CATALYTIC ASYMMETRIC SYNTHESIS ENABLED BY VANOL/VAPOL
BOROX CATALYSTS
By
Hong Ren

A THESIS
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of
Chemistry – Doctor of Philosophy
2013

ABSTRACT
CATALYTIC ASYMMETRIC SYNTHESIS ENABLED BY VANOL/VAPOL BOROX
CATALYSTS
By
Hong Ren
The development of a catalytic asymmetric method for the direct aminoallylation of
aldehydes is described that is based on a chiral polyborate catalyst generated from the
vaulted biaryl ligand VANOL. This method is scalable since it is chromatography free
and it gives rise to unprotected homo-allylic amines with excellent asymmetric
inductions over a broad range of substrates including both aryl and aliphatic aldehydes.
The unique catalyst system developed for this protocol involves the synergistic interplay
between a chiral Brønsted acid and a non-chiral Brønsted acid.
The mode of synergetic catalysis and the origin of enantioselection observed in this
reaction are investigated using a combination of experimental kinetic isotope effects
11

(KIEs), NMR spectroscopy ( B and

13

C) and theoretical calculations. The results from

these mechanistic studies provide fine details of the enantioselectivity determining
transition state geometry.
This direct aminoallylation of aldehydes protocol was then extended to the
preparation of 1,3-homo-allylic amino alcohols utilizing an unprecedented catalystcontrolled aza-Cope rearrangement and subsequently applied to the total syntheses of
the Sedum alkaloids.

A highly enantioselective route for the introduction of aziridines into functionalized
organic molecules was developed via a tandem acylation and aziridination of
TMSCHN2. The products are synthetically useful intermediates that can be readily
elaborated.

To,
my husband Quanxuan and our daughter Aimee

iv

ACKNOWLEDGEMENTS

One of the joys of completion is to look over the journey past and remember all the
people who have helped and supported me along this long but fulfilling road. It would
not have been possible to write this doctoral thesis without the help and support of the
kind people around me, to only some of whom it is possible to give particular mention
here.
First and foremost, my utmost gratitude to my advisor, William D. Wulff, for his
excellent guidance, patience, and providing me with an excellent atmosphere for doing
research. To work with you has been a real pleasure to me. You have been my
inspiration as I hurdle all the obstacles in the completion of this research work; you have
always been patient and encouraging in times of difficulties; you have listened to my
ideas and discussions with you frequently led to key insights. You have been a steady
influence throughout my Ph.D. career with your ability to approach compelling research
problems, your high scientific standards, and your hard work. I could not have asked for
better role model. I could not be prouder of my academic roots and hope that I can in
turn pass on the research values that he has given to me.
Special thanks to my committee, Dr. Babak Borhan, Dr. Xuefei Huang and Dr. Milton
R. Smith III for their support, guidance and helpful suggestions. Their guidance has
served me well and I owe them my heartfelt appreciation. Babak is a great teacher in
spectroscopic course, whose truly inspiring teaching made spectral analysis fascinating
to me and will definitely benefit my career. It is always fun to talk to Babak, and you
made me feel a friend, which I appreciate from my heart. I would like to say a big thank
you to Dr. Huang, for many “free lunches”, which give me a great chance to meet
v

different people and I have really enjoyed it. Also thank you for your prompt response to
all my recommendation letter requests, which definitely made my post-doc application
easier. I would also like to thank Dr. Smith for your helpful and insightful ideas and hard
questions during my second year oral examination. Thank you for making the Monday
night homework discussion so interesting in the organometallic course.
Members of the Wulff group also deserve my sincerest thanks, their friendship and
assistance has meant more to me than I could ever express. I greatly appreciate the
helps received from Dr. Aman Desai. Aman was my mentor when I joined the Wulff
group, and he has helped me whenever I need his help – seminar, oral examination and
job hunting – through my Ph.D. He is such an inspiring person, who always cheered
me up when I felt down in the lab with his positive attitudes of work and life. I would also
like to thank Dr. Zhenjie Lu for her helpful discussions on the first day after I joined the
Wulff group. Dr. Zhensheng Ding has been a really pleasure to work with, who always
made me laugh with his great humor. I had the great pleasure to work in the same
group with Dr. Li Huang. Li is one of the most hard-working people, I know. We are not
only colleagues but also close friends. I appreciate Li for making my life in the Wulff
group a lot more fun. Furthermore, I am very grateful to Dr. Yong Guan, Dr. Anil K.
Gupta, Dr. Munmun Mukherjee, Dr. Dima Berbasov and Dr. Nilanjana Majumdar for
creating a friendly research atmosphere and for their helps with my seminar practice.
From the present Wulff group, I have been very privileged to collaborate with Dr.
Mathew Vetticatt, an intelligent and passionate computational chemist. Mathew is one of
the most warm-hearted people I have ever known. He is always willing to help people in
need scientifically and personally. I also want to extend my sincere thanks to Wenjun

vi

Zhao. Wenjun is like my little sister in the past few years. She is a very precise person
when it comes to work in the lab. Besides, Wenjun is also a great cook, and I had the
fortune to taste many delicious foods she prepared. I also feel grateful to Wynter, who
sends greeting cards to every one in the group before Christmas every year. In addition,
I would like to thank Xin Zhang, a quite but very smart labmate. And I also want to thank
Yubai Zhou, Xiaopeng Yin, Yijing Dai and Prakash Shee for being wonderful labmates.
I must thank Dr. Dan Holmes for his kind help with NMR analysis. I have really
bugged him a lot. I thank Dr. Richard J. Staples for giving me so many suggestions on
how to grow crystals. I also thank Lijun Chen for her kind help whenever I needed to get
some HRMS samples.
My friends in US, China and other parts of the world are sources of joy and support.
Special thanks to Dottie Schmidt for being a caring landlord and friend. I want to thank
Bonnie and John Bankson for giving us kind support when we arrived in US in 2007. I
want to thank all the friends from the Baker’s group – Hui, Wen, Heyi and Zhe for their
friendship. I want to thank my friends from the babak group – Dr. Wenjing Wang, Dr.
Roozbeh Yousefi, Carmille Watson, Arvind Jaganathan and Kumar Ashtekar. I want to
thank my friends from the Huang group – Dr. Xiaowei Lu and Dr. Zhaojun Yin. I also
want to thank my friends from the Maleczka group – Dr. Luis Mori Quiroz and Dr.
Monica Norberg.
Last but not the least, I would like to thank my family. I wish to thank my parents.
Their love provided my inspiration and was my driving force. I owe them everything and
wish I could show them just how much I love and appreciate them. I wish to thank my
parents-in-law for coming to the US to help us with the baby. With their unconditional

vii

support, I can focus on my work in the lab and finish writing this thesis. I wish to thank
my sister, sisters-in-law and brothers-in-law for their endless love and support. Finally, I
would like to thank the two precious gifts in my life. Aimee Yihan Zhang was born on
th

May 17 , 2012. She is an angel to me. Thank you for letting me grow with you, Aimee. I
would not have contemplated this road if not for my husband, Quanxuan Zhang,
who accompanied me in good and bad times during my Ph.D study. His love and
encouragement allowed me to finish this journey. To Quanxuan, thank you.

viii

TABLE OF CONTENTS

CHAPTER ONE
CHIRAL HOMO-ALLYLIC AMINES IN ORGANIC CHEMISTRY
1.1 Introduction........................................................................................................... 1
1.2 Main approaches towards the catalytic asymmetric synthesis of chiral homoallylic amines .............................................................................................................. 1
CHAPTER TWO
DIRECT CATALYTIC ASYMMETRIC AMINO-ALLYLATION OF ALDEHYDES–
SYNERGISM OF A CHIRAL BOROX BRØNSTED ACID AND BENZOIC ACID
2.1 Introduction........................................................................................................... 5
2.2 Initial results of the catalytic asymmetric aza-Cope rearrangement with chiral
Brønsted acid BOROX 9 ............................................................................................ 6
2.3 Serendipitous discovery of the synergistic effect of benzoic acid on BOROX
catalyst 9 .................................................................................................................... 8
2.4 Mapping the protecting group for aza-Cope rearrangement with BOROX 9...... 11
2.5 Optimization of the solvent for the aza-Cope rearrangement with BOROX
catalyst 9 .................................................................................................................. 13
2.6 Study of different achiral acids as additive ......................................................... 14
2.7 Diversity of BOROX catalyst 9 ........................................................................... 16
2.7.1 Tuning the BOROX catalyst 9 with phenol modules ................................... 17
2.7.2 Tuning the BOROX catalyst 9 with various ligands..................................... 19
2.8 Direct aminoallylation of benzaldehyde.............................................................. 22
2.9 Substrate scope for direct aminoallylation of aryl aldehydes ............................. 23
2.10 Substrate scope for direct aminoallylation of aliphatic aldehyde...................... 25
2.11 Scale-up, recycle of starting amine and VANOL Ligand .................................. 27
2.12 Total synthesis of (R)-Coniine .......................................................................... 27
2.13 Determination of the absolute configuration of amine 27h and 27o from the
direct catalytic asymmetric aminoallylation of aldehydes 25h and 25o .................... 28
2.14 Conclusion........................................................................................................ 30
CHAPTER THREE
MECHANISTIC STUDIES OF THE CHIRAL BRØNSTED ACID CATALYZED
AZA-COPE REARRANGEMENT – UNDERSTANDING THE SYNERGISYM
OF CHIRAL AND ACHIRAL BRØNSTED ACIDS
3.1 Introduction......................................................................................................... 31
3.2 Probing the role of benzoic acid additive in the aza-Cope rearrangement
catalyzed by the chiral BOROX catalyst 9................................................................ 32
13
3.3 Experimental C kinetic isotope effects (KIEs) ................................................. 36
3.3.1 Design of experiment .................................................................................. 36

ix

3.3.2 Experimental KIEs....................................................................................... 38
3.4 Spectral data in support of a covalent modification of the catalyst-imine
complex by benzoic acid .......................................................................................... 39
13
11
3.4.1 Design of C and B NMR experiments .................................................. 40
3.4.2 Interpretation of
13

13

11

C NMR and

11

13

B NMR with 1- C-benzoic acid ............. 42

3.4.3 C NMR and B NMR with tetrabutylammonium benzoate and
methyl benzoate .................................................................................................. 47
3.5 Possible active catalyst structures ..................................................................... 48
3.6 Transition state models ...................................................................................... 50
3.6.1 Transition structures without benzoic acid .................................................. 51
3.6.2 Transition structures with benzoic acid ....................................................... 53
3.7 Spin saturation transfer experiment in support of the dynamic formation of
diastereomers of catalyst upon the addition of benzoic acid.................................... 55
3.8 Predicted KIEs and interpretation....................................................................... 60
3.9 Equilibrium study of the aza-Cope rearrangement with BOROX catalyst 9 and
benzoic acid ............................................................................................................. 62
3.10 Conclusion........................................................................................................ 63
CHAPTER FOUR
TOTAL SYNTHESIS OF SEDAM ALKALOIDS VIA CATALYST CONTROLLED
AZA-COPE REARRANGEMENT AND HYDROFORMYLATION
WITH FORMALDEHYDE
4.1 Introduction......................................................................................................... 65
4.2 Retrosynthetic analysis of (+)-allosedridine........................................................ 69
4.3 Direct aminoallylation of chiral b-alkoxy aldehydes............................................ 70
4.4 Direct aminoallylation of chiral !-alkoxy aldehydes............................................ 71
4.5 Optimization of the intramolecular amidocarbonylation with formaldehyde ....... 72
4.6 Synthesis of (-)-Coniine ...................................................................................... 73
4.7 Total synthesis of (+)-Sedridine and (+)-allosedridine........................................ 75
4.8 Conclusion.......................................................................................................... 76
CHAPTER FIVE
TRIMETHYLSILYLDIAZOMETHANE AS A VERSATILE STITCHING AGENT
FOR THE INTRODUCTION OF AZIRIDINES INTO FUNCTIONALIZED
ORGANIC MOLECULES
5.1 Introduction......................................................................................................... 77
5.2 Synthesis of diazo ketone via the diazo transfer method ................................... 79
5.3 Synthesis of diazo ketones with TMSCHN2 ....................................................... 80
5.3.1 Optimization of the number of equivalents of TMSCHN2 ............................ 82
5.3.2 Sovent study for the synthesis of diazo ketone 74b .................................... 84
5.3.3 Substrate scope for the synthesis of diazo ketones with TMSCHN2 .......... 84
5.4 Introduction of aziridines into functionalized organic molecules......................... 87

x

5.4.1 Optimization of the aziridination reaction with diazo ketone 74a................. 87
5.4.2 Optimization of the N-protecting group........................................................ 88
5.4.3 Substrate scope for tandem acylation/aziridination of TMSCHN2 ............... 89
5.5 Deprotection of MEDAM group .......................................................................... 91
5.6 Diastereoselective synthesis of tetrahydrofurylamines ...................................... 92
5.7 Conclusion.......................................................................................................... 93
CHAPTER SIX
EXPERIMENTAL SECTION.......................................................................................... 95
REFERENCES ............................................................................................................ 244

xi

LIST OF TABLES

Table 2. 1 Study of effect of the amount of benzoic acid on the asymmetric induction . 10
Table 2. 2 Solvent screening for the aza-Cope rearrangement of imine 23f ................. 13
Table 2. 3 Effects of various acids on the BOROX catalyst 9 in the aza-Cope
rearrangement ............................................................................................................... 15
Table 2. 4 Screening various phenols and alcohols ...................................................... 17
Table 2. 5 Tuning the BOROX catalyst 9 with 7,7’-substituted ligands ......................... 20
Table 2. 6 Tuning the BOROX catalyst 9 with 4,4’-substituted ligands ......................... 21
Table 2. 7 Optimization of molecular sieve loading ....................................................... 23
Table 3. 1 The integration of peaks observed in the

11

B NMR (Figure 3. 4) ................. 43

Table 4. 1 Direct aminoallylation of chiral "-alkoxy aldehydes ...................................... 70
Table 4. 2. Direct aminoallylation of a chiral !-alkoxy aldehyde .................................... 72
Table 4. 3 Optimization of the intramolecular amidocarbonylation with formaldehyde.. 73
Table 5. 1 Optimization of the number of equivalents of TMSCHN2 ............................. 82
Table 5. 2 Solvent study for the synthesis of diazo ketone 74b..................................... 84
Table 5. 3 Substrate scope for the synthesis of diazo ketones 74 via TMSCHN2 ......... 85
Table 5. 4 Optimization of the aziridination reaction...................................................... 87
Table 5. 5 Optimization of the N-protecting group ......................................................... 89
Table 5. 6 Aziridination of functionalized diazo ketones ................................................ 90

xii

LIST OF FIGURES

Figure 2. 1 Initial results with chiral Brønsted acid BOROX 9 ......................................... 7
Figure 2. 2 CH- " interaction between BOROX catalyst and imine in Wulff cisaziridination reaction ...................................................................................................... 11
Figure 2. 3 Optimization of the aryl groups for maximum asymmetric induction ........... 12
Figure 2. 4 Two dimensional diversity of the BOROX 9 catalyst ................................... 16
Figure 3. 1 Study of the effect of the equivalents of benzoic acid on enantioselectivity
and reaction rate of the aza-Cope rearrangement catalyzed by BOROX catalyst 9 ..... 33
Figure 3. 2 Allosteric regulation of BOROX catalyst 9 with benzoic acid....................... 36
13

Figure 3. 3 Experimental C KIEs for the aza-Cope rearrangement of 36 catalyzed
by (S)-VANOL-BOROX catalyst 9 ................................................................................. 39
Figure 3. 4

11

B NMR spectra of catalyst modification studies ....................................... 42

13

13

Figure 3. 5 C NMR spectra of catalyst modification studies using 1- C-benzoic
acid ................................................................................................................................ 44
13

Figure 3. 6 NMR spectra of catalyst modification studies with imine 39 using 1- Cbenzoic acid ................................................................................................................... 46
11

Figure 3. 7 B NMR with tetrabutylammonium benzoate and methyl benzoate
(Integrations shown in italic) .......................................................................................... 47
Figure 3. 8 Transition state geometries for the aza-Cope rearrangement of 23f
catalyzed by (S)-VANOL-BOROX without benzoic acid additive computed using the
ONIOM method described in Scheme 3. 7B.................................................................. 52
Figure 3. 9 Transition state geometries for the aza-Cope rearrangement of 23f
catalyzed by (S)-VANOL-BOROX with benzoic acid additive computed using the
ONIOM method described in Scheme 3. 7B.................................................................. 54
Figure 3. 10 Interconversion of diastereomeric catalyst species ................................... 56
Figure 3. 11 Spin saturation transfer with imine 23f (Precatalyst was prepared and
regents were added in the sequence as shown in Scheme 3. 5) .................................. 57

xiii

Figure 3. 12 NMR spin saturation transfer with imine 38 (Precatalyst was prepared
and regents were added in the sequence as shown in Scheme 3. 5) ........................... 58
Figure 3. 13 Predicted

13

C NMR KIEs for the aza-Cope rearrangement of 36 ............. 61

xiv

LIST OF SCHEMES

Scheme 1. 1 Two approaches for catalytic asymmetric synthesis of homo-allylic
amines ............................................................................................................................. 2
Scheme 1. 2 Kobayashi’s asymmetric amino-allylation of aldehydes ............................. 3
Scheme 1. 3 Ruiping’s catalytic asymmetric amino-allylation of aldehydes .................... 3
Scheme 2. 1 A new class of chiral Brønsted acid BOROX 9........................................... 5
Scheme 2. 2 Self-assembled BOROX catalyst 9 with imines.......................................... 6
Scheme 2. 3 Synergistic interplay of BOROX 9 and benzoic acid .................................. 8
Scheme 2. 4 Orthogonal interplay of chiral and non-chiral Brønsted acids..................... 9
Scheme 2. 5 Substrate scope for direct catalytic asymmetric aminoallylation of
aromatic aldehydes with VANOL BOROX catalyst........................................................ 24
Scheme 2. 6 Substrate scope for direct catalytic asymmetric aminoallylation of
aliphatic aldehydes with the VANOL BOROX catalyst .................................................. 26
Scheme 2. 7 Recycle of diaryl ketone 28 ...................................................................... 27
Scheme 2. 8 Total synthesis of (R)-Coniine .................................................................. 28
Scheme 2. 9 Absolute configuration in the direct catalytic asymmetric aminoallylation 29
Scheme 3. 1 Synergistic interplay of chiral BOROX catalyst 9 and benzoic acid.......... 32
Scheme 3. 2 Probing the role of benzoic acid ............................................................... 35
Scheme 3. 3 Design of starting material KIE measurement .......................................... 37
Scheme 3. 4 Design of product KIE measurement........................................................ 38
Scheme 3. 5 Design of

13

C and

11

B NMR experiments................................................ 41

Scheme 3. 6 Possible structures of modified catalyst ................................................... 49
Scheme 3. 7 Division of layers for ONIOM (DFT:Semi-empirical) calculations ............. 51
Scheme 3. 8 Equilibrium study of the aza-Cope rearrangement ................................... 63

xv

Scheme 4. 1 Sedum and related alkaloid natural products ........................................... 65
Scheme 4. 2 Direct aminoallylation of non-chiral aldehydes ......................................... 66
Scheme 4. 3 Kumar’s catalyst controlled synthesis of syn/anti-1,3-aminoalcohols
from a single substrate .................................................................................................. 67
Scheme 4. 4 Hydroformylation with formaldehyde ........................................................ 68
Scheme 4. 5 Retrosynthesis of (+)-sedridine and (+)-allosedridine............................... 69
Scheme 4. 6 Total synthesis of (-)-Coniine.................................................................... 74
Scheme 4. 7 Synthesis of (+)-Sedridine and (+)-Allosedridine...................................... 75
Scheme 5. 1 Three approaches towards catalytic asymmetric aziridination ................. 77
Scheme 5. 2 The Antilla-Wulff catalytic asymmetric aziridination.................................. 78
Scheme 5. 3 Synthesis of diazo ketone 74 via the diazo transfer method .................... 80
Scheme 5. 4 Tandem acylation/aziridination of TMSCHN2 ........................................... 80
Scheme 5. 5 Synthesis of diazo ketone 74a by TMSCHN2 ........................................... 81
Scheme 5. 6 Proposed mechanism for the formation of diazo ketone .......................... 83
Scheme 5. 7 Preparation of the diazo ketone 74k via the corresponding acid
anhydride ....................................................................................................................... 86
Scheme 5. 8 Deprotection of MEDAM group from (2R, 3R)-78i.................................... 92
Scheme 5. 9 Diastereoselective access to enantiomeric tetrahydrofurylamines........... 93

xvi

CHAPTER ONE
CHIRAL HOMO-ALLYLIC AMINES IN ORGANIC CHEMISTRY
1.1 Introduction
Chiral homo-allylic amines have been recognized in biologically active natural
products, including angustifoline

1

and cryptophycin 337.

2

They have also been
3

identified in synthetic medicinal compounds, such as eponemycin.

In addition, chiral homo-allylic amines have served as key intermediates in total
syntheses of complex natural product, such as indolizomycin,
5

6

4

the aminosugar of

vancosamine, and desoxoprosopinine, as well as halichlorinespirocycle.

7

Perhaps the most significant aspect of chiral homo-allylic amines relies on their
synthetic versatility as chiral building blocks for the construction of a broad range of
multi-functional organic compounds. The rich chemistry with the alkene moiety provides
8

great access to amino alcohols, aminoalkyl epoxides, amino acids and aminoalkyl
9

cyclopropane. Furthermore, with the development of ring-closing metathesis and the
hydroformylation reaction, various nitrogen-containing heterocycles, such as azetidines,
piperidines, azepines, and pyrrolidine derivatives can be assembled quickly.
1.2 Main approaches towards the catalytic asymmetric synthesis of chiral homoallylic amines
A measure of the value of chiral homo-allylic amines in organic synthesis is the large
volume of work that has been devoted to their construction. Two main methods have
been reported for the catalytic asymmetric synthesis of homo-allylic amines as outlined
in Scheme 1. 1.

1

Scheme 1. 1 Two approaches for catalytic asymmetric synthesis of homo-allylic amines
catalyst *

O
R

H

NH2
R

M

catalyst * R

Aminoallylation of aldehydes

N

PG
H

Allylation of imines

The development of catalytic asymmetric allylation of imines has received much
attention.

10

Although significant progress has been made in this area, the catalytic

asymmetric allylation of aliphatic imines remains a considerable challenge and the use
of basic allylmetallic reagents limits the application of the methodology for basesensitive substrates.
In contrast to allylation of imines, less progress has been made for the catalytic
asymmetric amino-allylation of aldehydes; only one report has appeared thus far.

11

Although amino-allylation of aldehydes is more direct given the fact that a huge variety
of aldehydes are commercially available, the purification of imines, especially aliphatic
imines, can be a hassle.
In 2006, Kobayashi reported a stoichiometric asymmetric amino-allylation of
aldehydes involving an aza-Cope rearragement of imines 3 derived from 3-bytenyl-1amines of the type 1 as shown in Scheme 1. 2. They were able to sterically drive the
reversible Cope-rearrangement to the isomer 4 which formally represents the “transfer
amino-allylation” of the aldehyde 2.

Kobayashi’s method involves a stoichiometric

auxiliary in the form of a chiral amine 1 and has been adopted for use in natural product
12

syntheses.

2

Scheme 1. 2 Kobayashi’s asymmetric amino-allylation of aldehydes

NH2

O

+
R

O

1, 1 equiv

N
H

R

O

3

2
CSA (10 mol%)
DCE, 24 h

R
H
NH2

H2NOH•AcOH

N

R
O

5

4

In 2008, Ruiping and co-workers developed a catalytic asymmetric amino-allylation
of aldehydes on the basis of a condensation – aza-Cope rearrangement sequence

11

(Scheme 1. 3).
It was found that two phenyl groups were sufficient to electronically drive the
equilibrium to the isomer 7. The aza-Cope rearrangement was catalyzed by 10 mol%
chiral phosphoric acid 8, affording moderate to good enantioselectivity with aromatic
aldehydes. However, a lacuna in the only existing method for the asymmetric catalytic
amino-allylation of aldehydes is the sub-class of aliphatic aldehydes.
Scheme 1. 3 Ruiping’s catalytic asymmetric amino-allylation of aldehydes

3

Scheme 1.3 (cont’d)

2-naphthyl
O
R

Ph
H

+

Ph

NH2

6

Ph

10 mol % cat. 8
MTBE, 3Å MS,
50 °C, 48 h

N

O
O
P
O
OH

Ph

R

7

Cat. 8

2-naphthyl

The development of a more efficient catalytic asymmetric amino-allylation of
aldehydes protocol that gives excellent enantioselectivity for both aromatic and aliphatic
substrates has remained an elusive, albeit an actively pursued goal in the field.

4

CHAPTER TWO
DIRECT CATALYTIC ASYMMETRIC AMINO-ALLYLATION OF ALDEHYDES
– SYNERGISM OF A CHIRAL BOROX BRØNSTED ACID AND BENZOIC ACID
2.1 Introduction
The field of chiral Brønsted acid catalysis has grown to great prominence in a very
short period of time.

13

Phosphoric acid derivatives of BINOL and BINOL derivatives are

by far the most important members of the family of strong chiral Brønsted acids, due to
the great diversity of catalysts by introduction of substituents primarily into the 3,3’positions of BINOL and to a lesser extent at the 6,6’-positions.
Scheme 2. 1 A new class of chiral Brønsted acid BOROX 9

R

2

R

OR

1

O
O
P
O
OH

R
1
R

O
O

3

O B
B

O
O B
OR

R

[H-imine]

3

R2

phosphoric acids derived from
BINOL and BINOL derivatives

BOROX catalyst 9

In the course of development of a catalytic asymmetric method for the synthesis of
cis-aziridines, our former group members have discovered a new class of strong chiral
Brønsted acids in the form of the boroxinate species 9 (Scheme 2. 1) that exists as an
ion pair consisting of a chiral boroxinate anion derived from either the VANOL 12 or
VAPOL 13 ligand (Figure 2. 1) and a protonated iminium.

14

A pre-catalyst mixture

mesoborate B1 and pyroborate B2 were formed initially when ligand VANOL or VAPOL
was heated with 4 equivalent of B(OPh)3 and 1equivalent of H2O. NMR and crystal

5

structure evidence revealed that addition of an imine to this pre-catalyst mixture resulted
in the self-assembly of BOROX catalyst 9 (Scheme 2. 2). Boroxinate assembly can be
induced by the imine either from the ligand and 4 equivalent of commercial B(OPh)3 or
from the ligand and 3 equivalnet of BH3•SMe2, 2 equivalent of phenol and 3 equivalent
of H2O.
Scheme 2. 2 Self-assembled BOROX catalyst 9 with imines

+ 2 HO R3
Ph
Ph

OH
OH

1) 100 °C, 1 h. toluene
+ 3 H2O 2) 100 °C, 0.5 h, 0.1 mm Hg Ph
Ph
+ 3 BH3•SMe2

Ligand

O
B OPh
O

B1 (mesoborate)
+
Imines
OPh
O B
O
B
O [H-imine]
O
O B
OPh

Ph
Ph

BOROX catalyst 9
self-assembled catalyst

Ph
Ph

OPh
O
B O B
O
OPh

B2 (pyroborate)
pre-catalyst mixture

2.2 Initial results of the catalytic asymmetric aza-Cope rearrangement with chiral
Brønsted acid BOROX 9

6

Figure 2. 1 Initial results with chiral Brønsted acid BOROX 9

Ph

20 mol% catalyst

Ph

Ph

Ph
N

N

toluene, 60 °C

Ph

10

*

11

Ph

R

R
Ph
Ph

OH
OH

Ph
Ph

OH
OH

OH
OH

R

(S)-VANOL (R=H)
% ee
12, R=H, 19
14, R=Ph, 3

% yield
82
70

R

(S)-VAPOL, 13
% ee
4

% yield
67

(R)-BINOL
% ee
15, R=H, 4
16, R=Ph, 5

% yield
49
ND

Catalyst made from 1 equiv of ligand, 3 equiv of BH3!SMe2, 2 equiv of phenol
and 3 equiv of H2O at 100 °C for 1 h, followed by full vacuum, 100 °C, 30 min.
For ease of optimization, imine 10 was chosen to initially examine the aza-Cope
rearrangement with BOROX catalysts derived from various ligands as shown in Figure 2.
1. The standard conditions for imine 10 will then be translated to other aldehydes later
on. We hoped that imine 10 could induce the self-assembly of the active BOROX
catalyst 9 and in the same time frame, that BOROX 9 would catalyze the aza-Cope
rearrangement to afford the masked homo-allylic amines 11. With 20 mol% BOROX
catalyst derived from (S)-VANOL 9, 19 % ee and 82% yield were obtained. When a
sterically hindered VANOL derivative 14 was utilized, the ee dropped to 3%. A decrease
in ee was also observed with BOROX catalysts prepared from VAPOL 13, BINOL 15
and BINOL derivative 16.

7

The background reaction test with imine 10 at 60 °C in toluene revealed that the
aza-Cope rearrangement did not occur under thermochemical conditions in the absence
of catalyst.
2.3 Serendipitous discovery of the synergistic effect of benzoic acid on BOROX
catalyst 9
Scheme 2. 3 Synergistic interplay of BOROX 9 and benzoic acid

O
Ph

Ph

+
H

H2N

Ph

MgSO4, CH2Cl2
rt

Ph Ph
N

Ph

17

H

20 mol% (R)-VANOL
BOROX 9
toluene, 60 °C

10

Ph
N

Ph

Ph

freshly distilled

100% conversion, 48 h

11
19% ee

two-week old

100% conversion, 12 h

benzoic acid 27% ee

[O]

During the course of optimization, it was found that the rearrangement of imine 10
prepared from a sample of benzaldehyde that had not been distilled for two-weeks led
to a higher induction with the VANOL BOROX catalyst 9 (27% ee, 69% yield, Scheme
2. 3). It was speculated that a small amount of benzaldehyde was oxidized to benzoic
acid, and that its presence in a catalytic amount was responsible for the enhanced
asymmetric induction (Scheme 2. 3).
To test this assumption, 10 mol% benzoic acid was thus added to the reaction
mixture. A significant increase in ee (from 27 % ee without benzoic acid vs. 45% ee with
benzoic acid) was observed for the VANOL-derived BOROX catalyst 9.

8

Scheme 2. 4 Orthogonal interplay of chiral and non-chiral Brønsted acids

EtO2C

NHAc

CO2Et

+ Ph

N

O

*

CH3

19

RO P OH

NHAc

+ AcOH

Ph

OR

18

Catalyst

H

R'

H

O
R'

N
H
O

RO P O
OR

AcO

NHAc
Ph

Ph

CH3

O

NHAc
CH3

RO P O
HN
RO
H
H

H

R'

R'
N
H

Antilla's asymmetric hydrogenation of enamides catalyzed by a dual acid system

R

2

P
ArO

O

21
O

O

ArO

1
R

OH

*BH

N

OH

R
O

ArO
P
ArO

1

R

2

H

20
H
N

O
R

1

2
R
H

Ruiping's coorperative Brønsted acid catalyzed synthesis of isoquinuclidines

The orthogonal interplay of a chiral Brønsted acid and a non-chiral Brønsted acid
has been reported by Rueping’s group in 2006 and Antilla’s group in 2009.

15,16

In the

former reaction, the two Brønsted acids were involved in two parallel steps, while for the

9

latter, an achiral Brønsted acid was utilized to keep a sufficient concentration of an aryl
iminium and the addition of the achiral acid did not affect the asymmetric induction.
However, for our approach, the addition of benzoic acid quickly led to a color change of
the reaction mixture and significant enhancement in the enantioselection was achieved,
which clearly indicated a synergistic interaction of these two Brønsted acids on the
asymmetric induction. To the best of our knowledge, this is the first example of the nonorthogonal coexistence of a chiral and an achiral Brønsted acid in asymmetric catalysis.
Table 2. 1 Study of effect of the amount of benzoic acid on the asymmetric induction

Ph Ph
N
Ph

10 mol% (R)-VANOL
BOROX 9
n mol% benzoic acid
toluene, 60 °C
18 h

H

a.

N

Ph

Ph

10

Entry
1
2
3
4
5
6
7
8

Ph

11
a

n
0
1
5
10
15
20
40
60

%Yield
77
80
85
81
81
83
84
84

b

%ee
25
40
69
72
72
70
68
66

c

Unless otherwise specified, all reactions were
performed on a 0.1 mmol scale in toluene at 0.2 M in
imine 10 for 18 h and went to 100% completion at the
indicated temperature. Catalyst 9 was prepared by
heating 1 equiv of ligand, 3 equiv of BH3!SMe2, 2
equiv of PhOH, and 3 equiv of H2O in toluene at 100
°C for 1 h followed by removal of volatiles at 100 °C
b.
for 0.5 h at 0.1 mm Hg. Isolated yield after silica gel
column chromatography.

c.

Chiral HPLC.

10

An equal amount of benzoic acid with the chiral VANOL-BOROX catalyst led to the
maximum ee (Table 2. 1, entry 5), and any further increase in the amount of benzoic
acid resulted in a marginal decrease in enantioselectivity (Table 2. 1, entry 3 and 4).
Under the same reaction conditions, with just benzoic acid itself, at the absence of
VANOL-BOROX 9 catalyst, the aza-Cope rearrangement did not occur.
2.4 Mapping the protecting group for aza-Cope rearrangement with BOROX 9
Figure 2. 2 CH- " interaction between BOROX catalyst and imine in Wulff cisaziridination reaction

H3C

OCH3
CH3

CH-! interaction
O
Ph
Ph

CH3

N
H
H

O
O

O B
B

O
O B
OPh

OCH3
CH3

Inspired by the crucial non-covalent CH-" interaction (Figure 2. 2) between the
boroxinate catalyst and the imine substrate in our previously reported aziridination
protocol,

14,17

we turned our attention to the engineering of this potential modular

interaction with different diarylmethyl groups in the aminoallylation of aldehydes. A
correlation between the asymmetric induction and the electronic and steric effects of
various diarylmethyl groups was established by comparing the diarylmethyl groups with
the benchmark diphenylmethyl group 10. As shown in Figure 2. 3, the introduction of an
electron-donating group (Figure 2. 3, compound 23a, 23% ee) into the aryl group greatly
abated the induction, while for 23c an electron-withdrawing substituent hardly caused a

11

change. However, installation of two methyl groups to the electron-rich aryl group
(compound 23e, 64% ee) could cancel the adverse effect of the methoxyl group,
conveying a notable gain in ee. Conversely, for the aziridination reaction that we have
previously examined, the presence of the methoxyl group and two methyl groups in the
3- and 5- positions was equally important to the enantioselection.

17h,k

We then decided

to replace the two methyl groups in 23e with even larger t-butyl groups (compound 23b,
39% ee), however, the ee greatly dropped by 25%. Based on the results obtained for
compounds 23a, 23b and 23e, a new modular group (compound 23f, 69% ee) was
designed for this reaction, which, as we expected, gave the optimal asymmetric
induction amongst all the diarylmethyl groups evaluated.
Figure 2. 3 Optimization of the aryl groups for maximum asymmetric induction

Ar
N

5 mol% benzoic acid
toluene, 60 °C, 18 h

Ph

10, 23a-f
O

Ar

10 mol % (R)-VANOLBOROX 9 a

Ar

N

Ar

Ph

11, 24a-f
F

O
t-Bu

O

t-Bu

Ar =

10

23a

23b

23c

23d

23e

23f

% yield b

76

47

51

76

71

70

85

% ee c

42

23

39

40

40

64

69

a.

Unless otherwise specified, all reactions were performed on a 0.1 mmol scale in
toluene at 0.2 M in imine for 18 h and went to 100% completion at the indicated
temperature. Catalyst 9 was prepared by heating 1 equiv of ligand, 3 equiv of
BH3!SMe2, 2 equiv of PhOH, and 3 equiv of H2O in toluene at 100 °C for 1 h
followed by removal of volatiles at 100 °C for 0.5 h at 0.1 mm Hg. The catalyst

12

Figure 2.3 (cont’d)
solution was transferred to a Schlenk test tube containing imine, directly followed
by addition of benzoic acid at room temperature. The reaction mixture was heated
b.
c.
to 60 °C.
Isolated yield after silica gel column chromatography. Chiral HPLC.
2.5 Optimization of the solvent for the aza-Cope rearrangement with BOROX
catalyst 9
Table 2. 2 Solvent screening for the aza-Cope rearrangement of imine 23f

Ar
N

Ar

10 mol % (R)-VANOLBOROX 9

Ar
N

Ph

5 mol % benzoic acid
23f
solvent, 60 °C
Ar = 3,5-Me2C6H3
(0.1 mmol, 0.2 M)

Entry

a.

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

a

Solvent
trifluorotoluene
benzene
toluene
xylenes
p-xylene
o-xylene
m-xylene
mesitylene
t-butylbenzene
anisole
THF
MTBE
CH3CN
ethylacetate
dichloroethane
CCl4
cyclohexane

Time
(h)
18
18
18
18
32
24
18
18
18
18
18
18
24
18
18
24
32

Ar

Ph

24f

%Yield
b
24f
73
78
85
86
82
83
92
86
63
80
77
79
75
83
79
82
78

%ee
c
24f
30
60
69
75
72
70
78
78
68
53
-15
33
-6
14
3
67
47

Unless otherwise specified, all reactions were performed on a
0.1 mmol scale in toluene at 0.2 M in imine 23f for 18 h and
went to 100% completion at the indicated temperature. Catalyst

13

Table 2.2 (cont’d)
9 was prepared by heating 1 equiv of ligand, 3 equiv of
BH3!SMe2, 2 equiv of PhOH, and 3 equiv of H2O in toluene at
100 °C for 1 h followed by removal of volatiles at 100 °C for 0.5
h at 0.1 mm Hg. The catalyst solution was transferred to a
Schlenk test tube containing imine, directly followed by addition
b.
of benzoic acid at room temperature. Isolated yield after silica
gel column chromatography.

c.

Chiral HPLC.

To further optimize the reaction conditions, we varied the solvent and found that the
highest asymmetric induction was observed when the reaction was carried out in mxylene and mesitylene at 60 °C (Table 2. 2, entry 7 and 8). However, considering the
high boiling point of mesitylene (165 °C), we decide to use m-xylene as the solvent of
choice. The solvent study was carried out before we found equal amount of benzoic
acid with respect to catalyst 9 gave the maximum enantioselectivity.
2.6 Study of different achiral acids as additive
Although a broad range of achiral acids were examined, benzoic acid as additive
gave superior yields and asymmetric induction than any of the other types of acids
screened (Table 2.3). Introduction of electron-donating substituents into benzoic acid
led to subtle changes in the enantioselectivity (entry 21 and 22). Electron-withdrawing
substituents greatly abated the asymmetric induction (entry 23). Steric tuning of various
benzoic acids seemed not to affect the asymmetric induction (entry 10-12) unless two
substituents were introduced into the ortho-positions simultaneously (entry 27 and 35).

14

Table 2. 3 Effects of various acids on the BOROX catalyst 9 in the aza-Cope
rearrangement
Ar

Ar

Ar
10 mol % (R)-VANOLBOROX 9
N
N
Ar
Ph
10 mol % acid
23f
Ph
m-xylene, 60 °C
Ar = 3,5-Me2C6H3
24f
(0.1 mmol, 0.2 M)

Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33

a

Acid (pKa)

Time (h)

TFA (-0.26)
diphenyl hydrogen phosphate (1)
benzoic acid (4.2)
acetic acid (4.8)
trimethylacetic acid
Adamantane Carboxylic Acid
Chloroacetic Acid (2.86)
CF3SO2NH2 (6.3)
diethyl phosphoramidate
phenylboronic acid (7)
phenol (10)
2-Naphthylacetic Acid (~4.31)
4-ethoxyphenylacetic acid
phenylacetic acid
Trifluoro-p-tolylacetic acid
Diphenylacetic acid
2-fluorobenzoic acid (3.3)
3-fluorobenzoic acid (3.9)
4-fluorobenzoic acid (4.1)
4-methoxybenzoic acid (4.6)
4-propoxybenzoic acid
4-dimethylaminobenzoic acid (5.1)
4-nitrobenzoic acid (3.3)
4-tert-butylbenzoic acid
4-trifluoromethylbenzoic acid
4-phenylbenzoic acid
2,4,6-trimethylbenzoic acid
1-naphthalenecarboxylic acid (3.7)
2-methylbenzoic acid (3.9)
3-methylbenzoic acid (4.2)
4-methylbenzoic acid (4.3)
3,5-dimethylbenzoic acid
3,5-di-tert-butylbenzoic acid

18
22
18
22
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18

15

%Yield
b
24f
79
77
92
78
82
79
74
86
76
78
76
79
79
76
77
78
82
81
84
72
78
81
76
72
78
76
71
79
78
78
75
79
78

%ee
c
24f
17
19
78
63
67
66
40
23
20
31
23
70
71
70
65
54
70
73
76
63
77
77
63
77
73
76
29
75
74
77
77
75
76

Table 2.3 (Cont’d)

a.

34
35

Phthalic acid
9-Anthracenecarboxylic acid

18
18

57
77

12
25

Unless otherwise specified, all reactions were performed on a 0.1 mmol scale in
toluene at 0.2 M in imine 23f for 18 h and went to 100% completion at the indicated
temperature. Catalyst 9 was prepared by heating 1 equiv of ligand, 3 equiv of
BH3!SMe2, 2 equiv of PhOH, and 3 equiv of H2O in toluene at 100 °C for 1 h
followed by removal of volatiles at 100 °C for 0.5 h at 0.1 mm Hg. The catalyst
solution was transferred to a Schlenk test tube containing imine, directly followed
b.
by addition of benzoic acid at room temperature.
Isolated yield after silica gel
column chromatography.

c.

Chiral HPLC.

2.7 Diversity of BOROX catalyst 9
Figure 2. 4 Two dimensional diversity of the BOROX 9 catalyst

R

2

R

+ 2 HO R3
1

R
1
R

OH

+ 3 H2O

OH

+ 3 BH3•SMe2
R

1. Toluene, 100 °C
2. imine

2
OR

1

R
1
R

O
O

O B
B

O
O B
OR

2

R

Ligand

3

[H-imine]

3

2

BOROX catalyst 9

As in the case for BINOL phosphoric acid, diversity in the boroxinate 9 can also be
achieved by preparing the catalyst from substituted biaryl ligands, most easily by
1

varying the nature of the substituents R and R

2

(Figure 2. 4). However, a second

dimension to the diversity of the boroxinate catalyst is possible by variation of the
3

substituent R that is derived from an alcohol or phenol (Figure 2. 4). The practicality of

16

this diversity is greatly enhanced by the fact that the catalysts are assembled in-situ
from the ligand, BH3•SMe2, phenol or alcohol and H2O upon the addition of imine.
2.7.1 Tuning the BOROX catalyst 9 with phenol modules
3

The effect of the change in the BOROX catalyst 9 structure by varying the R group
of the phenol or alcohol used in catalyst generation was explored (Table 2. 4). A
number of different phenols and alcohols were examined and the results are shown in
Table 2. 4. The highest selectivity is observed with 2,4,6-trimethylphenol (Table 2. 4,
entry 9). The asymmetric induction drops to 51% with electron poor para-nitrophenol
(Table 2. 4, entry 18). The largest perturbation is noted with bulky anthracen-9ylmethanol, where asymmetric induction drops dramatically to 35% (Table 2. 4, entry
26).
Table 2. 4 Screening various phenols and alcohols

+ 2 ROH
Ph
Ph

OH

+ 3 H2O

OH

+ 3 BH3•SMe2

VANOL

1. toluene, 100 °C
2. imine 23f

OR
Ph
Ph

O
O

O B
B

O
O B

[H-imine]

OR

12

BOROX catalyst 9
Ar

Ar

Ar
10 mol % (R)-VANOLBOROX 9
Ph
N
Ar
23f
10 mol % acid
Ar = 3,5-Me2C6H3
Ph
m-xylene, 60 °C
24f
(0.1 mmol, 0.2 M)
N

17

Table 2.4 (Cont’d)
b
c
Phenol
%Yield
%ee
phenol
89
78
2,6-dimethylphenol
79
81
2,6-diisopropylphenol
78
80
2,6-di-tert-butylphenol
76
76
2,6-diphenylphenol
74
76
2-isopropylphenol
72
80
2-tert-butylphenol
74
80
2-phenylphenol
72
78
2,4,6-trimethylphenol
79
83
2,4,6-tri-tert-butylphenol
72
72
4-methylphenol
72
77
4-isopropylphenol
73
77
4-phenylphenol
69
73
3,5-dimethylphenol
71
77
1-naphthol
74
77
2-naphthol
72
73
4-methoxyphenol
71
77
4-nitrophenol
74
51
9-phenanthrol
72
77
2,6-dimethoxyphenol
72
65
3,4,5-trimethoxyphenol
73
78
2,6-dipropyl-4-tert22
74
79
butylphenol
23
1-adamantanol
75
77
24
n-butanol
73
74
25
cyclohexanol
73
74
26
anthracen-9-ylmethanol
52
35
a.
Unless otherwise specified, all reactions were
performed on a 0.1 mmol scale in toluene at 0.2 M in
imine 23f for 18 h and went to 100% completion at the
indicated temperature. Catalyst 9 was prepared by
heating 1 equiv of ligand, 3 equiv of BH3!SMe2, 2 equiv

Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21

a

of PhOH, and 3 equiv of H2O in toluene at 100 °C for 1
h followed by removal of volatiles at 100 °C for 0.5 h at
0.1 mm Hg. The catalyst solution was transferred to a
Schlenk test tube containing imine, directly followed by
addition of benzoic acid at room temperature. b.
Isolated yield after silica gel column chromatography. c.
Chiral HPLC.

18

2.7.2 Tuning the BOROX catalyst 9 with various ligands
The second parameter that can be varied to produce large numbers of boroxinate
catalysts for screening is the ligand itself. The investigation was conducted after we
have optimized the reaction conditions for a direct aminoallylation of aldehydes which is
presented in section 2.8. Hence, the current study involves screening the aza-Cope
rearrangement with amine 22f and aldehydes with two different families of ligands; 7,7’substituted derivatives and 4,4’-substitued ligands. Benzaldehyde 25a, n-butyraldehyde
25o and trimethylacetaldehyde 25t were evaluated so that the optimization could
include the three major classes of aldehydes. Several different substituents at 7,7’
positions were investigated including t-butyl, para-t-butylphenyl, methoxyl, halide and
TMS protected acetylene. For benzaldehyde, with 7,7’-fluoro-VANOL as an exception
(Table 2.5, entry 12), all the ligands screened either give lower ee’s than VANOL ligand
(entry 18 and 21) or result in greatly reduced reaction conversions (entry 6, 9, 15, 24,
27). For n-butyraldehyde, all the ligands screened give lower ee’s in the range of 3793%. While for trimethylacetaldehyde, 7,7’-methyl-VANOL gives the optimal asymmetric
induction 79% ee, followed by 7,7’-fluoro-VANOL, which affords 74% ee. However,
similar to the benzaldehyde case, with other ligands screened for trimethylacetaldehyde,
compared with VANOL ligand, either lower enantioselectivity (entry 13, 19, 22) or
reduced conversion is observed (entry 4, 7, 25).

19

Table 2. 5 Tuning the BOROX catalyst 9 with 7,7’-substituted ligands
R
OH

amine 22f

OH

Ph
Ph

+ 3 BH3•SMe2 + 3 H2O + 2
OH

Ligand-BOROX catalyst 9

R

(S)-Ligand 28
Ar

O

Ar

+

H2N

R

1

H

Ar
5 mol% ligand-BOROX catalyst 9
5 mol% benzoic acid
N
Ar
1
m-xylene, 60 °C
R
18 h

22f
Ar = 3,5-Me2C6H3

Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22

a

25

R

R

H
H
H
tert-butyl
tert-butyl
tert-butyl
p-tertbutylphenyl
p-tertbutylphenyl
p-tertbutylphenyl
fluoro
fluoro
fluoro
Methoxy
Methoxy
Methoxy
Me
Me
Me
Br
Br
Br
I

tert-butyl
propyl
phenyl
tert-butyl
propyl
phenyl

Conversion
b
(%)
100
100
100
0
100
32

tert-butyl

R1 = propyl 29, tert-butyl 30 or Ph 24f

1

Yield (%)

c

ee (%)

94
81
91
ND
81
ND

72
95
80
ND
37
ND

69

ND

ND

propyl

92

82

77

phenyl

22

ND

ND

tert-butyl
propyl
phenyl
tert-butyl
propyl
phenyl
tert-butyl
propyl
phenyl
tert-butyl
propyl
phenyl
tert-butyl

100
100
100
100
100
21
100
100
100
100
100
100
100

83
91
81
64
55
ND
87
82
78
51
88
79
78

74
92
82
63
92
ND
79
93
75
45
92
51
30

20

d

Table 2.5

a.

23
24
25
26
27

propyl
phenyl
tert-butyl
propyl
phenyl

I
I
TMS
TMS
TMS

(cont’d)
100
37
36
88
0

83
ND
ND
71
ND

77
ND
ND
55
ND

Unless otherwise specified, all reactions were performed on a 0.1 mmol scale in
m-xylene at 0.2 M in amine 22f with 1.1 equiv. of aldehydes 25 for 18 h and went
to 100% completion at 60 °C. Catalyst was prepared by heating 1 equiv of VANOL
ligand, 3 equiv of BH3!SMe2, 2 equiv of 2, 4, 6-trimethylphenol, and 3 equiv of
H2O in toluene at 100 °C for 1 h followed by removal of volatiles at 100 °C for 0.5 h
at 0.1 mm Hg. Catalyst 9 was transferred to a Schlenk test tube containing flamedried molecular sieves and amine 22f. The mixture was stirred for 30 minutes at 60
b.
°C, followed by the direct addition of aldehyde 25 and benzoic acid.
Triphenylmethane as internal standard.
chromatography.

d.

c.

Isolated yield after silica gel

Chiral HPLC analysis.

A bromo substituent in the 4 and 4’-position also have large influence (Table 2. 6),
which was not expected given the fact that these positions are remote from the active
site of BOROX 9 catalyst.
Table 2. 6 Tuning the BOROX catalyst 9 with 4,4’-substituted ligands

Br

OH

Ph
Ph

amine 22f

OH

+ 3 BH3•SMe2 + 3 H2O + 2
OH

Ligand-BOROX catalyst 9

Br

(S)-Ligand 31
Ar

O

Ar

H2N

22f
Ar = 3,5-Me2C6H3

+

R

1

H

Ar

5 mol% ligand-BOROX catalyst 9
5 mol% benzoic acid
m-xylene, 60 °C
18 h

25

N
R

Ar

1

R1 = propyl 29, tert-butyl 30 or Ph 24f

21

Table 2.6 (cont’d)
Conversion
c
d
b
Yield (%)
ee (%)
(%)
1
tert-butyl
100
83
72
2
propyl
88
65
67
3
phenyl
100
74
43
a.
Unless otherwise specified, all reactions were performed on a
0.1 mmol scale in m-xylene at 0.2 M in amine 22f with 1.1 equiv.
of aldehydes 25 for 18 h and went to 100% completion at 60 °C.
Catalyst was prepared by heating 1 equiv of VANOL ligand, 3
equiv of BH3!SMe2, 2 equiv of 2, 4, 6-trimethylphenol, and 3
Entry

a

R

1

equiv of H2O in toluene at 100 °C for 1 h followed by removal of
volatiles at 100 °C for 0.5 h at 0.1 mm Hg. Catalyst 9 was
transferred to a Schlenk test tube containing flame-dried
molecular sieves and amine 22f. The mixture was stirred for 30
minutes at 60 °C, followed by the direct addition of aldehyde 25
c.
and benzoic acid.
Isolated yield after silica gel
chromatography.

d.

Chiral HPLC analysis.

2.8 Direct aminoallylation of benzaldehyde
At this point, it was decided to determine whether the conditions that have been
optimized for the Cope rearrangement of a pre-formed imine could be translated to a
direct aminoallylation of benzaldehyde. Interestingly, only 10% conversion was obtained
after 18 h with 4 Å MS (Table 2. 7, entry 1). However, with 5 Å MS, the reaction was
complete in 18 h, and to our delight, a comparable enantioselection was achieved
(Table 2. 7, entry3). It was found that 5 Å molecular sieves could slowly catalyze the
reaction (Table 2. 7, entry 7) and thus effort was extended to optimize the reaction for a
minimum amount of molecular sieves to palliate the background reaction and to find the
lowest effective catalyst loading. The optimal procedure gave 92% yield and 80% ee
with 5 mol % catalyst and 50 mg of 5 Å molecular sieves per 0.1 mmol of amine (Table
2. 7, entry 6).

22

Table 2. 7 Optimization of molecular sieve loading
Ar

O

Ar

H2N

+

22f
Ar = 3,5-Me2C6H3
(0.1 mmol, 0.2 M)

Entry
1

Ar
n mol % (R)-VANOLH
BOROX 9
N
Ar
n mol % benzoic acid
MS, m-xylene, 60 °C Ph
24f

n mol (%)

e

MS
4Å

Yield
b
(%)
–

MS loading
(mg)

10

a

300

Conv.
c
(%)
10

ee
d
(%)
–

e

10
5Å
300
84
100
71
2
3
10
5Å
100
82
100
76
4
10
5Å
10
72
100
53
5
5
5Å
100
82
100
75
6
5
5Å
50
92
100
80
7
0
5Å
300
–
15
–
a.
Unless otherwise specified, all reactions were performed on a 0.1 mmol
scale in m-xylene at 0.2 M in amine 22f with 1.1 equiv. of aldehydes for 18
h and went to 100% completion at 60 °C. Catalyst was prepared by
heating 1 equiv of VANOL ligand, 3 equiv of BH3!SMe2, 2 equiv of 2, 4, 6trimethylphenol, and 3 equiv of H2O in toluene at 100 °C for 1 h followed
by removal of volatiles at 100 °C for 0.5 h at 0.1 mm Hg. Catalyst 9 was
transferred to a Schlenk test tube containing flame-dried molecular sieves
and amine 22f. The mixture was stirred for 30 minutes at 60 °C, followed
b.
by the direct addition of benzaldehyde and benzoic acid. Isolated yield
after silica gel column chromatography.
1

c.

Percent completion of the

reaction as determined by the H NMR spectrum of the crude reaction
d.

e.

mixture.
Chiral HPLC.
Molecular sieves added after stirring VANOL
BOROX catalyst 9 and amine 22f for 30 min at 60 °C.
2.9 Substrate scope for direct aminoallylation of aryl aldehydes
Next, the scope of the catalytic asymmetric allylation of aromatic aldehydes with
VANOL BOROX catalyst 9 was tested (Scheme 2. 5). Notably, all the reactions were
run on gram-scale; the amines 27 were purified by dissolution into aqueous acid and
then extraction of the impurities with ethyl acetate, which afforded analytically pure

23

Scheme 2. 5 Substrate scope for direct catalytic asymmetric aminoallylation of aromatic
a,b
aldehydes with VANOL BOROX catalyst

O

+

R

H2N

H

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

25

22f
(4 mmol, 1.1 g)

NH2 •HCl
R

2) 2N HCl, THF/H2O, rt

NH2 • HCl

27

NH2 • HCl

O2N

NH2 • HCl

Br

27a, 80% y, 97% ee

27b, 94% y, 87% ee

27c, 81% y, 95% ee

NH2 • HCl

NH2 • HCl

NH2 • HCl

HO

MeO

27d, 94% y, 85% ee

27e, 84% y, 93% ee

NH2 • HCl

Cl

27f, 91% y, 80% ee

NH2 • HCl

NH2 • HCl

Br

27g, 83% y, 90% ee
F

NH2 • HCl

27h, 99% y, 93% ee

27i, 90% y, 80% ee

HCl • H2N

NH2 • HCl

Br

27j, 81% y, 95% ee
NO2

27k, 86% y, 90% ee
NH2 • HCl

27l, 77% y, 80% ee
NH2 • HCl

27m, 84% y, 94% ee

27n, 85% y, 90% ee

24

Scheme 2.5 (cont’d)
a.

Unless otherwise specified, all reactions were performed on a 4 mmol
scale in m-xylene at 0.2 M in amine 22f with 1.1 equi of aldehyde for 1830 h and went to 100% completion at the indicated temperature, except
for 25d, which was complete in 55 h. Catalyst was prepared by heating 1
equiv of VANOL ligand, 3 equiv of BH3!SMe2, 2 equiv of 2, 4, 6trimethylphenol, and 3 equiv of H2O in toluene at 100 °C for 1 h followed
by removal of volatiles at 100 °C for 0.5 h at 0.1 mm Hg. Catalyst 9 was
transferred to a Schlenk test tube containing flame-dried molecular sieves
and amine 22f. The mixture was stirred for 30 minutes at 60 °C, followed
by the direct addition of aldehydes and benzoic acid. Subsequent
b.
hydrolysis usually takes 3-18 h. Asymmetric inductions were measured
on corresponding imines 26a-n isolated from a separate aza-Cope
rearrangement.
homoallylic amine hydrochlorides suitable for prolonged storage or immediate use. A
wide range of aromatic aldehydes with varying electronic and steric demands were
found to undergo the aminoallylation with both high ee and yield. The asymmetric
inductions were measured in a separate reaction in which the corresponding imines
were isolated and fully characterized. Substrates bearing para-electron-withdrawing
substituents are particularly effective, with enantioselectivities between 93-97% ee
(Scheme 2. 5, 25a, c, e, j). The functionally rich substrates such as aldehydes 25m and
25n work exceedingly well, and upon hydrolysis, the former affords 84% yield with 94%
ee, and the latter, 85% yield and 90% ee. Electron-rich and sterically demanding
substrates such as aldehydes 25b and 25d also shows good ee and yields with this
methodology.
2.10 Substrate scope for direct aminoallylation of aliphatic aldehyde
Aminoallylation of aliphatic substrates had been a lacuna in the only existing report
of catalytic asymmetric aminoallylation of aldehydes;

25

11

thus in the development of a

general asymmetric aminoallylation protocol, inclusion of aliphatic aldehydes is a certain
prerequisite. It was found that 1° and 2° aldehydes both performed well and provided
good yields and excellent levels of asymmetric inductions with this new methodology
(Scheme 2. 6, entry 27o-s). Although an excellent yield was obtained for the sterically
demanding 3° substrate 25 t, only a moderate induction was observed.
Scheme 2. 6 Substrate scope for direct catalytic asymmetric aminoallylation of aliphatic
a,b
aldehydes with the VANOL BOROX catalyst

O

+
H2N

22f
(4 mmol, 1.1 g)
NH2 • HCl

27o, 81% y, 95% ee
NH2 • HCl

27r, 85% y, 92% ee

R

H

25

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

NH2 •HCl
R

2) 2N HCl, THF/H2O, rt

NH2 • HCl

27p, 71% y, 94% ee
NH2 • HCl

27s, 75% y, 93% ee

27

NH2 • HCl

27q, 57% y, 90% ee
NH2 • HCl

27t, 94% y, 72% ee

a.

Unless otherwise specified, all reactions were performed on a 4 mmol
scale in m-xylene at 0.2 M in amine 22f with 1.1 equi of aldehyde for 1830 h and went to 100% completion at the indicated temperature, except
for 25t, which was complete in 96 h. Catalyst was prepared by heating 1
equiv of VANOL ligand, 3 equiv of BH3!SMe2, 2 equiv of 2, 4, 6trimethylphenol, and 3 equiv of H2O in toluene at 100 °C for 1 h followed
by removal of volatiles at 100 °C for 0.5 h at 0.1 mm Hg. Catalyst 9 was
transferred to a Schlenk test tube containing flame-dried molecular sieves
and amine 22f. The mixture was stirred for 30 minutes at 60 °C, followed
by the direct addition of aldehydes and benzoic acid. Subsequent
b.
hydrolysis usually takes 3-18 h. Asymmetric inductions were measured
on corresponding imines 26o-t isolated from a separate aza-Cope
rearrangement.

26

2.11 Scale-up, recycle of starting amine and VANOL Ligand
Considering that a large fraction of the starting amine 22f is incorporated into diaryl
ketone 28 after hydrolysis, to make the current method more practical, we developed an
efficient route to recycle diaryl ketone 28 (Scheme 2. 7). Compound 28 was initially
converted to the corresponding diaryl ketimine via condensation with ammonia, and
without isolation, the ketimine was allylated and purified by crystallization to afford the
desired compound 22f with 87% yield in a one-pot manner.
Scheme 2. 7 Recycle of diaryl ketone 28
recycle of diarylketone

1) NH3, TiCl4, THF
MgCl

2)

Ar
H2N

Ar

1) 5 mol% (R)-VANOLBOROX 9,
5 mol% benzoic acid,
5A MS, m-xylene, 60 °C

O

+

n-Pr

, 87% y crystalization (2 steps, one pot)
Ar

organic
phase

H

2) 2N HCl, THF/H2O, rt
22f
25o
3) EtOAc wash
Ar = 3,5-Me2C6H3 1.1 equiv
(10 mmol scale)

aqueous
phase

Ar

+ (R)-VANOL
12, 86% y
28
92% y (recycled)
O

NH2 •HCl

27o
83% y, 95% ee
analytically pure
no purification required

2.12 Total synthesis of (R)-Coniine
The piperidine subunit is one of the ubiquitous pharmaceutical cores and widely
18

present in bioactive molecules and natural products.

Coniine, a popular target for the

demonstration of chiral methodology in the piperidine field, has been synthesized with
ring-closing metathesis approach.

19

However, all the synthesis with the RCM method

involved chiral auxiliaries which is mainly due to the limited catalytic asymmetric

27

methods for access to aliphatic homoallylic amines. To demonstrate the utility of our
methodology, especially for aliphatic substrates, the total synthesis of Coniine 35 was
conducted (Scheme 2. 8)
Scheme 2. 8 Total synthesis of (R)-Coniine

Ar

O
H

25o

Ar

+ H2N

1) 5 mol% (R)-VANOL BOROX 9
5 mol% benzoic acid,
5A MS, m-xylene, 60 °C

2) 2N HCl, THF/H2O, RT
22f
Ar = 3,5-Me2C6H3
10 mmol scale

NH2 •HCl

+

Ar

Ar
O

27o,
83% y, 95% ee

28

O
H

Br

THF, 0 °C to reflux
NaH

HN

Ph

32, 80% yield

NH2

MeOH, NaBH4

5 mol%
Grubb's Cat. II
N
Bn

33, 83% yield

toluene, 40 °C
10 mol%
benzoquinone

Pd(OH)2/C-H2
N
Bn

MeOH, rt

•HCl
N
H

(R)-Coniine
35, 81% yield

34, 89% yield

2.13 Determination of the absolute configuration of amine 27h and 27o from the
direct catalytic asymmetric aminoallylation of aldehydes 25h and 25o
The absolute configuration of the major enantiomer of amines 27h was determined
20

by comparing their optical rotations with literature values (Scheme 2. 9). The homoallylic amines 27h prepared by this protocol result from a Si face attack of the allyl
fragment on the imine complex by the catalyst prepared from (R)-VANOL. The absolute
configuration of all other homo-allylic amines were assumed to be the same as 27h.

28

Scheme 2. 9 Absolute configuration in the direct catalytic asymmetric aminoallylation
of aldehydes

Ar

Cl

Ar

H2N

O
H

+

22f
Ar = 3,5-Me2C6H3

1) 5 mol % (R)-VANOL-BOROX 9
5 mol% benzoic acid,
°
5A MS, m-xylene, 60 °C, 18 h
2) NH2OH•HCl, THF/H2O, rt

25h

Cl

NH2

Cl

NH2
(S)

(S)-27h
Optical rotation obtained:
c = 1.2, CHCl3, -72.0

(R)

Literature value for optical rotation:
c = 3.44, CHCl3, +61.0 (ref. 20)

Ar Ar

O
H

25o

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

+

H2N

Ar = 3,5-Me2C6H3
22f
(10 mmol, 2.79 g)

NH2 •HCl

2) 2N HCl, THF/H2O, rt

(R)-27o

•HCl

•HCl
N
H

N
H

(S)-Coniine
Literature value for optical rotation:
c = 0.5, EtOH, +7.8 (ref. 21)

(R)-Coniine 35
Optical rotation obtained:
c = 0.6, EtOH, -6.7

The product 27o from the reaction of n-butanal with the (R)-VANOL catalyst gave
the (R)-configuration also from Si-face addition. This was confirmed when (R)-27o was
converted to (R)-Coniine 35 and the comparison of its rotation with that reported in the

29

21

literature.

On this basis, it was assumed that the other aliphatic aldehydes substrates

also gave Si-face addition with (R)-VANOL. Note that common to both aryl and aliphatic
aldehydes is that the reaction occurs by addition to the Si-face of the aldehyde (imine).
2.14 Conclusion
In

summary,

we

have

developed

a

highly

enantioselective

protocol

for

aminoallylation of aldehydes, involving an aza-Cope rearrangement of an in-situ
generated imine which upon hydrolysis provides the homoallyic amine in high
asymmetric inductions over a broad range of aromatic, alkenyl and aliphatic substrates.
The successful catalyst system results from the incorporation of a molecule of benzoic
acid into the VANOL boroxinate catalyst. This method was applied to the asymmetric
total synthesis of Coniine.

30

CHAPTER THREE
MECHANISTIC STUDIES OF THE CHIRAL BRØNSTED ACID CATALYZED AZACOPE REARRANGEMENT – UNDERSTANDING THE SYNERGISYM OF CHIRAL
AND ACHIRAL BRØNSTED ACIDS
3.1 Introduction
Chapter 2 describes the development of a general protocol for the synthesis of chiral
homo-allylic amines via a direct catalytic asymmetric aminoallylation of aldehydes with
BOROX catalyst 9.

22

During the course of the optimization, we noticed an interesting

phenomenon that the addition of benzoic acid greatly enhanced the asymmetric
enantioselectivity of the aminoallylation reaction (Scheme 3. 1). The chiral Brønsted
acid BOROX 9 catalyzes the aza-Cope rearrangement of 23f in toluene to furnish 24f in
77% yield and 25% ee. The addition of 1.0 equivalent of benzoic acid (w.r.t. BOROX 9)
improves the enantioselectivity to 72%, while maintaining excellent yields. This chapter
focuses on a combined experimental and computational study that reveals a synergistic
interplay of the chiral BOROX catalyst 9 and benzoic acid. This work was carried out in
collaboration with Dr. Mathew Vetticatt.

31

Scheme 3. 1 Synergistic interplay of chiral BOROX catalyst 9 and benzoic acid in
aza-Cope rearrangement

+ 2 HO R3
Ph
Ph

OH

+ 3 H2O

OH

1) 100 °C, 1 h.
toluene

O

Ph
Ph

O

B OPh +

O

Ph
Ph

O

OPh
B O B
OPh

+ 3 BH3•SMe2 2) 100 °C, 0.5 h,
0.1 mm Hg
(S)-VANOL 12

B1 (mesoborate)

B2 (pyroborate)

pre-catalyst mixture
Ar

Ar

N
Ph
23f
Ar = 3,5-Me2C6H3

77% yield, 25% ee

No additive
OPh

Ar
N

Ph
Ph

Ar

O
O

O B
B

O
O B
OPh

Ph

Ar

Ar

HN
Ph

24f

81% yield, 72% ee

benzoic acid

BOROX catalyst 9 - imine complex

3.2 Probing the role of benzoic acid additive in the aza-Cope rearrangement
catalyzed by the chiral BOROX catalyst 9
Our initial studies focused on identifying the role played by benzoic acid in catalyzing
the aza-Cope rearrangement. The results from a systematic study of the effect of the
amount of benzoic acid on the enantioselectivity and rate of the aza-Cope
rearrangement catalyzed by BOROX catalyst 9 is presented in Figure 3. 1. Maximum
enantioselectivity was achieved with the addition of 1.0 equivalent of benzoic acid (w.r.t

32

BOROX 9), which also resulted in a 30% increase in reaction rate compared to the
reaction without any additives. A marginal decrease in enantioselectivity and an
approximate 30% decrease in reaction rate were observed when the amount of benzoic
acid was increased beyond 1.0 equivalent. It is hence reasonable to propose that the
active catalyst species consists of a 1:1 combination of chiral BOROX 9 and benzoic
acid.
Figure 3. 1 Study of the effect of the equivalents of benzoic acid on enantioselectivity
and reaction rate of the aza-Cope rearrangement catalyzed by BOROX catalyst 9
Ar

Ar

10 mol % (R)-VANOLBOROX 9

N

n mol % benzoic acid
23f
toluene, 60 °C
Ar = 3,5-Me2C6H3
(0.1 mmol, 0.2 M)
Ph

Ar

33

N
Ph

24f

Ar

Figure 3.1 (cont’d)

“For interpretation of the references to color in this and all other figures, the
reader is referred to the electronic version of this thesis (or dissertation).”
Three possible roles for benzoic acid were envisioned for this reaction, a) as a
Brønsted acid co-catalyst (proton donor); b) as a conjugate base (benzoate anion
donor); or c) inducing a steric effect. To further narrow down the role of benzoic acid,
the following experiments in Scheme 3.2 were designed and carried out.

34

Scheme 3. 2 Probing the role of benzoic acid
Ar

Ar

10 mol% (S)-VANOL
BOROX 9
10 mol% additive
m-xylene, 60 °C, 18 h

N
Ph

23f

Ar = 3,5-Me2C6H3
(0.1 mmol, 0.2 M)
O

O
OH

81% y, 78% ee

Ar
N

Ar

Ph

24f

O
O

N(nBu)4

82% y, 72% ee

OCH3

72% y, 28% ee

No additive, 77% y, 28% ee

When a structural surrogate – methyl benzoate – was used as additive, product 24f
was obtained in 72% yield and only 28% ee. This result is almost identical to the
reaction carried out with no achiral acid additive. However, when tetrabutylammonium
benzoate was used as the additive instead of benzoic acid, 24f was obtained in 82%
yield with 72% ee. Finally, there was no observable product formation when 23f was
heated to 60 ºC with 20 mol% benzoic acid as the sole Brønsted acid catalyst. These
results taken together suggest that the conjugate base of benzoic acid (and not the
proton of benzoic acid or steric factors) is vital to the enhancement of enantioselectivity
observed in this reaction. Any further reference to the role of benzoic acid in the
remainder of this chapter could also be a reference to the benzoate anion.
Our next question is how does benzoate anion increase the enantioselectivity of the
aza-Cope rearrangement? Is the benzoic acid intimately associated with the substrate
at the transition state of the reaction? Or is the dramatic increase in enantioselectivity a

35

result of a covalent modification of the catalyst-imine complex 9 by benzoic acid, in
which benzoate acid acts as an allosteric effector (Figure 3. 2)?
Figure 3. 2 Allosteric regulation of BOROX catalyst 9 with benzoic acid

3.3 Experimental
13

13

C kinetic isotope effects (KIEs)

C KIEs are powerful experimental probes of the TS geometry of a reaction and are

sensitive to small variations in the TS geometry. By measuring

13

C KIEs for the aza-

Cope rearrangement we can probe subtle differences, if any, in the transition state
geometry of the reaction, with and without added benzoic acid.
3.3.1 Design of experiment
The

13

C KIEs for the aza-Cope rearrangement of p-bromobenzaldehyde derived

imine 36 catalyzed by (S)-VANOL-BOROX catalyst 9, with and without benzoic acid
additive, were determined using Singleton’s NMR methodology

23

at natural abundance.

p-Bromobenzaldehyde is one of the best substrates in the aza-Cope rearrangement
(Scheme 2. 5, 27c, 81% yield and 95% ee), with which we expect to see a larger

36

difference in energy in the major transition state and minor transition state. There are
two main approaches to measure

13

C KIEs by this method; these are described below.

Starting material KIEs: Reactions proceed to high conversion (~ 80% conversion)
13

and the starting material is recovered. The

C isotopic composition of the recovered

starting material is measured using NMR method at natural abundance, which is
compared to that of unreacted starting material drawn from the same bottle.
Scheme 3. 3 Design of starting material KIE measurement
NH2

O

Ar
N

ac
ic
zo

Ar

H

Ar

id

2 N HCl

2:1 THF:water,
n
be
X 9 Br
RT
ut ol% RO
ho
O
26c
wit 5 m L-B
h/
O
e reaction stopped at ~80 %
wit
AN xylen
- oC
)-V
conversion of 36
m 0
(R
6
Ar

36
Ar = 3,5-Me2Ph

27c
Ar

H2N

Br

25c
Ar

Ar

Ar
O

22f

28

compare
13C isotopic

N
C6H4p-Br

Br

content
2 N HCl
2:1 THF:water, RT
quantitative hydrolysis
for NMR standard

Ar
H2N

O

Ar

22f

H
Br

25c

Product KIEs: Reactions proceed to low conversion (~ 20% conversion) and the
product is isolated. The isotopic composition of this product is measured using NMR
method at natural abundance, which is compared to that of a product isolated from a
100% conversion reaction (the starting material is drawn from the same bottle originally
used for the reaction).

37

Scheme 3. 4 Design of product KIE measurement
O

Ar
N

Ar

Ar

Ar

H

cid

H2N
2 N HCl
Br
a
oic
22f
nz
2:1 THF:water,
be
X 9 Br
ut ol% RO
o m
RT
h
Ar
Ar
O
26c
wit 1 L-B
th /
O
i
ne reaction stopped at ~20 %
w
O
le
AN
xy
conversion of 36
)-V
Br
m- 0 o C
28
(R
6
Ar Ar
(R
compare
)-V 10
N
AN m
13C isotopic
ol%
Ar
OL
-B
mC6H4p-Br
OR
36
content
N Ar
xy
OX
Ar = 3,5-Me2Ph 60 olene
9
2 N HCl
Ar
Ar
C

2:1 THF:water,
RT

Br

26c
100 % conversion reaction
for NMR standard

O

25c
NH2

27c

NH2

Br

28

27c

3.3.2 Experimental KIEs
For each case (with and without benzoic acid), three independent experiments – two
from product KIEs measurement (non-italicized) and one from starting material KIEs
measurement (italicized) – were conducted for the determination of KIEs. The resulting
KIEs, for the carbon atoms undergoing bonding changes, are shown in Figure 3. 3.
Each of the three KIE numbers comes from an independent experiment (with 6
measurements per experiment).
The observation of a non-trivial

13

C KIE on all carbon atoms of 36 involving bond-

forming and bond-breaking events with hybridization changes is consistent with the
concerted six-membered transition state that is expected for this reaction.
importantly, comparative analysis of the

13

24

More

C KIEs in the two cases (with and without

benzoic acid additive) reveals that the KIE at each of these carbon atoms are
indistinguishable. The qualitative interpretation of this result is that addition of benzoic

38

acid does not significantly alter the bond distances at the transition state of the azaCope rearrangement of 36.
Figure 3. 3 Experimental

Ar

13

C KIEs for the aza-Cope rearrangement of 36 catalyzed by
(S)-VANOL-BOROX catalyst 9

N

benzoic acid

N

Ar

(S)-VANOL-BOROX 9

C6H4p-Br

36
Ar = 3,5-Me2Ph

Br

m-xylene, 60

oC

Ar

Ar

26c
1.020(2) 1.004(4)
1.015(4) 1.005(2)
1.022(5) 1.001(3)

1.020(3) 0.999(4)
1.019(4) 1.000(3)
1.022(4) 0.997(1)

Ar

Ar

N
C6H4p-Br

Ar

with or without

Ar

N
H

1.029(5)1.014(5)
1.020(1) 1.031(3)1.010(3)
1.020(4) 1.033(3)1.017(4)
with benzoic acid

C6H4p-Br

H

1.029(4)1.016(4)
1.020(1) 1.030(4)1.013(3)
1.022(2) 1.032(3)1.016(2)
without benzoic acid

3.4 Spectral data in support of a covalent modification of the catalyst-imine
complex by benzoic acid
The results from the KIE study suggest that the benzoic acid might not be intimately
associated with the substrate at the transition state of the reaction. Is the dramatic
increase in enantioselectivity then a result of a covalent modification of the catalystimine complex 9 by benzoic acid? Our next step was to study the effect of addition of
13

benzoic acid on catalyst structure using 1- C labeled benzoic acid as a convenient
probe for NMR analysis under standard experimental conditions. From the change in

39

chemical shift of the
of

13

13

C label and the number of new species formed with incorporation

C, we could determine the nature of catalyst modification by benzoic acid. The

corresponding changes in the

11

B NMR could be used as an additional handle for

understanding modification of catalyst structure.
3.4.1 Design of

13

C and

11

B NMR experiments

Scheme 3.5 outlines the design of the NMR experiments. A 0.07 M stock solution of
precatalyst mixture was prepared in d8-toluene. For a standard experiment, ~0.05 mmol
of the precatalyst (0.7 mL of stock solution) was added to an NMR tube from the stock
solution. This was followed by addition of 0.2 mmol of an imine (23f/38/39 as a solid) at
room temperature leading to the assembly of a catalyst-imine complex. Finally 0.05
13

mmol of 1- C benzoic acid was added to the NMR tube and the resulting mixture
13

heated to 60 °C. A series of NMR spectra ( C,

11

1

B and H) were obtained at each

stage. Since imine 23f would react under these conditions, we used two additional
unreactive imines – MEDAM imine 38 and an unreactive substrate analogue imine 39,
where the allyl group was reduced to a propyl group – to aid in the interpretation of the
experiment using 23f as the imine.

40

Scheme 3. 5 Design of

O

Ph
Ph

O

B OPh +

O

Ph
Ph

B1 (mesoborate)

O

13

C and

11

B NMR experiments

OPh
B O B
OPh

B2 (pyroborate)

pre-catalyst mixture 37
catalyst-imine-benzoic acid
23f, Ar = 3,5-dimethylphenyl
complex under reaction conditions
C
R = -CH2CHCH2
R
N
38, Ar = 3,5-dimethyl-4-methoxyphenyl
rt
R=H
Ph
d8-toluene
39, Ar = 3,5-dimethylphenyl
0.3 M
23f/38//39
60 oC
R = -CH2CH2CH3
4 equiv.
Ar

Ar

(w.r.t. pre-catalyst)
catalyst-imine-benzoic acid
complex at RT
OPh
Ph
Ph

O
O

O B
B

Ar
H
N

O
O B
OPh

Ar
R

O

13C

Ph

OH

rt
BOROX catalyst 9 - imine complex
9a Ar = 3,5-dimethylphenyl, R =
CH2CHCH2
9b Ar = 3,5-dimethyl-4methoxyphenyl, R = H
9c Ar = 3,5-dimethylphenyl, R =
CH2CH2CH3

1 equiv.
(w.r.t. pre-catalyst)

41

3.4.2 Interpretation of

13

Figure 3. 4

C NMR and

11

11

13

B NMR with 1- C-benzoic acid

B NMR spectra of catalyst modification studies

Pre-catalyst was prepared by heating 0.050 mmol VANOL ligand,
0.15 mmol BH3!SMe2, 0.10 mmol 2, 4, 6-trimethylphenol, and 0.15
mmol H2O in 2 mL toluene at 100 °C for 1 h followed by removal of
volatiles at 100 °C for 0.5 h at 0.1 mm Hg. The resulting mixture was
dissolved in 0.7 mL of d8-toluene and transferred to a quartz NMR
tube. 4 equiv. of imine 23f or 38 was added to the NMR tube.
13
Lastly, 1- C-labeled benzoic acid was added.

Figure 3. 4 and Table 3. 1 show the results from the

11

B NMR experiments involving

the (S)-VANOL BOROX catalyst prepared from imines 23f and 38 as described in
Scheme 3. 5. Addition of imines 23f or 38 to the pre-catalyst mixture results in the

42

formation of boroxinate catalyst-imine complex 9a and 9b as evidenced by the
appearance of sharp peak for the tetra-coordinated boron at ~ 6.0 ppm and the broad
peak at ~ 16.0 ppm for the tri- coordinated boron atoms in the

11

B NMR spectra of

these complexes (Figure 3. 4, a and b).
Table 3. 1 The integration of peaks observed in the
Entry
a
b
c
d
e
f

The

13

Integration
(from 0 to 9 ppm)
1
1
2
2
2
2

11

B NMR (Figure 3. 4)

Integration
(from 13 to 20 ppm)
5
7
1
1
1
1

C label in benzoic acid appears at 172.9 ppm (Figure 3.5, b). The most

downfield carbon peak for 9a and 9b is the iminium carbon peak at 158.0 ppm and
157.0 ppm respectively and so there are no peaks in the expanded region of the

13

C

spectra of these catalyst-imine complexes (Figure 3.5, a). The addition of benzoic acid
to the catalyst-MEDAM imine complex 9b resulted in the appearance of two new peaks
at 174.2 and 175.6 ppm (Figure 3.5, c). Intriguingly, the corresponding

11

B NMR

spectrum revealed a new broad peak at ~ 4.0 ppm (in addition to the peak at 6.0 ppm)
and a significant decrease in the intensity of the peak at 16.0 ppm (Figure 3.5, c; Table
3.1, c), suggesting the in-situ formation of a tetra-coordinated boron via addition of
benzoate anion to one of the tri-coordinated boron centers in BOROX catalyst 9. These
characteristics persist when the sample is heated to 60 °C (Figure 3.5, d).

43

Figure 3. 5

13

13

C NMR spectra of catalyst modification studies using 1- C-benzoic acid

Pre-catalyst was prepared by heating 0.050 mmol VANOL ligand,
0.15 mmol BH3!SMe2, 0.10 mmol 2, 4, 6-trimethylphenol, and 0.15
mmol H2O in 2 mL toluene at 100 °C for 1 h followed by removal of
volatiles at 100 °C for 0.5 h at 0.1 mm Hg. The resulting mixture was
dissolved in 0.7 mL of d8-toluene and transferred to a quartz NMR
tube. 4 equiv. of imine 23f or 38 was added to the NMR tube. Lastly,
13
1- C-labeled benzoic acid was added.
Slightly different results were obtained when benzoic acid was added to the reactive
catalyst-imine complex 9a prepared from imine 23f (Scheme 3.5). Four new peaks were
observed – two peaks similar to those observed with complex 9b and two peaks of
lower intensity (Figure 3.5, e). The

11

B NMR however, looks near identical to that of the

complex 9b (Figure 3.4, e). Once again, these features remain unchanged when the

44

sample is heated to 60 °C (Figure 3.4 and Figure 3.5, f). Our initial thought was that the
two additional peaks in the

13

C NMR spectra e could be the product ketimine 24f

bound to the catalyst. A control experiment was conducted where 24f was added to the
pre-catalyst mixture, followed by the addition of

13

C labeled benzoic acid. This resulted

in the appearance of the same 4 peaks, indicating that (a) each of these peaks
correspond to a certain conformation of the catalyst-imine complex 9a and (b)
conversion of that conformation to the corresponding catalyst-product complex does not
change the chemical environment around the
additional peaks in the

13

13

C label in the modified catalyst. The two

C NMR spectra of the aza-Cope imine 23f as compared to

MEDAM imine 38 possibly results from that the imine substrate could be added either
from the top or from the bottom of the BOROX catalyst 9 – benzoate adduct. We probed
this hypothesis by using the structural analogue of 23f – imine 39 with the reduced allyl
group (Figure 3.6). When complexed with the catalyst 9c or in the catalyst-iminebenzoic acid complex, 39 should behave in a fashion very similar to 23f. As expected,
when 39 was added to the catalyst-imine complex 9c, we were able to observe the
appearance of four peaks in
corresponding

11

13

C NMR – similar to the spectra e and f in Figure 3.5. The

B NMR spectra were also very similar to e and f in Figure 3.4

45

13

Figure 3. 6 NMR spectra of catalyst modification studies with imine 39 using 1- Cbenzoic acid

Pre-catalyst was prepared by heating 1 equiv of VANOL
ligand, 3 equiv of BH3!SMe2, 2 equiv of 2, 4, 6trimethylphenol, and 3 equiv of H2O in toluene at 100 °C for 1
h followed by removal of volatiles at 100 °C for 0.5 h at 0.1
mm Hg.

46

3.4.3

13

C NMR and

11

B NMR with tetrabutylammonium benzoate and methyl

benzoate
Figure 3. 7

11

B NMR with tetrabutylammonium benzoate and methyl benzoate
(Integrations shown in italic)

Pre-catalyst was prepared by heating 0.050 mmol VANOL ligand, 0.15 mmol
BH3!SMe2, 0.10 mmol 2, 4, 6-trimethylphenol, and 0.15 mmol H2O in 2 mL
toluene at 100 °C for 1 h followed by removal of volatiles at 100 °C for 0.5 h at
0.1 mm Hg. The resulting mixture was dissolved in 0.7 mL of d8-toluene and
transferred to a quartz NMR tube. 4 equiv. of imine 23f was added to the NMR
tube. Lastly, TBAB or MB was added.
When a structural surrogate – methyl benzoate – was used as additive, product 24f
was obtained in 72% yield and only 28% ee. This result is almost identical to the
reaction carried out with no achiral acid additive. However, when tetrabutylammonium
benzoate was used as the additive instead of benzoic acid, an 82% yield and 72% ee of
24f was obtained. In the

11

B NMR study to probe the active catalyst for the aza-Cope

47

rearrangement, covalent modification of one of the tri-coordinated boron’s was observed
with

the

addition

of

benzoic

acid

(Figure

3.

4).

Not

tetrabutylammonium benzoate was utilized as an additive, the

11

surprisingly,

while

B NMR also presents

evidence for the covalent modification of one of the tri-coordinated boron’s (Figure 3. 7
A). However, when methyl benzoate was employed as an additive, we did not note a
change in the

11

B NMR spectra upon the addition of methyl benzoate to the pre-catalyst

mixture (Figure 3. 7 B).
3.5 Possible active catalyst structures
We have four pieces of information that give us a clue about how the catalyst is
modified upon addition of benzoic acid – (1) The likely role of benzoic acid is as a
benzoate anion donor, (2) The tetracoordinate boron center in 9a/9b is unchanged upon
addition of benzoic acid, (3) The benzoate anion covalently modifies the catalyst-imine
complex (9a/9b) by generating at least one additional tetra-coordinate boron center by
addition to one of the two tri-coordinated boron centers in 9a/9b and (4) In all cases,
there are two major NMR distinguishable catalyst species formed upon addition of
benzoic acid. We interpret these key observations as follows.
The tri-coordinate boron atoms in 9a/9b are prochiral centers. The addition of
benzoic acid to one of the tricoordinate boron atoms of 9a/9b forms a boronate ester
and new chiral boron center. This chiral center combined with the axial chirality of (S)VANOL leads to in-situ formed diastereomeric pairs of the catalyst-imine complex
(depending on the facial selectivity of boronate ester formation). At this point, we
tentatively assign the two major peaks in the

48

13

C NMRs in Figure 3. 4, c-f to these

diastereomeric catalyst species. Based on relative integration of these two

13

C (labeled)

peaks, it appears as though these diastereomeric complexes are formed in a 1.4:1 ratio.
Scheme 3. 6 Possible structures of modified catalyst

1:1:1 imine:catalyst:benzoate anion

(S)-VANOL

O
O

OPh
(S)-VANOL

O

O B

OPh

B
O

B

1O B
2

2 H-imine
O

B

3

OPh

O

O B

O

O

O

Ph

+

OPh
O
OH

+

Imine

2

OPh

2 H-imine

Ph

H-imine
Ph

OPh
3
O B
O
O
O
B
(S)-VANOL
O 1O B O
Ph

(S)-VANOL

O

O

O O
B OPh

3

B

O

1 O B
2 OPh
2 H-imine
O

OPh
B O Ph
O
O
O
B
(S)-VANOL
O
O 1O B
2 OPh

3

2 H-imine

A key issue to be considered is that of double addition of benzoic acid (or benzoate
anion) to the catalyst-imine complex i.e. all boron atoms being tetra-coordinated. In
order to probe this possibility, we conducted an experiment where we used a 10:1
equivalent mixture of MEDAM imine 38: pre-catalyst and allowed it to sit at room
temperature for 6 hours to ensure complete formation of 9b. This was followed by the
addition of 10 equivalents of benzoic acid. The

11

B NMR of this mixture revealed a

significant boron peak at ~16 ppm suggesting that at least one of the boron atoms is still
tri-coordinated. This observation, along with the results presented in Figure 3. 1 A, lend
support catalyst modification occurring by the addition of only one benzoate anion to the
catalyst-imine complex. Scheme 3. 6 represents the simplest, most likely model that is

49

consistent with our NMR and other mechanistic studies. The addition of the benzoate
anion to either face of one of the tri-coordinate boron atoms B2 or B3 results in a chiral
di-anion with two protonated imines to balance the -2 negative charges. The two
diastereomeric catalyst species can also be interconverted by migration of benzoate
anion from B2 to B3 (and vice versa) across the same face of the boroxinate ring. In the
following section, we present a thorough evaluation of this model using theoretical
calculations. The goal is to compare the experimental enantioselectivity and

13

C KIEs,

with and without benzoic acid additive, to the predicted energy difference and KIEs of
the relevant transition state geometries leading to the two enantiomers of product.
3.6 Transition state models
The division of layers for the initial screening of transition state geometries is shown
in Scheme 3.7A. All the oxygen and boron atoms, all heavy atoms (and attached
hydrogen atoms) involved in the six-membered aza-Cope transition state were modeled
using the DFT (B3LYP/6-31+G**) method. The aromatic groups in the substrate and
catalyst were modeled using the semi-empirical method (AM1). In calculations with the
benzoic acid additive, the carboxylate group was treated with the B3LYP/6-31+G** while
the phenyl ring was calculated using AM1 method. After the initial screening, all the
transition structures within 3 kcal/mol of the lowest energy structures for each
enantiomer were re-calculated using an expanded high layer using B3LYP (with a 631+G** basis set) method as shown in Scheme 3.7B. In the expanded model, the
following portions were calculated using the high level DFT method in order to get the
best possible energy predictions – (a) the imine substrate excluding the aromatic portion
of the protecting group, (b) the boroxinate core, (c) one of the phenoxy groups (proximal

50

to the substrate binding pocket) and (d) benzoic acid. For simplicity of presentation, the
transition state geometries presented in the following sections are only the lowest
energy transition structures for each enantiomer (with and without benzoic acid)
obtained using the ONIOM Scheme outlined in Scheme 3.7B. The relative energies of
the transition state geometries are derived from the Gibbs free energy estimates
obtained from the ONIOM calculations carried out as illustrated in Scheme 3.7B. The
arbitrary numbering scheme used in the discussion that follows is also included in
Scheme 3.6
Scheme 3. 7 Division of layers for ONIOM (DFT:Semi-empirical) calculations

(A) Preliminary calculations
O

(B) Final model energy calculations
O

O-

B O
B
B O

O

O-

Ph O
O

(C) KIE predictions

O
O

Ph
Ph

Ph O
Ar Ar
NH
Ph
Ar = 3,5-dimethylphenyl

Ph O
B O
O
O
B
O
B O
Ph O
Ar Ar
NH
Ph

OPh O
Ph
Ph

B O
B

O
B O
Ph O
Ar Ar
NH

O
O

Ph
Ph

p-BrPh

Red - B3LYP/6-31+G**
Black - AM1

3.6.1 Transition structures without benzoic acid
Figure 3. 8 shows the lowest energy transition structures leading to (R)-24f and (S)24f – the major and minor products – in the aza-Cope rearrangement catalyzed by (S)VANOL-BOROX catalyst without the benzoic acid additive. The top panel in Figure 3. 8
presents two views of TS1, the transition state leading to the major enantiomer of 24f.

51

Figure 3. 8 Transition state geometries for the aza-Cope rearrangement of 23f
catalyzed by (S)-VANOL-BOROX without benzoic acid additive computed using the
ONIOM method described in Scheme 3.7B

The key features of TS1 are (a) the protonated imine is bound to oxygen atom O2 via
a short, strong hydrogen bond (2.04 Å, top panel view 2), (b) the bond-making and
bond-breaking distances in the six membered chair-like transition state are almost
identical (top panel view 1), (c) the intramolecular allyl nucleophile attacks the re face of
the protonated iminum ion and (d) there is a stabilizing non-covalent –CH...O interaction
between one of the polarized –CH bonds at the bond-breaking end of the allyl fragment

52

and O1 of the boroxinate anion (2.26 Å, top panel view 2). It is interesting to note that
most of these features are also present in TS2 (see Figure 3. 8, bottom panel). The
protonated imine is still bound to O2 (2.19 Å, bottom panel view 2), but the key
difference between TS1 and TS2 is that it is bound ‘upside down’ relative to TS1. This
binding mode of the imine in TS2 allows for the same stabilizing non-covalent –CH...O
interaction seen in TS1, except that it is now between one of the polarized –CH bonds
at the bond-making end of the allyl fragment and O1 of the boroxinate anion (2.19 Å,
bottom panel view 2). The allyl nucleophile attacks the si face of the protonated imine.
Since TS1 and TS2 have very similar interactions with the catalyst, it is no surprise that
they are very close in energy (0.25 kcal/mol) – consistent with the low experimental ee
of 25 %. Transition structures that lacked the stabilizing non-covalent –CH...O interaction
present in TS1 and TS2 and transition structures with the protonated imine bound to
O1, O2 and O4 were all found to be higher in energy.
3.6.2 Transition structures with benzoic acid
Figure 3.9 shows the lowest energy transition structures leading to (R)-24f and (S)24f – the major and minor products – in the aza-Cope rearrangement catalyzed by the
benzoic acid modified (S)-VANOL-BOROX catalyst described in Scheme 3.7. Several
possibilities were explored before we arrived at TS3 and TS4 as the two lowest energy
geometries for each enantiomer of the product. A systematic approach was followed in
exploring the possibilities. For example, starting with the transition state geometry TS1,
the transition state leading to the (R) product catalyzed by the (S)-VANOL-BOROX

53

Figure 3. 9 Transition state geometries for the aza-Cope rearrangement of 23f
catalyzed by (S)-VANOL-BOROX with benzoic acid additive computed using the
ONIOM method described in Scheme 3.7B

catalyst without the benzoic acid additive, eight different transition state geometries
were explored by adding a benzoate anion to TS1- four from adding the benzoate anion
to each face of the two tricoordinate boron atoms and an additional four by rotating the
carbonyl of the resultant benzoate adduct in each case by 180˚ to either face toward or

54

away from the bound imine. The key findings from these explorations are detailed
below.
Firstly, for both TS3 and TS4 the benzoate anion has added in a similar orientation
to the same face of the boron atom B2. It is interesting that, of the four possible in-situ
generated diastereomers of the 1:1 catalyst-imine complex and the two explored
orientations for the benzoate in each diastereomer, the same orientation of the same
diastereomer leads to the lowest energy transition structures for the formation of both
enantiomers of the product. Secondly, the orientation of the imine with respect to the
catalyst is almost identical when comparing TS1 versus TS3 and TS2 versus TS4.
Intriguingly however, TS4 is 1.62 kcal/mol higher in energy that TS3 (as compared to
TS2 which is only 0.25 kcal/mol higher in energy than TS1). These results are
completely consistent with the increase in enantioselectivity upon addition of benzoic
acid. Thirdly, there is no significant change in the bond-making and bond-breaking
distance at the transition state, upon catalyst modification (compare the relevant
distances in Figure 3. 8 and Figure 3.9). This again is consistent with the identical

13

C

KIEs measured with and without added benzoic acid (since KIEs reflect the bondmaking and bond-breaking distances at the transition state of the rate-limiting step).
3.7 Spin saturation transfer experiment in support of the dynamic formation of
diastereomers of catalyst upon the addition of benzoic acid

55

Figure 3. 10 Interconversion of diastereomeric catalyst species by migration of
benzoate anion from B2 to B3
Ph

(S)-VANOL

O
O

O

OPh

3

B

migration

O

B

1O B
2

(S)-VANOL

OPh

O

O
B
(S)-VANOL
HO 1 O

3

OPh

B

2

B

O

2 H-imine

association/
dissociation

O

O

1 O B
2 OPh
2 H-imine

Ph

O

O
B

O

O

2 H-imine

O

O O
B OPh

3

OPh
O

O
O
B
(S)-VANOL
HO 1 O

3

OPh

B

O
B OPh
2
O

2 H-imine

Ph

O

Ph

As discussed previously in section 3.5, the two diastereomeric catalyst species can
also be interconverted by migration of benzoate anion from B2 to B3 (and vice versa)
across the same face of the boroxinate ring (Figure 3.10). Next, we tried to find
experimental evidence for the interconversion either via B2 to B3 migration or
dissociation/association. NMR spin saturation transfer is a powerful tool to detect
chemical exchange process on the NMR time scale. The NMR sample was prepared
according to the procedure described in section 3.4.1, ~0.05 mmol of the precatalyst
(0.7 mL of stock solution) was added to an NMR tube from the stock solution. This was
followed by addition of 0.2 mmol of an imine (23f as a solid) at room temperature
13

leading to the assembly of a catalyst-imine complex. Finally 0.05 mmol of 1- C benzoic
acid was added to the NMR tube.

56

Figure 3. 11 Spin saturation transfer with imine 23f (Precatalyst was prepared and
regents were added in the sequence as shown in (Scheme 3.5)

Pre-catalyst was prepared by heating 0.050 mmol VANOL ligand, 0.15 mmol
BH3!SMe2, 0.10 mmol 2, 4, 6-trimethylphenol, and 0.15 mmol H2O in 2 mL
toluene at 100 °C for 1 h followed by removal of volatiles at 100 °C for 0.5 h at
0.1 mm Hg. The resulting mixture was dissolved in 0.7 mL of d8-toluene and
transferred to a quartz NMR tube. 4 equiv. of imine 23f was added to the NMR
13
tube. Lastly, 1- C-labeled benzoic acid was added.
Figure 3.11 shows the spectra from spin saturation transfer experiments. Originally,
there are four

13

C enriched peaks in the full

13

C NMR spectrum, two of which we

propose correspond to the two diastereomers of the active catalysts upon the addition
of benzoic acid. Since peak 1 and 2 are so close in chemical shift in the spectra, both
peaks were saturated simultaneously, which resulted in the disappearance of peak 3
and decrease in the magnitude of peak 4. When peak 3 was irradiated, the magnitude
of peaks 1,2 and 4 were reduced. Lastly, when peak 4 was saturated, the magnitude of
peak 3 abated as well as that for peak 1 and 2. Although at this point, we could not

57

assign the peaks in the

13

C NMR spectra to the corresponding diasereomers of active

catalyst, the presence of chemical exchange as detected by NMR spin saturation
transfer clearly lends support to our proposal that the two diastereomeric catalyst
species can also be interconverted either by migration of benzoate anion from B2 to B3
(and

vice

versa)

across

the

same

face

of

the

boroxinate

ring

or

by

dissociation/association.
Figure 3. 12 NMR spin saturation transfer with imine 38 (Precatalyst was prepared and
regents were added in the sequence as shown in Scheme 3.5)

Pre-catalyst was prepared by heating 0.050 mmol VANOL ligand, 0.15
mmol BH3!SMe2, 0.10 mmol 2, 4, 6-trimethylphenol, and 0.15 mmol
H2O in 2 mL toluene at 100 °C for 1 h followed by removal of volatiles
at 100 °C for 0.5 h at 0.1 mm Hg. The resulting mixture was dissolved
in 0.7 mL of d8-toluene and transferred to a quartz NMR tube. 4 equiv.
13

of imine 23f was added to the NMR tube. Lastly, 1- C-labeled benzoic
acid was added.
An NMR spin saturation transfer experiment was also conducted with imine 38. The
results were shown in Figure 3. 12. There are two peaks formed upon the addition of

58

benzoic acid to the precatalyst mixture, which we propose correspond to the two
diastereomers of the active catalysts. When either peak 1 or peak 2 was saturated
during the experiment, the other peak disappeared immediately, indicating the existence
of a chemical exchange process between the two diastereomers.
We believe that a combination of factors is responsible for the observed increase in
enantioselectivity,
(a)

Charge of the counter-ion – Upon addition of benzoate to the boroxinate core,

the net charge of the modified counter-ion is -2. As a result, the substrate should be
‘bound’ tighter in the transition state to the chiral pocket of the catalyst as evidenced by
(i) the stronger hydrogen bonds between the protonated imine and the catalyst (1.87 Å
and 1.86 Å in TS3 and TS4 versus 2.04 Å and 2.19 Å in TS1 and TS2) and (ii) stronger
CH…O interactions between the –CHs of allyl fragment and the dianionic counter-ion
(2.10 Å and 2.06 Å in TS3 and TS4 versus 2.26 Å and 2.19 Å in TS1 and TS2). This
tighter binding of the transition states to the catalyst core could, in principle, amplify the
energy difference between the enantiomeric transition states since these structures now
experience a greater interaction with the chiral space of the catalyst.
(b)

Additional non-covalent interactions – In the (S)-VANOL-BOROX catalyst-imine

complex, due to the trigonal planar orientation of substituents on the boron atom B2,
there is minimal interaction between the phenol substituent on B2 and the imine
substrate (See Figure 3. 8). Addition of a benzoate anion to this boron generates a
tetrahedral boron center, which thrusts the phenol moiety into a geometry that can now
interact with the aromatic groups on the imine substrate via a CH-" interaction. This insitu generation of a tetrahedral boron center in the catalyst and the resulting altered

59

interactions between the phenol moiety and the imine substrate possibly contributes to
the increase in enantioselectivity observed upon addition of benzoic acid.
(c)

Stereodifferentiation by newly generated chiral center – From our NMR studies, it

is clear that there are at least two distinct diastereomers of the catalyst that are formed
upon addition of benzoic acid to (S)-VANOL-BOROX catalyst-imine complex.
Calculations suggest that one of these in-situ formed diastereomers catalyzes the
formation of both enantiomers of product faster than the other diastereomer (both TS3
and TS4, the lowest energy transition structures for formation of (R) and (S)
enantiomers of product, engage the same diastereomer of the catalyst). These results
lead to the conclusion that even though more than one catalyst species might be formed
upon addition of benzoic acid to the (S)-VANOL-BOROX catalyst-imine complex, only
one of these catalyst species might be relevant to catalysis. Therefore, it is likely that
the chirality of this lone catalytically active species helps differentiate the enantiomeric
transition states better than the catalyst without benzoic acid which has only one chiral
center. This is a novel idea in asymmetric catalysis and can be imagined to be
complementary to double-stereodifferentiation obtained by using substrate with chiral
centers, which prefer one chirality of the catalyst to the other.
3.8 Predicted KIEs and interpretation
Finally, for the quantitative interpretation of the experimental KIEs, transition
structures

were

located

for

the

aza-Cope

rearrangement

of

36,

the

p-

bromobenzaldehyde derived imine used for the determination of experimental KIEs,
catalyzed by the (S)-VANOL-BOROX catalyst, both with and without benzoic acid
additive. In order to obtain the highest accuracy in the theoretical prediction of KIEs,

60

transition structures corresponding to TS1 and TS3 (leading to major enantiomer of
product, with and without benzoic acid) were recalculated using the ONIOM scheme
outlined in Scheme 3.6 and Scheme 3.7C where all atoms in 36 were calculated using
the high-level DFT method (B3LYP/6-31+G**). The KIEs for the resultant structures
were computed from their scaled theoretical vibrational frequencies based on
conventional transition state theory using the program ISOEFF 98.

25

Tunneling

corrections were applied to the predicted KIEs using a one-dimensional infinite
26

parabolic barrier model.

The results from these predictions are shown in Figure 3.13.
13

Figure 3. 13 Predicted C NMR KIEs for the aza-Cope rearrangement of 36
(Calculated KIEs are shown in bold; Ar = 3,5-dimethylphenyl)
with benzoic acid additive
1.020(3) 0.999(4)
1.019(4) 1.000(3)
1.022(4) 0.997(1)
1.018 1.003
Ar

Ar

2

N

3

4

without benzoic acid additive
1.020(2) 1.004(4)
1.015(4) 1.005(2)
1.022(5) 1.001(3)
1.020 1.002

5

N

2

3

4

5

1

1
C6H4p-Br

Ar

Ar

H

1.027

C6H4p-Br

1.029

H

1.020
1.028

1.014(5)
1.029(5) 1.010(3)
1.020(1) 1.031(3) 1.017(4)
1.020(4) 1.033(3)

1.030

1.020

1.016(4)
1.029(4) 1.013(3)
1.020(1) 1.030(4)
1.022(2) 1.032(3) 1.016(2)

Overall, the theoretical KIE predictions are remarkably close to the experimentally
determined values. For carbon atoms C2, C3 and C4 the predicted values are almost
identical to the experimental measurement. The KIE predictions for the bond-forming
carbon atoms C1 and C5, though slightly higher than the experiment, is well within the

61

acceptable limits to validate the transition state model. The key observation here is that
the predicted KIE values are nearly identical for each carbon atom (C1-C5 in Figure
3.13) in both cases – models with and without the benzoic acid additive. This matches
the trend observed in the experiments where KIEs measured with and without benzoic
acid are almost identical at every carbon.
3.9 Equilibrium study of the aza-Cope rearrangement with BOROX catalyst 9 and
benzoic acid
Compound 26c was obtained from aza-Cope rearrangement catalyzed by BOROX
catalyst 9 (see supporting information for chapter 2) with 94% ee. Although the
presence of the two aryl groups (Ar) could stablize this product 26c, it has the tendency
to undergo a retro-aza-Cope rearrangement, which results in diminishing the
enantioselectivity of the aza-Cope rearrangement. Hence, compound 26c with 94% ee
was subjected to the equilibrium study as shown in Scheme 3. 8. In experiment B,
where 26c was stirred under standard aza-Cope rearrangent with imines (26c obtained
from imine 36 or aldehyde 25c provided the same enantioselectivity) as described in
chapter 2 with the exception that the temperature was elevated to 100°C, the ee’’
dropped slightly to 92% after 24 h (entry 3). Futhermore, the ee’’ diminished to 60%
after another 24 h at 150°C. Meanwhile, a control experiment A was also carried out,
where compound 26c was heated to 100°C at the absence of BOROX catalyst 9 and
benzoic acid. The enantioselectivity (ee’) remained 94% after 24 h at 100°C (entry 1)
and slightly dropped to 91% after stirring at 150°C for another 24 h (entry 2). As noted,
when experiment A and B were carried out at 60°C for 24 h, we did not observe a
decrease in enantioselectivity of compound 26c.

62

Scheme 3. 8 Equilibrium study of the aza-Cope rearrangement
Experiment A

Experiment B
Ar
N

m-xylene, temp., time

Ar

26c
Br

ee' % = ?

26c 94% ee

10 mol% (S)-VANOL
BOROX 9

26c
10 mol% benzoic acid
m-xylene, temp., time ee'' % = ?

Ar = 3,5-Me2Ph

Entry
1
2
3
4

Experiment No.
A
A
B
B

Temp. (°C)
100
150
100
150

Time (h)
24
24
24
24

ee’ %
94
91
ND
ND

ee’’ %
ND
ND
92
60

3.10 Conclusion
We have presented here a mechanistic study of the chiral Brønsted acid catalyzed
aza-Cope rearrangement and the role of an achiral acid (benzoic acid) in increasing the
enantioselectivity of the reaction. The observation of significant

13

C KIE on all bond-

making and bond-breaking carbon atoms supports a concerted mechanism proceeding
via a six-membered pericyclic transition state. The identical

13

C KIEs measured with

and without the benzoic acid additive suggest that the key features of the transition
state geometry remain unchanged upon addition of benzoic acid.

11

B and

13

C NMR

studies are used to probe the nature of catalyst modification that occurs upon addition
of benzoic acid. It is proposed that the benzoate anion adds to a tri-coordinated boron
atom to generate diastereomeric catalyst structures with a di-anionic counter ion. A
theoretical model is developed, which accurately predicts the experimental KIEs and the
observed enantioselectivity. The newly formed tetra-coordinated chiral boron center and

63

the increased charge of the counter-ion are likely instrumental in increasing asymmetric
induction.

64

CHAPTER FOUR
TOTAL SYNTHESIS OF SEDAM ALKALOIDS VIA CATALYST CONTROLLED AZA
– COPE REARRANGEMENT AND HYDROFORMYLATION WITH FORMALDEHYDE
4.1 Introduction
The sedum alkaloids exist widely in nature and these types of alkaloids have
memory-enhancing properties and are effective in the treatment of cognitive
disorders.

27

The most commonly occurring members of this alkaloid family are 2-

substituted piperidines with various combinations of hydroxyl functionalities in the side
chains, featuring the 1,3-amino alcohol moiety and a select set are shown in Scheme 4.
1.

28

A review of the syntheses of sedium alkaloids has appeared in 2002

28

and the

29

field has remained very active.

Scheme 4. 1 Sedum and related alkaloid natural products

OH
N
H

Me

N
H

(+)-Sedridine

N
Me

(+)-Sedamine

Ph

OH

(-)-Allosedridine

HO

O

OH
N
Me

N
H

(-)-Sedamine

Me

N
H

(+)-Allosedridine

OH

Ph

OH

Me

N
H

Me

(-)-Sedridine

OH
N
Me

OH

OH

(-)-Halosaline

Ph

(-)-Sedacryptine

We have recently discovered a catalytic asymmetric method for the preparation of
homo-allylic amines

22

directly from aldehydes (Scheme 4. 2). The key transformation

involves an aza-Cope rearrangement of an in-situ generated imine 41 to give imine 42

65

which upon hydrolysis provides homoallylic amines with excellent asymmetric
inductions over a broad range of aromatic, alkenyl and aliphatic achiral substrates. The
successful catalyst system results from the synergistic interplay between the boroxinate
species 9 and benzoic acid.
Scheme 4. 2 Direct aminoallylation of non-chiral aldehydes

O
R

H

+

1) 5 mol % VANOL BOROX 9,
5 mol% benzoic acid,
° MS, m-xylene, 60 °C, 18 h
5A

Ar Ar
H2N

25

R

2) 2N HCl /THF

22f

Ar = 3, 5-Me2C6H3

N
R

27

R = aryl, alkenyl,
alkyl (1°, 2°, 3°)

(gram scale)

Ar Ar

NH2•HCl

20 examples,
up to 97% ee

Ar

aza-Cope rearrangement
N

41

[H-imine]
Ph
Ph

R

Ar

42

OPh
O B
O B
O O B O
OPh

VANOL BOROX catalyst 9

Our interests for the present study were directed toward the catalytic asymmetric
direct aminoallylation of chiral aldehydes especially to those that would allow for the
highly diastereoselective introduction of homo-allylic amino alcohol moiety. Our goals
are three-fold. 1) Define a new facile method for the controlled syntheses of syn-1,3amino alcohols and anti-1,3-aminoalcohols. The controlled synthesis of both syn- and

66

anti-1,3-aminoalcohols from a single substrate have been reported from !aminoketones

30

and !-borylamines.

31

We only know of a single example where a

catalyst controlled process can be used to access syn- or anti-1,3-aminoalcohols from a
single substrate (Scheme 4. 3).

32

2) Determine the interplay of the synergistic chiral

VANOL-boroxinate/non-chiral benzoic acid catalyst system with an existing chiral
center. 3) Total synthesis of sedum alkaloids with a divergent synthesis of syn- and anti1,3-aminoalcohols.
Scheme 4. 3 Kumar’s catalyst controlled synthesis of syn/anti-1,3-aminoalcohols from a
single substrate
Cbz
NHCbz
1. DIBAL-H
N
TBSO
2. !-amination (D-proline) R

3. HWE-olefination
OTBS
R

CO2Et

ee > 94%

1. DIBAL-H
2. !-amination (L-proline)
3. HWE-olefination

CO2Et

anti/syn > 40:1

Cbz
NHCbz
N
TBSO
R
CO2Et

syn/anti > 10:1 to 6:1

Hydroformylation is an important process for the production of aldehydes from
olefins in industry. Conventionally, hydroformylation utilizes syngas (CO/H2) in the
presence of a transition metal catalyst to give homologous linear and/or branched
aldehydes. A recent innovation in hydroformylation chemistry features an experimentally
convenient alternative using formaldehyde as a syngas substitute. This synthetically
useful method was first described by Morimoto and coworkers when they smartly
applied two types of catalysts to the two cooperative catalytic processes simultaneously
involved in the hydroformylation with formaldehyde (Scheme 4.4).

67

33

Scheme 4. 4 Hydroformylation with formaldehyde

O

+

C8H17

43

H

H

1 mol% [RhCl(cod)]2
2 mol% BIPHEP
2 mol% NiXantphos
toluene , 90°C

BIPHEP 44

C8H17

l
95% yield (l/b = 97/3)
93% yield (l/b = 97/3)

formalin (20 h)
paraformaldehyde (40 h)

PPh2
PPh2

CHO
CHO

H
N
O
PPh2

PPh2

NiXantphos 45

a) Decarbonylation process
O
H

Ph Ph
H

P

1/2 [RhCl(BINAP)]2

H
H

Rh
P
Ph

Cl

O

Ph

– CO

RhCl(CO)(BINAP)

– H2

Ph Ph
P

H
Rh

P
Ph

68

Ph

Cl

H
CO

+

C8H17

b

b) Hydroformylation process

RhH(CO)2(xantphos)

Ph

Ph

– CO

Ph

Ph

P

CO

P

R

OC Rh H

Rh

P

H

Ph

Ph

Ph

O

P

H
Ph

R

R
H2

Ph

Ph
P

P

O

OC Rh

OC Rh
P
Ph

Ph

Ph

CO

R

Ph

R

P
Ph

Ph

4.2 Retrosynthetic analysis of (+)-allosedridine
We were attracted to the potential that hydroformylation presents for realization of
the total synthesis of sedum alkaloids when coupled with diastereoselective aza-Cope
rearrangement as illustrated in Scheme 4. 5 for synthesis of (+)-allosedridine. The key
intramolecular amidocarbonylation

34

involves hydroformylation of homo-allylic amino

alcohols with formaldehyde and was inspired by Morimoto’s work with simple alkenes.
Scheme 4. 5 Retrosynthesis of (+)-sedridine and (+)-allosedridine
hydroformylation with
O

NHP OP

formaldehyde

NH2 OP

H
Ar

aza-Cope
OH

(+)-sedridine

N
H

O

O

OP

H

OH
N
H

Ar
NH2

rearrangement

(+)-allosedridine
Ar
Ar
NH2
NHP OP

NH2 OP

H

69

4.3 Direct aminoallylation of chiral ! -alkoxy aldehydes
The initial screen of chiral aldehydes was carried out with the TBS protected
aldehyde (R)-46a derived from the commercially available methyl (R)-3-hydroxybutyrate
(Table 4. 1). The diastereoselectivity is nearly equal and opposite with the (R)- and (S)ligands of VANOL (33:1 vs 1:23) and thus this is a case of catalyst control (entries 1 &
2). The total yield of 47a and 48a was low and the elimination product 49 was observed
as a by-product. The reaction of the benzyl protected aldehyde 46b with amine 25 gave
a 4:1 mixture of aza-Cope product (47b+48b) and by-product 49. Incorporation of a
larger protecting group (TBDPS) lead to a mixture largely consisting of the eliminated
imine 49. However, when the sterically less hindered triethylsilyl protecting group (TES)
was installed, the formation of 49 was completely shut down (Table 4. 1, entry 5) giving
an 87% yield and a 1:20 diastereoselectivity in favor of 48 with (R)-VANOL and a 74%
yield and a 26:1 diastereoselectivity in favor of 47 with (S)-VANOL.
Table 4. 1 Direct aminoallylation of chiral "-alkoxy aldehydes
Ar
OPG O
H

46

+

Ar

H2N

Ar = 3, 5-Me2C6H3
22f
5 mol % VANOL BOROX catalyst,
5 mol% benzoic acid,
°
5 A MS, m-xylene, 60 °C, 18 h
Ar

Ar
OPG N

47

Ar

+

OPG N

48

70

Ar
Ar

+

N

49

Ar

Table 4.1 (cont’d)

a

series

ligand

PG

Conv (%)

1
2
3
4
f
5

d

a
a
b
c
d

(R)-VANOL
(S)-VANOL
(R)-VANOL
(R)-VANOL
(R)-VANOL

TBS
TBS
Bn
TBDPS
TES

73(70)
72(67)
(80)
(52)
100

6

f

d

(S)-VANOL

TES

100

entry

a.

b

(47+48)
%Yield
d
c
e
47 : 48
: 49
(47+48)
3:1
33:1
48
4:1
1:23
44
4:1
nd
nd
1:10
nd
nd
100:0
1:20
87
100:0

26:1

74

Unless otherwise specified all reactions were run at 0.2 M in amine 22f with 1.1
equiv 46. The catalyst was prepared from 1 equiv of the ligand, 2 equiv of 2,4,6b.
1
trimethylphenol, 3 equiv of H2O and 3 equiv of BH3!SMe2. Calculated from the H
NMR spectrum of the crude reaction mixture from the ratio of (47+48):22f (or
22f+imine) and the isolated yield of 47+48. The value in parentheses based on the
ratios of 22f (or 22f+imine 50), 47, 48 and 49 and assumption no other products are
formed. In most cases, the unreacted material is in the form of amine 22f, but in
c.
some cases a small amount of imine 50 formed from 46 and 22f is present.
1

Determined from the H NMR spectrum of the crude reaction mixture.
e.

d.

Isolated
f.

ratio.
Isolated yield of a mixture of 47+48 after chromatography on silica gel.
Reaction performed on (S)-46 also of 98% ee. This reaction gives the enantiomer of
47 and 48.
4.4 Direct aminoallylation of chiral !-alkoxy aldehydes

The interplay of the catalyst with a pre-existing !-chiral center in the aldehyde was
also investigated. As shown in Table 4. 2, the reaction of the chiral aldehyde (S)-51 is
not under catalyst control but rather displays a match and mis-matched relationship. A
12:1 selectivity was observed for the matched case with the (S)-VANOL catalyst
resulting in a 71% isolated yield. The same diasteromer predominated in the mismatched case with the (R)-VANOL catalyst but the selectivity dropped to 2.5:1. The
stereochemistry of 52 was assigned as anti since the matched case would be expected

71

to be with the Re-face addition to the imine with the (S)-VANOL catalyst since this is the
preference with non-chiral aldehydes.

22

Table 4. 2. Direct aminoallylation of a chiral !-alkoxy aldehyde
Ar
Ar

Ar

N

Ar

H2N

Ar = 3, 5-Me2C6H3

OTBS

5 mol % VANOL BOROX catalyst,
5 mol% benzoic acid,

22f
+

°
5A MS, m-xylene, 60 °C, 18 h

O

52
+
Ar
N

H

Ar

OTBS
OTBS

51

53
(R)-VANOL 52:53 = 2.5:1 %yield (52+53) = 71
(S)-VANOL 52:53 = 12:1 %yield (52+53) = 71

4.5 Optimization of the intramolecular amidocarbonylation with formaldehyde
In Morimoto’s hydryformylation protocol, extremely high regioselectivity was
obtained for simple alkenes. However, when this approach was first applied to an
intramolecular amidocarbonylation with homo-allylic amine, a disappointling low yield
was obtained. As indicated in Table 4. 3, Further studies show that the yield relies on
the formaldehyde source; when formalin was utilized, in the presence of methanol as a
stabilizer, a significant amount of the 2-alkoxypiperidine 56 was observed in the 1H
NMR spectrum of the crude reaction mixture (Table 4. 3, entry 1). para-Formaldehyde
gave didehydropiperidine 55 and its five-membered analog 57 along with some of the

72

olefin isomerization product 58. Therefore, paraformaldehyde was used instead, and
with the proper control of conditions the didehydropiperidine 55 could be obtained in
73% isolated yield (Table 4. 3, entry 3).
Table 4. 3 Optimization of the intramolecular amidocarbonylation with formaldehyde

NHPG

+

n-pr

PG = Cbz, 54a
= Boc, 54b
+

1 mol% [RhCl(cod)]2
2 mol% BIPHEP
2 mol% Nixantphos

N
PG

MeO

n-Pr

55
n-Pr

+

N
PG

H

n-Pr

56

toluene, temp, 30 h

O
H

N
PG

NHPG

+
n-pr

57

58

yield
c
b
55:57:58
55(%)
d
1
Cbz
formalin
90
46
2
Cbz
paraformaldehyde
90
69
6:1:1
3
Boc
paraformaldehyde
90
73
6:1:1
e
Boc
paraformaldehyde
90
nd
2:3:0
4
5
Boc
paraformaldehyde
120
nd
15:20:7
6
Boc
paraformaldehyde
70
nd
0:100:0
a.
Unless otherwise specified all reactions were run at 0.15 M in 54
entry

a

PG

formaldehyde
source

temp
(°C)

with 5.0 equiv formaldehyde. nd = not determined.
after chromatography on silica gel.

c.

formed in this reaction.

Isolated yield
1

Calculated from the H NMR

spectrum of the crude reaction mixture.
e.

b.

d.

A 38% yield of 56 also

5 mol% PPTS was added to this reaction.

4.6 Synthesis of (-)-Coniine
The intramolecular amidocarbonylation was then applied to the synthesis of (-)Coniine 35. Previously, we have developed a concise total synthesis of (-)-Coniine.
which involved two key reactions – asymmetric catalytic amino-allylation of n-butanal

73

and an RCM reaction.

22

Alternatively, for the current study, we are able to synthesize

this natural product by coupling the catalytic asymmetric aza-Cope rearrangement of
non-chiral aldehyde 27o with the intramolecular amidocarbonylation as illustrated in
Scheme 4. 6. The chiral center is installed in acyclic amine 27o in 83% yield and 95%
ee with catalytic asymmetric direct aminoallylation of n-butanal as shown in Scheme 2.
6, and the piperidine ring is closed using an intra-amidocarbonylation in 71% yield.
Subsequent reduction of the double bond and cleavage of Boc give the target
compound 35 in 91% yield over two steps.
Scheme 4. 6 Total synthesis of (-)-Coniine

NH2 •HCl

1) base
2) PhCHO,
NaBH4

allylBr
HN

27o, 95%ee

Ph

NaH
N
Bn

80%

(Boc)2O, Et3N
THF, reflux

83%

previous route

1) 5 mol%
Grubb's Cat. II

NHBoc

54b 76%
2 mol% Nixantphos
1 mol% [Rh(COD)Cl]2 paraformaldehyde
current route
2 mol% BIPHEP
toluene, 90 °C

N
Boc

2) Pd(OH)2/C-H2
MeOH, 25 °C

81%
over two steps

H2, Pd(OH)2/C HCl, MeOH
MeOH, rt

55b 71%

74

91%
over two steps

•HCl
N
H

35
(R)-Coniine

4.7 Total synthesis of (+)-Sedridine and (+)-allosedridine
Finally, we coupled the diastereoselective aza-Cope rearrangement and the
intramolecular amidocarbonylation reactions in the total synthesis of (+)-Sedridine and
(+)-Allosedridine. Chiral aldehyde 46d was subjected to a diastereoselective aza-Cope
Scheme 4. 7 Synthesis of (+)-Sedridine and (+)-Allosedridine
SETO

O

46d

H

1) 5 mol % VANOL BOROX catalyst , 2) 2N HCl/THF
5 mol% benzoic acid,
3) (Boc)2O, Et3N
°
5 A MS, m-xylene, 60 °C, 18 h
via (S)-catalyst
via (R)-catalyst
OR

NHBoc

OR

61% (over 3 steps)
63
syn-1,3-aminoalcohol
R=H

NHBoc

72% (over 3 steps)
59
anti-1,3-aminoalcohol
R=H
TBSCl
R = TBS 60
imidazole 86%

TBSCl

R = TBS 64 imidazole 74%

1 mol% [RhCl(cod)]2, 2 mol% BIPHEP
2 mol% Nixantphos, paraformaldehyde
toluene, 60 °C

OTBS

OTBS

N
Boc

65
72%
1) Pd(OH)2/C
H2/MeOH
2) HCl/MeOH

61

OH

OH
N
H

N
H

(+)-allosedridine 66
74%

N
Boc

78%
1) Pd(OH)2/C
H2/MeOH
2) HCl/MeOH

(+)-sedridine 62
83%

rearrangement catalyzed by the BOROX catalyst derived from (R)-VANOL. Following
hydrolysis and protection with Boc the anti-amino alcohol 59 was obtained in 72% yield
with good diastereoslectivity over three steps in a one-pot fashion. Compound 59 was

75

then protected with TBS and subjected to an intramolecular amidocarbonylation
reaction to afford 61 in 78% yield. Subsequent reduction and deprotection gave (+)sedridine 62 in 83% yield. (+)-allosedridine 66 was obtained with a similar route with
BOROX catalyst from (S)-VANOL. Presumably, we are able to access all four
stereoisomers of sedridine by combining the two enantiomers of aldehyde 46d with (R)or (S)-VANOL derived BOROX catalysts.
4.8 Conclusion
This work has demonstrated that the aldehydes bearing a chiral #–hydroxyl group
will undergo the aza-Cope rearrangement to give good yields of homo-allylic amino
alcohols with where there is a strong catalyst control case between the chiral aldehyde
and (S)-VANOL or (R)-VANOL derived catalysts. It is important to note that the very
high asymmetric inductions of the boroxinate catalyst/benzoic acid for the catalytic
asymmetric aza-Cope rearrangement were essentially unaffected by the nature of the
chiral group in the substrate. The highly diastereoselective aza-Cope rearrangement
can be coupled to the intramolecular amidocarbonylation with paraformaldehyde. The
coupling of these methods led to a direct and highly diastereoselective method for the
rapid introduction of substituted piperidine units, which was demonstrated in the
stereocontrolled synthesis of (+)-sedridine and (+)-allosedridine.

76

CHAPTER FIVE
TRIMETHYLSILYLDIAZOMETHANE AS A VERSATILE STITCHING AGENT FOR
THE INTRODUCTION OF AZIRIDINES INTO FUNCTIONALIZED ORGANIC
MOLECULES
5.1 Introduction
Aziridines are attractive synthetic building blocks. As with their epoxide analogs, the
highly strained ring structures of aziridines provide access to a wide range of important
nitrogen-containing products by undergoing several highly regio- and stereoselective
cycloadditions and ring opening reactions.

35

Aziridines also play a very important role,

through ring expansion reactions, in the formation of five membered heterocycles such
36

as oxazoline-2-ones and imidazolidin-2-ones.

Scheme 5. 1 Three approaches towards catalytic asymmetric aziridination

R
R2

MLn

R1

N

L nM

R1

R
N

R2
R
N

carbene pathway
R1

nitrene pathway
R2

Lewis/Brønsted acid pathway
R

LA or BA
N
R1

LG

R2

LG = leaving group

In the last two decades, a lot of effort has been put forth to develop effective
asymmetric catalytic aziridination protocols. Although quite a few successful systems
have been reported since then,

37

none of them are particularly general over a broad

77

range of substrates. So it is of great importance to develop a catalytic enantioselective
aziridination which could be applied to a wide range of substrates.
To date, there have mainly been three different approaches towards catalytic
asymmetric aziridinations. These are depicted in Scheme 5. 1.
Since 1999, our group has developed a catalytic asymmetric aziridination protocol
which involves a Brønsted acid mediated addition of a diazo compound to an imine
38

(Scheme 5. 2).

This aziridination protocol represents the most general and the most

diastereo- and enantioselective catalytic asymmetric aziridination system to date.
Scheme 5. 2 The Antilla-Wulff catalytic asymmetric aziridination

Ph

N2
R

N

10 mol% BOROX 9

O

Ph
O

Ph

67

toluene, 25 °C, 24 h R

68

Ph

Ph

H

N
O

N

EtO2C

Ph
R(H)

H(R)

O

70

(2R, 3R)-69

R = aromatic, aliphatic (1°, 2°, 3°)
yield 69 = 37-89%
% ee 69 = 77-94%
cis: trans 69 = 1.6:1- 100:1

Ph
Ph

OH
OH

or

Ph
Ph

B(OPh)3 (4 eq)

OH
OH

0.1 mm Hg

H2O (1 eq), toluene, 80 °C, 0.5 h
80 °C, 1 h
(S)-VANOL
12

BOROX 9

(S)-VAPOL
13

An enormous amount of work

39

has been carried out in our group towards

developing this aziridination protocol in the ten years since its discovery. Efforts towards

78

fine-tuning numerous aspects of the reaction,
the mechanism

39j-m

39a-e

expanding its scope,

and applying it in a synthetic sense
39f

However, with the exception of one study,

39n-p

39f-i

elucidating

have been undertaken.

commercially available ethyl

diazoacetate (EDA) has been the only diazo source used in all the cis-aziridination work
reported by our group. Our interest for the present study was directed towards the
development of the catalytic asymmetric cis-aziridination reaction with alternative diazo
sources especially to those that would allow for the straightforward introduction of a
variety of functional groups into the aziridine core. The goals are two-fold: define a
facile catalytic asymmetric method for the introduction of aziridine units into
functionalized organic molecules and determine the tolerance of the VAPOL/VANOL
chiral polyborate catalyst 9 to various common organic functional groups.
5.2 Synthesis of diazo ketone via the diazo transfer method
As a first step, a mild, simple and general approach for the synthesis of the diazo
compounds from precursors bearing the desired remote functional groups was required.
40

The diazo transfer method

(Scheme 5.3) was tried initially, but that route did not give

satisfactory results. The overall yield of 74a was only 13% after four steps, and the
purification of the final diazo ketone was extremely tedious, requiring at least three
purifications by column chromatography to obtain the pure product.

79

Scheme 5. 3 Synthesis of diazo ketone 74 via the diazo transfer method

OH

OLi

MeLi
DME, - 45 °C

O

OLi

MeLi

O

OLi

Et2O

71a
CF3

HMDS/n-BuLi

aq. HCl
O

72a

O

THF, CF3CO2CH2CF3

O

48%

SO2N3

C12H25
73

N2
O

H2O, Et3N, CH3CN, rt

30%

74a

Another well-known reagent for the synthesis of diazo compounds is diazomethane.
However, it is notorious because of its high toxicity, thermal lability and potentially
explosive nature. Diazomethane was thus decided to be avoided in our protocol.
5.3 Synthesis of diazo ketones with TMSCHN2
Scheme 5. 4 Tandem acylation/aziridination of TMSCHN2

O
O

FG

n OH

O

FG

N

n Cl

R

Me3Si

H
N2

H

FG n
O

80

R'
N H
R

R'

R

H

+
R'NH2

In 1981, Shioiri and co-workers reported trimethylsilyldiazomethane (TMSCHN2) as
a stable and safe substitute for the hazardous diazomethane in the Arndt-Eistert
synthesis.

41

They

also

reported

the

preparation

and

isolation

of

1-

(diazoacetyl)naphthalene from TMSCHN2 and the acid chloride of 1-naphthalene
carboxylic acid, but it was the only isolated diazo ketone mentioned. This made us
wonder if the same TMSCHN2 protocol could be used to prepare other aromatic diazo
ketones required for our study, and maybe aliphatic diazo ketones

as well. If

successful, this method would be much easier than the azide transfer method in terms
of the reaction manipulation and product purification, and would also be much safer
than the diazomethane option. Surprisingly, however, accessing diazo ketones via the
use of TMSCHN2 has never been explored to date, despite the wide spread use of
diazo compounds in organic synthesis. We were attracted to the potential that
trimethylsilyldiazomethane (TMSCHN2) presents for introduction of aziridine units into
functionalized organic molecules in a synthetically convergent manner (Scheme 5. 4).
Scheme 5. 5 Synthesis of diazo ketone 74a by TMSCHN2

O

(COCl)2
OH

O

DCM, rt

Cl

71a
2 eq. TMSCHN2
CH3CN, 0 °C
overnight

N2
O

74a
73% (overall from 71a)

81

We thus re-examines the synthesis of the diazo ketone 74a via TMSCHN2 (Scheme
5.5). We were delighted to discover that it worked very well with an overall yield of 73%
for 74a.
5.3.1 Optimization of the number of equivalents of TMSCHN2
Table 5. 1 Optimization of the number of equivalents of TMSCHN2

O

(COCl)2

O
OH

EtO

DCM, rt

O
EtO

Cl

71b

Entry

Equiv. of
TMSCHN2
1.1
1.5
2.0
2.5

a

1
2
3
4

a.

TMSCHN2

O

O

0 °C, overnight EtO
CH3CN

Yield 74b (%)

O
N2

74b

b

70
74
73
77

The acid 71 was reacted with oxalyl chloride for 1 h
and then after volatiles were removed, the acid chloride
was reacted with TMSCHN2 at 0°C for 12 h at 0.2 M in
b.

CH3CN.
Isolated yield after purification by column
chromatography on silica gel.
Considering the high cost of TMSCHN2, it was then decided to optimize the number
of equivalents of TMSCHN2 needed for this reaction (Table 5. 1). It was found that the
number of equivalents could be lowered from 2.5 to 1.1, while still providing a
satisfactory yield of the diazo ketone 74b. For the synthesis of diazo ketones from acyl
chlorides. All reported examples required at least 2 equivalent of diazomethane to
42

furnish good yield.

However, with TMSCHN2, 1.1 equivalent is sufficient to provide

82

satisfactory yield. Scheme 5. 6 depicts a proposed mechanism for the diazo ketone
formation with diazomethane and TMSCHN2, respectively, that explains the origin of the
difference. With TMSCHN2, in the second step of the proposed mechanism, chloride
anion serves as a nucleophile to attack TMS group, which furnishes the diazo ketone.
While with CH2N2, after the nucleophilic attack to the acyl chloride in the first step,
another equivalent of CH2N2 is required for deprotonation in the second step to afford
the diazo ketone.
Scheme 5. 6 Proposed mechanism for the formation of diazo ketone with
TMSCHN2 and CH2N2

Diazo ketone formation with 1 equivalent of TMSCHN2
TMS

O
R

I
Cl

+ TMSCHN2

O CHN2
R

O
II
CHN2 Cl
TMS

R

Cl

71
O

III
R

CHN2

+ TMSCl

74
Diazo ketone formation with 2 equivalent of CH2N2
O
R

I
Cl

+

CH2N2

O
O CH2N2
R

71
O

III
R

CHN2

+ CH3Cl + N2

74

83

Cl

II
R

CHN2 CH2N2
H

5.3.2 Sovent study for the synthesis of diazo ketone 74b
Subsequently, a variety of solvents were screened for diazo ketone formation with
TMSCHN2 and CH3CN was determined to be the optimum solvent (Table 5. 2).
Table 5. 2 Solvent study for the synthesis of diazo ketone 74b

O

(COCl)2

O
OH

EtO

DCM, rt

O

TMSCHN2

O

EtO

Cl

71b

Entry
1
2

a.

3
4
5
6
c
7

a

O

0 °C, overnight EtO
sovent

Solvent
Hexane
CH3CN

Yield 74b (%)
20
70

Et2O
Toluene
CH2Cl2
EtOH
DMF

O
N2

74b

b

13
21
27
0
68

The acid 71 was reacted with oxalyl chloride for 1 h
and then after volatiles were removed, the acid chloride
was reacted with TMSCHN2 at 0°C for 12 h at 0.2 M in
CH3CN.

b.

Isolated yield after purification by column

chromatography on silica gel.

c.

No quench with satd

NAHCO3.
5.3.3 Substrate scope for the synthesis of diazo ketones with TMSCHN2
We then examined the substrate scope of the reaction for the formation of various
diazo ketones (Table 5. 3). To our pleasure, this protocol worked very well for the
formation of aliphatic diazo ketones (entry 1-6 and 10). However the results for the
reaction of aromatic carboxylic acids were disappointing, giving no desired products at
all (Table 5. 3, entry 7-9). Triethylamine as an addictive was found to be necessary to

84

afford the diazo ketones from benzoic acid in acceptable yield (Table 5. 3, entry 7). The
reactions of trans-cinnamic acid and phenylpropiolic acid failed even with the addition of
triethylamine (Table 5. 3, entry 8 and 9).
Table 5. 3 Substrate scope for the synthesis of diazo ketones 74 via TMSCHN2
(COCl)2

O
R

1
OR

DCM, rt
2h

1.1 eq. TMSCHN2

O
R

R

CH3CN, 0 °C
24 h

Cl

N2
O

74a-11j

R1 = H 71a-i,
R1 = TBDMS 71j

a

Entry

Series

1

a

2

b

c

c

69

4

d

66

5

e

3

R

Yield 11 (%)
73
O
OEt

Br

70

78

O

6

d

f

82

N
O

7

c,e

g

c

h

8
9

c

j

Ph

i

d

52

10

Ph
O

a.

O

0
15
52

The acid 71 was reacted with oxalyl chloride for 1 h and
then after volatiles were removed, the acid chloride was
b.
reacted with TMSCHN2 at 0°C for 12 h at 0.2 M in CH3CN.
Isolated yield after purification by column chromatography on
c.
d.
silica gel.
1.2 eq of Et3N was added.
The starting
acids/ester were prepared according to reported
43 e.
procedures.
The product 74g was not observed without
Et3N.

85

The application of TMSCHN2 in the synthesis of diazo ketones starting from the
corresponding acyl chloride is efficient in practice. However, in the case of substrate
71k, other methods for acid activation, like forming the corresponding acid anhydrides
instead of the acid chlorides, are preferred. This is due to the predominant formation of
cyclic ester

44

of the type 75 (Scheme 5). Indeed, when acid 71k was subjected to the

standard acid chloride reaction, the undesired product 75 was obtained in quantitative
yield. Thus, we turned our attention towards forming the acid anhydride 76 to get to the
diazo ketone 74k (Scheme 5). However, the overall yield was disappointing and the
reaction was sluggish. We then tried to synthesize some relatively more active acid
anhydrides, such as the (4-nitrophenylcarbonic)-4-oxopentanoic anhydride and (2,2,2trichloroethylcarbonic)-4-oxopentanoic anhydride. But none of these anhydrides could
1

be made successfully, and the H NMR analysis of the crude reaction mixtures did not
match the desired anhydride products.
Scheme 5. 7 Preparation of the diazo ketone 74k via the corresponding acid anhydride
O

O
OH
O

(COCl)2
DCM, rt

71k
O
OH
O

71k

ClCO2Et
TEA, THF, 0°C

O

75
O
O
O

O
O

76

86

Cl

1.1 eq TMSCHN2
CH3CN, 0 °C
24 h

O
N2
O

74k 30%

5.4 Introduction of aziridines into functionalized organic molecules
Thus, with the requisite diazo ketones bearing the remote functional groups in hand,
the catalytic asymmetric aziridinations with the VAPOL and VANOL-borate catalysts
were then examined, using the optimal conditions previously developed in our group.

39b

5.4.1 Optimization of the aziridination reaction with diazo ketone 74a
Table 5. 4 Optimization of the aziridination reaction

O

O

O

N

toluene, 25 °C
N2

77

O

5 mol % or 10 mol% cat. 9

O

R

a

74a

N
R

78

O

Cat.
Conv.
Loading 9
b
(%)
(%)
1
a
Phenyl
(S)-VAPOL
24
5
100
2
Phenyl
(R)-VANOL
24
5
100
3
b
Cyclohexyl
(S)-VAPOL
96
5
67
4
Cyclohexyl
(R)-VANOL
96
5
68
5
Cyclohexyl
(S)-VAPOL
24
10
100
6
Cyclohexyl
(R)-VANOL
24
10
100
7
o
t-butyl
(S)-VAPOL
96
5
66
8
t-butyl
(R)-VANOL
96
5
64
a.
Unless specified, all reactions were run in toluene at 25 °C containing 1 mmol
imine 77 with 1.2 eq of diazo ketone 74a and 5 mol% or 10 mol% of the catalyst 9
which was prepared according to procedure presented in Scheme 5. 2. Ent-78 was
b.
1
obtained with (R)-VANOL. Determined form crude reaction mixture by H NMR.
Entry

Series

R

Time
(h)

Ligand

The catalytic asymmetric aziridination with remotely functionalized diazo ketones
was optimized successively in three steps. First, we tried to optimize the representative
imines

to

be

used

in

the

study.

The

N-MEDAM

(bis(4-methoxy-3,5-

dimethylphenyl)methanamine) phenyl imine 77a and the N-MEDAM t-butyl imine 77c

87

were selected at the beginning and the corresponding conversions were initially
checked (Table 5. 4). The phenyl imine 77a gave full conversion in 24 h with 5 mol%
catalyst loading (Table 5. 4, entry 1 and 2). The conversions for the N-MEDAM t-butyl
imine however were disappointing (Table 5. 4, entry 7 and 8). This might be due to the
steric interactions between the bulky t-butyl group and the aliphatic chain of the diazo
compounds. The less hindered N-MEDAM cyclohexyl imine 77b was then used to
replace the N-MEDAM t-butyl imine. But the conversions were still disappointing (Table
5. 4, entry 3 and 4). It was then decided to increase the catalyst loading in the second
step of the optimization. The catalyst loading was increased to 10 mol%, which led to
the complete conversion of the cyclohexyl imine 77b (Table 5. 4, entry 5 and 6).
5.4.2 Optimization of the N-protecting group
In the last optimization step, we looked at the N-protection group in the imine (Table
5.5). The initial aziridination studies in our group were done with the benzhydryl group
as the N protection group for the imine. However, recently, it has been shown that the
N-MEDAM group is far superior for the aziridination reaction, especially for aliphatic
imines.

39d

The benzhydryl amine was commercially available, while the MEDAM amine

has to be synthesized in 4 steps.

39d

Thus, both the N-MEDAM phenyl imine 77a and N-

benzhydryl phenyl imine 78 were evaluated for the aziridination reactions with diazo
ketone 74a. From the results obtained (Table 5.5), it was evident that the N-MEDAM
protection group was the protecting group of choice for this study.

88

Table 5. 5 Optimization of the N-protecting group

PG
N

O

PG
N

5 mol% Cat. 9

+

a

toluene, 25°C
N2

O

PG = MEDAM 77a

74a

PG = MEDAM 78a

PG = benzhydryl 79

PG = benzhydryl 80

Entry
PG
1
MEDAM
2
MEDAM
3
Benzhydryl
4
Benzhydryl

a.

Ligand
(S)-VAPOL
(R)-VANOL
(S)-VAPOL
(R)-VANOL

Yield cis (%)
72
85
66
58

b

ee cis (%)
99
94
92
85

c

Unless specified, all reactions were run in toluene at 25 °C
containing 1 mmol imine 77a or 79 with 1.2 equiv of diazo ketone
b.
74a.
Isolated yield after purification by column chromatography
on silica gel.

c.

Determined by HPLC analysis.

5.4.3 Substrate scope for tandem acylation/aziridination of TMSCHN2
Applying the optimized conditions, the aziridination reactions of the functionalized
diazo ketones 74a-f and 74j with the imine 77a and 77b were examined in toluene and
the results are presented in Table 5. 6. All reactions gave excellent asymmetric
inductions for all aziridines with both VANOL and VAPOL catalysts and with both
imines. The cis-aziridines were obtained with $ 50:1 selectivity in all cases. Higher
asymmetric inductions were observed with the VAPOL catalysts for both imines in all
cases with the curious exception of 5-bromo-1-diazopentan-2-one 74e (entries 19 and
20). With the diazoketone 74a as the control, it can be seen that the boroxinate catalyst
9 is remarkably tolerant of the presence of a variety of functional groups with essentially

89

no change in the asymmetric induction over the entire range of functional groups in the
diazo ketones.
Table 5. 6 Aziridination of functionalized diazo ketones 74a-f,j with imine 77a and 77b
O

O

O
O

N

Prod.
Entry
78
Series

16

(S)-VAPOL

24

91

(R)-VANOL

24

100

85

94

(S)-VAPOL

24

100

82

95

(R)-VANOL

36

93

65

91

Ph

(S)-VAPOL

24

98

76

99

(R)-VANOL

28

83

78

96

(S)-VAPOL

24

100

92

97

(R)-VANOL

24

100

90

94

Ph

(S)-VAPOL

24

100

77

99

(R)-VANOL

24

100

82

96

(S)-VAPOL

24

100

72

95

(R)-VANOL

24

100

79

91

Ph

(S)-VAPOL

24

100

89

99

Ph

f

g

14
15

Ph

Cy

e

12
13

c

Ph

d

10
11

78 O

Yield
cis 78
(%)
72

(R)-VANOL

24

100

95

99

(S)-VAPOL

24

100

79

96

(R)-VANOL

24

100

73

91

R

Cy

Ph

8
9

74

1

Cy

c

6
7

R

R

Cy

b

4
5

N

toluene, 25 °C

Ph

a

2
3

1

N2

77a R = Ph
77b R = Cy

1

5 mol % or 10 mol% cat. 9
R

R

O

h

Cy

Cy

Cy
Cy

R1

Ligand

74a

O

74b

74c

74d

OEt

90

b

Time
(h)

Conv
(%)

d

ee cis
78 (%)
99

Table 5.6
17

24

100

85

95

(R)-VANOL

24

100

78

98

(S)-VAPOL

28

93

61

92

(R)-VANOL

24

100

71

89

Ph

(S)-VAPOL

28

88

80

98

(R)-VANOL

28

87

85

93

(S)-VAPOL

36

70

63

88

(R)-VANOL

36

68

64

87

(S)-VAPOL
(R)-VANOL
(S)-VAPOL
(R)-VANOL

24
24
24
24

100
100
100
100

88
85
62
64

97
93
93
91

Ph
Br

Ph
j

20
21

(S)-VAPOL

Cy

i

18
19

(cont’d)

k

74e

Cy

O

22
23

Ph
l

24

a.

25
26
27
28

N

Cy

O

74f

Cy
m
n

Ph
Ph
Cy
Cy

O

O

74j

Unless specified, all reactions were run in toluene at 25 °C containing imine 77a
b.

and 77b with 1.2 eq of diazo ketone 74a-f and 74j. Catalyst loading was 5 mol%
for 77a and 10 mol% for 77b which was prepared according to procedure presented
c.
in Scheme 5. 2.
Isolated yield after purification by column chromatography on
d.

silica gel.
Determined by chiral HPLC analysis.
crude reaction mixture.

e.

1

Calculated from H NMR of

5.5 Deprotection of MEDAM group
The most efficient method for the deprotection of MEDAM-aziridines is treatment
with triflic acid in anisole.

39c,d

However, this method was optimized for simple

aziridines sans functionality. It was not clear if the functionalized aziridines generated in
the present study would be tolerant of these conditions. As a test, aziridine 78i, was
subjected to 5 equivalents of triflic acid in anisole for 2 h and, to our delight, cleavage of
the MEDAM group could be achieved to give the N-H aziridine 81i in excellent yield
(Scheme 5. 8). It was interesting to note that this molecule could be isolated and
purified on silica gel with no evidence for intramolecular alkylation on nitrogen.

91

Scheme 5. 8 Deprotection of MEDAM group from (2R, 3R)-78i
MEDAM
N
Ph

triflic acid
dry anisole,
0 °C to rt, 2 h

3 Br
O

H
N
Ph

3 Br
O

81i, 84% yield

(2R,3R)-78i

5.6 Diastereoselective synthesis of tetrahydrofurylamines
Tetrahydrofurylamines are widely used in the synthesis of various medical agents
such as ion channel modulators,
neuotropics,

49

45

enzyme inhibitors,

anticarcinogenic drugs

50

46

47

analgesics, antibiotics

and antifungal agents.

51

48

and

These types of

compounds are also of particular interest with regard to ligands for asymmetric
alkylation.
of

the

52

Despite the broad use and importance of tetrahydrofurylamines, a search

literature

produced

few

reports

for

the

asymmetric

preparation

of

tetrahydrofurylamines, especially those bearing two contiguous chiral centers. Key to
the general access to all the stereoisomers of tetrahydrofurylamines from the aziridinyl
ketone 78i is the ability to control the stereochemistry in the reduction of the ketone
function. The reduction was first examined with zinc borohydride, a well-known
chelation-controlled reducing agent.

39f

Despite our concerns with the presence of the

large MEDAM group on the nitrogen which might prevent the coordination of zinc, it
proved possible to reduce the ketone moiety with >50:1 selectivity for diastereomer 82
(Scheme 5. 9). Non-chelation-controlled reduction of the ketone functionality in 78i
could be effected with L-selectride at –78 °C in 68% yield and with a 15:1 selectivity for
diastereomer 85.

When the reduction with L-selectride was conducted at room

92

temperature, the stereochemistry of the reduction only dropped to 11:1 and the resulting
lithium alkoxide cyclized to give the tetrahydrofurylaziridine 86. Reductive opening of
the aziridine and reductive cleavage of the MEDAM group in the presence of (Boc)2O
afforded the tetrahydrofurylamine 87. After cyclization of 82 with NaH, the
diastereomeric tetrahydrofurylamine 84 could be obtained from 83 with the same
protocol used in the conversion of 86 to 87.
Scheme 5. 9 Diastereoselective access to enantiomeric tetrahydrofurylamines
MEDAM
Zn(BH4)2

Et2O, 25 °C

Ph

3 Br

L-selectride
THF, –78 °C

THF, rt

N
Ph

82 OH
91% (dr > 50:1)

83 O
94%
H2, Pd(OH)2,
(Boc)2O, MeOH

MEDAM

(S,S)-78i
98% ee

MEDAM

NaH,

N

NHBoc

N
Ph
Ph

3 Br

O

85 OH
68% (dr = 15:1)

84 70%

MEDAM

THF, 25 °C

Pd(OH)2

N

L-selectride
Ph

O

86
83% (dr = 11:1)

H2, MeOH
(Boc)2O,

NHBoc
Ph
O

87 72%

5.7 Conclusion
This work has demonstrated that the Shioiri acylation of trimethylsilyldiazomethane
with aliphatic acid chlorides can be coupled to the catalytic asymmetric aziridination of
aldimines with a chiral polyborate Brønsted acid catalyst derived from the vaulted biaryl
ligands VANOL and VAPOL. The coupling of these methods led to a direct and highly

93

enantioselective method for the rapid introduction of aziridine units into functionalized
organic molecules. It is important to note that the very high asymmetric inductions of
the boroxinate catalyst for the catalytic asymmetric aziridination were essentially
unaffected by the nature of the functional group in the diazo component. The products
of these tandem reactions are synthetically useful intermediates and this was
demonstrated in the stereocontrolled synthesis of tetrahydrofuryl amines.

94

CHAPTER SIX EXPERIMENTAL SECTION
6.1 Supporting information for chapter two
6.1.1 General information
All experiments were performed under an argon atmosphere. Flasks were flamedried and cooled under argon before use. All solvents were dried appropriately if used in
the reaction. Both VAPOL and VANOL ligands are commercially available from Aldrich
as well as Strem Chemicals. If desired, they could be purified using column
chromatography on regular silica gel with 2:1 dichloromethane/hexanes. Phenol was
sublimed and stored in a dry desiccator. Solid aldehydes were either used as purchased
from Aldrich or sublimed before use. Liquid aldehydes were either used as purchased
from Aldrich or distilled before use.
Melting points were measured on a Thomas Hoover capillary melting point
1

apparatus. H NMR and

13

C NMR were recorded on a Varian 300 MHz, VXR-500 MHz

or VXR-600 MHz instrument in CDCl3 unless otherwise noted. CHCl3 was used as the
1

internal standard for both H NMR (! = 7.24) and

13

C NMR (! = 77.0). The silica gel for

column chromatography was purchased from Sorbent Technologies with the following
specifications: standard grade, 60 Å porosity, 230 X 400 mesh particle size, 500-600
2

m /g surface area and 0.4 g/mL bulk density. Analytical thin-layer chromatography
(TLC) was performed on 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
phosphomolybdic acid in ethanol.

95

HPLC analyses were carried out using a Varian Prostar 210 Solvent Delivery
Module with a Prostar 330 PDA Detector and a Prostar Workstation. Optical rotation
was obtained on a Perkin-Elmer 341 polarimeter at a wavelength of 589 nm (Sodium D
line) using a 1.0 decimeter cell with a total volume of 1.0 mL.
6.1.2 General procedure for the preparation of the amines – Illustrated for the
synthesis of 1,1-bis(3,5-dimethylphenyl)but-3-en-1-amine 22f
CN
Br

Mg/I2

MgCl

THF, reflux, 8 h

reflux, 8 h

rt, 24 h
N

MgBr

H2N

22f

To a flame-dried 100 mL three-necked round bottomed flask filled with Nitrogen and
equipped with a refluxing condenser was added 1-bromo-3,5-dimethylbenzene (3.7 g,
20 mmol), magnesium (1.2 g, 50 mmol), THF (45 mL) and a few crystals of I2. The
mixture was slowly heated to reflux and kept at reflux for 8 h. The resulting light brown
solution was allowed to cool down to room temperature. At the same time, to a flamedried 250 mL three-necked round-bottomed flask filled with nitrogen was added 3,5dimethylbenzonitrile

53

(2.4 g, 18 mmol) and THF (45 mL). Then the freshly prepared

Grignard reagent was transferred at room temperature via syringe to the 250 mL flask
containing the nitrile compound over 5 min. The resulting mixture was heated to reflux
for 8 h under an nitrogen atmosphere, and then allowed to cool down to room
temperature, and then 0 °C. To this mixture was transferred a solution of allyl
magnesium chloride in THF (2.0 M, 44 mmol, 22 mL). The ice-bath was then removed
and the reaction mixture was stirred at room temperature for 24 h. The mixture was then

96

cooled down to 0 °C and carefully quenched by the slow addition of 1 N aqueous NaOH
(20 mL). THF was removed under reduced pressure and the aqueous layer was
extracted with EtOAc (20 mL x 3). The combined organic phase was dried over
Na2SO4, filtered and concentrated under reduced pressure to give the crude product as
a yellow solid, which was purified by silica gel chromatography (8:1 hexanes/EtOAc as
elute) to afford amine 22f as a white solid (mp 85-86 °C) in 24% yield after three steps
1

(1.2 g, 4.3 mmol). Spectral data for 22f: Rf = 0.2 (8:1 hexanes/EtOAc). H NMR (CDCl3,
300 MHz) % 1.72 (bs, 2H), 2.26 (s, 12H), 2.95 (d, 2H, J = 6.9 Hz), 5.04-5.16 (m, 2H),
5.44-5.53 (m, 1H), 6.82 (s, 2H), 6.97 (s, 4H);

13

C NMR (75 MHz, CDCl3) % 21.75, 47.98,

60.12, 119.04, 124.59, 128.18, 134.83, 137.60, 148.45; IR (thin film) 3410m, 3390m,
1

3072m, 2976m, 1604m cm- ; mass spectrum, m/z (% rel intensity) 278 (1.04) (1.04),
238 (100), 110 (70), 41 (53); Anal calcd for C20H25N: C, 85.97; H, 9.02; N, 5.01. Found:
C, 86.10; H, 8.95; N, 4.97.
CN
Br
O

Mg/I2
THF, reflux, 8 h

O

O

O

reflux, 8 h

MgCl

rt, 24 h
N

MgBr

O

O

H2N

22a

1,1-bis(4-methoxyphenyl)but-3-en-1-amine 22a. The general procedure described
above for the preparation and purification of amine 22f was followed for the synthesis of
22a, starting from 1-bromo-4-methoxybenzene (3.7 g, 20 mmol). Purification by column
chromatography on silica gel (1:15 ether/pentane) gave the pure amine 22a as an oil in

97

1

20% yield (1.0 g, 3.6 mmol). Spectral data for 22a: Rf = 0.2 (1:15 ether/pentane). H
NMR (CDCl3, 500 MHz) % 1.74 (bs, 2H), 2.94 (d, 2H, J = 6.5 Hz), 3.76 (s, 6H), 5.065.15 (m, 2H), 5.48-5.55 (m, 1H), 6.79-6.82 (m, 4H), 7.26-7.29 (m, 4H);

13

C NMR (125

MHz, CDCl3) % 48.16, 55.45, 59.66, 113.59, 119.20, 127.90, 134.65, 140.92, 158.21; IR
(thin film) 3372m, 3071m, 2934m, 1608m, 1248m, 1035m cm-1; HRMS (ES+) calcd for
C18H22NO2 m/z 284.1651 (M++1), meas 284.1665.

tBu
tBu

Br

tBu

O

Mg/I2

tBu

THF, reflux, 8 h

O

CN

reflux, 8 h

tBu

O

tBu
O

tBu

MgCl

tBu

tBu

N

rt, 24 h

MgBr

tBu

O

O

tBu

tBu
H2N

22b

1,1-bis(3,5-di-tert-butyl-4-methoxyphenyl)but-3-en-1-amine

22b.

The

general

procedure described above for the preparation and purification of amine 22f was
followed

for

the

synthesis

of

22b,

starting

from

5-bromo-1,3-di-tert-butyl-2-

methoxybenzene (4.5 g, 21 mmol). Purification by column chromatography on silica gel
(1:16:0.17 acetone/hexanes/TEA) gave the pure amine 22b as an oil in 22% yield (2.1 g,
1

4.2 mmol). Spectral data for 22b: Rf = 0.2 (1:16:0.17 acetone/hexanes/TEA). H NMR
(CDCl3, 500 MHz) % 1.35 (s, 36 H), 1.79 (bs, 2H), 2.94 (d, 2H, J = 7.0 Hz), 3.64 (s, 6H),
5.07-5.19 (m, 2H), 5.61-5.65 (m, 1H), 7.15 (s, 4H);

13

C NMR (125 MHz, CDCl3) % 32.38,

36.09, 48.29, 60.91, 64.30, 118.71, 125.36, 135.33, 142.15, 142.63, 157.88; IR (thin film)
2959m, 1653m, 1224, 1014m cm-1; HRMS (ES+) calcd for C34H54NO2 m/z 508.4155

98

(M++1), meas 508.4158.
CN
Br

Mg/I2
THF, reflux, 8 h

F

F

F

F

reflux, 8 h

MgCl F

rt, 24 h
N

F

H2N

MgBr

22c

1,1-bis(4-fluorophenyl)but-3-en-1-amine 22c. The general procedure described
above for the preparation and purification of amine 22f was followed for the synthesis of
22c, starting from 1-bromo-4-fluorobenzene (1.9 g, 11 mmol). Purification by column
chromatography on silica gel (1:2:0.1 DCM/hexanes/TEA) gave the pure amine 22c as
an oil in 21% yield (0.54 g, 2.1 mmol). Spectral data for 22c: Rf = 0.2 (1:2:0.1
1

DCM/hexanes/TEA). H NMR (CDCl3, 500 MHz) % 1.74 (bs, 2H), 2.95 (d, 2H, J = 7.0
Hz), 5.08-5.15 (m, 2H), 5.43-5.50 (m, 1H), 6.94-6.98 (m, 4H), 7.30-7.35 (m, 4H);

13

C

NMR (125 MHz, CDCl3) % 48.07, 59.83, 115.04-115.21 (d, J = 21.0 Hz), 119.84,
128.40-128.46 (d, J = 8.0 Hz), 133.86, 144.03-144.05 (d, J = 3.0 Hz), 160.70-162.65 (d,
J = 244 Hz); IR (thin film) 3400m, 3300m, 3076m, 2924m, 1601m, 1226m, 1014m cm-1;
HRMS (ES+) calcd for C16H16NF2 m/z 260.1251 (M++1), meas 260.1238.

Et

CN
Et

Et

Br

Mg/I2
THF, reflux, 8 h

Et

Et

Et

reflux, 8 h

Et

MgCl
Et

Et
N

Et

MgBr

rt, 24 h

Et

Et
H2N

22d

1,1-bis(3,5-diethylphenyl)but-3-en-1-amine 22d. The general procedure described

99

above for the preparation and purification of amine 22f was followed for the synthesis of
54

22d, starting from 1-bromo-3,5-diethylbenzene

(1.3 g, 6 mmol). Purification by column

chromatography on silica gel (1:24:0.25 acetone/hexanes/TEA) gave the pure amine
22d as an oil in 22% yield (0.40 g, 1.2 mmol). Spectral data for 22d: Rf = 0.2 (1:24:0.25
1

acetone/hexanes/TEA). H NMR (CDCl3, 500 MHz) % 1.21 (t, 12H, J = 8.0 Hz), 1.81 (bs,
2H), 2.62 (q, 8H, J = 7.5 Hz), 3.00-3.02 (d, 2H, J = 7.0 Hz), 5.08-5.19 (m, 2H), 5.54-5.58
(m, 1H), 6.90 (s, 2H), 7.06 (s, 4H);

13

C NMR (125 MHz, CDCl3) % 15.96, 29.29, 48.23,

60.63, 118.95, 123.91, 125.60, 135.01, 144.05, 148.50; IR (thin film) 3072m, 2984m,
1599m, 1458m cm-1; HRMS (ES+) calcd for C24H34N m/z 336.2691 (M++1), meas
336.2682.
CN
Br
O

O

Mg/I2
THF, reflux, 8 h

O

O

reflux, 8 h

MgCl

O

O

rt, 24 h
N

MgBr

H2N

22e

1,1-bis(4-methoxy-3,5-dimethylphenyl)but-3-en-1-amine 22e. The general procedure
described above for the preparation and purification of amine 22f was followed for the
synthesis of 22e, starting from 5-bromo-2-methoxy-1,3-dimethylbenzene (4.5 g, 21
mmol). Purification by column chromatography on silica gel (1:2 ether/pentane) gave
the pure amine 22e as an oil in 27% yield (1.7 g, 5.1 mmol). Spectral data for 22e: Rf =
1

0.2 (1:2 ether/pentane). H NMR (CDCl3, 500 MHz) % 1.71 (bs, 2H), 2.23 (s, 12H), 2.91
(d, 2H, J = 7.5 Hz), 3.68 (s, 6H), 5.05-5.15 (m, 2H), 5.45-5.52 (m, 1H), 6.99 (s, 4H);

100

13

C

NMR (125 MHz, CDCl3) % 16.60,48.16, 59.55, 59.83, 119.09, 127.16, 130.25, 134.88,
143.64, 155.53; IR (thin film) 2932m, 1653m cm-1; HRMS (ES+) calcd for C22H30NO2
m/z 340.2277 (M++1), meas 340.2264.
6.1.3 Large scale preparation of 1,1-bis(3,5-dimethylphenyl)but-3-en-1-amine 22f
Br

Mg/I2

HCO2Et

THF, reflux, 4 h

rt, 16 h
OH

To a flame-dried 2 L three-necked round-bottomed flask filled with Nitrogen and
equipped with a refluxing condenser was added 1-bromo-3,5-dimethylbenzene (100 g,
540 mmol), magnesium (32.5 g, 1.35 mol), THF (1.08 L) and a few crystals of I2. The
mixture was slowly heated to reflux and kept at reflux for 4 h. The resulting light brown
solution was allowed to cool down to room temperature and then 0 °C. Then ethyl
formate (18.6 g, 20.4 mL, 250 mmol) was slowly added to the freshly prepared Grignard
reagent and the mixture was stirred at room temperature for 16 h. The reaction was
quenched at 0 °C by addition of H2O (18 mL + 36 mL). The resulting slurry was filtered
through a Celite pad and washed with THF until no alcohol was left (as monitored by
TLC). The mixture was then concentrated under reduced pressure to afford an orange
solid. This solid was dissolved in dichloromethane (360 mL) and washed with water (60
mL x 2). The organic phase was then dried over Na2SO4, filtered and stripped of
solvent to give an off-white solid (60 g) which could be used in the next step without
1

further purification. Spectral data: H NMR (CDCl3, 600 MHz) % 2.10 (s, 1H), 2.29 (s,

101

12H), 5.67-5.68 (d, 1H, J = 3.0 Hz), 6.89 (s, 2H), 6.98 (s, 4H);

13

C NMR (150 MHz,

CDCl3) % 21.34, 76.37, 124.22, 129.14, 137.99, 143.89.

NaClO, n-Bu4NBr
EtOAc, rt, 4 h
O

OH

28

To a 2 L round-bottomed flask was sequentially added the unpurified alcohol (60 g,
250 mmol), n-BuN4Br (15 g, 47 mmol) and EtOAc (800 mL). Bleach (6% commercially
available Clorox regular bleach) (720 mL) was then added to the reaction mixture at
55

room temperature slowly to give a yellow solution.

Upon completion after 4 h, the

mixture turned colorless and the organic phase was separated. The aqueous phase
was then extracted with EtOAc (150 mL x 3). The combined organic phase was washed
with H2O (150 mL) and brine (150 mL), drided over Na2SO4, filtered and concentrated
under reduced pressure to afford a yellow solid. The crude product was purified by
crystallization with hexanes to give ketone 28 as an off-white solid (mp 110-112 °C) in
1

64 % yield over two steps (38 g, 160 mmol). Spectral data for 28: H NMR (CDCl3, 600
MHz) % 2.35 (s, 12H), 7.19 (s, 2H), 7.37 (s, 4H);
127.66, 133.85, 137.77,138.00, 197.55.

102

13

C NMR (150 MHz, CDCl3) % 21.16,

TiCl4, NH3 (g)
O

THF, 0 °C to reflux
24 h

28

MgCl

rt, 24 h

H2N

22f

To a flame-dried 2 L three-necked round bottomed flask filled with Nitrogen and
equipped with a refluxing condenser was added ketone 28 (25.7 g, 108 mmol) and THF
(500 mL). The resulting mixture was cooled down to 0 °C. Then TiCl4 (22 mL, 173
56

mmol) was quickly added to the cold solution and a yellow slurry was formed.

The

yellow slurry then turned dark green after gaseous ammonia was bubbled into the
stirred mixture for 5 min. With a continuous supply of gaseous ammonia, the dark green
slurry turned orange and NH3 (g) was kept for another 20 min and then the NH3 flow
was stopped. The resulting mixture was warmed up to room temperature and then
slowly heated to reflux for 24 h. Allyl magnesium chloride (2 M in THF, 864 mmol, 432
mL) was added at 0 °C. Stirring was continued at room temperature for 24 h. Upon
completion, the reaction mixture was merged into an ice-water bath and carefully
quenched with sat. Na2CO3 (400 mL). The white slurry was filtered through a Celite pad
and washed with EtOAc (600 mL). The organic phase was separated and washed with
water (100 mL x 2) and brine (50 mL x 2), dried over Na2SO4, filtered and concentrated
under reduced pressure to afford an off-white solid. The crude product was purified by
crystallization with hexanes to give amine 22f as a white solid in 86% yield (25.6 g, 93

103

st

mmol) (1 crop, 55%, mp 85-87°C; 2

nd

crop, 16%, mp 86-87°C; 3

rd

crop, 15%, mp 85-

86°C).
6.1.4 General procedure for the preparation of the imines – Illustrated for the
synthesis of (E)-N-benzylidene-1,1-diphenylbut-3-en-1-amine 10
Ph Ph

O

+

MgSO4, DCM
H

H2N

N

rt

H

10

17

To a flame-dried 50 mL round bottomed flask filled with argon was added MgSO4
(1.50 g, 12.5 mmol) and 10.0 mL dry CH2Cl2. This was followed by the addition of 1,1diphenylbut-3-en-1-amine 17

54

(0.670 g, 3.00 mmol, 1 equiv).

After stirring for 5

minutes, benzaldehyde (0.350 g, 3.30 mmol, 1.1 equiv) was added.

57

The reaction

mixture was stirred for 48 h at room temperature. Thereafter, the reaction mixture was
filtered through a Celite bed and the Celite bed was washed with CH2Cl2. The filtrate
was then concentrated by rotary evaporation and placed under high vacuum (0.05 mm
Hg) for 1 h to give the crude imine 10 as a light yellow oil which could be used in the
1

next step without further purification. Spectral data for 10: H NMR (CDCl3, 500 MHz) %
3.17 (d, 2H, J = 7.0 Hz), 4.95-5.00 (m, 2H), 5.80-5.88 (m, 1H), 7.24-7.45 (m, 13H), 7.817.86 (m, 2H), 7.86 (s, 1H);

13

C NMR (125 MHz, CDCl3) % 47.02, 72.29, 117.73, 126.78,

128.17, 128.58, 128.74, 128.76, 130.80, 134.78, 137.20, 146.58, 159.99.

104

O

O

Ar Ar

O

+

MgSO4, DCM
H

rt

H2N

N
H

23a

22a
(E)-N-benzylidene-1,1-bis(4-methoxyphenyl)but-3-en-1-amine

23a.

1,1-bis(4-

methoxyphenyl)but-3-en-1-amine 22a (0.43 g, 1.5 mmol) was reacted according to the
general procedure described above to afford the crude imine 23a as a light yellow oil
1

which was used in the next step without further purification. Spectral data for 23a: H
NMR (CDCl3, 500 MHz) % 3.09 (d, 2H, J = 7.0 Hz), 3.82 (s, 6H), 4.99-4.99 (m, 2H),
5.81-5.87 (m, 1H), 6.87 (d, 4H, J = 8.5 Hz), 7.28 (d, 4H, J = 9.0 Hz), 7.41-7.43 (m, 3H),
7.79-7.81 (m, 2H), 7.83 (s, 1H).

13

C NMR (125 MHz, CDCl3) % 47.06, 55.14, 55.16,

71.25, 113.16, 113.35, 117.24, 127.64, 128.28, 128.45, 129.72, 130.43, 134.80, 138.56,
158.00, 159.21.
tBu

tBu

O

tBu

tBu

Ar Ar

O

O

+

MgSO4, DCM
H

H2N

rt

N
H

23b

22b

(E)-N-benzylidene-1,1-bis(3,5-di-tert-butyl-4-methoxyphenyl)but-3-en-1-amine 23b.
1,1-bis(3,5-di-tert-butyl-4-methoxyphenyl)but-3-en-1-amine 22b (1.3 g, 2.5 mmol) was
reacted according to the general procedure described above to afford the crude imine
23b as a yellow solid. Crystallization (hexanes) afforded 23b in 77% isolated yield (1.14
g, 1.93 mmol) as white crystals

1

(mp 99–101 °C). Spectral data for 23b: H NMR

105

(CDCl3, 500 MHz) % 1.37 (s, 36H), 3.10 (d, 2H, J = 6.5 Hz), 3.68 (s, 6H), 4.99-5.06 (m,
2H), 5.85-5.91 (m, 1H), 7.11 (s, 4H), 7.42 (t, 3H, J = 6.5, 3.5 Hz), 7.78-7.80 (m, 2H),
7.91 (s, 1H);

13

C NMR (125 MHz, CDCl3) % 32.38, 36.04, 46.83, 64.32, 73.18, 117.17,

127.39, 128.41, 128.72, 130.51, 135.83, 137.42, 139.54, 142.34, 157.86, 159.20.
F

F

Ar Ar

O

+

MgSO4, DCM
H

H2N

N

rt

H

23c

22c

(E)-N-benzylidene-1,1-bis(4-fluorophenyl)but-3-en-1-amine

23c.

1,1-bis(4-

fluorophenyl)but-3-en-1-amine 22c (0.26 g, 1.0 mmol) was reacted according to the
general procedure described above to afford the crude imine 23c as a light yellow oil
1

which was used in the next step without further purification. Spectral data for 23c: H
NMR (CDCl3, 500 MHz) % 3.06-3.07 (m, 2H), 4.91-4.95 (m, 2H), 5.72-5.77 (m, 1H),
6.99-7.02 (m, 4H), 7.29-7.33 (m, 4H), 7.40-7.43 (m, 3H), 7.76-7.79 (m, 3H).
Et

Et

Ar Ar

O

+
Et

MgSO4, DCM
H

Et

rt

H2N

22d

N
H

23d

(E)-N-benzylidene-1,1-bis(3,5-diethylphenyl)but-3-en-1-amine

23d.

1,1-bis(3,5-

diethylphenyl)but-3-en-1-amine 22d (84 mg, 0.25 mmol) was reacted according to the
general procedure described above to afford the crude imine 23d as a light yellow oil

106

1

which was used in the next step without further purification. Spectral data for 23d: H
NMR (CDCl3, 500 MHz) % 1.06 (t, 12H, J = 7.5 Hz), 2.61 (q, 8H, J = 7.0 Hz), 3.13 (d, 2H,
J = 7.5 Hz), 4.93-4.99 (m, 2H), 5.80-5.86 (m 1H), 6.92 (s, 2H), 7.01 (s, 4H), 7.40-7.42
(m, 3H), 7.79-7.81 (m, 2H), 7.84 (s, 1H).

13

C NMR (125 MHz, CDCl3) % 15.72, 29.00,

46.86, 72.39, 117.01, 125.41, 125.59, 128.28, 128.41, 130.29, 135.13, 137.19, 143.45,
146.04, 159.28.

O

Ar Ar

O

O

+

MgSO4, DCM
H

N

rt

H

H2N

23e

22e

(E)-N-benzylidene-1,1-bis(4-methoxy-3,5-dimethylphenyl)but-3-en-1-amine 23e. 1,1bis(4-methoxy-3,5-dimethylphenyl)but-3-en-1-amine 22e (170 mg, 0.500 mmol) was
reacted according to the general procedure described above to afford the crude imine
23e as a light yellow oil which was used in the next step without further purification.
1

Spectral data for 23e: H NMR (CDCl3, 500 MHz) % 2.23 (s, 12H), 3.02 (d, 2H, J = 6.5
Hz), 3.70 (s, 6H), 4.90-4.95 (m, 2H), 5.71-5.76 (m, 1H), 6.98 (s, 2H), 7.38-7.40 (m, 4H),
7.75-7.77 (m, 3H), 7.80 (s, 1H).

Ar Ar

O

+

MgSO4, DCM
H

H2N

rt

N
H

23f

22f

107

(E)-N-benzylidene-1,1-bis(3,5-dimethylphenyl)but-3-en-1-amine

23f.

1,1-bis(3,5-

dimethylphenyl)but-3-en-1-amine 22f (0.56 g, 2.0 mmol) was reacted according to the
general procedure described above to afford the crude imine 23f as a yellow solid.
Crystallization with hexanes afforded 23f in 80% isolated yield (0.59 g, 1.6 mmol) as
1

white crystals (mp 117-118 °C). Spectral data for 23f: H NMR (CDCl3, 500 MHz) %
2.31 (s, 12H), 3.12 (d, 2H, J = 6.0 Hz), 4.94-4.99 (m, 2H), 5.78-5.83 (m, 1H), 6.88 (s,
2H), 6.99 (s, 4H), 7.42 (s, 3H), 7.82-7.86 (m, 3H);

13

C NMR (125 MHz, CDCl3) % 21.57,

46.79, 71.74, 117.10, 126.21, 128.07, 128.32, 128.42, 130.36, 134.93, 137.06, 137.12,
1

146.34, 159.57; IR (thin film) 3007m, 2916m, 1640m, 1450m cm- ; mass spectrum, m/z
(% rel intensity) 367 (M)+ (18.04), 326 (100), 180 (90), 140 (100); Anal calcd for
C20H25N: C, 88.24; H, 7.95; N, 3.81. Found: C, 88.24; H, 8.07; N, 3.78.
6.1.5 Optimization of diarylmethyl group for catalytic asymmetric Aza-cope
rearrangement with imines – Illustrated for the synthesis of (S)-N(diphenylmethylene)-1-phenylbut-3-en-1-amine 11
Ph Ph
N
H

10 mol% (R)-VANOLBOROX 9 catalyst
5 mol% benzoic acid
toluene, 60 °C

Ph
N

Ph

(S)

(S)-11

10

Preparation of catalyst stock solution.

58

A 50 mL Schlenk flask was flame dried

under high vacuum and cooled under a low flow of Argon. To the flask was added
sequentially (R)-VANOL (44 mg, 0.1 mmol), phenol (19 mg, 0.2 mmol), dry toluene (2.0
mL), BH3•SMe2 (2 M solution in toluene, 150 µL, 0.3 mmol) and water (5.4 µL, 0.3
mmol) under a low flow of Argon. The threaded Teflon valve on the Schlenk flask was

108

then closed, and the mixture heated at 100 °C for 1 h. The valve was carefully and
slowly opened to gradually apply high vacuum (0.1 mm Hg) and the solvent was
removed. The vacuum was maintained for a period of 30 min at 100 °C. The flask was
then removed from the oil bath and allowed to cool to room temperature under a low
flow of Argon. This was then completely dissolved in 2 mL of dry toluene to afford the
stock solution of the catalyst.
The Aza-cope rearrangement. A 5 mL Schlenk test tube fitted with a threaded Teflon
valve and a magnetic stir bar was flame dried under high vacuum and cooled down
under a low flow of Argon. To the test tube was then added imine 10 (31 mg, 0.10
mmol, 1 equiv), toluene (0.1 mL) and 0.20 mL of the catalyst stock solution (10 mol%
catalyst) via a plastic syringe fitted with a metallic needle. At the same time, to an ovendried 5 mL vial was added benzoic acid (12 mg, 0.1 mmol) and toluene (1 mL). Then 50
µL of the benzoic acid stock solution (5 mol%) was transferred to the above catalystimine complex via a plastic syringe fitted with a metallic needle. After addition of the rest
of the toluene (0.15 mL), the Schlenk test tube was closed and the reaction was stirred
at 60 °C for 18 h. Upon completion, the reaction mixture was directly loaded to a silica
gel column (2 cm x 20 cm) with a pipette. Purification with flash column chromatography
(1:30 EtOAc/hexanes) was complete in 5 min and gave the rearrangement product 11
as a white solid (mp 81-82 °C) in 76% yield (24 mg, 0.076 mmol). Spectral data for 11:
1

Rf = 0.2 (1:12 EtOAc/hexanes). H NMR (CDCl3, 500 MHz) % 2.59-2.62 (m, 1H), 2.692.73 (m, 1H), 4.46 (dd, 1H, J = 5.5 Hz, 8.0 Hz), 4.96-5.03 (m, 2H), 5.65-5.70 (m, 1H),
7.08-7.10 (m, 2H), 7.23-7.26 (m, 1H), 7.30-7.41 (m, 7H), 7.44-7.46 (m, 3H), 7.69-7.71
(m, 2H);

13

C NMR (125 MHz, CDCl3) % 44.21, 66.74, 116.96, 126.97, 127.41, 128.16,

109

128.24, 128.53, 128.55, 128.56, 128.85, 130.12, 136.03, 137.36, 140.30, 144.75,
1

166.93; IR (thin film) 3078m, 2929m, 1601m cm- ; The optical purity of 11 was
determined to be 42% ee by HPLC analysis (Chiralcel OD-H column, hexanes:21

propanol 99.7:0.3, 222 nm, flow rate 0.6 mL min- ). Retention times were 5.3 min (major
enantiomer, (S)-11) and 6.8 min (minor enantiomer, (R)-11).

Ar Ar
N
H

Ar

10 mol% (R)-VANOLBOROX 9 catalyst
5 mol% benzoic acid
toluene, 60 °C

N

Ar

Ar =

O

(S)-24a

23a

(S)-N-(bis(4-methoxyphenyl)methylene)-1-phenylbut-3-en-1-amine

24a.

(E)-N-

benzylidene-1,1-bis(4-methoxyphenyl)but-3-en-1-amine 23a (37 mg, 0.10 mmol) was
reacted according to the general procedure described above and purification with flash
column chromatography (1:6 ether/pentane) was complete in 5 min to afford the
rearrangement product 24a as a viscous oil in 54% yield ( 20 mg, 0.054 mmol). Spectral
1

data for 24a: Rf = 0.2 (1:6 ether/pentane). H NMR (CDCl3, 500 MHz) % 2.54-2.58 (m,
1H), 2.62-2.66 (m, 1H), 3.79 (s, 3H), 3.85 (s, 3H), 4.43 (dd, 1H, J = 5.5 Hz, 7.5 Hz),
4.91-4.97 (m, 2H), 5.59-5.68 (m, 1H), 6.82 (d, 2H, J = 8.5 Hz), 6.92 (d, 2H, J = 9.0 Hz),
6.97 (d, 2H, J = 8.5 Hz), 7.19-7.20 (m, 1H), 7.26-7.32 (m, 4H), 7.60 (d, 2H, J = 9.0 Hz);
13

C NMR (125 MHz, CDCl3) % 44.05, 55.25, 55.32, 66.25, 113.23, 113.57, 116.45,

126.55, 127.13, 128.21, 129.36, 129.46, 130.15, 133.43, 135.97, 144.89, 159.36,
1

161.01, 165.91; IR (thin film) 3003m, 2932m, 1606m, 1248m cm- ; mass spectrum, m/z

110

(% rel intensity) 371 (M+) (1.3), 330 (100), 165 (50), 91 (37); HRMS (ES+) calcd for
C25H26NO2 m/z 372.1964 (M++1), meas 372.1949. The optical purity of 24a was
determined to be 20% ee by HPLC analysis (Chiralcel OD-H column, hexanes:21

propanol 99.6:0.4, 222 nm, flow rate 0.3 mL min- ). Retention times were 21.2 min
(major enantiomer, (S)-24a) and 22.8 min (minor enantiomer, (R)-24a).
Ar

Ar Ar

10 mol% (R)-VANOLBOROX 9 catalyst
5 mol% benzoic acid
toluene, 60 °C

N
H

N

tBu
Ar

Ar =

O

tBu

(S)-24b

23b

(S)-N-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methylene)-1-phenylbut-3-en-1-amine
24b. (E)-N-benzylidene-1,1-bis(3,5-di-tert-butyl-4-methoxyphenyl)but-3-en-1-amine 23b
(60 mg, 0.1 mmol) was reacted according to the general procedure described above
and purification with flash column chromatography (1:40 EtOAc/hexanes) was complete
in 5 min to afford the rearrangement product 24b as a foamy solid (mp 42-44 °C) in 67%
1

yield (40 mg, 0.067 mmol). Spectral data for 24b: Rf = 0.2 (1:40 EtOAc/hexanes). H
NMR (CDCl3, 500 MHz) % 1.35 (s, 36H), 2.52-2.56 (m, 1H), 2.65-2.70 (m, 1H), 3.67 (s,
3H), 3.70 (s, 3H), 4.41 (dd, 1H, J = 5.0 Hz, 8.0 Hz), 4.90-4.97 (m, 2H), 5.63-5.70 (m,
1H), 6.85 (s, 2H), 7.14-7.17 (m, 1H), 7.23-7.29 (m, 4H), 7.59 (s, 2H);

13

C NMR (125

2

MHz, CDCl3) (1 sp Carbon missing) % 32.18, 32.34, 36.03, 36.05, 44.35, 64.42, 64.64,
66.87, 116.44, 126.50, 126.73, 127.51, 128.38, 131.96, 134.44, 136.58, 143.15, 143.56,
1

145.35, 159.24, 161.47, 167.31; IR (thin film) 2961m, 1653m, 1223m cm- ; mass

111

spectrum, m/z (% rel intensity) 367 (M+) (4.0), 554 (100), 269 (32), 234 (14); Anal calcd
for C41H57NO2: C, 82.64; H, 9.64; N, 2.35. Found: C, 82.07; H, 9.84; N, 2.25. To
measure the optical purity of 24b, the imine 24b was hydrolyzed with 18% aq. HCl in
THF and then protected with (Boc)2O. The optical purity was determined to be 39% ee
by HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 99.9:0.1, 222 nm, flow
1

rate 0.6 mL min- ). Retention times were 64.2 min (major enantiomer) and 81.2 min
(minor enantiomer).
Ar

Ar Ar

10 mol% (R)-VANOLBOROX 9 catalyst
5 mol% benzoic acid
toluene, 60 °C

N
H

N

Ar

Ar =

23c

F

(S)-24c

(S)-N-(bis(4-fluorophenyl)methylene)-1-phenylbut-3-en-1-amine

24c.

(E)-N-

benzylidene-1,1-bis(4-fluorophenyl)but-3-en-1-amine 23c (33 mg, 0.10 mmol) was
reacted according to the general procedure described above and purification with flash
column chromatography (1:30 EtOAc/hexanes) was complete in 5 min to afford the
rearrangement product 24c as a viscous oil in 75% yield ( 25 mg, 0.075 mmol). Spectral
1

data for 24c: Rf = 0.2 (1:30 EtOAc/hexanes). H NMR (CDCl3, 500 MHz) % 2.52-2.54 (m,
1H), 2.59-2.64 (m, 1H), 4.31 (dd, 1H, J = 5.5 Hz, 8.0 Hz), 4.89-4.95 (m, 2H), 5.54-5.60
(m, 1H), 6.94 (m, 4H), 7.07 (t, 2H, J = 9.0 Hz), 7.16-7.19 (m, 1H), 7.23-7.26 (m, 4H),
7.57-7.61 (m, 2H);

13

C NMR (125 MHz, CDCl3) % 43.96, 66.64, 114.96 (d, J = 21.5 Hz),

115.53 (d, J =21.0 Hz), 116.85, 126.85, 127.02, 128.38, 129.76 (d, J = 7.9 Hz), 130.47,

112

(d, J = 9.0 Hz), 132.62 (d, J = 3.0 Hz), 135.57, 136.11 (d, J = 3.0 Hz), 144.26, 161.60,
163.32 (d, J = 64 Hz), 164.79 (d, J = 63 Hz); IR (thin film) 3010m, 2938m, 1603m,
1

1224m cm- ; HRMS (ES+) calcd for C23H20NF2 m/z 348.1564 (M++1), meas 348.1551.
The optical purity of 24c was determined to be 41% ee by HPLC analysis (Chiralcel OD1

H column, hexanes:2-propanol 99.7:0.3, 222 nm, flow rate 0.3 mL min- ). Retention
times were 10.3 min (major enantiomer, (S)-24c) and 12.0 min (minor enantiomer, (R)24c).

Ar Ar
N
H

Ar

10 mol% (R)-VANOLBOROX 9 catalyst
5 mol% benzoic acid
toluene, 60 °C

N

Et
Ar

Ar =
Et

23d

(S)-24d

(S)-N-(bis(3,5-diethylphenyl)methylene)-1-phenylbut-3-en-1-amine

24d.

(E)-N-

benzylidene-1,1-bis(3,5-diethylphenyl)but-3-en-1-amine 23d (26 mg, 0.060 mmol) was
reacted according to the general procedure described above and purification with flash
column chromatography (1:20 EtOAc/hexanes) was complete in 5 min to afford the
rearrangement product 24d as a viscous oil in 70% yield (18 mg, 0.042 mmol). Spectral
1

data for 24d: Rf = 0.2 (1:20 EtOAc/hexanes). H NMR (CDCl3, 500 MHz) % 1.11-1.14
(m, 12H), 2.52-2.66 (m, 10H), 4.33 (dd, 1H, J = 8.0 Hz, 5.5 Hz), 4.85-4.92 (m, 2H), 5.565.62 (m, 1H), 6.61 (s, 2H), 6.98 (s, 2H), 6.98-7.14 (m, 1H), 7.17-7.26 (m, 6H);

13

C NMR

(125 MHz, CDCl3) % 15.52, 15.63, 28.73, 28.79, 43.98, 66.54, 116.30, 124.65, 125.67,
127.04, 127.26, 128.14, 128.96, 136.10, 137.44, 140.32, 143.82, 144.01, 144.25,

113

144.90, 167.67; To determine the optical purity of compound 24d, the compound was
hydrolyzed with 18% aq. HCl in THF and then protected with (Boc)2O. Spectral data for
1

the N-Boc amine: H NMR (CDCl3, 500 MHz) % 1.34 (s, 9H), 2.45 (bs, 2H), 4.73 (d, 2H),
4.99-5.05 (m, 2H), 5.58-5.64 (m, 1H), 7.15-7.20 (m, 3H), 7.24-7.27 (m, 2H); IR (thin film)
1

2980m, 1604m, 1522m, 1176m cm- ; Anal calcd for C15H21NO2: C, 72.84; H, 8.56; N,
5.66. Found: C, 72.66; H, 8.99; N, 5.53; The optical purity was determined to be 40% ee
by HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 99.9:0.1, 222 nm, flow
1

rate 0.6 mL min- ). Retention times were 64.5 min (major enantiomer) and 82.2 min
(minor enantiomer).
Ar

Ar Ar
N
H

23e

10 mol% (R)-VANOLBOROX 9 catalyst
5 mol% benzoic acid
toluene, 60 °C

N

Ar

Ar =

O

(S)-24e

(S)-N-(bis(4-methoxy-3,5-dimethylphenyl)methylene)-1-phenylbut-3-en-1-amine 24e.
(E)-N-benzylidene-1,1-bis(4-methoxy-3,5-dimethylphenyl)but-3-en-1-amine 23e ( 43 mg,
0.10 mmol) was reacted according to the general procedure described above and
purification with flash column chromatography (1:15 EtOAc/hexanes) was complete in 5
min to afford the rearrangement product 24e as a viscous oil in 70% yield (30 mg, 0.07
1

mmol). Spectral data for 24e: Rf = 0.2 (1:15 EtOAc/hexanes). H NMR (CDCl3, 500
MHz) % 2.28 (s, 6H), 2.30 (s, 6H), 2.54-2.56 (m, 1H), 2.67-2.71 (m, 1H), 3.69 (s, 3H),
3.73 (s, 3H), 4.39 (dd, 1H, J = 5.0 Hz, 8.0 Hz), 4.91-4.96 (m, 2H), 5.61-5.69 (m, 1H),

114

6.87 (s, 2H), 7.11-7.15 (m, 1H), 7.21-7.27 (m, 4H), 7.58 (s, 2H);

13

C NMR (125 MHz,

2

CDCl3) (1 sp carbon missing) % 21.27, 21.32, 64.44, 64.60, 66.85, 116.42, 126.52,
126.71, 127.54, 128.41, 131.95, 134.41, 136.62, 143.15, 143.54, 145.37, 159.21,
1

161.45, 167.28; IR (thin film) 3036m, 2924m, 1652m cm- . The optical purity of 24e was
determined to be 63% ee by HPLC analysis (Chiralcel OD-H column, hexanes:21

propanol 99.7:0.3, 222 nm, flow rate 0.6 mL min- ). Retention times were 7.3 min (major
enantiomer, (S)-24e) and 9.1 min (minor enantiomer, (R)-24e).
Ar

Ar Ar
N
H

10 mol% (R)-VANOLBOROX 9 catalyst
5 mol% benzoic acid
toluene, 60 °C

N

Ar

Ar =

(S)-24f

23f

(S)-N-(bis(3,5-dimethylphenyl)methylene)-1-phenylbut-3-en-1-amine

24f.

(E)-N-

benzylidene-1,1-bis(3,5-dimethylphenyl)but-3-en-1-amine 23f (37 mg, 0.1 mmol) was
reacted according to the general procedure described above and purification with flash
column chromatography (1:30 EtOAc/hexanes) was complete in 5 min to afford the
rearrangement product 24f as a viscous oil in 85% yield (31 mg, 0.085 mmol). Spectral
1

data for 24f: Rf = 0.2 (1:30 EtOAc/hexanes). H NMR (CDCl3, 500 MHz) % 2.27 (s, 6H),
2.28 (s, 6H), 2.55-2.59 (m, 1H), 2.63-2.68 (m, 1H), 4.37 (dd, 1H, J = 7.5 Hz, 5.5 Hz),
4.91-4.97 (m, 2H), 5.61-5.67 (m, 1H), 6.61 (s, 2H), 6.99 (d, 2H, J = 11 Hz), 7.16-7.21
(m, 1H), 7.25-7.29 (m, 6H);

13

2

C NMR (125 MHz, CDCl3) (1 sp carbon missing) %

21.29, 21.31, 44.17, 66.44, 116.37, 125.50, 126.36, 126.53, 127.24, 128.14, 129.65,

115

131.47, 135.99, 137.37, 137.59, 140.36, 144.82, 167.61; IR (thin film) 3024m, 2916m,
1

1959m, 1599m cm- ; mass spectrum, m/z (% rel intensity) 367 (M)+ (7.65), 326 (100),
180 (29), 103 (14); HRMS (ES+) calcd for C27H30N m/z 368.2378 (M++1), meas
368.2374. The optical purity of 24f was determined to be 69% ee by HPLC analysis
1

(Chiralcel OD-H column, hexanes:2-propanol 99.7:0.3, 222 nm, flow rate 0.3 mL min- ).
Retention times were 11.4 min (major enantiomer, (S)-24f) and 14.3 min (minor
enantiomer, (R)-24f).
6.1.6 General procedure for catalytic asymmetric aminoallylation of aldehydes –
Illustrated for the synthesis of (S)-N-(bis(3,5-dimethylphenyl)methylene)-1phenylbut-3-en-1-amine 24f (24f = 26f)
O

+
H

25f

Ar Ar
H2N

5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

Ar
N

Ar

(S)-24f (26f)

Preparation of catalyst stock solution. A 50 mL Schlenk flask was flame dried under
high vacuum and cooled under a low flow of Argon. To the flask was added sequentially
(R)-VANOL (44 mg, 0.1 mmol), 2,4,6-trimethylphenol (28 mg, 0.2 mmol), dry toluene
(2.0 mL), BH3•SMe2 (2 M solution in toluene, 150 µL, 0.3 mmol) and water (5.4 µL, 0.3
mmol) under a low flow of Argon. The threaded Teflon valve on the Schlenk flask was
then closed, and the mixture heated at 100 °C for 1 h. The valve was carefully opened
to gradually apply high vacuum (0.1 mm Hg) and the solvent was removed. The vacuum
was maintained for a period of 30 min at 100 °C. The flask was then removed from the
oil bath and allowed to cool to room temperature under a low flow of Argon. This was

116

then completely dissolved in 2 mL of dry m-xylene to afford the stock solution of the
catalyst.
The aminoallylation of aldehydes. A 5 mL Schlenk test tube charged with 5Å
powdered molecular sieves (50 mg) and fitted with a magnetic stir bar was flame dried
under high vacuum and cooled down under a low flow of Argon. To the test tube was
then added amine 22f (28 mg, 0.10 mmol, 1.0 equiv), 0.10 mL of the catalyst stock
solution (5 mol% catalyst) and m-xylene (0.35 mL) via a plastic syringe fitted with a
metallic needle. The mixture was stirred for 30 min at 60 °C. At the same time, to an
oven-dried 5 mL vial was added benzoic acid (12 mg, 0.1 mmol) and m-xylene (1 mL).
Then benzaldehyde 25f (12 mg, 11 µL) and 50 µL of the benzoic acid stock solution (5
mol%) were transferred to the above catalyst-amine complex under a high flow of Argon
via a plastic syringe fitted with a metallic needle. The test tube was closed and the
reaction was stirred at 60 °C for 18 h. Upon completion, the reaction mixture was
directly loaded to a silica gel column (2 cm x 20 cm) with a pipette. Purification by flash
column chromatography (1:30 EtOAc/hexanes) was complete in 5 min and gave the
rearrangement product 24f as a white solid in 92% yield. Spectral data matches that
given in section E. The optical purity of 24f was determined to be 80% ee by HPLC
analysis (Chiralcel OD-H column, hexanes:2-propanol 99.7:0.3, 222 nm, flow rate 0.3
1

mL min- ). Retention times were 11.4 min (major enantiomer, (S)-13a) and 14.3 min
23

(minor enantiomer, (R)-24f). ["]

D

= -2.9 (c = 3.0, CH2Cl2) on 80% ee S-24f.

117

O

+
H

O2N

25a

Ar

5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar Ar
H2N

Ar = 3,5-Me2C6H3
22f

N

O 2N

Ar

(S)-26a

(S)-N-(bis(3,5-dimethylphenyl)methylene)-1-(4-nitrophenyl)but-3-en-1-amine 26a. pNitrobenzaldehyde 25a (17 mg, 0.11 mmol, 1.1 equiv) was reacted according to the
general procedure described above and purification with flash column chromatography
(1:30 EtOAc/hexanes) was complete in 5 min to afford the rearrangement product 26a
as a viscous oil in 85% yield (35 mg, 0.085 mmol). Spectral data for 26a: Rf = 0.18 (1:15
1

EtOAc/hexanes). H NMR (CDCl3, 500 MHz) % 2.28 (s, 6H), 2.29 (s, 6H), 2.53-2.57 (m,
1H), 2.61-2.65 (m, 1H), 4.46 (t, 1H, J = 6.0 Hz), 4.92-4.96 (m, 2H), 5.60-5.65 (m, 1H),
6.57 (s, 2H), 7.02 (d, 2H, J = 6.0 Hz), 7.23 (m, 2H), 7.45 (dd, 2H, J = 9.0 Hz, 2.5 Hz),
8.13 (dd, 2H, J = 7.0 Hz, 1.5 Hz);

13

C NMR (125 MHz, CDCl3) % 21.30, 21.34, 43.76,

65.85, 117.37, 123.48, 125.16, 126.38, 128.02, 129.99, 131.94, 134.74, 136.92, 137.57,
137.93, 139.78, 146.76, 152.33, 168.94; IR (thin film) 3004m, 2917m, 1596m, 1521m,
1

1200m cm- ; HRMS (ES+) calcd for C27H29NO2 m/z 413.2229 (M++1), meas 413.2239.
The optical purity of 26a was determined to be 97% ee by HPLC analysis (Chiralcel OD1

H column, hexanes:2-propanol 99.6:0.4, 222 nm, flow rate 0.6 mL min- ). A second run
with (S)-VANOL gave (R)-26a with 95% ee. Retention times were 5.2 min (major
23

enantiomer, (S)-26a) and 6.0 min (minor enantiomer, (R)-26a). ["]
CH2Cl2) on 95% ee R -26a.

118

D

= +51.2 (c = 1.0,

O

Ar Ar

+
H

25b

H2N

5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

Ar
N

Ar

(S)-26b

(S)-N-(bis(3,5-dimethylphenyl)methylene)-1-(p-tolyl)but-3-en-1-amine

26b.

p-

tolualdehyde 25b (15 mg, 0.11 mmol, 1.1 equiv) was reacted according to the general
procedure described above and purification with flash column chromatography (1:30
EtOAc/hexanes) was complete in 5 min to afford the rearrangement product 26b as a
viscous oil in 92% yield (35 mg, 0.092 mmol). Spectral data for 26b: Rf = 0.25 (1:30
1

EtOAc/hexanes). H NMR (CDCl3, 500 MHz) % 2.29 (t, 15H), 2.55-2.59 (m, 1H), 2.632.67 (m, 1H), 4.35 (dd, 1H, J = 7.5 Hz, 6.0 Hz), 4.92-4.98 (m, 2H), 5.62-5.68 (m, 1H),
6.64 (s, 2H), 6.98 (s, 1H), 7.01 (s, 1H), 7.09 (d, 2H, J = 7.5 Hz), 7.18-7.24 (m, 4H);

13

C

NMR (125 MHz, CDCl3) % 21.08, 21.29, 21.32, 43.87, 66.18, 116.29, 125.53, 126.35,
127.11, 128.86, 129.62, 131.41, 136.00, 136.10, 137.33, 137.40, 137.56, 140.41,
1

141.79, 167.36; IR (thin film) 3004m, 2917m, 1596m, 1511m, 1198m cm- ; HRMS
(ES+) calcd for C28H32N m/z 382.2535 (M++1), meas 385.2522. To determine the
optical purity, the product 26b was hydrolyzed with NH2OH!HCl (31 mg, 0.45 mmol) in
THF (2 mL) and water (1 mL) to afford the homoallylic amine. The optical purity was
determined to be 87% ee by HPLC analysis (Chiralcel OD-H column, hexanes:21

propanol:diethylamine 95:5:0.05, 222 nm, flow rate 1.0 mL min- ). A second run with
(S)-VANOL gave (R)-26b with 87% ee. Retention times were 5.0 min (major

119

23

enantiomer) and 4.0 min (minor enantiomer). ["]

D

= +32.1 (c = 1.0, CH2Cl2) on 87%

ee R-26b.

O

+
H

Br

25c

Ar

5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar Ar
H2N

Ar = 3,5-Me2C6H3
22f

N

Br

Ar

(S)-26c

(S)-N-(bis(3,5-dimethylphenyl)methylene)-1-(4-bromophenyl)but-3-en-1-amine 26c.
p-Bromobenzaldehyde 25c (21 mg, 0.11 mmol, 1.1 equiv) was reacted according to the
general procedure described above and purification with flash column chromatography
(1:30 EtOAc/hexanes) was complete in 5 min to afford the rearrangement product 26c
as a viscous oil in 83% yield (38 mg, 0.083 mmol). Spectral data for 26c: Rf = 0.20 (1:15
1

EtOAc/hexanes). H NMR (CDCl3, 500 MHz) % 2.29 (s, 6H), 2.31 (s, 6H), 2.52-2.57 (m,
1H), 2.61-2.67 (m, 1H), 4.35 (dd, 1H, J = 7.0 Hz, 6.0 Hz), 4.94-4.99 (m, 2H), 5.60-5.69
(m, 1H), 6.62 (s, 2H), 7.02 (d, 2H, J = 7.5 Hz), 7.18 (d, 2H, J = 6.5 Hz), 7.25 (s, 2H),
7.41 (d, 2H, J = 6.5 Hz);

13

C NMR (125 MHz, CDCl3) % 21.28, 21.32, 43.79, 65.79,

116.75, 120.26, 125.33, 126.35, 128.98, 129.77, 131.22, 131.64, 135.46, 137.18,
137.43, 137.72, 140.10, 143.79, 168.03; IR (thin film) 3005m, 2918m, 1595m, 1485m,
1

1235m cm- ; HRMS (ES+) calcd for C27H29NBr m/z 446.1483 (M++1), meas 446.1471.
The optical purity of 26c was determined to be 95% ee by HPLC analysis (Chiralcel OD1

H column, hexanes:2-propanol 99.7:0.3, 222 nm, flow rate 0.3 mL min- ). A second run
with (S)-VANOL gave (R)-26c with 93% ee. Retention times were 10.0 min (major

120

23

enantiomer, (S)-26c) and 12.0 min (minor enantiomer, (R)-26c). ["]

D

= +53.3 (c = 1.0,

CH2Cl2) on 93% ee R -26c.

O

+
H

MeO

25d

Ar

5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar Ar
H2N

Ar = 3,5-Me2C6H3
22f

N

MeO

Ar

(S)-26d

(S)-N-(bis(3,5-dimethylphenyl)methylene)-1-(4-methoxyphenyl)but-3-en-1-amine
26d. p-Methoxybenzaldehyde 25d (15 mg, 0.11 mmol) was reacted according to the
general procedure described above and purification with flash column chromatography
(1:30 EtOAc/hexanes) was complete in 5 min to afford the rearrangement product 26d
as a viscous oil in 88% yield (35 mg, 0.088 mmol). Spectral data for 26d: Rf = 0.20
1

(1:30 EtOAc/hexanes). H NMR (CDCl3, 500 MHz) % 2.11 (s, 6H), 2.14 (s, 6H), 2.392.42 (m, 1H), 2.45-2.49 (m, 1H), 3.61 (s, 3H), 4.17 (dd, 1H, J = 8.0 Hz, 6.5 Hz), 4.754.82 (m, 2H), 5.45-5.51 (m, 1H), 6.47 (s, 2H), 6.60 (d, 2H, J = 9.0 Hz), 6.82 (s, 1H), 6.85
(s, 1H), 7.03-7.08 (m, 4H);

13

C NMR (125 MHz, CDCl3) % 21.29, 21.33, 43.90, 55.19,

65.80, 113.55, 116.30, 125.50, 126.34, 128.18, 129.62, 131.43, 136.08, 137.01, 137.35,
137.41, 137.58, 140.39, 158.25, 167.27; IR (thin film) 3001m, 2916m, 1597m, 1324m,
1

1037m cm- ; HRMS (ES+) calcd for C28H32NO m/z 398.2484 (M++1), meas 398.2498.
The optical purity was determined to be 86% ee by HPLC analysis (Chiralcel OD-H
1

column, hexanes:2-propanol 97.7:0.3, 222 nm, flow rate 0.6 mL min- ). A second run
with (S)-VANOL gave (R)-26d with 83% ee. Retention times were 5.7 min (major

121

23

enantiomer, (S)-26d) and 6.4 min (minor enantiomer, (R)-26d). ["]

D

= +24.1 (c = 1.0,

CH2Cl2) on 83% ee R-26d.

O

+
H

AcO

25e

Ar Ar
H2N

Ar

5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

N

AcO

(S)-4-(1-((bis(3,5-dimethylphenyl)methylene)amino)but-3-en-1-yl)phenyl

Ar

(S)-26e

acetate

26e. p-Acetoxybenzaldehyde 25e (18 mg, 0.11 mmol, 1.1 equiv) was reacted according
to the general procedure described above and purification with flash column
chromatography (1:15 acetone/hexanes) was complete in 5 min to afford the
rearrangement product 26e as a viscous oil in 85% yield (37 mg, 0.085 mmol). Spectral
1

data for 26e: Rf = 0.18 (1:15 acetone/hexanes). H NMR (CDCl3, 500 MHz) % 2.29 (t,
15H), 2.54-2.56 (m, 1H), 2.63-2.66 (m, 1H), 4.38 (dd, 1H, J = 8.0 Hz, 6.0 Hz), 4.93-4.98
(m, 2H), 5.62-5.67 (m, 1H), 6.62 (s, 2H), 6.99 (d, 4H, J = 8.5 Hz), 7.25 (s, 2H), 7.29 (d,
2H, J = 8.5 Hz);

13

C NMR (125 MHz, CDCl3) % 21.12, 21.28, 21.31, 43.91, 65.81,

116.57, 121.10, 125.41, 126.34, 128.13, 129.70, 131.55, 135.75, 137.24, 137.38,
137.65, 140.21, 142.31, 149.22, 167.76, 169.50; IR (thin film) 2918m, 1763m, 1504m,
1

1164m cm- ; HRMS (ES+) calcd for C29H32NO2 m/z 426.2433 (M++1), meas 426.2419.
The optical purity of 26e was determined to be 94% ee by HPLC analysis (Chiralcel OD1

H column, hexanes:2-propanol 99.6:0.4, 222 nm, flow rate 0.6 mL min- ). A second run
with (S)-VANOL gave (R)-26e with 92% ee. Retention times were 5.7 min (major

122

23

enantiomer, (S)-26e) and 6.7 min (minor enantiomer, (R)-26e). ["]

D

= +16.8 (c = 1.0,

CH2Cl2) on 92% ee R-26e.

O

+

Br

H

25g

Ar Ar
H2N

5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C
Br

Ar = 3,5-Me2C6H3
22f

Ar
N

Ar

(S)-26g

(S)-N-(bis(3,5-dimethylphenyl)methylene)-1-(3-bromophenyl)but-3-en-1-amine 26g.
m-Bromobenzaldehyde 25g (21 mg, 0.11 mmol) was reacted according to the general
procedure described above and purification with flash column chromatography (1:50
EtOAc/hexanes) was complete in 5 min to afford the rearrangement product 26g as a
viscous oil in 87% yield (39 mg, 0.087 mmol). Spectral data for 26g: Rf = 0.18 (1:30
1

EtOAc/hexanes). H NMR (CDCl3, 500 MHz) % 2.28 (s, 6H), 2.30 (s, 6H), 2.51-2.55 (m,
1H), 2.61-2.65 (m, 1H), 4.32 (dd, 1H, J = 8.0 Hz, 6.0 Hz), 4.93-4.97 (m, 2H), 5.59-5.65
(m, 1H), 6.59 (s, 2H), 7.01 (d, 2H, J = 9.5 Hz), 7.14 (t, 1H, J = 7.5 Hz), 7.20-7.22 (m,
3H), 7.30-7.32 (m, 1H), 7.41 (t, 1H, J = 2.0 Hz);

13

C NMR (125 MHz, CDCl3) % 21.30,

21.33, 43.79, 65.96, 116.81, 122.24, 125.36, 125.88, 126.39, 129.66, 129.77, 129.81,
130.40, 131.69, 135.43, 137.18, 137.45, 137.75, 140.05, 147.13, 168.29; IR (thin film)
1

3004m, 2916m, 1619m, 1472m, 1199m cm- ; HRMS (ES+) calcd for C27H29NBr m/z
446.1483 (M++1), meas 446.1481. The optical purity was determined to be 90% ee by
HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 99.7:0.3, 222 nm, flow rate
1

0.3 mL min- ). A second run with (S)-VANOL gave (R)-26g with 90% ee. Retention

123

times were 8.8 min (major enantiomer, (S)-26g) and 10.5 min (minor enantiomer, (R)23

26g). ["]

Cl

D

= +2.9 (c = 3.0, CH2Cl2) on 90% ee R-26g.

O
H

25h

Ar Ar

+

H2N

Ar

5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Cl

Ar = 3,5-Me2C6H3
22f

N

Ar

(S)-26h

(S)-N-(bis(3,5-dimethylphenyl)methylene)-1-(2-chlorophenyl)but-3-en-1-amine

26h.

2-Chlorobenzaldehyde 25h (30 mg, 0.22 mmol) was reacted according to the general
procedure described above and purification with flash column chromatography (1:30
EtOAc/hexanes) was complete in 5 min to afford the rearrangement product 26h as a
viscous oil in 88% yield (35 mg, 0.18 mmol). Spectral data for 26h: Rf = 0.18 (1:30
1

EtOAc/hexanes). H NMR (CDCl3, 500 MHz) % 2.32 (s, 6H), 2.34 (s, 6H), 2.59-2.66 (m,
2H), 4.95-5.03 (m, 3H), 5.72-5.78 (m, 1H), 6.60 (s, 2H), 7.05 (d, 2H, J = 8.0 Hz), 7.157.18 (m, 1H), 7.27-7.34 (m, 4H), 7.86 (dd, 1H, J = 8.0 Hz, 1.5 Hz);

13

C NMR (125 MHz,

CDCl3) % 21.32, 42.95, 61.98, 116.51, 125.44, 126.46, 126.86, 127.38, 128.96, 129.55,
129.73, 131.60, 131.97, 135.60, 137.13, 137.40, 137.66, 140.31, 142.76, 168.72; IR
1

(thin film) 3070m, 2916m, 1594m, 1470m, 1033m cm- ; HRMS (ES+) calcd for
C27H29NCl m/z 402.1989 (M++1), meas 402.1994. To determine the optical purity, the
product 26h was hydrolyzed with NH2OH!HCl (62 mg, 0.9 mmol) in THF (4 mL) and
water (2 mL) to afford the homoallylic amine. The optical purity was determined to be

124

92% ee by HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol:diethylamine
1

95:5:0.05, 222 nm, flow rate 0.4 mL min- ). A second run with (S)-VANOL gave (R)-26h
with 94% ee. Retention times were 10.1 min (major enantiomer) and 9.3 min (minor
23

enantiomer). ["]

O

= -156.2 (c = 1.0, CH2Cl2) on 94% ee R-26h.

Ar

5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar Ar

+
H

25i

D

H2N

N

Ar = 3,5-Me2C6H3
22f

Ar

(S)-26i

(S)-N-(bis(3,5-dimethylphenyl)methylene)-1-(o-tolyl)but-3-en-1-amine

26i.

o-

Tolualdehyde 25i (26 mg, 0.22 mmol) was reacted according to the general procedure
described

above

and

purification

with

flash

column

chromatography

(1:30

EtOAc/hexanes) was complete in 5 min to afford the rearrangement product 26i as a
viscous oil in 84% yield (64 mg, 0.17 mmol). Spectral data for 26i: Rf = 0.24 (1:30
1

EtOAc/hexanes). H NMR (CDCl3, 500 MHz) % 1.90 (s, 3H), 2.26 (s, 6H), 2.29 (s, 6H),
2.48-2.53 (m, 1H), 2.65-2.70 (m, 1H), 4.58 (dd, 1H, J = 7.0 Hz, 4.5 Hz), 4.93-5.00 (m,
2H), 5.67-5.73 (m, 1H), 6.52 (s, 2H), 6.99-7.04 (m, 3H), 7.09 (td, 1H, J = 1.5 Hz, 6.0 Hz,
12.0 Hz), 7.18 (t, 1H, J = 6.5 Hz), 7.28 (s, 2H), 7.68 (d, 1H, J = 6.5 Hz);

13

C NMR (125

MHz, CDCl3) % 18.87, 21.27, 21.31, 43.57, 62.26, 116.13, 125.29, 126.02, 126.10,
126.33, 127.66, 129.49, 129.80, 131.44, 134.13, 136.25, 137.36, 137.62, 137.78,
1

140.31, 143.86, 167.76; IR (thin film) 3070m, 2917m, 1619m, 1598m, 1198m cm- ;

125

HRMS (ES+) calcd for C28H32N m/z 382.2535 (M++1), meas 382.2540. The optical
purity was determined to be 80% ee by HPLC analysis (Chiralcel OD-H column,
1

hexanes:2-propanol 99.8:0.2, 222 nm, flow rate 0.1 mL min- ). A second run with (S)VANOL gave (R)-26i with 80% ee. Retention times were 24.2 min (major enantiomer,
23

(S)-26i) and 27.4 min (minor enantiomer, (R)-26i). ["]

D

= -94.5 (c = 1.0, CH2Cl2) on

80% ee R-26i.

F

O

+
H

Br

Ar Ar
H2N

Ar = 3,5-Me2C6H3
22f

25j

Ar

5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

F

Br

N

Ar

(S)-26j

(S)-N-(bis(3,5-dimethylphenyl)methylene)-1-(4-bromo-2-fluorophenyl)but-3-en-1amine 26j. 2-Fluoro-4-bromobenzaldehyde 25j (45 mg, 0.22 mmol) was reacted
according to the general procedure described above and purification with flash column
chromatography (1:50 EtOAc/hexanes) was complete in 5 min to afford the
rearrangement product 26j as a viscous oil in 87% yield (81 mg, 0.17 mmol). Spectral
1

data for 26j: Rf = 0.18 (1:50 EtOAc/hexanes). H NMR (CDCl3, 500 MHz) % 2.28 (s,
12H), 2.35-2.60 (m, 2H), 4.70 (t, 1H, J = 5.5 Hz), 4.92-4.96 (m, 2H), 5.62-5.67 (m, 1H),
6.57 (s, 2H), 7.01 (s, 2H), 7.12 (dd, 1H, J = 8.0 Hz, 1.5 Hz), 7.24-7.26 (m, 3H), 7.557.57 (m, 1H);

13

C NMR (125 MHz, CDCl3) % 21.31, 21.32, 42.68, 58.43, 116.99, 118.50

(d, J = 21.5 Hz), 119.97 (d, J = 8 Hz), 125.177, 126.40, 127.43 (d, J = 3.3 Hz), 129.88,
130.51, 130.54, 131.12 (d, J = 11 Hz), 131.77, 135.01, 136.89, 137.68 (d, J = 38 Hz),

126

140.04, 159.32 (d, J = 207.5 Hz), 168.99; IR (thin film) 3074m, 2917m, 1600m, 1480,
1

1199m cm- ; HRMS (ES+) calcd for C27H28NFBr m/z 464.1389 (M++1), meas
464.1402. The optical purity was determined to be 96% ee by HPLC analysis (Chiralcel
1

OD-H column, hexanes:2-propanol 99.9:0.1, 222 nm, flow rate 0.1 mL min- ). A second
run with (S)-VANOL gave (R)-26j with 94% ee. Retention times were 27 min (major
23

enantiomer, (S)-26j) and 31 min (minor enantiomer, (R)-26j). ["]

D

= +16.8 (c = 1.0,

CH2Cl2) on 94% ee R-26j.

O

Ar Ar

+
H

25k

H2N

5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

Ar
N

Ar

(S)-26k

(S)-N-(bis(3,5-dimethylphenyl)methylene)-1-(naphthalen-1-yl)but-3-en-1-amine 26k.
1-Naphthaldehyde 25k (34 mg, 0.22 mmol) was reacted according to the general
procedure described above and purification with flash column chromatography (1:30
EtOAc/hexanes) was complete in 5 min to afford the rearrangement product 26k as a
viscous oil in 90% yield (75 mg, 0.18 mmol). Spectral data for 26k: Rf = 0.40 (1:30
1

EtOAc/hexanes). H NMR (CDCl3, 500 MHz) % 2.14 (s, 6H), 2.30 (s, 6H), 2.70-2.73 (m,
1H), 2.81-2.85 (m, 1H), 4.92-5.00 (m, 2H), 5.18 (dd, 1H, J = 7.0 Hz, 4.0 Hz), 5.72-5.75
(m, 1H), 6.49 (s, 2H), 6.96 (s, 1H), 7.01 (s, 1H), 7.31 (s, 2H), 7.34-7.46 (m, 3H), 7.71 (d,
1H, J =7.0 Hz), 7.79-7.83 (m, 3H);

13

C NMR (125 MHz, CDCl3) % 21.18, 21.33, 43.83,

62.32, 116.18, 123.43, 125.03, 125.26, 125.34, 125.61, 125.70, 126.45, 126.85, 127.72,

127

128.66, 129.64, 130.42, 131.49, 133.84, 136.29, 137.21, 137.39, 137.58, 140.39,
1

141.44, 167.91; IR (thin film) 3006m, 2918m, 1601m, 1325m cm- ; HRMS (ES+) calcd
for C31H32N m/z 418.2535 (M++1), meas 418.2519. The optical purity was determined
to be 90% ee by HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 99.8:0.2,
1

222 nm, flow rate 0.2 mL min- ). A second run with (S)-VANOL gave (R)-26k with 88%
ee. Retention times were 15.0 min (major enantiomer, (S)-26k) and 17.0 min (minor
23

enantiomer, (R)-26k). ["]

O

+
H

25l

D

= -197.7 (c = 1.0, CH2Cl2) on 88% ee R-26k.

5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar Ar
H2N

Ar = 3,5-Me2C6H3
22f

Ar
N

Ar

(S)-26l

(S)-N-(bis(3,5-dimethylphenyl)methylene)-1-(naphthalen-2-yl)but-3-en-1-amine 26l.
2-Naphthaldehyde 25l (19 mg, 0.11 mmol) was reacted according to the general
procedure described above and purification with flash column chromatography (1:30
EtOAc/hexanes) was complete in 5 min to afford the rearrangement product 26l as a
viscous oil in 83% yield (35 mg, 0.083 mmol). Spectral data for 26l: Rf = 0.20 (1:15
1

EtOAc/hexanes). H NMR (CDCl3, 500 MHz) % 2.31 (s, 12H), 2.70-2.73 (m, 1H), 2.782.80 (m, 1H), 4.57 (t, 1H, J = 7.0 Hz), 4.96-5.04 (m, 2H), 5.69-5.75 (m, 1H), 6.67 (s,
2H), 7.02 (s, 1H), 7.05 (s, 1H), 7.31 (s, 2H), 7.43-7.45 (m, 2H), 7.55-7.57 (m, 1H), 7.67
(s, 1H), 7.78-7.82 (m, 3H);

13

C NMR (125 MHz, CDCl3) % 21.31, 21.32, 43.82, 66.65,

116.50, 125.29, 125.51, 125.63, 125.69, 125.84, 126.41, 127.58, 127.77, 127.83,

128

129.73, 131.54, 132.59, 133.49, 135.91, 137.39, 137.41, 137.65, 140.36, 142.30,
1

167.96; IR (thin film) 3052m, 2915m, 1618m, 1598, 1198m cm- ; HRMS (ES+) calcd for
C31H32N m/z 418.2535 (M++1), meas 418.2515. The optical purity was determined to
be 80% ee by HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 99.6:0.4,
1

222 nm, flow rate 0.4 mL min- ). A second run with (S)-VANOL gave (R)-26l with 80%
ee. Retention times were 6.9 min (major enantiomer, (S)-26l) and 8.0 min (minor
23

enantiomer, (R)-26l). ["]

NO2

O

+
H

25m

D

= +22.4 (c = 1.0, CH2Cl2) on 80% ee R-26l.

Ar Ar
H2N

5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

Ar
NO2

N

Ar

26m

(S,E)-N-(bis(3,5-dimethylphenyl)methylene)-1-(2-nitrophenyl)hexa-1,5-dien-3-amine
26m. (E)-3-(2-nitrophenyl)acrylaldehyde 25m ( 39 mg, 0.22 mmol) was reacted
according to the general procedure described above and purification with flash column
chromatography (1:15 acetone/hexanes) was complete in 5 min to afford the
rearrangement product 26m as a yellow solid (mp 87-88 °C) in 90% yield (80 mg, 0.18
1

mmol). Spectral data for 26m: Rf = 0.22 (1:15 acetone/hexanes). H NMR (CDCl3, 500
MHz) % 2.28 (s, 6H), 2.35 (s, 6H), 2.46-2.54 (m, 2H), 4.13 (dd, 1H, J = 12.5 Hz, 6.0 Hz),
5.01-5.08 (m, 2H), 5.71-5.76 (m, 1H), 6.37 (dd, 1H, J = 16 Hz, 6.5 Hz), 6.76 (d, 1H, J =
15.5 Hz), 6.80 (s, 2H), 7.02 (d, 2H, J = 18.0 Hz), 7.22 (s, 2H), 7.34 (td, 1H, J = 9.5 Hz,
8.5 Hz, 1.5 Hz), 7.50-7.53 (m, 1H), 7.59-7.61 (m, 1H), 7.87 (dd, 1H, J = 8.0 Hz, 1.0 Hz);

129

13

C NMR (125 MHz, CDCl3) % 21.27, 21.32, 41.49, 64.58, 116.95, 124.37, 124.83,

125.33, 126.37, 127.67, 128.70, 129.94, 131.69, 132.83, 133.14, 135.25, 137.17,
137.49, 137.73, 137.94, 140.26, 147.86, 169.24; IR (thin film) 3017m, 2916m, 1595m,
1

1345m cm- ; HRMS (ES+) calcd for C29H31N2O2 m/z 439.2386 (M++1), meas
439.2381. The optical purity was determined to be 95% ee by HPLC analysis (Chiralcel
1

OD-H column, hexanes:2-propanol 99.8:0.2, 222 nm, flow rate 0.5 mL min- ). A second
run with (S)-VANOL gave (R)-26m with 93% ee. Retention times were 8.5 min (major
23

enantiomer, (S)-26m) and 9.9 min (minor enantiomer, (R)-26m). ["]

D

= +91.7 (c = 1.0,

CH2Cl2) on 93% ee R-26m.

O

+
H

25n

Ar Ar
H2N

5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

Ar
N

Ar

26n

(S,E)-N-(bis(3,5-dimethylphenyl)methylene)-1-phenylhexa-1,5-dien-3-amine

26n.

Trans-cinnamaldehyde 25n (29 mg, 0.22 mmol) was reacted according to the general
procedure described above and purification with flash column chromatography (1:30
EtOAc/hexanes) was complete in 5 min to afford the rearrangement product 26n as a
viscous oil in 89% yield (73 mg, 0.18 mmol). Spectral data for 26n: Rf = 0.17 (1:30
1

EtOAc/hexanes). H NMR (CDCl3, 500 MHz) % 2.32 (s, 6H), 2.37 (s, 6H), 2.48-2.57 (m,
2H), 4.09 (dd, 1H, J = 13.0 Hz, 6.0 Hz), 5.02-5.10 (m, 2H), 5.73-5.80 (m, 1H), 6.31 (d,
1H, J = 16 Hz), 6.43 (dd, 1H, J = 16.0 Hz, 6.0 Hz), 6.80 (s, 2H), 7.07 (dd, 2H, J = 14.0

130

Hz, 2.0 Hz), 7.21-7.27 (m, 3H), 7.07-7.10 (m, 2H), 7.17-7.20 (m, 2H);

13

C NMR (125

MHz, CDCl3) % 21.27, 21.35, 41.76, 64.80, 116.60, 125.46, 126.27, 126.34, 127.13,
128.44, 129.40, 129.77, 131.58, 132.32, 135.66, 137.40, 137.48, 137.68, 140.39,
1

168.50; IR (thin film) 3025m, 2918m, 1619m, 1592m, 1198m cm- ; HRMS (ES+) calcd
for C29H32N m/z 394.2535 (M++1), meas 394.2541. The optical purity was determined
to be 92% ee by HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 99.9:0.1,
1

222 nm, flow rate 0.25 mL min- ). A second run with (S)-VANOL gave (R)-26n with 88%
ee. Retention times were 13.6 min (major enantiomer, (S)-26n) and 16.2 min (minor
23

enantiomer, (R)-26n). ["]

O

+
H

25o

D

= +109.7 (c = 1.0, CH2Cl2) on 88% ee R-26n.

Ar Ar
H2N

5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

Ar
N

Ar

26o

(R)-N-(bis(3,5-dimethylphenyl)methylene)hept-1-en-4-amine

26o.

Butyraldehyde

25o (16 mg, 0.22 mmol) was reacted according to the general procedure described
above and purification with flash column chromatography (1:30 EtOAc/hexanes) was
complete in 5 min to afford the rearrangement product 26o as a viscous oil in 90% yield
1

(60 mg, 0.18 mmol). Spectral data for 26o: Rf = 0.25 (1:30 EtOAc/hexanes). H NMR
(CDCl3, 500 MHz) % 0.83 (t, 3H, J = 7.0 Hz), 1.10-1.17 (m, 1H), 1.25-1.34 (m, 1H), 1.471.54 (m, 1H), 1.57-1.65 (m, 1H), 2.69-2.41 (m, 14H), 3.31-3.36 (m, 1H), 4.97-5.02 (m,

131

2H), 5.68-5.77 (m, 1H), 6.74 (s, 2H), 6.99 (d, 2H, J = 6.5 Hz), 7.20 (s, 2H);

13

C NMR

(125 MHz, CDCl3) % 14.17, 19.96, 21.26, 21.32, 38.47, 41.45, 61.56, 116.04, 125.61,
126.16, 129.36, 131.27, 136.51, 137.39, 137.52, 137.84, 140.62, 167.44; HRMS (ES+)
calcd for C24H32N m/z 334.2535 (M++1), meas 334.2527. To determine the optical
purity, the product 26o was hydrolyzed with NH2OH!HCl (62 mg, 0.9 mmol) in THF (4
mL) and water (2 mL) to afford the homoallylic amine. Then the amine was reacted with
benzoyl chloride (25 µL) and triethylamine (35 µL) in DCM (2.0 mL). Purification with
column

chromatography

(1:6

EtOAc/hexanes)

afforded

(R)-N-(hept-1-en-4-

yl)benzamide as a white solid in 60% yield. The optical purity was determined to be
96% ee by HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 94:6, 222 nm,
1

flow rate 1.0 mL min- ). A second run with (S)-VANOL gave (S)-26o with 94% ee.
Retention times were 21.8 min (major enantiomer) and 14.3 min (minor enantiomer).
23

["]

D

= -11.8 (c = 1.0, CH2Cl2) on 94% ee S-26o.

O
Ph

+
H

25p

Ar Ar
H2N

5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar
N

Ar

Ph

Ar = 3,5-Me2C6H3
22f

26p

(R)-N-(bis(3,5-dimethylphenyl)methylene)-7-phenylhept-1-en-4-amine
Phenylbutanal 25p (33 mg, 0.22 mmol)

59

26p.

4-

was reacted according to the general

procedure described above and purification with flash column chromatography (1:30
EtOAc/hexanes) was complete in 5 min to afford the rearrangement product 26p as a

132

viscous oil in 89% yield (73 mg, 0.18 mmol). Spectral data for 26p: Rf = 0.20 (1:30
1

EtOAc/hexanes). H NMR (CDCl3, 500 MHz) % 1.46-1.49 (m, 1H), 1.60-1.70 (m, 3H),
2.30 (s, 6H), 2.32 (s, 6H), 2.30-2.34 (m, 2H), 2.53 (t, 2H, J = 5.5 Hz), 3.37-3.38 (m, 1H),
4.98-5.03 (m, 2H), 5.71-5.75 (m, 1H), 6.73 (s, 2H), 7.01-7.02 (m, 2H), 7.13-7.18 (m,
3H), 7.20 (s, 2H), 7.25-7.27 (m, 2H);

13

C NMR (125 MHz, CDCl3) % 21.28, 21.32, 28.18,

35.81, 35.85, 41.42, 61.61, 116.19, 125.54, 125.61, 126.18, 128.17, 128.30, 129.45,
131.35, 136.37, 137.43, 137.58, 137.73, 140.53, 142.65, 167.62; IR (thin film) 3026m,
1

2901m, 1598m, 1324m cm- . To determine the optical purity, the product 26p was
hydrolyzed with NH2OH!HCl (62 mg, 0.9 mmol) in THF (4 mL) and water (2 mL) to
afford the homoallylic amine. Then the amine was reacted with benzoyl chloride (25 µL)
and triethylamine (35 µL) in DCM (2.0 mL). Purification with column chromatography
(1:6 EtOAc/hexanes) afforded (R)-N-(7-phenylhept-1-en-4-yl)benzamide as a white
solid in 67% yield. HRMS (ES+) calcd for C20H24NO m/z 294.1858 (M++1), meas
294.1869. The optical purity was determined to be 93% ee by HPLC analysis
1

(ChiralPAK AS column, hexanes:2-propanol 90:10, 222 nm, flow rate 1.0 mL min- ). A
second run with (S)-VANOL gave (S)-26p with 95% ee. Retention times were 15.8 min
23

(major enantiomer) and 12.4 min (minor enantiomer). ["]
95% ee S-26p.

133

D

= +8.2 (c = 1.0, CH2Cl2) on

O
Ph

25q

Ar Ar

+
H

5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

H2N

Ar
N

Ar

Ph

Ar = 3,5-Me2C6H3
22f

26q

(S)-N-(bis(3,5-dimethylphenyl)methylene)-1-phenylpent-4-en-2-amine

26q.

2-

Phenylacetaldehyde 25q (26 mg, 0.22 mmol) was reacted according to the general
procedure described above and purification with flash column chromatography (1:30
EtOAc/hexanes) was complete in 5 min to afford the rearrangement product 26q as a
viscous oil in 72% yield (55 mg, 0.14 mmol). Spectral data for 26q: Rf = 0.20 (1:30
1

EtOAc/hexanes). H NMR (CDCl3, 500 MHz) % 2.20 (s, 6H), 2.28 (s, 6H), 2.32-2.47 (m,
2H), 2.82-2.93 (m, 2H), 3.45-3.50 (m, 1H), 5.00-5.06 (m, 2H), 5.70-5.78 (m, 1H), 6.05
(s, 2H), 6.89 (s, 1H), 6.98 (s, 1H), 7.02 (d, 2H, J = 6.5 Hz), 7.15-7.22 (m, 5H);

13

C NMR

(125 MHz, CDCl3) % 21.26, 21.30, 41.32, 42.88, 64.10, 116.48, 125.16, 125.73, 126.13,
127.98, 129.15, 129.92, 131.31, 136.28, 137.16, 137.34, 137.46, 139.89, 140.35,
1

168.09; IR (thin film) 3023m, 2921m, 1595m, 1324m cm- . HRMS (ES+) calcd for
C28H32N m/z 382.2535 (M++1), meas 382.2516. To determine the optical purity, the
product 26q was hydrolyzed with NH2OH!HCl (62 mg, 0.9 mmol) in THF (4 mL) and
water (2 mL) to afford the homoallylic amine. Then the amine was reacted with benzoyl
chloride (25 µL) and triethylamine (35 µL) in DCM (2.0 mL). Purification with column
chromatography

(1:6

EtOAc/hexanes)

afforded

(S)-N-(1-phenylpent-4-en-2-

yl)benzamide as a white solid in 50% yield. The optical purity was determined to be

134

90% ee by HPLC analysis (ChiralPAK AS column, hexanes:2-propanol 90:10, 222 nm,
1

flow rate 1.0 mL min- ). A second run with (S)-VANOL gave (R)-26q with 90% ee.
Retention times were 14.5 min (major enantiomer) and 17.8 min (minor enantiomer).
23

["]

D

= -18.3 (c = 1.0, CH2Cl2) on 90% ee R-26q.

O
H

25r

Ar Ar

+

H2N

5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

Ar
N

Ar

26r

(S)-N-(bis(3,5-dimethylphenyl)methylene)-1-cyclohexylbut-3-en-1-amine

26r.

Cyclohexanecarbaldehyde 25r (25 mg, 0.22 mmol) was reacted according to the
general procedure described above and purification with flash column chromatography
(1:30 EtOAc/hexanes) was complete in 5 min to afford the rearrangement product 26r
as a viscous oil in 84% yield (63 mg, 0.17 mmol). Spectral data for 26r: Rf = 0.20 (1:30
1

EtOAc/hexanes). H NMR (CDCl3, 500 MHz) % 0.88-0.91 (m, 1H), 1.01-1.22 (m, 4H),
1.49-1.79 (m, 6H), 2.28 (s, 6H), 2.32 (s, 6H), 2.31-2.37 (m, 2H), 3.09-3.13 (m, 1H),
4.96-5.01 (m, 2H), 5.70-5.76 (m, 1H), 6.72 (s, 2H), 6.98 (s, 2H), 7.19 (s, 2H);

13

C NMR

(125 MHz, CDCl3) % 21.32, 21.37, 26.56, 26.58, 26.68, 29.28, 30.16, 38.40, 42.87,
66.35, 115.90, 125.85, 126.16, 129.24, 131.20, 136.98, 137.36, 137.82, 140.77, 167.01;
1

IR (thin film) 2923m, 1606m, 1323m cm- . HRMS (ES+) calcd for C27H36N m/z
374.2848 (M++1), meas 374.2849. To determine the optical purity, the product 26r was

135

hydrolyzed with NH2OH!HCl (62 mg, 0.9 mmol) in THF (4 mL) and water (2 mL) to
afford the homoallylic amine. Then the amine was reacted with benzoyl chloride (25 µL)
and triethylamine (35 µL) in DCM (2.0 mL). Purification with column chromatography
(1:6 EtOAc/hexanes) afforded (S)-N-(1-cyclohexylbut-3-en-1-yl)benzamide as a white
solid in 60% yield. The optical purity was determined to be 90% ee by HPLC analysis
(Chiralcel OD-H column, hexanes:2-propanol:diethylamine 95:5:0.05, 222 nm, flow rate
1

0.2 mL min- ). A second run with (S)-VANOL gave (R)-26r with 92% ee. Retention
23

times were 28.0 min (major enantiomer) and 25.9 min (minor enantiomer). ["]

D

= -

31.8 (c = 1.0, CH2Cl2) on 92% ee R-26r.

O
H

25s

Ar Ar

+

H2N

5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

Ar
N

Ar

26s

(S)-N-(bis(3,5-dimethylphenyl)methylene)-2-methylhex-5-en-3-amine

26s.

Isobutyraldehyde 25s (16 mg, 0.22 mmol) was reacted according to the general
procedure described above and purification with flash column chromatography (1:30
EtOAc/hexanes) was complete in 5 min to afford the rearrangement product 26s as a
viscous oil in 93% yield (62 mg, 0.19 mmol). Spectral data for 26s: Rf = 0.20 (1:30
1

EtOAc/hexanes). H NMR (CDCl3, 600 MHz) % 0.84 (d, 3H, J = 7.2 Hz), 0.93 (d, 3H, J =
6.6 Hz), 1.81-1.84 (m, 1H), 2.28 (s, 6H), 2.32 (s, 6H), 2.29-2.37 (m, 2H), 3.12 (dd, 1H, J
= 13.2 Hz, 6.0 Hz), 4.96-5.02 (m, 2H), 5.70-5.75 (m, 1H), 6.73 (s, 2H), 6.98 (s, 2H), 7.19

136

(d, 2H, J= 0.6 Hz);

13

C NMR (150 MHz, CDCl3) % 18.72, 19.77, 21.31, 21.36, 32.95,

38.65, 66.94, 115.91, 125.83, 126.19, 129.27, 131,23, 136.96, 137.37, 137.40, 137.79,
1

140.78, 167.21; IR (thin film) 2935m, 1595m, 1199m cm- . HRMS (ES+) calcd for
C24H32N m/z 334.2535 (M++1), meas 334.2539. To determine the optical purity, the
product 26s was hydrolyzed with NH2OH!HCl (62 mg, 0.90 mmol) in THF (4 mL) and
water (2 mL) to afford the homoallylic amine. Then the amine was reacted with benzoyl
chloride (25 µL) and triethylamine (35 µL) in DCM (2.0 mL). Purification with column
chromatography

(1:6

EtOAc/hexanes)

afforded

(S)-N-(2-methylhex-5-en-3-

yl)benzamide as a white solid in 67% yield. The optical purity was determined to be
92% ee by HPLC analysis (ChiralPAK AS column, hexanes:2-propanol 90:10, 222 nm,
1

flow rate 0.5 mL min- ). A second run with (S)-VANOL gave (R)-26s with 93% ee.
Retention times were 21.6 min (major enantiomer) and 17.2 min (minor enantiomer).
23

["]

D

= -41.4 (c = 1.0, CH2Cl2) on 93% ee R-26s.

O
H

25t

Ar Ar

+

Ar

5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

H2N

Ar = 3,5-Me2C6H3
22f

N

Ar

26t

(S)-N-(bis(3,5-dimethylphenyl)methylene)-2,2-dimethylhex-5-en-3-amine

26t.

Pivalaldehyde 25t (19 mg, 0.22 mmol) was reacted according to the general procedure
described

above

and

purification

with

flash

column

chromatography

(1:30

EtOAc/hexanes) was complete in 5 min to afford the rearrangement product 26t as a

137

viscous oil in 87% yield (60 mg, 0.18 mmol). Spectral data for 26t: Rf = 0.34 (1:30
1

EtOAc/hexanes). H NMR (CDCl3, 500 MHz) % 0.91 (s, 9H), 2.29 (s, 6H), 2.32 (s, 6H),
2.38-2.40 (m, 2H), 3.05 (dd, 1H, J = 7.2 Hz, 4.8 Hz), 4.95-5.00 (m, 2H), 5.64-5.69 (m,
1H), 6.76 (s, 2H), 6.98 (s, 2H), 7.21 (s, 2H);

13

C NMR (125 MHz, CDCl3) % 21.34,

26.99, 35.55, 36.01, 69.85, 115.59, 126.25, 126.37, 129.17, 131.15, 137.08, 137.31,
1

137.57, 138.45, 141.00, 166.58; IR (thin film) 2945m, 1581m, 1321m cm- . HRMS
(ES+) calcd for C25H34N m/z 348.2691 (M++1), meas 348.2706. To determine the
optical purity, the product 26t was hydrolyzed with NH2OH!HCl (62 mg, 0.9 mmol) in
THF (4 mL) and water (2 mL) to afford the homoallylic amine. Then the amine was
reacted with benzoyl chloride (25 µL) and triethylamine (35 µL) in DCM (2.0 mL).
Purification with column chromatography (1:6 EtOAc/hexanes) afforded (S)-N-(2,2dimethylhex-5-en-3-yl)benzamide as a white solid in 46% yield. The optical purity was
determined to be 73% ee by HPLC analysis (ChiralPAK AS column, hexanes:21

propanol 90:10, 222 nm, flow rate 0.5 mL min- ). A second run with (S)-VANOL gave
(R)-26t with 71% ee. Retention times were 12.4 min (major enantiomer) and 10.8 min
23

(minor enantiomer). ["]

D

= -46.7 (c = 1.0, CH2Cl2) on 71% ee R-26t.

6.1.7 General procedure for direct catalytic asymmetric synthesis of homoallylic
amines from aldehydes – Illustrated for the synthesis of (S)-1-phenylbut-3-en-1amine Hydrochloride 27f

138

O

+
H

25f

Ar Ar
H2N

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

NH2 •HCl

2) 2N HCl, THF/H2O, rt
(S)-27f

Preparation of catalyst stock solution. A 50 mL Schlenk flask was flame dried under
high vacuum and cooled under a low flow of Argon. To the flask was added sequentially
(R)-VANOL (0.35 g, 0.80 mmol), 2,4,6-trimethylphenol (0.21 g, 1.6 mmol), dry toluene
(16.0 mL), BH3•SMe2 (2 M solution in toluene, 1.2 mL, 2.4 mmol) and water (43.0 µL,
2.4 mmol) under a low flow of Argon. The threaded Teflon valve on the Schlenk flask
was then closed, and the mixture heated at 100 °C for 1 h. The valve was carefully
opened to gradually apply high vacuum (0.1 mm Hg) and the solvent was removed. The
vacuum was maintained for a period of 30 min at 100 °C. The flask was then removed
from the oil bath and allowed to cool to room temperature under a low flow of Argon.
This was then completely dissolved in 8.0 mL of dry m-xylene to afford the stock
solution of the catalyst.
The aminoallylation of aldehydes. A 100 mL Schlenk flask charged with 5Å
powdered molecular sieves (2.0 g) and fitted with a magnetic stir bar was flame dried
under high vacuum and cooled down under a low flow of Argon. To the test tube was
then added amine 22f (1.1 g, 4.0 mmol, 1.0 equiv), 2.0 mL of the catalyst stock solution
(5 mol% catalyst) and m-xylene (17.0 mL) via a plastic syringe fitted with a metallic
needle. The mixture was stirred for 30 min at 60 °C. At the same time, to an oven-dried
5 mL vial was added benzoic acid (1.0 g, 0.8 mmol) and m-xylene (4.0 mL). Then
benzaldehyde 25f (0.47 g, 0.44 mL) and 1.0 mL of the benzoic acid stock solution (5

139

mol%) were transferred to the above catalyst-amine complex under a high flow of Argon
via a plastic syringe fitted with a metallic needle. The test tube was closed and the
reaction was stirred at 60 °C for 18 h. Thereafter, 5Å MS was filtered off through a
Celite pad, and the pad was washed with EtOAc (10 mL). The filtrate was concentrated
by rotary evaporation and placed under high vacuum (0.5 mm Hg) for 1 h to further
remove m-xylene. The residual was then dissolved in THF (16 mL), followed by the
addition of 2N aqueous HCl solution (8.0 mL). The mixture was stirred at room
temperature for 4 h and monitored by TLC. Upon completion, THF was removed by
rotary evaporation and another 8.0 mL of H2O was added. The mixture was washed
with EtOAc (4 x 4 mL) and the combined organic phase was extracted with H2O (5 mL)
which was then washed with EtOAc (1.0 mL). The combined aqueous phase was
concentrated by rotary evaporation and placed under high vacuum (0.5 mm Hg) to
further remove H2O until no weight loss was observed. Compound 27f was obtained as
1

a white solid (mp 231-233 °C) in 91% yield (0.67 g, 3.6 mmol). Spectral data for 27f: H
NMR (CDCl3, 600 MHz) % 2.66-2.71 (m, 1H), 2.77-2.82 (m, 1H), 4.19 (s, 1H), 4.99-5.07
(m, 2H), 5.49-5.56 (m, 1H), 7.30-7.33 (m, 3H), 7.40-7.42 (m, 2H), 8.76 (bs, 3H);

13

C

NMR (150 MHz, CDCl3) % 38.79, 55.84, 120.13, 127.42, 128.96, 128.98, 131.43,
135.67; Anal calcd for C10H14ClN: C, 65.39; H, 7.68; N, 7.63. Found: C, 64.82; H, 7.35;
23

N, 7.49; ["]

D

23

= -8.8 (c = 1.0, H2O) on 80% ee S-27f (R configuration, ["]

60

c = 1.4, CHCl3 ).

140

D

= + 36.2,

O

O 2N

Ar Ar

+
H

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

H2N

Ar = 3,5-Me2C6H3
22f

25a

2) 2N HCl, THF/H2O, rt

O 2N

NH2 •HCl

(S)-27a

(S)-1-(4-nitrophenyl)but-3-en-1-amine hydrochloride 27a. p-Nitrobenzaldehyde 25a
(0.66 g, 4.4 mmol, 1.1 equiv) was reacted according to the general procedure described
above to afford product 27a as a white solid (mp 205-206 °C) in 80% yield (0.74 g, 3.2
1

mmol). Spectral data for 27a: H NMR (DMSO, 600 MHz) % 2.62-2.67 (m, 1H), 2.812.85 (m, 1H), 4.53 (dd, 1H, J = 9.0 Hz, 5.4 Hz), 4.99-5.03 (m, 2H), 5.58-5.65 (m, 1H),
7.82-7.84 (m, 2H), 8.25-8.27 (m, 2H), 8.96 (bs, 3H);

13

C NMR (150 MHz, DMSO) %

38.32, 53.05, 119.33, 123.55, 129.19, 132.23, 144.81, 147.40; Anal calcd for
23

C10H13ClN2O2: C, 52.52; H, 5.73; N, 12.25. Found: C, 53.30; H, 5.39; N, 12.12; ["]

D

= -11.0 (c = 1.0, H2O) on 97% ee S-27a.

O

+
H

25b

Ar Ar
H2N

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

2) 2N HCl, THF/H2O, rt

NH2 •HCl

(S)-27b

(S)-1-(p-tolyl)but-3-en-1-amine hydrochloride 27b. p-Tolualdehyde 25b (0.53 g, 4.4
mmol, 1.1 equiv) was reacted according to the general procedure described above to
afford product 27b as a white solid (mp 222-224 °C) in 94% yield (0.74 g, 3.8 mmol).
1

Spectral data for 27b: H NMR (CDCl3, 600 MHz) % 2.32 (s, 3H), 2.67-2.71 (m, 1H),

141

2.76-2.80 (m, 1H), 4.15 (bs, 1H), 5.00-5.07 (m, 2H), 5.51-5.55 (m, 1H), 7.12 (d, 2H, J =
7.8 Hz), 7.30-7.31 (m, 2H, J = 7.8 Hz), 8.71 (bs, 3H);

13

C NMR (150 MHz, CDCl3) %
23

21.18, 38.73, 55.62, 119.87, 127.38, 129.64, 131.67, 132.73, 138.67; ["]

D

= -13.5 (c =

1.0, H2O) on 87% ee S-27b.

O

+
H

Br

25c

Ar Ar
H2N

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

2) 2N HCl, THF/H2O, rt

NH2 •HCl

Br

(S)-27c

(S)-1-(4-bromophenyl)but-3-en-1-amine hydrochloride 27c. p-Bromobenzaldehyde
25c (0.81 g, 4.4 mmol, 1.1 equiv) was reacted according to the general procedure
described above to afford product 27c as a white solid (mp 265-266 °C) in 81% yield
1

(0.85 g, 3.2 mmol). Spectral data for 27c: H NMR (DMSO, 600 MHz) % 2.56-2.61 (m,
1H), 2.75-2.79 (m, 1H), 4.31 (dd, 1H, J = 9.0 Hz, 5.4 Hz), 4.99-5.03 (m, 2H), 5.55-5.62
(m, 1H), 7.47-7.49 (m, 2H), 7.59-7.61 (m, 2H), 8.75 (bs, 3H);

13

C NMR (150 MHz,

DMSO) % 38.72, 53.17, 119.00, 121.69, 129.95, 131.43, 132.56, 136.79; Anal calcd for
23

C10H13BrClN: C, 45.74; H, 4.99; N, 5.33. Found: C, 46.61; H, 4.55; N, 5.37; ["]
23

8.4 (c = 1.0, H2O) on 95% ee S-27c (R configuration, ["]

142

D

D

=60

= + 29.8, c = 1.3, CHCl3 ).

O

+
H

MeO

25d

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar Ar
H2N

Ar = 3,5-Me2C6H3
22f

2) 2N HCl, THF/H2O, rt

(S)-1-(4-methoxyphenyl)but-3-en-1-amine

NH2 •HCl

MeO

hydrochloride

(S)-27d

27d.

p-

Methoxybenzaldehyde 25d (0.60 g, 4.4 mmol, 1.1 equiv) was reacted according to the
general procedure described above to afford product 27d as a white solid (mp 158-160
1

°C) in 94% yield (0.81 g, 3.8 mmol). Spectral data for 27d: H NMR (DMSO, 600 MHz)
% 2.59-2.62 (m, 1H), 2.77-2.80 (m, 1H), 3.74 (s, 3H), 4.20 (t, 1H, J = 4.8 Hz), 4.97-5.02
(m, 2H), 5.54-5.59 (m, 1H), 6.93 (d, 2H, J = 8.4 Hz), 7.43-7.45 (m, 2H), 8.69 (bs, 3H);
13

C NMR (150 MHz, DMSO) % 38.41, 53.45, 55.14, 113.85, 118.57, 129.03, 129.28,

133.03, 159.21; Anal calcd for C11H16ClNO: C, 61.82; H, 7.55; N, 6.55. Found: C,
23

61.16; H, 7.06; N, 6.44; ["]

O

+
H

AcO

25e

D

= -9.2 (c = 1.0, H2O) on 86% ee S-27d.

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar Ar
H2N

Ar = 3,5-Me2C6H3
22f

2) 2N HCl, THF/H2O, rt

AcO

NH2 •HCl

(S)-27e

(S)-4-(1-aminobut-3-en-1-yl)phenol hydrochloride 27e. p-acetoxybenzaldehyde 25e
(0.72 g, 4.4 mmol, 1.1 equiv) was reacted according to the general procedure described
above to afford product 27e as a white solid (mp 178-180 °C) in 84% yield (0.67 g, 3.4
1

mmol). Spectral data for 27e: H NMR (DMSO, 600 MHz) % 2.55-2.59 (m, 1H), 2.70-

143

2.74 (m, 1H), 4.13 (bs, 1H), 4.98-5.04 (m, 2H), 5.53-5.58 (m, 1H), 6.77-6.79 (m, 2H),
7.27-7.29 (m, 2H), 8.49 (bs, 3H), 9.66 (s, 1H);

13

C NMR (150 MHz, DMSO) % 38.40,
23

53.56, 115.25, 118.56, 127.37, 128.84, 133.07, 157.61; ["]

D

= -13.3 (c = 1.0, H2O) on

94% ee S-27e.

O
Br

+
H

25g

Ar Ar
H2N

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
Br
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

2) 2N HCl, THF/H2O, rt

NH2 •HCl

(S)-27g

(S)-1-(3-bromophenyl)but-3-en-1-amine hydrochloride 27g. 3-Bromobenzaldehyde
25g (0.74 g, 4.4 mmol, 1.1 equiv) was reacted according to the general procedure
described above to afford product 27g as a white solid (mp 233-235 °C) in 83% yield
1

(0.87 g, 3.3 mmol). Spectral data for 27g: H NMR (DMSO, 600 MHz) % 2.58-2.63 (m,
1H), 2.77-2.81 (m, 1H), 4.32 (dd, 1H, J = 8.0 Hz, 5.4 Hz), 4.99-5.04 (m, 2H), 5.56-5.63
(m, 1H), 7.36 (t, 1H, J = 7.8 Hz), 7.53-7.55 (m, 2H), 7.85 (t, 1H, J = 1.8 Hz), 8.83 (bs,
3H);

13

C NMR (150 MHz, DMSO) % 38.32, 53.18, 119.03, 121.71, 126.83, 130.50,

130.69, 131.27, 132.52, 140.11; Anal calcd for C10H13BrClN: C, 45.74; H, 4.99; N,
23

5.33. Found: C, 45.12; H, 4.46; N, 5.52; ["]
90% ee S-27g.

144

D

= -20.2 (c = 1.0, H2O/CH3CN 4:1) on

Cl

O

+
H

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar Ar
H2N

Ar = 3,5-Me2C6H3
22f

25h

Cl

2) 2N HCl, THF/H2O, rt

NH2 •HCl

(S)-27h

(S)-1-(2-chlorophenyl)but-3-en-1-amine hydrochloride 27h. 2-Chlorobenzaldehyde
25h (0.62 g, 4.4 mmol, 1.1 equiv) was reacted according to the general procedure
described above to afford product 27h as a white solid (mp 173-175 °C) in 99% yield
1

(0.86 g, 4.0 mmol). Spectral data for 27h: H NMR (CDCl3, 600 MHz) % 2.74-2.79 (m,
1H), 2.82-2.86 (m, 1H), 4.88 (d, 1H, J = 5.4 Hz), 5.09-5.15 (m, 2H), 5.63-5.70 (m, 1H),
7.26-7.29 (m, 2H), 7.40 (d, 1H, J = 7.8 Hz), 7.68 (d, 1H, J = 7.2 Hz), 8.95 (bs, 3H);

13

C

NMR (150 MHz, CDCl3) % 38.22, 51.64, 120.84, 127.60, 127.85, 129.99, 130.05,
130.81, 133.24, 133.54; Anal calcd for C10H13Cl2N: C, 55.06; H, 6.01; N, 6.42. Found:
23

C, 54.60; H, 6.24; N, 6.44; ["]

O

+
H

25i

Ar Ar
H2N

D

= -16.0 (c = 1.0, H2O) on 92% ee S-27h.

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

2) 2N HCl, THF/H2O, rt

NH2 •HCl

(S)-27i

(S)-1-(o-tolyl)but-3-en-1-amine hydrochloride 27i. 2-Tolualdehyde 25i (0.53 g, 4.4
mmol, 1.1 equiv) was reacted according to the general procedure described above to
afford product 27i as a white solid (mp 174-176 °C) in 90% yield (0.71 g, 3.6 mmol).
1

Spectral data for 27i: H NMR (DMSO, 600 MHz) % 2.31 (s, 3H), 2.60-2.64 (m, 1H),

145

2.78-2.80 (m, 1H), 4.44 (t, 1H, J = 6.0 Hz), 4.99-5.06 (m, 2H), 5.58-5.62 (m, 1H), 7.207.28 (m, 3H), 7.65 (t, 1H, J = 1.2 Hz), 8.68 (bs, 3H);

13

C NMR (150 MHz, DMSO) %

19.15, 38.35, 49.57, 118.95, 126.25, 126.41, 128.13, 130.38, 132.63, 135.80, 135.85;
Anal calcd for C11H16ClN: C, 66.83; H, 8.16; N, 7.08. Found: C, 67.05; H, 8.06; N, 7.02;
23

["]

D

= -17.4 (c = 1.0, H2O) on 80% ee S-27i.

F

O

+
H

Br

25j

Ar Ar
H2N

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

2) 2N HCl, THF/H2O, rt

(S)-1-(4-bromo-2-fluorophenyl)but-3-en-1-amine

F

Br

hydrochloride

27j.

NH2 •HCl

(S)-27j

4-Bromo-2-

fluorobenzaldehyde 25j (0.89 g, 4.4 mmol, 1.1 equiv) was reacted according to the
general procedure described above to afford product 27j as a white solid (mp 158-160
1

°C) in 81% yield (0.89 g, 3.2 mmol). Spectral data for 27j: H NMR (DMSO, 600 MHz) %
2.59-2.64 (m, 1H), 2.80-2.84 (m, 1H), 4.49 (dd, 1H, J = 9.6 Hz, 5.4 Hz), 4.99-5.02 (m,
2H), 5.56-5.63 (m, 1H), 7.51 (dd, 1H, J = 9.0 Hz, 2.4 Hz), 7.59 (dd, 1H, J = 11.2 Hz, 1.8
Hz), 7.73-7.76 (m, 1H), 8.93 (bs, 3H);

13

C NMR (150 MHz, DMSO) % 37.55, 46.58,

118.84 (d, J = 25.8 Hz), 119.31, 122.05 (d, J = 9.8 Hz), 123.95 (d, J = 13.5 Hz), 127.99,
130.49 (d, J = 3.5 Hz), 132.08, 159.52 (d, J = 250 Hz); Anal calcd for C10H12BrClFN: C,
23

42.81; H, 4.31; N, 4.99. Found: C, 42.29; H, 4.12; N, 5.09; ["]
on 96% ee S-27j.

146

D

= -10.3 (c = 1.0, H2O)

O

Ar Ar

+
H

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

H2N

2) 2N HCl, THF/H2O, rt

Ar = 3,5-Me2C6H3
22f

25k

NH2 •HCl

(S)-27k

(S)-1-(naphthalen-1-yl)but-3-en-1-amine hydrochloride 27k. 1-Naphthaldehyde 25k
(0.68 g, 4.4 mmol, 1.1 equiv) was reacted according to the general procedure described
above to afford product 27k as a white solid (mp 227-229 °C) in 86% yield (0.80 g, 3.4
1

mmol). Spectral data for 27k: H NMR (DMSO, 600 MHz) % 2.77-2.81 (m, 1H), 2.882.91 (m, 1H), 4.94-5.06 (m, 2H), 5.22 (t, 1H, J = 6.6 Hz), 5.65-5.70 (m, 1H), 7.55-7.62
(m, 3H), 7.90-7.99 (m, 3H), 8.19 (d, 1H, J = 8.4 Hz), 8.85 (bs, 3H);

13

C NMR (150 MHz,

DMSO) % 38.59, 48.69, 119.03, 122.84, 124.33, 125.36, 126.02, 126.72, 128.72,
128.79, 130.38, 132.60, 133.21, 133.73; Anal calcd for C14H16ClN: C, 71.94; H, 6.90;
23

N, 5.99. Found: C, 71.88; H, 6.93; N, 5.93; ["]
23

27k (R configuration, ["]

O

+
H

25l

D

= -32.5 (c = 1.0, H2O) on 90% ee S60

= + 82.3, c = 1.3, CHCl3 ).

Ar Ar
H2N

D

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

2) 2N HCl, THF/H2O, rt

NH2 •HCl

(S)-27l

(S)-1-(naphthalen-2-yl)but-3-en-1-amine Hydrochloride 27l. 2-Naphthaldehyde 25l
(0.68 g, 4.4 mmol, 1.1 equiv) was reacted according to the general procedure described
above to afford product 27l as a white solid (mp 204-205 °C) in 77% yield (0.73 g, 3.1

147

1

mmol). Spectral data for 27l: H NMR (DMSO, 600 MHz) % 2.72-2.76 (m, 1H), 2.85-2.88
(m, 1H), 4.46 (dd, 1H, J = 8.0 Hz, 6.0 Hz), 4.97-5.06 (m, 2H), 5.60-5.65 (m, 1H), 7.537.55 (m, 2H), 7.69 (dd, 1H, J = 7.8 Hz, 2.4 Hz), 7.89-8.00 (m, 4H), 8.80 (bs, 3H);

13

C

NMR (150 MHz, DMSO) % 38.34, 54.05, 118.87, 124.91, 126.52, 126.55, 126.96,
127.60, 127.80, 128.30, 132.50, 132.69, 132.78, 134.82; Anal calcd for C14H16ClN: C,
23

71.94; H, 6.90; N, 5.99. Found: C, 71.48; H, 6.55; N, 5.99; ["]

D

= -8.0 (c = 1.0, H2O)

on 80% ee S-27l.

NO2

O

+
H

25m

Ar Ar
H2N

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

NO2

2) 2N HCl, THF/H2O, rt

(S,E)-1-(2-nitrophenyl)hexa-1,5-dien-3-amine

hydrochloride

NH2 •HCl

27m

27m.

(E)-3-(2-

nitrophenyl)acrylaldehyde 25m (0.78 g, 4.4 mmol) was reacted according to the general
procedure described above to afford product 27m as a white solid (mp 147-148 °C) in
1

84% yield (0.86 g, 3.4 mmol). Spectral data for 27m: H NMR (DMSO, 600 MHz) %
2.48-2.51 (m, 1H), 2.61 (s, 1H), 3.97 (bs, 1H), 5.12-5.19 (m, 2H), 5.74-5.81 (m, 1H),
6.25-6.30 (m, 1H), 7.00 (d, 1H, J = 15.6 Hz), 7.56-7.58 (m, 2H), 7.69-7.76 (m, 1H), 7.97
(d, 1H, J = 8.4 Hz), 8.54 (bs, 3H);

13

C NMR (150 MHz, DMSO) % 36.89, 51.70, 118.95,

124.32, 128.40, 128.45, 129.33, 130.42, 131.05, 132.69, 133.63, 147.71. Anal calcd for
23

C12H15ClN2O2: C, 56.58; H, 5.94; N, 11.00. Found: C, 55.69; H, 5.79; N, 10.80; ["]
= -18.8 (c = 1.0, H2O) on 95% ee S-27m.

148

D

O

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar Ar

+
H

H2N

Ar = 3,5-Me2C6H3
22f

25n

NH2 •HCl

2) 2N HCl, THF/H2O, rt

27n

(S,E)-1-phenylhexa-1,5-dien-3-amine hydrochloride 27n. Cinnamaldehyde 25n (0.58
g, 4.4 mmol) was reacted according to the general procedure described above to afford
product 27n as a white solid (mp 197-198 °C) in 85% yield (0.71 g, 3.4 mmol). Spectral
1

data for 27n: H NMR (DMSO, 600 MHz) % 2.47-2.50 (m, 1H), 2.60-2.64 (m, 1H), 3.88
(dd, 1H, J = 13.2 Hz, 8.4 Hz), 5.09-5.17 (m, 2H), 5.74-5.78 (m, 1H), 6.22 (q, 1H, J =
16.2 Hz, 7.8 Hz), 6.70 (d, 1H, J = 16.2 Hz), 7.27-7.41 (m, 5H), 8.53 (bs, 3H);

13

C NMR

(150 MHz, DMSO) % 37.08, 52.07, 118.81, 125.54, 126.42, 128.23, 128.75, 132.94,
23

133.71, 135.59. ["]

O

+
H

25o

D

= -1.3 (c = 1.0, H2O/CH3CN 2:1) on 92% ee S-27n.

Ar Ar
H2N

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

2) 2N HCl, THF/H2O, rt

NH2 •HCl

27o

(R)-hept-1-en-4-amine hydrochloride 27o. Butyraldehyde 25o (0.32 g, 4.4 mmol)
was reacted according to the general procedure described above to afford product 27o
as a white solid (mp 195-197 °C) in 81% yield (0.49 g, 3.2 mmol). The difference was
that upon completion, THF was removed by rotary evaporation and another 8.0 mL of
H2O was added. The mixture was washed with EtOAc (4 x 4 mL) and the combined

149

organic phase was extracted with H2O/CH3CN (10:1 5.5 mL). After removal of CH3CN,
H2O phase was then washed with EtOAc (1.0 mL). The combined aqueous phase was
concentrated by rotary evaporation and placed under high vacuum (0.5 mm Hg) to
1

further remove H2O until no weight loss was observed. Spectral data for 27o: H NMR
(CDCl3, 600 MHz) % 0.92 (t, 3H, J = 7.2 Hz), 1.43- 1.50 (m, 2H), 1.62-1.70 (m, 2H),
2.43-2.50 (m, 2H), 3.21 (bs, 1H), 5.12-5.23 (m, 2H), 5.77-5.82 (m, 1H), 8.31 (bs, 3H);
13

C NMR (150 MHz, CDCl3) % 13.65, 18.64, 34.28, 36.93, 51.88, 120.33, 131.67; Anal

calcd for C7H16ClN: C, 56.18; H, 10.78; N, 9.36. Found: C, 55.76; H, 10.31; N, 9.19;
23

["]

D

= -3.2 (c = 1.0, H2O/CH3CN 2:3) on 96% ee R-27o.

O
Ph

+
H

25p

Ar Ar
H2N

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
Ph
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

2) 2N HCl, THF/H2O, rt

NH2 •HCl

27p

(R)-7-phenylhept-1-en-4-amine hydrochloride 27p. 4-Phenylbutanal 25p (0.66 g, 4.4
mmol) was reacted according to the general procedure described above to afford
product 27p as a white solid (mp 83-85 °C) in 71% yield (0.64 g, 2.8 mmol). The
difference was that upon completion, THF was removed by rotary evaporation and
another 8.0 mL of H2O was added. The mixture was washed with EtOAc (4 x 4 mL) and
the combined organic phase was extracted with H2O/CH3CN (10:1 5.5 mL). After
removal of CH3CN, H2O phase was then washed with EtOAc (1.0 mL). The combined

150

aqueous phase was concentrated by rotary evaporation and placed under high vacuum
(0.5 mm Hg) to further remove H2O until no weight loss was observed. Spectral data for
1

27p: H NMR (DMSO, 600 MHz) % 1.52- 1.56 (m, 2H), 1.62-1.68 (m, 2H), 2.30-2.39 (m,
2H), 2.48-2.57 (m, 2H), 3.13 (bs, 1H), 5.09-5.15 (m, 2H), 5.74-5.80 (m, 1H), 7.15-7.20
(m, 3H), 7.27 (t, 2H, J = 7.2 Hz), 8.17 (bs, 3H);

13

C NMR (150 MHz, DMSO) % 26.27,
23

31.16, 34.81, 36.25, 49.89, 118.85, 125.75, 128.22, 128.27, 133.01, 141.61; ["]

D

=-

9.8 (c = 1.0, H2O/CH3CN 2:1) on 93% ee R-27p.
M
H
C
A
q
6
2
e
5
C

O
Ph

+
H

H

25q

Ar Ar
H2N

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

NH2
Ph

2

2) 2N HCl, THF/H2O,

,

(S)-1-phenylpent-4-en-2-amine hydrochloride 27q. 2-Phenylacetaldehyde 25q (0.53

g, 4.4 mmol) was reacted according to the general procedure described above to afford

product 27q as a light yellow solid (mp 122-123 °C) in 57% yield (0.45 g, 2.3 mmol).

The difference was that upon completion, THF was removed by rotary evaporation and

another 8.0 mL of H2O was added. The mixture was washed with EtOAc (4 x 4 mL) and
the combined organic phase was extracted with H2O/CH3CN (10:1 5.5 mL). After
removal of CH3CN, H2O phase was then washed with EtOAc (1.0 mL). The combined

aqueous phase was concentrated by rotary evaporation and placed under high vacuum
(0.5 mm Hg) to further remove H2O until no weight loss was observed. Spectral data for

151

1

27q: H NMR (DMSO, 600 MHz) % 2.29 (t, 2H, J = 1.2 Hz), 2.76-2.79 (m, 1H), 2.99-3.04
(m, 1H), 3.39 (bs, 1H), 5.09-5.13 (m, 2H), 5.80-5.85 (m, 1H), 7.23-7.26 (m, 3H), 7.307.33 (m, 2H), 8.28-8.34 (bs, 3H);

13

C NMR (150 MHz, DMSO) % 35.50, 37.53, 51.35,
23

119.17, 126.76, 128.55, 129.34, 132.78, 136.56; ["]

D

= +12.0 (c = 1.0, H2O) on 90%

ee S-27q.

O

+
H

25r

Ar Ar
H2N

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

NH2 •HCl

2) 2N HCl, THF/H2O, rt

27r

(S)-1-cyclohexylbut-3-en-1-amine hydrochloride 27r. Cyclohexanecarbaldehyde 25r
(0.50 g, 4.4 mmol) was reacted according to the general procedure described above to
afford product 27r as a white solid (mp 234-235 °C) in 85% yield (0.64 g, 3.4 mmol).
The difference was that upon completion, THF was removed by rotary evaporation and
another 8.0 mL of H2O was added. The mixture was washed with EtOAc (4 x 4 mL) and
the combined organic phase was extracted with H2O/CH3CN (10:1 5.5 mL). After
removal of CH3CN, H2O phase was then washed with EtOAc (1.0 mL). The combined
aqueous phase was concentrated by rotary evaporation and placed under high vacuum
(0.5 mm Hg) to further remove H2O until no weight loss was observed. Spectral data for
1

27r: H NMR (DMSO, 600 MHz) % 0.98-1.18 (m, 5H), 1.52-1.71 (m, 6H), 2.30-2.39 (m,
2H), 2.93 (bs, 1H), 5.10-5.19 (m, 2H), 5.78-5.85 (m, 1H), 8.11 (bs, 3H);

152

13

C NMR (150

MHz, DMSO) % 25.54, 25.62, 27.65, 27.78, 33.71, 38.71, 54.62, 118.66, 133.39; Anal
calcd for C10H20ClN: C, 63.31; H, 10.63; N, 7.38. Found: C, 62.58; H, 10.02; N, 7.26;
23

["]

D

= -5.8 (c = 1.0, H2O) on 90% ee S-27r.

O

+
H

25s

Ar Ar
H2N

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

2) 2N HCl, THF/H2O, rt

NH2 •HCl

27s

(S)-2-methylhex-5-en-3-amine hydrochloride 27s. Isobutyraldehyde 25s (0.32 g, 4.4
mmol) was reacted according to the general procedure described above to afford
product 27s as a white solid (mp 189-191 °C) in 75% yield (0.45 g, 3.0 mmol). The
difference was that upon completion, THF was removed by rotary evaporation and
another 8.0 mL of H2O was added. The mixture was washed with EtOAc (4 x 4 mL) and
the combined organic phase was extracted with H2O/CH3CN (10:1 5.5 mL). After
removal of CH3CN, H2O phase was then washed with EtOAc (1.0 mL). The combined
aqueous phase was concentrated by rotary evaporation and placed under high vacuum
(0.5 mm Hg) to further remove H2O until no weight loss was observed. Spectral data for
1

27s: H NMR (CDCl3, 600 MHz) % 1.04 (q, 6H, J = 13.2 Hz, 7.2 Hz), 2.03-2.08 (m, 1H),
2.42-2.49 (m, 2H), 3.01 (bs, 1H), 5.16-5.24 (m, 2H), 5.80-5.84 (m, 1H), 8.34 (bs, 3H);
13

23

C NMR (150 MHz, CDCl3) % 17.71, 18.51, 29.47, 34.22, 57.35, 119.88, 132.17. ["]

= +6.2 (c = 1.0, H2O/CH3CN 2:3) on 92% ee S-27s.

153

D

O

+
H

25t

Ar Ar
H2N

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

NH2 •HCl

2) 2N HCl, THF/H2O, rt

27t

(S)-2,2-dimethylhex-5-en-3-amine hydrochloride 27t. Pivalaldehyde 25t (0.38 g, 4.4
mmol) was reacted according to the general procedure described above to afford
product 27t as a white solid (mp 178-180 °C) in 94% yield (0.61 g, 3.8 mmol). The
difference was that upon completion, THF was removed by rotary evaporation and
another 8.0 mL of H2O was added. The mixture was washed with EtOAc (4 x 4 mL) and
the combined organic phase was extracted with H2O/CH3CN (10:1 5.5 mL). After
removal of CH3CN, H2O phase was then washed with EtOAc (1.0 mL). The combined
aqueous phase was concentrated by rotary evaporation and placed under high vacuum
(0.5 mm Hg) to further remove H2O until no weight loss was observed. Spectral data for
1

27t: H NMR (DMSO, 600 MHz) % 0.94 (s, 9H), 2.21-2.27 (m, 1H), 2.37-2.49 (m, 1H),
2.80 (d, 1H, J = 4.8 Hz), 5.05-5.19 (m, 2H), 5.88-5.95 (m, 1H), 8.07 (bs, 3H);
23

(150 MHz, DMSO) % 26.15, 33.21, 33.34, 59.39, 118.06, 134.82. ["]
H2O) on 73% ee S-27t.
6.1.8 Recrystalization of salt 27o

154

D

13

C NMR

= +8.9 (c = 1.0,

O
H

25o

Ar Ar

+

H2N

1) 5 mol % (R)-VANOL-BOROX 9,
5 mol% benzoic acid,
5 Å MS, m-xylene, 60 °C

Ar = 3,5-Me2C6H3
22f

NH2 •HCl

2) 2N HCl, THF/H2O, rt

Butyraldehyde 25o (0.80 g, 11 mmol) was reacted according to the general
procedure described above for the preparation of 27o to afford the product as a white
solid in 83% yield (1.26 g, 8.40 mmol). The optical purity of the unpurified 27o was
determined to be 93% ee, and ["]23D = -3.5 (c = 1.0, H2O/CH3CN). Compound 27o
(0.9 g, 6 mmol) was then purified with crystalization (EtOAc/CH2Cl2 12:1); the mixture
was brought to reflux and then cooled down to room temperature to afford a white
crystal in 92% yield (0.83 g, 0.55 mmol). The optical purity of the crystalized 27o was
determined to be 93% ee, and ["]23D = -3.8 (c = 1.0, H2O/CH3CN) on 93% ee R-27o.
6.1.9 Recycle of amine 22f and VANOL ligand 12
1) NH3, TiCl4, THF
MgCl

2)

Ar
H2N

Ar

n-Pr

, 87% y crystalization (2 steps, one pot)
1) 5 mol% (R)-VANOLBOROX 9,
5 mol% benzoic acid,
5A MS, m-xylene, 60 °C

O

+

recycle of diarylketone

Ar

organic
phase

H

22f
25o 2) 2N HCl, THF/H2O, rt
3) EtOAc wash
Ar = 3,5-Me2C6H3 1.1 equiv
(10 mmol scale)

aqueous
phase

Ar

+ (R)-VANOL
12, 86% y
28
92% y (recycled)
O

NH2 •HCl

27o
83% y, 95% ee
analytically pure
no purification required

155

Butyraldehyde 25o (0.80 g, 11 mmol) was reacted according to the general
procedure described above for the preparation of 27o to afford the product as a white
solid in 83% yield (1.25 g, 8.3 mmol). The organic phase was dried over Na2SO4,
filtered, and concentrated to afford a mixture containing 28. The mixture was then
purified by crystallization with hexanes to afford compound 28 in 80% yield from the first
crop (1.9 g, 8.0 mmol).
The same reaction described above was repeated. The difference was that the
mixture containing compound 28 and VANOL 12 was subjected to column
chromatography (EtOAc/Hexanes 1:20) to afford ketone 28 in 92% yield (2.2 g, 9.2
mmol) and VANOL 12 in 86% yield (0.19 g, 0.53 mmol).
Ketone 28 could be recycled back to amine 22f in 86% yield according to the
procedure described for large scale preparation of amine 22f in section C.
6.1.10 Asymmetric synthesis of (R)-Coniine 35
O
NH2 •HCl

H
2 N NaOH

NH2

HN

MeOH, NaBH4

(R)-27o,
83% y, 95% ee

Ph

(R)-32,
80% yield

Compound R-27o (0.9 g, 6.0 mmol) was treated with 2N NaOH until the pH reached
13. Then the mixture was extracted with DCM (3 mL x 3). The combined organic phase
was dried over Na2SO4, filtered and concentrated to afford crude amine, which was
used in the next step without further purification.

156

A solution of the crude amine and benzaldehyde (0.66 g, 6.3 mmol) in MeOH was
stirred at room temperature for 16 h.

59

Then NaBH4 (0.34 g, 9.0 mmol) was added and

the mixture was stirred for 12 h. The resulting mixture was treated with H2O (5 mL) and
1N NaOH and then extracted with DCM (5 mL x 3). The combined organic phase was
dried over Na2SO4 and concentrated. The mixture was purified by column
chromatography (EtOAc/Hexanes/TEA 1:6:0.1) to afford compound 32 as a clear
viscous oil in 80% yield (0.96 g, 5.0 mmol). Spectral data for 32: Rf = 0.20
1

(EtOAc/Hexanes/TEA 1:6:0.1). H NMR (CDCl3, 500 MHz) % 0.93-0.98 (m, 3H), 1.371.51 (m, 5H), 2.19-2.23 (m, 1H), 2.29-2.65 (m, 1H), 2.66-2.67 (m, 1H), 3.81 (s, 1H),
5.09-5.14 (m, 2H), 5.80-5.85 (m, 1H), 7.25-7.28 (m, 1H), 7.32-7.35 (m, 4H);

13

C NMR

(125 MHz, CDCl3) % 14.26, 18.92, 36.24, 38.34, 51.14, 55.96, 117.02, 126.73, 128.08,
1

128.28, 135.79, 140.87. IR (thin film) 3065m, 2957m, 1454, 912m cm- ; HRMS (ES+)
23

calcd for C14H22N m/z 204.1752 (M++1), meas 204.1745. ["]

D

CH2Cl2) on 96% ee R-32.

Br
HN

Ph

THF, 0 °C to reflux
NaH

(R)-32

N
Bn

(R)-33,
83% yield

157

= +19.7 (c = 1.0,

To a solution of R-32 ( 0.12 g, 0.50 mmol) in THF (5 mL) at 0 °C was added NaH
(0.48 mg, 2.0 mmol) and stirred for 30 min. To this mixture was added allyl bromide (73
mg, 0.60 mmol) and nBu4NI (37 mg, 0.10 mmol).

61

The resulting mixture was refluxed

for 12 h and then cooled down to room temperature. The reaction was quenched with
satd. NH4Cl solution and extracted with ether, washed with H2O and brine. The
combined organic phase was dried over Na2SO4, filtered and concentrated. The
mixture was purified by column chromatography (acetone/Hexanes/TEA 1:30:0.1) to
afford compound 33 as a light yellow oil in 83% yield (0.10 g, 0.42 mmol). Spectral data
1

for 33: Rf = 0.20 (acetone/Hexanes/TEA 1:30:0.1). H NMR (CDCl3, 500 MHz) % 0.84 (t,
3H, J = 8.4 Hz), 1.26-1.32 (m, 2H), 1.42-1.52 (m, 2H), 1.93-1.99 (m, 1H), 2.34-2.40 (m,
1H), 2.65-2.68 (m, 1H), 2.99-3.04 (m, 1H), 3.11-3.15 (m, 1H), 3.52 (d, 1H, J = 14.0 Hz),
3.69 (d, 1H, J = 14.5 Hz), 4.97-5.05 (m, 3H), 5.13-5.17 (m, 1H), 5.75-5.83 (m, 2H), 7.197.22 (m, 1H), 7.27-7.30 (m, 2H), 7.34 (d, 2H, J = 7.5 Hz);

13

C NMR (125 MHz, CDCl3) %

14.17, 20.09, 32.76, 34.31, 52.51, 53.28, 57.85, 115.45, 116.09, 126.53, 128.02,
1

128.64, 137.76, 137.90, 140.93. IR (thin film) 3076m, 2930m, 1641m, 1454, 912m cm- ;
23

HRMS (ES+) calcd for C17H26N m/z 244.2065 (M++1), meas 244.2076. ["]
(c = 1.0, CH2Cl2) on 96% ee R-33.

158

D

= +27.3

5 mol%
Grubb's Cat. II
N
Bn

toluene, 40 °C
10 mol%
benzoquinone

(R)-33,

N
Bn

(R)-34,
89% yield

To a flame-dried 250 mL round bottom flask was added diene R-33 (0.2 g, 0.8
mmol), toluene (80 mL) and benzoquinone (7 mg, 0.08 mmol). Grubb’s second
generation catalyst (34 mg, 0.040 mmol) was then added under nitrogen flow and the
resulting mixture was stirred at 40 °C for 12 h. Upon completion, the reaction mixture
was filtered through a Celite bed and the bed was washed with EtOAc. The resulting
crude was concentrated and subjected to purification by column chromatography
(acetone/Hexanes/TEA 1:30:0.1) to afford compound 34 as a light yellow oil in 89%
yield (0.16 g, 0.72 mmol). Spectral data for 34: Rf = 0.20 (acetone/Hexanes/TEA
1

1:30:0.1). H NMR (CDCl3, 600 MHz) % 0.84 (t, 3H, J = 7.5 Hz), 1.26-1.35 (m, 3H),
1.51-1.54 (m, 1H), 1.82-1.86 (m, 1H), 2.14-2.19 (m, 1H), 2.71-2.74 (m, 1H), 2.90-3.00
(m, 2H), 3.53 (d, 1H, J = 13.0 Hz), 3.62 (d, 1H, J = 13.0 Hz), 5.51-5.53 (m, 1H), 5.645.68 (m, 1H), 7.14-7.17 (m, 1H), 7.21-7.24 (m, 2H), 7.27-7.29 (m, 2H);

13

C NMR (150

MHz, CDCl3) % 14.37, 19.76, 27.99, 31.32, 48.26, 55.52, 56.17, 124.48, 125.03, 126.68,
1

128.13, 128.82, 139.92. IR (thin film) 3026m, 2928m, 1495m, 1095m cm- ; HRMS
23

(ES+) calcd for C15H22N m/z 216.1752 (M++1), meas 216.1762. ["]
1.0, CH2Cl2) on 96% ee R-34.

159

D

= +21.7 (c =

•HCl

Pd(OH)2/C-H2
N
Bn

N
H

MeOH, rt

(R)-Coniine
35, 81% yield

(R)-34,

To a 100 mL round bottom flask fitted with a magnetic stir bar was added (R)-34
(0.16 g, 0.76 mmol), Pd(OH)2 (0.47 g, 0.019 mmol, Pd(OH)2 on carbon powder, 20%
Pd, ca. 60% moisture) and methanol (30 mL). The flask was then equipped with a 3way valve connected to vacuum and a hydrogen balloon. The flask was opened to
vacuum for a few seconds, and then switched to the hydrogen balloon; this
manipulation was repeated three times. The reaction mixture was allowed to stir at room
temperature for 12 h. It was then filtered through a Celite pad and the pH of the filtrate
was adjusted to 2 with 2N HCl. Then the resulting mixture was concentrated and the
residual was dissolved in 10 mL of H2O, washed with ether (3x3 mL) and concentrated
23

to give (R)-Coniine as a white solid (mp 215-216 °C, lit.

215-216°C) which was further

dried at 40 °C under vacuum until no weight loss was observed in 76 % yield (91 mg, 0.
1

58 mmol). Spectral data for 35: H NMR (DMSO, 500 MHz) % 0.86 (t, 3H, J = 7.0 Hz),
1.29-1.49 (m, 5H), 1.59-1.82 (m, 5H), 2.79 (q, 1H, J = 22.5 Hz, 11 Hz), 2.93 (bs, 1H),
3.15 (d, 1H, J = 12.5 Hz), 8.44 (d, 2H, J =9.3 Hz);

13

C NMR (125 MHz, DMSO) % 13.71,

23

17.78, 21.71, 21.78, 27.76, 34.91, 43.68, 55.37. ["]
R-35.
Supporting information for chapter 3

160

D

= -6.7 (c = 0.6, EtOH) on 96% ee

All experiments were performed under an argon atmosphere. Flasks were flamedried and cooled under argon before use. All solvents were dried appropriately if used in
the reaction. VANOL ligand is commercially available from Aldrich as well as Strem
Chemicals. If desired, it could be purified using column chromatography on regular silica
gel with 2:1 dichloromethane/hexanes. Phenol was sublimed and stored in a dry
desiccator. Solid aldehydes were sublimed before use. Liquid aldehydes were distilled
before use.
11

1

B NMR, H NMR and

13

C NMR were recorded on a Varian 300 MHz, VXR-500

MHz or VXR-600 MHz instrument in CDCl3 or toluene-d8 unless otherwise noted. For
1

toluene-d8, toluene was used as the internal standard for both H NMR (! = 2.09) and
13

1

C NMR (! = 20.4). For CDCl3, CHCl3 was used as the internal standard for both H

NMR (! = 7.24) and

13

C NMR (! = 77.0). The silica gel for column chromatography was

purchased from Sorbent Technologies with the following specifications: standard grade,
2

60 Å porosity, 230 X 400 mesh particle size, 500-600 m /g surface area and 0.4 g/mL
bulk density. Analytical thin-layer chromatography (TLC) was performed on 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 phosphomolybdic acid in ethanol.
HPLC analyses were carried out using a Varian Prostar 210 Solvent Delivery
Module with a Prostar 330 PDA Detector and a Prostar Workstation. Optical rotation
was obtained on a Perkin-Elmer 341 polarimeter at a wavelength of 589 nm (Sodium D
line) using a 1.0 decimeter cell with a total volume of 1.0 mL.

161

6.2.2 General procedure for the preparation of the imines – Illustrated for the
synthesis of (E)-N-(4-bromobenzylidene)-1,1-bis(3,5-dimethylphenyl)but-3-en-1amien 36

O
H

MgSO4, DCM

+
H2N

Br

25c

N

5 mol% benzoic acid,
rt

22f

Br

36

To a flame-dried 50 mL round bottomed flask filled with argon was added MgSO4
(24 g, 0.20 mmol) and 240 mL dry CH2Cl2. This was followed by the addition of 1,1bis(3,5-dimethylphenyl)but-3-en-1-amine 22f (16.7 g, 60.0 mmol, 1 equiv). After stirring
for 5 minutes, p-bromobenzaldehyde (13.3 g, 72.0 mmol, 1.1 equiv) was added,
followed by the addition of 5 mol% benzoic acid (0.37 g, 3.0 mmol). The reaction
mixture was stirred for 48 h at room temperature. Thereafter, the reaction mixture was
filtered through a Celite bed and the Celite bed was washed with CH2Cl2. The filtrate
was then concentrated by rotary evaporation and placed under high vacuum (0.05 mm
Hg) for 1 h to give the crude imine 36 as a light yellow solid which was purified by
crystallization with pure hexanes to give a white solid (mp. 147-148°C) in 95% yield
1

(25.4 g, 57 mmol). Spectral data for 36: H NMR (CDCl3, 500 MHz) % 2.28 (s, 12H),
3.08-3.09 (d, 2H, J = 5.0 Hz, 4.92-4.96 (m, 2H), 5.72-5.76 (m, 1H), 6.86 (s, 2H), 6.93(s,
4H), 7.52-7.54(d, 2H, J = 8.5 Hz), 7.65-7.67 (d, 2H, J =8.0 Hz), 7.76 (s, 1H);

13

C NMR

(125 MHz, CDCl3) % 21.56, 46.76, 71.93, 117.20, 124.74, 126.16, 128.17, 129.75,

162

131.65, 134.79, 135.96, 137.13, 146.08, 158.35. IR (thin film) 2916, 1643, 1599, 1485
1

cm- ; HRMS (ES+) calcd for C27H29NBr m/z 446.1483 (M++1), meas 446.1504.

O
H

MgSO4, DCM

+
H2N

N

5 mol% benzoic acid,
rt

39

((E)-N-benzylidene-1,1-bis(3,5-dimethylphenyl)butan-1-amine

39.

1,1-bis(3,5-

dimethylphenyl)butan-1-amine (0.32 g, 1.1 mmol) was reacted according to the general
procedure described above to afford the crude imine 39 as a light yellow solid.
Crystallization with hexanes afforded 39 in 76% isolated yield (0.31 g, 0.84 mmol) as
1

white solid (mp 124-125 °C). Spectral data for 39: H NMR (CDCl3, 300 MHz) % 0.810.88 (t, 3H, J=7.5 Hz), 1.22-1.30 (m, 2H), 2.19-2.27 (m, 2H), 2.27 (s, 12H), 6.84 (s, 2H),
6.95 (s, 4H), 7.37-7.42 (m, 3H), 7.77-7.81 (m, 3H);

13

C NMR (75 MHz, CDCl3) % 14.78,

17.51, 21.60, 45.22, 71.92, 126.18, 127.85, 128.25, 128.43, 130.27, 136.95, 147.19,
1

159.01; IR (thin film) 3005, 2957, 1640, 1601, 1450 cm- .
6.2.3 Preparation of amine 1,1-bis(3,5-dimethylphenyl)butan-1-amine

(Boc)2O, Et3N
H2N

THF, reflux

22f

163

BocHN

To a flame-dried 100 mL round bottomed flask was added 1,1-bis(3,5dimethylphenyl)but-3-en-1-amine (1.1 g, 4.0 mmol) and 40 mL of dry THF. This was
followed by addition of (Boc)2O (1.6 g, 6.6 mmol) and triethylamine (1.2 g, 12 mmol).
The mixture was heated to reflux for 48 h. Upon completion, THF was removed by
rotary evaporation and the residue was dissolved in EtOAc (20 mL) , washed with H2O
(5 mLx3), dried over Na2SO4 , filtered and concentrated by rotary evaporation. The
crude material was purified by column chromatography (hexanes/EtOAc 12:1) to give
the product tert-butyl (1,1-bis(3,5-dimethylphenyl)but-3-en-1-yl)carbamate in 95% yield
1

(1.4 g, 3.8 mmol) as a colorless viscous oil. Spectral data for the product: H NMR
(CDCl3, 300 MHz) % 1.32 (bs, 9H), 2.27 (s, 12H), 3.28 (bs, 2H), 5.04-5.16 (m, 2H), 5.33
(bs, 1H), 6.83 (s, 2H), 6.93 (s, 4H);

13

C NMR (75 MHz, CDCl3) % 21.55, 27.39, 28.19,

63.27, 79.21, 118.63, 124.30, 128.22, 134.15, 137.29, 145.24; IR (thin film) 3007, 2978,
1

1732, 1698, 1483 cm- ; mass spectrum, m/z (% rel intensity) 379 M+ (0), 339 (1.91),
238 (100).

SO2NHNH2

+
NO2

BocHN

Et3N, DCM
rt

BocHN

NBSH

To a flame-dried 100 mL round bottomed flask was added tert-butyl (1,1-bis(3,5dimethylphenyl)but-3-en-1-yl)carbamate (1.4 g, 3.8 mmol) and 20 mL of dry DCM. This
was followed by addition of NBSH

62

(4.18 g, 19.0 mmol) and triethylamine (5.5 mL, 38

164

mmol) at room temperature. White suspension was formed in the flask, which then
disappeared after 5 h to give a clear orange solution. Upon completion, silica gel (5 g)
was added to the reaction mixture. DCM was removed by rotary evaporation. The
residue was directly loaded to a column and eluted with EtOAc/hexanes (1:15) to afford
the product tert-butyl (1,1-bis(3,5-dimethylphenyl)butyl)carbamate in 88% yield (1.2 g,
1

3.3 mmol) as an off-white solid (mp 135-136°C). Spectral data for the product: H NMR
(CDCl3, 300 MHz) % 0.89-0.94 (t, 3H, J = 7.2 Hz), 1.15-1.28 (m, 2H), 1.32 (bs, 9H), 2.26
(s, 12H), 2.47 (bs, 2H), 5.35 (bs, 1H), 6.80 (s, 2H), 6.90 (s, 4H);

13

C NMR (75 MHz,

CDCl3) % 14.35, 17.43, 21.55, 28.20, 63.81, 124.13, 128.02, 137.19, 146.08, 162.20; IR
1

(thin film) 3281, 3005, 2964, 1734, 1691cm- . mass spectrum, m/z (% rel intensity) 381
M+ (0), 339 (1.67), 238 (100).

Na-OtBu
BocHN

THF/H2O, rt

H2N

To a flame-dried 10 mL round bottomed flask was added tert-butyl (1,1-bis(3,5dimethylphenyl)butyl)carbamate (74 mg, 0.2 mmol) and 1.0 mL of dry THF. This was
t

followed by addition of H2O (3.6 µL, 0.2 mmol) and Na-O Bu (58 mg, 0.6 mmol) at room
t

temperature. The mixture turned purple after addition of Na-O Bu, then became brown
upon heat at 70°C for 5 min. Thereafter, the mixture was refluxed for 6 h. Upon
completion, solvent was removed by rotary evaporation. The residue was purified with
column chromatography with EtOAc/hexanes (1:6) to afford the product in 66% yield (37

165

1

mg, 0.13 mmol) as a viscous oil. Spectral data for the product: H NMR (CDCl3, 500
MHz) % 0.90-0.93 (t, 3H, 7.5 Hz), 1.18-1.21 (m, 2H), 1.71 (bs, 2H), 2.11-2.14 (m, 2H),
2.28 (s, 12H), 6.83 (s, 2H), 6.96 (s, 4H);

13

C NMR (125 MHz, CDCl3) % 14.59, 17.46,

21.51, 45.08, 60.67, 124.31, 127.72, 137.23, 148.98; IR (thin film) 3005, 2957, 1599,
1

1450 cm- . mass spectrum, m/z (% rel intensity) 281 M+ (0), 266 (7.89), 223 (100).
6.2.4 Probing the role of benzoic acid additive in the aza-Cope rearrangement
I. Benzoic acid equivalent study
Ar

Ar
N

10 mol% (S)-VANOLBOROX catalyst
n mol% benzoic acid
toluene, 60 °C, 18 h

Ar = 3,5-dimethylphenyl
23f

Ar
N

Ar

24f

Preparation of the catalyst stock solution.
A 50 mL Schlenk flask was flame dried under high vacuum and cooled under a low
flow of Nitrogen. To the flask was added sequentially (S)-VANOL (44 mg, 0.1 mmol),
phenol (19 mg, 0.2 mmol), dry toluene (2.0 mL), BH3•SMe2 (2 M solution in toluene,
150 µL, 0.3 mmol) and water (5.4 µL, 0.3 mmol) under a low flow of Nitrogen. The
threaded Teflon valve on the Schlenk flask was then closed, and the mixture heated at
100 °C for 1 h. The valve was carefully and slowly opened to gradually apply high
vacuum (0.1 mm Hg) and the solvent was removed. The vacuum was maintained for a
period of 30 min at 100 °C. The flask was then removed from the oil bath and allowed to

166

cool to room temperature under a low flow of Nitrogen. This was then completely
dissolved in 2 mL of dry toluene to afford the stock solution of the catalyst.
The Aza-cope rearrangement – Illustrated with 1 equivalent of benzoic acid with respect
to (S)-VANOL-BOROX catalyst.
A 5 mL Schlenk test tube fitted with a threaded Teflon valve and a magnetic stir bar
was flame dried under high vacuum and cooled down under a low flow of Nitrogen. To
the test tube was then added imine 23f (37 mg, 0.10 mmol, 1 equiv), toluene (0.1 mL)
and 0.20 mL of the catalyst stock solution (10 mol% catalyst) via a plastic syringe fitted
with a metallic needle. At the same time, to an oven-dried 5 mL vial was added benzoic
acid (24 mg, 0.2 mmol) and toluene (1 mL). Then 50 µL of the benzoic acid stock
solution (10 mol%) was transferred to the above catalyst-imine complex via a plastic
syringe fitted with a metallic needle. After addition of the rest of the toluene (0.15 mL),
the Schlenk test tube was closed and the reaction was stirred at 60 °C for 18 h. Upon
completion, the reaction mixture was directly loaded to a silica gel column (2 cm x 20
cm) with a pipette. Purification with flash column chromatography (1:30 EtOAc/hexanes)
was complete in 5 min and gave the rearrangement product 24f as a white solid in 81%
yield (30 mg, 0.081 mmol). The optical purity of 24f was determined to be 72% ee by
HPLC analysis (Chiralcel OD-H column, hexanes:2-propanol 99.7:0.3, 222 nm, flow rate
1

0.3 mL min- ).
The above described reaction was then carried out with 0, 0.1, 0.5, 1.5, 2.0, 4.0, and
6.0 equivalent of benzoic acid with respect to (S)-VANOL-BOROX catalyst. The data
was presented in table 1.

167

Table 1. Study of Equivalent of Benzoic Acid
a
b
c
n
Entry
%Yield
%ee
1
0
77
25
2
1
80
40
3
5
85
69
4
10
81
72
5
15
81
72
6
20
83
70
7
40
84
68
8
60
84
66
a.
Catalyst made from 1equiv ligand, 3 equiv BH3.SMe2, 2 equiv phenol and 3equiv

H2O at 100 °C for 1h, followed by full vacuum, 100 °C, 30 min.
HPLC analysis.

b.

Isolated yield.

c.

Chiral

II. Reaction rate study with/without benzoic acid
Ar

Ar
N

10 mol% (S)-VANOLBOROX catalyst
with or without
benzoic acid
m-xylene, 60 °C

Ar = 3,5-dimethylphenyl
23f

Ar
N

Ar

24f

Catalyst stock solution was prepared as described in 6.2.4, except that the catalyst
was dissolved in m-xylene, which was used for the rate study thereafter.
A 5 mL Schlenk test tube fitted with a threaded Teflon valve and a magnetic stir bar
was flame dried under high vacuum and cooled down under a low flow of Nitrogen. To
the test tube was then added imine 23f (37 mg, 0.10 mmol, 1 equiv), m-xylene (0.1 mL)
and 0.20 mL of the catalyst stock solution (10 mol% catalyst) via a plastic syringe fitted
with a metallic needle. At the same time, to an oven-dried 5 mL vial was added benzoic
acid (24 mg, 0.2 mmol) and m-xylene (1 mL). Then 50 µL of the benzoic acid stock
solution (10 mol%) was transferred to the above catalyst-imine complex via a plastic

168

syringe fitted with a metallic needle. After addition of the rest of the m-xylene (0.15 mL),
the Schlenk test tube was closed and the reaction was stirred at 60 °C. After 30
minutes, 50 µL of the reaction mixture was taken and quickly striped of solvent under
full vacuum, and the residue was then dissolved in 0.7 mL of CDCl3 for NMR analysis.
1

H NMR was taken on a VXR-500 MHz instrument. Conversion was calculated to be

35% based on the integrals of the allyl-CH2 of the starting material and methine of the
1

product. Thereafter, sample was prepared and subjected to H NMR analysis after 1 h,
4 h, and 8 h.
The same study was also performed without benzoic acid. The data was listed in
table 2.
Table 2. Effects of benzoic acid on reaction rate
a
Additive
time (h) conver.(%)b
Entry
1
10 mol% benzoic acid
0.5
35
2
10 mol% benzoic acid
1
50
3
10 mol% benzoic acid
4
77
4
10 mol% benzoic acid
8
91
5
10 mol% benzoic acid
20
100
6
none
0.5
25
7
none
1
35
8
none
4
52
9
none
8
65
10
none
20
82
Pre-catalyst was prepared by heating 0.050 mmol VANOL
ligand, 0.15 mmol BH3!SMe2, 0.10 mmol 2, 4, 6-

trimethylphenol, and 0.15 mmol H2O in 2 mL toluene at
100 °C for 1 h followed by removal of volatiles at 100 °C for
0.5 h at 0.1 mm Hg.
III. Aza-Cope rearrangement with tetrabutylammonium benzoate and methyl benzoate

169

Catalyst stock solution was prepared as described in 6.2.4, except that the catalyst
was dissolved in m-xylene, which was used for the aza-Cope rearrangement with
tetrabutylammonium benzoate.

Ar

Ar
N

10 mol% (S)-VANOLBOROX catalyst

Ar

10 mol% tetrabutylamonium
benzoate
m-xylene, 60 °C, 72 h

Ar = 3,5-dimethylphenyl
23f

N

Ar

2N HCl
THF/H2O
then NaOH

NH2

27f

24f

A 5 mL Schlenk test tube fitted with a threaded Teflon valve and a magnetic stir bar
was flame dried under high vacuum and cooled down under a low flow of Nitrogen. To
the test tube was then added imine 23f (37 mg, 0.10 mmol, 1 equiv), m-xylene (0.1 mL)
and 0.20 mL of the catalyst stock solution (10 mol% catalyst) via a plastic syringe fitted
with a metallic needle. At the same time, to an oven-dried 5 mL vial was added
tetrabutylammonium benzoate (73 mg, 0.2 mmol) and m-xylene (1 mL) and the mixture
was heated with a heat gun until tetrabutylammonium benzoate dissolved. Then 50 µL
of the warm tetrabutylammonium benzoate stock solution (10 mol%) was transferred to
the above catalyst-imine complex via a plastic syringe fitted with a metallic needle. After
addition of the rest of the m-xylene (0.15 mL), the Schlenk test tube was closed and the
reaction was stirred at 60 °C. The reaction turned bright yellow after addition of
tetrabutylammonium benzoate; white precipitates then quickly formed in the tube and
the mixture turned off-white. The reaction mixture was stirred for 3 days at 60 °C. Upon
completion, the reaction mixture was directly loaded to a silica gel column (2 cm x 20
cm) with a pipette. Purification with flash column chromatography (1:30 EtOAc/hexanes)

170

was complete in 5 min and gave the rearrangement product 24f as a white solid in 82%
yield (30 mg, 0.082 mmol). The product was then dissolved in 0.4 mL THF followed by
the addition of 0.2 mL of 2N HCl. Hydrolysis was complete in 6 h and THF was then
removed by rotary evaporation. Another 1 mL of H2O was added to the residue and the
aqueous phase was washed with EtOAc (0.2 mL X 3). The aqueous phase was then
treated with 10% NaOH solution until pH reached 12. The mixture was extracted with
DCM (0.5 mL X 3) and the combined organic phase was dried over Na2SO4 and
filtered. The optical purity of 27f was determined to be 72% ee by HPLC analysis
(Chiralcel OD-H column, hexanes:2-propanol:diethylamine 95:5:0.05, 222 nm, flow rate
1

1.0 mL min- ). Retention times were 3.8 min (major enantiomer, (R)-27f) and 4.8 min
(minor enantiomer, (S)-27f).

Ar

Ar
N

10 mol% (S)-VANOLBOROX catalyst

Ar
N

10 mol% methyl benzoate
m-xylene, 60 °C, 72 h

Ar

2N HCl

NH2

THF/H2O
then NaOH
27f

Ar = 3,5-dimethylphenyl

24f

23f

Aza-Cope rearrangement was carried out with methyl benzoate according to the
procedure described for tetrabutylammonium benzoate. However, color change after
addition of methyl benzoate was not observed (Reaction mixture turned bright yellow
after addition of benzoic acid or tetrabutylammonium benzoate). Purification with
column afforded the ketimine product 24f in 72% yield (27 mg, 0.72 mmol). The optical
purity of 27f was determined to be 28% ee by HPLC analysis (Chiralcel OD-H column,

171

1

hexanes:2-propanol:diethylamine 95:5:0.05, 222 nm, flow rate 1.0 mL min- ). Retention
times were 5.4 min (major enantiomer, (S)-27f) and 4.1 min (minor enantiomer, (R)27f).
6.2.6 Experimental

13

C Kinetic Isotope Effects

I. KIEs from Starting Material Analysis
NH2

O

Ar
N

a
oic

Ar

H

Ar

cid

2 N HCl

2:1 THF:water,
nz
be
X 9 Br
RT
ut ol% RO
ho
O
37
wit 5 m L-B
h/
O
e reaction stopped at ~80 %
wit
AN xylen
- oC
)-V
conversion of 36
m 0
(R
6
Ar

36
Ar = 3,5-Me2Ph

27c
Ar

H2N

Br

25c
Ar

Ar

Ar
O

22f

28

compare
13C isotopic

N
C6H4p-Br

Br

content
2 N HCl
2:1 THF:water, RT
quantitative hydrolysis
for NMR standard

Ar
H2N

O

Ar

22f

H
Br

25c

(R)-VANOL-BOROX Catalyst was prepared as described in 6.2.4, except that 2,4,6trimethylphenol was used.
Preparation of standard starting amine 22f. To a 25 mL round bottomed flask was
added imine 36 (0.89 g, 2.0 mmol), THF (8.0 mL) and 2N HCl (4.0 mL). Hydrolysis was
finished overnight and THF was then removed. To the residue was added another 10
mL of H2O and the aqueous phase was washed with ether (4 mL x 4). The aqueous
phase was then treated with NaOH to adjust pH to 13 and extracted with DCM (5 mL x
3). The combined organic phase was dried over Na2SO4, filtered and concentrated by

172

rotary evaporation to give the pure starting amine as a white solid in 75% yield (0.42 g,
1.5 mmol).
Recycle of sample starting amine with benzoic acid. Imine 36 (3.3 g, 7.5 mmol), from
the same batch as the imine used to prepare the standard starting amine, was
subjected to aza-Cope rearrangement according to the general procedure described in
6.2.4 except that 5 mol% catalyst and benzoic acid were used. When the reaction
reached 72% conversion after 6 h, m-xylene was removed under full vacuum at 60°C.
1

The residue was dissolved in 30 mL THF, and 0.1 mL of the mixture was taken for H
NMR analysis to determine the real conversion of the aza-Cope rearrangement after
1

removal of m-xylene. The actual conversion was determined to be 74% by H NMR
analysis. Thereafter, 15 mL of 2N HCl was added, and hydrolysis was finished in 12 h,
followed by the addition of 1N NaOH until the pH reached 13. The reaction mixture was
then extracted with DCM (8 mL x 3), and the organic phase was combined and
concentrated

by

rotary

evaporation.

The

residue

was

purified

by

column

chromatography (EtOAc/hexanes 1:40 then EtOAC/hexanes/triethylamine 1:6:0.07) to
give pure starting amine in 72% yield (0.38 g, 1.4 mmol) as a white solid.
Recycle of sample starting amine without benzoic acid. Imine 36 (3.3 g, 7.5 mmol),
from the same batch as the imine used to prepare the standard starting amine, was
subjected to aza-Cope rearrangement according to the general procedure described
above except that benzoic acid was not added to the reaction mixture. Reaction was
stopped at 70% conversion and 0.41 g of pure starting amine (1.5 mmol) was obtained
as a white solid.

173

NMR Sample preparation for experimental

13

C Kinetic Isotope Effect study. Starting

amine (250 mg, 0.9 mmol) was dissolved in 0.3 mL of CDCl3 in a small vial and the
mixture was transferred to a clean NMR tube. The vial was washed with another 0.2 mL
of CDCl3 and the solution was transferred to the NMR tube as well. Thereafter, the
NMR tube was filled up to exact 5.0 CM by adding CDCl3 slowly with a 0.5 mL syringe.
The sample was shaken carefully to get a homogeneous sample which will be used in
the experimental

13

C Kinetic Isotope Effect study.

II. KIEs from Product Analysis
NH2

O

Ar
N

ac
oic

Ar

H

Ar

id

2 N HCl

z
2:1 THF:water,
9
en
RT
t b l% OX Br
R
ou
ith 5 mo -BO
37
L
h/w
NO lene reaction stopped at ~80 %
wit
VA
xy
)conversion of 36
m- 0 o C
(R
6
Ar

36
Ar = 3,5-Me2Ph

27c
Ar

H2N

Br

25c
Ar

Ar

Ar
O

22f

28

compare
13C isotopic

N
C6H4p-Br

Br

content
2 N HCl
2:1 THF:water, RT
quantitative hydrolysis
for NMR standard

Ar
H2N

O

Ar

22f

H
Br

25c

(R)-VANOL-BOROX Catalyst was prepared as described in 6.2.4, except that 2,4,6trimethylphenol was used.
Synthesis of standard product amine 27c and diaryl ketone 28. Imine 36 (1.34 g,
3.00 mmol) was subjected to aza-Cope rearrangement according to the general
procedure described in 6.2.4. Upon completion, m-xylene was removed under reduced

174

pressure. The residue was dissolved in 8 mL of THF and 4 mL of 2N HCl for hydrolysis.
Hydrolysis was complete in 6 h, and THF was then removed by reduced pressure.
Another 10 mL of H2O was added, the aqueous phase was washed with EtOAc (4 mL x
4). The combined organic phase was dried over Na2SO4, filtered and concentrated to
give a yellow solid which was purified by crystallization with pure hexanes to afford the
pure product diaryl ketone in 59% yield (1

st

crop, 0.42 g, 1.76 mmol). The aqueous

phase was basified with 1N NaOH to pH = 12, and extracted with DCM (4 mL x 4). The
combined organic phase was dried over Na2SO4, filtered and concentrated to give pure
product amine 27c in 72% yield (0.49 g, 2.2 mmol) as a viscous oil.
Synthesis of standard product amine 27c and diaryl ketone 28 with benzoic acid.
Imine 36 (5.3 g, 12 mmol), from the same batch as the imine used to prepare the
standard product amine, was subjected to aza-Cope rearrangement according to the
general procedure described in 6.2.4. m-Xylene was removed under full vacuum at
60°C after the reaction mixture was stirred for 1 h. The residue was dissolved in 32 mL
1

THF, and 0.1 mL of the mixture was taken for H NMR analysis to determine the real
conversion of the aza-Cope rearrangement after removal of m-xylene. The actual
1

conversion was determined to be 17% by H NMR analysis. Thereafter, 16 mL of 2N
HCl was added, and hydrolysis was finished in 12 h, followed by the addition of 1N
NaOH until the pH reached 12. The reaction mixture was then extracted with DCM (8
mL x 3), and the organic phase was combined, dried over Na2SO4, filtered and
concentrated

by

rotary

evaporation.

The

175

residue

was

purified

by

column

chromatography (EtOAc/hexanes 1:20 then 1:3). A mixture of product ketone, parabromobenzaldehyde and a newly formed imine due to the condensation of product
amine 27c and para-bromobenzaldehyde was collected, which was subjected to
hydrolysis with THF (32 mL) and 2N HCl (16 mL). Upon completion, THF was removed
and the aqueous layer was washed with EtOAc (5 mL x 4). The aqueous phase was
basified to pH = 12 with 1N NaOH, and extracted with DCM, dried over Na2SO4, filtered
and concentrated to give the pure product amine 27c as a viscous oil in 76% yield
(0.330 g, 1.55 mmol). The combined EtOAc phase was then dried over Na2SO4, filtered
and concentrated. para-Bromobenzaldehyde was removed under vacuum, and the
residue was purified by crystallization with hexanes to give the product diaryl ketone as
an off-white solid in 71% yield (0.340 g, 1.42 mmol).
Synthesis of standard product amine 27c and diaryl ketone 28 without benzoic acid.
Imine 36 (5.3 g, 12 mmol), from the same batch as the imine used to prepare the
standard product amine and diaryl ketone, was subjected to aza-Cope rearrangement
according to the general procedure described above except that benzoic acid was not
added to the reaction mixture. Reaction was stopped at 20% conversion and 0.3 g of
pure product amine 27c (1.41 mmol) was obtained as a viscous oil. Diaryl ketone was
obtained as an off-white solid in 63% yield (0.36 g, 1.51 mmol).
NMR Sample preparation for experimental

13

C Kinetic Isotope Effect study. Sample

for NMR analysis was prepared following the procedure described in part I of 6.2.6.
6.2.7 NMR study

176

25 mol% (S)-VANOLBOROX catalyst
25 mol% benzoic acid -1-13C

N

toluene-d8 (0.7 mL)

13C NMR, 11B NMR

39
0.2 mmol

(S)-VANOL-BOROX Catalyst (0.25 mmol) was prepared as described in 6.2.4, and
the catalyst was dissolved in 3.0 mL of toluene-d8.
A flame-dried quartz NMR tube was charged with 0.6 mL of the catalyst stock
1

solution (0.05 mmol), and imine 39 (73 mg, 0.02 mmol) was added as a solid. H NMR,
13

C NMR,

11

13

B NMR were taken at room temperature and 60°C. Benzoic acid-!- C
1

was added in toluene-d8 solution (0.05 mmol, 0.1 mL). H NMR,

13

C NMR,

11

B NMR

were taken at room temperature and 60°C.

6.2.8 Kinetic experiment

N

10 mol% (R)-VANOLBOROX catalyst
10 mol% benzoic acid

Ar
N

Ar

toluene-d8 (0.7 mL)
24f

23f

(R)-VANOL-BOROX Catalyst (0.1 mmol) was prepared as described in 6.2.4, and
the catalyst was dissolved in 2 mL of toluene-d8. Imine 3 (0.22 g, 0.6 mmol) was
dissolved in 1.2 mL of toluene-d8; benzoic acid (25 mg, 0.2 mmol) was dissolved in 1

177

mL of toluene-d8; triphenylmethane (73 mg, 0.3 mmol), as an internal standard, was
dissolved in 0.3 mL of toluene-d8.
(R)-VANOL-BOROX Catalyst (0.01 mmol, 0.2 mL of catalyst stock solution) and
benzoic acid (0.01 mmol, 0.05 mL of acid stock solution) and triphenylmethane (0.005
mmol, 0.05 mL of triphenylmethane stock solution) were transferred to a flame-dried
NMR tube, followed by addition of imine 23f (37 mg, 0.2 mL of imine stock solution).
The NMR tube was then filled with toluene-d8 till the total volume reached 0.7 mL. The
reaction was warmed to 60 °C in the NMR probe, and the formation of product was
1

monitored by H NMR analysis.
Plot of Kobs vs. [benzoic acid] (R)-VANOL-BOROX Catalyst (0.01 mmol, 0.2 mL of
catalyst stock solution), triphenylmethane (0.005 mmol, 0.05 mL of triphenylmethane
stock solution) and imine 23f (37 mg, 0.2 mL of imine stock solution) with varying
1

benzoic acid in 0.7 mL of toluene-d8 at 60 °C. Conversions were determined by H NMR
analysis.
Supporting information for chapter 4
6.3.1 General information
All experiments were performed under a nitrogen atmosphere. Flasks were flamedried and cooled under nitrogen before use. All solvents were dried appropriately if used
in the reaction. VANOL ligand is commercially available from Aldrich as well as Strem
Chemicals. If desired, it could be purified using column chromatography on regular silica
gel with 2:1 dichloromethane/hexanes. Phenol was sublimed and stored in a dry
desiccator. Liquid aldehydes were either used as purchased from Aldrich or distilled

178

before use. (R)-methyl 3-hydroxybutanoate was used as purchased from Aldrich with
98% optical purity. (S)-methyl 2-hydroxypropanoate was used as purchased from
Aldrich with 96% optical purity.
6.3.2 Preparation of chiral aldehydes
Typical procedure for preparation of 46a and c-d – Illustrated for synthesis of (R)3-((tert-butyldimethylsilyl)oxy)butanal 46a
OH

O

TBSCl, imidazole TBSO
OCH3

O

DIBAL-H
OCH3

DMF, 0 °C to 25 °C

ether, -78°C

TBSO

O
H

46a

To a flame-dried 100 mL round-bottomed flask, fitted with a magnetic stirrer and a
nitrogen balloon was added (R)-methyl 3-hydroxybutanoate (98% ee, 0.96 g, 8.0 mmol)
and DMF (20 mL). The mixture was cooled down to 0 °C, then TBSCl (1.44 g, 9.60
mmol) and imidazole (0.680 g, 9.60 mmol) were added. Stirring was continued at room
temperature for 24 h. Upon completion, the mixture was charged with brine (60 mL) and
stirred for 5 minutes at room temperature. The resulting solution was then extracted with
hexanes (60 mL x 3). The combined organic layer was dried over Na2SO4, filtered and
concentrated under reduced pressure. Purification of the product by column
chromatography on silica gel (1:25 EtOAc/hexanes) gave the pure ester (R)-methyl 3((tert-butyldimethylsilyl)oxy)butanoate as a clear oil in 89% isolated yield (1.6 g, 7.1
mmol). Rf = 0.4 (1:25 ethyl acetate /hexanes). Spectral data:

1

H NMR (500 MHz,

CDCl3) % 0.013 (s, 3H), 0.035 (s, 3H), 0.84 (s, 9H), 1.16-1.17 (d, 3H, J = 6.0 Hz), 2.35
(dd, 1H, J = 14.5, 5.5 Hz), 2.46 (dd, 1H, J = 14.5, 7.5 Hz), 3.64 (s, 3H), 4.24-4.26 (m,

179

1H);

13

C NMR (125 MHz, CDCl3) % -5.08, -4.54, 17.93, 23.93, 25.70, 44.74, 51.37,

65.84, 172.04. The data matches that reported for this compound.

63

To a flame-dried 250 mL round-bottomed flask, fitted with a magnetic stirrer and a
nitrogen balloon was added (R)-methyl 3-((tert-butyldimethylsilyl)oxy)butanoate (2.0 g,
8.9 mmol) and ether (30 mL). The mixture was cooled to –78 °C and DIBAL-H (5.40 mL,
13.5 mmol) was added dropwise over a period of 4 minutes. The mixture was then
stirred at –78 °C for 2 h. Upon completion, the mixture was quenched with a mixture of
methanol and water (3.0 mL, 1:1 V/V), diluted with ether (40 mL) at –78 °C. The flask
was then allowed to warm up to room temperature. The mixture was stirred with
saturated potassium sodium tartrate solution until it became clear two layers. The
organic layer was separated and the aqueous layer washed with ether (30 mL x 3). The
combined organic layer was dried over Na2SO4, filtered and concentrated under
reduced pressure. Purification of the product by column chromatography on silica gel
(1:15 EtOAc/hexanes) gave the pure aldehyde (R)-46a as a clear oil in 71% isolated
yield (1.2 g, 6.3 mmol). Rf = 0.2 (1:15 ethyl acetate /hexanes). Spectral data for (R)64 1

46a : H NMR (500 MHz, CDCl3) % 0.04 (s, 3H), 0.06 (s, 3H), 0.85 (s, 9H), 1.21 (d,
3H, J = 6.0 Hz), 2.41-2.55 (m, 2H), 4.31-4.35 (m, 1H), 9.78 (t, 1H, J = 2.0 Hz).

13

C NMR

(125 MHz, CDCl3) % -4.95, -4.39, 17.94, 24.17, 25.71, 52.99, 64.55, 202.16. The data
matches that reported for this compound.

64

180

OH

O

TBDPSCl, imidazole TBDPSO
OCH3

O

DIBAL-H
OCH3

DMF, 0 °C to 25 °C

ether, -78°C

TBDPSO

O
H

46c

(R)-3-((tert-butyldiphenylsilyl)oxy)butanal 46c: (R)-methyl 3-hydroxybutanoate (98%
ee, 0.24 g, 2.0 mmol) was reacted according to the general procedure described above
with the exception that TBDPSCl (0.66 g, 2.4 mmol) was added for the preparation of
silyl protected ester. Purification of the product by column chromatography on silica gel
(1:15 ethyl acetate/hexanes) gave the pure ester as a clear oil in 84% isolated yield
65 1

(0.66 g, 1.8 mmol). Rf = 0.40 (1:15 ethyl acetate /hexanes). Spectral data : H NMR
(500 MHz, CDCl3) % 1.02 (s, 9H), 1.11 (d, 3H, J = 6.0 Hz), 2.38 (dd, 1H, J =15, 5.5 Hz),
2.55 (dd, 1H, J =15, 7.0 Hz), 3.58 (s, 3H), 4.28-4.32 (m, 1H), 7.34-7.43 (m, 6H), 7.657.69 (m, 4H);

13

C NMR (125 MHz, CDCl3) % 19.16, 23.60, 26.86, 44.42, 51.34, 66.86,

127.46, 127.53, 129.54, 129.60, 133.88, 134.30, 135.84, 171.76.
The ester (0.66 g, 1.8 mmol) was reduced according to the procedure described for
the preparation of (R)-46a. Purification of (R)-46c by column chromatography on silica
gel (1:12 ethyl acetate/hexanes) gave the pure aldehyde (R)-46c as a clear oil in 84%
isolated yield (0.54 g, 1.5 mmol). Rf = 0.20 (1:12 ethyl acetate /hexanes). Spectral data
65 1

for (R)-46c : H NMR (500 MHz, CDCl3) % 1.03 (s, 9H), 1.19 (d, 3H, J = 6.0 Hz), 2.422.48 (m, 2H), 4.28-4.32 (m, 1H), 7.35-7.43 (m, 6H), 7.62-7.69 (m, 4H), 9.78 (t, 1H, J =
2.0 Hz);

13

C NMR (125 MHz, CDCl3) % 19.14, 23.22, 26.92, 43.74, 66.71, 127.59,

127.68, 127.72, 129.75, 129.84, 133.56, 134.80, 135.80, 202.19.

181

OH

O

TESCl, imidazole
OCH3

TESO

O

DIBAL-H
OCH3

DMF, 0 °C to 25 °C

ether, -78°C

TESO

O
H

46d

(R)-3-((triethylsilyl)oxy)butanal 46d: (R)-methyl 3-hydroxybutanoate (98% ee, 3.50 g,
30.0 mmol) was reacted according to the general procedure described above with the
exception that TESCl (5.4 g, 36 mmol) was added for the preparation of silyl protected
ester. Purification of the product by column chromatography on silica gel (1:15 ethyl
acetate/hexanes) gave the pure ester as a clear oil in 87% isolated yield (6.08 g, 26.1
1

mmol). Rf = 0.40 (1:15 ethyl acetate /hexanes). Spectral data: H NMR (500 MHz,
CDCl3) % 0.57 (t, 6H, J = 8.0 Hz), 0.93 (t, 9H, J = 7.5 Hz), 1.19 (d, 3H, J = 6.5 Hz), 2.342.38 (m, 1H), 2.46-2.51 (m, 1H), 3.64 (s, 3H), 4.25-4.28 (m, 1H);

13

C NMR (125 MHz,

CDCl3) % 4.80, 6.72, 24.00, 44.74, 51.38, 65.06, 172.02.
The ester (6.08 g, 26.1 mmol) was reduced according to the procedure described for
the preparation of (R)-46a. Purification of (R)-46d by column chromatography on silica
gel (1:15 ethyl acetate/hexanes) gave the pure aldehyde (R)-46d as a clear oil in 68%
isolated yield (3.57 g, 17.7 mmol). Rf = 0.20 (1:15 ethyl acetate /hexanes). Spectral data
1

for (R)-46d: H NMR (500 MHz, CDCl3) % 0.58 (t, 6H, J = 7.5 Hz), 0.93 (t, 9H, J = 7.5
Hz), 1.23 (d, 3H, J = 6.0 Hz), 2.43-2.57 (m, 2H), 4.32-4.36 (m, 1H), 9.79 (t, 1H, J = 3.0
Hz);

13

C NMR (125 MHz, CDCl3) % 4.82, 6.76, 24.25, 53.05, 64.29, 202.16; IR (thin
1

film) 2957, 1730, 1458, 1016 cm- ; HRMS (ES+) calcd for C10H22O2Si m/z 203.1463
23

(M+1), meas 203.1467. ["]

D

= –11.3 (c = 1.0, CH2Cl2) on (R)-46d.

182

O

O

TBSCl, imidazole
OCH3

DIBAL-H

OCH3
OTBS

DMF, 0 °C to 25 °C

OH

ether, -78 °C

O
H
OTBS

51

(S)-2-((tert-butyldimethylsilyl)oxy)propanal

51:

(S)-methyl

2-hydroxypropanoate

(96% ee, 0.21 g, 2.0 mmol) was reacted according to the general procedure described
above. Purification of the product by column chromatography on silica gel (1:15 ethyl
acetate/hexanes) gave the pure ester as a clear oil in 75% isolated yield (0.33 g, 1.5
66 1

mmol). Rf = 0.30 (1:15 ethyl acetate /hexanes). Spectral data : H NMR (500 MHz,
CDCl3) % 0.05 (s, 3H), 0.07 (s, 3H), 0.88 (s, 9H), 1.41 (d, 3H, J = 7.0 Hz), 3.70 (s, 3H),
4.31 (dd, 1H, J = 13.0, 7.0 Hz);

13

C NMR (125 MHz, CDCl3) % -5.32, -5.12, 18.30,

21.35, 25.70, 51.85, 68.38, 174.56.
The ester (0.33 g, 1.5 mmol) was reduced according to the procedure described for
the preparation of (R)-46a. Purification of (S)-51 by column chromatography on silica
gel (1:15 ethyl acetate/hexanes) gave the pure aldehyde (S)-51 as a clear oil in 45%
isolated yield (0.13 g, 0.68 mmol). Rf = 0.20 (1:15 ethyl acetate /hexanes). Spectral data
67 1

for (S)-51 : H NMR (500 MHz, CDCl3) % 0.08 (s, 3H), 0.09 (s, 3H), 0.91(s, 9H), 1.25
(d, 3H, J = 6.5 Hz), 4.07 (dd, 1H, J = 6.5, 1.0 Hz), 9.59 (d, 1H, J = 1.0 Hz).
Procedure for preparation of (R)-3-(benzyloxy)butanal 46b
benzyl trichloroacetimidate

OH O
OCH3

triflic acid, 25 °C
cyclohexane:DCM = 2:1

183

OBn O

DIBAL-H
OCH3

ether, -78 °C

OBn O
H

46b

To a stirred solution of (R)-methyl 3-hydroxybutanoate (98% ee, 0.24 g, 2.0 mmol)
and benzyl trichloroacetimidate (1.0 g, 4.0 mmol) in co-solvent (20 mL, Vcyclohexane : VDCM
= 2:1) was added triflic acid (30 uL, 0.30 mmol) at room temperature. Stirring was
continued for 48 h. The reaction was quenched by addition of sat. NaHCO3 (20 mL),
followed by the separation of the organic phase. The aqueous phase was washed with
dichloromethane (5 mL x 3), and the combined organic layer was dried over Na2SO4,
filtered and concentrated under reduced pressure. Purification of the product by column
chromatography on silica gel (1:15 ethyl acetate/hexanes) gave the pure ester as a
clear oil in 60% isolated yield (0.25 g, 1.2 mmol). Rf = 0.20 (1:15 ethyl acetate
68 1

/hexanes). Spectral data : H NMR (500 MHz, CDCl3) % 1.26 (d, 3H, J = 6.0), 2.43 (dd,
1H, J = 15, 6.0 Hz), 2.65 (dd, 1H, J = 15, 7.5 Hz), 3.66 (s, 3H), 3.99-4.03 (m, 1H), 4.50
(d, 1H, J = 11.5 Hz), 4.57 (d, 1H, J = 11.5 Hz), 7.25-7.33 (5H, m);

13

C NMR (125 MHz,

CDCl3) % 19.65, 41.66, 51.32, 70.64, 71.72, 127.34, 127.44, 128.13, 138.38, 171.64.
The resulting ester (0.25 g, 1.2 mmol) was then subjected to the DIBAL-H reduction
as described for the synthesis of (R)-46b. Purification of 46b by column
chromatography on silica gel (1:12 ethyl acetate/hexanes) gave the pure 46b as a clear
oil in 63% isolated yield (0.12 g, 0.76 mmol). Rf = 0.20 (1:12 ethyl acetate /hexanes).
69 1

Spectral data : H NMR (500 MHz, CDCl3) %1.34 (d, 3H, J = 6.0 Hz), 2.53-2.58 (m,
1H), 2.71-2.76 (m, 1H), 4.10-4.12 (m, 1H), 4.51 (d, 1H, J = 11.5 Hz), 4.64 (d, 1H, J =
11.5 Hz), 7.29-7.39 (m, 5H), 9.83 (t, 1H, J = 2.0 Hz).
6.3.3 Optimization of the alcohol protecting group

184

Diastereoselective aza-Cope rearrangement with (R)-3-((tert-butyldimethylsilyl)oxy)
butanal 46a
Ar

Ar

OTBS O

+

H2N

Ar = 3, 5-Me2C6H3
22f

5 mol % (R) or (S)-VANOL
BOROX catalyst,
5 mol % benzoic acid,
H 5Å MS, m-xylene, 60 °C, 48 h

46a

Ar

Ar
OTBS N

Ar

+

OTBS N

47a

48a
Ar

+

Ar

Ar

N

49

Preparation of catalyst stock solution. A 50 mL Schlenk flask was flame dried under
high vacuum and cooled under a low flow of Nitrogen. To the flask was sequentially
added (R)-VANOL (44 mg, 0.10 mmol), phenol (19 mg, 0.20 mmol), dry toluene (2.0
mL), BH3•SMe2 (2 M solution in toluene, 150 µL, 0.300 mmol) and water (5.4 µL, 0.30
mmol) under a low flow of Argon. The threaded Teflon valve on the Schlenck flask was
then closed, and the mixture heated at 100 °C for 1 h. The valve was carefully and
slowly opened to gradually apply high vacuum (0.1 mm Hg) and the solvent was
removed. The vacuum was maintained for a period of 30 min at 100 °C. The flask was
then removed from the oil bath and allowed to cool to room temperature under a low
flow of Nitrogen. The residue was then completely dissolved in 2 mL of dry toluene to
afford the stock solution of the catalyst.
aza-Cope rearrangement with (R)-VANOL catalyst. A 5 mL Schlenk test tube
charged with 5Å powdered molecular sieves (50 mg) and fitted with a magnetic stir bar
was flame dried under high vacuum and cooled down under a low flow of Nitrogen. To
the test tube was then added amine 22f (28 mg, 0.10 mmol, 1.0 equiv), 0.10 mL of the
catalyst stock solution (5 mol% catalyst) and m-xylene (0.35 mL) via a plastic syringe

185

fitted with a metallic needle. The mixture was stirred for 30 min at 60 °C. At the same
time, to an oven-dried 5 mL vial was added benzoic acid (12 mg, 0.10 mmol) and mxylene (1 mL). Then (R)-46a (22 mg, 0.11 mmol) and 50 µL of the benzoic acid stock
solution (5 mol%) were transferred to the above catalyst-amine complex under a high
flow of Nitrogen via a plastic syringe fitted with a metallic needle. The test tube was
closed and the reaction was stirred at 60 °C for 18 h. Purification by flash column
chromatography on silica gel (1:40 EtOAc/hexanes) was complete in 5 min and gave a
mixture of the rearrangement products 47a+48a as a viscous oil in 48% (22 mg, 0.048
mmol) yield. The diastereoselective ratio of the reaction was determined to be 33:1 by
1

H NMR analysis on the crude material and this ratio was unchanged after purification.
1

Rf = 0.20 (1:40 ethyl acetate /hexanes). The H NMR analysis of the crude reaction
mixture of aza-Cope rearrangement with 46a suggests the formation of by-product 49,
which was lost on the column when purification of the products was carried out. The
1

ratio of (47a+48a):49 is 3:1. Spectral data for major diastereomer 47a: H NMR (600
MHz, CDCl3) % –0.01 (s, 3H), 0.01 (s, 3H), 0.80 (s, 9H), 0.86-0.87 (d, 3H, J = 6.0 Hz),
1.62-1.64 (m, 1H), 1.78-1.79 (m, 1H), 2.23-2.33 (m, 2H), 2.26 (s, 6H), 2.30 (s, 6H),
3.34-3.36 (m, 1H), 3.73-3.74 (m, 1H), 4.97-5.02 (m, 2H), 5.70-5.74 (m, 1H), 6.70 (s,
2H), 6.98 (s, 2H), 7.19 (s, 2H);

13

C NMR (150 MHz, CDCl3) % -4.83, -4.43, 18.14, 21.27,

21.32, 23.30, 25.89, 41.09, 46.19, 58.87, 66.09, 116.34, 125.49, 126.25, 129.61,
131.34, 136.23, 137.40, 137.45, 137.60, 140.43, 167.41; IR (thin film) 2957, 1595,

186

1

1474, 1199 cm- ; HRMS (ES+) calcd for C30H46NOSi m/z 464.3349 (M+1), meas
23

464.3340; ["]

D

= +16.1 (c = 1.0, CH2Cl2) on 47a.

aza-Cope rearrangement with (S)-VANOL catalyst. Chiral aldehyde (R)-46a (22 mg,
0.11 mmol) was also subjected to the aza-Cope rearrangement with 5 mol% (S)-VANOL
derived BOROX catalyst according to the procedure described for (R)-VANOL derived
catalyst above. Purification by flash column chromatography on silica gel (1:40
EtOAc/hexanes) was complete in 5 min and gave a mixture of the rearrangement
products 47a+48a as a viscous oil in 44% yield (20 mg, 0.044 mmol). The
diastereoselective ratio of the reaction with (S)-VANOL was determined to be 1:23 by
1

H NMR analysis fo the crude reaction mixture and the ratio is essentially the same
1

after purification (1:20). The H NMR analysis of the crude reaction mixture of azaCope rearrangement with 46a suggests the formation of by-product 49, which was lost
on the column when purification of the products was carried out. The ratio of
1

(47a+48a):49 is 4:1. The H NMR spectra of the major diastereomer matches that of
the minor diastereomer obtained with (R)-VANOL derived BOROX catalyst. Rf = 0.20
1

(1:12 ethyl acetate /hexanes). Spectral data for major diastereomer 47a: H NMR (600
MHz, CDCl3) % -0.11 (s, 3H), -0.04 (s, 3H), 0.79 (s, 9H), 0.96 (d, 3H, J = 6.0 Hz), 1.221.26 (m, 1H), 1.58-1.63 (m, 1H), 1.88-1.91 (m, 1H), 2.26-2.32 (m, 1H), 2.26 (s, 6H),
2.31 (s, 6H), 3.38-3.40 (m, 1H), 3.69-3.70 (m, 1H), 4.96-5.01 (m, 2H), 5.67-5.72 (m,
1H), 6.72 (s, 2H), 6.97 (s, 1H), 6.98 (s, 1H), 7.16 (s, 2H);

187

13

C NMR (150 MHz, CDCl3) %

-4.75, -4.43, 18.06, 21.28, 21.32, 24.14, 25.84, 41.21, 46.54, 59.71, 67.24, 116.21,
125.55, 126.23, 129.61, 131.34, 136.30, 137.40, 137.62, 137.66, 140.57, 167.15; IR
1

(thin film) 2957, 1595, 1474, 1199cm- ; HRMS (ES+) calcd for C30H46NOSi m/z
23

464.3349 (M+1), meas 464.3335; ["]

D

= –29.7 (c = 1.0, CH2Cl2) on 47a.

Diastereoselective aza-Cope rearrangement with chiral aldehydes 46b and 46c
Ar

OPG O

Ar

+

H2N

Ar = 3, 5-Me2C6H3
22f

Ar
OPG N

H

46

5 mol % (R)-VANOL BOROX catalyst,
5 mol % benzoic acid,
5Å MS, m-xylene, 60 °C, 18 h
Ar

Ar

(4S, 6R)-47

+

OPG N

Ar
Ar

+

Ar

(47+48):49

PG
Bn
TBDPS

46b
46c

4:1
1:10

N

49

(4R, 6R)-48

Further optimization of the alcohol protecting group were performed with 8b and 46c
to minimize the formation of by-product 49. Chiral aldehydes 46b and 46c were
subjected to the diasteraoselective aza-Cope rearrangement according to the method
1

described for aldehyde 46a. The H NMR analysis of the aza-Cope rearrangement with
aldehydes 46b-c were carried out on crude reaction mixture. As shown in Table 2, when
the reactions were incomplete, in most cases, the unreacted material is in the form of
amine 22f but in some cases a small amount of imine 50 formed from 46 and 22f is
present.

188

Ar

Ar

OPG N

Ar = 3, 5-Me2C6H3
50
Diastereoselective aza-Cope rearrangement with (S)-3-((triethylsilyl)oxy) butanal 46d
Ar

Ar

OTES O

+

H2N

Ar = 3, 5-Me2C6H3

5 mol % (R) or (S)-VANOL
BOROX catalyst,
5 mol % benzoic acid,
H 5Å MS, m-xylene, 60 °C, 48 h

OTES N

46d

22f

Ar

Ar
Ar

+

OTES N

47d

Ar

48d

aza-Cope rearrangement with (R)-VANOL catalyst. (S)-3-((triethylsilyl)oxy)butanal
46d (22 mg, 0.11 mmol) was subjected to the diastereoselective aza-Cope
rearrangement

according

to

the

procedure

for

46a.

Purification

by

column

chromatography on silica gel (EtOAc/hexanes 1:30) afforded a mixture of the
rearrangement products (4R, 6S)-47d and (4S, 6S)-48d as a viscous oil in 87% yield
(40 mg, 0.087 mmol). The diastereoselective ratio of the reaction was determined to be
1

1:20 (47d:48d) by H NMR analysis of the crude reaction mixture and was essentially
the same after purification (1:22). Rf = 0.20 (1:30 ethyl acetate /hexanes). Spectral data
1

for major diastereomer (4S, 6S)-48d: H NMR (500 MHz, CDCl3) % 0.51-0.55 (q, 6H, J
= 8.0 Hz), 0.89-0.92 (t, 9H, J = 8.0 Hz), 1.08-1.09 (d, 3H, J = 6.0 Hz), 1.67-1.71 (m, 1H),
1.92-1.97 (m, 1H), 2.34-2.42 (m, 2H), 2.32 (s, 6H), 2.36 (s, 6H), 3.45-3.48 (m, 1H),
3.74-3.77 (m, 1H), 5.01-5.07 (m, 2H), 5.73-5.79 (m, 1H), 6.78 (s, 2H), 7.03-7.05 (d, 2H,
J = 8.0 Hz), 7.22 (s, 2H);

13

C NMR (150 MHz, CDCl3) % 4.92, 6.83, 21.28, 21.31, 24.23,

41.20, 46.59, 59.66, 66.90, 116.23, 125.56, 126.23, 129.59, 131.33, 136.26, 137.40,

189

1

137.57, 137.65, 140.61, 167.20; ; IR (thin film) 2957, 1595, 1458, 1199 cm- ; HRMS
23

(ES+) calcd for C30H46NOSi m/z 464.3349 (M+1), meas 464.3362; ["]

D

= +15.8 (c =

1.0, CH2Cl2) on (4S, 6S)-48d.
aza-Cope rearrangement with (S)-VANOL catalyst. Chiral aldehyde (R)-46d (22 mg,
0.11 mmol) was also subjected to the aza-Cope rearrangement with 5 mol% (S)-VANOL
derived BOROX catalyst 9 according to the procedure described for (R)-VANOL derived
catalyst above. Purification by flash column chromatography on silica gel (1:30
EtOAc/hexanes) was complete in 5 min and gave a mixture of the rearrangement
products (4R, 6S)-47d and (4S, 6S)-48d as a viscous oil in 74% yield (34 mg, 0.074
mmol). The diastereoselective ratio of the reaction with (S)-VANOL was determined to
1

be 26:1 (47d:48d) by H NMR analysis of the crude reaction mixture and the ratio was
essentially unchanged after purification (23:1). The

1

H NMR spectra of the major

diastereomer matches that of the minor diastereomer obtained with (R)-VANOL derived
BOROX catalyst 9. Rf = 0.20 (1:30 ethyl acetate /hexanes). Spectral data for major
1

diastereomer (4R, 6S)-47d: H NMR (500 MHz, CDCl3) % 0.58-0.63 (q, 6H, J = 8.0 Hz),
0.89-0.90 (d, 3H, J = 6.0 Hz), 0.96-0.99 (t, 9H, J = 8.0 Hz), 1.65-1.70 (m, 1H), 1.89-1.95
(m, 1H), 2.34-2.42 (m, 2H), 2.30 (s, 6H), 2.36 (s, 6H), 3.37-3.38 (m, 1H), 3.74-3.78 (m,
1H), 5.02-5.07 (m, 2H), 5.74-5.80 (m, 1H), 6.76 (s, 2H), 7.04 (s, 2H), 7.25 (s, 2H);

13

C

NMR (150 MHz, CDCl3) % 4.88, 6.88, 21.26, 21.31, 23.11, 41.47, 46.42, 58.96, 65.85,
116.41, 125.56, 126.26, 129.59, 131.37, 136.08, 137.38, 137.40, 137.59, 140.40,

190

1

167.47; IR (thin film) 2957, 1595, 1458, 1199 cm- ; HRMS (ES+) calcd for C30H46NOSi
23

m/z 464.3349 (M+1), meas 464.3363. ["]

D

= –31.7 (c = 1.0, CH2Cl2) on (4R, 6S)-47d.

6.3.4
Diastereoselective
aza-Cope
butyldimethylsilyl) oxy)propanal 51
Ar

Ar

H2N

5 mol % (S)-VANOL
BOROX catalyst,
5 mol % benzoic acid,
5Å MS, m-xylene, 60 °C, 48 h

O

+

Ar = 3, 5-Me2C6H3
22f

aza-Cope

rearrangement

OTBS

with

Ar
N

(S)-2-((tert-

Ar
Ar

+

N

OTBS

rearrangement

with

OTBS

52

51

Ar

53

(S)-VANOL

catalyst.

(S)-2-((tert-

butyldimethylsilyl)oxy)propanal 51 (21 mg, 0.11 mmol ) was subjected to the
diastereoselective aza-Cope rearrangement according to the procedure for 46a except
(S)-VANOL was used. Purification by column chromatography on silica gel
(EtOAc/hexanes 1:40) afforded a mixture of the rearrangement products 52+53 as a
viscous oil in 71% yield (32 mg, 0.071 mmol). The diastereoselective ratio of the
1

reaction was determined to be 12:1 by H NMR analysis of the crude reaction mixture
and the ratio was unchanged after purification.

The following spectral data were

collected on a 12:1 ratio of isomers. Rf = 0.20 (1:40 ethyl acetate /hexanes). Spectral
1

data for diastereomer 52: H NMR (500 MHz, CDCl3) % -0.15 (s, 3H), 0.02 (s, 3H), 0.84
(s, 9H), 1.23-1.25 (d, 3H, J = 6.5 Hz), 2.31 (s, 6H), 2.35 (s, 6H), 2.42-2.44 (m, 2H), 3.403.42 (m, 1H), 3.77-3.79 (m, 1H), 4.95-5.03 (m, 2H), 5.67-5.72 (m, 1H), 6.80 (s, 2H),
7.02 (s, 2H), 7.24 (s, 2H);

13

C NMR (125 MHz, CDCl3) (C=N missing) % -4.99, -4.72,

17.99, 18.15, 19.02, 21.30, 25.83, 35.10, 67.47, 71.29, 115.66, 125.91, 126.27, 127.73,

191

129.37, 131.24, 133.90, 137.23, 137.39, 137.84, 140.59; IR (thin film) 2958, 1594,
1

1462, 1199 cm- ; HRMS (ES+) calcd for C29H44NOSi m/z 450.3192 (M+1), meas
23

450.3181. ["]

D

= +14.2 (c = 1.0, CH2Cl2) on 52.

aza-Cope rearrangement with (R)-VANOL catalyst. Chiral aldehyde (S)-51 (21 mg,
0.11 mmol) was also subjected to the aza-Cope rearrangement with 5 mol% (S)-VANOL
derived BOROX catalyst according to the procedure described for (S)-VANOL derived
catalyst above. Purification by flash column chromatography (1:40 EtOAc/hexanes) was
complete in 5 min and gave a mixture of the rearrangement products 52+53 as a
viscous oil in 71% yield (32 mg, 0.071 mmol). The diastereoselective ratio of the
1

reaction with (R)-VANOL was determined to be 2.5:1 by H NMR analysis of the crude
reaction mixture and was not changed after purification. Rf = 0.20 (1:30 ethyl acetate
/hexanes). The following spectral data for 53 was extracted from the spectra data of the
2.5:1 mixture with the aid of the 12:1 mixture described above.

Spectral data for

1

diastereomer 53: H NMR (500 MHz, CDCl3) % 0.07 (s, 3H), 0.09 (s, 3H), 0.91 (s, 9H),
1.12-1.13 (d, 3H, J = 6.5 Hz), 2.31 (s, 6H), 2.35 (s, 6H), 2.42-2.44 (m, 2H), 3.29-3.32
(m, 1H), 3.96-3.99 (m, 1H), 4.95-5.03 (m, 2H), 5.67-5.72 (m, 1H), 6.78 (s, 2H), 7.00 (s,
2H), 7.23 (s, 2H).
6.3.5 Optimization of the intramolecular amidocarbonylation with formaldehyde
I. Typical procedure for intramolecular amidocarbonylation with formalin

192

NHCbz

+
racemic
54a

1 mol % [RhCl(cod)]2
2 mol % BIPHEP

O
H

H

N
Cbz

2 mol % Nixantphos
toluene, 90 °C

+ MeO

N
Cbz

55a

56

To a 50 mL Schlenk flask equipped with a T-shaped threaded high vacuum Teflon
valve, containing a stirring bar, was added [RhCl(cod)]2 (2.5 mg, 0.0050 mmol),
BIPHEP (5.5 mg, 0.010 mmol), Nixantphos (6.0 mg, 0.010 mmol) and 3 mL of toluene
under nitrogen. After adding racemic 54a

70

(0.12 g, 0.50 mmol) and 37% formalin (0.19

mL, 2.5 mmol), the mixture was deoxygenated by the freeze-pump-thaw method (–196
°C to 25 °C, 3 cycles). The Schlenk flask was sealed under vacuum with Teflon valve at
–196 °C and then warmed to room temperature. The flask was then heated to 90 °C
and stirring continued for 22 h. Upon completion,

1

H NMR analysis on the crude

reaction mixture showed the formation of the desired product 55a and the by-product 56
with a ratio of 5:3. The formation of 56 was due to the presence of 15% methanol as a
stabilizer in the commercial formalin. The mixture was concentrated and the major
product purified by column chromatography on silica gel (1:12 EtOAc/hexanes) to afford
compound 55a as a viscous oil in 46% yield (60 mg, 0.23 mmol). Rf = 0.20 (1:12 ethyl
acetate /hexanes). A 5:4 mixture of rotamers was observed in

1

H NMR spectrum.

1

Spectral data for 55a: H NMR (600 MHz, CDCl3) % 0.84-0.94 (m, 3H), 1.24-1.40 (m,
3H), 1.49-1.53 (m, 1H), 1.69-1.83 (m, 1H), 1.91-1.96 (m, 1H), 2.02-2.07 (m, 1H), 4.24
(brs, 0.4H), 4.33 (brs, 0.5H), 4.81 (brs, 0.5H), 4.92 (brs, 0.4H), 5.16 (s, 2H), 6.72-6.74
(d, 0.5H, J = 6.5 Hz). 6.82-6.83 (d, 0.4H, J = 6.5 Hz), 7.30-7.37 (m, 5H);

193

13

C NMR (150

MHz, CDCl3) % 13.92, 13.99, 17.37, 17.54, 19.11, 23.90, 24.03, 32.63, 33.05, 50.16,
50.38, 67.25, 105.84, 106.21, 123.52, 123.99, 127.89, 127.99, 128.29, 128.42, 136.35,
1

136.43, 152.92, 153.45. IR (thin film) 3020, 2872, 1705, 1415, 1327 cm- . HRMS (ES+)
calcd for C16H22NO2 m/z 260.1651 (M+1), meas 260.1659. Compound 56 was
1

observed in the H NMR spectrum of the crude reaction mixture but was not isolated,
but the following absorptions have been reported for this compound: d = 3.25 (s, 1.5H),
70

3.32 (s, 1.5H), 4.19 (s, 0.5H), 4.27 (s, 0.5 H).

II. Typical procedure for intramolecular amidocarbonylation with paraformaldehyde

+
racemic
54b

1 mol % [Rh(COD)Cl]2
2 mol % BIPHEP

O

NHBoc
H

H

2 mol % Nixantphos
toluene, 90 °C

N
Boc

n-pr

+

N
Boc

55b

NHBoc

+

n-Pr

58

57

To a 50 mL Schlenk flask, containing a stirring bar, was added [RhCl(cod)]2 (10 mg,
0.020 mmol), BIPHEP (22 mg, 0.040 mmol), Nixantphos (24 mg, 0.040 mmol) and 12
mL of toluene under nitrogen. After adding racemic 54b

71

(0.42 g, 2.0 mmol) and

paraformaldehyde (0.30 g, 10 mmol), the mixture was deoxygenated by the freezepump-thaw method (–196 °C to 25 °C, 3 cycles). The Schlenk flask was sealed under
vacuum with the Teflon valve at –196 °C and then warmed to room temperature. The
flask was then heated to 90 °C and stirring continued for 24 h. Upon completion, the
mixture was concentrated and the products purified by column chromatography on silica
gel (1:40 EtOAc/hexanes). Compound 55b was obtained as a viscous oil in 73% yield

194

(0.33 g, 1.5 mmol). Rf = 0.25 (1:40 ethyl acetate /hexanes). A 5:4 mixture of rotamers
1

1

was observed in H NMR spectrum. Spectral data for 55b: H NMR (500 MHz, CDCl3)
% 0.91 (t, 3H, J = 7.0 Hz), 1.24-1.42 (m, 4H), 1.46 (s, 9H), 1.63-1.78 (m, 2H), 1.88-2.06
(m, 2H), 4.13 (brs, 0.44H), 4.26 (brs, 0.5H), 4.73 (bs, 0.55H), 4.84 (brs, 0.40H), 6.64 (d,
0.5H, J = 7.0 Hz), 6.78 (d, 0.4H, J = 5.0 Hz);

13

C NMR (125 MHz, CDCl3) % 14.06,

19.21, 23.99, 24.27, 28.35, 32.74, 33.22, 49.42, 50.33, 80.21, 104.61, 105.08, 123.96,
1

124.33; IR (thin film) 2961, 1703, 1653, 1410 cm- ; HRMS (ES+) calcd for C13H24NO2
m/z 226.1729 (M+1), meas 226.1723. Compound 57 was isolated as a viscous oil in
1

13% yield (58 mg, 0.26 mmol). Rf = 0.18 (1:40 ethyl acetate /hexanes) and the H NMR
1

spectrum revealed the presence of a 2:3 mixture of rotamers. Spectral data for 57: H
NMR (500 MHz, CDCl3) % 0.91 (t, 3H, J = 7.5 Hz), 0.95-1.78 (m, 4H), 1.45 (s, 9H), 1.65
(s, 3H), 2.08 (brs, 1H), 2.73 (brs, 1H), 4.02 (brs, 0.4H), 4.10 (brs, 0.6H), 6.10 (brs,
0.6H), 6.22 (brs, 0.4H);

13

C NMR (125 MHz, CDCl3) % 14.02, 18.05, 28.49, 36.45,

37.10, 40.45, 41.34, 57.46, 79.45, 117.1, 123.96; IR (thin film) 2965, 1704, 1653, 1418
1

cm- ; HRMS (ES+) calcd for C13H24NO2 m/z 226.1729 (M+1), meas 226.1732.
Compound 58 was isolated as a viscous oil in 12% yield (51 mg, 0.24 mmol). Spectral
1

data for 58: H NMR (500 MHz, CDCl3) % 0.92 (t, 3H, J = 7.0 Hz), 1.32-1.39 (m, 4H),
1.47 (s, 9H), 1.69 (d, 3H, J = 7.0 Hz), 4.03 (brs, 1H), 4.43 (brs, 1H), 5.32-5.36 (m, 1H),
5.56-5.61 (m, 1H);

13

C NMR (125 MHz, CDCl3) % 13.87, 17.60, 18.96, 28.41, 37.88,

195

1

52.12, 78.99, 125.55, 132.11, 155.34; IR (thin film) 3342, 3005, 2964, 1690, 1522 cm- ;
HRMS (ES+) calcd for C12H24NO2 m/z 214.1729 (M+1), meas 214.1725.
6.3.6 Total synthesis of (-)-Coniine
NH2•HCl

NHBoc

(Boc)2O, Et3N

(R)-27o, 95% ee

THF, reflux

(R)-54b

To a 100 mL round-bottomed flask was added amine 27o (0.34 g, 3.0 mmol) and
(Boc)2O (0.75 g, 3.3 mmol). The mixture was dissolved in THF (30 mL), followed by the
addition of triethylamine (0.9 mL, 6 mmol). The mixture was stirred at room temperature
for 24 hours. Upon completion, the mixture was concentrated and the product was
purified by column chromatography on silica gel (1:12 EtOAc/hexanes) to afford (R)-tertbutyl hept-1-en-4-ylcarbamate (R)-54b in 76% yield (0.46 g, 2.3 mmol) as a colorless
1

oil. Rf = 0.20 (1:12 ethyl acetate /hexanes). Spectral data for (R)-54b: H NMR (500
MHz, CDCl3) % 0.88 (t, 3H, J = 8.0 Hz), 1.26-1.40 (m, 13H), 2.11-2.22 (m, 2H), 3.60
(brs, 1H), 4.30 (brs, 1H), 5.01-5.05 (m, 2H), 5.70-5.76 (m, 1H).

13

C NMR (125 MHz,

CDCl3) % 13.92, 19.11, 28.37, 36.84, 39.53, 49.77, 78.84, 117.45, 134.56, 155.54. IR
1

23

(thin film) 3341, 3005, 2961, 1687, 1525 cm- . ["]
material derived from 95% ee (R)-27o.

196

D

= +15.8 (c = 1.0, CDCl3) on

NHBoc

(R)-54b

1 mol % [Rh(COD)Cl]2
2 mol % BIPHEP
N
Boc

2 mol % Nixantphos
paraformaldehyde
toluene, 90 °C

(R)-55b

(R)-tert-butyl hept-1-en-4-ylcarbamate (R)-54b (0.250 g, 1.25 mmol) was reacted
with paraformaldehyde according to the general procedure described in 6.3.5. The
reaction was complete in 40 hours. Upon completion, the reaction mixture was
concentrated and the product was purified by column chromatography on silica gel
(1:40 EtOAc/hexanes) to afford (R)-55b in 71% yield (0.20 g, 0.89 mmol) as a colorless
oil. Rf = 0.20 (1:40 ethyl acetate /hexanes). A 5:4 mixture of rotamers was observed in
1

H and

13

1

C NMR spectrum. Spectral data for (R)-55b: H NMR (500 MHz, CDCl3) %

0.91 (t, 3H, J = 7.0 Hz), 1.24-1.42 (m, 4H), 1.46 (s, 9H), 1.63-1.78 (m, 2H), 1.88-2.06
(m, 2H), 4.13 (brs, 0.44H), 4.26 (brs, 0.5H), 4.73 (brs, 0.55H), 4.84 (brs, 0.40H), 6.64 (d,
0.5H, J = 7.0 Hz), 6.78 (d, 0.4H, J = 5.0 Hz);

13

C NMR (125 MHz, CDCl3) (carbonyl

missing) % 14.06, 17.62, 19.21, 23.99, 24.27, 28.35, 32.74, 33.22, 49.42, 50.33, 80.21,
1

23

104.61, 105.08, 123.96, 124.33. IR (thin film) 2961, 1703, 1653, 1410 cm- . ["]
60.3 (c = 1.0, CDCl3) on material derived from 95% ee (R)-54b.

H2, Pd(OH)2/C
N
Boc

HCl, MeOH

•HCl
N
H

MeOH, rt

(R)-Coniine 35

(R)-55b

197

D

=–

To a 100 mL round bottom flask fitted with a magnetic stir bar was added (R)-55b
(0.2 g, 0.9 mmol), Pd(OH)2 (0.400 g, 0.225 mmol, Pd(OH)2 on carbon powder, 20% Pd,
ca. 60% moisture) and methanol (27 mL). The flask was then equipped with a 3-way
valve connected to vacuum and a hydrogen balloon. The flask was opened to vacuum
for a few seconds, and then switched to the hydrogen balloon; this manipulation was
repeated three times. The reaction mixture was allowed to stir at room temperature for
12 h. It was then filtered through a Celite pad and to the methanol solution was then
added 2 mL of 2N HCl at room temperature. Stirring was continued for 6 hours and the
mixture was concentrated thereafter by rotary evaporation to give (R)-Coniine
hydrochloride salt 35 which was further dried at 40 °C under vacuum until no weight
loss was observed to give a white solid in 91 % yield (0.13 g, 0. 82 mmol, mp 213-215
°C, lit.

23

23 1

215-216 °C). Spectral data for 35 : H NMR (DMSO, 500 MHz) % 0.86 (t, 3H,

J = 7.0 Hz), 1.29-1.49 (m, 5H), 1.59-1.82 (m, 5H), 2.81 (dd, 1H, J = 22.5, 11.0 Hz), 2.95
(brs, 1H), 3.15 (d, 1H, J = 12.5 Hz), 8.46 (d, 2H, J =9.3 Hz);

13

C NMR (125 MHz,

23

DMSO) % 13.74, 17.78, 21.71, 21.81, 27.76, 34.94, 43.68, 55.39. ["]

D

= – 6.3 (c = 1.0,

EtOH) on material derived from 95% ee (R)-55b. These data match that previously
reported

23

for this compound.

6.3.7 Total synthesis of (+)-Sedridine

TESO

Ar

O
H

(S)-46d

+

Ar

H2N

Ar = 3, 5-Me2C6H3
22f

1) 5 mol % (R)-VANOL
BOROX catalyst,
5 mol % benzoic acid,
MS, m-xylene, 60 °C
2) 2 N HCl /THF
3) (Boc)2O, NaHCO3, EtOH

198

HO

NHBoc

59

(S)-3-((Triethylsilyl)oxy)butanal 46d (0.70 g, 2.5 mmol) was subjected to the azaCope rearrangement according to the general procedure described in section III except
that 0.7 g of 5Å MS was used. Upon completion, m-xylene was removed by rotary
evaporation and the reaction mixture was dissolved in THF (10 mL) and 2N HCl (5.0
mL) was added for hydrolysis. Hydrolysis was finished in 12 h and THF was then
removed by rotary evaporation. To the residue was added another 4 mL of H2O and the
aqueous phase was washed with EtOAc (3 mL x 3). The aqueous phase was
concentrated to give an off-white solid which was dissolved in EtOH (20 mL). NaHCO3
and (Boc)2O were added at 0 °C. The reaction mixture was stirred at 0 °C for 30
minutes and then the ice-bath was removed. Stirring was maintained for 24 h at room
temperature. Upon completion, EtOH was removed and the residue was dissolved in 20
mL of H2O. The aqueous phase was extracted with EtOAc (10 mL x 3). The organic
phases were combined and dried over Na2SO4, filtered and concentrated. The product
was purified by column chromatography on silica gel (1:4 EtOAc/hexanes) to give tertbutyl ((4S,6S)-6-hydroxyhept-1-en-4-yl)carbamate 59 as a light yellow viscous oil and
as a single diastereomer in 72% yield (0.41 g, 1.8 mmol) over three steps. Rf = 0.20
1

(1:4 ethyl acetate /hexanes). Spectral data for 59: H NMR (500 MHz, CDCl3) % 1.15 (t,
3H, J = 6.0 Hz), 1.29-1.53 (m, 11 H), 2.16-2.23 (m, 2H), 3.76 (brs, 1H), 3.86 (brs, 1H),
4.50 (brs, 1H), 5.05-5.10 (m, 2H), 5.70-5.77 (m, 1H).

13

C NMR (125 MHz, CDCl3) %

22.70, 28.31, 39.71, 45.58, 46.88, 63.58, 79.85, 118.06, 134.08, 157.08. IR (thin film)

199

1

3339, 3078, 2976, 1684, 1531 cm- . HRMS (ES+) calcd for C12H24NO3 m/z 230.1756
23

(M+1), meas 230.1752. ["]

HO

D

= +22.9 (c = 1.0, CH2Cl2) on 59.

NHBoc

imidazole, DMF
0 °C to rt

59

NHBoc

TBSO

TBSCl

60

tert-Butyl ((4S,6S)-6-hydroxyhept-1-en-4-yl)carbamate 59 (0.62 g, 2.7 mmol) and
TBSCl (0.48 g, 3.2 mmol) were dissolved in 7 mL of dry DMF. Imidazole (0.23 g, 3.2
mmol) was added at 0 °C. The ice-bath was then removed and the reaction mixture was
stirred at room temperature for 18 h. Upon completion, 40 mL of brine was added to
quench the reaction. Stirring was maintained for 5 minutes and the aqueous phase was
extracted with hexanes (8 mL x 3). The combined organic phase was dried over
Na2SO4,

filtered

and

concentrated.

The

product

was

purified

by

column

chromatography on silica gel (1:8 EtOAc/hexanes) to give tert-butyl ((4S, 6S)-6-((tertbutyldimethylsilyl)oxy)hept-1-en-4-yl)carbamate 60 in 86% yield (0.80 g, 2.3 mmol) as a
white solid (mp 63-64 °C). Rf = 0.50 (1:8 ethyl acetate /hexanes). A 5:4 mixture of
1

1

rotamers was observed in H NMR spectra. Spectral data for 60: H NMR (500 MHz,
CDCl3) % 0.05 (t, 6H, J = 4.5 Hz), 0.87 (s, 9H), 1.12 (d, 3H, J = 6.0 Hz), 1.40 (s, 9H),
1.57-1.61 (m, 1H), 2.19-2.23 (m, 1H), 2.30 (brs, 2H), 3.71, (brs, 1H), 3.98 (brs, 1H),
4.97 (brs, 1H), 5.01-5.05 (m, 2H), 5.72-5.77 (m, 1H).

13

C NMR (125 MHz, CDCl3) % -

4.91, -4.17, 17.93, 23.94, 25.90, 28.41, 39.64, 42.67, 47.80, 66.10, 78.63, 117.22,
1

134.90, 155.38. IR (thin film) 3316, 2926, 1691, 1531, 1365 cm- . HRMS (ES+) calcd for

200

23

C18H38NO3Si m/z 344.2621 (M+1), meas 344.2625. ["]

D

= +49.4 (c = 1.0, CH2Cl2)

on 60.

NHBoc

TBSO

60

1 mol% [Rh(COD)Cl]2
2 mol% BIPHEP
2 mol% Nixantphos
paraformaldehyde
toluene, 90 °C

OTBS
N
Boc

61

tert-Butyl ((4S,6S)-6-((tert-butyldimethylsilyl)oxy)hept-1-en-4-yl)carbamate 60 (0.51
g, 1.5 mmol) was subjected to the intramolecular amidocarbonylation with
paraformaldehyde according to the typical procedure in 6.3.5. Purification by column
chromatography on silica gel (1:30 EtOAc/hexanes) afforded (S)-tert-butyl 2-((S)-2((tert-butyldimethylsilyl)oxy)propyl)-3,4-dihydropyridine-1(2H)-carboxylate 61 in 78%
yield (0.410 g, 1.17 mmol) as a colorless oil. Rf = 0.30 (1:30 ethyl acetate /hexanes). A
1

1

5:4 mixture of rotamers was observed in the H NMR spectrum. Spectral data for 61: H
NMR (500 MHz, CDCl3) % 0.05 (t, 6H, J = 4.5 Hz), 0.87 (s, 9H), 1.14 (d, 3H, J = 4.0 Hz),
1.45-1.52 (m, 10H), 1.64-1.68 (m, 2H), 1.77-1.83 (m, 1H), 1.90-1.94 (m, 1H), 2.02-2.09
(m, 1H), 3.87 (t, 1H, J = 6.0 Hz), 4.07 (brs, 0.4H, rotamer), 4.28 (brs, 0.5H), 4.73 (brs,
0.5H), 4.84 (brs, 0.4H, rotamer), 6.62 (d, 0.5H, J = 8.0 Hz), 6.76 (d, 0.4H, J = 8.0 Hz,
rotamer);

13

C NMR (125 MHz, CDCl3) % -4.71, -4.66, -4.48, 17.33, 17.66, 18.04, 23.44,

23.77, 23.87, 24.39, 25.84, 25.87, 28.30, 28.44, 40.73, 40.95, 47.70, 48.85, 66.63,
80.24, 80.38, 104.47, 104.71, 123.97, 124.35, 151.80, 152.26 . IR (thin film) 2927,

201

1

1699, 1367, 1169 cm- . HRMS (ES+) calcd for C19H38NO3Si m/z 356.2621 (M+1),
23

meas 356.2606. ["]

D

= – 7.5 (c = 1.0, CH2Cl2) on 61.

OTBS

Pd(OH)2/C
N
Boc

HCl, MeOH

N
H

rt

MeOH, rt

OH

61

(+)-Sedridine, 62

To a 100 mL round bottom flask fitted with a magnetic stir bar was added (S)-tertbutyl 2-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-3,4-dihydropyridine-1(2H)-carboxylate
61 (0.39 g, 1.1 mmol), Pd(OH)2 (0.49 g, 0.27 mmol, Pd(OH)2 on carbon powder, 20%
Pd, ca. 60% moisture) and methanol (32 mL). The flask was then equipped with a 3way valve connected to vacuum and a hydrogen balloon. The flask was opened to
vacuum for a few seconds, and then switched to the hydrogen balloon; this
manipulation was repeated three times. The reaction mixture was allowed to stir at room
temperature for 12 h. It was then filtered through a Celite pad and to the methanol
solution was then added 2 mL of 2N HCl at room temperature. Stirring was continued
for 6 hours and the mixture was concentrated thereafter by rotary evaporation to give
(+)-Sedridine hydrochloride salt as a white solid which was dissolved in 10 mL of 1N
NaOH and extracted with EtOAc (3 mL x 3). The combined organic phase was dried
over Na2SO4, filtered and concentrated to give (+)-Sedridine in 83% yield (0.13 g, 0.91
72

72

mmol) as a white solid (mp 82-83 °C, lit. 83-84 °C ). Spectral data for (+)-Sedridine :
1

H NMR (500 MHz, CDCl3) % 1.13 (d, 3H, J = 6.0 Hz), 1.31-1.35 (m, 3H), 1.7-1.43 (m,

1H), 1.50-1.55 (m, 3H), 1.76-1.77 (m, 1H), 2.58 (td, 1H, J =12.0, 3.0 Hz), 2.81-2.83 (m,

202

1H), 3.01 (dd, 1H, J = 11.5, 2.5 Hz), 3.05-3.35 (brs, 1H), 4.04-4.08 (m, 1H);

13

C NMR
23

(125 MHz, CDCl3) % 23.57, 24.73, 26.10, 31.38, 43.81, 46.90, 54.74, 65.04; ["]
+20.8 (c = 1.0, EtOH), Lit.

73

25

["]

D

D

=

= +28.36, (c = 1.13, EtOH). These spectral data

match that reported for this compound.

73

6.3.8 Total synthesis of (+)-Allosedridine

TESO

Ar

O
H

(S)-46d

+

1) 5 mol % (S)-VANOL
BOROX catalyst,
5 mol % benzoic acid,
MS, m-xylene, 60 °C

Ar

H2N

Ar = 3, 5-Me2C6H3
22f

HO

2) 2 N HCl /THF
3) (Boc)2O, NaHCO3, EtOH

NHBoc

63

(+)-Allosedridine was obtained in a similar manner to that described for (+)-sedridine
utilizing

the

boroxinate

catalyst

9

derived

from

(S)-VANOL.

(S)-3-

((Triethylsilyl)oxy)butanal (0.56 g, 2.0 mmol) was subjected to the aza-Cope
rearrangement according to the general procedure described for the synthesis of
compound 59 except that (S)-VANOL BOROX catalyst was used. Purification by column
chromatography on silica gel (1:2 EtOAc/hexanes) afforded tert-butyl ((4R,6S)-6hydroxyhept-1-en-4-yl)carbamate 63 in 60% yield (0.28 g, 1.2 mmol) and as a single
diastereomer as a light yellow viscous oil. Rf = 0.20 (1:2 ethyl acetate /hexanes).
1

Spectral data for 63: H NMR (500 MHz, CDCl3) % 1.24 (d, 3H, J = 6.0 Hz), 1.45 (s, 9H),
1.53-1.65 (m, 2H), 2.24-2.31 (m, 2H), 2.48 (brs, 1H), 3.76 (brs, 1H), 3.94 (t, 1H, J =5.0
Hz), 4.61 (brs, 1H), 5.09-5.13 (m, 2H), 5.74-5.83 (m, 1H);

13

C NMR (125 MHz, CDCl3)

% 23.81, 28.38, 40.21, 44.31, 48.69, 66.48, 79.50, 118.10, 134.11, 156.2. IR (thin film)

203

1

3339, 2978, 1686, 1527 cm- . HRMS (ES+) calcd for C12H24NO3 m/z 230.1756 (M+1),
23

meas 230.1765. ["]

D

= – 7.4 (c = 0.5, CH2Cl2) on 63.

HO

NHBoc

63

TBSCl

NHBoc

TBSO

imidazole, DMF
0 °C to rt

64

tert-Butyl ((4R,6S)-6-hydroxyhept-1-en-4-yl)carbamate 63 (0.25 g, 1.1 mmol) was
reacted with TBSCl as described for the synthesis of compound 60. Purification of the
product by column chromatography on silica gel (1:8 EtOAc/hexanes) afforded tert-butyl
((4R,6S)-6-((tert-butyldimethylsilyl)oxy)hept-1-en-4-yl)carbamate 64 in 74% yield (0.28
g, 0.82 mmol) as a clear viscous oil. Rf = 0.40 (1:8 ethyl acetate /hexanes). Spectral
1

data for 64: H NMR (500 MHz, CDCl3) % -0.02 (s, 6H), 0.81 (s, 9H), 1.10 (d, 3H, J =
6.0 Hz), 1.35 (s, 9H), 1.48 (brs, 2H), 2.18 (brs, 2H), 3.56-3.58 (m, 1H), 3.82 (q, 1H, J =
6.0 Hz), 4.55 (brs, 1H), 4.99 (d, 2H, J = 12.5 Hz), 5.66-5.71 (m, 1H);

13

C NMR (125

MHz, CDCl3) % -4.82, -4.38, 17.93, 23.81, 25.83, 28.31, 39.79, 44.37, 48.27, 66.82,
1

78.67, 117.51, 134.38, 155.29. IR (thin film) 2959, 1705, 1498, 1174 cm- . HRMS (ES+)
23

calcd for C18H38NO3Si m/z 344.2621 (M+1), meas 344.2631. ["]

D

= – 10.2 (c = 1.0,

CH2Cl2) on 64.

TBSO

NHBoc

64

1 mol % [Rh(COD)Cl]2
2 mol % BIPHEP
2 mol % Nixantphos
paraformaldehyde
toluene, 90 °C

204

OTBS

65

N
Boc

tert-Butyl ((4R,6S)-6-((tert-butyldimethylsilyl)oxy)hept-1-en-4-yl)carbamate 64 (0.26
g,

0.75

mmol)

was

subjected

to

intramolecular

amidocarbonylation

paraformaldehyde according to the typical procedure in 6.3.5.

with

Purification of the

product by column chromatography on silica gel (1:30 EtOAc/hexanes) afforded (R)tert-butyl

2-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-3,4-dihydropyridine-1(2H)-

carboxylate 65 in 72% yield (0.19 g, 0.54 mmol) as a clear viscous oil. Rf = 0.30 (1:30
ethyl acetate /hexanes). A 1:1 mixture of rotamers was observed in the

1

H NMR

1

spectrum. Spectral data for 65: H NMR (500 MHz, CDCl3) % 0.007 (s, 6H), 0.85 (s,
9H), 1.18-1.23 (m, 3H), 1.36-1.42 (m, 1H), 1.46 (s, 9H), 1.65-2.35 (m, 5H), 3.86 (d, 1H,
J = 5.5 Hz), 4.23 (brs, 0.6H), 4.33 (brs, 0.4H), 4.77 (brs, 0.5H), 4.85 (brs, 0.5H), 6.62 (d,
0.4H, J = 7.0 Hz), 6.77 (d, 0.5H, J = 7.0 Hz);

13

C NMR (125 MHz, CDCl3) % -4.85, -4.55,

-4.29, 17.61, 17.84, 18.10, 23.49, 24.07, 24.19, 25.34, 25.88, 28.38, 28.51, 29.68,
40.30, 41.14, 46.69, 47.84, 65.50, 66.26, 80.23, 80.36, 104.87, 105.15, 124.08, 152.11,
1

152.46. IR (thin film) 2957, 1705, 1653, 1410 cm- . HRMS (ES+) calcd for
23

C19H38NO3Si m/z 356.2621 (M+1), meas 356.2629 ["]

D

= +25.1 (c = 0.5, CH2Cl2)

on 65.
OTBS

65

Pd(OH)2/C
N
Boc

HCl, MeOH
rt

MeOH, rt

OH
N
H

(+)-Allosedridine, 66

(R)-tert-Butyl-2-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-3,4-dihydropyridine-1(2H)carboxylate 65 (0.17 g, 0.50 mmol) was subjected to the reduction conditions followed

205

by hydrolysis to remove the protecting groups as described for the synthesis of (+)Sedridine. The product was obtained in 74% yield (52 mg, 0.37 mmol) as white crystals
73

1

(mp 65-66 °C, lit. 62 °C ). Spectral data for (+)-Allosedridine: H NMR (500 MHz,
CDCl3) % 1.01-1.06 (m, 1H), 1.08 (d, 3H, J = 6.0 Hz), 1.11-1.26 (m, 2H), 1.41-1.49 (m,
2H), 1.53-1.59 (m, 2H), 1.74-1.78 (m, 1H), 2.50-2.56 (m, 1H), 2.63-2.68 (m, 1H), 2.98
(dd, 1H, J = 10, 4.5 Hz), 3.93-3.95 (m, 1H);

13

C NMR (125 MHz, CDCl3) % 23.80, 24.48,

23

27.36, 34.37, 44.40, 45.99, 58.14, 69.03. ["]

D

= +15.0 (c = 1.0, MeOH), Lit.

73

25

["]

D

=

+17.10, (c = 1.55, MeOH).
6.4 Supporting information for chapter 5
6.4.1 General information
All experiments were performed under an argon atmosphere. Flasks were flamedried and cooled under argon before use. All solvents such as benzene,
dichloromethane, ether, triethylamine, toluene, THF, DMF and CH3CN were dried if
used in the reaction. ACS-grade hexanes and ethyl acetate were used as purchased.
Triphenylborate and trimethylsilyldiazomethane were used as purchased from Aldrich.
Cyclohexanebutyric

acid,

hex-5-ynoic

acid,

5-ethoxy-5-oxopentanoic

acid,

4-

bromobutanoic acid, and levulinic acid were used as purchased. VAPOL and VANOL
were purified by column chromatography with 9:1 hexanes/ethyl acetate.
Melting points were measured on a Thomas Hoover capillary melting point
apparatus. 1H NMR and 13C NMR were recorded on a Varian 300 MHz or VXR-500
MHz instrument in CDCl3 unless otherwise noted. CHCl3 was used as the internal
standard for both 1H NMR (! = 7.24) and 13C NMR (! = 77.0). Column chromatography

206

was performed with silica gel 60 (230–450 mesh). Analytical thin-layer chromatography
(TLC) was performed on 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
phosphomolybdic acid in ethanol.
HPLC analyses were carried out using a Varian Prostar 210 Solvent Delivery
Module with a Prostar 330 PDA Detector and a Prostar Workstation.
6.4.2 General procedure for the preparation of diazoketones with the azide
transfer method
OH
O

OLi

MeLi
DME, - 45 °C

O

MeLi
Et2O

OLi
OLi

71a
aq. HCl
O

72a

Procedure for the synthesis of 5-cyclohexylpentan-2-one 72a: The following
74

procedure is adapted from one for related methyl ketones.

To a flame-dried 100 mL

round-bottomed flask, fitted with a magnetic stirrer and an argon balloon was added
DME (7.5 mL) and MeLi (7.5 mL, 12 mmol) at – 45°C. A solution of cyclohexanebutyric
acid 71a (1.7 g, 10 mmol) in DME (7.5 mL) was added dropwise. The mixture was
allowed to stir for 2 h, followed by the addition of MeLi (7.5 mL, 12 mmol) at 0°C. Stirring
was continued at room temperature for 3 hours. Then the mixture was siphoned into a
vigorously stirred flask charged with conc HCl (1.8 mL) and H2O (30 mL). The mixture
was stirred for about 30 min, and then NaCl was added to saturate the solution,

207

followed by the separation of the organic and aqueous phases. The aqueous phase was
washed with Et2O, dried over MgSO4, filtered and concentrated under reduced
pressure. Purification of the product by column chromatography on silica gel (1:25 ether
/pentane) gave the pure methyl ketone 72a as a clear oil in 49% isolated yield (0.82 g,
1

4.9 mmol). Spectral data for 72a: Rf = 0.25 (1:25 ether /pentane). H NMR (500 MHz,
CDCl3) % 0.70–0.88 (m, 2H), 1.02–1.22 (m, 6H), 1.43–1.62 (m, 7H), 2.03 (s, 3H), 2.36–
2.40 (t, 2H, J = 7.0 Hz);

13

C NMR (125 MHz, CDCl3) % 21.83, 27.12, 26.94, 31.22,

32.28, 36.63, 38.45, 40.55, 208.12.
CF3

HMDS/n-BuLi
O

O

THF, CF3CO2CH2CF3

O

72a
SO2N3

C12H25
73

N2
O

H2O, Et3N, CH3CN, rt

30%

74a

Procedure for the synthesis of 5-cyclohexyl-1-diazopentan-2-one 74a: The following
75

procedure is adapted from one for related diazoketone.

To a 250 mL round bottomed

flask was added dry tetrahydrofuran (25 mL) and 1,1,1,3,3,3-hexamethyldisilazane
(16.5 mmol, 3.89 mL). The mixture was then cooled to 0 °C while n-butyllithium (16.5
mmol, 7.01 mL) in hexane was added dropwise. After stirring for 10 min, the resulting
solution was cooled to –78°C, and a solution of methyl ketone (2.52 g, 15.0 mmol) in dry
tetrahydrofuran (25 mL) was added slowly over 10 min. Stirring was continued for 30
min at –78°C, and then 2,2,2-trifluoroethyl trifluoroacetate (16.5 mmol, 2.48 mL) was

208

added rapidly via syringe (over 5 sec). After 10 min, the reaction mixture was poured
into a separatory funnel containing 5% aqueous hydrochloric acid (50 mL) and diethyl
ether (25 mL). The aqueous layer was separated and extracted with diethyl ether. The
combined organic layers were washed with saturated sodium chloride solution, dried
over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure
using a rotary evaporator. The crude product was immediately dissolved in acetonitrile
(23 mL). Water (0.25 mL), triethylamine (22.5mmol, 3.20 mL), and a solution of 476

dodecylbenzenesulfonyl azide

(7.88 g, 22.5 mmol) in acetonitrile (23 mL) were then

added to the solution. The mixture was allowed to stir at room temperature for 12 h and
then was poured into a separatory funnel containing diethyl ether (23 mL) and aqueous
5% sodium hydroxide. The organic phase was separated, washed successively with 5%
aq NaOH, water and saturated sodium chloride, dried over anhydrous sodium sulfate,
filtered, and concentrated at reduced pressure. Purification of the product by column
chromatography on silica gel (1:4 ethyl acetate/hexane) gave 5-cyclohexyl-1diazopentan-2-one 74a. Pure product is only obtained if the column chromatography is
repeated at least two times which then gives 74a as a yellow oil in 30% isolated yield
77

1

(0.87 g, 4.5 mmol). Spectral data for 74a : Rf = 0.25 (1:4 ethyl acetate /hexanes). H
NMR (500 MHz, CDCl3) % 0.75–0.83 (m, 2H), 1.01–1.20 (m, 6H), 1.50–1.63 (m, 7H),
2.21 (bs, 2H), 5.21 (bs, 1H);

13

C NMR (125 MHz, CDCl3) % 22.82, 26.52, 26.84, 33.42,

37.13, 37.65, 41.55, 54.32, 195.53.
6.4.3 General procedure for the synthesis of diazo ketone 8a-k with
trimethylsilyldiazomethane (TMSCHN2) as a stable and safe substitute for

209

diazomethane – Illustrated for the synthesis of 5-cyclohexyl-1-diazopentan-2-one
74d.
(COCl)2

O

3

OH

DCM, rt

TMSCHN2

O

3

Cl

CH3CN, 0 °C
24 h

71d

O
N2

3

74d

The following procedure is one that is modified from that reported by Shroiri in that it
uses only 1.1 equiv of TMSCHN2 and workup with sat aq NaHCO3 is not
employed.

78,79

A 250 mL flame-dried round-bottomed flask with stir bar was charged

with hex-5-ynoic acid 71d (1.7 g, 15 mmol) and CH2Cl2 (15 mL). Oxalyl chloride
(COCl)2 (2.85 g, 22.5 mmol) was then added slowly at room temperature. Stirring was
continued for 1 h, and then the reaction mixture was concentrated by rotary evaporation
to give a brown liquid which can be used for the next step without further purification.
The residual from the above step was dissolved in CH3CN (75 mL), followed by the
addition of TMSCHN2 (16.5 mmol, 8.3 mL) at 0°C. The reaction mixture was allowed to
stir for 24 h. Volatiles were then removed by rotary evaporation. Purification of the
product by column chromatography on silica gel (1:6 ethyl acetate/hexane) gave the
pure 1-diazohept-6-yn-2-one 74d as a yellow oil in 66% isolated yield (1.35 g, 9.9
mmol). When the reaction was run at room temperature according to the general
procedure described above, a 60% yield of compound 74d was obtained. Spectral data
80

1

for 74d : Rf = 0.2 (1:6 ethyl acetate /hexanes). H NMR (500 MHz, CDCl3) % 1.57–

210

1.61 (m, 2H), 1.82–1.83 (m, 1H), 2.00-2.03 (m, 2H), 2.23 (bs, 2H), 5.24 (bs, 1H);

13

C

NMR (125 MHz, CDCl3) % 17.24, 32.10, 38.67, 53.94, 68.87, 82.82, 193.76.

(COCl)2

O
OH

3

TMSCHN2

O

DCM, rt

Cl

3

O
N2

CH3CN, 0 °C
24 h

3

71a

74a

5-cyclohexyl-1-diazopentan-2-one 74a: cyclohexanebutyric acid 71a (0.34g, 2.0
mmol) was reacted according to the general procedure described above except that the
reaction mixture from the second step was quenched with sat. NaHCO3, extracted with
ether and dried over NaSO4. Purification of 74a by column chromatography on silica gel
(1:4 ethyl acetate/hexane) gave the pure 5-cyclohexyl-1-diazopentan-2-one 74a as a
yellow oil in 73% isolated yield (0.28 g, 1.5 mmol).

The same reaction at room

temperature gave 74a in 59% yield and the same reaction at 25 °C with 2.0 equiv of
TMSCHN2 gave 62% yield.

O
EtO

(COCl)2

O

3

OH

DCM, rt

O
EtO

TMSCHN2

O

3

71b

Cl

CH3CN, 0 °C EtO
24 h

O

O
N2

3

74b

ethyl 6-diazo-5-oxohexanoate 74b: 5-ethoxy-5-oxopentanoic acid 71b (0.32g, 2.0
mmol) was reacted according to the general procedure described above except that the
reaction mixture from the second step was quenched with sat. NaHCO3, extracted with
ether and dried over NaSO4. Purification of 74b by column chromatography on silica gel

211

(1:3 ethyl acetate/hexane) gave the pure ethyl 6-diazo-5-oxohexanoate 74b as a yellow
oil in 70% isolated yield (0.26 g, 1.4 mmol). When the reaction was run at room
temperature according to the same procedure, a 91% yield of compound 74b was
81

1

obtained. Spectral data for 74b : Rf = 0.2 (1:3 ethyl acetate /hexanes). H NMR (500
MHz, CDCl3) % 1.14–1.17 (t, 3H, J = 7.0 Hz), 1.82–1.88 (m, 2H), 2.25-2.29 (m, 4H),
4.00-4.05 (q, 2H, J = 7.0 Hz), 5.23 (bs, 1H);

13

C NMR (125 MHz, CDCl3) % 14.00,

20.03, 33.08, 39.47, 54.27, 60.16, 172.77, 193.88.

(COCl)2

O

3

OH

DCM, rt

TMSCHN2

O

3

Cl

O
N2

CH3CN, 0 °C
24 h

3

71c

74c

1-diazohept-6-en-2-one 74c: Hex-5-enoic acid

82

71c (1.6 g, 14 mmol) was reacted

according to the general procedure described above. Purification of 74c by column
chromatography on silica gel (1:6 ethyl acetate/hexanes) gave the pure diazoketone as
a clear yellow liquid in 69% isolated yield (1.28 g, 9.00 mmol). When the reaction was
run at room temperature according to the general procedure described above, a 65%
yield of compound 74c was obtained. Spectral data for 74c

83

: Rf = 0.2 (1:6 ethyl

1

acetate /hexanes). H NMR (500 MHz, CDCl3) % 1.56–1.62 (m, 2H), 1.93–1.97 (m, 2H),
2.19 (bs, 2H), 4.83-4.91 (m, 2H), 5.21 (bs, 1H), 5.96-5.68 (m, 1H);

13

C NMR (125 MHz,

CDCl3) % 23.88, 32.72, 39.78, 53.75, 114.53, 137.28, 194.66. These data match that
reported for this compound.

212

(COCl)2

O
Br

OH

3

DCM, rt

TMSCHN2

O
Br

Cl

3

CH3CN, 0 °C
24 h

O
N2

Br

3

71e

74e

5-bromo-1-diazopentan-2-one 74e: 4-bromobutanoic acid 71e (0.33 g, 2.0 mmol)
was reacted according to the general procedure described above. Purification of 74e by
column chromatography on silica gel (1:6 ethyl acetate/hexanes) gave the pure
diazoketone as a clear yellow liquid in 78% isolated yield (0.30 mg, 1.6 mmol).
Compound 74e gradually turned orange at room temperature after evaporation of
solvent by rotary evaporator to remove most of the solvent. The yield was calculated
1

from the H NMR spectrum after integration of solvent peaks. Removing all solvents by
high vacuum was detrimental to the compound. Therefore, this compound should be
84

used immediately after purification by column chromatography. Spectral data for 74e :
1

Rf = 0.2 (1:6 ethyl acetate /hexanes). H NMR (500 MHz, CDCl3) % 2.13-2.18 (m, 2H),
2.48 (bs, 2H), 3.41-3.44 (m, 2H), 5.27 (bs, 1H);

13

C NMR (125 MHz, CDCl3) % 27.55,

33.07, 37.75, 54.68, 193.21.

O

O

(COCl)2

O

2

OH

O

DCM, rt

TMSCHN2

O

O

2

Cl

71f

CH3CN, 0 °C
24 h

O

O

O
N2

2

74f

1-diazo-4-(2-methyl-1,3-dioxolan-2-yl)butan-2-one 74f: tert-butyldimethylsilyl 3-(285

methyl-1,3-dioxolan-2-yl)propanoate

(0.15 g, 1.8 mmol) was reacted according to the

general procedure described above with the exception that a few drops of DMF were

213

added for the preparation of acid chloride. Purification of 74f by column chromatography
on silica gel (1:1 ethyl acetate/hexanes) gave the pure diazoketone as a clear yellow
86

liquid in 52% isolated yield (170 mg, 0.920 mmol). Spectral data for 74f : Rf = 0.20 (1:1
1

ethyl acetate /hexanes). H NMR (500 MHz, CDCl3) % 1.25 (s, 3H), 1.93–1.96 (t, 2H, J
= 7.5 Hz), 2.35 (bs, 2H), 3.83-3.91 (m, 4H), 5.21 (bs, 1H);

13

C NMR (125 MHz, CDCl3)

% 14.37, 24.09, 33.89, 54.45, 64.91, 109.40, 194.63.

O
N
O

2

O

(COCl)2

O
OH

N

DCM, rt

2

O

O

TMSCHN2

O
Cl

O
N2

N

CH3CN, 0 °C
24 h

2

O

74g

71g

2-(4-diazo-3-oxobutyl)isoindoline-1,3-dione
yl)propanoic acid

87

74g:

3-(1,3-dioxoisoindolin-2-

71g (0.88 g, 4.0 mmol) was reacted according to the general

procedure described above. Purification of 74g by column chromatography on silica gel
(1:9 ethyl acetate/dichloromethane) gave the pure diazoketone as a light yellow solid
88

(mp 126-128 oC) in 82% isolated yield (0.8 g, 3.3 mmol). Spectral data for 74g : Rf =
1

0.2 (1:9 ethyl acetate /dichloromethane). H NMR (500 MHz, CDCl3) % 2.72 (bs, 2H),
3.96-3.99 (t, 2H, J = 7.5 Hz), 5.29 (bs, 1H), 7.66-7.70 (m, 2H), 7.78-7.81 (m, 2H);

13

C

NMR (125 MHz, CDCl3) % 33.70, 38.53, 55.25, 123.27, 131.96, 133.99, 167.97, 191.26.

O

(COCl)2

O

2

OH

DCM, rt

TMSCHN2

O

O

2

Cl

71h

CH3CN, 0 °C
24 h

O

O
N2

2

74h

214

1-diazohexane-2,5-dione 74h was prepared as follow: A flame-dried flask was
charged with levulinic acid 71h (0.23 g, 2.0 mmol) and THF (10 mL). Then 1.05 eq. of
TEA was added at 0°C, followed by the addition of 1.05 eq of ethyl chloroformate. The
mixture was stirred for 2 h. After filtration and concentration at reduced pressure, the
anhydride was obtained which could be used in the next step without further purification.
The anhydride was dissolved in CH3CN (10 mL) at 0°C, followed by the addition of
TMSCHN2 (2.2 mmol, 1.1 mL). Stirring was continued overnight. The solvent was then
removed by rotary evaporator. The residual was dissolved in ether, and washed with
sat. NaHCO3 and water, dried over Na2SO4 and concentrated. Purification of 74h by
column chromatography on silica gel (1:1 ethyl acetate/hexanes) gave the pure
diazoketone as a clear yellow liquid in 30% isolated yield (84 mg, 0.60 mmol). Spectral
89

1

data for 74h : Rf = 0.30 (1:1 ethyl acetate /hexanes). H NMR (500 MHz, CDCl3) %
2.16 (s, 3H), 2.56 (s, 2H), 2.75-2.78 (t, J = 6.0 Hz, 2H), 5.28 (bs, 1H);

13

C NMR (125

MHz, CDCl3) % 29.03, 35.41, 39.49, 53.94, 194.83, 207.82.

O

(COCl)2
OH

DCM, rt

TMSCHN2, NEt3

O
Cl

71i

CH3CN, 0 °C
24 h

O
N2

74i

2-diazo-1-phenylethanone 74i: Benzoic acid 71i (0.24 g, 2.0 mmol) was reacted
according to the general procedure described above with the exception that 1.2 eq. of
triethylamine was added after the addition of TMSCHN2 (2.2 mmol, 1.1 mL). Purification

215

of 74i by column chromatography on silica gel (1: 6 ethyl acetate/hexanes) gave the
pure diazoketone as a yellow solid (mp 52-54 oC) in 55% isolated yield (160 mg, 1.10
90

1

mmol). Spectral data for 74i : Rf = 0.2 (1:6 ethyl acetate) H NMR (500 MHz, CDCl3) %
5.91 (bs, 1H), 7.37-7.41 (m, 2H), 7.47-7.50 (m, 1H), 7.71- 7.73 (m, 2H);

13

C NMR (125

MHz, CDCl3) % 54.42, 126.89, 128.89, 132.95, 136.87, 186.61.

O

(COCl)2
OH

TMSCHN2, NEt3

O
Cl

DCM, rt

O
N2

CH3CN, 0 °C
24 h
74j

71j

1-diazo-4-phenylbut-3-yn-2-one 74j: Phenylpropiolic acid 71j (0.29 g, 2.0 mmol)
was reacted according to the general procedure described above with the exception
that 1.2 eq. of triethylamine was added after the addition of TMSCHN2. Purification of
74j by column chromatography on silica gel (1: 9 ethyl acetate/hexanes) gave the pure
diazoketone as a clear yellow liquid in 15% isolated yield (51 mg, 0.3 mmol). Spectral
91

1

data for 74j : Rf = 0.2 (1:3 ethyl acetate /hexanes). H NMR (500 MHz, CDCl3) % 5.58
(bs, 1H), 7.34-7.42 (m, 3H), 7.51-7.54 (m, 2H);

13

C NMR (125 MHz, CDCl3) % 53.92,

89.92, 96.34, 127.99, 128.83, 133.84, 135.82, 184.21.
O

(COCl)2
OH

TMSCHN2, NEt3

O
Cl

DCM, rt

O
N2

CH3CN, 0 °C
24 h
74k

71k

216

(E)-1-diazo-4-phenylbut-3-en-2-one 74k: (E)-cinnamic acid 71k (0.3 g, 2 mmol) was
reacted according to the general procedure described above with the exception that 1.2
1

eq. of triethylamine was added after the addition of TMSCHN2. The H NMR spectrum
of the crude reaction mixture indicated that the desired diazo compound 74k was not
present due to the absence of the characteristic diazo methine peak at % 5.6 that has
been reported for this compound.

92

6.4.5 General procedure for the catalytic asymmetric aziridination of diazo
ketones 74a-g, j – Illustrated for the preparation of 1-((2R,3R)-1-(bis(4-methoxy3,5-dimethyl-phenyl)methyl)-3-phenylaziridin-2-yl)-4-cyclohexylbutan-1-one 78a
O

O

5 mol % (S)-VAPOL
BOROX cat. 9

O

O

O

N

toluene, 25 °C

N
Ph

77a

Ph

N2

O

74a

3

(2R, 3R)-78a
93

Procedure for catalyst preparation : To a flame-dried 50 mL Schlenk flask, fitted
with a magnetic stirrer and filled with argon, was added (S)-VAPOL (26.9 mg, 0.0500
mmol) and triphenylborate (58 mg, 0.20 mmol). Dry toluene (2 mL) was added under an
argon flow, followed by the addition of water (0.9 &L, 0.05 mmol). After capping the
flask, the mixture was heated at 80 ºC for 1 h with stirring. Thereafter a vacuum was
gradually applied to remove solvent (0.05 mm Hg). The vacuum was maintained for 30
min at 80 ºC. Then the flask was cooled down under argon flow to room temperature.
93

Procedure for the aziridination reaction : Aldimine 77a (387 mg, 1.00 mmol) and
dry toluene (2 mL) were added to this Schlenk flask under an argon flow. Thereafter, 5-

217

cyclohexyl-1-diazopentan-2-one 74a (232 mg, 1.20 mmol) was added via syringe.
Stirring was continued at room temperature for 24 h. The mixture was then diluted with
15 mL of hexanes and transferred to a 100 mL round bottom flask. The Schlenk flask
was rinsed with dichloromethane. Concentration of the solvent followed by applying high
vacuum (0.05 mm Hg) for 30 minutes provided the crude aziridine as an off-white solid.
1

The cis/trans ratios were determined by the H NMR spectrum of the crude reaction
mixture by integration of the aziridine methine protons. The coupling constants of the cis
(7-8 Hz) and the trans (2-3 Hz) were used to differentiate the two isomers. Purification
of the product by column chromatography (35 mm x 400 mm column) on silica gel with
an elutant mixture of ethyl acetate:hexanes (1:9) gave the pure aziridine (mp 45-47 °C)
as a white solid in 72% isolated yield (400 mg, 0.72 mmol). Cis/trans ratio: 100:1. The
optical purity of 78a was determined to be 99% ee by HPLC analysis (CHIRALCEL ODH column, 99:1 hexanes:2-propanol, 222 nm, flow rate 0.7 mL/min). Retention times: Rt
= 8.24 min (major enantiomer) and Rt = 6.70 min (minor enantiomer). Spectral data for
1

(2R, 3R)-78a: Rf = 0.15 (1:9 ethyl acetate/hexanes). H NMR (500 MHz, CDCl3) ! 0.601.30 (m, 11H), 1.45-1.65 (m, 5H), 1.85-2.00 (m, 1H), 2.21 (s, 6H), 2.24 (s, 6H), 2.562.59 (d, 1H, J = 7 Hz), 3.12-3.20 (d, 1H, J = 7 Hz), 3.59 (s, 1H), 3.63 (s, 3H), 3.67 (s,
3H), 7.12-7.14 (d, 4H, J = 7 Hz), 7.16-7.25 (m, 3H), 7.27-7.30 (d, 2H, J = 7 Hz);

13

C

3

NMR (125 MHz, CDCl3) (1 sp carbon missing) % 16.09, 16.15, 20.09, 26.19, 26.56,
33.01,33.03, 36.58, 37.21, 40.87, 49.17, 52.74, 59.40, 59.43, 77.64, 127.23, 127.35,
127.65, 127.72, 127.90, 130.56, 130.58, 135.36, 137.71, 137.87, 155.98, 156.05,
1

207.09; IR (thin film) 2922s, 1697m, 1483s, 1221s cm- ; mass spectrum, m/z (% rel

218

intensity) 553 M+ (2), 283 (100), 269 (100), 238 (46); Anal calcd for C37H47NO3: C,
23

80.25; H, 8.55; N, 2.53. Found: C, 79.73; H, 8.55; N, 2.32; ["]

D

= +54.0 (c 1.0,

CH2Cl2) on 99% ee material (HPLC).

O

O

O

O

10 mol % (S)-VAPOL
BOROX cat. 9

O
N

N

toluene, 25 °C
Cy

77b

Cy

N2

O

74a

3

(2R, 3R)-78b

1-((2R,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-cyclohexylaziridin-2-yl)-4cyclohexylbutan-1-one 78b: Aldimine 77b (275 mg, 0.700 mmol) was reacted with 5cyclohexyl-1-diazopentan-2-one 74a (163mg, 0.840 mmol) according to the general
procedure described above with the exception that the catalyst loading was 10 mol%.
Purification of the product by column chromatography on silica gel (1:15 ethyl
acetate/hexanes) gave the pure aziridine as a viscous oil in 82% isolated yield (319 mg,
0.570 mmol). The optical purity of 78b was determined to be 95% ee by HPLC analysis
(CHIRALCEL OD-H column, 98:2 hexanes:2-propanol, 222 nm, flow 0.7 mL/min).
Retention times: Rt = 5.05 min (major enantiomer) and Rt = 5.98 min (minor
1

enantiomer). Spectral data for (2R, 3R)-78b: Rf = 0.15 (1:15 ethyl acetate:hexanes). H
NMR (500 MHz, CDCl3) ! 0.42-0.58 (m, 1H), 0.70-1.70 (m, 25H), 1.40-1.58 (t, 1H, J =
7.5 Hz), 2.21(s, 6H), 2.22 (s, 6H), 2.26-2.27 (d, 1H, J = 7.5 Hz), 2.40-2.50 (m, 2H), 3.30
(s, 1H), 3.64 (s, 3H), 3.66 (s, 3H), 6.96 (s, 2H), 7.03 (s, 2H);

219

13

C NMR (125 MHz,

3

CDCl3) (1 sp carbon missing) ! 16.08, 16.19, 21.20, 25.40, 25.52, 26.13, 26.34, 26.65,
30.44, 30.98, 33.22, 33.24, 36.07, 37.01, 37.48, 42.41, 49.99, 54.85, 59.58, 59.66,
78.11, 127.35, 128.38, 130.34, 130.50, 137.77, 138.12, 155.83, 156.22, 207.77; IR (thin
1

film) 2924s, 1701w, 1483s, 1221s cm- ; mass spectrum, m/z (% rel intensity) 559 M+
(0.77), 283 (100), 95 (16), 55 (38); Anal calcd for C37H53NO3: C, 79.38; H, 9.54; N,
23

2.50. Found: C, 79.11; H, 9.26; N, 2.41; ["]

D

= +91.8 (c 1.0, CH2Cl2) on 95% ee

material (HPLC).

5 mol % (S)-VAPOL
BOROX cat. 9

O
N
Ph

79

toluene, 25 °C

N2

N
Ph
O

74a

3

(2R, 3R)-80

1-((2R,3R)-1-benzhydryl-3-phenylaziridin-2-yl)-4-cyclohexylbutan-1-one 80: Aldimine
79 (271 mg, 1.00 mmol) was reacted with 6-diazo-5-oxohexanoate 74a (232 mg, 1.20
mmol) according to the above mentioned procedure. Purification of the product by
column chromatography on silica gel (1:15 ethyl acetate/hexanes) gave the pure
aziridine (mp 138-139 °C) as a white solid in 66% isolated yield (289 mg, 0.66 mmol).
The optical purity of 80 was determined to be 92% ee by HPLC analysis (CHIRALCEL
OD-H column, 99:1 hexanes:2-propanol, 222 nm, flow 0.7 mL/min). Retention times: Rt
= 6.92 min (major enantiomer) and Rt = 10.64 min (minor enantiomer). Spectral data for
1

(2R, 3R)–80: Rf = 0.15 (1:15 ethyl acetate/hexanes). H NMR (500 MHz, CDCl3) ! 0.600.90 (m, 4H), 1.01-1.37 (m, 7H), 1.58-1.71 (m, 4H), 2.00-2.07 (m, 1H), 2.28-2.34 (m,

220

1H), 2.77-2.79 (d, 1H, J = 7 Hz), 3.33-3.52 (d, 1H, J = 7 Hz), 3.96 (s, 1H), 7.23-7.40 (m,
11H), 7.60-7.63 (t, 4H, J = 6.5 Hz);

13

2

3

C NMR (125 MHz, CDCl3) (1 sp and sp carbon

missing) ! 20.16, 26.29, 26.66, 33.07, 33.13, 36.60, 37.25, 40.95, 49.20, 52.85, 78.45,
127.25, 127.38, 127.43, 127.49, 127.53, 127.75, 128.07, 128.55, 135.19, 142.33,
1

142.50, 206.82; IR (thin film) 2918m, 1709s, 1653s, 1456w cm- ; mass spectrum, m/z
(% rel intensity) 437 M+ (1.82), 270 (100), 167 (95), 118 (43); Anal calcd for C31H35NO:
23

C, 85.08; H, 8.06; N, 3.20. Found: C, 85.00; H, 7.89; N, 3.22; ["]

= +55.5 (c 1.0,

D

CH2Cl2) on 92% ee material (HPLC).

O

O

O
O

5 mol % (S)-VAPOL
BOROX cat. 9

O

N

OEt
Ph

77a

O

N2

toluene, 25 °C

N
OEt

Ph
O

74b

3

O

(2R, 3R)-78c

ethyl-5-((2R,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridin-2-yl)5-oxopentanoate 78c: Aldimine 77a (387 mg, 1.00 mmol) was reacted with ethyl 6diazo-5-oxohexanoate 74b (222 mg, 1.20 mmol) according to the above mentioned
procedure. Purification of the product by column chromatography on silica gel (1:6 ethyl
acetate/hexanes) gave the pure aziridine as a viscous oil in 76% isolated yield (412 mg,
0.760 mmol). The optical purity of 78c was determined to be 99% ee by HPLC analysis
(CHIRALCEL OD-H column, 99:1 hexanes:2-propanol, 222 nm, flow 0.7mL/min).
Retention times: Rt = 19.36 min (major enantiomer) and Rt = 28.56 min (minor

221

1

enantiomer). Spectral data for (2R, 3R)–78c: Rf = 0.15 (1:6 ethyl acetate/hexanes). H
NMR (500 MHz, CDCl3) ! 1.18-1.22 (t, 3H, J = 7 Hz), 1.40-1.65 (m, 2H), 1.80-2.15 (m,
3H), 2.24 (s, 6H), 2.26 (s, 6H), 2.27-2.30 (m, 1H), 2.61-2.63 (d, 1H, J = 7.5 Hz), 3.203.21 (d, 1H, J = 7.5 Hz), 3.63 (s, 1H), 3.65(s, 3H), 3.69 (s, 3H), 4.01-4.07 (q, 2H, J = 7
Hz), 7.15-7.31 (m, 9H);

13

C NMR (125 MHz, CDCl3) ! 14.11, 16.13, 16.16, 18.05,

33.02, 39.68, 49.20, 52.55, 59.48, 59.50, 60.04, 77.67, 127.34, 127.36, 127.65, 127.73,
128.00, 130.65, 130.71, 135.23, 137.65, 137.80, 156.06, 156.12, 172.95, 206.21; IR
1

(thin film) 2934m, 1734s, 1653m, 1456s cm- ; mass spectrum, m/z (% rel intensity) 543
M+ (0.12), 283 (100), 91 (24), 55 (14); Anal calcd for C34H41NO5: C, 75.11; H, 7.60; N,
23

2.58. Found: C, 74.77; H, 7.71; N, 2.35; ["]

D

= –52.4 (c 1.0, CH2Cl2) on 99% ee

material (HPLC).

O

O

O
O

10 mol % (S)-VAPOL
BOROX cat. 9

O

N

OEt
Cy

77b

O

toluene, 25 °C

N2

N
OEt

Cy
O

74b

3

O

(2R, 3R)-78d

ethyl5-((2R,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-cyclohexylaziridin-2yl)-5-oxopentanoate 78d: Aldimine 77b (196.5 mg, 0.5000 mmol) was reacted with ethyl
6-diazo-5-oxohexanoate 74b (111 mg, 0.600 mmol) according to the above mentioned
procedure with the exception that the catalyst loading was 10 mol%. Purification of the
product by column chromatography on silica gel (1:5 ethyl acetate/hexanes) gave the

222

pure aziridine as a colorless viscous oil in 92% isolated yield (254 mg, 0.460 mmol).
The optical purity of 78d was determined to be 97% ee by HPLC analysis (CHIRALCEL
OD-H column, 99:1 hexanes:2-propanol, 222 nm, flow 0.7mL/min). Retention times: Rt
= 8.37 min (major enantiomer) and Rt = 11.04 min (minor enantiomer). Spectral data for
1

(2R, 3R)–78d: Rf = 0.20 (1:5 ethyl acetate/hexanes). H NMR (500 MHz, CDCl3) !
0.40-0.60 (m, 1H), 0.80-1.40 (m, 11H), 1.40-1.60 (m, 3H), 1.85-1.95 (m, 3H), 2.19 (s,
6H), 2.20 (s, 6H), 2.10-2.27 (m, 2H), 2.53-2.55 (m, 2H), 3.29 (s, 1H), 3.61 (s, 3H), 3.64
(s, 3H), 4.04-4.09 (q, 2H, J = 7 Hz), 6.96 (s, 2H), 7.02 (s, 2H);

13

C NMR (125 MHz,

CDCl3) ! 14.06, 15.92, 16.00, 18.76, 25.22, 25.35, 25.96, 30.28, 30.83, 33.11, 36.04,
40.80, 49.77, 54.71, 59.40, 59.47, 60.12, 77.93, 127.17, 128.19, 130.21, 130.41,
137.61, 137.90, 155.72, 156.10, 172.91, 206.60; IR (thin film) 2928m, 1734s, 1485m,
1

1375w cm- ; mass spectrum, m/z (% rel intensity) 549 M+ (0.62), 283 (100), 268 (14),
55 (10); Anal calcd for C34H47NO5: C, 74.28; H, 8.62; N, 2.55. Found: C, 74.05; H,
23

8.78; N, 2.34; ["]

O

D=

+86.3 (c 1.0, CH2Cl2) on 97% ee material (HPLC).

O

O

5 mol % (S)-VAPOL
BOROX cat. 9

O
N
Ph

77a

O

toluene, 25 °C

N2

N
Ph
O

74c

3

(2R, 3R)-78e

1-((2R,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridin-2-yl)hex-5en-1-one 78e: Aldimine 77a (387 mg, 1.00 mmol) was reacted with 1-diazohept-6-en-2-

223

one 74c (166 mg, 1.20 mmol) according to the general procedure described above.
Purification of the product by column chromatographyon silica gel (1:12 ethyl
acetate/hexanes) gave the pure aziridine as a colorless viscous oil in 77% isolated yield
(380 mg, 0.770 mmol). The optical purity of 78e was determined to be 99% ee by HPLC
analysis (CHIRALCEL OD-H column, 98:2 hexanes:2-propanol, 222 nm, flow 0.5
mL/min). Retention times: Rt = 9.89 min (major enantiomer) and Rt = 8.22 min (minor
1

enantiomer). Spectral data for (2R, 3R)–78e: Rf = 0.15 (1:12 ethyl acetate/hexanes). H
NMR (500 MHz, CDCl3) ! 1.27-1.31 (m, 1H), 1.39-1.43 (m, 1H), 1.73-1.79 (m, 2H),
1.99-2.06 (m, 1 H), 2.26-2.37 (m, 1 H), 2.28 (s, 6H), 2.31 (s, 6H), 2.65-2.67 (d, 1H, J =
7.5 Hz), 3.24-3.25 (d, 1H, J = 7.5 Hz), 3.67 (s, 1H), 3.69 (s, 3H), 3.73 (s, 3H), 4.86-4.90
(m, 2H), 5.57-5.64 (m, 1H), 7.20-7.24 (m, 5H), 7.26-7.30 (m, 2H), 7.36-7.38 (m, 2H);
13

C NMR (125 MHz, CDCl3) ! 16.15, 16.18, 21.96, 32.76, 39.91, 49.27, 52.76, 59.48,

59.51, 76.75, 114.67, 127.30, 127.40, 127.66, 127.75, 127.98, 130.64, 130.67, 135.34,
137.72, 137.85, 137.96, 156.03, 156.08, 206.91; IR (thin film) 3060w, 2934m, 1699m,
1

1485s, 1221s cm- ; mass spectrum, m/z (% rel intensity) 497 M+ (0.27), 283 (100), 91
(27), 41 (16); Anal calcd for C33H39NO3: C, 79.64; H, 7.90; N, 2.81. Found: C, 79.37; H,
23

7.61; N, 2.67; ["]

D=

+52.1 (c 1.0, CH2Cl2) on 99% ee material (HPLC).

224

O

O

O

10 mol % (S)-VAPOL
BOROX cat. 9

O
N
Cy

77b

O

N

toluene, 25 °C

N2

Cy
O

74c

3

(2R, 3R)-78f

1-((2R,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-cyclohexylaziridin-2yl)hex-5-en-1-one 78f: Aldimine 77b (196.5 mg, 0.5000 mmol) was reacted with 1diazohept-6-en-2-one 74c (83 mg, 0.60 mmol) according to the general procedure
described above with the exception that the catalyst loading was 10 mol%. Purification
of the product by column chromatography on silica gel (1:12 ethyl acetate/hexanes)
gave the pure aziridine as a colorless viscous oil in 72% isolated yield (182 mg, 0.360
mmol). The optical purity of 78f was determined to be 95% ee by HPLC analysis
(CHIRALCEL OD-H column, 98:2 hexanes:2-propanol, 222 nm, flow 0.7 mL/min).
Retention times: Rt = 4.42 min (major enantiomer) and Rt = 5.47 min (minor
1

enantiomer). Spectral data for (2R, 3R)–78f: Rf = 0.2 (1:12 ethyl acetate/hexanes). H
NMR (500 MHz, CDCl3) ! 0.44-0.56 (m, 1H), 0.91-1.30 (m, 7H), 1.40-1.63 (m, 5H),
1.75-1.78 (t, 1H, J = 7.5 Hz), 1.98-2.00 (m, 2H), 2.21 (s, 6H), 2.22 (s, 6H), 2.27-2.28 (d,
1H, J = 7.5 Hz), 2.47-2.50 (t, 2H, J = 7.5 Hz), 3.30 (s, 1H), 3.64 (s, 3H), 3.65 (s, 3H),
4.91-4.96 (m, 2H), 5.68-5.74(m, 1H), 6.98 (s, 2H), 7.04 (s, 2H);

13

C NMR (125 MHz,

CDCl3) ! 16.03, 16.12, 22.90, 25.34, 25.48, 26.08, 30.38, 30.94, 33.00, 36.05, 41.22,
49.92, 54.90, 59.53, 59.59, 78.08, 115.07, 127.32, 128.31, 130.30, 130.47, 137.73,
137.91, 138.02, 155.80, 156.18, 207.42; IR (thin film) 2928m, 1699m, 1483m, 1221m

225

1

cm- ; mass spectrum, m/z (% rel intensity) 503 M+ (0.82), 283 (100), 95 (30), 55 (59);
Anal calcd for C33H45NO3: C, 78.69; H, 9.00; N, 2.78. Found: C, 79.09; H, 8.89; N,
23

2.73; ["]

D=

+96.4 (c 1.0, CH2Cl2) on 95% ee material (HPLC).

O

O

O

5 mol % (S)-VAPOL
BOROX cat. 9

O
N
Ph

77a

O

toluene, 25 °C

N2

N
Ph

3
O

74d

(2R, 3R)-78g

1-((2R,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridin-2-yl)hex-5yn-1-one 78g: Adimine 77a (387 mg, 1.00 mmol) was reacted with 1-diazohept-6-yn-2one 74d (164 mg, 1.20 mmol) according to the general procedure described above.
Purification of the product by column chromatography on silica gel (1:12 ethyl
acetate/hexanes) gave the pure aziridine as a colorless viscous oil in 89% isolated yield
(440 mg, 0.890 mmol). The optical purity of 78g was determined to be 99% ee by HPLC
analysis (CHIRALCEL OD-H column, 99:1 hexanes:2-propanol, 222 nm, flow 0.5
mL/min). Retention times: Rt = 15.61 min (major enantiomer) and Rt = 7.92 min (minor
1

enantiomer). Spectral data for (2R, 3R)–78g: Rf = 0.15 (1:12 ethyl acetate/hexanes). H
NMR (500 MHz, CDCl3) ! 1.40-1.48 (m, 1H), 1.52-1.62 (m, 1H), 1.82-2.02 (m, 3H),
2.14-2.22 (m, 1H), 2.31 (s, 6H), 2.34 (s, 6H), 2.46-2.54 (m, 1H), 2.71-2.73 (d, 1H, J =
7.5 Hz), 3.29-3.31 (d, 1H, J = 7.5 Hz), 3.71 (s, 3H), 3.73 (s, 1H), 3.75 (s, 3H), 7.25-7.26
(m, 5H), 7.29-7.32 (m, 2H), 7.39-7.41(m, 2H);

226

13

C NMR (125 MHz, CDCl3) ! 16.05,

16.10, 17.42, 21.63, 39.31, 49.16, 52.52, 59.34, 59.37, 68.57, 77.55, 83.55, 127.25,
127.29, 127.57, 127.62, 127.93, 130.54, 130.61, 135.15, 137.62, 137.75, 155.96,
1

156.01, 206.18; IR (thin film) 2947m, 2118w, 1695s, 1221s cm- ; mass spectrum, m/z
(% rel intensity) 495 M+ (0.18), 283 (100), 118 (79), 91 (77); HRMS (ES+) calcd for
23

C33H38NO3 m/z 496.2852 (M++1), meas 496.2852; ["]

D

= +45.6 (c 1.0, CH2Cl2) on

99% ee material (HPLC).

O

O

O
O
N

toluene, 25 °C
Cy

77b

O

10 mol % (S)-VAPOL
BOROX cat. 9

N2

N
Cy
O

74d

3

(2R, 3R)-78h

1-((2R,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-cyclohexylaziridin-2yl)hex-5-yn-1-one 78h: Aldimine 77b (196.5 mg, 0.5000 mmol) was reacted with 1diazohept-6-yn-2-one 74d (82 mg, 0.60 mmol) according to the general procedure
described above with the exception that the catalyst loading was 10 mol%. Purification
of the product by column chromatography on silica gel (1:12 ethyl acetate/hexanes)
gave the pure aziridine as a colorless viscous oil in 79% isolated yield (199 mg, 0.390
mmol). The optical purity of 78h was determined to be 96% ee by HPLC analysis
(CHIRALCEL OD-H column, 99.5:0.5hexanes:2-propanol, 222 nm, flow 0.7 mL/min).
Retention times: Rt = 9.24 min (major enantiomer) and Rt = 14.86 min (minor
1

enantiomer). Spectral data for (2R, 3R)–78h: Rf = 0.15 (1:12 ethyl acetate/hexanes). H
NMR (500 MHz, CDCl3) ! 0.46-0.58 (m, 1H), 0.84-1.22 (m, 5H), 1.26-1.38 (m, 2H),

227

1.40-1.60 (m, 3H), 1.69-1.82 (m, 3H), 1.85-1.90 (t, 1H, J = 7.5 Hz), 2.12-2.19 (m, 2H),
2.21 (s, 6H), 2.22 (s, 6H), 2.29-2.31 (d, 1H, J = 7.0 Hz), 2,63-2.64 (m, 2H), 3.31 (s, 1H),
3.64 (s, 3H), 3.65 (s, 3H), 6.99 (s, 2H), 7.05 (s, 2H);

13

C NMR (125 MHz, CDCl3) !

15.96, 16.06, 17.60, 22.25, 25.25, 25.40, 25.99, 30.31, 30.87, 36.06, 40.33, 49.85,
54.79, 59.44, 59.50, 68.91, 77.96, 83.45, 127.22, 128.21, 130.24, 130.45, 137.67,
137.93, 155.71, 156.07, 206.98. IR (thin film) 2928m, 2118w, 1697w, 1483m, 1221s cm1

; mass spectrum, m/z (% rel intensity) 501 M+ (0.19), 283 (100), 95 (26), 55 (33);
23

HRMS (ES+) calcd for C33H44NO3 m/z 502.3321(M++1), meas 502.3287; ["]

D

=

+96.8 (c 1.0, CH2Cl2) on 96% ee material (HPLC).

O

O

O
O
Br

N
Ph

77a

O

5 mol % (S)-VAPOL
BOROX cat. 9
toluene, 25 °C

N2

N
Ph

3 Br
O

74e

(2R, 3R)-78i

1-((2R,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridin-2-yl)-4bromobutan-1-one 78i: Aldimine 77a (387 mg, 1.00 mmol) was reacted with 5-bromo-1diazopentan-2-one 74e (230 mg, 1.20 mmol) according to the general procedure
described above. Purification of the product by column chromatography on silica gel
(1:9 ethyl acetate/hexanes) gave the pure aziridine (mp 42-44°C) as a white solid in
85% isolated yield (469 mg, 0.850 mmol). The optical purity of 78i was determined to be
95% ee by HPLC analysis (CHIRALCEL OD-H column, 99:1 hexanes:2-propanol, 222

228

nm, flow 0.7 mL/min). Retention times: Rt = 14.06 min (major enantiomer) and Rt =
10.57 min (minor enantiomer). Spectral data for (2R, 3R)–78i: Rf = 0.2 (1:9 ethyl
1

acetate/hexanes). H NMR (500 MHz, CDCl3) ! 1.67-1.73 (m, 1H), 1.81-1.86 (m, 1H),
2.12-2.18 (m, 1H), 2.27 (s, 6H), 2.29 (s, 6H), 2.48-2.55 (m, 1H), 2.64-2.66 (d, 1H, J =
7.5 Hz), 3.03-3.14 (m, 2H), 3.24-3.26 (d, 1H, J = 7.0 Hz), 3.64 (s, 1H), 3.68 (s, 3H), 3.71
(s, 3H), 7.27-7.24 (m, 5H), 7.26-7.29 (m, 2H), 7.33-7.35 (m, 2H);

13

C NMR (125 MHz,

CDCl3) ! 16.12, 16.20, 25.83, 32.93, 38.88, 49.18, 52.50, 59.43, 59.46, 77.62, 127.29,
127.39, 127.56, 127.65, 128.05, 130.64, 130.74, 135.07, 137.57, 137.70, 156.01,
1

156.04, 205.88; IR (thin film) 2880w, 1701s, 1485s, 1221s cm- ; mass spectrum, m/z
81

79

(% rel intensity) 551 M+ (0.15, Br ), 549 M+ (0.28, Br ), 283 (100), 253 (54), 118
(100); Anal calcd for C31H36BrNO3: C, 67.63; H, 6.59; N, 2.54. Found: C, 67.28; H,
23

6.42; N, 2.40; ["]

O

D=

–42.0 (c 1.0, CH2Cl2) on 95% ee material (HPLC).

O

O
O
Br

N
Cy

77b

O

10 mol % (S)-VAPOL
BOROX cat. 9
toluene, 25 °C

N2

N
Cy
O

74e

3 Br

(2R, 3R)-78j

1-((2R,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-cyclohexylaziridin-2-yl)-4bromobutan-1-one 78j: Aldimine 77b (196.5 mg, 0.5000 mmol) was reacted with 5bromo-1-diazopentan-2-one 74e ( 115 mg, 0.600 mmol) according to the general

229

procedure described above with the exception that the catalyst loading was 10 mol%.
Purification of the product by column chromatography on silica gel (1:12 ethyl
acetate/hexanes) gave the pure aziridine as a colorless viscous oil in 61% isolated yield
(170 mg, 0.310 mmol). The optical purity of 74e was determined to be 92% ee by HPLC
analysis (CHIRALCEL OD-H column, 99:1 hexanes:2-propanol, 222 nm, flow 0.7
mL/min). Retention times: Rt = 6.58 min (major enantiomer) and Rt = 8.02 min (minor
1

enantiomer). Spectral data for (2R, 3R)–74e: Rf = 0.2 (1:15 ethyl acetate:hexanes). H
NMR (500 MHz, CDCl3) ! 0.51-0.53 (m, 1H), 0.90-1.1.16 (m, 5H), 1.28-1.1.59 (m, 5H),
1.77-1.81 (t, 1H, J = 7.0 Hz), 2.04-2.09 (m, 2H), 2.22 (s, 12H), 2.28-2.30 (d, 1H, J = 7.0
Hz), 2.67-2.71 (m, 2H), 3.31 (s, 1H), 3.37-3.39 (m, 2H), 3.67 (s, 3H), 3.73 (s, 3H), 6.98
(s, 2H), 7.05 (s, 2H);

13

C NMR (125 MHz, CDCl3) ! 16.02, 16.15, 25.28, 25.43, 26.37,

29.61, 30.34, 30.91, 33.18, 36.26, 39.81, 49.90, 54.81, 59.51, 59.57, 78.02, 127.23,
128.18, 130.32, 130.55, 137.63, 137.87, 155.77, 156.11, 206.44; IR (thin film) 2926s,
1

1701m, 1485s, 1221s cm- ; mass spectrum, m/z (% rel intensity) 557 M+ (0.06,
555 M+ (0.11,

79

81

Br),

Br), 283 (100), 192 (39), 55 (39). Anal calcd for C31H42BrNO3: C,
23

66.90; H, 7.61; N, 2.52. Found: C, 66.88; H, 7.96; N, 2.39. ["]
CH2Cl2) on 92% ee material (HPLC).

230

D

= +85.6 (c 1.0,

O

O

O
O

O
N

N

N2
Ph

77a

O

5 mol % (S)-VAPOL
BOROX cat. 9
toluene, 25 °C

O

O

N
Ph

2N
O

74f

O

(2R, 3R)-78k

2-(3-((2R,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridin-2-yl)-3oxopropyl)-1H-indene-1,3(2H)-dione 78k: Aldimine 77a (379 mg, 1.00 mmol) was
reacted with 2-(4-diazo-3-oxobutyl)isoindoline-1,3-dione 74f (292 mg, 1.20 mmol)
according to the general procedure described above. Purification of the product by
column chromatography on silica gel (1:2 ethyl acetate/hexanes) gave the pure aziridine
(mp 134-136 oC) as a white solid in 85% isolated yield (550 mg, 0.850 mmol). The
optical purity of 78k was determined to be 98% ee by HPLC analysis (CHIRALCEL ODH column, 98:2 hexanes:2-propanol, 222 nm, flow 0.7 mL/min). Retention times: Rt =
38.18 min (major enantiomer) and Rt = 78.62 min (minor enantiomer). Spectral data for
1

(2R, 3R)–78k: Rf = 0.2 (1:2 ethyl acetate/hexanes). H NMR (500 MHz, CDCl3) ! 2.26
(s, 6H), 2.29 (s, 6H), 2.40-2.47 (m, 1H), 2.70-2.71 (d, 1H, J = 7.0 Hz), 2.80-2.87 (m,
1H), 3.26-3.27 (d, 1H, J = 7.0 Hz), 3.58-3.71 (m, 3H), 3.65 (s, 3H), 3.69 (s, 3H), 7.077.10 (m, 1H), 7.17-7.21 (m, 6H), 7.30-7.32 (d, 2H, J = 7.5 Hz), 7.63-7.66 (m, 2H), 7.757.76 (m, 2H);

13

C NMR (125 MHz, CDCl3) ! 20.73, 31.93, 38.83, 49.06, 52.15, 59.25,

59.27, 60.07, 77.44, 122.81, 127.14, 127.23, 127.36, 127.46, 127.91, 130.46, 130.64,
131.77, 133.51, 134.72, 137.41, 137.60, 155.91, 155.92, 167.39, 204.02; IR (thin film)
1

2928m, 1716s, 1653m, 1485m cm- ; mass spectrum, m/z (% rel intensity) 602 M+

231

(1.03), 283 (100), 160 (75), 55 (62); Anal calcd for C38H38N2O5: C, 75.72; H, 6.35; N,
23

4.65. Found: C, 76.09; H, 6.68; N, 4.54; ["]

D

= +50.9 (c 1.0, CH2Cl2) on 98% ee

material (HPLC).

O

O

O
O

O
N

N

N2
Cy

77b

O

10 mol % (S)-VAPOL
BOROX cat. 9
toluene, 25 °C

O

O

N
2N

Cy
O

74f

O

(2R, 3R)-78l

2-(3-((2R,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-cyclohexylaziridin-2yl)-3-oxopropyl)-1H-indene-1,3(2H)-dione 78l: Aldimine 77b (160 mg, 0.400 mmol) was
reacted with 2-(4-diazo-3-oxobutyl)isoindoline-1,3-dione 74f (97 mg, 0.48 mmol)
according to the general procedure described above with the exception that the catalyst
loading was 10 mol%. Purification of the product by column chromatography on silica
°

gel (2:7 ethyl acetate/hexanes) gave the pure aziridine (mp 63-65 C) as a white foamy
solid in 63% isolated yield (150 mg, 0.25 mmol). The optical purity of 78l was
determined to be 87% ee by HPLC analysis (CHIRALCEL OD-H column, 97:3
hexanes:2-propanol, 222 nm, flow 0.7 mL/min). Retention times: Rt = 13.18 min (major
enantiomer) and Rt = 18.47 min (minor enantiomer). Spectral data for (2R, 3R)–78l: Rf
1

= 0.2 (2:7 ethyl acetate:hexanes). H NMR (500 MHz, CDCl3) ! 0.45-0.47 (m, 1H),
0.82-1.08 (m, 6H), 1.20-1.29 (m, 2H), 1.37-1.49 (m, 2H), 1.71-1.74 (t, 1H, J = 7.0 Hz),
2.17 (s, 6H), 2.18 (s, 6H), 2.24-2.25 (d, 1H, J = 7.0 Hz), 2.92-2.97 (m, 2H), 3.28 (s, 1H),

232

3.62 (s, 3H), 3.65 (s, 3H), 3.84-3.90 (m, 2H), 6.96 (s, 2H), 7.03 (s, 2H), 7.67-7.68 (m,
2H), 7.79-7.81 (m, 2H);

13

C NMR (125 MHz, CDCl3) ! 16.33, 16.41, 25.54, 25.65,

26.31, 30.62, 31.26, 33.05, 36.79, 40.09, 50.28, 54.95, 59.82, 59.89, 78.35, 123.45,
127.51, 128.48, 130.63, 130.95, 132.33, 134.18, 137.86, 138.23, 156.15, 156.45,
1

168.19, 205.18; IR (thin film) 2828m, 1772m, 1717s, 1485m cm- ; mass spectrum, m/z
(% rel intensity) 608 M+ (1.79), 283 (100), 160 (75), 55 (74); Anal calcd for
23

C38H44N2O5: C, 74.97; H, 7.29; N, 4.60. Found: C, 75.06; H, 7.54; N, 4.50; ["]

D

=

+72.6 (c 1.0, CH2Cl2) on 87% ee material (HPLC).

O

O

5 mol % (S)-VAPOL
BOROX cat. 9

O
N

N2

O

O

O

N

toluene, 25 °C

O

O

Ph

Ph

77a

O

O

74j

(2R, 3R)-78m

1-((2R,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-phenylaziridin-2-yl)-3-(2methyl-1,3-dioxolan-2-yl)propan-1-one 78m: Aldimine 77a (38.7mg, 0.100 mmol) was
reacted with 1-diazo-4-(2-methyl-1,3-dioxolan-2-yl)butan-2-one 74j (22.0 mg, 0.120
mmol) according to the general procedure described above. Purification of the product
by column chromatography on silica gel (1:3 ethyl acetate/hexanes) gave the pure
aziridine as a colorless viscous oil in 88% isolated yield (48 mg, 0.090 mmol). The
optical purity of 78m was determined to be 97% ee by HPLC analysis (CHIRALCEL
OD-H column, 98:2 hexanes:2-propanol, 222 nm, flow 0.7 mL/min). Retention times: Rt

233

= 13.31 min (major enantiomer) and Rt = 29.99 min (minor enantiomer). Spectral data
1

for (2R, 3R)–78m: Rf = 0.15 (1:3 ethyl acetate/hexanes). H NMR (500 MHz, CDCl3) !
1.09 (s, 3H), 1.42-1.48 (m, 1H), 1.60-1.66 (m, 1H), 2.01-2.07 (m, 1H), 2.24 (s, 6H), 2.25
(s, 6H), 2.32-2.39 (m, 1H), 2.62-2.63 (d, 1H, J = 7.5 Hz), 3.17-3.18 (d, 1H, J=7.0 Hz),
3.61 (s, 1H), 3.64 (s, 3H), 3.67 (s, 3H), 3.68-3.70 (m, 2H), 3.80-3.82 (m, 2H), 7.14-7.20
(m, 5H), 7.21-7.24 (m, 2H), 7.30-7.32 (m, 2H);

13

C NMR (125 MHz, CDCl3) ! 16.44,

16.46, 23.81, 31.92, 36.11, 49.50, 53.16, 59.80, 59.81, 64.70, 64.72, 78.07, 109.48,
127.57, 127.78, 127.98, 128.06, 128.29, 130.93, 130.98, 135.70, 137.99, 138.11,
1

156.36, 156.40, 206.51; IR (thin film) 2942m, 1653s, 1485s, 1221s cm- ; mass
spectrum, m/z (% rel intensity) 543 M+ (0.42), 283 (100), 91 (71), 87 (90). Anal calcd for
23

C34H41NO5: C, 75.11; H, 7.60; N, 2.58. Found: C, 74.06 ; H, 7.89; N, 2.47. ["]

D

=

+42.1 (c 1.0, CH2Cl2) on 97% ee material (HPLC).

O

O

10 mol % (S)-VAPOL
BOROX cat. 9

O
N

N2

O

O

O

N

toluene, 25 °C

O

O

Cy

Cy

77b

O

O

74j

(2R, 3R)-78n

1-((2R,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-3-cyclohexylaziridin-2-yl)-3(2-methyl-1,3-dioxolan-2-yl)propan-1-one 78n: Aldimine 77b (79 mg, 0.20 mmol) was
reacted with 1-diazo-4-(2-methyl-1,3-dioxolan-2-yl)butan-2-one 74j (44 mg, 0.24 mmol)
according to the general procedure described above with the exception that the catalyst

234

loading was 10 mol%. Purification of the product by column chromatography on silica
gel (2:9 ethyl acetate/hexanes) gave the pure aziridine as a viscous oil in 64% isolated
yield (70 mg, 0.13 mmol). The optical purity of 78n was determined to be 91% ee by
HPLC analysis (CHIRALCEL OD-H column, 99:1 hexanes:2-propanol, 222 nm, flow 0.7
mL/min). Retention times: Rt = 9.47 min (major enantiomer) and Rt = 14.11 min (minor
1

enantiomer). Spectral data for (2R, 3R)–78n: Rf = 0.2 (2:9 ethyl acetate:hexanes). H
NMR (500 MHz, CDCl3) ! 0.48-0.50 (m, 1H), 0.86-1.15 (m, 5H), 1.26 (s, 3H), 1.27-1.32
(m, 2H), 1.41-1.57 (m, 3H), 1.74-1.77 (t, 1H, J = 7.0 Hz), 1.85-1.90 (m, 2H), 2.20 (s,
6H), 2.21 (s, 6H), 2.29-2.30 (d, 1H, J = 7.0 Hz), 2.51-2.61 (m, 2H), 3.30 (s, 1H), 3.64 (s,
3H), 3.66 (s, 3H), 3.82-3.90 (m, 4H), 6.97 (s, 2H), 7.04 (s, 2H);

13

C NMR (125 MHz,

CDCl3) ! 16.04, 16.13, 23.82, 25.34, 25.51, 26.11, 30.38, 30.94, 32.51, 36.06, 36.88,
50.03, 54.70, 59.54, 59.61, 64.57, 64.60, 78.15, 109.27, 127.36, 128.35, 130.30,
130.48, 137.73, 138.07, 155.81, 156.20, 206.67; IR (thin film) 2928s, 1701m, 1650s,
1

1558m cm- ; mass spectrum, m/z (% rel intensity) 549 M+ (0.23), 283 (100), 87 (87), 43
23

(50); HRMS (ES+) calcd for C34H48NO5 m/z 550.3532 (M++1), meas 550.3546; ["]
+79.4 (c 1.0, CH2Cl2) on 91% ee material (HPLC).
6.4.6 General procedure for the deprotection of the N-MEDAM aziridine 78i.
MEDAM
N
Ph

3 Br
O

triflic acid
dry anisole,
0 °C to rt, 2 h

H
N
Ph

3 Br
O

81i, 84% yield

(2R,3R)-78i

235

D=

To a 25 mL flame-dried round bottom flask filled with argon was added compound
78i (110 mg, 0.200 mmol, 99% ee) and 2.2 mL of freshly distilled anisole at room
94

temperature.

The flask was cooled to 0 ºC and triflic acid (88 µL, 1.0 mmol) was

added. The ice-bath was removed and the reaction mixture was stirred for 2 h at room
temperature. The reaction mixture was quenched by addition of saturated aq Na2CO3
until the pH was greater than 9. After addition of 3 mL ether and 1 mL water, the organic
layer was separated and the water layer was extracted with ether (5 mL # 3). The
combined organic layer was washed with NaCl (aq. sat.) (2 x 10 mL) and dried over
MgSO4. The ether was removed by rotary evaporation. Purification of the product by
column chromatography on silica gel (1:1 ether/hexanes as eluent) afforded 81i as a
clear viscous oil in 84% isolated yield (45 mg, 0.17 mmol). Spectral data for (2R, 3R)–
1

81i: Rf = 0.2 (1:1 ethyl acetate:hexanes). H NMR (500 MHz, CDCl3) ! 1.89-2.01 (m,
3H), 2.59 (bs, 2H), 3.01-3.09 (m, 1H), 3.19-3.27 (m, 2H), 3.62-3.64 (d, 1H, J = 6.0 Hz),
7.26-7.38 (m, 5H);

13

3

C NMR (125 MHz, CDCl3) (1 sp carbon and 1 carbonyl carbon

missing) ! 25.92, 32.81, 39.67, 43.90, 127.35, 127.79, 127.99, 128.20; IR (thin film)
1

79

3310m, 2922m, 1701s, 1385m cm- ; HRMS (ES+) calcd for C12H14 BrNO m/z
268.0377 (M++1), meas 268.0328.
6.4.7 General procedure for preparation of (R)-1-((2S,3S)-1-(bis(4-methoxy-3,5dimethylphenyl)methyl)-3-phenylaziridin-2-yl)-4-bromobutan-1-ol 82 via reduction
of 78i with zinc borohydride.

236

MEDAM
N
Ph
O

(2S,3S)-78i
98% ee

MEDAM

3 Br

N
Zn(BH4)2

Et2O, 25 °C

Ph

3 Br

82 OH
91% (dr > 50:1)

An ethereal solution of zinc chloride (1.36 g, 10.0 mmol) was added dropwise to a
95

stirred suspension of sodium borohydride (25 mmol) in dry diethyl ether (60 mL).

The

mixture was stirred at room temperature under argon atmosphere for 12 h. The solid
that formed (NaCl) was allowed to settle and the liquid was removed and stored in a
stoppered bottle under argon atmosphere at –18 °C and was used as a 0.144 M zinc
borohydride solution in diethyl ether. To an ice-cold solution of the compound 78i (55
mg, 0.1 mmol, 98% ee) in dry diethyl ether (40 mL) was dropwise added a solution of
zinc borohydride (0.30 mL). After 2 h, the reaction was quenched with water, and then
the solution was stirred for another 30 min. The aqueous layer was extracted with
diethyl ether and the combined organic layer was washed with brine, dried over
magnesium sulfate, filtered, and concentrated under vacuum to afford a light-yellow oil.
Purification of the product by silica gel chromatography (1:4 ethylacetate/hexanes as
eluent) gave 82 as a white foamy solid (mp 55-57 °C) in 91 % isolated yield (50 mg,
1

0.91 mmol). No trace of the diastereomer 85 could be observed by H NMR in the crude
reaction mixture (dr $50:1). The stereochemistry of the product was assigned based on
a related reduction of an aziridinyl ketone reported previously.

94

Spectral data for (1R,

1

2S, 3S)–82: Rf = 0.2 (1:4 ethyl acetate:hexanes). H NMR (500 MHz, CDCl3) ! 1.081.09 (d, 1H, J = 3.0 Hz), 1.12-1.20 (m, 1H), 1.24-1.32 (m, 1H), 1.56-1.68 (m, 2H), 1.91-

237

1.94 (dd, 1H, J = 6.5 Hz, 8.5 Hz), 2.16 (s, 6H), 2.27 (s, 6H), 2.82-2.83 (d, 1H, J = 6.0
Hz), 3.10-3.12 (t, 2H, J = 6.5 Hz), 3.16-3.18 (m, 1H), 3.57 (s, 1H), 3.62 (s, 3H), 3.69 (s,
3H), 7.04 (s, 2H), 7.10 (s, 2H), 7.21-7.23 (t, 1H, J = 7.5 Hz), 7.29-7.32 (t, 2H, J = 7.5
Hz), 7.43-7.45 (d, 2H, J = 7.5 Hz);

13

C NMR (125 MHz, CDCl3) ! 16.43, 16.54, 28.63,

33.55, 34.05, 46.60, 50.89, 59.79, 59.91, 68.96, 78.31, 127.19, 127.64, 127.71, 128.51,
128.54, 130.65, 130.89, 137.08, 138.29, 138.75, 156.10, 156.57; IR (thin film) 3466m,
1

79

2920s, 1483s, 1221s cm- ; HRMS (ES+) calcd for C31H39NO3 Br m/z 552.2113
23

(M++1), meas. 552.2092; ["]

D=

+112.3 (c 1.0, CH2Cl2) on 98% ee material (HPLC).

6.4.8 General procedure for preparation of (S)-1-((2S,3S)-1-(bis(4-methoxy-3,5dimethylphenyl)methyl)-3-phenylaziridin-2-yl)-4-bromobutan-1-ol 85 via reduction
of 78i with L-selectride.
MEDAM
N
Ph
O

MEDAM

L-selectride
3 Br

THF, –78 °C

N
Ph

3 Br
OH

85
68% (dr = 15:1)

(2S,3S)-78i
98% ee

To a solution of ketoaziridine 78i (55 mg, 0.10 mmol) in 1 mL of THF under argon at
–78 °C was added L-Selectride (1M solution in THF, 0.20 mL, 0.20 mmol).

95

The

mixture was stirred for 60 min at –78 °C and then the reaction mixture was treated with
10% aqueous sodium hydroxide and the organic layer was separated. The aqueous
layer was extracted with ethyl acetate (3 X 3 mL) and the combined organic extracts
were dried over magnesium sulfate, filtered, and concentrated under vacuum.
Purification of the product by silica gel chromatography (1:4 ethylacetate/hexanes as
eluent) gave 85 as a viscous oil in 68 % yield (37 mg, 0.068 mmol). The ratio of the two

238

1

diastereomers 82 and 85 was 1:15 observed by H NMR in the crude reaction mixture.
The stereochemistry of the products was assigned based on a related reduction of
aziridinyl ketone reported previously.

95

Spectral data for (1S, 2S, 3S)–85: Rf = 0.2 (1:4

1

ethyl acetate:hexanes). H NMR (500 MHz, CDCl3) ! 1.30-1.39 (m, 2H), 1.59-1.65 (m,
2H), 1.86-1.89 (dd, 1H, J = 7.0 Hz, 8.0 Hz), 2.16 (s, 6H), 2.27 (s, 6H), 2.89-2.90 (d, 1H,
J = 7.0 Hz), 3.05-3.12 (m, 3H), 3.59 (s, 1H), 3.62 (s, 3H), 3.67 (s, 3H), 7.11 (s, 2H), 7.12
(s, 2H), 7.20-7.22 (t, 1H, J = 7.5 Hz), 7.27-7.30 (t, 2H, J = 7.5 Hz), 7.39-7.40 (d, 2H, J =
7.5 Hz);

13

C NMR (125 MHz, CDCl3) ! 16.45, 16.56, 28.60, 32.71, 33.80, 47.45, 51.75,

59.79, 59.90, 68.81, 78.03, 127.18, 127.57, 127.65, 127.83, 128.32, 130.76, 131.58,
1

136.76, 138.17, 139.47, 156.09, 156.69; IR (thin film) 3422s, 2924s, 1483s, 1221s cm- ;
79

23

HRMS (ES+) calcd for C31H39NO3 Br m/z 552.2113 (M++1), meas 552.2092; ["]

D=

+83.2 (c 1.0, CH2Cl2) on 98% ee material (HPLC).

6.4.9 Preparation of (2S,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-2phenyl-3-((S)-tetrahydrofuran-2-yl)aziridine 86.
MEDAM
N
Ph
O

MEDAM
N

L-selectride
3 Br

THF, 25 °C

Ph
O

86
83% (dr = 11:1)

(2S,3S)-78i
98% ee

When the above mentioned L-selectride reduction of compound 78i (0.275 g, 0.500
mmol) was carried out at room temperature for 24 h, compound 86 was isolated after
silica gel chromatography (1:5 ethylacetate / hexanes as eluent) as a white foamy solid

239

(mp 110-112 °C) in 83% yield (0.190 g, 0.415 mmol). Spectral data for (S, S, S)–86: Rf
1

= 0.2 (1:5 ethyl acetate:hexanes). H NMR (500 MHz, CDCl3) ! 1.41-1.54 (m, 2H),
1.59-1.76 (m, 2H), 1.90-1.93 (dd, 1H, J = 6.5 Hz, 8.5 Hz), 2.20 (s, 6H), 2.27 (s, 6H),
2.75-2.76 (d, 1H, J = 6.5 Hz), 3.31-3.36 (q, 1H, 7.5 Hz), 3.56-3.60 (m, 1H), 3.64 (s, 1H),
3.64-3.70 (m, 1H), 3.66 (s, 3H), 3.70 (s, 3H), 7.10 (s, 2H), 7.12 (s, 2H), 7.14-7.17 (m,
1H), 7.21-7.25 (m, 2H), 7.33-7.35 (m, 2H);

13

C NMR (125 MHz, CDCl3) ! 16.14, 16.15,

25.36, 28.76, 44.59, 50.13, 59.52, 59.57, 67.43, 76.75, 78.72, 126.41, 127.65, 127.77,
127.95, 128.19, 129.98, 130.24, 137.47, 138.18, 138.78, 155.62, 155.79; IR (thin film)
1

2963s, 1485s, 1221s,1016s cm- ; HRMS (ES+) calcd for C31H38NO3 m/z 472.2852
23

(M++1), meas 472.2840; ["]

D=

+28.6 (c 1.0, CH2Cl2) on 98% ee material (HPLC).

6.4.10 Preparation of (2S,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-2phenyl-3-((R)-tetrahydrofuran-2-yl)aziridine 83.
MEDAM

Ph

82 OH

MEDAM

NaH,

N

3 Br

THF, rt

N
Ph

83 O
94%

(2S,3S)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-2-phenyl-3-((R)-tetrahydro
furan-2-yl)aziridine 83 was prepared by treating compound 82 (83 mg, 0.15 mmol) with
NaH (60%, 12 mg, 0.30 mmol) in THF (6 mL) at room temperature for 24 h. The
reaction mixture was quenched by addition of 10 mL of H2O. The aqueous layer was
extracted with ethyl acetate (3 X 3 mL) and the combined organic extracts were dried
over sodium sulfate, filtered, and concentrated under vacuum. Purification of the

240

product by silica gel chromatography (1:3 ethylacetate/hexanes as eluent) gave 83 as a
white foamy solid (mp 54-56 °C) in 94 % yield (65 mg, 0.14 mmol). Spectral data for (S,
1

S, R)–83: Rf = 0.25 (1:3 ethyl acetate:hexanes). H NMR (500 MHz, CDCl3) ! 1.05-1.09
(m, 1H), 1.57-1.67 (m, 3H), 1.84-1.87 (dd, 1H, J = 6.5 Hz, 8.0 Hz), 2.18 (s, 6H), 2.27 (s,
6H), 2.83-2.84 (d, 1H, J = 6.5 Hz), 3.29-3.31 (q, 1H, 7.5 Hz), 3.48-3.52 (m, 1H), 3.56 (s,
1H), 3.63 (s, 3H), 3.68 (s, 3H), 3.66-3.70 (m, 1H), 7.10 (s, 2H), 7.12 (s, 2H), 7.16-7.19
(m, 1H), 7.24-7.28 (m, 2H), 7.39-7.40 (d, 2H, J = 7.0 Hz);

13

C NMR (125 MHz, CDCl3) !

16.43, 25.85,30.61, 47.24, 49.69, 59.80, 59.94, 68.50, 76.33, 78.50, 126.82, 127.82,
128.13, 128.19, 128.50, 130.62, 130.63, 137.39, 138.62, 139.06, 156.03, 156.34; IR
1

(thin film) 2947s, 1483s, 1221s,1016s cm- ; HRMS (ES+) calcd for C31H38NO3 m/z
23

472.2852 (M++1), meas 472.2836; ["]

D

= +73.4 (c 1.0, CH2Cl2) on 98% ee material

(HPLC).
6.4.11 Reductive ring-opening/deprotection/Boc-protection sequence
conversion of tetrahydrofurylaziridines to tert-butyl ((S)-2-phenyl-1-((R)tetrahydrofuran-2-yl)ethyl)carbamate 84.
MEDAM
N

H2, Pd(OH)2,
(Boc)2O, MeOH

Ph

83

for

NHBoc
Ph
O

84 70%

O

To a 25 mL round bottom flask fitted with a magnetic stir bar was added
tetrahydrufurylaziridine 83 (47 mg, 0.10 mmol), Pd(OH)2 (44 mg, 0.025 mmol, Pd(OH)2
on carbon powder, 20% Pd, ca. 60% moisture), (Boc)2O (65 mg, 0.30 mmol) and
methanol (3 mL). The flask was then equipped with a 3-way valve connected to vacuum

241

and a hydrogen balloon. The flask was opened to vacuum for a few seconds, and then
switched to the hydrogen balloon; this manipulation was repeated three times. The
reaction mixture was allowed to stir at room temperature for 24 h. It was then filtered
through a Celite pad and concentrated under vacuum. Purification of the product by
silica gel chromatography (1:7 ethylacetate/hexanes as eluent) gave 84 as a white solid
(mp 98-99 °C) in 70 % yield (20 mg, 0.070 mmol). Spectral data for (1R, 2S)–84: Rf =
1

0.15 (1:7 ethyl acetate:hexanes). H NMR (500 MHz, CDCl3) ! 1.37 (s, 9H), 1.77-1.78
(m, 1H), 1.89-1.98 (m, 3H), 2.82 (bs, 1H), 3.62-3.64 (dd, 1H, J = 4.5 Hz, 14.0 Hz), 3.763.83 (m, 2H), 3.87 (bs, 1H), 3.91-3.96 (m, 1H), 4.41 (bs, 1H), 7.20-7.23 (m, 3H), 7.287.31 (m, 2H);

13

C NMR (125 MHz, CDCl3) ! 25.69, 28.29, 28.39, 36.94, 54.32, 68.44,

79.16, 80.31, 126.19, 128.27, 129.65, 137.90, 155.45; IR (thin film) 3370s, 3030m,
1

2964s, 1684s, 1525s, 1365m, 1262s cm- ; HRMS (ES+) calcd for C17H26NO3 m/z
23

292.1913 (M++1), meas 292.1916; ["]

D

= –5.6 (c 1.0, CH2Cl2) on 98% ee material

(HPLC).
6.4.12 Reductive ring-opening/deprotection/Boc-protection sequence for
conversion of tetrahydrofurylaziridines to tert-butyl ((S)-2-phenyl-1-((S)tetrahydrofuran-2-yl)ethyl)carbamate 87.
MEDAM

Pd(OH)2

N
Ph

86

O

H2, MeOH
(Boc)2O,

NHBoc
Ph
O

87 72%

Tetrahydrufurylaziridine 86 (47 mg, 0.10 mmol), was subjected to the same ringopening/deprotection/Boc-protection sequence to afford compound 87 as a viscous oil

242

in 72% yield (21 mg, 0.72 mmol). Spectral data for (1R, 2R)–87: Rf = 0.17 (1:5 ethyl
1

acetate:hexanes). H NMR (500 MHz, CDCl3) ! 1.37 (s, 9H), 1.59-1.66 (m, 1H), 1.781.85 (m, 3H), 2.80-2.90 (m, 2H), 3.67-3.87 (m, 4H), 4.72-4.74 (d, 1H, J = 9.0 Hz), 7.177.27 (m, 5H);

13

C NMR (125 MHz, CDCl3) ! 26.04, 28.11, 28.35, 39.95, 54.09, 68.56,

78.47, 79.08, 126.17, 128.29, 129.46, 138.48, 155.93; IR (thin film) 3341m, 2976s,
1

1713s, 1496s, 1169s cm- ; HRMS (ES+) calcd for C17H26NO3 m/z 292.1913 (M++1),
23

meas 292.1924; ["]

D=

–23.0 (c 1.0, CH2Cl2) on 98% ee material (HPLC).

243

REFERENCES

244

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