chem. Soc. 2017, 139 (30), 1026710285.
57.

Mahlau, M.; List, B., Angew. Chem. Int. Ed. 2013, 52 (2), 518-533.

58.

Mayer, S.; List, B., Angew. Chem. Int. Ed. 2006, 45 (25), 4193-4195.

59.

Ishihara, K.; Yamamoto, H., J. Am. Chem. Soc. 1994, 116 (4), 1561-1562.

60.
Ishihara, K.; Kurihara, H.; Yamamoto, H., J. Am. Chem. Soc. 1996, 118 (12), 30493050.
61.
Ishihara, K.; Kurihara, H.; Matsumoto, M.; Yamamoto, H., J. Am. Chem. Soc. 1998,
120 (28), 6920-6930.
62.
Kawate, T.; Yamada, H.; Matsumizu, M.; Nishida, A.; Nakagawa, M., Synlett 1997,
1997 (07), 761-762.
63.
Yamada, H.; Kawate, T.; Matsumizu, M.; Nishida, A.; Yamaguchi, K.; Nakagawa,
M., J. Org. Chem. 1998, 63 (18), 6348-6354.
64.
Corey, E. J.; Shibata, T.; Lee, T. W., J. Am. Chem. Soc. 2002, 124 (15), 38083809.
65.
Ryu, D. H.; Lee, T. W.; Corey, E. J., J. Am. Chem. Soc. 2002, 124 (34), 99929993.
66.

Ryu, D. H.; Corey, E. J., J. Am. Chem. Soc. 2003, 125 (21), 6388-6390.

67.

Ryu, D. H.; Zhou, G.; Corey, E. J., J. Am. Chem. Soc. 2004, 126 (15), 4800-4802.

68.

Zhou, G.; Hu, Q.-Y.; Corey, E. J., Org. Lett. 2003, 5 (21), 3979-3982.

69.

Ryu, D. H.; Corey, E. J., J. Am. Chem. Soc. 2004, 126 (26), 8106-8107.

70.

Ryu, D. H.; Corey, E. J., J. Am. Chem. Soc. 2005, 127 (15), 5384-5387.

71.

Zhou, G.; Corey, E. J., J. Am. Chem. Soc. 2005, 127 (34), 11958-11959.

72.
Hu, Q.-Y.; Rege, P. D.; Corey, E. J., J. Am. Chem. Soc. 2004, 126 (19), 59845986.
73.

Hu, Q.-Y.; Zhou, G.; Corey, E. J., J. Am. Chem. Soc. 2004, 126 (42), 13708-13713.

74.

Snyder, S. A.; Corey, E. J., J. Am. Chem. Soc. 2006, 128 (3), 740-742.

83

75.
Lee, M. Y.; Kim, K. H.; Jiang, S.; Jung, Y. H.; Sim, J. Y.; Hwang, G.-S.; Ryu, D. H.,
Tetrahedron Lett. 2008, 49 (12), 1965-1967.
76.

Futatsugi, K.; Yamamoto, H., Angew. Chem. Int. Ed. 2005, 44 (10), 1484-1487.

77.
Shibatomi, K.; Futatsugi, K.; Kobayashi, F.; Iwasa, S.; Yamamoto, H., J. Am.
Chem. Soc. 2010, 132 (16), 5625-5627.
78.

Liu, D.; Canales, E.; Corey, E. J., J. Am. Chem. Soc. 2007, 129 (6), 1498-1499.

79.

Mukherjee, S.; Corey, E. J., Org. Lett. 2010, 12 (3), 632-635.

80.

Canales, E.; Corey, E. J., J. Am. Chem. Soc. 2007, 129 (42), 12686-12687.

81.
Senapati, B. K.; Hwang, G.-S.; Lee, S.; Ryu, D. H., Angew. Chem. Int. Ed. 2009,
48 (24), 4398-4401.
82.
775.

Lee, S. I.; Jang, J. H.; Hwang, G.-S.; Ryu, D. H., J. Org. Chem. 2013, 78 (2), 770-

83.
Gao, L.; Hwang, G.-S.; Ryu, D. H., J. Am. Chem. Soc. 2011, 133 (51), 2070820711.
84.
Shim, S. Y.; Kim, J. Y.; Nam, M.; Hwang, G.-S.; Ryu, D. H., Org. Lett. 2016, 18 (2),
160-163.
85.
Shim, S. Y.; Cho, S. M.; Venkateswarlu, A.; Ryu, D. H., Angew. Chem. Int. Ed.
2017, 56 (30), 8663-8666.
86.
Gao, L.; Hwang, G.-S.; Lee, M. Y.; Ryu, D. H., Chem. Commun. 2009, (36), 54605462.
87.
Gao, L.; Kang, B. C.; Hwang, G.-S.; Ryu, D. H., Angew. Chem. Int. Ed. 2012, 51
(33), 8322-8325.
88.
Kang, B. C.; Nam, D. G.; Hwang, G.-S.; Ryu, D. H., Org. Lett. 2015, 17 (19), 48104813.
89.

Kim, J. Y.; Kang, B. C.; Ryu, D. H., Org. Lett. 2017, 19 (21), 5936-5939.

90.
Shin, S. H.; Baek, E. H.; Hwang, G.-S.; Ryu, D. H., Org. Lett. 2015, 17 (19), 47464749.
91.

Gao, L.; Kang, B. C.; Ryu, D. H., J. Am. Chem. Soc. 2013, 135 (39), 14556-14559.

92.
Lee, S. I.; Hwang, G.-S.; Ryu, D. H., J. Am. Chem. Soc. 2013, 135 (19), 71267129.

84

93.

Antilla, J. C.; Wulff, W. D., J. Am. Chem. Soc. 1999, 121 (21), 5099-5100.

94.

Antilla, J. C.; Wulff, W. D., Angew. Chem. Int. Ed. 2000, 39 (24), 4518-4521.

95.
Zhang, Y.; Desai, A.; Lu, Z.; Hu, G.; Ding, Z.; Wulff, W. D., Chemistry – A European
Journal 2008, 14 (12), 3785-3803.
96.
Hu, G.; Huang, L.; Huang, R. H.; Wulff, W. D., J. Am. Chem. Soc. 2009, 131 (43),
15615-15617.
97.
Hu, G.; Gupta, A. K.; Huang, R. H.; Mukherjee, M.; Wulff, W. D., J. Am. Chem.
Soc. 2010, 132 (41), 14669-14675.
98.

Vetticatt, M. J.; Desai, A. A.; Wulff, W. D., J. Org. Chem. 2013, 78 (11), 5142-5152.

99.

Lu, Z.; Zhang, Y.; Wulff, W. D., J. Am. Chem. Soc. 2007, 129 (22), 7185-7194.

100. Mukherjee, M.; Gupta, A. K.; Lu, Z.; Zhang, Y.; Wulff, W. D., J. Org. Chem. 2010,
75 (16), 5643-5660.
101.

Zhang, Y.; Lu, Z.; Desai, A.; Wulff, W. D., Org. Lett. 2008, 10 (23), 5429-5432.

102. Deng, Y.; Lee, Y. R.; Newman, C. A.; Wulff, W. D., Eur. J. Org. Chem. 2007, 2007
(13), 2068-2071.
103.

Ren, H.; Wulff, W. D., Org. Lett. 2010, 12 (21), 4908-4911.

104.

Huang, L.; Wulff, W. D., J. Am. Chem. Soc. 2011, 133 (23), 8892-8895.

105.

Gupta, A. K.; Mukherjee, M.; Wulff, W. D., Org. Lett. 2011, 13 (21), 5866-5869.

106. Gupta, A. K.; Mukherjee, M.; Hu, G.; Wulff, W. D., J. Org. Chem. 2012, 77 (18),
7932-7944.
107. Guan, Y.; Ding, Z.; Wulff, W. D., Chemistry – A European Journal 2013, 19 (46),
15565-15571.
108.

Loncaric, C.; Wulff, W. D., Org. Lett. 2001, 3 (23), 3675-3678.

109. Patwardhan, A. P.; Pulgam, V. R.; Zhang, Y.; Wulff, W. D., Angew. Chem. Int. Ed.
2005, 44 (38), 6169-6172.
110. Zhou, Y.; Mukherjee, M.; Gupta, A. K.; Wulff, W. D., Org. Lett. 2017, 19 (9), 22302233.
111.

Desai, A. A.; Wulff, W. D., J. Am. Chem. Soc. 2010, 132 (38), 13100-13103.

85

112. Vetticatt, M. J.; Desai, A. A.; Wulff, W. D., J. Am. Chem. Soc. 2010, 132 (38),
13104-13107.
113. Newman, C. A.; Antilla, J. C.; Chen, P.; Predeus, A. V.; Fielding, L.; Wulff, W. D.,
J. Am. Chem. Soc. 2007, 129 (23), 7216-7217.
114.

Ren, H.; Wulff, W. D., J. Am. Chem. Soc. 2011, 133 (15), 5656-5659.

115.

Ren, H.; Wulff, W. D., Org. Lett. 2013, 15 (2), 242-245.

116. Zhao, W.; Huang, L.; Guan, Y.; Wulff, W. D., Angew. Chem. Int. Ed. 2014, 53 (13),
3436-3441.
117. Desai, A.; Wulff, W. A UNIVERSAL ASYMMETRIC CATALYTIC AZIRIDINATION
SYSTEM, AND OTHER FORAYS IN CHIRAL CATALYSIS, Ph.D thesis. Michigan State
University, 2010.
118. Gupta, A.; Wulff, W. BOROX CATALYSIS:A NEW FRONTIER IN CHIRAL
BRØNSTED ACID CATALYSIS DERIVED FROM CHIRAL BORATE ANIONS, Ph.D
thesis. Michigan State University, 2012.
119. Ouihia, A.; Rene, L.; Guilhem, J.; Pascard, C.; Badet, B., J. Org. Chem. 1993, 58
(7), 1641-1642.
120.

Guan, Y.; Wulff, W. D.

121.

Dai, Y.; Wulff, W. D., unpublished work.

122.

Vetticatt, M. J.; Singleton, D. A., Org. Lett. 2012, 14 (9), 2370-2373.

123.

Singleton, D. A.; Thomas, A. A., J. Am. Chem. Soc. 1995, 117 (36), 9357-9358.

124.

Vetticatt, M. J.; Wulff, W. D., Unpublished work. Michigan State University.

125. Hashimoto, T.; GĂĄlvez, A. O.; Maruoka, K., J. Am. Chem. Soc. 2015, 137 (51),
16016-16019.
126. Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A. T., J. Am. Chem.
Soc. 1971, 93 (9), 2325-2327.
127. Holton, R. A.; Somoza, C.; Kim, H. B.; Liang, F.; Biediger, R. J.; Boatman, P. D.;
Shindo, M.; Smith, C. C.; Kim, S., J. Am. Chem. Soc. 1994, 116 (4), 1597-1598.
128. Holton, R. A.; Kim, H. B.; Somoza, C.; Liang, F.; Biediger, R. J.; Boatman, P. D.;
Shindo, M.; Smith, C. C.; Kim, S., J. Am. Chem. Soc. 1994, 116 (4), 1599-1600.

86

129.
167.

Guenard, D.; Gueritte-Voegelein, F.; Potier, P., Acc. Chem. Res. 1993, 26 (4), 160-

130.

Ojima, I., Acc. Chem. Res. 1995, 28 (9), 383-389.

131. Denis, J. N.; Greene, A. E.; Serra, A. A.; Luche, M. J., J. Org. Chem. 1986, 51 (1),
46-50.
132.

Denis, J. N.; Correa, A.; Greene, A. E., J. Org. Chem. 1990, 55 (6), 1957-1959.

133. Ojima, I.; Habus, I.; Zhao, M.; Georg, G. I.; Jayasinghe, L. R., J. Org. Chem. 1991,
56 (5), 1681-1683.
134.

Deng, L.; Jacobsen, E. N., J. Org. Chem. 1992, 57 (15), 4320-4323.

135. Hattori, K.; Miyata, M.; Yamamoto, H., J. Am. Chem. Soc. 1993, 115 (3), 11511152.
136. Wang, Z.-M.; Kolb, H. C.; Sharpless, K. B., J. Org. Chem. 1994, 59 (17), 51045105.
137. Tosaki, S.-y.; Tsuji, R.; Ohshima, T.; Shibasaki, M., J. Am. Chem. Soc. 2005, 127
(7), 2147-2155.
138. Lubriks, D.; Sokolovs, I.; Suna, E., J. Am. Chem. Soc. 2012, 134 (37), 1543615442.
139. Ishihara, K.; Sakakura, A., 5.10 Hetero-Diels–Alder Reactions A2 - Knochel, Paul.
In Comprehensive Organic Synthesis II (Second Edition), Elsevier: Amsterdam, 2014; pp
409-465.
140. Danishefsky, S.; Kerwin, J. F.; Kobayashi, S., J. Am. Chem. Soc. 1982, 104 (1),
358-360.
141. Maruoka, K.; Itoh, T.; Shirasaka, T.; Yamamoto, H., J. Am. Chem. Soc. 1988, 110
(1), 310-312.
142. Corey, E. J.; Cywin, C. L.; Roper, T. D., Tetrahedron Lett. 1992, 33 (46), 69076910.
143.

Schaus, S. E.; BrĂĽnalt, J.; Jacobsen, E. N., J. Org. Chem. 1998, 63 (2), 403-405.

144. Simonsen, K. B.; Svenstrup, N.; Roberson, M.; Jørgensen, K. A., Chemistry – A
European Journal 2000, 6 (1), 123-128.
145.
11.

Long, J.; Hu, J.; Shen, X.; Ji, B.; Ding, K., J. Am. Chem. Soc. 2002, 124 (1), 10-

87

146.

Du, H.; Long, J.; Hu, J.; Li, X.; Ding, K., Org. Lett. 2002, 4 (24), 4349-4352.

147. Du, H.; Zhang, X.; Wang, Z.; Bao, H.; You, T.; Ding, K., Eur. J. Org. Chem. 2008,
2008 (13), 2248-2254.
148. Yamashita, Y.; Saito, S.; Ishitani, H.; Kobayashi, S., J. Am. Chem. Soc. 2003, 125
(13), 3793-3798.
149.

Guin, J.; Rabalakos, C.; List, B., Angew. Chem. Int. Ed. 2012, 51 (35), 8859-8863.

150.

Zhao, B.; Loh, T.-P., Org. Lett. 2013, 15 (12), 2914-2917.

151.

Passerini, M., Gazz. Chim. Ital 1921, 51, 181-189.

152.

Denmark, S. E.; Fan, Y., J. Am. Chem. Soc. 2003, 125 (26), 7825-7827.

153. Kusebauch, U.; Beck, B.; Messer, K.; Herdtweck, E.; DĂśmling, A., Org. Lett. 2003,
5 (22), 4021-4024.
154.

Andreana, P. R.; Liu, C. C.; Schreiber, S. L., Org. Lett. 2004, 6 (23), 4231-4233.

155. Wang, S.-X.; Wang, M.-X.; Wang, D.-X.; Zhu, J., Angew. Chem. Int. Ed. 2008, 47
(2), 388-391.
156. Zhang, J.; Lin, S.-X.; Cheng, D.-J.; Liu, X.-Y.; Tan, B., J. Am. Chem. Soc. 2015,
137 (44), 14039-14042.
157. Zhang, X.; Staples, R. J.; Rheingold, A. L.; Wulff, W. D., J. Am. Chem. Soc. 2014,
136 (40), 13971-13974.
158.

Mohammadlou, A.; Wulff, W. D., Unpublished work. Michigan State University.

159. Majik, M. S.; Parameswaran, P. S.; Tilve, S. G., J. Org. Chem. 2009, 74 (16), 63786381.
160. Konda, S.; Kurva, B.; Nagarapu, L.; Dattatray, A. M., Tetrahedron Lett. 2015, 56
(6), 834-836.
161. Romero-IbaĂąez, J.; Xochicale-Santana, L.; Quintero, L.; Fuentes, L.; Sartillo-Piscil,
F., J. Nat. Prod. 2016, 79 (4), 1174-1178.
162.

Boeckman, R. K.; Thomas, E. W., J. Am. Chem. Soc. 1977, 99 (8), 2805-2806.

163. Jakubowski, A. A.; Guziec, F. S.; Tishler, M., Tetrahedron Lett. 1977, 18 (28),
2399-2402.
164.

Corey, E. J.; Williams, D. R., Tetrahedron Lett. 1977, 18 (44), 3847-3850.

88

165. Jakubowski, A. A.; Guziec, F. S.; Sugiura, M.; Tam, C. C.; Tishler, M., J. Org.
Chem. 1982, 47 (7), 1221-1228.
166.

Pietraszkiewicz, M.; SinaĂż, P., Tetrahedron Lett. 1979, 20 (49), 4741-4744.

167.

Yoda, H.; Katagiri, T.; Takabe, K., Tetrahedron Lett. 1991, 32 (46), 6771-6774.

168.

Mani, N. S.; Townsend, C. A., J. Org. Chem. 1997, 62 (3), 636-640.

89

CHAPTER TWO
CHIRAL RESOLUTION OF VANOL/VAPOL DERIVATIVES

“Sometimes life is going to hit you in the head with a brick. Don't lose faith.”
–Steve Jobs

2.1 Strategies in optical resolution
The importance of chirality in the pharmaceutical and agrochemical industry has
been widely recognized. More than half or all the FDA-approved new molecular entities
are single enantiomers for the 2001-2011 period1 and in 2015, nine of the top-10 global
selling small molecule drugs have chiral active ingredients2. Over the last few decades,
the field of asymmetric synthesis enjoyed tremendous advances. However, the alternative
method – preparation of a racemic mixture followed by resolution can still be attractive,
especially when both enantiomers are desired1.
Scheme 2.1 General scheme of classical resolution

(S)-substrate/(R)-substrate
= 1:1
(racemate)

diastereomer A
(S:R > 1)

1) reaction
+ resolving agent

+

2) separation
diastereomer B
(R:S > 1)

decomposition

(S)-substrate/(R)-substrate
>1

diastereomer A
(S:R > 1)

(S)-substrate/(R)-substrate +
recovered
>1
resolving agent

enantioenrichment
enantiopure (S)-substrate

90

+ racemate

Since the first demonstration by Louis Pasteur in 18483, optical resolution has been
the most important method for obtaining enantiomers from racemates4. The proper choice
of resolving agent to form diastereomers is essential to realize the “classical resolution”
(Scheme 2.1). Two main categories of diastereomers can be distinguished: 1) noncovalent diastereomers and 2) covalently bound diastereomers. Resolution by noncovalent diastereomers is the most often used method of resolution. This involves salt
formation when the substrates are acidic or basic, and less efficiently, complex with
neutral racemates. Some commonly used acidic or basic resolving agents4 are shown
(Scheme 2.2). Most frequently used resolving agents in pharmaceutical industry are
natural L-tartaric acid II-1 and its derivatives, followed by (R)- or (S)-mandelic acid II-2 due
to their relative stability, commercial availability and cost. Basic resolving agents,
represented by ⍺-methylbenzylamine II-4 and natural alkaloids II-5 to II-10 are useful for
resolving acidic racemic compounds. Although the enantiomers of these natural products
are often not available (two pair of cinchona alkaloids are pseudoenantiomers), natural
alkaloids were used in about 25% of all resolutions reported in the 1990s5. A less
commonly used method for resolution, mostly when the substrate is not amenable to salt
formation, is by forming a covalent bond with the resolving agent. If these two strategies
of resolution fail for a compound, resolution of a simple derivatives could be attempt.
Examples of using these strategies to resolve BINOL will be given in the next section.

91

Scheme 2.2 Commonly used resolving agents
H 3C
OR O
HO

O
OH

O

CH3

OH

OR

OH

R = H, (R,R)-tartaric acid
(R,R)-II-1

(S)-mandelic acid
(S)-II-2

O

O
S
HO O
(+)-Camphor-10-sulfonic acid
(+)-II-3

NH2
(S)-1-phenylethylamine
(S)-II-4

N
H 3C
H 3C

O
O

H

H
N H
O
brucine

II-5

H

O

N

N

N

HO

R

R

H

N
(–)-sparteine
(–)-II-6

N

HO

R = H, (+)-cinchonidine II-7
R = OMe, (+)-quinidine II-8

N
R = H, (–)-cinchonine II-9
R = OMe, (–)-quinine II-10

Despite several researchers’ attempts to searching for a rational guide by many
approaches such as empirical correlations6, physical and phase properties7, analysis of
crystal structure data8 and computational modeling9-10, no methodology has been
developed to predict the resolution efficiency of a diastereomeric pair. Selecting a
resolving agent remains a method of trial and error instead of an engineering approach.
Moreover, a subtle structural change in the resolving agent or substrate would cause
unpredictable changes in the crystal structure of the diastereomers, thus affect the
efficiency of a resolution process substantially11. Therefore, there is only a limited number
of reported resolution process that could be applied to a broad scope of substrates12-14.
In spite of our lack of theory to predict the solubility difference between two
diastereomeric compounds, many approaches have been developed to facilitate the
searching for the optimal resolving process. Vries and coworkers first reported15 the
“family approach” in 1988 which was also known as “Dutch resolution”. In their method,

92

a mixture of (usually three, sometimes two) resolving agents with structural similarity
(family members) were used, and the results (yield and ee) of most cases were superior
to those achieved by any of the resolving agents alone. The chance of obtaining solid
salts with significant dr were improved from 20-30% for classical resolution to 90-95%16.
High-throughput screening and analysis were employed by pharmaceutical companies in
selection of resolution agent and condition optimization to aid pharmaceutical
development17. The resulting increase in productivity has allowed rapid access to pure
enantiomer of active pharmaceutical ingredient (API) in the early stage of development.
Once a suitable resolving agent is identified, the rest of the process development
is usually fast and easy, which is a fundamental advantage compared to other
stereoselective process. To develop an effective resolution, several parameters have to
be optimized, such as solvent system, concentration, temperature, time etc. Moreover,
chiral resolution does not always provide a product with an ee meeting the requirement
(>99% ee for chiral ligand). Often times, enantioenrichment by crystallization will be
required18.
2.2 Resolution of Bi-2-naphthol (BINOL)
Even though BINOL was first synthesized by von Richter19 via oxidative coupling
of 2-naphthol using FeCl3 in 1873 (also independently reported20 by Pummerer and
coworkers in 1926), its potential for providing a stereospecific process was not recognized
until nearly 100 years later. In 1971, Jacques and coworkers reported21 the first resolution
of BINOL II-11, procedures involving preparation of its phosphoric acid derivatives II-12,
resolution via cinchonine salt, followed by liberation by LiAlH4 (Scheme 2.3). They also

93

described the resolution of chiral amines utilizing optically pure BINOL phosphoric acid.
Two years later, Cram synthesized chiral crown ethers from optically pure BINOL and
demonstrated their application in chiral recognition22. The first application of BINOL in
asymmetric synthesis was reported23 by Noyori and coworkers, using a BINOL aluminum
hydride complex to reduce ketones and aldehydes in 1979. Over the last 30 years, BINOL
and its derivatives have been successfully used as chiral ligands in a broad range of
transformations in asymmetric synthesis24-25.
Although many asymmetric syntheses of BINOL by enantioselective oxidation of
2-naphthol have been developed24, chemical resolution is still the general approach to
obtain optically pure BINOL and its derivatives. Resolution of BINOL has been extensively
studied in the 1990s26. All of the reported examples can be categorized into the
aforementioned approaches. Selected examples for each approach are provided in
Scheme 2.3 to 2.6.
1) Via salt formation with phosphoric acid derivatives (Scheme 2.3)
Scheme 2.3 Resolution of BINOL (1)

OH 1) POCl3, py
OH
2) H2O, HCl
reflux
(Âą)-BINOL
(Âą)-II-11

O
O
P
+ CN II-9
O OH

methanol

precipitate

mother liquor

(S)-acid•CN salt + (R)-acid•CN salt
62% de
82% de
ethanol
recrystallization

(Âą)-II-12
6 N HCl
HO

N

N
CN = cinchonine II-9

94

(S)-II-12
28%, >99%ee

(R)-II-12
25%, >99%ee
LiAlH4

(S)-BINOL
(S)-II-11

(R)-BINOL
(R)-II-11

A large-scale procedure27 was developed by the Jacques and coworkers and had
been utilized by the Cram group. Instead of using cinchonine II-9 for (S)-BINOL and
cinchonidine II-7 for (R)-BINOL as in the original report, the complexes of cinchonine II-9
with both enantiomers of BINOL can be obtained in moderate yield by recrystallization
from ethanol, followed by cleavage using LiAlH4. The 7,7'-bis(benzyloxy) analog was
similarly resolved28 using the same procedure. The drawback of this procedure is that
some reagents involved (POCl3 and LiAlH4) require special handling.
2) Via diastereomeric esters (Scheme 2.4)
Scheme 2.4 Resolution of BINOL (2)

OH
OH

O
O

R*Cl, base

(Âą)-II-11

R*

separation

R*

H 3C

R*
+
R*

(R)-II-14a/14b

II-14a/14b

R* =

O
O

O

R*Cl II-13a

O

R*
R*

(S)-II-14a/14b

CH3
OH–, H2O

O

O
O

O
S
O
R*Cl II-13b

(R)-BINOL
(R)-II-11

OH–, H2O

(S)-BINOL
(S)-II-11

Diastereomeric BINOL bis-carbonates29-30 and bis-sulfonates31 can be derived
from racemic BINOL with commercially available chiral acyl chloride II-13a and sulfonyl
chloride II-13b. The diastereomer can be easily separated either by recrystallization or
column chromatography. After hydrolysis, both BINOL enantiomers can be obtained in
high yield.

95

3) Via diastereomeric borates (Scheme 2.5)
Scheme 2.5 Resolution of BINOL (3)
OH

B source

O

R*OH

B OR*

OH

B source

O

R*NH2

OH

B

O
R*NH3

OH
enantiopure BINOL

separation

hydrolysis

R*OH =

OH
OH
enantiopure BINOL

O
O
spiroborate complex
II-17

(Âą) BINOL
(Âą)-II-11

OH

hydrolysis

O
borate complex
II-16

(Âą) BINOL
(Âą)-II-11
OH

separation

R*NH2 =
HO

N

R
N
R = H, (–)-cinchonine II-9
R = OMe, (–)-quinine II-10

COOH
N
H

COOH
N
H

(S)-proline
(S)-II-15

(S)-proline
(S)-II-15

NH2
(R)-1-phenylethylamine
(R)-II-4

Resolution of BINOL via cyclic borate esters was first reported32 by Shan and
coworkers. Compared to resolution via other diastereomeric esters, the procedure with
borate ester is more convenient because formation and cleavage of B-O bonds are
easier. In their first report, BINOL-quinine complex II-16 was synthesized using either
BH3•Me2S or B(OMe)3 as boron source. (S)-BINOL complex precipitates from THF and
then is separated by filtration. Both (R)- and (S)-BINOL can be obtained with 100% ee in
high yield from hydrolysis and then recrystallization from Et2O. Subsequently, they
developed a complementary procedure33. Employing cinchonine II-9 as the resolving
agent provides (R)-BINOL complex as a precipitate from toluene. The same methodology

96

using (S)-proline II-15 has been reported34 with lower efficiency but was later improved35
by the same group.
Periasamy et al. discovered36 that racemic BINOL forms a 2:1 spiroborate ionic
complex II-17 with (S)-proline II-15 during their efforts at preparing the borate ester.
Although only moderate resolving efficiency was achieved using (S)-proline II-15, they
developed a procedure employing boric acid and readily accessible chiral amine, (R)-⍺methylbenzylamine (R)-II-4 to obtain both BINOL enantiomers in high yield after
recrystallization enantioenrichment.
4) Via diastereomeric inclusion complexes (Scheme 2.6)
Scheme 2.6 Resolution of BINOL (4)

OH
+
OH

HO

+
(R)-(+)-complex

Cl

Methanol
recrystallization

R
(0.55 equiv)
N
II-18

(Âą) BINOL
(Âą)-II-11

Other resolving
agents

COOH
N
H
(S)-proline
(S)-II-15

mother liquor

precipitate

CH3CN

N

NH2
NH2
(S,S)-II-19

(S)-BINOL
47%, 99% ee

1 N HCl
(R)-BINOL
47%, >99% ee
OCH3O
Me2N

NMe2
O

OCH3

(R,R)-II-20

CONHPh
O

N
H
(S)-II-21

equivalent

1.0

1.1

1.0

0.5

solvent

DCM/CH3OH 10:1

toluene

benzene/hexane 4:1

THF/ethanol 1:1.5

precipitate

(S), 32%, 78% ee

(R), 45%, >99% ee

(S), 36%, 100% ee

(R), 37%, 70% ee

Toda and coworker first applied37 inclusion crystallization in the resolution of
BINOL using a chiral host molecule. In their original report, the amide derivative (R,R)-II-

97

20 from inexpensive (R,R)-tartaric acid was utilized as the host compound. A complex of
(S)-BINOL was formed and was recrystallized. Upon column chromatography,
enantiopure (S)-BINOL was separated from the amide host. In 1993, they applied38 the
same methodology using commercially available N-benzylcinchonidinium chloride II-18
as the host compound. Subsequently, this procedure was optimized39-40 by the Pu group
and the Merck process team, and it was later applied41 to the synthesis of BINAP. This
process is arguably one of the most effective methods accessing both enantiomers of
BINOL in the literature. Only 0.55 equivalent of II-18 is required, with (R)-BINOL complex
crystallizing in very high yield, leaving 95% (S)-BINOL with >99%ee in the supernatant.
The same procedure can be applied39, 42 to four BINOL analogs with substituents on the
6-, 7- or 8-position, giving similar results. Other chiral host compounds, such as (S)proline

II-1543-45,

(S)-5-oxopyrrolidine-2-carboxanilide

II-2146

and

(1R,2R)-

diaminocyclohexane II-1947,48 were also explored and proved to be efficient by other
researchers.
2.3 VANOL/VAPOL derivatives and deracemization
Vaulted 2,2′-binaphthol (VANOL) and vaulted 3,3′-biphenanthrol (VAPOL) were
introduced49 in asymmetric catalysis by the Wulff group in 1993. They have been
successfully applied to a wide range of asymmetric reactions50 over the last two decades.
Comparing with BINOL, VANOL and VAPOL provide a deeper chiral pocket around the
metal center, thus usually give distinct results in the same system49, 51-57.
Modifying BINOL by introduction of substituents within the framework has proven
to be effective to improve their catalytic systems25,

98

58

. In most cases, by introducing

different functional groups into 3,3’- and 6,6’-positons, one can modify the steric and
electronic characteristics of BINOL, respectively, thereby changing the yield and
enantioselectivity of the reaction. Derivatives of VANOL and VAPOL were synthesized
and used in screening for aziridination59 and Ugi reaction56 by Wulff and coworkers. The
structure-activity relationship study on VANOL-BOROX catalyst in the aziridination59 of
benzhydryl imine and ethyl diazo acetate indicated that substituents in the 7,7’ positons
lead to improved asymmetric inductions in most cases, while substituents in 4,4’- and
8,8’-positions provide a negative impact. 7,7’-tBu2VANOL (tBuVANOL) was identified as
the optimal ligand, giving higher yield and ee than VANOL for 10 different imine
substrates. In the report of the first catalytic asymmetric three-component Ugi reaction,
13 biaryl ligands including two VANOL derivatives and five VAPOL derivatives were
screened. The best result was obtained with a boroxinate catalyst II-24b prepared from a
VAPOL derivative (Scheme 2.7). tBuVANOL was also found to be effective in aluminatecatalyzed ⍺-iminol rearrangement60, catalyst-controlled multicomponent aziridination with
chiral aldehydes61, and very recently, zirconium-catalyzed Kabachnik-Fields reaction62
(Scheme 2.7).

99

Scheme 2.7 Application of tBuVANOL and VAPOL derivatives
cis-Aziridination
imine-H

OR
O B
O
B
O
*
O
O B
OR
II-24
boroxinate cat. (5 mol%)

O
N2

N

R

OEt

N

toluene, rt, 24-48 h

120 mol%

R

II-25

II-23

II-22

COOEt

10 examples,
average 74% yield, 87% ee for VANOL
average 85% yield, 97% ee for tBuVANOL

R = aryl, 1Âş, 2Âş, 3Âş alkyl
Catalyst Controlled MCAZ

CO2Et

(R)-tBuVANOL
Boroxinate (R)-II-24a(10 mol%)

II-27

MEDAM-NH2

H

(S)-tBuVANOL
Boroxinate (S)-II-24a (10 mol%)

EDA II-23

O

90%, dr 96 : 4
N
MEDAM
CO2Et

II-26

95%, dr 96 : 4

II-28

N
MEDAM

⍺-Imino Rearangement
NPh
H

3 mol% (R)-tBuVANOL Al cat.

Ph
OH
Ph

Ph

toluene, 70 ÂşC, 8 h

NHPh
O

tBu
MeO
tBu

R

II-29

II-30
100%, 88% ee

tBu
MeO
tBu

O
H +

N
H

Bn

20 mol% (R)-BOROX cat. II-24b

Bn

+

CN

mesitylene, 4 A MS
25 ÂşC, 24 h

Br

II-31

II-32

II-33

0.5 mmol

2.0 mmol

1.5 mmol

N

Ph

R

R = 4-BrC6H4 II-24b

Three-Component Asymmetric Catalytic Ugi Reaction

Bn

O
O B Ph
O
B
O
O O B
O

Br

Bn

N

H
N
O

II-34
85%, 93:7 er

Kabachink-Fields Reaction
HO

O

OH
H +

+

NH2

O
5 mol% Zr-NMI-tBuVANOL cat.
4 A MS, 10 mol% PhCO2H
H P OEt
OEt
toluene, 23 ÂşC, 12 h

II-35

II-36

II-37

0.2 mmol

0.2 mmol

0.2 mmol

100

HN
PO(OEt)2

II-38
95%, 95% ee

Scheme 2.8 Most commonly used route to BINOL and VANOL derivatives
Synthesis of BINOL derivatives
B(OH)2
1) nBuLi
2) B(OEt)3

OR
OR

3) HCl
Br

Ar
OH Br2
OH DCM

B(OH)2
(R)-II-41

OR
OR

or

2. deprotection

X
Br
(R)-6,6’-Br2BINOL
(R)-II-39

(R)-BINOL R = H
(R)-II-11

1) nBuLi
2) Br2/I2

R = Me or MOM
(R)-II-40

1. Suzuki
Coupling

OH
OH
Ar
(R)-3,3’-Ar2BINOL
(R)-II-43

OR
OR
X
X = Br or I
(R)-II-42a/42b

Synthesis of VANOL derivatives

R5

R7

OH
O

R5

1) (COCl2) (2.0 equiv),
HO
cat. DMF, 0 ÂşC to rt, 1 h
then remove excess

Ar

air, heat

2)

R7

II-44

Ar (1.3 equiv)
(i-PrCO)2O (2 equiv),
190 ÂşC, 48 h
3) KOH, H2O, 100 ÂşC,
overnight

mineral oil

R7

Ar
Ar

HO
HO

R5
R7

II-45

R5 or R7 = Br
cross coupling (±)-5,5’-R2VANOL
or
(±)-7,7’-R2VANOL
II-46

R5

II-46

Scheme 2.9 Deracemization of tBuVANOL II-46b

Ph
Ph

OH
OH

air, 1.7 equiv CuCl,
3.2 equiv (+)-sparteine,
MeOH/CH2Cl2 2:1,
rt, 24 h

(Âą)-II-46b

Ph
Ph

OH
OH

(R)-tBuVANOL (R)-II-46b
77% yield, >99% ee

101

Unlike BINOL derivatives mostly being synthesized by modification of optically
pure binaphthol scaffold, VANOL and VAPOL derivatives are usually obtained56, 59 from
a cycloadditon/electrocyclization cascade (CAEC) process63 followed by oxidative
coupling (and then cross-coupling) (Scheme 2.8). To get access to the enantiopure
ligands, Wulff and coworkers developed64-65 a deracemization procedure involving a
copper complex of (–)- or (+)-sparteine (Scheme 2.9). This procedure has been proved
to be general and reliable on the laboratory scale, successfully being applied to >20
different ligands56, 59. One notable drawback in this deracemization process is that, it
usually requires >2.8 equivalent of sparteine which is expensive and not always
available66. Very recently, a gram-scale synthesis of (–)-sparteine was reported67 by
O’Brien and coworkers. This 10-step synthesis, including an enzymatic resolution to
introduce stereochemistry, afforded (–)-sparteine in 31% yield but is nevertheless lengthy
and not practical for large scale process. In addition, a large amount of solvent (135 mL
for 1 mmol) was used in the process, making it less practical for a large-scale process.
2.4 Discovery of resolution system for tBuVANOL by trial and error
To make both enantiomers of VANOL and VAPOL derivatives easily accessible to
the Wulff group and the scientific community, it was desired to develop a simple, practical
resolution process using inexpensive resolving agent. Racemic tBuVANOL was chosen
as our target substrate since it gave better performance in a variety of asymmetric
reactions (Scheme 2.7). The synthesis of (Âą)-tBuVANOL II-46b was carried out by
modification of the reported procedure59 (Scheme 2.10).

102

Scheme 2.10 Synthesis of (Âą)-tBuVANOL	II-46b
O

1) aq. NaOH,
rt, overnight,
MeOH/THF (1:1)

O

OMe 2) HCl

OH

II-47
100 g

O
OH

II-44b

1) (COCl2) (2.0 equiv),
cat. DMF, 0 ÂşC to rt, 1 h
then remove excess

II-44b
quant.

Ph

HO

air, 150 ÂşC,

2)

Ph (1.3 equiv)
(i-PrCO)2O (2 equiv),
190 ÂşC, 48 h
3) KOH, H2O, 100 ÂşC,
overnight

mineral oil, 24 h

HO
HO

Ph
Ph

100 mmol

II-45b
50-59%

150-240 mmol

II-46b
71-76%

We were determined to find a suitable resolution method for tBuVANOL by trial
and error. It was obvious that the resolution process of its congener, VANOL should be
first attempted (Scheme 2.11). VANOL II-46a was first resolved68 via its cyclic diester with
phosphoric acid by salt formation with (–)-brucine II-5. The cyclic phosphoric acid of
tBuVANOL II-48b was prepared in the same manner with excellent yield and its (–)brucine salt II-49 formation was carried out in DCE. After removing the solvent,
recrystallization condition was screened on a 2 mmol scale. No solid was observed in 5
mL of DCE, EtOH, 2:1 iPrOH/hexanes, 2:1 DCM/hexanes, and acetone at room
temperature. Only a trace amount of solid was observed from 2:1 iPrOH/hexanes and
acetone after cooling at –20 ºC for 12 h. However, no solid was obtained after filtration
was performed at rt. One patent69 on the chiral resolution of VANOL drew our attention.
They separated the diastereomers of VANOL camphor sulfonate by column
chromatography and then hydrolyzed to obtain pure (R)- and (S)-VANOL. (+)-

103

Camphosulfonyl chloride II-50 was prepared and used in the synthesis of tBuVANOL
camphorsulfonate II-53 (Scheme 2.12). The reaction gave an 88% yield of the
monosulfonate II-53 along with a 10% yield of the disulfonate. Unfortunately, the
diastereomers of the mono-camphorsulfonate did not show any separation on TLC using
the reported 1:10 EtOAc/hexanes as eluent and other combinations of Et2O, DCM,
toluene and benzene. The recrystallization was also performed in DCM, EtOH, iPrOH,
Acetone, EtOAc, hexanes and Et2O. Solid was observed in iPrOH, EtOAc and hexanes.
However, the diastereomeric ratio of the solid were always 1:1 based on the 1H NMR
spectra.
Scheme 2.11 Resolution of VANOL with (–)-brucine and 1st attempt with tBuVANOL
salt
Ph
Ph

OH
OH

1) POCl3
2) H2O

Ph
Ph

O
O
P
OH
O

(–)-brucine
II-5
ethanol
mother
liquor

II-46a

1) HCl
2) Me2SO4,
NaHCO3
3) Red-Al

(S)-II-46a
(S)-VANOL
80%, >99.8% ee

(R)-II-46a
(R)-VANOL
72%, >99.8% ee

II-48a

H
Ph
Ph

OH 1) POCl3
OH 2) H O
2

Ph
Ph

O
O
P
O
OH

(–)-brucine
II-5
DCE
reflux

H
Ph
Ph

O
O
P
O
O

H

N

H O

H N
O

O
O

II-46b
20 mmol

II-48b
95%

II-49
no solid from in DCE, EtOH,
iPrOH/hexanes, DCM/hexanes, acetone

104

Scheme 2.12 Resolution of VANOL via Camphorsulfonate and 2nd attempt with
tBuVANOL
H 3C

CH3

H 3C

O

S
Cl O
Ph
Ph

OH
OH

O
S
O
OH O

Ph
Ph

CH3
NaOH, MeOH

O

Ph
Ph

OH
OH

O
II-50
1.1 equiv

II-51

+

(S)-VANOL
(S)-II-46a

H 3C

Et3N (1.5 equiv)
DMAP (10 mol%)
DCM, 0Âş to rt, 20 h

O
S
O
O
OH

Ph
Ph

II-46a

CH3

NaOH, MeOH
O

II-52
H 3C

CH3

H 3C

Ph
Ph

OH
OH

(R)-VANOL
(R)-II-46a

CH3

SOCl2
O

O
S
HO O
(+)-II-3

reflux

O

S
Cl O
II-50
85%

O

H 3C

Ph
Ph

OH
OH

1.1 equiv II-50
Et3N (1.5 equiv)
DMAP (10 mol%)
DCM, 0Âş to rt, 20 h

II-46b

Ph
Ph

O
S
O
O
OH

O

CH3

+ 10% disulfonate

II-53
88%

To continue to pursue the resolution of tBuVANOL, attention was then turned to
the reported methods for the resolution of its biaryl analogue BINOL II-11 (Scheme 2.13).

105

The literature was surveyed and attempted resolution of tBuVANOL using the same
procedure reported for BINOL if 1) the resolving agent is an inexpensive, commercially
available compound or easily accessible from such a compound; 2) the synthesis and
separation are efficient and convenient. It was reported that BINOL could form
diastereomeric inclusion complexes II-54 and II-55 with (S)-proline45 and (1R,2R)diaminocyclohexane48. Such complexes were readily separated and crystallized to obtain
both enantiomers of BINOL in high ee. When tBuVANOL was employed under the same
conditions with (S)-proline II-15 and (1R,2R)-diaminocyclohexane II-19, no crystallization
occurred after cooling to –20 ºC for an extended period of time. Salt formation with (R,R)II-19 and tBuVANOL phosphoric acid II-48b was also attempted. Although salt II-56
formed, enantioenrichment by crystallization failed from benzene and EtOH, as judged by
the 31P NMR. In one report by Einhorn and coworkers, BINOL was efficiently resolved by
chromatography via N-Boc tryptophan esters70. We carried out the synthesis of N-Boc
tryptophan esters of tBuVANOL by Boc protection of tryptophan II-57 and then DCC
coupling (Scheme 2.14). The mono ester II-59 was obtained in excellent yield, however
the diastereomeric esters did not separate by TLC upon eluting with 95:5 DCM/ether
which is the reported condition for BINOL. Other combinations of common eluting solvent,
such as Et2O, DCM, toluene and benzene, were also attempted. In contrast to a 0.2 Rf
difference between the BINOL diastereomeric esters, only negligible separation was
observed with the tBuVANOL analogues.

106

Scheme 2.13 Resolution of BINOL via inclusion complex formation and 3rd and 4th
attempt with tBuVANOL

H 2N
OH
OH H2N

(R)-BINOL•(R,R)-1•toluene II-54

Ph
Ph

OH
OH

reflux,
overnight

H 2N

no
crystal

Ph
Ph

OH
OH

(R,R)-II-19

O

toluene,

HO

reflux,
overnight

O

II-46b

O
O
P
O
OH

H 2N

+

CH3CN

HN

+

(S)-II-15

II-46b

Ph
Ph

HO

(S)-BINOL•proline II-55

toluene,

H 2N

+

HN

OH
OH

toluene

benzene, reflux

H 2N

Ph
Ph

O
O
P
O
O

H 3N
H 2N

(R,R)-II-19

II-48b

II-56

107

no
crystal

Scheme 2.14 5th resolution attempt via Boc-tryptophan ester
Boc2O (1.5 equiv),
Et3N (1.5 equiv),

O
HO
NH2

NH

O
HO

MeOH, reflux

NHBoc NH
II-58
quant.

II-57

Ph
Ph

OH
OH

II-58 (1.0 equiv)
DCC (2.3 equiv),
DMAP (20 mol%),
DCM, 0 ÂşC to rt, 19 h

II-46b

O
Ph
Ph

O
OH

NHBoc NH

II-59
quant.

Focus was quickly moved on to a protocol reported32 and improved33 by Shan and
coworkers. They resolved racemic BINOL via a cyclic borate ester formed from the
reaction of BINOL and borane with cinchona alkaloids (Scheme 2.15). One diastereomer
was found to be soluble under their conditions while the other precipitates. After filtration
and simple hydrolysis, optically pure BINOL could be obtained in high yield and with
excellent ee. It was found that the (S)-BINOL quinine borate precipitates from THF in 42%
yield and with excellent ee, whereas the (R)-BINOL cinchonine borate precipitates from
toluene to obtain optically pure (R)-BINOL in 35% yield after hydrolysis. Resolution of
tBuVANOL was attempted using their most recent procedure33 with cinchonidine II-7.
tBuVANOL and 1.05 equivalent of borane dimethyl sulfide complex were stirred in Et2O
at rt for 0.5 h. The formation of cyclic borane II-61 was complete when the gas revolution
ceased. The solvent can be switched after removing Et2O using a rotavapor. Cinchonidine
108

Scheme 2.15 Resolution of BINOL via cyclic borate ester with quinine and 7th attempt
with tBuVANOL

N

HO

N

HO

R
N
R = H, (–)-cinchonine II-9
R = OMe, (–)-quinine II-10

N
(+)-cinchonidine II-7

precipitate hydrolysis
OH
OH

BH3•Me2S

O
BH
O

Et2O

separation

toluene/THF
hydrolysis

(Âą)-BINOL
(Âą)-II-11

Ph
Ph

II-9/II-10

2

Ph
Ph

(R)-BINOL
/(S)-BINOL

mother liquor

II-60

1.05 equiv
BH
3•Me2S
OH
OH Et O

(S)-BINOL
/(R)-BINOL

O
BH
O

1.05 equiv
cinchonidine
II-7

solid

2 N HCl

No tBuVANOL recoverd

toluene
100 ÂşC, 3 h
no solid from Et2O, DCM, THF

(Âą)-II-46b

Ph
Ph

OH
OH

II-61

1.05 equiv
quinine
II-10

1.05 equiv
BH3•Me2S Ph
Ph
Et O

O
BH
O
Et2O
45 ÂşC, overnight

2

precipitate 2 N HCl

(S)-II-46b
(S)-tBuVANOL
7%, 95% ee

2 N HCl

(R)-II-46b
(R)-tBuVANOL
70%, 7.6% ee

mother liquor
(Âą)-II-46b

II-61

II-7 was then added and the mixture was heated to reflux for 3-12 h. Solid was obtained
from toluene but not from DCM, Et2O or THF. However, no tBuVANOL was isolated after

109

hydrolysis, which suggested that the solid might be cinchonidine borate. We went back
to their original procedure32 using quinine II-10. After the cyclic borate was formed, 1.05
equivalent of quinine was added and the mixture was refluxed. A precipitate was
observed after 30 min. After 12 h, solid was filtered and hydrolyzed in 2 N HCl solution
for 30 min. It was delightful to find out that (S)-tBuVANOL was obtained with 95% ee from
the precipitate, leaving 70% of tBuVANOL in the mother liquor with an excess of the Renantiomer. Another related BINOL resolution36 via spiroborate formation with chiral
ammonium as gegen cation was also attempted (Scheme 2.16). Unfortunately, the solid
precipitating from THF was meso-spiroborate rather than chiral spiroborate.
Scheme 2.16 Resolution of BINOL via spiroborate ester with quinine and 8th attempt
with tBuVANOL

OH

NH2
1.5 equiv (R)-II-4
0.5 equiv B(OH)3

O

OH

CH3CN, reflux, 12 h

O

(Âą)-BINOL
(Âą)-II-11

Ph
Ph

B

OH

O
O

R*NH3

separation

hydrolysis

(Âą)-II-11
(S)-BINOL,
29%, >99% ee

spiroborate complex
II-62

OH
OH

OH

0.5 equiv BH3•Me2S

0.6 equiv (R)-II-4

crystals

THF, 80 ÂşC, 0.5 h
then remove volatiles

THF, reflux

separation

hydrolysis

Ph
Ph

OH
OH

(Âą)-II-46b
62%, 2% ee

(Âą)-tBuVANOL
(Âą)-II-46b

In summary, we successfully identified one resolution process that gave
enatioenrichment for tBuVANOL after a number of failed trials. We decided to further
110

optimize this protocol using quinine due to the readily availability of quinine and
convenience of the reaction procedure.
2.5 Condition optimization and scale up
Table 2.1 Optimization of the Resolution of tBuVANOL

precipitate 2 N HCl
Ph
Ph

OH
OH

1.0 equiv
BH3•Me2S

1.05 equiv
quinine

(S)-tBuVANOL

filter

THF, 80 ÂşC,
THF
0.5 h
80 ÂşC, overnight
then remove volatiles

wash by
THF

2 N HCl
mother liquor

(R)-tBuVANOL

(Âą)-II-46b
entry

scale
(mmol)

THF
(mL/mmol)

THF wash
(mL/mmol)

%yield of
(S)-tBuVANOL

%ee of
(S)-tBuVANOL

1
2
3
4a
5a
6
7c

2.0
4.0
4.0
4.0
4.0
16.0
16.0

7.5
5.0
3.75
5.0
2.5
4.0
4.0

5.0
2.5
2.5
4.0
2.5
4.0
4.0

28
40
44
19
28
36b
30

>99
95
85
>99
98
>99b
>99

a0.525

%yield of
%ee of
(R)-tBuVANOL (R)-tBuVANOL
58
45
45
85
64
48b
ND

54
72
92
18
41
86b
ND

equiv quinine was used. bAverage of 5 runs. cRecovered quinine was used. ND = not determined.

It was found that the resolution was more efficient using THF rather than Et2O as
solvent (entry 1, Table 2.1 vs Scheme 2.15) which was the solvent used in reported
resolution for BINOL32. The precipitate crashed out after 10 minutes of reflux subsequent
to the addition of quinine. By decreasing the volume of THF used in the formation of the
quinine borate complex, the yield of (S)-tBuVANOL increase at the sacrifice of ee (entry
1, 2 and 3, Table 2.1). The optimal volume was expected to be between 5.0 and 3.75
mL/mmol. The volume of THF used in the wash of the filter cake was found to affect the
result as well. Unsurprisingly, the more THF used in the wash, higher ee and lower yield

111

was observed for (S)-tBuVANOL. We determined that the optimal volume for the wash is
between 2.5 and 5.0 ml/mol. We also briefly tested resolution of tBuVANOL with a halfequivalent of resolving agent. This strategy was applied in many processes71 since its
first report in 189972. Although less efficient, the process proved to be effective using less
THF solvent (entry 4 and 5, Table 2.1). After weighing the pros and cons, we chose to
develop the more reliable procedure with 1.05 equivalent of quinine which is a reasonably
inexpensive natural product. In addition, the quinine used in the resolution could be easily
recycled (Scheme 2.17). The aqueous layer containing quinine after hydrolysis and
extraction was neutralized by addition of NaOH at 0 ÂşC until the pH > 8.0. The cloudy
solution was extract with DCM and dried. The crude quinine can be further purified by
crystallization from toluene (89% recovery). The conditions (indicated in entry 6, Table
2.1) with 1.05 equivalent of quinine at reflux in 4.0 mL/mmol THF and using 4.0 mL/mmol
THF for the wash was chosen for the multigram-scale (8.812 g) trial (entry 6, Table 2.1).
The procedure is robust and effective. Optically pure (S)-tBuVANOL could be prepared
with an average 36% yield in 5 separated runs (32-41%). And the remaining (R)tBuVANOL is recovered in an average of 48% yield (46-51%) and 82% ee (67-89% ee).
The recovered crystallized quinine was employed a second time in the resolution under
the same conditions (entry 7, Table 2.1), and proceed well with a slightly diminished yield.
Scheme 2.17 Recovery of quinine
Water phase
after the hydrolysis

NaOH

DCM extraction,

pH > 8

dried and rotavap

112

crude quinine crystallization
quant.
from toluene

quinine
89%

Scheme 2.18 Attempted resolution to get access to (R)-tBuVANOL

N

HO
MeO

Ph
Ph

OH
OH

1.05 equiv BH3•Me2S

THF, 80 ÂşC, 0.5 h
then remove volatiles

Ph
Ph

(Âą)-II-46b

O
BH
O

N
1.05 equiv II-7
No solid
THF
80 ÂşC, 6 h

(Âą)-II-61

H 3C

OH
CH3

Ph
Ph

OH
OH

(Âą)-II-46b

1.05 equiv BH3•Me2S

THF, 80 ÂşC, 0.5 h
then remove volatiles

Ph
Ph

O
BH
O

II-63 CH3
1.05 equiv L-menthol

No solid

THF
80 ÂşC, overnight

(Âą)-II-61

Access to enantiopure (R)-tBuVANOL via resolutions using cyclic borates was also
examined with other resolving agents (Scheme 2.18). The pseudo enantiomer quinidine
II-7 was first tested. In contrast to the tBuVANOL quinine borate, the quinidine derived
borate did not yield any precipitate after reflux in THF. Another inexpensive natural chiral
alcohol (–)-menthol II-63 was also applied to the same process. No solid was formed
either. Other than repeated resolution using another resolving agent, enantioenrichment
of (R)-tBuVANOL can be achieved simply by recrystallization. It is well known that
crystallizations of scalemic VANOL and its derivatives produce solid of racemates rather
than conglomerates. By performing crystallization, the racemic VANOL will crystallize
first, leaving the mother liquor with higher enantiomeric purity. To improve the purity of
113

(R)-tBuVANOL with 73% ee, crystallization was performed (Scheme 2.19) from 4:1
hexanes/DCM. It was not surprising that a racemic powdery solid was formed first. The
ee of the mother liquor was boosted to 92%. Repeated crystallization under the same
conditions, however led to solids with two distinct crystal forms. Aside from the powdery
racemate sitting in the bottom of the flask, a unique crystalline solid grew from the
saturated solution. As a tribute to Pasteur, the crystals were manually separated from the
powdery solid and then wash by the filtrate (Figure 2.1). The ee of the crystal was
determined to be >99%. To develop a reliable and convenient procedure, we adopted an
existing “wash in DCM” method for enantioenrichment of VANOL. Instead of using DCM,
we found that the enantiopure tBuVANOL is very soluble in hexanes while the racemic is
not. Therefore, after we mixed and stirred tBuVANOL with high ee in hexanes for one
hour, the racemic tBuVANOL would crashed out. After filtration, ee of the tBuVANOL in
the mother liquor was enhanced to >99%. The racemic precipitate can be recovered
(Scheme 2.20). This enantioenrichment procedure was practical and simple, providing
reproducible results from 5 separate runs.
Scheme 2.19 Enantiomeric excess enhancement by recrystallization

precipitate

Ph
Ph

OH
OH

(Âą)-tBuVANOL
0.52 g, 8% ee

recrystallization
hexanes/DCM
4:1

mother liquor

(R)-tBuVANOL
92% ee

(R)-tBuVANOL
4.51 g, 73% ee

Ph
repeated
Ph
recrystallization

OH
OH

hexanes/DCM
4:1

(R)-tBuVANOL, >99% ee
1st crop: 1.10g
2nd crop:1.83 g

114

a

b

Figure 2.1 a) Sorting (R)-tBuVANOL crystals by tweezers; b) One (R)-tBuVANOL crystal
Scheme 2.20 Enantiomeric excess enhancement by hexanes wash

precipitate

Ph
Ph

OH
OH

(Âą)-tBuVANOL
1.52 g

250 mL hexanes
1 h, rt

mother liquor

Ph
Ph

OH
OH

remove solvent

(R)-tBuVANOL
4.23 g, 77% ee

(R)-tBuVANOL
2.64 g, >99% ee

Finally, the overall procedure for the optimal resolution for tBuVANOL is shown in
Scheme 2.21. It is worth noting that, the resolution procedure is convenient and timeefficient. One cycle of the resolution of tBuVANOL only takes less than 24 hours to access
both (S)- and (R)-tBuVANOL as pure enantiomers in good yield (30-38% for each;
maximum is 50%). Moreover, most of the quinine (89%) and about 20% of racemic
tBuVANOL could be recovered by simple manipulations.

115

Scheme 2.21 Resolution of tBuVANOL

precipitate
Ph
Ph

OH
OH

1.05 equiv
quinine

1.0 equiv
BH3•Me2S

2 N HCl

filter

64 mL THF
THF, 80 ÂşC,
wash by
0.5 h
80 ÂşC, overnight 64 mL THF
then remove volatiles

2 N HCl
mother liquor

16 mmol
5 runs
HO

(Âą)-tBuVANOL
~ 20%

N

MeO
N
(–)-quinine II-10

precipitate

(S)-tBuVANOL
>99% ee
(32~41%, ave. 36%)

(R)-tBuVANOL
(67~89% ee, ave.
82%ee)
(46~51%, ave. 48%)

250 mL hexanes
1 h, rt

(R)-tBuVANOL
mother liquor
>99% ee,
(30~38%, ave. 35%)

2.6 Synthesis and resolution of VANOL derivatives
One of the objectives of this project is to develop a general resolution that can be
applied to a broad scope of VANOL derivatives. By introducing different substituent in the
chiral ligand, we can modify the electronic and steric effect of the catalyst to accommodate
the substrate. On most occasions, the optimal catalyst for various reactions (or even for
different substrates in the same reaction) are different. For example, the 7,7’-Cy2VANOL
proved to be superior in the parallel kinetic resolution of racemic ⍺-iminol73. In the case
of MPV reduction of ⍺-bromoacetophenone, VANOL with a longer linear alkyl chain at the
7,7’-positions gave the best results74 (Scheme 2.22). A library of optically pure VANOL
derivatives would be useful in developing new methodology and elucidating reaction
mechanisms.

116

Scheme 2.22 Application of selected 7,7’-disubstituted VANOL derivatives
PMP

PMP

N

OH

H
Ph

5 mol% Zr-(S)-ligand-catalyst

Cy

toluene, 40 ÂşC, 24 h
ligand

(Âą)-II-64

PMP

NH
O

Cy

Ph

Br

II-66
42%, 99% ee
44%, 92% ee

Ph
Ph

OH
OH

OH
Br

toluene, rt, 16 h
II-67

R

Cy

II-65

20 mol% (S)-ligand
10 mol% AlMe3

O

Ph

7,7’-Cy2VANOL 42%, 99% ee
53%, 88% ee
VANOL

O

NH

ligand

II-68

7,7’-nBu2VANOL
7,7’-tBu2VANOL
VANOL

72%, 85% ee
77%, 62% ee
43%, 42% ee

R
ligand = 7,7’-R2VANOL

2.6.1 Synthesis of 5,5’-disubstituted VANOL derivatives
A series of 5,5’-disubstituted VANOL derivatives were synthesized by reported
method59,

63

as shown in Table 2.2. Commercially available ortho-substituted phenyl

acetic acids II-44c–h were subjected to the general CAEC conditions. The corresponding
5-substituted VANOL monomers 3-phenylnaphthol II-45c–g, were obtained in good yield
(52-67%) after recrystallization. For the o-nitrophenyl acetic acid II-44h, the reaction
yielded an uncharacterizable black tar. The acid chloride (not shown) could be generated
under a milder condition using oxalyl chloride (COCl)2 with catalytic amount of DMF at rt.
The yield of the followed CAEC reaction on II-44c is similar with (COCl)2 as it is with
SOCl2 (60% vs 67%). The monomers were oxidatively dimerized under air with good
yields, some of which could be further improved by increasing reaction time (96% after
36 h for II-46c).

117

Table 2.2 Synthesis of 5,5’-R2VANOL
R

OH
R

O

II-44
100 mmol

1) SOCl2 (2.0 equiv),
70 ÂşC, 1 h then
remove excess

Ph

HO

mineral oil, air,

2)

Ph (1.3 equiv)
(i-PrCO)2O (2 equiv),
190 ÂşC, 48 h
3) KOH, H2O, 100 ÂşC,
overnight

165 ÂşC, 24 h

Ph
Ph

HO
HO

R
II-45
50 mmol

R
II-46

series

R

%yield of
monomer II-45a

%yield of
VANOL II-46

c
d
e
f
g
h

Br
Cl
Me
OMe
CF3
NO2

67
71
52
52
66
<5

96b
75
72
72
65
–

acombined

yield from 2 crops after crystallization. b36 h

5,5’-tBu2VANOL II-46i was also successfully synthesized (a and b, Scheme 2.21).
Rather than trying to develop an anticipated challenging synthesis from its 5,5’-dibromo
analog, it was decided to prepare the ligand in a direct method that was used for related
analogs (Table 2.2). To access its precursor ortho-t-butyl phenyl acetic acid II-44i, two
routes were designed and carried out. Both routes start with the preparation of 2-tertbutyliodobenzene II-70 via the Sandmeyer reaction of inexpensive 2-tert-butylaniline II69. This reaction could be performed on 95 mmol scale in 51-58% yield. This is not as
good of yield as observed on a 20 mmol scale (81%), which may be related to the cooling
capacity. In the first synthesis, the iodobenzene was first converted to benzaldehyde II71 using an established

118

Scheme 2.23 Synthesis of 5,5’-tBu2VANOL
pTsOH•H2O (3.0 equiv),
NaNO2 (2.0 equiv),
KI (2.5 equiv),

NH2

I

tBuOH/H2O,
0 ÂşC to rt, overnight
80-95 mmol

II-69

II-70
51-58%

a
1) nBuLi (2.0 equiv),
THF, –78 ºC, 30 min;

I

2) DMF (3.0 equiv);
–78 ºC to rt, 12 h
66 mmol

II-70

CHO

1) CH3PPh3I, nBuLi
THF, 0 ÂşC, 30 min
2) 0 ÂşC to rt, overnight

II-71
94%

1) disiamylborane (4.4 equiv)
THF, 0 ÂşC to rt, overnight

40 mmol

II-72
96%

PCC (2 mol%)
H5IO6 (2.2 equiv)

OH

COOH

MeCN, 0 ÂşC to rt, overnight

2) NaOH, 0 ÂşC then
H2O2, –10 ºC, 1 h
2 mmol

II-73
90%, rr 15:1

II-44i
54%
4 steps, 41% overall from iodide

b
I

1) iPrMgCl (1.1 equiv),
THF, 0 ÂşC, 2 h;

EtO

O
O

36-55 mmol

1) N2H4•H2O (5 equiv),
80 ÂşC, overnight

O

NaOH, H2O,

O

60 ÂşC, overnight

2) ClCOCOEt (1.25 equiv);
–78 ºC 2 h to rt, 12 h

II-70

HO

II-75

II-74

COOH

2) KOH (4.0 equiv);
triehtylene glycol, 150 ÂşC

II-44i
55%
over 3 steps, from iodide

COOH

1) (COCl)2 (2.0 equiv),
cat. DMF, 0 ÂşC to rt 2 h;

Ph

HO

mineral oil, air,
165 ÂşC, 24 h

2)

II-44i

Ph (1.3 equiv)
(i-PrCO)2O (2 equiv),
190 ÂşC, 48 h
3) KOH, H2O, 100 ÂşC,
overnight

Ph
Ph

HO
HO

20 mmol
II-45i
42%
II-46i
91%

50 mmol

119

procedure75, followed by Wittig reaction to yield the styrene II-72. These two
transformations gave excellent yield on gram-scale. A hydroboration/oxidation sequence
was then explored. Employing in-situ generated disiamylborane gave rise to the desired
linear alcohol II-73 in excellent yield and high regioselectivity, compared to 69% yield and
10:1 rr if BH3•Me2S was used. The chromium-catalyzed oxidation utilizing periodic acid
developed76 by process chemists at Merck successfully converted the alcohol to the
desired acid II-44i. The moderate yield of this reaction was due to the loss of product in
the work-up stage. This route was abandoned later, leaving the last two steps
unoptimized for scale-up, because of its low atom economy.
The second pathway begins with iodine/magnesium exchange followed by
coupling with ethyl chlorooxoacetate. After simple work up, the ⍺-ketoester II-74 is
hydrolyzed in aqueous NaOH to give the phenylglyoxylic acid II-75 in 93% over 2 steps.
It was delightful to find that the Wolff-Kishner reduction provided the desired phenyl acetic
acid II-44i in moderate yield. The isolated byproduct was the unreacted hydrazone
intermediate, which could be subjected to another basic cleavage. The second route
gives higher yield (55% vs 41%) with fewer steps, and only one column chromatography
is needed. Some other coupling reactions that are more straightforward were also
explored but failed (not shown). For example, the Grignard reagent generated from
iodo/magnesium exchange of iodobenzene II-70 did not couple with ethyl ⍺-bromo
acetate, nor did this coupling occur with CoCl2/TMEDA as catalyst77. The Pd-catalyzed
coupling78 of iodobenzene II-70 with ethyl diazoacetate and the Cu-catalyzed coupling79
with diethyl malonate were both attempted but both failed to yield any coupled product. It

120

appeared that these conditions were quite sensitive to the steric hindrance of the
iodobenzene component. With the o-tert-butylphenylacetic acid II-44i in hand, the CAEC
reaction was carried out to give the monomer II-45i in 42% yield, which is lower than
normal probably due to the greater steric hindrance of t-butyl group. Gratifyingly the
oxidative addition gave the 5,5’-tBu2VANOL II-46i in 91% yield.
Scheme 2.24 Synthesis of 5,5’-CN2VANOL
Br

CN

Ph
Ph

HO
HO

20 mol% CuI,
40 mol% KI,
DMEDA (2.0 equiv)
NaCN (2.4 equiv),
toluene, 130 ÂşC, 24 h

Br

HO
HO

Ph
Ph

CN
85%
II-46j

II-46c

CN

+

Ph
Ph

HO
HO

Br
~4%
II-46j’

5,5’-CN2VANOL II-46j was prepared by copper-catalyzed cyanation80 of racemic
5,5’-Br2VANOL II-46c (Scheme 2.24) in good yield. However, the solubility of this
compound is very poor in most organic solvents, even DMSO. The purification procedure
could be simply carried out by washing the solid with DCM. The cyanation from optically
pure II-46c also produced II-46j in excellent yield (not shown). Unexpectedly, the resulting
product, whose ee was not determined, has similar poor solubility as the racemic product.

121

2.6.2 Synthesis of 3,3’-disubstituted VANOL derivatives
Similarly, 3,3’-substituted VANOL derivatives were prepared from CAEC reaction
using various commercially available para-substituted phenylacetylene and then
oxidative coupling (Table 2.3) in moderate overall yields. The synthesis of 3,3’-dialkyl
VANOL derivatives will be discussed in Chapter 3.
Table 2.3 Synthesis of 3,3’-R2VANOL

1)

Cl
O
II-76

Ar (1.3 equiv),
(i-PrCO)2O (2 equiv),
190 ÂşC, 48 h

Ar

HO

mineral oil, air,

2) KOH, H2O, 100 ÂşC,
overnight

165 ÂşC, 24 h

Ar
Ar

HO
HO

50 mmol

100 mmol

II-45
II-46
%yield of
%yield of
monomer II-45a VANOL II-46

series

Ar

k
l
m

4-EtC6H4
4-CH3OC6H4
4-BuC6H4

a combined

62
47
58

63
68
49

yield from 2 crops after crystallization.

2.6.3 Synthesis of 7,7’-disubstituted VANOL
A number of 7,7’-substituted VANOL derivatives were prepared by Kumada
coupling from MOM protected 7,7-Br2VANOL (Scheme 2.25). 7,7-Br2VANOL II-46n was
prepared on large scale in good yield from acid II-44n via the CAEC reaction and
subsequent oxidative coupling. The protection with MOMCl went well, giving II-77 in 95%
yield along with 4% of the mono-MOM protected ligand as a side-product. The Kumada
coupling of II-77 with alkyl Grignard reagents were explored and optimized. The coupling
with freshly prepared 1Âş alkyl Grignard reagents, such as n-hexyl, isoamyl and 3-

122

phenylpropyl, can be catalyzed by 10 mol% Ni(dppp)Cl2 giving II-78o–q in excellent yield.
The partially deprotected products (not shown) were observed to some extent (14%
isolated for II-78o) after quenching the coupling reaction. Nevertheless, the deprotection
step was carried out successfully using the mixture of II-78 and its OH/OMOM analog.
Under the Ni-catalyzed conditions, the coupling with the 2Âş cyclohexyl Grignard reagent
was sluggish. Optimization attempts by varying solvent, the method for Grignard
generation and catalyst loading did not provide more than 56% yield of II-46r. It was thus
pleasing to find that the more reactive Pd(dppf)Cl2 was effective at rt for this substrate,
giving rise to the final 7,7’-Cy2VANOL II-46r in excellent yield.
Scheme 2.25 Synthesis of 7,7’-R2VANOL
Br

R

MOMO
MOMO

R

R MgBr (4 equiv)
Ni
or Pd cat (10 mol%),
Ph
MOMO
Ph
MOMO
Et2O, 0 ÂşC to reflux,
overnight
then quick column

Ph
Ph

amberlyst 15
MeOH/THF (1:1)
reflux, overnight

Ph
Ph

HO
HO

8 mmol

Br

R
II-77

R
II-78

II-46

series

R

catalyst

%yield of
VANOL II-46a

o
p
q
r
r

hexyl
isoamyl
3-phenylpropyl
cyclohexyl
cyclohexyl

Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Pd(dppf)Cl2b

93
74
87
32
93

a isolated

yield after 2 steps. b 5 mol%, –78 ºC to rt

123

2.6.4 Synthesis of 7,7’-Ad2VANOL
The greater enantiomeric induction often observed with tBuVANOL as ligand in
many different asymmetric reactions led to a consideration of introducing an adamantyl
(Ad) group into the 7,7’-positons of VANOL. The very rigid adamantyl group is thought to
be bulkier than a tbutyl group since it occupies a larger volume of space. A number of
ligands containing an adamantyl group have been reported, many of which have found
wide success in catalysis (Scheme 2.26).
The mono-, di- and tri-adamantyl phosphine ligands II-79–83 were developed by
Imamoto81, Buchwald82-83, Beller84-87, Hartwig88, Carrow89 and many other groups. Their
superior activity in palladium or rhodium catalysis can be attributed to the steric and
electronic properties of adamantyl group. First, it should be more sterically hindered than
a tBu group by comparison of the Charton steric parameter90 (1.33 vs 1.24). Second, the
adamantyl is more electron releasing than tBu indicated by the lower calculated89
carbonyl stretching frequency of Ni(CO)3(PR3) (2052.1 cm–1 for R = adamantyl vs 2056.1
cm–1 for R = tBu). Third, the adamantyl has better polarizability (Taft polarizability
parameter σα –0.95 for ad compared to –0.75 for tBu)89, which can facilitate electron
donation from phosphorus to metal. These distinct characters of adamantyl are also
reflected in other ligand system, such as the adamantylimido molybdenum alkylidene
complex II-84, reported by Schrock and Hoveyda91 and the N-Heterocyclic Carbene
(NHC) 1,3-Bisadamantylimi-dazolin-2-ylidene II-85a by Herrmann92. Another important
NHC II-85b was first synthesized93 by Mol and coworkers and was applied94 by Grubbs
and Endo for Z-selective olefin metathesis. The steric property of adamantyl has often

124

been exploited in the asymmetric catalysis, as in the examples II-8695, II-8796 and II-8897.
The adamantyl group has been incorporated into the 3,3’-positions of BINOL. In 2002, Pu
and

coworker

reported98

the

BINOL-based

catalyst

for

the

enantioselective

phenylacetylene addition to aromatic aldehydes in the presence of diethylzinc. List group
reported99 adamantyl-modified TRIP catalyst II-90 in 2008 and it was found100 to be the
optimal catalyst in fluorination of allylic alcohols by Toste et al in 2014. Yamamoto’s group
also reported101 the N-triflyl phosphoramide II-91 catalyzed cycloaddition of nitrones with
ethyl vinyl ether in 2008. By changing the isopropyl group to adamantyl in the para positon
of aryl group at the 3,3’-positions of BINOL to give catalyst II-91, they obtained higher
yield and greater stereoselectivity for the reaction. However, the reports of introduction of
an adamantyl group into the BINOL backbone is limited102, probably due to the lower
ligand activity with the bulky group right next to the phenol OH, and the less-developed
methodology for coupling of sterically hindered aryl bromides or boric acids with tertiary
bromides.

125

Scheme 2.26 Ligands/catalysts containing adamantyl group and their applications

P

P

P

P

P

cataCXium A II-81

II-80
II-79
Imamoto80, 1998
Buchwald81-82, 1999
[Rh], Asymmetric Hydrogenation [Pd], Bchwald Etherification

Beller83-86, 2000
[Pd], Suzuki-Miyaura Coupling

N

N
N
Mo
O
O

P

AdPtBu2 II-82
Hartwig87, 2001
[Pd], Heck Reaction

PPh2

Ph

IAd II-85a

N

Herrmann91, 2002
[Pd], Suzuki-Miyaura Coupling
PAd3 II-83
Carrow88, 2016
[Pd], Suzuki-Miyaura Coupling

II-84
Schrock and Hoveyda90, 2003
Asymmetric Olefin Metathesis

N

II-86
Togni94, 2002
[Pd], Asymmetric
Allylic Amination

N

Cl
H2IMesAd II-85b
Mol92, 2003
Grubbs93, 2011
[Ru], Z-Selective Olefin Metathesis

O
N

N

N

Fe

N
II-87
Hall and Burgess95, 2004
[Ir], Asymmetric hydrogenation

iPr

O

iPr
X
O
P
O
Y
iPr

Ad
O

OMe
OH
OH
OMe

O
O
O

P

Ad

O

iPr

O

O

O

II-89
Ad

II-88

Reetz96, 2009
[Rh], Asymmetric Hydrogenation

Pu97, 2002
Asymmetric Alkynylzinc
Addition to Aldehydes

126

II-90, X = O, Y = OH, List98, 2008
Asymmetric Aminal Formation
Toste99, 2014
Fluorination of Allylic Alcohols
II-91, X = O, Y = NHTf, Yamamoto100, 2008
Enantioselective 1,3-Dipolar Cycloaddition

Introducing adamantyl into 7,7’-position of VANOL hopefully would enable unique
reactivity in catalysis without adversely affect the activity because the phenol OH is much
farther away than it is in 3,3’-Ad2BINOL. Given that it would be challenging to develop a
coupling reaction of 7,7’-Br2VANOL and an adamantyl nucleophile, it was decided to
explore the synthesis the p-adamantylphenylacetic acid –– the requisite precursor for the
CAEC reaction. After several failed attempts at the Friedel-Crafts reaction of methyl
phenylacetate with 1-bromoadamantane II-92 catalyzed by AlCl3, FeCl3103 and
Mo(CO)6104, it was delightful to find that the cross coupling reaction of II-92 with freshlymade phenyl Grignard reagents in DCM gave 1-phenyladamantane II-93 in excellent yield
on 50 mmol scale. Converting II-93 to the 2-(p-adamantylphenyl)acetic acid II-44s was
achieved by an in-house route that had been developed for tBuVANOL59: Friedel-Crafts
acylation followed by the Willgerodt-Kindler reaction and then hydrolysis. The phenyl
acetic acid II-44s can be prepared on large scale with around 50% yield over 4 steps.
Gratifyingly, the subsequent CAEC reaction and dimerization went smoothly gave the
desired product in 53% and 94% yield, respectively. It is worth noting that to achieve full
conversion of the oxidative coupling, it was required to elevate the temperature from 150
ÂşC (optimal for tBuVANOL) to 195 ÂşC which is near the melting point of II-45s. The reaction
only reached ~50% conversion after 48 h at 170 ÂşC and was completely shut down at 150
ÂşC.

127

Scheme 2.27 Synthesis of 7,7’-Ad2VANOL
PhBr
Mg, Et2O,
0 ÂşC to reflux, 1 h
CH3COCl (1.1 equiv)
AlCl3 (1.1 equiv),

1.5 equiv PhMgBr

Br

Ph

DCM, reflux, overnight

II-92

91-96%
50 mmol 8 runs
short column w/hexanes

CS2, –78 ºC to 0 ºC, 1 h
rt, 4 h

II-93
~80 g combined
mp 76-78 ÂşC

88-91%
87-100 mmol 3 runs
short column w/
10:1 hexanes/EtOAc

N

S

O

HCl, AcOH,
dioxane, 120 ÂşC,
overnight

145 ÂşC, 12 h
88-167 mmol 3 runs
trituration w/ EtOH 55-62 %
and column chromatography ~23%

Ad
II-95
82% combined
mp 171-173 ÂşC
~100 g

96 mmol, 107 mmol
recrystalization from
EtOAc/Hexanes (1:3)

Ad

II-44s
86% combined
(1st 69%, 2nd 9.3%, 3rd 7.0%)
mp 186-187 ÂşC
~50 g

Ad

HO

Ph

mineral oil, air,

3) KOH, H2O, 100 ÂşC,
overnight

52-54%
2 ☓ 100 mmol
column and recrystallization

Ad

II-94
~89 g crude (~90% purity)
mp 97-100 ÂşC
HO

O
morpholine (3.8 equiv),
S (2.5 equiv),

1) (COCl2) (2.0 equiv),
cat. DMF, 0 ÂşC to rt, 1 h
then remove excess
2)
Ph (1.3 equiv)
(i-PrCO)2O (2 equiv),
190 ÂşC, 48 h

O

195 ÂşC, 24 h
Ad

II-45s
37.69 g
mp 201-203 ÂşC

HO
HO

100 mmol
Ad

Ph
Ph

II-46s
33.25 g, 94% (~98% pure)
mp 360 ÂşC (decomp.)

2.6.5 Resolution scope with quinine
With these newly prepared 5,5’-, 7,7’- and 3,3’-disubstituded VANOL derivatives
in hand, the scope of the resolution process with quinine borate (Scheme 2.21) was
investigated. It was delightful to find that a variety of 5,5’-, 7,7’- and 3,3’-substituted
VANOL derivatives could be resolved by this procedure. For 5,5’-disubstituted VANOLs,
excellent yield (42-45%) and perfect ee were observed for bromo, chloro and methyl
substitutents (II-46c–e, Table 2.4). Half of volume of hexanes was used when the quinine
borates of 5,5’-(OMe)2VANOL II-46f and 5,5’-(CF3)2VANOL II-46g were refluxed with THF
since this was necessary to increase the yields. It is worth noting that the procedure could
128

be easily scaled-up to 8 mmol, giving 1.82 g (40% yield) of optically pure 5,5’(CF3)2VANOL II-46g. The resolution could be applied to VANOL with branched or
unbranched aliphatic substituents at the 7,7’-positions (II-46o, 46p, 46r, 46s, Table 2.4),
providing the optically pure ligands in moderate to good yield (10-33%, single run,
unoptimized). The VANOL ligands with substituents on the 3,3’-phenyl rings are also
compatible (II-46k–m, Table 2.4). The limitation of this resolution has also been found.
The borate precipitation procedure of 7,7’-Br2VANOL II-46n with quinine failed to give any
diastereomeric enrichment, and refluxing of 7,7’-(3-phenylpropyl)2VANOL II-46q and 3,3’Cy2VANOL II-46t with borane and quinine did not produce any solid even if hexanes was
added.
The procedure was then applied to racemic VANOL II-46a, VAPOL II-96 and
isoVAPOL II-97105. It was important to find that VANOL and VAPOL could be resolved by
this process with slight modifications to the volume of refluxing THF. Excellent yields (4445%, 50% maximum) of optically pure (S)-enantiomer could be obtained. In the case of
isoVAPOL II-97, the diastereomeric borate complex did not precipitated from THF alone,
and the addition of hexanes was required to afford 33% of (S)-isoVAPOL. BINOL II-11
was also tested in this procedure but with a smaller amount of THF than in the original
report32, giving excellent yield, albeit 91% ee. Unexpectedly, the 6,6’-Br2BINOL II-39 did
not yield any solid borate complex even when a large amount of hexanes was added.

129

Table 2.4 Scope of resolution of VANOL derivatives with quinine borates

rac-ligand

2.0 mmol

R2

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

THF/Hexanes, 80 ÂşC,
overnight

filter

wash by
solvent
mother liquor

5,5’-disubstituted VANOL

(S)-Ligand
HCl

(R)-Ligand

3,3’-R2VANOL

R1 =

II-46c,
Br, (4.5), 45%, >99% ee
II-46d, R1 = Cl, (4.5), 44%, >99% ee R4
OH
II-46e, R1 = Me, (4.5), 42%, 99% ee
4
OH II-46f, R1 = OMe, (4/2), 47%, >99% ee R
II-46g, R1 = CF3, (4/2), 40%, >99% eea

Ph
Ph

HCl

II-46k, R4 = p-EtC6H4, (3/3), 36%, >99% ee
OH
II-46l, R4 = p-OMeC6H4, (3/3), 34%, >99% ee
OH
II-46m, R4 = p-BuC6H4, (3/4), 17%, >99% ee
II-46t, R4 = Cy, (3/6), trace, 10% ee

R2
R1

OH
OH

Ph
Ph

R1

R3

7,7’-disubstituted VANOL

II-46a, R1 = H, (3), 45%, >99% ee
II-46b, R1 = tBu, (4), 35%, >99% ee
II-46o, R1 = n-hexyl, (4/3),, 10%, >99% ee
II-46p, R1 = isopentyl, (3/3), 23%, >99% ee
II-46q, R1 = 3-phenylpropyl, (3/3), 0%
II-46r, R1 = Cy, (4), 26%, >99% ee
II-46n, R1 = Br, (3), 46%, 0% ee
II-46s, R1 = Ad, (4), 33%, >99% ee

Ph
Ph

R3

Ph
Ph

OH
OH

II-96, VAPOL, (3), 44%, >99% ee
a8.0

OH
OH BINOL derivatives
II-11, R 3 = H, (2.5), 46%, 91% ee
II-39, R3 = Br, (3/6), 0%

OH
OH

II-97, isoVAPOL, (4/2), 33%, >99% ee

mmol scale

2.6.6 Resolution scope with quinidine
The efforts to enrich the ee of the (R)-enantiomer of the VANOL derivatives from
the mother liquor from the quinine borate procedure were first directed to developing a
procedure involving the solubilization of optically pure ligand from a scalemic mixture with
hexanes (Scheme 2.21). However, the conditions are substrate-dependent. For example,

130

the optically pure 5,5’-Br2VANOL II-46c was not very soluble in hexanes. Thus stirring
72% ee 5,5’-Br2VANOL II-46c in hexanes and then filtering did not result in increasing ee
of II-46c in the mother liquor (71% ee). Repeated recrystallizations were time consuming
and often non-reproducible. Therefore, it was decided to develop a resolution with a
borate ester with quinidine, the pseudo-enantiomer of quinine (Table 2.5).
Gratifyingly, the 5,5’-disubstituted VANOL derivatives II-46c–g could be resolved
successfully with quinidine to afford the optically pure (R)-enantiomer in moderate to
excellent yields (13-46%) (Table 2.5). In general, the quinidine process was less efficient
than the quinine process for VAPOL II-96, VANOL II-46a and its 7,7’-substituted
derivatives. In contrast to the quinine process, the addition of hexanes was required for
some substrates to afford the precipitate with reasonable yield from the quinidine (II-46a,
e, s, Table 2.5). Surprisingly, the resolution of 7,7’-Ad2VANOL with the quinidine borate
process gave the same (S)-enantiomer as quinine process. In contrast, BINOL and 6,6’Br2BINOL were resolved more effectively with quinidine (II-11 and II-39, Table 2.5). The
application of this resolution in enantioenrichment was demonstrated for II-46l. The
scalemic mixture with 79% ee (R) was successfully enriched to >99% following the same
procedure, leaving 89% of the (S)-enantiomer in 18% yield in the mother liquor.
Unfortunately, refluxing of 7,7’-Br2VANOL II-46n gave a precipitate containing both
diastereomers in a 1:1 ratio.

131

Table 2.5 Scope of resolution of VANOL derivatives with quinidine borates

rac-ligand

2.0 mmol

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinidine,

THF, 80 ÂşC, 0.5 h
then remove volatile

THF/Hexanes, 80 ÂşC,
overnight

R2

wash by
solvent
mother liquor

(R)-Ligand
HCl

(S)-Ligand

5,5’-disubstituted VANOL

II-46c, R1 = Br, (4), 32%, >99% ee
II-46d, R1 = Cl, (4), 41%, >99% ee
OH
II-46e, R1 = Me, (4/2), 39%, 99% ee
OH II-46f, R1 = OMe, (4/2), 46%, >99% ee
II-46g, R1 = CF3, (4/2), 13%, >99% ee

Ph
Ph

filter

HCl

R4
R4

3,3’-R2VANOL
OH II-46l, R4 = p-OMeC6H4, (3/3),
OH 76%, >99% ee

R2
R1

R3
7,7’-disubstituted VANOL

Ph
Ph

OH
OH

OH BINOL derivatives
3
OH II-11, R = H, (2.5), 39%, 94% ee
II-39, R3 = Br, (3/1.5), 48%, >99% ee

R1 =

II-46a,
H, (4/4), 31%, 70% ee
II-46b, R1 = tBu, (4), 0%
II-46n, R1 = Br, (3), 0% ee
R3
II-46s, R1 = Ad, (4/4), 31%, >99% eea

R1

Ph
Ph

R4
R4

OH
OH

II-96, VAPOL, (3), 28%, >99% ee
a(S)-enantiomer

OH
OH

II-97, isoVAPOL, (4/2), 26%, >99% ee

was obtained from solid. b4.17 mmol scale.

2.7 Stability of 5,5’-substituted VANOL derivatives
During the development of the resolution of 5,5’-R2VANOL derivatives, it was
observed that the results of the resolution were inconsistent and it was suspected that
this was due to a variation of the reaction times for the hydrolysis step. Moreover, the
relative mass of the resulting (R)- and (S)-enantiomers has changed from 1:1. In an

132

attempt to increase the enantiomeric excess of 98% ee 5,5’-(CF3)2VANOL II-46g by
recrystallization, the ees of both the crystal and the mother liquor dropped (Scheme 2.28).
These observations led us to investigate the racemization of ligands under various
conditions (Table 2.6).
Scheme 2.28 Racemization of 5,5’-(CF3)2VANOL
F3C

Ph
Ph

OH
OH

solid, II-46g, 90% ee

recrystallization
from DCM/hexanes

mother liqour, II-46g, 95% ee

F3C

II-46g
98% ee

Table 2.6 Racemization experiments with 5,5’-R2VANOL
R

R

Ph
Ph

OH
OH

R

condtions
20 mL vial,
N2, rt, 24 h

Ph
Ph

R

conditions

1
2
3
4
5
6
7a
8
9a
10a
11a
12
13
14
15
16

OMe
Me
H
Br
CF3
CF3
OMe
Me
H
Br
CF3
OMe
Me
H
Br
CF3

1 mL DCM
1 mL DCM
1 mL DCM
1 mL DCM
1 mL DCM
1 mL EtOAc
1 mL DCM, 10 mg quinine
1 mL DCM, 10 mg quinine
1 mL DCM, 10 mg quinine
1 mL DCM, 10 mg quinine
1 mL DCM, 10 mg quinine
1 mL DCM, 0.5 mL 2 M HCl
1 mL DCM, 0.5 mL 2 M HCl
1 mL DCM, 0.5 mL 2 M HCl
1 mL DCM, 0.5 mL 2 M HCl
1 mL DCM, 0.5 mL 2 M HCl

OH
OH

R

II-46

%eeb (II-46)

entry

II-46

15 mg, >99% ee
II-46a, R = H,
II-46c, R = Br,
II-46e, R = Me,
II-46f, R = OMe,
II-46g, R = CF3,

a36

>99
74
>99
>99
22
>99
82
60
>99
80
94
>99
>99
>99
>99
93

h. bAs judged by chiral HPLC.

In 20-mL vials, VANOL II-46a and derivatives II-46c, II-46e–g were dissolved
separately in DCM and kept under N2 for at least 1 day then subjected to chiral HPLC
133

analysis. It was surprising to find that 5,5’-(CF3)2VANOL II-46g and 5,5’-Me2VANOL II46e racemized readily in DCM, while the other three ligands were resistant toward
racemization (entry 1-5, Table 2.6). The experiment in EtOAc did not result in any
racemization of II-46g (entry 6, Table 2.6). In basic media with quinine, although VANOL
demonstrated configurational stability after 24 h, derivatives of VANOL were more or less
racemized (entry 7-11, Table 2.6). Oddly, II-46g was racemized to a lesser extent under
basic conditions. It was found that VANOL ligands were less prone to epimerize under
acidic conditions (entry 12-16, Table 2.6). No racemization was observed under acidic
condition at room temperature after 24 h except for 5,5’-(CF3)2VANOL II-46g, to a less
extent compared to neutral conditions (entry 7-11, Table 2.6). It was demonstrated by
Cram and coworkers106 that BINOL can racemize under basic or acidic conditions upon
heating. The transition states for epimerization were proposed to involve a protonated
enol II-98, in which the naphthyl rings can rotate about the C(sp2)-C(sp3) bond, or dianion
II-99, which has a lower rotation barrier due to the loss of intermolecular hydrogen
bonding (Scheme 2.29). For the racemization of VANOL derivatives in the presence of
quinine, a similar transition state II-100a could also be envisioned and is depicted in
Scheme 2.29. After deprotonation by the quinuclidine nitrogen atom, the other phenol
group in VANOL can engage in the hydrogen bonding with the hydroxyl group of the same
(or another) quinine molecule, which will minimize the rotation barrier of the two naphthyl
rings. An alternative pathway of racemization would be the rotation about the C(sp2)C(sp3) bond in the enolate II-100b of the mono deprotonated VANOL.

134

Scheme 2.29 Proposed pathway for racemization BINOL and VANOL
R

H

OH
OH

O
O

Ph
Ph

R

O
O

H

N

H

Ph
Ph

O
OH

O
H
II-98

II-99

R

II-100a

R

II-100b

In light of the facile racemization of some VANOL derivatives, the solvent used for
hydrolysis and extraction was switch from DCM to EtOAc. And the time of hydrolysis was
decrease to 1 h. After the hydrolysis, a quick column chromatography was employed to
remove the remaining quinine in the mixture. The process became more consistent and
reproducible after these modifications.
2.8 Crystallization-induced dynamic resolution
One of the limitations for classical resolution is that a single enantiomer can only
be obtained with maximum 50% yield. Dynamic resolution, on the other hand, can convert
100% of a racemic compound into an enantiopure compound. One of the keys to realize
dynamic resolution is to find conditions to easily interconvert the (R) and (S) enantiomers
throughout the resolution process. We envisioned that we could develop a crystallizationinduced dynamic resolution (CIDR)107 of VANOL derivatives by epimerization of their
enantiomers under our resolution conditions. To the best of our knowledge, CIDR of
bisphenol ligands has not been reported in literature, even though several syntheses of
biaryl atropisomers by dynamic kinetic resolution process were reported108-112 recently. It
is known that a copper (II) complex with sparteine can induce deracemization of BINOL,

135

VANOL, VAPOL and their derivatives59, 64-65, 113. It was reasoned that a copper complex
with an achiral amine could racemize the soluble enantiomer of a VANOL derivative and
enable a CIDR process. The commercially available Cu(II)-TMEDA II-101 catalyst has
been applied to a variety of reactions, such as oxidative coupling of naphthol
derivatives114, cross coupling of aryl boronic acids with heterocycles115-117 and coupling
of terminal alkynes118-120. It was the catalyst of choice for initial examination of the
epimerization of VANOL derivatives.
Table 2.7 Crystallization-induced dynamic resolution of VANOL

Ph
Ph

OH
OH

1.05 equiv BH3•Me2S,

1.05 equiv quinine,
Cu-TMEDA

filter

THF, 80 ÂşC, 0.5 h
then remove volatile

THF, temp,
time

then HCl

Ph
Ph

(R)-II-46a,
>99% ee, 1 mmol

entry

(S)-II-46a
>99% ee

Cu-TMEDA THF

temp

time

(S)-II-46ab

3 mL
5 mL
5 mL
5 mL
5 mL

80 ÂşC
60 ÂşC
60 ÂşC
60 ÂşC
60 ÂşC

12 h
2h
12 h
24 h
12 h

mixturec
56%
0
0
0

1
2
3
4
5

20 mol%
10 mol%
5 mol%
1 mol%
—a

OH
OH

H 3C N

CH3
N
CH2

CH3
Cl

Cu
OH

Cu-TMEDA II-101

2

a10

mol% CuCl2 and 10 mol% 1,10-phenanthroline.
yield after hydrolysis and column
chromatography.
cUncharacterized.
bIsolated

To provide a proof of concept, the conversion of (R)-VANOL to (S)-VANOL using
quinine borate resolution in the presence of Cu-TMEDA catalyst was briefly explored
(Table 2.7). The resolution process for racemic VANOL was employed for (R)-VANOL
136

with 20 mol% Cu-TMEDA II-101. It was delightful to observe that a white solid precipitated
from THF after 20 min reflux, which was expected to be the (S)-VANOL borate complex
with quinine which has lower solubility than the other diastereomer. However, after reflux
overnight, the mixture became a brown solution without any solid. Acidic work up gave a
complex mixture with VANOL as the major spot on TLC (entry 1, Table 2.7). The
byproduct is likely to be the dimer of VANOL which was observed in deracemization65 by
Cu-sparteine complex. To avoid decomposition, the loading of the catalyst was decreased
to 10 mol%. In addition, the temperature and time of heating was reduced (60 ÂşC for 2 h).
Pleasingly, the optically pure (S)-VANOL could be obtained in 56% yield, leaving 36%
(S)-VANOL with 21% ee in the mother liquor (entry 2, Table 2.7). This result proved that
VANOL can be epimerized by catalytic amount of Cu-TMEDA and it is feasible to develop
a CIDR of VANOL. Further lower the Cu-TMEDA loading to 5 mol% or 1 mol% showed a
negative effect; No solid was formed after heating for a longer period of time and the color
of the solutions became darker, which indicated decomposition (entry 3 &4, Table 2.7).
Other copper catalyst for epimerization such as 10 mol% Cu(II)-1,10-phen was tested.
No solid was formed for the whole period of heating and the solution became dark brown
after 12 h (entry 5, Table 2.7).
Nevertheless, many challenges need to be addressed in order to develop a CIDR
of VANOL and derivatives. Firstly, the inclusion of copper catalyst in the borate precipitate
would inhibit the racemization process, especially when the concentration of the soluble
enantiomer become very dilute when the dynamic resolution reaches high conversion.
Secondly, high temperature, concentration and loading of copper catalyst would effect

137

dimerization or other side reaction of VANOL. On the other hand, they are necessary to
drive the resolution and racemization more effectively. A balance s to be reached by
extensively screening the conditions of the process.
2.9 Computational Model
Attempts to grow crystallographically characterizable crystals of quinine borate
complexes with VANOL and 7,7-Ad2VANOL failed. Therefore, an effort to elucidate their
structural properties was turned to computational methods. Quinine borate ester
complexes of (S)- and (R)-VANOL was constructed in Spartan 08. After conformational
analysis and ground state optimization in gas phase at the level of B3LYP/6-31g(d), a
spiroborate ester with quinuclidine N–>B coordination (1.69 Å distance) was identified as
the energy minimum (Figure 2.2).

Figure 2.2 spiroBorate ester of (S)-VANOL with quinine II-102

138

N
H

O
N

O

O
B
O
O

Ph
Ph

O B

O
O

Ph
Ph

N
N
(S)-VANOL-QN spiroborate II-102
0.825 kcal/mol

(S)-VANOL-QN mesoborate II-103
4.904 kcal/mol

N
H
O
O B
O

O
N

O

B
O

O
O

Ph
Ph

Ph
Ph

N
N
(R)-VANOL-QN spiroborate II-104
0

E/ kcal•mol–1

(R)-VANOL-QN mesoborate II-105
5.938 kcal/mol

R-QN II-105
5.938

S-QN II-103
4.904

R-QN II-104 0

S-QN II-102 0.825

Figure 2.3 Possible geometries of VANOL quinine borates at the B3LYP/6-31G(d) level
139

Both (S)- and (R)-VANOL spiroborate esters with quinine demonstrated
exceptional stabilization compared to their most stable mesoborate isomers from DFT
calculation at the B3LYP/6-31G(d) level (II-102 vs II-103, II-104 vs II-105, Figure 2.3). The
less THF-soluble (S)-VANOL spiroborate is slightly less stable at gas phase compared to
(R)-VANOL spiroborate probably due to the unfavorable steric interaction of quinuclidine
with naphthyl ring. It is worth noting that similar borate esters with O3BN framework have
been synthesized35,

121-127

and applied in BINOL resolution35, asymmetric ketone

reduction121, 124-125, 127 and aldol reaction123 by the Shan, Ortiz-Marciales and Krzemiński
groups.
In order to probe the correlation between the efficiency of resolution and DFT
structural properties, 5,5-Br2VANOL II-46c, 7,7-Br2VANOL II-46n and 7,7-Ad2VANOL II46s were constructed based on the optimized structure of the VANOL spiroborate of
quinine/quinidine and then further optimized at the B3LYP/6-31G(d) level. The distance
of N–B coordination and the angle of ligand O–B–O were measured. The results are
shown in Table 2.8. The O–B–O bond angles of spiroborates (114.1~116.0) clearly
indicated the boron is pyramidalized. It is interesting that the smaller angle difference
between their (R)- and (S)-diastereomers, the higher efficiency of the resolution in THF.
For example, for VANOL II-46a and II-46c, quinine resolution is more efficient than
quinidine (angle difference 0.2 vs 0.6, 0.1 vs 0.5). Resolution of VANOL II-46n did not
yield any diastereomeric excess, and the angle differences between diastereomeric
borates were larger than the other 3 ligands (1.0 for QN and 0.5 for QD). The distances
of N–B did not vary much (1.68~1.72) and no correlation was found between them and

140

the efficiency of the resolution. A similar trend was observed for the energy difference
between the (R)- and (S)-diastereomers and efficiency of the resolution of II-46a, II-46c
and II-46s: the energy difference of the pair of quinidine is larger, and the efficiency is
lower for quinidine than quinine. The abnormality of 7,7-Ad2VANOL II-46s was also
demonstrated in the computational structures. In contrast to ligand II-46a and II-46c, the
quinine borate with (R)-II-46s is more pyramidalized and higher in energy, than the
diastereomer with (S)-II-46s. Nevertheless, the solubility of the borate diastereomers
could not be correlated to these properties. The details of the crystal packing were not
available from DFT calculation.
Table 2.8 Structural properties of optimized DFT structures of quinine/quinidine borates
with VANOL derivatives
entry ligand QN/QD
R1

R2

d
N

Ph
Ph

O
O

B
O
∠a
R1

R2

II-46a, R1, R2 = H
II-46c, R1 = H, R2 = Br
II-46n, R1 = Br, R2 = H
II-46s, R1 = Ad, R2 = H

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16

II-46a
II-46a
II-46a
II-46a
II-46c
II-46c
II-46c
II-46c
II-46n
II-46n
II-46n
II-46n
II-46s
II-46s
II-46s
II-46s

aEnergy

(S)-QN
(R)-QN
(S)-QD
(R)-QD
(S)-QN
(R)-QN
(S)-QD
(R)-QD
(S)-QN
(R)-QN
(S)-QD
(R)-QD
(S)-QN
(R)-QN
(S)-QD
(R)-QD

∠a(º)

d(Å)

ΔE (kcal/mol)a

115.6
115.8
114.9
115.5
115.4
115.5
114.7
115.2
114.1
115.1
114.1
114.6
116.0
115.9
115.1
115.6

1.69
1.70
1.70
1.72
1.69
1.70
1.69
1.72
1.68
1.69
1.69
1.72
1.69
1.70
1.69
1.72

0.825
0
0
0.951
0.851
0
0
1.030
1.195
0
0
0.673
0
0.236
0
1.331

difference between the borate diastereomers of
(S)- and (R)-ligand.

141

2.10 Conclusion and outlook
In summary, a general resolution of VANOL, VAPOL and BINOL and their
derivatives via borates with quinine or quinidine was developed. A variety of optically pure
VANOL derivatives could be readily accessible by this method. The procedure is time
efficient and can be easily scaled up. Quinine and quinidine used in the resolution could
be recycled by simple manipulations. The borate esters of the ligands with quinine or
quinidine were proposed to consist of spiroborates with N–>B coordination based on DFT
calculations. The potential of developing a CIDR in the presence of Cu-TMEDA was
demonstrated. In order to resolve those ligands that did not yield any solid or gave solid
without significant diastereomeric excess from THF, other ether solvents such as Et2O
and methyl tert-butyl ether, could be tested.

142

REFERENCES

143

REFERENCES

1.

Federsel, H.-J., Nat Rev Drug Discov 2005, 4 (8), 685-697.

2.

IMS Institute for Healthcare Informatics, See www.imshealth.com.

3.

Pasteur, L., Ann. Chim. Phys. SĂŠr. 3 1848, 24, 442-459.

4.
Murakami, H., From Racemates to Single Enantiomers – Chiral Synthetic Drugs
over the last20 Years. In Novel Optical Resolution Technologies, Sakai, K.; Hirayama, N.;
Tamura, R., Eds. Springer Berlin Heidelberg: Berlin, Heidelberg, 2007; pp 273-299.
5.
Kacprzak, K.; Gawronski, J., Resolution of Racemates and Enantioselective
Analytics by Cinchona Alkaloids and Their Derivatives. In Cinchona Alkaloids in Synthesis
and Catalysis, Wiley-VCH Verlag GmbH & Co. KGaA: 2009; pp 419-469.
6.
Fogassy, E.; Lopata, A.; Faigl, F.; Darvas, F.; Ács, M.; Tþke, L., Tetrahedron Lett.
1980, 21 (7), 647-650.
7.
Anandamanoharan, P. R.; Cains, P. W.; Jones, A. G., Tetrahedron: Asymmetry
2006, 17 (12), 1867-1874.
8.
Bereczki, L.; Bombicz, P.; BĂĄlint, J.; Egri, G.; Schindler, J.; Pokol, G.; Fogassy, E.;
Marthi, K., Chirality 2009, 21 (3), 331-338.
9.
Karamertzanis, P. G.; Anandamanoharan, P. R.; Fernandes, P.; Cains, P. W.;
Vickers, M.; Tocher, D. A.; Florence, A. J.; Price, S. L., The Journal of Physical Chemistry
B 2007, 111 (19), 5326-5336.
10.
Karamertzanis, P. G.; Price, S. L., The Journal of Physical Chemistry B 2005, 109
(36), 17134-17150.
11.
Bolchi, C.; Pallavicini, M.; Fumagalli, L.; Marchini, N.; Moroni, B.; Rusconi, C.;
Valoti, E., Tetrahedron: Asymmetry 2005, 16 (9), 1639-1643.
12.
Guangyou, Z.; Yuquing, L.; Zhaohui, W.; Nohira, H.; Hirose, T., Tetrahedron:
Asymmetry 2003, 14 (21), 3297-3300.
13.
NovĂĄk, T.; Ujj, V.; Schindler, J.; Czugler, M.; Kubinyi, M.; Mayer, Z. A.; Fogassy,
E.; Keglevich, G., Tetrahedron: Asymmetry 2007, 18 (24), 2965-2972.
14.
Periasamy, M.; Kumar, N. S.; Sivakumar, S.; Rao, V. D.; Ramanathan, C. R.;
Venkatraman, L., J. Org. Chem. 2001, 66 (11), 3828-3833.

144

15.
Vries, T.; Wynberg, H.; van Echten, E.; Koek, J.; ten Hoeve, W.; Kellogg, R. M.;
Broxterman, Q. B.; Minnaard, A.; Kaptein, B.; van der Sluis, S.; Hulshof, L.; Kooistra, J.,
Angew. Chem. Int. Ed. 1998, 37 (17), 2349-2354.
16.
Kellogg, R. M.; Nieuwenhuijzen, J. W.; Pouwer, K.; Vries, T. R.; Broxterman, Q.
B.; Grimbergen, R. F. P.; Kaptein, B.; Crois, R. M. L.; de Wever, E.; Zwaagstra, K.; van
der Laan, A. C., Synthesis 2003, 2003 (10), 1626-1638.
17.
Variankaval, N.; McNevin, M.; Shultz, S.; Trzaska, S., 9.09 High-Throughput
Screening to Enable Salt and Polymorph Screening, Chemical Purification, and Chiral
Resolution A2 - Knochel, Paul. In Comprehensive Organic Synthesis II (Second Edition),
Elsevier: Amsterdam, 2014; pp 207-233.
18.
Wang, Y.; Chen, A. M., Organic Process Research & Development 2008, 12 (2),
282-290.
19.

v. Richter, V., Ber. Dtsch. Chem. Ges. 1873, 6 (2), 1249-1260.

20.
Pummerer, R.; Prell, E.; Rieche, A., Berichte der deutschen chemischen
Gesellschaft (A and B Series) 1926, 59 (8), 2159-2161.
21.

Jacques, J.; Fouquey, C.; Viterbo, R., Tetrahedron Lett. 1971, 12 (48), 4617-4620.

22.
Kyba, E. B.; Koga, K.; Sousa, L. R.; Siegel, M. G.; Cram, D. J., J. Am. Chem. Soc.
1973, 95 (8), 2692-2693.
23.
Noyori, R.; Tomino, I.; Tanimoto, Y., J. Am. Chem. Soc. 1979, 101 (11), 31293131.
24.

Brunel, J. M., Chem. Rev. 2007, 107 (9), PR1-PR45.

25.

Chen, Y.; Yekta, S.; Yudin, A. K., Chem. Rev. 2003, 103 (8), 3155-3212.

26.
Cai, D.; Hughes, D. L.; Verhoeven, T. R.; Reider, P. J., Resolution of 1,1′-bi-2Naphthol. In Org. Synth., John Wiley & Sons, Inc.: 2003.
27.

Jacques, J.; Fouquey, C., Org. Synth. 1989, 67, 1.

28.
Reeder, J.; Castro, P. P.; Knobler, C. B.; Martinborough, E.; Owens, L.; Diederich,
F., J. Org. Chem. 1994, 59 (11), 3151-3160.
29.

Li, Z.; Liang, X.; Wu, F.; Wan, B., Tetrahedron: Asymmetry 2004, 15 (4), 665-669.

30.

Fabbri, D.; Delogu, G.; De Lucchi, O., J. Org. Chem. 1995, 60 (20), 6599-6601.

31.

Chow, H.-F.; Wan, C.-W.; Ng, M.-K., J. Org. Chem. 1996, 61 (24), 8712-8714.

145

32.
Shan, Z.; Wang, G.; Duan, B.; Zhao, D., Tetrahedron: Asymmetry 1996, 7 (10),
2847-2850.
33.
Shan, Z.; Cheng, F.; Huang, S.; Zhao, D.; Jing, Z., Tetrahedron: Asymmetry 1997,
8 (8), 1175-1177.
34.
Shan, Z.; Xiong, Y.; Li, W.; Zhao, D., Tetrahedron: Asymmetry 1998, 9 (22), 39853989.
35.

Shan, Z.; Xiong, Y.; Zhao, D., Tetrahedron 1999, 55 (13), 3893-3896.

36.
Periasamy, M.; Venkatraman, L.; Sivakumar, S.; Sampathkumar, N.; Ramanathan,
C. R., J. Org. Chem. 1999, 64 (20), 7643-7645.
37.

Toda, F.; Tanaka, K., J. Org. Chem. 1988, 53 (15), 3607-3609.

38.
Tanaka, K.; Okada, T.; Toda, F., Angewandte Chemie International Edition in
English 1993, 32 (8), 1147-1148.
39.
Cai, D.; Hughes, D. L.; Verhoeven, T. R.; Reider, P. J., Tetrahedron Lett. 1995, 36
(44), 7991-7994.
40.
Qiao-Sheng, H.; Vitharana, D.; Lin, P., Tetrahedron: Asymmetry 1995, 6 (9), 21232126.
41.
Cai, D. P., J. F.; Bender, D. R.; Hughes, D.L.; Verhoeven, T. R.; and Reider, P. J.,
Org. Synth. 1999, 76, 6.
42.
Karnik, A. V.; Upadhyay, S. P.; Gangrade, M. G., Tetrahedron: Asymmetry 2006,
17 (8), 1275-1280.
43.
Periasamy, M.; Bhanu Prasad, A. S.; Bhaskar Kanth, J. V.; Kishan Reddy, C.,
Tetrahedron: Asymmetry 1995, 6 (2), 341-344.
44.

Venkatraman, L.; Periasamy, M., Tetrahedron: Asymmetry 1996, 7 (9), 2471-2474.

45.
Periasamy, M.; Venkatraman, L.; Thomas, K. R. J., J. Org. Chem. 1997, 62 (13),
4302-4306.
46.
Du, H.; Ji, B.; Wang, Y.; Sun, J.; Meng, J.; Ding, K., Tetrahedron Lett. 2002, 43
(30), 5273-5276.
47.

Kawashima, M.; Hirayama, A., Chem. Lett. 1990, 19 (12), 2299-2300.

48.
Schanz, H.-J.; Linseis, M. A.; Gilheany, D. G., Tetrahedron: Asymmetry 2003, 14
(18), 2763-2769.

146

49.
Bao, J.; Wulff, W. D.; Rheingold, A. L., J. Am. Chem. Soc. 1993, 115 (9), 38143815.
50.
Patwardhan, A. P.; Wulff, W. D.; Yin, X., 2,2′-Diphenyl-[3,3′-biphenanthrene]-4,4′diol (VAPOL) and 3,3′-Diphenyl-[2,2′-binaphthrene]-1,1′-diol (VANOL). In Encyclopedia
of Reagents for Organic Synthesis, John Wiley & Sons, Ltd: 2001.
51.

Antilla, J. C.; Wulff, W. D., Angew. Chem. Int. Ed. 2000, 39 (24), 4518-4521.

52.
Xue, S.; Yu, S.; Deng, Y.; Wulff, W. D., Angew. Chem. Int. Ed. 2001, 40 (12), 22712274.
53.
Newman, C. A.; Antilla, J. C.; Chen, P.; Predeus, A. V.; Fielding, L.; Wulff, W. D.,
J. Am. Chem. Soc. 2007, 129 (23), 7216-7217.
54.

Ren, H.; Wulff, W. D., J. Am. Chem. Soc. 2011, 133 (15), 5656-5659.

55.

Huang, L.; Wulff, W. D., J. Am. Chem. Soc. 2011, 133 (23), 8892-8895.

56.
Zhao, W.; Huang, L.; Guan, Y.; Wulff, W. D., Angew. Chem. Int. Ed. 2014, 53 (13),
3436-3441.
57.

Loncaric, C.; Wulff, W. D., Org. Lett. 2001, 3 (23), 3675-3678.

58.
Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M., Chem. Rev. 2014, 114 (18), 90479153.
59.
Guan, Y.; Ding, Z.; Wulff, W. D., Chemistry – A European Journal 2013, 19 (46),
15565-15571.
60.
Zhang, X.; Staples, R. J.; Rheingold, A. L.; Wulff, W. D., J. Am. Chem. Soc. 2014,
136 (40), 13971-13974.
61.
Zhou, Y.; Mukherjee, M.; Gupta, A. K.; Wulff, W. D., Org. Lett. 2017, 19 (9), 22302233.
62.

Dai, Y.; Wulff, W. D., unpublished work.

63.
Ding, Z.; Osminski, W. E. G.; Ren, H.; Wulff, W. D., Organic Process Research &
Development 2011, 15 (5), 1089-1107.
64.
Zhang, Y.; Yeung, S.-M.; Wu, H.; Heller, D. P.; Wu, C.; Wulff, W. D., Org. Lett.
2003, 5 (11), 1813-1816.
65.
Hu, G.; Holmes, D.; Gendhar, B. F.; Wulff, W. D., J. Am. Chem. Soc. 2009, 131
(40), 14355-14364.

147

66.

Ritter, S. K., Chem. Eng. News. 2017, 95, 18.

67.

Firth, J. D.; Canipa, S. J.; O'Brien, P.; Ferris, L., Angew. Chem. Int. Ed., n/a-n/a.

68.
Bao, J.; Wulff, W. D.; Dominy, J. B.; Fumo, M. J.; Grant, E. B.; Rob, A. C.;
Whitcomb, M. C.; Yeung, S.-M.; Ostrander, R. L.; Rheingold, A. L., J. Am. Chem. Soc.
1996, 118 (14), 3392-3405.
69.
Jiangtao, S.; Guangyang, X.; Xin, G.; Jian, L. CN102786391. CN102786391, Nov.
21, 2012.
70.
Panchal, B. M.; Einhorn, C.; Einhorn, J., Tetrahedron Lett. 2002, 43 (50), 92459248.
71.
Fogassy, E.; NĂłgrĂĄdi, M.; PĂĄlovics, E.; Schindler, J., Synthesis 2005, 2005 (10),
1555-1568.
72.
Pope, W. J.; Peachey, S. J., Journal of the Chemical Society, Transactions 1899,
75 (0), 1066-1093.
73.

Zhou, Y.; Wulff, W. D., manuscript in praparation.

74.

Zheng, L.; Wulff, W. D., unpublish work.

75.
Varela, J. A.; PeĂąa, D.; Goldfuss, B.; Denisenko, D.; Kulhanek, J.; Polborn, K.;
Knochel, P., Chemistry – A European Journal 2004, 10 (17), 4252-4264.
76.
Zhao, M.; Li, J.; Song, Z.; Desmond, R.; Tschaen, D. M.; Grabowski, E. J. J.;
Reider, P. J., Tetrahedron Lett. 1998, 39 (30), 5323-5326.
77.

YU, X.; CHEN, S. CN101508625 (A) 2009.

78.

Titanyuk, I. D.; Beletskaya, I. P., Synlett 2013, 24 (03), 355-358.

79.

Hennessy, E. J.; Buchwald, S. L., Org. Lett. 2002, 4 (2), 269-272.

80.
Zanon, J.; Klapars, A.; Buchwald, S. L., J. Am. Chem. Soc. 2003, 125 (10), 28902891.
81.
Imamoto, T.; Watanabe, J.; Wada, Y.; Masuda, H.; Yamada, H.; Tsuruta, H.;
Matsukawa, S.; Yamaguchi, K., J. Am. Chem. Soc. 1998, 120 (7), 1635-1636.
82.
Lee, H. G.; Milner, P. J.; Buchwald, S. L., J. Am. Chem. Soc. 2014, 136 (10), 37923795.
83.
Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L.,
J. Am. Chem. Soc. 1999, 121 (18), 4369-4378.

148

84.
Gowrisankar, S.; Sergeev, A. G.; Anbarasan, P.; Spannenberg, A.; Neumann, H.;
Beller, M., J. Am. Chem. Soc. 2010, 132 (33), 11592-11598.
85.
Neumann, H.; Sergeev, A.; Beller, M., Angew. Chem. Int. Ed. 2008, 47 (26), 48874891.
86.
Klaus, S.; Neumann, H.; Zapf, A.; StrĂźbing, D.; HĂźbner, S.; Almena, J.; Riermeier,
T.; Groß, P.; Sarich, M.; Krahnert, W.-R.; Rossen, K.; Beller, M., Angew. Chem. Int. Ed.
2006, 45 (1), 154-158.
87.
Zapf, A.; Ehrentraut, A.; Beller, M., Angew. Chem. Int. Ed. 2000, 39 (22), 41534155.
88.
Stambuli, J. P.; Stauffer, S. R.; Shaughnessy, K. H.; Hartwig, J. F., J. Am. Chem.
Soc. 2001, 123 (11), 2677-2678.
89.

Chen, L.; Ren, P.; Carrow, B. P., J. Am. Chem. Soc. 2016, 138 (20), 6392-6395.

90.

Charton, M., Steric Effects in Drug Design Springer: 1983.

91.
Tsang, W. C. P.; Jernelius, J. A.; Cortez, G. A.; Weatherhead, G. S.; Schrock, R.
R.; Hoveyda, A. H., J. Am. Chem. Soc. 2003, 125 (9), 2591-2596.
92.
GstĂśttmayr, C. W. K.; BĂśhm, V. P. W.; Herdtweck, E.; Grosche, M.; Herrmann, W.
A., Angew. Chem. Int. Ed. 2002, 41 (8), 1363-1365.
93.

Dinger, M. B.; Nieczypor, P.; Mol, J. C., Organometallics 2003, 22 (25), 5291-5296.

94.

Endo, K.; Grubbs, R. H., J. Am. Chem. Soc. 2011, 133 (22), 8525-8527.

95.
Togni, A.; Burckhardt, U.; Gramlich, V.; Pregosin, P. S.; Salzmann, R., J. Am.
Chem. Soc. 1996, 118 (5), 1031-1037.
96.
Fan, Y.; Cui, X.; Burgess, K.; Hall, M. B., J. Am. Chem. Soc. 2004, 126 (51), 1668816689.
97.
Reetz, M. T.; Guo, H.; Ma, J.-A.; Goddard, R.; Mynott, R. J., J. Am. Chem. Soc.
2009, 131 (11), 4136-4142.
98.

Xu, M.-H.; Pu, L., Org. Lett. 2002, 4 (25), 4555-4557.

99.
Cheng, X.; Vellalath, S.; Goddard, R.; List, B., J. Am. Chem. Soc. 2008, 130 (47),
15786-15787.
100.

Zi, W.; Wang, Y.-M.; Toste, F. D., J. Am. Chem. Soc. 2014, 136 (37), 12864-12867.

149

101. Jiao, P.; Nakashima, D.; Yamamoto, H., Angew. Chem. Int. Ed. 2008, 47 (13),
2411-2413.
102. Yang, B.; Qiu, Y.; Jiang, T.; Wulff, W. D.; Yin, X.; Zhu, C.; Bäckvall, J.-E., Angew.
Chem. Int. Ed. 2017, 56 (16), 4535-4539.
103.

Inabe, H.; Arayama, K. JP 2010070618. Apr 2, 2010.

104. Khusnutdinov, R. I.; Shchadneva, N. A.; Khisamova, L. F., Russ. J. Org. Chem.
2015, 51 (11), 1545-1550.
105. Gupta, A. K.; Zhang, X.; Staples, R. J.; Wulff, W. D., Catalysis Science &
Technology 2014, 4 (12), 4406-4415.
106. Kyba, E. P.; Gokel, G. W.; De Jong, F.; Koga, K.; Sousa, L. R.; Siegel, M. G.;
Kaplan, L.; Sogah, G. D. Y.; Cram, D. J., J. Org. Chem. 1977, 42 (26), 4173-4184.
107.

Brands, K. M. J.; Davies, A. J., Chem. Rev. 2006, 106 (7), 2711-2733.

108. Liu, Y.; Tse, Y.-L. S.; Kwong, F. Y.; Yeung, Y.-Y., ACS Catalysis 2017, 7 (7), 44354440.
109. Staniland, S.; Adams, R. W.; McDouall, J. J. W.; Maffucci, I.; Contini, A.; Grainger,
D. M.; Turner, N. J.; Clayden, J., Angew. Chem. Int. Ed. 2016, 55 (36), 10755-10759.
110.

Gustafson, J. L.; Lim, D.; Miller, S. J., Science 2010, 328 (5983), 1251.

111.

Jolliffe, J. D.; Armstrong, R. J.; Smith, M. D., Nature Chemistry 2017, 9, 558.

112. Yu, C.; Huang, H.; Li, X.; Zhang, Y.; Wang, W., J. Am. Chem. Soc. 2016, 138 (22),
6956-6959.
113. Smrcina, M.; Lorenc, M.; Hanus, V.; Sedmera, P.; Kocovsky, P., J. Org. Chem.
1992, 57 (6), 1917-1920.
114. Nakajima, M.; Miyoshi, I.; Kanayama, K.; Hashimoto, S.-i.; Noji, M.; Koga, K., J.
Org. Chem. 1999, 64 (7), 2264-2271.
115.

Collman, J. P.; Zhong, M., Org. Lett. 2000, 2 (9), 1233-1236.

116. Collman, J. P.; Zhong, M.; Zeng, L.; Costanzo, S., J. Org. Chem. 2001, 66 (4),
1528-1531.
117. Onaka, T.; Umemoto, H.; Miki, Y.; Nakamura, A.; Maegawa, T., J. Org. Chem.
2014, 79 (14), 6703-6707.

150

118. LĂłpez-Alberca, M. P.; MancheĂąo, M. J.; FernĂĄndez, I.; GĂłmez-Gallego, M.; Sierra,
M. A., Org. Lett. 2008, 10 (3), 365-368.
119. Su, L.; Dong, J.; Liu, L.; Sun, M.; Qiu, R.; Zhou, Y.; Yin, S.-F., J. Am. Chem. Soc.
2016, 138 (38), 12348-12351.
120. Zhang, G.; Yi, H.; Zhang, G.; Deng, Y.; Bai, R.; Zhang, H.; Miller, J. T.; Kropf, A.
J.; Bunel, E. E.; Lei, A., J. Am. Chem. Soc. 2014, 136 (3), 924-926.
121. Liu, D.; Shan, Z.; Zhou, Y.; Wu, X.; Qin, J., Helv. Chim. Acta 2004, 87 (9), 23102317.
122. Shan, Z.; Zhou, Y.; Liu, D.; Ha, W., Synthesis and Reactivity in Inorganic, MetalOrganic, and Nano-Metal Chemistry 2005, 35 (4), 275-279.
123.

Zhou, Y.; Shan, Z., Tetrahedron 2006, 62 (24), 5692-5696.

124. Stepanenko, V.; Ortiz-Marciales, M.; Correa, W.; De JesĂşs, M.; Espinosa, S.; Ortiz,
L., Tetrahedron: Asymmetry 2006, 17 (1), 112-115.
125.

Krzemiński, M. P.; Ćwiklińska, M., Tetrahedron Lett. 2011, 52 (30), 3919-3921.

126. Stepanenko, V.; de JesĂşs, M.; Garcia, C.; Barnes, C. L.; Ortiz-Marciales, M.,
Tetrahedron Lett. 2012, 53 (8), 910-913.
127. Ćwiklińska, M.; Krzemiński, M. P.; Tafelska-Kaczmarek, A., Tetrahedron:
Asymmetry 2015, 26 (24), 1453-1458.

151

CHAPTER THREE
DEVELOPMENT OF OTHER STRATEGIES FOR THE SYNTHESIS OF
VANOL MONOMER

“VAPOL doesn’t grow on trees.”
– William D. Wulff

3.1 Strategies of 1-naphthol synthesis
1-Naphthols are important building blocks for organic synthesis. There is
nonetheless a need for developing convenient and efficient methodologies for the
synthesis of 1-naphthols especially because they are precursors to the VANOL ligands1.
A variety of methods for 1-naphthol synthesis have been developed. They can be
classified into five categories in terms of their reaction pathways.
The benzannulation reaction of diphenylketene and phenyl acetylene was
reported2 by Smith et al. in 1939 (eq 1, Scheme 3.1). Interestingly, the addition product is
1-naphthol III-3 instead of a 2-naphthol, which would have been the product if the reaction
occurs by a [4+2] cycloadditon. The mechanism was studied and proposed3 by Smith and
Hoehn in 1941. It involves a [2+2] cycloaddition with phenyl acetylene and ketene to form
a cyclobutenone (not shown). The cyclobutenone ruptures readily to give the vinylketene
intermediate III-4 which undergoes a 6 electron electrocyclic ring closure to give
naphthalen-1-one and then, upon tautomerization, generates the 1-naphthol. This
process has been recently modified by Wulff and coworkers and is now one of the most

152

widely used method for the synthesis of VANOL and VAPOL derivatives4-5. Another
important benzannulation reaction involving Fischer carbine complexes was first
discovered6 by DĂśtz in 1975. Recognizing the synthetic potential of the DĂśtz reaction, the
Wulff group started developing and applying this benzannulation reaction in the syntheses
of phenols and quinones7-9. Subsequently, this reaction has become known as Wulff–
DĂśtz reaction. The intermediacy of vinylketene complex III-7 was supported by DFT
studies7. The product 1-napthol III-6 could be oxidatively liberated from the chromium by
exposure its complex to air (eq 2, Scheme 3.1). Danheiser and coworkers reported10 that
the vinylketene could be generated from a Wolff rearrangement by irradiation (or
thermolysis) of diazo ketones such as III-8 (eq 3, Scheme 3.1). Moore and coworkers
synthesized 1-naphthols from the relatively stable substituted cyclobutenone III-1111-12
(eq 4, Scheme 3.1). Upon heating, an electrocyclic ring opening occurred to give a
vinylketene intermediate similar to III-4. Vinylketene III-15 could also be formed by
photoinduced rearrangement of cyclopropane III-1313 (eq 5, Scheme 3.1). Ma and
coworkers reported14 a Michael addition/cyclization cascade of allenoates III-16 with
organo zinc compounds III-17 (eq 5, Scheme 3.1). The mechanism likely involves a
vinylketene intermediate.

153

Scheme 3.1 Benzannulation via a vinylketene intermediate
Smith et al.2 (1939)
OH
O

C

O

rt, 3 days
+

Ph

Ph
III-1

C

(1)
Ph

Ph

III-3 Ph

III-2

III-4 Ph

81%

CO2tBu

Wulff et al.8 (1985)
OH

OMe
Cr(CO)5

O
O

1) THF, 45 ÂşC, 12 h

+
OMe

CO2tBu
III-4

C

OtBu

(2)

2) air

Cr(CO)3
OMe OMe
III-7

OMe OMe
III-6
66%

III-5

Danheiser et al.10(1990)

OH
hν, ClCH2CH2Cl,

O

+
MeO
3 equiv

N2
III-8

(3)

5-8 h
49%

III-9

OMe

III-10

Moore et al.11 (1995)
O

OH
toluene, reflux, 1 h
(4)

O
III-11

III-12
96%

Park et al.13 (2001)

O

OH
O
hν, C6H6

C

O

(5)
80-90%
III-14

III-13

Ar
III-15

Ma et al.14 (2009)
OH
Ph
•

CH3
COOEt

III-16

CH3

xylenes, 140 ÂşC
+

Ph2Zn

0.5 h
56%

3 equiv
III-17

(6)

Ph

III-18

Hauser first described15 the annulation of stabilized phthalide derivative such as
III-19 with Michael acceptor III-20 in 1978 (eq 1, Scheme 3.2). The phenylsulfonyl group

154

functioned as a leaving group to allow aromatization following annulation. The same
annelation strategy was studied and applied in the total synthesis of (–)-Hongconin by
Swenton and coworkers16. A similar reaction using the anion of phthalide III-25 was
developed17 by Mal (eq 3, Scheme 3.2). The proposed mechanism involves Michael
addition, followed by Dieckmann cyclization, then intramolecular nucleophilic attack to
form carbonate and finally fragmentation to give III-27 with loss of CO2 and MeO–. With
the

advance

in

the

transition-metal

catalyzed

coupling

reactions,

cross-

coupling/condensation strategy has been used to make 1-naphthols. Jiang and coworkers
developed18 the synthesis of 1-naphthols containing multifunctional groups catalyzed by
CuCl under mild condition (eq 2, Scheme 3.2). Arylation of methyl 3-(2-bromophenyl)-3oxopropanoate III-22 with a variety of β-keto esters, ketones and nitriles, followed by aldol
condensation provided a desired 1-naphthol such as III-24 with good yield. In 2014, Chen
and coworkers reported an arylation/cyclization cascade of o-iodoacetophenones and
methyl ketones catalyzed by CuI/1,10-phen in the presence of NaOtBu condition (eq 4,
Scheme 3.2). This gave 1-naphthols with aryl or alkyl substituent on the 3-position in good
to excellent yields under mild conditions19. In 2016, Yu, Bao and coworkers
demonstrated20 a similar CuI catalyzed NaOtBu promoted SNAr reactions between two
molecules of o-haloacetophenones (I, Br, Cl) to provide 3-(2-halophenyl)-naphthalen-1ol derivatives in moderate to good yield (22-76%) (not shown).

155

Scheme 3.2 Synthesis of 1-naphthols via addition/condensation cascade
Hauser et al.15 (1978)
SOAr

OH O
LDA, THF

+

O

CO2Et
III-19

III-20

III-21
70%

Jiang, Fu et al.18 (2010)
O

O

O
OCH3 +

OH O

10 mol% CuCl,
2 equiv Cs2CO3,

O

OCH3
CH3

N2, rt, 1 h

OCH3
1.2 equiv
III-23

Br
III-22

(1)

–78 ºC then reflux 2 h

O

(2)

OCH3

III-24

Mal et al.17 (2011)

OH

O

3.2 equiv LHMDS

+
CO2Me
1.2 equiv
III-26

O
III-25

CH3
(3)

–78 ºC to rt, 7 h
III-27
66%

Chen et al.19 (2014)
O

O

10 mol% CuI,
20 mol% 1,10-phen,
6 equiv NaOtBu

OH

+
I
III-28

(4)
3 equiv
III-29

toluene
N2, rt, 4.5 h

Ph
85%
III-30

The higher energy π-system of alkynes have also been employed in the formation
of naphthol rings. The cycloaromatization could be promoted by Lewis and Brønsted
acids or bases. Ciufolini and Weiss described21 the use of camphorsulfonic acid (CSA)
as a trigger for cyclization of ortho-alkynylphenyl-β-ketoesters III-31 to form 2,3disubstituted 1-naphthols in excellent yields (eq 1, Scheme 3.3). Yamamoto and
coworkers reported22 one preliminary example of the benzannulation of silyl enol ether
III-33 promoted by the Lewis acid EtAlCl2 (eq 2, Scheme 3.3). Similar reactions of silyl
enol ethers have been reported using transition metal catalysts such as AgSbF423 and

156

[Rh(CO)2Cl]224. In 1995, Makra and coworkers reported the syntheses of a variety of 3alkyl-1-naphthols by treating the ortho-alkynylalkyl acetophenone substrates such as III35 with potassium bases (e.g. KOtBu, KHMDS or KOH) (eq 3, Scheme 3.3). They
proposed25 a mechanism involving acetylene to allene isomerization, followed by rapid
allenyldiene electrocyclization. A similar strategy has been developed26 for the syntheses
of a series of multi-substituted-1-naphthols.
Scheme 3.3 Acid/base-promoted cycloaromatization
Ciufolini et al.21 (1994)
O
CO2Me

OH O
1.0 equiv CSA,
OMe
CHCl3, reflux

Ph

89%
III-32

III-31
Yamamoto et al.22 (1999)
OTMS
1) 1.2 equiv
EtAlCl2, toluene,

(1)

Ph

OH
(2)

2) H+
40%
III-34

III-33
Makra et al.25 (1995)
O

OH
1.2 equiv KHMDS,
–78 ºC to 80 ºC, 1 h

(3)
92%

III-35

III-36

Another way to make substituted 1-naphthols that has been used frequently is via
Diels Alder reactions of alkynes or benzynes. Charlton and coworkers have utilized27
hydroxyl acetals, such as III-37, as precursors to isobenzofurans III-39 which can react
with acetylenes to make the multi-substituted 1-naphthol III-38 in 80% yield (eq 1,

157

Scheme 3.4). Hoye and coworkers reported28 a DA reaction of the transient benzyne III41 with preformed dienolate anion III-39 to form naphthol III-42 and III-43 as a mixture in
only 25% yield despite considerable attempts at optimization (eq 2, Scheme 3.4). They
had to developed an alternative, multistep synthesis in order to get access to their desired
product III-43. Akai and coworkers utilized29 a 3-TBDMS-substitutedbenzyne, generated
in situ by treatment of III-44 with nBuLi, to react with 2-tbutylfuran III-45 to afford the DA
adduct III-46 with high regioselectivity. The isomerization to 1-naphthol III-47 was
achieved by treatment with pTsOH•H2O in good yield (eq 3, Scheme 3.4).
Scheme 3.4 Synthesis of 1-naphthols via Diels Alder [4+2] cycloaddition
Charlton et al.27 (1996)
O
MeO
O
OH

MeO

OH

MeO

CO2Et

Br

O

(1)

O

III-38 O
80%

III-39 O

OLi
Br

LICA

NEt2

OH

III-39

THF, 0 ÂşC
OMe
III-40

MeO

O

O

Hoye et al.28 (1999)

Br

CO2Et

MeO

AcOH, DCM;
EtO2C
CO2Et
140 ÂşC, 1 h

III-37 O

MeO

Br

OH OMe
(2)

+

25%
OMe
III-41

OMe
Br
III-42
III-43
(ratio was not reported)

Akai et al.29 (2008)
TBDMS

TBDMS
OTf
+

O

O

–78 ºC, 15-30 min

Br
III-44

nBuLi, toluene,

III-45

TBDMS

(3)

THF, rt

III-46
69%

158

OH

pTSOH•H2O

III-47
61%

Scheme 3.5 Synthesis of 1-naphthols via ring expansion
Suzuki et al.30 (2006)

OMe

OMe
OH
Ph

III-48

OMe OH

O

ICl, THF,

I

0 ÂşC to rt

OAc

OAc

Magauer et al.31 (2016)

THF/CH3CN
0 Âş to rt

III-50a, dr 1.6:1

O

OMe

OH

SmI2
(1)
Ph

Me
III-50b OAc

III-49
96%

OH
Me
OMe

Me

sulfolane
190 ÂşC

Cl O
III-51

CO2Me

(2)

Cl
III-52
70%

Ring expansion strategies have not yet been employed extensively in the synthesis
1-naphthols. Suzuki and coworkers reported30 a 4–>5–>6 tandem ring expansion process
to generate 1-naphthol derivatives (eq 1, Scheme 3.5). After the first reaction with ICl, III48 was converted into the iodomethyl indanone III-50a in excellent yield, which will
generate intermediate III-50b upon treatment of SmI2 in one pot. Subsequent Grob
fragmentation of cyclopropanol intermediate III-50b gave III-49 in excellent yield. More
recently, Magauer demonstrated31 a thermally induced electrocyclic ring opening with
simultaneous 1,2-chlroride migration of indanone-cyclopropane III-51, which is readily
available from indanones via oxidation and cyclopropanation (eq 2, Scheme 3.5). The
usefulness of their methodology was demonstrated in the total synthesis of chartarin.
3.2 Syntheses of 3-phenyl-1-naphthol
The original route1 to the VANOL monomer 3-phenyl-1-naphthol III-30 developed
by Wulff and coworkers involved a benzannulation reaction of vinylketene intermediates
generated either from the reaction of alkyne with carbene complex (a, Scheme 3.6) or

159

from

the

reaction

of

alkyne

with

an

aryl

ketene.

The

large-scale

of

cycloaddition/electrocyclization cascade (CAEC) of the latter has also been developed by
the Wulff group4 (b, Scheme 3.6). This route proved to be effective for the syntheses of a
large number of VANOL derivatives5.
Scheme 3.6 Synthesis of VANOL monomer III-30
a)
OMe

Br 1) nBuLi

Cr(CO)5

2) Cr(CO)6
3) MeOTf
III-53

OAc

1) Ph
THF, 45 ÂşC
2) Ac2O, Et3N
THF, 60 ÂşC, 4 h

Cl

1)

O

Ph (1.3 equiv)
(i-PrCO)2O (2 equiv),
190 ÂşC, 48 h

CH2Cl2,
0Âş to rt

OMe
III-55

III-54

b)

Ph

HO

O

C

OH

OH

III-58

Ph
III-30
70%

c)

SO2Cl2

AlCl3

ClCH2CH2Cl
0 to 25 ÂşC, 6 h

benzene
reflux, 1 h

Cl

OH
III-30
62% from III-53

2) KOH, H2O, 100 ÂşC,
overnight

III-56

Ph

Ph AlCl , EtSH,
3

III-59

III-57

OH

OH

Ph

III-30
74% from III-58

Ph
III-60

Several alternative routes were examined32 in an effort to identify a more costefficient process for the VANOL monomer. It was found that the most efficient approach
involves a AlCl3-assisted tautomerization and a 1,2-migration of the phenyl group in 4phenyl-1-naphthol III-60, which is generated in situ from the reaction of 4-chloro-1naphthol III-59 with AlCl3 and benzene (c, Scheme 3.6). However, the substrate scope of
this process is limited. Therefore, the CAEC process is the route of choice when it comes
to the synthesis of VANOL and VAPOL derivatives.
160

Even though the CAEC process has a broad scope in constructing VANOL ligands
with substituents on the 5,5’- and 7,7’- positions with good yields, it suffers from several
drawbacks. First, the process requires heating at a high temperature over a long period
of time (48 h). Second, large amounts of sensitive reagents (acid chloride, SOCl2 or
(COCl)2 and KOH) that need special handling are used in the process. Third, various
substituted phenyl acetylenes are not commercially available or are costly. In an effort to
develop an alternative synthesis of substituted VANOL monomers, the recent method
developed by Chen and coworkers (eq 4, Scheme 3.2) seemed to have practical
potentials. This procedure starts from commercially available o-iodoacetophenones and
methyl ketones, many of which are inexpensive compared with phenylacetylene
derivatives. A large amount of base (6 equiv) was employed but the reaction time is
relatively short at room temperature. Attempts to reproduce their method and to utilize it
in the synthesis of VANOL monomers were undertaken.
Although 2'-iodoacetophenone III-28 is commercially available, the relative high
cost ($95/25 g, combi-blocks) prompted an exploration of alternative synthetic routes from
cheap

aromatic

precursors.

Two

starting

materials

were

identified:

2'-

aminoacetophenone III-62 ($55/100 g, combi-blocks) and 2-iodobenzoic acid III-61
($40/100 g, combi-blocks). The syntheses were planned and carried out as shown in
Scheme 3.7. The optimized synthesis from III-61 involves reduction to (2iodophenyl)methanol by BH3•Me2S, followed by oxidation to aldehydes and then reacting
with methyl Grignard reagent. Finally, oxidation of the secondary alcohol with MnO2
afforded desired III-28. The whole process required only one flash column

161

chromatography and gave 78% overall yield. Shorter routes such as direct reaction33 of
benzoic acid with 3 equiv of MeMgBr or a Weinreb ketone synthesis were attempted but
did not gave clean conversions. The Sandmeyer reaction34 with III-62 as starting material
on the same scale proved to be more effective and provided ketone III-28 in quantitative
yield.
Scheme 3.7 Synthesis of 2'-iodoacetophenone III-28
O

O
OH

I

BH3•Me2S (1.15 equiv)
THF, 0ÂşC to rt, 16 h

III-61
20 mmol
4.96 g
O
CH3
NH2
III-62
20 mmol
2.70 g

MnO2 (7 equiv), MeMgBr (3 equiv), MnO2 (7 equiv),
DCM, rt, 30 h

THF, 0ÂşC to rt,
overnight

NaNO2 (2.0 equiv),
KI (2.5 equiv),
pTsOH•H2O (3.0 equiv),
CH3CN, H2O,
0Âş to rt, 2 h

DCM, reflux,
overnight

CH3
I
III-28
78%, over 4 steps
3.83 g

O
CH3
I
III-28
100%
4.92 g

With the 2'-iodoacetophenone in hand, an attempt was made to repeat the reaction
by Chen et al. (eq 4, Scheme 3.2) under the reported conditions except that the reaction
was carried out in a round bottom flask instead of in a sealed tube (Scheme 3.8). The
yield of desired product III-30 was significantly lower than the 85% yield reported and was
formed along with a 7% yield (NMR analysis) of the major side product III-70b from selfcoupling/cyclization. It should be noted that the CuI catalyst used was not freshly purified
(purified ~ 4 weeks ago), which might be one of the sources of the inconsistency.

162

Scheme 3.8 Copper-catalyzed coupling/cycloaromatization reaction
O

10 mol% CuI
20 mol% 1,10-phen
NaOtBu (6.0 equiv),

O
CH3 +

CH3

I

3.0 equiv
III-29

III-28

toluene, rt, N2
overnight

OH

OH
+
33%
III-30

7%
I
III-30b

Scheme 3.9 Base-promoted arylation of acetophenone III-29 with iodobenzene
O
KOtBu (5.0 equiv)
I
III-61

+

CH3

O

DMF, rt, 48 h

III-29
2.0 equiv

III-62
92%

Nevertheless, it was still deemed worthwhile to develop the reaction into a more
reliable and efficient process that could be applied to the synthesis of VANOL ligands.
Attention was quickly drawn to a transition-metal-free Îą-arylation of enolizable aryl
ketones with aryl iodides using KOtBu in DMF as reported35 by Taillefer et al (Scheme
3.9). The mechanistic studies and DFT calculations suggested a radical process. A
plausible arylation/aldol condensation/rearromatization process was envisioned and
attempted. 2'-iodoacetophenone III-28 was added to a mixture of 2 equiv acetophenone
and KOtBu solution in DMF. Pleasingly, the desired 3-aryl-1-naphthol III-30 was isolated
in 57% yield after stirring for 12 h. The side product III-30b resulted from self-coupling of
III-28 was difficult to isolated from the major product III-30 by column chromatography but
could be observed in the 1H NMR spectrum.
The combined yield of III-30 and III-30b is reported for the initial optimizations
(Table 3.1- Table 3.5) without taking a 1H NMR analysis. This was done because when
the ratio of III-30 and III-30b was large (>10:1), as in the cases of the reactions with

163

KOtBu, they can be partially separated with some efforts by silica gel column
chromatography. However, later findings (Scheme 3. 11, Table 3.5- Table 3.6) indicated
that when the ratio became closer (<5:1), these two compounds were indistinguishable
by flash column chromatography (silica gel) or TLC analysis, which casted a shadow on
the results of the initial optimizations.
Not surprisingly, the aldol condensation product of acetophenone III-63 could be
isolated (5-18%) as a major side product in the reactions (entry 1-3, Table 3.1). For the
development later, it was isolated out and its amount was not determined. Decreasing the
equivalent of acetophenone from 2.0 to 1.5 increase the yield slightly (entry 1 vs 2, Table
3.1). Further decrease to 1.2 equiv did not show a positive effect (entry 7, Table 3.1). The
temperature effect was studied (entry 3 and 4, Table 3.1). Significant increase of side
reaction (18% III-63) was observed from the reaction at 60 ÂşC, and yield of 1-naphthol
dropped to 33%. Higher temperature did not increase the yield for the reaction. Amount
of the base was also screened. Both the reaction with higher or lower equiv of KOtBu
afford the desired 1-naphthol in lower yield (entry 5 and 6, Table 3.1). In agreement of the
original report35, the reaction proved to be sensitive to the effect of solvent: yield of product
dropped to 26% in DMSO and only trace amount of 1-naphthol is produced in toluene
(entry 8 and 9, Table 3.1). Elongation of the reaction time decreased the yield, presumably
due to the decomposition of the product (entry 10, Table 3.1). And lastly, the concentration
effect was not significant (entry 11 and 12, Table 3.1). Therefore, it was decided to quench
the reaction early to avoid decomposition. The reaction with 1.1 equiv III-29 in a more
concentrated (0.67 M) DMF solution was quenched after 3 h and afford the 1-naphthol in

164

57% yield (entry 13, Table 3.1). Sticking with 1.1 equiv of acetophenone, more solvent
and less reaction time gave only 30% yield, expectedly (entry 14, Table 3.1). The yield
can be improved by increasing the reaction time (entry 15 vs 14, Table 3.1), increasing
the amount of base (entry 16, Table 3.1) or increasing the reaction temperature (entry 17,
Table 3.1). The sodium base NaOtBu gave poor conversion, which is also consistent with
the original report35.
Table 3.1 Initial optimization of the arylation/cycloaromatization reaction
O

KOtBu (5.0 equiv)
CH3 +

I
1 mmol
III-28

OH

O

O

CH3
1.5 equiv
III-29

entry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18

R

DMF, 80 ÂşC,
12 h, N2

+

III-30, R = H
III-30b, R = I

variation from “standard conditionsa” %yieldb (III-30+III-30b)
none
2.0 equiv III-29
2.0 equiv III-29, 60 ÂşC
2.0 equiv III-29, 100 ÂşC
4.0 equiv KOtBu, 15 h
8.0 equiv KOtBu
1.2 equiv III-29
toluene instead of DMF
DMSO instead of DMF
24 h
1.5 mL DMF
6.0 mL DMF
1.5 mL DMF, 1.1 equiv III-29, 3 h
1.1 equiv III-29, 1 h
1.1 equiv III-29, 3 h
1.1 equiv III-29, 7.0 equiv KOtBu, 1 h
1.1 equiv III-29, 100 ÂşC, 1 h
entry 15, NaOtBu instead of KOtBu

aReaction

61c
57d
33e
59
39
44
59
trace
26
55
60
56
57
30
53
48
52
14

was carried out in Schlenk Flask. bIsolated yield of mixuture of III30/III-30b after chromatography on silica gel. c6% of III-63 was isolated.
d5%

of III-63 was isolated. e18% of III-63 was isolated.

165

III-63

In order to increase the yield of the desired 1-naphthol product, the effects of
additives were extensively studied. The conditions in entry 13 Table 3.1 was selected as
optimal condition for the additive study (Table 3.2). Inorganic potassium salts did not have
a positive effect on the yield (entry 2-4 vs 1, Table 3.2). Amine bases, such as Et3N and
iPr2NEt, showed slightly positive to no effect on the yield (entry 5-6 vs 1, Table 3.2).
Coordinating N-containing heteroaromatics as well as PPh3 decreased the yield slightly
(entry 7-11 vs 1, Table 3.2). Surprisingly, the yield decreased significantly with 5 mol%
Pd(OAc)2 (entry 12 vs 1, Table 3.2). Common Lewis acids, such as AlCl3, ZnCl2 and
B(OPh)3, as well as nickel complexes and silver nitrate decreased the yield considerably
(entry 16-21 vs 1, Table 3.2). It was delightful to observed that almost all of the copper
salts tested (except Cu-TMEDA) showed positive effects on the yield of the 1-naphthol
(III-30 and III-30b) (entry 13-15, 22-28 vs 1, Table 3.2). The reaction with Cu(II) additive
gave slightly higher yield than Cu(I) salt (entry 24-28 vs 13-15 & 22, Table 3.2). In the
presence of TEMPO additive, the reaction did not shut down but became less effective
(entry 29, Table 3.2)., which suggested that a closed-shell mechanism might be operative
alongside the radical pathway. CuCl2 was identified as the optimal additive and the
reaction with 20 mol% CuCl2 was subjected to further optimizations.

166

Table 3.2 Additive effect study of the arylation/cycloaromatization reactiona
OH

O

O

O

KOtBu (5.0 equiv)
CH3

+

I
1 mmol
III-28

CH3
1.5 equiv
III-29

R
+

20 mol% additive
1.5 mL DMF, 80 ÂşC,
3 h, N2
III-30, R = H
III-30b, R = I

III-63
yield ND

entry

additive

%yieldb (III-30+III-30b)

entry

additive

%yieldb (III-30+III-30b)

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15

none
KI
KOAc
K3PO4
Et3N
DIPEA
PPh3
imidazole
pyridine
pyrrolidine
phenanthroline
5 mol% Pd(OAc)2
CuI
CuBr
CuCl

57
50
56
52
59
57
53
53
54
55
38
29
61
58
59

16
17
18
19
20
21
22
23
24
25
26
27
28
29

AlCl3
ZnCl2
B(OPh)3
AgNO3
Ni(acac)2
dppeNiCl2
CuCN
Cu-TMEDA
Cu(acac)2
CuBr2
CuCl2
CuSO4
Cu(OTf)2
TEMPO

42
48
34
25
31
26
65
53
64
66
71
67
68
21

aReaction

were carried out in a Schlenk Flask. bIsolated yield of mixuture of III-30/III-30b after chromatography on silica gel.

The additive and solvent screening for CuCl2-catalyzed reaction was carried out
(Table 3.3). It was indicated that the reaction was not relatively sensitive to the water
residue in the acetophenone and solvent (entry 2 vs 1, Table 3.3). Addition of common
ligand for coppers such as 1,10-phenanthroline, BINAP and DMEDA did not increase the
yield of the 1-naphthol product (entry 3-6 vs 1, Table 3.3). Interestingly, the CuCl2
catalyzed reaction still gave 59% of 1-naphthol (III-30 and III-30b) in the presence of 20
mol% TEMPO, indicating the major pathway should be a two-electron process (entry 7,
Table 3.3). Reactions in other common solvents did not gave better results, and no III-30
was isolated from the reactions in Et3N or hexanes, probably due to the unfavorable
coordination and solubility, respectively (entry 8-15 vs 1, Table 3.3). In contrast to the
167

reaction without CuCl2 (entry 18 vs 1, Table 3.1), other strong sodium base such as
NaOtBu or NaH gave comparable results under the CuCl2-catalyzed conditions (entry 1617 vs 1, Table 3.3). Finally, the catalyst loading study showed that 10 mol% catalyst was
sufficient to provide III-30 in 72% yield (entry 18-20 vs 1, Table 3.3).
Table 3.3 Optimization of CuCl2-catalyzed arylation/cycloaromatization reaction
OH

O

O

KOtBu (5.0 equiv)

CH3 +

CH3

I
1 mmol
III-28

1.1 equiv
III-29

O
R

20 mol% CuCl2
1.5 mL DMF, 80 ÂşC,
3 h, N2

+

III-63
yield ND

III-30, R = H
III-30b, R = I

entry

variation from “standard conditionsa”

%yieldb (III-30+III-30b)

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20

none
III-29 and DMF used without distillation
with 20 mol% Phen
with 20 mol% BINAP
with 20 mol% Et3N
with 20 mol% DMEDA
with 20 mol% TEMPO
DMA instead of DMF
Et3N instead of DMF
tBuOH instead of DMF
THF instead of DMF
dioxane instead of DMF
HMPA instead of DMF
DMSO instead of DMF
hexanes instead of DMF
NaOtBu instead of KOtBu
NaH instead of KOtBu
100 mol% CuCl2
5 mol% CuCl2
10 mol% CuCl2

73
71
67
69
72
70
59
59
0
49
32
55
15
14
0
73
74
53
62
72

aReaction

was carried out in Schlenk Flask. bIsolated yield of mixuture of III-30/III-30b
after chromatography on silica gel.

The conditions with 10 mol% CuCl2 were further optimized (Table 3.4). It was found
that the yield of (III-30 and III-30b) increased when 1.5 equiv acetophenone was
employed (entry 2 vs 1, Table 3.4). However, a further increase in the amount of

168

acetophenone to 2.0 equiv led to a decreased yield, presumably due to the side aldol
reaction (yield not determined) that consumed the KOtBu (entry 3 vs 2, Table 3.4).
Modifications to the temperature, concentration, catalyst loading and reaction time did not
give higher yield (entry 4-7 vs 2, Table 3.4). The reaction with 50 mg 3 Å MS gave the
same result, whereas the 4 Å and 5 Å MS gave lower yield (entry 8-10 vs 2, Table 3.4).
Expectedly, using NaH and NaOtBu instead of KOtBu gave comparable results (entry 1112 vs 2, Table 3.4). In contrast to the experiment with 20 mol% CuCl2 (entry 18 vs 1, Table
3.3). the reaction in dimethylacetamide (DMA) provide the 1-naphthol in slightly higher
yield (entry 13 vs 2, Table 3.4). It was found that the reaction with 5 mol% loading of
CuCl2 in 3 mL DMF provided the highest yield with either KOtBu or NaH (entry 14 & 17
vs 2, Table 3.4). Under these new conditions, using DMA as solvent instead of DMF with
NaOtBu as base were found to be less effective (entry 15 & 16 vs 14, Table 3.4). The
reaction with 5 equiv NaH and 2 mol% CuCl2 at rt afforded the 3-aryl-1-naphthol in 92%
yield but a longer reaction time was needed (entry 19, Table 3.4). The reactions using
NaH as base can be reproduced in a round bottom flask and can be scaled up to 5 mmol
with comparable yield.

169

Table 3.4 Further optimization of CuCl2-catalyzed arylation/cycloaromatization reaction
OH

O

O

KOtBu (5.0 equiv)
CH3 +

CH3

I
1 mmol
III-28

1.5 equiv
III-29

entry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21

O
R +

10 mol% CuCl2
1.5 mL DMF, 80 ÂşC,
3 h, N2
III-30, R = H
III-30b, R = I

III-63
yield ND

variation from “standard conditionsa” %yieldb (III-30+III-30b)
1.1 equiv III-29
none
2.0 equiv III-29
100 ÂşC
3 mL DMF, 5 h
5 mol% CuCl2, 5 h
12 h
with 50 mg 3 A MS
with 50 mg 4 A MS
with 50 mg 5 A MS
NaH instead of KOtBu
NaOtBu instead of KOtBu
DMA instead of DMF
5 mol% CuCl2, 3 mL DMF
entry 14, NaOtBu instead of KOtBu
entry 14, DMA instead of DMF, 1.5 h
entry 14, NaH instead of KOtBu
entry 17, 1 h
entry 17, 2 mol% CuCl2, 15 h, rt
entry 17, in RBF
entry 17, 5 mmol scale

72
85
64
81
71
81
79
85
71
48
78
80
87
88
68
65
91
84
92
87
88

aReactions

were carried out in a Schlenk Flask. bIsolated yield of mixuture of
III-30/III-30b after chromatography on silica gel.

The reactions with other ortho-haloacetophenones were explored (Scheme 3.10).
For the ortho-bromoacetophenone III-64 and ortho-chloroacetophenone III-65, the
reactions with KOtBu at 80 ÂşC only provide the 3-aryl-1-naphthol in low yields. The
reactions were less effective with NaH at 80 ÂşC and only a trace amount of 3-aryl-1naphthol was observed at rt. Interestingly, migration of sulfur group to the methyl occurred
to give the sulfone III-67 when 2’-OTf acetophenone III-66 was subjected to the conditions
with NaH.
170

Scheme 3.10 CuCl2-catalyzed arylation/cycloaromatization reaction with other ohaloacetophenone substrates
OH

O

O

KOtBu (5.0 equiv)

CH3 +
Br
1 mmol
III-64

CH3
1.5 equiv
III-29

R

5 mol% CuCl2
3.0 mL DMF, 80 ÂşC,
3 h, N2

28%
III-30, R = H
III-30c, R = Br
trace with 5.0 equiv NaH, rt
OH

O

O
CH3 +
Cl
1 mmol
III-65

KOtBu (5.0 equiv)
CH3
1.5 equiv
III-29

5 mol% CuCl2
3.0 mL DMF, 80 ÂşC,
3 h, N2

R

32%
III-30, R = H
III-30d, R = Cl
trace with 5.0 equiv NaH, rt
22% with 5.0 equiv NaH, 80 ÂşC

O

O
CH3 +

NaH (5.0 equiv)
CH3

OTf
1 mmol
III-66

1.5 equiv
III-29

5 mol% CuCl2
3.0 mL DMF, 80 ÂşC,
3 h, N2

O O
CF3
S
O
OH
89%
III-67

It was a disappointment to find out from the 1H NMR spectrum that the isolated
product obtained consist of a 3.6 : 1 ratio of desired product III-30 and III-30b under the
optimal conditions with NaH, together with a small amount of unreacted III-29 and mineral
oil (from NaH). To confirm the structure of III-30b, arylation/cycloaromatization was
carried out without acetophenone. The 3-(2-iodophenyl)-1-naphthol III-30b was obtained
in 85% isolated yield.

171

Scheme 3.11 1H NMR analysis of the mixtures of 3-aryl-1-naphthols
entry 19 in Table 3.4
OH

OH
+

O

O

NaH (5.0 equiv)
CH3

I
1 mmol
III-28

+

CH3
1.5 equiv
III-29

2 mol% CuCl2
3 mL DMF, rt,
3 h, N2

III-30

“92%”

+

3.6

III-30b I
1

O
CH3

+

mineral oil

OH
O

NaH (5.0 equiv)
CH3

I
1 mmol
III-28

5 mol% CuCl2
3 mL DMF, rt,
3 h, N2

I
85% isolated yield
III-30b

In order to reduce the amount of III-30b, further optimization was performed where
the yield and ratio of III-30/III-30b was monitored by 1H NMR analysis (Table 3.5). It was
found that KOtBu is the best base in terms of yield and selectivity of the reaction (entry 1
vs 2 & 4, Table 3.5). The effectiveness of NaH in the synthesis of III-30 judged by the
previous optimization was not very accurate because of the larger weight of the III-30b in
the inseparable mixture. The reaction in DMA gave III-30 in lower yield and selectivity
than that in DMF (entry 3 vs 1, Table 3.5). The yield and selectivity went down when the
CuCl2 loading was reduced to 5 mol% (entry 5 vs 4, Table 3.5). Portionwise addition of
the base only provide negligible improvement (entry 6 vs 5, Table 3.5). For the reactions
with KOtBu as base, increasing the equivalents of III-29 did not increase the selectivity in
spite of the minimal increase in yield (entry 8 vs 7, Table 3.5). Addition of KOtBu at 0 ÂşC
did not have a positive effect on the result of the reaction (entry 9 vs 10, Table 3.5).

172

Table 3.5 Optimization of conditions for CuCl2-catalyzed arylation/cycloaromatization
reactiona
OH

OH

O

O
CH3

+

base (5.0 equiv)
CH3

I
1 mmol
III-28

+

CuCl2
solvent, temp,
3 h, N2

III-29

I

III-30

entry

equiv
(III-29)

base

mol%
(CuCl2)

solvent

temp
(ÂşC)

1
2
3
4
5
6c
7
8
9
10

1.5
1.5
1.5
1.5
1.5
1.5
2.0
2.5
1.5
1.5

KOtBu
NaOtBu
KOtBu
NaH
NaH
NaH
KOtBu
KOtBu
KOtBu
KOtBu

10
10
10
10
5
5
5
5
5
5

1.5 mL DMF
1.5 mL DMF
1.5 mL DMA
1.5 mL DMF
1.5 mL DMF
1.5 mL DMF
3.0 mL DMF
3.0 mL DMF
3.0 mL DMF
3.0 mL DMF

80
80
80
rt
rt
rt
rt
rt
0 to 40
rt to 40

III-30b
%yieldb
ratiob
(III-30) (III-30/III-30b)
62
51
56
42
30
32
61
63
53
54

12.6
11.9
6.9
3.0
1.7
1.9
7.5
7.6
7.1
8.4

aReactions

were carried out in a round bottom flask. Yield of aldol adduct was not determined.
by NMR analysis of the mixture of III-30 and III-30b after chromatography on silica
gel with Ph3CH added as standard. cIII-29 was added in 3 portions within 1.5 h.
bDetermined

More procedural optimization was performed with 5 equiv KOtBu in DMF (Table
3.6). The yield and ratio of III-30/III-30b increased when the volume of DMF increased
from 1.5 mL to 5 mL (entry 1-3, Table 3.6). However, increasing the CuCl2 loading
decreased the yield and selectivity (entry 4-5 vs 1, Table 3.6). On the other hand, both
the yield and selectivity for III-30 increased as the reaction temperature increased (entry
6-7 vs 1, Table 3.6). The effect of method for the addition of III-28 was studied. It was
found that a longer waiting time after the addition of III-29 led to lower selectivities (entry
8-9 vs 6, Table 3.6). Not surprisingly, slower addition was found to increase the selectivity
(entry 10 vs 11, Table 3.6). Further reducing the loading of CuCl2 did not increase the

173

ratio of III-30/III-30b and it was found that the reaction time could be reduced to 30 min
(entry 12 & 13, Table 3.6). And finally, it was found that under the optimal conditions, the
CuCl2-catalyzed arylation/cycloaromatization reaction was complete after 30 min to give
the desire product III-30 in 63% yield with 3% yield of the side product III-30b (entry 14,
Table 3.6, Scheme 3.12). Additionally, when 10 mol% 1,10-phen19 was added, the
reaction was less effective (entry 15 vs 14, Table 3.6).
Table 3.6 Further optimazation of conditions for CuCl2-catalyzed
arylation/cycloaromatization reactiona
OH

OH

O

O
CH3

+

I
1 mmol
III-28

KOtBu (5.0 equiv)
CH3

1.5 equiv
III-29

entry

addition sequence
(III-28)

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15c

after 1 min, within 1 min
after 1 min, within 1 min
after 1 min, within 1 min
after 1 min, within 1 min
after 1 min, within 1 min
after 1 min, within 1 min
after 1 min, within 1 min
after 10 min, within 1 min
after 20 min, within 1 min
after 5 min, within 5 min
after 5 min, within 2.5 min
after 5 min, within 5 min
after 5 min, within 5 min
after 1 min, within 5 min
after 1 min, within 5 min

+

CuCl2
DMF, temp,
time, N2

I

III-30
mol% DMF time
(CuCl2) (mL) (h)
5
5
5
10
20
5
5
5
5
5
5
2.5
2.5
5
5

3.0
1.5
5.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0

aReactions

3
3
3
3
3
3
3
3
3
2
0.5
1
0.5
0.5
0.5

temp
(ÂşC)
40
40
40
40
40
60
80
60
60
80
80
80
80
80
80

III-30b
ratiob
%yieldb
(III-30) (III-30/III-30b)
53
32
55
50
45
55
63
56
60
58
55
60
60
63
52

4.9
1.4
5.2
4.3
3.7
10.6
37.3
8.4
7.7
10.6
6.9
9.4
8.5
22.6
13.2

were carried out in a round bottom flask. o-Iodocetophenone III-28 was added to the
mixure of KOtBu, acetophenone III-29 and CuCl2 in DMF under the indicated temperature.
Yield of aldol adduct was not determined. bDetermined by NMR analysis of the mixture of III-30
and III-30b after chromatography on silica gel with Ph3CH added as standard.
c10 mol% 1,10-phen was added.

174

The mechanism of the CuCl2-catalyzed arylation/cycloaromatization reaction is
proposed (Scheme 3.12) base on literature reports. Two catalytic cycles are thought to
be operational: A SRN1 and B SNAr. In catalytic cycle B, in the absence of CuCl2 the
radical III-28c can be formed35 with DMF and KOtBu. Nucleophilic attack by enolate III29b generated from acetophenone III-29 and KOtBu affords radical anion III-72b. A final
SET from III-72b to another molecule of III-28 releases the diketone III-72. In the presence
of CuCl2, copper enolate III-29c can be generated by transmetallation. Copper enolate
III-29c can undergo addition-elimination with III-28 to generate diketone III-72. A
crossover pathway might occur: the radical III-28c react with copper enolate III-29c to
generate a copper (III) species. Reductive elimination give rise to diketone III-72. The
Cu(II) could be regenerate by SET process with III-28. Diketone III-72 subsequently
undergo aldol condensation to form the potassium base of the desire product III-30’. The
side product III-30b’ came from a similar process of the enolate III-28b. The higher ratio
of III-30/III-30b for the reaction with the bulky KOtBu than NaH is thought to due to the
higher selectivity in generating III-29b vs the more hindered III-28b.

175

Scheme 3.12 Proposed mechanism for CuCl2-catalyzed arylation/cycloaromatization
reaction
OK

OK

KOtBu
O
III-30’

CH3
OK

aldol
KOtBu
condensation
O

III-29
A
O

O

III-29b

I

III-72

CuCl2

O

O

–I

I
III-30b’

OK
CH3

III-70

I
III-28
III-28b

CuCl

I

O
O

SET

CuCl
KOtBu
III-29c

Cu Cl

Cu(II)

O

O

O

III-71
CH3

OK

III-28c
B

III-29b

KOtBu

CH3

DMF

I
III-28

Propagation
O

OK

O
O
III-70

III-72b

Based on this proposed mechanism, it was reasoned that if the acetophenone
forms an enolate more thermodynamically favorable than III-28b, the side product
formation

would

be

slowed

down.

Therefore,

electron

deficient

4’-

(trifluoromethyl)acetophenone III-68 was subjected to the reaction conditions, the desired
product III-69 could be isolated in excellent yield, no self-coupling side-product was
observed.

176

Scheme 3.13 Synthesis of 3-(4-(trifluoromethyl)phenyl)-1-naphthol

CH3 +
I
1 mmol
III-28

F3C

OH

5 mol% CuCl2
KOtBu (5.0 equiv)

O

O

CH3
1.5 equiv
III-68

3.0 mL DMF, 80 ÂşC,
0.5 h, N2
CF3
III-69, 98% isolated yield

In summary, the CuCl2-catalyzed arylation/cycloaromatization reaction of orthoiodoacetophenone III-28 with acetophenone has been developed. Under the optimal
conditions, the VANOL monomer can be afforded in good yield within 0.5 h. Compared
with the methodology developed by Chen, the conditions are more tolerant with catalyst
purity and reaction vessel (entry 14, table 3.3 vs Scheme 3.8). Even though the scope of
this methodology was not explored, it was thought be preferable for the synthesis of
VANOL monomers with an electron-poor aryl ring at 3-positions.
3.3 Syntheses of 3,3’-dialkyl-VANOL
A variety VANOL derivatives have been prepared5, 36 in the Wullf Group with alkyl
or aryl substituents at 4,4’-, 5,5’-, 6,6’-, 7,7’- and 8,8’-postitions either by oxidative
coupling of monomers or derivatization by coupling reactions. However, the synthesis of
VANOL derivatives with alkyl groups at the 3,3’-position has not been established. The
synthesis of 3,3’-didecylVANOL was reported37 using the CAEC process by Schuster and
Redic. Attempt to synthesize 3,3’-Bu2VANOL by Raney-Ni reduction of 3,3’-dithiophen-2yl-VANOL was made38 by Guan. However, no yield was reported. In order to investigate
the substituent effect of alkyl groups on the 3,3’-positions of VANOL, an effort was made
to synthesize 3,3’-dialkyl VANOLs by employing the base-promoted cycloaromatization
reported by Makra (eq 3, Scheme 3.3)25.

177

The

substrates

o-alkynylacetophenone

III-74a-f

were

prepared

by

the

Sonogashira coupling reaction of o-iodoacetophenone III-28 with the terminal alkynes III73a-f. After a brief optimization of reaction temperature, equivalence of Et3N and catalyst
loading, the optimal conditions with 1mol% PdCl2(PPh3)2 and 1 mol% CuI (purified)
delivered the desired coupling products III-74a-f in excellent yield (67%-100%) on 20
mmol scale (Scheme 3.14). The diminished yield of the coupling product from the
benzylacetylene was thought to be caused by allene formation by prototropic
rearrangement39.
Scheme 3.14 Syntheses of o-alkynylacetophenones III-74 via the Sonogashira
Coupling
O
CH3

+
R

I

1.1 equiv
III-73
O

1 mol% PdCl2(PPh3)2
1 mol% CuI

III-74a
100%
O

CH3

Et3N (7.2 equiv),
60 ºC, 5–12 h

20 mmol
III-28

R
III-74

O
CH3

O

O
CH3

CH3

III-74b
97%

III-74c
67%

O

O

CH3

CH3

CH3
TMS

III-74d
92%

III-74e
97%

178

III-74f
100%

o-Alkynylacetophenone III-74a was chosen as the model substrate for the
optimization of the cycloaromatization reaction (Table 3.7). It was found that the 3cyclohexyl-1-naphthol was obtained in 60% yield under the reported procedure25 (entry
1, Table 3.7). It was worth noting that the yield is affected by the quality of the KHMDS
solution that was purchased and directly used from bottle. It was delightful to find that the
reaction provided III-75a in a higher yield with KOtBu in THF (entry 2, Table 3.7). The
solid base KOtBu was easier to handle and the addition at low temperature (–78 ºC) was
not necessary. The weaker base KOH and sodium base NaOtBu did not promote the
cycloaromatization, in support of the original finding by Makra and coworkers25(entry 3 &
4, Table 3.7). An unexpected solvent evaporation caused the reduced yield of the product
(entry 5 vs 2, Table 3.7)., which led us to investigate the concentration effect. Gratifyingly,
the reaction performed at a lower concentration gave III-75a in higher yield (entry 6 vs 2,
Table 3.7). The yield increased when the reaction was run for 2 h (entry 7 vs 6, Table
3.7). The reaction at 70 ÂşC only gave 1-naphthol in 53% yield after 4.5 h (entry 8, Table
3.7). However, the yield could not be increased by running at a higher temperature (entry
9 vs 7, Table 3.7). Finally, the reaction could be carried out on a 10 mmol scale under the
optimal conditions to afford the desired product III-75a in excellent yield (entry 10, Table
3.7).

179

Table 3.7 Optimization of base-promoted cycloaromatization
O

OH

base (1.2 equiv), solvent,
concentration

CH3

temperature, time
2 mmol
III-74a

III-75a

entry

base

solvent

conc. (M)

time (h)

temp (ÂşC)

%yielda (III-75a)

1
2
3
4
5
6
7
8
9
10b

KHMDS
KOtBu
KOH
NaOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu

toluene
THF
THF
THF
THF
THF
THF
THF
THF
THF

1.0
1.0
1.0
1.0
>1.0
0.5
0.5
0.5
0.5
0.5

1
1
1
1
1
1
2
4.5
2
2

–78 to 75
80
80
80
80
80
80
70
90
80

60 (92)
76
trace
trace
65
85
94
53
94
96c

aIsolated
b10

yield after column chromatography. Yield in parenthesis was reported in the literature.
mmol scale. cAverage of 3 trials

Other

acetophenone

substrates

III-74b-f

were

next

examined.

The

cycloaromatization reaction only works for o-alkynylacetophenones III-74 with R is an
aliphatic group. The reaction delivered the 1-naphthol with 1Âş (III-75b), 2Âş (III-75a), 3Âş (III75e), or a benzyl group (III-75c), at the 3-position in moderate to excellent yield (51-96%).
Substrate III-75d (R = phenyl) did not cyclized under the same conditions while the III-75f
gave complex mixtures. The subsequent oxidative coupling reactions for III-75a-c and III75e were carried out under the general procedure. It was a delight to find that 3,3’Cy2VANOL and 3,3’-nBu2VANOL were obtained in moderate yield. The reaction with III75c gave multiple products (isolation was not attempted). Interestingly the oxidation
coupling of III-75e gave 2,4 coupling product as the major product, no 3,3’-tBu2VANOL
was obtained probably due to the steric hindrance of the t-butyl group.
180

Scheme 3.15 Syntheses of 3,3’-dialkylVANOL

O

OH
CH3

KOtBu (1.2 equiv), 80 ÂşC

air, mineral oil

THF, 0.5 M, 2 h

R

R
10 mmol
III-74

165 ÂşC, 24-36 h

R
R

HO
HO

III-75
III-76
OH
OH

III-75a
96%

OH

III-75b
94%

III-75c
59% (93%)b

OH

OH

OH

TMS

Ph
III-75d
0%

III-75e
65%a

III-75f
0%
OH

HO
HO

Cy
Cy

III-76a
51%
aKHMDS

Bu
Bu

HO
HO

Bn
Bn

HO
HO

III-76b
44%

III-76c
mixture

HO

III-76e
35%

instead of KOtBu, reflux in toluene for 110 ÂşC, 20 mmol scale. bAddition of KOtBu at 0 ÂşC.

With 3,3’-Cy2VANOL and 3,3’-nBu2VANOL in hand, efforts to obtain optically pure
ligand turned to resolution with quinine borate and deracemization. Resolution by making
borate with quinine or quinidine did not form precipitates from THF and hexanes (Table
2.4). Nevertheless, the deracemization with Cu(II)-sparteine did provided optically pure
III-76a and 95% ee III-76b in 70% and 19% yield, respectively (Scheme 3.16).

181

Scheme 3.16 Deracemization of 3,3’-dialkylVANOL

Cy
Cy

OH
OH

air, 1.7 equiv CuCl,
3.2 equiv (+)-sparteine,
MeOH/CH2Cl2 2:1,
rt, 24 h

OH
OH

OH
OH

(R)-3,3’-Cy2VANOL
(R)-III-76a
70%, >99% ee

III-76a

Bu
Bu

Cy
Cy

air, 1.7 equiv CuCl,
3.2 equiv (+)-sparteine,
MeOH/CH2Cl2 2:1,
rt, 24 h

Bu
Bu

OH
OH

(R)-3,3’-Bu2VANOL
(R)-III-76b
19%, 95% ee

III-76b

182

Scheme 3.17 Aziridination catalyzed by boroxinate of 3,3’-dialkylVANOL

5 mol%
(R)-ligand

base-H

20 mol% B(OPh)3
5 mol% H2O

100 mol% I-77

toluene, 80 ÂşC, 1 h,
then 0.5 mm Hg, 80 ÂşC, 0.5 h

rt

OPh
O B
O
O
* O B
O B
OPh
boroxinate catalyst
Ph

+

N
Iii-77
0.5 mmol

O

OEt

5 mol% boroxinate

Ph
N

toluene, 0.5 M, rt, 24 h

N2

COOEt

Iii-78
1.2 equiv

Iii-79

Ligand

(R)-3,3’-Cy2VANOL
(R)-3,3’-Bu2VANOLd
(S)-VANOL (10%)e

cis:transa %yieldb %eec
(Iii-79) (Iii-79)
(Iii-79)
28:1
32:1
>50:1

72
74
84

11
–7
93

aAs

judged by 1H NMR of crude product. bIsolated yield after
chromatography on silica gel. cAs judged by chiral HPLC. d95 %
ee. ePrepared by VANOL, BH3•Me2S, PhOH and H2O (see
Table 1.22 method D for details)

The boroxinate-catalyzed aziridination reactions of imine III-77 and EDA III-78 was
examined with the 3,3’-dialkylVANOL (Scheme 3.17). It was disappointing to find that the
reaction with boroxinate prepared from 3,3’-Cy2VANOL (>99% ee) and 3,3’-nBu2VANOL
(95% ee) gave rise to the cis-aziridine III-79 in good yields but with poor
enantioselectivities. These results suggest that the phenyl group, with the ability to form
a π-π interaction outside of the catalytic pocket, might play an important role leading an
asymmetric induction in the aziridination reactions.

183

REFERENCES

184

REFERENCES

1.
Bao, J.; Wulff, W. D.; Rheingold, A. L., J. Am. Chem. Soc. 1993, 115 (9), 38143815.
2.

Smith, L. I.; Hoehn, H. H., J. Am. Chem. Soc. 1939, 61 (10), 2619-2624.

3.

Smith, L. I.; Hoehn, H. H., J. Am. Chem. Soc. 1941, 63 (5), 1178-1179.

4.
Ding, Z.; Osminski, W. E. G.; Ren, H.; Wulff, W. D., Organic Process Research &
Development 2011, 15 (5), 1089-1107.
5.
Guan, Y.; Ding, Z.; Wulff, W. D., Chemistry – A European Journal 2013, 19 (46),
15565-15571.
6.
645.

DĂśtz, K. H., Angewandte Chemie International Edition in English 1975, 14 (9), 644-

7.
Waters, M. L.; Wulff, W. D., The Synthesis of Phenols and Quinones via Fischer
Carbene Complexes. In Organic Reactions, John Wiley & Sons, Inc.: 2004.
8.
Wulff, W. D.; Tang, P.-C.; Chan, K.-S.; McCallum, J. S.; Yang, D. C.; Gilbertson,
S. R., Tetrahedron 1985, 41 (24), 5813-5832.
9.
Wulff, W. D.; Tang, P. C.; McCallum, J. S., J. Am. Chem. Soc. 1981, 103 (25),
7677-7678.
10.
Danheiser, R. L.; Brisbois, R. G.; Kowalczyk, J. J.; Miller, R. F., J. Am. Chem. Soc.
1990, 112 (8), 3093-3100.
11.

Turnbull, P.; Moore, H. W., J. Org. Chem. 1995, 60 (3), 644-649.

12.
Tiedemann, R.; Turnbull, P.; Moore, H. W., J. Org. Chem. 1999, 64 (11), 40304041.
13.

Jo Chang, D.; Ser Park, B., Tetrahedron Lett. 2001, 42 (4), 711-713.

14.
Chai, G.; Lu, Z.; Fu, C.; Ma, S., Chemistry – A European Journal 2009, 15 (42),
11083-11086.
15.

Hauser, F. M.; Rhee, R. P., J. Org. Chem. 1978, 43 (1), 178-180.

16.
Swenton, J. S.; Freskos, J. N.; Dalidowicz, P.; Kerns, M. L., J. Org. Chem. 1996,
61 (2), 459-464.

185

17.

Mal, D.; Jana, A. K.; Mitra, P.; Ghosh, K., J. Org. Chem. 2011, 76 (9), 3392-3398.

18.

Xu, H.; Li, S.; Liu, H.; Fu, H.; Jiang, Y., Chem. Commun. 2010, 46 (40), 7617-7619.

19.
Lou, Z.; Zhang, S.; Chen, C.; Pang, X.; Li, M.; Wen, L., Adv. Synth. Catal. 2014,
356 (1), 153-159.
20.
Yu, X.; Zhu, P.; Bao, M.; Yamamoto, Y.; Almansour, A. I.; Arumugam, N.; Kumar,
R. S., Asian Journal of Organic Chemistry 2016, 5 (5), 699-704.
21.

Ciufolini, M. A.; Weiss, T. J., Tetrahedron Lett. 1994, 35 (8), 1127-1130.

22.
Imamura, K.-i.; Yoshikawa, E.; Gevorgyan, V.; Yamamoto, Y., Tetrahedron Lett.
1999, 40 (21), 4081-4084.
23.

Godet, T.; Belmont, P., Synlett 2008, 2008 (16), 2513-2517.

24.

Dankwardt, J. W., Tetrahedron Lett. 2001, 42 (34), 5809-5812.

25.
Makra, F.; Rohloff, J. C.; Muehldorf, A. V.; Link, J. O., Tetrahedron Lett. 1995, 36
(38), 6815-6818.
26.
Fang, J.; Akwabi-Ameyaw, A.; Britton, J. E.; Katamreddy, S. R.; Navas Iii, F.; Miller,
A. B.; Williams, S. P.; Gray, D. W.; Orband-Miller, L. A.; Shearin, J.; Heyer, D., Bioorg.
Med. Chem. Lett. 2008, 18 (18), 5075-5077.
27.
Charlton, J. L.; Oleschuk, C. J.; Chee, G.-L., J. Org. Chem. 1996, 61 (10), 34523457.
28.
Hoye, T. R.; Chen, M.; Hoang, B.; Mi, L.; Priest, O. P., J. Org. Chem. 1999, 64
(19), 7184-7201.
29.
Akai, S.; Ikawa, T.; Takayanagi, S.-i.; Morikawa, Y.; Mohri, S.; Tsubakiyama, M.;
Egi, M.; Wada, Y.; Kita, Y., Angew. Chem. Int. Ed. 2008, 47 (40), 7673-7676.
30.
Hamura, T.; Suzuki, T.; Matsumoto, T.; Suzuki, K., Angew. Chem. 2006, 118 (38),
6442-6444.
31.
Unzner, T. A.; Grossmann, A. S.; Magauer, T., Angew. Chem. Int. Ed. 2016, 55
(33), 9763-9767.
32.
Ding, Z.; Xue, S.; Wulff, W. D., Chemistry – An Asian Journal 2011, 6 (8), 21302146.
33.
Lunniss, C.; Eldred, C.; Aston, N.; Craven, A.; Gohil, K.; Judkins, B.; Keeling, S.;
Ranshaw, L.; Robinson, E.; Shipley, T.; Trivedi, N., Bioorg. Med. Chem. Lett. 2010, 20
(1), 137-140.
186

34.
Krasnokutskaya, E. A.; Semenischeva, N. I.; Filimonov, V. D.; Knochel, P.,
Synthesis 2007, 2007 (01), 81-84.
35.
Pichette Drapeau, M.; Fabre, I.; Grimaud, L.; Ciofini, I.; Ollevier, T.; Taillefer, M.,
Angew. Chem. Int. Ed. 2015, 54 (36), 10587-10591.
36.
Guan, Y.; Wulff, W. CONSTRUCTION OF A VAULTED BIARYL LIGAND
LIBRARY FOR THE AZIRIDINATION REACTION, Ph.D thesis. Michigan State
University, 2012.
37.
Redic, R.; Schuster, G. B., Journal of Photochemistry and Photobiology A:
Chemistry 2006, 179 (1), 66-74.
38.

Guan, Y.; Wulff, W. D., experimental notebook.

39.

Marshall, J. A.; Wang, X. J., J. Org. Chem. 1991, 56 (22), 6264-6266.

187

CHAPTER FOUR
EXPERIMENTAL SECTION

“If you want to have good ideas you must have many ideas. Most of them will be
wrong, and what you have to learn is which ones to throw away.”
– Linus Pauling

4.1 General Experimental
All reactions were carried out in flame-dried glassware under an atmosphere of
nitrogen unless otherwise indicated. Unless otherwise specified, all solvents were strictly
dried before use: dichloromethane were distilled over calcium hydride under nitrogen;
tetrahydrofuran, and ether were distilled from sodium and benzophenone; toluene was
distilled from sodium under nitrogen. Hexanes and ethyl acetate were ACS grade and
used as purchased. Formations of water-sensitive precatalyst were carried out in the
home-made Schlenk flask (Figure 4. 1) equipped with a stir bar under nitrogen unless
otherwise noted.
Melting points were recorded on a Thomas Hoover capillary melting point
apparatus and are uncorrected. IR spectra were recorded in KBr matrix (for solids) and
on NaCl disc (for liquids) on a Nicolet IR/42 spectrometer. The 1H NMR and

13

C NMR

spectra were recorded on a Varian Inova 300 MHz or Varian Unity Plus 500 MHz or Varian
Inova 600 MHz spectrometer using CDCl3 as solvent (unless otherwise noted). The
residual peak of CDCl3 or TMS was used as the internal standard for both 1H NMR (δ =
7.24 ppm for CDCl3 or δ = 0 ppm for TMS) and

188

13

C NMR (δ = 77.0 ppm). The

11

B NMR

spectra were recorded on a Varian 500 MHz instrument spectrometer in CDCl3 unless
otherwise noted. The

11

B NMR spectra were done in a NorellÂŽ quartz NMR tube and

referenced to external standard BF3•Et2O (δ = 0 ppm). Chemical shifts were reported in
parts per million (ppm). High Resolution Mass Spectrometry was performed in the
Department of Chemistry at Michigan State University Mass Facility.
Analytical thin-layer chromatography (TLC) was performed on Silicycle silica gel
plates with F-254 indicator. Visualization was by short wave (254 nm) and long wave (365
nm) ultraviolet light, or by staining with potassium permanganate. Column
chromatography was performed with silica gel 60 (230 – 450 mesh). HPLC analyses were
performed using a Varian Prostar 210 Solvent Delivery Module with a Prostar 330 PDA
Detector and a Prostar Workstation.
Optical rotations were obtained at a wavelength of 589 nm (sodium D line) using
a 1.0 decimeter cell with a total volume of 1.0 mL. Specific rotations are reported in
degrees per decimeter at 20 °C and the concentrations are given in gram per 100 mL in
DCM unless otherwise noted.
All reagents were purified by simple distillation or crystallization with simple
solvents unless otherwise indicated. Triphenylborate was obtained from Aldrich Chemical
Co., Inc. and used as received. VAPOL and VANOL were made according to published
procedure. Unless otherwise noted, all NMR analysis has been carried out using Ph3CH
as the internal standard.

189

Figure 4. 1 Home-made 50 mL Schlenk flask

190

4.2 Experimental for Chapter One
4.2.1 Preparations of diazo compounds

H 2N

H
N

O
p-Ts

+

HO

I-105

2.5 M HCl

OH
OH
I-106

H 2O
0.5 mol

O
p-Ts

N
H

N

OH

I-107
86%

2-(2-tosylhydrazono) acetic acid I-107: To a 1 L single-necked round bottom flask
was added glyoxylic acid monohydrate I-106 (46.3 g, 500 mmol) and water (500 mL). The
mixture was stirred at 65 ÂşC (oil bath) until I-106 dissolved completely. To this solution
was

then

added

a

warm

suspension

(at

approximately

65

ÂşC)

of

p-

toluenesulfonylhydrazide I-105 (93.1 g, 500 mmol) in 2.5 M aqueous hydrochloric acid
(300 mL). The reaction mixture was stirred at 65 °C for 15 min, then allowed to cool to
room temperature gradually until all of the oil solidified and then the flask was kept in a
refrigerator overnight. The crude product was collected on filter paper using a BĂźchner
funnel (8 cm diameter), washed with cold water (70 mL), and dried for 2 days in open air
followed by exposure to high vacuum overnight. To a 1 L single-necked round bottom
flask containing acid I-107 and equipped with a stir bar and with a condenser was added
boiling EtOAc until all of the solids dissolved. Hexanes were added until the solution
became cloudy. Thereafter, hot EtOAc was added until it just became clear again. The
solution was then allowed to cool to room temperature and then allowed to set in a freezer
overnight (–20 ºC). The solid was filtered and washed with ice-cold 1:2 EtOAc/hexanes
to afford I-107 as a white solid (mp 150-152 ÂşC) in 86% isolated yield (105 g, 432 mmol).

191

Spectral data for I-107: Rf = 0.45 (1:1, EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 2.46 (s, 3H), 3.40 (br, 2H), 7.34 (s, 1H), 7.47 (d, 2H, J = 8.0 Hz), 7.85 (d, 2H, J = 8.0
Hz); 13C NMR (CD3COCD3, 126 MHz) δ 21.89, 128.94, 131.07, 137.42, 137.85, 145.77,
163.23. These spectral data match those previously reported for this compound except
for the exchanging protons.1
O
p-Ts

N
H

N

I-107
86%

2 equiv SOCl2

OH

benzene, reflux
210 mmol

O
p-Ts

N
H

N

Cl

I-108
70%

2-(2-tosylhydrazono)acetyl chloride I-108: To a suspension of acid I-107 (50.2 g,
210 mmol) in benzene (250 mL) was added SOCl2 (30 mL, 420 mmol, freshly distilled).
The reaction mixture was heated to reflux (90 ÂşC oil bath) until vigorous gas evolution
ceased and most of the suspended solid dissolved (~2 h). The reaction mixture then was
cooled under nitrogen and filtered through a CeliteÂŽ pad on a sintered-glass funnel. The
filtrate was then concentrated to dryness under reduced pressure. The residual solid was
mixed with anhydrous benzene (50 mL, warmed to ~40 to 50 ÂşC), and the solid mass was
broken up to give a fine suspension. The suspension was cooled and filtered quickly using
a BĂźchner funnel (8 cm diameter) and then the solid was washed quickly with cold
benzene (30 mL × 2) to remove most of the residual colored impurities. The combined
filtrates were stripped of solvent on the rotary evaporator and the residue was washed
quickly with cold benzene (30 mL × 2) to give a second crop of the crude product.
Purification by crystallization was achieved by dissolving the crude product in boiling
benzene (~100 mL), followed by the addition of hexanes (~100 mL, bp. 60-90 ÂşC). The
mixture was allowed to cool down to room temperature, and stand overnight. The acid
192

chloride I-108 was collected as a white solid (mp. 100-103 ÂşC) in 70% isolated yield (38.3
g, 147 mmol).
Spectral data for I-108: 1H NMR (CDCl3, 500 MHz) δ 2.46 (s, 3H), 7.25 (d, 1H, J =
0.9 Hz), 7.38 (d, 2H, J = 8.0 Hz), 7.86 (d, 2H, J = 8.4 Hz), 9.38 (s, 1H); 13C NMR (CDCl3,
126 MHz) δ 21.70, 128.10, 130.14, 133.78, 136.05, 145.81, 165.01.
O
1.2 equiv

O
p-Ts

N
H

N

I-108

Cl

N

OH
O I-109

Na2CO3 , CH2Cl2
0 °C to rt, 6 h
50 mmol

O
N2

O
O

N
O

I-110
60%

2,5-dioxopyrrolidin-1-yl 2-diazoacetate I-110: To a flame dried 500 mL singlenecked round bottom flask was added N-hydroxysuccinimide I-110 (6.33 g, 55.0 mmol)
and Na2CO3 (7.95 g, 75.0 mmol) and anhydrous CH2Cl2 (75 mL). The flask was then
brought to 0 ÂşC using a chiller over a period of 30 min. Meanwhile, to another flame-dried
250 mL single-necked round-bottom flask was added acid chloride I-108 (13.04 g, 50.00
mmol) and dry CH2Cl2 (100 mL). This solution was added to the suspension of
succinimide I-109 at 0 ÂşC over a period of 2 h utilizing two syringe pumps. The resulting
mixture was stirred for an additional hour at 0 ÂşC. After 1 h, the solution was warmed to
room temperature and then stirred for 3 h at room temperature. The reaction mixture was
then filtered using a BĂźchner funnel (8 cm diameter) with filter paper and the filtrate was
collected in a 500 mL round-bottom flask. The residue was then washed with EtOAc (200
mL × 2). A small amount of solid was observed in the filtrate. The solid impurities
remaining in the filtrate were removed by passing through a short plug (35 mm × 60 mm)
193

of silica gel. The filtrate was collected in a 500 mL round-bottom flask. The silica plug was
then washed with EtOAc (150 mL × 2). The washing was monitored by TLC. The
combined EtOAc layer was then concentrated under reduced pressure to provide crude
succinimidyl diazoacetate as a light yellow solid (~6.36 g). The crude diazo compound
was kept under vacuum for a period of 1 h. Recrystallization from CH2Cl2/ hexanes (55
mL, 4:1) gave diazo I-110 (mp 113.5-115.0 ÂşC) as light yellow solid crystals in 29% yield
(2.68 g, 14.5 mmol, first crop). Successive crystallization yielded the diazo compound I110 in a combined yield of 60% (29%, 2.68 g, mp 113.5-115.0 ÂşC, first crop; 15%, 1.40 g,
mp 115.0-118.0 °C, second crop; 16%, 1.43 g, mp 115.0-118.0 °C, third crop). The
amounts of solvent (CH2Cl2/ hexanes, 4:1) used for second and third crystallizations are
29 mL and 19 mL respectively. The amounts of the solid residue from the mother liquor
after the first and second crystallizations are 3.57 g and 2.15 g respectively.
Spectral data for I-110: Rf = 0.13 (3:1 ether/hexanes); 1H NMR (CDCl3, 500 MHz)
δ 2.81 (s, 4H), 5.10 (brs, 1H); 13C NMR (CDCl3, 126 MHz) δ 25.44, 45.11, 162.24, 169.36;
IR (thin film) 3105w, 2135s, 1736vs, 1375s, 1206s, 1105s cm-1; These spectral data
match those previously reported for this compound.2
1.1 equiv aniline
2 equiv. DBU

O
p-Ts

N
H

N

I-108
70%

Cl

CH2Cl2,
0 ÂşC to rt, 2 h
50 mmol

O
N2

N
H
I-23b
63%

2-diazo-N-phenylacetamide I-23b: To a flame-dried 500 mL round bottom flask
equipped with a magnetic stir bar and flushed with argon was added acid chloride I-108
(14.4 g, 55.2 mmol, 1.00 equiv) and dry CH2Cl2 (120 mL). The flask was then fitted with

194

a rubber septum and an Argon balloon and cooled to 0 °C in an ice-bath. The reaction
mixture was stirred at 0 ÂşC for 15 min. Aniline (5.60 mL, 60.8 mmol, 1.10 equiv) and DBU
(16.6 mL, 110 mmol, 2.00 equiv) were then added sequentially to the reaction flask at 0
ÂşC via plastic syringe. The reaction mixture was stirred at 0 ÂşC for 2 h, and then warmed
up to room temperature. The mixture was then added to sat. NH4Cl (~120 mL), and the
layers separated. The aqueous layer was extracted with CH2Cl2 once, the organic layers
combined, washed with brine once, dried over Na2SO4, and filtered. The product solution
thereafter was transferred to a 500 mL round bottom flask and enough silica gel was
added for subsequent column chromatography (“dry load”). This solid was then subjected
to rotary evaporation to dryness, and directly loaded onto a silica gel column (30 mm ×
270 mm). An eluent mixture of 3:1 hexanes:EtOAc was used for the flash
chromatography, all yellow colored fractions were collected, and subjected to rotary
evaporation until dry and finally high vacuum to afford the impure product I-23b as a
yellow solid. This solid was then washed with ether (1-4 times) until all impurities had
been removed as indicated by TLC (3:1 hexanes/EtOAc), this afforded pure
diazoacetamide I-23b (mp. 147-149 ÂşC) as a bright yellow solid in 63% yield (5.59 g, 34.7
mmol).
Spectral data for I-23b: Rf = 0.18 (1:50 MeOH:CH2Cl2); 1H NMR (CDCl3, 500 MHz)
δ 5.16 (s, 1H), 6.95 (t, J = 7.5 Hz, 1H), 7.19 (t, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H),
8.98 (s, 1H); 13C NMR (CDCl3,126 MHz) δ 47.60, 118.96, 122.73, 128.36, 138.87, 163.86.
The spectral data of I-23b match those previously reported for this compound.3

195

General Procedure A for synthesis of N-alkyl diazoacetamides -- illustrated for
synthesis of N-butyl-2-diazoacetamide I-23a
O
N2

2.0 equiv
BuNH2

O
O

N

THF, rt, 1 h
O

I-110

O
N2

N
H
I-23a
90%

Bu

N-butyl-2-diazoacetamide I-23a: To a flame dried 500 mL single-necked roundbottom flask was added succinimidyl diazoacetate I-110 (7.33 g, 40.0 mmol) and THF
(330 mL). To the solution was added N-butylamine (8 mL, 80 mmol, freshly distilled) in
one portion. Appearance of a yellow solid was observed after 1-2 min. The reaction
mixture was stirred for 1 h at room temperature. The reaction was complete and the
solvent was removed under reduced pressure. Purification of the crude diazo compound
by silica gel chromatography (30 mm × 300 mm column, 1:3 hexanes/EtOAc) afforded
pure diazoacetamide I-23a as a yellow solid (mp 75-76 ÂşC) in 90-93% isolated yield (5.105.25 g, 35-37.2 mmol). Alternatively, the crude product, after the evaporation of the
solvent, was directly loaded to a short plug (35 mm × 60 mm) of silica gel. The silica plug
was then washed with 1:3 hexanes/EtOAc (100 mL). The washing was continued until
the yellow eluent stopped coming down the plug. All yellow fractions can be collected in
a flask and the solvent was evaporated to afford pure diazoacetamide I-23a as a yellow
solid (mp 75-76 ÂşC). No difference in the yield was observed when the purification was
performed in this way compared to column chromatography.
Spectral data for I-23a: Rf = 0.33 (1:1 EtOAc/hexanes); 1H NMR (CDCl3, 500 MHz)
δ 0.89 (t, J = 7.3 Hz, 3H), 1.32 (dq, J = 14.7, 7.3 Hz, 2H), 1.46 (p, J = 7.3 Hz, 2H), 3.25

196

(brs, 2H), 4.73 (brs, 1H), 5.38 (brs, 1H); 13C NMR (CDCl3,126 MHz) δ 13.69, 19.97, 32.03,
39.83, 46.92, 165.32. These spectral data match those previously reported for this
compound.3
O
N2

2.0 equiv
BnNH2

O
O

N

THF, rt, 1 h

O
N2

O
I-110

N
H
I-23c
92%

Bn

N-benzyl-2-diazoacetamide I-23c: Diazoacetamide I-23c was prepared by the
General Procedure A with succinimidyl diazoacetate I-110 (1.83 g, 10.0 mmol) and
benzylamine (2.2 mL, 20 mmol, freshly distilled) to afford pure diazoacetamide I-23c as
a yellow solid (mp 100-103 ÂşC) in 92% isolated yield (1.62 g, 9.24 mmol).
Spectral data for I-23c: Rf = 0.15 (1:1 EtOAc/hexanes); 1H NMR (CDCl3, 500 MHz)
δ 4.39 (d, J = 5.0 Hz, 2H), 4.68 (s, 1H), 5.44 (brs, 1H), 7.19-7.28 (m, 5H);

13

C NMR

(CDCl3,126 MHz) δ 43.95, 47.20, 127.55, 127.67, 128.70, 138.25, 165.40. These spectral
data match those previously reported for this compound.3
O
N2

O
O

+ H 2N

N
O

I-110

H
N

THF, rt, 1 h

Ph

2.0 equiv

N2

Ph

O
I-23d
93%

N-phenethyl-2-diazoacetamide I-23d: Diazoacetamide I-23d was prepared by the
General Procedure A with succinimidyl diazoacetate I-110 (915.6 mg, 5.000 mmol) and
2-phenylethan-1-amine (1.26 mL, 10.0 mmol, freshly distilled) to afford pure
diazoacetamide I-23d as a yellow solid in 93% isolated yield (883 mg, 4.65 mmol).

197

Spectral data for I-23d: Rf = 0.38 (3:1 EtOAc/hexanes); 1H NMR (500 MHz, CDCl3)
δ 2.81 (t, J = 7.2 Hz, 2H), 3.51 (q, J = 7.6, 7.1 Hz, 2H), 4.85 (s, 1H), 6.17 (s, 1H), 7.03 –
7.43 (m, 5H). 13C NMR (126 MHz, CDCl3) δ 36.08, 41.22, 47.06, 126.50, 128.60, 128.72,
138.85, 165.97.
O
N2

O

+

N

O
I-110

H
N

THF, rt, 1 h

H 2N

N2
O

O

2.0 equiv

I-23e
82%

N-cyclohexyl-2-diazoacetamide I-23e: Diazoacetamide I-23e was prepared by the
General Procedure A with succinimidyl diazoacetate I-110 (915.6 mg, 5.000 mmol) and
cyclohexanamine (1.15 mL, 10.0 mmol, freshly distilled) to afford pure diazoacetamide I23e as a yellow solid in 82% isolated yield (683 mg, 4.09 mmol).
Spectral data for I-23e: Rf = 0.33 (3:1 EtOAc/hexanes); 1H NMR (500 MHz, CDCl3)
δ 0.76 – 1.32 (m, 6H), 1.19 – 1.98 (m, 5H), 4.80 (s, 1H), 6.30 (s, 1H). 13C NMR (126 MHz,
CDCl3) δ 24.83, 25.43, 33.27, 46.56, 48.51, 164.79.
O
N2

O
O

I-110

+

N
O

H 2N

H
N

THF, rt, 1 h
N2
O

2.0 equiv

I-23f
84%

N-tert-butyl-2-diazoacetamide I-23f: Diazoacetamide I-23f was prepared by the
General Procedure A with succinimidyl diazoacetate I-110 (915.6 mg, 5.000 mmol) and
tert-butylamine (1.05 mL, 10.0 mmol, freshly distilled) to afford pure diazoacetamide I-23f
as a yellow solid in 84% isolated yield (591 mg, 4.19 mmol).

198

Spectral data for I-23f: Rf = 0.5 (1:1 EtOAc/hexanes); 1H NMR (500 MHz, CDCl3)
δ 1.32 (s, 9H), 4.69 (s, 1H), 5.24 (s, 1H).

13

C NMR (126 MHz, CDCl3) δ 29.16, 47.48,

51.85, 164.94.
O
N2

O

+

N

O

H
N

THF, rt, 1 h
N2

H 2N

O

O

2.0 equiv

I-110

I-23g
79%

N-allyl-2-diazoacetamide I-23g: Diazoacetamide I-23g was prepared by the
General Procedure A with succinimidyl diazoacetate I-110 (915.6 mg, 5.000 mmol) and
allylamine (0.75 mL, 10.0 mmol, freshly distilled) to afford pure diazoacetamide I-23g as
a yellow semisolid in 79% isolated yield (494 mg, 3.95 mmol).
Spectral data for I-23g: Rf = 0.27 (1:1 EtOAc/hexanes); 1H NMR (500 MHz, CDCl3)
δ 3.77 – 3.94 (s, 2H), 4.98 (s, 1H), 5.04 – 5.21 (m, 2H), 5.79 (ddt, J = 17.0, 10.6, 5.4 Hz,
1H), 6.46 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 42.21, 47.02, 116.01, 134.34, 166.12.
O
N2

O
O

I-110

+

N
O

H
N

THF, rt, 1 h

N2

H 2N

O
2.0 equiv

I-23h
68%

N-propargyl-2-diazoacetamide I-23h: Diazoacetamide I-23h was prepared by the
General Procedure A with succinimidyl diazoacetate I-110 (915.6 mg, 5.000 mmol) and
propargylamine (0.64 mL, 10.0 mmol, freshly distilled) to afford pure diazoacetamide I23h as a yellow semisolid in 68% isolated yield (417 mg, 3.39 mmol).

199

Spectral data for I-23h: Rf = 0.26 (1:1 EtOAc/hexanes); 1H NMR (500 MHz, CDCl3)
δ 2.14 (t, J = 2.6 Hz, 1H), 3.91 (dd, J = 5.5, 2.6 Hz, 2H), 4.94 (s, 1H), 7.22 (d, J = 50.8
Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 29.05, 46.83, 71.06, 80.20, 165.90.
O
N2

O
O

O
+ H 2N

N
O

I-110

H
N

THF, rt, 1 h
N2

OEt

O
OEt

O

2.0 equiv

I-23i
84%

ethyl (2-diazoacetyl)glycinate I-23i: Diazoacetamide I-23i was prepared by the
General Procedure A with succinimidyl diazoacetate I-110 (915.6 mg, 5.000 mmol) and
ethyl glycinate (1.031 g, 10.0 mmol) to afford pure diazoacetamide I-23i as a yellow
semisolid in 84% isolated yield (417 mg, 4.19 mmol).
Spectral data for I-23i: Rf = 0.28 (3:1 EtOAc/hexanes); 1H NMR (500 MHz, CDCl3)
δ 1.22 (t, J = 7.2 Hz, 3H), 3.98 (d, J = 5.7 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H), 5.02 (s, 1H),
6.70 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 14.04, 41.57, 47.17, 61.44, 166.57, 170.46.
O
N2

O
O

+ H 2N

N
O

I-110

H
N

THF, rt, 1 h
N2

OMe

O

O

2.0 equiv

I-23j
80%

N-methoxyethyl-2-diazoacetamide I-23j: Diazoacetamide I-23j was prepared by
the General Procedure A with succinimidyl diazoacetate I-110 (915.6 mg, 5.000 mmol)
and 2-methoxyethylamine (0.87 mL, 10.0 mmol, freshly distilled) to afford pure
diazoacetamide I-23j as a yellow semisolid in 80% isolated yield (517 mg, 3.99 mmol). Rf
= 0.34 (1:1 EtOAc/hexanes);

200

O
N2

H
N

O
O

THF, rt, 1 h

+

N

H
N

N2
O

N
H

O
I-110

2.0 equiv

NH2

I-23l

74%
Boc2O (1.2 equiv)
THF, 5 mol% DMAP

H
N

N2
O

I-23m 77%

N
Boc

N-(2-(1H-indol-3-yl)ethyl)-2-diazoacetamide I-23l: Diazoacetamide I-23l was
prepared by the General Procedure A with succinimidyl diazoacetate I-110 (915.6 mg,
5.000 mmol) and tryptamine (1.602 g, 10.0 mmol) to afford pure diazoacetamide I-23l as
a pale yellow solid in 74% isolated yield (849 mg, 3.72 mmol).
Spectral data for I-23l: Rf = 0.13 (1:1 EtOAc/hexanes); 1H NMR (500 MHz, CDCl3)
δ 2.86 (t, J = 6.9 Hz, 2H), 3.49 (q, J = 6.4 Hz, 2H), 4.75 (s, 1H), 6.35 (s, 1H), 6.77 – 7.12
(m, 3H), 7.27 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 9.34 (s, 1H).

13

C NMR (126

MHz, CDCl3) δ 25.69, 40.22, 46.75, 111.42, 112.37, 118.51, 118.91, 121.59, 122.41,
127.29, 136.47, 165.82.
tert-butyl 3-(2-(2-diazoacetamido)ethyl)-1H-indole-1-carboxylate I-23m: To a 25
mL round bottomed flask was added diazoacetamide I-23l (537 mg, 2.35 mmol), di-tertbutyl dicarbonate (617 mg, 2.82 mmol, 1.20 equiv), DMAP (14.4 mg, 0.118 mmol) and
THF (15 mL). The reaction mixture was stirred at rt for 1 h. When the reaction was
complete, the reaction mixture was concentrated and purified by column chromatography

201

(EtOAc/hexanes 1:1, silica gel) to afford I-23m (594 mg, 1.81 mmol) as a pale-yellow solid
in isolated 77% yield.
Spectral data for I-23m: Rf = 0.20 (1:1 EtOAc/hexanes); 1H NMR (500 MHz, CDCl3)
δ 1.67 (s, 9H), 2.92 (t, J = 6.9 Hz, 2H), 3.61 (d, J = 7.3 Hz, 2H), 4.69 (s, 1H), 5.35 (d, J =
51.6 Hz, 1H), 7.17 – 7.63 (m, 4H), 8.13 (s, 1H).

13

C NMR (126 MHz, CDCl3) δ 25.55,

28.22, 39.58, 47.19, 83.70, 115.32, 117.57, 118.92, 122.58, 123.23, 124.56, 130.31,
135.54, 149.70, 165.55.
O
N2

O
O

+ H 2N

N
O

I-110

N-(3,3-diethoxypropyl)

OEt

H
N

THF, rt, 1 h
N2
O

OEt
2.0 equiv

OEt
OEt

I-23n
87%

diazoacetamide

I-23n:

Diazoacetamide

I-23n

was

prepared by the General Procedure A with succinimidyl diazoacetate I-110 (1.831 g,
10.00 mmol) and 3,3-diethoxypropan-1-amine (3.3 mL, 20 mmol) to afford pure
diazoacetamide I-23n as a yellow liquid in 87% isolated yield (1.882 g, 8.74 mmol).
Spectral data for I-23n: Rf = 0.30 (3:1 EtOAc/hexanes); 1H NMR (500 MHz, CDCl3)
δ 0.99 (t, J = 7.1 Hz, 6H), 1.62 (q, J = 6.5 Hz, 2H), 3.14 (d, J = 7.2 Hz, 2H), 3.25 – 3.38
(m, 2H), 3.45 (dd, J = 9.2, 6.8 Hz, 2H), 4.35 (t, J = 5.5 Hz, 1H), 4.85 (s, 1H), 6.80 (t, J =
5.7 Hz, 1H).

13

C NMR (126 MHz, CDCl3) δ 15.08, 33.51, 35.74, 46.58, 61.53, 101.37,

165.90.

202

4.2.2 General Procedure B for symmetric epoxidation catalyzed by Boroxinate I103a (Table 1.2) -- illustrated for benzaldehyde I-51a and N-butyl-2-diazoacetamide I23a

10 mol%
(R)-VANOL

30 mol% BH3•Me2S
20 mol% PhOH
30 mol% H2O

10 mol% DMSO

toluene, 100 ÂşC, 1 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

toluene, rt, 1 h,
then cool to –60 ºC

O

O
H

I-51
1.1 equiv

+

N2

N
H
I-23a

DMSO-H

0.2 mmol

O

O

10 mol% I-103
toluene, –60 ºC,
24 h, 0.05 M

OPh
O B
O
O
* O B
O B
OPh
Boroxinate catalyst I-103a

Ph

CONHBu
CONHBu

I-108a
88%, >99% ee

+

I-114a

Preparation of the catalyst stock solution I-103a: To a 50 mL flame-dried homemade Schlenk flask, prepared from a single-necked 50 mL pear-shaped flask that had its
14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir
bar and flushed with nitrogen was added (R)-VANOL (26.3 mg, 0.0600 mmol) and PhOH
(11.3 mg, 0.120 mmol, freshly sublimed). Under a nitrogen flow through the side-arm of
the Schlenk flask, dry toluene (2 mL) was added through the top of the Teflon valve to
effect dissolution. After the addition of the toluene, BH3•Me2S (90 μL, 0.18 mmol, 2 M in
toluene) and water (3.2 ÎźL, 0.18 mmol) were added. The flask was sealed by closing the
Teflon valve, and then placed in a 100 ÂşC oil bath for 1 h. After 1 h, a vacuum (0.5 mm
Hg) was carefully applied by slightly opening the Teflon valve to remove the volatiles.
After the volatiles were removed completely, a full vacuum was applied and maintained
for a period of 30 min at a temperature of 100 ÂşC (oil bath). The flask was then allowed to
cool to room temperature and opened to nitrogen through the side-arm of the Schlenk

203

flask. This residue was then completely dissolved in dry toluene (3 mL) under a nitrogen
flow through side-arm of the Schlenk flask. An aliquot of 1 mL (0.020 mmol) of the precatalyst was then transferred to a 10 mL flame-dried home-made Schlenk flask equipped
with a stir bar and flushed with argon. To the flask containing the pre-catalyst (1 mL aliquot
from 0.02 M stock solution) was added the dimethyl sulfoxide (1.4 ÎźL, 0.020 mmol) under
a nitrogen flow through side-arm of the Schlenk flask. The resulting mixture was stirred
for 1 h at room temperature to afford the solution of the catalyst.
Asymmetric epoxidation protocol: The flask containing the catalyst I-103a (0.020
mmol) was cooled to –60 °C for 10 min. To this solution was added a solution of
diazoacetamide I-23a (28.2 mg, 0.200 mmol in 2.5 mL toluene). The flask containing the
diazoacetamide I-23a was then rinsed with toluene (0.5 mL) and the rinse was then
transferred to the flask containing the catalyst at –60 °C. Then the Teflon valve was closed
and the resulting mixture was stirred for 10 min at –60 °C. To the mixture containing
diazoacetamide I-23a and the catalyst was added neat benzaldehyde I-51a (22 ÎźL, 0.22
mmol) dropwise using a microsyringe and the resulting mixture was stirred for 24 h at –
60 °C. The reaction was quenched by the addition of Et3N (0.5 mL) and then was warmed
to room temperature. The reaction mixture was then transferred to a 50 mL round bottom
flask. The reaction flask was rinsed with EtOAc (3 mL × 2) and the rinse was added to
the 50 mL round bottom flask. The resulting solution was then concentrated under
vacuum followed by exposure to high vacuum (0.5 mm Hg) for 1 h to afford the crude
epoxide as an off-white semi-solid.

204

The cis/trans ratio was determined by comparing the 1H NMR integration of the
ring methine protons (δ 3.77 for cis, δ 3.60 for trans) for each epoxide in the crude
reaction mixture. The yield of the acyclic β-ketoamide side product was determined by 1H
NMR analysis of the crude reaction mixture by integration of the methylene protons (δ
3.94) relative to the internal standard (Ph3CH). Purification of the crude epoxide by silica
gel chromatography (20 mm × 300 mm column, 2:1 to 1:1 hexanes/EtOAc as eluent)
afforded pure cis-epoxide I-108a as a white solid (mp 52-53 ÂşC on 99% ee material) in
88% isolated yield (38.6 mg, 0.176 mmol); cis/trans: 100:1. β-ketoamide side product:
<1% yield. The optical purity of I-108a was determined to be 99% ee by HPLC (PIRKLE
COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1
mL/min): retention times; Rt = 13.8 min (minor enantiomer, ent-I-108a) and Rt = 24.6 min
(major enantiomer, I-108a). Each enantiomer was obtained and confirmed by a separate
reaction using (R)-VANOL as ligand. Side product β-ketoamide I-114a was isolated in a
separate experiment and characterized by NMR.
Spectral data for I-108a: Rf = 0.61 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.72 (t, J = 7.2 Hz, 3H), 0.89-1.04 (m, 4H), 2.82-2.88 (m, 1H), 3.08 (dq, J = 13.6, 6.9
Hz, 1H), 3.77 (d, J = 4.8 Hz, 1H), 4.31 (d, J = 4.8 Hz, 1H), 5.84 (s, 1H), 7.35-7.28 (m,
5H);

13

C NMR (CDCl3, 126 MHz) δ 13.53, 19.62, 31.17, 38.21, 56.27, 58.08, 126.49,

128.31, 128.38, 133.19, 165.95; IR (thin film) 3316 br, 2959 vs, 2932 vs, 1651 vs, 1545
s, 1454 s cm-1; HRMS (ESI-TOF) m/z 220.1334 [(M+H+); calcd. for C13H18NO2: 220.1338];
[𝛼]%&
$ 	+18.6 (c 1.0, EtOAc) on 99.3% ee material (HPLC).

205

Spectral data for I-114a: Rf = 0.40 (1:3 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.92 (t, J = 7.4 Hz, 3H), 1.33-1.39 (m, 2H), 1.49-1.55 (m, 2H), 3.30 (td, J= 7.1, 5.7 Hz,
2H), 3.94 (s, 2H), 7.07-7.15 (m, 1H), 7.47-7.51 (m, 2H), 7.61 (ddt, J = 8.4, 6.5, 1.6 Hz,
1H), 8.00 (dt, J = 8.4, 1.6 Hz, 2H);

13

C NMR (CDCl3, 126 MHz) δ 13.69, 20.04, 31.43,

39.40, 45.26, 128.56, 128.85, 134.04, 136.23, 165.55, 196.37. These spectral data match
those previously reported for this compound.10
O

O

O
H

I-51b
1.1 equiv

+

N2

10 mol% I-103a

N
H
I-23a

toluene, –60 ºC,
24 h, 0.05 M

0.2 mmol

CONHBu

I-120
81%, 99% ee

(2R,3R)-N-butyl-3-(p-tolyl)oxirane-2-carboxamide I-120: Aldehyde I-51b was
reacted according to the General Procedure B with (R)-VANOL as ligand. Purification of
the crude epoxide by silica gel chromatography (17 mm × 300 mm column, 2:1 to 1:1
hexanes/EtOAc as eluent) afforded pure cis-epoxide I-120 as a white solid (mp 58-59 ÂşC
on 99% ee material) in 81% isolated yield (37.9 mg, 0.162 mmol); cis/trans: >100:1. βketoamide side product: <1% yield. The optical purity of I-120 was determined to be 99%
ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 23.76 min (minor
enantiomer, ent-I-120) and Rt = 35.09 min (major enantiomer, I-120).
Spectral data for I-120: Rf = 0.56 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.72 (t, J = 7.2 Hz, 3H), 0.88-0.96 (m, 2H), 1.00-1.06 (m, 2H), 2.32 (s, 3H), 2.83-2.89
(m, 1H), 3.11 (dq, J = 13.6, 6.9 Hz, 1H), 3.74 (d, J = 4.8 Hz, 1H), 4.27 (d, J = 4.7 Hz, 1H),
5.83 (s, 1H), 7.13 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H); 13C NMR (CDCl3, 126 MHz)

206

δ 13.58, 19.66, 21.15, 31.28, 38.26, 56.32, 58.09, 126.45, 128.99, 130.21, 138.21,
166.12; IR (thin film) 3310 br, 2961 s, 2932 s, 1653 vs, 1547 vs, 1433 s cm-1; HRMS (ESITOF) m/z 234.1504 [(M+H+); calcd. For C14H20NO2: 234.1494]; [𝛼]%&
$ +22.0 (c 1.0, EtOAc)
on 99% ee material (HPLC).
O

O
H

I-51c
1.1 equiv

+

N2

N
H
I-23a

O
10 mol% I-103a
toluene, –60 ºC,
24 h, 0.05 M

0.2 mmol

CONHBu

I-119
53%, 79% ee

(2R,3R)-N-butyl-3-(o-tolyl)oxirane-2-carboxamide I-119: Aldehyde I-51c was
reacted according to the General Procedure B with (R)-VANOL as ligand. Purification of
the crude epoxide by silica gel chromatography (17 mm × 300 mm column, 2:1 to 1:1
hexanes/EtOAc as eluent) afforded pure cis-epoxide I-119 as a white solid (mp 41-43 ÂşC
on 79% ee material) in 53% isolated yield (24.1 mg, 0.106 mmol); cis/trans: >100:1. βketoamide side product: <1% yield. The optical purity of I-119 was determined to be 79%
ee by HPLC analysis (PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2propanol at 228 nm, flow-rate: 1 mL/min): retention times; Rt = 17.11 min (minor
enantiomer, ent-I-119) and Rt = 20.61 min (major enantiomer, I-119).
Spectral data for I-119: Rf = 0.58 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.70 (t, J = 7.1 Hz, 3H), 0.87-0.96 (m, 4H), 2.36 (s, 3H), 2.78-2.83 (m, 1H), 3.07 (dq, J
= 13.7, 6.9 Hz, 1H), 3.84 (d, J = 4.7 Hz, 1H), 4.25 (d, J = 4.7 Hz, 1H), 5.72 (s, 1H), 7.15
(dd, J = 11.6, 7.5 Hz, 2H), 7.21 (t, J = 7.2 Hz, 1H), 7.30 (d, J = 7.4 Hz, 1H);

13

C NMR

(CDCl3, 126 MHz) δ 13.56, 18.69, 19.59, 31.20, 38.20, 56.13, 57.69, 125.46, 126.15,
128.31, 130.02, 131.77, 136.73, 166.11; IR (thin film) 3330 br, 2959 s, 2930 s, 1666 vs,

207

1539 vs, 1458 m cm-1; HRMS (ESI-TOF) m/z 234.1503 [(M+H+); calcd. for C14H20NO2:
234.1494]; [𝛼]%&
$ +39.8 (c 1.0, EtOAc) on 80% ee material (HPLC).
O

O

O
H

I-51d
1.1 equiv

+

N2

10 mol% I-103a

N
H
I-23a

toluene, –60 ºC,
24 h, 0.05 M

0.2 mmol

CONHBu

I-138a
54%, 67% ee

(2R,3R)-N-butyl-3-cyclohexyloxirane-2-carboxamide I-138a: Aldehyde I-51d was
reacted according to the General Procedure B with (R)-VANOL as ligand. Purification of
the crude epoxide by silica gel chromatography (17 mm × 300 mm column, 2:1 to 1:1
hexanes/EtOAc as eluent) afforded pure cis-epoxide I-138a as a colorless oil in 54%
isolated yield (24.1 mg, 0.107 mmol); cis/trans: >100:1. β-ketoamide side product: <1%
yield. The optical purity of I-138a was determined to be 67% ee by HPLC analysis
(PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm,
flow-rate: 1 mL/min): retention times; Rt = 6.72 min (minor enantiomer, ent-I-119) and Rt
= 10.61 min (major enantiomer, I-119).
Spectral data for I-138a: Rf = 0.23 (1:2 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.87 (t, J = 7.1 Hz, 3H), 1.00-1.20 (m, 6H), 1.24-1.32 (m, 2H), 1.40-1.46 (m, 2H), 1.561.76 (m, 4H), 1.84 (br, 1H), 2.82 (dd, J = 4.5, 9.0 Hz, 1H), 3.14 (dt, J = 13.0, 7.5 Hz, 1H),
3.32 (dt, J = 14.0, 7.0 Hz, 1H), 3.43 (d, J = 4.5 Hz, 1H), 6.11 (s, 1H);

13

C (CDCl3, 125

MHz) δ 13.62, 20.01, 25.28, 25.29, 25.98, 28.37, 30.44, 31.62, 36.81, 38.44, 55.30,
62.54, 167.32; HRMS (ESI-TOF) m/z 226.1812 [(M+H+); calcd. for C13H24NO2: 226.1807].

208

O
6

O

O
H

I-51d
1.1 equiv

+

N2

10 mol% I-103a

N
H
I-23a

toluene, –60 ºC,
24 h, 0.05 M

0.2 mmol

6

CONHBu

I-137a
81%, 79% ee

(2R,3R)-N-butyl-3-octyloxirane-2-carboxamide I-137a: Aldehyde 35 was reacted
according to the General Procedure B with (R)-VANOL as ligand. Purification of the crude
epoxide by silica gel chromatography (17 mm × 300 mm column, 3:1 to 1:1 hexanes/ ethyl
acetate as eluent) afforded pure cis-epoxide I-137a as a white semi-solid in 81% isolated
yield (41.3 mg, 0.162 mmol); cis/trans: nd. β-ketoamide side product: 6% yield. The
optical purity of I-137a was determined to be 79% ee by HPLC analysis (PIRKLE
COVALENT (R,R) WHELK-O 1 column, 97:3 hexane/2-propanol at 228 nm, flow-rate: 1
mL/min): retention times; Rt = 22.64 min (minor enantiomer, ent-I-137a) and Rt = 27.43
min (major enantiomer, I-137a).
Spectral data for I-137a: Rf = 0.32 (1:2 EtOAc/hexane); 1H NMR (CDCl3, 600 MHz) δ
0.85 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H), 1.21-1.27 (m, 8H), 1.28-1.35 (m, 4H),
1.40-1.53 (m, 6H), 3.11-3.14 (m, 1H), 3.21 (dq, J = 13.2, 6.6 Hz, 1H), 3.30 (dq, J = 13.5,
6.7 Hz, 1H), 3.46 (d, J = 4.8 Hz, 1H), 6.11 (s, 1H);

13

C NMR(CDCl3, 126 MHz) δ 13.63,

14.04, 20.05, 22.61, 26.01, 27.64, 29.12, 29.30, 29.33, 31.63, 31.80, 38.55, 55.36, 58.57,
167.26; IR (thin film) 3312 br, 2957 s, 2938 s, 2857 m, 1661 vs, 1539 vs, 1458 m, cm-1;
HRMS (ESI-TOF) m/z 256.2271 [(M+H+); calcd. for C15H30NO2: 256.2277]; [𝛼]%&
$ +2.1 (c
1.0, EtOAc) on 79% ee material (HPLC).

209

4.2.3 Protonation/nucleophilic addition to I-23b
O
N2

SO3H

+

N
H
I-23b

O

CDCl3, 0.1 M

TsO

N
H
I-113
74%

rt, 3 h
I-112

2-oxo-2-(phenylamino)ethyl 4-methylbenzenesulfonate I-113: To a 10 mL round
bottomed flask was added diazo acetamide I-23b (16.1 mg, 0.1 mmol), TsOH•H2O (19.0
mg, 0.100 mmol) and CDCl3 (1 mL). The reaction was then followed by 1H NMR and after
3 h, the reaction mixure was purified by column chromatography (1:1 DCM/hexanes) to
afford I-113 (22.6 mg, 0.0740 mmol) in 74% yield.
Spectral data for I-113: 1H NMR (500 MHz, CDCl3) δ 2.43 (s, 3H), 4.53 (s, 2H),
7.14 (dt, J = 7.7, 1.3 Hz, 1H), 7.22 – 7.41 (m, 4H), 7.41 – 7.56 (m, 2H), 7.76 – 7.89 (m,
2H), 7.97 (s, 1H). These spectral data match those previously reported for this
compound4.
4.2.4 Optimization of asymmetric epoxidation using N-phenyl diazoacetamide I-107b
(Table 1.3) -- illustrated by entry 16

10 mol%
(R)-VANOL
or VAPOL

10 mol% base

toluene, 80 ÂşC, 1 h,
then 0.5 mm Hg, 80 ÂşC, 0.5 h

toluene, rt, 1 h,
then cool to –60 ºC

O
H

I-51a
1.1 equiv

+

base-H

30 mol% B(OPh)3
30 mol% H2O

O
N2

N
H
I-23b

OPh
O B
O
O
* O B
O B
OPh
Boroxinate catalyst I-103

O
10 mol% I-103
CHCl3, –60 ºC,
24 h

O
CONHPh

I-111b
70%, 67% ee

CONHPh
+

I-114b
5.1%

Preparation of the catalyst stock solution I-103: To a 50 mL flame-dried homemade Schlenk flask, prepared from a single-necked 50 mL pear-shaped flask that had its

210

14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped with a stir
bar and flushed with nitrogen was added (R)-VANOL (22.0 mg, 0.0500 mmol) and
commercial B(OPh)3 (43.5 mg, 0.150 mmol) and water (2.7 ÎźL, 0.050 mmol). Under an
argon flow through the side-arm of the Schlenk flask, dry THF (1 mL) was added through
the top of the Teflon valve to effect dissolution. The flask was sealed by closing the Teflon
valve, and then placed in an 80 ÂşC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was
carefully applied by slightly opening the Teflon valve to remove the volatiles. After the
volatiles were removed completely, a full vacuum was applied and maintained for a period
of 30 min at a temperature of 80 ÂşC (oil bath). The flask was then allowed to cool to room
temperature and opened to nitrogen through the side-arm of the Schlenk flask. This was
then completely dissolved in dry CHCl3 (1 mL) under an argon flow through side-arm of
the Schlenk flask. To the flask was added the dimethyl sulfoxide (3.6 ÎźL, 0.050 mmol) or
orther base indicated in the table (0.050 mmol) under a nitrogen flow through side-arm of
the Schlenk flask. The resulting mixture was stirred for 1 h at room temperature to afford
the solution of the precatalyst.
Asymmetric epoxidation protocol: The flask containing the precatalyst was cooled
to –60 °C for 10 min. To the catalyst was then added diazoacetamide I-23b (80.6 mg,
0.500 mmol) followed by closing the Teflon valve and stirring the resulting mixture for 10
min at –60 °C. To the mixture containing diazoacetamide I-23b and catalyst was then
added neat benzaldehyde I-51a (61 ÎźL, 0.60 mmol) dropwise using a microsyringe and
the resulting mixture was stirred for 24 h at –60 °C. The reaction was quenched by the
addition of H2O (0.5 mL) and was then warmed to room temperature. The reaction mixture

211

was then transferred to a 60 mL separatory funnel. The water layer was extracted with
CH2Cl2 (2 mL × 3) and dried over Na2SO4. The combined organic layer was filtered to the
50 mL round bottom flask. The resulting solution was then concentrated in vacuo followed
by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude epoxide as an offwhite semi-solid. Purification of the crude epoxide epoxide by silica gel chromatography
(17 mm × 300 mm column, 3:1 to 1:1 hexanes/ ethyl acetate as eluent) afforded pure cisepoxide I-111b as a white solid (mp 101-103 ºC) in 70% isolated yield (83.9 mg, 0.351
mmol); cis/trans: 64:1. β-ketoamide side product I-114b: 5.1% yield. The optical purity of
I-111b was determined to be 67% ee by HPLC analysis (CHIRALCEL OD-H column,
90:10 hexane/2-propanol at 222 nm, flow-rate: 1 mL/min): retention times; Rt = 8.17 min
(minor enantiomer, ent-I-111b) and Rt = 10.33 min (major enantiomer, I-111b).
4.2.5 KIE samples preparation (Table 1.4) -- illustrated by set 2

10 mol%
(S)-VANOL

10 mol%
(S)-VANOL

30 mol% BH3•Me2S
20 mol% PhOH
30 mol% H2O
toluene, 100 ÂşC, 1 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

30 mol% BH3•Me2S
20 mol% PhOH
30 mol% H2O
toluene, 100 ÂşC, 1 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

O

O
H

I-51a

+

N2

DMSO-H
10 mol% DMSO
toluene, rt, 1 h,
then cool to –60 ºC

base-H
100 mol% I-23b
cool to –60 ºC

10 mol% A or B

N
H

OPh
O B
O
O
* O B
O B
OPh
boroxinate catalyst A

CHCl3, 0.2 M, –60 ºC,
24 h

I-23b

OPh
O B
O
O
* O B
O B
OPh
boroxinate catalyst B
O
CONHPh

I-111b

212

Asymmetric epoxidation protocol for boroxinate catalyst A: Catalyst A was
prepared according to the general procedure in 4.2.2 described above on 0.24 mmol
scale in two 50 mL Schlenk flasks. Both flasks containing the catalyst were cooled to –60
°C for 10 min and were diluted to 0.02 M by adding CHCl3. Sample 1 (20% conversion for
I-23b): To the catalyst was then added diazoacetamide I-23b (1.934 g, 12.00 mmol)
followed by closing the Teflon valve and stirring the resulting mixture for 10 min at –60
°C. To the mixture containing diazoacetamide I-23b and catalyst was then added neat
benzaldehyde I-51a (243 ÎźL, 2.40 mmol) dropwise using a microsyringe and the resulting
mixture was stirred for 24 h at –60 °C. Sample 2 (20% conversion for I-51a): To the
catalyst was then added benzaldehyde I-51a (1.22 mL, 12.0 mmol) followed by closing
the Teflon valve and stirring the resulting mixture for 10 min at –60 °C. To the mixture
containing benzaldehyde I-51a and catalyst was then added diazoacetamide I-23b (387
g, 2.40 mmol) and the resulting mixture was stirred for 24 h at –60 °C. Both reactions
were quenched by the addition of H2O (2.0 mL) and was then warmed to room
temperature. The reaction mixture was then transferred to a 60 mL separatory funnel.
The water layer was extracted with CH2Cl2 (5 mL × 3) and dried over Na2SO4. The
combined organic layer was filtered to the 100 mL round bottom flask. The resulting
solution was then concentrated in vacuo followed by exposure to high vacuum (0.05 mm
Hg) for 1 h to afford the crude epoxide as an off-white semi-solid. Purification of the crude
epoxide epoxide by silica gel chromatography (17 mm × 300 mm column, 3:1 to 1:1
hexanes/ ethyl acetate as eluent) afforded pure cis-epoxide I-111b as a white solid (mp
101-103 ÂşC) in 80% isolated yield (458 mg, 1.91 mmol) for sample 1 and in 67% isolated

213

yield (386 mg, 1.61 mmol) for sample 2. The optical purity of I-111b was determined to
be 90% ee for sample 1 and 93% ee for sample 2 by HPLC analysis (CHIRALCEL OD-H
column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 1 mL/min): retention times; Rt =
8.17 min (major enantiomer, 22a) and Rt = 10.33 min (minor enantiomer, ent-22a).
General procedure for boroxinate catalyst B: Catalyst B was prepared following
general procedure in 4.2.2 except for no DMSO was added. The two samples were
obtained and analyzed by the same procedure above.
4.2.6 Epoxidation catalyzed by boroxinate with aniline (Table 1.5) -- illustrated by
entry 16

10 mol%
(R)-VANOL

toluene, 100 ÂşC, 1 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

H

+

N2

OPh
O B
O
B
O
*
O
O B
OPh
Boroxinate catalyst I-103b

[I-117-H]
10 mol% aniline I-117
CHCl3, rt, 1 h,
then cool to –60 ºC

O

O

O

I-51a

30 mol% BH3•Me2S
20 mol% PhOH
30 mol% H2O

10 mol% I-103b

N
H

CHCl3, 0.5 M, –60 ºC,
24 h

I-23b

O
CONHPh +

I-111b
47%, 76% ee

CONHPh

I-114b
9%

Preparation of the catalyst solution: Precatalyst for I-103b was prepared according
to the general procedure in 4.2.2 described above. To the flask containing the pre-catalyst
was added CHCl3 (1 mL) and then aniline I-117a (0.05 mmol) under a nitrogen flow
through side-arm of the Schlenk flask. The resulting mixture was stirred for 1 h at room
temperature to give the precatalyst.
Asymmetric epoxidation protocol: The flask containing the catalyst was cooled to
–60 °C for 10 min. To the catalyst was then added diazoacetamide I-23b (80.6 mg, 0.500

214

mmol) followed by closing the Teflon valve and stirring the resulting mixture for 10 min at
–60 °C. To the mixture containing diazoacetamide I-23b and catalyst was then added
neat benzaldehyde I-51a (56 ÎźL, 0.55 mmol) dropwise using a microsyringe and the
resulting mixture was stirred for 24 h at –60 °C. The reaction was quenched by the
addition of H2O (0.5 mL) and was then warmed to room temperature. The reaction mixture
was then transferred to a 60 mL separatory funnel. The water layer was extracted with
CH2Cl2 (2 mL × 3) and dried over Na2SO4. The combined organic layer was filtered to the
50 mL round bottom flask. The resulting solution was then concentrated in vacuo followed
by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude epoxide as an offwhite semi-solid. Purification of the crude epoxide epoxide by silica gel chromatography
(17 mm × 300 mm column, 3:1 to 1:1 hexanes/ ethyl acetate as eluent) afforded pure cisepoxide I-111b as a white solid (mp 101-103 ºC) in 47% isolated yield (56.2 mg, 0.235
mmol); cis/trans: 64:1. β-ketoamide side product I-114b: 9% yield. The optical purity of I111b was determined to be 76% ee by HPLC analysis (CHIRALCEL OD-H column, 90:10
hexane/2-propanol at 222 nm, flow-rate: 1 mL/min): retention times; Rt = 8.17 min (minor
enantiomer, ent-I-111b) and Rt = 10.33 min (major enantiomer, I-111b).

215

4.2.7 Evolution of catalyst (Table 1.6) -- illustrated by entry 3

10 mol%
(R)-VANOL

Ph

10 mol% DMSO

toluene, 100 ÂşC, 1 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

toluene, rt, 1 h,
then cool to –60 ºC

O

O

+

H

I-51a
1.1 equiv

DMSO-H

30 mol% BH3•Me2S
30 mol% H2O

N2

Bu

N
H
I-23a
0.50 mmol

10 mol% I-103?
toluene, –60 ºC,
time, 0.05 M

O
Ph

CONHBu

I-111a
92%, 99% ee

OH
O B
O
O
* O B
O B
OH
Boroxinate catalyst I-103?
O

+

Ph

CONHBu

I-114a
<1%

Preparation of the catalyst solution: To a 50 mL flame-dried home-made Schlenk
flask, prepared from a single-necked 50 mL pear-shaped flask that had its 14/20 glass
joint replaced with a high vacuum threaded Teflon valve, equipped with a stir bar and
flushed with nitrogen was added (R)-VANOL (22.0 mg, 0.0500 mmol). Under a nitrogen
flow through the side-arm of the Schlenk flask, dry toluene (1.5 mL) was added through
the top of the Teflon valve to effect dissolution. After the addition of the toluene, BH3•Me2S
(75 ÎźL, 0.15 mmol, 2 M in toluene) and water (2.7 ÎźL, 0.050 mmol) were added. The flask
was sealed by closing the Teflon valve, and then placed in a 100 ÂşC oil bath for 1 h. After
1 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to
remove the volatiles. After the volatiles were removed completely, a full vacuum was
applied and maintained for a period of 30 min at a temperature of 100 ÂşC (oil bath). The
flask was then allowed to cool to room temperature and opened to nitrogen through the
side-arm of the Schlenk flask. This was then completely dissolved in dry toluene (2 mL)
under an argon flow through side-arm of the Schlenk flask to afford the solution of the
pre-catalyst. To the flask containing the pre-catalyst was added the dimethyl sulfoxide

216

(3.6 ÎźL, 0.050 mmol) under a nitrogen flow through side-arm of the Schlenk flask. The
resulting mixture was stirred for 1 h at room temperature to give the precatalyst.
Asymmetric epoxidation protocol: The flask containing the catalyst was cooled to
–60 °C for 10 min. Meanwhile, to a separate 15 mL flame-dried round bottom flask was
added diazoacetamide I-23a (70.6mg, 0.500 mmol) and dry toluene (6.0 mL) to give the
pre-made solution. To the catalyst solution was added pre-made solution of
diazoacetamide I-23a via syringe. The flask containing the diazoacetamide I-23a was
then rinsed with toluene (2 mL) and the rinse was then transferred to the flask containing
the catalyst at –60 °C. This was then followed by closing the Teflon valve and stirring the
resulting mixture for 10 min at –60 °C. To the mixture containing diazoacetamide I-23a
and catalyst was then added neat benzaldehyde I-51a (56 ÎźL, 0.55 mmol) dropwise using
a microsyringe and the resulting mixture was stirred for 24 h at –60 °C. The reaction was
quenched by the addition of H2O (0.5 mL) and was then warmed to room temperature.
The reaction mixture was then transferred to a 60 mL separatory funnel. The water layer
was extracted with CH2Cl2 (2 mL × 3) and dried over Na2SO4. The combined organic layer
was filtered to the 50 mL round bottom flask. The resulting solution was then concentrated
in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude
epoxide as an off-white semi-solid. Purification of the crude epoxide by silica gel
chromatography (17 mm × 300 mm column, 3:1 to 1:1 hexanes/ ethyl acetate as eluent)
afforded pure cis-epoxide I-111a as a colorless semi-solid (105-106 ÂşC) in 92% isolated
yield (100 mg, 0.457 mmol); cis/trans: >100:1. β-ketoamide side product I-114a: <1 %
yield. The optical purity of I-111a was determined to be 99% ee by HPLC analysis

217

(PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm,
flow-rate: 1 mL/min): retention times; Rt = 16.26 min (minor enantiomer, ent-I-111a) and
Rt = 19.95 min (major enantiomer, I-111a).
4.2.8 Optimization of condition for epoxidation catalyzed by mesoborate I-118 (Table
1.7) -- illustrated by entry 9
H O

10 mol%
(R)-VANOL

10 mol% DMSO

toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

toluene, rt
then cool to –40 ºC

O

O
Ph

5 mol% BH3•Me2S

+

H

I-51a
1.1 equiv

N2

N
H

Bu

10 mol% I-118

spiroborate catalyst I-118

O

toluene, –40 ºC,
Ph
4 Å MS, 1 h, 0.10 M

I-23a
0.50 mmol

*

CONHBu

I-111a
97%, 99% ee

*
O
B O
O
O S

O

+

Ph

CONHBu

I-114a
<1%

Preparation of the catalyst stock solution I-118: To a 50 mL flame-dried homemade Schlenk flask, prepared from a single-necked 50 mL pear-shaped flask that had its
14/20 glass joint replaced with a T-shaped high vacuum threaded Teflon valve, equipped
with a stir bar and flushed with nitrogen was added (R)-VANOL (33.0 mg, 0.0750 mmol).
Under a nitrogen flow through the side-arm of the Schlenk flask, dry toluene (3 mL) was
added through the top of the Teflon valve to effect dissolution. After the addition of the
toluene, BH3•Me2S (19.0 μL, 0.0375 mmol, 2 M in toluene) was added. The flask was
sealed by closing the Teflon valve, and then placed in a 100 ÂşC oil bath for 0.5 h. After
0.5 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve
to remove the volatiles. After the volatiles were removed completely, a full vacuum was
applied and maintained for a period of 30 min at a temperature of 100 ÂşC (oil bath). The
218

flask was then allowed to cool to room temperature and opened to nitrogen through the
side-arm of the Schlenk flask. The residue was then completely dissolved in dry toluene
(3 mL) under a nitrogen flow through side-arm of the Schlenk flask to afford the solution
of the pre-catalyst. To the flask containing the pre-catalyst was added the dimethyl
sulfoxide (5.4 ÎźL, 0.075 mmol) under a nitrogen flow through side-arm of the Schlenk
flask to give the solution of catalyst which was immediately cooled to –40 °C in preparation
for initiation of the reaction.
Asymmetric epoxidation protocol: A 25 mL round bottom flask was added 100 mg
4 Å MS and then flame dried under vacuum. After the flask cooled to rt under N2, the
vacuum adapter was replaced with a rubber septum. The septum was removed briefly to
allow introduction of diazoacetamide I-23a (70.6 mg, 0.500 mmol). Subsequently, the
septum was removed again to allow for the addition of a dry stir bar and anhydrous
toluene (3 mL). Neat benzaldehyde I-51a (60 ÎźL, 0.60 mmol, freshly distilled) was then
added via syringe and a N2 balloon was attached via a needle in the septum. The mixture
was stirred at rt for 10 min to effect dissolution. The round bottom flask and the Schlenk
flask containing the catalyst were both cooled to –40 °C in a cold bath with a recirculating
chiller for 10 min. The catalyst solution (2.0 mL, 0.025 mmol catalyst) was quickly
transferred to the round bottom flask using a syringe. The resulting mixture was stirred
until the yellow color disappeared. The reaction was quenched after 1 h by the addition
of H2O (1 mL) and was then warmed to room temperature. The reaction mixture was then
transferred to a 60 mL separatory funnel. The water layer was extracted with EtOAc (2
mL × 3) and dried over Na2SO4. The combined organic layer was filtered into a 50 mL

219

round bottom flask. The resulting solution was then concentrated under vacuum followed
by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude epoxide as an offwhite semi-solid. No trans epoxide and β-ketoamide side product was observed by 1H
NMR in the crude reaction mixture. Purification of the crude epoxide by silica gel
chromatography (20 mm × 300 mm column, 3:1 to 1:1 hexanes/EtOAc as eluent) afforded
pure cis-epoxide I-111a as a white solid in 99% isolated yield (106 mg, 0.483 mmol);
cis/trans: >100:1. β-ketoamide side product: <1% yield. The optical purity of I-111a was
determined to be >99% ee by HPLC (PIRKLE COVALENT (R,R) WHELK-O 1 column,
93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt = 24.63 min
(minor enantiomer, ent- I-111a) and Rt = 31.46 min (major enantiomer, I-111a).
4.2.9 Catalyst loading and stability study (Table 1.8 & 1.9) -- illustrated by entry 3 for
both
H O

4 mol%
(S)-VANOL

2 mol% BH3•Me2S
toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

O

O
Ph

4 mol% DMSO

+

H

I-51a
1.2 equiv

N2

N
H
I-23a

Bu

*

toluene, rt, 1 h,
then cool to –40 ºC

*
O
B O
O
O S

spiroborate catalyst I-118
2 mol% I-118

toluene, –40 ºC,
1 h, 0.25 M

O
Ph

CONHBu

I-111a
88%, 99% ee

Catalyst I-118 was prepared according to the general procedure in 4.2.8
described above.
Asymmetric epoxidation with 4 mol% I-118: A 25 mL round bottom flask was flame
dried under vacuum and cooled to rt under N2. The vacuum adapter was replaced with a

220

rubber septum. The septum was removed briefly to allow introduction of diazoacetamide
I-23a (70.6 mg, 0.500 mmol). Subsequently, the septum was removed again to allow for
the addition of a dry stir bar and anhydrous toluene (1.2 mL). Neat benzaldehyde I-51a
(60 ÎźL, 0.60 mmol, freshly distilled) was then added via syringe and a N2 balloon was
attached via a needle in the septum. The mixture was stirred at rt for 10 min to effect
dissolution. The round bottom flask and the Schlenk flask containing the catalyst were
both cooled to –40 °C in a cold bath with a recirculating chiller for 10 min. The catalyst
solution (0.8 mL, 0.01 mmol catalyst) was quickly transferred to the round bottom flask
using a syringe. The resulting mixture was stirred until the yellow color disappeared. The
reaction was quenched after 1 h by the addition of H2O (1 mL) and was then warmed to
room temperature. The reaction mixture was then transferred to a 60 mL separatory
funnel. The water layer was extracted with EtOAc (2 mL × 3) and dried over Na2SO4. The
combined organic layer was filtered into a 50 mL round bottom flask. The resulting
solution was then concentrated under vacuum followed by exposure to high vacuum (0.05
mm Hg) for 1 h to afford the crude epoxide as an off-white semi-solid. No trans epoxide
and β-ketoamide side product was observed by 1H NMR in the crude reaction mixture.
Purification of the crude epoxide by silica gel chromatography (20 mm × 300 mm column,
3:1 to 1:1 hexanes/EtOAc as eluent) afforded pure cis-epoxide I-111a as a white solid in
88% isolated yield (96.6 mg, 0.441 mmol); cis/trans: >100:1. β-ketoamide side product:
<1% yield. The optical purity of I-111a was determined to be 99% ee by HPLC (PIRKLE
COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1

221

mL/min): retention times: Rt = 24.63 min (major enantiomer, I-111a) and Rt = 31.46 min
(minor enantiomer, ent-I-111a).
O
H
+

Br
I-51f
1.2 equiv

10 mol%
37-days-old I-118

O
N2

N
H

Bu

I-23a
0.50 mmol

O
CONHBu

toluene, –40 ºC,
30 min, 0.10 M Br

I-129a
97%, 99% ee

Catalyst I-118 was prepared according to the general procedure in 4.2.8
described above. The Schlenk flask containing I-118 was sealed by closing the Teflon
valve, and then clamped on benchtop for 37 days.
Asymmetric epoxidation with 37-day-old I-118: A 25 mL round bottom flask was
flame dried under vacuum and cooled to rt under N2. The vacuum adapter was replaced
with a rubber septum. The septum was removed briefly to allow introduction of
diazoacetamide I-23a (70.6 mg, 0.500 mmol). Subsequently, the septum was removed
again to allow for the addition of a dry stir bar and anhydrous toluene (3 mL). 4bromobenzaldehyde I-51f (111 mg, 0.600 mmol) was then added and a N2 balloon was
attached via a needle in the septum. The mixture was stirred at rt for 10 min to effect
dissolution. The round bottom flask and the Schlenk flask containing the catalyst were
both cooled to –40 °C in a cold bath with a recirculating chiller for 10 min. The catalyst
solution (2.0 mL, 0.025 mmol catalyst) was quickly transferred to the round bottom flask
using a syringe. The resulting mixture was stirred until the yellow color disappeared. The
reaction was quenched after 30 min by the addition of H2O (1 mL) and was then warmed
to room temperature. The reaction mixture was then transferred to a 60 mL separatory
funnel. The water layer was extracted with EtOAc (2 mL × 3) and dried over Na2SO4. The

222

combined organic layer was filtered into a 50 mL round bottom flask. The resulting
solution was then concentrated under vacuum followed by exposure to high vacuum (0.05
mm Hg) for 1 h to afford the crude epoxide as a white solid. No trans epoxide and βketoamide side product was observed by 1H NMR in the crude reaction mixture.
Purification of the crude epoxide by silica gel chromatography (20 mm × 300 mm column,
3:1 to 1:1 hexanes/EtOAc as eluent) afforded pure cis-epoxide I-129a as a white solid in
97% isolated yield (145 mg, 0.485 mmol); cis/trans: >100:1. β-ketoamide side product:
<1% yield. The optical purity of I-129a was determined to be 99% ee by HPLC (PIRKLE
COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1
mL/min): retention times: Rt = 28.91 min (major enantiomer, I-129a) and Rt = 45.53 min
(minor enantiomer, ent-I-129a).
4.2.10 Ligand effect in epoxidation catalyzed by mesoborate I-118 (Table 1.10) -illustrated by entry 6

10 mol%
(R)-BINOL

Ph

toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

O

O

+

H

I-51a
1.2 equiv

H O

5 mol% BH3•Me2S

N2

N
H

Bu

*

*

spiroborate catalyst I-118’

10 mol% I-118’
toluene,
0 ÂşC, 0.5 h, 0.10 M

I-23a
0.50 mmol

O
B O
O

O
Ph

CONHBu

I-111a
62%, 62% ee

Preparation of the catalyst stock solution I-118: To a 50 mL flame-dried homemade Schlenk flask, prepared from a single-necked 50 mL pear-shaped flask that had its
14/20 glass joint replaced with a T-shaped high vacuum threaded Teflon valve, equipped
with a stir bar and flushed with nitrogen was added (R)-BINOL (21.5 mg, 0.0750 mmol).
223

Under a nitrogen flow through the side-arm of the Schlenk flask, dry toluene (3 mL) was
added through the top of the Teflon valve to effect dissolution. After the addition of the
toluene, BH3•Me2S (19.0 μL, 0.0375 mmol, 2 M in toluene) was added. The flask was
sealed by closing the Teflon valve, and then placed in a 100 ÂşC oil bath for 0.5 h. After
0.5 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve
to remove the volatiles. After the volatiles were removed completely, a full vacuum was
applied and maintained for a period of 30 min at a temperature of 100 ÂşC (oil bath). The
flask was then allowed to cool to room temperature and opened to nitrogen through the
side-arm of the Schlenk flask. The residue was then completely dissolved in dry toluene
(3 mL) under a nitrogen flow through side-arm of the Schlenk flask to afford the solution
of the pre-catalyst. The precatalyst was immediately cooled to –40 °C.
Asymmetric epoxidation protocol: A 25 mL round bottom flask was flame dried
under vacuum and cooled to rt under N2. The vacuum adapter was replaced with a rubber
septum. The septum was removed briefly to allow introduction of diazoacetamide I-23a
(70.6 mg, 0.500 mmol). Subsequently, the septum was removed again to allow for the
addition of a dry stir bar and anhydrous toluene (3 mL). Neat benzaldehyde I-51a (60 ÎźL,
0.60 mmol, freshly distilled) was then added via syringe and a N2 balloon was attached
via a needle in the septum. The mixture was stirred at rt for 10 min to effect dissolution.
The round bottom flask and the Schlenk flask containing the catalyst were both cooled to
–40 °C in a cold bath with a recirculating chiller for 10 min. The catalyst solution (2 mL,
0.025 mmol catalyst) was quickly transferred to the round bottom flask using a syringe.
The resulting mixture was stirred until the yellow color disappeared. The reaction was

224

quenched after 0.5 h by the addition of H2O (1 mL) and was then warmed to room
temperature. The reaction mixture was then transferred to a 60 mL separatory funnel.
The water layer was extracted with EtOAc (2 mL × 3) and dried over Na2SO4. The
combined organic layer was filtered into a 50 mL round bottom flask. The resulting
solution was then concentrated under vacuum followed by exposure to high vacuum (0.05
mm Hg) for 1 h to afford the crude epoxide as an off-white semi-solid. No trans epoxide
and β-ketoamide side product was observed by 1H NMR in the crude reaction mixture.
Purification of the crude epoxide by silica gel chromatography (20 mm × 300 mm column,
3:1 to 1:1 hexanes/EtOAc as eluent) afforded pure cis-epoxide I-111a as a white solid in
62% isolated yield (68.2 mg, 0.311 mmol). The optical purity of I-111a was determined to
be 62% ee by HPLC (PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt = 24.63 min (minor
enantiomer, ent- I-111a) and Rt = 31.46 min (major enantiomer, I-111a).

225

4.2.11 PhOH additive studies (Table 1.11) -- illustrated by entry 3
H O
10 mol%
(R)-VANOL

5 mol% BH3•Me2S

10 mol% DMSO

toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

toluene, rt,
then cool to –40 ºC

toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

25 mol% BH3•Me2S
20 mol% PhOH,
30 mol% H2O,

H +

N2

7

I-51g
1.2 equiv

N
H

O
B O
O
O S

spiroborate catalyst I-118

“complement” to boroxinate

10 mol% I-118
“complement”

O

O

*

O

Ph

CONHPh
toluene, –40 ºC,
24 h, 0.10 M

I-23b
0.50 mmol

7

I-137b
92%, 83% ee

Catalyst I-118 was prepared according to the general procedure in 4.2.8 described
above. In another Schlenk flask, a solution of 25 mol% BH3•SMe2, 20 mol% PhOH and
30 mol% of H2O was heated in toluene for 1 h and then all volatiles were removed at 100
°C at 0.5 mm Hg for 0.5 h to afford the mixture (complement substances of boroxinate
catalyst). To the “complement” flask was added 3 mL toluene to dissolve all the solid. The
solution was transfer to the catalyst I-118. And to the catalyst was added the dimethyl
sulfoxide (5.4 ÎźL, 0.075 mmol) under a nitrogen flow through side-arm of the Schlenk
flask to give the solution of catalyst which was immediately cooled to –40 °C in preparation
for initiation of the reaction.
Asymmetric epoxidation protocol: A 25 mL round bottom flask was flame dried
under vacuum and cooled to rt under N2. The vacuum adapter was replaced with a rubber
septum. The septum was removed briefly to allow introduction of diazoacetamide I-23b
(80.6 mg, 0.500 mmol). Subsequently, the septum was removed again to allow for the

226

addition of a dry stir bar and anhydrous toluene (3 mL). Neat benzaldehyde I-51g (103
ÎźL, 0.60 mmol, freshly distilled) was then added via syringe and a N2 balloon was
attached via a needle in the septum. The mixture was stirred at rt for 10 min to effect
dissolution. The round bottom flask and the Schlenk flask containing the catalyst were
both cooled to –40 °C in a cold bath with a recirculating chiller for 10 min. The catalyst
solution (2.0 mL, 0.025 mmol catalyst) was quickly transferred to the round bottom flask
using a syringe. The resulting mixture was stirred until the yellow color disappeared. The
reaction was quenched after 24 h by the addition of H2O (1 mL) and was then warmed to
room temperature. The reaction mixture was then transferred to a 60 mL separatory
funnel. The water layer was extracted with EtOAc (2 mL × 3) and dried over Na2SO4. The
combined organic layer was filtered into a 50 mL round bottom flask. The resulting
solution was then concentrated under vacuum followed by exposure to high vacuum (0.05
mm Hg) for 1 h to afford the crude epoxide as a colorless oil. No trans epoxide and βketoamide side product was observed by 1H NMR in the crude reaction mixture.
Purification of the crude epoxide by silica gel chromatography (20 mm × 300 mm column,
10:1 to 4:1 hexanes/EtOAc as eluent) afforded pure cis-epoxide I-137b as a colorless oil
in 92% isolated yield (127 mg, 0.461 mmol). The optical purity of I-137b was determined
to be 83% ee by HPLC (Daicel Chirapak OD-H column, 94:6 hexane/2-propanol at 228
nm, flow-rate: 1 mL/min): retention times: Rt = 4.89 min (minor enantiomer, ent-I-137b)
and Rt = 9.23 min (major enantiomer, I-137b).

227

4.2.12 Nonlinear effect study on two catalytic systems (Table 1.12) -- illustrated by
entry 7

10 mol%
57% ee (R)-VANOL

30 mol% BH3•Me2S
20 mol% PhOH
30 mol% H2O

DMSO-H

10 mol% DMSO
toluene, rt, 1 h,
then cool to –40 ºC

toluene, 100 ÂşC, 1 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

OPh
O B
O
O
* O B
O B
OPh
boroxinate catalyst A

H O
10 mol%
57% ee (R)-VANOL

5 mol% BH3•Me2S

10 mol% DMSO

toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

toluene, rt,
then cool to –40 ºC

*

O
B O
O
O S

spiroborate catalyst B
O
H +

Br
I-51f
1.2 equiv

O
N2

N
H

Bu

I-23a
0.50 mmol

10 mol% catalyst
toluene, –40 ºC, 0.10 M
12 h for A
Br
20 min for B,

O
CONHBu

I-129a

A: 68%, 58% ee
B: 86%, 95% ee

Catalyst A was prepared according to the general procedure in 4.2.2 described
above on a 0.075 mmol scale. Catalyst B was prepared according to the general
procedure in 4.2.8 described above.
Asymmetric epoxidation protocol for A: A 25 mL Schlenk flask was flame dried
under vacuum and cooled to rt under N2. Under a nitrogen flow through the side-arm of
the Schlenk flask, diazoacetamide I-23a (70.6 mg, 0.500 mmol), a dry stir bar and
anhydrous toluene (3 mL) was added. 4-bromobenzaldehyde I-51f (111 mg, 0.600 mmol)
was then added. The mixture was stirred at rt for 10 min to effect dissolution. This Schlenk
flask and the Schlenk flask containing the catalyst were both cooled to –60 °C in a cold
bath with a recirculating chiller for 10 min. The catalyst solution (2.0 mL, 0.025 mmol

228

catalyst) was quickly transferred to the Schlenk flask using a syringe. The resulting
mixture was stirred until the yellow color disappeared. The reaction was quenched after
12 h by the addition of H2O (1 mL) and was then warmed to room temperature. The
reaction mixture was then transferred to a 60 mL separatory funnel. The water layer was
extracted with EtOAc (2 mL × 3) and dried over Na2SO4. The combined organic layer was
filtered into a 50 mL round bottom flask. The resulting solution was then concentrated
under vacuum followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the
crude epoxide as as a white solid. Purification of the crude epoxide by silica gel
chromatography (20 mm × 300 mm column, 3:1 to 1:1 hexanes/EtOAc as eluent) afforded
pure cis-epoxide I-129a as as a white solid in 68% isolated yield (112 mg, 0.342 mmol).
The optical purity of I-129a was determined to be 58% ee by HPLC (PIRKLE COVALENT
(R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min):
retention times: Rt = 28.91 min (major enantiomer, I-129a) and Rt = 45.53 min (minor
enantiomer, ent-I-129a).
Asymmetric epoxidation protocol for B: A 25 mL round bottom flask was flame
dried under vacuum and cooled to rt under N2. The vacuum adapter was replaced with a
rubber septum. The septum was removed briefly to allow introduction of diazoacetamide
I-23a (70.6 mg, 0.500 mmol). Subsequently, the septum was removed again to allow for
the addition of a dry stir bar and anhydrous toluene (3 mL). 4-bromobenzaldehyde I-51f
(111 mg, 0.600 mmol) was then added and a N2 balloon was attached via a needle in the
septum. The mixture was stirred at rt for 10 min to effect dissolution. The round bottom
flask and the Schlenk flask containing the catalyst were both cooled to –40 °C in a cold

229

bath with a recirculating chiller for 10 min. The catalyst solution (2.0 mL, 0.025 mmol
catalyst) was quickly transferred to the round bottom flask using a syringe. The resulting
mixture was stirred until the yellow color disappeared. The reaction was quenched after
30 min by the addition of H2O (1 mL) and was then warmed to room temperature. The
reaction mixture was then transferred to a 60 mL separatory funnel. The water layer was
extracted with EtOAc (2 mL × 3) and dried over Na2SO4. The combined organic layer was
filtered into a 50 mL round bottom flask. The resulting solution was then concentrated
under vacuum followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the
crude epoxide as a white solid. Purification of the crude epoxide by silica gel
chromatography (20 mm × 300 mm column, 3:1 to 1:1 hexanes/EtOAc as eluent) afforded
pure cis-epoxide I-129a as a white solid in 86% isolated yield (129 mg, 0.432 mmol); The
optical purity of I-129a was determined to be 95% ee by HPLC (PIRKLE COVALENT
(R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min):
retention times: Rt = 28.91 min (major enantiomer, I-129a) and Rt = 45.53 min (minor
enantiomer, ent-I-129a). The absolute configuration of I-111b, I-137b and I-138b are
known5 and that of I-111a was determined by conversion to the taxol side chain I-146
(Scheme 1.17) and the rest were assumed to be homo-chiral.

230

4.2.13 General procedure C for substrate scope study with respect to aldehydes
(Scheme 1.14) -- illustrated for I-111a
H O

10 mol%
(R)-VANOL

5 mol% BH3•Me2S

10 mol% DMSO

toluene, 100 ÂşC, 1 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

toluene, rt,
then cool to –40 ºC

*

*
O
B O
O
O S

spiroborate catalyst I-118

O

O

Ph

H

I-51a
1.2 equiv.

+

N2

N
H
I-23a
0.5 mmol

Bu

O

5 mol% I-118,
toluene, –40 ºC
10 min, 0.1 M
(2 h, without DMSO)

Ph

CONHBu

I-111a
99%, >99% ee
(86%, 93% ee)

Preparation of the catalyst I-118 stock solution: To a 50 mL flame-dried homemade Schlenk flask, prepared from a single-necked 50 mL pear-shaped flask that had its
14/20 glass joint replaced with a T-shaped high vacuum threaded Teflon valve, equipped
with a stir bar and flushed with nitrogen was added (R)-VANOL (33.0 mg, 0.0750 mmol).
Under a nitrogen flow through the side-arm of the Schlenk flask, dry toluene (3 mL) was
added through the top of the Teflon valve to effect dissolution. After the addition of the
toluene, BH3•Me2S (19.0 μL, 0.0375 mmol, 2 M in toluene) was added. The flask was
sealed by closing the Teflon valve, and then placed in a 100 ÂşC oil bath for 0.5 h. After
0.5 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve
to remove the volatiles. After the volatiles were removed completely, a full vacuum was
applied and maintained for a period of 30 min at a temperature of 100 ÂşC (oil bath). The
flask was then allowed to cool to room temperature and opened to nitrogen through the
side-arm of the Schlenk flask. The residue was then completely dissolved in dry toluene
(3 mL) under a nitrogen flow through side-arm of the Schlenk flask to afford the solution
231

of the pre-catalyst. To the flask containing the pre-catalyst was added the dimethyl
sulfoxide (5.4 ÎźL, 0.075 mmol) under a nitrogen flow through side-arm of the Schlenk
flask to give the solution of catalyst which was immediately cooled to –40 °C in preparation
for initiation of the reaction.
Asymmetric epoxidation protocol: A 25 mL round bottom flask was flame dried
under vacuum and cooled to rt under N2. The vacuum adapter was replaced with a rubber
septum. The septum was removed briefly to allow introduction of diazoacetamide I-23a
(70.6 mg, 0.500 mmol). Subsequently, the septum was removed again to allow for the
addition of a dry stir bar and anhydrous toluene (3 mL). Neat benzaldehyde I-51a (60 ÎźL,
0.60 mmol, freshly distilled) was then added via syringe and a N2 balloon was attached
via a needle in the septum. The mixture was stirred at rt for 10 min to effect dissolution.
The round bottom flask and the Schlenk flask containing the catalyst were both cooled to
–40 °C in a cold bath with a recirculating chiller for 10 min. The catalyst solution (2 mL,
0.025 mmol catalyst) was quickly transferred to the round bottom flask using a syringe.
The resulting mixture was stirred until the yellow color disappeared (10 min). The reaction
was quenched by the addition of H2O (1 mL) and was then warmed to room temperature.
The reaction mixture was then transferred to a 60 mL separatory funnel. The water layer
was extracted with EtOAc (2 mL × 3) and dried over Na2SO4. The combined organic layer
was filtered into a 50 mL round bottom flask. The resulting solution was then concentrated
under vacuum followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the
crude epoxide as an off-white semi-solid. The cis/trans ratio was determined by
comparing the 1H NMR integration of the ring methine (δ 3.77 for cis, δ 3.60 for trans) for

232

each epoxide in the crude reaction mixture. The yield of the acyclic β-ketoamide side
product was determined by 1H NMR analysis of the crude reaction mixture by integration
of the methylene protons (δ 3.94) relative to the internal standard (Ph3CH). Purification of
the crude epoxide by silica gel chromatography (20 mm × 300 mm column, 3:1 to 1:1
hexanes/EtOAc as eluent) afforded pure cis-epoxide I-111a as a white solid (mp 50-53
ÂşC on >99% ee material) in 99% isolated yield (109 mg, 0.498 mmol); cis/trans: >100:1.
β-ketoamide side product: <1% yield. The optical purity of I-111a was determined to be
>99% ee by HPLC (PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt = 24.63 min (minor
enantiomer, ent-I-111a) and Rt = 31.46 min (major enantiomer, I-111a). The reaction
without DMSO with a reaction time of 2 hours afforded epoxide I-111a in 86% yield and
93% ee.
Spectral data for I-111a: Rf = 0.26 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.65 (t, J = 7.5 Hz, 3H), 0.80-1.00 (m, 4H), 2.75-2.83 (m, 1H), 2.98-3.07 (m, 1H), 3.70
(d, J = 5.0 Hz, 1H), 4.24 (d, J = 5.5 Hz, 1H), 5.85 (brs, 1H), 7.20-7.32 (m, 5H); 13C NMR
(CDCl3, 126 MHz) δ 13.46, 19.51, 31.06, 38.10, 56.17, 57.96, 126.38, 128.20, 128.27,
133.07, 165.86; IR (thin film) 3316 br, 3067 w, 2959 s, 2932 s, 2872 m, 1653 vs, 1545 s,
1456 m cm-1; HRMS (ESI-TOF) m/z 219.1268 [(M+); calcd. for C13H17NO2: 219.1259];
[𝛼]%&
$ 	-4.3 (c 1.0, CH2Cl2) on >99% ee material (HPLC).

233

O

O
H
Ph
I-51a
1.2 equiv.

+

N2

N
H
I-23b

Ph

O

5 mol% I-118,
toluene, –40 ºC
12 h, 0.1 M

0.5 mmol

Ph

CONHBu
I-111b

93%, 98% ee

(2R,3R)-N,3-diphenyloxirane-2-carboxamide I-111b: The epoxide I-111b was
prepared from aldehyde I-51a (61 ÎźL, 0.60 mmol, 1.2 equiv), diazo compound I-23b (80.6
mg, 0.50 mmol, 1.0 equiv) and the (R)-VANOL catalyst solution by the general procedure
C with a reaction time of 12 hours. The reaction went to 100% conversion. The crude
epoxide was purified by column chromatography (silica gel, 20 × 250 mm, 10:1 to 4:1
hexanes/EtOAc as eluent) to give I-111b as a white solid (mp 105-108 ÂşC on 98% ee
material) in 93% isolated yield (111d mg, 0.465 mmol); cis/trans: >100:1. The optical
purity of I-111b was determined to be 98% ee by HPLC (Daicel Chirapak OD-H column,
94:6 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt = 12.09 min
(minor enantiomer, ent-I-111b) and Rt = 15.49 min (major enantiomer, I-111b).
Spectral data for I-111b: Rf = 0.42 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 3.81 (d, J = 5.0 Hz, 1H), 4.29 (d, J = 4.0 Hz, 1H), 6.90-6.97 (m, 1H), 7.06-7.12 (m, 4H),
7.14-7.22 (m, 3H), 7.29-7.32 (m, 2H), 7.58 (brs, 1H); 13C NMR (CDCl3, 126 MHz) δ 56.46,
58.50, 120.14, 124.73, 126.25, 128.38, 128.52, 128.71, 132.64, 135.88, 164.35; IR (thin
film) 3222 br, 3059 w, 1671 vs, 1597 m, 1526 vs, 1445 s cm-1; HRMS (ESI-TOF) m/z
239.0954 [(M+); calcd. for C15H13NO2: 239.0946]; [𝛼]%&
$ 	-30.8 (c 1.0, CH2Cl2) on 98% ee
material (HPLC). These data match that previously reported for this compound for the
12
(2S,3S)-enantiomer: [𝛼]%&
$ 	19.1 (c 0.90, CH2Cl2) on 99% ee material.

234

O

O
H
Ph
I-51a
1.2 equiv.

+

N2

N
H
I-23c

0.5 mmol

Bn

O

5 mol% I-118,
toluene, –40 ºC
1 h, 0.1 M
(3 h, without DMSO)

CONHBn

Ph

I-111c
88%, >99% ee
(98%, 97% ee)

(2R,3R)-N-benzyl-3-phenyloxirane-2-carboxamide I-111c: The epoxide I-111c
was prepared from aldehyde I-51a (61 ÎźL, 0.60 mmol, 1.2 equiv), diazo compound I-23c
(87.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution by the general
procedure C with a reaction time of 1 hour. The reaction went to 100% conversion. The
crude epoxide was purified by column chromatography (silica gel, 20 × 250 mm, 4:1 to
2:1 hexanes/EtOAc as eluent) to give I-111c as a white solid (mp 63-65 ÂşC on >99% ee
material) in 93% isolated yield (118 mg, 0.467 mmol); cis/trans: >100:1. The optical purity
of I-111c was determined to be >99% ee by HPLC (Daicel Chirapak OD-H column, 95:5
hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt = 14.70 min (major
enantiomer, I-111c) and Rt = 16.90 min (minor enantiomer, ent-I-111c). The reaction
without DMSO with a reaction time of 3 hours afforded epoxide I-111c in 47% yield and
91% ee.
Spectral data for I-111c: Rf = 0.23 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 3.73 (d, J = 4.5 Hz, 1H), 3.96 (dd, J = 15.0, 5.0 Hz, 1H), 4.21 (dd, J = 15.5, 5.5 Hz, 2H),
6.17 (brs, 1H), 6.61 (d, J = 7.0 Hz, 2H), 7.04-7.10 (m, 3H), 7.18-7.25 (m, 5H);

13

C NMR

(CDCl3, 126 MHz) δ 42.51, 56.24, 58.11, 126.41, 127.12, 127.26, 128.35, 128.38, 132.91,
136.93, 165.99 (one sp2 carbon not located); IR (thin film) 3317 br, 3059 w, 3040 w, 2931
w, 1654 vs, 1535 s, 1454 m cm-1; HRMS (ESI-TOF) m/z 254.1195 [(M+H+); calcd. for
C16H16NO2: 254.1181]; [𝛼]%&
$ 	-37.0 (c 1.0, CH2Cl2) on >99% ee material (HPLC).

235

O

O
H +

N2

N
H

Bu

O

5 mol% I-118,

CONHBu

toluene, –40 ºC
2 h, 0.1 M

I-23a
1.2 equiv.

I-119

0.5 mmol

89%, 97% ee

(2R,3R)-N-butyl-3-(o-tolyl)oxirane-2-carboxamide I-119: The epoxide I-119 was
prepared from o-tolualdehyde (70 ÎźL, 0.60 mmol, 1.2 equiv), diazo compound I-23a (70.6
mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution by the general
procedure C with a reaction time of 2 hours. The reaction went to 100% conversion. The
crude epoxide was purified by column chromatography (silica gel, 20 × 250 mm, 3:1 to
1:1 hexanes/EtOAc as eluent) to give I-119 as an off-white semi-solid (mp 38-40 ÂşC on
97% ee material) in 89% isolated yield (104 mg, 0.447 mmol); cis/trans: >100:1. The
optical purity of I-119 was determined to be 97% ee by HPLC (PIRKLE COVALENT (R,R)
WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention
times: Rt = 17.95 min (minor enantiomer, ent-I-119) and Rt = 20.89 min (major enantiomer,
I-119).
Spectral data for I-119: Rf = 0.29 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.63 (t, J = 7.0 Hz, 3H), 0.74-0.92 (m, 4H), 2.29 (s, 3H), 2.68-2.77 (m, 1H), 2.95-3.07
(m, 1H), 3.77 (d, J = 3.5 Hz, 1H), 4.18 (d, J = 3.0 Hz, 1H), 5.70 (brs, 1H), 7.04-7.11 (m,
2H), 7.12 (d, J = 7.0 Hz, 1H), 7.23 (d, J = 7.0 Hz, 1H);

13

C NMR (CDCl3, 126 MHz) δ

13.49, 18.60, 19.49, 31.10, 38.10, 56.02, 57.58, 125.37, 126.05, 128.22, 129.92, 131.67,
136.61, 166.05; IR (thin film) 3331 br, 2959 vs, 2932 s, 2872 m, 1667 vs, 1537 vs, 1493
w, 1462 m cm-1; HRMS (ESI-TOF) m/z 233.1419 [(M+); calcd. for C14H19NO2:
233.1416];	[𝛼]%&
$ 	-24.8 (c 1.0, CH2Cl2) on 97% ee material (HPLC).
236

O

O
H +

N2

N
H

Bu

O

5 mol% I-118,

CONHBu

toluene, –40 ºC
10 min, 0.1 M

I-23a
1.2 equiv.

I-120

0.5 mmol

94%, 99% ee

(2R,3R)-N-butyl-3-(p-tolyl)oxirane-2-carboxamide I-120: The epoxide I-120 was
prepared from p-tolualdehyde (71 ÎźL, 0.60 mmol, 1.2 equiv), diazo compound I-23a (70.6
mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution by the general
procedure C with a reaction time of 10 minutes. The reaction went to 100% conversion.
The crude epoxide was purified by column chromatography (silica gel, 20 × 250 mm, 3:1
to 1:1 hexanes/EtOAc as eluent) to give I-120 as an off-white solid (mp 54-57 ÂşC on 99%
ee material) in 94% isolated yield (110 mg, 0.471 mmol); cis/trans: >100:1. The optical
purity of I-120 was determined to be 99% ee by HPLC (PIRKLE COVALENT (R,R)
WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention
times: Rt = 25.13 min (minor enantiomer, ent-I-120) and Rt = 37.54 min (major enantiomer,
I-120).
Spectral data for I-120: Rf = 0.23 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.65 (t, J = 7.0 Hz, 3H), 0.80-0.88 (m, 2H), 0.91-0.99 (m, 2H), 2.25 (s, 3H), 2.74-2.82
(m, 1H), 3.01-3.10 (m, 1H), 3.67 (d, J = 4.5 Hz, 1H), 4.20 (d, J = 4.5 Hz, 1H), 5.84 (brs,
1H), 7.06 (d, J = 7.5 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H);

13

C NMR (CDCl3, 126 MHz) δ

13.50, 19.54, 21.03, 31.16, 38.13, 56.21, 57.95, 126.31, 128.86, 130.08, 138.05, 166.01;
IR (thin film) 3310 br, 2957 vs, 2932 s, 2869 m, 1653 vs, 1545 vs, 1453 s cm-1; HRMS
(ESI-TOF) m/z 233.1436 [(M+); calcd. for C14H19NO2: 233.1416]; [𝛼]%&
$ 	-4.7 (c 1.0,
CH2Cl2) on 99% ee material (HPLC).
237

O

O
H +

N2

N
H

Bu

O

5 mol% I-118,

CONHBu

toluene, –40 ºC
1 h, 0.1 M

I-23a
1.2 equiv.

I-121

0.5 mmol

88%, 97% ee

(2R,3R)-N-butyl-3-(naphthalen-1-yl)oxirane-2-carboxamide I-121: The epoxide I121 was prepared from 1-naphthaldehyde (82 ÎźL, 0.60 mmol, 1.2 equiv), diazo compound
I-23a (70.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution by the
general procedure C with a reaction time of 1 hour. The reaction went to 100%
conversion. The crude epoxide was purified by column chromatography (silica gel, 20 ×
250 mm, 3:1 to 1:1 hexanes/EtOAc as eluent) to give I-121 as a colorless viscous oil in
88% isolated yield (119mg, 0.440 mmol); cis/trans: >100:1. The optical purity of I-121 was
determined to be 97% ee by HPLC (PIRKLE COVALENT (R,R) WHELK-O 1 column, 93:7
hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt = 26.82 min (minor
enantiomer, ent-I-121) and Rt = 59.42 min (major enantiomer, I-121).
Spectral data for I-121: Rf = 0.24 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.47 (t, J = 7.0 Hz, 3H), 0.54-0.62 (m, 2H), 0.63-0.70 (m, 2H), 2.58-2.65 (m, 1H), 2.852.93 (m, 1H), 3.92 (d, J = 5.5 Hz, 1H), 4.57 (d, J = 5.0 Hz, 1H), 5.71 (brs, 1H), 7.32 (t, J
= 7.5 Hz, 1H), 7.39-7.49 (m, 3H), 7.72 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 8.01
(d, J = 8.5 Hz, 1H);

13

C NMR (CDCl3, 126 MHz) δ 13.29, 19.26, 30.93, 37.97, 56.03,

57.23, 123.49, 124.33, 124.62, 126.17, 126.66, 128.33, 128.78, 129.33, 130.97, 133.10,
166.03; IR (thin film) 3320 br, 3056 w, 2959 vs, 2932 s, 2872 m, 1663 vs, 1539 vs, 1464
w cm-1; HRMS (ESI-TOF) m/z 269.1428 [(M+); calcd. for C17H19NO2: 269.1416];
[𝛼]%&
$ 	-112.0 (c 1.0, CH2Cl2) on 97% ee material (HPLC).
238

O

O
H +

N2

N
H

Bu

5 mol% I-118,

CONHBu

toluene, –40 ºC
15 min, 0.1 M

I-23a
1.2 equiv.

O

I-122

0.5 mmol

91%, >99% ee

(2R,3R)-N-butyl-3-(naphthalen-2-yl)oxirane-2-carboxamide I-122: The epoxide I122 was prepared from 2-naphthaldehyde (93.7 mg, 0.600 mmol, 1.20 equiv), diazo
compound I-23a (70.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution
by the general procedure C with a reaction time of 15 minutes. The reaction went to 100%
conversion. The crude epoxide was purified by column chromatography (silica gel, 20 ×
250 mm, 3:1 to 1:1 hexanes/EtOAc as eluent) to give I-122 as a white solid (mp 103-104
ÂşC on >99% ee material) in 91% isolated yield (122 mg, 0.454 mmol); cis/trans: >100:1.
The optical purity of I-122 was determined to be >99% ee by HPLC (PIRKLE COVALENT
(R,R) WHELK-O 1 column, 90:10 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min):
retention times: Rt = 26.15 min (minor enantiomer, ent-I-122) and Rt = 67.17 min (major
enantiomer, I-122).
Spectral data for I-122: Rf = 0.16 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.29 (t, J = 7.0 Hz, 3H), 0.52-0.61 (m, 2H), 0.68-0.76 (m, 2H), 2.63-2.71 ( b m, 1H),
2.93-3.02 (m, 1H), 3.76 (d, J = 5.0 Hz, 1H), 4.35 (d, J = 4.5 Hz, 1H), 5.92 (brs, 1H), 7.347.40 (m, 3H), 7.67-7.74 (m, 4H); 13C NMR (CDCl3, 126 MHz) δ 13.04, 19.31, 31.05, 38.07,
56.36, 58.08, 123.84, 125.50, 126.20, 126.31, 127.57, 127.63, 128.09, 130.47, 132.62,
132.95, 165.80; IR (thin film) 3308 br, 3056 w, 2959 vs, 2932 s, 2872 m, 1651 vs, 1545
vs, 1437 w cm-1; HRMS (ESI-TOF) m/z 269.1434 [(M+); calcd. for C17H19NO2: 269.1416];
[𝛼]%&
$ 	+55.7 (c 1.0, CH2Cl2) on >99% ee material (HPLC).

239

OMe O

O
H +

N2

N
H

Bu

5 mol% I-118,

O
CONHBu

toluene, –40 ºC
10 min, 0.1 M

I-23a
1.2 equiv.

OMe

I-123

0.5 mmol

92%, 94% ee

(2R,3R)-N-butyl-3-(2-methoxyphenyl)oxirane-2-carboxamide I-123: The epoxide I123 was prepared from o-Anisaldehyde (81.7 mg, 0.600 mmol, 1.20 equiv), diazo
compound I-23a (70.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution
by the general procedure C with a reaction time of 10 minutes. The reaction went to 100%
conversion. The crude epoxide was purified by column chromatography (silica gel, 20 ×
250 mm, 3:1 to 1:1 hexanes/EtOAc as eluent) to give I-123 as an off-white solid (mp 5558 ÂşC on 94% ee material) in 92% isolated yield (114 mg, 0.458 mmol); cis/trans: >100:1.
The optical purity of I-123 was determined to be 94% ee by HPLC (PIRKLE COVALENT
(R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min):
retention times: Rt = 28.21 min (minor enantiomer, ent-I-123) and Rt = 33.36 min (major
enantiomer, I-123).
Spectral data for I-123: Rf = 0.23 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.66 (t, J = 7.5 Hz, 3H), 0.84-0.92 (m, 2H), 0.93-1.01 (m, 2H), 2.76-2.84 (m, 1H), 2.993.08 (m, 1H), 3.73 (d, J = 4.5 Hz, 1H), 3.76 (s, 3H), 4.24 (d, J = 5.0 Hz, 1H), 5.80 (brs,
1H), 6.78 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 7.17-7.24 (m, 2H); 13C NMR (CDCl3,
126 MHz) δ 13.47, 19.53, 31.15, 38.08, 55.41, 55.96, 56.17, 110.26, 119.79, 121.68,
127.07, 129.49, 158.03, 166.10; IR (thin film) 3310 br, 3075 w, 2959 vs, 2932 s, 2872 m,
1663 vs, 1539 vs, 1497 s, 1464 m cm-1; HRMS (ESI-TOF) m/z 249.1373 [(M+); calcd. for
C14H19NO3: 249.1365]; [𝛼]%&
$ 	-64.8 (c 1.0, CH2Cl2) on 94% ee material (HPLC).

240

O

MeO

O
H +

N2

N
H

Bu

5 mol% I-118,

CONHBu

toluene, –40 ºC
10 min, 0.1 M

I-23a
1.2 equiv.

O

MeO

I-124

0.5 mmol

92%, 97% ee

(2R,3R)-N-butyl-3-(3-methoxyphenyl)oxirane-2-carboxamide I-124: The epoxide I124 was prepared from m-Anisaldehyde (73 ÎźL, 0.60 mmol, 1.2 equiv), diazo compound
I-23a (70.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution by the
general procedure C with a reaction time of 10 minutes. The reaction went to 100%
conversion. The crude epoxide was purified by column chromatography (silica gel, 20 ×
250 mm, 3:1 to 1:1 hexanes/EtOAc as eluent) to give I-124 as a white solid (mp 58-60 ÂşC
on 97% ee material) in 92% isolated yield (115 mg, 0.462 mmol); cis/trans: >100:1. The
optical purity of I-124 was determined to be 97% ee by HPLC (PIRKLE COVALENT (R,R)
WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention
times: Rt = 32.24 min (minor enantiomer, ent-I-124) and Rt = 53.87 min (major enantiomer,
I-124).
Spectral data for I-124: Rf = 0.19 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.66 (t, J = 7.5 Hz, 3H), 0.82-0.91 (m, 2H), 0.94-1.01 (m, 2H), 2.75-2.83 (m, 1H), 3.023.11 (m, 1H), 3.69 (d, J = 5.0 Hz, 1H), 3.70 (s, 3H), 4.22 (d, J = 5.0 Hz, 1H), 5.89 (brs,
1H), 6.76 (d, J = 8.0 Hz, 1H), 6.82 (s, 1H), 6.86 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 8.0 Hz,
1H);

13

C NMR (CDCl3, 126 MHz) δ 13.45, 19.49, 31.13, 38.12, 55.04, 56.17, 57.87,

111.85, 113.83, 118.57, 129.36, 134.54, 159.039, 165.82; IR (thin film) 3287 br, 3077 w,
2959 vs, 2934 s, 2872 m, 1655 vs, 1604 s, 1543 vs, 1493 w, 1466 m, 1435 m cm-1; HRMS

241

(ESI-TOF) m/z 249.1365 [(M+); calcd. for C14H19NO3: 249.1365];	[𝛼]%&
$ 	+1.6 (c 1.0,
CH2Cl2) on 97% ee material (HPLC).
O

O
H +

N2

MeO

N
H

Bu

toluene, –40 ºC
24 h, 0.1 M

I-23a
1.2 equiv.

O

10 mol% I-118,

CONHBu

MeO

0.5 mmol

I-125
65% conversion
19% NMR yield

(2R,3R)-N-butyl-3-(4-methoxyphenyl)oxirane-2-carboxamide I-125: The epoxide I125 was prepared from p-Anisaldehyde (73 ÎźL, 0.60 mmol, 1.2 equiv), diazo compound
I-23a (70.6 mg, 0.500 mmol, 1.00 equiv) and the 10 mol% (R)-VANOL catalyst solution
by the general procedure C with a reaction time of 24 hours. The reaction went to 65%
conversion. The NMR yield was determined to be 19% from the crude 1H NMR spectrum
by integration of the methylene protons relative to the internal standard (Ph3CH).
O

O
H +

AcO
1.2 equiv.

N2

N
H

Bu

O

5 mol% I-118,
toluene, –40 ºC
15 min, 0.1 M

I-23a
0.5 mmol

CONHBu

AcO

I-126
92%, 99% ee

4-((2R,3R)-3-(butylcarbamoyl)oxiran-2-yl)phenyl acetate I-126: The epoxide I-126
was prepared from 4-formylphenyl acetate (84 ÎźL, 0.60 mmol, 1.2 equiv), diazo
compound I-23a (70.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution
by the general procedure C with a reaction time of 15 minutes. The reaction went to 100%
conversion. The crude epoxide was purified by column chromatography (silica gel, 20 ×
250 mm, 3:1 to 1:1 hexanes/ EtOAc as eluent) to give I-126 as a white solid (mp 112-113
ÂşC on >99% ee material) in 92% isolated yield (127 mg, 0.459 mmol); cis/trans: >100:1.
The optical purity of I-126 was determined to be >99% ee by HPLC (PIRKLE COVALENT
242

(R,R) WHELK-O 1 column, 90:10 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min):
retention times: Rt = 53.00 min (minor enantiomer, ent-I-126) and Rt = 90.09 min (major
enantiomer, I-126).
Spectral data for I-126: Rf = 0.15 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 600 MHz)
δ 0.68 (t, J = 7.0 Hz, 3H), 0.87-0.96 (m, 2H), 0.96-1.04 (m, 2H), 2.20 (s, 3H), 2.77-2.85
(m, 1H), 2.95-3.07 (m, 1H), 3.69 (d, J = 4.5 Hz, 1H), 4.20 (d, J = 4.0 Hz, 1H), 5.93 (brs,
1H), 7.99 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H);

13

C NMR (CDCl3, 126 MHz) δ

13.27, 19.46, 20.83, 30.96, 38.04, 56.11, 57.37, 121.38, 127.51, 130.54, 150.49, 165.61,
168.86; IR (thin film) 3308 br, 3056 w, 2957 s, 2932 s, 2874 m, 1761 vs, 1657 vs, 1541
m, 1514 vs, 1431 w, 1219 vs, 1200 vs cm-1; HRMS (ESI-TOF) m/z 277.1322 [(M+); calcd.
for C15H19NO4: 277.1314]; [𝛼]%&
$ 	-2.9(c 1.0, CH2Cl2) on >99% ee material (HPLC).
Br

O

O
H +

N2

N
H

Bu

5 mol% I-118,

O
CONHBu

toluene, –40 ºC
30 min, 0.1 M

I-23a
1.2 equiv.

Br

I-127

0.5 mmol

94%, 90% ee

(2R,3R)-3-(2-bromophenyl)-N-butyloxirane-2-carboxamide I-127: The epoxide I127 was prepared from 2-bromobenzaldehyde (71 ÎźL, 0.60 mmol, 1.2 equiv), diazo
compound I-23a (70.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst
solution by the general procedure C with a reaction time of 30 minutes. The reaction
went to 100% conversion. The crude epoxide was purified by column chromatography
(silica gel, 20 × 250 mm, 3:1 to 1:1 hexanes/ EtOAc as eluent) to give I-127 as a yellow
oil in 94% isolated yield (141 mg, 0.472 mmol); cis/trans: >100:1. The optical purity of I127 was determined to be 90% ee by HPLC (PIRKLE COVALENT (R,R) WHELK-O 1

243

column, 90:10 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt =
19.69 min (minor enantiomer, ent-I-127) and Rt = 30.57 min (major enantiomer, I-127).
Spectral data for I-127: Rf = 0.34 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.65 (t, J = 7.0 Hz, 3H), 0.82-0.91 (m, 2H), 0.91-1.00 (m, 2H), 2.75-2.85 (m, 1H), 3.003.10 (m, 1H), 3.82 (d, J = 5.4 Hz, 1H), 4.21 (d, J = 5.4 Hz, 1H), 5.84 (brs, 1H), 7.12 (t, J
= 7.5 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H);
13

C NMR (CDCl3, 126 MHz) δ 13.40, 19.45, 31.12, 38.08, 56.28, 58.56, 122.51, 126.72,

128.02, 129.68, 132.34, 133.03, 165.14; IR (thin film) 3308 br, 3069, 2959 vs, 2932 vs,
2872 s, 1662 vs, 1539 s, 1474, 1439 s cm-1; HRMS (ESI-TOF) m/z 297.0348 [(M+); calcd.
for C13H1679BrNO2: 297.0364]; [𝛼]%&
$ 	-63.5 (c 1.0, CH2Cl2) on 90% ee material (HPLC).
O

Br

O
H +

N2

N
H

Bu

5 mol% I-118,

CONHBu

toluene, –40 ºC
10 min, 0.1 M

I-23a
1.2 equiv.

O

Br

I-124

0.5 mmol

96%, 98% ee

(2R,3R)-3-(3-bromophenyl)-N-butyloxirane-2-carboxamide I-124: The epoxide I124 was prepared from 3-bromobenaldehyde (70 ÎźL, 0.60 mmol, 1.2 equiv), diazo
compound I-23a (70.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution
by the general procedure C with a reaction time of 10 minutes. The reaction went to 100%
conversion. The crude epoxide was purified by column chromatography (silica gel, 20 ×
250 mm, 3:1 to 1:1 hexanes/ EtOAc as eluent) to give I-124 as an off-white solid (mp 7476 ÂşC on 98% ee material) in 96% isolated yield (143 mg, 0.478 mmol); cis/trans: >100:1.
The optical purity of I-124 was determined to be 98% ee by HPLC (PIRKLE COVALENT
(R,R) WHELK-O 1 column, 90:10 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min):

244

retention times: Rt = 18.05 min (minor enantiomer, ent-I-124) and Rt = 26.19 min (major
enantiomer, I-124).
Spectral data for I-124: Rf = 0.19 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.70 (t, J = 7.5 Hz, 3H), 0.86-0.95 (m, 2H), 0.99-1.06 (m, 2H), 2.77-2.85 (m, 1H), 3.083.16 (m, 1H), 3.72 (d, J = 4.5 Hz, 1H), 4.21 (d, J = 5.0 Hz, 1H), 5.93 (brs, 1H), 7.14 (t, J
= 7.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.44 (s, 1H);

13

C NMR

(CDCl3, 126 MHz) δ 13.53, 19.61, 31.26, 38.22, 56.30, 57.16, 122.34, 125.18, 129.36,
129.85, 131.45, 135.34, 165.33; IR (thin film) 3299 br, 2959 vs, 2932 s, 2872 m, 1659 vs,
1599 w, 1541 vs, 1437 w cm-1; HRMS (ESI-TOF) m/z 297.0393 [(M+); calcd. for
C13H1679BrNO2: 297.0364]; [𝛼]%&
$ 	+26.1 (c 1.0, CH2Cl2) on 98% ee material (HPLC).
O

O
H +

Br

N2

N
H

Bu

toluene, –40 ºC
10 min, 0.1 M

I-23a
1.2 equiv.

O

5 mol% I-118,

CONHBu

Br

I-129a
99%, >99% ee
(2 h, 72%, 90% ee)

0.5 mmol

(2R,3R)-3-(4-bromophenyl)-N-butyloxirane-2-carboxamide I-129a: The epoxide I129a was prepared from 4-bromobenzaldehyde (111 mg, 0.600 mmol, 1.20 equiv), diazo
compound I-23a (70.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution
by the general procedure C with a reaction time of 10 minutes. The reaction went to 100%
conversion. The crude epoxide was purified by column chromatography (silica gel, 20 ×
250 mm, 3:1 to 1:1 hexanes/ EtOAc as eluent) to give I-129a as a white solid (mp 109111 ÂşC on >99% ee material) in 99% isolated yield (148 mg, 0.495 mmol); cis/trans:
>100:1. The optical purity of I-129a was determined to be >99% ee by HPLC (PIRKLE
COVALENT (R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1
245

mL/min): retention times: Rt = 28.91 min (minor enantiomer, ent-I-129a) and Rt = 45.53
min (major enantiomer, I-129a). The reaction without DMSO with a reaction time of 2
hours afforded epoxide I-129a in 72% yield and 90% ee.
Spectral data for I-129a: Rf = 0.16 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.70 (t, J = 7.5 Hz, 3H), 0.86-0.95 (m, 2H), 0.99-1.06 (m, 2H), 2.77-2.85 (m, 1H), 3.023.12 (m, 1H), 3.71 (d, J = 4.5 Hz, 1H), 4.19 (d, J = 4.0 Hz, 1H), 5.87 (brs, 1H), 7.17 (d, J
= 7.5 Hz, 2H), 7.40 (d, J = 7.5 Hz, 2H); 13C NMR (CDCl3, 126 MHz) δ 13.51, 19.57, 31.20,
38.19, 56.14, 57.34, 122.41, 128.14, 131.37, 132.14, 165.48; IR (thin film) 3299 br, 2957
s, 2930 s, 2863 m, 1653 vs, 1545 vs, 1491 w, 1435 w cm-1; HRMS (ESI-TOF) m/z
297.0387 [(M+); calcd. for C13H1679BrNO2: 297.0364]; [𝛼]%&
$ 	-7.2 (c 1.0, CH2Cl2) on >99%
ee material (HPLC).
O

Cl

O
H +

N2

N
H

Bu

5 mol% I-118,

Cl

CONHBu

toluene, –40 ºC
10 min, 0.1 M

I-23a
1.2 equiv.

O

I-130
93%, 98% ee

0.5 mmol

(2R,3R)-N-butyl-3-(3-chlorophenyl)oxirane-2-carboxamide I-130: The epoxide I130 was prepared from 3-chlorobenzaldehyde (68 ÎźL, 0.60 mmol, 1.2 equiv), diazo
compound I-23a (70.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution
by the general procedure C with a reaction time of 10 minutes. The reaction went to 100%
conversion. The crude epoxide was purified by column chromatography (silica gel, 20 ×
250 mm, 3:1 to 1:1 hexanes/ EtOAc as eluent) to give I-130 as a white solid (mp 61-63
ÂşC on 98% ee material) in 93% isolated yield (119 mg, 0.467 mmol); cis/trans: >100:1.
The optical purity of I-130 was determined to be 98% ee by HPLC (PIRKLE COVALENT

246

(R,R) WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min):
retention times: Rt = 26.05 min (minor enantiomer, ent-I-130) and Rt = 38.42 min (major
enantiomer, I-130).
Spectral data for I-130: Rf = 0.21 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.69 (t, J = 7.0 Hz, 3H), 0.84-0.95 (m, 2H), 0.97-1.06 (m, 2H), 2.76-2.85 (m, 1H), 3.063.12 (m, 1H), 3.72 (d, J = 5.0 Hz, 1H), 4.21 (d, J = 4.5 Hz, 1H), 5.97 (brs, 1H), 7.26-7.24
(m, 3H), 7.28 (s, 1H);

13

C NMR (CDCl3, 126 MHz) δ 13.45, 19.55, 31.21, 38.18, 56.27,

57.21, 124.67, 126.46, 128.47, 129.56, 134.21, 135.08, 165.32; IR (thin film) 3270 br,
3073 w, 2961 s, 2932 s, 2874 m, 1653 vs, 1601 w, 1549 vs, 1435 m cm-1; HRMS (ESITOF) m/z 253.0868 [(M+); calcd. for C13H1635ClNO2: 253.0870]; [𝛼]%&
$ 	+18.0 (c 1.0,
CH2Cl2) on 98% ee material (HPLC).
O

Cl

O
H +

Cl

N2

N
H

Bu

5 mol% I-118,
toluene, –40 ºC
15 min, 0.1 M

I-23a
1.2 equiv.

O

Cl
Cl

CONHBu

I-131
96%, 99% ee

0.5 mmol

(2R,3R)-N-butyl-3-(3,4-dichlorophenyl)oxirane-2-carboxamide I-131: The epoxide
I-131 was prepared from 3,4-dichlorobenzaldehyde (105 mg, 0.600 mmol, 1.20 equiv),
diazo compound I-23a (70.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst
solution by the general procedure C with a reaction time of 15 minutes. The reaction went
to 100% conversion. The crude epoxide was purified by column chromatography (silica
gel, 20 × 250 mm, 3:1 to 1:1 hexanes/ EtOAc as eluent) to give I-131 as an off-white semisolid (mp 48-50 ºC on 99% ee material) in 96% isolated yield (138 mg, 0.480 mmol);
cis/trans: >100:1. The optical purity of I-131 was determined to be 99% ee by HPLC

247

(PIRKLE COVALENT (R,R) WHELK-O 1 column, 90:10 hexane/2-propanol at 228 nm,
flow-rate: 1 mL/min): retention times: Rt = 17.75 min (minor enantiomer, ent-I-131) and Rt
= 26.29 min (major enantiomer, I-131).
Spectral data for I-131: Rf = 0.18 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.70 (t, J = 7.0 Hz, 3H), 0.86-0.95 (m, 2H), 1.00-1.09 (m, 2H), 2.79-2.87 (m, 1H), 3.103.19 (m, 1H), 3.73 (d, J = 5.0 Hz, 1H), 4.18 (d, J = 4.5 Hz, 1H), 6.00 (brs, 1H), 7.15 (d, J
= 8.5 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H); 13C NMR (CDCl3, 126 MHz) δ 13.47,
19.61, 31.33, 38.28, 56.34, 56.69, 125.88, 128.38, 130.29, 132.54, 132.59, 133.32,
165.13; IR (thin film) 3299 br, 2959 vs, 2932 s, 2872 m, 1660 vs, 1543 vs, 1474 m cm-1;
HRMS (ESI-TOF) m/z 287.0502 [(M+); calcd. for C13H1535Cl2NO2: 287.0480]; [𝛼]%&
$ 	10.9 (c
1.0, CH2Cl2) on 99% ee material (HPLC).
O

Br

O
H +

F
1.2 equiv.

N2

N
H

Bu

5 mol% I-118,
toluene, –40 ºC
24 h, 0.1 M

I-23a

O

Br

CONHBu

F

I-132

82%, 63% ee

0.5 mmol

(2R,3R)-3-(5-bromo-2-fluorophenyl)-N-butyloxirane-2-carboxamide

I-132:

The

epoxide I-132 was prepared from 5-bromo-2-fluorobenzaldehyde (72 ÎźL, 0.60 mmol, 1.2
equiv), diazo compound I-23a (70.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL
catalyst solution by the general procedure C with a reaction time of 24 hours. The reaction
went to 100% conversion. The crude epoxide was purified by column chromatography
(silica gel, 20 × 250 mm, 3:1 to 1:1 hexanes/ EtOAc as eluent) to give I-132 as a white
solid (mp 70-73 ÂşC on 63% ee material) in 82% isolated yield (129 mg, 0.409 mmol);
cis/trans: >100:1. The optical purity of I-132 was determined to be 63% ee by HPLC

248

(PIRKLE COVALENT (R,R) WHELK-O 1 column, 90:10 hexane/2-propanol at 228 nm,
flow-rate: 1 mL/min): retention times: Rt = 18.55 min (minor enantiomer, ent-I-132) and Rt
= 25.68 min (major enantiomer, I-132).
Spectral data for I-132: Rf = 0.39 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.72 (t, J = 7.0 Hz, 3H), 0.90-1.01 (m, 2H), 1.03-1.15 (m, 2H), 2.80-2.89 (m, 1H), 3.153.24 (m, 1H), 3.79 (d, J = 4.5 Hz, 1H), 4.26 (d, J = 5.0 Hz, 1H), 6.03 (brs, 1H), 6.90 (t, J
= 9.0 Hz, 1H), 7.32-7.37 (m, 1H), 7.39 (d, J = 6.0 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ
13.55, 19.68, 31.38, 38.33, 53.46 (d, JCF = 3.9 Hz), 56.02, 116.23 (d, JCF = 3.5 Hz), 117.22
(d, JCF = 21.8 Hz), 122.95 (d, JCF = 15.8 Hz), 130.65 (d, JCF = 3.7 Hz), 132.90 (d, JCF =
7.9 Hz), 160.12 (d, JCF = 249.6 Hz), 164.93; IR (thin film) 3285 br, 3071 w, 2959 vs, 2932
s, 2872 m, 1655 vs, 1547 vs, 1485 vs, 1439 w, 1408 m cm-1; HRMS (ESI-TOF) m/z
315.0287 [(M+); calcd. for C13H1579BrFNO2: 315.0270]; [𝛼]%&
$ 	+49.5 (c 1.0, CH2Cl2) on 63%
ee material (HPLC).
O

O
H +

NC

N2

N
H

Bu

toluene, –40 ºC
15 min, 0.1 M

I-23a
1.2 equiv.

O

5 mol% I-118,

CONHBu

NC

I-133
98%, 96% ee

0.5 mmol

(2R,3R)-N-butyl-3-(4-cyanophenyl)oxirane-2-carboxamide I-133: The epoxide I133 was prepared from aldehyde 31 (78.7 mg, 0.600 mmol, 1.20 equiv), diazo compound
I-23a (70.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution by the
general procedure C with a reaction time of 15 minutes. The reaction went to 100%
conversion. The crude epoxide was purified by column chromatography (silica gel, 20 ×
250 mm, 2:1 to 1:2 hexanes/ EtOAc as eluent) to give I-133 as an off-white semi-solid

249

(mp 76-78 ÂşC on 96% ee material) in 98% isolated yield (120 mg, 0.489 mmol); cis/trans:
>100:1. The optical purity of I-133 was determined to be 96% ee by HPLC (PIRKLE
COVALENT (R,R) WHELK-O 1 column, 90:10 hexane/2-propanol at 228 nm, flow-rate: 1
mL/min): retention times: Rt = 74.00 min (minor enantiomer, ent-I-133) and Rt = 79.59 min
(major enantiomer, I-133).
Spectral data for I-133: Rf = 0.07 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.70 (t, J = 7.5 Hz, 3H), 0.85-0.95 (m, 2H), 0.98-1.07 (m, 2H), 2.80-2.89 (m, 1H), 3.003.08 (m, 1H), 3.78 (d, J = 5.5 Hz, 1H), 4.28 (d, J = 5.0 Hz, 1H), 6.01 (brs, 1H), 7.44 (d, J
= 7.5 Hz, 2H), 7.59 (d, J = 7.5 Hz, 2H); 13C NMR (CDCl3, 126 MHz) δ 13.37, 19.46, 31.09,
38.13, 56.31, 57.08, 112.11, 118.07, 127.22, 131.88, 138.31, 164.92; IR (thin film) 3310
br, 3065 w, 2961 vs, 2934 s, 2874 s, 2230 vs, 1663 vs, 1612 m, 1541 vs, 1466 m, 1437
m cm-1; HRMS (ESI-TOF) m/z 244.1218 [(M+); calcd. for C14H16N2O2: 244.1212];
[𝛼]%&
$ 	-18.3 (c 1.0, CH2Cl2) on 96% ee material (HPLC).
O

O
H +

O2N

N2

N
H

Bu

toluene, –40 ºC
3 h, 0.1 M

I-23a
1.2 equiv.

O

5 mol% I-118,

CONHBu

O2N

I-134
87%, 94% ee

0.5 mmol

(2R,3R)-N-butyl-3-(4-nitrophenyl)oxirane-2-carboxamide I-134: The epoxide I-134
was prepared from 4-nitrobenzaldehyde (90.7 mg, 0.600 mmol, 1.20 equiv), diazo
compound I-23a (70.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution
by the general procedure C with a reaction time of 3 hours. The reaction went to 100%
conversion. The crude epoxide was purified by column chromatography (silica gel, 20 ×
250 mm, 2:1 to 1:2 hexanes/ EtOAc as eluent) to give I-134 as a white solid (mp 92-95

250

ÂşC on 94% ee material) in 87% isolated yield (115 mg, 0.434 mmol); cis/trans: >100:1.
The optical purity of I-134 was determined to be 94% ee by HPLC (PIRKLE COVALENT
(R,R) WHELK-O 1 column, 90:10 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min):
retention times: Rt = 50.34 min (minor enantiomer, ent-I-134) and Rt = 57.11 min (major
enantiomer, I-134).
Spectral data for I-134: Rf = 0.07 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.65 (t, J = 7.5 Hz, 3H), 0.84-0.94 (m, 2H), 0.98-1.06 (m, 2H), 2.82-2.90 (m, 1H), 2.983.07 (m, 1H), 3.80 (d, J = 5.0 Hz, 1H), 4.32 (d, J = 4.5 Hz, 1H), 5.97 (brs, 1H), 7.51 (d, J
= 9.0 Hz, 2H), 8.15 (d, J = 8.5 Hz, 2H); 13C NMR (CDCl3, 126 MHz) δ 13.36, 19.57, 31.22,
38.28, 56.45, 57.09, 123.42, 127.52, 140.27, 147.78, 164.91; IR (thin film) 3314 br, 3081
w, 2959 vs, 2934 s, 2872 m, 1661 vs, 1605 s 1522 vs, 1466 w, 1437 w, 1346 vs cm-1;
HRMS (ESI-TOF) m/z 264.1132 [(M+); calcd. for C13H16N2O4: 264.1110]; [𝛼]%&
$ 	-30.5 (c
1.0, CH2Cl2) on 94% ee material (HPLC).
O

O2N

O
H +

Cl

N2

N
H

Bu

5 mol% I-118,
toluene, –40 ºC
1 h, 0.1 M

I-23a
1.2 equiv.

O

O2N
Cl

CONHBu

I-135
98%, 89% ee

0.5 mmol

(2R,3R)-N-butyl-3-(4-chloro-3-nitrophenyl)oxirane-2-carboxamide

I-135:

The

epoxide I-135 was prepared from 4-chloro-3-nitrobenzaldehyde (111.3 mg, 0.600 mmol,
1.20 equiv), diazo compound I-23a (70.6 mg, 0.500 mmol, 1.00 equiv) and the (R)VANOL catalyst solution by the general procedure C with a reaction time of 1 hour. The
reaction went to 100% conversion. The crude epoxide was purified by column
chromatography (silica gel, 20 × 250 mm, 2:1 to 1:2 hexanes/ EtOAc as eluent) to give I-

251

135 as a white solid (mp 59-62 ÂşC on 89% ee material) in 98% isolated yield (146 mg,
0.488 mmol); cis/trans: >100:1. The optical purity of I-135 was determined to be 89% ee
by HPLC (PIRKLE COVALENT (R,R) WHELK-O 1 column, 90:10 hexane/2-propanol at
228 nm, flow-rate: 1 mL/min): retention times: Rt = 43.78 min (minor enantiomer, ent-I135) and Rt = 53.87 min (major enantiomer, I-135).
Spectral data for I-135: Rf = 0.08 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.71 (t, J = 7.0 Hz, 3H), 0.88-0.98 (m, 2H), 1.02-1.14 (m, 2H), 2.85-2.93 (m, 1H), 3.063.15 (m, 1H), 3.80 (d, J = 4.0 Hz, 1H), 4.27 (d, J = 4.5 Hz, 1H), 6.21 (brs, 1H), 7.46-7.52
(m, 2H), 7.85 (s, 1H);

13

C NMR (CDCl3, 126 MHz) δ 13.39, 19.58, 31.25, 38.38, 56.27,

56.58, 123.55, 126.88, 131.20, 131.77, 133.77, 147.54, 164.76; IR (thin film) 3303 br,
3081 w, 2961 s, 2934 s, 2874 m, 1661 vs, 1537 vs, 1493 w, 1466 w, 1350 s cm-1; HRMS
(ESI-TOF) m/z 298.0731 [(M+); calcd. for C13H1535ClN2O4: 298.0720]; [𝛼]%&
$ 	-18.2 (c 1.0,
CH2Cl2) on 89% ee material (HPLC).
O

O
H

+

N2

N
H

Bu

5 mol% I-118,
toluene, –40 ºC
15 min, 0.1 M

I-23a
1.2 equiv.

O
CONHBu

I-136a
87%, 96% ee

0.5 mmol

(2R,3R)-N-butyl-3-propyloxirane-2-carboxamide I-136a: The epoxide I-136a was
prepared from butyraldehyde (55 ÎźL, 0.60 mmol, 1.2 equiv), diazo compound I-23a (70.6
mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution by the general
procedure C with a reaction time of 15 minutes. The reaction went to 100% conversion.
The crude epoxide was purified by column chromatography (silica gel, 20 × 250 mm, 10:1
to 4:1 hexanes/ EtOAc as eluent) to give I-136a as a colorless oil in 87% isolated yield

252

(80.6 mg, 0.435 mmol); cis/trans: >100:1. The optical purity of I-136a was determined to
be 96% ee by HPLC (PIRKLE COVALENT (R,R) WHELK-O 1 column, 90:10 hexane/2propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt = 11.83 min (minor
enantiomer, ent- I-136a) and Rt = 15.07 min (major enantiomer, I-136a).
Spectral data for I-136a: Rf = 0.24 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.83 (t, J = 7.0 Hz, 3H), 0.85-0.90 (m, 3H), 1.26 (td, J = 10.0 Hz, 8Hz, 2H), 1.38-1.46
(m, 6H), 3.06-3.10 (m, 1H), 3.16 (septet, J = 6.5 Hz, 1H), 3.23 (septet, J = 6.5 Hz, 1H),
3.41 (d, J = 5.0 Hz, 1H), 6.12 (brs, 1H); 13C NMR (CDCl3, 126 MHz) δ 13.56, 13.76, 19.32,
19.95, 29.53, 31.51, 38.48, 55.16, 58.30, 167.29; IR (thin film) 3303 br, 2961 vs, 2931 vs,
2874 s, 1661 vs, 1539 vs, 1466 m, cm-1; HRMS (ESI-TOF) m/z 185.1419 [(M+); calcd. for
C10H19NO2: 185.1416]; [𝛼]%&
$ 	+24.4 (c 1.0, CH2Cl2) on 96% ee material (HPLC).
O

O
H

+

N2

N
H

Ph

5 mol% I-118,
toluene, –40 ºC
12 h, 0.1 M

I-23b
1.2 equiv.

O
CONHPh

I-136b
94%, 90% ee

0.5 mmol

(2R,3R)-N-phenyl-3-propyloxirane-2-carboxamide I-136b: The epoxide I-136b
was prepared from butyraldehyde (55 ÎźL, 0.60 mmol, 1.2 equiv), diazo compound I-23b
(80.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution by the general
procedure C with a reaction time of 12 hours. The reaction went to 100% conversion. The
crude epoxide was purified by column chromatography (silica gel, 20 × 250 mm, 10:1 to
4:1 hexanes/ EtOAc as eluent) to give I-136b as a colorless oil in 94% isolated yield (96.3
mg, 0.469 mmol); cis/trans: >100:1. The optical purity of I-136b was determined to be
90% ee by HPLC (Daicel Chirapak OD-H column, 94:6 hexane/2-propanol at 228 nm,

253

flow-rate: 1 mL/min): retention times: Rt = 5.63 min (minor enantiomer, ent-I-136b) and Rt
= 10.66 min (major enantiomer, I-136b).
Spectral data for I-136b: Rf = 0.48 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.88 (t, J = 7.0 Hz, 3H), 1.41-1.55 (m, 4H), 3.18 (q, J = 5.5Hz, 1H), 3.41 (d, J = 5.0 Hz,
1H), 7.06 (t, J = 7.5 Hz, 1H), 7.26 (t, J = 7.5 Hz, 2H), 7.47 (d, J = 7.5 Hz, 2H), 7.85 (brs,
1H);

13

C NMR (CDCl3, 126 MHz) δ 13.73, 19.38, 29.60, 55.35, 58.94, 119.68, 124.69,

128.99, 136.44, 165.45; IR (thin film) 3297 br, 3141 w, 3061 w, 2963 vs, 2934 s, 2874 m,
1680 vs, 1601 vs, 1536 vs, 1499 s, 1444 vs cm-1; HRMS (ESI-TOF) m/z 205.1113 [(M+);
calcd. for C12H15NO2: 205.1103]; [𝛼]%&
$ 	+31.3 (c 1.0, CH2Cl2) on 90% ee material (HPLC).
These data match that previously reported for this compound for the (2S,3S)-enantiomer:
5
[𝛼]%&
$ 	–31.6 (c 0.78, CH2Cl2) on >99% ee material .

O

O
H

+

N2

N
H

Bn

5 mol% I-118,
toluene, –40 ºC
12 h, 0.1 M

I-23c
1.2 equiv.

O
CONHBn

I-136c
93%, >99% ee

0.5 mmol

(2R,3R)-N-benzyl-3-propyloxirane-2-carboxamide I-136c: The epoxide I-136c was
prepared from butyraldehyde (55 ÎźL, 0.60 mmol, 1.2 equiv), diazo compound I-23c (87.6
mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution by the general
procedure C with a reaction time of 12 hours. The reaction went to 100% conversion. The
crude epoxide was purified by column chromatography (silica gel, 20 × 250 mm, 10:1 to
4:1 hexanes/ EtOAc as eluent) to give I-136c as an off-white solid (mp 46-48 ÂşC on >99%
ee material) 96% isolated yield (105 mg, 0.478 mmol); cis/trans: >100:1. The optical purity
of I-136c was determined to be >99% ee by HPLC (Daicel Chirapak OD-H column, 94:6

254

hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt = 8.23 min (minor
enantiomer, ent-I-136c) and Rt = 9.03 min (major enantiomer, I-136c).
Spectral data for I-136c: Rf = 0.28 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.82 (t, J = 7.0 Hz, 3H), 1.38 (m, 4H), 3.06 (d, J = 4.5 Hz, 1H), 3.43 (d, J = 4.5 Hz, 1H),
4.31 (dd, J = 14.5, 5.5 Hz, 1H), 4.43 (dd, J = 14.5, 6.0 Hz, 1H), 6.52 (brs, 1H), 7.17-7.25
(m, 5H); 13C NMR (CDCl3, 126 MHz) δ 13.66, 19.20, 29.45, 42.74, 55.02, 58.31, 127.49,
127.74, 128.44, 137.62, 167.19; IR (thin film) 3308 br, 3141 w, 3061 w, 2961 vs, 2932 s,
2873 m, 1665 vs, 1535 vs, 1497 w, 1455 s, 1428 w cm-1; HRMS (ESI-TOF) m/z 220.1348
[(M+H+); calcd. for C13H18NO2: 220.1338]; [𝛼]%&
$ 	−2.8 (c 1.0, CH2Cl2) on >99% ee material
(HPLC).
O

O
H

6

+

N2

N
H

Ph

toluene, –40 ºC
12 h, 0.1 M

I-23b
1.2 equiv.

O

5 mol% I-118,

CONHPh
6

I-137b
88%, 89% ee

0.5 mmol

(2R,3R)-3-octyl-N-phenyloxirane-2-carboxamide I-137b: The epoxide I-137b was
prepared from nonanal (103 ÎźL, 0.600 mmol, 1.20 equiv), diazo compound I-23b (80.6
mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution by the general
procedure C with a reaction time of 12 hours. The reaction went to 100% conversion. The
crude epoxide was purified by column chromatography (silica gel, 20 × 250 mm, 10:1 to
4:1 hexanes/ EtOAc as eluent) to give I-137b as a colorless oil in 88% isolated yield (121
mg, 0.441 mmol); cis/trans: >100:1. The optical purity of I-137b was determined to be
89% ee by HPLC (Daicel Chirapak OD-H column, 94:6 hexane/2-propanol at 228 nm,

255

flow-rate: 1 mL/min): retention times: Rt = 4.89 min (minor enantiomer, ent-I-137b) and Rt
= 9.23 min (major enantiomer, I-137b).
Spectral data for I-137b: Rf = 0.60 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.78 (t, J = 7.0 Hz, 3H), 1.09-1.28 (m, 10H), 1.36-1.47 (m, 2H), 1.48-1.55 (m, 2H), 3.16
(q, J = 6.0 Hz, 1H), 3.53 (d, J = 4.5 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 7.24 (t, J = 8.0 Hz,
2H), 7.47 (d, J = 7.5 Hz, 2H), 7.87 (brs, 1H); 13C NMR (CDCl3, 126 MHz) δ 13.95, 22.47,
25.92, 27.58, 28.96, 29.07, 29.19, 31.65, 55.40, 59.07, 119.68, 124.65, 128.94, 136.44,
165.47; IR (thin film) 3299 br, 3141 w, 3061 w, 2928 vs, 2857 s, 1682 vs, 1603 vs, 1536
vs, 1501 s, 1445 vs cm-1; HRMS (ESI-TOF) m/z 275.1901 [(M+); calcd. for C17H25NO2:
275.1885]; [𝛼]%&
$ 	+25.9 (c 1.0, CH2Cl2) on 89% ee material (HPLC).
O

O
H

6

+

N2

N
H

Bn

toluene, –40 ºC
12 h, 0.1 M

I-23c
1.2 equiv.

O

5 mol% I-118,

CONHBn
6

I-137c
93%, >99% ee
(12 h, 82%, >99% ee)

0.5 mmol

(2R,3R)-N-benzyl-3-octyloxirane-2-carboxamide I-137c: The epoxide I-137c was
prepared from nonanal (103 ÎźL, 0.600 mmol, 1.20 equiv), diazo compound I-23c (87.6
mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution by the general
procedure C with a reaction time of 12 hours. The reaction went to 100% conversion. The
crude epoxide was purified by column chromatography (silica gel, 20 × 250 mm, 10:1 to
4:1 hexanes/ EtOAc as eluent) to give I-137c as a white solid (mp 53-55 ÂşC on >99% ee
material) in 93% isolated yield (134 mg, 0.464 mmol); cis/trans: >100:1. The optical purity
of I-137c was determined to be >99% ee by HPLC (Daicel Chirapak OD-H column, 94:6
hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt = 6.52 min (minor
256

enantiomer, ent-I-137c) and Rt = 7.25 min (major enantiomer, I-137c). The reaction
without DMSO with a reaction time of 12 hours afforded epoxide I-137c in 82% yield and
99% ee.
Spectral data for I-137c: Rf = 0.39 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.81 (t, J = 7.0 Hz, 3H), 1.17-1.23 (m, 10H), 1.33-1.41 (m, 4H), 3.06 (dd, J = 11.0, 6.0
Hz, 1H), 3.44 (d, J = 5.0 Hz, 1H), 4.30 (dd, J = 14.5, 6.0 Hz, 1H), 4.34 (dd, J = 14.5, 6.5
Hz, 1H), 6.49 (brs, 1H); 7.17-7.25 (m, 5H);

13

C NMR (CDCl3, 126 MHz) δ 13.97, 22.51,

25.85, 27.53, 20.01, 29.14, 29.18, 31.67, 42.77, 55.13, 58.53, 127.51, 127.77, 128.57,
137.62, 167.19; IR (thin film) 3330 br, 3141 w, 3061 w, 2953 s, 2926 vs, 2855 s, 1656 vs,
1533 vs, 1455 m, 1425 m cm-1; HRMS (ESI-TOF) m/z 290.2132 [(M+H+); calcd. for
C18H28NO2: 290.2120]; [𝛼]%&
$ 	−12.7 (c 1.0, CH2Cl2) on >99% ee material (HPLC).
O

O
H

+

N2

N
H

Ph

5 mol% I-118,
toluene, –40 ºC
2 h, 0.1 M

I-23b
1.2 equiv.

O
CONHPh

I-138b
99%, 98% ee

0.5 mmol

(2R,3R)-3-cyclohexyl-N-phenyloxirane-2-carboxamide I-138b: The epoxide I138b was prepared from cyclohexanecarbaldehyde (73 ÎźL, 0.60 mmol, 1.2 equiv), diazo
compound I-23b (80.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution
by the general procedure C with a reaction time of 12 hours. The reaction went to 100%
conversion. The crude epoxide was purified by column chromatography (silica gel, 20 ×
250 mm, 10:1 to 4:1 hexanes/ EtOAc as eluent) to give I-138b as a white solid (mp 7072 ÂşC on 96% ee material) in 99% isolated yield (122 mg, 0.497 mmol); cis/trans: >100:1.
The optical purity of I-138b was determined to be 98% ee by HPLC (Daicel Chirapak OD-

257

H column, 94:6 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt =
5.73 min (minor enantiomer, ent-I-138b) and Rt = 8.45 min (major enantiomer, I-138b).
Spectral data for I-138b: Rf = 0.55 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 1.00-1.22 (m, 6H), 1.52-1.71 (m, 4H), 1.90 (d, J = 4.5 Hz, 1H), 2.91 (q, J = 4.5 Hz, 1H),
3.56 (d, J = 5.0 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 7.27 (t, J = 8.0 Hz, 2H), 7.47 (d, J = 7.5
Hz, 2H), 7.85 (brs, 1H); 13C NMR (CDCl3, 126 MHz) δ 25.00, 25.84, 28.29, 30.42, 36.81,
55.46, 63.17, 119.83, 124.71, 129.02, 136.47, 165.53 (one sp3 carbon not located); IR
(thin film) 3293 br, 3141 w, 3061 w, 2928 vs, 2853 m, 1676 vs, 1601 vs, 1536 vs, 1499 s,
1446 vs cm-1; HRMS (ESI-TOF) m/z 245.1428 [(M+); calcd. for C15H19NO2: 245.1416];
[𝛼]%&
$ 	+25.7 (c 1.0, CH2Cl2) on 98% ee material (HPLC). These data match that previously
reported for this compound for the (2S,3S)-enantiomer: [𝛼]%&
$ 	–20.9 (c 0.76, CH2Cl2) on
>99% ee material5.
O

O
H

+

N2

N
H

Bn

5 mol% I-118,
toluene, –40 ºC
2 h, 0.1 M

I-23c
1.2 equiv.

O
CONHBn

I-138c
92%, >99% ee
(1 h, 93%, >99% ee)

0.5 mmol

(2R,3R)-N-benzyl-3-cyclohexyloxirane-2-carboxamide I-138c: The epoxide I-138c
was prepared from cyclohexanecarbaldehyde (73 ÎźL, 0.60 mmol, 1.2 equiv), diazo
compound I-23c (87.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution
by the general procedure C with a reaction time of 2 hours. The reaction went to 100%
conversion. The crude epoxide was purified by column chromatography (silica gel, 20 ×
250 mm, 10:1 to 4:1 hexanes/ EtOAc as eluent) to give I-138c as a white solid (mp 70-73
ÂşC on >99% ee material) in 99% isolated yield (129 mg, 0.498 mmol); cis/trans: >100:1.
258

The optical purity of I-138c was determined to be >99% ee by HPLC (Daicel Chirapak
OD-H column, 94:6 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times:
Rt = 7.56 min (minor enantiomer, ent-I-138c) and Rt = 7.83 min (major enantiomer, I138c).
Spectral data for I-138c: Rf = 0.34 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.85-1.10 (m, 6H), 1.52-1.61 (m, 4H), 1.75 (d, J = 11.0 Hz, 1H), 2.79 (s, 1H), 3.45 (d, J
= 3.5 Hz, 1H), 4.22 (dd, J = 14.5, 5.0 Hz, 1H), 4.55 (dd, J = 14.5, 7.0 Hz, 1H), 6.51 (brs,
1H), 7.18-7.25 (m, 5H); 13C NMR (CDCl3, 126 MHz) δ 25.06, 25.85, 28.22, 30.30, 36.50,
42.70, 55.08, 62.60, 127.51, 127.79, 128.60, 137.80, 167.26 (one sp3 carbon not located);
IR (thin film) 3307 br, 3141 w, 3061 w, 2928 vs, 2852 m, 1666 vs, 1532 vs, 1499 w, 1450
vs cm-1; HRMS (ESI-TOF) m/z 260.1660 [(M+H+); calcd. for C16H22NO2: 260.1651];
[𝛼]%&
$ 	−31.9 (c 1.0, CH2Cl2) on >99% ee material (HPLC).
O

O
H

+

N2

N
H

Ph

5 mol% I-118,
toluene, –40 ºC
36 h, 0.1 M

I-23b
1.2 equiv.

O
CONHPh

I-139b
70%, 92% ee

0.5 mmol

(2R,3R)-3-(tert-butyl)-N-phenyloxirane-2-carboxamide I-139b: The epoxide I-139b
was prepared from pivalaldehyde (65 ÎźL, 0.60 mmol, 1.2 equiv), diazo compound I-23b
(80.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution by the general
procedure C with a reaction time of 36 hours. The reaction went to 100% conversion. The
crude epoxide was purified by column chromatography (silica gel, 20 × 250 mm, 10:1 to
4:1 hexanes/ EtOAc as eluent) to give I-139b as a white solid (mp 86-89 ÂşC on 92% ee
material) in 70% isolated yield (76.7 mg, 0.350 mmol); cis/trans: >100:1. The optical purity

259

of I-139b was determined to be 92% ee by HPLC (Daicel Chirapak OD-H column, 94:6
hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt = 6.38 min (minor
enantiomer, ent-I-139b) and Rt = 8.97 min (major enantiomer, I-139b).
Spectral data for I-139b: Rf = 0.55 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.95 (s, 9H), 2.99 (d, J = 5.0 Hz, 1H), 3.51 (d, J = 5.0 Hz, 1H), 7.06 (t, J = 8.0 Hz, 1H),
7.26 (t, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.95 (brs, 1H);

13

C NMR (CDCl3, 126

MHz) δ 26.46, 31.80, 56.07, 67.83, 119.59, 124.69, 129.04, 136.72, 165.45; IR (thin film)
3324 br, 3141 w, 3061 m, 2961 vs, 2870 m, 1682 vs, 1601 vs, 1537 vs, 1501 s, 1483 s,
1466 m, 1445 vs cm-1; HRMS (ESI-TOF) m/z 219.1245 [(M+); calcd. for C13H17NO2:
219.1259]; [𝛼]%&
$ 	+41.6 (c 1.0, CH2Cl2) on 92% ee material (HPLC).
O

O
H

+

N2

N
H

Bn

10 mol% I-118,
toluene, –40 ºC
24 h, 0.1 M

I-23c
1.2 equiv.

O
CONHBn

I-139c
47%, >99% ee

0.5 mmol

(2R,3R)-N-benzyl-3-(tert-butyl)oxirane-2-carboxamide I-139c: The epoxide I-139c
was prepared from pivalaldehyde (65 ÎźL, 0.60 mmol, 1.2 equiv), diazo compound I-23c
(87.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution by the general
procedure C (10 mol% catalyst loading) with a reaction time of 24 hours. The reaction
went to 78% conversion. The crude epoxide was purified by column chromatography
(silica gel, 20 × 250 mm, 10:1 to 4:1 hexanes/ EtOAc as eluent) to give I-139c as a white
solid (mp 120-122 ÂşC on >99% ee material) in 47% isolated yield (55.1 mg, 0.236 mmol);
cis/trans: >100:1. The optical purity of I-139c was determined to be >99% ee by HPLC
(Daicel Chirapak OD-H column, 94:6 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min):

260

retention times: Rt = 7.14 min (major enantiomer, I-139c) and Rt = 13.32 min (minor
enantiomer, ent-I-139c).
Spectral data for I-139c: Rf = 0.35 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.89 (s, 9H), 1.47 (d, J = 5.0 Hz, 1H), 1.37 (d, J = 5.0 Hz, 1H), 4.20 (dd, J = 14.0, 5.0
Hz, 1H), 4.48 (dd, J = 14.0, 6.0 Hz, 1H), 6.45 (brs, 1H), 7.20-7.30 (m, 5H);

13

C NMR

(CDCl3, 126 MHz) δ 26.46, 31.78, 43.35, 55.93, 67.25, 127.73, 128.24, 128.71, 136.90,
167.27; IR (thin film) 3328 brs, 2953 s, 2870 m, 1653 vs, 1546 s, 1496 w, 1481 w, 1452
m, 1422 m, 1363 m cm-1; HRMS (ESI-TOF) m/z 234.1508 [(M+H+); calcd. for C14H20NO2:
234.1494]; [𝛼]%&
$ 	+5.0 (c 1.0, CH2Cl2) on >99% ee material (HPLC).
O

O
H

12

+

N2

N
H

Bu

O

5 mol% I-118,
toluene, –40 ºC
24 h, 0.1 M

CONHBu
12

I-23a
1.2 equiv.

I-141a
63%, 91% ee

0.5 mmol

(2R,3R)-N-butyl-3-(pentadec-1-yn-1-yl)oxirane-2-carboxamide

I-141a:

The

epoxide I-141a was prepared from hexadec-2-ynal (167.5 ÎźL, 0.600 mmol, 1.20 equiv,
prepared6 by 1-pentadecyne and DMF), diazo compound I-23a (70.6 mg, 0.500 mmol,
1.0 equiv) and the (R)-VANOL catalyst solution by the general procedure C with a reaction
time of 24 hours. The reaction went to 100% conversion. The crude epoxide was purified
by column chromatography (silica gel, 20 × 250 mm, 3:1 to 1:1 hexanes/ EtOAc as eluent)
to give I-141a as a white solid (mp 43-45 ÂşC on 91% ee material) in 63% isolated yield
(111 mg, 0.317 mmol); cis/trans: >100:1. The optical purity of I-141a was determined to
be 91% ee by HPLC (Daicel Chirapak OD-H column, 94:6 hexane/2-propanol at 228 nm,

261

flow-rate: 1 mL/min): retention times: Rt = 5.35 min (minor enantiomer, ent-I-141a) and Rt
= 5.66 min (major enantiomer, I-141a).
Spectral data for I-141a: Rf = 0.45 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.81 (t, J = 7.0 Hz, 3H), 0.86 (t, J = 7.0 Hz, 3H), 1.19 (s, 18H), 1.25-1.34 (m, 4H), 1.371.47 (m, 4H), 2.10 (t, J = 7.5 Hz, 2H), 3.13-3.20 (m, 1H), 3.25-3.32 (m, 1H), 3.49 (d, J =
4.0 Hz, 1H), 3.56 (d, J = 4.0 Hz, 1H), 6.27 (t, J = 6.0 Hz, 1H); 13C NMR (CDCl3, 126 MHz)
δ 13.41, 13.75, 18.38, 19.69, 22.36, 27.92, 28.53, 28.80, 29.03, 29.17, 29.32, 29.33,
29.35, 31.42, 31.60, 38.29, 45.69, 55.47, 72.55, 87.63, 165.82 (one sp3 carbon not
located); IR (thin film) 3295 br, 2924 vs, 2853 s, 2245 w,1657 vs, 1545 vs, 1468 s cm-1;
HRMS (ESI-TOF) m/z 349.3003 [(M+); calcd. for C22H39NO2: 349.2981]; [𝛼]%&
$ 	-13.0 (c
1.0, CH2Cl2) on 91% ee material (HPLC).
O

O
H

12

+

N2

N
H

Bn

toluene, –40 ºC
24 h, 0.1 M

I-23c
1.2 equiv.

O

5 mol% I-118,

CONHBn
12

I-141c
63%, >99% ee
(1 h, 79%, 93% ee)

0.5 mmol

(2R,3R)-N-benzyl-3-(pentadec-1-yn-1-yl)oxirane-2-carboxamide

I-141c:

The

epoxide I-141c was prepared from hexadec-2-ynal (168 ÎźL, 0.600 mmol, 1.20 equiv,
prepared13 by 1-pentadecyne and DMF), diazo compound I-23c (87.6 mg, 0.500 mmol,
1.00 equiv) and the (R)-VANOL catalyst solution by the general procedure C with a
reaction time of 24 hours. The reaction went to 100% conversion. The crude epoxide was
purified by column chromatography (silica gel, 20 × 250 mm, 3:1 to 1:1 hexanes/ EtOAc
as eluent) to give I-141c as a white solid (mp 55-57 ÂşC on >99% ee material) in 63%

262

isolated yield (123 mg, 0.322 mmol); cis/trans: >100:1. The optical purity of I-141c was
determined to be >99% ee by HPLC (Daicel Chirapak OD-H column, 94:6 hexane/2propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt = 6.01 min (minor
enantiomer, ent-I-141c) and Rt = 7.15 min (major enantiomer, I-141c). The reaction
without DMSO with a reaction time of 24 hours afforded epoxide I-141c in 75% yield and
93% ee.
Spectral data for I-141c: Rf = 0.43 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.81 (t, J = 7.0 Hz, 3H), 1.18-1.22 (m, 20H), 1.32 (m, 2H), 1.96 (t, J = 7.0 Hz, 2H), 3.53
(d, J = 4.5 Hz, 1H), 3.57 (d, J = 4.5 Hz, 1H), 4.32 (dd, J = 15.0, 5.5 Hz, 1H), 4.50 (dd, J =
14.5, 6.5 Hz, 1H), 6.47 (t, J = 5.5 Hz, 1H), 7.18-7.26 (m, 5H); 13C NMR (CDCl3, 126 MHz)
δ 14.05, 18.54, 22.61, 28.08, 28.77, 29.02, 29.28, 29.40, 29.55, 29.57, 29.59, 31.83,
42.86, 46.13, 55.73, 72.56, 88.49, 127.46, 127.77, 128.54, 137.53, 166.15 (one sp3
carbon not located); IR (thin film) 3293 br, 2917 vs, 2849 s, 2245 w,1658 vs, 1543 s, 1467
w, 1452 w cm-1; HRMS (ESI-TOF) m/z 384.2912 [(M+H+); calcd. for C25H38NO2:
384.2903]; [𝛼]%&
$ 	-34.2 (c 1.0, CH2Cl2) on >99% ee material (HPLC).
O

O
H

+

N2

N
H

Bu

5 mol% I-118,

CONHBu

toluene, –40 ºC
4 h, 0.1 M

I-23a
1.2 equiv.

O

I-142
53%, 93% ee

0.5 mmol

(2R,3R)-N-butyl-3-(phenylethynyl)oxirane-2-carboxamide I-142: The epoxide I142 was prepared from 3-phenylpropiolaldehyde (74 ÎźL, 0.60 mmol, 1.2 equiv,
prepared13 by phenylacetylene and DMF), diazo compound I-23a (70.6 mg, 0.500 mmol,
1.00 equiv) and the (R)-VANOL catalyst solution by the general procedure C with a
263

reaction time of 4 hours. The reaction went to 89% conversion. The crude epoxide was
purified by column chromatography (silica gel, 20 × 250 mm, 3:1 to 1:1 hexanes/ EtOAc
as eluent) to give I-142 as a white solid (mp 59-62 ÂşC on 93% ee material) in 53% isolated
yield (64.9 mg, 0.267 mmol); cis/trans: >100:1. The optical purity of I-142 was determined
to be 93% ee by HPLC (Daicel Chirapak OD-H column, 94:6 hexane/2-propanol at 228
nm, flow-rate: 1 mL/min): retention times: Rt = 8.15 min (minor enantiomer, ent-I-142) and
Rt = 8.74 min (major enantiomer, I-142).
Spectral data for I-142: Rf = 0.31 (1:1 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.70 (t, J = 7.0 Hz, 3H), 1.16-1.27 (m, 2H), 1.33-1.43 (m, 2H), 3.10-3.19 (m, 1H), 3.293.37 (m, 1H), 3.63 (d, J = 4.0 Hz, 1H), 3.80 (d, J = 4.5 Hz, 1H), 6.22 (brs, 1H), 7.20-7.36
(m, 5H);

13

C NMR (CDCl3, 126 MHz) δ 13.52, 19.96, 31.72, 38.68, 46.17, 56.07, 81.54,

86.45, 121.16, 128.33, 129.21, 131.88, 165.77; IR (thin film) 3297 br, 3085 w, 2957 vs,
2930 vs, 2870 m, 2200 w, 1657 vs, 1599 w, 1549 vs, 1493 s, 1445 s cm-1; HRMS (ESITOF) m/z 243.1269 [(M+); calcd. for C15H17NO2: 243.1259]; [𝛼]%&
$ 	-6.2 (c 1.0, CH2Cl2) on
93% ee material (HPLC).

264

4.2.14 Substrate scope with respect to diazoacetamides (Scheme 1.15)
O

O
H

+

N2

N
H

Br

Bn

toluene, –40 ºC
3 h, 0.1 M

I-23c
1.2 equiv.

O

5 mol% I-118,

CONHBn

Br
I-129c
90%, >99% ee

0.5 mmol

(2R,3R)-N-benzyl-3-(4-bromophenyl)oxirane-2-carboxamide I-129c: The epoxide
I-129c was prepared from 4-bromobenzaldehyde (111 mg, 0.60 mmol, 1.2 equiv), diazo
compound I-23c (87.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution
by the general procedure C with a reaction time of 3 hours. The reaction went to 100%
conversion. The crude epoxide was purified by column chromatography (silica gel, 20 ×
250 mm, 4:1 to 1:1 hexanes/ EtOAc as eluent) to give I-129c as a white solid (mp 104107 ÂşC on >99% ee material) in 90% isolated yield (150 mg, 0.450 mmol); cis/trans:
>100:1. The optical purity of I-129c was determined to be >99% ee by HPLC (Daicel
Chirapak OD-H column, 94:6 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min):
retention times: Rt = 14.53 min (major enantiomer, I-129c) and minor enantiomer was not
located.
Spectral data for I-129c: Rf = 0.30 (1:1 EtOAc/hexane); 1H NMR (500 MHz, CDCl3)
δ 3.83 (d, J = 4.8 Hz, 1H), 3.98 (dd, J = 14.8, 4.6 Hz, 1H), 4.25 (d, J = 4.8 Hz, 1H), 4.43
(dd, J = 14.8, 7.5 Hz, 1H), 6.28 (t, J = 6.1 Hz, 1H), 6.63 – 6.81 (m, 2H), 7.11 – 7.25 (m,
5H), 7.32 – 7.43 (m, 2H).

13

C NMR (126 MHz, CDCl3) δ 42.73, 56.27, 57.68, 122.69,

127.46, 127.51, 128.24, 128.58, 131.68, 131.99, 136.95, 165.88. HRMS (ESI-TOF) m/z
330.0126 [(M–H+); calcd. for C16H1379BrNO2: 330.0130]; [𝛼]%&
$ 	+57.6 (c 1.0, CH2Cl2)
on >99% ee material (HPLC).

265

O

O
H

Br

+

N2

N
H

Ph

toluene, –40 ºC
3 h, 0.1 M

I-23d
1.2 equiv.

O

5 mol% I-118,

H
N
O

Br

I-129d
88%, >99% ee

0.5 mmol

(2R,3R)-3-(4-bromophenyl)-N-phenethyloxirane-2-carboxamide

I-129d:

The

epoxide I-129d was prepared from 4-bromobenzaldehyde (111 mg, 0.600 mmol, 1.20
equiv), diazo compound I-23d (94.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL
catalyst solution by the general procedure C with a reaction time of 3 hours. The reaction
went to 100% conversion. The crude epoxide was purified by column chromatography
(silica gel, 20 × 250 mm, 4:1 to 1:1 hexanes/ EtOAc as eluent) to give I-129d as a white
solid (mp 122-124 ÂşC on >99% ee material) in 88% isolated yield (153 mg, 0.442 mmol);
cis/trans: >100:1. The optical purity of I-129d was determined to be >99% ee by HPLC
(Daicel Chirapak OD-H column, 94:6 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min):
retention times: Rt = 14.22 min (major enantiomer, I-129d) and minor enantiomer was not
located.
Spectral data for I-129d: Rf = 0.34 (1:1 EtOAc/hexane); 1H NMR (500 MHz, CDCl3)
δ 2.44 (ddt, J = 43.3, 13.9, 7.1 Hz, 2H), 3.21 – 3.36 (m, 2H), 3.75 (d, J = 4.8 Hz, 1H), 4.19
(d, J = 4.8 Hz, 1H), 5.99 (t, J = 6.0 Hz, 1H), 6.97 – 7.03 (m, 2H), 7.07 – 7.13 (m, 2H), 7.18
– 7.30 (m, 3H), 7.35 – 7.41 (m, 2H).

13

C NMR (126 MHz, CDCl3) δ 35.01, 39.68, 56.30,

57.62, 122.58, 126.68, 128.21, 128.46, 128.72, 131.56, 132.01, 138.09, 166.21. HRMS
(ESI-TOF) m/z 344.0283 [(M–H+); calcd. for C17H1579BrNO2: 344.0286]; [𝛼]%&
$ 	+24.4 (c 1.0,
CH2Cl2) on >99% ee material (HPLC).

266

O

O
H

Br

+

N2

O

5 mol% I-118,
N
H

toluene, –40 ºC
1 h, 0.1 M

O

Br

I-23e
1.2 equiv.

H
N

I-129e
91%, >99% ee

0.5 mmol

(2R,3R)-3-(4-bromophenyl)-N-cyclohexyloxirane-2-carboxamide

I-129e:

The

epoxide I-129e was prepared from 4-bromobenzaldehyde (111 mg, 0.600 mmol, 1.20
equiv), diazo compound I-23e (83.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL
catalyst solution by the general procedure C with a reaction time of 1 hour. The reaction
went to 100% conversion. The crude epoxide was purified by column chromatography
(silica gel, 20 × 250 mm, 4:1 to 1:1 hexanes/ EtOAc as eluent) to give I-129e as a white
solid (mp 176-177 ÂşC on >99% ee material) in 91% isolated yield (148 mg, 0.456 mmol);
cis/trans: >100:1. The optical purity of I-129e was determined to be >99% ee by HPLC
(Daicel Chirapak OD-H column, 94:6 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min):
retention times: Rt = 5.74 min (major enantiomer, I-129e) and minor enantiomer was not
located.
Spectral data for I-129e: Rf = 0.35 (1:1 EtOAc/hexane); 1H NMR (500 MHz, CDCl3)
δ 0.48 – 0.66 (m, 1H), 0.93 – 1.34 (m, 5H), 1.34 – 1.67 (m, 3H), 1.75 (d, J = 12.5 Hz, 1H),
3.51 (tt, J = 10.9, 9.1, 6.7 Hz, 1H), 3.67 – 3.75 (m, 1H), 4.23 (dd, J = 4.9, 2.2 Hz, 1H),
5.69 (d, J = 8.9 Hz, 1H), 7.16 – 7.27 (m, 3H), 7.40 – 7.51 (m, 2H).

13

C NMR (126 MHz,

CDCl3) δ 24.45, 24.59, 25.26, 32.38, 32.76, 47.32, 56.19, 57.57, 122.53, 128.34, 131.49,
132.27, 164.61. HRMS (ESI-TOF) m/z 322.0445 [(M–H+); calcd. for C15H1779BrNO2:
322.0443]; [𝛼]%&
$ 	+15.1 (c 1.0, CH2Cl2) on >99% ee material (HPLC).

267

O

O
H

Br

+

N2

N
H

toluene, –40 ºC
12 h, 0.1 M

I-23g
1.2 equiv.

O

5 mol% I-118,

Br

H
N
O

I-129g
47%, >99% ee

0.5 mmol

(2R,3R)-N-allyl-3-(4-bromophenyl)oxirane-2-carboxamide I-129g: The epoxide I129g was prepared from 4-bromobenzaldehyde (111 mg, 0.600 mmol, 1.20 equiv), diazo
compound I-23g (62.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution
by the general procedure C with a reaction time of 12 hours. The crude epoxide was
purified by column chromatography (silica gel, 20 × 250 mm, 4:1 to 1:1 hexanes/ EtOAc
as eluent) to give I-129g as a white solid (mp 96-98 ÂşC on >99% ee material) in 47%
isolated yield (66.2 mg, 0.235 mmol); cis/trans: >100:1. The optical purity of I-129e was
determined to be >99% ee by HPLC (Daicel Chirapak OD-H column, 94:6 hexane/2propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt = 9.58 min (major
enantiomer, I-129g) and minor enantiomer was not located.
Spectral data for I-129g: Rf = 0.42 (1:1 EtOAc/hexane); 1H NMR (500 MHz, CDCl3)
δ 3.46 – 3.57 (m, 1H), 3.65 (dddt, J = 15.5, 6.9, 5.4, 1.6 Hz, 1H), 3.76 (d, J = 4.8 Hz, 1H),
4.24 (d, J = 4.8 Hz, 1H), 4.71 – 4.81 (m, 1H), 4.93 (dq, J = 10.2, 1.3 Hz, 1H), 5.33 (dddd,
J = 17.1, 10.3, 6.1, 5.4 Hz, 1H), 5.92 (s, 1H), 7.14 – 7.23 (m, 2H), 7.42 – 7.48 (m, 2H).
13

C NMR (126 MHz, CDCl3) δ 41.04, 56.27, 57.62, 116.79, 122.66, 128.28, 131.63,

132.08, 132.85, 165.84. HRMS (ESI-TOF) m/z 279.9986 [(M–H+); calcd. for
C12H1179BrNO2: 279.9979]; [𝛼]%&
$ 	ND.

268

O

O
H

+

Br

N2

O

5 mol% I-118,
N
H

toluene, –40 ºC
15 h, 0.1 M

O

Br

I-23h
1.2 equiv.

H
N

I-129h
97%, 94% ee

0.5 mmol

(2R,3R)-3-(4-bromophenyl)-N-(prop-2-yn-1-yl)oxirane-2-carboxamide I-129h: The
epoxide I-129h was prepared from 4-bromobenzaldehyde (111 mg, 0.600 mmol, 1.20
equiv), diazo compound I-23h (61.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL
catalyst solution by the general procedure C with a reaction time of 15 hours. The crude
epoxide was purified by column chromatography (silica gel, 20 × 250 mm, 4:1 to 1:1
hexanes/ EtOAc as eluent) to give I-129h as a white solid (mp 118-119 ÂşC on >99% ee
material) in 97% isolated yield (136 mg, 0.487 mmol); cis/trans: >100:1. The optical purity
of I-129h was determined to be 94% ee by HPLC (Daicel Chirapak OD-H column, 94:6
hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt = 14.21 min (major
enantiomer, I-129h) and Rt = 12.89 min (minor enantiomer, ent-I-129h).
Spectral data for I-129h: Rf = 0.44 (1:1 EtOAc/hexane); 1H NMR (500 MHz, CDCl3)
δ 2.05 (t, J = 2.6 Hz, 1H), 3.71 (ddd, J = 17.6, 5.1, 2.6 Hz, 1H), 3.77 (d, J = 4.8 Hz, 1H),
3.79 (dd, J = 6.3, 2.6 Hz, 1H), 4.23 (d, J = 4.7 Hz, 1H), 6.14 (t, J = 5.7 Hz, 1H), 7.09 –
7.27 (m, 2H), 7.33 – 7.53 (m, 2H).

13

C NMR (126 MHz, CDCl3) δ 28.11, 56.27, 57.64,

71.48, 78.32, 122.70, 128.21, 131.67, 131.85, 165.63. HRMS (ESI-TOF) m/z 277.9817
[(M–H+); calcd. for C12H979BrNO2: 277.9817]; [𝛼]%&
$ 	+51.0 (c 1.0, CH2Cl2) on 94% ee
material (HPLC).

269

O

O
H

+

N2

N
H

Br
1.2 equiv.

O
OEt

O

5 mol% I-118,
toluene, –40 ºC
24 h, 0.1 M

H
N

OEt
O

O

Br

I-23i

I-129i

0.5 mmol

90%, >99% ee

ethyl ((2R,3R)-3-(4-bromophenyl)oxirane-2-carbonyl)glycinate I-129i: The epoxide
I-129i was prepared from 4-bromobenzaldehyde (111 mg, 0.600 mmol, 1.20 equiv), diazo
compound I-23i (85.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL catalyst solution
by the general procedure C with a reaction time of 24 hours. The crude epoxide was
purified by column chromatography (silica gel, 20 × 250 mm, 4:1 to 1:1 hexanes/ EtOAc
as eluent) to give I-129i as a white solid (mp 75-77 ÂşC on >99% ee material) in 90%
isolated yield (147 mg, 0.448 mmol); cis/trans: >100:1. The optical purity of I-129i was
determined to be >99% ee by HPLC (Daicel Chirapak OD-H column, 94:6 hexane/2propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt = 11.95 min (major
enantiomer, I-129i) and minor enantiomer was not located.
Spectral data for I-129i: Rf = 0.31 (1:1 EtOAc/hexane); 1H NMR (500 MHz, CDCl3)
δ 1.20 (t, J = 7.2 Hz, 3H), 3.62 (dd, J = 18.4, 5.2 Hz, 1H), 3.77 (d, J = 4.7 Hz, 1H), 3.82
(dd, J = 18.3, 5.3 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 4.22 (d, J = 4.7 Hz, 1H), 6.51 (t, J =
5.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H). 13C NMR (126 MHz, CDCl3)
δ 14.09, 40.51, 56.56, 57.71, 61.68, 122.59, 128.19, 131.54, 131.54, 166.03, 168.89.
HRMS (ESI-TOF) m/z 326.0035 [(M–H+); calcd. for C13H1379BrNO4: 326.0033]; [𝛼]%&
$ 	–1.0
(c 1.0, CH2Cl2) on >99% ee material (HPLC).

270

O

O
H

+

N2

N
H

Br

OMe

O

5 mol% I-118,
toluene, –40 ºC
1 h, 0.1 M

OMe

O

Br

I-23j
1.2 equiv.

H
N

I-129j
93%, 90% ee

0.5 mmol

(2R,3R)-3-(4-bromophenyl)-N-(2-methoxyethyl)oxirane-2-carboxamide

I-129j:

The epoxide I-129j was prepared from 4-bromobenzaldehyde (111 mg, 0.600 mmol, 1.20
equiv), diazo compound I-23j (71.6 mg, 0.500 mmol, 1.00 equiv) and the (R)-VANOL
catalyst solution by the general procedure C with a reaction time of 1 hour. The crude
epoxide was purified by column chromatography (silica gel, 20 × 250 mm, 4:1 to 1:1
hexanes/ EtOAc as eluent) to give I-129j as a white solid (mp 76-79 ÂşC on >99% ee
material) in 93% isolated yield (140 mg, 0.467 mmol); cis/trans: >100:1. The optical purity
of I-129j was determined to be 90% ee by HPLC (Daicel Chirapak OD-H column, 94:6
hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt = 14.21 min (major
enantiomer, I-129j) and Rt = 12.89 min (minor enantiomer, ent-I-129j)
Spectral data for I-129j: Rf = 0.36 (1:1 EtOAc/hexane); 1H NMR (500 MHz, CDCl3)
δ 2.76 – 2.82 (m, 1H), 3.05 (dddd, J = 13.8, 8.1, 4.9, 3.4 Hz, 1H), 3.16 (s, m, 4H), 3.25
(dddd, J = 13.9, 6.9, 5.6, 3.4 Hz, 1H), 3.74 (d, J = 4.7 Hz, 1H), 4.20 (d, J = 4.8 Hz, 1H),
6.26 (t, J = 6.1 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H). 13C NMR (126
MHz, CDCl3) δ 38.25, 56.37, 57.49, 58.68, 70.73, 122.44, 128.27, 131.45, 132.16,
165.72. HRMS (ESI-TOF) m/z 298.0084 [(M–H+); calcd. for C12H1379BrNO3: 298.0084];
[𝛼]%&
$ 	+44.8 (c 1.0, CH2Cl2) on 90% ee material (HPLC).

271

4.2.15 Gram-scale synthesis of cis-epoxide I-108a (Scheme 1.16)
O

O
H

+
N2

I-51a
1.2 equiv

N
H

I-23a
6 mmol

Bu

5 mol% I-118
toluene, –40 ºC
0.5 h

O
CONHBu
I-111a

1.254 g
95% yield, 99% ee
98% VANOL recovered

Preparation of the catalyst I-118 solution: To a 50 mL flame-dried home-made
Schlenk flask, prepared from a single-necked 50 mL pear-shaped flask that had its 14/20
glass joint replaced with a T-shaped high vacuum threaded Teflon valve, equipped with
a stir bar and flushed with nitrogen was added (R)-VANOL (289 mg, 0.660 mmol). Under
a nitrogen flow through the side-arm of the Schlenk flask, dry toluene (12 mL) was added
through the top of the Teflon valve to effect dissolution. After the addition of the toluene,
BH3•Me2S (165 μL, 0.330 mmol, 2 M in toluene) was added. The flask was sealed by
closing the Teflon valve, and then placed in a 100 ÂşC oil bath for 0.5 h. After 0.5 h, a
vacuum (0.5 mm Hg) was carefully applied by slightly opening the Teflon valve to remove
the volatiles. After the volatiles were removed completely, a full vacuum was applied and
maintained for a period of 30 min at a temperature of 100 ÂşC (oil bath). The flask was then
allowed to cool to room temperature and opened to nitrogen through the side-arm of the
Schlenk flask. The residue was then completely dissolved in dry toluene (12 mL) under a
nitrogen flow through side-arm of the Schlenk flask to afford the solution of the precatalyst. To the flask containing the pre-catalyst was added the dimethyl sulfoxide (48 ÎźL,
0.66 mmol) under a nitrogen flow through side-arm of the Schlenk flask to give the solution
of catalyst which was then directly cooled to –40 °C to initiate the reaction.

272

Asymmetric epoxidation: A 250 mL round bottom flask was flame dried under
vacuum and cooled to rt under N2. The vacuum adapter was replaced with a rubber
septum. The septum was removed briefly to allow introduction of diazoacetamide I-23a
(846.5 mg, 6.000 mmol). Subsequently, the septum was removed again to allow for the
addition of a dry stir bar and anhydrous toluene (50 mL). Neat benzaldehyde I-51a (0.730
mL, 7.20 mmol, freshly distilled) was then added via syringe and a N2 balloon was
attached via needle in the septum. The mixture was stirred at rt for 10 min to effect
dissolution. The round bottom flask and the Schlenk flask containing the catalyst were
both cooled to –40 °C in a cold bath with a recirculating chiller for 10 min. The catalyst
solution (10 mL, 5% catalyst) was quickly transferred to the round bottom flask using a
syringe. The resulting mixture was stirred until the yellow color disappeared (0.5 h). The
reaction was quenched by the addition of H2O (5 mL) and was then warmed to room
temperature. The reaction mixture was then transferred to a 125 mL separatory funnel.
The water layer was extracted with EtOAc (10 mL × 3). The combined organic layer was
dried over Na2SO4 and then filtered into a 250 mL round bottom flask. The resulting
solution was then concentrated under vacuum followed by exposure to high vacuum (0.05
mm Hg) for 1 h to afford the crude epoxide as an off-white semi-solid. Purification of the
crude epoxide by silica gel chromatography [20 mm × 300 mm column, 5:1 to recover
VANOL ligand (281.4 mg, 98.6%) then 1:1 hexanes/EtOAc as eluent] afforded pure cisepoxide I-111a as a white solid in 95% isolated yield (1.254 g, 5.720 mmol). The optical
purity of I-111a was determined to be >99% ee by HPLC (PIRKLE COVALENT (R,R)
WHELK-O 1 column, 93:7 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention

273

times: Rt = 23.31 min (minor enantiomer, ent-I-111a) and Rt = 32.32 min (major
enantiomer, I-111a).
If this large-scale reaction was carried out in the presence of 4 Å molecular sieves,
the reaction was much slower. After 17 h the epoxide I-111a was obtained in 54% yield
and 92% ee. After 80 h, epoxide I-111a was obtained in 86% yield and 97% ee.
4.2.16 Synthesis of Taxol-side chain I-146 (Scheme 1.18)
O
CONHBu
I-111a
99% ee

1) BuLi, THF,
-78 ÂşC, 30 min
2) Boc2O, –78 ºC, 2 h
then -45 ÂşC, 2 h
3 mmol

O

Boc
N
O
I-25’
90%, 99% ee

t-butyl butyl((2R,3R)-3-phenyloxirane-2-carbonyl)carbamate I-25’: A 100 mL round
bottom flask was flame dried under vacuum and cooled to rt under N2. The vacuum
adapter was replaced with a rubber septum. The septum was removed briefly to allow
introduction of I-111a (657.8 mg, 3.000 mmol, 99% ee). Subsequently, the septum was
removed again to allow for the addition of a dry stir bar and anhydrous THF (20 mL). A
N2 balloon was attached via a needle in the septum. The mixture was stirred at –78 °C
for 10 min. A solution of n-butyllithium (1.25 mL, 3.00 mmol, 2.42 M in hexanes) was
added dropwise to the round bottom flask using a syringe over a period of 5 minutes. The
resulting mixture was stirred was stirred at –78 °C for 30 min. Meanwhile, to another
flame-dried 25 mL single-necked round-bottom flask was added Boc anhydride (1.31 g,
6.00 mmol) and dry THF (10 mL). This solution was added to the 100 mL round bottom
flask at –78 °C using a syringe over a period of 5 min. The resulting mixture was stirred
at –78 °C for 2 h then warmed up to –45 °C. After a total reaction time of 4 h, the reaction

274

was quenched by the addition of saturated aq NH4Cl solution (5 mL) and was then
warmed to room temperature. The reaction mixture was then transferred to a 60 mL
separatory funnel. The water layer was extracted with diethyl ether (10 mL × 3). The
combined organic layer was dried over Na2SO4 and then filtered into a 100 mL round
bottom flask. The resulting solution was then concentrated under vacuum to afford the
crude product as an off-white oil. Purification of the crude product by silica gel
chromatography [20 mm × 300 mm column, 6:1 hexanes/EtOAc as eluent] afforded the
pure title compound as a colorless oil in 90% isolated yield (865 mg, 2.71 mmol). The
optical purity of the title compound was determined to be 99% ee by HPLC (Daicel
Chirapak OD-H column, 94:6 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min):
retention times: Rt = 3.30 min (minor enantiomer, ent-I-25’) and Rt = 5.09 min (major
enantiomer, I-25’).
Spectral data for I-25’: Rf = 0.26 (1:6 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.67 (t, J = 7.5 Hz, 3H), 0.84-0.98 (m, 4H), 1.43 (s, 9H), 3.26 (dt, J = 14.0, 7.0 Hz, 1H),
3.42 (dt, J = 14.0, 6.5 Hz, 1H), 4.28 (d, J = 4.5 Hz, 1H), 4.33 (d, J = 4.5 Hz, 1H), 7.177.24 (m, 5H);

13

C NMR (CDCl3, 126 MHz) δ 13.97, 19.61, 27.91, 29.92, 43.54, 75.83,

61.46, 83.30, 126.10, 127.96, 128.09, 133.76, 152.58, 167.95; IR (thin film) 3451 br w,
2965 vs, 2934 s. 2874 w, 1734 vs, 1707 vs, 1497 w, 1456 w, 1370 s, 1219 w, 1148 s cm1

; HRMS (ESI-TOF) m/z 320.1860 [(M+H+); calcd. for C18H26NO4: 320.1862]; [𝛼]%&
$ 	+106.4

(c 1.0, CH2Cl2) on 99% ee material (HPLC). The product I-25’ was obtained in 97% yield
in a separate run on 2.6 mmol scale.

275

O

Boc
N

EtONa, EtOH,
0 ÂşC to rt, 30 min

O

O
OEt
O
I-25

I-25’

80%

2.64 mmol

ethyl (2R,3R)-3-phenyloxirane-2-carboxylate I-25: A solution of the above
carbamate I-25’ (844 mg, 2.64 mmol) in 30 mL ethanol was cooled in an ice bath. A
solution of EtONa (5.28mL, freshly prepared by sodium with ethanol, 1M in EtOH) was
added dropwise using a syringe. After being stirred at 0°C for 10 min, the reaction mixture
was warmed up to rt for 30 min. The reaction was quenched by the addition of saturated
aq. NH4Cl solution (5 mL). The reaction mixture was then transferred to a 60 mL
separatory funnel. The water layer was extracted with CH2Cl2 (10 mL × 3). The combined
organic layer was dried over Na2SO4 and then filtered into a 100 mL round bottom flask.
The resulting solution was then concentrated under vacuum to afford the crude product
as an off-white oil. Purification of the crude product by silica gel chromatography [20 mm
× 300 mm column, 2:1 to 1:1 hexanes/ CH2Cl2 as eluent] afforded I-25 as a colorless oil
in 80% isolated yield (405 mg, 2.11 mmol). The optical purity of title compound was
determined to be 99% ee by HPLC (Daicel Chirapak OD-H column, 94:6 hexane/2propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt = 4.03 min (minor
enantiomer, ent-I-25) and Rt = 5.24 min (major enantiomer, I-25).
Spectral data for I-25: Rf = 0.11 (1:1 CH2Cl2/hexane); 1H NMR (CDCl3, 500 MHz)
δ 0.90 (t, J = 7.5 Hz, 3H), 3.71 (d, J = 7.0 Hz, 1H), 3.84-3.93 (m, 2H), 4.15 (d, J = 7.0 Hz,
1H), 7.16-7.24 (m, 3H), 7.32 (d, J = 6.5 Hz, 2H);

13

C NMR (CDCl3, 126 MHz) δ 13.60,

55.49, 57.07, 60.87, 126.39, 127.72, 128.14, 132.70, 166.33; IR (thin film) 3440 br, 2984

276

w, 1754 vs, 1653s, 1204 vs cm-1; HRMS (ESI-TOF) m/z 193.0869 [(M+H+); calcd. for
12
C11H13O3: 193.0865]; [𝛼]%&
$ 	+8.5 (c 1.0, CH2Cl2) on 99% ee material (HPLC). (lit.

[𝛼]%&
$ 	22.2 (c 1.12, CHCl3)). These NMR data match that previously reported for this
compound5, 7.
O

O
OEt
O
I-25

1) 0.1 equiv ZnCl2,
TMSN3, 70 ÂşC, 24 h

N3

OEt
OH

2) HCl, HOAc, THF,
rt, 1 h

I-153

2.11 mmol

96%

ethyl (2R,3S)-3-azido-2-hydroxy-3-phenylpropanoate I-153: A neat mixture of
epoxy ester I-25 (405 mg, 2.11 mmol), azidotrimethylsilane (0.340 mL, 2.53 mmol) and
zinc chloride (28.6 mg, 0.210 mmol) was stirred at 70°C for 24 h. The reaction mixture
was cooled to rt followed by addition of THF (2 mL), acetic acid (0.2 mL) and conc HCl
(0.1 mL). The resulting solution was stirred for 1 h and then quench with saturated aq
NaHCO3 solution (5 mL). The reaction mixture was then transferred to a 60 mL separatory
funnel. The water layer was extracted with CH2Cl2 (10 mL × 3). The combined organic
layer was dried over Na2SO4 and then filtered into a 100 mL round bottom flask. The
resulting solution was then concentrated under vacuum to afford the crude product as
colorless oil. Purification of the crude product by silica gel chromatography [20 mm × 300
mm column, 5:1 hexanes/ether as eluent] afforded I-153 as a colorless oil in 96% isolated
yield (475 mg, 2.02 mmol). The optical purity of title compound was determined to be 99%
ee by HPLC (Daicel Chirapak OD-H column, 94:6 hexane/2-propanol at 228 nm, flowrate: 1 mL/min): retention times: Rt = 4.80 min (major enantiomer, I-153) and Rt = 6.78
min (minor enantiomer, ent-I-153).
277

Spectral data for I-153: Rf = 0.13 (1:4 ether/hexane); 1H NMR (CDCl3, 500 MHz) δ
1.23 (t, J = 7.0 Hz, 3H), 3.04 (br, 1H), 4.22 (t, J = 7.0 Hz, 2H), 4.31 (br, 1H), 4.78 (d, J =
3.5 Hz, 1H), 7.28-7.37 (m, 3H), 7.39 (d, J = 8.0 Hz, 2H);

13

C NMR (CDCl3, 126 MHz) δ

14.08, 62.46, 67.11, 73.83, 127.83, 128.77, 128.83, 135.52, 171.89; IR (thin film) 3470
br, 2984 w, 2107 vs, 1736 vs, 1455 w cm-1; HRMS (ESI-TOF) m/z 258.0861 [(M+Na+);
calcd. for C11H13N3O3Na: 258.0855]; [𝛼]%&
$ 	+144.6 (c 1.0, CH2Cl2) on 99% ee material
(HPLC). (lit.15 [𝛼]%&
$ 	133.5 (c 2.0, CHCl3)). These NMR data matches that previously
reported for this compound7.
O
N3

OEt
OH

BzCl, Et3N
0.05 equiv DMAP
CH2Cl2, rt, 1 h

I-153

1.91 mmol

O
N3

OEt
OBz
I-154
99%

ethyl (2R,3S)-3-azido-2-O-benzoyl-3-phenylpropionate I-154: To a solution of the
above hydroxyl azide I-153 (450 mg, 1.91 mmol) and triethylamine (0.32 mL, 2.30 mmol)
in CH2Cl2 (5 mL) was added benzoyl chloride (0.250 mL, 2.11 mmol) and 4dimethylaminopyridine (12.2 mg, 0.100 mmol). After being stirred at rt for 1 h, the reaction
mixture was quenched by addition of H2O (1 mL). The reaction mixture was then
transferred to a 60 mL separatory funnel. The water layer was extracted with CH2Cl2 (10
mL × 3). The combined organic layer was dried over Na2SO4 and then filtered into a 100
mL round bottom flask. The resulting solution was then concentrated under vacuum to
afford the crude product as a colorless oil. Purification of the crude product by silica gel
chromatography [20 mm × 300 mm column, 10:1 hexanes/EtOAc as eluent] afforded I154 as a colorless oil in 99% isolated yield (646 mg, 1.90 mmol). The optical purity of title
278

compound was determined to be 99% ee by HPLC (Daicel Chirapak OD-H column, 94:6
hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt = 3.77 min (minor
enantiomer, ent-I-154) and Rt = 5.36min (major enantiomer, I-154).
Spectral data for I-154: Rf = 0.24 (1:8 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 1.08 (t, J = 7.0 Hz, 3H), 4.04-4.14 (m, 2H), 5.09 (d, J = 5.5 Hz, 1H), 5.39 (d, J = 5.5 Hz,
1H), 7.26-7.38 (m, 5H), 7.41 (t, J = 8.0 Hz, 2H), 7.54 (t, J = 7.5 Hz, 1H), 8.03 (d, J = 8.5
Hz, 2H);

13

C NMR (CDCl3, 126 MHz) δ 13.86, 61.98, 65.59, 75.60, 127.54, 128.54,

128.75, 128.90, 129.12, 130.02, 133.64, 134.55, 165.55, 167.31; IR (thin film) 3438 br,
2107 vs, 1728 vs, 1653 w, 1603 w, 1495 w, 1453 w cm-1; HRMS (ESI-TOF) m/z 340.1295
[(M+H+); calcd. for C18H18N3O4: 340.1297]; [𝛼]%&
$ 	+125.7 (c 1.0, CH2Cl2) on 99% ee
material (HPLC). These NMR data matches that previously reported for this compound.14
O
N3

OEt
OBz

0.2 equiv CuCl
aq. (NH4)2S
MeCN, rt, overnight

I-154

0.45 mmol

O
BzHN

OEt
OH

I-146
90%, 99% ee

Ethyl (2R,3S)-3-benzamido-2-hydroxy-3-phenylpropanoate I-146: To a solution of
the azido benzoate I-154 (153 mg, 0.45 mmol) and CuCl (8.9 mg, 0.090 mmol) in CH3CN
(3 mL) was added aqueous (NH4)2S (40−48 wt% solution in water, 1.13 mmol, 192 μL).5
After being stirring for 12 h at room temperature, the reaction mixture was poured into a
mixture of water (50 mL) and saturated aqueous NaHCO3 (25 mL) and extracted with
CH2Cl2 (3 × 30 mL). The organic extracts were combined, dried over Na2SO4, filtered,
and evaporated. Purification of the crude product by silica gel chromatography [20 mm ×
300 mm column, 3:1 hexanes/EtOAc as eluent] afforded I-146 as a white solid (mp 165279

167 ÂşC on 99% ee material) in 90% isolated yield (128 mg, 0.410 mmol). The optical purity
of title compound was determined to be 99% ee by HPLC (Daicel Chirapak AD-H column,
80:20 hexane/2-propanol at 220 nm, flow-rate: 1 mL/min): retention times: Rt = 9.47 min
(major enantiomer, I-146) and Rt = 10.98 min (minor enantiomer, ent-I-146).
Spectral data for I-146: Rf = 0.12 (1:2 EtOAc/hexane); 1H NMR (CDCl3, 500 MHz)
δ 1.21 (t, J = 7.0 Hz, 3H), 3.65 (br, 1H), 4.18 (m, 2H), 4.52 (d, J = 2.0 Hz, 1H), 5.67 (dd,
J = 9.0, 2.0 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.28 (t, J = 7.5 Hz, 2H), 7.32-7.49 (m, 6H),
7.74 (d, J = 7.5 Hz, 2H); 13C NMR (CDCl3, 126 MHz) δ 14.02, 55.14, 61.93, 73.56, 126.83,
127.13, 127.45, 128.34, 128.38, 131.43, 134.27, 138.98, 166.83, 172.62; IR (thin film)
3416 br, 3351 vs, 2977 w, 2926 w,1719 vs, 1638 vs, 1528 s cm-1; HRMS (ESI-TOF) m/z
314.1399 [(M+H+); calcd. for C18H20NO4: 314.1392]; [𝛼]%&
$ 	-19.7 (c 1.0, CHCl3) on 99%
7
%&
ee material (HPLC). (lit.6 [𝛼]%&
$ 	-21.6 (c 1.0, CHCl3); lit. [𝛼]$ 	-21.7 (c 1.0, CHCl3)). These

NMR data matches that previously reported for this compound7.

280

4.2.17 NMR studies and DFT calculations8
3D Geometries of DFT optimized structrues

Figure 4.2 Geometries of 2:1 mesoborate catalyst at the B3LYP/6-31G(d) level

Figure 4.3 Geometries of DMSO-mesoborate complex at the B3LYP/6-31G(d) level

281

Cartesian coordinates & SCF energies for computed structures
Conformational searches were carried out using Spartan’0816,17 with Molecular
Mechanics. Full geometry optimizations were carried out using the Gaussian 03
package18 at the B3LYP/6-31G(d) level of theory in the gas phase.
2:1 mesoborate catalyst
H -2.149907 6.741085
C -2.059818 5.739062
H -4.178442 5.441892
C -3.189485 5.017288
C -0.641607 3.914162
C -3.088129 3.705433
C -0.776598 5.182024
C -1.791793 3.145626
C -4.225360 2.952167
H 0.109603 5.761267
H 0.342616 3.494664
C -4.134088 1.671159
H -5.201176 3.425236
C -2.836181 1.046726
C -1.722699 1.822578
C -2.687693 -0.384298
C -1.853240 -0.727114
C -3.413912 -2.707989
C -1.829467 -2.024410
C -3.420451 -1.441922
C -2.671367 -3.025381
C -1.023256 -2.345580
H -3.317505 -5.084758
H -3.948567 -3.507014
C -1.064960 -3.610828
H -0.383902 -1.578387
H -0.448716 -3.849700
C -1.901143 -4.606241
H -1.920255 -5.600920
C -2.682122 -4.320508
O -0.973492 0.202166
O -0.436366 1.332146
C -4.085325 -1.248659
C -5.261038 -1.046303
C -3.402351 -0.626751

C
C
C
H
H
H
H
H
C
C
C
C
C
C
H
H
H
H
H
H
C
H
C
C
C
C
C
C
H
H
C
H
C
C
C
C

2.028961
1.618366
1.458460
1.304036
0.880567
0.770437
1.402976
0.560628
0.390102
1.646750
0.708351
-0.119037
0.453793
-0.232528
0.040344
-0.633257
-1.684592
-0.530973
-2.269010
0.020056
-1.695735
-3.391706
-1.836297
-0.025023
-3.935281
-3.813304
-4.797661
-3.374798
-3.811984
-2.277085
-2.231273
-0.159914
1.339114
3.891103
2.398446

282

-5.365161
-5.947379
-3.985922
-2.398005
-5.914492
-6.942465
-3.437626
-5.714796
-5.386867
-7.815342
-6.565265
-5.450809
-6.651889
-7.766813
-6.528586
-4.557988
-6.678946
-8.664040
-8.751062
3.599722
3.320557
4.771893
3.972922
1.918041
3.622346
2.287727
2.568008
4.279740
1.784970
1.137348
3.939870
5.069467
2.884332
2.228217
2.567690
1.568167

-1.770790
-1.671095
-0.525721
-0.246432
-2.234469
-2.075625
-0.047270
-0.967708
1.035420
0.016920
1.092680
0.457972
-0.046633
0.590001
1.512001
0.419874
-0.482742
0.639271
-0.376023
6.369644
5.346613
5.145111
4.667599
3.419082
3.328670
4.714183
2.700088
2.598753
5.254751
2.933559
1.296660
3.088289
0.642487
1.361630
-0.806220
-1.169241

1.585183
2.848289
3.660778
2.237432
0.770973
3.015036
4.468089
4.875591
-0.619031
-1.625422
0.143550
-1.898104
-2.394826
-0.353479
1.144810
-2.514017
-3.389974
0.258126
-2.014278
-2.117407
-1.880443
-0.314305
-0.876264
-2.324582
-0.555428
-2.613491
-1.286530
0.465386
-3.410561
-2.900235
0.778144
1.028997
0.047435
-0.938283
0.288306
1.181894

C
C
C
C
C
H
H
C
H
H
C
H
C
O
H
O
C
C
C
C

3.143203
1.317423
3.363143
2.132417
0.295418
2.514336
3.745209
0.092414
-0.324837
-0.695105
0.899813
0.729362
1.894162
0.805165
0.778064
1.249935
4.449950
6.514745
4.185093
5.765952

-3.157576
-2.532628
-1.835677
-3.540461
-2.909018
-5.666460
-3.930894
-4.236372
-2.137051
-4.516243
-5.239944
-6.283566
-4.898831
-0.248385
0.584236
0.739090
-1.519088
-1.029024
-0.861897
-1.930698

0.009590
1.524082
-0.322967
0.926556
2.433700
0.810348
-0.459726
2.743181
2.874555
3.437633
2.156262
2.407808
1.267128
1.851276
1.346920
-1.703806
-1.296599
-3.148087
-2.508763
-1.032018

C 6.789891 -1.686484
C 5.208464 -0.620403
H 3.169101 -0.558538
H 5.984045 -2.429502
H 7.803282 -2.008448
H 4.982645 -0.115716
H 7.310970 -0.838135
C 4.697305 0.608701
C 6.181587 -0.575774
C 6.096440 0.521338
C 4.053024 0.095504
C 4.790617 -0.490126
C 6.832676 -0.068059
H 6.602995 0.900712
H 2.973599 0.169610
H 4.275191 -0.878101
H 7.914773 -0.132602
H 6.753148 -1.035243
B -0.068160 0.756704
SCF energy: -2789.467451

DMSO-mesoborate complex 1
H 0.251693 -6.113521 2.168677
C 0.509882 -5.111922 1.834842
H 2.563361 -5.593005 1.442103
C 1.794340 -4.824018 1.433212
C -0.166801 -2.828526 1.381206
C 2.147820 -3.520268 0.996556
C -0.477884 -4.101384 1.807547

C
C
H
H
C
H
C
C
283

1.150039
3.453337
-1.494469
-0.939375
3.814067
4.173529
2.850959
1.533096

-2.497839
-3.220291
-4.328029
-2.074556
-1.952730
-4.029656
-0.880364
-1.185724

-1.948288
-3.425055
-2.740829
-0.092004
-1.721815
-4.361015
-3.862969
1.864900
3.941768
1.788385
3.001935
4.030184
2.816826
0.905415
3.087621
4.904827
2.735796
4.743957
-1.356994

0.968884
0.542120
2.116850
1.364871
0.136375
0.461783
0.210458
0.538253

C
C
C
C
C
C
C
H
H
C
H
H
C
H
C
O
O
C
C
C
C
C
C
H
H
H
H
H
C
C
C
C
C
C
H
H
H
H
H
H
C
H
C
C

3.277284
2.605595
4.893449
3.136963
4.406856
4.321334
2.542036
5.743271
5.723446
3.091901
1.663574
2.640119
4.250532
4.673399
4.848407
1.407649
0.550183
5.015779
6.171181
4.212955
6.408777
6.980961
4.785048
3.133441
7.046593
8.062001
4.143648
6.616220
5.172570
7.721344
6.298637
5.350079
6.610430
7.559334
6.181590
4.491069
6.722409
8.416482
8.703074
-0.363253
-0.625535
-2.294505
-1.699454
-0.175616

0.520507
1.233807
2.340968
2.432957
1.140783
2.985905
3.074444
4.615230
2.823525
4.228080
2.623260
4.702877
4.793816
5.705368
4.186721
0.790788
-0.225152
0.590583
-0.291373
0.126965
0.604804
0.169593
-0.309929
0.123761
0.933076
0.181057
-0.661345
-0.634701
-1.786708
-1.669057
-2.330615
-1.184394
-1.125902
-2.274145
-2.783589
-0.776592
-0.661611
-2.698254
-1.623504
-4.766821
-3.930442
-4.936763
-4.027434
-1.672298

-0.082125
-1.065223
0.076283
-1.626644
0.563710
-1.047282
-2.746309
-1.149950
0.584848
-3.265004
-3.195643
-4.132169
-2.679138
-3.093328
-1.595789
-1.545319
0.525644
1.806709
4.221999
2.862589
1.988125
3.182490
4.056412
2.751447
1.172594
3.296294
4.860463
5.152289
-0.458119
-1.659563
0.180914
-1.715185
-2.308131
-0.412242
1.161095
-2.238415
-3.284764
0.104854
-2.124017
-4.348958
-3.706256
-2.811027
-2.851011
-2.942858

C
C
C
C
H
H
C
H
C
C
C
C
C
C
C
C
C
H
H
C
H
H
C
H
C
O
H
O
C
C
C
C
C
C
H
H
H
H
H
C
C
C
C
C

284

-2.057741 -2.943263
0.138012 -2.740183
-1.273066 -1.749576
-3.167201 -3.010877
0.980714 -2.669659
0.410739 -0.762475
-3.532184 -1.946879
-3.737643 -3.934641
-2.771150 -0.726162
-1.648932 -0.662593
-3.268285 0.479210
-2.750742 0.824240
-4.981569 2.205597
-3.348344 1.843869
-4.393412 1.218457
-4.496588 2.530753
-2.828195 2.188452
-5.967995 4.058902
-5.827898 2.758901
-3.429840 3.170654
-1.954515 1.657077
-3.027348 3.425665
-4.574026 3.849544
-5.042223 4.619021
-5.091436 3.538908
-1.703673 0.172544
-1.013118 -0.073043
-0.929839 0.503847
-4.967114 0.957507
-6.112838 0.577358
-4.172204 0.990535
-6.346072 0.732702
-6.913795 0.542742
-4.740918 0.803572
-3.105411 1.172575
-6.967411 0.684800
-7.982244 0.362108
-4.108526 0.834904
-6.553452 0.427461
-4.708235 -2.112052
-6.923791 -2.536949
-5.952540 -2.490977
-4.592259 -1.953454
-5.689620 -2.165153

-2.006722
-3.755306
-2.045060
-1.129562
-4.437965
-2.976956
-0.329504
-1.079329
-0.379039
-1.194190
0.366691
1.610726
0.629684
2.417618
-0.142637
1.920301
3.693060
2.347382
0.231475
4.450602
4.053104
5.427409
3.964696
4.573098
2.726935
2.191567
1.538494
-1.263520
-1.495851
-4.040595
-2.653471
-1.638354
-2.898428
-3.912699
-2.567335
-0.748727
-2.986063
-4.796144
-5.022813
0.575047
2.262134
0.047165
1.965908
2.799823

C
H
H
H
H
H
B
O
S

-7.051024
-6.057375
-3.634258
-5.577572
-8.007105
-7.778402
0.330813
0.201781
-0.177872

-2.700097 0.882236
-2.602107 -1.028297
-1.676985 2.396586
-2.041841 3.874015
-2.988209 0.452052
-2.699236 2.913922
0.683885 -0.585829
2.073786 0.194453
3.360566 -0.651196

DMSO-spiroborate complex 2
H -2.500565 -6.486789 -2.177798
C -2.394091 -5.429078 -1.950978
H -4.153705 -5.356918 -0.724688
C -3.315456 -4.802513 -1.140565
C -1.156197 -3.361985 -2.212430
C -3.199518 -3.417996 -0.844907
C -1.310191 -4.701148 -2.497522
C -2.090444 -2.694816 -1.379029
C -4.125872 -2.737808 -0.015121
H -0.593333 -5.204107 -3.140389
H -0.329987 -2.794045 -2.624278
C -4.045033 -1.376950 0.217004
H -4.908150 -3.315098 0.470114
C -2.980310 -0.621948 -0.393359
C -1.977228 -1.302473 -1.077794
C -2.958648 0.870245 -0.356102
285

C -1.789868 3.859317
H -2.026244 4.848177
H -1.756224 3.870306
H -2.520049 3.125787
C 0.863163 4.609562
H 1.896877 4.393231
H 0.722928 4.536706
H 0.572175 5.595371
SCF energy: -3342.674345

0.004966
-0.399245
1.096099
-0.339489
0.151700
-0.121248
1.232769
-0.221099

C
C
C
C
C
C
H
H
C
H
H
C
H
C
O
O
C

0.143650
-0.583173
0.417157
-0.806317
0.059972
1.058722
0.052715
-0.942003
1.328376
1.338239
1.819745
0.960870
1.174733
0.336761
0.452391
-1.557053
-1.575601

-1.861812
-4.071865
-1.837708
-4.079319
-2.999477
-0.754357
-3.907198
-4.906866
-0.822102
0.121502
0.011688
-1.963276
-1.997009
-3.026523
-0.704606
-0.896991
-5.214600

1.543709
3.022116
2.936033
1.658501
3.687327
3.590823
5.650528
3.617851
4.939460
3.017943
5.432669
5.692062
6.756970
5.079386
0.807093
-0.635887
1.075875

C
C
C
C
C
H
H
H
H
H
C
C
C
C
C
C
H
H
H
H
H
H
C
H
C
C
C
C
C
C
H
H
C
H
C
C
C
C
C
C
C
C
C
H

-7.365579
-4.989347
-6.537901
-7.602960
-6.054216
-3.972684
-6.729551
-8.619897
-5.856035
-8.194897
-5.014295
-6.842193
-6.375909
-4.587652
-5.492887
-7.279810
-6.727726
-3.541337
-5.138847
-8.329653
-7.546137
2.511616
2.399317
4.409482
3.456683
1.002616
3.330905
1.159467
2.081175
4.389272
0.319676
0.042322
4.283960
5.293828
3.075672
1.979056
3.003558
1.972977
4.008650
2.005545
4.010982
3.060072
1.050798
3.900515

0.114451
0.230575
1.432777
0.956381
-0.245589
-0.039721
2.066436
1.238675
-0.893933
-0.257625
-0.770111
0.227513
-1.113009
0.087025
0.578557
-0.621110
-1.748452
0.367203
1.237701
-0.894116
0.614138
-6.844548
-5.768229
-5.461600
-5.000000
-3.795358
-3.591940
-5.158627
-2.976089
-2.782454
-5.771108
-3.334769
-1.408135
-3.268048
-0.759367
-1.552554
0.726711
1.411072
2.871562
2.826408
1.493167
3.565683
3.503797
5.538517

-3.120796
-2.674879
-1.269655
-2.032978
-3.438245
-2.942131
-0.408220
-1.772348
-4.287736
-3.716679
1.174583
3.078636
1.119728
2.205011
3.145909
2.060200
0.312495
2.279512
3.934512
1.990232
3.811030
0.356339
0.255295
-0.427614
-0.178956
0.428782
-0.310462
0.558710
0.005664
-0.787459
0.875659
0.623457
-0.868772
-1.142666
-0.417917
-0.094301
-0.291477
-0.925161
0.291246
-1.113124
0.402648
-0.499359
-1.914996
-0.207322

H 4.743567 3.450856
C 1.136067 4.867020
H 0.266304 2.924602
H 0.404803 5.378486
C 2.165247 5.609339
H 2.215964 6.685763
C 3.103291 4.973165
O 0.922012 0.745827
O 0.772035 -0.994279
C 5.019402 0.876138
C 6.914269 -0.152712
C 4.674151 -0.140066
C 6.339414 1.358808
C 7.274642 0.854467
C 5.609458 -0.648673
H 3.661948 -0.530249
H 6.638835 2.114495
H 8.290548 1.241238
H 5.316257 -1.433396
H 7.642815 -0.550315
C 5.407372 -0.666453
C 7.546566 0.591563
C 6.739837 -0.965507
C 5.168438 0.276117
C 6.226815 0.898249
C 7.798766 -0.344539
H 6.941595 -1.670994
H 4.146966 0.510175
H 6.018138 1.619472
H 8.821807 -0.586451
H 8.370841 1.077739
B 0.102086 -0.097798
H -0.661316 0.552594
O -0.903279 0.525765
S -0.667837 -0.643889
C -1.476169 -2.109442
H -2.549928 -1.910009
H -1.266721 -2.976650
H -1.105551 -2.268482
C 1.062714 -1.165377
H 1.235378 -1.366109
H 1.254147 -2.052706
H 1.692893 -0.338924
SCF energy: -3342.670736

286

0.842994
-2.095225
-2.388126
-2.715080
-1.467800
-1.610585
-0.684578
-1.478013
0.241818
1.310082
3.134766
2.216962
1.336201
2.237838
3.117277
2.217929
0.616282
2.230405
3.810565
3.836529
-1.509952
-2.846537
-1.181268
-2.523943
-3.184141
-1.842425
-0.380099
-2.806102
-3.970116
-1.565324
-3.362169
-0.685997
1.451299
2.962154
3.936786
3.214581
3.196225
3.847912
2.200005
3.705572
2.646062
4.316070
4.042068

DMSO-mesoborate complex 3
H -0.390757 -6.820630 -0.346274
C -0.577422 -5.754663 -0.450931
H -2.151141 -5.727089 1.006275
C -1.556596 -5.148249 0.303202
C -0.035371 -3.641328 -1.507742
C -1.821037 -3.758559 0.174170
C 0.187166 -4.994260 -1.368227
C -1.037232 -2.993026 -0.741128
C -2.836381 -3.111593 0.919052
H 0.958229 -5.478779 -1.961426
H 0.549952 -3.055507 -2.205803
C -3.113477 -1.768129 0.758532
H -3.409343 -3.690626 1.638315
C -2.351507 -0.988254 -0.178250
C -1.311156 -1.596835 -0.867307
C -2.801150 0.400484 -0.536353
C -2.340438 1.522192 0.143300
C -4.355419 1.813035 -1.782788
C -2.943870 2.807974 -0.045547
C -3.825854 0.562448 -1.535171
C -3.953845 2.951495 -1.045964
C -2.625801 3.931067 0.761655
H -5.302148 4.327702 -2.027335

H
C
H
H
C
H
C
O
O
C
C
C
C
C
C
H
H
H
H
H
C
C
C
C
287

-5.114102
-3.237462
-1.904058
-2.992315
-4.195868
-4.665146
-4.547258
-1.370220
-0.552908
-4.375177
-5.493487
-3.570218
-5.748774
-6.303585
-4.126789
-2.508683
-6.377722
-7.368596
-3.488247
-5.922953
-4.230729
-6.341918
-5.513818
-4.022679

1.927441
5.148270
3.797978
5.995347
5.304872
6.272087
4.226479
1.387348
-0.915238
-0.588827
-2.668482
-1.362697
-0.871221
-1.904138
-2.392309
-1.148683
-0.284377
-2.111506
-2.979845
-3.473760
-1.183298
-0.188175
-1.748814
-0.110475

-2.552386
0.557327
1.554677
1.194035
-0.472019
-0.632198
-1.251086
1.105894
-1.781934
-2.314035
-3.846204
-3.164849
-2.249077
-3.005716
-3.922991
-3.237333
-1.585382
-2.935509
-4.577803
-4.436768
1.556877
3.134571
1.482879
2.438659

C
C
H
H
H
H
H
H
C
C
C
C
C
C
C
H
C
H
C
C
C
C
C
C
C
C
C
H
H
C
H
H
C
H
C
O
O

-5.068951
-6.560965
-5.687627
-3.032643
-4.887695
-7.548432
-7.155756
0.243205
0.472070
1.288355
0.191041
1.597642
-0.082598
1.040291
2.403742
-0.237946
2.718857
2.731252
2.246849
1.375474
2.685255
1.727040
4.409421
2.055242
4.077000
3.432021
1.066173
4.821671
5.457252
1.430769
0.025374
0.667785
2.794852
3.067487
3.772695
0.398457
0.865462

0.379693
-1.255132
-2.571323
0.326035
1.207245
-1.703676
0.198286
-4.203341
-3.399838
-3.637163
-1.086429
-2.599335
-2.113778
-1.303385
-2.815288
-0.100814
-1.802709
-3.827673
-0.467204
-0.267120
0.707259
1.557327
2.028658
2.612632
1.000174
2.829240
3.441857
4.036338
2.263660
4.437874
3.271008
5.062717
4.655317
5.445066
3.871785
1.387290
0.981323

3.219581
2.262465
0.794647
2.520322
3.901410
2.185081
3.743064
5.017443
4.322253
3.238942
3.654522
2.320914
4.530458
2.539091
1.176206
3.795805
0.290952
0.958605
0.555589
1.620391
-0.256522
-0.799142
-1.368818
-1.699125
-0.504309
-2.009771
-2.290889
-3.148630
-1.533985
-3.170393
-2.040400
-3.626822
-3.484563
-4.179743
-2.913018
-0.495149
1.870257

C 5.191818 0.301977
C 7.393766 -0.853809
C 5.151494 0.055498
C 6.358284 -0.050898
C 7.447115 -0.620017
C 6.239103 -0.515789
H 4.259594 0.306732
H 6.390442 0.089039
H 8.333757 -0.893502
H 6.182469 -0.695488
H 8.240476 -1.301171
C 3.476193 -2.158324
C 4.847219 -2.950291
C 4.593304 -3.006613
C 3.054121 -1.720357
C 3.734176 -2.111397
C 5.271841 -3.398840
H 4.948921 -3.333033
H 2.169424 -1.097201
H 3.384944 -1.766102
H 6.139881 -4.048298
H 5.376089 -3.254122
B 0.018234 1.616338
H 1.704098 -4.626710
H -0.465311 0.016089
H -0.735826 -1.941408
O 0.347823 3.184760
S 1.120437 3.573294
C 0.739804 5.347883
H -0.320185 5.448219
H 0.946236 5.780672
H 1.346676 5.817791
C 2.869483 3.681267
H 3.199570 2.668049
H 3.432534 4.084499
H 2.965162 4.316167
SCF energy: -3342.671877

288

0.199607
1.533788
1.582297
-0.499433
0.158558
2.241654
2.147701
-1.575780
-0.407616
3.312201
2.047822
-0.942042
-3.275511
-0.870765
-2.209343
-3.362409
-2.023740
0.102410
-2.290856
-4.332188
-1.941963
-4.175269
0.881911
3.065663
-1.491386
5.381730
1.137132
2.460456
2.507177
2.747548
1.525621
3.285858
1.977710
1.747951
2.824775
1.094217

4.2.18 Synthesis of Danishefsky’s diene I-56a and related compound I-56b-d
(Scheme 1.21)

O
MeO

2 equiv Et3N
2.2 equiv TMSCl
3 mol% ZnCl2
Et2O, –20 ºC to 0 ºC, 2 h

I-164

OTMS
MeO
68%
I-56a

4-Methoxy-2-trimethylsilyloxy-1,3-butadiene I-56a: To a 250 mL round bottomed
flask anhydrous powdered zinc chloride (164 mg, 1.20 mmol) was added to dry
triethylamine (11.2 mL, 80.0 mmol), and the mixture was stirred for 1 h at rt until the salt
was suspended in the amine. The mixture was cooled to –20 ºC in a cold bath for 10 min.
To this mixture was added 4-methoxy-3-buten-2-one I-164 (4.5 mL, 40 mmol) in dry Et2O
(10 mL) at –20 ºC followed by trimethylchlorosilane (10.2 mL, 80.0 mol) in one portion. A
slight exothermic reaction ensued. After 30 min the reaction temperature was raised to 0
ÂşC and stirring continued for 2 h. The reaction mixture was added to dry ether (100 mL)
and filtered through a pad of celite. The filtrate and combined ethereal washings were
concentrated. Purification by vacuum distillation (15 mm Hg, 77 ÂşC) gave 4-methoxy-2trimethylsilyloxy-1,3-butadiene I-56a (4.687 g, 27.20 mmol) as a light-yellow liquid in 68%
yield.
Spectral data for I-56a: 1H NMR (500 MHz, CDCl3) δ 0.21 (d, J = 0.8 Hz, 9H), 3.57
(d, J = 0.8 Hz, 3H), 4.07 (dq, J = 20.7, 0.8 Hz, 2H), 5.34 (dd, J = 12.4, 0.8 Hz, 1H), 6.81
(d, J = 12.3 Hz, 1H). These spectral data match those previously reported for this
compound9.

289

General procedure D9 for synthesis of silyl enol dienes (Scheme 1.21) -- illustrated
for the synthesis of (E)-triethyl((4-methoxybuta-1,3-dien-2-yl)oxy)silane I-56b.
O
MeO

2.7 equiv Et3N
1.1 equiv Et3SiOTf
Et2O, –20 ºC to 0 ºC, 2 h

I-164

OTES
MeO
quant
I-56b

(E)-triethyl((4-methoxybuta-1,3-dien-2-yl)oxy)silane I-56b: An oven-dried 100 mL
round-bottomed flask equipped with an egg-shaped stirring bar (30 mm × 15 mm) is
placed under an N2 atmosphere through a gas inlet. After cooling to 23 °C, a solution of
(E)-4-methoxybut-3-en-2-one I-164 (1.53 mL, 15.0 mmol) and Et3N (5.70 mL, 40.8 mmol,
2.73 equiv) in anhydrous Et2O (30 mL) was added and cooled to –20 °C in a cold bath.
TESOTf (3.80 mL, 16.8 mmol, 1.12 equiv) was then added dropwise at –20°C. The
mixture was then warmed to 0 °C and stirred for 2 h at the same temperature. The mixture
was then diluted with hexanes (20 mL) and washed with ice cold saturated aqueous
NaHCO3, and brine. After volatile material was removed under reduced pressure,
purification of the crude product by flash column chromatography (neutral alumina,
EtOAc/hexanes 1:3) gave I-56b (3.218 g, 15.00 mmol) as a yellow liquid in 100% yield.
Spectral data for I-56b: 1H NMR (500 MHz, CDCl3) δ 0.68 – 0.78 (m, 6H), 0.99 (t,
J = 7.9 Hz, 9H), 3.58 (s, 3H), 4.02 – 4.16 (m, 2H), 5.35 (d, J = 12.4 Hz, 1H), 6.89 (d, J =
12.4 Hz, 1H).

13

C NMR (126 MHz, CDCl3) δ 4.94, 6.74, 56.42, 90.46, 103.13, 150.19,

154.11. These spectral data match those previously reported for this compound9.

290

O
MeO

2.7 equiv Et3N
1.1 equiv iPr3SiOTf
Et2O, –20 ºC to 0 ºC, 2 h

I-164

OTIPS
MeO
quant
I-56c

(E)-triisopropyl((4-methoxybuta-1,3-dien-2-yl)oxy)silane I-56c: Silane I-56c was
prepared by General Procedure D with TIPSOTf (4.60 mL, 16.8 mmol) and was obtained
(3.850 g, 15.00 mmol) as a yellow liquid in 100% yield.
Spectral data for I-56c: 1H NMR (500 MHz, CDCl3) δ 1.10 (d, J = 7.3 Hz, 18H),
1.15 – 1.33 (m, 3H), 3.59 (s, 3H), 4.05 (q, J = 1.2 Hz, 2H), 5.34 (d, J = 12.4 Hz, 1H), 6.96
(d, J = 12.4 Hz, 1H).

13

C NMR (126 MHz, CDCl3) δ 12.81, 18.08, 56.34, 90.04, 103.25,

150.15, 154.33. These spectral data match those previously reported for this compound9.

O
MeO

2.7 equiv Et3N
1.1 equiv TBSOTf
Et2O, –20 ºC to 0 ºC, 2 h

OTBS
MeO

I-164

quant
I-56d

(E)-tert-butyl((4-methoxybuta-1,3-dien-2-yl)oxy)dimethylsilane I-56d: Silane I-56d
was prepared by General Procedure D with TBSOTf (3.86 mL, 16.8 mmol) and was
obtained (3.216 g, 15.00 mmol) as a yellow liquid in 100% yield.
Spectral data for I-56d: 1H NMR (500 MHz, CDCl3) δ 0.19 (s, 6H), 0.96 (s, 9H),
3.58 (s, 3H), 4.01 – 4.18 (m, 2H), 5.35 (d, J = 12.4 Hz, 1H), 6.88 (d, J = 12.4 Hz, 1H). 13C
NMR (126 MHz, CDCl3) δ -4.64, 25.69, 25.82, 56.38, 90.87, 103.25, 150.20, 154.14.
These spectral data match those previously reported for this compound9.

291

4.2.19 General procedure E for HDA reactions catalyzed by mesoborate I-118 (Table
1.13) -- illustrated for the reaction of 4-bromobenzaldehyde I-51f and Danishefsky’s diene
I-56a with VANOL ligand
H O
20 mol%
(S)-VANOL

10 mol% BH3•Me2S
toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

OMe

O
+

O
B O
O

mesoborate catalyst

10 mol% mesoborate

H

TMSO
I-56a

*

I-51f

Br

toluene, –40 ºC,
24 h

O
O

Br

H
I-155b

2.0 equiv

89%, 83% ee

Preparation of the pre-catalyst solution: mesoBorate precatalyst was prepared
(0.125 mmol in 2.50 mL toluene) according to the General Procedure C (4.2.13) without
adding DMSO.
(R)-2-(4-bromophenyl)-2,3-dihydro-4H-pyran-4-one I-155b: To another 50 mL
flame-dried home-made Schlenk flask was added 4-bromobenzaldehdye (92.5 mg, 0.500
mmol) and dry toluene (3 mL) and cooled to –40 ºC for 10 min. To the aldehyde solution
was then added diene I-56a (195 ÎźL, 1.00 mmol, 2.00 equiv). Precatalyst stock solution
(2.0 mL, 0.10 mmol) at –40 ºC was transferred to the reaction mixture using syringe. After
the reaction mixture was stirred at –40 ºC for 1 h, 0.5 mL of 1 M HCl was added to quench
the reaction and was warmed to rt. After the mixture was stirred for 0.5 h, saturated
NaHCO3 (5 mL) was added and the mixture was stirred for 10 min, and the layers were
separated. The aqueous layer was extracted with EtOAc (3x5 mL), and the combined
organic layers were dried over anhydrous Na2SO4 and concentrated. The crude product

292

was purified by flash chromatography (hexanes/EtOAc, 4:1, silica gel) to afford I-155b as
a yellow solid (113 mg, 0.446 mmol) in 89% yield. The optical purity of I-155b was
determined to be 83% ee by HPLC (Chiralcel OD column, 90:10 hexane/2-propanol at
228 nm, flow-rate: 1 mL/min): retention times: Rt = 13.30 min (minor enantiomer, ent-I155b) and Rt = 17.83 min (major enantiomer, I-155b).
Spectral data for I-155b: Rf = 0.27 (1:4 EtOAc/hexane); 1H NMR (500 MHz, CDCl3)
δ 2.52 – 2.76 (m, 1H), 2.74 – 2.96 (m, 1H), 5.26 – 5.48 (m, 1H), 5.44 – 5.65 (m, 1H), 7.18
– 7.38 (d, J = 10 Hz, 2H), 7.46 (dd, J = 6.2, 2.8 Hz, 1H), 7.51 – 7.63 (d, J = 10 Hz, 2H).
13

C NMR (126 MHz, CDCl3) δ 43.29, 80.31, 107.53, 122.90, 127.74, 132.01, 136.90,

162.98, 191.62. These spectral data match those previously reported for this
compound10.
H O
20 mol%
(S)-BINOL

10 mol% BH3•Me2S
toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

OMe

O
+

O
B O
O

mesoborate catalyst

10 mol% mesoborate

H

TMSO
I-56a

*

I-51f

Br

toluene, –40 ºC,
24 h

2.0 equiv

O
O

Br

H
I-155b

96%, 91% ee

(R)-2-(4-bromophenyl)-2,3-dihydro-4H-pyran-4-one I-155b: Pyranone product I155b was obtained in 96% yield following General Procedure E using (S)-BINOL ligand.
The optical purity of I-155b was determined to be 91% ee by HPLC.

293

4.2.20 General procedure F for 3C Passerini reaction catalyzed by VANOL
mesoborate I-118 (Scheme 1.23) -- illustrated for the reaction with 4-bromobenzaldehyde
I-51f, and tbutyl isocyanide I-101 with benzoic acid I-174a
H O
10 mol% BH3•Me2S

20 mol%
(S)-VANOL

toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

*

O
B O
O

mesoborate catalyst

Br
O

O
NC
0.5 mmol
I-101

+

H
Br

0.5 mmol
I-51f

+

OH
0.5 mmol
I-174a

10 mol% (S)-VANOL
mesoborate

O
toluene, 0 ÂşC,
24 h, 0.25 M

Ph

O

H
N

I-175a O
81% conv., 52%, 35% ee

1-(4-bromophenyl)-2-(tert-butylamino)-2-oxoethyl benzoate I-175a: To a 50 mL
flame-dried home-made Schlenk flask, prepared from a single-necked 50 mL pearshaped flask that had its 14/20 glass joint replaced with a T-shaped high vacuum threaded
Teflon valve, equipped with a stir bar and flushed with nitrogen was added (S)-VANOL
(43.8 mg, 0.100 mmol). Under a nitrogen flow through the side-arm of the Schlenk flask,
dry toluene (3 mL) was added through the top of the Teflon valve to effect dissolution.
After the addition of the toluene, BH3•Me2S (25 μL, 0.050 mmol, 2 M in toluene) was
added. The flask was sealed by closing the Teflon valve, and then placed in a 100 ÂşC oil
bath for 0.5 h. After 0.5 h, a vacuum (0.5 mm Hg) was carefully applied by slightly opening
the Teflon valve to remove the volatiles. After the volatiles were removed completely, a
full vacuum was applied and maintained for a period of 30 min at a temperature of 100
ÂşC (oil bath). The flask was then allowed to cool to room temperature and opened to
nitrogen through the side-arm of the Schlenk flask. To this Schlenk flask containing
294

precatalyst was added 4-bromobenzaldehdye I-51f (92.5 mg, 0.500 mmol) and tbutyl
isocyanide I-101 (57 ÎźL, 0.50 mmol) and toluene (2 mL) under a nitrogen flow through
side-arm of the Schlenk flask. The mixture was cooled to 0 ÂşC for 10 min and then was
added benzoic acid (61.1 mg, 0.500 mmol) in one portion. After stirred at 0 ÂşC for 24 h,
to the reaction flask was added brine (5 mL). The resulting mixture was extracted with
EtOAc (3 × 10 mL). The combined organic layer was washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The conversion
of aldehyde was determined using 1H NMR analysis of crude product by integration of the
CHO relative to the internal standard (Ph3CH). The crude product was purified by flash
column chromatography (silica gel, eluted with hexanes/EtOAc 9:1 to 4:1) to give the pure
product I-175a as a white solid (102 mg, mp 183-185 ÂşC, 0.261 mmol) in 52% yield. The
optical purity of I-175a was determined to be 35% ee by HPLC (Chiralcel OD-H column,
95:5 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt = 9.67 min
(major enantiomer, I-175a) and Rt = 10.69 min (minor enantiomer, ent-I-175a).
Spectral data for I-175a: Rf = 0.14 (1:9 EtOAc/hexane); 1H NMR (500 MHz, CDCl3)
δ 1.35 (s, 9H), 6.01 (s, 1H), 6.14 (s, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.41 – 7.53 (m, 4H),
7.56 – 7.63 (m, 1H), 8.05 (dd, J = 8.4, 1.3 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 28.68,
51.70, 75.30, 123.08, 128.73, 129.04, 129.08, 129.71, 131.92, 133.78, 135.00, 164.69,
166.85. HRMS (ESI-TOF) m/z 388.0553 [(M–H+); calcd. for C19H1979BrNO3: 388.0548];
[𝛼]%&
$ 	+1.0 (c 1.0, CH2Cl2) on 35% ee material (HPLC).

295

Br

O

O
NC

0.5 mmol
I-101

+

H
Br

0.5 mmol
I-51f

+

OH
0.5 mmol
I-174b

O

10 mol% (S)-VANOL
mesoborate

H
N

O

toluene, 0 ÂşC,
24 h, 0.25 M

O
I-175b
69% conv., 43%, 37% ee

1-(4-bromophenyl)-2-(tert-butylamino)-2-oxoethyl 1-naphthoate I-175b: The Îąacyloxyamides I-175b was prepared following the general procedure C with 1-naphthoic
acid I-174b (86.1 mg, 0.500 mmol). The crude product was purified by flash column
chromatography (silica gel, eluted with hexanes/EtOAc 9:1 to 4:1) to give the pure product
I-175b as a white solid (95.4 mg, mp 128-131 ÂşC, 0.217 mmol) in 43% yield. The optical
purity of I-175b was determined to be 37% ee by HPLC (Chiralcel OD-H column, 95:5
hexane/2-propanol at 228 nm, flow-rate: 1 mL/min): retention times: Rt = 13.56 min (major
enantiomer, I-175b) and Rt = 22.33 min (minor enantiomer, ent-I-175b).
Spectral data for I-175b: Rf = 0.15 (1:9 EtOAc/hexane); 1H NMR (500 MHz, CDCl3)
δ 1.40 (s, 9H), 6.20 (s, 1H), 6.31 (s, 1H), 7.41 – 7.78 (m, 7H), 7.92 (dd, J = 8.2, 4.6 Hz,
1H), 8.00 – 8.15 (m, 1H), 8.25 (d, J = 7.2 Hz, 1H), 8.89 (d, J = 8.6 Hz, 1H). 13C NMR (126
MHz, CDCl3) δ 28.71, 51.83, 75.60, 123.15, 124.53, 125.46, 126.57, 128.05, 128.23,
128.74, 129.19, 130.31, 131.70, 132.00, 133.86, 134.22, 134.46, 135.04, 165.56, 167.25,
172.57. HRMS (ESI-TOF) m/z 438.0713 [(M–H+); calcd. for C23H2179BrNO3: 438.0705];
[𝛼]%&
$ 	+12.0 (c 1.0, CH2Cl2) on 37% ee material (HPLC).

296

Br
O
NC

0.5 mmol
I-101

+

H +
Br

0.5 mmol
I-51f

10 mol% (S)-VANOL
mesoborate

O
0.5 mmol
I-174c

OH

toluene, 0 ÂşC,
24 h, 0.25 M

O
O

H
N

O
I-175c
72% conv., 40%, 35% ee

1-(4-bromophenyl)-2-(tert-butylamino)-2-oxoethyl 2-(naphthalen-2-yl)acetate I175c: The Îą-acyloxyamides I-175c was prepared following the general procedure C with
2-(naphthalen-2-yl)acetic acid I-174c (93.1 mg, 0.500 mmol). The crude product was
purified by flash column chromatography (silica gel, eluted with hexanes/EtOAc 9:1 to
4:1) to give the pure product I-175c as a white solid (89.7 mg, mp 120-122 ÂşC, 0.197
mmol) in 40% yield. The optical purity of I-175c was determined to be 35% ee by HPLC
(Chiralcel OD-H column, 95:5 hexane/2-propanol at 228 nm, flow-rate: 1 mL/min):
retention times: Rt = 29.05 min (minor enantiomer, ent-I-175c) and Rt = 39.81 min (major
enantiomer, I-175c).
Spectral data for I-175c: Rf = 0.15 (1:9 EtOAc/hexane); 1H NMR (500 MHz, CDCl3)
δ 1.03 (s, 9H), 3.88 (d, J = 2.5 Hz, 2H), 5.62 (s, 1H), 5.92 (s, 1H), 7.21 (d, J = 8.2 Hz,
2H), 7.27 – 7.59 (m, 5H), 7.61 – 7.94 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 28.29, 41.74,
51.30, 75.04, 123.01, 126.27, 126.61, 127.01, 127.62, 127.71, 128.03, 128.76, 128.97,
130.72, 131.82, 132.59, 133.47, 134.93, 166.63, 169.08. HRMS (ESI-TOF) m/z 458.0868
[(M–H+); calcd. for C24H2379BrNO3: 452.0861]; [𝛼]%&
$ 	+1.3 (c 1.0, CH2Cl2) on 35% ee
material (HPLC).

297

Br
O

O
NC

0.5 mmol
I-101

+

OH

H +
Br

10 mol% (S)-VANOL
mesoborate
20 mol% DMSO
toluene, 0 ÂşC,
24 h, 0.25 M

MeO
0.5 mmol
I-51f

0.5 mmol
I-174d

O

H
N

O
MeO

O

I-175d
55% conv., 14% NMR yield
(66% conv., 50%, 49% ee)

1-(4-bromophenyl)-2-(tert-butylamino)-2-oxoethyl 4-methoxybenzoate I-175d: The
Îą-acyloxyamides I-175d was prepared following the general procedure C with 4methoxybenzoic acid I-174d (76.1 mg, 0.500 mmol) with DMSO (7.0 ÎźL, 0.10 mmol). The
crude product was purified by flash column chromatography (silica gel, eluted with
hexanes/EtOAc 9:1 to 4:1) to give the pure product I-175d as a white solid (105 mg, mp
159-162 ÂşC, 0.250 mmol) in 50% yield. The optical purity of I-175d was determined to be
49% ee by HPLC (Chiralcel OD-H column, 95:5 hexane/2-propanol at 228 nm, flow-rate:
1 mL/min): retention times: Rt = 16.07 min (major enantiomer, I-175d) and Rt = 18.77 min
(minor enantiomer, ent-I-175d).
Spectral data for I-175d: Rf = 0.17 (1:9 EtOAc/hexane); 1H NMR (500 MHz, CDCl3)
δ 1.36 (s, 9H), 3.86 (s, 3H), 6.16 (s, br, 2H), 6.95 (d, J = 8.6 Hz, 2H), 7.25 – 7.48 (m, 2H),
7.50 (d, J = 8.2 Hz, 2H), 8.03 (dd, J = 8.5, 3.3 Hz, 2H).13C NMR (126 MHz, CDCl3) δ
28.66, 51.64, 55.54, 64.01, 69.19, 75.02, 113.99, 121.30, 122.93, 128.34, 129.04, 129.65,
131.84, 133.01, 135.22, 164.00, 164.45, 167.18. HRMS (ESI-TOF) m/z 418.0657 [(M–
H+); calcd. for C20H2179BrNO4: 418.0654]; [𝛼]%&
$ 	+6.8 (c 1.0, CH2Cl2) on 49% ee material
(HPLC).

298

Br
O

O
NC

0.5 mmol
I-101

+

OH

H +
Br

10 mol% (S)-VANOL
mesoborate
20 mol% DMSO
toluene, 0 ÂşC,
24 h, 0.25 M

O2N
0.5 mmol
I-51f

0.5 mmol
I-174e

O

H
N

O
O2N

O

I-175e
62% conv., 12% NMR yield
(66% conv., 32%, 3% ee)

1-(4-bromophenyl)-2-(tert-butylamino)-2-oxoethyl 4-nitrobenzoate I-175e: The Îąacyloxyamides I-175e was prepared following the general procedure C with 4nitrobenzoic acid I-174e (76.1 mg, 0.500 mmol) with DMSO (7.0 ÎźL, 0.10 mmol). The
crude product was purified by flash column chromatography (silica gel, eluted with
hexanes/EtOAc 9:1 to 4:1) to give the pure product I-175e as a yellow solid (70.4 mg, mp
172-174 ÂşC, 0.162 mmol) in 32% yield. The optical purity of I-175e was determined to be
3% ee by HPLC (Chiralcel OD-H column, 95:5 hexane/2-propanol at 228 nm, flow-rate:
1 mL/min): retention times: Rt = 37.44 min (major enantiomer, I-175e) and Rt = 34.05 min
(minor enantiomer, ent-I-175e).
Spectral data for I-175e: Rf = 0.14 (1:9 EtOAc/hexane); HRMS (ESI-TOF) m/z
433.0417 [(M–H+); calcd. for C19H1879BrN2O5: 433.0399];

299

Br
O
O
NC

0.5 mmol
I-101

+

MeO

OH 10 mol% (S)-VANOL
mesoborate

H + MeO
Br

0.5 mmol
I-51f

20 mol% DMSO
toluene, 0 ÂşC,
24 h, 0.25 M

OMe
0.5 mmol
I-174f

1-(4-bromophenyl)-2-(tert-butylamino)-2-oxoethyl

O
MeO
MeO

H
N

O
O
OMe I-175f
(32%, 37% ee)
(rt, 92%, 24% ee)

3,4,5-trimethoxybenzoate

I-

175f: The Îą-acyloxyamides I-175f was prepared following the general procedure C with
3,4,5-trimethoxybenzoic acid I-174f (106.1 mg, 0.500 mmol) with DMSO (7.0 ÎźL, 0.10
mmol). The crude product was purified by flash column chromatography (silica gel, eluted
with hexanes/EtOAc 9:1 to 4:1) to give the pure product I-175f as a white solid (222 mg,
mp 185-187ÂşC, 0.461 mmol) in 92% yield. The optical purity of I-175d was determined to
be 24% ee by HPLC (Chiralcel OD-H column, 95:5 hexane/2-propanol at 228 nm, flowrate: 1 mL/min): retention times: Rt = 8.82 min (major enantiomer, I-175d) and Rt = 12.78
min (minor enantiomer, ent-I-175d).
Spectral data for I-175d: Rf = 0.20 (1:9 EtOAc/hexane); 1H NMR (500 MHz, CDCl3)
δ 1.35 (s, 9H), 3.89 (d, J = 4.4 Hz, 9H), 5.95 (s, 1H), 6.09 (s, 1H), 7.37 (d, J = 8.3 Hz,
2H), 7.46 – 7.59 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 28.67, 51.72, 56.30, 61.01, 75.48,
107.02, 123.16, 123.91, 129.11, 131.97, 134.86, 143.00, 153.12, 164.48, 166.79. HRMS
(ESI-TOF) m/z 478.0881 [(M–H+); calcd. for C22H2579BrNO6: 478.0865]; [𝛼]%&
$ 	+0.3 (c 1.0,
CH2Cl2) on 24% ee material (HPLC).

300

4.2.21 General procedure G for aziridination reaction of benzhydryl imine I-176 and
ethyl diazoacetate I-94 (Table 1.22) -- illustrated by using VANOL boroxinate catalyst I90b

10 mol%
(S)-VANOL

30 mol% BH3•Me2S
20 mol% PhOH
30 mol% H2O

I-176–H

OPh
O B
O
O
* O B
O B
I-90b OPh
boroxinate catalyst

100 mol% I-176

toluene, 100 ÂşC, 1 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

Ph
+
N
I-176
0.5 mmol

O

OEt

N2

10 mol% I-90b

N

solvent, 0.5 M, rt, 24 h

I-94
1.2 equiv

Ph

COOEt

I-177
>50:1 cis/trans, 84%, 93% ee

Preparation of the pre-catalyst solution: Precatalyst I-90b was prepared
according to the General Procedure B (4.2.2) without adding DMSO.
(2R,3R)-ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate I-177: To the flask
containing the precatalyst (made by General Procedure B) was first added the aldimine
I-176 (136 mg, 0.500 mmol) and then dry toluene (1 mL) under a nitrogen flow through
side-arm of the Schlenk flask. The reaction mixture was stirred for 5 min to give a light
orange solution. To this solution was rapidly added ethyl diazoacetate (EDA) I-94 (72 ÎźL,
0.60 mmol) followed by closing the Teflon valve. The resulting mixture was stirred for 24
h at room temperature. Immediately upon addition of ethyl diazoacetate the reaction
mixture became an intense yellow, which changed to light yellow towards the end of the
reaction. The reaction was dilluted by addition of hexane (6 mL). The reaction mixture
was then transferred to a 100 mL round bottom flask. The reaction flask was rinsed with

301

dichloromethane (5 mL × 2) and the rinse was added to the 100 mL round bottom flask.
The resulting solution was then concentrated in vacuo followed by exposure to high
vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as an off-white solid. A measure
of the extent to which the reaction went to completion was estimated from the 1H NMR
spectrum of the crude reaction mixture by integration of the aziridine ring methane protons
relative to either the imine methine proton or the proton on the imine carbon. The cis/trans
ratio was determined by comparing the 1H NMR integration of the ring methine protons
for each aziridine in the crude reaction mixture. The cis (J = 7-8 Hz) and the trans (J = 23 Hz) coupling constants were used to differentiate the two isomers. Purification of the
crude aziridine by silica gel chromatography (35 mm × 400 mm column, 19:1
hexanes/EtOAc as eluent, under gravity) afforded pure cis-aziridine I-177 as a white solid
(mp 127.5-128.5 °C on 93% ee material) in 84% isolated yield (149 mg, 0.420 mmol);
cis/trans: >50:1. The optical purity of I-177 was determined to be 93% ee by HPLC
analysis ((CHIRALCEL OD-H column, 90:10 hexanes/iPrOH at 222 nm, flow-rate: 0.7
mL/min): retention times; Rt = 9.01 min (major enantiomer, I-177) and Rt = 4.67 min (minor
enantiomer, ent-I-177).
Spectral data for I-177: Rf = 0.3 (1:9 EtOAc/hexanes); 1H NMR (CDCl3, 500 MHz)
δ 0.95 (t, 3H, J = 7.3 Hz), 2.64 (d, J = 6.8 Hz, 1H), 3.19 (d, J = 6.8 Hz, 1H), 3.91 (q, J =
7.1 Hz, 2H), 3.93 (s, 1H), 7.16-7.38 (m, 11H), 7.47 (d, J = 7.1 Hz, 2H), 7.58 (d, J = 7.6
Hz, 2H); 13C NMR (CDCl3, 126 MHz) δ 13.93, 46.36, 48.01, 60.57, 77.68, 127.18, 127.31,
127.39, 127.52, 127.76, 127.78, 128.48, 135.00, 142.37, 142.49, 167.75. These spectral
data match those previously reported for this compound11.

302

I-176–H
20 mol%
(S)-VANOL

100 mol%
I-176

10 mol% BH3•Me2S

*

toluene, 100 ÂşC, 0.5 h,
then 0.5 mm Hg, 100 ÂşC, 0.5 h

O
O
B
*
O
O

I-118b
spiroborate catalyst

Ph
+
N
I-176
0.5 mmol

O

OEt

N2

5 mol% I-118b

N

solvent, 0.5 M, rt, 24 h

I-94
1.2 equiv

Ph

COOEt

I-177
30:1 cis/trans, 82%, 52% ee

(2R,3R)-ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate I-177: The General
Procedure G was followed using precatalyst I-118 (made by General Procedure C).
Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column,
19:1 hexanes/EtOAc as eluent, under gravity) afforded pure cis-aziridine I-177 as a white
solid in 82% isolated yield (147 mg, 0.410 mmol); cis/trans: 30:1. The optical purity of I177 was determined to be 52% ee by HPLC analysis ((CHIRALCEL OD-H column, 90:10
hexanes/iPrOH at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.01 min (major
enantiomer, I-177) and Rt = 4.67 min (minor enantiomer, ent-I-177).

303

4.3 Experimental for Chapter Two
4.3.1 Synthesis of (Âą)-tBuVANOL II-46b (Scheme 2.10)
O
O

1) aq. NaOH, rt, overnight,
MeOH/THF (1:1)

O
OH

2) HCl

II-44b
quant.

II-47
100 g

2-(4-(tert-butyl)phenyl)acetic acid II-44b. An oven-dried 2 L round-bottomed flask
equipped with an egg-shaped stirring bar (50 mm × 20 mm) is placed under an N2
atmosphere through a gas inlet. After cooling to 23 °C, methyl 2-(4-(tertbutyl)phenyl)acetate II-47 (100 g, 48.5 mmol, 1.00 equiv) is added followed by addition of
methyl alcohol (500 mL) (Note), tetrahydrofuran (500 mL) and 6 M aq. NaOH solution
(160 mL, 2.00 equiv). The mixture is stirred at room temperature (23 °C) for 12 h. The
reaction mixture is concentrated in vacuo using a rotary evaporator (40 °C, 15 mm Hg)
then cooled in the ice bath for 10 min. To the the reaction mixture 6N aq. HCl is added in
portion (10×10 mL) and the white precipitate is then filtered and allowed to dry overnight.
The white solid is put under high vacuum (23 °C, 0.2 mmHg) for 30 min to yield 93.23 g
of the product II-47 as a white solid at >99% purity (48.50 mmol, mp 80-82 ÂşC, 100%
yield).
Spectral data for II-47: 1H NMR (500 MHz, CDCl3) δ 1.31 (s, 9H), 3.61 (s, 2H), 7.21
(d, J = 7.0 Hz, 2H), 7.34 (m, J = 7.0 Hz, 2H) 10.2 (br s, 1 H). 13C NMR (126 MHz, CDCl3)
δ 31.33, 34.54, 40.53, 125.61, 129.02, 130.24, 150.26, 177.67. These spectral data
match those previously reported for this compound11.

304

General Procedure H’ for CAEC process with (COCl)2 -- illustrated for synthesis of
7-(tert-butyl)-3-phenylnaphthalen-1-ol II-45b from 2-(4-(tert-butyl)phenyl)acetic acid II44b:
O
OH

II-44b
150-240 mmol

1) (COCl2) (2.0 equiv),
cat. DMF, 0 ÂşC to rt, 1 h
then remove excess

HO

Ph

2)

Ph (1.3 equiv)
(i-PrCO)2O (2 equiv),
190 ÂşC, 48 h
3) KOH, H2O, 100 ÂşC,
overnight

II-45b
50-59%

7-(tert-butyl)-3-phenyl-1-naphthol II-45b. An oven-dried 1 L round-bottomed flask
equipped with an egg-shaped stirring bar (30 mm ×	15 mm) is placed under an N2
atmosphere through a gas inlet. After cooling to 23 °C, 2-(4-(tert-butyl)phenyl)acetic acid
II-44b (46.34 g, 241.0 mmol, 1.000 equiv) is added followed by addition of anhydrous
dichloromethane (241 mL) before cooling in the ice bath for 10 min. To the solution oxalyl
chloride (50.0 mL, 600 mmol, 2.50 equiv) is added in one portion followed by addition of
10 drops of anhydrous DMF. The ice bath is removed. The mixture is stirred and allowed
to warm up to room temperature (23 °C). After 2 h, the reaction mixture is concentrated
in vacuo using a rotary evaporator (40 °C, 15 mmHg) then put under high vacuum (23 °C,
0.2 mmHg) for 30 min to completely remove excess (COCl)2. The reaction flask containing
the crude acid chloride is filled with N2, and then phenylacetylene (34.0 mL, 313 mmol,
1.30 equiv) and (i-PrCO)2O (80.0 mL, 482 mmol, 2.00 equiv) are added. The flask is fitted
with a condenser flushed with nitrogen with a Teflon sleeve in the joint and Teflon tape
wrapped around the joint to secure a tight seal. The reaction mixture was heated and
stirred in a 190 ÂşC oil bath for 48 h with a gentle nitrogen flow across the top of the

305

condenser. The brown reaction mixture is cooled to about 60 ÂşC (oil bath temperature),
and aq KOH (80.0 g, 1.43 mol) in 320 mL of H2O is slowly added. After stirring in a 100
ÂşC oil bath overnight (15 h), the orange solution is cooled to rt, ether (300 mL) is added,
and the mixture stirred for 30 min before the organic layer is isolated in a 2 L separatory
funnel. The water layer is extracted twice with ether (300 mL×2), and the combined
organic layer is washed with brine (300 mL), dried over MgSO4 and filtered. The darkcolored organic solution is concentrated in vacuo using a rotary evaporator (40 °C, 15
mmHg) and the residue is dried under high vacuum (23 °C, 0.2 mmHg) overnight to give
40 g of the dark brown crude product. Recrystallization from CH2Cl2/hexanes gave 26.46
g product II-45b (mp 135-136 °C) as solid crystals (95.70 mmol, 40%, first crop).
Successive crystallization yields the product II-45b a combined yield of 59% (8.7%, 5.77
g, mp 137-138 °C, second crop; 10.1%, 6.72 g, mp 135-138°C, third crop).
Spectral data for II-45b: Rf = 0.34 (EtOAc/hexanes 1:4); 1H NMR (500 MHz, CDCl3)
δ 1.43 (s, 9H), 5.36 (s, 1H), 7.06 (d, J = 1.6 Hz, 1H), 7.30 – 7.39 (m, 1H), 7.45 (dd, J =
8.5, 7.0 Hz, 2H), 7.57 – 7.70 (m, 4H), 7.80 (d, J = 8.7 Hz, 1H), 8.09 (dd, J = 1.8, 0.9 Hz,
1H). 13C NMR (126 MHz, CDCl3) δ 31.30, 35.10, 108.34, 116.24, 118.34, 123.25, 125.82,
127.22, 127.29, 127.78, 128.78, 133.16, 138.13, 141.01, 148.25, 151.65. These spectral
data match those previously reported for this compound11.

306

air, 150 ÂşC, mineral oil, 24 h

Ph

Ph
Ph

HO
HO

OH
II-45b
100 mmol

II-46b
71-76%

7,7'-di-tert-butyl-3,3'-diphenyl-[2,2'-binaphthalene]-1,1'-diol (tBuVANOL) II-46b.
An oven-dried 250 mL three-necked round-bottomed flask equipped with an egg-shaped
stirring bar (30 mm × 15 mm) is placed under an N2 atmosphere through a gas inlet. After
cooling to 23 °C, naphthol II-45b (27.64 g, 100.0 mmol) is added by a funnel followed by
the addition of 110 mL of light mineral oil through the same funnel and then an oven-dried
reflux condenser is attached. A glass tube (6 mm id) is introduced into the flask via the
second neck to about 5 cm above the surface of the naphthol solution and is used to
provide a stream of house air which is maintained at a flow rate of 0.15 0.20 L/min. The
third neck is sealed with a rubber septum. The stir bar in the oil bath was removed before
the flask is introduced into the oil bath to warm it up for about 15 min until the solid was
melted. Airflow is allowed to flow into the flask while the molten II-45b was stirred as fast
as possible. The airflow is switched to N2 after the reaction is kept at 150 ÂşC for 24 h. The
flask is removed from the oil bath and cooled to rt before hexanes (500 mL) is added to
the flask. The mixture was stirred for 30 min, and then it was cooled to –20 ºC overnight
(12 h) before the solid is collected by suction filtration. The crude product is dried on high
vacuum and crystallized from CH2Cl2. The dark-colored solution is cooled to room

307

temperature and then to –20 ºC overnight (12 h). The brown crystals are collected via
suction filtration, washed with hexanes (3 x 30 mL), and dried under vacuum to give the
first crop product of (Âą)-tBuVANOL (9.60 g, 17.4 mmol, 34.9%, 154-157 ÂşC). Successive
crystallization from CH2Cl2 yield the product II-46b a combined yield of 71% (5.35 g, 9.70
mmol, 19.4%, mp 155-158 °C, second crop; 4.67 g, 8.50 mmol, 16.9%, mp 155-156°C,
third crop).
Spectral data for II-46b: Rf = 0.39 (EtOAc/hexanes 1:4); 1H NMR (500 MHz, CDCl3)
δ 1.47 (s, 18H), 5.82 (s, 2H), 6.60 (dt, J = 7.0, 1.3 Hz, 4H), 6.95 (t, J = 7.7 Hz, 4H), 6.98
– 7.09 (m, 2H), 7.27 (s, 2H), 7.60 – 7.75 (m, 4H), 8.29 (d, J = 1.9 Hz, 2H). 13C NMR (126
MHz, CDCl3) δ 31.32, 35.20, 112.67, 117.68, 121.61, 122.60, 126.38, 126.40, 127.42,
127.43, 128.87, 132.79, 139.98, 140.35, 148.54, 150.20. These spectral data match
those previously reported for this compound11.

308

4.3.2 Resolution of tBuVANOL and recovery of quinine (Scheme 2.18)

precipitate
Ph
Ph

OH
OH

1.05 equiv
quinine

1.0 equiv
BH3•Me2S

2 N HCl

filter

64 mL THF
THF, 80 ÂşC,
wash by
0.5 h
80 ÂşC, overnight 64 mL THF
then remove volatiles

2 N HCl
mother liquor

16 mmol
5 runs
HO

N

precipitate

(R)-tBuVANOL
(67~89% ee, ave.
82%ee)
(46~51%, ave. 48%)

250 mL hexanes
1 h, rt

MeO
N
(–)-quinine II-10

Water phase
after the hydrolysis

(Âą)-tBuVANOL
~ 20%

(S)-tBuVANOL
>99% ee
(32~41%, ave. 36%)

(R)-tBuVANOL
mother liquor
>99% ee,
(30~38%, ave. 35%)

NaOH

DCM extraction,

pH > 8

dried and rotavap

crude quinine crystallization
quant.
from toluene

quinine
89%

(S)-tBu2VANOL (S)-II-46b and (R)-tBu2VANOL (R)-II-46b. An oven-dried 250 mL
round-bottomed flask equipped with an egg-shaped stirring bar (30 mm × 15 mm) is
placed under an N2 atmosphere through a gas inlet. After cooling to 23 °C, (¹)-tBuVANOL
4 (8.81 g, 16.0 mmol) is added followed by addition of anhydrous tetrahydrofuran (65 mL)
and BH3•Me2S (8.16 mL, 2 M solution in toluene, 16.3 mmol, 1.02 equiv). An oven-dried
reflux condenser with an outlet connected to a bubbler is attached to the flask. The
mixture is stirred and refluxed in an 80 ÂşC oil bath for 30 min, and the evolution of gas
ceases. After cooling to rt (23 ÂşC), the clear solution is concentrated in vacuo using a
rotary evaporator (40 °C, 15 mmHg) and the residue is dried under high vacuum (60 °C,
0.2 mmHg) for 30 min. After cooling to 23 °C, anhydrous tetrahydrofuran (65 mL) is added
followed by addition of quinine (5.294 g, 16.32 mmol, 1.020 equiv). The reflux condenser

309

is reconnected and the mixture is stirred and refluxed in an 80 ÂşC oil bath for overnight
(12 h). A white precipitate begins to crash out after 10 min of refluxing. The flask
containing reaction mixture is cooled to rt then to –20 ºC for 30 min before the solid is
collected by suction filtration, washed with ice-cold anhydrous tetrahydrofuran (60 mL).
The solid is transferred to a 100 mL round-bottomed flask and CH2Cl2 (15 mL) is
added followed by addition of aq. HCl (15 mL, 2 M) and an egg-shaped stirring bar (30
mm × 15 mm). The mixture was stirred for 30 min at rt before the organic layer is isolated
in a 60 mL separatory funnel. The water layer is extracted twice with CH2Cl2 (15 mL	×	2),
and the combined organic layer is washed with brine (10 mL), dried over MgSO4 and
filtered. The water layer containing chloride salt of protonated quinine is transferred to a
clean container for recovery. The organic solution is concentrated in vacuo using a rotary
evaporator (40 °C, 15 mmHg). The residue was dissolved in a minimum amount of CH2Cl2
and loaded onto a silica gel column wet loaded with hexanes. The column was eluted
with a mixture of CH2Cl2 and hexanes (1:2) to afford (S)-tBu2VANOL (S)-II-46b as a white
solid (3.375 g, 6.128 mmol, 38%, >99% ee).
The mother liquor is transferred to a 100 mL round-bottomed flask and
concentrated in vacuo using a rotary evaporator (40 °C, 15 mmHg). CH2Cl2 (15 mL) is
added followed by addition of aq. HCl (15 mL, 2M) and an egg-shaped stirring bar (30
mm × 15 mm). The mixture was stirred for 30 min at rt before the organic layer is isolated
in a 60 mL separatory funnel. The water layer is extracted twice with CH2Cl2 (15 mL	×	2),
and the combined organic layer is washed with brine (10 mL), dried over MgSO4 and
filtered. The water layer containing chloride salt of protonated quinine is transferred to a

310

clean container for recovery. The organic solution is concentrated in vacuo using a rotary
evaporator (40 °C, 15 mmHg). The residue was dissolved in a minimum amount of CH2Cl2
and loaded onto a silica gel column wet loaded with hexanes. The column was eluted
with a mixture of CH2Cl2 and hexanes (1:2) to afford crude (R)-tBuVANOL (R)-II-46b as
a white solid (3.589 g, 6.517 mmol, 41%, 87% ee). The crude (R)-II-46b is transferred to
a 500 mL round-bottomed flask and hexanes (250 mL) is added. The mixture was stirred
for 60 min at rt before the precipitate (tBuVANOL racemate) is filtered by suction filtration.
The mother liquor is transferred to a 250 mL round-bottomed flask and concentrated in
vacuo using a rotary evaporator (40 °C, 15 mmHg) and dried under vacuum (23 °C, 0.2
mmHg) for 1 h to afford (R)-tBu2VANOL (R)-II-46b as a white solid (3.312 g, 6.014 mmol,
38%, >99% ee).
Recovery of quinine: The combined water phase after the extraction after the
hydrolysis was transferred to a 500 mL Erlenmeyer flask. After cooling to 0 ÂşC for 10 min,
NaOH solution (aq. 1 M) was added until pH > 8.0. The suspension was extract with DCM
(50 mL x 3) and the combined organic layer is washed with brine (50 mL), dried over
anhydrous Na2SO4 and filtered. The organic solution is concentrated in vacuo using a
rotary evaporator (40 °C, 15 mmHg) to give the crude quine (5.356 g, 101%). Purification
by crystallization from toluene gave the recovered quinine (4.712 g, 14.50 mmol) in 89%
yield (>98% pure based on 1H NMR).

311

4.3.3 Synthesis of 5,5’-R2VANOL (Table 2.2)
Br

OH
Br

O

II-44c
100 mmol

1) SOCl2 (2.0 equiv),
70 ÂşC, 1 h then
remove excess

Ph

HO

mineral oil, air,

2)

Ph (1.3 equiv)
(i-PrCO)2O (2 equiv),
190 ÂşC, 48 h
3) KOH, H2O, 100 ÂşC,
overnight

165 ÂşC, 36 h

Ph
Ph

HO
HO

Br
II-45c
50 mmol
67%

Br
II-46c
96%

General Procedure H for CAEC process with SOCl2 -- illustrated for synthesis of
5-bromo-3-phenyl-1-naphthol II-45c from 2-(2-bromophenyl)acetic acid II-44c:
5-bromo-3-phenyl-1-naphthol II-45c: An oven-dried 500 mL round-bottomed flask
equipped with an egg-shaped stirring bar (30 mm ×	15 mm) and a condenser is placed
under an N2 atmosphere through a gas inlet. After cooling to 23 °C, 2-(2bromophenyl)acetic acid II-44c (21.505 g, 100.00 mmol, 1.0000 equiv) is added followed
by addition of SOCl2 (15.0 mL, freshly distilled, 200 mmol, 2.00 equiv). The condenser is
vented by an adaptor to a bubbler and then into a beaker filled with aq. NaOH to trap acid
gases. The mixture is heated in a 70 °C oil bath until the gas evolution ceases (1 h). The
excess of thionyl chloride was removed by distillation under aspirator pressure (60 °C oil
bath, ~ 25 mm Hg). Anhydrous toluene (40 mL) is added, and the mixture is distilled under
aspirator pressure again. The process is repeated twice to ensure complete removal of
all excess thionyl chloride. The crude mixture is then vacuum-dried at rt for 1 h to remove
the excess toluene. The reaction flask containing the crude acid chloride is filled with N2,
and then phenylacetylene (15.0 mL, 130 mmol, 1.30 equiv) and (i-PrCO)2O (33.0 mL, 200
mmol, 2.00 equiv) are added. The flask is fitted with a condenser flushed with nitrogen
312

with a Teflon sleeve in the joint and Teflon tape wrapped around the joint to secure a tight
seal. The reaction mixture was heated and stirred in a 190 ÂşC oil bath for 48 h with a
gentle nitrogen flow across the top of the condenser. The brown reaction mixture is cooled
to about 60 ÂşC (oil bath temperature), and aq KOH (33.4 g, 1.43 mol) in 120 mL of H2O is
slowly added. After stirring in a 100 ÂşC oil bath overnight (12 h), the orange solution is
cooled to rt, ether (300 mL) is added, and the mixture stirred for 30 min before the organic
layer is isolated in a 2 L separatory funnel. The water layer is extracted twice with ether
(300 mL×2), and the combined organic layer is washed with brine (300 mL), dried over
MgSO4 and filtered. The dark-colored organic solution is concentrated in vacuo using a
rotary evaporator (40 °C, 15 mmHg) and the residue is dried under high vacuum (23 °C,
0.2 mmHg) overnight to give 40 g of the dark brown crude product. Recrystallization from
CH2Cl2/hexanes and column chromatography (silica gel, DCM/hexanes 1:3 to 1:1) gave
the product II-45c as an off-white solid in a combined yield of 67% (20.07 g, mp 133-134
ÂşC, 67.10 mmol).
Spectral data for II-45c: Rf = 0.48 (EtOAc/hexanes 1:4); 1H NMR (500 MHz, CDCl3)
δ 5.42 (br, 1H), 7.12 (d, J = 1.5 Hz, 1H), 7.29 (dd, J = 8.4, 7.4 Hz, 1H), 7.35 – 7.44 (m,
1H), 7.41 – 7.53 (m, 2H), 7.63 – 7.75 (m, 2H), 7.80 (dd, J = 7.4, 1.1 Hz, 1H), 8.02 (dd, J
= 1.5, 0.9 Hz, 1H), 8.18 (dt, J = 8.4, 1.0 Hz, 1H).

13

C NMR (126 MHz, CDCl3) δ 109.12,

118.11, 121.59, 122.95, 124.80, 125.41, 127.46, 127.79, 128.90, 131.07, 133.42, 140.24,
140.62, 151.85. These spectral data match those previously reported for this
compound11.

313

General Procedure I for oxidative coupling of VANOL monomer -- illustrated for
synthesis of 5,5’-Br2VANOL II-46c from 5-bromo-3-phenyl-1-naphthol II-45c:
5,5’-Br2VANOL II-46c: An oven-dried 250 mL three-necked round-bottomed flask
equipped with an egg-shaped stirring bar (30 mm × 15 mm) is placed under an N2
atmosphere through a gas inlet. After cooling to 23 °C, naphthol II-45c (29.92 g, 100.0
mmol) is added by a funnel followed by the addition of 110 mL of light mineral oil through
the same funnel and then an oven-dried reflux condenser is attached. A needle is
introduced into the flask via the second neck to about 5 cm above the surface of the
naphthol solution and is used to provide a stream of house air which is maintained at a
flow rate of 0.15-0.20 L/min. The third neck is sealed with a rubber septum. The stir bar
in the oil bath was removed before the flask is introduced into the oil bath to warm it up
for about 15 min until the solid was melted. Airflow is allowed to flow into the flask while
the molten II-45c was stirred as fast as possible. The airflow is switched to N2 after the
reaction is kept at 165 ÂşC for 36 h. The flask is removed from the oil bath and cooled to rt
before hexanes (100 mL) is added to the flask. The mixture was stirred for 30 min, and
then it was cooled to –20 ºC overnight (12 h) before the solid is collected by suction
filtration. The crude product is dried on high vacuum and crystallized from CH2Cl2. The
dark-colored solution is cooled to room temperature and then to –20 ºC overnight (12 h).
The brown crystals are collected via suction filtration, washed with hexanes, and dried
under vacuum to give II-46c (27.49 g, mp > 260 ÂşC, 17.40 mmol, 92%).
Spectral data for II-46c: Rf = 0.40 (EtOAc/hexanes 1:4); 1H NMR (500 MHz, CDCl3)
δ 5.81 (s, 2H), 6.61 – 6.82 (m, 4H), 6.96 – 7.22 (m, 6H), 7.41 (dd, J = 8.4, 7.4 Hz, 2H),

314

7.73 (d, J = 0.8 Hz, 2H), 7.89 (dd, J = 7.5, 1.1 Hz, 2H), 8.36 (dt, J = 8.3, 1.0 Hz, 2H). 13C
NMR (126 MHz, CDCl3) δ 113.29, 121.35, 122.67, 122.73, 124.13, 126.03, 127.07,
127.67, 128.87, 131.78, 133.17, 139.70, 141.90, 150.46. These spectral data match
those previously reported for this compound11.
Cl

OH
Cl

O

II-44d
100 mmol

1) SOCl2 (2.0 equiv),
70 ÂşC, 1 h then
remove excess

Ph

HO

2)

Ph (1.3 equiv)
(i-PrCO)2O (2 equiv),
190 ÂşC, 48 h
3) KOH, H2O, 100 ÂşC,
overnight

mineral oil, air,

HO

165 ÂşC, 24 h

HO

Ph
Ph

Cl
II-45d
50 mmol
71%

Cl
II-46d
75%

5-chloro-3-phenyl-1-naphthol II-45d: 1-naphthol II-45d was prepared from 2-(2chlorophenyl)acetic acid II-44d (17.06 g, 100.0 mmol) by the General Procedure H. The
crude product was purified by recrystallization from CH2Cl2/hexanes and column
chromatography (silica gel, DCM/hexanes 1:3 to 1:1) to give II-45d as a white crystal in
71% combined isolated yield (18.01 g, mp 127-128 ÂşC, 70.70 mmol).
Spectral data for II-45d: Rf = 0.28 (EtOAc/hexanes 1:4); 1H NMR (500 MHz, CDCl3)
δ 5.36 (br, 1H), 7.11 (d, J = 1.6 Hz, 1H), 7.29 – 7.44 (m, 2H), 7.42 – 7.56 (m, 2H), 7.60
(dd, J = 7.4, 1.1 Hz, 1H), 7.63 – 7.74 (m, 2H), 8.06 (dd, J = 1.5, 1.0 Hz, 1H), 8.13 (dt, J =
8.4, 1.0 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 109.18, 115.34, 120.85, 124.77, 124.96,
127.29, 127.45, 127.78, 128.90, 132.08, 132.28, 140.04, 140.65, 151.88. HRMS (ESI–)
m/z 253.0430 [calcd. for C16H10OCl (M–H): 253.0420].
5,5’-Cl2VANOL II-46d: VANOL derivative II-46d was prepared from 5-chloro-3phenylnaphthalen-1-ol II-45d (12.74 g, 50.0 mmol) by the General Procedure I with
315

heating at 165 ÂşC for 24 h. The crude product was purified by recrystallization from
CH2Cl2/hexanes and column chromatography (silica gel, DCM/hexanes: 1:3 to 1:1) to
give II-46d as an off-white solid in 75% combined isolated yield (9.500 g, mp 253-255 ÂşC
18.70 mmol).
Spectral data for II-46d: Rf = 0.40 (EtOAc/hexanes 1:4); 1H NMR (500 MHz, CDCl3)
δ 5.87 (s, 2H), 6.63 – 6.74 (m, 4H), 6.96 – 7.07 (m, 4H), 7.13 (td, J = 7.3, 1.3 Hz, 2H),
7.47 (dd, J = 8.4, 7.5 Hz, 2H), 7.68 (dd, J = 7.5, 1.1 Hz, 2H), 7.76 (d, J = 1.0 Hz, 2H), 8.31
(dt, J = 8.4, 1.0 Hz, 2H).

13

C NMR (126 MHz, CDCl3) δ 113.40, 118.63, 121.99, 124.13,

125.57, 127.04, 127.64, 127.97, 128.89, 131.89, 132.00, 139.77, 141.73, 150.53. HRMS
(ESI–) m/z 505.0805 [calcd. for C32H19O2Cl2 (M–H): 505.0762].
Me

OH
O
Me
II-44e
100 mmol

1) SOCl2 (2.0 equiv),
70 ÂşC, 1 h then
remove excess

Ph

HO

2)

Ph (1.3 equiv)
(i-PrCO)2O (2 equiv),
190 ÂşC, 48 h
3) KOH, H2O, 100 ÂşC,
overnight

mineral oil, air,

HO

165 ÂşC, 24 h

HO

Ph
Ph

Me
II-45e
50 mmol
52%

Me
II-46e
72%

5-methyl-3-phenyl-1-naphthol II-45e: 1-naphthol II-45e was prepared from 2-(2methylphenyl)acetic acid II-44e (15.02 g, 100.0 mmol) by the General Procedure H.The
crude product was purified by recrystallization from CH2Cl2/hexanes and column
chromatography (silica gel, DCM/hexanes 1:3 to 1:1) to give II-45e as a white crystal in
52% combined isolated yield (12.166 g, 51.90 mmol).
Spectral data for II-46e: Rf = 0.48 (EtOAc/hexanes 1:4); 1H NMR (500 MHz, CDCl3)
δ 2.71 (d, J = 0.9 Hz, 3H), 7.08 (d, J = 1.5 Hz, 1H), 7.33 – 7.40 (m, 2H), 7.44 – 7.51 (m,
316

3H), 7.59 – 7.71 (m, 2H), 7.71 – 7.89 (m, 1H), 8.01 – 8.13 (m, 1H). 13C NMR (126 MHz,
CDCl3) δ 19.94, 108.29, 115.30, 119.60, 123.50, 124.98, 127.41, 127.45, 127.68, 128.82,
134.12, 134.47, 138.70, 141.38, 152.08. HRMS (ESI–) m/z 232.0890 [calcd. for C17H13O
(M–H): 232.0888].
5,5’-Me2VANOL II-46e: VANOL derivative II-46e was prepared from 5-methyl-3phenyl-1-naphthol II-45e (11.72, 50.0 mmol) by the General Procedure I with heating at
165 ÂşC for 24 h. The crude product was purified by recrystallization from CH2Cl2/hexanes
and column chromatography (silica gel, DCM/hexanes 1:3 to 1:1) to give II-46e as an offwhite solid in 72% combined isolated yield (8.452 g, mp 248-251 ÂşC, 18.10 mmol).
Spectral data for II-46e: Rf = 0.53 (EtOAc/hexanes 1:4); 1H NMR (500 MHz, CDCl3)
δ 2.67 (s, 6H), 5.85 (dd, J = 2.6, 1.3 Hz, 2H), 6.63 – 6.82 (m, 4H), 6.97 – 7.18 (m, 6H),
7.40 – 7.55 (m, 7H), 8.27 (d, J = 8.2 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 19.67, 112.52,
118.58, 121.00, 122.96, 125.39, 126.59, 127.52, 128.25, 129.00, 133.83, 134.29, 140.41,
140.67, 150.72. HRMS (ESI–) m/z 465.1839 [calcd. for C34H25O2 (M–H): 465.1855].
OMe

OH
O
OMe
II-44f
100 mmol

1) SOCl2 (2.0 equiv),
70 ÂşC, 1 h then
remove excess

Ph

HO

2)

Ph (1.3 equiv)
(i-PrCO)2O (2 equiv),
190 ÂşC, 48 h
3) KOH, H2O, 100 ÂşC,
overnight

mineral oil, air,

HO

165 ÂşC, 24 h

HO

Ph
Ph

OMe
II-45f
50 mmol
52%

OMe
II-46f
72%

5-methoxy-3-phenyl-1-naphthol II-45f: 1-naphthol II-45f was prepared from 2-(2methylphenyl)acetic acid II-44f (16.618, 100.00 mmol) by the General Procedure H. The
crude product was purified by recrystallization from CH2Cl2/hexanes and column
317

chromatography (silica gel, DCM/hexanes 1:3 to 1:1) to give II-45f as a white crystal in
52% combined isolated yield (3.884 g, mp 142-143 ÂşC, 51.60 mmol).
Spectral data for II-46f: Rf = 0.42 (EtOAc/hexanes 1:4); 1H NMR (500 MHz, CDCl3)
δ 4.00 (s, 3H), 6.86 (dd, J = 7.7, 0.9 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H), 7.27 – 7.52 (m,
4H), 7.70 (ddt, J = 10.6, 7.8, 1.0 Hz, 3H), 8.07 (dd, J = 1.7, 0.9 Hz, 1H).

13

C NMR (126

MHz, CDCl3) δ 55.58, 104.81, 109.02, 112.97, 113.47, 124.44, 125.36, 127.07, 127.29,
127.33, 128.74, 138.12, 141.13, 151.50, 155.64. HRMS (ESI–) m/z 249.0937 [calcd. for
C17H13O2 (M–H): 249.0916].
5,5’-OMe2VANOL II-46f: VANOL derivative II-46f was prepared from 5-methoxy3-phenyl-1-naphthol II-45f (12.520, 50.000 mmol) by the General Procedure I with heating
at 165 ÂşC for 24 h. The crude product was purified by recrystallization from
CH2Cl2/hexanes and column chromatography (silica gel, DCM/hexanes: 1:3 to 1:1) to
give II-46f as an off-white solid in 72% combined isolated yield (8.996 g, mp > 260 ÂşC
18.00 mmol).
Spectral data for II-46f: 1H NMR (500 MHz, CDCl3) δ 3.99 (s, 6H), 5.80 (s, 2H),
6.64 – 6.74 (m, 4H), 6.92 (dd, J = 7.8, 0.9 Hz, 2H), 6.94 – 7.01 (m, 4H), 7.03 – 7.11 (m,
2H), 7.47 (dd, J = 8.5, 7.7 Hz, 2H), 7.76 (d, J = 0.9 Hz, 2H), 7.93 (dt, J = 8.4,

13

C NMR

(126 MHz, CDCl3) δ 29.70, 55.51, 76.75, 77.00, 77.25, 105.33, 113.39, 114.83, 116.20,
123.82, 125.72, 126.43, 126.70, 127.36, 128.93, 139.91, 140.45, 150.04, 155.31. HRMS
(ESI–) m/z 465.1649 [calcd. for C34H25O2 (M–H): 465.1655].

318

CF3

OH
O
CF3
II-44g
100 mmol

1) SOCl2 (2.0 equiv),
70 ÂşC, 1 h then
remove excess

Ph

HO

2)

Ph (1.3 equiv)
(i-PrCO)2O (2 equiv),
190 ÂşC, 48 h
3) KOH, H2O, 100 ÂşC,
overnight

mineral oil, air,

HO

165 ÂşC, 24 h

HO

Ph
Ph

CF3
II-45g
50 mmol
66%

CF3
II-46g
65%

5-trifluoromethyl-3-phenyl-1-naphthol II-45g: 1-naphthol II-45g was prepared from
2-(2-methylphenyl)acetic acid II-44g (20.42 mL, 100.0 mmol) by the General Procedure
H. The crude product was purified by recrystallization from CH2Cl2/hexanes and column
chromatography (silica gel, DCM/hexanes 1:3 to 1:1) to give II-45g as a white crystal in
66% combined isolated yield (19.21 g, mp 122-123 ÂşC 66.60 mmol).
Spectral data for II-46g: Rf = 0.48 (EtOAc/hexanes 1:4); 1H NMR (500 MHz, CDCl3)
δ 5.46 (s, 1H), 7.14 (d, J = 1.4 Hz, 1H), 7.32 – 7.55 (m, 4H), 7.61 – 7.73 (m, 2H), 7.78 –
8.03 (m, 2H), 8.43 (d, J = 8.4 Hz, 1H).

13

C NMR (126 MHz, CDCl3) δ 109.08, 115.18,

115.20, 123.46, 124.19, 125.80 (q, J = 5 Hz), 125.86, 126.46, 127.52, 127.93, 128.96,
130.50, 140.63, 140.80, 152.04. HRMS (ESI–) m/z 287.0682 [calcd. for C17H10F3O (M–
H): 287.0684].
5,5’-(CF3)2VANOL II-46g: VANOL derivative II-46g was prepared from 5-methyl3-phenyl-1-naphthol II-45g (14.41, 50.0 mmol) by the General Procedure I with heating
at 165 ÂşC for 24 h. The crude product was purified by recrystallization from
CH2Cl2/hexanes and column chromatography (silica gel, DCM/hexanes 1:3 to 1:1) to give
II-46d as an off-white solid in 65% combined isolated yield (9.382 g, mp > 260 ÂşC, 16.30
mmol).
319

Spectral data for II-46g: Rf = 0.32 (DCM/hexanes 1:1); 1H NMR (500 MHz, CDCl3)
δ 5.84 (d, J = 18.0 Hz, 2H), 6.58 – 6.71 (m, 4H), 7.00 (td, J = 7.8, 2.8 Hz, 4H), 7.06 – 7.18
(m, 2H), 7.54 – 7.68 (m, 4H), 7.96 (d, J = 7.2 Hz, 2H), 8.58 (d, J = 8.4 Hz, 2H).13C NMR
(126 MHz, CDCl3) δ 113.18, δ 118.46, 123.55, 123.57, 124.13, 125.94 (q, J = 120 Hz),
126.47 (q, J = 5.8 Hz), 127.23, 127.45, 127.73, 128.80, 130.31, 139.54, 142.35, 150.71.
19

F NMR (470 MHz, CDCl3) δ -59.76 (d, J = 3.9 Hz). HRMS (ESI–) m/z 573.1265 [calcd.

for C34H19F6O2 (M–H): 573.1289].
4.3.4 Synthesis of 5,5’-tBu2VANOL (Scheme 2.23)
General Procedure J for preparation of aryl iodide by the Sandmeyer reaction -illustrated for synthesis of 1-(tert-butyl)-2-iodobenzene II-70

NH2

pTsOH•H2O (3.0 equiv),
NaNO2 (2.0 equiv),
KI (2.5 equiv),

I

tBuOH/H2O,
0 ÂşC to rt, overnight
II-69

80-95 mmol

II-70
51-58%

1-(tert-butyl)-2-iodobenzene II-70: To a solution of p-TsOH¡H2O (11.40 g, 60.00
mmol) in tBuOH (80 mL) was added the 2-(tert-butyl) aniline (3.19 mL, 20.0 mmol). The
resulting suspension of amine salt was cooled to 0–10 °C and to this was added,
gradually, a solution of NaNO2 (2.76 g, 40.0 mmol) and KI (8.30 g, 50.0 mmol) in H2O (12
mL). The reaction mixture was stirred for 10 min then allowed to come to 20 °C and stirred
for 2 h. To the reaction mixture was then added H2O (35 mL), NaHCO3 (sat., 70 mL) and
Na2S2O3 (sat., 40 mL). The aromatic iodide was extracted with EtOAc (3 × 100 mL) and
purified by flash chromatography (hexanes) to afford II-70 as a as a colorless liquid (4.213
g, 16.20 mmol, 81%).
320

Spectral data for II-70: Rf = 0.72 (hexanes); 1H NMR (500 MHz, CDCl3) δ 1.52 (s,
9H), 6.81 (ddd, J = 7.8, 7.2, 1.7 Hz, 1H), 7.22 – 7.28 (m, 1H), 7.42 (dd, J = 8.0, 1.7 Hz,
1H), 7.98 (dd, J = 7.8, 1.5 Hz, 1H).13C NMR (126 MHz, CDCl3) δ 29.84, 36.71, 95.12,
127.50, 127.53, 127.89, 143.56, 150.14. These spectral data match those previously
reported for this compound12.
I

II-70

EtO

1) iPrMgCl (1.1 equiv),
THF, 0 ÂşC, 2 h;

O
NaOH, H2O,

O

O
O

60 ÂşC, overnight

2) ClCOCOEt (1.25 equiv);
–78 ºC 2 h to rt, 12 h
36-55 mmol

II-74

1) N2H4•H2O (5 equiv),
80 ÂşC, overnight
2) KOH (4.0 equiv);
triehtylene glycol, 150 ÂşC

HO

II-75

COOH

II-44i
55%
over 3 steps, from iodide

ethyl 2-(2-(tert-butyl)phenyl)-2-oxoacetate II-74: An oven-dried 100 mL roundbottomed flask equipped with an egg-shaped stirring bar (30 mm × 15 mm) is placed
under an N2 atmosphere through a gas inlet. After cooling to 23 °C, 1-(tert-butyl)-2iodobenzene II-70 (9.32 g, 35.8 mmol) and THF (30 ml) was added and the solution was
cooled to 0 °C in an ice bath for 10 min. Isopropylmagnesium chloride (2 M in THF, 20.0
mL, 40 mmol) was added dropwise to the round-bottomed flask at 0 °C for 10 min and
stirred for 2 h. The resulting reaction solution was added dropwise to another 250 mL
round-bottomed flask containing ethyl chlorooxoacetate (5.0 mL, 50 mmol) in THF (30
mL) at –78 °C and warmed to room temperature for 12 h. The reaction was quenched
with saturated NH4Cl solution (75 mL), extracted with EtOAc (100 mL x 3), washed with

321

brine, dried (Na2SO4) and evaporated under reduced pressure to give II-74 as a
colourless liquid, which appeared pure by 1H NMR analysis and was used without
purification.
Spectral data for II-74: Rf = 0.32 (EtOAc/hexanes 1:4); 1H NMR (500 MHz, CDCl3)
δ 1.16 (t, J = 7.1 Hz, 3H), 1.28 – 1.31 (m, 9H), 4.02 (q, J = 7.2 Hz, 2H), 7.11 – 7.20 (m,
2H), 7.34 (ddd, J = 8.2, 5.2, 3.6 Hz, 1H), 7.46 (dt, J = 8.1, 0.8 Hz, 1H).

13

C NMR (126

MHz, CDCl3) δ 13.84, 21.31, 31.76, 62.50, 124.96, 127.35, 127.76, 130.70, 135.59,
149.33, 162.27, 191.49. HRMS (ESI-TOF) m/z 234.1249 [calcd. for C14H18O3 (M+):
234.1256];
2-(2-(tert-butyl)phenyl)-2-oxoacetic acid II-75: Crude ethyl 2-(2-(tert-butyl)phenyl)2-oxoacetate II-74 was transferred to an oven-dried 100 mL round-bottomed flask
equipped with an egg-shaped stirring bar. To the round-bottomed flask was added 2.5 M
NaOH (aq) (30 mL). The resulting suspension was heated and maintained at 60 ÂşC with
stirring for 12 h. The reaction mixture was quenched with 4 M HCl (aq) (~30 mL) and the
resulting aqueous mixture was extracted with DCM (3 x 15 mL). The combined organic
extract was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated
in vacuo to give the II-74 as a yellow liquid. This product appeared pure by 1H NMR
analysis and was used without purification.
Spectral data for II-75: Rf = 0.30 (EtOAc/hexanes 1:2); 1H NMR (500 MHz, CDCl3)
δ 1.23 – 1.41 (m, 9H), 7.21 – 7.32 (m, 2H), 7.41 – 7.49 (m, 1H), 7.55 (dt, J = 8.2, 0.9 Hz,
1H).13C NMR (126 MHz, CDCl3) δ 32.06, 36.11, 125.06, 127.65, 127.93, 131.30, 131.32,

322

149.92, 191.91, 191.96. HRMS (ESI–) m/z 205.0866 [calcd. for C12H13O3 (M–H):
205.0865].
2-(2-(tert-butyl)phenyl) acetic acid II-44i: Hydrazine hydrate (7.00 mL, 220 mmol)
was added to an oven-dried 100 mL round-bottomed flask equipped with an egg-shaped
stirring bar. The hydrazine hydrate was cooled to 0 ÂşC and the crude 2-(2-(tertbutyl)phenyl)-2-oxoacetic acid II-75 (8.673 g, 42.00 mmol) was added in one portion. The
resulting suspension was then heated and maintained at 80 ÂşC with stirring for 12 h. The
round-bottomed flask was removed from oil bath and cooled briefly. To the reaction
mixture was added KOH (9.45 g, 168 mmol) in one portion and triethylene glycol (34 mL).
The resulting reaction mixure was heated in oil bath and maintained at 150 ÂşC for 12 h
after which time the round bottom flask was cooled to rt and diluted with water (20 mL).
The aqueous mixture was extracted with EtOAc (3 x 40 mL). The combined organic phase
was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated in vacuo.
The crude product was purified by flash column chromatography (silica gel,
EtOAc/hexane 1:4 to 1:2) to provide the desired product II-44i (5.49 g, 68%) as a white
solid.
Spectral data for II-44i: Rf = 0.33 (EtOAc/hexanes 1:2); 1H NMR (500 MHz, CDCl3)
δ 1.39 (s, 9H), 3.96 (s, 2H), 7.10 – 7.29 (m, 3H), 7.35 – 7.48 (m, 1H). 13C NMR (126 MHz,
CDCl3) δ 31.56, 35.47, 40.07, 126.10, 126.43, 127.41, 131.49, 133.07, 148.06, 178.70.
HRMS (ESI–) m/z 191.1075 [calcd. for C12H15O2 (M–H): 191.1072].

323

COOH

1) (COCl)2 (2.0 equiv),
cat. DMF, 0 ÂşC to rt 2 h;

Ph

HO

2)

II-44i

Ph (1.3 equiv)
(i-PrCO)2O (2 equiv),
190 ÂşC, 48 h
3) KOH, H2O, 100 ÂşC,
overnight

mineral oil, air,

HO

165 ÂşC, 24 h

HO

Ph
Ph

20 mmol
II-45i
42%
II-46i
91%

50 mmol

5-tert-butyl-3-phenyl-1-naphthol II-45i: 1-naphthol II-45i was prepared from 2-(2(tert-butyl)phenyl)acetic acid II-44i (9.610 g, 50.00 mmol, 1.000 equiv) by the General
Procedure H. The crude product was purified by recrystallization from CH2Cl2/hexanes
and column chromatography (silica gel, DCM/hexanes: 1:3 to 1:1) to give II-45i as a white
crystal in 42% combined isolated yield (5.845 g, mp 104-106 ÂşC, 21.10 mmol).
Spectral data for II-45i: Rf = 0.33 (EtOAc/hexanes 1:4); 1H NMR (500 MHz, CDCl3)
δ 1.71 (s, 9H), 5.57 (s, 1H), 7.04 (d, J = 1.4 Hz, 1H), 7.39 – 7.56 (m, 4H), 7.61 (dd, J =
7.4, 1.2 Hz, 1H), 7.65 – 7.73 (m, 2H), 8.21 (dt, J = 8.3, 1.0 Hz, 1H), 8.31 (t, J = 1.1 Hz,
1H). 13C NMR (126 MHz, CDCl3) δ 32.07, 36.26, 107.48, 118.62, 120.39, 124.40, 124.88,
125.14, 127.39, 127.45, 128.96, 133.05, 137.30, 141.77, 146.27, 152.48. HRMS (ESI–)
m/z 275.1437 [calcd. for C20H19O (M–H): 275.1436].
5,5’-tBu2VANOL II-46i: VANOL derivative II-46i was prepared from 5-tert-butyl-3phenyl-1-naphthol II-45i (5.528 g, 20.00 mmol) by the general procedure with heating at
165 ÂşC for 24 h. The crude product was purified by recrystallization from CH2Cl2/hexanes
and column chromatography (silica gel, DCM/hexanes: 1:3 to 1:1) to give II-46i as an offwhite solid in 91% combined isolated yield (5.031 g, mp 287-288 ÂşC, 9.140 mmol).

324

Spectral data for II-46i: Rf = 0.41 (EtOAc/hexanes 1:4); 1H NMR (500 MHz, CDCl3)
δ 1.67 (s, 18H), 5.97 (s, 2H), 6.73 (d, J = 7.6 Hz, 4H), 7.04 (t, J = 7.8 Hz, 4H), 7.14 (t, J
= 7.4 Hz, 2H), 7.54 (t, J = 7.9 Hz, 2H), 7.69 (d, J = 7.4 Hz, 2H), 8.02 (s, 2H), 8.41 (d, J =
8.3 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 31.99, 36.19, 111.76, 121.62, 121.72, 124.59,
124.88, 125.15, 126.50, 127.59, 128.99, 132.83, 139.03, 141.05, 146.07, 151.18. HRMS
(ESI–) m/z 549.2844 [calcd. for C40H37O2 (M–H): 549.2794].
4.3.5 Synthesis of 5,5’-CN2VANOL (Scheme 2.24)
Br

CN

Ph
Ph

HO
HO

20 mol% CuI,
40 mol% KI,
DMEDA (2.0 equiv)
NaCN (2.4 equiv),
toluene, 130 ÂşC, 24 h

Br

HO
HO

Ph
Ph

CN
85%
II-46j

II-46c

CN

+

Ph
Ph

HO
HO

Br
~4%
II-46j’

5,5’-CN2VANOL II-46j: VANOL derivative II-46j was synthesized from a modified
procedure13 by Buchwald et al. To a 50 mL Schlenk flask was charged with NaCN (118
mg, 2.40 mmol, 2.40 equiv), CuI (38.1 mg, purified, 0.200 mmol), 5,5’-Br2VANOL II-46c
(596 mg, 1.00 mmol), and KI (66.4 mg, 0.400 mmol). The flask was then briefly evacuated
and backfilled with nitrogen three times. Anhydrous toluene (2 mL) and N,N dimethylethylenediamine (216 ÂľL, 2.00 mmol, 2.00 equiv) were added under argon. The
Schlenk flask was sealed with a Teflon valve and the reaction mixture was stirred at
130 °C for 24 h. The resulting suspension was allowed to reach room temperature, diluted
with 30% aq ammonia (3 mL), and extracted with EtOAc (4 × 2 mL). The water layer was
discarded, and the suspension of II-46j in EtOAc was purified by filtration then wash with
325

cold DCM to afford II-46j as a yellow solid (416 mg, mp > 320 ÂşC (decomposed), 0.851
mmol) in 85% yield.
Spectral data for II-46j: Rf = 0.30 (DCM/hexanes 1:1); HRMS (ESI–) m/z 487.1480
[calcd. for C34H19N2O2 (M–H): 487.1447].
4.3.6 Synthesis of 3,3’-R2-phenyl VANOL (Table 2.3)

1)
(1.3 equiv),
(i-PrCO)2O (2 equiv),
190 ÂşC, 48 h

Cl
O

HO

2) KOH, H2O, 100 ÂşC,
overnight

II-76

100 mmol

mineral oil, air,

HO

165 ÂşC, 24 h

HO

Ar
Ar

50 mmol
II-45k
62%
II-46k, Ar =4-EtC6H4
63%

General Procedure K for CAEC process with 2-phenylacetyl chloride II-76 -illustrated

for

synthesis

of

3-(4-ethylphenyl)-1-naphthol

II-45k

with

1-ethyl-4-

ethynylbenzene:
3-(4-ethylphenyl)-1-naphthol II-45k: An oven-dried 500 mL round-bottomed flask
equipped with an egg-shaped stirring bar (30 mm ×	15 mm) and a condenser is placed
under an N2 atmosphere through a gas inlet. After cooling to 23 °C, 2-phenylacetyl
chloride II-76 (13.22 mL, 100.0 mmol, 1.000 equiv) is added followed by 1-ethyl-4ethynylbenzene (18.2 mL, 130 mmol, 1.30 equiv) and (i-PrCO)2O (33.0 mL, 200 mmol,
2.00 equiv). The flask is fitted with a condenser flushed with nitrogen with a Teflon sleeve
in the joint and Teflon tape wrapped around the joint to secure a tight seal. The reaction
mixture was heated and stirred in a 190 ÂşC oil bath for 48 h with a gentle nitrogen flow

326

across the top of the condenser. The brown reaction mixture is cooled to about 60 ÂşC (oil
bath temperature), and aq KOH (33.4 g, 1.43 mol) in 120 mL of H2O is slowly added. After
stirring in a 100 ÂşC oil bath overnight (12 h), the orange solution is cooled to rt, ether (300
mL) is added, and the mixture stirred for 30 min before the organic layer is isolated in a 2
L separatory funnel. The water layer is extracted twice with ether (300 mL×2), and the
combined organic layer is washed with brine (300 mL), dried over MgSO4 and filtered.
The dark-colored organic solution is concentrated in vacuo using a rotary evaporator
(40 °C, 15 mmHg) and the residue is dried under high vacuum (23 °C, 0.2 mmHg)
overnight to give 40 g of the dark brown crude product. Recrystallization from
CH2Cl2/hexanes and column chromatography (silica gel, DCM/hexanes: 1:3 to 1:1) gave
the product II-45k as an off-white solid (15.30 g, mp 117-120 ÂşC, 61.60 mmol) in a
combined yield of 62%.
Spectral data for II-45k: 1H NMR (500 MHz, CDCl3) δ 1.28 (td, J = 7.6, 1.2 Hz, 3H),
2.70 (q, J = 7.6 Hz, 2H), 5.26 (s, 1H), 7.07 (d, J = 1.7 Hz, 1H), 7.26 – 7.35 (m, 2H), 7.48
(dddd, J = 18.0, 8.1, 6.8, 1.4 Hz, 2H), 7.56 – 7.68 (m, 3H), 7.79 – 7.89 (m, 1H), 8.15 (ddd,
J = 8.0, 1.6, 0.8 Hz, 1H).

13

C NMR (126 MHz, CDCl3) δ 15.63, 28.56, 108.38, 118.51,

121.43, 123.40, 125.19, 126.86, 127.22, 127.99, 128.39, 134.99, 138.23, 138.86, 143.69,
151.62. HRMS (ESI–) m/z 247.1138 [calcd. for C18H15O (M–H): 247.1123].
3,3’-pEtPh2VANOL II-46k: VANOL derivative II-46k was prepared from 3-(4ethylphenyl)-1-naphthol II-45k (12.42 g, 50.00 mmol, 1.000 equiv) by the General
Procedure I with heating at 165 ÂşC for 36 h. The crude product was purified by
recrystallization from CH2Cl2/hexanes and column chromatography (silica gel,

327

DCM/hexanes: 1:3 to 1:1) to give II-46k as an off-white solid in 63% combined isolated
yield (7.823 g, mp 178-180 ÂşC, 15.80 mmol).
Spectral data for II-46k: 1H NMR (500 MHz, CDCl3) δ 1.15 (td, J = 7.6, 0.9 Hz, 6H),
2.51 (q, J = 7.6 Hz, 4H), 5.79 (d, J = 1.1 Hz, 2H), 6.51 – 6.63 (m, 4H), 6.79 (d, J = 8.0 Hz,
4H), 7.34 (s, 2H), 7.47 – 7.61 (m, 4H), 7.73 – 7.84 (m, 2H), 8.34 (ddd, J = 7.4, 2.2, 0.9
13

Hz, 2H).

C NMR (126 MHz CDCl3) δ 15.64, 28.44, 112.86, 121.92, 122.84, 122.85,

125.49, 127.00, 127.42, 127.65, 128.77, 134.62, 137.52, 140.71, 142.64, 150.25. HRMS
(ESI–) m/z 493.2176 [calcd. for C36H29O2 (M–H): 493.2168].
O

1)

Cl
O
II-76

(1.3 equiv),
(i-PrCO)2O (2 equiv),
190 ÂşC, 48 h

O
HO

2) KOH, H2O, 100 ÂşC,
overnight

100 mmol

mineral oil, air,

HO

165 ÂşC, 24 h

HO

Ar
Ar

50 mmol
II-45l
47%
II-46l, Ar = 4-CH3OC6H4
68%

3-(4-methoxyphenyl)-1-naphthol II-45l: 1-naphthol II-45l was prepared from 4ethynylanisole (17.2 mL, 130 mmol, 1.30 equiv) by the General Procedure K. The crude
product

was

purified

by

recrystallization

from

CH2Cl2/hexanes

and

column

chromatography (silica gel, DCM/hexanes: 1:3 to 1:1) to give II-45l as an off-white crystal
in 47% combined isolated yield (11.85 g, mp 155-156 ÂşC, 47.40 mmol).
Spectral data for II-45l: 1H NMR (500 MHz, CDCl3) δ 3.85 (s, 3H), 5.29 (s, 1H),
6.96 – 7.02 (m, 2H), 7.03 – 7.06 (m, 1H), 7.47 (dddd, J = 20.2, 8.1, 6.8, 1.4 Hz, 2H), 7.57
– 7.64 (m, 3H), 7.80 – 7.86 (m, 1H), 8.14 (ddd, J = 8.2, 1.5, 0.8 Hz, 1H).

13

C NMR (126

MHz, CDCl3) δ 55.39, 108.24, 114.27, 118.05, 121.40, 123.20, 125.05, 126.86, 127.88,
328

128.31, 133.39, 135.02, 138.49, 151.64, 159.27. HRMS (ESI–) m/z 249.0937 [calcd. for
C17H13O (M–H): 249.0916].
3,3’-pOMePh2VANOL II-46l: VANOL derivative II-46l was prepared from 5-methyl3-phenylnaphthalen-1-ol II-45l (11.264 g, 45.00 mmol) by the General Procedure I with
heating at 165 ÂşC for 36 h. The crude product was purified by recrystallization from
CH2Cl2/hexanes and column chromatography (silica gel, DCM/hexanes: 1:3 to 1:1) to
give II-46l as an off-white solid in 68% (76% brsm) combined isolated yield (7.600 g, mp
243-244 ÂşC, 15.20 mmol).
Spectral data for II-46l: 1H NMR (500 MHz, CDCl3) δ 3.68 (s, 3H), 5.79 (s,1H), 6.44
– 6.73 (m, 4H), 7.30 (s, 1H), 7.43 – 7.60 (m, 2H), 7.70 – 7.85 (m, 1H), 8.32 (dd, J = 7.4,
1.9 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 55.16, 112.89, 112.93, 121.81, 122.74, 122.80,
125.46, 127.45, 127.60, 129.96, 132.82, 134.62, 140.30, 150.27, 158.43. HRMS (ESI–)
m/z 497.1792 [calcd. for C34H25O4 (M–H): 497.1753].
Bu

1)

Cl
O
II-76

(1.3 equiv),
(i-PrCO)2O (2 equiv),
190 ÂşC, 48 h

Bu
HO

2) KOH, H2O, 100 ÂşC,
overnight

100 mmol

mineral oil, air,

HO

165 ÂşC, 24 h

HO

Ar
Ar

50 mmol
II-45m
58%
II-46m, Ar = 4-BuC6H4
49%

3-(4-butylphenyl)-1-naphthol II-45m: 1-naphthol II-45m was prepared from 1-butyl4-ethynylbenzene (22.7 mL, 130 mmol, 1.30 equiv) by the General Procedure K. The
crude product was purified by recrystallization from CH2Cl2/hexanes and column

329

chromatography (silica gel, DCM/hexanes: 1:3 to 1:1) to give II-45m as a yellow crystal
in 58% combined isolated yield (15.96 g, mp 110-111 ÂşC, 57.70 mmol).
Spectral data for II-45m: 1H NMR (500 MHz, CDCl3) δ 0.94 (t, J = 7.3 Hz, 3H), 1.27
– 1.52 (m, 2H), 1.54 – 1.78 (m, 2H), 2.53 – 2.77 (m, 2H), 5.24 (d, J = 1.4 Hz, 1H), 7.07
(d, J = 1.6 Hz, 1H), 7.22 – 7.30 (m, 2H), 7.48 (dddd, J = 18.1, 8.2, 6.8, 1.5 Hz, 2H), 7.55
– 7.61 (m, 2H), 7.63 (t, J = 1.1 Hz, 1H), 7.72 – 7.95 (m, 1H), 7.95 – 8.22 (m, 1H).

13

C

NMR (126 MHz, CDCl3) δ 14.01, 22.43, 33.67, 35.33, 108.37, 118.49, 121.42, 123.38,
125.18, 126.85, 127.12, 127.98, 128.93, 134.99, 138.16, 138.87, 142.37, 151.61. HRMS
(ESI–) m/z 275.1458 [calcd. for C20H19O (M–H): 275.1436].
3,3’-pBuPh2VANOL II-46m: VANOL derivative II-46m was prepared from 1-butyl4-ethynylbenzene (13.82 g, 50.00 mmol, 1.300 equiv) by the General Procedure I with
heating at 165 ÂşC for 36 h. The crude product was purified by recrystallization from
CH2Cl2/hexanes and column chromatography (silica gel, DCM/hexanes: 1:3 to 1:1) to
give II-46i as a yellow solid in 49% combined isolated yield (6.798 g, mp 161-163 ÂşC,
12.30 mmol).
Spectral data for II-46m: 1H NMR (500 MHz, CDCl3) δ 0.89 (tt, J = 7.4, 1.5 Hz, 6H),
1.28 (dddd, J = 17.2, 7.3, 5.2, 3.7 Hz, 4H), 1.35 – 1.64 (m, 4H), 2.22 – 2.62 (m, 4H), 5.63
– 5.89 (m, 2H), 6.43 – 6.68 (m, 4H), 6.68 – 6.92 (m, 4H), 7.24 – 7.45 (m, 2H), 7.54 (qd, J
= 7.4, 5.2 Hz, 4H), 7.78 (dd, J = 7.2, 2.1 Hz, 2H), 8.33 (dd, J = 7.8, 2.2 Hz, 2H). 13C NMR
(126 MHz, CDCl3) δ 13.96, 22.25, 33.57, 35.15, 112.86, 121.85, 122.82, 122.83, 125.46,
127.39, 127.53, 127.63, 128.68, 134.62, 137.44, 140.69, 141.24, 150.22. HRMS (ESI–)
m/z 549.2801 [calcd. for C40H37O2 (M–H): 549.2794].

330

4.3.7 Synthesis of 7,7’-R2VANOL (Scheme 2.25)
Br
1) SOCl2, 70 ÂşC, 2 h

OH

2)

O

Ph (1.3 equiv)
(i-PrCO)2O (2 equiv),
190 ÂşC, 48 h

3) KOH, H2O, 100 ÂşC,
overnight

Br
II-44n

250 mmol

Ph

HO

RO
RO

mineral oil,

Ph
Ph

165 ÂşC, 24 h

Br

150 mmol
59%
II-45n

Br
1) NaH (2.5 equiv ),
THF 0 ÂşC, 30 min
2) MOMCl (2.5 equiv),
0 ÂşC to rt, overnight

R = H, II-46n 60%
R = MOM, II-77 95%

7-bromo-3-phenyl-1-naphthol II-45n: 1-naphthol II-45n was prepared from 2-(4bromophenyl)acetic acid II-44n (53.76 g, 250.0 mmol) by the General Procedure H. The
crude product was purified by recrystallization from CH2Cl2/hexanes and column
chromatography (silica gel, DCM/hexanes: 1:3 to 1:1) to give II-45n as an off-white solid
in 59% combined isolated yield (44.35 g, mp 94-97 ÂşC, 148.0 mmol).
Spectral data for II-45n: Rf = 0.35 (DCM). 1H NMR (CDCl3, 500 MHz) δ 5.24 (s,
1H), 7.08 (d, 1H, J = 1.7 Hz), 7.34-7.39 (m, 1H), 7.44-7.48 (m, 2H), 7.57 (dd, 1H, J = 8.5,
1.5 Hz), 7.59 (s, 1H), 7.62-7.65 (m, 2H), 7.71 (d, 1H, J = 9.0 Hz), 8.36 (d, 1H, J = 1.5 Hz);
13

C NMR (CDCl3, 125MHz) δ 109.28, 118.63, 119.32, 124.28, 124.66, 127.24, 127.71,

128.93, 129.61, 130.32, 133.37, 139.43, 140.51, 150.86. These spectral data match
those previously reported for this compound11.
5,5’-tBu2VANOL II-46n: VANOL derivative II-46n was prepared from 7-bromo-3phenylnaphthalen-1-ol II-45n (44.88 g, 150.0 mmol) by the general procedure with
heating at 165 ÂşC for 24 h. The crude product was purified by recrystallization from
CH2Cl2/hexanes and column chromatography (silica gel, DCM/hexanes: 1:3 to 1:1) to

331

give II-46n as a light brown solid in 60% combined isolated yield (26.88 g, mp 136-138
ÂşC, 45.10 mmol).
Spectral data for II-46n: Rf = 0.51 (DCM). 1H NMR (CDCl3, 500 MHz) δ 5.76 (s,
2H), 6.59-6.61 (m, 4H), 6.95-6.98 (m, 4H), 7.05-7.10 (m, 2H), 7.28 (s, 2H), 7.62-7.63 (m,
4H), 8.49-8.52 (m, 2H);

13

C NMR (CDCl3, 125 MHz) δ 113.57, 119.92, 121.94, 123.97,

125.30, 126.96, 127.57, 128.77, 129.37, 131.09, 133.13, 139.65, 141.08, 149.49; These
spectral data match those previously reported for this compound11.
7,7’-BrVANOL-MOM2 II-77: To a flame-dried 250 mL round bottom flask were
added NaH (2.00 g, 60% in mineral oil, 50.0 mmol, 2.50 equiv) and THF (80 mL). The
resulting mixture was cooled to 0 °C and a solution of 7,7’-Br2VANOL II-46n (11.93 g,
20.00 mmol) in THF (20 mL) was added. The mixture was stirred at 0 °C for 30 min and
then allowed to warm up to room temperature for 15 minutes. The mixture was re-cooled
to 0 °C and MOMCl (3.80 mL, 50.0 mmol) was added. The mixture was warmed up to
room temperature and stirred for an additional 12 h. NH4Cl (sat. aq. 30 mL) was added
to the mixture and the organic solvent was removed on a rotary evaporator. The residue
was extracted with CH2Cl2 (50 mL × 3). The combined organic layer was washed with
brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness.
Purification of the crude product by column chromatography on silica gel (DCM:hexanes
1:2 to 3:4 to 1:1) gave II-77 as a white solid (13.05 g, 19.10 mmol, mp 97-98 °C) in 95%
yield.
Spectral data for II-77: Rf = 0.22 (DCM/hexanes 1:1). 1H NMR (CDCl3, 500 MHz)
δ 2.77 (s, 6H), 5.05-5.09 (m, 4H), 6.71 (dd, 4H, J = 8.5, 1.0 Hz), 6.89-6.93 (m, 4H), 7.03-

332

7.09 (m, 2H), 7.46 (s, 2H), 7.57 (dd, 2H, J = 8.5, 2.0 Hz), 7.68 (d, 2H, J = 9.0 Hz), 8.328.34 (m, 2H); 13C NMR (CDCl3, 126 MHz) δ 56.50, 99.51, 120.46, 125.18, 125.49, 126.31,
127.52, 127.55, 128.17, 129.04, 129.87, 130.02, 132.84, 140.42, 141.13, 151.52; These
spectral data match those previously reported for this compound11.
General Procedure L for synthesis of 7,7’-dialkyl VANOL by the Kumada coupling
-- illustrated for synthesis of 7,7’-hexyl2VANOL II-45o.
Br
Br

Mg (4 equiv), Et2O,
rt to reflux, 1 h

hexylMgBr (4 equiv)
Ni(dppp)Cl
2 (10 mol%), MOMO
Ph
MOMO
Ph
Et2O, 0 ÂşC to reflux,
overnight
then quick column

MOMO
MOMO

8 mmol

Br
II-77

R

R

Ph
Ph

R
II-78o, R = hexyl

amberlyst 15
MeOH/THF (1:1)
reflux, overnight

HO
HO

Ph
Ph

R
II-46o, R = hexyl
93%

7,7’-hexyl2VANOL-MOM2 II-78o: An oven-dried 100 mL round-bottomed flask
equipped with an egg-shaped stirring bar (30 mm × 15 mm) is placed under an N2
atmosphere through a gas inlet. After cooling to 23 °C, 1-bromohexane (4.50 mL, 32.0
mmol, 4.00 equiv) and Et2O (15 mL) was added. The solution was cooled to 0 °C in an
ice bath for 10 min. To the round bottom flask magnesium (800 mg, 32.9 mmol) was
added and activated with 1 drop of TMSCl under nitrogen. The reaction mixture was
stirred at rt for 0.5 h then was refluxed for 1 h until most of the magnesium disappeared.
To a separate oven-dried 250 mL round-bottomed flask was added II-77 (5.476 g, 8.000
mmol), Ni(dppp)Cl2 (432 mg, 0.800 mmol) and dry THF (40 mL) and then cooled to 0 ÂşC
for 10 min. To this mixture was added dropwise the resulting solution of Grignard reagent

333

from the 100 mL round-bottomed flask at 0 ÂşC. The reaction mixture was then warmed to
rt and heated to reflux (45 ÂşC) for 12 h. After cooling to room temperature, NH4Cl (sat. aq.
20 mL) was added to the mixture. and the layers were separated. The aqueous layer was
extracted with EtOAc (30 mL x 3). The combined organic layer was washed with water
and dried over anhydrous Na2SO4. It was revealed by TLC and 1H NMR analysis that the
partial deproctection occurred (mono-MOM:di-MOM 1:4.7).Therefore the residue was
purified by column chromatography (silica gel, DCM/hexanes 1:3) to give a mixture of II78o and the partially deprotected procduct as a white solid (6.362 g). The crude mixture
was used in the next step without further separation.
Spectral data for II-78o: Rf = 0.67 (DCM/hexanes 1:1). 1H NMR (500 MHz, CDCl3)
δ 0.78 – 1.05 (m, 6H), 1.21 – 1.57 (m, 12H), 1.76 (q, J = 7.7 Hz, 4H), 2.68 (s, 6H), 2.84
(dd, J = 8.8, 6.6 Hz, 4H), 5.09 – 5.22 (m, 4H), 6.70 – 6.78 (m, 4H), 6.91 (t, J = 7.8 Hz,
4H), 6.99 – 7.10 (m, 2H), 7.38 (dd, J = 8.3, 1.7 Hz, 2H), 7.49 (s, 2H), 7.76 (d, J = 8.3 Hz,
2H), 7.92 – 8.05 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 14.17, 22.67, 29.10, 31.28, 31.81,
36.55, 56.28, 99.33, 121.04, 125.51, 125.74, 126.84, 126.99, 127.38, 128.02, 128.11,
129.15, 133.00, 139.71, 140.72, 141.12, 151.95.
Spectral data for mono-MOM-II-78o: Rf = 0.58 (DCM/hexanes 1:1). 1H NMR (500
MHz, CDCl3) δ 0.92 (td, J = 6.1, 5.2, 2.4 Hz, 6H), 1.30 – 1.53 (m, 12H), 1.77 (tdd, J =
11.6, 8.9, 5.5 Hz, 4H), 2.76 – 2.89 (m, 4H), 2.93 (s, 3H), 5.09 – 5.26 (m, 2H), 6.13 (s, 1H),
6.54 – 6.64 (m, 2H), 6.73 – 6.82 (m, 2H), 6.86 – 7.02 (m, 4H), 7.01 – 7.14 (m, 2H), 7.26
(s, 1H), 7.40 (ddd, J = 28.5, 8.4, 1.7 Hz, 2H), 7.49 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.77
(d, J = 8.3 Hz, 1H), 7.96 (d, J = 1.7 Hz, 1H), 8.09 – 8.27 (m, 1H).

334

13

C NMR (126 MHz,

CDCl3) δ 14.14, 14.15, 22.66, 29.09, 29.23, 31.44, 31.48, 31.78, 31.80, 36.49, 36.54,
56.96, 99.28, 117.73, 120.93, 121.10, 121.49, 123.79, 124.73, 126.01, 126.21, 126.51,
127.25, 127.30, 127.34, 127.40, 128.21, 128.24, 128.61, 128.97, 129.32, 132.52, 133.29,
139.27, 139.99, 140.42, 140.52, 141.16, 141.33, 149.08, 151.29.
7,7’-hexyl2VANOL II-46o: To a 500 mL round-bottomed flask, the purified mixture
obtained above was dissolved in a mixture of THF and MeOH (160 mL, 1:1) and
Amberlyst 15 (4.00 g) was added. The mixture was stirred at 65 ÂşC for 15 h under N2.
After cooling down to rt, the mixture was filtered through filter paper and concentrated to
dryness. Purification of the crude product by column chromatography on silica gel
(DCM:hexanes 2:1) gave II-46o as a white solid (4.525 g, mp 107-108 ÂşC, 7.450 mmol)
in 93% yield over two steps.
Spectral data for II-46o: Rf = 0.38 (DCM/hexanes 1:1). 1H NMR (500 MHz, CDCl3)
δ 0.79 – 1.04 (m, 6H), 1.19 – 1.57 (m, 12H), 1.66 – 1.93 (m, 4H), 2.85 (t, J = 7.8 Hz, 4H),
5.82 (d, J = 1.4 Hz, 2H), 6.64 (dt, J = 8.3, 1.2 Hz, 4H), 6.97 (t, J = 7.6 Hz, 4H), 7.07 (t, J
= 7.4 Hz, 2H), 7.30 (s, 2H), 7.44 (dd, J = 8.4, 1.7 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 8.13
(s, 2H).

13

C NMR (126 MHz, CDCl3) δ 14.16, 22.66, 29.18, 31.55, 31.80, 36.43, 112.72,

121.12, 121.83, 122.94, 126.43, 127.42, 127.61, 128.89, 129.05, 133.05, 139.74, 140.34,
140.61, 149.91. HRMS (ESI–) m/z 607.3593 [calcd. for C44H47O2 (M–H): 607.3576].

335

Br
Br

Mg (4 equiv), Et2O,
rt to reflux, 1 h

R

R

hexylMgBr(4 equiv)
Ni(dppp)Cl
2 (10 mol%), MOMO
Ph
MOMO
Ph
Et2O, 0 ÂşC to reflux,
overnight
then quick column

MOMO
MOMO

8 mmol

Br
II-77

Ph
Ph

amberlyst 15
MeOH/THF (1:1)
reflux, overnight

R
II-78p, R = isoamyl

Ph
Ph

HO
HO

R
II-46p, R = isoamyl
74%

7,7’-isopentyl2VANOL II-46p: VANOL derivatives II-46p was obtained by following
General Procedure L with 1-bromo-3-methylbutane (3.84 mL, 32.0 mmol, 4.00 equiv).
Crude mixture (4.5750 g) of II-78p and the mono-deprocteced compound was used for
the next step to give II-46p as a white solid (3.898 g, mp 192-193 ÂşC, 6.730 mmol) in 84%
yield over two steps.
Spectral data for II-46p: Rf = 0.36 (DCM/hexanes 1:1). 1H NMR (500 MHz, CDCl3)
δ 1.01 (dd, J = 6.2, 1.9 Hz, 12H), 1.60 – 1.87 (m, 6H), 2.86 (dd, J = 9.1, 6.5 Hz, 4H), 5.82
(s, 2H), 6.54 – 6.70 (m, 4H), 6.97 (t, J = 7.7 Hz, 4H), 7.04 – 7.15 (m, 2H), 7.30 (s, 2H),
7.44 (dd, J = 8.4, 1.8 Hz, 2H), 7.72 (d, J = 8.3 Hz, 2H), 8.06 – 8.19 (m, 2H).

13

C NMR

(126 MHz, CDCl3) δ 22.60, 22.67, 27.91, 34.26, 40.88, 112.72, 121.04, 121.84, 122.96,
126.44, 127.42, 127.65, 128.88, 129.04, 133.04, 139.74, 140.34, 140.77, 149.89. HRMS
(ESI–) m/z 577.3130 [calcd. for C42H41O2 (M–H): 577.3107].

336

Ph
Br

Br
Mg (4 equiv), Et2O,
rt to reflux, 1 h

R

R

hexylMgBr (4 equiv)
Ni(dppp)Cl
2 (10 mol%), MOMO
Ph
MOMO
Ph
Et2O, 0 ÂşC to reflux,
overnight
then quick column

MOMO
MOMO

8 mmol

Br
II-77

Ph
Ph

R
II-78q, R = 3-phenylpropyl

amberlyst 15
MeOH/THF (1:1)
reflux, overnight

HO
HO

Ph
Ph

R
II-46q, R = 3-phenylpropyl
87%

7,7’-(3-phenylpropyl)2VANOL II-46q: VANOL derivatives II-46q was obtained by
following General Procedure L with (3-bromopropyl)benzene (4.9 mL, 32 mmol, 4.0
equiv). Crude mixture (6.752 g) of II-78q and the mono-deprocteced compound was used
for the next step to give II-46q as a white solid (4.686 g, mp 129-131 ÂşC, 6.940 mmol) in
87 % yield over two steps.
Spectral data for II-46q: Rf = 0.39 (DCM/hexanes 1:1). 1H NMR (500 MHz, CDCl3)
δ 2.07 – 2.20 (m, 4H), 2.72 – 2.81 (m, 4H), 2.88 – 2.95 (m, 4H), δ 5.82 (s, 2H), 6.61 –
6.66 (m, 4H), 6.97 (t, J = 7.7 Hz, 4H), 7.04 – 7.11 (m, 2H), 7.19 – 7.28 (m, 6H), 7.28 –
7.36 (m, 6H), 7.44 (dd, J = 8.4, 1.8 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 8.05 – 8.30 (m, 2H).
13

C NMR (126 MHz, CDCl3) δ 33.03, 35.62, 35.88, 112.77, 121.28, 121.83, 122.94,

125.81, 126.48, 127.43, 127.73, 128.37, 128.52, 128.88, 128.99, 133.12, 139.85, 139.92,
140.30, 142.26, 149.94. HRMS (ESI–) m/z 675.3296 [calcd. for C50H43O2 (M–H):
675.3263].

337

Br

Br

Ph
Ph

MOMO
MOMO

hexylMgBr(4 equiv)
Pd(dppf)Cl2 (5 mol%),
Et2O, –78 ºC to rt,
overnight
then quick column

Cy

Cy

Mg (4 equiv), Et2O,
rt to reflux, 1 h

MOMO
MOMO

8 mmol

Br
II-77

Ph
Ph

amberlyst 15
MeOH/THF (1:1)
reflux, overnight

Ph
Ph

HO
HO

Cy

Cy
II-78r

II-46r
93%

7,7’-Cy2VANOL II-46r: VANOL derivatives II-46r was obtained by following
General Procedure L with bromocyclohexane (4.0 mL, 32 mmol, 4.0 equiv) using 5 mol%
Pd(dppf)2Cl2 as catalyst instead of Ni(dppp)Cl2. Crude mixture of II-78r and the monodeprocteced compound was used for the next step to give II-46r as a white solid (4.503
g, mp 135-137 ÂşC, 7.470 mmol) in 93% yield over two steps.
Spectral data for II-46q: Rf = 0.38 (DCM/hexanes 1:1). 1H NMR (500 MHz, CDCl3)
δ 1.22 – 1.38 (m, 2H), 1.40 – 1.66 (m, 8H), 1.75 – 1.83 (m, 2H), 1.89 (d, J =12.1 Hz, 4H),
2.02 (d, J = 12.1 Hz, 4H), 2.74 (tt, J = 12.0, 3.4 Hz, 2H), 5.79 (s, 2H), 6.56 – 6.65 (m, 4H),
6.94 (t, J = 7.7 Hz, 4H), 7.00 – 7.10 (m, 2H), 7.27 (s, 2H), 7.45 (dd, J = 8.5, 1.8 Hz, 2H),
7.71 (d, J = 8.4 Hz, 2H), 8.13 (d, J = 1.8 Hz, 2H).13C NMR (126 MHz, CDCl3) δ 26.20,
26.96, 34.42, 34.48, 44.95, 112.65, 119.46, 121.79, 122.94, 126.40, 127.42, 127.62,
127.75, 128.88, 133.23, 139.79, 140.37, 145.63, 150.04. HRMS (ESI–) m/z 603.3262
[calcd. for C44H43O2 (M–H): 603.3263].

338

4.3.8 Synthesis of 7,7’-Ad2VANOL (Scheme 2.27)
PhBr
Mg, Et2O,
0 ÂşC to reflux, 1 h
1.5 equiv PhMgBr

Br

Ph

DCM, reflux, overnight

II-92
50 mmol

II-93
91-96%
~80 g combined

1-phenyladamantane II-93: An oven-dried 250 mL round-bottomed flask equipped
with an egg-shaped stirring bar (30 mm × 15 mm) is placed under an N2 atmosphere
through a gas inlet. After cooling to 23 °C, bromobenzene (7.9 mL, 75 mmol) and Et2O
(75 mL) was added. The solution was cooled to 0 °C in an ice bath for 10 min. To the
round bottom flask magnesium (1.82 g, 75.0 mmol) was added and activated with 1 drop
of TMSCl under nitrogen. The reaction mixture was stirred at room temperature for 2 h.
After completion of the reaction, the Et2O solution of Grignard reagent was transferred to
another oven-dried 250 mL round-bottomed flask to remove the residual magnesium.
Et2O was removed in vacuo to give a solid. A solution of 1-bromoadamantane II-92 (9.832
g, 50.00 mmol) in CH2Cl2 (40 mL) was added to the solidified Grignard reagent diluted
with CH2Cl2 (60 mL) at room temperature under nitrogen, and then the mixture was
refluxed for 12 h. After cooling, the reaction system was carefully poured into 2 N HCl at
0ÂşC and the layers were separated. The aqueous layer was extracted with hexanes (100
mL x 3). The combined organic layer was washed with water and dried over anhydrous
Na2SO4. After filtration and evaporation, the residue was purified by column
chromatography (silica gel, hexanes) to give II-93 (9.615 g, 91%, 45.30 mmol, m.p. 7678 ÂşC) as a white solid.
339

Spectral data for II-93: Rf = 0.24 (hexanes); 1H NMR (500 MHz, CDCl3) δ 1.65 –
1.86 (m, 6H), 1.91 (d, J = 3.0 Hz, 6H), 2.01 – 2.13 (m, 3H), 7.12 – 7.20 (m, 1H), 7.25 –
7.40 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 28.95, 36.16, 36.80, 43.14, 124.83, 125.48,
128.07, 151.30. These spectral data match those previously reported for this
compound14.

Ph

II-93
87-100 mmol

CH3COCl (1.1 equiv)
AlCl3 (1.1 equiv),
CS2, –78 ºC to 0 ºC, 1 h
rt, 4 h

O

Ad

II-94
88-91%
~89 g crude (~90% purity)

4-adamantylacetophenone II-93: To a flame-dried 100 mL round bottom flask was
added AlCl3 (14.7 g, 110 mmol) and CS2 (30 mL). The solution was cooled to –78 °C for
10 min. To the stirred mixture at –78 °C was added a solution of 1-phenyladamantane II93 (21.23 g, 100.0 mmol), acetyl chloride (7.85 mL, 110 mmol) in CS2 (20 mL). The
reaction mixture was warmed up to 0 °C and maintained for 1 h, after which time the ice
bath was removed to stir at rt for 4 h. The mixture was poured into a mixture of ice (300
g) and 2 M H2SO4. The organic layer was separated and the aqueous layer was extracted
with EtOAc (50 mL x 3). The combined organic layer was washed with brine (100 mL),
dried over anhydrous Na2SO4. After filtration and evaporation, the residue was purified
by flash column chromatography (silica gel, hexanes/EtOAc 10:1) to give II-94 (22.70 g,
89%, 89.20 mmol, m.p. 97-100 ÂşC) as a white solid.
Spectral data for II-94: Rf = 0.52 (EtOAc/hexanes 1:10); 1H NMR (500 MHz, CDCl3)
δ 1.62 – 1.79 (m, 6H), 1.85 (d, J = 3.6 Hz, 6H), 2.04 (p, J = 3.0 Hz, 3H), 2.48 (s, 3H), 7.31

340

– 7.43 (m, 2H), 7.80 – 7.87 (m, 2H).

13

C NMR (126 MHz, CDCl3) δ 28.76, 31.57, 36.55,

36.58, 42.80, 124.97, 128.23, 134.58, 156.65, 197.37. These spectral data match those
previously reported for this compound15.
O

O

morpholine (3.8 equiv),
S (2.5 equiv),

N

S

Ad

II-94
88-167 mmol

145 ÂşC, 12 h

Ad

II-95
82% combined
~100 g

1-morpholino-2-(4-adamantylphenyl) ethane-1-thione II-95: To a flame-dried 250
mL round bottom flask was added 4-adamantylacetophenone II-93 (22.33 g, 87.80 mmol)
sulfur (7.04 g, 220 mmol) and morpholine (29.0 mL, 330 mmol). The mixtrure was heated
to 145 ÂşC for 12 h. After being cooled to rt, the mixture was refluxed with EtOH (50 mL)
for 1 h. The mixture was cooled to –20 ºC for 1 h then the precipitated solid was collected
by suction filtration and wash by EtOH. This crude II-95 (26.53 g, 85%, 74.60 mmol, m.p.
171-174 ÂşC) appeared pure by 1H NMR analysis and was used in the next step without
further purification.
Spectral data for II-95: Rf = 0.19 (EtOAc/hexanes 1:4); 1H NMR (500 MHz, CDCl3)
δ 1.78 (q, J = 10 Hz, 6H), 1.87 (d, J = 2.9 Hz, 6H), 2.07 (p, J = 3.2 Hz, 3H), 3.31 – 3.43
(m, 2H), 3.56 – 3.66 (m, 2H), 3.66 – 3.78 (m, 2H), 4.31 (s, 2H), 4.32 – 4.38 (m, 2H), 7.19
– 7.24 (m, 2H), 7.26 – 7.32 (m, 2H).

13

C NMR (126 MHz, CDCl3) δ 28.89, 35.98, 36.73,

43.14, 50.14, 50.19, 50.79, 66.11, 66.35, 125.41, 127.41, 132.59, 150.31, 200.31. HRMS
(ESI-TOF) m/z 356.2053 [calcd. for C18H26NO4 (M+H+): 356.2048].

341

O
N

HO

S

dioxane, 120 ÂşC,
overnight

II-95

O

HCl, AcOH,

Ad

Ad

II-44s
86% combined
~50 g

96 mmol, 107 mmol

2-(4-adamantylphenyl)acetic acid II-44s: To a flame-dried 500 mL round bottom
flask was added morpholinyl ethanethione II-95 (37.98 g, 106.8 mmol), dioxane (100 mL),
HCl (12 N, 50 mL) and acetic acid (25 mL). The resulting mixtrure was heated to reflux at
120 ÂşC for 12 h. After being cooled to rt, the solvent was evaporated. The mixture was
stirred with 1N HCl and cooled to 0 ÂşC for 1 h. The precipitated solid was collected by
suction filtration and wash by cold 1 N HCl followed by exposure to high vacuum
overnight. This crude product can be purified by recrystallization from EtOAc/hexanes
(1:3) to afford II-44s (24.71 g, 86% combined yield from 3 crops, 91.40 mmol, m.p. 186187 ÂşC) as a yellow solid.
Spectral data for II-44s: Rf = 0.21 (DCM); 1H NMR (500 MHz, CDCl3) δ 1.81 (q, J
= 10 Hz, 6H), 1.91 (d, J = 2.9 Hz, 6H), 2.01 – 2.20 (m, 3H), 3.63 (s, 2H), 7.20 – 7.30 (m,
2H), 7.31 – 7.36 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 28.91, 36.00, 36.76, 40.50, 43.13,
125.20, 129.05, 130.23, 150.47, 177.57. HRMS (ESI–) m/z 269.1544 [calcd. for C18H21O2
(M–H): 269.1542].

342

Ad

HO

1) (COCl2) (2.0 equiv),
cat. DMF, 0 ÂşC to rt, 1 h
then remove excess

O

HO

mineral oil, air,

2)

Ad

II-44s
100 mmol

Ph (1.3 equiv)
(i-PrCO)2O (2 equiv),
190 ÂşC, 48 h
3) KOH, H2O, 100 ÂşC,
overnight

Ph

195 ÂşC, 24 h
100 mmol

Ad

II-45s
52-54%
37.69 g

HO

Ph

HO

Ph

Ad

II-46s
94% (~98% pure)
33.25 g

7-adamantyl3-phenyl-1-naphthol II-45s: 1-naphthol II-45s was prepared from 2-(4adamantylphenyl)acetic acid II-44s (27.04 g, 100.0 mmol) by the General Procedure
H’.The crude product was purified by recrystallization from CH2Cl2/hexanes and column
chromatography (silica gel, DCM/hexanes: 1:3 to 1:1) to give II-45s as a white crystal in
54% combined isolated yield (19.13 g, mp 201-203 ÂşC, 53.90 mmol).
Spectral data for II-45s: Rf = 0.35 (DCM); 1H NMR (500 MHz, CDCl3) δ 1.69 – 1.87
(m, 6H), 2.03 (d, J = 2.8 Hz, 6H), 2.14 (p, J = 3.1 Hz, 3H), 5.31 (s, 1H), 7.06 (d, J = 1.5
Hz, 1H), 7.26 – 7.39 (m, 1H), 7.40 – 7.53 (m, 2H), 7.51 – 7.71 (m, 4H), 7.80 (d, J = 8.7
Hz, 1H), 8.03 (dd, J = 1.9, 0.9 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 28.96, 36.60, 36.84,
43.11, 108.23, 116.18, 118.35, 123.35, 125.16, 127.22, 127.26, 127.74, 128.77, 133.27,
138.08, 141.04, 148.52, 151.69. HRMS (ESI–) m/z 353.1917 [calcd. for C26H25O (M–H):
353.1905].
7,7’-Ad2VANOL II-46s: VANOL derivative II-46s was prepared from 7-adamantyl3phenyl-1-naphthol II-45s (35.45 g, 100.0 mmol) by the General Procedure I with heating
at 195 ÂşC for 24 h. The crude product was purified by recrystallization from
CH2Cl2/hexanes and column chromatography (silica gel, DCM/hexanes: 1:3 to 1:1) to

343

give II-46s as an off-white solid in 94% combined isolated yield (33.25 g, mp 360 ÂşC
(decomposed), 47.00 mmol).
Spectral data for II-46s: 1H NMR (500 MHz, CDCl3) δ 1.77 – 1.88 (m, 12H), 2.08
(d, J = 2.9 Hz, 12H), 2.09 – 2.25 (m, 6H), 5.83 (s, 2H), 6.52 – 6.70 (m, 4H), 6.94 (t, J =
7.7 Hz, 4H), 6.98 – 7.11 (m, 2H), 7.27 (s, 2H), 7.56 – 7.84 (m, 4H), 8.23 (d, J = 1.9 Hz,
2H).

13

C NMR (126 MHz, CDCl3) δ 28.98, 36.71, 36.85, 43.12, 112.61, 117.65, 121.61,

122.74, 125.76, 126.37, 127.41, 127.42, 128.89, 132.91, 139.97, 140.40, 148.80, 150.30.
HRMS (ESI–) m/z 705.3748 [calcd. for C52H49O2 (M–H): 705.3733].
4.3.9 General Procedure M for chiral resolution of VANOL derivatives with quinine
borates (Table 2.4) -- illustrated for resolution of (±)-5,5’-Br2VANOL rac-II-46c
Br

Ph
Ph

HO
HO

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

9.0 mL THF,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(S)-II-46c
45%, >99% ee
(R)-II-46c
69%, 72% ee

Br
rac-II-46c
2.0 mmol

(S)-5,5’-Br2VANOL (S)-II-46c: An oven-dried 100 mL round-bottomed flask
equipped with an egg-shaped stirring bar (30 mm × 15 mm) is placed under an N2
atmosphere through a gas inlet. After cooling to 23 °C, (±)-5,5’-Br2VANOL II-46c (1.192
g, 2.000 mmol) is added followed by addition of anhydrous tetrahydrofuran (10 mL) and
BH3•Me2S (1.10 mL, 2 M solution in toluene, 2.20 mmol, 1.10 equiv). An oven-dried reflux
condenser with an outlet connected to a bubbler is attached to the flask. The mixture is
stirred and refluxed in an 80 ÂşC oil bath for 30 min, and the evolution of gas ceases. After

344

cooling to rt (23 ÂşC), the clear solution is concentrated in vacuo using a rotary evaporator
(40 °C, 15 mmHg) and the residue is dried under high vacuum (60 °C, 0.2 mmHg) for 30
min. After cooling to 23 °C, anhydrous tetrahydrofuran (9 mL) is added followed by
addition of quinine (681 mg, 2.10 mmol, 1.05 equiv). The reflux condenser is reconnected
and the mixture is stirred and refluxed in an 80 ÂşC oil bath for overnight (12 h). The flask
containing reaction mixture is cooled to rt then to –20 ºC for 30 min before the solid is
collected by suction filtration, washed with ice-cold anhydrous tetrahydrofuran (9 mL).
The solid is transferred to a 100 mL round-bottomed flask and EtOAc (10 mL) is
added followed by addition of aq. HCl (10 mL, 2M) and an egg-shaped stirring bar (30
mm × 15 mm). The mixture was stirred for 30 min at rt before the organic layer is isolated
in a 60 mL separatory funnel. The water layer is extracted twice with EtOAc (15 mL×2),
and the combined organic layer is washed with brine (10 mL), dried over MgSO4 and
filtered. The water layer containing chloride salt of protonated quinine is transferred to a
clean container for recovery. The organic solution is concentrated in vacuo using a rotary
evaporator (40 °C, 15 mmHg). The residue is dissolved in a minimum amount of CH2Cl2
and loaded onto a silica gel column wet loaded with hexanes. The column is eluted with
a mixture of CH2Cl2 and hexanes (1:2) to afford (S)-5,5’-Br2VANOL (S)-II-46c as a white
solid (0.549 g, 0.921 mmol, 46%). The optical purity of (S)-II-46c is determined to be
>99% ee by HPLC analysis. (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254
nm, flow-rate: 1.0 mL/min). Retention times: Rt = 24.99 min for (R)-II-46c (minor) and Rt
= 27.43 min for (S)-II-46c (major). [α]20D = –148.7 (c 1.0, CH2Cl2) on >99% ee (S)-II-46c
(HPLC).

345

(R)-5,5’-Br2VANOL (R)-II-46c: The mother liquor is transferred to a 100 mL roundbottomed flask and concentrated in vacuo using a rotary evaporator (40 °C, 15 mmHg).
CH2Cl2 (15 mL) is added followed by addition of aq. HCl (15 mL, 2M) and an egg-shaped
stirring bar (30 mm × 15 mm). The mixture was stirred for 30 min at rt before the organic
layer is isolated in a 60 mL separatory funnel. The water layer is extracted twice with
CH2Cl2 (15 mL×2), and the combined organic layer is washed with brine (10 mL), dried
over MgSO4 and filtered. The water layer containing chloride salt of protonated quinine is
transferred to a clean container for recovery. The organic solution is concentrated in
vacuo using a rotary evaporator (40 °C, 15 mmHg). The residue was dissolved in a
minimum amount of CH2Cl2 and loaded onto a silica gel column wet loaded with hexanes.
The column is eluted with a mixture of CH2Cl2 and hexanes (1:2) to afford (R)-5,5’Br2VANOL (R)-II-46c as a white solid (825 mg, 1.38 mmol, 69%). The optical purity of
(R)-II-46c is determined to be 72% ee by HPLC analysis.
Cl

Ph
Ph

HO
HO

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

9.0 mL THF,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(S)-II-46d
45%, >99% ee
(R)-II-46d
69%, 72% ee

Cl
rac-II-46d
2.0 mmol

(S)-5,5’-Cl2VANOL (S)-II-46d: VANOL derivative (±)-II-46d (1.015 g, 2.000 mmol)
was resolved by the General Procedure M with 9 mL refluxing THF to afford (S)-5,5’Cl2VANOL (S)-II-46d as a white solid (452 mg, 0.890 mmol, 45%). The optical purity of
(S)-II-46d is determined to be >99% ee by HPLC analysis. (Pirkle D-Phenylglycine

346

column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 21.73
min for (R)-II-46d (minor) and Rt = 24.79 min for (S)-II-46d (major). [Îą]20D ND.
(R)-5,5’-Cl2VANOL (R)-II-46d: VANOL derivatives (R)-II-46d was obtained by
following General Procedure M. Its optical purity is determined to be 72% ee by HPLC
analysis.
Me

Ph
Ph

HO
HO

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

9.0 mL THF,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(S)-II-46e
44%, >99% ee
(R)-II-46e
54%, 76% ee

Me
rac-II-46e
2.0 mmol

(S)-5,5’-Me2VANOL (S)-II-46e: VANOL derivative (±)-II-46e (933.2 mg, 2.000
mmol) was resolved by the General Procedure M with 9 mL refluxing THF to afford (S)5,5’-Me2VANOL (S)-II-46e as a white solid (412 mg, 0.882 mmol, 44%). The optical purity
of (S)-II-46e is determined to be >99% ee by HPLC analysis. (Pirkle D-Phenylglycine
column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 17.28
min for (R)-II-46e (minor) and Rt = 20.72 min for (S)-II-46e (major). [Îą]20D ND
(R)-5,5’-Me2VANOL (R)-II-46e: VANOL derivatives (R)-II-46e was obtained by
following General Procedure M. Its optical purity is determined to be 76% ee by HPLC
analysis.

347

OMe

Ph
Ph

HO
HO

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

8 mL THF
/4 mL Hexanes,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(S)-II-46f
47%, >99% ee
(R)-II-46f
60%, 80% ee

OMe
rac-II-46f
2.0 mmol

(S)-5,5’-OMe2VANOL (S)-II-46f: VANOL derivative (±)-II-46f (997.2 mg, 2.000
mmol) was resolved by the General Procedure M refluxing with 8 mL THF and 4 mL
hexanes to afford (S)-5,5’-OMe2VANOL (S)-II-46f as a white solid (469 mg, 0.941 mmol,
47%). The optical purity of (S)-II-46f is determined to be >99% ee by HPLC analysis.
(Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min).
Retention times: Rt = 32.05 min for (R)-II-46f (minor) and Rt = 36.45 min for (S)-II-46f
(major). [α]20D = –178.6 (c 1.0, CH2Cl2) on >99% ee (S)-II-46f (HPLC).
(R)-5,5’-OMe2VANOL (R)-II-46f: VANOL derivatives (R)-II-46f was obtained by
following General Procedure M. Its optical purity is determined to be 80% ee by HPLC
analysis.
CF3

HO
HO

Ph
Ph

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

8 mL THF
/4 mL Hexanes,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(S)-II-46g
39%, >99% ee
(R)-II-46g
69%, 12% ee
(racemized)

CF3
rac-II-46g
8.0 mmol

(S)-5,5’-(CF3)2VANOL (S)-II-46g: VANOL derivative (±)-II-46g (1.149 g, 2.000
mmol) was resolved by the General Procedure M refluxing with 8 mL THF and 4 mL
348

hexanes to afford (S)-5,5’-(CF3)2VANOL (S)-II-46g as a white solid (0.449 g, 0.783 mmol,
39%). The optical purity of (S)-II-46g is determined to be >99% ee by HPLC analysis.
(Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min).
Retention times: Rt = 11.65 min for (R)-II-46g (minor) and Rt = 12.93 min for (S)-II-46g
(major). [Îą]20D ND
(R)-5,5’--(CF3)2VANOL (R)-II-46g: VANOL derivatives (R)-II-46g was obtained by
following General Procedure M. Its optical purity is determined to be 12% ee by HPLC
analysis.

Ph
Ph

HO
HO

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

6 mL THF,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(S)-II-46a
46%, >99% ee
(R)-II-46a
64%, 69% ee

rac-II-46a
2.0 mmol

(S)-VANOL (S)-II-46a: VANOL (Âą)-II-46a (877.0 mg, 2.000 mmol) was resolved by
the General Procedure M with 6 mL refluxing THF to afford (S)-VANOL (S)-II-46a as a
white solid (0.407 g, 0.928 mmol, 46%). The optical purity of (S)-II-46a is determined to
be >99% ee by HPLC analysis. (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at
254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 16.93 min for (R)-II-46a (minor) and
Rt = 19.70 min for (S)-II-46a (major). [α]20D = –310 (c 1.0, CH2Cl2) on >99% ee (S)-II-46a
(HPLC).
(R)-VANOL (R)-II-46a: VANOL derivatives (R)-II-46a was obtained by following
General Procedure M. Its optical purity is determined to be 69% ee by HPLC analysis.

349

tBu

Ph
Ph

OH
OH

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

8 mL THF,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(S)-II-46b
35%, >99% ee
(R)-II-46b
48%, 77% ee

tBu
rac-II-46b
2.0 mmol

(S)-tBuVANOL (S)-II-46b: VANOL derivative (Âą)-II-46b (1.102 g, 2.000 mmol) was
resolved by the General Procedure M with 8 mL refluxing THF to afford (S)-tBuVANOL
(S)-II-46b as a white solid (0.389 g, 0.706 mmol, 35%). The optical purity of (S)-II-46b is
determined to be >99% ee by HPLC analysis. (Pirkle D-Phenylglycine column, 98:2
hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 8.50 min for (R)II-46b (minor) and Rt = 9.50 min for (S)-II-46b (major). [α]20D = –210.9 (c 1.0, CH2Cl2) on
>99% ee (S)-II-46b (HPLC).
(R)-tBuVANOL (R)-II-46b: VANOL derivatives (R)-II-46b was obtained by following
General Procedure M. Its optical purity is determined to be 77% ee by HPLC analysis.
R

Ph
Ph

OH
OH

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

8 mL THF
/6 mL Hexanes,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(S)-II-46o
10%, >99% ee
(R)-II-46o
86%, 5% ee

R
rac-II-46o, R = n-hexyl
2.0 mmol

(S)-7,7’-hexyl2VANOL (S)-II-46o: VANOL derivative (±)-II-46o (1.214 g, 2.000
mmol) was resolved by the General Procedure M refluxing with 8 mL THF and 6 mL
hexanes to afford (S)- 7,7’-hexyl2VANOL (S)-II-46o as a white solid (0.130 g, 0.214 mmol,

350

10%). The optical purity of (S)-II-46o is determined to be >99% ee by HPLC analysis.
(Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min).
Retention times: Rt = 6.16 min for (R)-II-46o (minor) and Rt = 6.51 min for (S)-II-46o
(major).
(R)-7,7’-hexyl2VANOL (R)-II-46o: VANOL derivatives (R)-II-46o was obtained by
following General Procedure M. Its optical purity is determined to be 5% ee by HPLC
analysis.
R

Ph
Ph

OH
OH

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

6 mL THF
/6 mL Hexanes,
80 ÂşC, overnight

filter

wash by
solvent

HCl

(S)-II-46p
23%, >99% ee

mother HCl
liquor

(R)-II-46p
76%, 19% ee

R
rac-II-46p, R = isopentyl
2.0 mmol

(S)-7,7’-isopentyl2VANOL (S)-II-46p: VANOL derivative (±)-II-46p (1.158 g, 2.000
mmol) was resolved by the General Procedure M refluxing with 6 mL THF and 6 mL
hexanes to afford (S)-7,7’-isopentyl2VANOL (S)-II-46p as a white solid (0.268 g, 0.463
mmol, 23%). The optical purity of (S)-II-46p is determined to be >99% ee by HPLC
analysis. (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0
mL/min). Retention times: Rt = 6.75 min for (R)-II-46p (minor) and Rt = 7.25 min for (S)II-46p (major). [α]20D = –235.9 (c 1.0, CH2Cl2) on >99% ee (S)-II-46p (HPLC).
(R)-7,7’-isopentyl2VANOL (R)-II-46p: VANOL derivatives (R)-II-46p was obtained
by following General Procedure M. Its optical purity is determined to be 19% ee by HPLC
analysis.

351

R

Ph
Ph

OH
OH

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

6 mL THF
/6 mL Hexanes,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(S)-II-46q
0%
(R)-II-46p
NA

R
rac-II-46q, R = 3-phenylpropyl
2.0 mmol

(S)-7,7’-(3-phenylpropyl)2VANOL (S)-II-46q: No precipitate formed when VANOL
derivative (Âą)-II-46q (1.350 g, 2.000 mmol) was attempted to be resolved by the General
Procedure M refluxing with 6 mL THF and 6 mL hexanes.
Cy

Ph
Ph

OH
OH

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

8 mL THF,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(S)-II-46r
26%, >99% ee
(R)-II-46r
80%, 17% ee

Cy
rac-II-46r
2.0 mmol

(S)-7,7’-Cy2VANOL (S)-II-46r: VANOL derivative (±)-II-46r (1.206 g, 2.000 mmol)
was resolved by the General Procedure M with 8 mL refluxing THF to afford (S)-7,7’Cy2VANOL (S)-II-46r as a white solid (0.313 g, 0.519 mmol, 26%). The optical purity of
(S)-II-46r is determined to be >99% ee by HPLC analysis. (Pirkle D-Phenylglycine
column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 7.70
min for (R)-II-46r (minor) and Rt = 8.65 min for (S)-II-46r (major). [α]20D = –206.1 (c 1.0,
CH2Cl2) on >99% ee (S)-II-46r (HPLC).

352

(R)-7,7’-Cy2VANOL (R)-II-46r: VANOL derivatives (R)-II-46r was obtained by
following General Procedure M. Its optical purity is determined to be 17% ee by HPLC
analysis.
Ad

Ph
Ph

OH
OH

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

8 mL THF,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(S)-II-46s
33%, >99% ee
(R)-II-46s
68%, ee ND

Ad
rac-II-46s
2.0 mmol

(S)-7,7’-Ad2VANOL (S)-II-46s: VANOL derivative (±)-II-46s (1.414 g, 2.000 mmol)
was resolved by the General Procedure M with 8 mL refluxing THF to afford (S)-7,7’Ad2VANOL (S)-II-46s as a white solid (0.470 g, 0.665 mmol, 33%). The optical purity of
(S)-II-46s is determined to be >99% ee by HPLC analysis. (Pirkle D-Phenylglycine
column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 8.52
min for (R)-II-46s (minor) and Rt = 9.58 min for (S)-II-46s (major). [α]20D = –160.6 (c 1.0,
CH2Cl2) on >99% ee (S)-II-46s (HPLC).
(R)-7,7’-Ad2VANOL (R)-II-46s: VANOL derivatives (R)-II-46s was obtained by
following General Procedure M. Its optical purity was not determined due to overlapping
peaks.

353

Ar
Ar

OH
OH

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

6 mL THF
/6 mL Hexanes,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(S)-II-46k
36%, >99% ee
(R)-II-46k
69%, 60% ee

rac-II-46k, Ar = p-EtC6H4
2.0 mmol

(S)-3,3’-pEtPh2VANOL (S)-II-46k: VANOL derivative (±)-II-46k (989.3 mg, 2.000
mmol) was resolved by the General Procedure M refluxing with 6 mL THF and 6 mL
hexanes to afford (S)-3,3’-pEtPh2VANOL (S)-II-46k as a white solid (0.358 g, 0.724 mmol,
36%). The optical purity of (S)-II-46k is determined to be >99% ee by HPLC analysis.
(Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min).
Retention times: Rt = 14.83 min for (R)-II-46k (minor) and Rt = 16.42 min for (S)-II-46k
(major).
(R)-3,3’-pEtPh2VANOL (R)-II-46k: VANOL derivatives (R)-II-46k was obtained by
following General Procedure M. Its optical purity is determined to be 60% ee by HPLC
analysis.

Ar
Ar

OH
OH

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

6 mL THF
/6 mL Hexanes,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(S)-II-46l
34%, >99% ee
(R)-II-46l
50%, 59% ee

rac-II-46l, Ar = p-MeOC6H4
2.0 mmol

(S)-3,3’-pOMePh2VANOL (S)-II-46l: VANOL derivative (±)-II-46l (997.2 mg, 2.000
mmol) was resolved by the General Procedure M refluxing with 6 mL THF and 6 mL

354

hexanes to afford (S)-3,3’-pOMePh2VANOL (S)-II-46l as a white solid (0.342 g, 0.686
mmol, 34%). The optical purity of (S)-II-46l is determined to be >99% ee by HPLC
analysis. (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0
mL/min). Retention times: Rt = 6.31 min for (R)-II-46l (minor) and Rt = 7.02 min for (S)-II46l (major). [Îą]20D ND.
(R)-3,3’-pOMePh2VANOL (R)-II-46l: VANOL derivatives (R)-II-46l was obtained by
following General Procedure M. Its optical purity is determined to be 59% ee by HPLC
analysis.

Ar
Ar

OH
OH

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

6 mL THF
/8 mL Hexanes,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(S)-II-46m
17%, >99% ee
(R)-II-46m
79%, 24% ee

rac-II-46m, Ar = p-BuC6H4
2.0 mmol

(S)-3,3’-pOMePh2VANOL (S)-II-46m: VANOL derivative (±)-II-46m (1.101 g, 2.000
mmol) was resolved by the General Procedure M with refluxing with 6 mL THF and 8 mL
hexanes to afford (S)-3,3’-pOMePh2VANOL (S)-II-46m as a white solid (191 mg, 0.346
mmol, 17%). The optical purity of (S)-II-46m is determined to be >99% ee by HPLC
analysis. (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0
mL/min). Retention times: Rt = 13.01 min for (R)-II-46m (minor) and Rt = 15.06 min for
(S)-II-46m (major). [Îą]20D ND.

355

(S)-3,3’-pOMePh2VANOL (S)-II-46m: VANOL derivatives (R)-II-46m was obtained
by following General Procedure M. Its optical purity is determined to be 24% ee by HPLC
analysis.

Cy

OH

Cy

OH

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

6 mL THF
/12 mL Hexanes,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(S)-II-46t
3%, 10% ee
(R)-II-46t
NA

rac-II-46t
2.0 mmol

(S)-3,3’-Cy2VANOL (S)-II-46t: VANOL derivative (±)-II-46t (901.2 mg, 2.000 mmol)
was resolved by the General Procedure M with refluxing with 6 mL THF and 12 mL
hexanes to afford (S)-3,3’-Cy2VANOL (S)-II-46t as a white foamy solid (27 mg, 0.060
mmol, 3%). The optical purity of (S)-II-46t is determined to be 10% ee by HPLC analysis.
(Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min).
Retention times: Rt = 8.36 min for (R)-II-46t (minor) and Rt = 9.16 min for (S)-II-46t
(major).
Br

Ph
Ph

OH
OH

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

6 mL THF,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(S)-II-46n
46%, 0% ee
(R)-II-46n
N/A

Br
rac-II-46n
2.0 mmol

(S)-7,7’-Br2VANOL (S)-II-46n: VANOL derivative (±)-II-46n (1.192 g, 2.000 mmol)
was attempted to be resolved by the General Procedure M with 6 mL refluxing THF to

356

afford (±)-7,7’-Br2VANOL (S)-II-46n as a white solid (0.549 g, 0.921 mmol, 46%). The
optical purity of (S)-II-46n is determined to be 1% ee by HPLC analysis. (Pirkle DPhenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention
times: Rt = 26.90 min for (R)-II-46n and Rt = 31.17 min for (S)-II-46n.

Ph
Ph

OH
OH

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

6 mL THF,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(S)-II-96
44%, >99% ee
(R)-II-96
56%, 68% ee

rac-II-96
2.0 mmol

(S)-VAPOL (S)-II-96: VAPOL (Âą)-II-96 (1.077 g, 2.000 mmol) was resolved by the
General Procedure M with 6 mL refluxing THF to afford (S)-VAPOL (S)-II-96 as a white
solid (476 mg, 0.884 mmol, 44%). The optical purity of (S)-II-96 is determined to be >99%
ee by HPLC analysis. (Pirkle D-Phenylglycine column, 75:25 hexane/iPrOH at 254 nm,
flow-rate: 1.0 mL/min). Retention times: Rt = 14.69 min for (R)-II-96 (minor) and Rt = 21.96
min for (S)-II-96 (major). [Îą]20D ND.
(R)-VAPOL (R)-II-96: VANOL derivatives (R)-II-96 was obtained by following
General Procedure M. Its optical purity is determined to be 68% ee by HPLC analysis.

357

Ph
Ph

OH
OH

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

8 mL THF
/4 mL Hexanes,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(S)-II-97
33%, >99% ee
(R)-II-97
68%, 45% ee

rac-II-97
2.0 mmol

(S)-isoVAPOL (S)-II-97: isoVAPOL (Âą)-II-97 (1.077 g, 2.000 mmol) was resolved
by the General Procedure M with 6 mL refluxing THF to afford (S)-isoVAPOL (S)-II-97 as
a white solid (359 mg, 0.666 mmol, 33%). The optical purity of (S)-II-97 is determined to
be >99% ee by HPLC analysis. (Pirkle D-Phenylglycine column, 75:25 hexane/iPrOH at
254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 17.69 min for (R)-II-97 (minor) and
Rt = 21.68 min for (S)-II-97 (major). [Îą]20D ND.
(R)-isoVAPOL (R)-II-97: VANOL derivatives (R)-II-97 was obtained by following
General Procedure M. Its optical purity is determined to be 45% ee by HPLC analysis.

OH
OH

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

5 mL THF,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(S)-II-11
46%, 91% ee
(R)-II-11
47%, 85% ee

rac-II-11
2.0 mmol

(S)-BINOL (S)-II-11: BINOL (Âą)-II-11 (572.7 g, 2.000 mmol) was resolved by the
General Procedure M with 5 mL refluxing THF to afford (S)-BINOL (S)-II-11 as a white
solid (264 mg, 0.461 mmol, 46%). The optical purity of (S)-II-11 is determined to be 91%
ee by HPLC analysis. (Pirkle D-Phenylglycine column, 75:25 hexane/iPrOH at 254 nm,

358

flow-rate: 1.0 mL/min). Retention times: Rt = 3.70 min for (R)-II-11 (minor) and Rt = 3.12
min for (S)-II-11 (major). [Îą]20D ND.
(R)-BINOL (R)-II-11: VANOL derivatives (R)-II-11 was obtained by following
General Procedure M. Its optical purity is determined to be 85% ee by HPLC analysis.
Br
OH
OH

1.1 equiv BH3•Me2S,

1.05 equiv quinine,

THF, 80 ÂşC, 0.5 h
then remove volatile

6 mL THF
/12 mL Hexanes,
80 ÂşC, overnight

Br

HCl

solid
filter

wash by
solvent

(S)-II-39
0%

mother HCl
liquor

(R)-II-39
N/A

rac-II-39
2.0 mmol

(S)-6,6’-Br2BINOL (S)-II-39: No precipitate formed when BINOL derivative (±)-II39 (888.2 mg, 2.000 mmol) was attempted to be resolved by the General Procedure M
refluxing with 6 mL THF and 12 mL hexanes.
4.3.10 General Procedure N for chiral resolution of VANOL derivatives with quinidine
borates (Table 2.5) -- illustrated for resolution of (±)-5,5’-Br2VANOL rac-II-46c
Br

Ph
Ph

HO
HO

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinidine,

THF, 80 ÂşC, 0.5 h
then remove volatile

8 mL THF,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(R)-II-46c
32%, >99% ee
(S)-II-46c
65%, 84% ee

Br
rac-II-46c
2.0 mmol

(R)-5,5’-Br2VANOL (R)-II-46c: An oven-dried 100 mL round-bottomed flask
equipped with an egg-shaped stirring bar (30 mm × 15 mm) is placed under an N2
atmosphere through a gas inlet. After cooling to 23 °C, (¹)-Br2VANOL II-46c (1.192 g,
2.000 mmol) is added followed by addition of anhydrous tetrahydrofuran (10 mL) and

359

BH3•Me2S (1.10 mL, 2 M solution in toluene, 2.20 mmol, 1.10 equiv). An oven-dried reflux
condenser with an outlet connected to a bubbler is attached to the flask. The mixture is
stirred and refluxed in an 80 ÂşC oil bath for 30 min, and the evolution of gas ceases. After
cooling to rt (23 ÂşC), the clear solution is concentrated in vacuo using a rotary evaporator
(40 °C, 15 mmHg) and the residue is dried under high vacuum (60 °C, 0.2 mmHg) for 30
min. After cooling to 23 °C, anhydrous tetrahydrofuran (8 mL) is added followed by
addition of quinidine (681 mg, 2.10 mmol, 1.05 equiv). The reflux condenser is
reconnected and the mixture is stirred and refluxed in an 80 ÂşC oil bath for overnight (12
h). The flask containing reaction mixture is cooled to rt then to –20 ºC for 30 min before
the solid is collected by suction filtration, washed with ice-cold anhydrous tetrahydrofuran
(8 mL).
The solid is transferred to a 100 mL round-bottomed flask and EtOAc (10 mL) is
added followed by addition of aq. HCl (10 mL, 2M) and an egg-shaped stirring bar (30
mm × 15 mm). The mixture was stirred for 30 min at rt before the organic layer is isolated
in a 60 mL separatory funnel. The water layer is extracted twice with EtOAc (15 mL×2),
and the combined organic layer is washed with brine (10 mL), dried over MgSO4 and
filtered. The water layer containing chloride salt of protonated quinine is transferred to a
clean container for recovery. The organic solution is concentrated in vacuo using a rotary
evaporator (40 °C, 15 mmHg). The residue is dissolved in a minimum amount of CH2Cl2
and loaded onto a silica gel column wet loaded with hexanes. The column is eluted with
a mixture of CH2Cl2 and hexanes (1:2) to afford (R)-5,5’-Br2VANOL (S)-II-46c as a white
solid (386 mg, 0.648 mmol, 32%). The optical purity of (R)-II-46c is determined to be

360

>99% ee by HPLC analysis. (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254
nm, flow-rate: 1.0 mL/min). Retention times: Rt = 24.99 min for (R)-II-46c (major) and Rt
= 27.43 min for (S)-II-46c (minor). [α]20D = –148.7 (c 1.0, CH2Cl2) on >99% ee (S)-II-46c
(HPLC).
(S)-5,5’-Br2VANOL (R)-II-46c: The mother liquor is transferred to a 100 mL roundbottomed flask and concentrated in vacuo using a rotary evaporator (40 °C, 15 mmHg).
CH2Cl2 (15 mL) is added followed by addition of aq. HCl (15 mL, 2 M) and an egg-shaped
stirring bar (30 mm × 15 mm). The mixture was stirred for 30 min at rt before the organic
layer is isolated in a 60 mL separatory funnel. The water layer is extracted twice with
CH2Cl2 (15 mL	×	2), and the combined organic layer is washed with brine (10 mL), dried
over MgSO4 and filtered. The water layer containing chloride salt of protonated quinine is
transferred to a clean container for recovery. The organic solution is concentrated in
vacuo using a rotary evaporator (40 °C, 15 mmHg). The residue was dissolved in a
minimum amount of CH2Cl2 and loaded onto a silica gel column wet loaded with hexanes.
The column is eluted with a mixture of CH2Cl2 and hexanes (1:2) to afford (S)-5,5’Br2VANOL (S)-II-46c as a white solid (775 mg, 1.30 mmol, 65%). The optical purity of (S)II-46c is determined to be 84% ee by HPLC analysis.

361

Cl

Ph
Ph

HO
HO

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinidine,

THF, 80 ÂşC, 0.5 h
then remove volatile

8 mL THF,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(R)-II-46d
41%, >99% ee
(S)-II-46d
55%, 84% ee

Cl
rac-II-46d
2.0 mmol

(R)-5,5’-Cl2VANOL (S)-II-46d: VANOL derivative (±)-II-46d (1.015 g, 2.000 mmol)
was resolved by the General Procedure N with 8 mL refluxing THF to afford (R)-5,5’Cl2VANOL (R)-II-46d as a white solid (416 mg, 0.820 mmol, 41%). The optical purity of
(S)-II-46d is determined to be >99% ee by HPLC analysis. (Pirkle D-Phenylglycine
column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 21.73
min for (R)-II-46d (major) and Rt = 24.79 min for (S)-II-46d (minor). [Îą]20D = +178.3 (c 1.0,
CH2Cl2) on >99% ee (R)-II-46d (HPLC).
(S)-5,5’-Cl2VANOL (S)-II-46d: VANOL derivatives (S)-II-46d was obtained by
following General Procedure N. Its optical purity is determined to be 84% ee by HPLC
analysis.
Me

HO
HO

Ph
Ph

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinidine,

THF, 80 ÂşC, 0.5 h
then remove volatile

8 mL THF
/4 mL Hexanes,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(R)-II-46e
39%, >99% ee
(S)-II-46e
60%, 71% ee

Me
rac-II-46e
2.0 mmol

(R)-5,5’-Me2VANOL (R)-II-46e: VANOL derivative (±)-II-46e (933.2 mg, 2.000
mmol) was resolved by the General Procedure N refluxing with 8 mL THF and 4 mL
362

hexanes to afford (R)-5,5’-Me2VANOL (R)-II-46e as a white solid (364 mg, 0.781 mmol,
39%). The optical purity of (R)-II-46e is determined to be >99% ee by HPLC analysis.
(Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min).
Retention times: Rt = 17.28 min for (R)-II-46e (major) and Rt = 20.72 min for (S)-II-46e
(minor). [Îą]20D = +105.2 (c 1.0, CH2Cl2) on >99% ee (R)-II-46e (HPLC).
(S)-5,5’-Me2VANOL (S)-II-46e: VANOL derivatives (R)-II-46e was obtained by
following General Procedure N. Its optical purity is determined to be 76% ee by HPLC
analysis.
OMe

HO
HO

Ph
Ph

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinidine,

THF, 80 ÂşC, 0.5 h
then remove volatile

8 mL THF
/4 mL Hexanes,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(R)-II-46f
46%, >99% ee
(S)-II-46f
63%, 81% ee

OMe
rac-II-46f
2.0 mmol

(R)-5,5’-OMe2VANOL (R)-II-46f: VANOL derivative (±)-II-46f (997.2 mg, 2.000
mmol) was resolved by the General Procedure N refluxing with 8 mL THF and 4 mL
hexanes to afford (R)-5,5’-OMe2VANOL (R)-II-46f as a white solid (463 mg, 0.928 mmol,
46%). The optical purity of (S)-II-46f is determined to be >99% ee by HPLC analysis.
(Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min).
Retention times: Rt = 32.05 min for (R)-II-46f (major) and Rt = 36.45 min for (S)-II-46f
(minor). [Îą]20D ND.

363

(S)-5,5’-OMe2VANOL (S)-II-46f: VANOL derivatives (S)-II-46f was obtained by
following General Procedure N. Its optical purity is determined to be 81% ee by HPLC
analysis.
CF3

Ph
Ph

HO
HO

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinidine,

THF, 80 ÂşC, 0.5 h
then remove volatile

8 mL THF
/4 mL Hexanes,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(R)-II-46g
13%, >99% ee
(S)-II-46g
87%, 16% ee

CF3
rac-II-46g
2.0 mmol

(R)-5,5’-(CF3)2VANOL (R)-II-46g: VANOL derivative (±)-II-46g (1.149 g, 2.000
mmol) was resolved by the General Procedure N refluxing with 8 mL THF and 4 mL
hexanes to afford (R)-5,5’-(CF3)2VANOL (R)-II-46g as a white solid (0.152 g, 0.264 mmol,
13%). The optical purity of (R)-II-46g is determined to be >99% ee by HPLC analysis.
(Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min).
Retention times: Rt = 11.65 min for (R)-II-46g (major) and Rt = 12.93 min for (S)-II-46g
(minor). [Îą]20D = +163.4 (c 1.0, CH2Cl2) on >99% ee (R)-II-46g (HPLC).
(S)-5,5’--(CF3)2VANOL (R)-II-46g: VANOL derivatives (S)-II-46g was obtained by
following General Procedure N. Its optical purity is determined to be 16% ee by HPLC
analysis.

364

HO
HO

Ph
Ph

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinidine,

THF, 80 ÂşC, 0.5 h
then remove volatile

8 mL THF
/8 mL Hexanes,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(R)-II-46a
31%, 70% ee
(S)-II-46a
71%, 25% ee

rac-II-46a
2.0 mmol

(R)-VANOL (R)-II-46a: VANOL (Âą)-II-46a (877.0 mg, 2.000 mmol) was resolved by
the General Procedure N refluxing with 8 mL THF and 8 mL hexanes to afford (R)-VANOL
(S)-II-46a as a white solid (0.274 g, 0.624 mmol, 31%). The optical purity of (R)-II-46a is
determined to be 70% ee by HPLC analysis. (Pirkle D-Phenylglycine column, 98:2
hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 16.93 min for (R)II-46a (major) and Rt = 19.70 min for (S)-II-46a (minor). [Îą]20D ND.
(S)-VANOL (S)-II-46a: VANOL derivatives (S)-II-46a was obtained by following
General Procedure N. Its optical purity is determined to be 25% ee by HPLC analysis.
Br

Ph
Ph

OH
OH

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinidine,

THF, 80 ÂşC, 0.5 h
then remove volatile

6 mL THF,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(R)-II-46n
52%, 0% ee
(S)-II-46n
N/A

Br
rac-II-46n
2.0 mmol

(S)-7,7’-Br2VANOL (S)-II-46n: VANOL derivative (±)-II-46n (1.192 g, 2.000 mmol)
was attempted to be resolved by the General Procedure N with 6 mL refluxing THF to
afford (±)-7,7’-Br2VANOL (±)-II-46n as a white solid (0.621 g, 1.042 mmol, 52%). The
optical purity of (S)-II-46n is determined to be 0% ee by HPLC analysis. (Pirkle D-

365

Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention
times: Rt = 26.90 min for (R)-II-46n and Rt = 31.17 min for (S)-II-46n

Ar
Ar

OH
OH

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinidine,

THF, 80 ÂşC, 0.5 h
then remove volatile

13 mL THF
/13 mL Hexanes,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(R)-II-46l
76%, >99% ee
(S)-II-46l
18%, 89% ee

(R)-II-46l, 79% ee,
Ar = p-MeOC6H4
4.17 mmol

(R)-3,3’-pOMePh2VANOL (R)-II-46l: VANOL derivative (R)-II-46l (2.079 g, 4.170
mmol, 79% ee) was resolved by the General Procedure N refluxing with 13 mL THF and
13 mL hexanes to afford (R)-3,3’-pOMePh2VANOL (S)-II-46l as a white solid (1.585 g,
3.178 mmol, 76%). The optical purity of (S)-II-46l is determined to be >99% ee by HPLC
analysis. (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0
mL/min). Retention times: Rt = 6.31 min for (R)-II-46l (major) and Rt = 7.02 min for (S)-II46l (minor). [Îą]20D = +271.3 (c 1.0, CH2Cl2) on >99% ee (R)-II-46l (HPLC).
(R)-3,3’-pOMePh2VANOL (R)-II-46l: VANOL derivatives (R)-II-46l was obtained by
following General Procedure N. Its optical purity is determined to be 89% ee by HPLC
analysis.

366

Ph
Ph

OH
OH

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinidine,

THF, 80 ÂşC, 0.5 h
then remove volatile

6 mL THF,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(R)-II-96
28%,
% ee
(S)-II-96
68%, 31% ee

rac-II-96
2.0 mmol

(R)-VAPOL (R)-II-96: VAPOL (Âą)-II-96 (1.077 g, 2.000 mmol) was resolved by the
General Procedure N with 6 mL refluxing THF to afford (R)-VAPOL (R)-II-96 as a white
solid (302 mg, 0.560 mmol, 28%). The optical purity of (R)-II-96 is determined to be >99%
ee by HPLC analysis. (Pirkle D-Phenylglycine column, 75:25 hexane/iPrOH at 254 nm,
flow-rate: 1.0 mL/min). Retention times: Rt = 14.69 min for (R)-II-96 (major) and Rt = 21.96
min for (S)-II-96 (minor). [Îą]20D ND.
(S)-VAPOL (S)-II-96: VANOL derivatives (S)-II-96 was obtained by following
General Procedure N. Its optical purity is determined to be 31% ee by HPLC analysis.

Ph
Ph

OH
OH

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinidine,

THF, 80 ÂşC, 0.5 h
then remove volatile

7 mL THF
/3 mL Hexanes,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(R)-II-97
26%, >99% ee
(S)-II-97
70%, 35% ee

rac-II-97
2.0 mmol

(R)-isoVAPOL (R)-II-97: isoVAPOL (Âą)-II-97 (1.077 g, 2.000 mmol) was resolved
by the General Procedure N refluxing with 7 mL THF and 3 mL hexanes to afford (R)isoVAPOL (R)-II-97 as a white solid (284 mg, 0.528 mmol, 26%). The optical purity of (R)-

367

II-97 is determined to be >99% ee by HPLC analysis. (Pirkle D-Phenylglycine column,
75:25 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 17.69 min
for (R)-II-97 (major) and Rt = 21.68 min for (S)-II-97 (minor). [Îą]20D ND.
(S)-isoVAPOL (S)-II-97: VANOL derivatives (S)-II-97 was obtained by following
General Procedure N. Its optical purity is determined to be 35% ee by HPLC analysis.

OH

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinidine,

THF, 80 ÂşC, 0.5 h
then remove volatile

5 mL THF,
80 ÂşC, overnight

OH

filter

wash by
solvent

HCl

mother HCl
liquor

(R)-II-11
39%, 94% ee
(S)-II-11
61%, 57% ee

rac-II-11
2.0 mmol

(R)-BINOL (R)-II-11: BINOL (Âą)-II-11 (572.7 g, 2.000 mmol) was resolved by the
General Procedure N with 5 mL refluxing THF to afford (R)-BINOL (R)-II-11 as a white
solid (225 mg, 0.786 mmol, 39%). The optical purity of (S)-II-11 is determined to be 94%
ee by HPLC analysis. (Pirkle D-Phenylglycine column, 75:25 hexane/iPrOH at 254 nm,
flow-rate: 1.0 mL/min). Retention times: Rt = 3.70 min for (R)-II-11 (major) and Rt = 3.12
min for (S)-II-11 (minor). [α]20D = –6.0 (c 1.0, CH2Cl2) on 94% ee (R)-II-11 (HPLC).
(S)-BINOL (S)-II-11: VANOL derivatives (S)-II-11 was obtained by following
General Procedure N. Its optical purity is determined to be 57% ee by HPLC analysis.
Br
OH
OH

Br

solid

1.1 equiv BH3•Me2S,

1.05 equiv quinidine,

THF, 80 ÂşC, 0.5 h
then remove volatile

6 mL THF
/3 mL Hexanes,
80 ÂşC, overnight

filter

wash by
solvent

HCl

mother HCl
liquor

(R)-II-39
48%, >99% ee
(S)-II-39
55%, 88% ee

rac-II-39
2.0 mmol

(R)-6,6’-Br2BINOL (R)-II-39: BINOL (±)-II-39 (888.2 mg, 2.000 mmol) was
resolved by the General Procedure N refluxing with 6 mL THF and 3 mL hexanes to afford
368

(R)-BINOL (R)-II-39 as a white solid (427 mg, 0.962 mmol, 48%). The optical purity of
(R)-II-39 is determined to be >99% ee by HPLC analysis. (Pirkle D-Phenylglycine column,
75:25 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 2.832 min
for (R)-II-39 (major) and Rt = 3.31 min for (S)-II-39 (minor). [Îą]20D = +129.6 (c 1.0, CH2Cl2)
on >99% ee (R)-II-39 (HPLC).
(S)-BINOL (S)-II-39: VANOL derivatives (S)-II-39 was obtained by following
General Procedure N. Its optical purity is determined to be 88% ee by HPLC analysis.
4.3.11 Crystallization-induced dynamic resolution of VANOL (Table 2.7)

Ph
Ph

OH
OH

1.05 equiv BH3•Me2S,

1.05 equiv quinine,
5 mol% Cu-TMEDA

filter

THF, 80 ÂşC, 0.5 h
then remove volatile

5 mL THF, 60 ÂşC,
2h

then HCl

(R)-II-46a,
>99% ee, 1 mmol

Ph
Ph

OH
OH

(S)-II-46a
56%, >99% ee

(S)-VANOL (S)-II-46a: An oven-dried 100 mL round-bottomed flask equipped with
an egg-shaped stirring bar (30 mm × 15 mm) is placed under an N2 atmosphere through
a gas inlet. After cooling to 23 °C, (R)-VANOL (438 mg, 1.00 mmol) is added followed by
addition of anhydrous tetrahydrofuran (5 mL) and BH3•Me2S (0.550 mL, 2 M solution in
toluene, 1.10 mmol, 1.10 equiv). An oven-dried reflux condenser with an outlet connected
to a bubbler is attached to the flask. The mixture is stirred and refluxed in an 80 ÂşC oil
bath for 30 min, and the evolution of gas ceases. After cooling to rt (23 ÂşC), the clear
solution is concentrated in vacuo using a rotary evaporator (40 °C, 15 mmHg) and the
residue is dried under high vacuum (60 °C, 0.2 mmHg) for 30 min. After cooling to 23 °C,
369

anhydrous tetrahydrofuran (5 mL) is added followed by addition of quinine (681 mg, 2.10
mmol, 1.05 equiv) and Cu-TMEDA (11.6 mg, 0.0500 mmol). The reflux condenser is
reconnected and the mixture is stirred and refluxed in an 80 ÂşC oil bath for 2 h. The flask
containing reaction mixture is cooled to rt then to –20 ºC for 30 min before the solid is
collected by suction filtration, washed with ice-cold anhydrous tetrahydrofuran (5 mL).
The solid is transferred to a 100 mL round-bottomed flask and EtOAc (10 mL) is
added followed by addition of aq. HCl (5 mL, 2 M) and an egg-shaped stirring bar (30 mm
× 15 mm). The mixture was stirred for 30 min at rt before the organic layer is isolated in
a 60 mL separatory funnel. The water layer is extracted twice with EtOAc (15 mL	×	2),
and the combined organic layer is washed with brine (10 mL), dried over MgSO4 and
filtered. The water layer containing chloride salt of protonated quinine is transferred to a
clean container for recovery. The organic solution is concentrated in vacuo using a rotary
evaporator (40 °C, 15 mmHg). The residue is dissolved in a minimum amount of DCM
and loaded onto a silica gel column wet loaded with hexanes. The column is eluted with
a mixture of DCM and hexanes (1:2) to afford (S)-VANOL (S)-II-46a as a white solid (246
mg, 0.561 mmol, 56%). The optical purity of (S)-II-46a is determined to be >99% ee by
HPLC analysis. (Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate:
1.0 mL/min). Retention times: Rt = 16.93 min for (R)-II-46a (minor) and Rt = 19.70 min for
(S)-II-46a (major).
The mother liquor is transferred to a 100 mL round-bottomed flask and
concentrated in vacuo using a rotary evaporator (40 °C, 15 mmHg). DCM (15 mL) is
added followed by addition of aq. HCl (15 mL, 2 M) and an egg-shaped stirring bar (30

370

mm × 15 mm). The mixture was stirred for 30 min at rt before the organic layer is isolated
in a 60 mL separatory funnel. The water layer is extracted twice with DCM (15 mL ×	2),
and the combined organic layer is washed with brine (10 mL), dried over MgSO4 and
filtered. The organic solution is concentrated in vacuo using a rotary evaporator (40 °C,
15 mmHg). The residue was dissolved in a minimum amount of DCM and loaded onto a
silica gel column wet loaded with hexanes. The column is eluted with a mixture of DCM
and hexanes (1:2) to afford (S)-VANOL (S)-II-46a as a white solid (159 mg, 0.364 mmol,
36%). The optical purity of (S)-II-46a is determined to be 21% ee by HPLC analysis.
4.3.12 Computational Model of VANOL borates with quinine/quinidine
(R)-VANOL-quinine-borate complex at the B3LYP/6-31G(d) level8

scf done: -2442.816507
C 2.124868 2.971184
C 3.215709 3.454013
C 2.667002 0.659543
C 3.949871 2.533096
C 1.875335 1.569656
C 3.695592 1.174461
C 1.179457 -1.347277

C
C
C
C
C
H
H
C

-0.733922
0.049962
-0.048817
0.837427
-0.731144
0.823345
-0.090998
371

2.445370
2.032563
3.525679
0.928362
3.300362
4.108770
4.706549
1.810162

-0.803701
-3.621709
-1.693968
-2.749944
-3.056389
-3.721007
2.921465
-5.024100

-0.250095
-0.343681
-0.604134
-0.100023
-0.624473
-0.915965
1.513232
-0.348128

H
C
H
H
C
H
C
C
H
C
H
H
C
H
C
C
C
H
H
C
C
H
C
H
H
C
C
C
H
C
H
C
H
H
C
H
C
O
O
C
C
N
C
C

2.652308
-0.357466
-1.195820
-1.525538
-0.536818
0.397770
0.554841
1.344518
0.523265
3.488343
4.315414
1.045106
1.641969
2.943151
2.721836
4.860395
6.037113
5.969799
8.182503
7.285310
4.974071
4.077121
6.222325
6.285368
8.356213
7.383721
4.436504
5.820333
6.362128
3.762354
2.689944
6.508093
7.580292
3.906710
4.450204
6.360645
5.825812
0.065819
0.774003
-2.620464
-3.209988
-4.337285
-4.059906
-2.966027

-5.684309
-3.305591
-2.645002
-5.084850
-4.671603
-6.614713
-5.539429
3.886690
3.504640
4.847850
5.216515
5.927417
5.232177
6.781311
5.717414
-1.204207
-1.816812
-2.584025
-1.913345
-1.429786
-0.191636
0.280329
0.197493
0.978844
-0.116135
-0.419390
0.317229
0.478316
1.164503
-0.602277
-0.730014
-0.254283
-0.118104
-2.037890
-1.336735
-1.739229
-1.166427
-0.546339
1.147199
0.335078
-0.677782
-2.536727
-1.731616
-0.608502

-0.541092
0.130284
0.315147
0.305318
0.126633
-0.119055
-0.114873
-1.487701
-2.083602
0.052492
0.654486
-2.052052
-1.468018
-0.682926
-0.691128
-1.053736
-0.592089
0.173703
-0.699760
-1.077612
-2.020754
-2.408743
-2.504946
-3.257854
-2.414731
-2.035832
1.791924
1.972281
1.327942
2.612783
2.505723
2.938464
3.053996
4.205847
3.577898
4.498522
3.745455
0.111769
-1.460222
-0.278311
-1.246452
-3.085515
-0.769993
-2.599640

C
C
C
C
C
C
O
C
C
N
O
C
C
C
C
C
C
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C
H
C
H
H
B

372

-3.552408
-4.593500
-4.388842
-5.210482
-5.737067
-5.429138
-5.462868
-6.302697
-3.674083
-3.416095
-1.479351
-2.267959
-2.474468
-3.858351
-3.873398
-4.616140
-4.931468
-2.301928
-2.321663
-3.353934
-4.018122
-6.379860
-5.819235
-6.360430
-7.312306
-5.883050
-4.613312
-2.162493
-1.359890
-2.417052
-1.692704
-4.048943
-4.812265
-3.066666
-5.459550
-4.461090
-4.792444
-6.346199
-6.653742
-7.237044
-8.250180
-6.986172
-0.213361

-1.556498
-2.636515
-1.926234
-2.971979
-3.867626
-3.693939
-3.065444
-4.109599
1.397157
1.924127
0.975875
2.853108
4.047701
3.889448
2.553377
2.658947
3.895603
-0.174168
0.165982
-1.488444
-1.262318
-4.687419
-4.365687
-3.980279
-4.040568
-5.099504
0.842503
3.201756
2.296364
5.006494
4.058373
4.720176
2.424438
2.562403
1.958382
2.983890
4.819741
3.884370
2.994163
4.860239
4.794319
5.765391
0.504782

-3.475686
-1.747476
0.593305
0.984577
0.018873
-1.312282
2.322040
2.789987
0.136833
1.497269
-0.866980
1.522064
0.541477
-0.119019
-0.891314
1.930679
1.007682
0.635536
-3.000938
-4.544962
1.367000
0.318291
-2.070442
3.872185
2.364236
2.567517
0.232116
2.555462
1.283386
1.071952
-0.226682
-0.807747
-1.440571
-1.629968
1.937838
2.965470
1.584465
0.498843
-0.053417
0.685278
0.297389
1.235498
-0.732899

(S)-VANOL-quinine-borate complex at the B3LYP/6-31G(d) level

scf done: -2442.818155
C -0.818470 -2.329392
C -1.823646 -2.919805
C -2.364121 -0.481064
C -3.041021 -2.223617
C -1.116243 -1.081766
C -3.327861 -1.036583
C -1.857529 1.787170
C -2.692367 0.682617
C -3.401849 3.034400
C -3.870456 0.704022
C -2.178979 2.993024
C -4.198218 1.864671
H -5.071081 1.869973
H -3.754692 -2.622690
C -3.747432 4.230749
H -4.675985 4.259300
C -1.342487 4.139415
H -0.417301 4.096649
H -1.069986 6.162464
C -1.712267 5.286545
H -3.201250 6.244031
C -2.924055 5.333445
C 0.412158 -3.011230
H 1.158300 -2.579737
C -1.550462 -4.164376

H
H
C
H
C
C
C
H
H
C
C
H
C
H
H
C
C
C
H
C
H
C
H
H
C
H

-1.130964
-1.955389
-0.585800
-2.152275
-0.510133
-1.506617
0.316255
0.291582
1.736757
1.126315
1.001790
1.801112
2.447763
-2.867414
2.419429
2.984411
0.970787
0.407100
1.606613
1.638556
2.893753
2.369465
-0.938648
-0.281541
-2.582384
373

-2.313505
1.572891
0.635977
-0.155199
-0.348719
-4.707617
-6.109278
-6.577239
-7.985068
-6.902362
-4.125011
-3.044008
-4.917867
-4.444607
-6.926818
-6.309883
-4.586983
-5.793324
-5.821304
-4.582872
-3.658109
-6.956385
-7.879749
-5.717759
-5.746307
-7.844483

-4.605223
-4.751750
-4.227496
-5.762317
-4.806109
-0.504066
-0.409832
0.528615
-1.413996
-1.509350
-1.737148
-1.829293
-2.837632
-3.779508
-3.587480
-2.729212
-0.328947
-1.037981
-2.088803
1.037368
1.601317
-0.404095
-0.971861
2.728487
1.672104
1.450521

-3.219250
-1.377380
-1.546567
-2.861361
-2.382776
1.376819
1.376649
1.093801
1.687075
1.701099
1.713882
1.741262
2.037025
2.301845
2.285271
2.032294
-1.875438
-1.999856
-1.726809
-2.202537
-2.134912
-2.434369
-2.515067
-2.889548
-2.635466
-3.091574

C
O
O
C
C
N
C
C
C
C
C
C
C
C
O
C
C
N
O
C
C
C
C
C
C
H

-6.938325
-0.643431
-0.071310
2.683183
2.912004
3.368788
3.649147
2.445260
2.700181
3.840246
4.189412
4.882692
5.066534
4.558512
5.438072
5.305177
3.953977
4.051703
1.573605
3.058140
3.183011
4.396730
4.125405
5.397377
5.653619
2.464234

0.954823
1.781950
-0.506778
0.314709
-0.126042
-0.921059
-1.321095
0.610180
0.173838
-1.669343
-2.166283
-3.311648
-3.659294
-2.857754
-4.183779
-3.908024
0.980955
0.757676
1.216955
1.559563
3.077818
3.266885
2.490159
1.172657
2.710069
-0.563231

-2.753375
-0.349418
0.197785
0.126467
1.562425
4.251656
1.839523
2.630756
3.951588
3.214681
0.827248
1.173214
2.539577
3.527331
0.286728
-1.100047
-0.467186
-1.929815
0.031626
-2.674996
-2.345401
-1.413949
-0.108819
-2.360701
-2.143525
-0.488879

H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C
H
C
H
H
B

374

1.878307
2.329659
4.066412
5.616167
4.687046
5.819614
4.250966
5.771485
4.795896
3.230917
2.058130
3.310750
2.276061
4.544997
4.942073
3.219507
6.130398
5.514205
5.709648
6.944770
7.057234
7.946251
8.860374
7.889692
0.280013

1.520302
0.762122
-1.901121
-4.567469
-3.101225
-4.719769
-3.888605
-2.950725
0.421413
1.368729
1.187085
3.669999
3.439177
4.329517
2.624845
2.888032
0.579438
0.910758
3.206722
2.976939
2.503173
3.724714
3.878733
4.213569
0.807761

2.466695
4.790488
-0.215199
2.766370
4.577180
-1.617105
-1.406943
-1.366309
-0.047291
-3.740151
-2.444571
-3.260102
-1.847637
-1.191802
0.608611
0.357398
-1.800540
-3.418379
-3.121408
-1.421065
-0.443855
-1.888404
-1.321132
-2.859355
-0.032479

(R)-VANOL-quinine-cyclicborate complex at the B3LYP/6-31G(d) level

scf done: -2442.825970
C -2.727090 -0.233341
C -3.887991 0.129706
N -6.009927 0.838627
C -5.214778 -0.343590
C -3.678585 0.886887
C -4.766439 1.217880
C -6.240697 0.057349
C -5.558735 -1.191458
C -6.863501 -1.612241
C -7.883164 -1.195151
C -7.574718 -0.385321
O -7.294485 -2.432226
C -6.339555 -2.926653
C -2.650788 0.522821
N -1.445480 1.428375
C -1.817142 2.727882
C -2.807317 3.523496
C -3.299043 2.602162
C -3.843545 1.317329
C -0.936759 1.726641
C -2.083063 2.302909
H -4.593343 1.824095
H -4.786552 -1.518838
H -8.894971 -1.545875
H -8.332776 -0.062513

H
H
H
H
H
H
H
H
H
H
H
H
H
C
H
C
H
H
O
H
C
C
C
C
C
C

-0.616022
-1.530391
-3.285774
-1.277576
-2.664594
-3.504003
-2.193635
-0.185351
-0.009543
-0.908180
-1.968445
0.990219
1.914662
0.773817
0.651743
-0.009009
0.874774
2.002602
1.341499
2.029126
2.925998
-4.392734
0.499073
-0.730897
-2.674889

375

-6.892299
-5.562144
-5.865610
-0.887218
-2.239447
-2.323845
-3.653071
-4.086823
-4.394075
-4.552679
-0.523432
-0.113096
-1.749147
-2.415439
-2.667794
-2.415145
-2.666117
-2.159761
-1.496463
-2.336510
0.626066
1.577684
2.216421
2.797478
0.970858
3.128075

-3.566843
-3.517109
-2.111222
3.269976
2.483036
4.413618
3.870449
3.089726
0.700352
1.594142
0.799842
2.437022
3.262518
1.399564
0.365707
1.778661
1.089848
2.794617
0.002513
-0.223552
-2.778074
-3.706289
-0.938756
-3.213738
-1.393805
-1.871748

2.604283
1.412080
2.477924
-0.176424
-0.982470
1.293918
0.271087
2.585443
2.058095
0.555386
2.426990
1.919104
3.339186
4.086220
3.844865
5.364648
6.166497
5.659724
-1.256954
1.506504
0.095340
-0.427181
-0.304065
-0.952050
0.107024
-0.915529

C
C
C
C
C
C
H
H
C
H
C
H
H
C
H
C
C
H
C
H
H
C
H
C
C
C

1.734050
2.569425
3.406379
3.775381
2.163572
4.158754
5.048064
3.472217
3.829908
4.768841
1.421055
0.515622
1.301145
1.870988
3.422692
3.080347
-0.605917
-1.311639
1.249130
1.971329
-1.834999
-0.889840
-0.191058
0.044853
4.587217
5.990106

1.495222
0.495578
3.215024
0.883015
2.859215
2.210739
2.503141
-3.913195
4.570105
4.839522
3.857556
3.564075
5.910605
5.160009
6.554310
5.523542
-3.264220
-2.553197
-5.088350
-5.791811
-4.974394
-4.612453
-6.594815
-5.533982
-0.082272
-0.062687

-0.581377
-0.087247
-0.040509
0.601491
-0.648202
0.615182
1.166500
-1.437724
-0.092072
0.386113
-1.333716
-1.852758
-1.925504
-1.384007
-0.783470
-0.744902
0.603369
1.018334
-0.437983
-0.845783
0.986572
0.589844
0.047867
0.059424
1.397166
1.329487

H
H
C
C
H
C
H
H
C
C
C
H
C
H
C
H
H
C
H
C
O
O
B
H
H

376

6.476128
7.843555
6.759496
3.979150
2.896981
4.747648
4.255033
6.739940
6.141502
4.382441
5.577647
5.600745
4.383346
3.466194
6.735006
7.650026
5.515868
5.540501
7.623066
6.721706
0.502128
0.052153
-0.475939
-2.817072
-2.672726

0.596820
-0.871989
-0.899442
-0.969092
-0.990247
-1.806863
-2.481290
-2.430162
-1.776134
-1.445395
-2.157325
-2.963163
-0.384821
0.166815
-1.822176
-2.383288
0.770869
-0.048981
-0.502612
-0.765497
1.217336
-0.503552
0.467189
-1.304846
1.201713

0.616466
2.060913
2.137159
2.301378
2.380722
3.108329
3.804120
3.659325
3.030369
-1.599216
-1.405106
-0.677246
-2.520794
-2.700507
-2.106767
-1.934265
-3.935573
-3.222282
-3.566520
-3.018826
-1.096416
0.590350
-0.361559
-0.384917
-2.918962

(S)-VANOL-quinine-cyclicborate complex at the B3LYP/6-31G(d) level

scf done: -2442.824655
C -1.575080 3.040076
C -2.623323 3.688742
C -2.439355 0.848515
C -3.505723 2.900703
C -1.503777 1.617088
C -3.428440 1.520848
C -1.212455 -1.325574
C -2.393722 -0.639011
C -2.398711 -3.480510
C -3.561126 -1.401721
C -1.203858 -2.746563
C -3.540029 -2.780020
H -4.410646 -3.350333
H -4.234161 3.407034
C -2.389207 -4.890729
H -3.297842 -5.446549
C -0.058926 -3.444315
H 0.827117 -2.872475
C -0.087674 -4.811858
H -1.272598 -6.623253
C -1.261374 -5.544695
C -0.660748 3.822807
H 0.126039 3.316701
C -2.713703 5.105311
H -3.507951 5.598482
C -0.781855 5.194908
H -1.899507 6.926074

C
C
C
H
H
C
C
H
C
H
H
C
C
C
H
C
H
C
H
H
C
H
C
O
O
C
C
N

-0.579544
0.140867
0.151299
0.919975
-0.526525
0.957085
0.303179
0.023993
0.214003
-0.344396
0.483408
-0.245105
-0.556324
1.547291
0.384527
0.165007
0.951872
1.205955
1.125692
0.961843
0.828893
-1.330682
-1.878419
0.087021
0.642642
-1.370216
-0.687903
377

-1.816608
-4.777599
-6.059793
-6.156758
-8.184119
-7.202546
-4.677428
-3.696614
-5.819712
-5.717369
-7.977676
-7.087754
-4.318643
-5.680913
-6.100500
-3.804903
-2.751410
-6.502150
-7.554907
-4.204251
-4.625808
-6.617032
-5.978163
-0.028998
-0.488192
2.670927
3.813655
5.906331

5.842930
-0.768125
-1.179629
-1.893197
-0.988298
-0.659894
0.184491
0.506476
0.705909
1.438035
0.693800
0.286160
0.802698
1.132860
1.848160
-0.149627
-0.406849
0.533767
0.800890
-1.478895
-0.749957
-0.879755
-0.411449
-0.682507
1.002237
0.540340
1.542560
3.465541

-0.653013
-0.929837
-0.530001
0.282914
-0.804147
-1.136452
-1.957772
-2.292725
-2.563579
-3.360534
-2.628993
-2.156429
1.913851
2.006130
1.304685
2.809989
2.768528
2.960420
3.007751
4.451235
3.763775
4.588355
3.843994
0.498405
-1.211980
0.478016
0.452884
0.384172

C
C
C
C
C
C
C
C
O
C
C
N
C
C
C
C
C
C
H
H
H
H
H
H

5.107476
3.616212
4.689643
6.120983
5.427988
6.700622
7.710060
7.422810
7.106877
6.155975
2.740367
1.562151
1.924375
3.002461
3.551827
3.998800
1.173551
2.403426
2.629242
4.527518
4.661210
8.696557
8.173220
6.683086

1.210705
2.821986
3.741525
2.220260
-0.049640
-0.294598
0.702515
1.922793
-1.456020
-2.495096
-0.640526
-0.393767
0.586498
-0.011444
-1.287250
-0.916266
-1.688434
-2.336352
3.123411
4.747840
-0.809886
0.467017
2.703718
-3.307627

0.966158
-0.023918
-0.041476
0.893995
1.547982
2.028845
1.937960
1.386835
2.614878
2.780214
-0.581921
-1.494734
-2.585005
-3.518065
-2.860892
-1.429832
-2.135648
-2.854981
-0.356624
-0.426607
1.626986
2.324707
1.316136
3.283093

H
H
H
H
H
H
H
H
H
H
H
H
C
H
C
H
H
B
O
H
H
H
H

378

5.309592
5.778575
0.994703
2.268018
2.582481
3.807306
4.399858
4.585893
4.650383
0.776787
0.360782
2.134348
2.797445
2.949389
2.963134
3.254309
2.808719
0.490197
1.437468
2.467447
-0.079801
0.791086
2.668103

-2.170403 3.399594
-2.852137 1.812200
0.823824 -3.102449
1.493345 -2.089976
-0.242177 -4.503988
0.715487 -3.672897
-1.681681 -3.429456
-1.719001 -0.974240
-0.038079 -1.476153
-2.339879 -1.357240
-1.468979 -2.832567
-2.521681 -3.902128
-3.658995 -2.247753
-3.676921 -1.167649
-4.787237 -2.938658
-5.716291 -2.456654
-4.826964 -4.015297
0.330382 -0.407341
1.182637 0.262770
-1.550497 -0.042801
5.786402 -1.952233
-5.331437 1.499120
0.066567 1.471047

(R)-VANOL-quinidine-cyclicborate complex at the B3LYP/6-31G(d) level

scf done: -2442.825823
C 2.898517 0.018690
C 3.805429 1.236643
N 5.397179 3.590890
C 5.210365 1.142714
C 3.261236 2.492203
C 4.092378 3.632822
C 5.956575 2.368269
C 5.899299 -0.072268
C 7.259812 -0.070055
C 7.999861 1.142194
C 7.359821 2.323928
O 8.004587 -1.173303
C 7.345059 -2.422859
C 2.766031 -0.504820
N 1.488694 -1.314681
C 1.734330 -2.667839
C 2.751046 -3.473086
C 3.296472 -2.566388
C 3.904629 -1.317333
C 1.004315 -1.510893
C 2.105384 -2.193362
H 2.192930 2.601912
H 3.652497 4.618183

H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C
H
C
H
H
O
H
H

-0.577088
-0.681911
-0.713462
-0.940244
-0.506116
-0.527754
-0.929198
-1.228407
-1.470336
-1.425034
-1.165074
-1.769264
-1.877437
0.872808
0.833442
0.227382
1.074906
2.189966
1.521405
2.238017
3.116532
-0.364896
-0.378007
379

5.343982
9.067485
7.896922
8.116924
6.879611
6.578762
0.766747
2.075018
2.271584
3.572895
4.059129
4.442316
4.641790
0.723754
0.093769
1.701990
2.502002
2.830989
2.468868
2.768980
2.136218
1.579703
3.303276
2.520698

-0.998778
1.097836
3.266707
-3.148923
-2.716364
-2.406953
-3.163846
-2.515042
-4.359328
-3.830470
-3.091370
-0.695688
-1.632747
-0.529548
-2.112957
-3.133788
-1.337276
-0.321479
-1.735979
-1.080616
-2.734139
0.311663
-0.780120
0.362068

-1.284500
-1.615758
-1.140855
-2.138759
-0.926278
-2.663832
0.166321
-0.797241
1.505891
0.443772
2.773922
2.243204
0.775447
2.618293
2.186983
3.511884
4.292310
4.067317
5.564264
6.377097
5.842818
-0.971394
-1.218878
1.493416

C
C
C
C
C
C
C
C
C
C
C
C
H
H
C
H
C
H
H
C
H
C
C
H
C
H
H
C

-1.870770
-3.129660
-2.519827
-4.016758
-1.561034
-3.745858
-1.127481
-2.282573
-1.954272
-3.232188
-0.954764
-3.051183
-3.749707
-4.924312
-1.794767
-2.550236
0.145123
0.882258
1.104439
0.261853
-0.608175
-0.713327
-0.993584
-0.070090
-3.436481
-4.389016
-0.658223
-1.331744

-2.874935
-3.386912
-0.626002
-2.521661
-1.500361
-1.176346
1.367482
0.847021
3.657025
1.755371
2.769576
3.117199
3.801807
-2.938244
5.053476
5.727231
3.305311
2.621815
5.061873
4.664800
6.619357
5.548761
-3.730390
-3.316205
-4.752546
-5.141694
-5.683978
-5.045242

-0.963719
-0.523934
-0.200225
0.160684
-0.706027
0.324010
0.327003
-0.241914
0.031811
-0.834446
0.535738
-0.683212
-1.156198
0.588460
0.237164
-0.160328
1.254406
1.660082
2.012613
1.452413
1.085970
0.931403
-1.682653
-2.070953
-0.767253
-0.415009
-2.489123
-1.923540

H
C
C
C
H
H
C
C
H
C
H
H
C
C
C
H
C
H
C
H
H
C
H
C
O
O
B

380

-2.812635 -6.606510
-2.558884 -5.566474
-4.361417 1.293745
-5.639509 1.860221
-5.820045 2.570232
-7.662488 1.947597
-6.680223 1.500295
-4.158873 0.352994
-3.174368 -0.082615
-5.199545 -0.008480
-5.017578 -0.733247
-7.275264 0.280685
-6.464999 0.563014
-4.704696 -0.369851
-6.089252 -0.491820
-6.451173 -1.104073
-4.258433 0.456886
-3.193485 0.555095
-6.996970 0.186843
-8.063619 0.082857
-4.796522 1.766739
-5.165263 1.136645
-7.245131 1.535911
-6.538877 1.004796
-0.146036 0.528969
-0.316942 -1.076874
0.538865 -0.314155

-1.636156
-1.448689
-1.691603
-1.554405
-0.752588
-2.279425
-2.409674
-2.715433
-2.852425
-3.569928
-4.359341
-4.088798
-3.421491
1.133111
0.929636
0.108905
2.177798
2.362047
1.741888
1.559636
3.794981
2.989621
3.408918
2.776016
0.773054
-1.065816
-0.194482

(S)-VANOL-quinidine-cyclicborate complex at the B3LYP/6-31G(d) level

scf done: -2442.827338
C 1.438145 -3.023878
C 2.469069 -3.775030
C 2.369445 -0.947983
C 3.377640 -3.099518
C 1.412880 -1.611895
C 3.340054 -1.729917
C 1.197847 1.225040
C 2.362168 0.544862
C 2.440592 3.340959
C 3.550578 1.314973
C 1.224633 2.612962
C 3.564648 2.671166
H 4.450428 3.252244
H 4.093629 -3.690452
C 2.468222 4.719482
H 3.392566 5.273091
C 0.095877 3.278876
H -0.808440 2.707475
C 0.161361 4.613684
H 1.395807 6.397890
C 1.356037 5.344583
C 0.494181 -3.697161
H -0.286732 -3.115341
C 2.517475 -5.180126
H 3.299708 -5.751576
C 0.573716 -5.060302
H 1.644976 -6.884926

C
C
C
H
H
C
C
H
C
H
H
C
C
C
H
C
H
C
H
H
C
H
C
O
O
C
C
N

-0.980775
-0.339439
-0.028376
0.512043
-0.782931
0.696929
0.363185
0.009186
0.540123
-0.265841
0.715326
-0.001015
-0.241626
1.076511
0.881722
0.733668
1.263416
1.443965
1.603261
1.665579
1.400897
-1.797764
-2.273410
-0.542201
-0.047890
-1.981195
-1.496665

381

1.594556
4.747878
6.043122
6.164889
8.159717
7.167670
4.616246
3.625003
5.740217
5.613324
7.897203
7.021435
4.255063
5.607427
6.002091
3.774394
2.728789
6.451082
7.495668
4.221361
4.617657
6.616260
5.959942
-0.005950
0.426320
-2.871791
-3.514921
-4.584187

-5.809453
0.723815
1.057083
1.671184
0.848123
0.582960
-0.102702
-0.361108
-0.578456
-1.212622
-0.609663
-0.237693
-1.143570
-1.521064
-2.171453
-0.275918
0.014551
-1.048305
-1.349322
0.863487
0.198313
0.185137
-0.185044
0.594724
-0.895920
-0.683543
-0.580848
-0.246828

-1.347612
-0.929426
-0.499692
0.387678
-0.817165
-1.173934
-2.058106
-2.416401
-2.731802
-3.605529
-2.819065
-2.293594
1.718045
1.764962
0.989755
2.713066
2.708029
2.769439
2.780123
4.479989
3.717030
4.533684
3.750273
0.472855
-1.408415
-0.057031
1.321644
3.932150

C
C
C
C
C
C
C
C
O
C
C
N
C
C
C
C
C
C
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C
H
C
H
H
B
O
H

-4.914658 -0.770243
-2.717453 -0.267756
-3.296150 -0.110665
-5.390060 -0.579485
-5.849038 -1.146752
-7.185839 -1.313416
-7.655740 -1.102091
-6.777741 -0.748095
-8.153108 -1.684001
-7.770280 -1.957287
-2.793170 0.703548
-1.546647 0.607894
-1.815943 -0.182072
-2.867187 0.538087
-3.435634 1.730836
-3.981262 1.196225
-1.117133 1.985915
-2.275412 2.741368
-1.647886 -0.149080
-2.661962 0.141629
-5.501228 -1.322479
-8.714413 -1.240461
-7.107280 -0.591872
-8.683216 -2.252673
-7.347347 -1.068064
-7.040915 -2.776748
-0.853819 -0.303112
-2.142523 -1.175233
-2.414808 0.885059
-3.671056 -0.155419
-4.236409 2.218525
-4.538743 1.966238
-4.687417 0.382457
-0.814428 2.507517
-0.232194 1.879360
-1.920180 3.047714
-2.702408 3.985099
-2.966382 3.861628
-2.771935 5.200006
-3.091877 6.065846
-2.505274 5.377388
-0.552445 -0.279437
-1.546362 -1.157204
-3.457758 -1.375736

1.546412
2.404864
3.682651
2.886701
0.536994
0.843309
2.167930
3.156664
-0.044836
-1.381528
-0.758983
-1.604438
-2.859197
-3.739077
-2.951826
-1.609727
-1.995143
-2.727701
2.268686
4.531910
-0.472136
2.363594
4.178891
-1.901710
-1.869205
-1.431563
-3.356483
-2.549421
-4.675155
-4.011092
-3.516656
-1.068594
-1.811426
-1.087591
-2.627401
-3.719150
-1.990230
-0.939025
-2.534770
-1.962008
-3.575000
-0.555375
0.010044
-0.679727

H
H
H

382

-2.545503
-0.152584
-0.705179

1.443163
-5.567651
5.106781

0.006773
-2.610969
2.035962

4.4 Experimental for Chapter Three
4.4.1 Synthesis of 2'-iodoacetophenone III-28 (Scheme 3.7)

O
CH3

NaNO2 (2.0 equiv),
KI (2.5 equiv),
pTsOH•H2O (3.0 equiv),
CH3CN, H2O,
0Âş to rt, 2 h

NH2
III-62
20 mmol
2.70 g

O
CH3
I
III-28
100%
4.92 g

1-(tert-butyl)-2-iodobenzene III-28: Acetophenone III-28 was was prepared by the
General Procedure J with 2-aminoacetophenone (2.43 mL, 20.0 mmol). The crude iodide
was purified by flash chromatography (hexanes) to afford II-28 as a as a yellow liquid
(4.920 g, 20.00 mmol, 100%).
Spectral data for III-28: Rf = 0.53 (hexanes); 1H NMR (500 MHz, CDCl3) δ 2.58 (s,
3H), 7.10 (dd, J = 7.5, 1.8 Hz, 1H), 7.39 (dt, J = 7.5, 1.0 Hz, 1H), 7.44 (dd, J = 7.5, 1.8
Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H);

13

C NMR (126 MHz, CDCl3) δ 29.71, 91.18, 128.23,

128.51, 131.98, 141.13, 144.20, 201.93. These spectral data match those previously
reported for this compound.16

383

4.4.2 CuCl2-catalyzed arylation/cycloaromatization reaction
entry 19 in Table 3.4

OH

O

O

OH

NaH (5.0 equiv)

CH3

+

I
1 mmol
III-28

CH3
1.5 equiv
III-29

+

2 mol% CuCl2
3 mL DMF, rt,
3 h, N2

III-30b I

III-30

III-30/III-30b = 3.6:1

General Procedure O for CuCl2-catalyzed arylation/cycloaromatization reaction
with

NaH

--

illustrated

for

synthesis

of

3-phenyl-1-naphthol

III-30

from

o-

iodoacetophenone III-28 and acetophenone III-29:
3-phenyl-1-naphthol III-30: To an oven-dried 25 mL round bottom flask was added
NaH (200 mg, 60% in mineral oil, 5.00 mmol, 5.00 equiv), CuCl2 (2.2 mg, 0.020 mmol,
2.0 mol%), DMF (3 mL) and acetophenone III-29 (0.175 mL, 1.50 mmol, 1.50 equiv) was
added in one portion at room temperature under N2 atmosphere. After 1 min, to the
reaction mixture was added iodoacetophenone III-28 (0.143 mL, 1.00 mmol) portionwise
in 5 min and then was kept stirring at rt for 3 h. After completion, the mixture was acidified
with 2 M HCl (3 mL) at 0 ÂşC and then extracted with EtOAc (10 mL x 3). The combined
organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The residue was purified by silica gel flash column chromatography
(hexane/EtOAc 5:1 to 3:1) to obtain a mixture of III-30 and III-30b (202.9 mg) as a brown
semi solid. Ratio of the III-30 and III-30b was determined to be 3.6 :1 by 1H NMR analysis
of the proton signal of 8-position (8.27 ppm for III-30 and 8.31 ppm for III-30b). Yield of
the desired naphthol product the III-30 was determined to be 65% by 1H NMR analysis of

384

the crude reaction mixture by integration of the methylene protons (δ 3.94) relative to the
internal standard (Ph3CH).
Spectral data for III-30: Rf = 0.31 (hexanes/EtOAc 4:1); 1H NMR (500 MHz, CDCl3)
δ 6.38 (s, 1H), 6.85 (d, J = 1.6 Hz, 1H), 7.05 (td, J = 7.6, 2.0 Hz, 1H), 7.37 (ddd, J = 15.7,
7.5, 1.7 Hz, 3H), 7.52 (qd, J = 6.9, 3.3 Hz, 2H), 7.80 – 7.91 (m, 1H), 7.98 (dd, J = 8.0, 1.2
Hz, 1H), 8.22 – 8.32 (m, 1H).

13

C NMR (126 MHz, CDCl3) δ 98.60, 110.59, 120.88,

121.81, 123.88, 125.60, 126.89, 128.02, 128.17, 128.93, 130.36, 134.38, 139.53, 141.90,
146.44, 151.07. These spectral data match those previously reported for this
compound17.
Scheme 3. 10
O

O
CH3 +

CH3

OTf
1 mmol
III-66

O O
CF3
S
O

NaH (5.0 equiv)

1.5 equiv
III-29

5 mol% CuCl2
3.0 mL DMF, 80 ÂşC,
3 h, N2

OH
89%
III-67

1-(2-hydroxyphenyl)-2-((trifluoromethyl)sulfonyl)ethan-1-one III-67: Phenol III-67
was obtained as a white solid (239 mg, 0.890 mmol) in 89% yield by following General
Procedure O with 2-acetylphenyl trifluoromethanesulfonate III-66 (268 mg, 1.00 mmol).
Spectral data for III-30: Rf = 0.38 (hexanes/EtOAc 4:1); 1H NMR (500 MHz, CDCl3)
δ 4.85 (s, 2H), 6.90 – 7.13 (m, 2H), 7.47 – 7.70 (m, 2H), 11.35 (s, 1H).

13

C NMR (126

MHz, CDCl3) δ 56.74, 118.78, 119.10, 119.94, δ 128.45 (d, J = 33.5 Hz), 130.72, 138.80,
163.37, 189.51. 19F NMR (470 MHz, CDCl3) δ -77.00. HRMS (ESI–) m/z 266.9962 [calcd.
for C9H6O4F3S (M–H): 266.9939].

385

OH

Scheme 3. 11
O

NaH (5.0 equiv)

CH3

5 mol% CuCl2
3 mL DMF, rt,
3 h, N2

I
1 mmol
III-28

I
85% isolated yield
III-30b

3-(2-iodophenyl)-1-naphthol III-30b: Naphthol III-30b was obtained as a yellow
liquid (155 mg, 0.449 mmol) in 89% yield. by following General Procedure O without
acetophenone with 5 mol% CuCl2.
Spectral data for III-30b: Rf = 0.29 (hexanes/EtOAc 4:1); 1H NMR (500 MHz,
CDCl3) δ 6.38 (s, 1H), 6.85 (d, J = 1.6 Hz, 1H), 7.05 (td, J = 7.6, 2.0 Hz, 1H), 7.37 (ddd,
J = 15.7, 7.5, 1.7 Hz, 3H), 7.52 (qd, J = 6.9, 3.3 Hz, 2H), 7.80 – 7.91 (m, 1H), 7.98 (dd, J
= 8.0, 1.2 Hz, 1H), 8.22 – 8.32 (m, 1H).

13

C NMR (126 MHz, CDCl3) δ 98.60, 110.59,

120.88, 121.81, 123.88, 125.60, 126.89, 128.02, 128.17, 128.93, 130.36, 134.38, 139.53,
141.90, 146.44, 151.07. These spectral data match those previously reported for this
compound18.
General procedure P for CuCl2-catalyzed arylation/cycloaromatization reaction
with KtOBu -- illustrated for o-iodoacetophenone III-28 and acetophenone III-29:
entry 14 in Table 3.6
O

O
CH3
I
1 mmol
III-28

+

5 mol% CuCl2
KOtBu (5.0 equiv)
CH3

1.5 equiv
III-29

OH

OH
+

3.0 mL DMF, 80 ÂşC,
0.5 h, N2
III-30
63%

III-30b I
3%

3-phenyl-1-naphthol III-30: To an oven-dried 25 mL round bottom flask was added
KOtBu (561 mg, 5.00 mmol, 5.00 equiv), CuCl2 (5.4 mg, 0.050 mmol, 5.0 mol%), DMF (3

386

mL) and acetophenone III-29 (0.175 mL, 1.50 mmol, 1.50 equiv) was added in one portion
at room temperature under N2 atmosphere and was heated in an 80 ÂşC oil bath. After 1
min, to the reaction mixture was added iodoacetophenone III-28 (0.143 mL, 1.00 mmol)
portionwise in 5 min and then was kept stirring at 80 ÂşC for 30 min. After completion, the
mixture was acidified with 2 M HCl (3 mL) at 0 ÂşC and then extracted with EtOAc (10 mL
x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified by silica gel flash column
chromatography (hexane/EtOAc 5:1 to 3:1) to obtain a mixture of III-30 and III-30b (162.9
mg) as a brown semi solid. Ratio of the III-30 and III-30b was determined to be 22.6 : 1
by 1H NMR analysis of the proton signal of 8-position (8.27 ppm for III-30 and 8.31 ppm
for III-30b). Yield of the desired naphthol product the III-30 was determined to be 63% by
1

H NMR analysis of the crude reaction mixture by integration of the methylene protons (δ

3.94) relative to the internal standard (Ph3CH).

CH3 +
I
1 mmol
III-28

5 mol% CuCl2
KOtBu (5.0 equiv)

O

O

F3C

CH3
1.5 equiv
III-68

OH

3.0 mL DMF, 80 ÂşC,
0.5 h, N2
CF3
III-69, 98% isolated yield

3-(4-(trifluoromethyl)phenyl)-1-naphthol III-69: Naphthol III-69 was obtained as a
yellow solid (155 mg, 0.449 mmol) in 89% yield. by following General Procedure P without
acetophenone with 5 mol% CuCl2.
Spectral data for III-30b: Rf = 0.29 (hexanes/EtOAc 4:1); 1H NMR (500 MHz,
CDCl3) δ 6.36 (s, 1H), 7.03 (d, J = 1.6 Hz, 1H), 7.43 – 7.59 (m, 2H), 7.59 – 7.76 (m, 6H),
7.86 (dd, J = 7.5, 1.7 Hz, 1H), 8.16 – 8.29 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 108.05,

387

119.13, 121.66, 123.26, 124.09, 125.70 (q, J = 3.8 Hz), 125.89, 127.21, 127.47, 128.18,
128.77, 129.36 (q, J = 32.4 Hz), 134.87, 137.30, 144.33, 144.34, 152.15.

19

F NMR (470

MHz, CDCl3) δ –62.29. These spectral data match those previously reported for this
compound16.
4.4.3 Syntheses of o-alkynylacetophenone III-74 (Scheme 3.14)
O

O
CH3

+
I
1.1 equiv
III-73a

1 mol% PdCl2(PPh3)2
1 mol% CuI

CH3

Et3N (7.2 equiv),
60 ºC, 5–12 h

20 mmol
III-28

III-74a
100%

General Procedure Q for the Sonagashira reaction -- illustrated for oiodoacetophenone III-28 and ethynylcyclohexane III-73a:
o-(cyclohexylethynyl)acetophenone III-74a: To a flame-dried 500 mL round bottom
flask was added PdCl2(PPh3)2 (140 mg, 0.200 mmol), CuI (38.2 mg, freshly purified, 0.200
mmol),

ethynylcyclohexane

III-73a

(3.17

mL,

22.0

mmol,

1.10

equiv),

2′-

iodoacetophenone III-28 (2.86 mL, 20.0 mmol) and triethylamine (40 mL, 7.2 equiv) at
room temperature and the reaction mixture was heated to 60 °C under N2 atmosphere.
After 12 h, triethylamine was removed under reduced pressure. The residue was then
diluted with DCM and water. The organic layer was separated and the aqueous layer was
extracted DCM (3 x 30 mL). The combined organic layer was dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by
silica gel flash column chromatography (hexane/EtOAc 40:1 to 20:1) to obtain III-74a
(4.530 g, 20.00 mmol) as a yellow liquid in 100% isolated yield.

388

Spectral data for II-74a: Rf = 0.63 (hexanes); 1H NMR (500 MHz, CDCl3) δ 1.33
(m, 3H), 1.55 (m, 3H), 1.74 (m, 2H), 1.78 – 1.95 (m, 2H), 2.63 (m, 1H), 2.68 – 2.77 (s,
3H), 7.30 (t, J = 7.7 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.64 (d, J
= 7.8 Hz, 1H).

13

C NMR (126 MHz, CDCl3) δ 24.94, 25.84, 29.98, 30.27, 32.36, 79.67,

100.83, 122.50, 127.51, 128.29, 131.04, 133.93, 141.04, 201.26. These spectral data
match those previously reported for this compound19.
O
O
CH3

+

CH3

Et3N (7.2 equiv),
60 ºC, 5–12 h

I
1.1 equiv
III-73b

1 mol% PdCl2(PPh3)2
1 mol% CuI

III-74b
97%

20 mmol
III-28

o-(butylethynyl)acetophenone III-74a: Acetophenone III-74b was prepared from 1hexyne III-73b (2.60 mL, 22.0 mmol, 1.10 equiv) by the general procedure with a reaction
time of 12 hours. The crude product was purified by column chromatography (silica gel,
hexanes/EtOAc 40:1 to 20:1) to give III-74b as a yellow liquid in 97% isolated yield (3.884
g, 19.40 mmol).
Spectral data for II-74b: Rf = 0.65 (hexanes); 1H NMR (500 MHz, CDCl3) δ 0.93 (t, J = 7.3
Hz, 3H), 1.34 – 1.52 (m, 2H), 1.52 – 1.62 (m, 2H), 2.44 (t, J = 7.1 Hz, 2H), 2.70 (s, 3H),
7.30 (td, J = 7.6, 1.4 Hz, 1H), 7.38 (td, J = 7.5, 1.5 Hz, 1H), 7.46 (dd, J = 7.7, 1.3 Hz, 1H),
7.64 (ddd, J = 7.7, 1.5, 0.6 Hz, 1H).

13

C NMR (126 MHz, CDCl3) δ 13.62, 19.40, 22.09,

30.10, 30.51, 79.62, 96.87, 122.45, 127.51, 128.28, 131.05, 133.95, 141.01, 201.14.
These spectral data match those previously reported for this compound20.

389

O
CH3

+

O
CH3

Et3N (7.2 equiv),
60 ºC, 5–12 h

I
1.1 equiv
III-73c

1 mol% PdCl2(PPh3)2
1 mol% CuI

20 mmol
III-28

III-74c
67%

o-(benzylethynyl)acetophenone III-74c: Acetophenone III-74c was prepared from
3-phenyl-1-propyne (2.86 mL, 22.0 mmol, 1.20 equiv, prepared by a reported two step
procedure21 from benzylbromide and ethynyltrimethylsilane in 51% overall yield) by the
general procedure with a reaction time of 12 hours. The crude product was purified by
column chromatography (silica gel, hexanes/EtOAc 40:1 to 20:1) to give III-74c as a
yellow liquid in 67% isolated yield (3.142 g, 13.40 mmol).
Spectral data for II-74c: Rf = 0.60 (hexanes); 1H NMR (500 MHz, CDCl3) δ 2.63 (d,
J = 27.6 Hz, 3H), 3.87 (s, 2H), 7.21 – 7.27 (m, 1H), 7.31 – 7.36 (m, 3H), 7.37 – 7.43 (m,
3H), 7.53 (dd, J = 7.7, 1.3 Hz, 1H), 7.66 (ddd, J = 7.7, 1.4, 0.5 Hz, 1H).

13

C NMR (126

MHz, CDCl3) δ 26.09, 30.01, 81.59, 93.73, 121.99, 126.77, 127.86, 127.99, 128.40,
128.63, 131.13, 134.12, 136.17, 140.99, 200.83. HRMS (ESI–) m/z 233.0969 [calcd. for
C17H13O (M–H): 233.0966].
O
CH3

+
I
1.1 equiv
III-73d

1 mol% PdCl2(PPh3)2
1 mol% CuI

O
CH3

Et3N (7.2 equiv),
60 ºC, 5–12 h

20 mmol
III-28

III-74d
92%

o-(pheylethynyl)acetophenone III-74d: Acetophenone III-74d was prepared from
phenylacetylene III-73d (2.42 mL, 22.0 mmol, 1.20 equiv) by the General Procedure Q
with a reaction time of 12 hours. The crude product was purified by column
390

chromatography (silica gel, hexanes/EtOAc 19:1 to 9:1) to give III-74d as a yellow liquid
in 92% isolated yield (4.053 mg, 18.40 mmol).
Spectral data for II-74d: Rf = 0.45 (hexanes); 1H NMR (500 MHz, CDCl3) δ 2.78 (s,
3H), 7.32 – 7.41 (m, 4H), 7.46 (td, J = 7.5, 1.4 Hz, 1H), 7.48 – 7.57 (m, 2H), 7.62 (ddd, J
= 7.7, 1.4, 0.6 Hz, 1H), 7.74 (ddd, J = 7.8, 1.4, 0.5 Hz, 1H).

13

C NMR (126 MHz, CDCl3)

δ 30.03, 88.46, 95.02, 121.69, 122.86, 128.28, 128.45, 128.70, 128.77, 131.31, 131.51,
133.88, 140.74, 200.40. These spectral data match those previously reported for this
compound20.
O
O
CH3

+
I
1.1 equiv
III-73e

1 mol% PdCl2(PPh3)2
1 mol% CuI

CH3

Et3N (7.2 equiv),
60 ºC, 5–12 h
III-74e
97%

20 mmol
III-28

o-(tButylethynyl)acetophenone III-74e: Acetophenone III-74e was prepared from
3,3-Dimethyl-1-butyne III-73e (2.71 mL, 22.0 mmol, 1.20 equiv) by the General Procedure
Q with a reaction time of 12 hours. The crude product was purified by column
chromatography (silica gel, hexanes/EtOAc 40:1 to 20:1) to give III-74e as a colorless
liquid in 97% isolated yield (3.885 g, 18.40 mmol).
Spectral data for II-74e: Rf = 0.67 (hexanes); 1H NMR (500 MHz, CDCl3) δ 1.31 (s,
9H), 2.72 (s, 3H), 7.25 – 7.33 (m, 1H), 7.37 (td, J = 7.6, 1.5 Hz, 1H), 7.45 (ddd, J = 7.7,
1.4, 0.6 Hz, 1H), 7.64 (ddd, J = 7.8, 1.5, 0.6 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 28.28,
30.30, 30.63, 78.46, 104.66, 122.41, 127.56, 128.30, 131.04, 133.81, 141.04, 201.30.
These spectral data match those previously reported for this compound22.

391

O
CH3

+

TMS

CH3

Et3N (7.2 equiv),
60 ºC, 5–12 h

I
1.1 equiv
III-73f

O

1 mol% PdCl2(PPh3)2
1 mol% CuI

TMS

20 mmol
III-28

III-74f
100%

o-(trimethylsilylethynyl)acetophenone III-74f: Acetophenone III-74f was prepared
from ethynyltrimethylsilane III-73f (3.41 mL, 22.0 mmol, 1.20 equiv) by the General
Procedure Q with a reaction time of 12 hours. The crude product was purified by column
chromatography (silica gel, hexanes/EtOAc 40:1 to 20:1) to give III-74f as a colorless
liquid in 100% isolated yield (4.330 g, 20.00 mmol);
Spectral data for II-74f: Rf = 0.70 (hexanes); 1H NMR (500 MHz, CDCl3) δ 0.24 (d,
J = 1.0 Hz, 9H), 2.73 (d, J = 1.3 Hz, 3H), 7.33 – 7.44 (m, 2H), 7.50 – 7.56 (m, 1H), 7.62
– 7.70 (m, 1H).

13

C NMR (126 MHz, CDCl3) δ -0.33, 30.18, 101.12, 103.83, 121.40,

128.41, 128.57, 131.10, 134.21, 141.51, 200.80. These spectral data match those
previously reported for this compound23.
4.4.4 Base-promoted cycloaromatization (Scheme 3.15)
O

OH
CH3

KOtBu (1.2 equiv), 80 ÂşC
THF, 0.5 M, 2 h

10 mmol
III-74a

III-75a
96%

General Procedure R for the KtOBu promoted cycloaromatization -- illustrated for
the synthesis of 3-cyclohexyl-1-naphthol III-75a:
3-cyclohexyl-1-naphthol III-75a: To an oven-dried 100 mL round bottom flask was
added KtOBu (1.347 g, 12.00 mmol, 1.200 equiv) and THF (20 mL). o392

(cyclohexylethynyl)acetophenone III-74a (2.264 g, 10.00 mmol) was added in one portion
at room temperature and the reaction mixture was heated to 80 °C under N2 atmosphere.
After 2 h, the reaction mixture was acidified with 1 M H2SO4 (50 mL) at 0 ÂşC and then
extracted with EtOAc (50 mL x 3). The combined organic layer was dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by
silica gel flash column chromatography (hexane/EtOAc 20:1 to 10:1) to obtain III-75a
(2.124 g, mp 100-101 ÂşC, 9.380 mmol) as a white solid in 94% isolated yield.
Spectral data for III-75a: Rf = 0.41 (hexanes/EtOAc 8:1); 1H NMR (500 MHz,
CDCl3) δ 1.25 – 1.55 (m, 6H), 1.76 – 2.00 (m, 5H), 2.57 (tt, J = 11.5, 3.2 Hz, 1H), 6.31 (s,
1H), 6.69 (d, J = 1.4 Hz, 1H), 7.28 – 7.38 (m, 1H), 7.51 (dddd, J = 25.4, 8.1, 6.8, 1.3 Hz,
2H), 7.78 – 7.93 (m, 1H), 8.27 (dd, J = 8.4, 1.3 Hz, 1H).

13

C NMR (126 MHz, CDCl3) δ

26.28, 27.01, 34.32, 44.74, 109.29, 117.62, 121.54, 123.29, 124.65, 126.52, 127.58,
135.03, 146.32, 151.14. HRMS (ESI–) m/z 225.1296 [calcd. for C16H17O (M–H):
225.1279].
O

OH
CH3

KOtBu (1.2 equiv), 80 ÂşC
THF, 0.5 M, 2 h
III-75b
94%

10 mmol
III-74b

3-butyl-1-naphthol

III-75b:

Naphthol

III-75b

was

prepared

from

o-

(butylethynyl)acetophenone III-74a (2.003 g, 10.00 mmol) by the General Procedure R.
The crude product was purified by column chromatography (silica gel, hexanes/EtOAc
40:1 to 9:1) to give III-75b as a yellow liquid in 94% isolated yield (1.889 g, 9.430 mmol).

393

Spectral data for III-75b: Rf = 0.45 (hexanes/EtOAc 8:1); 1H NMR (500 MHz,
CDCl3) δ 0.92 (td, J = 7.3, 1.1 Hz, 3H), 1.37 (qd, J = 7.5, 1.9 Hz, 2H), 1.65 (tt, J = 9.0, 6.8
Hz, 2H), 2.55 – 2.76 (m, 2H), 5.14 (s, 1H), 6.67 (d, J = 1.3 Hz, 1H), 7.21 (d, J = 1.6 Hz,
1H), 7.35 – 7.50 (m, 2H), 7.72 (dt, J = 7.6, 1.4 Hz, 1H), 8.02 – 8.13 (m, 1H).13C NMR (126
MHz, CDCl3) δ 13.99, 22.37, 33.33, 35.81, 110.08, 119.23, 121.28,122.77, 124.38,
126.42, 127.19, 134.82, 140.85, 151.10. HRMS (ESI–) m/z 199.1129 [calcd. for C14H15O
(M–H): 199.1123].
O

OH

KOtBu (1.2 equiv),
0ÂşC to 80 ÂşC

CH3

THF, 0.5 M, 2 h

Ph

III-75c
93%

10 mmol
III-74c

3-benzyl-1-naphthol

III-75c:

Naphthol

III-75c

was

prepared

from

o-

(benzylethynyl)acetophenone III-74c (2.003 g, 10.00 mmol) by the General Procedure R.
The crude product was purified by column chromatography (silica gel, hexanes/EtOAc
40:1 to 9:1) to give III-75c as a colorless liquid in 59% isolated yield (1.370 g, 5.850 mmol).
The reaction with modification that the KOtBu was added at 0 ÂşC and then slowly heated
to 80 ÂşC gave III-75b (2.182 g, 9.310 mmol) in 93% yield.
Spectral data for III-75b: Rf = 0.44 (hexanes/EtOAc 8:1); 1H NMR (500 MHz,
CDCl3) δ 4.09 (s, 2H), 5.29 (s, 1H), 6.59 (d, J = 1.4 Hz, 1H), 7.21 – 7.31 (m, 3H), 7.31 –
7.39 (m, 3H), 7.50 (dddd, J = 21.9, 8.2, 6.8, 1.4 Hz, 2H), 7.80 (dd, J = 8.0, 1.3 Hz, 1H),
8.17 (dd, J = 8.3, 1.4 Hz, 1H).

13

C NMR (126 MHz, CDCl3) δ 42.15, 110.30, 120.07,

121.56, 123.17, 124.86, 126.30, 126.72, 127.44, 128.57, 129.14, 134.87, 139.06, 140.90,
151.45. HRMS (ESI–) m/z 233.0972 [calcd. for C17H13O (M–H): 233.0966].
394

O

OH
CH3

KHMDS (1.2 equiv),
toluene
0 ÂşC to 125 ÂşC, 12 h

10 mmol
III-74e

III-75e
65%a

3-tert-butyl-1-naphthol III-75e: To an oven-dried 100 mL round bottom flask
equipped with a condenser was added o-(tert-butylethynyl)acetophenone III-74e (4.002
g, 20.00 mmol) and toluene (20 mL). The mixture was cooled to 0 ÂşC for 10 min. KHMDS
(48 mL, 0.5 M in toluene, 1.2 equiv) was added in one portion. The resulting mixture was
warmed to rt and then was heated in an oil bath at 125 ÂşC for 12 h. The reaction mixture
was acidified with 1 M H2SO4 (100 mL) at 0 ÂşC and then extracted with EtOAc (100 mL x
3). The combined organic layer was dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified by silica gel flash column
chromatography (hexane/EtOAc 20:1 to 10:1) to obtain III-75e (2.599 g, 9.380 mmol) as
a yellow semisolid in 94% isolated yield.
Spectral data for III-75e: Rf = 0.52 (hexanes/EtOAc 8:1); 1H NMR (500 MHz,
CDCl3) δ 1.37 (s, 9H), 6.91 (d, J = 1.7 Hz, 1H), 7.36 (s, 1H), 7.36 – 7.49 (m, 2H), 7.71 –
7.80 (m, 1H), 8.08 (ddd, J = 8.1, 1.6, 0.9 Hz, 1H).

13

C NMR (126 MHz, CDCl3) δ 31.20,

34.84, 107.75, 115.87, 121.08, 122.64, 124.65, 126.40, 127.75, 134.58, 149.14, 150.97.
HRMS (ESI–) m/z 199.1136 [calcd. for C14H15O (M–H): 199.1123].

395

4.4.5 Syntheses of 3,3’-dialkylVANOL (Scheme 3.15)

OH
air, mineral oil
165 ÂşC, 36 h

HO
HO

Cy
Cy

III-75a
III-76a
51%

3,3’-Cy2VANOL II-76a: VANOL derivative III-76a was prepared from 3-cyclohexyl1-naphthol III-75a (6.64 mL, 29.3 mmol) by the General Procedure I with heating at 165
ÂşC for 36 h. The crude product was purified by column chromatography (silica gel,
DCM/hexanes: 1:3 to 1:1) to give II-76a as an off-white solid in 51% combined isolated
yield (3.360 g, mp 196-198 ÂşC, 7.460 mmol).
Spectral data for III-76a: Rf = 0.41 (hexanes/EtOAc 8:1); 1H NMR (500 MHz,
CDCl3) δ 0.74 – 1.38 (m, 8H), 1.52 – 1.81 (m, 12H), 2.20 (tt, J = 11.8, 3.3 Hz, 2H), 5.19
(s, 2H), 7.42 – 7.58 (m, 6H), 7.83 (dt, J = 8.3, 0.8 Hz, 2H), 8.22 (ddd, J = 8.3, 1.3, 0.6 Hz,
2H).

13

C NMR (126 MHz, CDCl3) δ 26.01, 26.78, 26.81, 33.71, 36.09, 41.42, 112.75,

117.92, 122.44, 122.70, 124.78, 127.11, 127.23, 134.96, 146.15, 149.80. HRMS (ESI–)
m/z 449.2519 [calcd. for C32H33O2 (M–H): 449.2481].

396

OH
air, mineral oil
165 ÂşC, 24 h

Bu
Bu

HO
HO

III-75b

III-76b
44%

3,3’-Bu2VANOL II-76b: VANOL derivative III-76b was prepared from 3-butyl-1naphthol III-75b (6.822 g, 34.10 mmol) by the General Procedure I with heating at 165 ºC
for 24 h. The crude product was purified by column chromatography (silica gel,
DCM/hexanes: 1:3 to 1:2) to give II-76b as a yellow semi solid in 44% combined isolated
yield (3.360 g, 7.550 mmol).
Spectral data for III-76b: Rf = 0.39 (hexanes/EtOAc 8:1); 1H NMR (500 MHz,
CDCl3) δ 0.86 (t, J = 7.4 Hz, 6H), 1.30 (qd, J = 7.3, 2.0 Hz, 4H), 1.60 (p, J = 7.6 Hz, 4H),
2.52 (qt, J = 14.8, 7.8 Hz, 4H), 5.41 (s, 2H), 7.52 – 7.59 (m, 4H), 7.64 (ddd, J = 8.2, 6.8,
1.3 Hz, 2H), 7.92 (d, J = 8.3 Hz, 2H), 8.36 (d, J = 8.3 Hz, 2H). 13C NMR (126 MHz, CDCl3)
δ 13.97, 22.62, 32.22, 33.32, 113.42, 120.00, 122.73, 122.80, 124.95, 127.21, 127.29,
134.95, 140.41, 150.20. HRMS (ESI–) m/z 397.2189 [calcd. for C28H29O2 (M–H):
397.2168].

397

OH
OH
air, mineral oil
165 ÂşC, 36 h

HO

III-75e
65%a
III-76e
35%

2,3'-di-tert-butyl-[1,2'-binaphthalene]-1',4-diol II-76e: VANOL isomer III-76e was
obtained from 3-tert-butyl-1-naphthol III-75e (1.856 g, 9.270 mmol) by the General
Procedure I with heating at 165 ÂşC for 24 h. The crude product was purified by column
chromatography (silica gel, DCM/hexanes 1:3 to 1:2) to give II-76e as an off-white
semisolid in 35% combined isolated yield (649.1 g, 1.629 mmol).
Spectral data for III-76e: Rf = 0.29 (hexanes/DCM 8:1); 1H NMR (500 MHz, CDCl3)
δ 0.86 (t, J = 7.4 Hz, 6H), 1.30 (qd, J = 7.3, 2.0 Hz, 4H), 1.60 (p, J = 7.6 Hz, 4H), 2.52 (qt,
J = 14.8, 7.8 Hz, 4H), 5.41 (s, 2H), 7.52 – 7.59 (m, 4H), 7.64 (ddd, J = 8.2, 6.8, 1.3 Hz,
2H), 7.92 (d, J = 8.3 Hz, 2H), 8.36 (d, J = 8.3 Hz, 2H).

13

C NMR (126 MHz, CDCl3) δ

13.97, 22.62, 32.22, 33.32, 113.42, 120.00, 122.73, 122.80, 124.95, 127.21, 127.29,
134.95, 140.41, 150.20. HRMS (ESI–) m/z 397.2173 [calcd. for C28H29O2 (M–H):
397.2168].

398

4.4.6 General Procedure S for deracemization of 3,3’-dialkylVANOL (Scheme 3.16) - illustrated for 3,3’-Cy2VANOL III-76a

Cy
Cy

OH
OH

air, 1.7 equiv CuCl,
3.2 equiv (+)-sparteine,
MeOH/CH2Cl2 2:1,
rt, 24 h

Cy
Cy

OH
OH

(R)-3,3’-Cy2VANOL
(R)-III-76a
70%, >99% ee

III-76a

(R)-3,3’-Cy2VANOL (R)-III-76a: To a 100 mL round bottom flask was added (+)sparteine (0.81 mL, 3.5 mmol, 3.5 equiv), CuCl (168 g, 1.70 mmol) and MeOH (27 mL)
under an atmosphere of air. The reaction mixture was sonicated in a water bath for 60
minutes with exposure to air. The flask was then sealed with a septum and purged with
argon, which was introduced by a needle under the surface for 60 minutes. At the same
time, to a 250 mL flame-dried round bottom flask was added racemic III-76a (451 mg,
1.00 mmol) and DCM (54 mL). The resulting solution was purged with argon for 60
minutes under the surface. The green Cu(II)-sparteine solution was then transferred via
cannula to the solution of racemic III-76a under argon and then the combined mixture
was sonicated for 15 minutes and then allowed to stir at room temperature overnight with
an argon balloon attached to the flask which was covered with aluminum foil. The reaction
was quenched by slow addition of NaHCO3 (sat. aq. 15 mL), H2O (40 mL) and most of
the organic solvent was removed under reduced pressure. The residue was then
extracted with DCM (30 mL × 3). The combined organic layer was dried over anhydrous

399

Na2SO4, filtered through Celite and concentrated to dryness. Purification of the crude
product by column chromatography on silica gel (DCM/hexanes 1:2) gave the product
(R)-III-76a as an off-white foamy solid (315 mg, mp 196-198 ÂşC, 0.699 mmol, 70%). The
optical purity was determined to be >99% ee by HPLC analysis (Pirkle DPhenylglycine
column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 8.69
min for (R)-III-76a (major) and Rt = 10.36 min for (S)-III-76a (minor).

Bu
Bu

OH
OH

air, 1.7 equiv CuCl,
3.2 equiv (+)-sparteine,
MeOH/CH2Cl2 2:1,
rt, 24 h

Bu
Bu

OH
OH

(R)-3,3’-Bu2VANOL
(R)-III-76b
19%, 95% ee

III-76b

(R)-3,3’-Bu2VANOL (R)-III-76b: The General Procedure S was followed with (±)3,3’-nBu2VANOL (1.568 g, 3.930 mmol). Purification of the crude product by column
chromatography on silica gel (DCM:hexanes 1:2) gave the product (R)-III-76b as an offyellow foamy semisolid (293 mg, 0.735 mmol, 19%). The optical purity was determined
to be 95% ee by HPLC analysis (Pirkle DPhenylglycine column, 98:2 hexane/iPrOH at
254 nm, flow-rate: 1.0 mL/min). Retention times: Rt = 8.73 min for (R)-III-76b (major) and
Rt = 10.37 min for (S)-III-76b (minor).

400

4.4.7 Aziridination catalyzed by boroxinate of 3,3’-dialkylVANOL (Scheme 3.17)

5 mol%
(R)-III-76a
(R)-3,3’-Cy2VANOL

III-77
0.5 mmol

O

OEt

N2

OPh
O B
O
O
* O B
O B
OPh
boroxinate catalyst

100 mol% III-77

rt

toluene, 80 ÂşC, 1 h,
then 0.5 mm Hg, 80 ÂşC, 0.5 h

+
N

I-176–H

20 mol% B(OPh)3
5 mol% H2O

Ph

5 mol% (R)-III-76a
boroxinate catalyst

N

solvent, 0.5 M, rt, 24 h

III-78
1.2 equiv

Ph

COOEt

III-79
28:1 cis/trans, 72%, 11% ee

Preparation of the boroxinate catalyst stock solution: To a 50 mL flame-dried
home-made Schlenk flask, prepared from a single-necked 50 mL pear-shaped flask that
had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped
with a stir bar and flushed with nitrogen was added (R)-3,3’-Cy2VANOL (11.3 mg, 0.0250
mmol), B(OPh)3 (29.0 mg, 0.100 mmol) and H2O (0.45 ÎźL, 0.025 mmol). Under a nitrogen
flow through the side-arm of the Schlenk flask, dry toluene (1 mL) was added through the
top of the Teflon valve to effect dissolution. The flask was sealed by closing the Teflon
valve, and then placed in an 80 ÂşC oil bath for 1 h. After 1 h, a vacuum (0.5 mm Hg) was
carefully applied by slightly opening the Teflon valve to remove the volatiles. After the
volatiles were removed completely, a full vacuum was applied and maintained for a period
of 30 min at a temperature of 80 ÂşC (oil bath). The flask was then allowed to cool to room
temperature and opened to nitrogen through the side-arm of the Schlenk flask. This
residue was then completely dissolved in dry toluene (1 mL) under a nitrogen flow through
side-arm of the Schlenk flask to afford the solution of the catalyst.

401

(2R,3R)-ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate III-79: The General
Procedure G was followed using (R)-3,3’-Cy2VANOL boroxinate catalyst prepared by the
procedure mentioned above (4.4.7). Purification of the crude aziridine by silica gel
chromatography (35 mm × 400 mm column, 19:1 hexanes/EtOAc as eluent, under
gravity) afforded pure cis-aziridine III-79 as a white solid in 72% isolated yield (129 mg,
0.360 mmol); cis/trans: 28:1. The optical purity of III-79 was determined to be 11% ee by
HPLC analysis ((CHIRALCEL OD-H column, 90:10 hexanes/iPrOH at 222 nm, flow-rate:
0.7 mL/min): retention times; Rt = 9.01 min (major enantiomer, III-79) and Rt = 4.67 min
(minor enantiomer, ent-III-79).

+
N
III-77
0.5 mmol

O

OEt

N2

Ph

5 mol% (R)-III-76b
boroxinate catalyst

N

solvent, 0.5 M, rt, 24 h

III-78
1.2 equiv

Ph

COOEt

III-79
32:1 cis/trans, 74%, –7% ee

(2R,3R)-ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate III-79: The General
Procedure G was followed using boroxinate catalyst prepared by the procedure
mentioned above (4.4.7) with (R)-3,3’-nBu2VANOL (10.0 mg, 0.0250 mmol, 95% ee).
Purification of the crude aziridine by silica gel chromatography (35 mm × 400 mm column,
19:1 hexanes/EtOAc as eluent, under gravity) afforded pure cis-aziridine III-79 as a white
solid in 74% isolated yield (133 mg, 0.371 mmol); cis/trans: 32:1. The optical purity of III79 was determined to be 7% ee by HPLC analysis ((CHIRALCEL OD-H column, 90:10
hexanes/iPrOH at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.01 min (minor
enantiomer, ent-III-79) and Rt = 4.67 min (major enantiomer, III-79).

402

REFERENCES

403

REFERENCES

1.
Mukherjee, M.; Gupta, A. K.; Lu, Z.; Zhang, Y.; Wulff, W. D., J. Org. Chem. 2010,
75 (16), 5643-5660.
2.
Ouihia, A.; Rene, L.; Guilhem, J.; Pascard, C.; Badet, B., J. Org. Chem. 1993, 58
(7), 1641-1642.
3.

Desai, A. A.; Wulff, W. D., J. Am. Chem. Soc. 2010, 132 (38), 13100-13103.

4.
JAMES, T.; M, S. S. SMALL MOLECULE INHIBITORS OF STAT3 WITH ANTITUMOR ACTIVITY WO2007136858 (A2). 2007-11-29.
5.

Liu, W.-J.; Lv, B.-D.; Gong, L.-Z., Angew. Chem. Int. Ed. 2009, 48 (35), 6503-6506.

6.
Kuroda, H.; Hanaki, E.; Izawa, H.; Kano, M.; Itahashi, H., Tetrahedron 2004, 60
(8), 1913-1920.
7.

Shing, T. K. M.; Luk, T.; Lee, C. M., Tetrahedron 2006, 62 (28), 6621-6629.

8.
Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J.
M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega,
N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.;
Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts,
R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V.
G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin,
R. L.; Fox, D. J.; Keith, T.; Laham, A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.;
Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A., Gaussian
03, Revision C.02. 2003.
9.

Hiraoka, S.; Harada, S.; Nishida, A., J. Org. Chem. 2010, 75 (11), 3871-3874.

10.
11.

Long, J.; Hu, J.; Shen, X.; Ji, B.; Ding, K., J. Am. Chem. Soc. 2002, 124 (1), 10-

11.
Guan, Y.; Ding, Z.; Wulff, W. D., Chemistry – A European Journal 2013, 19 (46),
15565-15571.
12.
Gan, Z.; Kawamura, K.; Eda, K.; Hayashi, M., J. Organomet. Chem. 2010, 695
(17), 2022-2029.
404

13.
Zanon, J.; Klapars, A.; Buchwald, S. L., J. Am. Chem. Soc. 2003, 125 (10), 28902891.
14.

Matsubara, K.; Ishibashi, T.; Koga, Y., Org. Lett. 2009, 11 (8), 1765-1768.

15.

Primer, D. N.; Molander, G. A., J. Am. Chem. Soc. 2017, 139 (29), 9847-9850.

16.
Lou, Z.; Zhang, S.; Chen, C.; Pang, X.; Li, M.; Wen, L., Adv. Synth. Catal. 2014,
356 (1), 153-159.
17.
Ding, Z.; Xue, S.; Wulff, W. D., Chemistry – An Asian Journal 2011, 6 (8), 21302146.
18.
Yu, X.; Zhu, P.; Bao, M.; Yamamoto, Y.; Almansour, A. I.; Arumugam, N.; Kumar,
R. S., Asian Journal of Organic Chemistry 2016, 5 (5), 699-704.
19.
Reddy, V.; Jadhav, A. S.; Vijaya Anand, R., Organic & Biomolecular Chemistry
2015, 13 (12), 3732-3741.
20.
Bhunia, S.; Wang, K.-C.; Liu, R.-S., Angew. Chem. Int. Ed. 2008, 47 (27), 50635066.
21.
Louvel, J.; Carvalho, J. F. S.; Yu, Z.; Soethoudt, M.; Lenselink, E. B.; Klaasse, E.;
Brussee, J.; Ijzerman, A. P., J. Med. Chem. 2013, 56 (23), 9427-9440.
22.
Chen, X.; Jin, J.; Wang, N.; Lu, P.; Wang, Y., Eur. J. Org. Chem. 2012, 2012 (4),
824-830.
23.

Shen, H.; Fu, J.; Gong, J.; Yang, Z., Org. Lett. 2014, 16 (21), 5588-5591.

405