III; .1

 

4‘ _
LIBRARY

2006 MiCL‘f" State
University

 

 

This is to certify that the
dissertation entitled

Symmetry as a Guiding Tool in the Development of Strategies
for the Synthesis of Calix[4]arenes and Related Macrocycles

presented by

Vijayagopal Gopalsamuthiram

has been accepted towards fulfillment
of the requirements for the

Ph.D. degree in Chemistry

 

 

Major Professor’SVSigr/tatureyb

5/716;

Date

MSU is an Affirmative Action/Equal Opportunity Institution

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2/05 cmeouemms

SYMMETRY
STRATEGIES IN T'

SYMMETRY AS A GUIDING TOOL FOR DEVELOPMENT OF
STRATEGIES IN THE SYNTHESIS OF CALIX[4]ARENES AND RELATED
MACROCYCLES

By

Vijayagopal Gopalsamuthiram

A DISSERTATION
Submitted to
Michigan State University

in partial fulfillment of the requirements
for the degree of

DOCTOR OF PHILOSOPHY
Department of Chemistry

2005

SYMMETRY

SmmuncW'
many objects nutur.
molecular structure
molecular properties i
this thesis rel) primcrr

three dlmcnsiunal slru

 

A new com cr:

regard for the prepuru

The studies described

mtegy and fall into tl

Calix[4]arenes with A

52-31mm)" were sx'nthe

dimes. This method

10171131101] in that it im

tallxareme and the Ir

ABSTRACT
SYMMETRY AS A GUIDING TOOL IN THE DEVELOPMENT OF
STRATEGIES FOR SYNTHESIS OF CALIXARENES AND RELATED
' MACROCYCLES
By
Vijaygopal Gopalsamuthiram

Symmetry commonly associated with beauty is a distinct feature present in
many objects natural or artificial. Sometimes the symmetry embedded in
molecular structures is either obvious or subtler nevertheless it affects the
molecular properties to a significant extent. The synthetic strategies explored in
this thesis rely principally on targeting certain symmetry elements present in the
three dimensional structure of calix[4]arenes.

A new convergent “Triple Annulation” approach has been realized in this
regard for the preparation of several calixarenes and other related macrocycles.
The studies described herein are exploratory so as to examine the scope of this
strategy and fall into three broad categories.

Calix[4]arenes with ABAB and ABAC substitution pattern exhibiting C 2 and C5
symmetry were synthesized directly via the reaction of bis-carbene complexes and
diynes. This method is unique compared to existing methods for calix[4]arene
formation in that it involves the formation of two of the four benzene rings of the

calixarene and the macrocyclic ring of the calixarene in the same step. The

ssntheses of calixll

outer rims “as. also ;~.

 

macrocycles was cm:

One of the n:
approach is that the
identical and this ur.
sinthesis of chiral n

simmetn'. These cali

 

to this study and hol
blocks for \arict} oi
stereoisomers ol‘ n‘.
demonstrated during ‘-

Homocalixli
conformational rigid
preparation. The ma
the construction of

horn ~ . .
Okah"‘I'iiarcnc.

syntheses of calix[4]arenes with specific substitution patterns in the inner and
outer rims was also accomplished by this strategy and the conformations of these
macrocycles was examined in detail.

One of the most important attractive features of the “Triple Annulation ”
approach is that the two adjacent arene rings of the calix skeleton are non-
identical and this unique feature has been exploited in developing an efficient
synthesis of chiral methylene substituted calix[4]arenes with either C 2 or C1
symmetry. These calix[4]arenes were an unknown class of supramolecules prior
to this study and hold significant potential for development as chiral building
blocks for variety of applications. Moreover, the syntheses of several regio and
stereoisomers of methylene functionalized calix[4]arenes has also been
demonstrated during the course of this work.

Homocalix[4]arenes have been less examined due to the lack of
conformational rigidity in these macrocycles and the limited methods for their
preparation. The macrocyclization of bis-carbene complex and diyne allows for
the construction of larger macrocycles as illustrated in the synthesis of 3 bis-

homocalix[4]arene.

”I grand!“

Dedicated to the loving memory of
My grandparents Mr. GK. Venkatraman, Mrs.Lakshmi Venkatraman

and Mr.A. T immalachari

iv

I would dCC
for his immense hel
me user the past to
commitment to all
Professor \l'uli‘l‘ In
times in the lab and

I would also
been of immense h:
other committee me:

I would also
their useful commcn
Abhi Nianasi. Bani
alot through my doc
Wm group membe;

my Studies.

Finally. I \M

ACKNOWLEDGEMENTS

I would deeply like to express my gratitude to Professor William D. Wulff
for his immense help, patience, innovative ideas and suggestions that he has given
me over the past five years. It has been truly an honour to work with him and his
commitment to all aspects of synthetic chemistry is profoundly appreciated.
Professor Wulff has been more like a father to me guiding me through difficult
times in the lab and also has been a tremendous source of inspiration.

I would also like to thank my second reader Professor Maleczka who has
been of immense help in tackling problems related to my research and also my
other committee members Professor Smith and Professor Tepe.

I would also like to thank my former lab mates Mike, Hongjao, Jun for
their useful comments and suggestions. I would also like to thank Manish, Reddy,
Abhi / Manasi, Bani, Somnath whose fiiendship and moral support has helped me
a lot through my doctoral study. I would like to express my gratitude to all other
Wulff group members with whom I have had memorable experiences throughout
my studies.

Finally, I would like to thank my parents Dr.K.V.Raman, Mrs.Usha
Raman, my brother Arvind and my grand mother Mrs.Komalam Tirumalachari

for their never-ending love and support throughout the past five years. I would

3-11 "P‘f. r. «all

 

also like to extend r.

appreciation over the

 

 

also like to extend my gratitude to Miss. Lavenya for her constant support and

appreciation over the last few months.

vi

-‘ril‘vrii '

inrorSCHEXHJ
tnrorrABLES'
usrorFIGL'RlES
usrorABBREVI
CHAPTER()\E:|

ll fhstoi
12 lmt”
r3 Cbnh
l4 Funct
15 Chira'
1.6 Xicth}
1.7 Home
1.3 Sumrr

CHAPTER TWO: '
nrrusrouct’t

lntem‘
Pre\l0
Triple

Intesu

'9 rd ’4
94 'J H

CIIIPTER TH RE E
St IIIIETRICAL A

3.1
3.2
3.3
3.4

Triple
Practic
Synthe
ETI‘CCIl
annular
Calix[l
1 Examir
3-6 Confi
3.7 S on
umma

3.5

TABLE OF CONTENTS

LIST OF SCHEMES ..................................................................... viii
LIST OF TABLES ........................................................................ xiv
LIST OF FIGURES ........................................................................ xv
LIST OF ABBREVIATIONS .......................................................... xviii

CHAPTER ONE: INTRODUCTION TO CALIXARENES

1.1 Historical perspective on calixarene syntheses ...................... 1

1.2 Physical properties of calix[4]arenes ................................ 12
1.3 Conformations of calix[4]arenes ..................................... 14
1.4 Functional group modifications of calix[4]arenes ................. 17
1.5 Chiral calix[4]arenes ................................................... 23
1.6 Methylene functionalized calix[4]arenes ............................ 28
1 .7 Homocalix[4]arenes .................................................... 44
1.8 Summary and Future directions ...................................... 48

CHAPTER TWO: INTRODUCTION TO THE INTER AND
INTRAMOLECULAR BENZANNULATION REACTION

2.1 Intermolecular benzannulation ...................................... 50

2.2 Previous studies on intramolecular benzannulation ............... 60

2.3 Triple annulation strategy to calixarenes: A systematic
investigation ............................................................ 75

CHAPTER THREE: EVOLUTION OF A NEW STRATEGY TOWARDS
SYMMETRICAL AND UNSYMMETRICAL CALIXARENES

3.1 Triple annulation approach towards calixarenes .................. 81
3.2 Practical synthesis of bispropargyl arenes .......................... 85
3.3 Synthesis of the bis-carbene complex ............................... 89
3.4 Effect of solvent, temperature and concentration on tn'ple
annulation ............................................................... 90
3.5 Calix[4]arenes with ABAB and ABAC substitution pattern ——
Examination of substrate scope .................................... 92
3.6 Conformational elucidation of calix[4]arenes ..................... 93
3.7 Summary ............................................................... 109

vii

'r-gv‘

37 Inlhesigt

CHAPTER FOl'R
SYNTHESIS OF F
4d I)C\l
4.1.1
4.1.2
4.1.3
7
4.. SUmman_
Sign?“ FIVE: H
i E“: COMPL
5.1
5.2 HOmOCali\
33 repar3U(n
5.4 I'thSis (
reparallor

56 Tnpie annL

”mman'. '

 

CHAPTER FOUR: CHEMO, REGIO AND ENANTIOSELECTIVE
SYNTHESIS OF METHYLENE FUNCTIONALIZED CALIX[4]ARENES

4.1 Design of a new method for chiral calix[4]arene syntheses... . ..1 10

4.1.1 Triple annulation strategy towards di and tetrasubstituted
calix[4]arenes ................................................. 1 12
4.1.1.1 Chiral bis-propargyl alcohols 274 .................. 113
4.1.1.2 Chiral and mesa bis-carbene complexes 268. . ...1 19
4.1.1.3 1,2-Disubstituted calix[4]arenes 257 .............. 121
4.1.1.4 Tetramethoxy calix[4]arene (rtct isomer)
263 ..................................................... 124
4.1.1.5 Tetramethoxy calix[4]arene (rcct isomer)
261 ..................................................... 125
4.1.1.6 Tetramethoxy calix[4]arene 262 (rctt
isomer) ................................................. 126
4.1.2 Triple annulation strategy towards mono and trisubstituted
calix[4]arenes ................................................. 127
4.1.2.1 Synthesis of monochiral bis-propargyl alcohol
285 ...................................................... 128
4.1.2.2 Chiral monomethoxy calix[4]arene
256 ..................................................... 132
4.1.2.3 Trimethoxy calix[4]arene (rtc isomer)
260 ...................................................... 133
4.1.2.4 Trimethoxy calix[4]arene (rcc isomer)
259 ..................................................... 134
4.1.3 1,3-Disubstituted calix[4]arene 258 by triple annulation/
dimerization pathway ........................................ 136
4.2 Summary .................................................................... 144

CHAPTER FIVE: HOMOCALIX|4]ARENE BY REACTION OF BIS-
CARBENE COMPLEX 318 AND DIYNE 317

5.1 Homocalix[4]arenes by triple annulation strategy ..................... 145
5.2 Preparation of the diyne 320 ............................................. 146
5.3 Synthesis of bis-carbene complex 318 .................................. 146
5.4 Preparation of bishomocalix[4]arene 211 ............................... 147
5.5 Triple annulation by dimerization of complex 319 .................... 148
5.6 Synthesis of complex 319 ................................................. 150
5.7 Summary .................................................................... 153

viii

man-—

 

 

CHAPTER SIX C1

CHAPTER SE\'E\

REFERENCES .A.\l

CHAPTER SIX CONCLUSIONS AND FUTURE DIRECTIONS. . . . . ....154

CHAPTER SEVEN EXPERIMENTAL PROCEDURES ................... 159
APPENDIX .............................................................................. 261
REFERENCES AND NOTES ........................................................ 294

ix

Jun: l‘qt"! ..

Schemfi 1-1 Pi
Scheme 1-2 SI
scheme 1.3 0‘
Scheme 1.4 13*
Scheme 1.5 12°
Scheme 1-6 SC]
Scheme 1.7 I"
Scheme 1 .8 I I“
Scheme 1.9 14" I
Scheme 1.10 3X1

Scheme 1.11 Rin!

Scheme 1.12 Sle'

Scheme 1. 13

Selec
Scheme 1.14 Steret
calixl-

Scheme 1.15 E iL‘Cirt

Scheme 1.16

Selecti

Scheme 1.17 Chiral .

Scheme 1.18 Chiral
functio

 

Scheme 1.1
Scheme 1.2
Scheme 1.3
Scheme 1.4
Scheme 1.5
Scheme 1.6
Scheme 1.7
Scheme 1.8
Scheme 1.9
Scheme 1.10
Scheme 1.11
Scheme 1.12
Scheme 1.13

Scheme 1.14

Scheme 1.15
Scheme 1.16
Scheme 1.17

Scheme 1.18

LIST OF SCHEMES
Possible pathway for oligomerization under basic conditions ....... 4
Stepwise calixarene synthesis ............................................ 6

Oxo-methylene bridged calix[4]arenes by stepwise condensation..7

[3+1] Fragment condensation of trimer 22 and phenol 23. . . ...8
[2+2] Fragment condensation of dimer 26 and 27 .................... 9
Self condensation of dimer 28 ............................................ 9
[2+1+1] Fragment condensation of dimer 30 and 31 ................ 10
Head to Tail linked double calix[4]arene 36 .......................... 10
[4x1] Fragment condensation to 38 .................................... 11
[2x 1+ 2x1] Fragment condensation of 39 and 40 ................... 11
Ring inversion in calix[4]arene ........................................ 17

Synthesis of specific conformers of calix[4]arene tetraethers. . 19
Selective functionalization of calix[4]arene .......................... 20

Stereochemical control in formation of unsymmetrical
calix[4]arenes ............................................................. 22

Electrophilic aromatic substitutions on 53 and 54 ................... 22
Selective functional group transformations of calix[4]arenes. . ...23
Chiral calix[4]arene with molecular asymmetry .................... 24

Chiral calixarene 68 and 70 by lower and upper rim
functionalization ........................................................ 25

Scheme I I 9 I:
Scheme 1.20 L“
Scheme 1.21 13‘

Scheme 1.22 0“

Scheme 1.23 .\1ic
{rd/.7

Scheme 1.2-l Tetr.
Scheme 1.25 First

Scheme 1.26 Lewi

Cinna

Scheme 1.27 Milllt
and 1.

Scheme 1.28 Malor

 

Scheme1.29 Sulfur

homoc
Scheme1.30 Coupli
Scheme1.31 Basec

mnme
S‘Cht’mell Reach:
55116111622 Oteral
Scheme23 Regim
Scheme24 Asymri

 

Scheme 1.19

Scheme 1.20

Scheme 1.21

Scheme 1.22

Scheme 1.23

Scheme 1.24

Scheme 1.25

Scheme 1.26

Scheme 1.27

Scheme 1.28

Scheme 1.29

Scheme 1.30

Scheme 1.31

Scheme 2.1

Scheme 2.2

Scheme 2.3

Scheme 2.4

[2+2] Fragment condensation to monomethylene substituted
calix[4]arene ............................................................ 33

Lithiation / Trapping with electrophile to monofunctionalized

calix[4]arene 86 ...................................................... 34
[2+2] Fragment condensation to methylene disubstituted
calix[4]arene ........................................................... 35
Oxidation of 19d to spirodienones 98, 99 and 100 ............... 37
Michael addition to spirodienone in preparation of

trans-104 ............................................................... 38
Tetrafunctionalization of calixarenes 19d and 52 ................ 39
First examples of inherently chiral resorcinarenes. . . . . . . . . . . .....42
Lewis acid catalyzed tetrametrization of 2,4-dimethoxy
cinnamic acid derivatives ............................................ 43
Miiller Roscheisen cyclization to homocalix[4]arenes 120

and 121 ................................................................. 45
Malonate cyclization ................................................. 45
Sulfur extrusion approach to unsymmetrical

homocalix[4]arene 127 .............................................. 46
Coupling by intramolecular displacement on 129 ................ 47
Base catalyzed phenol formaldehyde condensation in

synthesis of 132 ...................................................... 47
Reaction pathway of the intermolecular benzannulation ....... 50
Overall mechanistic picture for phenol formation ............... 51
Regioselectivity in phenol formation .............................. 5 3

Asymmetric benzannulation with chiral center on heteroatom

xi

 

Scheme 2.5
Scheme 2.6

Scheme 2.7
Scheme 2.8

Scheme 2.9

Scheme 2.10
Scheme 2.1 1

Scheme 2.12
S'Cheme 2.13
53161116 2.14
SChcme 2.15
Siheme 2.16
Scheme 3.17
Scheme 2.18

scheme 2.19

Scheme 220

S

cheme 2.2]

and
As)
Ster

Asy

on

Cycl
onh

Cycl

As} r
and a

Intrar
the 1

Semn
Finn‘
Et‘t‘ec
C} cll
Aldol
[)0le
Regin

[2'1]ch
fIOm

MCCh;

MCChe

Scheme 2.5

Scheme 2.6

Scheme 2.7

Scheme 2.8

Scheme 2.9

Scheme 2.10

Scheme 2.11

Scheme 2.12

Scheme 2.13

Scheme 2.14

Scheme 2.15

Scheme 2.16

Scheme 2.17

Scheme 2.18

Scheme 2.19

Scheme 2.20

Scheme 2.21

and carbon substituents ............................................... 55
Asymmetric benzannulation with chiral propargyl ethers ....... 56
Stereochemical model for formation of 150A ..................... 57

Asymmetric cyclohexadienone annulation with chiral center
on or carbon ........................................................... 5 7

Cyclohexadienone annulation with imidazolidinone auxillary
on heteroatom ......................................................... 58

Cyclohexadieone annulation with chiral propargyl ethers..... . .58

Asymmetric benzannulation in generation of planar and

and axial chirality ..................................................... 59
Intramolecular benzannulation by tethering alkyne through

the heteroatom ........................................................ 61
Semmelhack’s study toward dexoyfrenolicin ...................... 61
Finn’s formal synthesis of deoxyfrenolicin ....................... 62
Effect of tether length on product formation ...................... 63
Cyclophane synthesis by macrocyclization ....................... 63

Aldol methodology to form unsaturated carbene complexes...64
Double benzannulation of bis-carbene complex and diyne. . ...66
Regiochemistry switch in intramolecular benzannulation... . ..67

Unexpected formation of metacyclophane 178D

from cyclization of 192B ............................................ 69
Mechanism of intramolecular benzannulation of 192. . . . . ........71
Mechanism of formation of meta-bridged phenol 202 ........... 73

xii

2 ' 1.
Scheme 2.2- Post

. 1, ‘
Scheme 2.-) C an

Scheme 2.24 Tan.

Scheme 3.1

Scheme 32
Scheme 3_3
Scheme 34
Scheme 35

SCheme 4.1

Scheme 43

SCIICme 4.3

SChEme 44

Scheme 46
Scheme 4.7

Sfileme 4.9

3 C3\

hum .

Genet
S)'1r..'

Pdl 11
Dom,
Prep;

1
Niecl.

Genet

Cain‘.
Cant;

Tranxf
[mo 1th

C0mp

Prci‘ar
1551-1

5.1mm
COmph

 

Scheme 2.22

Scheme 2.23

Scheme 2.24

Scheme 3.1

Scheme 3.2
Scheme 3.3
Scheme 3.4
Scheme 3.5

Scheme 4.1

Scheme 4.2

Scheme 4.3

Scheme 4.4
Scheme 4.5

Scheme 4.6

Scheme 4.7

Scheme 4.8

Scheme 4.9

Postulated mechanism to explain solvent effect ................... 74

Cartoon illustrating typical reaction process within
a cavitand ............................................................... 76

Triple annulation strategy towards calix[4]arenes and
homocalix[4]arenes ................................................... 80

General strategy towards calix[4]arenes with specific
symmetry elements ................................................... 83

Pd(II) and Cu(I) catalyzed coupling in synthesis of 239A. . .....85

Domino cross coupling sequence to bis-propargyl arenes. . .....86
Preparation of aryl triflate 241 ...................................... 87
Mechanism of conformational exchange ......................... 108

General strategy towards 1,2—di and tetrasubstituted
calix[4]arenes ........................................................ 1 13
Carreira’s method of asymmetric alkyne addition. . . . . . .....1 14

Transformation of mesa-propargyl alcohol

Into optically active 274A .......................................... 116
Addition of ethynyl Grignard to 273 .............................. 1 18
Comparison of Midland reduction of diynones 276A-C.....119
Preparation of chiral biscarbene complexes (RR) and

(S,S)-268 ............................................................. 120
Synthesis of pentacarbonyl methoxy t-butyl carbene

complex 281 ......................................................... 120
(S,R)-Biscarbene complex 284 ..................................... 121
Steric destabilization of cone conformation in 257A .......... 122

xiii

 

Scheme 4.10
Scheme 4.1 1
Scheme 4.12
Scheme 4.13
Scheme 4.14

Scheme 4.15
Scheme 4.16
Scheme 4.17.

Scheme 4. 18
Séheme 4,19
SChcme 4.20

Scheme tn

S~ , ‘
themetzj

gimme 4.24

Stem
dNI

   

TCIT.:
COIIII‘

T6111:
bis-c.

Cain

and d

 

Genet

calix
Chen
Kine:
Syntl~

Mont
comp‘

TF1 III C
Comp}

Tlime
DIS-Cd

 

Tl”little
AIICm

9111le
“no u.

AIdQ] 1

Aldo] r

Scheme 4.10

Scheme 4.11

Scheme 4.12

Scheme 4.13

Scheme 4.14

Scheme 4.15
Scheme 4.16
Scheme 4.17

Scheme 4.18

Scheme 4.19

Scheme 4.20

Scheme 4.21
Scheme 4.22

Scheme 4.23

Scheme 4.24

Scheme 4.25

Steric effect on triple annulation and conformer
distribution .......................................................... 123

Tetramethoxy calix[4]arene 263 by triple annulation of

complex (R,R)-268 and diyne (R,R)-267A ..................... 124
Tetramethoxy calix[4]arene 261 from reaction of chiral
bis-carbene complex (S,S)-268 and diyne (S,R)-282 ......... 125
Calix[4]arene 262 from reaction of complex (R,R)-268

and diyne (S,S)-267A ............................................. 127
General strategy towards mono and trisubstituted
calix[4]arenes ...................................................... 128
Chemoselective alkyne addition to dialdehyde 273 .......... 129

Kinetic resolution of terminal propargyl alcohol (S)-290. . . 130
Synthesis of unsymmetrical diyne (S)-285 .................... 132

Monomethoxy calix[4]arene by triple annulation of
complex 229A and diyne (S)-285 .............................. 133

Trimethoxy calix[4]arene 260 by triple annulation of
complex (S,S)-268 and diyne (S)-285 ......................... 134

Trimethoxy calix[4]arene 259 by reaction of mesa
bis-carbene complex 284 and diyne (S)-285 .................. 135

Triple annulation by dimerization of complex 298. . . 1 36

Attempted synthesis of alkynyl carbene complex 298A ..... 137

Alternative approach to alkynyl carbene complex 298A
with desilylation as the last step ................................ 138

Aldol methodology to carbene complexes 298 and 305 ..... 139

Aldol reactions with phenyl acetaldehyde .................... 139

xiv

Scheme 4.26
Scheme 4.27
Scheme 4.28
Scheme 4.29
Scheme 5.1
Scheme 5.2
Scheme 5.3

Scheme 54
Scheme 5.5
Scheme 5.6

Scheme 57
Scheme 5. 8
Scheme 59
SL1"Hoe 5.10

Scheme 6.4

 

 

Scheme 4.26

Scheme 4.27

Scheme 4.28

Scheme 4.29

Scheme 5.1

Scheme 5.2

Scheme 5.3

Scheme 5 .4

Scheme 5.5

Scheme 5.6

Scheme 5.7

Scheme 5.8

Scheme 5.9

Scheme 5.10

Scheme 6.1

Scheme 6.2

Scheme 6.3

Scheme 6.4

Mechanism of elimination of mesylate 308 ................ 140
Preparation of chiral vinyl iodide 314 ....................... 141
Triple annulation / dimerization of complex 298 .......... 142
Possible explanation for observed diastereoselectivity...144
Triple annulation strategy towards larger macrocycles...145
Synthesis of the bis-carbene complex 318 .................. 147
Triple annulation to bis-homocalix[4]arene 211 ........... 148

Triple annulation of complex 327 and diyne 326- Not a
feasible route towards target 212 ............................. 148

Triple annulation by dimerization of complex 329 to

chiral bis-homocalix[4]arene 212 ............................ 149
Inter vs intramolecular benzannulation leading to 211

or 330 ............................................................. 150
Dianion approach to carbene complex formation .......... 151
Aldol approach for carbene complex formation ............ 151
Attempted preparation of aldehyde 340 ..................... 152
Alternative approach to carbene complex 319. . . . . ....153

Synthetic strategy towards conformationally locked
calix[4]arenes in the partial cone and 1,2-alternate
conformation ................................................... 1 5 5
Double calix[4]arene by heptannulation ................... 156

Triple annulation approach towards equatorially
substituted calix[4]arene 354 ................................. 157

Proposed synthesis of chiral bis-homocalix[4]arene

XV

 

'3
'1!
~ I

Scheme 6.5 Syn
329

357 ............................................................... 158

Scheme 6.5 Synthetic strategy for chiral alkynyl carbene complex
329 ............................................................... 158

xvi

 

Table 2.1
Table 2.2

Table 2.3

Table 2.4
Table 3.1
Table 3.2
Table 3.3

Table 3.4

Tab1e35
Tab1e3.6

Table 3.7
Table :11

Table 42

\Iac'

 

Prep.

Slat:
leng'

Solx .
CTO\~
S} m:
Synt‘!

SOD c
annui

SUI\ c

 

Chem
as the

Dldxlg
Sbeu

EnZyr

Table 2.1

Table 2.2

Table 2.3

Table 2.4

Table 3.1

Table 3.2

Table 3.3

Table 3.4

Table 3.5

Table 3.6

Table 3.7

Table 4.1

Table 4.2

LIST OF TABLES

Macrocyclizations of Fischer carbene complexes ................ 65
Preparation of alkenyl complexes 192 .............................. 68
Macrocyclizations of complexes 192 as function of tether

length ................................................................... 70
Solvent effect on product distribution .............................. 72
Cross coupling reactions of aryl triflate 226 ....................... 88
Synthesis of bis-propargyl arenes ................................... 89
Synthesis of bis-carbene complexes ................................ 89

Solvent, temperature and concentration effect on triple

annulation .............................................................. 91
Triple benzannulation of complex 229 and diyne 228 ........... 92
Solvent effect on conformer distribution in 247A ............... 101

Chemical shifts of aromatic hydrogens of 247A in DMSO-d6
as the solvent ......................................................... 102

Diastereo and enantioselectivity in double alkyne addition to
substituted isophthaldehyde ........................................ 1 16

Enzymatic resolution on 287: Optimization studies. . . . . . 132

xvii

 

Figure 1.1 A cu
Figure 1.2 H} d:
Figure 1.3 Sche
Figure 1.4 Calls
Figure 1.5 Chtra
Figure 1.6 l :1 c.

Figure 1.7

 

 

Stere
Figure 1.8 51ch
Figure 1.9 Sterc‘

C31“:
Figure 1.10 List 0
Figure 1.11 Resor
Figure 1.12 COTTII
Flgme 1.13 Steret
Flgwe 1.14 Homt
FIE’UFE 1.15 Conft
Flglll’e 2.1 SVnth
Figure 2.2 pow

17713
F1Elite 2.3

B‘Elu

 

Figure 1.1
Figure 1.2
Figure 1.3
Figure 1.4
Figure 1.5
Figure 1.6
Figure 1.7
Figure 1.8

Figure 1.9

Figure 1.10
Figure 1.11
Figure 1.12
Figure 1.13
Figure 1.14
Figure 1.15
Figure 2.1

Figure 2.2

Figure 2.3

LIST OF FIGURES
(Images in this thesis are presented in color)

A calix[4]arene in the cone conformation ............................ 1

Hydrogen bonding in calix[4]arene monoanion from 42 .......... 12
Schematic representation of all four possible conformers. . . . . 14
Calixarene mono and dianions ........................................ 21
Chiral calix[4]arenes for molecular recognition .................... 27
1:1 complex between N-acetyl D-alanyl alanine and 76 .......... 27
Stereoisomers formed upon monosubstitution ..................... 29
Stereoisomerism in 1,3 disubstituted calix[4]arene ................ 31

Stereoisomerism in proximal or 1,2-disubstituted

calix[4]arene ............................................................ 32
List of calixarene carbamates and amides ........................... 36
Resorcinarene with all cis methylene substituents ................. 39
Conformations of resorcinarenes ...................................... 40
Stereoisomerism at the methylene bridges .......................... 41
Homocalix[4]arene ..................................................... 44
Conformers of homocalix[4]arene .................................... 48
Synthetic targets of the benzannulation reaction .................... 60
Possible intermediates in the intramolecular benzannulation of

177B ...................................................................... 65
B-Endo and exo pathways for macrocyclization ................... 66

xviii

 

Hgme24
hgue25
hguelb
Fgmell

nge31

hmm32

3

(I)

FQME

nge34
FlE’Ure35

Figure 3.6
Figure 3.7
Hgge38
Figure 3.9

Figure 3.10
HRHe3il

Figure 42

(t-Ef

 

Con:
Bub-
Can

Shh?
synm

Eflbt
conR

Cont

 

Enerd
247A

Enen
CORR

Tron
N01.
N01;
SAME

600!
8151

Chrn
inten

Sure
SubSt

(lura

Figure 2.4
Figure 2.5
Figure 2.6
Figure 2.7

Figure 3.1

Figure 3.2

Figure 3.3

Figure 3.4

Figure 3.5

Figure 3.6
Figure 3.7
Figure 3.8

Figure 3.9

Figure 3.10

Figure 3.11

Figure 4.1

Figure 4.2

or-Endo and exo pathways for macrocyclization ................... 67

Common approaches to obtaining larger cavity sizes ............. 77
Bishomocalix[4]arene 211 and its chiral analog 212 .............. 78
Cavitand hosts and cavitate 216 ...................................... 79

Methods of calix[4]arene synthesis based on

symmetry classification ................................................ 81
Effect of hydrogen bonding on the stability of cone

conformation ............................................................ 84
Conformations of calix[4]arenes 246A-D ........................... 95

Energy minimized structure of the 1,2-a1temate conformer of

247A ...................................................................... 96
Energy minimized structures of partial cone and 1,3-alternate
conformers .............................................................. 97
Typical modes of weak aromatic interactions ...................... 98
NOE’s observed on major isomer ................................... 99
NOE’s observed on minor isomer .................................. 100
Syn and anti conformations of 1,2-dimethyl ether 255 .......... 101

600 MHz EXSY spectrum of 247A in DMSO-d6
at 50°C ................................................................ 104

Currently accepted pathway for conformational
interconversion ....................................................... 1 07

Stereoisomers resulting upon introduction of a single
substituent at the bridge .............................................. 1 10

Chiral calix[4]arenes 256—263 with C1 and C2 symmetry... . ....1 ll

xix

 

Figure 4.3

Figure 4.4

Figure 4.5
Figure 4.6
Figure A1
Figure A2

Figure A3

RL'I.:
and

Prop
rcdt.

Cont

 

Tth

Con.

Cali»

Struc

 

Figure 4.3

Figure 4.4

Figure 4.5
Figure 4.6
Figure A.1
Figure A.2

Figure A.3

Relative stereochemical assignment by correlation to alkoxy

and thio substituted analogs 264-266 ........................... 112
Proposed intermediates by Midland in asymmetric ketone

reduction ............................................................ 117
Conformation of tetrahydroxy calixarene 257C ............... 124

Theoretical distribution in cyclization of complex 298 ...... 143

Cone conformer of calix[4]arene 246A ........................ 262
Calix[4]arene 246C-I in cone conformation ................... 271
Structure of 246C-Il- 1,2-altemate .............................. 279

XX

 

DSIF
.AlC 13
BINOL
.\'.\1R
ESl MS
LDA

C DC 1;.
THF
HPLC
C11 C01,
NOE
D1130
cs:
C2D3CL
CC14
EXSY
Mxnr
HMPA

TBS

TBSort

 

 

DMF
AlCl3
BINOL
NMR
ESI/MS
LDA
CDCI3
THF
HPLC
Cr(CO)6
NOE
DMSO
CS2
C2D2Cl4
CC14
EXSY
MM94
HMPA
TBS

TBSOTf

LIST OF ABBREVIATIONS

N,N-Dimethyl formamide
Aluminum trichloride

1, 1 ’-Bi—2-naphthol

Nuclear magnetic resonance
Electrospray ionization mass spectrometry
Lithium diisopropylamide
Chloroform-d

Tetrahydrofuran

High pressure liquid chromatography
Chromium hexacarbonyl

Nuclear overhauser effect

Dimethyl sulfoxide

Carbon disulfide
Tetrachloroethane-d2

Carbon tetrachloride

Chemical exchange spectroscopy
Molecular mechanics 94 calculations
Hexamethyl phosphoramide

tert-butyl dimethylsilyl

tert-butyldimethylsilyl trifluoromethanesulfonate

xxi

 

D30
TLC
HSIQC

S-PHOS

 

D20 Deuterated water

TLC Thin layer chromatography
HMQC Heteronuclear multiple quantum coherence
S-PHOS Buchwald’s biaryl phosphine ligand 324

xxii

1.1 Historical 1
Many of l:
ingenious (011 1h"
Zinke found that
protided cyclic t
identification of th.
atailable till the
subsequently deyc
oligomers that con.
be cyclic tetramer l'
The classical defin:
the non-planar aro:
‘0 PTOVide a CUp
conformation. A ca-
Well as an "annulus

Fitzure 1.1

ATTITUIL

 

CHAPTER ONE

INTRODUCTION TO CALIXARENES

1.1 Historical perspective of calix[4]arene synthesis

Many of the discoveries in science are often made by accident rather by an
ingenious (or) thought provoking ideas. Such a discovery was made in 1940’s when
Zinke found that the base induced reaction of p-alkyl phenols with formaldehyde
provided cyclic oligomers as the predominant products.1 The exact structural
identification of the original Zinke mixture as well as a practical synthesis was not made
available till the 19705 when Gutsche and coworkers reinterpreted his results and
subsequently developed methods for selectively accessing three of the major cyclic
oligomers that comprised the Zinke mixture in reproducible yields.2 These were found to
be cyclic tetramer (Calix[4]arene), hexamer (Calix[6]arene) and octamer (Calix[8]arene).
The classical definition of the term calix[4]arene refers to macrocycles wherein four of
the non-planar aromatic rings are linked by methylene bridges in the meta position so as
to provide a cup or bowl-like structure, more commonly referred to as the cone
conformation. A calix[4]arene is often characterized by an “Upper and Lower rim” as

well as an “annulus”. (Figure 1.1)

Figure 1.1 Calix[4]arene in a cone conformation

Upper Rim :>

Annulus 1:9

 

Lower Rim 12:9 ()11 ()11 OH HO

After three

 

remarkable adsar.
calixarene synthe
ranging from meta
delivery systems.
(enzyme mimicsl

chapter will briefly

 

 

the preparation of c

1.1.1 Base cataly
The base in
step synthesis of 11

a the “Modified

“Modified Petrolil
Petrolite Procedur
will enumerate th

Efllnlng access to c
.\

lodifred Zinke-(

formaldehyde sol!

resPtct to the pher

Pfecursor” The
‘ T

cooled and tr

33161

After three decades since the pioneering work done by Gutsche, there have been
remarkable advances made not only with respect to development of new methods for
calixarene synthesis but also in their applications, which display a broad spectrum
ranging from metal-ion complexation, inclusion of organic molecules pertinent as drug
delivery systems, ligands in coordination chemistry and catalysis, synthetic receptors
(enzyme mimics) and even as stationary phases in chromatography.3 The following
chapter will briefly address the different synthetic routes that have been instrumental for
the preparation of calixarenes designed for such specific applications.

1.1.1 Base catalyzed phenol formaldehyde condensation process

The base induced synthesis is still regarded as the method of choice for a single
step synthesis of the cyclic oligomers. These processes have now been widely classified
as the “Modified Zinke-Comforth Procedure” which affords p-tert-butyl calix[4]arene,
“Modified Petrolite Procedure” which yields p-tert-butyl calix[6]arene and “ Standard
Petrolite Procedure” which yields p-tert-butyl calix[8]arene.4 The following discussion
will enumerate the reaction variables, which have been successfully implemented in
gaining access to each of the calixarenes.

Modified Zinke-Comforth Procedure: A mixture containing p-tert-butyl phenol, 37 %
formaldehyde solution, and sodium hydroxide corresponding to 0.045 equivalents with
respect to the phenol is heated for 2 h at 110-120°C to produce a resinous mass called the
“precursor”. The precursor is then heated in diphenyl ether for 2 h, the reaction mixture is
cooled and treated with ethyl acetate upon which a copious precipitate is removed by
filtration. Re-crystallization from toluene produces p-tert-butyl calix[4]arene [R = t-Bu

F igl.1] in 49 % yield as glistening white crystals.

    
  
  

WWI
fonnaldehy de sole.
respect to the phc'
heated in xylene ‘.
afford p-terl-bu:
chloroform aceto:

Standard Petrolite_

 

and sodium hydro‘
xylene is stirred a
precipitate is cry
glistening cry stals

The mech:
formaldehyde he
reactions that a
hI‘dmtytnethyl p
in Scheme 1.1 i
fOrrnation. Dehy
Conditions. Thug

dlbenzy] ether j

HPLC Studies W.

Modified Petrolite Procedure: A mixture containing p-tert-butyl phenol, 37 %
formaldehyde solution, and potassium hydroxide corresponding to 0.35 equivalents with
respect to the phenol is heated for 2 h to produce the precursor. The precursor is then
heated in xylene for 2 h, the reaction mixture is then cooled and treated as before to
afford p-tert-butyl calix[6]arene as the exclusive product. Crystallization from
chloroform / acetone provides the hexamer as white powder in 85 % yield.

_S_ta_nd_ard Petrolite Procedure: Slurry prepared from p-tert—butyl phenol, formaldehyde
and sodium hydroxide corresponding to 0.03 equivalents with respect to the phenol in
xylene is stirred and refluxed for 4 h. The cooled solution is filtered and the copious
precipitate is crystallized from chloroform to afford p-tert-butyl calix[8]arene as
glistening crystals in 65 % yield.

The mechanism by which calixarenes are formed from the reaction of phenol and
formaldehyde has been a matter unresolved for decades.5 The initial sequence of
reactions that are believed to occur involves hydroxymethylation to form an 0-
hydroxymethyl phenol 5 followed by an arylation via an o-quinone methide 7 as depicted
in Scheme 1.1 to form 8. Further sequence of reactions result in linear oligomer
formation. Dehydration to form dibenzyl ethers is also conceivable under the reaction
conditions. Thus, calixarenes probably arise from a mixture of diphenyl methane type and
dibenzyl ether intermediates in various degrees of oligomerization as was shown by

HPLC studies wherein at least three dozen non-cyclic components were present.

Scheme 1.1 Possible pathway for oligomerization under basic conditions

E) Q’V’o‘ —* {5&9
OH 0'“ H 3 o

(9
0) 086—— :30)” 90H:w

2

”—4 _. Linear Oligomers

Gutsche and coworkers have addressed the issue of how either of these putative

 

 

 

intermediates could be transformed to the cyclic oligomers.S They propose that a
hemicalix[8]arene is initially formed by dimerization induced by intermolecular
hydrogen bonding in a linear tetramer. The resultant hemicalix[8]arene undergoes an
extrusion of water and formaldehyde to yield calix[8]arene as the major product which
transforms to calix[4]arene by fragmentation / recombination pathway to a pair of cyclic
tetramers. The exact mechanism for calix[6]arene formation is not well understood but
believed to arise due to a template effect. Overall, cyclic octamer is postulated to be the
product of kinetic control, hexamer the product of template control and tetramer the

product of thermodynamic control.

The caret.
calixarene has ho.
phenols. The onl;
hexamer can be or
any of the cych
phenols"O afford t
octamers in poor
calixarenes with d.
affording mixture
Si“.916 step syntht

methodology.

 

 

1.1.2 Non comer

Slultistep s)
the method has the
the preparation of s

by hydroxymethy

The careful control of reaction conditions in the synthesis of p-tert-butyl
calixarene has however failed to provide useful calixarene syntheses from other p-alkyl
phenols. The only other successful example is in the case of p-cresol wherein only the
hexamer can be obtained in 74 “/0 yield.6 Electronically deactivated phenols do not afford
any of the cyclic oligomers. p-Benzyl7, p-etlry18,p-isopropyl9 and p-isopropenyl
phenolslo afford difficult to separate mixtures of cyclic hexamers, heptamers and
octamers in poor yields. p-phenyl phenol is an important substrate for synthesis of
calixarenes with deepened hydrophobic cavities,” but the reaction again is not selective
affording mixture of all the above in very low yields. The major disadvantage with the
single step synthesis is that only symmetrical calixarenes are accessible by this

methodology.

1.1.2 Non convergent stepwise strategy

Multistep syntheses of calix[4]arenes are often long and the yields are modest but
the method has the advantage of introducing different groups into p-positions allowing
the preparation of several unsymmetrical calixarenes. o-bromination of phenol 1 followed
by hydroxymethylation affords the o-hydroxymethyl phenol 10, which upon
deprotonation affords the phenoxide species 11. Loss of a hydroxide ion from 11 results
in the formation of o-quinone methide 12, which undergoes Michael addition from a
different phenol 13 to afford the dimer 14. A second Michael addition on the o-quinone
methide obtained from phenol 15 that has a different p-substituent affords the trimer 16,
which upon dehalogenation by hydrogenation affords the linear trimer 17. As the last step

in the sequence, the condensation reaction of this trimer 17 with another 2,6-bis-

 

hydroxymethil t"

another water mvl
Scheme 1.3

OH

\

l

/
Rt
I

 

An edep

calix[4‘5v618ren
CE

rDorated “m8

hydroxymethyl substituted phenol l8 affords the linear tetramer, which upon loss of

another water molecule results in formation of calix[4]arene 19 (Scheme 1.2).12

Scheme 1.2 Stepwise calixarene synthesis

0H , 0H on E?)

Br
E: —» I: —-» WU —» 3' ”SH
RI R1 R1

R1
1 9 10 11

on on OH 0H 0H B 0
Br Repeat Br r
O O O O O on
r
l 2 3 OH R' R2 R
R R R 14 12

 

   

 

16
3 R2 13
- 15
Dchalogenation
OH OH on R: R2 R4 R3
0 o o .. . ,
Rl R2 R2 OH HO
HO OH OH OH
17 19
R418

 

19a] R'= t-Bu, R2 = R3 = R4: Me, 52 %
Il9b]R'= R3 = t-Bu, R2 = R4: Me, 53 %
19c]R'= R2 = t-Bu, R3 = R4 = Me, 62 %
l9d]R' = R2 = R3 = R4 = t-Bu, 84 %

 

 

 

An example of this strategy was reported in the synthesis of carbonyl containing
calix[4,5,6]arenes 21 in modest yields by the acid catalyzed cyclization of the carbonyl

incorporated linear oligomers 20 (Scheme 1.3).l3

Schemlj 0mmem

 

 

1.13 Com erg?“
The non-Cr

preparation 01‘th

 

 

exem under hi gh d
convergent proccw
used.£4 Fragment «
substituents on ar
calixarenes. There
form the macrocyc

fiagment condense

Wis acid which .

Scheme 1.3 Oxo methylene bridged calixarene by stepwise condensation t-Bu

High Dilution
H
HCl-HOAc

 

= t-Bu

   

la 40 %
, 21b 37 "/0
, 21c 61 %

NNN

1.1.3 Convergent syntheses (Fragment condensation)

The non-convergent strategy suffers from the tedious and often cumbersome
preparation of the linear oligomers and also from the need to carry out the cyclization
event under high dilution conditions. Hence, it has been abandoned largely in favor of the
convergent processes for which the term “fragment condensation” has been frequently
used.14 Fragment condensation offers the same advantage of incorporating different
substituents on aromatic rings resulting in synthesis of asymmetrically substituted
calixarenes. There are four different strategies and, depending upon the fragments used to
form the macrocycle, they are conveniently labeled as [3+1], [2+2], [2+1+1], [1+l+1+1]
fragment condensations. All of them require the presence of a stoichiometric amount of

Lewis acid, which acts as a template for the formation of the macrocycle.

1.1.3.1 [3+1] Fragment coupling
Two successful approaches are known in the literature wherein Method A: The
condensation of the linear trimer with a bis-(halomethyl)-phenol affords the cyclic

tetramer15 and Method B: The condensation of bromomethyl containing linear trimers

with a phenol aft}
out under the in?
dioxane for extcr.
(Scheme 1.4). Tl‘

stnthesis of calix;

Scheme L4 [34}

 

OH OH

'H

Maths-1A i" - H. t?

t

“that 8 Y: (14.8, _

The reaction \icltL

 

as phenyl. benzox'l

1.13.2 [2+2] Frat".
The [2‘2] l
bis~t bromometth)

in - '.
‘~ C

with a phenol affords the same product in modest yields. Both these processes are carried
out under the influence of titanium tetrachloride as the lewis acid in hot or refluxing
dioxane for extended period of time and the yields of the products never exceed 40 %
(Scheme 1.4). The [3+1] Fragment condensation strategy is extremely useful for the

synthesis of calix[4]arenes with either C 2, CS or C1 symmetry.

Scheme 1.4 [3+1] Fragment condensation of trimer 22 and phenol 23

RI R2 R3 R4
Z
0 0 0
+ _—>
Y1 yl Y2 Y2 Dioxane, heat R3
OH OH OH OH
22 23

Method A: Y1: H, Y2: CHzBr or CHZOH
Method B: Y‘= CHzBr or CHZOH, Y2 = H

 

24Z=H
252=Me

The reaction yields are insensitive to varying substitution patterns at the p-positions such

as phenyl, benzoyl, chloro, propionate and nitro groups.

1.1.3.2 [2+2] Fragment coupling
The [2+2] Fragment condensation is similar to the previous strategy except that a
bis-(bromomethyl) or bis—(hydroxymethyl) dimer 27 with phenolic dimer 26 to form 24

in which again the same p-substituents as mentioned above can be introduced (Scheme

1.5).‘6

 

Scheme 1.5 i

T /—\' T

Br

h-..

A

Self-condensation
been used to prep;

Scheme Lb

 

Scheme 1.5 [2+2] Fragment condensation of dimer 26 and 27 R2

-.——,——~,::::.

Self-condensation of dimer 28, which possesses a single hydroxymethyl group, has also

 

been used to prepare C2 symmetric calixarenes such as 29 (Scheme 1.6).17

Scheme 1.6 Self condensation of dimer 28

 

1.1.3.3 [2+1+1] Fragment coupling
The [2+l+1] approach has been used predominantly in the synthesis of bridged
calixarene 32 from the reaction of bis(p-hydroxyphenyl)alkanes 30 with bis-

(bromomethyl) arene 31 (Scheme 1.7).18

 

1 951's“ ' u '

Semi? I24”) F'

(x)

\ \

J)” 0H

30

The yields
be dependent upor
conelation doesn‘t

of “head to tail" ltr

 

35 tethered \ia the

Scheme 1.8 "

()H “H

      

Scheme 1.7 l2+1+1] Fragment condensation of dimer 30 and 31

X
Me
TiCl
O O + B. . _4._.
OH OH OH
30 31

 

The yields for the calixarenes typically range from 2-20% and they were found to
be dependent upon the nature of the tether length and the p-substituent although a direct
correlation doesn’t seem to exist. Another unique example was reported in the synthesis
of “head to tail” linked double calixarene 36 in 4-5% yield from the reaction of diphenols

35 tethered via the lower rim of a calix[4]arene with 31 (Scheme 1.8).19

Scheme 1.8 "Head to Tail" linked double calixarene 36

,Bn

0 OR OR

.. p... E: :3 Q
' ’ (CH2)

. CH

OTs n (HZC)\ ( 2)“

  

33a n=3
33h n =4

 

34a, 34b R = Bn, 70-89%

Hz. Pd/C
35a, 35b R = H, 85-92%

‘Dibromide 31

 

10

k

l.13.4|l+l+l+l

A[I*l~t

 

formation of cal
present in the st,
hydroxymethylat-
carboxylic acids.

38 in npieally 1x-

 

 

Scheme l.9

An interesting a!
callxl‘ilarene 41 .

SCheme 1‘0 i2‘i*7x

1.1.3.4 [l+1+1+1]Fragment coupling

A [l+1+1+l] or (4x1) fragment condensation is analogous to the single step
formation of calix[4]arenes from phenols except that the methylene unit is already
present in the starting phenol. The starting materials are conveniently prepared by
hydroxymethylation of the phenols with formaldehyde and base or by reduction of
carboxylic acids. The reaction of o-(hydroxymethyl) phenol 37 produces calix[4]arenes

38 in typically 18-30 % yields (Scheme 1.9).l7

Scheme 1.9 [4 x 1] Fragment condensation to 38 R'
R1
R2 TiCl4
OH
OH
37

aR' =l-Pr,R2=Me
hR' =Ci,R2=Me

c R' = R2 = CH=CH-CH=CH2 R‘
d R1 = R2 = (CH2)4 38

 

An interesting application of this strategy was reported recently in the preparation of

calix[4]arene 41 with four axo-hydroxyl groups in 66 % yield (Scheme 1.10).20

Scheme 1.10 [2x1+2x1] Fragment condensation of 39 and 40

Me Me
C1 C1 SnCL;
+ ————>
Me Me Me Me EtN02
OH OH
39 40

 

ll

The abOVC my“

 

in 39 is bloech
cyclization prOdh
13 Physical p
1.2.] Acidity CO

The phen
intramolecular h}
Oning to the loo
soluble derit'atit e
3.36) was found It
relative to phenol.
regions than phen
calixarenes contatr
bonds. The net rese
however, the mot

ht -
.dIOgen-bgndg is

 

IhiPKal drops (10“

 

The above transformation is rather unique in that the ortho position of the phenolic group
in 39 is blocked and hence cyclization occurs from the meta position to give the
cyclization product 41.
1.2 Physical properties of calixarenes
1.2.1 Acidity constants and Hydrogen bonding

The phenolic hydroxy groups in calixarenes are known to form strong
intramolecular hydrogen bonds and hence its acid dissociation properties are affected.
Owing to the low solubility of proto-typical calixarenes such as 19d in water, water-
soluble derivative 42 was prepared. The dissociation of the first proton of 42 (pKal =
3.26) was found to occur at unusually low pH values representing a shift by 8 pKa units
relative to phenol. Subsequent dissociation of the protons occurs at normal or higher pH
regions than phenol (Pka; = 11.8, Pka3 = 12.8 and Pk... = 14).” The undissociated
calixarenes contain a circular hydrogen-belt composed of four intramolecular hydrogen
bonds. The net result of this stabilization may suppress the dissociation of the first proton,
however, the mono-dissociated species comprised of one oxide anion and three
hydrogen-bonds is more stabilized by stronger intramolecular hydrogen bonding. Hence,

the pKai drops down to 3.3 (Figure 1.2).

Figure 1.2 Hydrogen bonding in calixarene monoanion from 42

 

 

  
 
 

 

 

 

 
 

 

 

 

 

Q ....... llH-O ' H 9 Q ....... "Hp
H i 5

. , 5 1'; H H

I I ' ........ ' G) '

OH OH OH HO OH O H O O

 

 

42 R = SO3Na

12

1R topically are;
obsen‘ed for en
en'stallography h
1.22 Melting p

Almost 31
high melting poll
the p-position can
the calixarenes ust

Another it

aqueous base and

 

 

lower the melting
Water-soluble ear’
ofTer interesting pt
1.23 Spectral p

A 1‘31th d1:
frequency of the s

"11.1. This love fl

bonding that ext:

IR (typically around 3150 cm'l) and 1H NMR spectroscopy (8 = 9-10 for OH) have been
observed for calixarenes which indicate strong hydrogen bonding as has X-ray
crystallography by examination of O."'O internuclear distances.

1.2.2 Melting points and Solubility

Almost all of the calixarenes having free —OH groups are characterized by very
high melting points typically around 350°C. It is also well known that the substituent at
the p-position can significantly influence the melting point temperature. Derivatization of
the calixarenes usually results in slightly lower melting points.

Another important feature of these macrocycles is their insolubility in water,
aqueous base and low solubility in organic solvents. Furthermore, p-substituents that
lower the melting point of the calixarene offer enhanced solubility in organic solvents.
Water-soluble carboxyl and sulfonate containing calixarenes have been prepared which
offer interesting properties.22
1.2.3 Spectral properties

A rather distinct feature in the infrared spectra of calixarenes is the unusually low
fi'equency of the stretching vibrations of the OH groups, which are in the range of ~3150
cm‘l. This low frequency has been attributed to the strong intramolecular hydrogen
bonding that exists in these macrocycles. In the 1HNMR spectra of calixarene 19d
(Scheme 1.2), the OH, ArH and tert-butyl resonances appear as singlets and the
methylene resonance appears as a pair of doublets indicating that the minimum energy
conformation contains equivalent methylene groups carrying non—equivalent hydrogens.23

1.3 Conformational behaviour of calix[4]arenes

l3

One of If
conformations it.
blocks for the co
mentioned earlie-
adopted by the It
simplistic pictur,
conformers poss'
articles written 0
originally realize;
convert by the re:
aryl groups on to
groups sin and on

out as “1.2-alien:

ones anti as "1 ‘

a~

conformers are dc;

Figure 1.1 schemn

 

 

 

   

 

 

One of the most challenging facets of calixarene chemistry concerns their
conformations in solution, which subsequently impact the utilization of these building
blocks for the construction of supramolecular systems and artificial receptors. As it was
mentioned earlier, the name calixarene arises due to the fact that the conformation
adopted by the macrocycle is “bowl-like” or a cone conformation. However, this is a
simplistic picture of a calixarene conformation as there are at-least four different
conformers possible for a calix[4]arene. There have been quite a number of review
articles written or published concerning this field over the past two decades.24 It was
originally realized by Comforth that these conformers are stereoisomers, which can inter-
convert by the rotation of the aryl groups with respect to the annulus.25 The one with all
aryl groups syn to one another is referred to as the “Cone” conformer, one with three aryl
groups syn and one anti as “Partial-Cone”, one with adjacent pairs of aryl groups syn and
anti as “1,2-alternate” and one with non-adjacent pairs of aryl groups syn and adjacent
ones anti as “1,3-altemate”. The different schematic representations for all these

conformers are depicted below in Figure 1.3.

Figure 1.3 Schematic representation of all four possible conformers
R2 R2

  

l
OR] OR] OR]

    

Cone Partial- Cone R2 1,3- Alternate
R2 R2 R2
R2 R R
2 2
m ‘
OR, OR, R2
OR, OR. R2 OR]

 

l4

 

All of ”—
desctiPtors are 0 I
conetp3C0l CS' 1
of each of these .
changes in alignf
adopt a "pinched
are splayed out“
Molecular mod.
stereochemistry ;:
gained from the
development of at
information about

One Of ihc‘
by single crystal .‘
quality is the fact
fairly large molec,
and many Structc
hydm‘e’en atoms.
IIK‘l‘t‘cules inside ti

Often been that the

 

All of these representations are mere idealized structures and symmetry
descriptors are often assigned to each of these conformers [Cone conformer Cay, partial
cone (paco) Cs, 1,3-alternate C211 and 1,2-altemate D2d symmetry]. The actual structures
of each of these conformers in solution may be slightly different as a result of torsional
changes in alignment of the aryl groups. The cone conformer for example may tend to
adopt a “pinched” or “flattened-cone” conformation in which case two of the aryl rings
are splayed outward and the other two aryl groups are almost parallel to each other.26
Molecular models and theoretical calculations have aided the assignment of
stereochemistry and evaluate inter as well as intramolecular interactions. Information
gained from these modeling studies as well as crystallographic results and the
development of advanced two-dimensional spectroscopic techniques has provided ample
information about their structures.

One of the main problems associated with structure determination of calixarenes
by single crystal X-ray diffraction aside from the fact that the crystals may not of good
quality is the fact that many parameters need to be determined and refined as they are
fairly large molecules. The net result is that hydrogen atoms are located with difficulty
and many structures have been reported over the years with calculated positions of
hydrogen atoms. Disorder problems frequently arise due to inclusion of solvent
molecules inside the cavity. An advantage of structure elucidation in the solid state has
often been that the macrocycle is relatively rigid and hence accurate'representation of the
molecular conformation is obtained. p-tert-Butyl calix[4]arene obtained in the solid state
as 1:1 complex with toluene was the first to be studied by diffraction studies for which

cone conformation was ascribed with a four-fold symmetry axis.27

15

In genera
stabilized by l
thermodynamic .
(Scheme 1.2) ad.
ther as sell as
“Mendoza rulc“ }
and ll has bCL‘n
macrocylic 3m}
Whom fOr 3 SCI {
[0 38': PM {Dr

rationalized by ex

 

 

 

confonnations. o l|
bond angle and at
Panial-cone and
respectively due

macrocycle.

Ring inye

PTOblem in

In general, it has been found that calixarenes with free hydroxy groups are
stabilized by intra-molecular hydrogen bonding which consequently imparts
thermodynamic stability to the cone conformer. The tetramethoxy derivative of 19d
(Scheme 1.2) adopts a partial cone conformation in solid-state whereas the 1,2-dimethyl
ether as well as 1,3-dimethyl and trimethyl ethers adopt cone conformations.28 The
“Mendoza rule” has been frequently applied to structure determination in calix[4]arenes
and it has been found that for adjacent aryl rings that are syn to each other in the
macrocylic array the 13C chemical shifts of the corresponding bridging methylene
carbons for a set of known calix[4]arenes range from 30.2 to 32.7 ppm for cone and 36.7
to 38.2 ppm for 1,3-alternate.29 The observed chemical shift differences were then
rationalized by examining the X-ray data of some calixarenes in cone and 1,3-alternate
conformations, which displayed for the methylene carbons a shorter C(sp2)-C(sp3)-C(sp2)
bond angle and an increased van der Waals energy in the former compared to the latter.
Partial-cone and 1,2-alternate had two methylene resonances at 31 and 37 ppm
respectively due to the presence of two syn and anti orientations of the arenes in the
macrocycle.

Ring inversion is another phenomenon, which increases the complexity of the
problem in structural assignment. Calixarenes with free hydroxy groups are
conformationally mobile as indicated by the variable temperature 1H NMR spectra. At
room temperature, a pair of doublets is observed for the bridging methylene hydrogens,
which are conveniently labeled as equatorial and axial hydrogens as their positions in a

cyclic array resemble those set of hydrogens in cyclohexane derivatives. At high

16

temperatures. ll
reminiscent 3513i"

Sche

\r

Theconflt
the calix to a less
to decrease the be
Tc: 153C) comp
mechanism for .
possible}; The 1..
concomitant dim
Which can either

aryl

 

groups can 8‘
r -‘
e5tfrtlbles a 5km

thr
OUghout the pro

temperatures, these pair of doublets coalesces to a singlet at high temperatures

reminiscent again of similar pattern observed in cyclohexane (Scheme 1.11).23

Scheme 1.11 Ring inversion in calix[4]arene

3‘ OH OH OH HO
\

      

The conformational ring-flip is dependent upon the nature of the p-substituents in
the calix to a lesser extent than the solvent. Polar solvents such as pyridine-d5 are known
to decrease the barrier for ring inversion (AG;é = 57.3 kJ mol'1 at coalescence temperature
Tc = 15°C) compared to chloroform-d (AGi = 63-67 kJ mol"). Gutsche has studied the
mechanism for conformational inversion in detail and two distinct scenarios are
possible.23 The 1,3-alternate conformer formed by rotation of two opposite aryl rings by
concomitant disruption of hydrogen bonding has been believed to be an intermediate
which can either revert to the original cone or inverted cone conformer. Alternatively,
aryl groups can swing through the annulus in se quence via an activated complex that
resembles a skewed 1,2-alternate conformer thereby maintaining hydrogen bonding
throughout the process with minimal distortion of bond angles.

Nuclear Overhauser Effect has been useful for structure elucidation by identifying
through space interactions between hydrogens on aryl rings and methylene bridges
whereas chemical exchange spectroscopy (EXSY) has been used to analyze inter-
conversion processes between conformers.

1.4 Functional group modification of calixarenes
The commercial availability of p-tert-butyl calixarene 19d (Scheme 1.2) enables

the development of strategies towards further functional group manipulations. Such

l7

transtTmaIlOHS
upper and low
Functionalizatior'
aseparate SOC”
methylene bride-W
1.“ Function

Complete
wide variety of r.
as a mixture of a
rim.30 Control of
For example. ally.
the solyents inx.
triallcylated prod
affords l,3-alt ct

Potassium (err-bu

 

Obtained in four 8
from incomplete

Conditions The n
- 1

under different re

derOPEd for Se].

b .
ehlnd chemo s
s‘ e

T]

Ofa Slight etc

transformations can be done at three different locations on a calix[4]arene namely the
upper and lower rims of the macrocycle as well as on the methylene bridges.
Functionalization at the upper and lower rims will only be addressed in this section while
a separate section (Section 1.5) will be entirely devoted to functionalization of the
methylene bridges.
1.4.1 Functionalization at the lower rim (Transformations involving —OH group)
Complete alkylation or acylation of 19d (Scheme 1.2) can be performed under a
wide variety of reaction conditions to give tetraalkyl ethers and ester derivatives normally
as a mixture of all possible conformers if larger substituents are introduced at the lower
rim.30 Control of stereochemistry can be achieved by proper choice of base and solvent.
For example, alkylation of 19d using sodium hydride in dimethyl formamide and THF as
the solvents invariably yields the cone conformer 43.2124“31 No other mono, di or
trialkylated products was observed in this reaction. Cesium carbonate in acetonitrile
affords 1,3-alt conformer 45 whereas partial cone 44 is exclusively obtained using
potassium tert-butoxide in benzene (Scheme 1.12).24°’32 1,2-Alternate conformer 46 was
obtained in four steps from 19d in 56 % yield.30 Again, no other side products resulting
from incomplete alkylation at the intermediate stage was observed under these
conditions. The mechanistic picture for selective formation of either of these conformers
under different reaction conditions has not been described. Several methods have been
developed for selective functionalization of calixarenes at the lower rim. The premise
behind chemo-selective functional group manipulations relies on the difference in
acidities of the phenolic hydroxy groups in the calix[4]arene (Section 1.2.1). Often, the

use of a slight excess of a weak base such as cesium fluoride in DMF and an excess of

18

alkylating agent
dialltoxy calixa
carbonate in ace
using sodium h}.
Alkylation ugh:-
calixarenes 50. 1‘

Scheme l.l2 syn

  

0R3 (3R: (ll I

R: = n-Pr. Ri
CODC 43 34 o 5,

 

 

alkylating agent results in selective formation of monoalkoxy calixarene 47 .33 Distal 1,3-
dialkoxy calixarenes 48 can be obtained chemoselectively by the use of potassium
carbonate in acetone or acetonitrile34 whereas adjacent 1,2-dialkoxy calixarenes 49 by
using sodium hydride in DMF as the solvent and 2.2 equivalents of the alkylating agent.35
Alkylation using barium hydroxide / barium oxide in DMF affords the trialkoxy

calixarenes 50. (Scheme 1.13).36

Scheme 1.12 Synthesis of specific conformers of calix[4]arene tetraethers
R1 R1 R1

 
    

l
0R2 0R2 0R2
R2 = O-CHZCHZOCHZCHZOMe,
R] = t-BIJ

R
R2 = n-Pr, R. = t-Bu 1
Nail, THF +DMF - ,3 n2 - 0
Cone 43 34 % \ t BUCK e m Partial cone 44 80 /o

 

R2x sz
19“ may)

C82C03 Si - - _
cps (ll-(1V) K co BnB CH CN
CH3CN RZX 1) 2 3, 1‘. 3
W [ 2=1°AlkyL ii) Etl, KOt—Bu,THF
R1
R

R1 = t-Bu] iii) 2 equiv Me3SiBr, CHCl3
Rl iv) EtI, KOt-Bu, THF

R1

 
 

9R2

    

+ 5 % partial cone

R
I R] R] R1
1,3- Alternate 45 48 % 1,2-altemate 46 55 %
R2 = CH2CH20MC, RI = I-BU R2 = Et, RI = t-Bu

The rationale behind the exclusive formation of (1,3) distal isomer with potassium
carbonate was explained by an initial formation of monoanionic species a, which is
stabilized by three intramolecular hydrogen bonds. Subsequent alkylation yields the
monoalkyl ethers 47, which upon further deprotonation afford another monoanionic

species b. This species is stabilized by two intramolecular hydrogen bonds to the

19

 

neighbouring p
disubstituted cal
occur only unde -
than dianionic sp
former and one I
has been CXlL‘iN

of control by pro

Scheme insane“

 

 

 

 

 

l -\\.
/
R. 0R:
K
(if).
EXCeHem :
C‘ and c.

‘ Shmmg

neighbouring phenols. Alkylation of the monoanion h leads to the (1,3) distal
disubstituted calix[4]arene 48. The formation of the (1,2) proximal isomer was invoked to
occur only under the influence of a strong base that leads to the formation of dianion c
than dianionic species (1 due to the presence of two intramolecular hydrogen bonds in the
former and one in the latter (Figure 1.4).37 While the selective formation of alkyl ethers
has been extensively studied, ester formation can be accomplished with a similar degree

of control by proper choice of reaction variables.

Scheme 1.13 Selective functionalization of calix[4]arene
R1

  
    

 

VMF
M ch0,, MeCN R1
41;] , . 19d RZX 48 95-99 % yields
37-88 % yields BaO, Ba(OH)2 Nan, DMF
RI 0V sz R‘
W [R2 = 1° Alkyl,
. R1 = t-Bu]

R1

 

R1
50 49 65-70 % yields
60-63 % yields Only few examples

Excellent stereoselectivity can be achieved in the preparation of calixarenes with

C3 and C 2 symmetry by acylation of distal 1,3-dialkoxy calix[4]arenes 48 with acetyl

20

chloride in 6”"
513 while the“:

1.14,}:

“2“" i

.

 

Although
mention templat
favors the format
oxygen substituen

partial cone by rot

 

chloride in ethyl ether. The use of sodium hydride as a base yields the cone conformer
51a while thallium ethoxide gives the partial cone isomer 51b in high yields (Scheme

1.14).38

Figure 1.4 Calixarene mono and dianions

 

Although the precise origin of the stereoselectivity is not completely understood,
metal-ion template effect is believed to be operative wherein the smaller sodium cation
favors the formation of the cone conformer due to its tighter chelating ability to the
oxygen substituents at the lower rim compared to the larger thallium cation which gives

partial cone by rotation of one phenol unit.

21

Selle!!! ”4 Sum

Bu i-Bu r-B
I.

r we!

0 0R ore
M 0 51'
L:

1.4.2 1

The repl.

and the tetramer}

acatalyst in toll:

is followed by e‘:

allows for the ir. I

sulfonate. halogc

Scheme l.lS Electrop

1.31,; that tho
i

h

 

\m
.K/V

t l l

OR OR OR

19d R = H

52 R = Me

These fU
transformations :
functional group
selectivity that is
based on the difft
preparation

diallylation of S4

Scheme 1.14 Stereochemical control in formation of calixarenes with C2 and C, symmetry
t’Bu I-Bll l-BU

  

      

t-Bu t-Bu t—Bu t-Bu 2.3“ t-Bu t-Bu t-Bu i
1101;: H3O 0 g
l ’ MeCOCl OR dR 0
on OR OR HO Ego >_CH3
R = “‘3" t-Bu 51b
48 C.

 

1.4.2 Functionalization at the upper rim

The replacement of the t-butyl groups with other substituents on calixarene 19d
and the tetramethyl ether 52 has been done by Friedel-Crafis dealkylation using A1C13 as
a catalyst in toluene, which acts as the solvent and acceptor for the tert-butyl cation. This
is followed by electrophilic aromatic substitutions at the free p-positions.39 This process
allows for the introduction of a variety of substituents into the p-position such as nitro,

sulfonate, halogens (Br or I), formyl, acetyl etc (Scheme 1.15).

Scheme 1.15 Electrophilic aromatic substitutions on 53 and 54
t-Bu t-Bu t-Bu t-Bu

ms i
Ale, Toluene $, T v ' 1563
_——_> I

OR OR OR R0

  
   

‘ I I
OR OR OR R0
l9dR=H 53R=Me
52R=Me 54R=H

 

55R=Me
56R=H

E = Br, 803“, N02, CORz, CH2NR2, Alb/l, CHO, I etc.

These functionalized calixarenes are amenable towards further chemical
transformations at the lower rim. In addition, it has been demonstrated that selective
functional group introduction at the p-position could be accomplished by transferring the
selectivity that is normally obtained in the alkylation or esterification of -OH groups
based on the difference in reactivity of phenols and phenol ethers or esters leading to the
preparation of C2 symmetric calixarenes (Scheme 1.16). Chemoselective distal

diallylation of 54 to 57 followed by Claisen rearrangement affords p-allyl calix[4]arene

22

58 which upon
Sequential elect

towards formant

Scheme 1.16

   

on on

641

| ..

t 5
EN ‘
I r“.

 

 

58 which upon further electrophilic aromatic substitution resulted in formation of 59.40
Sequential electrophilic aromatic substitutions on 60 have been used as a versatile route

towards formation of calixarene 62.

Scheme 1.16 Selective functional group transformations of calixarenes
54

Selective Alkylation

     

I I
OH OR OR Ho

60 / 57 \

I Selective .
Electrophilic Claisen
Substitution Rearrangement

E1 El

           

 

' l I EX
61
52x Different l I l ’
Electrophile OH OH on HO 0H OH on H0
58 59
13' 132 132 E'

   
 

I
OH OR OR H0
62

 

1.5 Chiral calixarenes

Chiral calixarenes have been of recent interest due to their applications as potential
drug candidates (vancomycin mimics), molecular receptors for recognition of specific
cell lines (glycocalixarenes, peptido-calixarenes etc.) and non-enzymatic reagents for
chiral recognition of racemic carboxylic acids. Two approaches have been successful in
the preparation of such calixarenes a] molecular asymmetry is a consequence of the

presence of aryl rings having different substitution patterns and b] functionalization at the

23

lower rim with
strategies taking
15.1 Traditio
1.5.1.1 S'lolecul;

The inco
I

cone confonnatt
three aromatic r
The substituent~
group in order tr
calix[4]arene w r:
to formation of c
be resolyed into
reagent.

Scheme 1.17 Chit

Qt“

#
(fit

 

lower rim with a chiral reagent. The following section briefly elaborates on these
strategies taking into consideration the advantages and disadvantages of each methods.
1.5.1 Traditional methods for induction of chirality
1.5.1.1 Molecular asymmetry

The incorporation of different substituents on at-least three of the aryl moities in a
cone conformation or two different aryl groups with one of aryl groups anti to the other
three aromatic rings (i.e., partial cone) renders molecular asymmetry to the calixarene.
The substituents which are introduced on the lower rim must be larger than an ethyl
group in order to slow the ring-inversion process that would result in racemization of a
calix[4]arene with molecular asymmetry. However, the larger substituent could also lead
to formation of other conformers than the cone. The resulting chiral calixarene 65 could
be resolved into a pair of diastereomers 66a and 66b by derivatization with a chiral

reagent.

Scheme 1.17 Chiral calixarene with molecular asymmetry

OH OH OH OH
W i) K2C03, n- -:Prl
001,?
ii) TMSI
54

l K2CO3, BnBr

 

 

 

 

—r~

O

l; l\ O /I 7| Pr OBn OH OBn
0 0 1 OPr (- )Menthoxy NaH n pr]
on T qgjo

OPr n OPr acetyl chloride
0

‘ <Me
Me—Om< Me >m-C>_ (racemate)
Me
Me Me
661)
P
P

Me4NOH
THF / H20, reflux

O r OBn OBn OPr

H 65 (+) 65
24

Hydroly
hydroxide resul
1.17).“Another
calixcrown whl.
diastereomers r’
hydrolysis result
the crown motif
racemization is r‘
1.5.1.21ntroduC

There all“
the low er rim, M

example. L-yalin

 

 

The chiral diamit
with the calixare
25% yield tScher

In contra'

alanine under 8121

modified peptid
molecular recool

Peptidoealixareni

which exhibited a

Hydrolysis of either diastereomer so formed with aqueous tetramethyl ammonium
hydroxide results in formation of enantiomers of 65 in excellent optical purity (Scheme
1.17).“Another example that has been reported recently is in the preparation of
calixcrown which was resolved by using BINOL as the chiral derivatizing agent.42 The
diastereomers formed could be separated by preparative thin layer chromatography and
hydrolysis results in the formation of either antipode of the chiral crown. The presence of
the crown motif imparts rigidity to the macrocycle and thus ring inversion leading to
racemization is not observed.
1.5.1.2 Introduction of chiral functionalities on the lower and upper rim

There are several known methods for the incorporation of chiral functionalities on
the lower rim, which involve several steps from calix[4]arene as the starting material. For
example, L-valine was used as the starting material in the synthesis of calixazacrown 68.
The chiral diamine 67 was prepared from L-valine by conventional methods and reaction
with the calixarene diacid chloride 66 resulted in the formation of calixazacrown 68 in
25% yield (Scheme 1.18). 43

In contrast, the reaction of calix[4]arene tetra-acid 69 with the methyl ester of
alanine under standard peptide coupling conditions resulted in the formation of upper rim
modified peptido-calixarene 70 in good yield.”'4 The calixazacrown 68 was used in
molecular recognition of specific enantiomer of racemic carboxylic acids, whereas the
peptidocalixarene 70 was designed in an effort to synthesize hybrid molecular receptors

which exhibited anti-microbial activity against Gram-positive bacteria.

25

Scheme 1.18 Chiral calixarene 68 by lower and 70 by upper rim functionalization

Tslel Allie NHTs t-Bu t—Bu t-Bu t-Bu
t-Bu t-Bu t-Bu t-Bu Me Y\/ N\/'"wr Me

Me 67 MC

CH2C12.Et3N,rt, 2d

L-Alanine methyl ester

Coupling reagent, Et3N, CHZClz, rt

«9 is???

OMe 62%

 

1.5.2 Applications of chiral calix[4]arenes

The facile preparation of chiral calixarenes by reaction of suitable stoichiometric
chiral reagents with reactive functionalities either on the lower or upper rim in recent
years has provided the necessary tools for developing a variety of applications. There are
numerous reports on the utility of chiral calix[4]arenes in molecular recognition where
the basic recognition element is non-covalent interactions between polar substituents on
the calixarene and the chiral reagent. For example, calixarene 71 bearing chiral amino
alcohol groups tethered at the lower rim preferentially interacted with the (S)-enantiomer
of racemic mono carboxylic acids 73, 74 and with (L)-isomer of dicarboxylic acid 75.45
The extent of the chiral recognition event was monitored by the difference in chemical
shifts of the methine protons of the carboxylic acids and the selectivity for one

enantiomer over the other was ascertained by determination of the association constants.

26

The phenyl-sub
due to an addi:
with the chiral

1.5). For racem

carboxylic acid

 

 

llt‘l

Recentlj
PTOfile Similar
resistance to i]
prOiOnated at
formation Of 2
InOdel 78 “a,
could a“ be ir

also bEen S\.

binding pro“

The phenyl-substituted analogue 72 displayed remarkable recognition ability for (S)-74
due to an additional CH3-Jt interaction. Mono carboxylic acids formed 2:1 complexes
with the chiral calixarene whereas dicarboxylic acids resulted in 1:1 complexes (Figure
1.5). For racemic 73, 74 and 75, the selectivity of binding of the hosts 71 or 72 for the

carboxylic acids (S)-73, (S)-74 and (L)-75 was calculated to be 96 %.

Figure 1.5 Chiral calixarenes for molecular recognition

 

1-311 t-Bu t-Bu t-Bu
HO H OH
Ph—)—C00H H3CHCOOH
H H3C H
73 74
H OCOPh
HOOCHCOOH
PhOCO H
75
R = H, 71
R = Ph, 72

Recently, the macrobicyclic calixarene 76 has been reported to have a biological
profile similar to that of Vancomycin, which is an important glycopeptide antibiotic for
resistance to infection by gram-positive bacteria.46 The basic nitrogen group in 76 is
protonated at physiological pH and NMR as well as ESI/MS studies indicated the
formation of a 1:1 complex with N-acetyl-D-alanyl-alanine 77. Furthermore, a binding
model 78 was proposed where electrostatic, hydrogen-bonding and CH-Jt interactions
could all be involved (Figure 1.6). Glycocalixarenes bearing multiple sugar residues have
also been synthesized and they show remarkable binding affinities with carbohydrate

binding proteins such as lectin.47

27

 

H..
Me

H.\'

1.6 Methyl?

 

There ha
methylene bridg=
has often been
inclusion of sul
introduction of
S§mmetric calix
We have been r
1.6.1 Stereoisi

In order
substitution at ti

be considered in

1.6.1.1 Monosu

Figure.l.6 1:1 Complex between N-Acetyl D-Alanyl Alanine and 76

0 fl/W o
0 mm NHH'E‘HHN H

N O
H"- -“ Me
Me
HN

        

 

1.6 Methylene functionalized calix[4]arenes

There have been very few reports in the literature on the functionalization of the
methylene bridges in a calix[4]arene. The difficulty in accessing this class of compounds
has often been attributed to the complex mixture of stereoisomers that occur upon
inclusion of substituents at the methylene bridges.48 Chiral calixarenes result from
introduction of a substituent at a methylene position of either C2 symmetric or C4
symmetric calix[4]arene but so far no examples of optically active calixarenes of this
type have been reported.
1.6.1 Stereoisomerism in methylene functionalized calixarenes

In order to present a simplified picture of the stereoisomers that result upon
substitution at the methylene bridges, only cone conformers of the starting material will
be considered in the following discussion.

1.6.1.1 Monosubstitution at the methylene bridges

28

 

Demo:

formation of to

 

 

functionality at

  
  

Figur

Derivatization of the methylene bridge by monosubstitution results in the
formation of two diastereomers. These diastereomers differ by introduction of the new

functionality at either the axial or equatorial positions of the calixarene (Figure 1.7).

Figure 1.7 Stereoisomers formed upon monosubstitution

 

(9

The stereoisomerism that results upon substitution at one methylene bridge by a

methyl, ethyl, isopropyl or tert-butyl group (R3 = Me, Et or t-Bu) has been studied in
detail and it was found that the bulkier the alkyl group, the greater is the preference for
the equatorial position as in isomer A.49 The interconversion barrier between the axial
isomer C and equatorial isomer A was estimated by theoretical calculations to be
increasing from methyl to isopropyl (AGi = 15-17 .2 kcal/mol) but then decreases for tert-
butyl group. The decrease for the tert-butyl group was attributed to a low inversion
barrier due to steric destabilization of the axial isomer C.

Monoaryl methylene substituted calixarenes (R3 = Ar) were also studied by NMR
spectroscopy and they exist as 1:1 mixtures of axial and equatorial isomers. This result is

in stark contrast to phenyl substitution at cyclohexane derivatives wherein an equatorial

29

 

phenyl group is
concievable tho
exist but no 51:
these specific s:
l.6.l.2 Disubsti

Proxima.
|
introduction or
COml‘0unds is l.
trans isomers (
relative to the 3

known to “Net;

Possible diaster

 

methylene bridr,

diastereomeTS F
l
|

phenyl group is 2.8 kcal/ mol more stable than axial phenyl group. Moreover, it would be
concievable that enantiomers B and D for each of these diastereomers if R2 a: R1 would
exist but no studies have been reported concerning either the existence or isolation of
these specific stereoisomers.
1.6.1.2 Disubstitution at methylene bridges

Proximal (1,2) and distal (1,3) disubstituted calixarenes are obtained by the
introduction of a second substituent at the methylene bridges. Each of these two
compounds is known to have two distinct stereoisomeric forms labeled as the cis and
trans isomers depending upon the position of introduction of the second substituent
relative to the first one. Furthermore, the 1,3-cis and 1,3-trans isomers E and G are
known to undergo ring inversion by rotation of the aryl rings through the annulus to their
diastereomers F and H (Figure 1.8).50 Finally, there are two enantiomers for each of those
possible diastereomers (not shown). Extensive theoretical investigations have been
carried out on the relative stability of the 1,3- cis isomers and the two alkyl groups at the
methylene bridges (R3 = R4 = alkyl) are known to increase the energy barrier for ring
inversion from the equatorial to axial forms. Aryl substituents (R3 = R4 = Ar) do not
affect the inversion process at all and an equal mixture of cis and trans isomers are often
found in solution at room temperature. Interconversion between cis and trans isomers for
alkyl and aryl substituted calixarenes was not observed but was found to occur for
heteroatoms introduced on the bridges (e.g. thiomethoxy, anilino) wherein the cis isomer
was found to be the most thermodynamically stable. The interconversion process occurs
via the cleavage of the Ar-CH-R4 bond.50 The analogy between the cyclohexane chair

conformation and the calixarene cone conformation still exists for the trans isomer G.

30

One of t}
|

in G or H. Hem
trans distal-subs
cone and 1.2-all
substituents occ.
atial equatorial c
bulky axial subs
thereby rendered
The proxi
There are four di;
Si

creoisomers ( l

lltnctionalized cai

not exist.

 

 

Figure 1.8 Stereoisomerism in 1,3 or distal disubstituted calixarene

   

H OH OH OH HO H H OH OH OH HO R4
1-3 Cis 150W?" 1,3 Trans isomer
Ring Inversion Ring Inversion

 

 

 

 

 

One of the substituents in the cone conformer is forced to adopt an axial position
in G or H. Hence, 1,2-alternate conformer has been observed as the only conformer for
trans distal-substituted calixarenes with bulky groups (eg., R3 = R4 = t-Bu ). Mixtures of
cone and 1,2-alternate conformers was observed for groups of smaller size as both the
substituents occupy equatorial position in 1,2-altermate conformation compared to an
axial equatorial orientation in the former.48 This is very similar to cyclohexanes wherein a
bulky axial substituent destabilizes the chair form of cyclohexane and a twist form is
thereby rendered the most preferred conformation.

The proximal (1,2) disubstituted calix[4]arene also exhibits cis / trans isomerism.
There are four diastereomers, each of which has an enantiomer resulting in a total of eight
stereoisomers (If R2 a: R‘) (Figure 1.9). Computational studies on proximally
fimctionalized calixarenes with regard to measurement of inversion barriers however do

not exist.

31

l.6.l.3 Tri and
No exar‘

.

different metht
analyses of the kl
as there are on.
I

syntheses of thr
discussion in the
“-2 Synthesil
There ha
monosubstitutcd

lithiation Q 0 (

L62" l2+2l Fra

 

Figure 1.9 Stereoisomerism in 1.2 or proximal disubstituted calixarene

l
R2 R R1 R2

   

D 1.2 Trans lsomer 1,2 Cis Isomer @

Ring Inversion Ring Inversion

R3
(IN-I OH ('31-! HO

   

1.2 Inverted Trans [,2 Inverted Cis

1.6.1.3 Tri and tetrasubstitution at methylene bridges

No examples of trisubstituted calixarenes resulting from substitution at three
different methylene bridges are currently known in the literature. Conformational
analyses of the corresponding tetrafunctionalized calixarenes have not been reported yet
as there are only a few methods for their preparation (See Following section). The
syntheses of this family of methylene substituted calixarenes will be the subject of
discussion in the forthcoming sections.
1.6.2 Synthesis of monomethylene substituted calixarenes

There have been a few successful methods for the preparation of calixarenes
monosubstituted at the bridges. They include fragment condensation of linear dimers and
lithiation / carboxylation of tetramethoxy-p-tert-butyl calixarene.

1.6.2.1 [2+2] Fragment condensation

32

 

The {illxlI
aldchl'de 79 o
fragment “mm
under reaction .
0m (Scheme
meth.‘Icne brid-
this manner in 3

Scheme l.l9 l3"

A -

H 0

79

8! . Br/\'/

 

 

1.6.2.2 Lithiatii

In this n
methylene brid
treatment with

e‘anlonally disp

The alkanediyl phenols 81 were obtained by the condensation of the appropriate
aldehyde 79 with an excess of the corresponding phenol 80 in 58-80 % yields. [2+2]
fiagment condensation of an alkanediyl phenol 81 and the bis-bromomethylated dimer 82
under reaction conditions similar to that mentioned earlier in Sec 1.1.3.2 for preparation
of 24 (Scheme 1.5) resulted in the formation of calixarene 83 that is monosubstituted at a
methylene bridge.49 Alkyl and aryl substituted calixarenes are conveniently prepared in

this manner in 12-36 % yields (Scheme 1.19).

Scheme 1.19 [2+2] Fragment condensation to monomethylene substituted calix[4]arenes

 

 

OH OH R2 OH
R _ Neat, Cat.HCl O O
A + 2 equV. >
H 0 60-150 °C
58 - 82 % yields RI
OH OH
81 + Br“ Br TiCl4, Dioxane
R3 R3 R3
82

 

83 R' = Me, R2 = Me, Et, i-Pr, t-Bu, p—Nit
R3 = Me or t-Bu
12-36 % yields

1.6.2.2 Lithiation / alkylation of calix[4]arene

In this method, tetramethoxy-p-tert-butyl calix[4]arene 52 is metalated at the
methylene bridge with n-butyl lithium to give lithio derivative 84 and subsequent
treatment with an electrophile gives 85 which can be demethylated to afford the

equatorially disposed monosubstituted derivative 86 (Scheme 1.20).51

33

Scheme 1'

r-B”

0V. ..

{-813
()li

L63 Soothe“

The syni
been widely 5“:
include [3‘3]
derivatives and t I
l.63.l [2+2] Fr:

The frag
substituted bis-hr
synthesis of cis
disubstituted call

toll and in lS-I

 

Scheme 1.20 Lithiation / trapping with electrophile to monofunctionalized calixarene 86

t-Bu t-Bu t-Bu (-31, Ft-Bu t-BU t-Bu t-Bu

4.5 eq BuLi
THF, rt

   

\
OMe OMe OMe OMe OMe OMe OMe OMe

52 34
Electrophile = Mel, EtI, BnBr, C 02

 

 

I Electrophile

   

t-Bu t-Bu t—Bu t-Bu t-Bu t-Bu t-Bu t-Bu
BBF3
CHZCIZ
OM“ OMe 0M6 OMe
86 85
62-68 % yields 64 - 75 % yields

1.6.3 Synthesis of methylene disubstituted calixarenes

The synthesis of calixarenes substituted at two different methylene bridges has
been widely studied in the past few years. A number of available methods exist that
include [2+2] fragment condensation, Ortho-Fries rearrangement of carbamate
derivatives and nucleophilic addition to spirodienones.
1.6.3.1 [2+2] Fragment condensation

The fragment condensation strategy of an alkanediyl phenol 81 and methylene
substituted bis-bromomethyl arene 87 has been successfully applied in the stereoselective
synthesis of cis 1,3-dialkylsubstituted calixarenes 88 in 19-28 % yields and 1,3-diary]
disubstituted calixarenes 89 as mixture of cis and trans isomers in ratios varying from 1:1

to 2:1 and in 15-21 % yields (Scheme 1.21).49

34

Scheme 1'2]
81 - 5'”

HCHO. 33 “a l
09 - H 3'6 :

1.63.2 Ortho-I

The hon
expedient mcthr
calixarenes.” C.
order to prosid
substituted pro
deprotonation at
stirring the reac
that good contro
Furtherrnore, th.
determining the
[he diaxial proxj
allal‘equatorial .
With m

0n0~rearrz

 

Scheme 1.21 [2+2] Fragment condensation to methylene disubstituted calix[4]arenes

 

RI
OH R2 OH
81 + Br 0 Br TiCl4,Dioxane
R' 87 R' R]

 

/

HCHO, 33 % HBr in AcOH
69 - 84 % yields

 

88 RI = Me or t-Bu
R2 = Me, Et, i-Pr, t-Bu
89 R' = Me or t—Bu
R2 = p-Tol, p-Nit

1.6.3.2 Ortho-Fries rearrangement of calixarene carbamates

The homologous anionic Ortho-Fries rearrangement was recently developed as an
expedient methodology to both proximal (1,2) and distal (1,3) methylene functionalized
calixarenes.52 Careful control over the reaction conditions was needed to be exercised in
order to provide for the selective formation of either the proximally or the distally
substituted products (Figure 1.10 & Table 1.1). The reaction is carried out by
deprotonation at the bridge usually with a large excess of LDA as the base, followed by
stirring the reaction mixture for varied reaction times and temperatures with the result
that good control over stereo and regioselectivity could be attained in product formation.
Furthermore, the conformation of the starting calixarene often played a crucial role in
determining the product distribution with the cone conformer 90 predominantly yielding
the diaxial proximally functionalized product 93 upon Fries rearrangement. A mixture of
axial-equatorial and equatorial-equatorial proximally substituted products 94, 95 along

with mono-rearranged product 97 resulted from partial cone 91 whereas proximal, distal

35

  
 

diequatorial pr

alternate carba:

EI:\ I“

 

Tal

diequatorial products 95, 96 and mono equatorial substituted product 97 from 1,3-

alternate carbamate derivatives 92 as starting materials.

Figure 1.10 List of calixarene carbamates and amides

 

97

96

___.‘) LDA’ THF 93, 94, 95, 96, 97
ii) NH4C1

90, 91, 92

Table 1.1 Results of migration studies on carbamates

94 95 96 97

Entry SM imM) RC“ 93

 

l 90 A 63-80 ’
2 91 B - 42 21 - 23
3 92 A ‘ ' 16-17 64—65 11-18

 

" Reaction Conditions:
A] Add SM in THF to a solution of 12 equiv of LDA in THF at 0°C and warm to room

temperature for 4h before quenching with NH4CI (aq)

B] same as Method A except reaction temperature is -24°C for 6h followed
by warming to room temperature and stirring overnight

36

The pr.

described.

 

1.633 Spirodi
The oxr
, i

tnbromide un.

calixspirodienc

Scheme 1.22 Otida

    

\/1
l l 1
OH Oil ("in
19d

 

BrOmjn
“1ng Fields,
hldride affOr d1
isomers emu,

”Edemem isor

The precise mechanism for the stereo and regioselectivity obtained was not
described.
1.6.3.3 Spirodienone method of functionalization

The oxidation of p-tert-butyl calix[4]arene 19d with phenyl trimethyl ammonium
tribromide under biphasic conditions resulted in the formation of three isomeric

calixspirodienone derivatives 98, 99 and 100 (Scheme 1.22).53

Scheme 1.22 Oxidationof 19d to spirodienones 98, 99 and 100
I-Bu

 

   

69
PhNMe3 3139
I I CH2C12, Aq NaOH
OH OH OH HO

19d

 

Bromination of spirodienone 99 gave 101, which upon thermolysis afforded 102
in good yields. Bis-Michael addition to 102 followed by reduction with lithium aluminum
hydride afforded the respective distal methylene functionalized calixarenes 104 as trans
isomers exclusively (Scheme 1.23). The bis-thiomethyl ether and bis-anilino derivative

underwent isomerization from trans to the more thermodynamically stable cis isomer.

37

Scheme 1.!

 

 

 

 

“-4 Si'nthe:

In Cont:
disubstituted c
“‘0 method, t1
19d 10 tetrakc.
Sec0nd mi'lltm
(Scheme 1.7)
conformerS ( S
used as [0018 t

Winona] dISp

Scheme 1.23 Michael addition to spirodienone in preparation of trans-104
t-Bu

t-Bu

 

t-Bu
10‘ 64 % 102 84 %
Nucleophile
Nucleophiles
NaOR, NaBD4, t-Bu
NaSMe, NaN3,

   

PhNHz, CH(COOR)2

t-Bu t-Bu t'B“ t-Bu

LiA1H4

 

t-Bu
H on OH on “0 Nu
t-Bu
104 . 103
38-66 % Yields 66-88 % yields

1.6.4 Synthesis of tetrasubstituted derivatives

In contrast to the available methods for the preparation of either cis or trans 1,3-
disubstituted calixarenes, there are very few reports on the tetrasubstituted analogs. The
two methods that are known so far include the over oxidation of the methylene bridges of
19d to tetraketone calixarenes followed by reduction to tetraols 105 in four steps.54 The
second method involves the direct bromination of the bridges in the tetramethyl ether 52
(Scheme 1.7) to give the tetrabromoderivative 106 as mixture of cone and partial cone
conformers (Scheme 1.24).55 Molecular mechanics and semi-empirical calculations were
used as tools to predict the stereochemistry at the bridges wherein it was found that the

equatorial disposition of bromine substituents is more favored.

38

SCht

1%

115.5 Stereo”
RCSOTL‘ ]
Often Prepared

aldehyde.56

 

 

 

The non-pram”:

existence in se.

Scheme 1.24 Tetrafunctionalization of calixarenes 19d and 52
t-Bu

   
  

 

1 Ac O,P

19d ) 2 y e
2)C1'03 t-Bu
3)K2CO3/ MeOH
4] NaBH4

I 1
CR1 0R10R1R10

  

106a
83:17 ratio in CDC13 at R2

25 °C

1.6.5 Stereoisomerism in resorcinarenes

Resorcinarenes 107 (Figure 1.11) are analogous to calixarenes in that they are

often prepared by the acid catalyzed condensation of a phenol (resorcinol) and an

aldehyde.56

Figure 1.11 Resorcinarene with all cis methylene substitutents

 

The non-planarity of the arene rings in the resorcarene framework also accounts for its

existence in several stereoisomeric forms. The stereochemistry is often defined as a

39

K-

combination .
mamodeb
the absolute er
I

are in equator
expected to re»
1.6.5.1
The co:
arrangements

1C.) and saddl.

The Crow“ forn

 

“.
hereas the Sad

 

 

combination of three stereochemical elements, which include a] conformation of the
macrocycle b] the relative configuration of substituents at the methylene bridges and c]
the absolute configuration of the substituents at the bridges with respect to whether they
are in equatorial or axial positions. A vast number of possible stereoisomers would be
expected to result from a combination of these stereochemical elements.
1.6.5.1 Conformation of the macrocycle

The conformation of the macrocyclic ring can exist in five different symmetrical
arrangements whch are referred to as the crown (C4,), boat (sz), chair (Czh), diamond

(Cs) and saddle (Dzd) conformations respectively (Figure 1.12).

Figure 1.12 Conformations of resorcinarenes

    
 

,0
.2: e o

OH
HO Saddle (D 2,)

Diamond (Cs)

The crown form in resorcinarene is similar to the cone conformer of a calix[4]arene

whereas the saddle form resembles 1,3-alternate conformer of the calixarene. The ratio

in which the»

substrate and
homogeneom
stability of
Interconx'erss
diamond—rep
_ I
believed to fa.
the free mere

1

is to be contr

 

 

 

 

calix[4]arene \
1.6.5.2

Each 0
C0“figltration:
fomaIIOn 0f 1
ltans-cis-tm,
later for def”

Substituted C,

in which these conformers are formed is again dependent upon choice of the aldehyde
substrate and the reaction conditions for the acid catalyzed condensation. Under
homogeneous acidic conditions, the product distribution reflects the thermodynamic
stability of the different isomers, as the condensation reaction is reversible.
Interconversion between two conformers (boat—> crown, chair—e crown and
diamond->crown) was observed where the rotation of aryl rings about the annulus is
believed to facilitate such a process. In the case of resorcarene 107 (R1 = C6Hl3, R2 = H),
the free energy AG " for the confomational interconversion process is 18.4 k] mol'l. This
is to be contrasted with the barrier for the cone to cone inversion in p-tert-butyl
calix[4]arene which has been found to be 63-67 kJ/ mol in CDCI3.
1.6.5.2 Control of relative configuration about the methylene bridges

Each of the five different conformers discussed above can differ in the relative
configurations of the substituents at the methylene bridges, which would result in the
formation of four stereoisomers (all-cis (ccc), cis-cis-trans (cct), cis-trans-trans (ctt) and
trans—cis-trans (tct) arrangements (Figure 1.13). This nomenclature will also be adopted
later for defining the relative stereochemistry at the bridges in corresponding methylene

substituted calix[4]arenes in Chapter 4.

Figure 1.13 Stereoisomerism at the methylene bridges
R R R R
R R
R R R
R R
R R R
CCC CC! ctt tct

A cis-cis-trans arrangement of substituents at the bridges would be expected to

yield a pair of enantiomers for resorcinarenes in crown conformation and having

41

identical sub
. l

croon confo:
l

The r

|
unsymmetric.
l
a pair of enar
l
)-l09 were pr
108. Separatrr

sulfonyl chlo;

I
and l-l-IIO. \

Scheme 1.25 n,

no . ,
\ (W.

l

/
108

 

identical substitution patterns on the aryl rings whereas the other stereoisomers in the
crown conformation would primarily result in optically inactive meso compounds.

The reduction of symmetry from C4. to C 2., such as would be seen in
unsymmetrical resorcarenes having different subsituents on the aryl rings would result in
a pair of enantiomeric crown or boat conformations. The racemic macrocycles (+) and (-
)-109 were prepared by Lewis-acid mediated cyclization of resorcinol monoalkyl ether
108. Separation of the enantiomers was then accomplished by using (S)-(+)-10-camphor
sulfonyl chloride as the chiral auxillary to afford the diastereomeric sulfonate esters (+)
and (-)-110, which upon saponification yielded the two enantiomers of 109 (Scheme

1.25).57

Scheme 1.25 First examples of inherently chiral resorcinarenes

 

(+)-110, 13 % (+110, 16 %
lKOH/Hzo lKOH/Hzo

   

(+109, 72 % (+)-109. 70 %

42

Anoth
ether was use
by column cl‘.

As an
synthesis. Le
amido derit
amidolilrcso:

cinnamic acid

Scheme 1

 

 

Another successful approach was reported wherein a chiral resorcinol monoalkyl
ether was used for the cyclization and the two resulting diastereomers could be separated
by column chromatography.

As an alternative to the use of phenols as precursors for chiral resorcarene
synthesis, Lewis acid catalyzed tetramerisation of chiral 2,4-dimethoxy cinnamic acid
amido derivatives 111 has been developed as an efficient route towards chiral

amido[4]resorcinarenes 112. The chiral amides 111 were obtained from 2,4-dimethoxy

cinnamic acid 113 and (L) or (D)-va1ine 114 (Scheme 1.26).58
Scheme 1.26 Lewis Acid catalyzed tetramerization of 2,4-dimethoxy cinnamic acid derivatives

MeO OMe
m BF3.0EI2
/ COR

111

 

 

(L)-lll R= _§
COOEt

(D)-111R= _§\)\ (L)—112 R= _§\l/k
£3005: Conformer COOEt

MeO OMe 1,2- alternate 30 %
m H2N\|/l\ F lattened cone 8 %
/ COOH C OOEt Flattened partial cone(1) 34 %
Flattened partial cone (2) 3 "/0

113 (L)-114
*1sz (mm R= J‘vk

COOEt Similar conformer 6005:
(9)414 ratios were observed

1.7 Homocalix[4]arenes

Homocalix[4]arenes by definition and in contrast to simple calixarenes includes

all classes of [n]-metacyclophanes in which each of the four benzene rings are bridged

by more than single methylene group (Figure 1.14).59

43

Despri.
homocalixarc
degree of co:
tine. Typical
broad categr
calix[4]arene
”-1 Onep
l-7.1.1 )Ifille

The re
E‘raphcnstcnr
the Preparam.
hydroxy gm“
observed fOr t

 

Figure 1.14 Homocalix[4]arene

Y
Y (CH2)
r; .
X X
X (CH2)
(“2(7) X P
n
Omit)
0 Y
Y
x = 011, OR; Y = H, Alkyl

115

Despite the fact that a variety of methods exist for the preparation of
homocalixarenes, this class of cyclophanes has been less examined due to the enhanced
degree of conformational mobility introduced by the presence of a larger macrocyclic
ring. Typical synthetic approaches for all carbon tethered homocalixarenes fall into two
broad categories, one pot and convergent methods analogous to methods for
calix[4]arene synthesis.

1.7.1 One pot methods
1.7.1.1 Miiller-Riischeisen cyclization

The reaction of 1,3-(bis-bromomethyl)-benzene 116 or 117 with sodium
tetraphenylethene in THF at —80°C under free radical conditions has been successful in
the preparation of homocalix[4]arenes 120 and 121 with both exo and endo directed
hydroxy groups. The yields of the cyclization step are typically lower than those
observed for the calix[4]arenes and endo directed substituents favor the formation of

large macrocyclic ring systems (Scheme 1.27).60

Sch

”-1.2 Malon

HOmoc.
bis.lbf0m0mc

l.28y61

Si

 

Scheme 1.27 Miiller roscheisen cyclization to homocalix[4]arenes 120 and 121
R2 R2

   
   

R2 R2
118 R,=OMe,R2=H 120 R1=0H,R2=H
n = 5-8, 2-8 % yields 11 = 5-8, 67-93 % yields
119 R,=H,R2=0Me 121 R1=H,R2=OH
n = 3-6, 2.21 % yields n = 3-6, 87-99 % yields
TPENa
THF
Rt
Br Br
R2

116 R1: OMe. R2 = H
117 R. = H, R2 = OMe

1.7.1.2 Malonate cyclization
Homocalix[n]arenes 124 can also be synthesized in low yields by the reaction of
bis-(bromomethyl) arene 122 and the sodium salt of diethyl malonate 123 (Scheme

1.28).61

Scheme 1.28 Malonate cyclization

 

OMe
0 NaOEt,
Br Br OEt EtOH, Et20
+ A
OEt
122 O
123

“-
R=C02Et 124 (n=3)6%
(n=4)4%

45

1.7.2 Com
1.7.2.1 Sulfu

L'nsyn-
2‘2] frame
125 was con
followed by 1

(Scheme 1.3H

Scheme

 

 

1.7.2 Convergent methods
1.7.2.1 Sulfur dioxide extrusion

Unsymmetrical homocalix[4]arene 127 was obtained by a method related to the
[2+2] fragment condensation in calix[4]arene synthesis wherein bis-(chloromethyl)arene
125 was condensed with dithiol 126 in the presence of cesium hydroxide as the base
followed by oxidation of the sulfide to sulfate and thermal extrusion of sulfur dioxide

(Scheme 1.29).62

Scheme 1.29 Sulfur extrusion approach to unsymmetrical homocalixarene 127

t-Bu

 

t-Bu
O I-Bu (Bu
a “S O O O
OMe
OMe 1 C OH, EtOH
OMe + 0M6 ] s e OR OR
2]m-CPBA OR OR
Cl
0 HS 0 3]470°C,0.4mmHg O O
t-Bu
"B“ t-Bu t-Bu
125 126 127

1.7.2.2 Cross-coupling with organometallic reagents

The reaction of dibromo arene 128 with tert—butyl lithium generated the dianion
which upon coupling with bis-alkyl halide 129 yielded the bis-homocalix[4]arene 130
along with several linear by-products (Scheme 1.30).63 This method suffers from the
tedious purification procedure using analytical HPLC that has to be employed to
separate the desired [3.3.3.3]metacyclophane from a mixture of undesired by-products.
The strategy is convergent as both the starting materials 128 and 129 were prepared

from 2-bromo anisole in six and eight steps respectively.

46

Scheme 1.30 C .

1.7.2.3 Base

The Ct
been utilized
yields ( Schen

Scl

”‘3 Strum

Hom0C
analoe-’Ous [0 _\
isomers are p1

 

shorter bridge

 

Scheme 1.30 Coupling by intramolecular SNZ displacement on 129

OMe OMe

Br Br 1] t-BuLi, ether _
O O 2]
OMe OMe
128
Br Br
129

15-20 %

 

 

1.7.2.3 Base catalyzed condensation with aldehydes
The condensation of phenol 131 with formaldehyde in the presence of a base has
been utilized in the synthesis of an unsymmetrical homocalix[4]arene 132 in excellent

yields (Scheme 1.31).64

Scheme 1.31 Base catalyzed phenol formaldehyde condensation in synthesis of 132

 

1'3“ t-Bu
OH OH
(HCHO) n, NaOH 0 O
O O p-xylene 90 % (3%! 111%
t-Bu t-Bu O Q
131

t-Bu 132 I-Bu

1.7.3 Structure and Conformational properties

Homocalix[4]arenes with identical bridges display conformational isomerism
analogous to simple calix[4]arenes as cone, partial-cone, 1,2-a1temate and 1,3-alternate
isomers are possible. For unsymmetrical homocalix[4]arenes with varying bridges, two
inequivalent 1,2-alternate conformers are known to exist depending upon the location of
the symmetry plane. Conforrners with the symmetry plane parallel to the longer and

shorter bridge have been defined as 1,2-alternate and 1,4-alternate respectively. The net

47

result is a 1

illustrated be
Fi

0R

V

In cor
calix[4]arene
weaker hydr
interconyers
rOtation w he
1.8 sum"

In sun
chiral calix[4
While there :
met the pas
mOIeCular R.
examp]es of
bridges Offer
their Synlheg;
are anmhCr 1.]
blocks fOF dc

that Can be pr

result is a minimum of five different conformers for a homocalixarene, which are

illustrated below (Figure 1.15).

Figure 1.15 Conformers of homocalix[4]arenes

OR
OR OR OR OR OR
W“ W“ wk I (1130“
OR R
OR 0R 0 OR
C _ OR OR
one partial-cone 1 ,2-a1temate 1,3-alternate 1 ,4-alternate

In contrast to intramolecular hydrogen-bonding which rigidifies the skeleton of
calix[4]arenes, homocalixarenes are much more conformationally flexible owing to the
weaker hydrogen-bonds. The steric bulk of the oxygen substituent again dictates the
interconversion process in homocalix[4]arenes via the oxygen-through-the-annulus
rotation wherein rotation is completely inhibited with butyl or benzoyl groups.

1.8 Summary and Future directions

In summary, the synthesis as well as conformational properties of calix[4]arenes,
chiral calix[4]arenes and homocalix[4]arenes have been thoroughly elaborated in detail.
While there are numerous reports on the preparation and applications of calix[4]arenes
over the past few decades, chiral calix[4]arenes have been only of recent interest in
molecular recognition and in bioorganic chemistry. Furthermore, the lack of any
examples of calix[4]arenes that are chiral as a result of substitution at the methylene
bridges offer a challenging avenue for further research in exploring methods aimed at
their synthesis and designing new applications of these macrocycles. Homocalixarenes
are another important class of metacyclophanes, which seem to be promising building
blocks for development of supramolecular assemblies. The presence of a larger cavity

that can be properly adjusted by varying the length of the bridges and the possibility of

48

 

building in re

developing s_\

 

 

building in restraints to restrict the conformation represent some attractive incentives for

developing synthetic methods towards these macrocycles.

49

2.1 Intern

Since
B-unsaturatet
inyestigated .
complexity 31
Preparation 1‘
PIOdUCt fom
fragment of :
from the me'
fragm‘ents 1hk
a5 Ihe initial
Phenols 13m

schf‘me

RIVP
li

R3’\

 

 

CHAPTER TWO
INTRODUCTION TO THE INTER AND INTRAMOLECULAR

BEN ZANNULATION REACTIONS

2.1 Intermolecular benzannulation (Diitz-Wulff reaction)

Since the initial discovery by Dotz in 1975, the benzannulation reaction of an a,
B-unsaturated carbene complex and an alkyne has been one of the most extensively
investigated reactions of Fischer carbene complexes.65 This is due to its mechanistic
complexity and to the fact that it is one of the most synthetically useful reactions for the
preparation of a wide variety of aromatic compounds. The overall process leading to
product formation can be perceived as occurring via incorporation of the organic
fragment of the carbene complex 133, the alkyne 134 and a carbon monoxide ligand
from the metal. The metal center acts as the template in the assembly of the three
fragments thereby furnishing highly functionalized hydroquinone arene complexes 135
as the initial product. Demetalation by exposure to air subsequently affords the free

phenols 136 (Scheme 2.1).

Scheme 2.1 Reaction pathway of the intermolecular benzannulation

 

 

 

 

RI R2
l OM OH OH
6
Cr(CO)5 R2: H Air oxidation
’ ' 3
133 R3/ R5 R RS
OMe
+ (OC)3Cr OMe
136
RS E —RL f 135
9 R
134 R H C L
R2,.
R3
OMe

 

 

 

50

The followin
around the
reviews on th
2.1.1 Mech
The n
Fischer caibc
various mech
of the steps a
exist in the it
the formant

understandin;

Scheme 2.: (

 

 

The following discussion will serve as an introduction to the methodology developed
around the benzannulation reaction and will be brief since several comprehensive
reviews on this topic have appeared in the past few years.
2.1.1 Mechanistic considerations

The mechanism for the formation of 4-alkoxy phenols from the reaction of
Fischer carbene complexes and alkynes is not completely understood as there have been
various mechanisms proposed by several researchers. The differences exist in the order
of the steps and the nature of intermediates in the reaction sequence. Uncertainties also
exist in the reversible nature of certain steps and in the location of the branch points for
the formation of the various side products. A simplified current mechanistic

understanding is illustrated below (Scheme 2.2).66

Scheme 2.2 Overall mechanistic picture for phenol formation

 

 

 

 

 

 

 

CO CO R1

| FCC 0M6 -CO l go OMe 134
00"“0' — R2 0C Cr” 2 =

OC’ l l -' __ R RL larger than Rs
CO R3 R‘ co R3 R'
133 137

OH R2 O

R' RL R' RL
A R2 = H A Electrocyclization

R3 RS R3 RS

OMe OMe

136A (0C)3Cr 140 139

Based on kinetic studies, the first and rate limiting step of the reaction was

proposed by Dotz in 1982 to be loss of a CO ligand from the coordinatively saturated 18

51

electron chro
137. thereby '

coordination

 

 

vinyl carbene
in intermedia
an llTCVCl‘Sll
chromaeyclol
0f the cycloht
lntem;
form a mixtui
manner in \\l
the Steric dit
the one in
mnk‘tionalip
formmiOn .
influenCe 0
the interac
“Inlav’my
the ”Suits
pOSitlon 0
neareSt C
Wherem

IEglOSCICC

electron chromium carbene complex 133 to form the 16 electron unsaturated complex
137, thereby resulting in a vacant coordination site for association of alkyne 134. Alkyne
coordination to the vacant site followed by insertion results in the formation of 111313-
vinyl carbene complex 138. The next step is the insertion of the carbon monoxide ligand
in intermediate 138, which provides the n4-vinyl ketene complex 139 and this is usually
an irreversible step. Complex 139 then undergoes an electrocyclization to the
chromacyclohexadienone species 140. The last step in the reaction is the tautomerization
of the cyclohexadienone 140 followed by demetalation to afford the free phenol 136A.
Internal alkynes are known to react with a, B-unsaturated carbene complexes to
form a mixture of two regioisomeric phenol products 136A and 136B, which differ in the
manner in which the alkyne is incorporated. The regioselectivity is mostly determined by
the steric difference between the alkyne substituents and the major product is normally
the one in which the larger substituent is introduced adjacent to the phenol
functionality.67 The reaction with terminal acetylenes is highly regioselective for the
formation of a single regioisomer with selectivities in most cases as >100:1. The
influence of sterics on the regiochemical outcome is believed to arise from differences in
the interaction of the alkyne substituents with the CO ligand in the two regioisomeric
nlzn3-vinyl carbene complexed intermediates 138A and 138B (Scheme 2.3). Based on
the results of the extended Huckel calculations, it was shown that the subsituent at the 2-
position of the vinyl carbene complexed intermediate is atleast one angstrom closer to its
nearest CO ligand than substituent at the 1-position.66“ Only a few examples exist
wherein electronic factors predominate over steric factors in determining the

regioselectivity.68

52

2.].2 Sc0p

The r
reaction cor;
different pm.
PFOducts by I
With the rear»
of alkenl'l c.
non‘POlar sU
POlar COOlel

in lllCl'CaSlng

 

The n;
alSO affect ll'

ChIOml‘Um ls

 

Scheme 2.3 Regioselectivity in phenol formation

 

RL

 

OMe
1363 Minor product 138A Favored

2.1.2 Scope and Limitations

The benzannulation reaction is extremely sensitive to the substrate and to the
reaction conditions such as the solvent, temperature and concentration. A variety of
different products other than phenols are known to result as either side products or major
products by the proper choice of reaction conditions or substrates. This is especially true
with the reactions of aryl carbene complexes and alkynes and less so with the reactions
of alkenyl carbene complexes. Higher alkyne concentration, lower temperatures and
non-polar solvents favor the formation of the normal 4-alkoxy phenol products, while
polar coordinating solvents, higher reaction temperatures and lower concentration result
in increasing amount of indenes and in some cases as the major products.69

The nature of the metal and the heteroatom substituent on the carbene complex
also affect the product distribution. For reactions with internal and terminal alkynes,

chromium is the most suitable metal for phenol formation. Tungsten and molybdenum

53

carbene com
heteroatom s
is found that
phenols that
products der
electron den.
strengthens t
in amino cor
electron n 1"
products:: A
allord only p

\Vhile
3great deal
asl'mmetrie \
been explore
Stereoselect:

planar and a,

2.1.2.] AS)“

Three

 

Preparing did

.‘lmOng [h 65 C

carbene complexes give increased amounts of non-CO insertion products.70 The effect of
heteroatom substituents on the carbene carbon have also been evaluated and generally it
is found that alkoxy carbene complexes afford much higher yields of the corresponding
phenols than do amino carbene complexes which give indenes as the predominant
products depending upon the substituent on nitrogen and the solvent.71 The greater Ir-
electron density on nitrogen increases the electron density at the metal center and thereby
strengthens the back-bonding to the CO ligand, disfavoring CO insertion from occurring
in amino complexes. Consistent with this hypothesis, it was found that introduction of an
electron withdrawing substituent on nitrogen results in higher yields of phenol
products.72 Amino alkenyl carbene complexes upon reaction with terminal alkynes also
afford only phenols.73

While the careful optimization of the reaction conditions has certainly contributed
a great deal to the application of carbene complexes in natural product synthesis,
asymmetric variants have only been a recent development. Three distinct processes have
been explored which can be broadly categorized as i) Asymmetric benzannulation, ii)
Stereoselective cyclohexadienone annulation and iii) Stereoselective construction of

planar and axial centers of chirality.

2.1.2.1 Asymmetric benzannulation
Three successful approaches have been realized over the past decade for
preparing diastereomerically pure planar arene chromium tricarbonyl complexes from the
benzannulation reaction of or, B-unsaturated vinyl carbene complexes with alkynes.

Among these methods, the reaction of alkynes with carbene complexes having a chiral

54

auxillary on the heteroatom substituent or a stereogenic center on the carbon substituent
have resulted in only modest selectivities in the formation of planar chirality in the arene

complexes via chirality transfer (Scheme 2.4).74

Scheme 2.4 Asymmetric benzannulation with chiral center on heteroatom and carbon substituents

 

 

 

OTBS
011* 143 OTBS
- —_—_—- t-B
(005 Cr 1] (Bu H / u
t-BuOMe, 55°C \I
: \ (l)
6 2] TBSCI, Et3N “CO”
one
142 1443
R" = Menthyl dr > 10:], 55 % yield
MC
(OC)5Cr "’Pr .
2
TBSCl, EtN(iPr)2 ,6:O\cf(co)3 ( )
Benzene
8,0°C 11 20h

 

147A
dr> 1.4:], 83 % yield

On the other hand, reactions of carbene complexes with chiral propargyl ethers
provided the first general method for obtaining chiral arene chromium tricarbonyl
complexes in good yields and diastereoselectivities.75 The asymmetric induction seen in
this reaction is dependent on the size of the propargylic oxygen substituent. Higher
diastereoselectivities were observed for larger substituents such as trityl ethers and
triisopropylsilyl ethers whereas smaller substituents afforded lower diastereoselectivities
(Scheme 2.5). These results indicated the absence of chelation effects in determining the
stereochemical outcome and instead a stereoelectronic effect was postulated. Further
experimental proof for a stereoelectronic effect was obtained when the propargylic
substituent was changed from a (p-methoxyphenyl) dimethyl silyl group to a

(pentafluorophenyl) dimethylsiloxy group.

55

 

Scheme 2.5 As

(H.
(0050i

I48

The stereose
Similarly. re;
and 3-phen}
COml‘lertes.
benzannulari
ChIOmium or
immediate
Complexes 15
arises as a re
allylie Strain
1513 (Sch,

chirality Iran

 

 

Scheme 2.5 Asymmetric benzannulation with chiral propargyl ethers

  

 

 

OR! OR OR]
OMe _E—-< Me
(OC)5Cr CH3 149 Me
(19 6(1) ””1,
Me Cr(CO)3
148 CH2C12, 0.05M, 60 0C OMe
5-6 eq Hunig's base or 2. 6-lutidine 150A
Ratio
3-5 eq TBSC]
R=TBS,R1=MC 85'15
R = TBS, R, = TMS 90.10
R = R,=TBS 91.9
R=TBS, R1=TIPS 95 :5
R = TBS, R, = C(Ph); > 96:4

The stereoselectivity of the benzannulation reaction dropped from 7.3:1 to 1.6:].
Similarly, reactions of the trans-propenyl complex 148 with 3,4,4-trimethyl-1-pentyne
and 3-pheny1-1-butyne yielded an equal proportion of the diastereomeric arene
complexes. The mechanistic rationale to account for the stereoselectivity in this
benzannulation primarily is based on a proposed stereoelectronic effect that has the
chromium oriented anti to the propargylic oxygen in the n': 113 vinyl carbene complexed
intermediate 151. The two possible isomers of this intermediate are the vinyl carbene
complexes 151A and 1518 and they are likely to be in equilibrium. The stereoselectivity
arises as a result of a greater stability of 151B. The species 151A is unfavorable due to
allylic strain between the methyl group and the alkenyl substituent which is absent in
151B (Scheme 2.6). These studies represent the first examples of central to planar

chirality transfer in a benzannulation reaction.

56

Sche

(004

2.1.2.2 AS}:
A net

carbene con
the Product
acetylene re
154A in go"

St

 

Similarly! the

CFClOlleXadic:

 

Scheme 2.6 Stereochemical model for formation of 150A

 

MM"
149 ' ~ /
,C.’\c0

(OC)5CI' 0C 3

 

O“
0

RI R2 151A
Disfavored

 

ISlB

Favored

2.1.2.2 Asymmetric cyclohexadienone annulation

A new chiral center would also be created when both of the B-substituents of the
carbene complex are non-hydrogen and non-identical resulting in a cyclohexadienone as
the product of the reaction. The reaction of cyclohexenyl complex 153 with phenyl
acetylene resulted in the formation of a single diastereomer of the cyclohexadienone

154A in good yield (Scheme 2.7).76

Scheme 2.7 Asymmetric cyclohexadienone annulation with chiral center on a carbon

OMe
(OC)5Cr Me Ph — H

 

Mc THF, 45°C
24h

 

153

dr > 95:5 , 58 % yield

Similarly, the indolyl carbene complex 155 with a chiral imidazolidinone auxillary as the
heteroatom substituent reacted with l-pentyne in acetonitrile to afford the

cyclohexadienone 156 as a single diastereomer in moderate yields (Scheme 2.8).

57

Stere
for the reac
ether 149 oh

the stereoehc

Scheme 2.

@050:

lOleklr:

2.1.2.3 Seer

The 1.

recently de'~

 

TESll‘icted It

 

Scheme 2.8 Cyclohexadienone annulation with imidazolidinone auxillary on heteroatom

Ph

 

 

.Me =. _~Me
N f“'\ = n-Pr
’ NYN‘Me CH3CN.'
Me C,._O 45-50°C
(co)4 24h Me
155 0.005M in 155 156
61 %yield

> 96 % de
Stereoselective and stereospecific cyclohexadienone annulations were reported
for the reaction of the B,B-disubstituted carbene complexes 157 with chiral propargyl
ether 149 which gave either 158A or 1583 with good diastereoselectivity depending upon

the stereochemistry of the carbene complex (Scheme 2.9).77

Scheme 2.9 Cyclohexadienone annulation with chiral propargyl ethers

 

 

 

OCPh3 O OCPh3 O OCPh3
0M6 % Me El
149 .- Me ,
90 °C, 18h +
Me
(2)-157
ocph3
OMe :
(OC)5Cr Me CH3 “9 ‘
90 °C, 18h
Et
(E)-157 GM: 66% OMe

9:91 1583

158A

2.1.2.3 Stereoselctive construction of planar and axial centers of chirality

The reaction of alkenyl Fischer carbene complexes with aryl alkynes has been
recently developed as a versatile synthetic route to atropisomerically pure biaryls. Both
control of planar chirality resulting from preferential coordination of the Cr(CO)3 tripod
to one of the diastereotopic faces of the arene and axial chirality occurring due to

restricted rotation about the biaryl bond can be accomplished with good to excellent

58

diastereose

conditions .

Scheme 2.

(0Cth

f
.
v
-

 

In contrast t
obtained for

2.1-3 SF“!

    
  
  
  
   
   
 

Des‘p
reaCIlOn C01]
Sl'nthSis ()1
applications
organic S_\'n

11311113] prOd

 

appllCatiOn l
1D a83mmet

diastereoselectivities for either the syn or anti isomers depending upon the reaction

conditions (Scheme 2.10).78

Scheme 2.10 Asymmetric benzannulation in generation of planar and axial chirality

     

  

 

    

B4 OMe
(0C)3C; OE , ' (0C)5Cr
R222 TBSCl R' — R2 TBSCI 4v
. EtNi-Prz 159 SEtNi-Ptrizl
t + equen a

R] . ' One po 3 4 Toluene ,-
Med Me 161A R R M60 1613

Syn kinetic Me—z—‘C; E 2 TBS Anti Thermodynamic

dr 57:43 to >99:1 dr 94:6 to > 99:1
160

In contrast to the anti-products, high selectivities for the kinetic syn-product are only
obtained for the trans-alkenyl carbene complexes.
2.1.3 Synthetic applications

Despite the fact that the benzannulation reaction is stoichiometric in Cr, the mild
reaction conditions and ability to tolerate a wide variety of functional groups enables the
synthesis of a diverse array of aromatic ring systems. There has been a plethora of
applications of the benzannulation reactions of carbene complexes with alkynes in
organic synthesis. Many of these efforts have been directed towards fairly complex
natural products some of which have been completed and some for which advanced
intermediate has been prepared by the benzannulation methodology.79 Besides
application in natural product synthesis, some unnatural products useful as chiral ligands
in asymmetric catalysis have also been synthesized by the above methodology.80 A brief

compilation of selected examples is shown below (Fig 2.1).

59

Figure 2.1 Synthetic targets of the benzannulation reaction

OMe OH R 1.
' port 110 R5

. G
R ()8
OH on 0 $0 on1
R

   

(+)-Olivin Total synthesis

Colchicine Analogues
Wulm‘m Wulff 2001
O
HO O OMe
O OH /
M” 00 °0 9 "
O OH

Y- Rubromycin Kozlowski 2001
Napthazarin core

 

Kendomycin core
White J .D. 2005

     

(S)- VAPOL (S)- VANOL 25 Landomycinone
Highly effective Ligands for Asymmetric aziridination of Imines ROUSh 2004

Wulff 1996
2.2 Previous studies on intramolecular benzannulation
Compared to the enormous amount of work that has been done on the
intermolecular benzannulation reaction, the intramolecular version has not been fully
explored. While the benzannulation of an alkyne tethered to the heteroatom of the
carbene complex has been studied in some detail, the analogous reaction of carbene
complexes with a pendant alkyne to either the a or B carbon of the vinyl carbene

complex has only been recently studied. The following discussion will briefly highlight

the heterou
tether to en
2.2.1 Tetl

Nun:
have been r
nitrogen he

phenol prod

Sem:
benzannulan
COmelet 165
alcoholysis
1e"ltteratrtre
alkynes and

Scheme 2

(0C ’SCr:

 

the heteroatom-tethered approach and then will focus mainly on the approach with the

tether to either or or B carbon of the vinyl group.

2.2.1 Tethering the alkyne through the heteroatom of the carbene complex
Numerous examples exist in the literature wherein carbene complexes of type 162

have been prepared which have an alkyne functionality tethered through the oxygen or

nitrogen heteroatom substituent. Upon thermolysis, these complexes afford only the

phenol products 163 (Scheme 2.11).

Scheme 2.11 Intramolecular benzannulation by tethering
alkyne through heteroatom

x/\ X
(ochre/11 _ Id:

Ra RB PB OHR

162 163

Semmelhack reported the first example of this type of intramolecular
benzannulation in 1982 in a synthetic endeavour towards deoxyfrenolicin.81 Aryl carbene
complex 165 was prepared from the tetramethylammonium salt 164 by acetylation and
alcoholysis with w-alkynol. The resultant complex upon stirring in ether at room
temperature afforded the tricycle 166 as single regioisomer in good yields for internal

alkynes and low yields for terminal alkyne substrates (Scheme 2.12).

Scheme 2.12 Semmelhack's study towards deoxyfrenolicin
(CH2)n

GONMC4

ACCl Ether, rt
(OC)5Cr >(OC)5Cr O:;\R-—_’ or 35 °C Jn= 2 ,,3 4
ACZO, PPh3

ForR=H,16—38%
Rae H,62-81%

 

61

Finn reported another approach to the same target with an intramolecular
benzannulation of complex 169 wherein a silyloxy tether was introduced between the
carbene fragment and the alkyne. The advantage of the silyloxy linker was that it could
be easily cleaved in 170 to afford the expected regisomer of the benzannulated product
171 (Scheme 2.13).82

Scheme 2.13 F inn's formal synthesis of deoxyfrenolicin

ONMe4 SiMe2
(OC)5C1‘ MeQSiClz (OC)5Cr

v

 

168 169 100 %\

0.01M, hexane

 

 

reflux,1h
Me\ [Me
,Si.
0MB 0 OMC 0 0
IV
00 °“ C6 ’“NO’ 00
\ \
O OH

As a final example, the intramolecular benzannulation has also been achieved by
tethering the alkyne through the nitrogen of an amino carbene complex. These reactions
were found to be extremely sensitive to the substitution pattern on the carbene complex
and alkyne and also on the tether length. On the basis of studies done by Wulff and

Rahm, amino alkenyl carbene complexes with two carbon tethers primarily result in non-
CO insertion product 173 whereas those with three carbon tethers afford the normal

benzannulation product 175 (Scheme 2.14).83

62

Scheme 2.14 Effect of tether length on product formation

TMS
HN Benzene
(OC)5Cr LT—TMS ——> ph
_ -80—88°C \N
Pb 12h, 57-60% \
172 173 CF(C0)3
Ph
(OC)5Cri Benzene m
\ 85°C Ph N
P“ \ 59% H
174 P" 175

2.2.2 Cyclophane synthesis by tethering the alkyne through carbon substituent of
the carbene complex
The first examples of intramolecular benzannulation reactions involving the
tethering of the alkyne to either the a or B-carbon of an alkenyl carbene complex was
carried out by a former graduate student of the Wulff group, Huan Wang. He envisioned
that such a process would afford a direct entry to an entire library of cyclophanes and his

general synthetic Strategy is depicted below (Scheme 2.15).

Scheme 2.15 Cyclophane synthesis

by macrocyclization
XR
(OC)5Cr
(1
process
XR
[n]-Metacyclophane
XR
(OC)5Cr [or] O
\ a _l3 process

XR

[n]-paracyclophane

63

2.2.2.1 [Bl-Process to metacyclophanes
The carbene complexes required for the evaluation of this approach to m-
cyclophanes were obtained from the aldol reaction of (methoxy)methy1ene pentacarbonyl

chromium(0) and 01,00-alkynals (Scheme 2.16). Both tin tetrachloride and titanium

tetrachloride were effective as Lewis acids in the two-step aldol reaction sequence.84

Scheme 2.16 Aldol methodology to form unsaturated carbene complexes

 

OMe I) n-BuLi, -78 °C OMe
(OC)5Cr:< Ether ¢ (OC)5Cr
CH3 2) 2 eq RCHO/ SnCi4 R
-78°C, CHZCIZ
R = /

3) MsCl (2 eq), Et3N (2.2 eq)

0°C, CH2C12_ 5 min "

n = 2 to 13
33-57 % yields

All these complexes were isolated exclusively as the trans isomers in modest
yields. Thermolysis of carbene complex 177 (n = 6) was initially investigated and was
found to yield the dimerized product [6,6]-metacyclophane 1793 in 39 % yield and the
trimer 180 in 18 % yield. The effect of tether length was then studied and it was found
that for complexes with tether lengths greater than six, the corresponding [n]-
metacyclophanes were obtained in higher yields (Table 2.1).85 The formation of the dimer
179B suggested that complex 177 (n=6) doesn’t have a long enough tether to permit
intramolecular benzannulation perhaps because the 11‘: 713 vinyl carbene complexed
intermediate 18] is too strained to form. In any event, an intermolecular process must
then occur with formation of a new phenol ring in arene complex 182, which undergoes
an intramolecular benzannulation to form the [6,6]-metacyclophane 1798 as the major

PI’Oduct (Figure 2.2).

 

Table 2.1 F

lOClsCl’:-<

‘ L’nidentit

111

The internk
'83 uith b
(Scheme 2_
0r B‘endo P

CYCllzan'On

 

fragment ls

 

Table 2.1 Macrocyclization of Fischer carbene complexes OMe

 

 

 

 

 

 

CH2)n
OH
OH
THF, 0.005M
4? + (CH2)n (CI-12),,
100 °C 0
OMe
__ _ .___-.__ OMe
11 Series % Yield % Yield °/oYield
178 179 180 MeO (CH2) OMe

- —— - - - n

2" A - - _
+ 01-11-10
6 B - 39 18 OH
(CH2) (CH )
n 2n
8 C 43 15 2
10 D 58 5 -
13 E 65 - , OMe
180

 

 

 

 

 

 

“ Unidentified mixtures were obtained

Figure 2.2 Possible intermediates in the intramolecular benzannulation of 1778

 

(CH2)6 I~ H
\/
OC_lCr-__CO OH .
0C co (OC)3Cr
181 182

The intermediacy of complex 182 is also presumed in the double benzannulation of diyne
183 with bis-carbene complex 184 which afforded the same product in similar yield
(Scheme 2.17). Intramolecular alkyne insertion can occur via two different modes, B-CXO
or fi-endo processes that differ in the direction of alkyne insertion (Figure 2.3). The above
cYclization process leading to 178 is an example of a B-endo process, wherein the alkyne

fragment is endo with respect to the newly formed macrocyclic ring.

65

Scheme 2.17 Double benzannulation of bis-carbene complex and diyne

THF,0.005M : M60 0 O OMe
100°C 39%

179B
100 /°C 31 %

 

 

(OC)5Cr 184 Cr(CO)5
OMe MeO

\

183

Figure 2 .3 B- Endo and Exo pathways for macrocyclization

<2 2

oc— Cr/—CO OC- [Cr—C0
0C CO 0C CO
1 B-endo l fi-exo
Metacyclophane Paracyclophane

It was anticipated that if the regiochemistry of alkyne insertion were reversed then

B-exo process would be favored leading to formation of paracyclophane.

Scheme 2.18 Regiochemistry switch in intramolecular benzannulation

  

THF, 100 °C

+
R O O
13 Total Yield R

Carbene Complex of Cyclophanes

 

OMe OMe
185 R = Ph 66% 187A R = Ph 80:20 1878 R =Ph
186R=SiMe3 31% a C188AR=TMS a C1883R=TMS
139 R r H 39:61 178 R = H
l77ER=H >65% 189R=H <l:30 178R=H

a) TFAA, rt, 0.5h

66

The viability of this idea was demonstrated when an internal alkyne functionality
was introduced into the tether that has either a phenyl or trimethylsilyl group at the end of
the alkyne as in carbene complexes 185 and 186. The thermolysis of these complexes led
to the formation of both para and metacyclophanes with modest regioselectivity (Scheme
2.18).

2.2.2.2 [cl-Process to paracyclophanes86

In an effort to demonstrate the versatility of the macrocyclization strategy, the
direct synthesis of paracyclophanes was examined with the idea that tethering the alkyne
through the or-carbon of an alkenyl carbene complex would lead to paracyclophane if an
a-endo process would be operative (Fig 2.4). The normal regiochemical factors would
be expected to favor an or-endo process since the larger substituent would prefer to be
introduced on the newly formed carbene carbon of the vinyl carbene complexed

intermediate (See Section 2.1.1).

Figure 2. 4 01- Exo and Endo pathways For macrocyclization

2 Se“

OC— [CZ—CO —lCr—CO
0C CO OC CO
1 a-exo la-endo
Metacyclophane Paracyclophane

The required carbene complexes for the investigation of this strategy were
prepared by the dianion approach. The vinyl bromides 191 were prepared by
monobromoboration of dialkynes 190. In each case, the reaction gave a statistical mixture
0f the dibromide, monobromide 191 and unreacted dialkyne 190 from which the

monobromide was readily separated. The dianion was generated from the monobromide

67

 

by sequent
by terI-but
attack of II‘
Meemein'
(Table 2.2)

I

\\

[lotml‘pan

DIOductS \\

 

l78D mm]

the “01.11131

was eXtrem

 

by sequential treatment with phenyl lithium to deprotonate the terminal alkyne followed
by tert-butyl lithium to effect the halogen metal exchange. Chemoselective nucleophilic
attack of the vinylic carbanion on chromium hexacarbonyl followed by methylation using
Meerwein’s salt resulted in the formation of carbene complexes 192 in modest yields

(Table 2.2).

Table 2.2 Preparation of alkenyl complexes 192

 

 

 

 

 

Br I) PhL' (OC)5Cr OMe
- _ 1
A l) 9 Br 9BBN¢ M . : i
190 2) ACOH 2) 2 t-BULI
191 " 3) Cr(C0)o 192 °
4) MC3OBF4
Entry 11 Series %Yield 191 % Yield 192
l 6 A 54 44
2 10 B 47 43
3 13 C 51 48
4 16 D 45 41

 

The cyclization of the carbene complex 1928 was first examined and it was found
that in addition to the formation of the expected _[10]—paracyclophane 1933 and the
[lO,10]-paracyclophane 194B, this reaction produced the [lO]-metacyclophane 178D and
bicyclo[3.l.0]hexenone 1958 (Scheme 2.19). Furthermore, these two unexpected
products were produced as the major products. The formation of the metacyclophane
178D involves an or-exo process and as discussed above was not expected on the basis of
the normal regiochemical outcome observed for the benzannulation reaction. Hence, it

was extremely intriguing to ascertain the mechanistic pathway that led to its formation.

68

Scbem

(0Cl_<(..r

Fur.
as such a p
Based on th
hl'POIhesize
Cycl0pr0pa.
from the ex; l

Base
p rOdUCl dist
(n=6) affom
13) gave the
with the 10
Selectit-jty (_

lengh hem“

 

Scheme 2.19 Unexpected formation of metacyclophane 178D from cyclization of 1923

(OC)5Cr OMe
THF
100 °C 0

D

9D

1923
n = 10
178D 30 % 1933 8 %
(CH2)IO
+
OMe
1953 26 % (CHM)
194 3 9 %

Furthermore, the formation of bicyclo[3. 1 .0]hexenone 195B was quite fascinating
as such a product type had never been observed before for the benzannulation reaction.
Based on the similar structural connectivity in 195B and in metacyclophane 178D, it was
hypothesized that the formation of metacyclophane might have occurred by cleavage of
cyclopropane bond in 1958. Subsequently, it was proven that this interconversion results
from the exposure of 195B to either heat or acid catalysis.

Based on a comprehensive study to determine the effect of tether length on
product distribution, it was determined that carbene complexes 192 with short tethers
(n=6) afforded mixtures of dimers and trimers. Those with medium tether lengths (n=10,
13) gave the metacyclophane 178 along with bicyclohexenone 195 whereas the complex
with the longest tether (n=16) studied gave paracyclophanes 193 with very high

selectivity (Table 2.3). The reaction profile is thus completely dependent upon the tether

length between the alkyne and the vinyl carbene complex.

69

Wu
length on
n0nnalc0t
compkx l
insenion t
cydohexad
193 as the
complex 1'
Mddsltn
(192C) that

lisomerizat;

 

 

Table 2.3 Macrocyclization of complexes 192 as function of tether length“

 

 

Entry Series 11 Time Yield Yield Yield Yield
(h) 178 193 194 195
1 A 6 2 36 b
2 B 10 10 30 7 9 26
3 ‘ C 13 20 I6 3 10 38
4 D 16 12 I 56 10 2

 

a Reaction performed at 100 °C in 0.002M of 192

b13 % yield of the trimer was also isolated

Wang and Wulff proposed a mechanism to account for the influence of tether
length on formation of bicyclohexenone 195 and metacyclophane 178. The expected
normal course of events would involve intramolecular alkyne insertion in the carbene
complex 192 to give an 11': n3 vinyl carbene complex, which would undergo CO
insertion to give the 114-vinyl ketene complex 196. Electrocyclization of 196 to the
cyclohexadienone species 197 followed by tautomerization would yield paracyclophane
193 as the expected product of the reaction. This process indeed occurs for carbene
complex 192D (n=16), which forms the corresponding [l6]-paracyclophane in good
yields. It was proposed that for complexes with tether lengths of n=10 (192B) and n=l3
(192C) that the strain in the 114-vinyl ketene complex 196 could be partially relieved by
isomerization to the s-cis, s-trans configuration in 198. Cyclization to form the
metallabicyclo[4.1.0]heptenone 199 followed by reductive elimination then result in 195.
C-C bond cleavage of the cyclopropane unit perhaps by acid catalysis would then give
metacyclophane 178. Finally, it was proposed that for complex 192A, the very large

strain expected for the vinyl ketene complex 196 causes a change to an intermolecular

7O

reaction 0

 

(Scheme 2

Sc

 

\\-’
the metac
IHVOIV ed
benzannu

eXp10red

reaction of complex 192 and then leads to the formation of dimers and trimers of 193

(Scheme 2.20).

Scheme 2.20 Mechanism of intramolecular benzannulation of 192

 

(OC)5Cr OMe OMe
W —-—_' RS v-————
n \\/
192 [Cr—CO
DC Co 196

O 0M6 Q OMe (

193 197

H
H

( @ OMe

201

   

( O OMe

178
While the above mechanism outlines a reasonable pathway for the formation of
the metacyclophane 178, the precise identity of the intermediates and sequence of steps
involved could not be deduced by experimental studies. The effect of solvent on the
benzannulation reaction of carbene complexes and alkynes has been well documented
over the years and the sensitivity of the intramolecular process to the solvent was

explored only recently. When the reaction of 192 was carried out in benzene, the meta-

71

methoxy phenol 202 was isolated as a new product.87 It is noteworthy to point out that
meta-methoxy phenols have never been observed before from the reaction of carbene
complexes and terminal acetylenes. A solvent study was then performed to determine the
product distribution for carbene complexes with varying tether lengths 192A-D and the
results are summarized in Table 2.4. For complex 192A (n=6) only the [6,6]-

paracyclophane and [6,6,6]-paracyclophane were observed as the primary products.

Table 2.4 Solvent effect on product distribution

(3112),, CH2)n CH2)
(OC)5Cr OMe 03> H0 ‘63
\‘l 100 °C q: T T
n OMe
OMe 193 OMe

192
202
178
CH
CH2)" ( 2)n
+
-+- O > OH OMe
M60 HO
OMe
195 (CH2),,
I94

 

Entry Series 11 Solvent Yield 178 Yield 202 Yield 193 Yield 195 Yield 194

 

l A 6 THF - - - - 36 a
2 A 6 Benzene - - - - 28 b
3 B 10 THF 15 Tr 4 42 8

4 B 10 Benzene Tr 21 4O 12

5 C 13 THF 16 2 5 38 10
6 C 13 Benzene - 18 I4 - 26
7 D 16 THF - — 56 - -

8 D 16 Benzene - 2 48 - -

 

“ A 13 % yield of trimer was isolated from this reaction
b A 9 % yield of the trimer was also isolated

72

In general, products 178 and 195 were favored in coordinating solvents (i.e.,THF)
whereas non-coordinating solvents (i.e., benzene) favored 202 and 193 respectively. An
alternative mechanistic pathway has been proposed recently to account for the formation
of these products and their solvent and tether length dependence. It is believed that the
solvent dependent branch point is the vinyl ketene complex 196. In the absence of a
coordinating solvent (THF) and with medium tether lengths (n=10, 13), the vinyl ketene
196 can either cyclize directly to 193 or undergo reorganization of the olefin to form
complex 203 which then undergoes a crossed [2+2] cycloaddition with the alkenyl group

to form bicyclo[2. 1.1]hexenone intermediate 204.

Scheme 2.21 Mechanism of formation of meta-bridged phenol 202

Me
CH2)n
. . Rs HO
\\/ \\/
Cr—CO , Cr—CO
' ‘— l " 196
0C CO 203 0C C0 OMe

    

l 202
193 141+
fir
(CH ) CH2)n
2,
(arm '9” H0
$0Me
+ 209
204 OMe

OMe 208
l‘“

l l

HO
CH
(CH® (CHE ( fl
OMe OMe OMe
+
205 206 207

The resulting benzvalenone intermediate would be expected to be susceptible to
protonation affording a non-classical carbocation 205 which would have significant
resonance contributions from the cyclopropyl carbinyl cations 206 and 207. Cleavage of
the internal cyclopropane bond from either of these two resonance structures would form
cyclohexadienyl cations 208 or 209. Proton loss would then yield paracyclophane 202
with a meta-methoxy phenol or the paracyclophane 193 (Scheme 2.21).The solvent effect
was then rationalized by assuming that solvent coordination to 114-vinyl ketene complex
198 would occur with displacement of the weakly coordinating alkenyl substituent to
give a new vinyl ketene complex 210 wherein the alkenyl group would adopt an s-trans
conformation thereby relieving strain and promoting cyclization to form the products 195

and 178 (Scheme 2.22).

Scheme 2.22 Postulated mechanism to explain solvent effect

 

\Cr—CO S- -lC/r—CO
OC CO OC CO
193 210
6‘ OMe

I95
178

This solvent effect is limited to the macrocyclic intermediates that exhibit ring strain (n

=10, 13). This effect is not observed for the formation of larger macrocycles ([16]-

74

paracyclophane) wherein the isolated yields are the same for both benzene and
tetrahydrofuran.
2.3 Triple annulation strategy towards calixarenes - A systematic investigation

At this juncture, it is very clear that the Intramolecular Benzannulation reaction of
Fischer carbene complexes has provided a number of surprises including the formation
of products not previously seen in the intramolecular reaction and a reasonable
understanding of the scope of the reaction and the effects of solvent and tether now exist.
This methodology has now attained significant maturity so that novel applications in
supramolecular chemistry can be considered. Since the pioneering work of Cram in the
early eighties,88cyclophanes have been ubiquitous as hosts for the inclusion of guest
molecules inside its cavity but the lack of rigidity of all carbon-tethered analogs have
limited their applications in host-guest chemistry. In the last decade, this science has
advanced to the point where it is widely recognized as a highly mature field particularly
as a result of remarkable contributions by Gutsche, Atwood and Rebek. Undoubtedly,
stimulating research on calixarenes and resorcarenes became the backbone of this
discipline thereby contributing to its richness as well as its diversity.
2.3.1 Design of new calixarene based templates for generation of supramolecular
cavitand

Recent studies have shown that calixarenes and resorcarenes have been used in

the synthesis of cavitands and other self-assembled capsules with a well-defined cavity
large enough to trap organic molecules inside, thereby permitting investigation of
reaction processes in such systems.89 A simplified cartoon representation is shown below

(Scheme 2.23).

75

Th
catalyzed
9:and Cop
Specific st
the difficu
in certain ,

All
to trap n6
example,
toluene dl

scum] St:

 

wllhin tile“

based on S

 
 
 
 

ofmulripl,

0f the hOx

Scheme 2.23 Cartoon illustrating typical reaction sequence within a cavitand

"Solvent"

Cavitand - Solvent Complex Cavitand - Reactant Complex

Reactant B

 

Product C c f

"Re generated

Cavitand" Cavrtand - Product Complex

There have been some successful examples of reactions such as palladium
catalyzed allylic alkylation,90 Diels-Alder reactions,91 [3+2] and [2+2] cycloadditions
92and Cope rearrangements 93 inside these molecular cavities but they are very limited to
specific substrates and no asymmetric variants have been reported to date. Furthermore,
the difficulty in generating these macromolecular assemblies and their restricted stability
in certain organic solvents ofien limits the study of reactions within the cavities.

Although calix[4]arenes have been known to encapsulate metal ions, its capability
to trap neutral organic molecules is much more limited due to smaller cavity size. For
example, a 1:1 p-tert-butyl calix[4]arene : toluene complex has the methyl group of
toluene directed inside the cavity rather than the aromatic group. In this respect, a
general strategy was sought to access a variety of cavitands for investigation of reactions
within the cavity. The criteria for host design in supramolecular chemistry is largely
based on size and shape complementarities with the guest species as well as the presence
of multiple identical binding sites on the host which would increase the binding constant

of the host-guest complex. A larger cavity size has been known to be induced by two

76

different
rings ant
approacl
rings ( eg

Figure 2.5

@

" A C8ll\l~l

\1
guest m0}
and Other
Of a suita

l
CTIICTla, 0
examining

IS Slow in

mOleCtlles

 

large_ To ;
lie; muh
e”Capstlla
006:1anr

the Scenar,

 

different methods, the first of which would involve either increasing the number of aryl
rings and methylenes in the bridge (eg., Calix[6]arene, Calix[10]arene), whereas the latter
approach would involve an increase in the tether length connecting the adjacent aromatic
rings (eg., Homocalixarenes) (Figure 2.5).

Figure 2.5 Common approaches to obtaining larger cavity sizes

Phenyl rings and methylenes

 

calix[ 6]arene, calix

@ [8]arene etc...
" A calix[4]arene" A
More methylene carbons Homocalix[4]arenes

While there has been numerous studies towards encapsulation of neutral organic

 

 

guest molecules inside the cavity done by several research groups with Calix[6]arenes
and other larger macrocycles, homocalix[4]arenes have been less examined. The design
of a suitable supramolecular host based on a homocalix[4]arene has to obey certain
criteria, one of them being the specific guest molecule that is targeted. Furthermore, for
examining reactions within the cavity it is imperative that the reaction under investigation
is slow in the absence of the host species. The extent of association of the host and guest
molecules in solution measured by calculation of binding constants must be significantly
large. To achieve this last requirement, the host species must have multiple binding sites
(i.e.; multivalency), which are structurally similar to the guest molecule that needs to be
encapsulated. Finally, the host must possess a rigid conformation for otherwise the
orientation of the guest species inside the cavity would be altered thereby complicating

the scenario for stereoselective reactions.

77

Based on a careful examination and analysis of different homocalix[4]arenes by space
filling models, it was clear that a bishomocalix[4]arene 211 and its chiral analog 212
would be an ideal candidates for initial investigation (Figure 2.6). One of the most
important requirements in rendering the middle carbon of the propylene tether chiral
would be the adjacent arenes of the macrocycle to be diversely substituted (R1 at OH and
R2 :4 OMe). At the outset, it was expected that this requirement would be fulfilled by an

extension of the Double benzannulation strategy (See Scheme 2.17, Pg.89).

Figure 2.6 Bis-homocalix[4]arene 211 and its chiral analog 212

 

OH
211 212

These supramolecules would be expected to be extremely floppy due to rapid rotation of
the aryl rings about the annulus. A locked conformation would result if the opposite
phenols were converted to a diester 214 and 215 (eg., R1 = OMe and R2 = Me) by
bridging with a rigid bi-functional reagent such as 2,7-Naphthalene dicarboyl chloride
213. The lowest energy conformation of 214 and 215 is expected to be the one shown
wherein the two anisole rings would be parallel to each other and also to the naphthalene
bridge at the bottom of the molecule. The two distally anchored arene rings would then
be splayed outward, thereby creating a cavity large enough to permit inclusion of guest
molecules. Furthermore, the distance between the two non-anchored arene rings would

be 7.4 A, exactly the right distance for the inclusion of an arene ring.

78

 

C0n
fBCl

aret

bfi;

Figure 2.7 Cavitand hosts and cavitate 216

   

0
‘ Acid Chloride 213

I Acid chloride 213

211 212

 
  
  

Edge-Face Interaction

Face to Face Interaction

 

Host-Guest complex (Cavitate) 216

Face to Face Interaction Edge-Face Interaction

Thus, it is expected that cavitands 214, 215 would form very stable host-guest
complexes with functionalized naphthalene derivatives due to presence of several edge-
face and face-face interactions between aromatic rings on the calixarene and the host
arenes (Figure 2.7).

In the host—guest complex 216, the hydroxyl group on the propylene tether would

be in close proximity to the alkenyl moiety of vinyl naphthalene. Thus, it is conceivable

79

 

    
   

that hydr
epoxidat
Chapter
synthesis
differentl
followed
with sub:
det'eloptr
toward al

Wltll a (ll:

 

2.24).

 

 

that hydroxy directed reactions such as Simmons-smith cyclopropanation and asymmetric
epoxidation of unfunctionalized olefins could be examined with the cavitand 215.94
Chapter three will focus on the development of the triple annulation strategy for the
synthesis of calix[4]arenes with C2 or C 1 symmetry by having either two or three
differently substituted arene rings (ABAB or ABAC substitution patterns). This will be
followed by an examination of the feasibility of obtaining optically active calix[4]arenes
with substituent(s) at the methylene bridge(s). Finally, Chapter 5 will focus upon the
development of methodology for synthesis of homocalix[4]arenes. The general strategy
toward all these macrocycles will involve either the reaction of bis-carbene complex 217
with a diyne 218 or the dimerization of akynyl vinyl carbene complex 219 (Scheme

2.24).

Scheme 2.24 Triple annulation strategy towards unsymmetrical calix[4]arenes
and homocalixarenes

OMe R' OMe

 

”1 R3 ”1 +
2 I 7 218

???

 

Rl OMe
WWW '-"-’*’
m R3 n ()11 R3 R4 HO n
219 220

80

CHAPTER THREE
EXPLORATORY STUDIES ON SYNTHESIS OF CALIX[4]AREN ES WITH C2
AND C; SYMMETRY

3.] Triple annulation approach to calix[4]arenes

The existing methods for calix[4]arene synthesis can be classified based on the
symmetry introduced in the macrocycle as shown below (Fig 3.1). The most prominent
method for calix[4]arene synthesis is the one developed by Gutsche, but its drawback is
that only certain substituents can be introduced in the p-position and also calix[4]arenes
with C4 symmetry only can be obtained. The fragment condensation methods either by
[3+1] or [2+2] approaches circumvents this problem because calixarenes with C2 or C2
symmtery can be obtained but still suffers from low overall yields in the cyclization step
as well as the inability to introduce different substituents at the lower rim. Calix[4]arenes
with C1 symmetry are special class of macrocycles as they exhibit molecular asymmetry
depending upon the substitution pattern (ABCD or ABAC with one inverted phenol ring)
on the arene rings. Consequently, enantiomers for these calixarenes exist and synthetic
strategies developed by Biali (See section 1.5.1.1) are circuitous involving sequential
introduction of functionality followed by resolution with chiral reagent. Neverthless, the
inherent chirality due to molecular asymmetry in such calix[4]arenes presents an
attractive feature to develop synthetic applications for these scaffolds.

In this context, development of a new synthetic route to directly access
calixarenes exhibiting C2 and C1 symmetry would represent significant advancement over

existing methods.

81

Fig 3.1 Methods of calixarene synthesis based on symmetry classification

R' R?- R3 R4
O O O +
z 2 Y Y
OH OH OH OH

    

 

 

3 + l Fragment Condensation
1 R1
l 2 RI R
RI R4 R R3 R
Single Step : Q,| IEQ
Manipulation
OH OH OH OH H0
224
221
R1 R4
O O + O 0
Z Z Y Y
OH OH OH OH
225 226
Z (or) Y = CHZOH, CHzBr, H
Method Substituents Pattern Symmetry
Single Step 0 R' = R2 = R3 = R4 AAAA C 4
Fragment R' ¢ R2 ¢ R3 gé R4 ABCD C I
° 0
Condensation R' = R3, R2 = R4 AB AB C2
R'= 123,122 26 R4 ABAC C,
Functional Group R'= R3, R2 = R4 ABAB C 2
Manipulation R5 = R7, R6 = H
R' = R2 = R3 = R4 ABCD C,
R5 i R6 at R7

 

“ Substituents R5 = R6 = R7 = H
Thus, a novel method was envisioned based on the reaction of a bis-carbene
complex 229 and diyne 228 that could enable direct access to calix[4]arenes 230 with the

ABAB substitution pattern and C2 symmetry when the substituents on the arene ring

82

were identical (R3 = R4 and R2 = R'). Calix[4]arenes with C, symmetry would exist for
ABAC substitution pattern only in the case of partial-cone or 1,2-alternate conformers
231 and 232 and calix[4]arenes with Cs symmetry 233 would be expected in a cone
conformation when the substituents on the arene ring were non-identical (R3 gt R4 and R1
¢ R2). Intuitively, a general approach was conceived for these calix[4]arenes adorned
with specific symmetry elements by proper choice of aryl substituents in the bis-carbene

complex and the bis-propargyl arene (Scheme 3.1).

Scheme 3.1 General synthetic strategy to calix[4]arenes with specific symmetry elements

as

R3
Cone 230 C 2 OMe 231 partial cone C 1

 

7 OMe

   
  

   

   

 

 

 

, 3
R“ OMe OH R R4 H0
232 1,2-altemate C1 Cone 233 Cs
OMe R' OMe R2
(0050' I I Cr(CO)5
+
R3 R4
229 228

The choice of substituents was governed by factors that would either favor or

disfavor the cone conformation and would thereby enable access to calix[4]arenes 230-

83

233. Intramolecular hydrogen bonding is solely responsible for stability of cone
conformer (See section 1.2.1). It has further been shown that replacement of hydroxyl
groups by amino or thio] substituents in calix[4]arenes 234 and 235 do not disrupt the
hydrogen-bonding pattern because the cone conformation is still observed in solution.”96
Thus, heteroatom substituents at the lower rim would enable access to ABAB
calix[4]arenes 230 with C2 symmetry. In contrast to 234 and 235, alkyl and hydrogen
substituted analogs 236, 237 were found to exist in the 1,3-alternate and 1,2-alternate

conformations respectively (Fig 3.2),”98

Fig 3.2 Effect of hydrogen bonding on the stability of cone conformation

2.13“ l-BU I—Bu t-Bu t-Bu t-Bu t-Bu t-Bu

    

 

I
OH NH; NH: HO OH SH SH H0
234 235
t-Bu t—Bu 1-311 t-Bu
Cl no
I \ 1
OH H
t-Bu t-Bu
236 237

Based on these results, it was anticipated that introduction of long chain alkyl or aryl
substituents (R3 = R4 = Ar (or) 1° alkyl, Scheme 3.1) at the lower rim would disfavor the
cone conformation and could possibly enable access to calix[4]arenes with molecular
asymmetry (C1). These substituents were also expected to inhibit the ring-inversion
process that is known to racemize such inherently chiral calix[4]arenes (See section

1.5.1.1).

84

3.2 Practical synthesis of bis-propargyl arenes 228

Preparative routes for bis-propargyl arene 228A with R4 = OMe and R2 = Me
(239A, Scheme 3.2) were initially investigated. After screening a wide variety of
methods, two were found to be successful.

The benzyl bromide 238A upon coupling with trimethylsilyl ethynyl Grignard
reagent in the presence of catalytic amount of Cu (1)99 or with trialkynyl indium reagent
in the presence of catalytic amount of Pd (11) species100 afforded the bis-silylsubstituted
diyne 239A in excellent yields (Scheme 3.2). While the success of both methods added
greater flexibility to the desired synthetic objective, each had its own advantages and
disadvantages. For example, the copper bromide catalyzed coupling had to be done with
at least 8 equivalents of the alkynyl Grignard reagent at high concentrations as the
reaction is typically slow at low concentration and with a low stoichiometric amount of
the Grignard reagent. Despite this inherent problem, the low cost as well as the ease of
handling of the reagents enabled this process to be the most advantageous. The palladium
catalyzed coupling despite suffering from expensive Pd (11) source was still a highly
atom-efficient process as an excess of the organo-indium reagent was not required for the
cross coupling and all the three alkynyl groups on the indium were transferred. With a
convenient route to 239A secured, the synthesis of bis-propargyl arenes with different

aryl substituents was then explored.
Scheme 3.2 Pd(Il) and Cu“) catalyzed coupling in synthesis of 239A

 

 

 

 

 

Me method A
TMS = MgBr Me
CuBr (15 mol %)7TMS TMS
—— THF, reflux \ /
Br 0M6 Br method B
TMS = ) In OMe
238A ( 3 .
> 239A Method A 73 % yield
2 mol % Pd(dppf)C12 .
THF, reflux Method B 80 % yield

85

A Domino cross-coupling sequence was envisioned wherein the electronically
activated aryl triflate 241 with formyl groups in two ortho positions would afford the aryl
and alkyl substituted aldehydes upon the initial coupling step (Scheme 3.3). The formyl
groups would then be transformed into bromomethyl groups in arene 238 and a second
coupling process using either method A or B would yield a family of substituted bis-

propargyl arenes of the type 239.

Scheme 3.3 Domino cross couping sequence to his-propargyl arenes

Me Me
1. Cross Coupling
"""""" ,"""'" Br Br
OHC CHO 2. Reduction and
OTf Bromination
241 238
Me
3 Cross cou Iin R R
; ........ l3- - £3, \ i
using method A or
B R
239

The aryl triflate 241 was prepared in good yields by two methods that differ in the
source of the triflating agent. Triflation of phenol 240 using N-phenyl bis-
(trifiuoromethane) sulfonimide resulted in good yields of the product on a smaller scale
but difficulties were encountered in its separation from the N-phenyl trifluoromethane
sulfonamide by-product on a larger scale. An alternative approach was developed using
triflic anhydride under biphasic conditions and potassium phosphate as the basemThis
protocol circumvented the purification problem that was encountered in the former
method and the aryl triflate could be conveniently prepared in multigram quantities in
excellent yields (Scheme 3.4). The cross coupling of triflate 241 with organoboranes and
organoindiums was next examined and optimized by screening a wide variety of reaction

conditions.

86

Scheme 3.4 Preparation of aryl triflate 241
Me Me

Condition A or B

 

OHC CHO OHC CHO
OH OTf
240 A. PhNsz, Et3N 83 % 241 by
CHZCIZ either Methods A or B

B. 30 % Aq.K3PO4, “)0

Recent studies by Molander and others have indicated that alkyl boronic acids are
viable partners in the cross coupling reactions with aryl tn'flates.102 The cross coupling of
triflate 241 with n-hexyl boronic acid in the presence of a weak base and 1,1 ’-
bis(diphenylphosphino)ferrocene palladium (II) chloride as the catalyst resulted in only a
49 % yield of the product 242A (Entry 1, Table 3.1). The yields were significantly lower
when the stronger base cesium carbonate was employed under identical reaction
conditions (Entry 2). The use of 9-hexyl-borabicyclononane resulted only in complex
mixtures with two different palladium catalysts (Entries 3 and 4). Alternatively, the use
of potassium hexyl trifluoroboratem as the alkylating reagent resulted in predominantly
the hydrolysis of 241 under strongly alkaline conditions. Weaker bases such as potassium
carbonate and potassium phosphate facilitated nucleophilic addition to the carbonyl of the
aryl triflate 241 (Entries 5-7 &10). Finally, cross coupling with trihexyl indium reagent
afforded the product 242A in similar yields to the boronic acid (entries 8 & 9 vs entryl).
In contrast to the difficulties observed in forging the formation of a sp3-sp2 C-C bond,
Suzuki coupling of aryl triflate 241 with phenyl boronic acid using tetrakis triphenyl
phosphine Pd (0) in the presence of potassium phosphate as the base resulted in formation

of the biaryl 2423 in excellent yields (entry 11).104 Both the aldehydes 242A and 24213

87

 

WCI'C 5L

 

using st
Table 3.1 t

Me

OHC l

OTf
241

 

S..\'o

 

8-)

DJ

 

 

were subsequently transformed to bis-bromomethyl arenes 238B and 238C by reduction

using sodium borohydride followed by bromination (Table 3.2).

Table 3.] Cross coupling reactions of aryl triflate 241

 

 

 

Me Me Me Me
Pd catalyst ; R R
OHC CHO Reaction Conditions? OHC CH0 OHC CH0

OTf R + OH + OH OH OH
241 242 A R = n-C6Hl3 240 243

+ R'” 242 B R = Ph
S.No R-M Conditionsa'b Yield 242A / 242 B Yield 240 / 243

l C6H13B(OH)2 A 49 Observed Ol'l TLC

2 n B 17 Observed on TLC

3 C6H139—BBN C - Complex mixture of Products

4 " D ‘ Complex mixture of Products

5 C 6H] 3BF3K E - Only Products

6 " F - Only Products

7 " G Ratio 240 : 243 (>10:l) by GC/MS

8 (CbH 13)3In H 47 None

9 " I 45 None

10 C6H13BF3K .1 Ratio 240 : 243 (>10: 1) by GC/MS

1 1 PhB (OH)2 C 85 None

 

0
Reaction Conditions
A 1(2CO3 (2.73eq), THF reflux B C52CO3 (3 eq), THF reflux C 1(3PO4 (1.5 eq), 1.4-Dioxane, 85°C

D K3PO4.H20, THF, reflux E CszCO3 (3.6 eq), THF:H20 (10:1) reflux F CszCO3 (3.6 eq), THF, reflux

G K2C03 (3.6 eq), K 3PO4(3 eq) H THF reflux I THF / Dioxane (l :1), 100 °C J K3P04(3-6 eq). THF, reflux

b Reactions in entries 1-3, 5-7 and 10 were carried out using 10 mol % Pd(dppf)Cl2

Reaction in entry 4 was carried out using 2 mol % Pd(OAc)2, 1 mol % (S)-PHOS and those in entries 8, 9

were carried out using 10 mol % Pd(PPh3)2Cl2. Reaction in entry 11 was carried out using 2.5 mol % of Pd (PPh3)4

88

Bromomethyl arene 238D could be obtained from 4-phenyl phenol in a straightforward
manner and the details can be found in the experimental section. A second cross coupling
of these substrates using either method A or method B yielded the bis-trimethylsilyl
substituted diynes 239A—D in high yields from which desilylation could be accomplished

using silver nitrate to provide the bis-propargyl arenes 228A-D (Table 3.2).

Table 3.2 Synthesis of bis-propargyl arenes

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

R2 R2 method A
TMS = MgBr
PBr3 (2.4 eq) e
CHC13 CuBr (15 mol %) R
t ' THF, reflux
OH R4 OH Br R4 Br method B
. TMS — )3ln
244A-D 238A-D 59-86 % . = 239A-D R = TMS
2 mol % Pd(dppt)C12 AgNO3
NaBH4, MeOH THF, reflux KCN E 228A-D R= H
Me Yield, %
sen'es R2 R4 Method 239 228
R B MC n-C6Hl3 A 73 73
C Me ~ Ph A 71 77
242A R = n-C6H13 D Ph OMe B 77 90
2428 R = Pb
3.3 Synthesis of bis-carbene complexes
R2
1) szznnxtl I 1
R 4 2) NIS
4
228 245 R
OMe Rl OMe
(0050 I CttCO)5 1) "3““ l
2) Cr(C0)6
3 M OBF
229 R3 ) e3 4
Table 3.3. Synthesis of his-carbene complex 229
R2 R4 245 % yield 245 R‘ R3 229 % yield 229
Me OMe 245A 86 Me OMe 229A 36
Me n-C6H13 24513 77 Me n-C6HI3 229B 44
Me Ph 245C 73 Me Ph 229C 47
Ph OMe 245D 78 Ph OMe. 2290 32

 

89

 

 

follou
excellc
the F is
obtainc

3.4

Fischer
conditlt
of van
undcna
Consislt
and 31k}
1‘5. Th
PYOducl
P012” c(
abSCHCe
”0‘ Caust
t0 the 01
(Scheme
deteqed
”while 3]

thCSe rea

 

Hydrozirconation of the bis-propargyl arenes 228 using Schwartz’s reagent105
followed by iodination resulted in the formation of bis—trans vinyl iodides 245 in
excellent yields which could be converted to the bis-carbene complexes 229 following
the Fischer procedure (Table 3.3). Improved yields of the carbene complexes were not
obtained by using the bis-trans bromo analogs.

3.4 Triple annulation: Effect of solvent, temperature and concentration

Since the efficiency of formation of phenols from the benzannulation reaction of
Fischer carbene complexes and alkynes is known to be very sensitive to the reaction
conditions as discussed earlier (See Section 2.2.2.2), a careful investigation of the effect
of various reaction parameters on formation of ABAB calix[4]arene 246A was
undertaken in the reaction of bis-carbene complex 229A with diyne 228A (Table 3.4).
Consistent with the general trends observed in the reactions of alkenyl carbene complexes
and alkynes, only minor solvent effects were observed in this reaction as shown in entries
1-5. The non-polar non-coordinating solvent benzene afforded a lower yield (26 %) of the
product compared to polar non-coordinating solvents such as ethylene dichloride (36 %).
Polar coordinating solvents did not influence product yields (Entries 1 and 2). The
absence of a significant solvent effect suggests that solvent coordination to the metal does
not cause a shift in product distribution in the triple annulation process. This is in contrast
to the observations of p-cyclophane formation via an intramolecular benzannulation
(Scheme 2.21). No other cyclic oligomers (i.e., Calix[8]arene, Calix[12]arene etc.) were
detected in any of these reactions. TLC analysis of these reactions revealed only a single
mobile spot with some amount of baseline material. Analysis of the crude 1H NMR of

these reactions revealed only the presence of the calix[4]arene 246A. Further studies

revealed that higher reaction temperature is optimal. Significantly lower product yields

and longer reaction times were observed at lower temperatures.

Since the

macrocyclization involves the intramolecular benzannulation of intermediate carbene

complex 248, it is not suprising that it is sensitive to concentration. The yield drops to 16

% at 0.025M and could not be improved by adding a mixture of carbene complex and

alkyne to hot 1,2-dichloroethane (Entry 1.1).

Table 3.4 Solvent, temperature and concentration effect on triple annulation

 

  

OMe

   

 

 

 

Me M
OMe Me MeO e
(OC)5CI' I I Cr(CO)5
\
OMe OH OMe OMe HO
229A 22:: 246A
% Yield
Entry Solvent Temperature ( ° C) 246 A Concentration Reaction time

1 Tetrahydrofuran 100 28 00025 50 min
2 Acetonitrile 100 29 0.0025 20 min
3 Benzene 100 26 0.0025 3 h

4 1,4 - dioxanc 100 30 0.0025 40 min
5 1,2 - dichloroethane 100 36 0.0025 20 min
6 " 83 33 0.0025 90 min
7 " 50 25 0.0025 > 2 d

a
8 " 83 32 0.0025 30 min
9 " 83 16 0.025 50 min
10 .. 33 17 0.025 a 8-10 h
a
l l " 83 8 0.25 1h

 

a) Performed by syringe pump addition

0 0 O 0““
\‘ cncon

e0(OC )3Cf/()

91

3.5 Calix[4]arenes with ABAB and ABAC substitution pattern - Exploration of
substrate scope
Having determined the optimal conditions for synthesis of calix[4]arene 246A,
the reaction was screened for preparation of calixarenes with ABAB and ABAC
substitution patterns by appropriate combination of the diyne 228 and bis-carbene
complex 229 in the triple annulation process.
As shown in Table 3.5, the yields in all the cases range from 30-41% except in entries 2
and 7.106 The examples in entries 3-6, 8 and 9 further illustrate the flexibility of this

methodology in the preparation of either inner or outer-rim phenyl substituted

 

calixarenes.
OMe RI ( )_\-'1 c
(OC)5Cr I
229 R3
R2 +
R4
228
O M 0
246/247

Table 3.5 Triple Benzannulation of Complex 229 and Diyne 228.a

 

 

entry complex R' R3 Arene 228 R2 R4 246/247 % yield
1 229A Me OMe 228A Me OMe 246A 36
2 22913 Me "£611.3 2sz Me new” 2463 22
3 229C Me Pb 228C Me Ph 246C 35 b
4 229D Ph OMe 228D Pb OMe 246D 41
5 229A Me OMe 228C Me Ph 247A 31 c
6 2290 Pb OMe 228C Me Ph 2478 35 d
7 229A Me OMe 22813 Me n-C(,lll3 247C 22 c
8 2298 Me new,3 228D Pb OMe 247D 35 c
9 229A Me OMe 228D Pb OMe 247E 40

 

1‘All reactions were carried out in 1,2-dichloroethane at 100 °C at 2.5 mM in 229
with 1.0 equivalent of alkyne 228 for 20 to 40 minutes. b Isolated as a separable
1.7 : 1 mixture of 2 conformers. ° Isolated as a non-separable 3.8 : 1 mixture

of 2 conformers. d Isolated as a non-separable 3.3:1 mixture of 2 conformers.

c Isolated as a non-separable 7.9 : 1 mixture of 2 conformers

92

 

Some
structu
3.6

3.6.1

crystal!
known
examir.
correspt
in the 11
(Hill, the

the pan

 

Obsen-e(
chemical
31.67, 3 j
analysis
intrigum
Upon tht‘
24GB, 1}
COHfOI-m
that 1116.5,
a l23~al

hydl‘Oge

Some of the calix[4]arenes were obtained as a mixture of different conformers and their
structural elucidation will be discussed below.
3.6 Conformation elucidation
3.6.1 Calixarenes with ABAB substitution pattern

The conformational elucidation of calixarenes was accomplished by use of X-ray
crystallography and the Mendoza rule by correlating l3C chemical shifts of the four
known conformers (See Section 1.3). Based on a comprehensive spectroscopic
examination of several symmetrical calix[4]arenes the 13C chemical shifts of the
corresponding methylene carbons between adjacent aryl rings that are syn to each other
in the macrocylic array must be 31 ppm for cone.29 When the adjacent aryl rings are
anti, the chemical shift of the methylene carbons has been found to be at 37 ppm. Since
the partial cone and 1,2- alternate would have two syn and two anti aryl rings, the
observed l3C resonances were at 31 and 37 ppm. Consistent with this rule, the 13C
chemical shifts of the methylene carbons in calix[4]arenes 246A, 2468, 246D were at
31.67, 31.53 and 31.73 ppm. Based on this observation as well as the single crystal X-ray
analysis of 246A these were assigned the cone conformers with C2 symmetry. It is
intriguing to note that the conformational preferences of the macrocycle are dependent
upon the size of the alkyl group as in contrast to the dihexyl substituted calix[4]arene
2468, the dimethyl analog 236 (Fig 3.2) was reported to exist only as the 1,3-alternate
conformer. The chemical shifts of the methyl groups at 6 1.3 ppm in the latter suggested
that they are under the shielding effect of neighbouring aryl rings as would be expected in
a 1,3-alternate conformation in contrast to the corresponding shifts of the benzylic

hydrogens in the former at 2.52 ppm.

93

The diphenyl substituted calix[4]arene 246C was isolated as a separable mixture
of two conformers. X-ray determined the structure of each and it was found that the
minor isomer 246C-I crystallized in the cone conformation with C2 symmetry whereas
the major isomer 246C-II crystallized in the 1,2-alternate conformation with C.-
symmetry (Fig 3.3). However, inconsistent with the Mendoza rule is the observation that
the chemical shifts of the methylene carbons in 246C-I and 246C-II resonate at 36.12
and 36.95 ppm respectively. This suggested that the 1,3-alternate conformation may be
preferred in chlroform-d as the solvent for these compounds. Further spectral differences
between 246C-I and 246C-II existed in the aromatic region that showed only four peaks
4, 2, 2, 2 hydrogens respectively in the former whereas the latter showed five sets of
aromatic hydrogens integrating to two hydrogens each. Thus, it was conceived that
rotation of the phenyl group about the biaryl axis was completely surpressed at room
temperature for 246C-II but not in 246C-I. At this stage, NOE analysis was performed
on both these compounds to determine the conformational preferences in solution. It was
indeed quite surprising to note that in both the cases the same conformation was observed
in solution as in the solid state. Thus, clearly inner rim phenyl substituted calix[4]arene
246C is an exception to Mendoza rule as 1,3-alternate conformer was predicted on the
basis of observed 13 C chemical shifts. This possibly arises due to the elongation of the
C(sp2)-C(sp3)-C(sp2) bond angles due to the inclusion of the two phenyl rings within the
smallest diameter of the macrocycle. The hydrogen bonding is completely disrupted as
indicated by the 1H NMR chemical shifts at 4.12 for 246C-I and 4.24 ppm for 246C-II

respectively as well as by IR (3472 & 3509 cm'l).

94

Figure 3.3 Conformations of calix[4]arenes 246A-D

 
   

M e0 Me Me OMe Md)

 

l /
OH R3 R4 HO

Ratio 246A R3=R4=0Me, Rlsz:Me
M60 246C-1 /11 3 4 I 2
=1/1.7 “63 R =R :Il-C6H13,R =R =Me
~ h 0“ 2461) R3 = R“ = OMe, R' = R2 = Ph
r \ I
246C-11 Mc OMe

3.6.2 Conformations of calix[4]arenes with ABAC substitution pattern
3.6.2.1 Phenyl substituted Calix[4]arenes 247A and 247B

The conformation of calix[4]arene 247A with three heteroatom substituents in the
inner rim was next analyzed. The 1H NMR spectra displayed a complex pattern of signals
that definitely could not be assigned to a single compound. The presence of well defined
sharp peaks in chloroform-d as solvent ruled out the possibility of rapid inter—conversion
processes between conformers on NMR time scale. Careful examination of the spectra
revealed that at-least two different compounds were present in CDC13 solution in a ratio
of 3.8: 1. These two compounds were not separable by thin-layer chromatography as well
as by high-pressure liquid chromatography. The MS analysis of the mixture of these two
compounds showed M+ ion at m/z 586 suggesting that they might be stereoisomers. The
aromatic region for both these compounds showed a pair of doublets (J =3 Hz, i.e., meta-
coupling) and a pair of singlets for a total of eight protons each. Based on this
information 1,2-alternate 249 was ruled out as possible structure for either of these two

compounds, as it would be expected to have eight in-equivalent aromatic hydrogens

95

(Figure 3.4). Intrigued by the possibility of finding a conformer with C1 symmetry,

extensive molecular modeling and examination of the 1H NMR spectra was undertaken.

Figure 3.4 Energy minimized structure of 1,2-alternate conformer of 247A

   

247A
Conformers I and II
Ratio 1 : II = 3.8:]

249

A careful scrutiny of the aromatic region revealed that the phenyl group showed
five different hydrogens due to the hindered rotation about the biaryl bond. A rather
puzzling observation was made during spectroscopic analysis when it was found that one
of the ortho-aryl hydrogens of the phenyl group in major isomer was shifted upfield
(60,1110 Ar-” = 4.78 ppm). Such unusual chemical shifts are observed in situations involving
close edge-face association of two adjacent aromatic rings due to ring current shielding.
While the 1,2-alt conformer shown above would possibly have such an interaction
between the phenyl substituent and the aromatic ring of the calix backbone, it had already
been ruled out as a possible structure due to its lack of symmetry. Thus, four other
possible structures are proposed of which three are partial-cone conformers 250-252
differing in the aryl ring that is flipped with respect to the annulus and the last is 1,3-

alternate 253 (Figure 3.5).

96

    

Figure 3.5 Energy minimized structures of partial cone and 1,3-alternate conformers
a Partial cone
251

Partial cone 250

ll"

1,3-alternate 253

 

Partial cone 252

The chemical shifts of the methoxy groups in the p—alkoxy phenols (s, 6H) for the
major isomer was at 6 = 3.46 whereas in the minor was at 6 = 3.78 ppm. On the other
hand, the methoxy group in the anisole (s, 3H) was unaffected in both the isomers at 3.84
and 3.86 ppm respectively. This difference suggests that the two p-methoxy phenols are

aligned parallel to each other and are under the influence of ring current shielding while

97

one of the other two arenes may be oriented anti-parallel. Thus, it seemed reasonable that
paco 252 with C1 symmetry was not the major conformer observed in solution.

Weak attractive aromatic interactions are often defined by a low stabilization
enthalpy (1.6: 0.2 kcal/ mol) and have been known to play a very important role in many
diverse areas such as protein folding, base-pair stacking in DNA, host-guest binding in
supramolecular assemblies, crystal engineering, drug receptor interactions and other
widely studied molecular recognition processes.107 These non-covalent interactions
typically can be classified into a) T-shaped edge to face structure b) Edge tilted T-
structure c) Face tilted T-structure d) Offset parallel stacking e) Face to face (Jr-stacking)
(Figure 3.6). Theoretical studies favor T-shaped structure for benzene dimer wherein the
center-to-center distance is 5-5.2A and the perpendicular distance between the interacting
H and the ring center is 2.5-2.7A. The observed upfield shift of the ortho aromatic
hydrogen would be consistent with either of the three structures paco 250 and 251 or 1,3-

alt isomer 253.

Figure 3.6 Typical modes of weak aromatic interactions

[IO-H H—©—H H—Q—H HQQ HOE

T-Shaped Edge tilted T Face tilted T Offst parallel stacking Face to face parallel
a) b) c) d) stacked e)

H

It would be reasonable to expect that the unexpected upfield chemical shifts could
be explained by offset parallel rt-stacking in the latter whereas edge-face interactions

between opposite arene rings in the former. Neverthless, partial cone conformer (Paco

98

251) appeared to be the most likely candidate based on the shielding effect experienced
by the two-methoxy groups. The observed chemical shifi at 8 3.46 is likely an average of
two chemical shifts that correspond to its in and out orientations. An in orientation would
represent the situation when the two methyl groups are pointing into the shielding cone of
the aryl ring and hence would be shifted upfield relative to an out orientation wherein the
two methyl groups would be far away from the phenyl group to experience any shielding
effect. Paco 250 with Cs symmetry is disfavored, as ring current would shield the
methoxy group of the anisole ring because it is pointing inside the cavity. At this
juncture, NOE studies were performed on the major conformer, which confirmed that it
was indeed the paco 251 with C, symmetry (Figure 3.7). In contrast to the major isomer,
the minor isomer gave only three peaks for the phenyl group integrating to a total of five
hydrogens, which indicated free rotation about the biaryl bond. The corresponding proton
spectrum of the minor isomer was markedly different with all the aromatic hydrogens of

the calixarene falling in the expected chemical shifi range between 8 6.34 and 6.65 ppm.

Figure 3.7 NOE's observed on major isomer

   

CH CH
0’ 03’ 3

CH3

paco-251

99

In contrast to the upfield shift observed for the ortho-phenyl hydrogen in the
major isomer, the corresponding proton in the minor isomer was shifted extremely
downfield at 7.92 ppm. Furthermore, the phenolic hydrogens were shifted upfield relative
to the major isomer (5.01 vs 5.75) indicating that they might be under the shielding cone

of a neighbouring aryl ring.

Figure 3.8 NOE's observed on minor isomer

   

247A-II

254

NOE analysis in CDC13 indicated that the minor conformer to be the cone 254
(Fig 3.8). The ratio of the two conformers is highly dependent on the solvent. The non-
polar solvent chloroform-d favors the partial cone conformation 247A-I whereas for the
polar solvent dimethyl sulfoxide-d6 the partial cone is less favored (Table 3.6). The
variation in conformer distribution upon changing the solvent from CDC13 to DMSO-d6
may be accounted for by a shift in equilibrium towards the conformer with the higher

dipole.

Table 3.6'| Solvent effect on conformer distribution in 247A.

 

 

Entry Solvent Temperature Ratio Dielectric constants
°C may]; cone-ll of non-deuterated solvents
1 toluene-(13 25 2.63:1 2.38
2 CD0 - -
3 30 3.94 .1 4.81
25 3.9: l
50 3.4: 1
3 Acetone-d6 25 2.7: 1 20.7
4 DMSO-dé 25 1.71 46.7

 

a) Ratio determined from the relative integral values of methyl hydrogens in major and
minor isomer

From molecular mechanics calculations, the calculated dipole moments for 247A-
1 and 247A-II were found to be 2.54 D and 3.71 D, which validate this rationale. Similar
solvent effects on conformer distribution was reported by Reinhoudt in 1992, wherein
calix[4]arene 1,2-dimethyl ether was found to exist as a mixture of syn (cone) and anti
(paco) conformers 255A and 255B the ratio of which was dependent upon the solvent:

4.3:1 (cs2), 301 (open), 201 (CDC12CDC12) and 121 (C04) (Figure 3.9).108

Figure 3.9 Syn and Anti Conformations of 1,2-Dimethyl ether 255

bBu bBu

(-811 {-81.1 {-811 t-Bu

 

255-A

 

Analogous studies on the rate of conformational inter-conversion in tetrahydroxy
derivatives has shown that the barrier is significantly reduced in polar solvents and such

an effect has been attributed to the weakening of hydrogen bonding in calixarene. Thus, it

101

may be reasonable to postulate that changing the solvent to dimethyl sulfoxide results in
disruption of hydrogen bonding and thereby inter-conversion between two conformers
occurs to a reasonable extent to afford a new equilibrium mixture of 1.721. The presence
of a weak hydrogen bond in either of these two conformers was shown by IR
spectroscopy in dichloromethane wherein a broad signal for the hydroxyl groups were

observed at higher wave numbers ~3499 cm".

 

247A-II cone 247A-I partial-cone

Table 3.7 Chemical shift of Aromatic hydrogens of 247A

 

 

 

in DMSO-d6 as solvent
Proton Chemical shift Multiplicity
11(1) 4.68 d
H(2) 5.27 t
H(3) ND t
H(4) 6.99 t
H(5) 6.74-6.79 d
H (l ') 7.73 d
H (2') 7.26-7.29 t
H (3') ND t
H (4') 6.58-6.62 t

H (5') 6.74-6.79 d

 

 

This rationale was supported by an EXSY experiment, which showed that these two

conformers were inter-converting in DMSO as the solvent at 50°C. The cross peaks from

102

the phenyl hydrogens in both the major and the minor isomer were carefully examined. It
was found that the ortho-phenyl hydrogen in the major isomer (6 = 4.68) displayed two
cross peaks, one of which could be attributed to the other ortho-phenyl hydrogen (6 =
6.74-6.79) and the other to the ortho hydrogen in the minor isomer (6 = 7.73). Similar
cross peaks were observed for the other aromatic hydrogens in both the isomers (Table
3.7 & Figure 3.9). The next issue to be addressed was which of the two conformers of
247A was the thermodynamic or kinetically favored product. A 1.7:1 mixture of the two
conformers were heated to 90°C in DMSO-d6 and subsequently cooled to 25°C with the
spectra recorded at both temperatures. Based on the identical conformer distribution that
was observed prior to and after the experiment as well as the results from the solvent
effect suggest that their ratio at ambient temperature depicts the equilibrium population.
In order to determine the relative energies of the two conformers, molecular mechanics
calculations were performed using MM94 force field. The relative energy of the cone
isomer was 144.6 Kcal / mol whereas that of the partial cone isomer was 139.87 Kcal /
mol indicating that the partial-cone isomer is thermodynamically more stable by 3.78
Kcal / mol. The results of the computational study are in agreement with the experimental
observations described herein but clearly over-estimates the energy difference between
the two compounds as this would represent a ratio of > 200:1.

Based on comparison of the chemical shifts of the methylene carbons (6 31.33,
39.98 - major, 32.06, 36.10 - minor) with 247A, the major and minor isomers of 2478
were deduced to be a partial cone and a cone with C, symmetry (Ratio of pacozcone =

39:1).

103

“I... .,.__. T..-

 

6
’3 (WI)

 

 

 

 

 

 

i
_.__._ 2 3:5-- 1n
..\\ .
-fi: o
’5 .
_ _, _. .-x' 0
K O
F
_'_T::'r‘
W n
O
l‘
l—
% . ° 0 *-
‘T—T’I A T‘ Y Y ‘r I r a I .
E O n O "I O n O
O O O
F. m n to U 8‘ F O
h U

7771”” Im rim"

 

 

 

 

 

 

Figure 3.10 600 MHz lH EXSY spectrum (6 4.5 — 8.0 ppm) of 247A in DMSO-d6 at

50 °C.

104

The observed chemical shifts for the minor isomer of 247B are consistent with
Mendoza rule for unsymmetrical calix[4]arenes wherein two of the methylene carbons
such as in a cone conformer are magnetically inequivalent giving rise to two different
chemical shifts at 30.9, 31.1. Again as observed before for calix[4]arene 247A, the major
isomer of 247B showed the presence of five different aromatic hydrogens indicating
restricted rotation about the biaryl bond whereas the minor isomer showed only three
peaks. One of the ortho phenyl hydrogens in the major isomer was again found to be at
4.78 ppm influenced by the shielding effect of the opposite aryl ring as well as the
methoxy groups (s, 6H) which were observed to resonate at 3.46 ppm.
3.6.2.2 Alkyl substituted calix[4]arenes 247C, 247D

Complete structural identification of the alkyl substituted unsymmetrical
calix[4]arenes 247C and 247D could not be accomplished as the minor product was
present in only small amounts (7.9:1). NOE analysis was again extremely valuable in
deducing the structure of the predominant product as the cone for 247C with C,
symmetry. The benzylic hydrogens were found at 3.29 and 3.35 ppm in 247C and 247D
indicated that they are not under the shielding effect of adjacent aryl rings and the
hydroxyl groups at 5.63, 5.78 ppm suggested'the presence of a weak intramolecular
hydrogen bond. The structure of the major conformer of 247D was assigned by similarity
of the observed chemical shifts as the cone whereas that of the minor isomer was not
deduced.

3.6.2.3 Outer rim modified calix[4]arene 247E

105

 

 

cahx
confi
and :
“en
subsr

3AL3

111 \‘erfi

 

 

the enl
“i011
DIOpQ
protol
tempé
seun
and}...

r0tati

form}

then

Sigm‘

In contrast to the inner rim modified calix[4]arenes 247A and 2478, the
calix[4]arene 247E with phenyl and methyl substituents at the outer rim adopted a cone
conformation in solution based on the 13 C NMR shifts for the methylene carbons at 31.54
and 31.72 ppm. Based on comparison of the solution structures for 246A and 247E as
well as the examples discussed earlier, it is reasonable to postulate that the outer rim
substituent does not affect the conformational preferences of the calix skeleton.

3.6.3 Mechanism of conformational interconversion

At present, two different mechanisms have been proposed for the conformational
inversion in tetrahydroxy calixarenes.23 Analysis of the intermediates and evaluation of
the energetics of these proposed pathways have been accomplished over the past decade
with the help of extensive theoretical studies.109 A “continuous-chain” pathway was
proposed by Gutsche to account for the cone-to-cone inversion whereby the methylene
protons coalesced from a pair of doublets at low temperature to singlet at above room
temperature. They postulated that the aryl groups would swing through the annulus in
sequence possibly via the intermediacy of a skewed 1,2-altemate complex. Based on
analysis of space filling models, it was expected that some hydrogen bond stretching or
disruption of single hydrogen bond would be necessary to reach this transition state.

An alternative pathway that was invoked by Kammerer involved a stepwise
rotation of the opposite or adjacent aryl group through the annulus to result either in the
formation of partial cone or 1,3-alternate conformer. Either of these intermediates was
then expected to revert either to the cone or the inverted-cone isomer. Now, there is

significant evidence that cone to inverted-cone proceeds in a stepwise manner with the

106

110

partial cone conformer playing a key role (Figure 3.11). Recently, Shinkai has also

proposed similar pathways for calixarenes lacking free hydroxyl groups.1 1‘
Figure 3.11 Currently accepted pathway for conformational ionverslon

- _ t-Bu
t-Bu ’B“ ‘3“ Ha OH on 0H no

; ee

    

He

     

t-B

t'Bu t'Bu [-811
I Cone 19d-l Inverted Cone 19-d III
Disfavored :
High Energy Barrier :
1
t-Bu t-Bu t-Bu

   

t-Bu
t-Bu t-Bu

1,3 Alternate 19-d IV

Partial-Cone l9-d II

Analogous to these proposed mechanisms, the conformational ring flip from cone
to partial cone that has been observed in the case of unsymmetrical calix[4]arene 247A
could possibly occur via at least two different pathways. The first route A would involve
the direct rotation of the phenyl ring about the annulus while the second path B would be
stepwise with the formation of partial cone 252 and then 1,3-alternate conformer 253 via
sequential rotation of the two phenolic rings and subsequent rotation of the methoxy
group of the anisole about the annulus. Considering that the rotation of methoxy group
through the annulus has a high activation barrier in partially alkylated calixarenes, it is
presumed that similar steric barrier would be encountered in the process involving a

phenyl group. The hydroxyl moieties forming hydrogen bonds will have to make place

107

for the phenyl group. This will elongate the OH.....O distances and either weaken or

completely disrupt the intramolecular hydrogen bonding (Scheme 3.5).

Scheme 3.5 Mechanism of conformational exchange

   

 

   

Route B
Rotation of
phenol
Rotation of second A = CH3, 2494-1 : 2493-n l Route A
Phenol . = 3 9-1 h 1
- ' ' R z t' P '
: A = Pb, 2493-1 : 2493-11 0 a m of my mg
: = 3.3:1 me
A i CH3 1
OMe on GR
- _ 5953209- _
of anisole
A .
o 0
001300113 \CH3\CH3
253 . 247A-I

The ring flip of the first p-alkoxy phenol leading to the formation of partial cone
isomer 252 would likely occur with minimal weakening of hydrogen-bonding and the
barrier for the second rotation would also be significantly low. Due to the lack of
hydrogen bonding in 253 caused by the protrusion of the bulky phenyl substituent in the
smallest diameter of the annulus formed by the hydroxy groups, the methoxy group
would encounter minimal resistance in accomplishing the desired rotation to give the
observed calix[4]arene 247A-I at room temperature. If Route A was the viable pathway,
it was expected that replacement of the outer rim methyl group at the distal arene ring
with a larger substituent (A= Ph) would interfere with the rotational process and thereby

would likely lead to a mixture of separable cone and partial cone conformers. As the

108

calixarene 2478 was also found to exist as an inseparable 3.3:1 mixture of partial cone

and cone conformers, Route B is believed to be operative in the inter-conversion process.

3.7 Summary

In summary, the triple annulation method has been developed as a new route for the
synthesis of calix[4]arenes with C2 symmetry. Although the objectives in this regard was
to exploit the methodology for direct synthesis of calix[4]arenes with C1 symmetry, none
were found by introducing alkyl or aryl substituents in the inner rim. Alternative
approaches to access these class of calix[4]arenes will be mentioned in Chapter 6. In
general, the effect of introducing non-heteroatom substituents in the inner rim of
calix[4]arene on the conformation was explored in detail wherein larger phenyl group
introduces significant conformational rigidity to give a mixture of separable or
inseparable conformers in certain cases. The overall process affords calix[4]arenes in
which two of the adjacent arene rings are non-identical and the distal arene rings are
identical and this inherent feature will be exploited in the synthesis of chiral

calix[4]arenes which will be the subject of discussion in the following chapter.

109

 

 

 

Cl

 

4A

C3 211

and 1

 

aha
rend:

Figur

.9

24g

dia:

dra

CHAPTER FOUR
CHEMO, REGIO, ENANTIO AND DIASTEREOSELECTIVE SYNTHESIS OF

METHYLENE SUBSTITUTED CALIX[4]ARENES

4.1 Design of a new method for chiral calix[4]arene syntheses

In the preceding chapter it has been demonstrated that various calix[4]arenes with
C2 and Cs symmetry can be formed from the triple annulation of bis-carbene complexes
and diynes. One of the most unique features of this strategy has been that the two
adjacent arene rings in the macrocycle so generated are non-identical which thereby

renders the methylene hydrogens diasterotopic (Figure 4.1).

Figure 4.1 Stereoisomers resulting upon introduction of single substituent at the bridge
OMe

1
M60 R R2

R2 0M6

 

OMe

 

 

246/247
Diastereotopic

 

Thus, replacement of either the axial or the equatorial methylene hydrogens in
248/249 with a single substituent A would be expected to result in the formation of
diastereomers 256A and 2568 along with their enantiomers (not shown in the Figure). As
a consequence, an increase in the degree of substitution at the methylene bridges

drastically increases the number of possible stereoisomers that would result (See Section

110

1.6.1). Hence, the primary objectives in this regard were to not only devise an
enantioselective approach but also to render the triple benzannulation process highly
diastereoselective and regioselective for formation of specific stereoisomers of
calix[4]arenes with different substitution patterns at the bridges. As illustrated below,
introduction of a second substituent in calix[4]arene 256 would result in formation of
regioisomeric calix[4]arenes 257 and 258 with 1,2-anti and 1,3-syn stereo-relationship of

the substituent at the bridges possessing C1 and C2 symmetry.

Fig 4.2 Chiral calix[4]arenes 256-263 with C, and C2 symmetry
R' R2 0M6 MeO R‘

R2 OMB

MeO R' R2 0M6 MeO

    
  

   

R5
/ I
OH R3 R4 HO OH R3 R4 HO
R3
256 Monosubstitution 257 1,2-Anti disubstitution 258 1,3-Disubstitution
C, C1 C2
R: R2 OMe M60 R' R2 0M6

 

I
OH R3 R4 HO

 

259 Trisubstitution (syn, syn) 260 Trisubstitution (anti, 53’”) 11C (1" ans,cis)
C1
R1 R2 OMe M e0 R' R2 OMe

          

R5
3 4 R5 Hci OH R3 4
OH R R R5 R 5 R R5
26] Tetrasubstitution (syn, anti, syn) 262 Tetrasubstitution (syn, anti, anti) 263 Tetrasubstitution (anti, syn, anti)
R R R
R
R R
R
R
R R

R

rctt (cis,trans,trans) rtct (trans,cis. trans)

rcct (cis,cis,trans)

111

The two diastereomers of the trisubstituted analogs would be 259 and 260 with C 2
symmetry whereas those with tetrasubstitution would be 261, 262 and 263 with C 2, C3
and C2 symmetry. The trisubstituted calix[4]arene 260 for example can be assigned either
the stereochemical descriptors anti, syn or rtc indicating the relative trans and cis
disposition of the substituents at the bridges. The relative stereochemical assignment for
other methylene substituted calix[4]arenes are shown in Fig 4.2. The establishment of
relative stereochemistry at the bridges was anticipated to be accomplished based on the
known chemical shifts of the axial and equatorial hydrogens in alkoxy and thio

substituted analogs 264-266 (Fig 4.3).53

Fig 4.3 Relative stereochemical assignment by correlation to thio and alkoxy substituted analogs 264-266

t-Bu t-Bu t-Bu "B“

t-Bu t-Bu t-Bu

  

,_Bu t-Bu (Bu "3"

s
}l_1C‘/

 

265
6 Ha, = 5.72
6 Heq = 5.00

4.1.1 Triple annulation strategy towards di and tetrasubstituted Calix[4]arenes

As discussed in earlier chapters of this thesis, optically active calix[4]arenes with
chiral centers at the bridges have not been previously reported. Our initial targets for this

class of molecules are 1,2-dialkoxy calix[4]arene 257 and tetraalkoxy calix[4]arenes 261-

112

263. The 1,2-dialkoxy calix[4]arene 257 with C2 symmetry was envisioned to arise from
the triple annulation reaction of non-chiral biscarbene complex 229A and the C2
symmetry element present in chiral bis-propargyl arene (S,S)-267 whereas the
tetrasubstituted calix[4]arene 263 with C2 symmetry from the reaction of chiral C2
symmetric biscarbene complex (R,R)-268 with the bis-propargyl arene (R,R)-267

(Scheme 4.1).
Scheme 4.1 General synthetic strategy toward 1,2-di and tetrasubstituted calix[4]arenes

 

 

M60 MC MC OMC
Me OMe Me
Cr(C0)5
I % é
OMC + ()R OMe ()R
229A (S,S)-267
MeO M° Me OMe Me OMe Me
C CO
L. + DR OMe 0R
2. OH OMe OMe HO OR OMe 0R
UR OR
263 (R.R)-268 (R.R)-267

4.1.1.1 Chiral bis-propargyl alcohols

The studies toward the calix[4]arenes 257, 263 as well as the stereoisomers 261
and 262 began with devising synthetic routes toward chiral bis-propargyl alcohols. The
most reasonable and practical approach in this regard was Carreira’s method of
asymmetric addition of alkyne 269 to aldehyde 270 in the presence of Zinc
trifluromethanesulfonate as the Lewis acid and N-methyl ephedrine 271 as the chiral
ligand to afford chiral propargyl alcohols 272 (Scheme 4.3).112 Thus, asymmetric
nucleophilic addition of a silyl alkyne 269 (R2 = SiR3) to aldehyde 273 followed by

desilyation and alkylation was expected to furnish the required bis-propargyl ether 267.

113

Scheme 4.2 Carreira's method of asymmetric alkyne addition

 

 

 

R2
0-Alkylation
2)
0R5 R4 6R5 Erlantioselective OHC CH0
A Home Addition R4
267 273
OH
O 20(01‘92 (20 mol %)
A + H — R2 > RI
R H 269 Et3N (50 mol %) 272 R2
270 (2 equiv.) :3 °C’ when“ 86 - 99 % ee
Me(22 mol 0/) 5 5 - 94 % yields
0
HO NM62
271

When Carreira’s standard conditions were applied to the reaction of 2,6-diformyl
4-methyl anisole 273 (R4 = OMe, R2 = Me) with two equivalents of trimethyl silyl
acetylene 269 (R2 = SiMe3), none of the product was detected and starting material was
recovered. The use of higher reaction temperatures (~100°C) afforded no improvement.
Also, benzoin adducts that are known to result from reactions of substituted
benzaldehydes were not observed. The inertness of the aryl dialdehyde 273 to this
protocol was rather unexpected but Marshall had reported similar results in his studies on
alkyne addition to a-branched aldehydes.‘ ‘3

The recently developed BINOL based methodology described by Pu et.al was
next examined.114 While this method is known to work exceptionally well with aromatic
aldehydes, this process had not been extended to aryl dialdehydes, which possibly could
yield a mixture of diastereomers.

Hence, optimal reaction conditions were screened for aryl dialdehyde 273 and the
results are shown below in Table 4.1. In general, these reactions were carried out by first
deprotonating the terminal acetylene by refluxing with diethyl zinc in toluene for several

hours and then sequentially adding (S)-BINOL, titanium isopropoxide and the aldehyde

114

in regular intervals. As can be seen by comparing entries 1 and 2 (Table 4.1), lower
catalyst loading is detrimental to enantioselectivity of the reaction while the
diastereoselectivity in formation of either the (R,R)-alkynol 274A or the (R,S)-Alkynol

275A is unaffected.

Table 4.1 Diastereo and Enantioselectivity in double alkyne addition to substituted isophthalaldehyde
273

       

 

 

 

 

 

 

 

 

 

 

 

TIPS
EtZZn Ti (0- i - Pr)4 i
“PS—2 1 Ar = OH OMe OH
to uene (S)-BINOL 274 A 275A
[Step 1] CH2C121,TBAF ether TBAF. ether
[Step 2]
m::3ew0\ Me
OH OMe OH OH OMe OH
274C 275C
Entry Ligand(mol%) Ti (mol%) Concentrationa Temperatureb drc %eed
l 20 50 0.52M 25 °C 1.3:1 42
2 40 100 0.52 25 1.2:] 96.7
3 20 100 0.52 25 1:15 92
4 100 100 0.52 25 - -
5c 40 100 0.52 25 1.221 99.2
6 40 100 0.72M 25 1.3:] 99.2
7 " " 1M 25 1.3:1 99.1

 

“ Concentration refers to the amount of the Alkynyl ethyl zinc reagent generated in situ

 

by refluxing an equimolar ratio of the alkyne and diethyl zinc in toluene for 5-7 h b The
temperature indicated refers to the reaction temperature for step 2 when the aldehyde is
added to the reaction C The diastereomeric ratio refers to the ratio of 274A to 275Ad The
enantioselectivities reported are that of the terminal alkyne 274C obtained afier
desilylation of 274A ‘ The reaction was carried out using 10 mmol of aldehyde 273 as
compared to entries 1-4 where 2 mmol of aldehyde was used

115

Lower ligand loading led to lower enantiomeric excesses of the product (Entry 3
vs Entry 2). The concentration of the alkynyl zinc reagent does not affect the reaction as
indicated in entries 5-7. Overall, the advantage of this approach is that a lack of facial
selectivity in addition to either of the aldehyde moieties leads to the mesa compound,
which is readily separated. Either enantiomer of the terminal bis-propargyl alcohol 274C
thereby obtained is essentially enantiomerically pure (> 99 % ee) by choice of the chiral
ligand and is amenable to further functional group manipulations.

Pu’s method is remarkably synthetically useful as a single enantiomer of the
(R,R)-bis-propargyl alcohol 274A is obtained. However, the formation of a significant
amount of the mesa (R,S)-alcohol 275A rendered this protocol less atom-economical,
expensive and aesthetically unattractive. Henceforth, it was anticipated that if the meso
alcohol could be transformed into optically active starting materials the overall process

would meet the above-discussed critieria.

Scheme 4.3 Transformation of mesa propargyl alcohol into optically active 274A

  

 

 

 

 

TIPS TIPS
PCC, C It '
(R.S)-275A A e I e = (RM'p‘ne hm” ; (R.R)-274A
4 M H Cl ' '
S, C 2 2 O OM e 0 See Table for Conditions
276A 97 %
Entry Reagents Reaction time Ratio 274A / mesa-275A % yield 274A %ee
1 Alpine borane a 26 h i/ 1.5 38 97.84
2 Alpine boraneb 19 h Not determined 35 > 99-5

 

' (R)-Alpine borane generated in situ from (+)-pinene and 9—BBN in THF
b (R)-Alpine borane (0.5 M) purchased from Aldrich

The (R,R)-alkynol 274A was accessible from (R,S)-meso alcohol 275A by a two-

step sequence involving oxidation by pyridinium chlorochromate to diynone 276A

116

followed by reduction using (R)-Alpine borane ”5 in overall modest yield due to the
formation of significant amount of the mesa alkynol 275A (yield not determined) in the
second step but with > 99% ee. Similar results were observed using the same borane
reagent that was generated in-situ from [a]-pinene and 9-borabicyclononane. The
enantiomer of the bis-propargyl alcohol thus obtained was found to be the same as that
prepared by alkyne addition using (S)-BINOL (Scheme 4.2).

Midland et.al had postulated the mechanism for asymmetric ketone reductions
with Alpine borane to involve a boat like cyclohexane structure whereby the major
product arises fiom the intermediate 277 that has a larger group at the equatorial position

rather than 278 which has the larger group at axial position (Fig 4.3).

Figure 4.4 Proposed intermediates by Midland in asymmetric ketone

9 9

 

-"B“O ,"B‘~o
'-H~ %RL ‘ IvH~ ’ RS
CH3 RS CH3 RL
- 277 278
FAVORED DISFAVORED

In general, the reduction of ketones with the Alpine borane derived from (+)-
pinene led to the (R)-enantiomer of the alcohol, which was consistent with the proposed
transition state structure 277 for the reduction step. Thus, the poor diastereoselection
observed in reduction of 276A could be attributed to two factors. The sterics of the bulky
triisopropyl silyl group possibly could have a detrimental effect on the facial selectivity
of the ketone reduction. The rate of decomposition of (R)-Alpine borane is known to be
significant for ketones that are reduced slowly. As a significant amount of 9-BBN is
produced by dehydroboration, this could also account for the non-selective pathway

resulting in a greater amount of the mesa diol. So, it was not that surprising to note that

117

when the trimethyl silyl substituted diynone 276B was subjected to identical reduction
conditions only (R,R)-274B was isolated in 76 % yield (Scheme 4.4). None of the mesa
diastereomer (R,S)-27SB could be observed by TLC. Moreover, the enantiomeric

enrichment of (S,S)-274C was greater than 99.5 %.

Scheme 4.4 Addition of ethynyl Grignard to aldehyde 273

  

    

 

   

CH3 CH3 CH3
E—MgBr
OHC CHO THF ; + , ,
OCH3 OH 03430}; OH 0013011
273 \(d/0-274C (meso)-275Cj

 

72 % yield

Although the optically active bis-propargyl alcohol 274C could be obtained as
single diastereomer by the use of this two-step sequence, the need for a practical and
highly efficient synthesis of chiral calix[4]arenes necessitated the investigation of
alternative routes that would avoid the desilylation step. To this extent, it was found that
simple addition of ethynyl Grignard reagent to the dialdehyde 273 afforded 274C and
275C as inseparable mixture (Scheme 4.4). Jones oxidation of the mixture afforded the
terminal diynone 276C in 82 % yield. The reduction of the terminal diynone under
standard conditions resulted in the formation of a single diastereomer of 274C albeit in
moderate chemical yield and purity (Scheme 4.4). However, the enantiomeric purity was
still greater than 99.5 % indicating complete control of stereoselectivity in the reduction
process exhibited by the organoborane reagent. With the chiral and meso bis-propargylic
alcohols in hand, the preparation of the (R,R) and meso-bis-carbene complexes 268 was

next examined.

118

Scheme 4.5 Companion of the Midland reduction of diynones 276A-C

 

 

Me Me
. R R R R
(R,R)-274A PCC,Ce11te _ \ (R)_Alpine borane
(mama +(R,S)-274B , t ‘
s 274C SR 27sc 4AMS’CH2C'2 See Table for ;
( "9' H ' * o OM o - on
(or) Jones oxidation e Conditions 0“ OMe
276 (R,R)-274A,274B
and (S,S)-274C

 

Reaction time for

 

Entry R Series % Yield 276 Reduction Ratio 274/ 275 b % yield 274 %ee C
l TIPS A 97 19 h Not determined 35 > 99.5
2 TMS B 67 12 h > 20:1 76 > 99.5
3 H C 82 3h > 20.1 56 > 99.5

 

" (R)-Alpine borane (0.5 M) purchased from Aldrich
b The ratio refers to the diastereomeric ratio afier Midland reduction

° % ee refers to the enantiomeric purity of (S.S)-274C obtained by desilylation

4.1.1.2 Chiral and mesa bis-carbene complexes 268, 284

The bis-propargyl alcohol (R,R)-274C was converted to the bis-propargyl methyl
ether (R,R)-267A in excellent yield . The bis-propargyl TBS ether (R,R)-267B can be also
obtained similarly using tert-butyl dimethyl silyl trifluoromethanesulfonate and
imidazole. Hydrozirconation of the terminal alkyne in (R,R)-267A followed by iodination
resulted in the formation of bis-trans vinyl iodide (S,S)-279 (not shown) which was
subsequently converted to the chiral bis-carbene complex (R,R)-268 in modest yields
following a similar procedure reported earlier for preparation of bis-carbene complex 229
(Scheme 4.6).

The mesa bis-propargyl alcohol 275C was transformed via a similar sequence to
the mesa bis-trans vinyl iodide 283 in 50 % yield. Upon subjecting the resultant vinyl
iodide to the routine conditions for carbene complex formation, it was puzzling to note

that none of the carbene complex had formed. During the initial metalation step upon

119

addition of tert-butyl lithium, the color of the solution changed from deep red to light

yellow within a few minutes.

Scheme 4.6 Preparation of chiral bis-carbene complexes (R,R) and (S,S)-268

   

 

Me
NaH, c331, THF
61 1 OMe OH (or) TBSOTf, imidazole OR OMe OR
(R,R)-274C (R,R)—267A R = OMe, 99 %

(R,R)-267B R = TBS, 92 %

1) szzmum (0050
NIS, THF

   

OMe OMe ()Mc 2) t-BuLi OMe OMe OMe

CKC0)6

(S,S)-274C EL. (S,S)-268 15 %
as above

It is conceivable that the dianion 280 was not stable even at —78°C and decomposed prior
to reaction with chromium hexacarbonyl as the color of the solution faded from deep red
upon addition of tert-butyl lithium to light yellow in a few seconds. It is known that 3°
alkyl lithiums will not undergo nucleophilic addition to chromium carbonyl and the
maximum isolated yield for the pentacarbonyl t-butyl carbene complex 281 is only 8%

(Scheme 4.12).119

Scheme 4.7 Synthesis of pentacarbonyl methoxy t-butyl
carbene complex 281

, OMe
Cr(CO)6 __." 3““ (OC)5Cr
1"‘193013F 4 t-Bu
281

8 %
Thus, it was hypothesized that ifCr(CO)6 were to present in the same reaction flask

when the dianion is generated, the decomposition could be avoided and the carbene

120

complex would be prepared. Indeed, this slight change in the procedure afforded the (SR)

bis-carbene complex 284 in 21 % yield (Scheme 4.8).

Scheme 4.8 (S.R) Bis-carbene complex 284

 

 

Me
1 I
I I l]NaH, Mel
2 C 2 H I -
OMe OMe OMc lmgzndlpfl 0H OMe OH
(R 52233 ’ (S.R)-275C

55%

11) t- BuLi
One- Pat Metalatian and
0
Method A -78 C luwn Method B
3) Me3OBF4

OMe OMe OMe O-Vlc OMe O'Nlc

By Method A 20%
By Method 3 21%

Under these newly developed conditions, the yield of the (S,S)-bis carbene complex 268
was found to be 24 %.
4.1.1.3 1,2-Disubstituted calix[4]arenes 257

With the chiral bis-carbene complexes and bis-propargyl arenes in hand, the
formation of the 1,2-disubstituted calixarenes was next investigated. Thermolysis of the
complex 229A with chiral bis-propargyl arene (S,S)-267A resulted in the formation of
1,2-dimethyl ether 257A in 32 % yield as a mixture of two inseparable conformers in a
ratio of 2.6:1 (Scheme 4.9). The structures of the major and minor isomes of 257A were
deduced by NOESY-1D and NOESY experiments to be the cone and the partial cone
with C2 symmetry. The corresponding chemical shifts for the axial and equatorial
methine hydrogens were located at 6.01 and 5.06 ppm in the cone conformer whereas

those in the minor partial cone conformer were at 6.35 and 5.13 ppm respectively.

121

Scheme 4.9 Steric destabilization of the cone form by axial methoxy group in 257A

 

 

OMe Me OMe
(OCkCr I I cmcok
OMe 1,2 - DCE, 100 0C
229A :
+ [Alkynez Carbene complex
= 1:1]
M6 Concentration 2.5mM
\ /
\ _ / OMe
OMe OMe OMe 257A 32 %
(5,5).267A 99_ 2 % ee Mixture of two conformers ratio 2.6:]
0M6 OMe Me
Me OMe OMe Me

    

I
OMe '3 OH Meo

 

/o 0
H 2(‘ .
' 257A-1 cone 257A-II pamal-cone
Major Minor
isomer isomer

In contrast to 246A which exists as cone conformer, the formation of significant
amount of partial cone conformer in the above case suggests that the introduction of
second substituent in the proximal axial position destabilizes the cone conformation due
to steric repulsion between the methoxy group attached to the bridge and the adjacent
hydroxy as well as methoxy groups. Apparently, the steric congestion is relieved by
rotation of the methoxy group through the annulus to provide the conformer 257A-II. To
validate this hypothesis, introduction of a larger substituent at the axial position was next
examined.

It was not surprising to note that the reaction of the same carbene complex 229A

with chiral bis-propargyl arene (R,R)-267B resulted only in 13 % yield of the product

122

257B, which was again obtained as mixture of two inseparable conformers in a ratio of
1321. Although the structures of the two conformers were not identified by NOE
experiments, it is likely that partial cone and cone conformers of 257B were again present
in solution. Furthermore, the mixture of these two unidentified conformers could be

transformed to a single conformer of 257C upon desilylation (Scheme 4.10).

Scheme 4.10 Steric effect on triple annulation and conformer distribution

 

 

 

 

OMe Me OMe
OMe
229A 192 ' DCE, 100 0C
+ [Alkynez Carbene complex
M6 = 1.1]
Concentration 2.5mM
§ é
_.‘ OMe
RO OMe ()R 2573 13%
(111072673, 992 °/0 66 Mixture of Two conformers ratio 1 .3 :1
_TE’EL 257C

84 % A Single conformer

The equatorial and axial methine hydrogens in 257C were observed in the lH
NMR at 5.55 and 6.32 ppm. It is also of interest to note that the equatorial hydrogen was
split into a doublet by the hydroxylgroup whereas the axial hydrogen appeared only as a
singlet as evidenced by D20 exchange experiment wherein the coupling between Heq and
OH disappeared and a singlet was observed at 5.56 ppm. The corresponding ‘3 C chemical
shift for the methine carbon bearing the equatorial hydroxy group was located at 79.64
ppm whereas that with the axial hydroxy group could not be located. The conformation
of the calix[4]arene 257C was deduced to be the cone based on NOESY experiment (Fig

4.4).

123

Fig 4.5 Conformation of tetrahydroxy
calix[4]arene 257C

 

Cane-257C

4.1.1.4 Tetramethoxy calix[4]arene 263 (rtct isomer) by reaction of (R,R)-268 and
(R,R)-267A
The preparation of the tetrasubstituted calix[4]arene 263 with anti, syn, anti
(relative trans, cis, trans) arrangement of the substituents at the methylene bridges and C2
symmetry was next studied. The cyclization of the bis-carbene complex (R,R)-268 (99.2
% ee) with the bis-propargyl methyl ether (R,R)-267A (99.2 % ee) proceeded

uneventfully to give the calix[4]arene tetramethyl ether 263 in 30 % yield (Scheme 4.11).

Scheme 4.11 Tetramethoxy calix[4]arene 263 by reaction of chiral bis-carbene complex
(R.R)-268 and chiral diyne (R, R)—267A

OMe Me OMe

 

CMe OM: OM e
(R,R)—268

 

CICHZCHZCI
+ :
Me 100 °C, 2.5 mM

 

263 30 % yield

(z) Me OMe OMe
(R,R)-267A

No other higher oligomers were detectable either by TLC, proton spectra of the
crude compound or by mass spectra of the purified sample. The structure of the chiral
calix[4]arene 263 was determined to be the cone with an trans,cis,trans orientation of the

methoxy substituents at the bridges. The specific rotation was found to be +25.4°. The

124

stereochemical arrangement of the methoxy substituents at the bridges is also discernible
by the 1H NMR spectra, which displayed a pair of singlets (6 5.05, 2H and 6 6.08, 2H).
These protons could be attributed to the pair of axial and equatorial hydrogens in 263.
The aromatic region revealed the presence of a pair of singlets and a pair of doublets
integrating to a total of eight protons. The C2 axis of symmetry results in the splitting of
the aromatic hydrogens of the p-alkoxy phenol to the observed doublet pattern with a
coupling constant of 3Hz.
4.1.1.5 Tetramethoxy calix[4]arene 261 (rear-isomer) by reaction of (S,S)-268 and
(S,R)-282
The diastereomeric tetramethoxy calix[4]arene 261 (relative cis, trans, cis) was
synthesized in 26 % yield from the reaction of the chiral bis-carbene complex (S,S)-268

(94 % ee) and bis propargyl methyl ether (S,R)-282 (Scheme 4.12).

Scheme 4.12 Tetramethoxy calix[4]arene (rcct isomer) 261 by reaction of
chiral bis-carbene complex (S,S)-268 and diyne (S,R)-282

OMe Me OMe

Me Me OMe

    

 

 

(SS-268 ClCH CH C1

+ 2 2 ; MeO OMe

. 0
Me '00 OC’ 2 5 “‘M on OMe 0Me\ HO
Me
261 26 % yield
OMe OMe OMC

(am-232

The proton and carbon spectral data obtained was consistent with cone conformation in
solution. The three axial methine hydrogens were observed at 5.71, 5.94 and 5.96 ppm
whereas the equatorial methine hydrogen was located at 5.04 ppm suggesting the

presence of three equatorial and one axial methoxy groups. The resultant macrocycle had

125

a specific rotation of —15.4° in chloroform. Mass spectral data also confirmed only the
presence of tetramer as no other high molecular weight compounds were seen.
4.1.1.6 Tetramethoxy calix[4]arene (rctt isomer) 262 by reaction of (R,R)-268 and

(S,S)—267A

It must be noted that reaction of the matched pair i.e., biscarbene complex (R,R)-
268 with the bispropargyl methyl ether (R,R)-267A gave the tetramethoxy calix[4]arene
263 in 30 % yield as single enantiomer. The reaction of his carbene complex (R,R)-268
(88 % ee) with the diyne (S,S)-267A (94 % ee) was next examined to probe mismatched
selectivity in the triple annulation process. The resultant calix[4]arene would be a mesa
compound with relative stereochemistry at the bridges being cis, trans, cis and therefore
was expected to be Optically inactive. The reaction afforded the desired calix[4]arene in
26 % yield (Scheme 4.13). None of the higher cyclic oligomers were observable either by
TLC/ crude 1H NMR or by mass spectra. The proton spectra of 262 exhibited rather
unique features. Two extra singlets were observed at 3.83 and 3.87 ppm integrating to
1.4 hydrogens each. Besides these anomalous peaks, only seven methoxy groups were
identified in the proton spectra of the pure compound. The carbon spectra on the other
hand showed signals corresponding to nine methoxy groups between 55.62 and 63.84
ppm respectively. The peak intensities for two methoxy carbons were less compared to
the other seven and DEPT analysis confirmed that these two chemical shifts were
indicative only of methoxy groups. By the use of an HMQC experiment, it was confirmed
that the two extra singlets in proton spectra that were observed indeed corresponded to

the carbons that had chemical shifis of 55 .62 and 55.82 ppm.

126

At this stage, it was hypothesized that a mixture of two inseparable conformers
were present in 1:1 ratio in solution. NOESY and lD-NOE experiments could not

elucidate the structures of these two conformers.

Scheme 4.13 Calix[4]arene 262 from reaction of (R,R)-268 and (S,S)-267A

OMe Me OMe Me

   

OMe OMe OMe
(S,S)-267A

one OMe ()Mc
(R,R)—268 1,2- Dichloroethane
100 °C, 2.5 mM

OMe

 

262
26 %

4.1.2 Triple annulation strategy towards mono and trisubstituted calix[4]arenes
Having demonstrated the feasibility of the methodology for synthesis of di and
tetrasubstituted calix[4]arenes, mono and trisubstituted calix[4]arenes were chosen as the
next targets. The C2 symmetry element present in monoalkoxy calix[4]arene 256 and
trialkoxy calix[4]arene 260 were anticipated to arise from the C1 symmetry present in the
mono-chiral propargyl arene (.S')-285 and its reaction with either non-chiral bis-carbene

complex 229A or the C2 symmetric bis-carbene complex (S,S)-268 (Scheme 4.14).

127

Scheme 4.14 General strategy towards mono and trisubstituted calix[4]arenes

MOO Me Me OMe

 

 

Me OMe Me
CnCO)
l 5 \\ é
I
OH OMe OMe HO OMe + ()R OMe
256 229A 285
C, CI
Meo Me Me OMe Me OMe Me
cacok
l \\ é
OR OMe OR + 0R CM:
268 285
260 C2 C1

4.1.2.1 Synthesis of monochiral bis-propargyl alcohol 287

The synthesis of the coupling partner 285 that would be necessary for introduction
of C2 symmetry in either 256, 259 or 260 was next examined. During the course of the
optimization studies in alkyne additions, it was accidentally found that a reduction in the
stoichiometry of the alkynyl zinc reagent, titanium isopropoxide and 1,1 ’-binaphthol by
factor of two resulted in exclusive formation of mono-alkynol (R)-286 as the only
product in excellent yield. Desilylation of (R)-286 to (S)-287 and analysis by HPLC by
comparison of the retention times of an authentic racemic sample of 287 revealed an
induction of only 65 %. The modest level of enantioselectivity obtained is in contrast to
that observed for phenyl acetylene addition to a-methoxy benzaldehyde, wherein 93 % ee
was observed for the adduct 288 under identical conditions (Scheme 4.15). The
enantiomeric excess and yield of the alkynol (S)-287 obtained by desilylation of (R)-286
was dependent upon the purity of the BINOL and quality of the diethyl zinc used for the

alkyne additions.

128

Scheme 4.15 Chemoselective alkyne addition to dialdehyde 273
Me

 

 

 

 

Me
273 R
(2 equiv ) OHC CH0 (50 mol %) CHO
EI Zn OMe TI (0- l - PT)4
TIPS _ 2 t 4, OH OMe
. toluene (1 equiv.) (StBINOL R = TIPS 286 78-90 °/
(2 equiv.) (20 mol %) TB AF I: , o
R = H 287, 58-65 % ee
on OMe on ”“02
31./Hi) 93 % “3 ///©
288 73 % yield 1’“
(R)-289
96 % ee
77 % yield

 

 

 

Re-use of the recovered bi-naphthol under the above-mentioned conditions
afforded (S')-287 in only 58 % ee. An alternative procedure for alkyne addition was
recently reported by Pu, which involved the use of hexamethyl phosphoramide as an
additive.”6 According to this procedure, (S)-BINOL in dichloromethane is mixed with
HMPA, alkyne and diethyl zinc in one pot. Titanium isopropoxide and the aldehyde were
then added in one-hour intervals and the reaction was complete in 3-4 h. Under these new
conditions, (R)-1,3-diphenylprop-2-yn-l-ol 289 was obtained in 72 % yield and 93 % ee.
Although this protocol resulted in lower enantiomeric excess for 289 compared to the one
without HMPA, the asymmetric addition to dialdehyde 273 was neverthless examined
under these conditions in an effort to improve the enantioselectivity of 287. However,
analysis of the crude proton NMR of the product using these conditions indicated that the
reaction did not proceed to completion with the ratio of starting material 273 and mono-
adduct 286 being 1.6: 1.

Next, it was anticipated that the enantiomeric purity of alkynol 287 could be

improved by chemical separation of the two enantiomers using enzymatic kinetic

129

resolution. Recently, Porto had demonstrated that racemic terminal propargyl alcohols
such as 290 could be resolved by lipase (Novozyme 435) to give the chiral propargyl
alcohols (S)-290 and propargyl acetate (R)-29l in high enantiomeric purity (Scheme 4.6).
The enzyme preferentially reacts only with the (R)-enantiomer of the propargyl alcohol

and hence the unreacted (S)-enantiomer is also obtained optically pure.117

Scheme 4.16 Kinetic resolution of terminal propargyl alcohol (5)2900

OH QAc
Novozyme 435
H + /\0AC Hexanes (HPLC +©/\H

(+/-)-290 0.1 mL 160 mL, n (61290 (3}291

 

50 1‘ L After 520 min % ee > 99 > 99

Enzymatic resolution of the enantiomers of 286 / 287 was next examined by screening a
wide variety of reaction conditions and the results can be found below in Table 4.2.
Consistent with the results reported by Porto, the kinetic resolution doesn’t work on the
silylated alkyne 286 (entry 1). In contrast, the terminal propargyl alcohol 287 can be
resolved either in a mixture of dichloromethane and hexanes or in hexanes (compare
entries 5 and 3). As the enzyme is immobilized on acrylic resin, rigorous stirring of the
contents of the flask can accelerate the heterogeneous reaction. Longer reaction times are
often necessary to attain complete kinetic resolution of the enantiomers in a single cycle
(entry 7 vs entry 1). The results obtained here are consistent with the general observation
made by Porto as only the (R)-alcohol 287 reacts to form the propargyl acetate 292
although the selectivity obtained is not quite as high (two cycles are necessary for
achieving high enantiomeric purity of 287). Based on the results obtained in the

enzymatic resolution, it would be a reasonable assumption that the absolute configuration

130

of the chiral alkynol 287 resulting from alkyne addition process using (S)-BINOL as the

 

chiral ligand would be (R).
Table 4.2 Enzymatic resolution on 287 : Optimization studies
Me
MC Me
Novozyme 435
CH0 CH Cl /h > +
2 2 exanes
OH OMe CHO ‘ CH O
(S)-287 0H OMe OAc OMe
-287 292
+ %OAC (S)

 

Entry No of. cycles Solvent ratio % cc of 287” Reaction Time % Yield 287 % Yield 292 % cc of 287C

 

l lst cycle 1/ 2 57.5 4 h 77 6 71

2 20d cycle 1/ 3 71 12 h 81 ND 98.5
3 lst cycle 1/ 6 56.5 12 h 77 17 84.7
4 2nd cycle 1/ 6 84.7 " 92 5.4 96.3
5 lst cycle 0/ 1a 63.47 13 h 82 12.2 84.97
6 2nd cycle 0 /l 84.97 " 75 6.5 93.7
7 lst cycle 1/ 3 70 20 h 83 10.6 93.4

 

" The allkynol 287 was insoluble in hexanes and hence added directly to solution of vinyl acetate and Novozyme
435 in hexanes

b The % ee refers to the enantiomeric purity prior to enzymatic resolution

c The % ee refers to the enantiomeric purity after enzymatic resolution

Lin Pu had reported that alkyne addition to benzaldehyde using (S)-BINOL gave
the (R) enantiomer of 1,3-diphenylprop-2-yn-1-ol 289, whereas the absolute
configuration of the propargyl alcohol 288 resulting from similar addition to a-
anisaldehyde was not proven. As the assignment of absolute configuration for these
substrates principally relied on comparison of the observed optical rotation values to
literature ones, it was reasoned that similar approach could not be pursued for deducing
the stereochemistry in 274C and 287 because of the disparity in the direction of the
observed rotation for alcohols 288 and 289. In general, the difficulty in unambiguous

assignement of configuration in propargyl alcohols arises due to the scarcity of available

131

methods and the only known example involves the use of circular dichroism studies on
propargyl benzoates.118 Hence, significant amount of effort was expended to
unambiguously deduce the absolute configuration in chiral alkynols 274C and 287.
Finally, Horeau’s method was used to establish the absolute configuration as (R,R)-274A
and (R)-286 by preparation of the 2-phenyl butyrate ester 293 and the necessary
information can be found in the experimental section.
4.1.2.2 Chiral monomethoxy calix[4]arene 256

The chiral propargyl alcohol (S)-287 obtained by enzymatic resolution in 93.4 %
ee could be transformed to the unsymmetrical diyne (S)-285 in six steps in good overall
yield Methylation of the propargyl alcohol followed by reduction afforded the benzyl
alcohol 295 which could then be transformed to the benzyl bromide 296 by a two step

sequence with the intermediacy of benzyl tosylate.

Scheme 4.17 Synthesis of chiral unsymmetrical diyne 285

 

 

 

 

 

 

Me Me Me
1) Nail, CH3] = OH l)p - TsCl, Py _ Br
CH0 r111: CHZCIZ *
OH OMe 2) NaBHt. MeOH OMe OMe 2) LiBr, DMF, 50 °C OMe CM:
287 295 65 % 296 66 %
93.4 % ee
(55 mol %)
(TMSa—)ln
3
Pd (dpp0C12
(2.6 mol %)
v THF, reflux
Me
AAgNO3 / KCN TMS
OMe OMe OMe OMe
285 72 % 297 68 %

Palladium catalyzed coupling with tris-trimethylsilyl ethynyl indium reagent followed by

desilylation gave the diyne 285 in 21 % yield from (S)-287 (Scheme 4.17). The reaction

132

of the non-chiral bis-carbene complex 229A and chiral diyne (S)-285 was next examined.
The chiral monomethoxy calix[4]arene 256 with C2 symmetry could be isolated in 31 %

yield (Scheme 4.18).

Scheme 4.18 Monomethoxy calix[4]arene 256 by triple annulation of complex 229A and diyne 285

 

 

OMe Me OMe
(OC)5Cr I I Cr(C0)5 M80 Me Me 0M6

OMe 1,2 - DCE, 100 °C

229A 47

+ [Alkynez Carbene complex

M = 1:1] 2.5 mM OH OMe OMe HO

6 256 31%
k /
OMe OMe
285

Analysis of the 1H NMR spectrum of 256 showed the axial methine hydrogen at 5.98
ppm as a singlet indicating that methoxy group preferred to occupy the equatorial
position of the macrocycle. Also, in agreement with the 13C chemical shifts for
equatorially substituted calix[4]arenes was the chemical shifi of the methine signal of 256
at 73.83 ppm.
4.1.2.3 Trimethoxy calix[4]arene (rte isomer) 260

Macrocyclization of chiral bis-carbene complex (S,S)-268 (97.8 % ee) with the
diyne (S)-285 (93.4 % ee) afforded the trimethoxy derivative 260 with C 2 symmetry in 31
% yield as a cone conformer (Scheme 4.19). The relative stereochemistry at the bridges
in 260 is defined by the stereochemical descriptor rtc (relative trans cis). Analysis of the
mass spectra revealed that indeed the tetramer was only formed and none of the octamer
was present. Notably, this represents the first synthesis of a calix[4]arene resulting from

substitution at three different methylene bridges. Examination of the 1H NMR spectrum

133

revealed similar features observed for other methylene substituted calix[4]arenes. Three
distinct singlets were observed for the methine hydrogens on the benzylic carbon bearing
the methoxy substituents. Two of the methine hydrogens were observed at 5.99 and 6.04
ppm indicating these correspond to axial hydrogens on the calix scaffold whereas the
equatorial hydrogen was observed at 5.04 ppm respectively. The observed specific

rotation of the trimethyl ether of calix[4]arene was found to be —16.2°.

Scheme 4.19 Trimethoxy calix[4]arene 260 by triple annulation of complex 268 and diyne 285

 

M 60 M6 M6 OMC

OMe OMe OMe
(S,S)-268 97.8 % cc 1.2 - DCE, 100°C

 

 

= OMe
+ [Alkyne: Carbene complex M CO
=1:1]2.5mM OH OMe OMe HO
MC /0
Me
260 31 %
OMe OMe

(S)-285, 93.4 % ee

4.1.2.4 Trimethoxy calix[4]arene (rec isomer) 259

Next, cyclization of the (S,R) bis-carbene complex 284 with the diyne (S)-285
(93.4 % ee) was probed under optimal conditions for the formation of the chiral
calix[4]arene 259 (Scheme 4.20). This reaction was anticipated to afford a mixture of
diastereomers, either with an all syn or syn, anti relative stereochemical disposition of the
substituents at the bridges. Although the TLC analysis of the crude indicated a broad
streak, the presence of only one mobile spot was evident. Chromatographic purification
gave a product that exhibited a very complicated proton and carbon NMR spectra.
Careful examination of the proton spectra revealed the presence of four methyl groups,

fourteen methoxy groups and six methine hydrogens.

134

Scheme 4.20 Trimethoxy calix[4]arene 259 by reaction of mesa bis-carbene complex 284
and chiral diyne 285

OMe Me OMe
(0C)sCr I I Cr(C0)s

OMe OMe ()Me

 

 

(S'fHM ClCHZCHZCI M60 Me Me (Me
Me 100 °C, 2.5 mM 259-I (diequatorial axial)
29 % +
MeO Me Me OMe
0M6 OMe
(5)285

 

on OMe OMe HO

259-II (all equatorial)

The methine protons appeared as distinct singlets at 5.05, 5.70, 5.81, 5.92 and
5.94 ppm. Furthermore, sixteen aromatic protons and four hydroxyl groups were also
evident in the region between 6.58 and 7.82 ppm. The carbon spectra was much more
complex embedded with alteast seventy different carbons. Again, four methyl carbons
corresponding to the p-methyl anisole fragment were in the chemical shift range 20.77-
21.26 ppm respectively. Also, the presence of thirty aromatic carbon resonances required
the existence of atleast eight aryl rings in the macrocyclic framework which possibly
could indicate the presence of either calix[8]arene or a mixture of two conformers of
calix[4]arenes in roughly 1:1 ratio. HPLC Analysis confirmed that there were indeed two
compounds (ratio 1.36:1) and mass spectra of the mixture also suggested them to be
isomeric (m/z 630 only observed). The exact structure of these two isomeric compounds
could not be deduced but tentatively these are assigned as the diastereomers 259-I and
259-II based on the chemical shifts of 5.05 and 5.80 in the former compared to 5.69, 5.91

and 5.93 ppm in the latter.

135

4.1.3 1,3- Disubstituted chiral calix[4]arene

The preparation of the 1,3-disubstituted analog 258 (See Scheme 4.1, R5 = OMe)
was expected to be accomplished by the triple annulation via dimerization of alkynyl
carbene complex 298. This strategy was anticipated to be extremely useful as direct
examination of matched / mismatched selectivity could possibly be accomplished using

the alkynyl carbene complex of specific enantiomeric purity

(Scheme 4.21).
Scheme 4.21 Triple annulation by dimerization of complex 298

Triple annulation
by dimerization (OC)5Cr

 

    

OMe OR
% cc of 298 Diasteromer expected (S)-298

> 99 % ec (KR)

 

 

 

OMe Case B < 70 % ee (RR) HRS)
258

 

4.1.5.1 Case A: Attempted preparation of enantiomerically pure complex (S)-298
and regioisomer (S)-298A

The synthesis commenced with the chemoselective hydrozirconation of the
terminal alkyne in 297 followed by iodination to afford the mono-vinyl iodide which was
subsequently desilylated to afford the (lo-alkynyl vinyl iodide 300 in good overall yield.
Deprotonation of the terminal alkyne in 300 with phenyl lithium and subsequent halogen-
metal exchange afforded the presumed intermediate dianion 301 which upon attempted

reaction with chromium hexacarbonyl followed by methylation afforded none of the

136

carbene complex 298A and a significant amount of immobile baseline material was

observed by TLC (Scheme 4.22).

Scheme 4.22 Attempted synthesis of the alkynyl carbene complex 298A

 

 

 

Me Me
TMS l C ZrHCl NIS
\ / ) p2 , ¢ I / /
OMe OMe THF OMe OMe
l) PhLi, -78 °C
t - BuLi, -78 °C
F 7 Cr(CO)6‘ rt
Me Me3OBF4
/ Li l’
' /
Ll /
OMe OMe 301

 

 

 

 

OMe OMe

298A Failed

An alternate approach was then envisioned which involved desilylation as the last
step in the preparation of carbene complex 298A. The diyne 297 was subjected to
hydrozirconation / iodination sequence using Schwartz reagent to afford the mono-vinyl
iodide 299 in 70 % yield. The reaction of the vinyl iodide with tert-butyl lithium to
facilitate halogen-metal exchange followed by nucleophilic addition of the vinylic
carbanion on chromium hexacarbonyl did not yield the carbene complex 302 either
(Scheme 4.23). The difficulty in preparation of carbene complexes 298A and 302 might
be attributed to the instability of the intermediate vinylic carbanions with respect to
decomposition even when the reaction is conducted at very low temperatures (-78°C) or

the instability of these complexes with respect to air oxidation.

137

Scheme 4.23 Alternative approach to alkynyl carbene complex 298A
with desilylation as the last step

 

 

Me Me
Fischer
C C TM
Carbene complex Alli) r( /O)5 S procedure TMS
=> 1 /
298A KCN M60
OMe OMe OMe OMe
302 299
CpZZrHCl _ . _ t - BuLi (2 eq) .
Diyne 297 Vlnyl lodlde : Decomposed basellne
le, THF 299 70 % Cr(C0)o (2 eq) material
MC3OBF4 ( 3 6(1)

To examine the reasons for the stability of these carbene complexes, a different
route was explored that avoided the generation and reaction of vinylic carbanions such as
those mentioned earlier. More specifically, the aldol reaction between the enolate of
pentacarbonyl methoxy methyl chromium carbene complex 176 and enolizable aldehyde
303 was expected to furnish the carbene complex 298. Although complex 298 is a
structural isomer of complex 298A, it was still anticipated to afford the chiral 1,3-
dimethoxy calixarene by macrocyclization. Aldehydic substrates similar to 303 are
expected to be extremely sensitive to polymerization and hence the initial studies were
examined with phenyl acetaldehyde 304 for the preparation of analogous complex 305
(Scheme 4.24). The aldol methodology was probed using titanium tetrachloride as the
Lewis acid. Deprotonation of 176 in ether to generate the enolate as shown above
followed by addition to the phenyl acetaldehyde-titanium tetrachloride complex in
dichloromethane afforded the aldol adduct 306 in 67 % yield. Upon purification by a
silica gel column and removal of the solvent, the aldol adduct was found to be extremely
unstable with respect to decomposition. Treatment of 306 with methanesulfonyl chloride

and triethylamine yielded the complex 305 in 26 % yield.

138

Scheme 4.24 Aldol methodology to carbene compli’ixe: 298 and 305

(OC)5CY=<
cacok
SnCl4 or TiCl, 1

O9Me OMe [Aldol addition] 3OMe OMe

MsCl, Et3N
[Dehydration]

©/\CHO Same as above / 0M9
.............. ,,
CKCOB
304 305

It is noteworthy to mention that no other side products were observed as mobile

 

 

spots on the TLC plate by this sequential method whereas 307 was the minor product in

one step method that was carried out without the purification of the intermediate 306

 

(Scheme 4.25).
Scheme 4.25 Aldol reactions with phenyl acetaldehyde
OMe . OMe
(OC)5CI'=< n-BULI : Aldehyde 304 ; (OC)5CI' OH
176 CH3 -78 cc "rich, ~78 °C

EtZO (Step1) 012% 306 67% Ph

   
    
 
 

MsCl, Et3N Method A

(Steps 1 and 2) CH2C12 (Step 2)

No intermediate

isolation
Method 3 OMe
(OC),Cr=<_\'
I . . lat Pb

W 305 26 %

(00 C OMe 16 % Overall by Method A
5 1'
R 10 % Overall by Method B
307 P“
~ 20 %

The formation of 305 occurs by elimination via pathway A whereas 307 presumably is

formed by elimination via pathway B (Scheme 4.26).

139

Scheme 4.26 Mechanism of elimination of mesylate 308

 

 

306
I MsCl,Et3N
OMe
OMe OMe
CC C OM
«waftk PM” ( )5 222% PM” - <oc>sCr=Lk
— H
Ph
Ph F H H \ Ph
305 .. B Ii. 307
08

° B

Although, it is surprising to note that a slight difference in the procedures resulted
in varied product distributions in favor of either regioisomer, this methodology again
suffered from poor yields of the desired complex 305. Since the energetics of the
elimination process would be expected to be relatively similar due to the presence of
extended conjugation both in 305 and 307, the aldol approach had to be abandoned at this
stage.
4.1.5.2 Case B: Preparation of carbene complex (S)-298 with low enantiomeric

purity

The preparation of the alkynyl carbene complex 298 in low enantiomeric purity
could be accomplished by the dianion approach in very low yield by a different sequence.
First, the chiral propargyl alcohol (R)-286 (61 % ee) was methylated and then reduced to
the benzylic alcohol 310. Bromination using carbon tetrabromide and triphenyl
phosphine afforded the benzyl bromide, which was then subjected to palladium catalyzed
coupling with trialkynyl indium reagent to give the unsymmetrical diyne 312 in 63 %
yield. The diyne 312 was then converted to the vinyl iodide (R)-3l4 in two steps

(Scheme 4.27).

140

Scheme 4.27 Preparation of chiral vinyl iodide 314

 

Me Me
TIPS \ l] NaH (1 l ) TIPS
. eq ‘
CHO 7 HO .
OH OMe Me] (5 “9 OM OM
THF, rt '3 e
61% CC (R)—286 2] NaBH4 (12 eq) 310 89 %
MeOH, rt

11C3r4 (1.2 eq), PPh3 (1.2 eq)

2] 40 mol % (TMS __ 1n
3
2 mol % Pd[dppf]C12, THF, reflux

 

Me Me

 

  

TIPS J] AgNO3, KCN TMS

. VEtOH mzo .

OMe OMe 2] szszl, le OMe OMe
314 79% 312 63%

 

The vinyl iodide 314 was next subjected to desilylation and then exposed to the
standard conditions for carbene complex formation as described earlier in an attempted
preparation of 298A. Gratifyingly, the carbene complex (S)-298 could be isolated in pure
form albeit in only 8 % yield. Cyclization of complex (S)-298 (61 % ee) under the
optimized conditions at a concentration of 2.5 mM resulted in a smooth cyclization to
yield only the (R,R)-1,3-dimethoxy substituted calix[4]arene 258 in 19 % yield. No other
mobile spots were seen on the crude TLC plate as well as by crude 1H NMR (Scheme
4.28). This result is surprising considering the fact that the starting material was enriched
in the (S)-enantiomer to only 61% ee. It was expected that a mixture of diastereomers
would result from the triple annulation / dimerization sequence with the statistical

distribution being in favor of the (R,R)-258 than (R,S)-258 in a ratio of 2.24:1.

141

Scheme 4.28 Triple annulation / dimerization of complex 298 OMe

 

314
1] TBAF, ether, rt
2] PhLi (1.1 eq),
t- BuLi (2.2 eq)
Cl’(CO)6, MC3OBF4 MC
E 100C
M 9
e in 296

1,2 - DC

2.5 mM .
OMe MeO‘
\‘ CKCOB

()Mc OMe OMe
298 6 % 258 19 % yield

 

While certainly a small amount of the minor diastereomer (R,S)-258 could have
possibly formed that perhaps escaped detection by either TLC or crude proton spectra,
there definitely exists a clear preference for the matched (R,R)-isomer. The calix[4]arene
obtained was unambiguously determined to be the (R,R)-diastereomer by examination of
proton spectra, Optical rotation measurement and NOESY data. The (R, S)-diastereomer
would have Cs symmetry with a trans relationship of the substituents at the methine
bridges thereby would be achiral whereas the (R,R)-diasteromer would have C2V
symmetry in the cone conformation and therefore would be chiral. The proton NMR
spectra indicated that both the methine hydrogens appeared downfield at 5.98 ppm
indicating that the two-methoxy groups must occupy equatorial positions. Furthermore, it
was found that the 1,3-dimethoxy substituted calix[4]arene had an Optical rotation of -
38° in chloroform and the diastereomeric assignment was further confirmed by NOESY
experiment (See Experimental section for Details) (Figure 4.6). The origin of the
selectivity in the macrocyclization is not well understood. Two hypothetical scenarios
emerge wherein a] matched vs mismatched selectivity might contribute to only the
formation of the observed (R,R)-diastereomer b] the intermediate alkynyl carbene

complex 316 does not undergo the macrocyclization event (Scheme 4.29).

142

Figure 4.6 Theoretical product distribution in cyclization of 298

MeO Me Me OMe

   

(R, R)-258 65.6 % (R,S)-258 30.8 %
C2,, symmetry C,1 symmetry

 

03,10 OH 0M6 OMe HO
(S.S)-258 3.6 %
sz symmetry

O M c

It is also possible that the planar chirality present in né-Chromium tricarbonyl
arene complex 316 interferes with the cyclization step as it is expected that the mode of
coordination of the chromium tricarbonyl tripod is the one wherein the metal center is
anti to the neighbouring methoxy substituent based on studies done by Hsung (See
section 2.1.2.1 Pg.55), and syn to the methoxy substituent at the propargylic position. In
the event Of alkyne terminus approaching the carbene fragment in 316 to form the nlzn3
vinyl carbene complex, it is anticipated that the CO ligands on the metal would be in
close vicinity to the propargylic methoxy group and thereby would result in an
unfavorable steric interaction prohibiting the alkyne insertion step. The net result would
then be subsequent intermolecular benzannulation event leading to oligomerization

(Scheme 4.29).

143

Scheme 4.29 Possible explanations for observed diastereoselectivity

 

   

Me Me
OMe OMe
\
Cr(C0)5 \ Cr(C0)s
OMe OMe OMe OMe
298 80.5 % S 298 80.5 % S
+ Mlsmatched ; (R, S)-2 58 (R, R)-258 "Matched" +
Me Me
OMe
(OC)5Cr / (OC)5Cr ;
OMe OMe OMe OMe
298 298 80.5 % s
18.5 % R

Me MeO Me (R,S)—258 Not Obtained!

Intramolecular

.
C r( CO)5 Benzannulation

,O MeO / OH O, MeO
Me (OC)3Cr Me
316 ”Higher Oligomers

By Repetitive Intermolecular
Benzannulations"

  

4.2 Summary

In summary, the triple annulation approach has been established as a unique
synthetic approach towards methylene substituted chiral calix[4]arenes. This
methodology provides for a versatile synthesis of specific stereo and regioisomers with

varying substitution patterns at the methylene bridges.

144

CHAPTER FIVE
MODEL STUDY TOWARDS LARGER MACROCYCLES WITH
DEEPER CAVITIES- SYNTHESIS OF A BISHOMOCALIXHIARENE

CAVITAN D

5.1 Homocalix[4]arenes by triple annulation strategy

The preceding chapter demonstrated the utility of the triple annulation
methodology in the synthesis of calix[4]arenes that are chiral as a result of substitution at
the methylene bridges and also by the presence of adjacent aryl rings that are non-
identical. In this chapter, the synthesis of bis-homocalix[4]arene model substrate 211 by
reaction of bis-carbene complex 318 and diyne 317 as well as some initial studies
examining the feasibility of the triple annulation / dimerization strategy of carbene

complex 319 will be discussed (Scheme 5.1). '

      

Scheme 5.1 Triple annulation strategy towards larger macrocycles OMe Me OMe
(0C)5Cr I I Cr(CO)5
Triple Annulation by
Reaction of OMe
Bis-Carbene Complex 318 318
and Diyne 317 +
Vvé/V
OMe
317
Triple
Annulation
By Dimerization
of 319 Me 0M3
OMe
319

145

5.2 Preparation of diyne 320

The study begins with the targeted synthesis of diyne 317. After examination of a
number of different strategies towards this substrate, only one viable approach was found.
This involved the palladium catalyzed Suzuki coupling of an alkyl borane 322 that was in
turn obtained by hydroboration of the skipped enyne 321 with 2,6-dibromo-4-methyl
anisole 323.120 This Suzuki coupling involves the use Of the biaryl phosphine ligand S-
PHOS 324 recently introduced by Buchwalmehe reaction works extremely well to
provide the bis-trimethyl silyl substituted diyne 320 in excellent yield. Although the
ligand is quite expensive, the reaction can basically be carried out using only 2 mol % of

ligand with no significant drop-off in isolated chemical yields even at room temperature

 

 

 

 

(Table 5.1).
Table 5.1 Suzuki coupling with Buchwald's ligand as an efficient route to 320
Me
1
Me
Br Br 323
/ 9-BBN(H) OMe TMS TMS
//\/ ___§ 322 > \ /
TMS THF, reflux
32‘ Pd(OAC)2, S-PHOS
2h OMe
THF 324 320
K3PO4 2 equiv
Entry Catalyst Loading Amt. of Ligand Temperature Time % Yield
1 1 mol % 2 mol % 25°C 24b 76
2 2 mol % 4 mol % 75°C 9h 79
S-PHOS = PCYZ
/\/\ 9-BBN MeO OMe
TMS 322 O 324

5.3 Synthesis of bis-carbene complex 318
With the diyne 320 in hand, the bis-carbene complex 318 could be prepared

conveniently in three steps. Desilylation of 320 provided the terminal diyne 317, which

146

was subjected to hydrozirconation/ iodination protocol to give the bis-trans vinyl iodide

325 in good overall yields. The vinyl iodide in turn could be transformed into the bis-

carbene complex 316 in 36 % yield (Scheme 5.2).

Scheme 5.2 Synthesis of bis-carbene complex 318

 

   

 

 

TBAF, ether
rt
320 317 96 %
CerHCl (4 eq)
NIS (4 eq) THF, rt
R1
OMe Me OMe
t- BuLi (4 eq) 1 l
(OC)5Cr Cr(C0)s =
| | cacow eq) I I
Me3OBF4 (6 eq) R3
OMe
318 36 % 325 63 %

5.4 i Bishomocalix[4]arene by triple annulation of bis-carbene complex 318 and
diyne 317 i I
Cyclization of the bis-carbene complex 318 with the diyne 317 was then
investigated under Optimal conditions in 1,2-dichloroethane as the solvent. Quite
fascinatingly, the reaction afforded the bis-homocalix[4]arene 211 in 39 % yield (Scheme
5.3). Interestingly, there is no drop in the yield compared to the synthesis of an analogous

calix[4]arene 246A (See section 3.4 and 3.5), which has eight less atoms in the

macrocycle.

147

Scheme 5.3 Triple annulation to bis-homocalix[4]arene 211

Me

 

 

 

0M6 1,2-DCE,100°C
317 _ ;
2.5 mM in carbene
+ complex and Diyne
OMe Me OMe
(OC)5Cr I I Cr(CO)5
OMe
318

39 % yield

5.5 Triple annulation by dimerization of 319

One of the primary reasons for pursuing the synthesis of this family of larger
macrocyles was to examine the possibility of preparing chiral bis-homocalixarene
cavitand 215 (See Section 2.3.1) for its intended use as a chiral ligand in asymmetric

reactions.

Scheme 5.4 Triple annulation of complex 327 and diyne 326 - Not a
feasible route towards target 212

 

328 R1=R3=OR,R2=H
212RI=H,R2=R3=OR

326

Thus, it could be perceived that the above strategy in Scheme 5.3 would not be directly

useful in Obtaining the chiral macrocycle 212 as it would require the cyclization of mono-

148

chiral carbene complex 326 with mono-chiral diyne 327 (Scheme 5.4). Such a process
would be inefficient as a mixture of adjacent and distal propylene functionalized bis-
homo calix[4]arenes 328 and 212 would result upon deprotection.

An alternative strategy would then involve cyclization Of alkynyl carbene

complex 329 to form the bis-homocalix[4]arene 212 (Scheme 5 .5).

Scheme 5.5 Triple annulation by dimerization of complex 329 to chiral bis-homocalix[4]arene 212
OMe

 

 

 

 

 

In this regard, the examination of the dimerization of carbene complex 319 was
considered extremely crucial for the targeted chiral macrocycle 212. Also, it was
anticipated to provide an Opportunity to examine the effect of tether length on intra vs
inter-molecular benzannulation of carbene complexes. Based on the results obtained in
intramolecular benzannulation as function of tether lengths (See section 2.2.2.1), it was
expected that thermolysis of complex 317 would give only the desired bis-
homocalix[4]arene 211. As the tether length is increased, intramolecular benzannulation
was anticipated to compete with the dimerization process leading to [n,n]-

metacyclophane 330 (Scheme 5.6).

149

Scheme 5.6 Inter vs Intramolecular benzannulations leading to 211 or 330

Me OMe
I CKCOB
\
m OMe n
319

 

OMe
Me
(or)
OMe
330

5.6 Synthesis of alkynyl carbene complex 319
5.6.1 The dianion approach

Preparation of the carbene complex 319 was initially examined by the dianion
methodology developed by a former graduate student in the Wulff group.86 In this regard,
the diyne 317 was subjected to hydrozirconation / iodination sequence using only 1.5
equivalents Of the Schwartz reagent. The reaction afforded a mixture of mono-vinyl
iodide 331, bis-trans vinyl iodide 325 and starting material roughly as a statistical mixture
from which 331 was isolable in 39 % yield. The vinyl iodide 331 was then subjected to
similar sequence of reaction conditions that were used in the synthesis of 298 (Scheme

4.22) to give only 8 % of the desired carbene complex 319 (Scheme 5 .7).

150

Scheme 5.7 Dianion approach to carbene complex formation

Me Me OMe
\/\/©\/\/ WCKCOB

OMe OMe

317

319 8 %
PhLi (1 equiv.)

szerCI (1-5 eq) t- BuLi ( 2 equiv.)
N18 (15 eq). THF

 
   
 

Cr(CO)6, Me3OBF4

Me
Me
1 1
I l
W + W
OMe OMe
325 24 % 331 39 %
+ 317 25 %
The isolated carbene complex was not of sufficient purity to allow an examination of the
dimerization approach. Based on prior studies done in the Wulff group, it has been well
established that aldol reactions of pentacarbonyl methoxymethyl chromium carbene
complex 176 with enolizable aldehydes (See scheme 2.16) afford alkenyl carbene
complexes in good yields. Hence, the aldol approach was next examined for the synthesis
of complex 319.
5.6.2 Aldol approach for carbene complex formation

The synthesis of complex 319 was envisaged to arise from the aldol reaction/

dehydration of carbene complex 176 and enolizable aldehyde 332 (Scheme 5.8).

Scheme 5.8 Aldol approach for carbene complex formation

Me
Me OMe \ CHO
I Cr(CO)5 2:2; OMe
\
332
OMC +
317 OMe
(OC)5Cr=<
CH3

176

151

Commercially available 2-bromo-4-methyl-phenol 333 was converted into 2-bromo-6-
hydroxymethyl-4-methylanisole 335 following literature procedure. Bromination of the
benzyl alcohol using carbon tetrabromide and chain extension using allyl magnesium

bromide gave the terminal alkene 337 in 94 % yield over two steps.

Scheme 5.9 Attempted preparation of aldehyde 340

 

 

 

Me Me Me
/
1) (CHzO)n _ l) CBr4,PPh3
Br KOH ' PrOH/HO Br OH 2 73’
OH . t 2 OMe ) AMgBr OMe
2) K2CO3 . M62504 0
333 acetone 335 71 % Et20 337 94 /o
1) B2H6.
H202 / N80“
2) PCC,CH2C12
NaOAc
TMS =
TMS Me Me
% CHO 9-3319 CHO
Pd (OAc)2 (1 mol %) Br
OMe S-PHOS (2 mol %) OMe
340 THF, reflux 339 63 %
‘ 1
Not Obtained. K3PO4 2 equiv

Mixture of 3 Unknown
Compounds m/z 336

No Fonnyl Group present
in Crude ‘H NMR

Hydroboration of Olefin 337 followed by oxidation of the intermediate alkyl borane
resulted in the formation of alcohol, which was oxidized to the aldehyde 339 in good
yields. The aldehyde 339 was then subjected to the Suzuki coupling conditions using S-
PHOS ligand but unfortunately none of the desired coupled product was detected by TLC
/ crude 1H NMR or mass spectroscopic analysis. The proton spectra showed that the
formyl group had disappeared indicating that such reactive functionality may not be
suitable under the Suzuki coupling conditions (Scheme 5.9). An alternative method that
would prevent interference Of the formyl group was examined wherein the coupling step

preceded the installation of the reactive aldehyde functionality (Scheme 5.10). The cross

152

coupling of bromide 337 with the alkyl borane under identical conditions led to the

formation of the desired product 341 in 84 % yield.

Scheme 5.10 Alternative approach to carbene complex 319
Me TMS

 
 
 

/ "same conditions

 

Br as above"

OMe
337

5.7 Summary

This chapter examines the feasibility of construction of larger macrocycles by
reaction of carbene complexes and alkynes. A representative example is the synthesis of
bis-homo calix[4]arene in 39 % yield from the reaction of bis-carbene complex 318 and
diyne 317. An advanced intermediate for exploration of the dimerization strategy has also

been prepared by using Suzuki cross coupling as the key step.

153

CHAPTER SIX
CONCLUSIONS AND

FUTURE DIRECTIONS

A versatile and expedient methodology has been described that affords access to
calix[4]arenes, chiral calix[4]arenes and bis-homocalix[4]arene adorned with specific
symmetry elements from the triple annulation reactions of carbene complexes and
alkynes. Further advancements in methodology can arise in several different ways and
this chapter is intended to provide an insight into some of the avenues for further
exploration.

6.1 Calix[4]arenes with molecular asymmetry

One of the direct ways to gain access to calix[4]arenes with C 2 symmetry would
be to tether either the distal arene rings or“ the proximal arene rings at the lower rim as in
calix[4]arenes 342 and 343. It is expected that cone conformation would not be preferred
in solution for either Of these compounds due to disruption of intramolecular hydrogen
bonding and thereby the only preferred conformers in solution would be the partial cone
and 1,2-alternate. The intramolecular triple annulation process of 344 wherein two
equivalents of alkynyl carbene complex 345 are tethered by using bifiinctional reagent
348 prior to the cyclization event can possibly accomplish the synthesis of 342.
Alternatively, calix[4]arene 343 should be directly accessible from the reaction of bis-
carbene complex 346 with bis-propargyl arene 347 bearing different substituents on the
arene rings followed by deprotection to give 349 and selective 1,2-alkylation at the lower

rim halide 348 (Scheme 6.1).

154

Scheme 6.1 Synthetic strategy to conformationally locked macrocycles in partial cone and 1,2-alternate conformation

CKC0)5 \OMCXZZE/Q/
MeO Cr(CO)5

M60 R2 R1

    

OMe

 

 

345R]
M60 R1 R2 0M6
$3
+ OR4 346
343 1,2- alternate OMe
(0C)sCr I I Cr(CO)5
R3 347

6.2 Double calix[4]arenes by tandem heptannulation

Double calix[4]arenes wherein two of the cavities formed by calix[4]arenes are
linked together can also be accessed by the triple annulation of carbene complexes and
alkynes. More specifically, the reaction Of tetrakis—carbene complex 351 and tetrayne 350
would be expected to furnish the double calix[4]arene 352 by a formal heptannulation
process (Scheme 6.2). Despite their potential synthetic utility, this class of clathrand has
been less popular due to the difficulty in their preparation. It has been known for example
that quartenary ammonium ions can be held inside the cavity and thereby presents an
attractive feature for examining reactions that generate such species in its vicinity. The
tetrayne should be readily accessible from the known tetrabromide 353135 by Pd-
catalyzed coupling with alkynyl indium reagent. The conversion of the tetrayne 350 to
the tetrakis-carbene complex 351 would then follow a similar route as mentioned in this

thesis earlier.

155

Scheme 6.2 Double calix[4]arene by heptannulation

MeO \ / OMe
Cr(C0)5 CrtC0)s

OMe MeO

 

X
:2 (&Hz)n X=O,CH2,NR
It
Cr(CO)5 O Cr(C0)s
MeO / \ OMe
351
,.

 

 

 

Br Br
’1‘ e
(C H2)n
|
X
Br Br
353

6.3 Equatorially substituted chiral calix[4]arenes with C2 symmetry by
desymmetrization of mesa bis-propargyl arene

It is well known that resorcinarenes in crown conformation adopt axial orientation
of the substituents at the bridges. This intrinsic feature has enabled development of
several supramolecular cavitands based on resorcinarene framework by covalently
linking the endo hydroxy groups by rigid tethers. Analogously, it is postulated that
calix[4]arenes 354 would exhibit superior synthetic utility as they would be chiral by
virtue of the presence of non-identical substituents at the adjacent positions and identical
substituents at the distal positions on the methylene bridges. Such class of calix[4]arenes

would be attainable by the reaction of bis-carbene complex 356 and bis-propargyl arene

156

355. The bis-propargyl arene with C 2 symmetry in turn can be Obtained by
desymmetrization of the bis-propargyl alcohol (S,R)-274C with C, symmetry (Schemem

6.3).

Scheme 6.3 Triple annulation approach towards equatorially substituted calix[4]arene 354

R' OMe OMe R' OMe Me OMe

 

Desymmetrization
Lof Meso 2° Alcohol

   

 

 

v

6H OMe 6H 6R2 OMe 6R3

(S,R)-274C 355

6.4 Chiral bishomocalix[4]arenes and synthesis of conformationally locked

cavitand 215

One of the possible applications of this chemistry is in the synthesis and
development of chiral bis-homocalixarene cavitand 215 as a chiral ligand for asymmetric
reactions. The feasibility of triple annulation by dimerization of alkynyl carbene complex
319 will solely determine the applicability of this strategy towards the target chiral
cavitand 212. Hence, the dimerization of complexes 319 will have to be examined
carefully in favor of either homocalix[4]arenes 211 or m-cyclophanes 330 by varying the
tether length and concentration (See Scheme 5.6). If the cyclization to form 211 can be
optimized by adjusting the reaction conditions, it would be reasonable to expect that the

macrocyclization of chiral carbene complex 329 would yield 357 (Scheme 6.4).

157

Scheme 6.4 Proposed synthesis of chiral bis-homo calix[4]arene 357

 

The alkynyl carbene complex 329 could be prepared from 2-(bromomethyl)oxirane 361

in a relatively straightforward sequence as shown in Scheme 6.5.

Scheme 6.5 Synthetic strategy for chiral alkynyl carbene complex 329

   

(OC)5Cr
— 359
359 — TMS
([)>/\ Br ‘22: /\(‘):\TIPS
361 360

The transformation of the chiral bishomocalix[4]arene 357 into the chiral cavitand 215
could then be accomplished by ester formation as discussed earlier(Section 2.3.1). The

potential utility of the chiral bis-homocalix[4]arene 215 has been discussed already in

chapter 2.

158

CHAPTER SEVEN

EXPERIMENTAL SECTION

General Experimental

All reactions were run using either oven-dried or flame-dried glassware under an inert
atmosphere of argon. Chemicals used were reagent grade and used as supplied except
where noted. The following solvents were distilled from the listed drying agents:
Tetrahydrofuran (Na, benzophenone), diethyl ether (Na, benzophenone), toluene (Na),
dichloromethane (CaH2). Anhydrous 1,2-dichloroethane was purchased from Aldrich and
used under atmosphere of argon. Silver nitrate (99.9995 % Ag) was purchased from
Strem chemicals. Chromatographic purifications were performed on Merck silica gel
grade (230-400 mesh) and TLC’s were performed on silica coated plastic baked TLC
plates from Silicycle. The general solvent systems used were either a combination of
ethyl acetate / hexanes or dichloromethane / hexanes unless otherwise specified.
Compounds were visualized by dipping the plate into a solution of KMn04 followed by
heating With a heat-gun. 1H NMR data Obtained either on a Varian 300 MHz or 500 MHz
instrument are reported in parts per million (6) relative to tetramethyl silane (0.00 ppm)
or chloroform (7.24 ppm) for spectra run in CDCl3 and multiplicities are indicated by s
(singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet Of
triplets) and br (broad). 13C NMR data were obtained on the Varian 300 MHz or 500
MHz instruments respectively and are reported in 6 relative to CDCl3 (77 ppm). Infrared
spectra were recorded on Perkin Elmer FT IR instrument and the peaks are reported in

cm". l-D NOE experiments and NOESY experiments were performed on a Varian 600

159

MHz NMR instrument. Mass spectral data and elemental analysis were Obtained from
Michigan State University Biochemistry Mass spectrometry facility and in—house facility.
The mass spectra were obtained using direct probe EI (Electron impact) using chloroform
as solvent on JEOL AX-505 double focusing mass spectometer, FAB (Fast atom
bombardment) conditions using 2-nitrobenzyl alcohol as solvent on JEOL HX-llO
double focusing mass spectrometer in the positive ionization mode. Data are reported in
the form of m/z (intensity relative to base peak = 100). Organolithium reagents were
purchased from Aldrich and titrated by the Watson-Eastham procedure'22 in benzene as
the solvent whereas Grignard reagents purchased from Strem Chemicals and titrated to a
known concentration following the procedure developed by Paquette et.al.122 The
indicated reaction temperatures are of the oil bath temperature monitored by a digital
temperature controller. The reactions were often monitored for completion by quenching
an aliquot of the reaction mixture in ether/water and then the ethereal layer was subjected
to GC/MS analyses on Saturn 2000R mass spectrometer and 3800 GC using chrome—pack
capillary column. Melting points (uncorrected) were recorded on 8 Thomas Hoover
capillary melting point apparatus using 1.5-1.8x90 mm capillary tubes. Substrate 244A
(R4 = OMe, R2 = Me) was prepared in two steps from 2,6-bis-hydroxy-methyl-p-cresol in
73% overall yield following a literature procedure.123 Compound 244D (R4 = OMe, R2 =
Ph) is also a known compound but a slightly different procedure was used for its
preparation.124 Optical rotation measurements were made on a Perkin Elmer 141
polarimeter at 589 nm (Sodium D Line) using ldm cells. Specific rotations are reported
in degrees per decimeter at 25 °C and the concentration is given in grams per 100 mL. For

rotation measurements, zero error correction was taken into account.

160

Me Me

O 30% K3PO4 O
———->
OHC CHO szO, Toluene OHC CHO

OH OSOZCF3
240 241

T rifluaramethanesulfanic acid 2, 6-a'iformyl-4—methyl—phenyl ester 24]:
2-Hydroxy-5-methyl-benzene-1,3-dicarbaldehyde was either purchased from
Trans-World Chemicals or obtained by manganese dioxide oxidation of 2,6-bis-
hydroxymethyl-p-cresol just prior to use following the literature procedure.l25 The
following procedure for preparation of the aryl triflate 241 was modified from that
reported recently.98 The phenol 240 (6.1 g, 37.2 mmol) was dissolved in 30 % aqueous
solution of potassium phosphate (150 mL) and toluene (75 mL) was added. The resulting
solution was red-orange in color and was stirred at ambient temperature for 15 min.
Triflic anhydride (11.2 mL) was added dropwise at 0 °C with vigorous stirring and the
resulting solution was warmed to room temperature and was stirred overnight. The
reaction was subjected to an aqueous workup by washing with water (2 x 100 mL). The
organic layer was dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. Purification by column chromatography yielded 64 % (7.05 g) of the
desired compound as a white flaky solid. The phenol 240 was recovered by eluting with
ethyl acetate and re-subjected to the reaction conditions and the overall yield of the
triflate 241 could be improved to 83% (9.09 g, 30.73 mmol). Rf = 0.15 (10 % EtOAc /
hexanes). Mp = 57-59 °C. Spectral data for 241: ‘H NMR(CDC13, 300 MHz) d 2.49 (s,
3H), 8.02 (s, 2H), 10.22 (s, 2H); 13’C NMR(CDC13, 75 MHz) 6 20.79, 118.55 (q, J= 319

Hz), 129.53, 135.91, 140.26, 147.24, 185.55; IR (CH2Cl2) 3063, 2893, 1699, 1597, 1466,

161

1435, 1389, 1292, 1248, 1203, 1122 cm". Anal calcd for C10H7F3058: C, 40.55; H, 2.38.

Found: C, 40.64; H, 2.30.

Me Me
Pd (0)
———->
R -M
OHC CHO OHC CHO
0802CF3 R
241 242

Palladium catalyzed Cross Coupling in the Preparation of the Dialdehyde 242.

2-Hexyl—5-methyl-1,3-benzenedicarbaldehyde (R = CW; 3) 242A: Aryl triflate
241 (4.13 g, 15.18 mmol) and dich1orobis(tripheny1phosphine)palladium II (490 mg, 5
mol %) were transferred to a 100 mL three necked round bottomed flask and 50 mL of
1,4-dioxane was added. To another flask was added indium (III) chloride (1.122 g, 5.06
mmol), which was dried under vacuum with a heat gun. Tetrahydrofuran 45 mL was then
added. Hexyl lithium (2.3M, 15.18 mmol) was subsequently added to the flask at —78 °C.
The reaction mixture was then stirred at this temperature for 30 min and then warmed up
to ambient temperature. The resulting trihexyl indium reagent generated in situ was
added to the reaction mixture containing aryl triflate 241 and the catalyst in refluxing
tetrahydrofuran under argon. The reaction was continued till the disappearance of the
starting material was indicated by GC/MS. A few drops of methanol were added to
quench the reaction. The mixture was concentrated in vacuo and ether (100 mL) was
added. The organic phase was washed with aqueous hydrochloric acid (10 %, 50 x 2
mL), saturated aqueous sodium bicarbonate (60 x 2 mL), and saturated aqueous sodium
chloride (60 x 2 mL), and then dried over anhydrous MgSOa, filtered and concentrated in
vacuo. The residue was purified by silica gel chromatography (5 % ethyl acetate /

hexanes) to afford, afier concentration and drying under high vacuum, 1.65 g (47 %, 7.14

162

mmol) of the cross-coupled product as an yellow Oil. Rf (hexanes/ethyl acetate 19/1) =
0.25. Spectral data for 242A: 1H NMR (CDC13, 300MHz) 6 0.90 (t, 3 H, J = 6.3 Hz),
1.32-1.65 (m, 8 H), 2.46 (s, 3 H), 3.42 (t, 2 H, J= 6.9 Hz), 7.90 (s, 2 H), 10.39 (s, 2 H);
13C NMR (CDC13, 75 MHz) 6 13.95, 20.54, 22.49, 25.64, 29.29, 31.45, 33.49, 134.69,
136.40, 136.56, 145.15, 191.16; IR (neat) 2959, 2928, 2857, 2756, 2731, 1689, 1608,
1570, 1462, 1396, 1281, 1234, 1107 cm]; mass spectrum m/z (% rel. intensity) 232 M+
(20), 175 (25), 84 (100), HRMS calcd for C15H2OO2 m/z 232.1463, measd 232.1464.

4— Methylbiphenyl-2,6—dicarbaldehyde (R = Ph) 2428: Aryl triflate 241 (6.22
g, 21 mmol), phenyl boronic acid (282 mg, 23.1 mmol),
tetrakis(tripheny1phosphine)palladium (0) (606 mg, 2.5 mol %), and anhydrous potassium
phosphate (6.69 g, 31.5 mol) were placed in a 250 mL Schlenk flask under Argon
atmosphere. Degassed 1,4-dioxane (100 mL) was added. The resulting mixture was
deoxyge‘nated by the freeze-thaw method (-l96 to 25°C, 2 cycles), backfilled with argon
and subsequently stirred at 85 ° C till the conversion was > 95 % as estimated by GC /
MS. The mixture was diluted with benzene (200 mL) and treated with 30 % aqueous
basic hydrogen peroxide. The product was extracted with ether (200 mL) and subsequent
removal of solvent under reduced pressure afforded the crude material. Purification by
column chromatography on silica gel 5 % to 10 % ethyl acetate/hexanes yielded (4.0 g,
5.29 mmol, 85 %) Of the desired compound 242B as a white solid. Mp = 124 °C; Rf
(hexanes/ethyl acetate 9/ 1) = 0.35. Spectral data for 242B: 1H NMR (CDC13, 300MHz) O
2.49 (s, 3H), 7.30-7.49 (m, 5H), 8.03 (s, 2H), 9.77 (s, 2H); 13C NMR (CDC13, 75 MHz) 8
20.84, 128.32, 128.74, 130.87, 132.42, 132.82, 134.56, 138.46, 145.56, 190.95; IR

(CH2Cl2) 3053, 3034, 2893, 2868, 2762, 1687, 1560, 1450, 1397, 1230 cm"; mass

163

spectrum m/z (% rel intensity) 224 M+ (100), 195 (93), 181 (43), 165 (60), 152 (55),
HRMS calcd for C15H12O2 m/z 224.0837, measd 224.0836. Anal Calcd for C15H1202I C,

80.34; H, 5.39. Found: C, 80.08; H, 5.20.

HO OH
OHC CHO M60”
R4 R4
242 244

Reduction of the Dialdehyde 242 to the bis-Hydroxymethylarene 244.
(2-HexyI-3-hydraxymethyl-5methylphenyl)methanal (R4 = C61113, R2 = Me)
2443: The aldehyde 242A (0.74 g, 3.2 mmol) was dissolved in 25 mL of methanol in a
50 mL three necked round bottomed flask and sodium borohydride was added at 0°C.
The resultant clear solution was left stirring for 30 min at this temperature and then
warmed to room temperature upon which further stirring was continued for l h. The
reaction was quenched by addition Of water and then the organic layer was extracted into
ether (100 mL). Drying over anhydrous magnesium sulfate followed by removal of the
solvent under reduced pressure yielded the product 244B in 91 % yield (0.69 g, 2.92
mmol). Mp = 78-80 °C. Spectral data for 244B: Rf = 0.19 (hexanes/ethyl acetate 3/ 1); 1H
NMR (CDC13, 300 MHz) 6 0.85 (t, 3 H, J: 6.9 Hz), 1.30-1.51 (m, 10 H), 2.32 (s, 3 H),
2.67 (t, 2 H, J= 6.6 Hz), 4.70 (s, 4 H), 7.17 (s, 2 H); 13C NMR (CDC13, 75 MHz) 6 14.08,
20.96, 22.65, 27.97, 29.94 31.63, 31.79, 63.18, 128.83, 135.85, 136.09, 138.84; IR
(CH2C12) 3350, 3260, 2953, 2920, 2870, 1469, 1265 cm]. Anal calcd for C15H2402: C,
76.23; H, 10.24. Found: C, 75.89; H, 10.43.
(6-Hydraxymethyl—4-methylbiphenyl—Z-yl)methanol (R4 = Ph, R2 = Me) 244C :

Following the above procedure, the aldehyde 242B (3.68 g, 16.42 mmol) afforded upon

164

workup 244C as a white solid in 95 % yield (3.55 g, 15.6 mmol). Mp = 131-133 °C.
Spectral data for 244C: Rf = 0.16 (hexanes/ethyl acetate 3/1); 1H NMR (CDC13, 300
MHz) 6 2.39 (s, 3 H), 3.85 (t, 2 H, J = 5.2 Hz), 4.26 (d, 4 H, J= 5.4 Hz), 7.17 (d, 2 H, J=
7.0 Hz), 7.348 (s, 2 H), 7.352 (t, 1 H, J = 7.5 Hz), 7.41 (t, 2 H, J = 7.5 Hz); 13C NMR
(CDC13, 75 MHz) 15 20.84, 61.95, 126.34, 127.11, 128.33, 129.67, 135.78, 136.65,
138.89, 139.70; IR (CH2C12) 3424, 2926, 1645, 1221 cm"; mass spectrum m/z (% rel.
intensity) 228 M+ (100), 210 (97), 192 (93), 181 (97), 165 (97), HRMS calcd for
C15H16O2 m/z 228.1150, measd 228.1154. Anal calcd for C15H1602: C, 78.92; H, 7.06.
Found: C, 78.58; H, 6.99.

3,5-bis-hydroxymethyl—4-methaxybiphenyl (R4 = OMe, R2 = Ph) 244D: 2,6-bis-
(hydroxymethyl)-4-phenylpheno1 was prepared in 90 % yield by formylation of 4-phenyl

‘26 The phenol was then converted to 244D following

phenol under basic conditions.
Cram’s procedure for the methylation of 2,6—bis-(hydroxymethyl)-p-cresol in 87%
yield.123 R. = 0.21 (hexanes/ ethyl acetate = 1/1). Mp = 96-98 °C. Spectral data for 2441):
1H NMR (CDC13, 500 MHz) 6 2.07 (s, 2 H), 3.87 (s, 3 H), 4.78 (s, 4 H), 7.32 (t, l H, J=
7.5 Hz), 7.41 (t, 2 H, J = 8.0 Hz), 7.546 (s, 2 H), 7.55 (d, 2 H, J = 8.0 Hz); 13C NMR

(CDC13, 75 MHz) 61.10, 61.25, 126.99, 127.27, 127.57, 128.76, 134.25, 137.79, 140.29,

155.59.
R2 R2
PBT3 O
O —>
HO OH CHC13 Br Br
R4 R4
244 238

Conversion of the bis-Hydroxymethylarenes 244 to the bis-Bromomethylarenes 238.

165

1,3- Bis-bromomethyl—Z—hexyl—5—methylbenzene '(R4 = C611”, R2 = Me) 2383: The
alcohol 244B (0.64 g, 2.71 mmol) was dissolved in 20 mL of chloroform and phosphorus
tribromide (1M in dichloromethane, 5.6 mL) was added dropwise and the mixture was
stirred at ambient temperature until complete conversion to the product had occurred. The
reaction was quenched by the addition of saturated aqueous sodium bicarbonate (50 mL)
and the organic layer washed once with water (100 mL). Concentration of the solvent
under vacuum gave the desired product as yellow oil. Purification by silica gel
chromatography (10 % dichloromethane/hexanes) gave the bromide 238B as a white
solid in 59 % yield (0.52 g, 1.59 mmol). Mp = 47-49 °C. Rf = 0.44
(hexanes/dichloromethane = 9/1). Spectral data for 238B: 1H NMR (CDC13, 300 MHz) 8
0.92 (t, 3 H, J = 7.1 Hz), 1.33 (m, 4 H), 1.52 (m, 2 H), 1.64 (m, 2 H), 2.28 (s, 3 H), 2.80
(t, 2 H, J = 8.1 Hz), 4.50 (s, 4 H), 7.13 (s, 2 H); 13C NMR (CDC13, 75 MHz) 6 14.07,
20.62, 22.61, 28.45, 29.89, 31.33, 31.55, 31.69, 132.31, 136.31, 136.39, 137.91; IR
(CH2C12) 3049, 2955, 2926, 2860, 1479, 1462, 1265, 1209 cm'l; mass spectrum m/z (%
rel. intensity) 360.01 M+ (793a 79Br, 51), 362.01 M+ (793a 813r, 100), 364.01 M+ (S'Br,
8‘Br, 50), 281 (15), 211 (100), 132 (43), 91 (13), HRMS calcd for C15H22Br2 m/z
360.0088, measd 360.0089. Anal calcd for C15H22Br2: C, 49.75; H, 6.12. Found: C,
49.86; H, 6.44.

2, 6-bis-bromamethyl—4-methylbiphenyl (R4 = Ph, R2 = Me) 238C: Following the
procedure mentioned above for synthesis of 240A, the alcohol 244C (3.55 g, 15.57
mmol) was transformed into 238C as a white solid in 86 % yield (4.74 g, 13.39 mmol).
Mp = 101-103 °C. Rf = 0.34 (hexanes/dichloromethane = 9/1) Spectral data for 238C: 1H

NMR (CDC13, 300 MHz) 6 2.38 (s, 3H), 4.16 (s, 4H), 7.27 (s, 2H), 7.32-7.42 (m, SH);

166

13C NMR (CDC13, 75 MHz) 8 20.96, 31.96, 127.87, 128.27, 129.49, 131.32, 136.54,
136.56, 138.27, 139.02; IR (CH2C12) 3053, 2982, 1614, 1458, 1442, 1285, 1213 cm";
mass spectrum m/z (% rel intensity) 351.94 M+ (79Br, 79Br, 6.6), 353.94 M+ (79Br,
8113r,13), 355.94 M+ (81Br, 8'3r, 6.5), 193 (100), 178 (35), 83 (60), HRMS calcd for
C15H14Br2 m/z 351.9462, measd 351.9441. Anal calcd for CisHlaBr2: C, 50.88; H, 3.99.
Found: C, 50.98; H, 3.90.

3,5-Bis-bramamethyl-4-methaxybiphenyl (R4 = OMe, R2 = Ph) 2380: The
procedure above for 238B was followed and the alcohol 244D (3.66 g, 15 mmol) gave
4.38 g (11.85 mmol, 79 %) Of 238D as white solid. Mp = 100-103 °C. Spectral data for
238D: 'H NMR (CDCl,, 300 MHz) 6 3.93 (s, 3 H), 4.48 (s, 4 H), 7.23 (t, 1 H, J = 6.9 Hz),
7.31 (t, 2 H, J = 7.2 Hz), 7.42 (d, 2 H, J = 7.2 Hz), 7.46 (s, 2 H); ”C NMR (CDCl,, 75
MHz) 6 27.56, 62.36, 126.94, 127.62, 128.86, 130.84, 132.19, 138.19, 139.45, 155.91;
mass spectrum m/z (% rel intensity) 372 M” (S'Br, 8'Br, 50), 370 M+ (79Br, 81Br, 100), 368
M+ (79Br, 79.Br, 51), 291 (93), 289 (094), 182 (45), 181 (100).

Preparation of the Silyl Substituted Diynes 239.

 

 

MethadA
RI R1
TMS = MgBr TMS / TMS
B Br > \ /
r CuBr (cat) \
R2 THF, reflux R2
238 239

Trimethylsilylethynylmagnesium bromide127 (8 eq) was generated in situ by the
addition of ethylmagnesium bromide (3 M solution in THF, 8 eq) to
ethynyltrimethylsilane (8 eq) in tetrahydrofuran (c = 1.6-2.4 M) at 0 °C followed by

stirring at this temperature for 30 min. The resulting slurry was stirred at room

167

temperature over 0.5 h. Copper (1) bromide (15 mol %) was added and stirred for another
0.5 h. Benzyl halides 238 (1 mmol) were subsequently added and then the reaction
mixture was refluxed until disappearance of the starting material was indicated by thin-
. layer chromatography or GC / MS. Saturated ammonium chloride (40 mL) was then
added to quench the reaction and the organic layer was separated and extracted with ether
(2 x 50 mL). The combined organic layer was washed once with water (equal volume)
and then dried over anhydrous magnesium sulfate. The resultant organic layer was
filtered through a silica gel pad and stripped of solvent under reduced pressure to give the
crude compound 239. For consistency in yields, it is highly important that the starting

benzyl halides are purified and the reagents are either freshly prepared or titrated to verify

 

concentration.
Method B

R2 68 mol %

(ms—==——)L—ln
Br Br 3 t
2 mol % Pd(dPPflC12
R4 THF, reflux
238

 

127 (19.2 mmol) was prepared by addition of n-

Trimethylsilylethynyllithium
butyllithium (12 mL, 19.2 mmol) to trimethylsilylacetylene (3 mL, 21.22 mmol) in
tetrahydrofuran (20 mL) in a 100 mL flame-dried round bottom flask under argon at —78
°C. The resulting solution was allowed to warm to room temperature for 10 to 15 min.
Indium (III) chloride (1.42 g, 6.4 mmol) was added to a three-necked 100 mL round
bottom flask and dried under vacuum with a heat gun. Positive argon pressure was then

established and THF (30 mL) was added. The resulting solution was cooled to —78 °C

and trimethylsilylethynyllithium was added drop-wise via syringe. The mixture was

168

subsequently warmed to room temperature. The bis-benzyl halide 238 (8 mmol) and
Pd(dppi)Cl2 (131 mg, 0.16 mmol) were introduced into a flame-dried three-necked 200
mL round-bottomed flask and THF (32 mL) was added. The solution of trialkynylindium
reagent was added to this flask under refluxing conditions and the reaction was continued
until the disappearance of the starting material was determined as monitored by GC/mass
spec. The reaction was then quenched by the addition of 50 mL of methanol and the
solvent was removed under vacuum. Ether (200 mL) was added and the organic layer
was washed with 10 % hydrochloric acid (2 x 100 mL), saturated sodium bicarbonate (2
x 100 mL) and saturated sodium chloride solution (2 x 100 mL). The resulting solution
was filtered through a pad of silica gel to remove any inorganic impurities and upon
concentration under reduced pressure the crude product was Obtained. Indium trichloride
is extremely moisture sensitive and therefore needs to be handled carefully in order to
obtain the best results.
2-Methaxy-5-methyl—1,3-bis-[3-(trimethylsilanyl)prop-2-ynyl]benzene (R4 =
OCH 3, R2 = CH3 ) 239A: Following method B, the bromide 238A (2.46 g, 8 mmol)
gave upon purification by silica gel chromatography (20 % dichloromethane/hexanes)
diyne 239A as an yellow oil in 80 % yield (2.19 g, 6.4 mmol). Rf = 0.36
(hexanes/dichloromethane = 4/1). Spectral data for 239A: 1H NMR (CDC13, 300 MHz) 6
0.22 (s, 18 H), 2.37 (s, 3 H), 3.65 (s, 4 H), 3.79 (s, 3 H), 7.23 (s, 2 H); 13C NMR (CDC13,
75 MHz) 6 0.04, 20.47, 20.91, 61.02, 86.49, 104.64, 128.98, 129.16, 133.82, 153.05; IR
(neat) 2961, 2901, 2832, 2178, 1482, 1250 cm"; mass spectrum m/z (% rel intensity) 342
M+ (100), 327 (80), 239 (50), 156 (35), 73 (90), HRMS calcd for C20H3OOSi2 m/z

342.1835, measd 342.1835.

169

2- Hexyl-5-methyl—1,3—bis-[3-(trimethylsilanyl)prap—2-ynyl]benzene (R4 = C6H13,
R2 = CH3 ) 239B : Following method A, the bromide 238B (2.79 g, 7.5 mmol) gave
upon purification by silica gel chromatography with 15 % dichloromethane/hexanes the
diyne 239B as a yellow oil in 66 % yield (1.95 g, 4.95 mmol). The average yield for three
runs using varied amounts of the benzyl bromide was found to be 73 %. Rf
(dichloromethane/hexanes = 15/85) = 0.49. Spectral data for 239B: lH NMR(CDC13, 300
MHz) 5 0.19 (s, 18 H), 0.95 (t, 3 H, J = 6.5 Hz), 1.36-1.53 (m, 8 H), 2.35 (s, 3 H), 2.64 (t,
2 H, J = 8.0 Hz), 3.62 (s, 4 H), 7.23 (s, 2 H); 13C NMR (CDC13, 75 MHz) 6 0.04, 14.10,
20.96, 22.72, 24.04, 28.55, 29.73, 29.97, 31.61, 86.79, 104.85, 128.56, 134.37, 135.45,
135.52; IR (neat) 2989, 2176, 1614, 1468, 1410, 1250 cm"; HRMS calcd for C25H40Si2
m/z 396.2669, measd 396.2664. Anal calcd for C25H40Si2: C, 75.68; H, 10.16. Found: C,
75.76; H, 9.87.

4—Methyl—2,6—bis-[(3-(trimethylsilanyl)prap-2-ynyl]biphenyl (R4 = Ph, R2 = Me)
239C : Following method A, the bromide 238C (3.79 g, 10.78 mmol) gave the diyne
239C in 71 % yield (2.9 g, 7.66 mmol) as a yellow oil after purification by silica gel
chromatography (15 % dichloromethane/hexanes). Following method B, an 81 % yield
of 239C was obtained. The resulting Oil if left in the freezer at -20°C became a light
yellow solid. Mp: 55-58°C .Rf (hexanes/dichloromethane 85/15) = 0.45. Spectral data
for 239C: 1H NMR (CDC13, 300 MHz) 6 0.14 (s, 18 H), 2.41 (s, 3 H), 3.23 (s, 4 H), 7.12
(d, 2 H, J = 7.3 Hz), 7.3-7.4 (m, 5 H); 13C NMR (CDC13, 75 MHz) 6 0.14, 21.32, 24.90,
86.69, 104.94, 127.22, 127.59, 128.54, 129.39, 134.42, 137.44, 137.59, 138.57; IR (neat)

2959, 2899, 2176, 1466, 1410, 1250 cm]; mass spectrum m/z (% rel intensity) 388 M+

170

(8), 315 (18), 285 (15), 179 (17), 83 (100), calcd for C15H22Si2 m/z 388.2043, measd
388.2044.

4—Methoxy-3,5-bis—[3-(trimethylsilanyl)prop-2—ynyl]biphenyl (R4 = 0CH3, R2 =
Ph) 239D: Following method B, bromide 238D (2.85 g, 7.7 mmol) gave upon
purification in 20 % dichloromethane/hexanes 239D in 77 % yield (2.39 g, 5.93 mmol) as
a white solid. Mp = 72-74 °C. Rf = 0.31 (hexanes/dichloromethane 4/1). Spectral data for
239D: 1H NMR (CDC13, 300 MHz) 6 0.08 (s, 18 H), 3.59 (s, 4 H), 3.69 (s, 3 H), 7.21 (t, l
H, J = 7.2 Hz), 7.32 (t, 2 H, J = 7.5 Hz), 7.49 (d, 2 H, J = 7.2 Hz), 7.57 (s, 2 H); 13C
NMR (CDC13, 75 MHz) 6 0.05, 20.75, 60.89, 87.12, 104.34, 126.85, 127.08, 127.13,
128.73, 129.87, 137.19, 140.64, 154.86; IR (neat) 3130, 3100, 2957, 2899, 2178, 1690,

1590, 1456, 1404, 1248 cm". Anal calcd for C25H32OSi2: C, 74.20; H, 7.97. Found: C,

 

74.51; H, 7.89.
R2
TMS TMS AgNO3/KCN
\ / t
EtOH/HZO
R4
239

 

Preparation of the Diynes 228 by Desilylation of 239.

A solution of the diyne 239 (1 mmol) in ethanol (4.5 mL) was added to a 12 mL
aqueous ethanol solution (ethanol / water = 2.3 / 1 v/v) Of silver nitrate (3 eq) whereupon
a milky white precipitate appeared immediately upon addition indicating the presence of
silver acetylide. The resulting slurry was stirred shielded from light at ambient
temperature for 5 h or overnight. A solution of potassium cyanide (8 eq) in 1 mL of water
was then added. The mixture was stirred for another hour and then the solution was

diluted with 100 mL ether. The organic layer was washed with water (4 x 25 mL), brine

171

(4 x 25 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum.
Purification was either achieved by column chromatography on silica gel or by
crystallization.

2-Methaxy-5—methyl—1,3-dtprap-2-ynylbenzene (R4 = OMe, R2= Me) 228A: The
diyne 239A (2.28 g, 6.66 mmol) upon desilylation following the general procedure and
purification by crystallization from hexanes at 0 °C gave 228A as a white solid in 91 %
yield (1.2 g, 6.06 mmol). Mp = 40-42 °C. Rf = 0.25 (20 % CH2Cl2/hexanes). Spectral
data for 228A: 1H NMR (CDC13, 300 MHz) 6 2.21 (t, 2 H, J: 2.7 Hz), 2.37 (s, 3 H), 3.63
(d, 4 H, J = 2.7 Hz), 3.81 (s, 3 H), 7.26 (s, 2 H); 13C NMR (CDC13, 75 MHz) 6 19.05,
20.79, 61.03, 70.06, 82.16, 129.06, 134.17, 152.99 (1 aryl carbon not observed); IR
(CH2C12) 3294, 2943, 2830, 2150, 1653, 1479, 1223 cm]. Anal calcd for C14H140: C,
84.81; H, 7.12. Found: C, 84.84; H, 6.94.

2-Hexyl-5-methyl-1,3-diprop-2-ynylbenzene (R4 = Cd]; 3, R2= Me) 2288: The
diyne 239B (1.81 g, 4.55 mmol) upon desilylation and purification by silica gel
chromatography (hexanes) in gave 228B in 69 % yield (0.79 g, 3.14 mmol) as colorless
Oil. The average yield for three runs with varying amounts of 239B in this case was
found to be 73 %. Rf (hexanes) = 0.32. Spectral data for 228B: 1H NMR (CDC13, 300
MHz) 6 0.95 (t, 3 H, J = 6.6 Hz), 1.37-1.49 (m, 8 H), 2.21-2.24 (m, 2 H), 2.37 (s, 3 H),
2.67 (t, 2 H, J = 6.6 Hz), 3.59 (s, 4 H), 7.26 (s, 2 H); 13C NMR (CDC13, 75 MHz) 6 14.06,
20.92, 22.54, 22.62, 28.54, 29.89, 29.96, 31.58, 70.53, 82.36, 128.56, 134.24, 135.29,
135.82; IR (neat) 3304, 2926, 2856, 2120, 1684, 1466 cm'l; mass spectrum m/z (% rel

intensity) 252 M+ (70), 181 (100), 165 (100), 141 (75), 128 (65), 115 (50), calcd for

172

C19H24 m/z 252.1878, measd 252.1880. Anal calcd for C19H24: C, 90.42; H, 9.58. Found:
C, 90.03; H, 9.82.

4-Methyl—2,6—diprap-2-ynylbiphenyl (R4 = Ph, R2= Me) 228C: The diyne 239C
(1.03 g, 2.66 mmol) upon desilylation and purification by silica gel chromatography (10
% dichloromethane in hexanes) afforded 228C as a white solid in 77 % yield (0.50 g,
2.05 mmol). [Note: This compound is light sensitive; the white solid turns orange over a
few weeks]. Mp = 36-39 °C. Rf = 0.28 (dichloromethane/hexanes = 1/9). Spectral data
for 228C: 1H NMR (CDC13, 300 MHz) 6 2.16 (s, 2 H), 2.48 (s, 3 H), 3.26 (s, 4 H), 7.19
(d, 2 H, J = 7.8 Hz), 7.43-7.48 (m, 5 H); 13C NMR (CDC13, 75 MHz) 6 21.26, 23.34,
70.39, 82.45, 127.39, 127.59, 128.71, 129.37, 134.33, 137.45, 137.77, 138.60; IR
(CH2C12) 3300, 2918, 2849, 2120, 1736, 1464, 1246 cm]; mass spectrum m/z (% rel
intensity) 244 M+ (80), 229 (100), 205 (55), 189 (40), 101 (30), calcd for C19H16 m/z
244.1252, measd 244.1256.

4-Methaxy-3,5—prop-2-ynylbiphenyl (R4 = OMe, R2 = Ph) 2280: The diyne
239D (2.69 g, 6.66 mmol) upon and purification by crystallization from hexanes at 0 °C
gave 228D as a white solid in 90 % yield (1.55 g, 5.94 mmol). Mp = 64-67 °C. Rf = 0.21
(20 % CH2C12/ hexanes). Spectral data for 228D: 1H NMR (CDC13, 300 MHz) 5 2.17 (t,
2 H, J= 2.7 Hz), 3.67 (d, 4 H, J: 2.7 Hz), 3.82 (s, 3 H), 7.32 (t, 1 H, J = 7.4 Hz), 7.40-
7.45 (t, 2 H, J = 7.4 Hz), 7.58 (d, 2 H, J= 7.4 Hz), 7.64 (s, 2 H); l3C NMR (CDC13, 75
MHz) 6 19.35, 61.12, 70.51, 81.88, 127.09, 127.32, 128.72, 129.77, 137.66, 140.54,
154.76, 156.99; IR (CH2C12) 3294, 2941, 2831, 2120, 1686, 1473, 1240 cm'l. Anal calcd

for C19H16OI C, 87.66; H, 6.19. Found: C, 87.27; H, 6.36.

173

R2 R2

CpZZrHCl : [I I I
NIS,THF

R4 R4
228 245

 

Synthesis of the bis-(E)-Vinyl Iodides 245 by Hydrozirconation.

Schwartz’s reagent was prepared following a literature procedure:105 a solution of
bis-cyclopentadienylzirconium dichloride (4 eq) in tetrahydrofuran (c = 0.12-0.15 M) was
treated with Super Hydride (4 eq) and subsequently stirred for 1 h shielded from light.
To this freshly prepared Schwartz reagent was added the diyne (1 mmol) and the mixture
was stirred at room temperature for 1 h. N-Iodosuccinimide (4 eq) was subsequently
added and stirring continued for 4 h. The reaction was quenched by pouring it into
saturated sodium bicarbonate solution (40 mL). A solution of 10 % ethyl acetate/hexanes
(100 mL) was added and the organic layer separated and washed with brine (40 mL),
dried over anhydrous magnesium sulfate. After filtration through a bed of Celite atop a
short plug of silica gel with 10 % ethyl acetate/hexanes the solvents were removed to
give the crude compound as a oil. Purification by column chromatography on silica gel
afforded the desired product as a clear oily liquid.

I,3-Bis-(3-iadaallyl)-2-methaxy-5—methylbenzene (R4=0Me, R2=Me) 245A:
The diyne 228A (0.297 g, 1.5 mmol) was subjected to hydrozirconation/iodination
following the general procedure and vinyl iodide 245A was obtained by silica gel
chromatography (20 % dichloromethane/hexanes) in 86 % yield as colorless oil (0.59 g,
1.29 mmol). Rf = 0.43 (hexanes/dichloromethane 4/1). Spectral data for 245A: 1H NMR
(CDC13, 300 MHz) 6 2.26 (s, 3H), 3.35 (d, 4H, J = 6.9 Hz), 3.65 (s, 3 H), 6.06 (dt, 2 H, J

= 14.0, 1.5 Hz), 6.62-6.67 (m, 2 H), 6.88 (s, 2 H); 13C NMR (CDC13, 75 MHz) 6 20.76,

174

36.16, 61.48, 76.14, 129.53, 131.02, 133.94, 144.49, 153.88; IR (neat) 3045, 2931, 2828,
1604, 1478, 1232, 1209 cm]; mass spectrum m/z (% rel intensity) 454 M (85), 307 (36),
200 (30), 154 (100), calcd for C14H1612O m/z 453.9291, measd 453.9291.
2-Hexyl-1,3-bis-(3-iadaallyl)-5-methylbenzene(R4=C6H23,R2=Me) 2458: The
product was purified by silica gel chromatography (hexanes) and obtained in 77 % yield
as a colorless oil. Rf (hexanes) = 0.24. Spectral data for 245B: 1H NMR (CDC13, 300
MHz) 6 0.92-0.96 (t, 3 H, J = 6.4 Hz), 1.34-1.42 (m, 8 H), 2.31 (s, 3 H), 2.53 (t, 2 H, J =
7.3 Hz), 3.38 (d, 4 H, J = 6.6 Hz), 6.02 (d, 2 H, J = 14.5 Hz), 6.63-6.78 (m, 2 H), 6.87 (s,
2 H); 13C NMR (CDC13, 75 MHz) 6 14.04, 20.86, 22.68, 28.77, 29.92, 30.94, 31.68,
39.55, 75.92, 129.25, 135.68, 136.18, 136.31, 145.08; IR (neat) 3045, 2955, 2924, 2870,
1610, 1466, 1202 cm'l; mass spectrum m/z (% rel intensity) 508 M“ (100), 381 (8), 310
(8), 297 (5), 254 (55), 183 (40), 155 (20), 143 (50), 128 (30).
2,6-Bis-(3—i0daallyl)-4-methylbiphenyl (R4=Ph, R2=Me) 245C: The diyne 228C
(0.366 g, 1.5 mmol) was subjected to the general procedure and upon purification by
silica gel chromatography in 15 % dichloromethane/hexanes gave the vinyl iodide 245C
in 73 % yield (0.554 g, 1.1 mmol) as a colorless oil. Rf (hexanes/dichloromethane 85/15)
= 0.4. Spectral data for 245C: 1H NMR (CDC13, 500 MHz) 6 2.36 (s, 3 H), 3.02 (d, 4 H, J
= 6.9 Hz), 5.68 (d, 2 H, J = 13.5 Hz), 6.36-6.45 (m, 2 H), 6.95 (s, 2 H), 7.05 (d, 2 H, J=
6.5 Hz), 7.33 (t, 1 H, J: 7.0 Hz), 7.38 (t, 2 H, J= 6.5 Hz); 13C NMR (CDC13, 75 MHz) 6
21.12, 40.26, 75.96, 127.22, 128.26, 128.36, 129.61, 136.46, 137.52, 138.64, 139.06,
144.59; IR (neat) 3053, 3020, 2918, 2853, 1611, 1466, 1441, 1209 cm]; mass spectrum
m/z (% rel intensity) 500 M+ (30), 374 (100), 247 (65), 206 (80), 85 (55), calcd for

C19H1312 m/z 499.9498, measd 499.9499.

175

3,5-Bis-(3-iadaallyl)-4—methaxybiphenyl (R4 = OMe, R2 = Ph) 2450: Following
the general procedure, diyne 228D (0.686 g, 2.64 mmol) gave vinyl iodide 245D in 78
% yield (1.06 g, 2.06 mmol) upon purification by silica gel chromatography 20 %
dichloromethane/hexanes as white solid. Mp = 69-71 ° C. Rf = 0.33
(hexanes/dichloromethane 4/1). Spectral data for 245D: 1H NMR (CDC13, 300 MHz)
3.32 (d, 4 H, J = 6.9 Hz), 3.59 (s, 3 H), 5.98 (d, 2 H, J = 14.5 Hz), 6.52-6.59 (m, 2 H),
7.11 (s, 2 H), 7.19 (t, 1 H, J= 6.9 Hz), 7.28 (t, 2 H, J= 7.5 Hz), 7.37 (d, 2 H, J: 7.2 Hz);
13C NMR (CDC13, 125 MHz) 5 36.46, 61.59, 76.35, 127.04, 127.26, 127.81, 128.78,
131.82, 137.71, 140.49, 144.29, 155.79; IR (CH2C12) 3053, 2943, 2828, 1603, 1472, 1242
cm"; mass spectrum m/z (% rel intensity) 516 M+ (100), 404 (8), 390 (5), 373 (20), 262

(35), 222 (100), 207 (30). Anal. Calcd for C19H1312O: C, 44.21; H, 3.52. Found: C,

 

44.51; H, 3.79.
R2 OMe R1 OMe
1 1
I | t-BuLi(4eq),-78°C _ (0050 I I Cr(CO)s
Cr(CO)6 (4 eq)
R4 Me3OBF4 (6.5 eq) R3
245 229
+
0M6 R1
(OC),Cr I I
R3
229-1

Preparation of the Bis-Carbene complexes 229.

To a solution of vinyl iodide 245 (1 mmol) in tetrahydrofuran (c = 0.05 M) at —78
°C was added t -Butyllithium (4 eq, 1.7 M in pentane) and the reaction mixture was
stirred at —78 °C for 30 min. Chromium hexacarbonyl (4 eq) was dissolved in 45 mL of

tetrahydrofuran and then transferred via cannula to the organolithium solution under

176

argon at —78 °C. The resulting deep red solution was warmed to room temperature and
stirred for 3 h. The solvent was evaporated under vacuum and water/ dichloromethane
(1:1, 50 mL) was added and then trimethyl oxonium tetrafluoroborate (6.5 eq) was added
and the mixture stirred for 30 min. The organic layer (150 mL) was washed with water
(2 x 50 mL) and dried over anhydrous magnesium sulfate. After filtration the solvent
was removed and crude product was purified by silica gel chromatography to give
carbene complex as a red oil. In each case a small amount of a less polar product is
formed that is tentatively identified by 1H NMR as the mono-carbene complex 229-1 (5-
10 %).

1,3-bis-[2 ’-prapenyl(methaxy)methylene pentacarbonylchromium (0)]-2-methaxy-
5-methylbenzene (R 3 = OMe , R1 = Me) 229A: The vinyl iodide 245A (0.454 g, 1.05
mmol) following the general procedure gave upon purification by silica gel
chromatography in 20 % dichloromethane/hexanes 229A in 36 % yield (0.253 g, 0.378
mmol) as a reddish oil. R2= 0.34 (hexanes/dichloromethane 4/1). Spectral data for 229A:
lH NMR(CDC13, 300 MHz) 6 2.23 (s, 3 H), 3.47 (d, 4 H, J = 6.0 Hz), 3.67 (s, 3 H), 4.72
(s, 6 H), 6.33 (dt, 2 H, J = 14.0, 6.5 Hz), 6.85 (s, 2 H), 7.32 (d, 2 H, J = 14.5 Hz); 13C
NMR (CDCl;, 75 MHz) 8 20.60, 32.59, 61.59, 66.47, 130.22, 130.74, 133.26, 134.39,
144.77, 154.25, 216.61, 223.92, 335.96; IR (CH2C12) 2959, 2255, 2088, 1934, 1603,
1479, 1452, 1228 cm]; mass spectrum (FAB) m/z (% rel intensity) 670 M+ (1), 530 (8),

446 (7), 418 (8), 390 (14), HRMS calcd for C23H22Cr2013 m/z 669.9871, measd 669.9874.

1,3-bis-[2 ’-prapenyl(methaxy)methylene pentacarbonylchramium (0)]-2-hexyl-5-

methylbenzene (R3= C6HI3 , R, = Me) 2293: Following the general procedure

177

described above the vinyl iodide 245B (0.341 g, 0.67 mmol) gave the carbene complex
2298 in 44 % yield (0.213 g, 0.295 mmol) as a reddish oil after purification by silica gel
chromatography in hexanes. RI— (hexanes) = 0.30. Spectral data for 229B: 1H NMR
(CDC13, 500 MHz) 6 0.87 (t, 3 H, J = 7.0 Hz), 1.34 (m, 8 H), 2.23 (s, 3 H), 2.49 (t, 2 H, J
= 7.2 Hz), 3.44 (d, 4 H, J: 6.0 Hz), 4.75 (s, 6 H), 6.31 (dt, 2 H, J: 15.5, 6.5 Hz), 6.84 (s,
2 H), 7.23 (d, 2 H, J = 15.0 Hz); 13C NMR (CDCl;, 75 MHz) 6 14.02, 22.62, 28.86,
29.78, 31.21, 31.58, 35.96, 66.44, 129.87, 133.56, 136.07, 136.14, 136.59, 144.63,
216.59, 223.93, 336.02; IR (CH2C12) 2959, 2928, 2856, 2060, 1925, 1599, 1425, 1228
cm"; mass spectrum (FAB) m/z (% rel intensity) 724 M+ (3), 668 (1), 640 (15), 584(7),
500 (3), 472 (2), 444 (100), HRMS calcd for C33H32Cr2012 m/z 724.0704, measd
724.0707.

2,6-bis-[2'-prapenyl(methaxy)methylene pentacarbonylchramium (0)]-4-
methylbiphenyl (R 3 = Ph, R2 = Me) 229C: Following the above procedure, the vinyl
iodide 245C (0.334 g, 0.64 mmol) gave the carbene complex 229C in 47 % yield (0.21 g,
0.30 mmol) as a reddish oil. Rf (hexanes) = 0.24. Spectral data for 229C: 1H NMR
(CDC13, 500 MHz) 6 2.33 (s, 3 H), 3.15-3.17 (d, 4 H, J: 6.3 Hz), 4.69 (s, 6 H), 6.15 (dt,
2 H, J: 15.0, 7.0 Hz), 6.97 (s, 2 H), 7.05 (d, 2 H, J= 15.0 Hz), 7.09 (d, 2 H, J: 6.5 Hz),
7.33-7.38 (m, 3 H); 13C NMR (CDC13, 75 MHz) 6 20.93, 36.95, 55.36, 127.48, 128.50,
128.95, 129.46, 134.05, 136.27, 137.87, 138.92, 139.08, 144.45, 216.62, 223.92, 335.86;
IR (CH2C12) 3022, 2959, 2924, 2058, 1921, 1599, 1452, 1226 cm"; mass spectrum (FAB)
m/z (% rel intensity) 716 MI (60), 660 (2), 632 (3), 604 (30), 576 (8), 548 (4), 492 (20),

464 (25), 436 (100), HRMS calcd for C33H24Cr2012 m/z 716.0078, measd 716.0077.

178

3,5-bis-[2’-prapenyl(methaxy)methylene pentacarbonylchromium (0)]-4-
methaxybiphenyl (R3 = OMe , R2 = Ph) 229D: Following the general procedure as
described above the vinyl iodide 245D (0.67 g, 1.3 mmol) gave carbene complex 229D in
32 % yield (0.30 g, 0.42 mmol) as a reddish oil after purification by silica gel
chromatography in 20 % dichloromethane/hexanes. Rf = 0.23 (hexanes/dichloromethane
= 4/1). Spectral data for 229D: 1H NMR (CDC13, 500 MHz) 5 3.56 (d, 4 H, J = 7.0 Hz),
3.61 (s, 3 H), 4.66 (s, 6 H), 6.37 (dt, 2 H, J: 15.0, 7.0 Hz), 7.26 (s, 2 H), 7.31 (t, 1 H, J=
7.5 Hz), 7.36 (d, 2 H, J = 15.0 Hz), 7.39 (t, 2 H, J = 7.5 Hz), 7.48 (d, 2 H, J = 7.5 Hz);
13C NMR (CDC13, 75 MHz) 5 32.86, 61.64, 66.49, 126.99, 127.31, 128.38, 128.75,
131.56, 132.98, 138.03, 140.21, 144.77, 156.01, 216.61, 223.89, 336.02; IR (CH2C12)
2959, 2926, 2060, 1921, 1603, 1473, 1425, 1233 cm’l; mass spectrum (FAB) m/z (% rel
intensity) 732 M+ (8), 648 (25), 592 (l), 460 (6), 452 (2), HRMS calcd for C33H24Cr2013

732.0027, measd 732.0038.

OMe R'

(OC)5CI' I

 

246/247

Calixarene Formation by the Triple Annulation of Bis-Carbene Complex 229 with

diyne 228.

179

The bis-carbene complex 229 and the diyne 228 (1 :1 molar ratio) were dissolved in 1,2-
dichloroethane (2.5 mM) in a flame dried 100 mL or 250 mL Schlenk flask under Argon.
The solution was deoxygenated by the freeze pump thaw method in three cycles (-196 to
25 °C) and then backfilled with argon at ambient temperature. The flask was sealed with
a threaded high-vacuum Teflon stopcock and heated to 100 °C for 20-40 min during
which time the deep red solution turned yellow. The yellow solution was stirred
overnight exposed to air to facilitate demetalation Of the arenechromium tricarbonyl
complex. The solvent was removed under vacuum and the residue dissolved in ethyl
acetate (50 mL) and then filtered through a short pad Of silica gel. Further washing of the
SiO2 pad with ethyl acetate and evaporation Of the solvent gave the crude calixarene

which was purified by flash chromatography on silica gel.

 

5,17—dimethyl-11,23,26,28-dimethaxy-25,27-dihydraxycalix(4)arene 246A: The bis-
carbene complex 229A (0.188 g, 0.28 mmol) and diyne 228A (0.055 g, 0.28 mmol) were
dissolved in 112 mL of 1,2-dichloroethane and subjected to the reaction conditions
described above which gave the calixarene 246A in 36 % yield (0.054 g, 0.101 mmol) as
a white solid and as a single conformer afier purification by silica gel chromatography

(25 % ethyl acetate/hexanes). This compound was crystallized from acetonitrile and

180

subjected to single crystal X-ray diffraction analyses, which revealed it to be the cone
conformer of 246A. Mp = > 298 °C with decomposition. R2 = 0.32 (hexanes/ ethyl
acetate = 3/1). Spectral data for 246A: 1H NMR(CDC13, 300 MHz) 6 2.03 (s, 6 H), 3.27
(d, 4 H, J= 13.2 Hz), 3.74 (s, 6 H), 3.93 (s, 6 H), 4.27 (d, 4 H, J: 12.9 Hz), 6.61 (s, 4 H),
6.72 (s, 4 H), 7.59 (s, 2 H, OH); 13C NMR (CDC13, 75 MHz) 5 20.86, 31.53, 55.78,
63.49, 113.72, 129.12, 129.69, 132.74, 134.32, 146.91, 151.30, 152.19; IR (CH2C12)
3297br, 3055w, 2988, 2937, 2835, 1600, 1481, 1433, 1285, 1228, 1124, 1055, 1009 cm];
HRMS calcd for C34H3606 m/z 540.2512, measd 540.2512. Anal calcd for C34H3606: C,

75.53; H, 6.71. Found: C, 75.62; H, 6.60.

 

5,1 7-dimethyl—1I,23-dimethaxy-25,27-dihydraxy-26,28-dihexylcalix(4)arene 2463: A
solution of the bis-carbene complex 229B (0.221 g, 0.306 mmol) and diyne 228B (0.082
g, 0.32 mmol) in 120 mL of 1,2-dichloroethane was subjected to the reaction conditions
described above and the resulting calixarene 2468 was purified by silica gel
chromatography (5 % ethyl acetate/hexanes) to give a 22 % yield (0.044 g, 0.067 mmol)
of 246B as white solid and as a single conformation, whose structure was assigned as the
cone based on Mendoza rule.29 R2 = 0.39 (hexanes / ethyl acetate = 19/ 1) Mp = 158-160

°C. Spectral data for 2468: 'H NMR (CDC13, 500 MHz) d 0.82 (t, 6 H, J = 7.3 Hz),

181

1.15-1.23 (m, 16 H), 2.21 (8,6 H), 2.52 (t, 4 H, J = 7.5 Hz), 3.62 (d, 4 H, J = 15.0 Hz),
3.81(s, 6 H), 3.91(s, 2 H), 4.05 (d, 4 H, J = 15.0 Hz), 6.66 (s, 4 H), 6.96 (s, 4 H); 13C
NMR(CDC13, 75 MHz) 8 14.04, 20.89, 22.59, 27.73, 29.29, 31.67, 31.81, 36.86, 55.69,
113.86, 128.53, 130.32, 135.57, 137.87, 138.63,147.49, 152.66; IR(CH2C12) 3499,2924,

2855, 1606, 1466, 1377, 1246, 1147, 1059 cm".

 

Me 246C

5,] 7-dimethyl-1 1,23-dimeth0xy-25,2 7 -dihydr0xy-26, 28-diphenylcalix( 4)arene
246C: The bis-carbene complex 229C (0.121 g, 0.165 mmol) and diyne 228C (0.0403
g, 0.165 mmol) were subjected to the benzannulation reaction in 66 mL of 1,2-
dichloroethane following the general procedure and afforded a separable 1.0 : 1.7 mixture
of two conformers 246C-I and 246C-II that were separated by silica gel chromatography
(10 % ethyl acetate / hexanes) and obtained as solids in 13 % yield (0.0135 g, 0.021
mmol) and 22 % yield (0.023 g, 0.036 mmol) respectively. Each was crystallized from
dichloromethane/hexanes to give single crystals, which upon X-ray diffraction analysis,
revealed that the minor isomer 246C-I exists as a pinched cone conformation and the
major isomer 246C—II exists as a pinched 1,2-alternate conformation. The following

physical and spectral data were collected for the two conformers. Conformer 246C-I:

182

Rf = 0.37 (hexanes/ ethyl acetate = 9/1) Mp = 221-224 °C. 1H NMR (CDC13, 500 MHz)
6 2.01 (s, 6 H), 3.33 (d, 4 H, J = 14.5 Hz), 3.74 (d, 4 H, J= 15.5 Hz), 3.77 (s, 6 H), 4.24
(s, 2 H, OH), 6.51 (s, 4 H), 6.55 (s, 4 H), 6.98 (d, 2 H, J = 6.5 Hz), 7.35-7.38 (m, 4 H),
7.50-7.52 (m, 2 H), 8.14 (d, 2 H, J = 8.0 Hz); 13C NMR (CDC13, 75 MHz) 6 20.89, 36.12,
55.68, 114.44, 126.99, 128.14, 130.32, 131.73, 132.15, 136.89, 138.15, 138.87, 139.27,
146.78, 152.72; IR (CH2C12) 3472, 3056, 2988, 1635, 1610, 1479, 1412, 1265, 1145 cm];
mass spectrum m/z (% rel intensity) 632 M+ (100), 315 (30), 193 (10), 179 (15), 149 (20),
calcd for C44H4004 m/z 632.2927, measd 632.2924. Conformer 246C-II: Rf = 0.45
(hexanes/ ethyl acetate = 9/1) Mp = 260-262 °C. 1H NMR(CDC13, 500 MHz) 6 2.36 (s,
6 H), 3.53 (d, 4 H, J: 15.0 Hz), 3.61 (d, 4 H, J = 14.5 Hz), 3.66 (s, 6 H), 4.12 (s, 2 H,
OH), 6.26 (d, 2 H, J = 7.5 Hz), 6.35 (s, 4 H), 6.82 (t, 2 H, J = 7.8 Hz), 6.97 (d, 2 H, J =
7.5 Hz), 7.10 (s, 4 H), 7.16 (t, 2 H, J = 7.3 Hz), 7.25 (m, 2 H); 13C NMR (CDCl3, 75
MHz) 6 21.02, 36.95, 55.59, 113.76, 126.48, 127.15, 128.87, 129.24, 130.00, 130.78,
137.28, 138.83, 139.70, 147.34, 152.16; IR (CH2C12) 3509, 3052, 3005, 2918, 2837,

1590,1481,1441,1244, 1149,1057 cm".

 

5,1 7—diphenyl-11,23,26,28-tetramethoxy-25,27—dz'hydroxycalzbc(4)arene 246D: A

solution of the bis-carbene complex 229D (0.105 g, 0.145 mmol) and diyne 228D (0.038

183

g, 0.145 mmol) in 58 mL of 1,2-dichloroethane was subjected to the benzannulation
conditions described above and the calixarene 246D was isolated as a white solid in 41 %
yield (0.039 g, 0.059 mmol) as a single conformation after purification by silica gel
chromatography (25 % EtOAc/hexanes). Mp = 276-279 °C with decomposition. Rf: 0.25
(hexanes/ethylacetate = 3/1). The conformation of 246D was assigned as the cone
conformation based on the chemical shift of the phenol hydrogens (6 = 7.36) and again
by the Mendoza rule (carbon chemical shift of the methylene hydrogen 6 = 31.73). The
chemical shift of the phenol protons of 246D (cone conformer) is 6 = 7.59, whereas, the
chemical shift of the phenol protons of the partial cone of 247A is 6 = 5.75. The
chemical shifts of the phenol hydrogens of a 1,3-alternate conformer of a related
calixarene is 6 = 4.01.128 Spectral data for 246D: 1H NMR (CDC13, 500 MHz) 6 3.39 (d,
4 H, J: 13.0 Hz), 3.73 (s, 6 H), 4.01 (s, 6 H), 4.38 (d, 4 H, J: 13.0 Hz), 5.28 (s, 2 H),
6.66 (s, 4 H), 7.09 (s, 4 H), 7.16-7.21 (m, 3 H), 7.24-7.25 (m, 5 H), 7.36 (s, 2 H, OH); 13C
NMR (CDC13, 125 MHz) 6 31.73, 55.85, 63.54, 113.93, 126.86, 126.95, 127.85, 128.45,
129.09, 133.41, 137.96, 140.56, 146.9, 152.48, 153.25; IR (CH2C12) 3327, 2934, 2829,
1483, 1431, 1234, 1138, 1003, 906 cm"; mass spectrum m/z (% rel intensity) 664 (100),
633 (5), 602 (40), 332 (15), 301 (10); HRMS calcd for C44H4006 m/z 664.2825, measd

664.2825.

184

 

Me 247A

5, 1 7—dimethyl-1 1,23,26-trimethoxy-25,2 7—dihydroxy—28phenylcalix(4)arene 24 7A:
The bis-carbene complex 229A (0.124 g, 0.185 mmol) and diyne 228C (0.045 g, 0.185
mmol) in 74 mL of 1,2-dichloroethane were reacted according to the procedure described
above to give the calixarene 247A as a 38:1 mixture of inseparable conformers in 31 %
yield (0.034 g, 0.058 mmol) as a white solid after purification by silica gel
chromatography (25 % EtOAc/hexanes). Mp = 240-242 °C. R; (hexanes/ethylacetate
3/ 1) = 0.44. HPLC analysis showed the presence of a single peak at 10.19 min upon
gradient elution with a hexane/iso-propanol mixture of that was varied from 99.5/0.5 to
97/3 over 40 min at a flow rate of lmL/min using a silica gel column (R0086100C5).
The 1H NMR in CDC13 showed the presence of two conformers in a ratio of 3.821 as
measured by integration of the peaks at 6 = 2.02 and 2.45. The different ratio of isomers
in different solvents shows that these conformers do equilibrate rapidly but not on the
NMR time scale (Table 3). Also, variable temperature 1H NMR was recorded from 25 to
95 0C in DMSO-d6 but no coalescence of peaks was observed. EXSY experiments at 50
0C (t mix = 0.758, ni = 64, nt = 256, threefold forward linear prediction along F1
dimension) reveal that rotation about the phenyl group and interconversion between

conformers is rapid but not on the NMR time scale (See Figure 3.10, Pg.104). On the

185

basis of NOE experiments the major conformer was assigned as a partial cone and the
minor as the cone conformation. The mass spectrum of 247A shows a trace peak at m/z
= 1172 (0.13). This is attributed to a trace of a calix[8]arene that can not be detected by
1H NMR. The two conformers observed by 1H NMR are shown to be interconverting by
the solvent experiments and EXSY experiments shown below. A calix[8]arene would
not be expected to exists as conformers that could be observed on the 1H NMR time
scale. The following spectral data were obtained on a mixture of the two conformers.
Spectral data for 247A: ‘H NMR ((315013, 500 MHz) major; 6 2.25 (s, 3 H), 2.43 (s, 3
H), 3.25 (d, 2 H, J= 13.5 Hz) 3.46 (s, 6 H), 3.49 (d, 2 H, J= 13.0 Hz), 3.84 (s, 3 H), 3.88
(d, 2 H, J = 13 Hz overlapping with peak at 6 3.84), 4.11 (d, 2 H, J = 13.0 Hz), 4.78 (d, 1
H, J= 7.5 Hz), 5.51 (t, 1 H, J: 7.5 Hz), 5.64 (d, 2 H, J= 3.0 Hz), 5.75 (s, 2 H, OH), 6.48
(d, 2 H, J: 3.5 Hz), 6.67 (t, 1 H, J: 6.5 Hz), 6.83 (d, 1 H, J= 7.5 Hz), 6.90 (s, 2 H), 7.03
(t, 1 H, J= 7.5 Hz), 7.23 (s, 2 H); minor; 6 1.81 (s, 3 H), 2.02 (s, 3 H), 3.29 (d, 2 H, J:
13.5 Hz overlapping with peak at 6 3.26 of major isomer), 3.35 (d, 2 H, J = 14.0 Hz),
3.73 (d, 2 H, J: 14.0 Hz), 3.78 (s, 6 H), 3.86 (s, 3 H), 4.11(d, 2 H, J= 14.0 Hz), 5.01 (s,
2 H), 6.34 (s, 2 H), 6.51 (d, 2 H, J= 2.5 Hz), 6.58 (s,l2 H), 6.65 (d, 2 H, J= 3 Hz), 7.29-
7.33 (m, 1 H), 7.41 (t, 2 H, J= 7.5 Hz), 7.92 (d, 2 H, J= 8.0 Hz); 13C NMR (CDCl;, 125
MHz) major; 6 20.86, 21.15, 31.12, 40.10, 55.32, 63.16, 113.03, 113.99, 125.19, 125.97,
126.61, 126.90, 128.12, 129.61, 129.96, 130.06, 130.40, 133.54, 134.78, 137.51, 138.59,
139.34, 146.61, 152.56, minor; 6 25.60, 29.50, 32.04, 36.24, 55.69, 63.02, 113.78,
114.50, 127.52, 127.70, 127.83, 129.49, 130.92, 131.15, 132.06, 132.11, 134.10, 136.20,
138.90, 139.01, 139.60, 147.11, 151.81, 152.40; IR (CH2C12) 3499, 3055, 2988, 1606,

1481, 1468, 1421, 1265, 1055 cm"; mass spectrum (FAB MS in 4-nitrobenzyl alcohol]

186

m/z (% rel intensity) 586 M+ (100), 307 (10), 154 (37), 137 (26), 77 (6), HRMS calcd for
C39H3805 m/z 586.2719, measd 586.2715. Anal calcd for C39H3305: C, 79.84; H, 6.53.

Found: C, 80.04; H, 6.22.

187

 

Chemical Shifts For H. - Hn Major
H1 Hi ”m --- sawmfimw ___,.-

Ha = 5.64(d) Hj = 184(8)

Hb = 6.49(d) Hk = 5.75(s)

 

Hc = 7.23(s) H; = 4.78(d)
Hd = 6.90(s) Hm = 243(8)
He = 3.25(d) Hn = 2.25(s)
Hf= 4.1 1(d)
Hg = 3.49(d)

247A Partial Cone conformation ”h = 3.88(d)

H; = 3.46(s)

 

 

Table 7.1 Results of Homonuclear 'H-‘H NOE experiments on Major isomer of 247A (Partial cone).

 

 

Nuclei Irradiated Adjacent H Enhancement Nuclei irradiated Adjacent H Enhancement

5.64 (Ha) Hg y 4.11 (Hf) Hc y
Hi y “k y

6.49 (Hb) H y
d 3.49 (Hg) Hh y
”1 y a y
He y “I y

H

7.23(Hc) “11 y 3.88 (Hh) g y
Hc Y

Hrn y
”k y 3.46 (Hi ) Ha y
3.84 (H- ) H Y

6.90(Hd ) Hb y J 8
HD y H11 y
3.25 (He) Hf y H. y
H d y Hc Y
4.78 (HI)

“6 y Hk y
Meta (Ar-H) y

 

188

 

247A Cone Conformation

 

6 mom i
Ha = 6.51(d)
Hb = 6.66(d)
Hc = 6.34(s)

Hd = 6.58(s)
He = 3.29(d)
Hf = 3.73(d)
Hg = 3.35(d)
Hh = 4.1 1(d)

H, = 3.78(s)

 

Chemical Shifts For H. - Hm Mino

Hj = 3.86(s)
Hk = 5.01(s)
H, = 7.92(d)
Hm = 2.02(s)
H" = 1.81(s)

 

Table 7.2 Results of Homonuclear IH-‘H NOE experiments on Minor Isomer of 247A (Cone).

 

 

Nuclei irradiated Adjacent H Enhancement Nuclei irradiated Adjacent H Enhancement
6.51 (Ha) Hj y 3.35(Hg) Hh
He y Hb y
Hd y
Hc y
4.11 (Hh) Hg y
6.65 (Hb) Hj y
“R y
Hg y
Hi y
6.34(Hc) Ha y
3.78 (Hi) Ha y
He y
H
Hm y b Y
6.58 H
( d ) Hb y 3.86 (Hj) obscured by major isomer
Hg y
“I y 5.01 (Hk) Hr y
3-29 (He) Hf y 792 (H1) No NOE Enhancements
H
a y 1.81(Hm) Hc Y
Hc y
2.02 H H Y
3.73 (Hf) He y ( “) d
“1 y

189

An EXSY experiment revealed that these two conformers were inter-converting but not

on the NMR time scale. For the results of EXSY experiment see Chapter 3, Pg 126-127.

 

5 -methyl-1 7, 28-diphenyl-1 1,23,26—trimethoxy—25,2 7-dihydroxycalix(4)arene
24 7B: The bis-carbene complex 229D (0.109 g, 0.149 mmol) and diyne 228C (0.037 g,
0.149 mmol) were dissolved in 60 mL of 1,2-dichloroethane and reacted according to the
general procedure to give calixarene 247B as an inseparable 3.3:1 mixture of conformers
in 35 % total yield (0.034 g, 0.052 mmol) as a white solid afier purification by silica gel
chromatography (25 % ethyl acetate/hexanes). Rf = 0.45 (hexanes/ ethyl acetate = 3/1).
HPLC analysis showed the presence of single peak at 4.02 min upon gradient elution
with mixtures of hexane/iso-propanol varying from 99.5/0.5 to 97/3 over 40 min at a flow
rate of 1 mL/min using a silica gel column (R0086100C5). However, the 1H NMR
reveals a mixture of two conformers in a 3.3: 1 ratio. The assignment of the major
isomer as a partial cone conformer and minor as cone was made on the basis of the
similarity of the proton spectra with that of 247A. The product was further purified by
crystallization from hexanes/dichloromethane and the following spectral data was
recorded on the mixture of the two conformers. The mass spectrum of 247B shows a

trace peak at m/z = 1297 (0.13). This is attributed to a trace of a calix[8]arene that can

190

not be detected by 1H NMR. A calix[8]arene would not be expected to exists as
conformers that could be observed on the 1H NMR time scale. Mp = 243-245 °C.
Spectral data for 247B: lH NMR(CDC13, 500 MHz) major; 6 2.43 (s, 3 H), 3.37 (d, 2 H,
J = 13.0 Hz), 3.46 (s, 6 H), 3.50 (d, 2 H, J= 16.0 Hz), 3.86 (d, 2 H, J= 16.0 Hz), 3.90 (s,
3 H), 4.18 (d, 2 H, J = 13.0 Hz), 4.86 (d, 1 H, J= 7.5 Hz), 5.50 (t, 1 H, J: 7.7 Hz), 5.66
(d, 2 H, J= 3.0 Hz), 5.77 (s, 2 H), 6.53 (d, 2 H, J: 3.0 Hz), 6.61 (t, 1 H, J= 7.5 Hz), 6.83
(d, 1 H, J = 7.5 Hz), 7.01 (t, 1 H, J = 7.5 Hz), 7.24 (s, 2 H), 7.30 (s, 2 H), 7.33 (m, 1 H),
7.42 (t, 2 H, J = 7.5 Hz), 7.48 (d, 2 H, J = 7.0 Hz), minor; 1.60 (s, 3 H), 3.27 (d, 2 H, J =
14.0 Hz), 3.43 (d, 2 H, J = 14.0 Hz), 3.74 (d, 2 H, J = 14.0 Hz), 4.21 (d, 2 H, J = 14.5
Hz), 5.02 (s, 2 H), 6.28 (s, 2 H), 6.69 (d, 2 H, J= 3.0 Hz), 6.91 (d, l H, J= 7.5 Hz), 6.96
(s, 2 H). The remaining 11 Ar-H’s of the minor conformer overlap with the peak
resonances of the major isomer and hence their positions could not be precisely assigned.
13C NMR (CDC13, 125 MHz) 6 20.54, 21.19, 31.33, 32.06, 36.10, 39.98, 55.33, 55.68,
63.18, 63.31, 113.11, 113.67, 113.92, 114.64, 125.35, 126.15, 126.65, 126.91, 126.95,
127.03, 127.19, 127.66, 127.74, 127.79, 127.91, 128.47, 128.79, 129.53, 129.74, 130.11,
130.72, 131.28, 132.09, 132.84, 133.52, 133.60, 134.22, 136.48, 136.80, 137.71, 138.38,
138.50, 138.53, 139.01, 139.26, 139.57, 140.56, 140.64, 146.61, 147.01, 152.47, 152.54,
153.52, 153.70; IR (CH2C12) 3493, 3055, 2988, 1653, 1609, 1481, 1421, 1265, 1147 cm];
mass spectrium (FAB MS in 4-nitrobenzy1 alcohol) m/z (% rel intensity) 648 M+ (100),
307 (30), 154 (100), 136 (60), 107 (20), 77 (20), HRMS calcd for C44H4005 m/z

648.2876, measd 648.2874.

191

 

5,1 7-dimethyl-1 1,23,26—trimeth0xy-25,27-dihydr0xy-28—hexylcalix(4)arene 24 7C:
A solution of the bis-carbene complex 229A (0.207 g, 0.31 mmol) and diyne 228B (0.077
g, 0.307 mmol) in 122 mL of 1,2-dichloroethane was allowed to react according to the
general procedure described above. The product of this reaction was purified by silica
gel chromatography (hexanes/ethyl acetate = 85/ 15) to give calixarene 247C in 22 %
yield (0.04 g, 0.068 mmol) as an off-white solid and as a inseparable 7.9:1 mixture of
conformers. Rf = 0.31 (15 % EtOAc / hexanes). Mp = 172-174 °C. HPLC analysis
showed the presence of single peak at 6.02 min under gradient elution with a mixture of
hexane/iso-propanol starting at 99.5/0.5 and decreasing to 97/3 over 40 min at a flow rate
of 1 mL/min on a silica gel column (R0086100C5). The 1H NMR indicates the presence
of a 7.921 mixture of conformers as measured by integration of the peaks at 6 = 1.91 and
2.16. The major isomer was assigned as the cone conformer on the basis of NOE and
NOESY experiments (see below). The minor isomer was not assigned. NOESY
experiment on 247C: Tm = 0.5 sec, nt = 256, mi = 64, linear prediction along F1
dimension.

The following spectral data were obtained on a mixture of the conformers. The

mass spectrum of 247C shows a trace peak at m/z = 1189 (0.20). This is attributed to a

192

trace of a calix[8]arene that can not be detected by 1H NMR. A calix[8]arene would not
be expected to exists as conformers that could be observed on the 1H NMR time scale.
Spectral data for 247C: 1H NMR (CDC13, 500 MHz) major; 6 0.74 (t, 3 H, J = 7.2 Hz),
1.31 (m, 4 H), 1.39 (m, 4 H), 1.91 (s, 3 H), 2.04 (s, 3 H), 3.29 (t, 2 H, J = 7.3 Hz), 3.39
(d, 2 H, J: 14.0 Hz), 3.40 (d, 2 H, J: 14.0 Hz), 3.79 (s, 6 H), 3.88 (s, 3 H), 4.00 (d, 2 H,
J = 14.0 Hz), 4.21 (d, 2 H, J = 13.5 Hz), 5.78 (s, 2 H), 6.54 (s, 2 H), 6.63 (d, 2 H, J= 3.0
Hz), 6.69 (s, 2 H), 6.71 (d, 2 H, J= 2.5 Hz), minor; 0.88 (t, 3 H, J= 7.2 Hz), 1.24 (bs, 4
H), 1.48 (bs, 4 H), 2.16 (s, 3 H), 2.35 (s, 3 H), 3.23 (d, 2 H, J: 12.5 Hz), 3.69 (s, 6 H),
3.77 (s, 3 H), 3.91 (d, 2 H, J= 12.5 Hz), 3.99 (d, 2 H, J: 12.5 Hz), 4.08 (d, 2 H, J: 12.5
Hz ), 5.75 (s, 2 H), 6.52 (d, 2 H, J= 3.0 Hz), 6.58 (d, 2 H, J= 3.5 Hz), 6.87 (s, 2 H), 7.14
(s, 2 H) (2 benzylic hydrogens not observed); 13C NMR (CDC13, 125 MHz) major; 6
14.11, 20.71, 20.72, 22.72, 28.48, 29.56, 31.96, 32.34, 32.87, 35.68, 55.77, 63.38, 113.35,
114.4, 128.37, 128.98, 129.95, 131.58, 132.16, 134.01, 134.99, 137.27, 137.73, 147.10,
150.72, 152.58; IR (CH2C12) 3437, 2924, 2855, 1605, 1482, 1225, 1145, 1053 cm"; mass
spectrum m/z (% rel intensity) 594 M+ (100), 307 (10), 154 (35), 136 (20), calcd for

calculated for C39H4605 m/z 594.3345, measd 594.3344.

193

 

 

 

Chemical Shifts For H. - Hll Major Isomer of 247C

-_ _-_P1’_“3_ _ ”_V ______ _ _ _.
Ha = 6.63 ((1) HJ- = 3.80(s)
Hb = 6.71 (d) H, = 3.88(s)
Hc = 6.69 (s) ”I = 192(5)
Hd= 6.54 (s) ”m = 204(5)
Hc = 3.39 (d) Hn = 3.290)
Hf: 4.00 (d)
Hg = 3.40 (d)
Hh = 4.21(d)

247C Major Isomer (Cone Conformer) Hi = 5,78 (s)

 

 

Table 7.3 Results of Homonuclear 'H-‘H NOE Experiments on the major conformer of 247C

 

Nuclei irradiated Adjacent H Enhancement Nuclei irradiated Adjacent H enhancement

 

6.63 (Ha) Hg y 3.40 (Hg) or He Hh y
Hj y ”C y
6.71 (Hb) H,- y a y
4.21 (Hh) Hg y
He (0f) “3 n “n y
6.69(Hc) Hg (or) Hc y “it n
Hm y 5.78(Hi ) NO NOE
6.54(Hd ) H1 y 3.80 (Hj ) Ha y
He n Hb
3.39 (He) Hf y 3-88 (Hk) Hr y
or (Hg) Hb y 1.91 (H1) Hd y
”d y
4.00010 H, y 204%) Hc y
He y 3.29 (Hn) Ht.
Hk y "0

 

194

 

 

 

 

F2 (pm)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 2. Expanded region of the 600 MHz NOESY spectrum of 247C in CDC13 at 25

0C.

195

 

5 -phenyl-1 7—methyl—1 1, 23,26—trimethoxy-25,2 7-dihydr0x—28-henzlcalix(4)arene
24 7D: The reaction of the bis-carbene complex 229B (0.103 g, 0.142 mmol) and diyne
228D (0.037 g, 0.142 mmol) in 56 mL of 1,2-dichloroethane was carried out according to
the general procedure. The calixarene 247D was obtained as an inseparable 7.9:1
mixture of conformers in 35 % yield (0.032 g, 0.05 mmol) as an off-white solid after
purification by silica gel chromatography (25 % EtOAc / hexanes). Rf = 0.38 (25 %
EtOAc / hexanes). The resulting product was further purified by crystallization from
dichlormethane/hexanes (mp = 170—172 °C). HPLC analysis showed the presence of
single peak at 4.08 min with gradient elution with hexane/iso—propanol from 99.5/0.5 to
97/3 over 40 min at a flow rate of 1 mL/min on a silica gel column (R0086100C5). The
structure of neither conformer was assigned. The following spectral data was taken on
the mixture of conformers of 247D: 1H NMR (CDC13, 500 MHz) major; 6 0.95 (t, 3 H, J
= 7.2 Hz), 1.38 (m, 4 H), 1.46 (m, 4 H), 1.89 (s, 3 H), 3.35 (t, 2 H, J= 7.5 Hz), 3.49 (d, 2
H, J= 14.0 Hz), 3.56 (d, 2 H, J= 14.0 Hz), 3.87 (s, 6 H), 4.00 (s, 3 H), 4.18 (d, 2 H, J =
14.0 Hz), 4.28 (d, 2 H, J = 14.0 Hz), 5.63 (s, 2 H), 6.58 (s, 2 H), 6.74 (d, 2 H, J = 2.5 Hz),
6.79 (d, 2 H, J = 3 Hz), 7.12 (s, 2 H), 7.30-7.38 (m, 5 H); 13C NMR (CDC13, 125 MHz)

major + minor; 6 13.75, 14.11, 20.65, 20.92, 22.48, 22.72, 28.44, 28.66, 29.38, 29.53,

196

29.82, 31.27, 31.61, 31.91, 32.38, 32.76, 35.59, 40.42, 55.51, 55.76, 63.01, 63.39, 113.39,
113.83, 114.44, 126.94, 127.07, 127.63, 127.99, 128.54, 128.57, 128.61, 128.87, 128.98,
130.68, 131.35, 131.60, 132.88, 134.29, 134.34, 136.92, 137.72, 138.29, 139.41, 140.41,
147.07, 152.64, 152.75, 152.82 (9 carbons not located); IR (CH2C12) 3485, 2926, 2855,
2836, 1605, 1481, 1236, 1146, 1055 cm]. Anal calcd for CaaHagOsz C, 80.46; H, 7.37.

Found: C, 80.50; H, 7.32.

 

5 -phenyl-1 7-methy1- 1 1, 23, 26, 28-tetramethoxy-25, 2 7-dihydroxycalix( 4 )arene
24 7E: The reaction of the bis-carbene complex 229D (0.105 g, 0.143 mmol) and diyne
228A (0.029 g, 0.145 mmol) was performed as described in the general procedure to
give, after purification by silica gel chromatography (25 % EtOAc / hexanes), the
calixarene 247E as a single conformer in 40 % yield (0.035 g, 0.057 mmol). The
conformation of the calixarene was assigned as the cone conformer. The resultant
product was further purified by crystallization from hexanes/dichloromethane to afford
shiny white crystals of 247E. Mp = 236-239 ° C. Rf = 0.37 (hexanes / ethyl acetate =
3/1). Spectral data for 247E: 1H NMR (CDC13, 500 MHz) 6 2.02 (s, 3 H), 3.31 (d, 2 H, J
= 13.0 Hz), 3.41 (d, 2 H, J = 13.0 Hz), 3.76 (s, 6 H), 3.97 (s, 3 H), 4.02 (s, 3 H), 4.29 (d,

2 H, J= 13.0 Hz), 4.39 (d, 2 H, J= 13.0 Hz), 6.64 (d, 2 H, J: 3.0 Hz), 6.68 (d, 2 H, J=

197

3.0 Hz), 6.71 (s, 2 H), 7.13 (s, 2 H), 7.23 (m, 1 H), 7.31 (s, 2 H), 7.32 (s, 2 H), 7.42 (s, 2
H); 13c NMR(CDC13, 125 MHz) 6 20.82, 31.54, 31.72, 55.85, 55.89, 63.52, 113.85,
113.93, 126.89, 127.80, 128.54, 129.08, 129.21, 129.74, 132.64, 133.49, 134.41, 137.72,
140.62, 146.96, 151.35, 152.39, 153.39 (1 aryl carbon not located); IR (CH2C12) 3354,
2930, 2829, 1599, 1483, 1435, 1244, 1142, 1053 cm'l; mass spectrum EI m/z (% rel
intensity) 602 M+ (100), 571 (5), 539 (8), 301 (10), HRMS calcd for C39H3306 m/z

602.2668, measd 602.2668.

Synthesis of the racemic bis-propargyl alcohols 274 and Mesa-2 75

 

 

Me Me Me
. _ . R3Si SiR3 R3Si SiR3
“33‘ — 1 % é % é
+ . .
OHC CHO : ;
OMe OH OMe OH OH OMe OH
273 Rac Mesa
274A R = TIPS 275A R = TIPS
274B R = TMS 2758 R = TMS

To a flame dried 50 mL round bottomed flask was added triisopropyl silyl
acetylene (1 mL, 4.45 mmol) and 20 mL of tetrahydrofuran as the solvent. n-butyl
lithium (2.5 M in hexanes, 2.8 mL, 4.48 mmol) was dispensed via syringe at -78°C and
the resulting solution was warmed to room temperature with stirring for another 1h. The
aldehyde 273129(0.356 g, 2 mmol) was added at 0°C and the mixture was left to stir at
room temperature for 12 h. Water (40-50 mL) was added and the organic layer extracted
with methylene chloride (50 mL). After drying over anhydrous magnesium sulfate, the
solvent was removed under vacuum and the crude product purified to afford 274A (0.197
g, 0.365 mmol, 18 %) and 275A (0.67 g, 1.24 mmol, 62 %) as white solids in a combined

80 % yield. Similarly, the addition of trimethyl silyl ethynyl lithium to aldehyde 273

198

(1.78 g, 10 mmol) afforded 274B (1.09 g, 2.91 mmol, 29 %) and 275B (2.18 g, 5.82
mmol, 58 %) by silica-gel chromatography in a combined 87 % yield as white solids.

(i) -2, 6-bis(-3-hydroxy- I -triisopropylsilylpropynyl)-4—methylanisole 2 74A

Mp = 78-81°C. Rf = 0.56 (hexanes/ ethyl acetate = 85/15). Spectral data for 274A:
lHNMR (CDC13, 300MHz) 6 1.06 (s, 42H), 2.29 (s, 3H), 2.67 (d, 2H, J = 5.7 Hz), 3.93
(s, 3H), 5.72 (d, 2H, J = 5.7 Hz), 7.49 (s, 2H); l3CNMR (CDCl3, 125MHz): 6 11.16,
18.56, 20.88, 60.33, 63.77, 87.89, 107.01, 129.52, 133.84, 134.53 (One of aryl carbons
not seen); IR (CH2C12) 3434, 2944, 2892, 2866, 2172, 1482, 1464, 1383, 1215 cm'l. Anal
calcd for C32H5403S12: C, 70.79; H, 10.02. Found: C, 70.43; H, 9.76

(5.9-2, 6-bis(-3-hydr0xy-1 -trimethylsilylpropynyl)-4-methyl-anisole 2 74B

Mp = 97-100°C. Rf (hexanes/ ethylacetate = 3/1) = 0.40. Spectral data for 274B: ‘HNMR
(CDC13, 300MHz) 6 0.15 (s, 18H), 2.34 (s, 3H), 2.66 (d, 2H, J = 6.3Hz), 3.99 (s, 3H),
5.64 (d, 2H, J = 6.3 Hz), 7.37 (s, 2H); l3CNMR (CDCl3, 125MHz): 6 -0.25, 20.97, 60.58,
63.77, 91.31, 105.26, 129.34, 133.84, 134.72 (One aryl carbon missing); IR (CDC13)
3393, 2961, 2901, 2837, 2174, 1481, 1437, 1408, 1250 cm]; mass spectrum m/z (%
re1.intensity) 374 (M, 28), 357 (100), 73 (36), HRMS calcd for C20H3OO3Si2 m/z

374.1734, measd 374.1736.

(Mesa) -2, 6-bis(-3-hydr0xy- I -triisopropylsilylpropynyl)-4-methylam'sole 2 75A

Mp = 96-98°C. Rf = 0.40 (hexanes/ ethyl acetate = 85/15). Spectral data for 275A:
lHNMR (CDCl3, 300MHz) 6 1.059 (s, 42H), 2.304 (s, 3H), 2.56 (d, 2H, J = 6.0 Hz),
3.96 (s, 3H), 5.70 (d, 2H, J = 5.7 Hz), 7.48 (s, 2H); l3’C NMR (CDC13, 125MHz) 6 11.17,

18.56, 20.86, 60.49, 63.87, 87.86, 107.14, 129.53, 133.91, 134.46, 153.09; IR (CH2C12)

199

3379, 2946, 2867, 2170, 1645, 1464, 1383, 1265 cm'l; mass spectrum m/z (%
rel.intensity) 542 (MI, 10), 525 (100), 165 (16), 115 (28), 87 (36), 75 (70), 59 (84),

HRMS calcd for C32H5403Si2 m/z 542.3612, measd 542.3608.

(Mesa) -2, 6—bis (-3-hydraxy-1 -trimethylsilylprapynyl)-4-methylanisale 2 758

Mp = 103-105°C. Rf (hexanes/ ethylacetate = 3/ 1) = 0.30. Spectral data for 275B:
lHNMR (CDC13, 300MHz) 6 0.15 (s, 18H), 2.34 (s, 3H), 2.66 (d, 2H, J = 6.0 Hz), 3.95
(s, 3H), 5.65 (d, 2H, J = 6.0 Hz), 7.38 (s, 2H); 13C NMR (CDC13, 125MHz) 6 -0.25,
20.97, 60.53, 63.66, 91.33, 105.20, 129.28, 133.87, 134.75 (One aryl carbon missing); IR
(CDClg) 3405, 2961, 2174, 1481, 1437, 1250 cm"; mass spectrum m/z (% rel.intensity)
374 (NF, 28), 357 (100), 154 (16), 136 (16), 73 (40), HRMS calcd for C20H3oO3Si2 m/z

374. 1734, measd 374. 1736.

2, 6-bis- (3 —h ydraxy- l-prapyn yl)-4-methylanisale 2 74C, 2 75C

Me Me

    

274A,B TBAF’E‘20=\\ é 275A,B TBAF’E‘20= Q é

 

 

OH OMe OH OH OMe OH
roe-274C mesa-275C

To 1 mmol (0.542 g) of (:)-274A or 2.9 mmol (1.09 g) of 274B was added 5 equiv. of
tetrabutyl ammonium fluoride (1M in tetrahydrofuran) followed by anhydrous ether (10
or 30 mL) and the reaction mixture was stirred at room temperature until consumption of
the starting material as observed by TLC. Aqueous workup followed by removal of
solvent and purification by silica gel chromatography (50 % ethyl acetate/hexanes)

afforded the racemic alkynol 274C (0.207 g, 0.9 mmol, 90 %) from 274A and (0.48 g,

200

2.09 mmol, 72 %) from 274B. The desilylation of mesa-275A (2.3 g, 4.24 mmol) or
275B (2.17 g, 5.8 mmol) using 5 equiv of tetrabutyl ammonium fluoride afforded (0.87 g,
3.78 mmol, 89 %) or (1.33 g, 5.78 mmol, 99.6 %) of mesa-275C as white solid.

Rf: 0.53 (hexanes / ethylacetate = 1/1). Mp = 145-147°C. Spectral data for rac-274C: 1H
NMR (CDC13, 300MHz): 6 2.34 (s, 3H), 2.58 (d, 2H, J = 5.7 Hz), 2.63 (d, 2H, J = 1.3
Hz), 3.94 (s, 3H), 5.68 (d, 2H, J = 5.4 Hz), 7.42 (s, 2H); 13C NMR (CDC13, 125MHz): 6
20.94, 59.76, 63.77, 74.65, 83.61, 129.26, 133.58, 135.02, 152.78; IR (CHC13) 3350,
3289, 2925, 2800, 2090, 1481 cm". Anal calcd C14H1403: C, 73.03; H, 6.13. Found: C,
73.08; H, 6.33.

Rf: 0.50 (50 % EtOAc / hexanes). Mp = 103-105°C. Spectral data for mesa-275C: 1H
NMR (CDC13, 300MHz): 6 2.35 (s, 3H), 2.62 (brs, 2H), 2.63 (d, 2H, J = 4.0 Hz), 3.96 (s,
3H), 5.68 (d, 2H, J = 3.5 Hz), 7.42 (s, 2H); 13C NMR (CDC13, 125MHz) : 6 20.94, 59.76,
63.77, 74.65, 83.61, 129.26, 133.58, 135.02, 152.78; IR (CHC13) 3299, 3200, 2920,
2840, 2080, 1481 cm’l. Anal calcd for C14H1403: C, 73.03; H, 6.13. Found: 73.07; H,
5.94.

Asymmetric Alkyne Addition using (R) or (S)-Binaphthol and Ti(O-i-Pr)4

 

 

Me Me Me
—— TIPS TIPS TIPS TIPS
TIPS _ ZHEI> \\ // \\ é
OHC CHO Ti (O-i- Pr)4 g + a a
OMe 0H OMe 0H 0H OMe OH
(R)- BINOL
273 (S,S)-274A (S,R)-275A

toluene/ CH2C12

2, 6-bis ((R)-3-hydraxy— I -triisopropylsilylprapynyl)-4-methylanisale 2 74A
The following procedure was modified from that reported recently by Pu et.al114
so as to avoid the use of extremely pyrophoric neat diethyl zinc. Diethyl zinc [1.1M in

toluene] was purchased from Sigma-Aldrich and used under an atmosphere of dry argon.

201

Into a clean flame dried three necked round bottomed flask fitted with a reflux condenser
was added triisopropylsilyl acetylene (9.9 mL, 44 mmol) under argon. Toluene (18 mL)
and diethyl zinc (1.1M in toluene, 36mL) were added and the resulting solution was
refluxed for 6h upon which time the resulting solution turned grey in color. (R)-BINOL
(1.14 g, 4 mmoL) in dichloromethane (40 mL), predried over anhydrous 4A molecular
sieves, was added to this grey solution and stirred for 15 min. Titanium isopropoxide (3
mL, 10 mmol) was then transferred to the flask via syringe. The solution turned deep red
and stirring was continued for another 1h. Aldehyde 27 3 (1.78 g, 10 mmoL) in
dichloromethane (40 mL) was added and the reaction was monitored by thin-layer
chromatography for completion. Saturated ammonium chloride (50 mL) was added to
quench the reaction. Extraction with dichloromethane (60 mL), drying over anhydrous
magnesium sulfate, and evaporation of the solvent resulted in an yellow oil that was
purified by column chromatography (5 % to 15 % ethylacetate / hexanes) to afford the
major diastereomer (274A, 3.03 g, 5 .6 mmol, 56 %) and the minor diastereomer (275A,
2.28 g, 4.2 mmol, 42 % ). 0.1) for 274A = -22.7 (c = 1.06 in CHC13)

(R,R)-274A was prepared accordingly using the (S)-enantiomer of 1,1’-Binaphthol. The
assignment of the stereochemistry of 274A as either the (5,5) or (R,R) enantiomer was
made on the basis of the stereochemical assignment of the mono addition product 289 via
derivative 293 (See page 210).

Following the procedure described earlier for synthesis of 274C, (R,R)-274A
(3.03 g, 5.6 mmol) was subjected to desilylation and subsequent purification by silica-gel
chromatography (10 % to 50 % ethylacetate/ hexanes) afforded (S,S)-274C (1.07 g, 4.65

mmol, 83 %) as a crystalline white solid. The optical purity was determined to be 99.2 %

202

ee by HPLC analysis by comparison of retention times with that of the racemic 274C
(Chiralcel OD Column, 94:6 hexane: i-PrOH to 85:15 hexane : i-PrOH, 254 nm),
Retention time: t major = 47.60 min, t minor = 53.79 min. 0.1) for (S,S)-274C = -20.5 (c =

0.66 in CHC13).

Oxidation / Reduction Sequence Using (R)-A1pine Borane to Optically Active Bis-

 

Propargyl Alcohols
Me
275A PCC,4AMS,Celite R \ / R
(or) ’
274B+27SB CH2CIZ (01') Jones \ /
(or) 274c+27sc reagent 0 OMe o
276

Diynane 276A (R = TIPS)

To a solution of the bis-propargyl alcohol (R,S)-275A (2.71 g, 5 mmol) in 60 mL of
dichloromethane was added 4A MS (2.7 g) and celite (2.7 g) followed by slow addition
of pyridinium chlorochromate (2.71 g) and the resultant dark brown slurry stirred at rt for
12 h. Filtration of the reaction mixture over a pad of silica-gel and removal of the solvent
under reduced pressure afforded the diynone 276A (2.69 g, 5 mmol, 100 %) as an orange-
yellow oil. The crude product was of sufficient purity to be taken on directly to the next
step. Rf (hexanes / ethylacetate = 95/5) = 0.39. Spectral data for 276A: 1H NMR (CDC13,
500MHz) 6 1.12 (s, 42H), 2.36 (s, 3H), 3.91 (s, 3H), 8.00 (s, 2H); ‘3 CNMR (CDC13,
125MHz) 6 11.13, 18.53, 20.50, 64.19, 97.68, 104.67, 132.10, 133.09, 137.57, 158.56,
175.98; IR (neat) 2946, 2893, 2868, 2145, 1655, 1570, 1471 cm"; mass spectrum FAB in
NBA m/z (% rel.intensity) 539 (M +1, 100), 495 (36), 357 (28), HRMS calcd for

C32H51O3Si2 (M++1) m/z 539.3377, measd 539.3374.

203

Diynane 2768 (R = T MS)

A mixture of bis-propargyl alcohols (d/l-274B and mesa-2758, 7.42 g, 20 mmol) was
subjected to oxidation following the above procedure and gave 276B (6.46 g, 17.4 mmol,
87 %) as an yellow oil. Rf (hexanes / ethyl acetate = 95/5) = 0.20. Spectral data for 276B:
1H NMR (CDC13, 500MHz) 6 0.27 (s, 18H), 2.37 (s, 3H), 3.90 (s, 3H), 7.91 (s, 2H); ‘3
CNMR (CDC13, 125MHz) 6 0.75, 20.59, 64.10, 100.07, 102.64, 131.75, 133.37, 137.35,
158.82, 176.08; IR (CDCl3) 2963, 2151, 1653, 1570, 1472, 1421, 1307 cm"; mass
spectrum FAB in NBA m/z (% rel.intensity) 371 (M++l, 60), 307 (28), 273 (20), 154

(100), 136 (72), 107 (20), HRMS calcd for C20H27O3Siz m/z 371.1499, measd 371.1501.

Diynane 2 76C (R = H)

A mixture of the alkynols (d/l)-274C and mesa-275C (0.575 g, 2.5 mmol) was dissolved
in 15 mL of acetone in a 50 mL round bottomed flask and freshly prepared Jones reagent
was added until the red color indicative of the excess Cr(VI) salts persisted. The reaction
was quenched by addition of excess isopropanol and the insoluble Cr(III) salts were
removed by filtration through a celite pad. The filtrate was diluted with ether (100 mL)
and washed sequentially with satd aq NaHCO, solution (50 mL), water (50 mL), and
brine (50 mL). The organic layer was dried over anhydrous magnesium sulfate. Filtration
followed by removal of the solvent under reduced pressure afforded the crude material
that was purified by silica-gel chromatography (25 % ethyl acetate/ hexanes) to yield
276C (0.466 g, 2.05 mmol, 82 %) as a light yellow solid. Mp = 98-100°C. Rf (hexanes /

ethyl acetate = 3/ 1) = 0.23. Spectral data for 276C: lH NMR (CDCl,, 300MHz) 6 2.05 (s,

204

3H), 3.45 (s, 2H), 3.93 (s, 3H), 7.98 (s, 2H); '3 CNMR (CDC13, 125MHz) 6 20.57, 64.30,
80.42, 81.86, 131.38, 133.76, 137.80, 158.99, 175.59; IR (neat) 3271, 3250, 2957, 2094,
1667, 1630, 1570, 1472, 1419 cm"; mass spectrum FAB in NBA m/z (% rel.intensity)
227 (M*+1,100), 154 (52), 136 (36), HRMS calcd for CMHHO3 m/z 227.0707, measd

227.0708.

R R .
R -Al ine borane
Q // ( ) p a 274,275

0 OMe O
276

General Procedure For Midland Reductions of Acetylenic Ketones 276

To one equiv. of the diynone 276 in tetrahydrofuran (1.1 M) was added (R)-A1pine
borane (4 equiv, 0.5 M in tetrahydrofuran prepared from (+)-a-pinene) and the resultant
solution was stirred at ambient temperature for the times specified below. After the
indicated time period, solvent was removed under reduced pressure by applying a water
aspirator. The resultant mixture was heated to 40°C for 20 min to afford thick reddish oil,
which was subsequently dissolved in anhydrous ether (10-15 mL). Ethanolamine (2-3
mL) was added dropwise at 0°C to facilitate the formation of the borane-ethanolamine
adduct that precipitates as a light yellow solid. This residue was then filtered over a
medium porosity glass fiitted funnel and the solid was repeatedly washed with ether (50
mL). Removal of the solvent under reduced pressure afforded the crude alkynol that was
purified by silica-gel chromatography to afford the pure alkynol in the diastereomeric
ratio specified. The reduction of diynone 276C (R = H) under these conditions gave
impure alcohol 274C (> 99 % ee) after chromatographic purification while the reduction

of the silylated diynones gave the corresponding alcohols 274A and 274B of high purity.

205

2, 6-bis((R)-3-hydraxy- 1 -triisaprapylsilylprapynyl)-4-methylanisale) 2 74A

Diynone 276A (2.69 g, 5 mmol) upon subjecting to the reduction according to the general
procedure afforded (R,R)-274A in 35 % yield (0.95 g, 1.75 mmol). The amount of meso-
275A could not be determined as it could not be isolated pure. The enantiomeric purity of
(R,R)-274A was determined upon desilylation to (S,S)-274C as > 99.5 % ee [(R,R)-274C
not seen in the HPLC trace].

2, 6-bis((R)-3-hydraxy-1 -trimethylsilylprapynyl)-4-methylanisale 2 74B

Upon subjecting diynone 276B (2.05 g, 5.5 mmol) to the reduction according to the
general procedure (R,R)-274B was obtained exclusively in 76 % yield (1.55 g, 4.18
mmol). None of the (R,S)-275B was observed by TLC. The enantiomeric enrichment of
(R,R)-274B was determined upon desilylation to (S,S)-274C as > 99.5 % ee [(R,R)-274C

not seen in the HPLC trace].

 

 

Me Me Me
TIPS : ZnEt TIPS TIPS TIPS
: \\ \\ é
OHC CHO Ti (0-7- pr)4 CHO + i
OM OH OMe OH
e (S)- BINOL OH OMe
273 (R)—286 (R,R)-274A
Toluene/CH2C12
+ Mesa
(R,S)- 275A

(R )-3 - ( I -hydraxy-3 -( triisopropylsilyl )prap-2-ynyl)-2-methaxy—5 -methylbenzaldehyde 286

Into a clean flame dried three necked round bottomed flask was added triisopropyl silyl
acetylene (4.5 mL, 20 mmol) under argon. Toluene (10 mL) and diethyl zinc [1.1M in
toluene, 18 mL) were added and the resulting solution was refluxed for 5h upon which
time the resulting solution turned grey in color. (S)-BINOL (0.572 g, 2 mmoL) in 20 mL
of dichloromethane, predried over anhydrous 4A molecular sieves, was added to this grey

solution and after stirring for 15 min, titanium isopropoxide (1.5 mL, 5 mmol) was added

206

via syringe. The solution turned deep red and stirring was continued for another 1h.
Aldehyde 273 (1.78 g, 10 mmoL) in dichloromethane (20 mL) was added and the
reaction was monitored by GC/MS for completion. Saturated ammonium chloride (80
mL) was added to quench the reaction. Extraction with dichloromethane (100 mL),
drying over anhydrous magnesium sulfate, and evaporation of the solvent resulted in an
yellow oil which was purified by column chromatography (5% to 15 % ethylacetate /
hexanes) to afford 3.0 g (8.2 mmol, 82 %) of the alkynol (R)-286 as an yellow oil along
with 0.63 g (1.16 mmol, 11.6 %) of the bis-alkynol 274A. The (R,S)-isomer 275A co-
eluted with (R)-BINOL and hence its yield could not be determined accurately. Rf
(hexanes / ethylacetate = 85/15) = 0.34. Spectral data for (R)-286 : 1H NMR (CDC13,
500MHz) 6 1.06 (s, 21H), 2.35 (s, 3H), 2.52 (d, 1H, J = 5.5 Hz), 3.99 (s, 3H), 5.78 (d,
1H, J = 6.0 Hz), 7.62 (d, 1H, J = 2.5 Hz), 7.78 (d, 1H, J = 2.0 Hz), 10.31 (s, 1H); ‘3
CNMR (CDC13, 125MHz) 6 11.19, 18.59, 20.72, 63.68, 65.73, 90.76, 103.34, 128.90,
129.67, 132.93, 134.48, 136.95, 159.15, 189.82; IR (neat) 3429, 2943, 2988, 2172, 1689,
1606, 1587, 1477 cm]; mass spectrum m/z (% rel.intensity) 360 M+ (2), 343 (47), 318
(100), 303 (30), 288 (50), 260 (13). Anal calcd for C21H3203Si: C, 69.95; H, 8.95. Found:
C, 69.49; H, 9.11. Racemic alkynol 286 was prepared in an analogous manner by using

(+/-)—BINOL instead of (S)-BINOL.

207

TlPS

//

TBAF, Ether %
CH0 CHO

OH 0M6 OH 0M6
(R)-286 (S)-287

 

(S )-3 -( 1 -hydraxyprap-2-yn yl )-2-methaxy-5 -meth ylbenzaldeh yde 28 7
To a clean flame dried 100mL flask was added 2.95 g (8.2 mmol) of (R)-286 and 35 mL
of ether followed by dropwise addition of 5 equiv. of tetra-butyl ammonium fluoride (1M
in tetrahydrofuran). The resultant solution was stirred for 4 h at room temperature.
Aqueous workup followed by removal of solvent afforded the crude product which was
purified by silica-gel chromatography (50 % ethylacetate / hexanes) to afford 1.54 g (7.5
mmol, 92 %) of (S)-287 as an yellow oil. Rf (hexanes / ethylacetate = 1/ 1) = 0.69. Mp of
(S)-287 = 60-62 °C. Spectral data for (S)-287 : 1H NMR (CDC13, 500MHz) 6 2.36 (s,
3H), 2.65 (d, 1H, J = 2.1 Hz), 2.74 (s, 1H), 3.98 (s, 3H), 5.72 (dd, 1H, J = 3.6, 2.4 Hz),
7.62 (d, 1H, J = 2.1 Hz), 7.66 (d, 1H, J = 2.4 Hz), 10.29 (s, 1H); 13C NMR (CDC13,
125MHz) 6 20.97, 59.73, 65.85, 75.14, 83.61, 129.24, 130.37, 134.64, 135.06, 135.20,
189.71 (One aryl carbon missing); IR (neat) 3425, 3289, 2910, 2875, 2100, 1088, 1609,
1479 cm"; mass spectrum FAB in NBA m/z (% rel.intensity) 204 (M+, not found) 187
(94), 173 (20), 115 (15), 93 (40), HRMS calcd for CanO3 (W—17) m/z 187.0759,
measd 187.076.

Similarly, racemic alkynol 287 was prepared by desilylation of racemic 286.
HPLC Analysis of (S)-287 revealed the enantiomeric excess to be 65.4 % (Chiralpak AS
column, 94:6 hexane: i—PrOH to 85 :15 hexane : i -—PrOH, 254 nm, Flow rate 0.5 mL /
min) Retention time t majo, = 47.09, t minor = 42.99. The major enantiomer was assigned as

(S) based on Horeau’s method via derivative 293.

208

 

Me Me
Q ”OAC \ \
CHO \ CH0 + \ CHO
OH OMe Novozyme 435 i
CHzClz/Hexanes 0" 0M6 OAc OMe
(S)-287 65 % ee (S)-287 (R)-292

Enzymatic resolution of enantiomers of 287

To 1.54 g (7.54 mmol) of (S)-287 of 65 % ee in a round-bottomed flask was added
dichloromethane and hexanes (1/3 ratio, 45 mL) followed by the addition of 1.5 mL of
vinyl acetate. Novozyme 435 (300 mg) was sequentially added with vigorous stirring and
the reaction mixture was left at room temperature for overnight. Filtration of the resin and
evaporation of the solvent under reduced pressure afforded the crude product from which
upon purification by silica-gel chromatography afforded 1.27 g (6.26 mmol, 83 %) of (S)-
287 in 93.4 % ee as a light-yellow solid and 0.196 g (0.80 mmol, 10.6 %) of (R)-292 as
white solid. Mp = 52-54°C. The enantiomeric purity of the (R)-292 was not determined.
The % cc of (S)-287 was determined as described in the previous experiment. Rf(hexanes
/ ethylacetate = 3/1) of (R)-2921= 0.41. Spectral data for (R)-292: 1H NMR (CDC13,
500MHz) 6 2.10 (s, 3H), 2.37 (s, 3H), 2.63 (d, 1H, J= 2.5 Hz), 3.92 (s, 3H), 6.72 (d, 1H,
J = 2.0 Hz), 7.65 (d, 1H, J = 2.5 Hz), 7.69 (d, 1H, J: 2.5 Hz), 10.29 (s, 1H); 13C NMR
(CDC13, 125MHz) 20.70, 20.91, 59.40, 65.40, 75.39, 80.04, 128.95, 130.48, 130.96,
134.79, 135.68, 158.48, 169.32, 189.29; IR (neat) 3292, 2938, 2861, 2753, 2257, 2125,
1745, 1686, 1606, 1481 cm"; mass spectrum m/z (% rel.intensity) 246 M+ (3), 231 (14),
187 (100), 115 (12). Anal calcd for C14H1404: C, 68.28; H, 5.73. Found: C; 68.19, H;

5.68. Specific rotation of (S)-287 up = -5 .0 (c = 1.02 in i -PrOH).

209

Application of Horeau’s Method of Partial Kinetic Resolution For Determination of

Absolute Configuration of Chiral Propargylic alcohol 287

Me Me
\ Q
\ CHO DMAP CH 0
0H OMe c1120, 0 OMe

287 I 0 g 293

Ph COCl Ph €sz

The Alcohol 287 (93.4 % ee, 0.204 g, 1 mmol) and N,N-dimethyl amino pyridine
(25 mg, 0.20 mmol) were transferred to a 25 mL three necked round bottomed flask and
pyridine (2 mL) was added. To this solution was added 2-phenyl butyryl chloride (0.35
mL, 2 mmol) and the resultant mixture stirred at ambient temperature for 15 h. After 15
h, pyridine was removed under high vacuum and the residue was dissolved in
dichloromethane (50 mL) and the organic layer was washed with saturated sodium
bicarbonate (100 mL). Removal of the solvent under reduced pressure afforded the ester
as an oil in a 2.26 : 1 mixture of inseparable diastereomers of 293 in 96 % yield (0.336 g,
0.96 mmol). The aqueous layer was acidified to pH ~ 3 and then extracted with
dichloromethane (4x50 mL). Drying the organic layer over anhydrous magnesium sulfate
followed by removal of the solvent afforded the 2-pheny1 butanoic acid (26 mg, 0.16
mmol, 16 %) as oil. Further acidification followed by extraction with dichloromethane
did not afford any more carboxylic acid. The specific rotation of the acid was recorded in

two different solvents and the results are tabulated below.

210

Table 7.4. Optical Rotations at Isolated 2-Phenyl Butanolc Acid

 

Literature value of Optically pure

 

Solvent Concentration c Specufic rotation ( ”-2 ph e nyl but a n oi c acid Optical Punty
Toluene 0.9 -15.1 ° -93 ° 16.34 °/o
Chloroform 1.0 -11.4° -74.8 ° 15.3 °/o

 

Based on the Sign of the optical rotation of the isolated carboxylic acid and adopting
Horeau’s rule, the absolute configuration of the propargylic alcohol 287 can be deduced
to be the (S)--isomer.130

(S)-1—(3-farmyl-2—methaxy-5-methylphenyl)prap-2—ynyl 2-phenylbutanaate 293:

Rf (hexanes / ethylacetate = 85 / 15) = 0.32. Spectral data for (2.2:1) mixture of
diastereomers of 293: 1H NMR (CDC13, 500MHz) a 0.86-0.91 (m, 4H), 1.76-1.84 (m,
2H), 2.07-2.14 (m, 2H), 2.20 (s, 3H), 2.33 (s, 1.4 H), 2.54 (d, 0.4 H, J = 2.0 Hz), 2.61 (d,
0.9 H, J = 2.0 Hz), 3.50 (t, 0.45 H, J = 8.0 Hz), 3.51 (t, 0.9 H, J=7.5 Hz), 3.70 (s, 3H),
3.84 (s, 1.41H), 6.67 (d, 0.9H, J = 2.5 Hz), 6.70 (d, 0.41 H, J = 2.5 Hz), 7.19-7.23 (m,
4H), 7.25 (d, 0.71 H, J = 1.5 Hz), 7.26 (d, 0.32 H, J: 2.0 Hz), 7.28—7.29 (m, 2H), 7.30
(d, 0.58 H, J= 2.0 Hz), 7.56—7.58 (m, 1.3H), 7.64 (d, 0.4 H, J= 2.5 Hz),10.23 (s, 0.9 H),
10.29 (s, 0.39 H); 13C NMR (CDC13, 125MHz) 6 12.04 , 12.07, 20.64, 20.71, 26.49,
26.58, 53.08, 53.31, 59.67, 59.72, 65.19, 65.34, 75.39, 75.45, 79.73, 80.04, 127.32,
127.36, 128.02, 128.55, 128.78, 128.91, 129.97, 130.26, 131.01, 131.06, 134.62, 134.72,
134.96, 135.53, 138.17, 138.25, 158.39, 158.51, 172.29, 172.33, 189.37 (3 aryl carbons
not seen); IR (neat) 3285, 2967, 2936, 2876, 1741, 1891, 1604, 1589, 1479 cm'l; mass
spectrum m/z (% rel.intensity) 350 NF (10), 320 (20), 203 (20), 187 (40), 119 (55), 91

(100), HRMS calcd for szszOa m/z 350.1518, measd 350.1517.

211

 

Me
Na“, THF \ /
% ¢ = \ /
; Mel 2
OH OMe OH OMe OMe OMe
(S,S)—274C (S,S)-267A

2-Methaxy-1 , 3 -bis-( (S )- I -methaxy—prap-2-ynyl)-5-methylbenzene (S, S) -26 7A

To a preweighed flame dried three necked 100 mL round bottomed flask was added 350
mg (14.6 mmol) sodium hydride (60 % dispersion in oil) and pentane (10 mL). The
resulting slurry was stirred at ambient temperature for 15 minutes. Pentane was then
extracted using a syringe and the residual solvent was removed under vacuum to afford
210 mg of sodium hydride. Tetrahydrofuran (30 mL) was added to this flask under argon
and then the (S,S)- alkynol 274C (0.782 g, 3.4 mmol) was slowly added over 5 minutes.
Upon completion of the addition, the yellow slurry was stirred for another 45 min.
Iodomethane (0.7 mL) was added and the reaction was left to stir overnight. Ether (25
mL) was added and the reaction was worked up by addition of saturated ammonium
chloride solution (15 mL). The product was extracted with ether (100 mL) and the
organic layer was washed with water (100 mL). Drying over anhydrous magnesium
sulfate, removal of ether under reduced pressure, and purification by silica gel
chromatography (15 % ethylacetate / hexanes) afforded 0.87 g (3.36 mmol, 99 %) of
(S,S)-267A as white oil. Rf = 0.37 (hexanes / ethyl acetate = 85 / 15). Spectral data for
(S,S)-267A: lHNMR (CDC13, 500MHz) 6 2.33 (s, 3H), 2.58 (d, 2H, J = 2.5 Hz), 3.44 (s,
6H), 3.83 (s, 3H), 5.34 (d, 2H, J = 2.5 Hz), 7.44 (s, 2H); 13CNMR (CDCl3, 125MHz) 6
20.92, 56.35, 63.60, 67.05, 75.14, 81.68, 129.93, 131.40, 134.59, 153.19; IR (CH2C12)
3297, 3053, 2992, 2939, 2903, 2824, 2114, 1662, 1593, 1481, 1435, 1331, 1261. an =

+168 (0 = 0.5 in CHC13); mass spectrum FAB in NBA m/z (% rel.intensity) 258 W (60),

212

227 (100), 154.1 (100), 136.1 (100), 107 (35), 77 (30), HRMS calcd for C16H1803 m/z

258.1256, measd 258.1257.

 

Me Me
NaH, THF
% // = % é
Mel
OH OMe OH OMe OMe OMe
(S.R%275C (S,R)-282

2-Methaxy-3-((S)-1 -methaxyprap-2-ynyl)- I -((R)-1 -methaxyprap—2—ynyl)-5-methyl-
benzene (S,R)-282

Following the general procedure as described above for the preparation of (S,S)-267A,
the diastereomer (S,R)-282 could be obtained in 70 % yield (0.46 g, 1.82 mmol) from
(S,R)-275C (0.598 g, 2.6 mmol). Rf = 0.37 (hexanes / ethyl acetate = 85 / 15). Spectral
data for (S,R)-282: 1H NMR (CDC13, 500MHz) 6 2.34 (s, 3H), 2.58 (d, 2H, J = 2.5 Hz),
3.44 (s, 6H), 3.84 (s, 3H), 5.35 (d, 2H, J = 2.0 Hz), 7.44 (S, 2H); 13C NMR (CDC13,
125MHz) 6 20.93, 56.28, 63.57, 67.01, 75.12, 81.74, 129.85, 131.42, 134.60, 153.16; IR
(neat) 3290, 2990, 2939, 2903, 2824, 2114, 1664, 1591, 1481 cm]; mass spectrum FAB
in NBA m/z (% rel.intensity) 258 (M+, 50), 227 (100), 154 (100), 136 (60), HRMS calcd

for C16H1803 m/z 258.1256, measd 258.1257.

 

Me Me
TBSOTf
\\ / . . e \\ é
_ ImIdazole .
OH OMe OH CHZC'Z TBSO OMe OTBS
(R,R)-274C (R,R)-267B

2-Methaxy— 1, 3 -bis-( (R )- 1-(tert-butyldimethylsilylaxy)prap-2-ynyl-5-methyl-benzene 2678
To a solution of the alkynol 274C (99.2 % ee, 0.735 g, 3.2 mmol) in 35 mL of
dichloromethane was added imidazole (0.522 g, 7.7 mmol) followed by TBSOTf (1.6

mL, 7.04 mmol) at 0°C. The reaction mixture was subsequently warmed to room

213

temperature and stirred for 24 h. Addition of water (50 mL), extraction of the organic
layer with dichloromethane and removal of the solvent under reduced pressure afforded
the bis-propargyl TBS ether 267B in 92 % yield (1.35 g, 2.92 mmol) as a white solid. Mp
= 124-126°C. Spectral data for (R,R)-267B: 1H NMR (CDCl3, 500MHz) 6 0.08 (S, 6H),
0.16 (s, 6H), 0.88 (s, 18H), 2.32 (s, 3H), 2.47 (d, 2H, J = 2.4 Hz), 3.82 (s, 3H), 5.71 (d,
2H, J = 2.1 Hz), 7.39 (s, 2H); 13C NMR (CDCl3, 125MHz) 6 -4.90, -4.57, 18.23, 21.32,
25.77, 58.93, 63.03, 72.95, 82.57, 128.34, 134.38, 134.47; IR (neat) 3436, 3277, 2951,
2928, 2899, 2859, 2112, 1644, 1473, 1252 cm'l. mass spectrum m/z (% rel.intensity) 458
(M+ not found), 443 (M-CH3 , 2), 401 (100), 330 (9), 256 (17). Specific rotation up of

267B prepared from (R,R)-274C (99.2 % ee) = +1°(c = 1.57 in CHCl3)

 

Me
C ZrHCl
\ L...
, NIS ,
OMe OMe OMe OMe OMe OMe
(S,S)-267A (R,R)-279

I, 3 -Bis-( (R, E )-3 ~iada-I -methaxyallyl) -2-meth0xy-5 -methyl-benzene 2 79

Following the procedure described earlier for the synthesis of 245, the diyne (S,S)-267A
(0.69 g, 2.66 mmol) gave upon purification by column chromatography on silica gel (5 %
ethyl acetate / hexanes) the vinyl iodide (R,R)-279 in 76 % yield (1.02 g, 2.02 mmol) as
an orange oily liquid. Rf (ethyl acetate / hexanes = 19/ 1) = 0.35. Spectral data for (R,R)-
279: 1H NMR (CDCl;, 300MHz) 6 2.31 (s, 3H), 3.30 (s, 6H), 3.69 (s, 3H), 4.98 (d, 2H, J
= 6.5 Hz), 6.41 (d, 2H, J = 14.5 Hz), 6.65 (dd, 2H, J = 14.5, 6.5 Hz), 7.11 (s, 2H); ‘3
CNMR (CDC13, 125MHz) 6 21.04, 56.66, 62.86, 78.71, 78.19, 128.34, 132.24, 134.99,
145.38, 153.43; IR (CH2C12) 2982, 2930, 2822, 1605, 1478, 1431, 1340, 1277, 1091 cm";

mass spectrum FAB in NBA m/z (% rel.intensity) 514 (16), 483 (44), 387 (52), 361 (36),

214

197 (100), HRMS calcd for C16H20038i2 m/z 513.9503, measd 513.9504. 019 = -93.7 (c =

1.49 in CHC13)

 

 

Me
I 1
szerCl l I
NIS
OMe OMe OMe OMe OMe OMe
(S,R)-282 (R,S)-283

3 -( (R,E)-3 Jada-1 -methaxyallyl)-I -( (S, E)-3 Jada-l -methaxyallyl)-2-methaxy—5-methyal-
benzene 283

Following the procedure described earlier for synthesis of 245, the diastereomeric. vinyl
iodide (R,S)-283 was obtained in 72 % yield (0.93 g, 1.8 mmol) as light-yellow solid
from (S,R)-282 (0.575 g, 2.5 mmol). Mp = 104-106°C. Spectral data for (R,S)-283: ‘H
NMR (CDC13, 500MHz) 6 2.30 (s, 3H), 3.29 (s, 6H), 3.68 (s, 3H), 4.91 (d, 2H, J = 6.5
Hz), 6.42 (d, 2H, J = 14.5 Hz), 6.65 (dd, 2H, J = 14.5, 6.5 Hz), 7.11 (s, 2H); 13 C NMR
(CDC13, 125MHz) 6 21.04, 56.59, 62.93, 78.79, 79.20, 128.34, 132.25, 135.03, 145.35,
153.48; IR (neat) 2982, 2930, 2822, 1605, 1477, 1432, 1338, 1277 cm'l. Anal calcd for

C16H201203: C, 37.38; H, 3.92. Found: C, 37.55; H, 3.88.

   

 

OMe Me OMe
r- BuLi
i CI'(CO)6 i
OMe OMe OMe Me3OBF4 OMe OMe OMe
(R,R)-279 (S,S)-268

Chiral Bis-Carbene complex (S, S)-268

Procedure A:

To a solution of vinyl iodide 14 (0.92 mmol) in tetrahydrofuran (20 mL) at —78 0C was
added t -Butyllithium (4 eq, 1.7 M in pentane) and the reaction mixture was stirred at —78

°C for 30 min. Chromium hexacarbonyl (0.81 g, 3.68 mmol) was dissolved in 40 mL of

215

tetrahydrofuran and then transferred via cannula to the organolithium solution under
argon at —78 °C. The resulting deep red solution was warmed to room temperature and
stirred for 3 h. The solvent was evaporated under vacuum and water/ dichloromethane
(1: 1, 50 mL) was added and then trimethyl oxonium tetrafluoroborate (6.5 eq) was added
and the mixture stirred for 30 min. The organic layer (150 mL) was washed with water
(2 x 50 mL) and dried over anhydrous magnesium sulfate. After filtration the solvent
was removed and crude product was purified by silica gel chromatography (10 % ethyl

acetate / hexanes) to give carbene complex in 24 % yield (0.162 g, 0.22 mmol) as red oil.

Procedure B:

To a solution of vinyl iodide 279 (99.5 % ee, 0.651 g, 1.26 mmol) and chromium
hexacarbonyl (5.04 mmol, 1.11 g) in 55 mL of tetrahydrofuran at —78 °C was added t-
butyllithium (4 equiv, 1.7 M in pentane) and the reaction mixture was stirred at this
temperature for 30 min. The resulting deep red solution was then warmed to room
temperature and stirred for 3 h. The solvent was evaporated under vacuum and water/
dichloromethane (1:1, 50 mL) was added and then trimethyl oxonium tetrafluoroborate
(6.5 eq) was added and the mixture stirred for 30 min. The organic layer (150 mL) was
washed with water (2 x 50 mL) and dried over anhydrous magnesium sulfate. After
filtration the solvent was removed and crude product was purified by silica gel
chromatography (10 % ethyl acetate / hexanes) to give carbene complex 268 in 24 %
yield (0.224 g, 0.31 mmol) as red oil. Rf (hexanes / ethyl acetate = 9/ 1) = 0.4. Spectral
data for (S,S)-268: 1H NMR (CDCl;, 300MHz) 6 2.26 (s, 3H), 3.33 (s, 6H), 3.76 (s, 3H),
4.73 (s, 6H), 5.09 (s, 2H), 6.11 (d, 2H, J = 11.5 Hz), 7.10 (s, 2H), 7.54 (d, 2H, J= 14.5

Hz); ‘3CNMR(CDC13, 125MHz) 20.85, 56.95, 63.06, 66.58, 76.22, 129.08, 131.13,

216

132.09, 135.34, 142.12, 153.68, 216.43, 223.98, 337.19; IR (neat) 2934, 2828, 2060,
1927, 1605, 1452, 1226 cm"; mass spectrum m/z (% rel.intensity) 730 M (10), 699 (10),
590 (45), 450 (100), 154 (80), HRMS calcd for C301126Cr2015 m/z 730.0082, measd
730.0084. Specific rotation of (S,S)-268 prepared from (S,S)-274C (99.5 % ee) up = -69

°(c = 1.22 in CHCl3).

Me OMe Me OMe
l 1
I l t_ BuLi (OC)5Cr | l Cr(C0)s
CKCOR
OMe OMe OMe Me3OBF4 OMe OMe OMe
(R,S)-283 (S,R)-284

Achiral Bis-Carbene complex (S,R)-284

Following procedure A described above for the synthesis of (S, S)-284, the diastereomer
(R,S)-vinyl iodide 283 gave none of the diastereomeric bis-carbene complex (S,R)-284.
On the other hand, by applying procedure B, (R,S)-283 (0.91 g, 1.77 mmol) gave 0.275 g
(0.38 mmol, 21 %) of the bis-carbene complex (S,R)-284 as deep-red oil upon workup
and purification by silica-gel chromatography in 15 % ethyl acetate / hexanes. Rf (ethyl
acetate / hexanes = 85/15) = 0.30. Spectral data for (S,R)-284 : 1H NMR (CDC13,
300MHz) 6 2.25 (s, 3H), 3.34 (s, 6H), 3.76 (s, 3H), 4.71 (s, 6H), 5.08 (d, 2H, J = 5.1
Hz), 6.07 (dd, 2H, J = 15.0, 5.7 Hz), 7.10 (s, 2H), 7.52 (d, 2H, J: 15.0 Hz); ‘3 CNMR
(CDC13, 125MHz) 20.87, 56.98, 62.96, 66.57, 76.18, 128.90, 130.84, 132.10, 135.39,
141.96, 153.46, 216.41, 223.98, 337.01; IR (neat) 2934, 2828, 2060, 1917, 1605, 1477,
1452, 1275, 1228 cm" ; mass spectrum m/z (% rel.intensity) 730 (MI, 2.8), 699 (3.5), 590
(64), 450.0 (100), 418.9 (28), 179.1 (40), HRMS calcd for C30H26Cr2015 m/z 730.0082,

measd 730.0080.

217

H NaH H

A
V

OHC 3 Mel, THF OHC ,
0M9 0” OMe OMe
287 294

(S) -2-Meth 0xy-3- (I -methaxyprap-2-ynyl)-5-methylbenzaldehyde 292

Following the procedure described above for the preparation of (S,S)-267A, (2.10 g,
10.31 mmol, 94.1 % ee) of (S)-287, 1.3 equiv. of sodium hydride and excess of
iodomethane afforded upon purification by silica-gel chromatography (15 % ethylacetate
/ hexanes) 1.51 g (6.91 mmol, 67 %) of (S)-294 as colorless oil. Rf(hexanes / ethylacetate
= 85/15) = 0.43. Spectral data for (S)-294: 1H NMR (CDCl3, 500MHz) 6 2.37 (s, 3H),
2.65 (d, 1H, J = 2.5 Hz), 3.49 (s, 3H), 3.94 (s, 3H), 5.40 (d, 1H, J = 2.0 Hz), 7.64 (s, 1H),
7.73 (s, 1H), 10.32 (s, 1H); ‘3 CNMR(CDC13, 125MHz) 6 20.64, 56.42, 65.38, 66.39,
75.60, 81.05, 128.76, 129.77, 132.56, 134.63, 135.56, 158.62, 189.52; IR (neat) 3285,
2938, 2826, 2753, 2114, 1693, 1589, 1479 cm"; mass spectrum m/z (% rel.intensity) 219
(M++1, 22), 218 (M+, 33), 203 (36), 187 (100), 140 (44), 123 (36), HRMS calcd for
C13H1503 (M++1) m/z 219.1021, measd 219.1020. The above alkylation step was
performed several times to optimize the yield of (S)-294 and the rotation was recorded on
material that was obtained from (S)-287 (93.4 % ee). Specific rotation an of (S)-294

prepared from (S)-287 (93.4 % ee) = + 15.4 °(c = 1.06 in CHC13)

 

Me Me
H H
/ NaBH4 Ho /
OHC ; MCOH ;
OMe OMe OMe OMe
294 29s

(S)-(2-Meth0xy-3 -(1 -meth0xyprap-2-ynyl)-5 ~methylphenyl) -methanol 295

218

The aryl aldehyde 294 (1.52 g, 6.94 mmol, 94.1 % ee) was dissolved in methanol (c =
0.22M) and transferred to a clean 100 mL round-bottomed flask. Sodium borohydride
(1.1 eq) was added portion-wise to allow the exothermic reaction to subside and the
resultant mixture was stirred at room temperature for 3-4 h. Aqueous workup followed by
three-fold extraction with ether and removal of solvent under reduced pressure afforded
1.41 g (6.38 mmol, 92 %) of the benzyl alcohol (S)-295 as an oil. Rp(hexanes /
ethylacetate = 1/1) = 0.44. Spectral data for (5)295: lH NMR(CDC13, 500MHz) 6 2.31
(s, 3H), 2.59 (d, 1H, J = 2.5 Hz), 3.46 (s, 3H), 3.91 (s, 3H), 4.52 (s, 2H), 5.32 (d, 1H, J=
2.0 Hz), 7.19 (d, 1H, J = 2.5 Hz), 7.40 (d, 1H, J = 2.0 Hz); ‘3 CNMR (CDC13, 125MHz)
6 20.43, 27.49, 56.11, 62.58, 66.66, 74.90, 81.24, 129.73, 130.69, 131.54, 132.30, 134.33,
153.50; IR (neat) 3431, 3287, 2937, 2828, 2114, 1595, 1481 cm'l; mass spectrum m/z (%
rel.intensity) 220 (W, 68) 203 (44), 189 (100), 159 (26), HRMS calcd for C13H1603
220.1099, measd 220.1098. The above reduction step was carried out several times to
optimize yield of (S)-295 but the rotation was recorded on material obtained from (S)-287
(93.7 % ee). Specific rotation up of (S)-295 prepared from (S)-287 (93.7 % ee) = + 20.6

(c = 0.58 in CHCl3)

 

Me Me
H
HO 1) p - TsCl Br /
OMe OMe pyridine, OMe OMe
295 2) LiBr, DMF 296

(S)-1 -(Bromomethyl)-2-methaxy-3-(1-methaxyprap-2—ynyI)-5-methylbenzene 296
The benzyl alcohol 295 (1.4 g, 6.36 mmol, 94.1 % ee) was dissolved in 40 mL of
dichloromethane in a 100 mL three necked round bottomed flask and p-toluene sulfonyl

chloride (1.82 g, 9.54 mmol) was added followed by pyridine (0.77 mL, 9.54 mmol). The

219

reaction was monitored for completion by TLC and excess dichloromethane (100 mL)
was added. The organic layer was washed with 2N HCl (100 mL) followed by saturated
sodium bicarbonate and brine solution (100 mL each). Drying over anhydrous
magnesium sulfate followed by removal of the solvent under reduced pressure afforded
the crude tosylate as a solid that was immediately taken to the next step.

The crude benzyl tosylate was dissolved in N,N-dimethyl formamide (40 mL) in a
100 mL flask and anhydrous lithium bromide (0.66 g, 7.55 mmol) was added. The
resultant mixture was heated to 50 °C and stirred for 3-4 h. The reaction mixture was
poured into water (100 mL) and then extracted with ether (100 mL). Drying over
anhydrous magnesium sulfate followed by removal of the solvent afforded the crude
product which was purified by silica-gel chromatography (10 % ethylacetate / hexanes) to
afford 57 % (1.0 g, 3.55 mmol) of the bromide (S)-296 as colorless oil. Rf(hexanes /
ethylacetate = 9/1) = 0.39. Spectral data for (S)-296: lH NMR(CDC13, 300MHz) 6 2.31
(s, 3H), 2.59 (d, 1H, J = 2.1 Hz), 3.45 (s, 3H), 3.82 (s, 3H), 4.68 (s, 2H), 5.34 (d, 1H, J=
2.4 Hz), 7.16 (d, 1H, J = 2.4 Hz), 7.39 (d, 1H, J = 2.1 Hz); ‘3 CNMR (CDC13, 125MHz)
6 20.87, 56.38, 61.10, 62.85, 66.99, 75.13, 81.72, 128.79, 130.48, 131.41, 133.62, 134.49,
153.40; IR (neat) 3290, 2942, 2824, 2114, 1591, 1483, 1435 cm'l. mass spectrum m/z (%
rel. intensity) 284 M+ +2 (11, 8‘13:), 282 M+ (12, 79st), 260 (12,8‘Bt), 258 (45, 79131:), 240
(32, 81Hr), 238 (85, 79m), 203 (90), 171 (100), 128 (65), 69 (45), HRMS calcd for
C13H1579Br02 m/z 282.0255, measd 282.0254. The bromination sequence was subjected
to several attempts to optimize the yield of (S)-296 but the rotation was recorded on
material obtained from (S)-287 (91 % ee). Specific rotation an of (S)-296 prepared from

(S)-287 (91 % ec) = + 8.6° (C = 0.62 in ch13).

220

/ (Tqu==—)— In TMS

Br 3

A

OMe OMe Pd “”002

296

 

(S)-(3-(2-Metharv-3-(I -methaxyprap-Z-ynyl)-5-methylphenyl)prap-1-ynyl)trimethylsilane
297

By following the procedure discussed earlier for the preparation of 239 and reducing the
reagent stoichiometry by a factor of two, the benzyl halide 296 (1.0 g, 3.55 mmol, 94.1 %
ee) afforded the diyne 297 in 98 % yield (1.04 g, 3.46 mmol) as yellow oil. R,(hexanes /
dichloromethane = 19/ 1) = 0.42. Spectral data for (S)-297: 1H NMR (CDC13, 300MHz) 6
0.13 (s, 9H), 2.31 (s, 3H), 2.58 (d, 1H, J = 2.5 Hz), 3.44 (s, 3H), 3.60 (s, 2H), 3.77 (s,
3H), 5.32 (d, 1H, J = 2.1 Hz), 7.28 (s, 1H), 7.33 (s, 1H); '3 CNMR (CDC13, 125MHz) 6
0.29, 20.71, 21.19, 56.63, 62.53, 67.43, 75.27, 82.11, 87.00, 104.67, 128.03, 129.79,
131.33, 134.52, 153.34 (one aryl carbon missing); IR (neat) 3289, 2959, 2899, 2822,
2175, 1482, 1435 cm". Anal calcd for c.8H240281: c, 71.95; H, 8.05. Found: c, 72.19;
H, 8.06. The cross coupling step was subjected to several attempts to optimize the yield
of (S)-297 but the rotation was recorded on material that was obtained from (S)-287 (93.4

% ee). Specific rotation (19 of (S)-297 prepared from (S)-287 (93.4 % ee) = +13.1°(c =

 

0.45 m CHC13)
Me
TMS
\ / AgNO3 / KCN;
OMe OMe
297

 

(S)-2-Methaxy—I (-meth0xyprap—2-ynyl)-5-methyl—3-(prap-2-ynyl)benzene 285

221

By following the procedure reported earlier for the synthesis of 228, the diyne 297 (1.04
g, 3.48 mmol, 94.1 % ee) upon desilylation and purification by silica-gel chromatography
(5 % Ethyl acetate / hexanes) afforded 0.633 g (2.78 mmol, 80 %) of diyne 285 as an oil.
a. (hexanes / ethyl acetate = 19 / 1) = 0.23. Spectral data for (S)-285: lH NMR(CDC13,
300MHz) 6 2.14 (t, 1H, J: 2.7 Hz), 2.32 (s, 3H), 2.58 (d, 1H, J= 2.1 Hz), 3.45 (s, 3H),
3.58 (d, 2H, J = 2.7 Hz), 3.79 (s, 3H), 5.33 (d, 1H, J= 2.4 Hz), 7.29 (s, 1H), 7.34 (s, 1H);
l3CNMR (CDC13, 125MHz) 6 19.04, 20.91, 56.37, 62.72, 67.15, 70.24, 75.07, 81.79,
81.98, 127.95, 129.23, 130.93, 131.19, 134.41, 153.04; IR (CDC13) 3292, 2946, 2826,
21 18, 1479, 1433 cm}; mass spectrum m/z (% rel.intensity) 228 (MI, 30), 197 (50), 154
(100), 136 (60), HRMS calcd for C15H16Oz 228.1150, measd 228.1151. Specific rotation

of (S)-285 up obtained from (S)-287 (93.4 % ee) = + 3.5°(c = 0.43 in CHC13)

 

 

Me Me
TIPS
NaH (1.1 eq) _
OH OM CHO Mel (5 eq) OHC
e THF, rt

(IO-286 (R)-309
(R )-2-Methaxy-3 - ( 1 -methaxy—3 -( triisopropylsilyl)prap-2-ynyl) -5 -methylbenzaldehyde 3 09
Following a similar procedure to that described for the preparation of 294, the propargyl
methyl ether 309 was obtained from (R)-286 (61 % ee, 2.74 g, 7.6 mmol) in 92 % yield
(2.62 g, 6.99 mmol) upon purification by silica-gel chromatography (5 % ethyl acetate /
hexanes) as colorless oil. Rf (hexanes / ethylacetate = 85/15) = 0.61. Spectral data for (R)-
309: 1H NMR(CDC13, 500MHz) 6 1.07 (s, 21H), 2.34 (s, 3H), 3.49 (s, 3H), 3.93 (s, 3H),
5.43 (s, 1H), 7.62 (d, 1H, J: 2.5 Hz), 7.80 (d, 1H, J = 2.5 Hz), 10.31 (s, 1H); '3 CNMR
(CDCl3, 125MHz) 6 11.16, 18.55, 20.66, 56.14, 65.46, 67.13, 89.40, 104.25, 128.87,

129.58, 133.11, 134.46, 136.33, 158.97, 189.73; IR (neat) 2944, 2866, 2820, 2170, 1694,

222

1605, 1589, 1479 cm "1; mass spectrum m/z (% rel.intensity) 373 (M+-1,40) 359 (40), 343
(100), 331(32), 89 (32), 73 (36), HRMS calcd for C22H33O3Si m/z 373.2199, measd

373.2196. Specific rotation of (R)-309 obtained from (R)-286 (61 % ee) up = -11.2°(c =

 

2.86 in CHCI3)
Me Me
TIPS TIPS
NaBH4, MeOH k
OHC ; ' ”0 .
OMe OMe OMe OMe
309 310

(R)-(2-methaxy-3-(l -methaxy-3-(trz'isaprapylsilyl)prap-2-ynyl)-5-methylphenyl)methanal
310

Following the procedure described earlier for the synthesis of 295, the aldehyde 309
(2.52 g, 6.73 mmol) was reduced to the benzyl alcohol (R)-310 in 97 % yield (2.45 g,
6.53 mmol) as colorless oil. Rf (hexanes / ethyl acetate = 1/1) = 0.71. Spectral data for
(R)-3l0: 1H NMR (CDC13, 500MHz) 6 1.07 (s, 21H), 2.29 (s, 3H), 3.47 (s, 3H), 3.82 (s,
3H), 4.71 (s, 2H), 5.39 (s, 1H),17.14 (d, 1H, J = 2.0 Hz), 7.48 (d, 1H, J = 2.0 Hz)
(hydroxyl group not observed); ‘3 CNMR (CDC13, 125MHz) 6 11.17, 18.56, 20.86,
60.50, 63.87, 87.86, 107.14, 129.53, 133.91, 134.46, 153.10 (two aryl carbons, benzylic
and propargylic carbons missing); IR (neat) 3416, 2944, 2867, 2170, 1646, 1433, 1382,
1327 cm]. mass spectrum m/z (% rel.intensity) 376 (MI, 32), 359 (35), 345 (100), 259
(20), 141 (26), HRMS calcd for C22H3603Si m/z 376.2434, measd 376.2432. Specific

rotation of (R)-310 obtained from (R)—286 (61 % ee) up = -9°(c = 0.58 in CHC13)

 

Me Me
TIPS TIPS
Ho ¢ CBr4, PPh3 3 Br /
OMe OMe OMe OMe
310 311

223

(R)-(3-(3-(bromomethyl)-2-methaxy—5-methylphenyl)-3-methaxyprap-I-
ynyl)triisaprapylsilane 311

The alcohol 310 (61 % ee, 2.25 g, 5.99 mmol) was dissolved in dichloromethane (30 mL)
and triphenylphosphine (1.88 g, 7.18 mmol) was added at room temperature. Carbon
tetrabromide (2.38 g, 7.18 mmol) was slowly added to the solution at room temperature
and the resultant mixture was stirred for 5 h. The solution was concentrated to 20 % of
the total volume and diluted with ether (40 mL). The white precipitate was filtered and
the filtrate was concentrated. The residue was then purified by silica-gel chromatography
(5 % ethyl acetate / hexanes) to afford the benzyl bromide 311 (2.15 g, 4.91 mmol, 82 %)
as colorless oil. Rf (hexanes / ethyl acetate = 19/1)= 0.56. Spectral data for (R)-311: lH
NMR(CDC13, 300MHz) 6 1.07 (s, 21H), 2.28 (s, 3H), 3.47 (s, 3H), 3.91 (s, 3H), 4.53 (s,
2H), 5.37 (s, 1H), 7.17 (d, 1H, J = 2.4 Hz), 7.49 (d, 1H, J = 2.1 Hz); ‘3 CNMR (CDC13,
125MHz) 6 10.82, 18.23, 20.37, 27.67, 55.69, 62.64, 67.36, 88.53, 100.20, 104.48,
130.54, 131.95, 132.07, 133.98 (one aryl carbon missing); IR (neat) 2946, 2891, 2866,
2820, 2170, 1693, 1591, 1481, 1464, 1435 cm]. Specific rotation up of (R)-311 obtained

from (R)-286 61 % ee = -6.45 °(c = 4.5 in CHC13)

Me

TIPS (TMS=-)-— 31a TMS

Br %—
Pd (dPP0C12

 

OMe OMe
311

 

(R)-2-methaxy— I -(1 -methaxy-3-(triisopropylsilyl)prap-2-ynyl)-5-methyl-3-(3-
(trimethylsilprrap-Z-ynyl)benzene 312
Following the same procedure as reported earlier for the synthesis of 239 and reducing

the reagent stoichiometry by a factor of two, benzyl bromide 311 (2.08 g, 4.91 mmol, 61

224

% ee) gave 312 in 77 % yield (1.63 g, 3.78 mmol) upon purification by Silica-gel
chromatography (20 % dichloromethane/ hexanes) as an yellow oil. Rf (hexanes /
dichloromethane = 4/ 1) = 0.32. Spectral data for (R)-312: 1H NMR (CDCI3, 300MHz) 6
0.15 (s, 9H), 1.06 (s, 21H), 2.29 (s, 3H), 3.45 (s, 3H), 3.60 (s, 2H), 3.77 (s, 3H), 5.37 (s,
1H), 7.27 (d, 1H, J = 2.0 Hz), 7.42 (d, 1H, J = 3.0 Hz); 13 CNMR (CDCI3, 125MHz) 6
0.04, 11.19, 18.58, 20.48, 55.94, 62.30, 67.85, 86.72, 88.55, 104.54, 105.14, 128.59,
129.33, 130.81, 131.46, 133.91, 153.28 (one methine carbon missing); IR (neat) 2944,
2895, 2867, 2818, 2175, 1693, 1479, 1435, 1280 cm'l; mass spectrum m/z (%
rel.intensity) 455 (NF-1, 32), 207 (16), 147 (30), 73 (100), HRMS calcd for C27Ha302Si2
m/z 455.2802, measd 455.2805. Specific rotation (19 of (R)-312 obtained from (R)-286 =
-2.4°(c = 2 in CHC13)

‘IMS llPS
A NO , KCN
/ g 3

//

 

OMe OMe
312

 

(R)-tri isopropyl (3 -methaxy-5 -methyl-3 -(prap-2-ynyl)phenyl)prap-1 -ynyl)silane 313

Following the procedure reported earlier for the synthesis of 228, desilylation of diyne
312 (1.62 g, 3.55 mmol, 61 % ee) afforded 313 in 90 % yield (1.22 g, 3.20 mmol) upon
purification by silica-gel chromatography (5 % ethyl acetate / hexanes) as an yellow oil.
Rf (hexanes / ethylacetate = 19/ 1) = 0.56. Spectral data for (R)-313: 1H NMR (CDC13,
300MHz) 6 1.07 (s, 21H), 2.13 (t, 1H, J= 3.0 Hz), 2.30 (s, 3H), 3.46 (s, 3H), 3.58 (t, 2H,
J= 2.5 Hz), 3.79 (s, 3H), 5.39 (S, 1H), 7.27 (d, 1H, J= 2.5 Hz), 7.43 (d, 1H, J: 2.0 Hz);
‘3 CNMR (CDC13, 125MHz) 6 11.20, 18.58, 19.05, 20.85, 55.91, 62.32, 67.83, 70.16,

82.11, 88.61, 105.09, 128.79, 129.05, 130.70, 131.61, 134.06, 153.26; IR (neat) 3314,

225

2943, 2886, 2820, 2170, 1479, 1464, 1435, 1280 cm"; mass spectrum m/z (%
rel.intensity) 383 (M+-1, 20), 141 (76), 89 (88), 73 (96), 59 (100), HRMS calcd for
C24H3502Si m/z 383.2406, measd 383.2408. Specific rotation of (R)-313 obtained from

(R)-286 (61 % ee) up = -6°(c = 0.88 in CHC13).

 

Me Me
TIPS I
\ CpZZrHCl _ l TIPS
i NIS i
OMe OMC 0M6 0M6
313 314

(R,E)-(3-(3-iadaallyl)-2-methaxy-5-methylphenyl)-3-methaxyprap-1-
ynyl)triisaprapylsilane 314

Following the procedure discussed earlier for the synthesis of (R,R)-279, the alkyne 313
(1.36 g, 3.55 mmol, 61 % ee) was reacted with only 1.6 equiv. of the Schwartz reagent
and N-iodosuccinimide to give the vinyl iodide 314 in 88 % yield (1.44 g, 3.12 mmol) as
an orange oil upon purification by silica-gel chromatography (5 % ethyl acetate /
hexanes). Rf (hexanes / ethylacetate = 19/1)= 0.55. Spectral data for (R)-314: 1H NMR
(CDC13, 500MHz) 6 1.07 (s, 21H), 2.27 (s, 3H), 3.35-3.37 (m, 2H), 3.47 (s, 3H), 3.74 (s,
3H), 5.38 (s, 1H), 6.05 (d, 1H, J= 14.0 Hz), 6.63 (dt, 1H, J= 14.5, 6.5 Hz), 6.92 (d, 1H, J
= 1.0 Hz), 7.42 (d, 1H, J= 1.5 Hz); ‘3 CNMR (CDC13, 125MHz) 6 11.45, 18.85, 21.07,
36.29, 56.23, 62.79, 68.17, 76.49, 88.87, 105.35, 128.85, 130.96, 131.67, 132.16, 134.20,
144.68, 153.90; IR (neat) 2944, 2891, 2868, 2251, 2170, 1478, 1468 cm"; mass spectrum
m/z (% rel.intensity) 512 (M+, 20), 497 (100), 481 (68), 315 (46), 59 (80), HRMS calcd

for C24H37lOle m/z 512.1608, [1'16an 512.1605

226

I TIPS TB AF

i 0 °C
OMe OMe

314

 

(S, E )-1 -(3 -iodoallyl)-2-methoxy-3 -( I -methoxyprop2-ynyl)-5 -methylbenzene 315

To a solution of the vinyl iodide 314 (1.28 g, 2.51 mmol) in ether at 0°C was added
tetrabutyl ammonium fluoride (3.8 mL, 1.5 equiv) dropwise via a syringe and after
addition stirring at this temperature was continued for 30 min. Addition of water (50 mL),
extraction with ether (100 mL) followed by drying the organic layer over anhydrous
magnesium sulfate and removal of the solvent afforded the crude product that was
purified by silica-gel chromatography (30 % dichloromethane / hexanes) to give 0.71 g
(2.01 mmol, 80 %) of the iodide 315 as yellow oil. Rf (hexanes / dichloromethane =
70/30)= 0.34. Spectral data for (S)-315: lH NMR (CDC13, 500MHz) 6 2.29 (s, 3H), 2.58
(d, 1H, J = 2.5 Hz), 3.36 (d, 2H, J = 7.0 Hz), 3.46 (s, 3H), 3.74 (s, 3H), 5.34 (d, 1H, J =
2.5 Hz), 6.07 (d, 1H, J = 14.0 Hz), 6.64 (dt, 1H, J = 14.0, 7.0 Hz), 6.94 (d, 1H, J = 2.0
Hz), 7.33 (d, 1H, J = 2.0 Hz); ‘3 CNMR(CDC13, 125MHz) 6 21.12, 36.24, 56.67, 62.76,
67.47, 75.33, 76.59, 82.08, 127.06, 128.04, 131.11, 131.78, 134.56, 144.56, 153.71; IR
(neat) 3298, 2942,2865, 1479, 1464, 1433 cm". mass spectrum m/z (% rel.intensity) 356

(56), 325 (100), 197 (36), 159 (36), 115 (40), 69 (52), HRMS calcd for C15H17Ozl m/z

 

356.0274, measd 356.274.

Me OMe Me

I
l 1] PhLi (0050 I
/ 4'
; 2] I-BuLi ;

OMe OMe 3] Cr(CO)6, Me3OBF4 OMe OMe

315 298
C arbene Complex 298

227

To a solution of the vinyl iodide 315 (0.71 g, 2 mmol) in 20 mL of dry tetrahydrofuran
was added phenyl lithium (1.1 equiv, 1.9 M in cyclohexane) at —78°C and the resulting
solution was stirred at this temperature for another 30 min. t-Butyl lithium (2.4 mL, 2
equiv, 1.7 M in pentane) was added at this temperature and the resultant mixture was
stirred for another 45 min. Chromium hexacarbonyl (0.88 g, 2 equiv) was then added and
then upon warming to room temperature the deep red solution turned purple. The reaction
was continued for another 3 h after which solvent was removed under reduced pressure.
The residue was redissolved in a 1:1 mixture of dichloromethane and water (60 mL)
followed by addition of trimethyl oxonium tetrafluoroborate (0.89 g, 6 mmol), which
caused the solution to turn brown. Extraction with dichloromethane (100 mL), drying the
organic layer over magnesium sulfate, and removal of solvent afforded the crude product
which was purified by silica-gel chromatography (15 % ethylacetate / hexanes) to yield
the carbene complex 298 as an deep-red oil in 8 % yield (0.074 g, 0.16 mmol). Rf
(hexanes / ethylacetate = 85/15)= 0.38. Spectral data for (S)-298: 1H NMR (CDCI3,
500MHz) 6 2.32 (s, 3H), 2.62 (s, 1H), 3.49 (broad s, 5H), 3.78 (s, 3H), 4.75 (s, 3H), 5.38
(S, 1H), 6.28 (s, 1H), 6.97 (s, 1H), 7.39 (s, 2H) (It appears that two benzylic hydrogens
overlap with methoxy singlet at 3.49); ‘3 CNMR (coca, 125MHz) 6 20.76, 31.57,
56.31, 62.49, 66.46, 67.27, 75.07, 82.34, 128.15, 130.51, 131.90, 133.18, 134.47, 144.80,
153.72, 216.61, 223.91, 336.17 (One vinyl carbon missing).
Chiral Calixarenes by Triple Annulation
General Procedure

Unless otherwise specified, the bis-carbene complex and the diyne (1:1 molar

ratio) were dissolved in 1,2-dichloroethane (2.5 mM) in a flame dried 100 mL or 250 mL

228

Schlenk flask under argon. The solution was deoxygenated by freeze pump thaw method
in three cycles (~196 to 25 0C) and then backfilled with argon at ambient temperature.
The flask was sealed with a threaded high-vacuum Teflon stopcock and heated to 100 °C
for 20-40 min during which time the deep red solution turned yellow. The yellow
solution was stirred overnight exposed to air to facilitate demetalation of the
arenechromium tricarbonyl complex. The solvent was removed under vacuum and the
residue dissolved in ethyl acetate (50 mL) and then filtered through a short pad of silica
gel. Further washing of the SiOz pad with ethyl acetate and evaporation of the solvent
gave the crude calixarene, which was purified by flash chromatography on silica gel. The
amount of dimer formed in all of the reactions was either none or in negligible amounts
based on mass spectra of the purified calixarenes.

5,17-dimethyl—2(R) ,II, 23, 26, 28-pentamethoxy— 25,27—dihydroxycalix[4]arene 256

(OC)5Cr I O I Cr(CO)5
Me Me 0M6

 

 

/
Me 0H 0M6 OMe HO
(R)-256 31%

 

A mixture of the bis-carbene complex 229A (0.122 g, 0.183 mmol) and diyne (S)—285 (93
% ee, 0.043 g, 0.183 mmol) in 72 mL of 1,2—dichloroethane was subjected to three
freeze-pump thaw cycles and heated to 100 °C for 20-40 min. TLC analysis of the crude

material revealed only one spot that was mobile on the TLC plate and examination of the

229

crude lH NMR indicated no other side products. Purification by silica-gel
chromatography (50 % ethylacetate / hexanes) afforded the calix[4]arene pentamethyl
ether in 31 % yield (0.032 g, 0.057 mmol) as an off-white solid. Mp = 270-273 °C.
Spectral data for (R)-256: 2.03 (s, 6H), 3.22 (d, 1H, J = 12.6 Hz), 3.32 (d, 2H, J = 13.2
Hz), 3.44 (s, 3H), 3.72 (s, 3H), 3.74 (s, 3H), 3.94 (s, 3H), 3.98 (S, 3H), 4.11 (d, 1H, J =
12.3 Hz), 4.14 (d, 1H, J= 13.2 Hz), 4.35 (d, 1H, J= 12.9 Hz), 5.94 (s, 1H), 6.58 (d, 1H, J
= 3.0 Hz), 6.60 (d, 1H, J = 3.0 Hz), 6.65 (d, 1H, J = 3.0 Hz), 6.72 (s, 1H), 6.75 (d, 2H, J
= 5.5 Hz), 6.90 (d, 1H, J = 2.0 Hz), 6.96 (d, 1H, J= 3.0 Hz), 7.59 (s, 1H), 7.69 (S, 1H); 13
CNMR (CDCl3, 125MHz) 6 20.86, 21.02, 31.03, 31.82, 31.95, 55.78, 55.81, 57.36,
63.51, 63.74, 73.83, 108.12, 113.42, 114.00, 114.32, 126.87, 128.36, 128.73, 129.41,
129.63, 130.06, 130.49, 130.92, 132.07, 132.37, 133.22, 134.36, 134.56, 134.88, 145.79,
146.78, 150.87, 151.04, 152.25, 152.91; IR (CH2C12) 3333, 2943, 2829, 1603, 1461,
1433, 1346 cm'hmass spectrum m/z (% rel.intensity) 570 (100), 539 (60), 507 (92), 475
(52), 154 (64), HRMS calcd for C35H3gO7 m/z 570.2616, measd 570.2618. Specific
rotation up of 256 isolated by silica gel chromatography and obtained from (S)-287 (93.4
% ee) = -5.4 (c = 0.91 in CHC13)

5,1 7-dimethyl—2(R), 8(R), 1 1,23,26,28-hexamethoxy-25,2 7-dihydroxycalix[4]arene 25 7A

230

OMe Me OMe

 

 

OMe
229A 4
+
Me
§ é
OMe OMe OMe 257A 32 %
267A Mixture of two conformers ratio 2.6:]

A mixture of carbene complex 229A (0.161 g, 0.24 mmol) and diyne 267A (0.082 g, 0.32
mmol, 99.2 % ee), in 96 mL of 1,2- dichloroethane was subjected to thermolysis
following the generic procedure and upon purification by silica-gel chromatography (25
% ethylacetate / hexanes) afforded 46 mg (32 %) of 2.6 / 1 inseparable mixture of
conformers of 257A as a light-yellow solid. TLC analysis of the crude material revealed
only one mobile spot present on the TLC plate when developed with KMnO4 and
examination of the crude 1H NMR indicated no other side products. Mp = > 320°C with
decomposition. Rf = 0.22 (hexanes / ethyl acetate = 3/1) Spectral data for 257A: Major
conformer : 1H NMR (CDC13, 600MHz) 6 2.10 (s, 3H), 2.12 (s, 3H), 3.35 (d, 2H, J =
13.5 Hz), 3.41 (s, 3H), 3.47 (s, 3H), 3.78 (s, 6H), 3.94 (s, 3H), 3.99 (s, 3H), 4.10 (d, 1H, J
= 13.0 Hz), 4.39 (d, 1H, J: 13.0 Hz), 5.06 (s, 1H), 6.01 (s, 1H), 6.61 (d, 1H, J: 3.0 Hz),
6.65 (d, 1H, J = 2.0 Hz), 6.73 (s, 1H), 6.77 (s, 2H), 6.85 (s, 1H), 6.93 (s, 1H), 6.97 (d, 1H,
J = 2.5 Hz), 7.07 (s, 1H), 7.78 (s, 1H); Minor conformer: 1H NMR (CDC13, 600MHz) 6
2.31 (s, 3H), 2.38 (s, 3H), 3.34 (s, 3H), 3.36 (s, 3H), 3.38 (s, 3H), 3.43 (s, 3H), 3.52 (s,

3H), 4.12 (d, 1H, J= 11.5 Hz), 5.13 (s, 1H), 6.35 (s, 1H), 6.64 (1H overlapping with Ar-

231

H’s of major), 6.87 (s, 1H), 7.09 (s, 1H), 7.16 (d, 1H, J = 2.0 Hz), 7.40 (s, 1H), 7.59
(broad peak undefined no. of H), Three of the methylene hydrogens, one methoxy, two
aromatic hydrogens from the minor conformer are not seen. 13C NMR (125MHz) data
reported is on a mixture of the two conformers. 6 20.85, 20.89, 20.92, 21.20, 29.68,
31.44, 31.71, 32.05, 37.78, 55.71, 55.74, 55.78, 57.16, 57.28, 57.30, 57.75, 60.99, 62.96,
63.66, 64.26, 73.33, 81.73, 87.93, 107.68, 108.32, 109.84, 112.78, 113.49, 114.14,
114.89, 115.52, 126.30, 127.01, 128.35, 128.46, 128.83, 128.91, 129.31, 129.45, 129.96,
130.01, 130.06, 130.11, 130.18, 130.94, 131.20, 132.34, 132.63, 132.85, 133.10, 133.38,
133.45, 134.13, 134.46, 134.59, 134.74, 135.46, 136.55, 144.41, 145.89, 146.04, 146.30,
151.33, 151.71, 151.76, 151.80, 152.62, 152.93, 153.01, 153.24 (one aryl and methoxy
carbon not located) ; IR (CH2C12) 3328, 2936, 2829, 2247, 1607, 1461, 1435 cm'l. mass
spectrum m/z (% rel.intensity) 600 (W, 40), 569 (18), 537 (35), 505 (60), 307 (36), 154
(100), HRMS calc’d for C36H4003 m/z 600.2720, measd 600.2730. Specific rotation up of
the material isolated by silica gel chromatography = - 11.6 (c = 0.94 in CHC13). From an
extensive analysis of the lD-NOE and NOESY experiments, the major and minor
isomers were deduced to be the cone and partial cone conformations. Exchange peaks
from major isomer were observed in the NOE spectra of the minor isomer indicating that
the minor conformer was inter-converting to the major conformer by a process involving
rotation through the annulus but was not fast enough on the NMR time scale to give an
average spectrum of the two conformers. HPLC analysis revealed the presence of only
one peak (99.5105 hexanes: i-PrOH to 95:5 hexanes: i -PrOH, flow rate 0.5 mL/min, 254

nm, retention time = 38.62 min).

232

 

 

 

U!

U!

 

 

 

0'!

ll Lil LLU
A”
p
c. a a3
llltjulllll
a 8
. -

QQGOUIMQOUUN
O

in'o

O
111111111111llllllLlJIlLLlillllllllilllllllllllllllll

 

 

 

Fig 1. NOESY of mixture of major and minor conformers of 257A in CDC13 at 25°C

233

 

257A-I - Major Isomer

Table 7.5 Results of lD-NOE Experiment on the Major Conformer of 257A-I“

 

 

Chemical Shitt PM?“ NOE Observed Chemical Shift Nuclei Irradiated NOE Observed
Irradiated

2.08 (s) a r, s 5.03 (s) l e,p,s
2.10 (s) b u, p 5-93 (S) m Cl
3.31 (d) c --- 6-53 (d) n c, g
3.35 (d) d 6.64 (d) o l
3.38 (s) e m 6.71 (s) p b, l
3.44 (s) f 6.74 (s) dis
3.75 (s) g NR 6-74 (s) a, d
3.91(s) h NR 6-82 (s) a
3.97 (s) i m 6.94 (d) 8
4.11(d) j c, -OH 7'05 (s) b
4.34 (d) k d

 

" The closeness of the chemical shifts of the methylene hydrogens and overlap with those from the minor
isomer does not permit accurate assignments of NOE effects

Although a precise assignment of all the protons and their through space interactions with
the neighbouring ones could not be made either by NOE or by NOESY, the tentative
assignment for the minor conformer based on some of the results in the lD-NOE

experiment is the partial cone (Fig.1).

234

OMe OMe Me

Minor
isomer

 

257A partial-cone
Fig.2 Structure of Minor isomer of 257A-II
5,1 7-dimethyI-1 1,23,26,28-tetramethoxy-2(S),8(S)-tert—bqudimethylsilyloxy-Zi27-
dihydroxycalixarene 25 7B and 5,1 7-dimethyl-I1,23,26,28-tetramethoxy-2(S),8(S),25,27-

tetrahydroxycalixarene 25 7C

OMe Me OMe

(OC)5C1' I I CKCOB

OMe
229A

Me

 

Q é

. OMe
TBSO OMe OTBS 2573, R = TBS l3 % Mixture afTwa

 

2 67B TB AF conformers ratio
1 .3: 1

 

—> 257C, R = H84 %

Single conformer

Following the general procedure, a mixture of carbene complex 229A (0.21 g, 0.23
mmol) and diyne (R,R)-267B (99.2 % ee, 0.059 g, 0.23 mmol) in 90 mL of 1,2-
dichloroethane as solvent afforded upon purification in 15 % ethyl acetate / hexanes the
chiral calixarene 257B as 1.3:1 mixture of two inseparable conformers in 13 % yield
(0.038 g, 0.0498 mmol). Rf (hexanes / ethylacetate = 85 / 15) = 0.39. Complete spectral

data and structure elucidation was carried out on the desilylated derivative 257C . The

235

chiral calix[4]arene 257B (0.024g, 0.28 mmol) was dissolved in 10 mL of anhydrous
ether and tetrabutyl ammonium fluoride (0.5 mL, 0.5 mmol) was added. The resulting
slurry was stirred at ambient temperature for 3-4 h. Aqueous workup, drying the organic
layer over anhydrous magnesium sulfate and concentration under vacuum afforded the
crude product which was purified on a silica-gel column by elution with 50 % ethyl
acetate / hexanes to give 56 % (0.015 g, 0.0265 mmol) of 257C as a single conformer as
an oil. The structure of this conformer was ascertained by NOESY as the cone. Rf
(hexanes / ethylacetate = 1/1) = 0.3. Spectral data for 257C : 1H NMR (CDCI3, 500MHz)
6 2.04 (s, 3H), 2.07 (s, 3H), 3.29 (d, 1H, J= 13.0 Hz), 3.37 (d, 1H, J= 14.0 Hz), 3.74 (s,
3H), 3.77 (s, 3H), 3.98 (s, 3H), 4.04 (s, 3H), 4.05 (d, 1H, J= 13.5 Hz), 4.31 (d, 1H, J =
12.5 Hz), 5.55 (dd, 2H, J= 24.0, 11.0 Hz), 6.32 (s, 1H), 6.57 (d, 1H, J= 2.0 Hz), 6.62 (s,
2H), 6.67 (d, 1H, J = 3.0 Hz), 6.74 (d, 1H, J = 2.0 Hz), 6.81 (d, 1H, J = 2.0 Hz), 6.98 (d,
1H, J = 2.0 Hz), 7.05 (d, 1H, J = 3.5 Hz), 7.32 (s, 1H), 7.76 (s, 1H) (OH proton not
located); l3C NMR (125MHz) 6 20.90, 20.97, 30.78, 31.93, 55.79, 55.83, 63.84, 64.53,
65.16, 79.64, 106.94, 112.64, 114.49, 114.54, 126.65, 128.56, 129.41, 129.54, 129.57,
130.31, 131.86, 132.09, 132.43, 133.14, 133.56, 134.41, 135.17, 136.49, 144.65, 146.39,
150.41, 151.03, 152.37, 153.00 ; IR (neat) 3360, 2924, 2850, 1650, 1590, 1481 cm";
mass spectrum m/z (% rel.intensity) FAB in NBA 572 (M, 0.2), 460 (8.4), 307 (76),107
(36), HRMS calcd for C34H3603 m/z 572.2410, measd 572.2408. Specific rotation on =
+2.7 (c = 0.34 in CHC13)

Structure Elucidation by NOESY in CDCl;

Me OMe OMe Me

 

236

 

 

 

 

 

WM)

 

 

 

 

 

 

 

 

5—
. ' - 1" o
4
4 l 0 l
. i I It .
7: l I
a i i
: I I O
81 ‘
I I I I T TC! T‘I’ I I I I I
8 7 6 4 3 2
3'2 (P!!!)

Fig 3. NOESY of 257C in CDC13 at 25 °C

237

 

5, I 7 -Dimethyl-2(R), 8(R), 1 4 (R), 1 1,23, 26, 28-heptamethoxy—25, 2 7dihydroxycalix[4]arene-

260

OMe Me OMc

OMe

(005Cr l I CKCOH

()Mc OMe OMC
(S,S)-268
+

 

Me

 

OMe OMe
(S)-285

A mixture Of chiral bis-carbene complex (S,S)-268 (0.216 g, 0.29 mmol, 97.8 % cc) and
chiral alkyne (S)-285 (0.11 g, 0.48 mmol, 93.4 % ee) in 118 mL of 1,2—dichloroethane
was subjected to the freeze-thaw deoxygenated according to the general procedure. The
reaction mixture was then heated at 100°C for 8 h. Work up according to the general
procedure followed by purification on silica gel with 25 % ethylacetate / hexanes
afforded the heptamethyl ether 260 in 32 % yield (0.058 g, 0.093 mmol) as white solid
and as a single cone conformer. TLC analysis of the crude material revealed the presence
of only one spot when developed with KMnO4 and examination of the crude 1H NMR
indicated no other side products. Mp = 105-108°C . Rf (hexanes / ethylacetate = 1/ 1) =
0.30. Spectral data for 260 : 1H NMR (CDC13, 500MHz) 6 2.07 (s, 6H), 3.35 (d, 1H, J =
13.0 Hz), 3.38 (s, 3H), 3.43 (s, 3H), 3.44 (s, 3H), 3.73 (s, 3H), 3.74 (s, 3H), 3.99 (s, 3H),
4.00 (s, 3H), 4.09 (d, 1H, J = 13.0 Hz), 5.04 (s, 1H), 6.00 (s, 1H), 6.05 (s, 1H), 6.53 (d,
1H, J = 2.5 Hz), 6.57 (d, 1H , J = 3.0 Hz), 6.66 (d, 1H , J = 2.0 Hz), 6.78 (d, 1H, J = 2.0

Hz), 6.92 (d, 1H, J = 3.0 Hz), 6.99 (d, 1H, J = 2.0 Hz), 7.01 (d, 1H, J = 3.0 Hz), 7.08 (d,

238

1H, J = 2.0 Hz), 7.81 (s, 2H); 13C NMR (125MHz) 6 20.96, 21.08, 29.69, 32.10, 55.76,
55.81, 57.16, 57.25, 57.41, 63.64, 64.42, 73.18, 108.45, 110.45, 114.11, 114.59, 126.36,
126.78, 128.14, 128.99, 129.54, 130.34, 131.03, 131.33, 132.31, 132.52, 134.46, 134.49,
135.01, 136.74, 145.82, 145.91, 150.88, 151.05, 152.10, 153.03 (One methoxy carbon not
located); IR (neat) 3312, 2934, 2826, 1607, 1482, 1435, 1236 cm". mass spectrum FAB
in NBA (m/z, % rel.intensity) 630 (M*, 20), 567 (40), 535 (90), 294 (80), 263 (100),
HRMS calcd for C37H4209 m/z 630.2829, measd 630.2832. Specific rotation (ID of the
material isolated by silica-gel chromatography = - 16.2 (c = 1.61 in CHC13). The
enantiomeric purity of the calix[4]arene was judged to be beyond detection limits by
HPLC analysis (Chiralcel OD column, 99.5:0.5 hexanes : i-PrOH to 95:5 hexanes : i-
PrOH, retention time = 8.35 min). Analyses using several other chiral HPLC columns did
not show the presence of any other small peaks due to the enantiomer.
5,17-dimethyl—2(R), 8(R), 11, 14(5), 23, 26, 28-heptamethoxy—25,27-dihydroxy calixarene
and5, I 7-dimethyl-2(R), 8(5), 1 I, I 4 (R), 23, 26, 28-heptamethaxy—25, 2 7-dihydroxy calixarene
— 259-1 and 25 9-11

OMe Me

(OC)5CI' I I

OMe OMe OMe
(S,R)-284 M30

 

Me Me OMe

Me OMe

 

OMe OMe
(S)- 285 113C

    

OH OMe OMe H0

259-II (all equatorial)

239

A mixture of mesa bis-carbene complex (S,R)-284 (0.137 g, 0.188 mmol) and chiral
alkyne (5)285 (0.048 g, 0.211 mmol, 93.4 % ee) in 118 mL of 1,2-dichloroethane was
subjected to the freeze-thaw deoxygenation according to the general procedure. The
reaction mixture was then heated at 100°C for 8 h. Workup according to the general
procedure followed by purification on silica-gel with 25 % ethylacetate / hexanes
afforded the calix[4]arene 259 in 29 % yield (0.034 g, 0.055 mmol) as light yellow solid
and as a 1.4210 mixture of diastereomers 259-I and 259-II. Both diastereomers had the
same Rf value. TLC analysis of the crude material revealed the presence of only one spot
as revealed by development with KMn04 and examination of the crude 1H NMR
indicated no other side products. Mp of mixture = 165-168°C. Analysis by HPLC
indicated the presence of a mixture of compounds 259-1 and 259-II in a ratio of 1.36:1
(R001086C5 Silica column, 254 nm, hexanes / i-PrOH 99.5/ 0.5 to 95/ 5, flow rate 0.5
mL/min, retention time for 259-I = 46.15 min and 259-II = 55.13 min). The mixture was
purified again by gradient elution (5 % ethyl acetate / hexanes to 25 % ethyl acetate /
hexanes) and thereby 259-I could be obtained in a pure form and 259-II was obtained as
an enriched mixture (ratio 4.1:1). Rf (hexanes / ethylacetate = 1/ 1) = 0.62. Spectral data
for 259-I: 1H NMR (CDCI3, 500MHz) 6 2.03 (s, 3H), 2.09 (S, 3H), 3.29 (d, 1H, J = 13.0
Hz), 3.38 (s, 3H), 3.44 (s, 3H), 3.46 (s, 3H), 3.76 (s, 3H), 3.77 (s, 3H), 3.93 (s, 6H), 4.09
(d, 1H, J = 12.5 Hz), 5.05 (s, 1H), 5.80 (s, 2H), 6.60 (d, 1H, J = 3.0 Hz), 6.69 (s, 2H),
6.79 (s, 1H), 6.86 (s, 1H), 6.93 (s, 1H), 6.99 (d, 1H, J = 2.7 Hz), 7.10 (S, 1H) (two OH
protons not located); 13C NMR (125MHz) (mixture) 6 14.16, 20.71, 21.05, 21.26, 29.67,
30.74, 31.56, 31.75, 55.74, 56.98, 57.12, 57.33, 57.53, 60.38, 63.35, 63.71, 63.87, 64.32,

73.44, 73.60, 73.86, 74.15, 107.61, 108.17, 108.39, 109.15, 114.16, 114.32, 126.62,

240

127.64, 128.55, 130.44, 130.75, 130.79, 131.31, 131.38, 131.58, 132.25, 132.77, 133.79,
133.86, 134.35, 134.52, 134.64, 135.37, 135.69, 144.27, 145.41, 145.57, 149.94, 150.25,
150.74, 151.96, 152.39, 152.88, 153.02, 153.81 (259-I) 20.71, 21.05, 29.67, 30.74, 55.74,
57.12, 57.33, 57.53, 64.32, 74.15, 107.61, 114.16, 127.64, 131.31, 132.77, 133.86,
134.52, 145.41, 151.96, 152.39, 152.88 (two methoxy groups not located); Spectral data
for 259-II: 1H NMR (CDCI3, 500MHz) 6 2.07 (s, 3H), 2.08 (s, 3H), 3.42 (s, 3H), 3.43 (s,
3H), 3.72 (s, 3H), 3.73 (s, 3H), 3.74 (s, 3H), 3.99 (s, 3H), 4.04 (s, 3H), 5.69 (s, 1H), 5.91
(s, 1H), 5.93 (s, 1H), 6.58 (d, 1H, J = 3.0 Hz), 6.75 (s, 1H), 6.86 (s, 1H), 6.91 (s, 1H),
6.92 (s, 1H), 6.96 (s, 2H), 6.98 (s, 1H), 7.40 (s, 1H), 7.81 (s, 1H) (two methylene
hydrogens not located); 13C NMR (125MHz) 6 14.16, 21.26, 31.56, 31.75, 56.98, 60.38,
63.35, 63.71, 63.87, 73.44, 73.60, 73.86, 108.17, 108.39, 109.15, 114.32, 126.62, 128.55,
130.44, 130.75, 130.79, 131.38, 131.58, 132.25, 133.80, 134.35, 134.64, 135.37, 135.69,
144.27, 145.57, 149.94, 150.25, 150.74, 153.02, 153.81 (two methoxy groups not
located). IR of mixture (neat) 3350, 2932, 2828, 1604, 1491, 1435, 1346, 1234 cm".
mass spectrum of mixture FAB in NBA m/z (% rel.intensity) 630 (10), 567 (16), 535
(40), 197 (30), 135 (72) HRMS calcd for C37H4209 m/z 630.2829, measd 630.2832.
Specific rotation up of the 1.36:1 mixture of diastereomers prepared fi'orn (S)-287 (93 %
ee) = - 3.2° (c = 1.7 in CHC13). The structures of the two conformers are assigned as the
diequatorial axial 259-1 and all equatorial 259-II respectively based on the chemical
shifts of the methine hydrogens. The equatorial methine proton and the two axial protons
are located at 5.05 ppm and 5.80 ppm respectively in 259-I whereas the axial protons in

259-II are Observed at 5.69, 5.91 and 5.93 ppm.

241

5,17-dimethyl—2(S), 8(5), 11, 14(S), 20(S), 23, 26, 28-0ctamethoxy-25,27-dihydroxy

calixarene —263

 

 

(OC)5CI'
OMe OMe OMe MeO Me Me OMe
(R,R)-268
+ _>
Me
\ i 263

OMe OMe ()Mc
(R,R)— 267A

The bis carbene complex (R,R)-268 (0.158 g, 0.216 mmol, 99.2 % ee) and the
diyne (R,R)-267A (0.056g, 0.216 mmol, 99.2 % ee) were dissolved in 86 mL of 1,2-
dichloroethane in a flame dried 250 mL Schlenk flask under argon and subjected to
freeze-thaw deoxygenation according to the general procedure. The reaction mixture was
then heated to 100°C for 30 min. Workup according to the general procedure gave the
crude calixarene which was purified by flash chromatography on silica gel with 5 % to 25
% ethyl acetate / hexanes to give 263 in 30 % yield (0.043 g, 0.065 mmol) as powdery
white solid. This compound was a single conformer as judged by 1H NMR and is
tentatively assigned as the cone. TLC analysis of the crude material revealed the presence
of only one spot upon development with KMnOa and examination of the crude 1H NMR
indicated no other side products. Mp = 83-86 °C. Rf = 0.32 (hexanes / ethyl acetate =
3/1). Spectral data for 263: 1H NMR (CDC13, 600MHz) 6 2.12 (s, 6H), 3.40 (s, 6H), 3.43
(S, 6H), 3.67 (s, 6H), 3.99 (s, 6H), 5.05 (s, 2H), 6.08 (s, 2H), 6.39 (d, 2H, J = 3.0 Hz),

6.69 (s, 2H), 6.87 (d, 2H, J = 3.0 Hz), 7.15 (s, 2H) (2 OH protons not located); 13C NMR

242

(125MHz) 20.99, 29.69, 55.78, 57.03, 57.49, 64.18, 72.89, 89.39, 110.61, 114.49, 126.28,
127.89, 129.44, 131.21, 132.85, 134.17, 136.91, 146.41, 152.02; IR (CHC13) 3343, 2930,
2826, 1609, 1483, 1345 cm'l; mass spectra m/z (% rel.intensity) FAB in NBA 660 (M+,
56), 629 (20), 597 (60), 565 (100), 535 (20), 149 (60), HRMS calcd for C33H44010 m/z
660.2929, measd 660.2934. Anal.calcd for C33H44010: C, 69.07; H, 6.71. Found: C,

69.43; H, 7.14. 019 = + 25.1 (c= 0.695 in CDC13)

5,17-dimethyl-2(R), 8(5), 11, 14(R), 20(R), 23, 26, 28- octamethoxy—25,27-dihydroxy

calix[4]arene—261
OMe Me OMe
(OChCr l I cacoh
OMe OMe OMe M60 Me Me OMe
(S,S)-268
+ ——>

   

OMe OMe OMe
(S,R)- 267A

A mixture of chiral bis-carbene complex (S,S)-268 (0.206 g, 0.24 mmol, 94 % ee) and
meso alkyne (S,R)-267A (0.073 g, 0.24 mmol) in 96 mL of 1,2-dichloroethane was
subjected to the freeze-thaw deoxygenation according to the general procedure. The
reaction mixture was then heated at 100°C for 8 h. Purification by silica-gel
chromatography (50 % ethyl acetate / hexanes) afforded the desired calix[4]arene 261 in
26 % yield (0.04 g, 0.061 mmol) as off-white solid and exclusively as the cone

conformer. TLC analysis of the crude material revealed the presence of only one spot

243

upon development with KMnOa and examination of the crude 1H NMR indicated no
other side products. Rf = 0.34 (hexanes / ethyl acetate = 1/1). Mp = 137-140°C . Spectral
data for 261: 1H NMR (CDC13, 500MHz) 6 2.08 (s, 6H), 3.38 (s, 3H), 3.42 (s, 3H), 3.44
(s, 3H), 3.45 (s, 3H), 3.74 (s, 6H), 4.00 (s, 3H), 4.01 (s, 3H), 5.05 (s, 1H), 5.72 (s, 1H),
5.94 (s, 1H), 5.95 (S, 1H), 6.55 (s, 1H), 6.67 (s, 1H), 6.88 (d, 1H, J= 1.8 Hz), 6.90 (d,
1H, J = 1.9 Hz), 6.96 (s, 1H), 7.00 (d, 2H, J = 2.7 Hz), 7.11 (s, 1H) (2 OH protons not
located); 13)C NMR (CDC13, 125MHz) 21.02, 21.32, 55.75, 55.81, 57.14, 57.23, 57.43,
63.62, 64.38, 73.00, 74.04, 108.35, 109.23, 114.29, 126.62, 127.28, 127.93, 130.20,
131.64, 132.49, 134.08, 134.18, 134.79, 135.11, 136.67, 144.32, 145.73, 149.35, 150.73,
150.84, 152.18, 153.93 (3 aryl carbons, one methoxy group and two methine carbons
missing); IR (CH2C12) 3349, 2984, 2936, 2824,1607, 1481, 1433, 1345, 1311 cm]. mass
spectrum m/z (% rel.intensity) FAB in NBA 660 (M+, 9), 565 (20), 307 (40), 154 (100),
HRMS calcd for C33HaaOto m/z 660.2937, measd 660.2940. Specific rotation of the

material isolated by silica-gel chromatography OLD = -14.6 (c = 1.43 in CHC13)

5,17-dimethyl-2(R), 8(R), 11, 14(5), 20(5), 23, 26, 28- octamethoxy-25,27-dihydroxy

calix[4]arene -262

244

OMe Me

(OC)5CI

OMe OMe OMe
(R,R)-268

\ /

 

OMcOMeOMc
(S,S)-267A

262

A mixture of chiral bis-carbene complex (R,R)-268 (0.081 g, 0.11 mmol, 88 % ee) and
alkyne (S,S)-267A (0.035 g, 0.13 mmol, 94 % ee) in 44 mL of 1,2-dichloroethane was
subjected to the freeze-thaw degassing according to the general procedure. The reaction
mixture was then heated at 100°C for 8h. Purification by silica-gel chromatography (50
% ethyl acetate / hexanes) afforded the calix[4]arene in 26 % yield (0.018 g, 0.028
mmol) as white solid and as mixture of two conformers in 1:1 ratio. TLC analysis of the
crude material revealed the presence of only one spot upon development with KMnOa
and examination of the crude 1H NMR indicated no other side products. Rf = 0.62
(Hexanes / ethyl acetate = 1/1). Mp = > 284 ° with decomposition . Spectral data for 262
on a 1:1 mixture of the two conformers: 1H NMR (CDCI3, 500MHz) 6 2.14 (s, 3H), 2.36
(s, 3H), 3.34 (s, 3H), 3.39 (s, 3H), 3.40 (s, 3H), 3.42 (s, 3H), 3.47 (s, 3H), 3.79 (s, 3H),
3.80 (s, 3H), 3.82 (s, 1.5H), 3.88 (s, 1.5H), 4.98 (s, 1H), 5.06 (s, 1H), 5.47 (s, 1H), 5.49
(s, 1H), 6.28 (s, 1H, OH), 6.64 (s, 0.5H, OH), 6.89 (d, 1H, J = 3.0 Hz), 6.93 (s, 1H), 6.95
(s, 1H), 6.99 (s, 1H), 7.04 (d, 1H, J= 2.0 Hz), 7.15 (d, 1H, J= 2.5 Hz), 7.27 (S, 1H), 7.42
(d, 1H, J = 2.0 Hz) (1 OH group of one of the conformers not seen); 13C NMR (CDC13,

125MHz) 6 20.85, 21.22, 29.69, 55.63, 55.75, 55.82, 56.96, 57.12, 57.55, 57.72, 63.73,

245

63.82, 72.94, 73.35, 81.42, 81.58, 108.07, 108.34, 109.88, 110.01, 126.02, 129.26,
129.68, 129.96, 130.66, 131.04, 131.21, 132.28, 132.35, 132.81, 134.07, 134.91, 135.59,
135.72, 143.69, 151.28, 153.25, 153.82; IR (CHCl3) 3345, 2928, 2826, 1774, 1605,
1481, 1465, 1433 cm"; mass spectrum FAB in NPOE (m/z, % rel.intensity) 660 (M*, 10),
565 (20), 486 (15), 252 (95), 140 (100), 57 (64), HRMS calcd for C33H44010 m/z
660.2934, measd 660.2932. Optical rotation of 262 in chloroform as the solvent indicated
no rotation of the plane-polarized light. Otp = 0.0 (c = 0.834 in CHC13). Based on DEPT
and HMQC experiments, the calix[4]arene 262 was determined to exist as a (1:1) mixture
of two conformers in solution which were not assigned. The parameters that were used
for the HMQC experiment are ni = 128, nt=16 and the NOESY experiment are ni= 64,

tmix = 0.78, nt=32 and linear prediction along the F 1 dimension.

246

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

H _—

P—

)-

)-

b

Ill " "

I I -

k

t r

L

O. )-

I.

p—

b-

r-

l.

u r

| r—

. e

)-

I-

. h-

. ._

II "

IIIIIIIIIIIJ‘1I]IIIIIIJII‘ITIIIIIIIIIIIIVIUIIIIIIIIIIIIIIJI'I]

E O In 0 an O In 0 In 0 In 0

N to n v v In to to o r~ i~ do
“so

 

ll'I I IIIWIT“

 

Fig 6. HMQC of 262 in CDCl3 at 25°C

247

120 110 100 90 00 70 60 50 40 30 20

130

1’1 (ml

 

 

 

 

 

 

 

 

 

O
___1 fl. - t a
I
. - i o
I M
g 1- “a '_
C
I v
I.
:_ A
-—4 - I—-
_ 2. .3 - : in
t; N
I O
)— a
E 0
1 o - - ..
- - E
- - )-
-- I- b
- I-
? - - - -_
IIIIII'LI[IIIIIIIIIITIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIlllh

01001-001100“)
MMVVlnl-ODOI‘PO

.0

H
“V

I . IITI IlllIl

 

-l

 

 

 

Fig.7 NOESY of 262 in CDCl3 at 25°C
The structures of the two isomers could not be elucidated by either lD-NOE or NOESY
experiments but the chemical shifts corresponding to both the isomers could be defined

(See Table 2 below).

248

 

Table 7.6 Results from the lD-NOE / NOESY experiments

Unknown Conformer 262-A

 

 

 

 

 

Chemical Shift Number of Protons NOE Observed Chemical Shift No.of protons NOE Observed
2.14 (s) 6H ND 4.98 (s) 2H 6.96, 3.422
3.403 (s) 6H ND 5.49 (s) 2H 6.66, 3.804, 3.403
3.42 (s) 6H ND 6.66 (s) 2H 5.49
3.804 (s) 6H ND 6.93 (s) 2H No NOE
6.96 (s) 2H 4.99, 2.14
3.89 (s) 3H 7.27
3.83 (5) 3H 6.99 6.996 (s) 2H 3.83, 3.403
7.27 (s) 2H 3.89, 3.803
Unknown Conformer 262-B
Chemical Shift Number of Protons NOE Observed Chemical Shift No.of protons NOE Observed
2.36 (s) 6H ND 5.06 (s) 2H 7.045, 3.47
3-34 (8) 6” ND 5.47 (s) 2H 6.30, 3.39. 3.34
3.395 (s) 6H ND 6.30 (s) 2H 5.47, 3,39
3.47 (5) 6H ND 6.89 (s) 2H 7.41, 3.800
7.046(5) 2H 5.06, 3.47, 2.36
3.800(5) 6H ND
7.16 (s) 2H 3.80, 3.47, 3.39
7.41 (s) 2H 6.89, 2.36

 

249

Triple annulation by dimerization of complex 298

5,1 7-dimethy1-2(S), I 4 (S), I 1, 23, 26,28-hexamethoxy—25, 2 7-dihydroxycalix[4]arene 258

OMe Me

(OC)5Cr I

OMe OMC
298

 

The alkynyl carbene complex (S)-298 (61 % ee, 0.074 g, 0.16 mmol) was dissolved in 64
mL of 1,2-dichloroethane and subjected to freeze-thaw deoxygenation according to the
general procedure described for the reaction of bis-carbene complex and diyne (See pg
216). After thermolysis at 100°C for 30 min, the mixture was opened to air and stirred for
overnight. Removal of the solvent and purification by silica-gel chromatography (25 %
ethyl acetate / hexanes) afforded 18 mg (19 %, 0.03 mmol) of calix[4]arene 258 as an
yellow oil. No other mobile spots were observed on TLC plate and in the 1H NMR
spectra of the crude compound. Rf (hexanes / ethylacetate = 3/1) = 0.25. Spectral data for
258: 1H NMR (CDC13, 600MHz) 6 2.06 (s, 6H), 3.36 (d, 2H, J = 13.8Hz), 3.44 (s, 6H),
3.74 (s, 6H), 4.00 (S, 6H), 4.07 (d, 2H, J = 13.8Hz), 6.01 (s, 2H), 6.60 (d, 2H, J = 4.2Hz),
6.79 (d, 2H, J = 2.4Hz), 6.97 (d, 2H, J = 1.8Hz), 6.98 (d, 2H, J = 4.2Hz), 7.83 (s, 2H); 3C
NMR (125MHz) 6 21.05, 32.05, 55.86, 57.32, 63.76, 73.73, 108.51, 114.34, 127.21,
128.27, 130.41, 131.24, 131.95, 134.65, 135.12, 145.89, 150.85, 153.03; IR (CHC13)
3339, 2926, 2890, 1665, 1611, 1480 cm"; mass spectrum m/z (% rel.intensity) FAB in

NBA 600.2 (M*, 2), 460(7), 307 (56),289 (32), 252 (16), HRMS calcd for Campos

250

m/z 600.2723, measd 600.2720. None Of the calix[8]arene was observed by mass spectra.
Specific rotation of (R,R)-258 prepared from (S)-287 (61% ee) = -3.8 (c = 1.0 in CHC13).
The conformation of (R,R)-258 was deduced to be the cone based on NOESY experiment
(ni = 64, tm = 0.78, three fold forward linear prediction along the F l dimension, See Fig 4

below).

Me OMe OMe Me

 

258

Fig.4 Structure of 1,3-Dimethoxy Calix[4]arene

251

 

 

 

 

- - WWW

 

 

IIYIIIIIVTIIIIIIIYIFIIIIIlITrT—rlIII]!IIIIIIIIITIITIUIIIIIVIII]

 

 

 

J-m
EN m V
v

 

 

 

 

Fig 5. NOESY of 258 in CDC13 at 25°C

252

3.0 2.5

3.5

4.5

6.0 5.5 5.0

6.5

7.0

8.0

5'2 (m)

/
TMS —-:_ -—>

TMS
269 W Br 321

Cat.Cu(I)

trimethyl(pent-4-en-I-ynyl)5ilanel32321: Into a clean dry three necked 500 mL round
bottomed flask was added sequentially trimethyl silyl acetylene (40 mL, 178 mmol) and
170 mL of tetrahydrofuran under argon. The mixture was cooled to -78°C and ethyl
magnesium bromide (3M in diethyl ether, 70 mL, 210 mmol) was added dropwise. After
stirring for 30 min at this temperature, copper (I) chloride (1.32 g, 7.5 mol %) was then
added and stirring was continued for another 30 min at room temperature. Allyl bromide
(30 mL, 350 mmol) was then added to the light brown colored slurry at 0°C dropwise to
minimize exotherrnicity of the reaction. The reaction was continued for another 2 h
before it was quenched by the addition of saturated ammonium chloride (100 mL). The
organic layer was then extracted with ether (200 mL) and then concentrated under
reduced pressure to yield the crude enyne 321. The crude product was then distilled at
60°C (1 mm Hg) to afford 22.11 g (160.2 mmol, 90 %) of the enyne as a white oil.
Spectral data for 321: 1H NMR (CDC13, 300MHz) 6 0.14 (s, 9H), 2.98-3.00 (m, 2H),
5.08-5.12 (m, 1H), 5.28-5.34 (m, 1H), 5.75-5.84 (m, 1H); 13 C NMR (CDC13, 75 MHz) 6

0.06, 24.13, 53.84, 116.21, 132.13 (1 sp carbon not located).

 

 

Me
Me
Br Br
/\/ 9-BBN(H) OMe 323 ‘ TMS \ TMS
TMS THF, reflux \
2" THF 324 OMe
320

253

2-Methoxy-5-methyl—I,3-bis(5-trimethylsilyl)pent-4-ynyl-benzene 320: Into a clean three
necked 100 mL flask fitted with a 14/20 reflux condenser was added 9-
borabicyclononane (44 mL, 22 mmol, 0.5M in tetrahydrofuran) followed by trimethyl(4-
penten-l-ynyl)silane (2.76 g, 20 mmol) at room temperature. The reaction mixture was
then heated to reflux for 2 h after which the solution of the organoborane was transferred
by a syringe under argon into a schlenk flask containing the aryl bromide 323127 (2.24 g,
8 mmol), potassium phosphate monohydrate (3.68 g, 16 mmol), palladium (II) acetate (36
mg, 2 mol %) and S-PHOS ligand 12' (132 mg, 4 mol %) in 40 mL of tetrahydrofuran.
The resultant mixture was deoxygenated by freeze-pump thaw method (three cycles) after
which the Schlenk flask was back-filled with argon. At room temperature, the flask was
sealed and then heated to 75°C for 9 h. The contents of the flask were then poured over a
Celite pad and the pad was rinsed repeatedly with 25 mL of ether (4 times). The solvent
was then removed under vacuum to give the crude material, which was purified by silica-
gel chromatography (20 % dichloromethane / hexanes) to afford 2.52 g (6.32 mmol, 79
%) of 320 as a yellow oil. Rf = 0.62 (Hexanes / ethyl acetate = 1/1). Spectral data for 320:
1H NMR (CDC13, 300MHz) 6 0.17 (8, 18H), 1.81-1.86 (m, 4H), 2.27 (s, 3H), 2.29 (t, 4H,
J = 7.0 Hz), 2.70 (t, 4H, J = 7.5 Hz), 3.74 (s, 3H), 6.86 (s, 2H); 13C NMR (CDC13,
125MHz) 6 0.18, 19.87, 20.82, 29.07, 29.65, 61.26, 84.81, 107.33, 128.74, 133.22,
134.39, 154.51; IR (neat) 2959, 2901, 2864, 2828, 2174, 1477, 1429, 1258, 1223 cm'l;
mass spectrum FAB in CHCl3 m/z (% rel.intensity) 398 (M+, 8%), 383 (5), 89 (15), 73

(100), HRMS calcd for C24H3gOSi2 m/z 398.2461, measd 298.2463.

254

MS

TMS
" TBAF

 

OMe OMe
320 317

2-methoxy-5-methyl—I,3-di(pent-4-ynyl)benzene 317 : To a solution of the diyne 320
(2.52 g, 6.32 mmol) in 40 mL of ether was added tetrabutyl ammonium fluoride (1M in
tetrahydrofuran, 32 mL, 5 equiv) and the resulting mixture was stirred at room
temperature for 3 h. Water (50 mL) was then added and the organic layer was extracted
with ether (100 mL). The organic layer was then dried over MgSOa and the solvent
removed under vacuum to afford the crude product. Purification by silica-gel
chromatography (5 % ethyl acetate / hexanes) gave the pure diyne 317 (1.57 g, 6.19
mmol, 98 %) as a yellow oil. Rf = 0.55 (hexanes / ethyl acetate = 19/1). Spectral data for
317: 1H NMR (CDC13, 500MHz) 6 1.78-1.86 (m, 4H), 1.97 (t, 2H, J = 2.7Hz), 2.20 (t,
2H, J = 2.7 Hz), 2.23 (t, 2H, J = 6.9 Hz), 2.25 (s, 3H), 2.69 (t, 4H, J = 7.5 Hz), 3.70 (s,
3H), 6.84 (s, 2H); 13C NMR (CDCI3, 125MHz) 6 18.33, 20.79, 28.91, 29.44, 61.27,
68.49, 84.35, 128.71, 133.28, 134.22, 154.42; IR (neat) 3300, 2939, 2864, 2828, 2118,
1607, 1498, 1478, 1431, 1286 cm". mass spectrum m/z (% rel.intensity) 254 (100), 201

(52), 73 (90), HRMS calcd for C13H220 m/z 254.1671, measd 254.1672.

Me Me

W CpZZrHCl 1%]
CM, N15 OMe
317 325

I,3-bis((E)-5-iodapent-4-enyl)-2-methaxy-5-methylbenzene 3 25 .' Following the same
procedure as reported earlier for the synthesis of (S,S)-279, the vinyl iodide 325 (0.97 g,

1.89 mmol) could be obtained as yellow oil from 317 (0.76 g, 3 mmol) in 63 % yield. Rf

255

= 0.57 (hexanes / ethyl acetate = 19 / 1). Spectral data for 325: 1H NMR (CDC13,
500MHz) 6 1.66-1.72 (m, 4H), 2.08-2.12 (m, 4H), 2.24 (s, 3H), 2.56 (t, 4H, J = 8.0 Hz),
3.67 (8, 3H), 6.01 (d, 2H, J = 14.5 Hz), 6.54 (dt, 2H, J: 14.0, 6.5 Hz), 6.80 (8, 2H); 13C
NMR (CDC13, 125 MHz) 6 20.84, 29.09, 29.34, 35.86, 61.25, 128.54, 133.33, 134.50,
146.26, 154.25 (1 8p2 carbon not located); IR (neat) 3405, 2930, 2859, 1605, 1477, 1458,
1219 cm'l. mass spectrum m/z (% rel.intensity) 510 (M+, 42), 329 (20), 307 (40), 289

(20), 154 (100), 136 (96), HRMS calcd for C13H24120 m/z 509.9917, measd 509.9918.

 

Me OMe Me OMe
l l
I I I- BuLi (4 eq) (OOSCYWCKCOB
Cr(C0)6 (4 6(1)
OMe Me3OBF4 (6 eq) OMe
325 318

Bis-carbene complex 318: To a solution of the vinyl iodide 325 (0.66 g, 1.3 mmol) in 25
mL of tetrahydrofuran was added tert-butyl lithium (4 equiv, 1.7 M in pentane) at -78°C
and the resulting mixture was stirred for 30 min. Chromium hexacarbonyl (1.14 g, 4
equiv) was dissolved in tetrahydrofuran (40 mL) and transferred to the above solution.
The resultant slurry was then warmed to room temperature and stirred for 3h. The general
workup procedure described earlier for (S,S)-268 was employed upon purification by
silica-gel chromatography (5 % ethyl acetate / hexanes) to afford 0.339 g (36 %, 0.47
mmol) of 318 as a deep-red oil. Rf (hexanes / ethyl acetate = 19/ 1) = 0.25. Spectral data
for 318: 1H NMR (CDC13, 500MHz) 6 1.78 (t, 4H, J: 7.5 Hz), 2.24 (t, 4H, J: 7.0 Hz),
2.25 (s, 3H), 2.62 (t, 4H, J = 7.0 Hz), 3.66 (s, 3H), 4.72 (s, 6H), 6.31-6.37 (m, 2H), 6.83
(8, 2H), 7.29 (d, 2H, J = 14.5 Hz); 13C NMR (CDC13, 125MHz) 6 20.83, 29.33, 29.43,
32.27, 61.27, 66.34, 128.69, 133.49, 134.36, 137.18, 144.50, 154.32, 216.75, 223.94,

335.89; IR (neat) 2932, 2863, 2829, 2058, 1932, 1477, 1452, 1230 cm"; mass spectrum

256

m/z (% rel.intensity) 726 (3.2), 586 (16), 446 (60), 351 (100), 332 (66), HRMS calcd for

C32H30CrzOI3 m/z 726.0497, measd 726.0495.

Me

W

OMe
__ 0
31.7 1,2 DCE,100 C ‘

+

OMe Me OMe

(OC)5Cr I Cr(CO)5

 

OMe
318

Bis-homocalix[4]arene 211: The following is a representative procedure for large scale
synthesis. Into a 500 mL Schlenk flask under an atmosphere of argon was added the bis-
carbene complex 318 (0.361 g, 0.497 mmol), the diyne 317 (0.126 g, 0.497 mmol) and
200 mL of 1,2-dichloroethane. The resultant solution was subjected to freeze-thaw
degassing according to the general procedure described in Pg 216. The reaction mixture
was then heated to 100°C for 30 min during which time the deep-red colored solution
turned yellow. Work up and purification by silica-gel chromatography (25 % ethyl
acetate / hexanes) afforded the macrocycle 211 in 39 % yield (0.125 g, 0.194 mmol) as a
white solid. Rf (hexanes / ethyl acetate = 3/1) = 0.33. Spectral data for 211: lH NMR
(CDC13, 500MHz) 6 1.88-1.94 (m, 8H), 2.23 (s, 6H), 2.51 (t, 8H, J = 8.5Hz), 2.64 (t,
8H, J = 7H2), 3.56 (s, 6H), 3.73 (s, 6H), 5.99 (s, 2H), 6.53 (8, 4H), 6.82 (s, 4H); 13C
NMR (CDC13, 75MHz) 6 20.78, 29.52, 29.78, 31.12, 48.06, 53.84, 55.58, 61.00, 112.54,
129.21, 130.59, 133.90, 134.71, 146.05, 153.12, 154.05 (1 sp3 carbon not located); IR

(neat) 3414, 2930, 2860, 2832, 1605, 1478, 1318, 1196 cm'l; mass Spectrum m/z (%

257

rel.intensity) 652 (M+, 66), 386 (10), 307 (30), 154 (100), 136 (60), 117 (74), HRMS

calcd for C42H5206 m/z 652.3764, measd 652.3767.

 

Me Me
I) K2CO3, M82804
3, O” 2) CBr4, PPh3 ' B, 3'
OH OMe
334 336

1-Bramo-3-(bromomethyl)-2-methaxy-5-methylbenzene 336: The intermediate methyl

ether 335 is known in the literature133

but a different procedure was used for its
preparation. 2—Bromo-6-hydroxymethyl-p-cresol 334 was obtained following the
procedure reported by Cram in 95 % yield.134 The alcohol 334 (9.71 g, 44.94 mmol) was
dissolved in 220 mL of acetone and potassium carbonate (9.07 g, 65.61 mmol) was then
added. The resultant slurry was stirred for a few minutes after which dimethyl sulfate (4.7
mL, 49.43 mmol) was added dropwise with constant stirring. The reaction was continued
for 24 h and the insoluble residue was filtered through a fritted glass funnel. The filtrate
was concentrated under reduced pressure and purified by silica-gel chromatography (50
% ethyl acetate/ hexanes) to afford 8.16 g (35.5 mmol, 79 %) of the title compound as
white oil.

The alcohol 335 (8.16 g, 35.5 mmol) was dissolved in dichloromethane (200 mL) and
triphenyl phosphine (11.17 g, 42.6 mmol) was then added. Carbon tetrabromide (14.13 g,
42.6 mmol) was added in portions carefully and the resulting mixture was stirred for 4 h.
The solvent was removed and the crude material was purified by silica-gel

chromatography (5 % ethyl acetate/ hexanes) to give 9.6 g (32.66 mmol, 92 % yield) of

bromide 336 as white oil. Rf (hexanes / ethylacetate = 19/1) = 0.49. Spectral data for 336:

258

1H NMR (CDC13, 300MHz) 6 2.27 (s, 3H), 3.93 (s, 3H), 4.51 (s, 2H), 7.12 (d, 1H, J=

1.5 Hz), 7.30 (d, 1H, J: 1.8 Hz).

 

Me Me
Bl" Bf E120 ' Br

OMe OMe

336 337

1-Bromo-3-(but-enyl)-2-methoxy-5-methylbenzene 33 7: The bromide 336 3.44 g (11.7
mmol) was transferred into a 100 mL three-necked round-bottomed flask. Ether (20 mL)
was added followed by allyl magnesium bromide (1M in ether, 1.3 equiv) at room
temperature and the reaction mixture was stirred overnight. The reaction mixture was
poured into water (50 mL) and extracted with ether (100 mL). The organic layer was then
concentrated under reduced pressure to afford the crude material, which was then purified
by Silica-gel chromatography (5 % ethyl acetate / hexanes) to give 2.79 g (11.04 mmol,
94 %) of 337 as white oil. Rf (hexanes / ethyl acetate = 19/1) = 0.68. Spectral data for
337: 'H NMR (CDC13, 500MHz) 6 2.25 (s, 3H), 2.29-2.37 (m, 2H), 2.69 (t, 2H, J = 8.1
Hz), 3.78 (8, 3H), 4.95-5.07 (m, 2H), 5.80-5.87 (m, 1H), 6.91 (d, 1H, J = 1.5 Hz), 7.19 (d,
1H, J = 1.8 Hz); 13‘C NMR (CDCI3, 125MHz) 6 20.51, 29.83, 34.65, 60.94, 115.02,
116.89, 130.04, 131.54, 134.98, 136.39, 137.95, 152.85; IR (neat) 3077, 2928, 2867,
2828, 1642, 1476, 1450 cm"; mass spectrum m/z (% rel.intensity) NBA in FAB 256
M++2 (Br81, 21), 254 M+ (Br79, 19), 215 (Br3‘, 100), 213 (Br79, 99), 174.1 (20), 135.1
(44), 105 (44), 81(56), 55(68), HRMS calcd for ClelsOBr79 m/z 254.0306, measd

254.0307

259

 

hde 1” TEAS hde
/\/ k
/ TMS 9-BBN /
Br Pd(OAc)2, S-PHOS

OMe OMe
337 341

(5 -(3 -but—3 -enyl)-2-methoxy—5 -methylphenyl)pent-I -ynyl)trimethylsilane 341:

Following the procedure described earlier for the synthesis of 320, the aryl bromide 337
(5.58 g, 22 mmol) was converted into the cross-coupled product 341 in 83 % yield (5.73
g, 18.3 mmol) after purification by silica-gel chromatography (15 % dichloromethane /
hexanes). Rf (hexanes / dichloromethane = 85/15) = 0.43. Spectral data for 341: 1H NMR
(CDCI3, 300MHz) 6 0.14 (s, 9H), 1.76-1.85 (m, 2H), 2.25 (s, 3H), 2.27 (t, 2H, J = 6.9
Hz), 2.31-2.38 (m, 2H), 2.64-2.70 (m, 4H), 3.74 (s, 3H), 4.94-5.09 (m, 2H), 5.81—5.95 (m,
1H), 6.84 (s, 2H); 13C NMR (CDC13, 125MHz) 6 0.17, 19.84, 20.86, 29.01, 29.27, 29.61,
34.81, 61.28, 84.76, 107.31, 114.64, 128.52, 128.64, 133.22, 134.29, 134.50, 138.49,
154.31; IR (neat) 3078, 2975, 2862, 2174, 1641, 1477, 1452, 1429 cm"; mass spectrum
FAB in NPOE m/z (% rel.intensity) 314 (M, 88), 273 (44), 252 (24), 73 (100), HRMS

cacld for C20H3oOSl m/z 314.2066, measd 314.2065.

260

APPENDIX-I
Crystallographic Data of Selected Compounds

246A, 246C-I and 246C-II

261

               

o o 830.) 8.0

’2

                   

on”, .90
e

 
 

o 1;.0 WMZ, o
530 \ =30 '0‘

   

Fig 3.1 ORTEP Diagram of Calix[4]arene 246A

ES ., ago) .
O z. I ~
.85 1
ago»,
r 83 ago ( o 68 o
.857 o o
o ,6

262

Table A.3.1.
246A.

Crystal data and structure refinement for

 

Identification code
Empirical formula
Formula weight
Temperature
Wavelength

Crystal system
Space group

Unit cell dimensions

deg.
deg.

deg.
Volume
2
Density (calculated)
Absorption coefficient
F(000)
Crystal size

Theta range for data collection
-13<=h<=12, -13<=k<=10, -

Index ranges
13<=l<=18

Reflections collected / unique

=0.0190]
Completeness to theta = 28.27
Refinement method
squares on F“2
Data / restraints / parameters
Goodness—Of-fit on F‘2
Final R indices [I>Zsigma(I)]
0.1618
R indices (all data)
0.1671
Largest diff. peak and hole
e.A‘-3

263

223C

C36 H39 N 06
581.68
173(2) K
0.71073 A
Triclinic
P-l

a 10.817(2) A
b 10.839(2) A
c 13.945(3) A
alpha = 104.68(3)

beta 101.53(3)

gamma = 92.22(3)

1542.7(5) A‘3

2

1.252 Mg/m‘3

0.085 mm‘-1

620

0.8 x 0.8 x 0.2 mm
1.55 to 28.27 deg.

9671/6813 [R(int)

89.0%

Full-matrix least-

6813 / 0 / 396
1.189
R1 = 0.0499, wRZ

R1 = 0.0603, wRZ

0.440 and -0.325

Table A.3.2. Atomic coordinates ( x 10‘4), equivalent
isotropic displacement parameters (A‘Z x 10‘3), and
occupancies for 246A.

 

 

x y z U(eq) Occ.
0(1) 7639(1) 9450(1) 4209(1) 29(1) 1
C(2) 8243(2) 9423(1) 3424(1) 22(1) 1
C(3) 7636(2) 9969(1) 2656(1) 23(1) 1
C(4) 8215(2) 9978(2) 1849(1) 25(1) 1
C(5) 9348(2) 9423(2) 1770(1) 26(1) 1
0(6) 9801(1) 9460(1) 920(1) 36(1) 1
C(7) 10781(2) 8652(2) 696(2) 40(1) 1
C(8) 9936(2) 8883(2) 2529(1) 25(1) 1
C(9) 9397(1) 8888(1) 3367(1) 23(1) 1
C(10) 6324(2) 10429(1) 2661(1) 23(1) 1
C(11) 5300(2) 9338(1) 2070(1) 22(1) 1
C(12) 5128(2) 8867(2) 1016(1) 25(1) 1
C(13) 4300(2) 7787(2) 460(1) 27(1) 1
C(14) 4170(2) 7299(2) -677(1) 40(1) 1
C(15) 3646(2) 7146(2) 989(1) 26(1) 1
C(16) 3766(1) 7588(1) 2039(1) 22(1) 1
C(17) 4564(1) 8716(1) 2560(1) 22(1) 1
0(18) 4655(1) 9188(1) 3606(1) 24(1) 1
C(19) 3771(2) 10127(2), 3851(1) 31(1) 1
C(20) 3081(2) 6828(2) 2597(1) 25(1) 1
C(21) 3775(2) 5707(2) 2842(1) 23(1) 1
C(22) 3304(2) 4447(2) 2278(1) 27(1) 1
C(23) 3906(2) 3409(2) 2512(1) 28(1) 1
0(24) 3515(1) 2132(1) 2018(1) 38(1) 1
C(25) 2522(2) 1859(2) 1133(2) 43(1) 1
C(26) 4981(2) 3620(2) 3295(1) 26(1) 1
C(27) 5487(2) 4855(2) 3843(1) 24(1) 1
C(28) 4865(2) 5903(1) 3623(1) 23(1) 1
0(29) 5377(1) 7088(1) 4234(1) 33(1) 1
C(30) 6728(2) 5075(2) 4633(1) 25(1) 1
C(31) 7838(2) 5356(2) 4170(1) 23(1) 1
C(32) 8182(2) 4404(2) 3404(1) 25(1) 1
C(33) 9122(2) 4650(2) 2900(1) 25(1) 1
C(34) 9426(2) 3640(2) 2026(1) 32(1) 1
C(35) 9741(2) 5889(2) 3183(1) 25(1) 1
C(36) 9433(2) 6867(2) 3947(1) 24(1) 1
C(37) 8495(2) 6574(2) 4438(1) 22(1) 1
0(38) 8173(1) 7566(1) 5187(1) 25(1) 1
C(39) 8841(2) 7610(2) 6199(1) 35(1) 1
C(40) 10038(2) 8233(2) 4160(1) 25(1) 1
C(41) 6823(2) 6350(2) 1746(2) 52(1) 1
C(42) 7616(3) 6116(2) 1012(2) 54(1) 1
N(43) 8244(3) 5905(3) 420(2) 79(1) 1

 

264

 

U(eq) is defined as one third of the trace of the
orthogonalized

Uij tensor.

Table A.3.3.

Bond lengths [A] and angles [deg] for 246A.

 

0(1)—C(2)
C(2)-C(9)
C(2)-C(3)
C(3)-C(4)
C(3)-C(10)
C(4)-C(5)
C(5)—0(6)
C(5)-C(8)
O(6)-C(7)
C(8)-C(9)
C(9)-C(40)
C(10)-C(11)
C(11)-C(12)
C(11)-C(17)
C(12)-C(13)
C(13)-C(15)
C(13)-C(14)
C(15)-C(16)
C(16)-C(17)
C(16)-C(20)
C(17)-0(18)
O(18)-C(19)
C(20)-C(21)
C(21)-C(28)
C(21)-C(22)
C(22)-C(23)
C(23)-0(24)
C(23)-C(26)
O(24)-C(25)
C(26)-C(27)
C(27)-C(28)
C(27)-C(30)
C(28)—0(29)
C(30)-C(31)
C(31)-C(37)
C(31)-C(32)
C(32)-C(33)
C(33)-C(35)
C(33)-C(34)
C(35)-C(36)
C(36)-C(37)

265

HHHHI—IHHHHI—aHt—H—It—H—IHHHHHHHHHHHHHHHHHHHHHHHHHH

.378(2)
.405(2)
.414(2)
.394(2)
.524(2)
.399(2)
.379(2)
.393(2)
.433(2)
.404(2)
.529(2)
.530(2)
.400(2)
.402(2)
.397(2)
.399(2)
.515(2)
.398(2)
.408(2)
.530(2)
.4001(19)
.4480(19)
.529(2)
.404(2)
.408(2)
.398(2)
.387(2)
.394(2)
.422(2)
.390(2)
.410(2)
.524(2)
.373(2)
.527(2)
.399(2)
.405(2)
.399(2)
.401(2)
.517(2)
.402(2)
.402(2)

 

C(36)—C(40)
C(37)-0(38)
O(38)-C(39)
C(41)-C(42)
C(42)-N(43)

0(1)-C(2)-C(9)
O(1)-C(2)-C(3)
C(9)-C(2)-C(3)
C(4)—C(3)-C(2)
C(4)-C(3)-C(10)
C(2)-C(3)-C(10)
C(3)-C(4)-C(S)
O(6)-C(5)-C(8)
O(6)-C(5)-C(4)
C(8)-C(5)-C(4)
C(5)-O(6)-C(7)
C(5)-C(8)-C(9)
C(8)-C(9)-C(2)
C(8)-C(9)-C(40)
C(2)-C(9)-C(40)
C(3)-C(10)-C(11)
C(12)-C(11)-C(17)
C(12)-C(11)—C(10)
C(17)-C(11)-C(10)
C(13)-C(12)-C(11)
C(12)-C(13)-C(15)
C(12)-C(13)-C(14)
C(15)-C(13)—C(14)
C(13)-C(15)-C(16)
C(15)—C(16)-C(17)
C(15)-C(16)-C(20)
C(17)-C(16)-C(20)
0(18)-C(17)—C(11)
0(18)-C(17)-C(16)
C(11)-C(17)-C(16)
C(17)-0(18)-C(19)
C(21)-C(20)-C(16)
C(28)-C(21)-C(22)
C(28)-C(21)-C(20)
C(22)—C(21)-C(20)
C(23)-C(22)—C(21)
0(24)-C(23)-C(26)
O(24)-C(23)-C(22)
C(26)-C(23)-C(22)
C(23)-0(24)-C(25)
C(27)-C(26)-C(23)
C(26)-C(27)-C(28)

266

HHHHD—I

123.
116
120.
118.
120.
120
121
124.
115.
119
116.
120.
119.
119.
121.
110.
117.
120.
121.
122.
118.
120.
121.
121.
118.
120.
121.
119.
118.
121.
113.
113.
119.
121.
119.
120.
115.
124.
120.
117.
121.
118.

527(2)

4048(19)

440(2)
444(4)
156(4)

12(14)

.34(14)

54(15)
61(14)
59(14)

.57(14)
.47(15)

82(15)
78(15)

.41(15)

79(14)
62(15)
30(15)
05(14)
54(14)
22(12)
37(15)
53(15)
96(14)
46(16)
19(15)
37(16)
39(15)
70(15)
05(15)
16(14)
75(14)
59(14)
39(14)
96(14)
01(12)
81(13)
19(15)
49(14)
31(14)
03(16)
08(15)
90(16)
02(15)
60(15)
07(15)
94(15)

 

C(26)-C(27)-C(30)
C(28)-C(27)-C(30)
O(29)-C(28)-C(21)
O(29)-C(28)-C(27)
C(21)—C(28)—C(27)
C(27)-C(30)-C(31)
C(37)-C(31)-C(32)
C(37)-C(31)-C(30)
C(32)-C(31)—C(30)
C(33)-C(32)-C(31)
C(32)-C(33)-C(35)
C(32)-C(33)-C(34)
C(35)—C(33)-C(34)
C(33)-C(35)-C(36)
C(37)-C(36)-C(35)
C(37)-C(36)-C(40)
C(35)-C(36)—C(40)
C(31)-C(37)-C(36)
C(31)-C(37)-O(38)
C(36)—C(37)-O(38)
C(37)-O(38)-C(39)
C(36)—C(40)-C(9)

N(43)-C(42)-C(41)

120.
120.
123.
115.
.69(14)
.36(13)
.51(15)
122.
120.
.26(15)
.22(15)
121.
119.
.55(15)
.24(15)
121.
119.
122.
119.
117.
113.
111.
.7(3)

120
110
117

122
118

121
118

178

49(14)
50(14)
66(14)
63(14)

00(14)
37(14)

82(15)
87(16)

82(14)
75(15)
19(14)
84(14)
88(14)
08(13)
01(13)

 

267

Symmetry transformations used to generate equivalent atoms:

Table A.3.4.
10‘3) for 2463

Anisotropic displacement parameters (A‘Z x

 

 

U11 U22 U33 023 U13 U12
0(1) 31(1) 34(1) 28(1) 12(1) 11(1) 9(1)
C(2) 24(1) 20(1) 22(1) 3(1) 4(1) -2(1)
C(3) 23(1) 17(1) 26(1) 2(1) 4(1) 0(1)
0(4) 26(1) 23(1) 27(1) 9(1) 4(1) 1(1)
0(5) 26(1) 26(1) 26(1) 6(1) 7(1) -2(1)
0(6) 33(1) 48(1) 35(1) 20(1) 16(1) 13(1)
C(7) 42(1) 45(1) 43(1) 17(1) 23(1) 15(1)
C(8) 20(1) 25(1) 30(1) 6(1) 4(1) 0(1)
C(9) 22(1) 20(1) 24(1) 4(1) 2(1) 3(1)
C(10) 24(1) 19(1) 25(1) 5(1) 5(1) 3(1)
C(11) 21(1) 20(1) 25(1) 6(1) 4(1) 6(1)
C(12) 24(1) 28(1) 26(1) 9(1) 6(1) 3(1)
C(13) 26(1) 31(1) 23(1) 6(1) 3(1) 6(1)
C(14) 46(1) 47(1) 24(1) 4(1) 4(1) 5(1)
C(15) 22(1) 24(1) 27(1) 4(1) 1(1) 2(1)
C(16) 19(1) 22(1) 27(1) 7(1) 5(1) 5(1)
C(17) 20(1) 22(1) 22(1) 5(1) 4(1) 7(1)
0(18) 27(1) 24(1) 22(1) 4(1) 7(1) 6(1)
C(19) 31(1) 28(1) 33(1) 2(1) 12(1) 8(1)
C(20) 19(1) 26(1) 30(1) 8(1) 6(1) 2(1)
C(21) 22(1) 24(1) 26(1) 7(1) 9(1) 1(1)
C(22) 24(1) 26(1) 28(1) 6(1) 7(1) 1(1)
C(23) 32(1) 19(1) 32(1) 2(1) 11(1) 2(1)
0(24) 45(1) 21(1) 41(1) 2(1) 4(1) 3(1)
C(25) 43(1) 32(1) 43(1) -2(1) 3(1) -5(1)
C(26) 29(1) 22(1) 31(1) 8(1) 12(1) 5(1)
C(27) 24(1) 24(1) 26(1) 9(1) 10(1) 3(1)
C(28) 24(1) 22(1) 24(1) 6(1) 8(1) 1(1)
0(29) 36(1) 20(1) 37(1) 6(1) -5(1) 2(1)
C(30) 27(1) 27(1) 26(1) 11(1) 8(1) 3(1)
C(31) 21(1) 27(1) 23(1) 11(1) 3(1) 5(1)
C(32) 24(1) 24(1) 27(1) 8(1) 4(1) 3(1)
C(33) 23(1) 28(1) 25(1) 7(1) 4(1) 7(1)
C(34) 33(1) 33(1) 32(1) 5(1) 10(1) 9(1)
C(35) 21(1) 30(1) 27(1) 10(1) 7(1) 5(1)
C(36) 20(1) 26(1) 24(1) 9(1) 1(1) 2(1)
C(37) 22(1) 26(1) 20(1) 7(1) 2(1) 5(1)
0(38) 28(1) 27(1) 19(1) 5(1) 3(1) 5(1)
C(39) 42(1) 39(1) 21(1) 7(1) 1(1) 6(1)
C(40) 20(1) 28(1) 25(1) 6(1) 1(1) 0(1)
C(41) 49(1) 36(1) 59(1) 6(1) -12(1) 11(1)
C(42) 71(2) 34(1) 42(1) 9(1) -16(1) 4(1)
N(43) 106(2) 66(2) 56(2) 13(1) 2(1) -13(1)

 

The anisotropic displacement factor exponent takes the

268

 

form:

-2 pi‘2 [ h‘2 a*‘2 U11 + ... + 2 h k a* b* U12 ]

Table A.3.5.

Hydrogen coordinates ( x 10‘4), isotropic

displacement parameters (A‘Z x 10‘3), and occupancies for

 

 

269

246A.
x y z U(eq) Occ.
H(l) 7930(30) 8860(30) 4540(20) 58(7) 1
H(4) 7838 10362 1352 30 1
H(7A) 11025 8762 96 60 1
H(7B) 10473 7774 587 60 1
H(7C) 11501 8879 1256 60 1
H(8) 10692 8517 2481 31 1
H(10A) 6232 11139 2354 28 1
H(10B) 6223 10729 3355 28 1
H(12) 5581 9288 672 30 1
H(14A) 3559 6563 -938 61 1
H(14B) 4974 7067 —820 61 1
H(14C) 3893 7959 -995 61 1
H(15) 3117 6407 632 31 1
H(19A) 3879 10423 4575 46 1
H(19B) 2920 9742 3557 46 1
H(19C) 3926 10837 3584 46 1
H(20A) 2973 7404 3225 30 1
H(ZOB) 2244 6502 2182 30 l
H(22) 2593 4306 1750 32 1
H(25A) 2339 949 867 64 1
H(25B) 2780 2214 632 64 1
H(25C) 1778 2231 1305 64 1
H(26) 5367 2924 3454 31 1
H(29) 5020(20) 7600(20) 4066(19) 48(7) 1
H(30A) 6855 4320 4881 30 1
H(3OB) 6688 5791 5204 30 1
H(32) 7771 3583 3225 30 1
H(34A) 8923 2851 1929 49 1
H(34B) 10309 3509 2180 49 1
H(34C) 9239 3921 1418 49 1
H(35) 10371 6066 2858 30 1
H(39A) 8586 8304 6677 52 1
H(39B) 9737 7739 6247 52 1
H(39C) 8646 6817 6349 52 1
H(40A) 10932 8213 4152 30 1
H(4OB) 9966 8721 4829 30 1
H(41A) 5951 6125 1402 79 1

 

H(41B)
H(41C)

6942
7048

7240
5840

2110
2214

79
79

 

270

Fig A.2 Calix[4]arene 246C-I in the Cone Conformation

271

 

Table A.1.l.
for 246C-I

Crystal data and structure refinement

 

Identification code
Empirical formula
Formula weight
Temperature
Wavelength

Crystal system
Space group

Unit cell dimensions

Volume

Z

Density (calculated)
Absorption coefficient
F(000)

Crystal size

mm
Theta range for data collection
Index ranges

20<=k<=20, -20<=l<=21
Reflections collected / unique

[R(int) = 0.7337]

Completeness to theta = 28.24
Refinement method
squares on F‘2
Data / restraints / parameters
Goodness-of-fit on F‘2
Final R indices [I>Zsigma(I)]
0.3515
R indices (all data)
0.4137
Absolute structure parameter
Largest diff. peak and hole

eoAA-3

272

223a-I

C44 H40 04
xx640.74
173(2) K
0.71073 A
tetragonal
P 4(1)2(1)2

a = 15.699(2) A
b = 15.699(2) A
c = 16.214(3) A

alpha = 90 deg.
beta 90 deg.
gamma = 90 deg.
3996.2(11) A‘3

4

xx1.065 Mg/m‘3
xx0.070 mm‘-1
xx1360

0.22 x 0.20 x 0.14

1.81 to 28.24 deg.
-20<=h<=20, -

47415 / 4877

99.2%
Full-matrix least-

4877 / 0 / 237
1.493
R1 = 0.1875, wR2

R1 = 0.4414, wR2

2(8)
0.995 and -o.44o

Table A.1.2.

occupancies for 246C-I

Atomic coordinates ( x 10‘4), equivalent
isotropic displacement parameters (A‘Z x 10‘3), and

 

 

x y z U(eq) Occ.
0(1) 7575(4) 8381(6) 697(5) 41(2) 1
0(2) 8632(5) 5081(6) —3104(5) 59(3) 1
C(3) 6084(7) 8615(7) -390(7) 33(3) 1
C(4) 7513(8) 7887(8) -2176(6) 47(3) 1
C(5) 8090(8) 6471(8) -2678(8) 46(3) 1
C(6) 5016(9) 6410(9) -790(10) 69(4) 1
C(7) 6187(8) 8836(7) 1130(7) 39(3) 1
C(8) 6666(7) 8690(8) -1021(6) 33(3) 1
C(9) 6783(7) 7957(8) —1537(7) 38(3) 1
C(10) 7890(13) 11012(9) -1537(8) 62(4) 1
C(11) 7959(10) 9579(9) -1051(8) 53(4) 1
C(12) 5626(9) 7247(9) -832(10) 59(4) 1
C(13) 6036(8) 9269(7) 277(6) 34(3) 1
C(14) 5563(8) 8910(7) 1749(8) 45(3) 1
C(15) 6910(8) 8422(7) 1295(7) 35(3) 1
C(16) 5553(9) 7922(9) -287(8) 50(4) 1
C(17) 8397(11) 10336(10) -1224(8) 64(4) 1
C(18) 6276(8) 7283(8) -1469(7) 42(3) 1
C(19) 8267(12) 5212(10) -3927(8) 75(5) 1
C(20) 7061(10) 10933(9) -1628(7) 49(4) 1
C(21) 6687(9) 10183(10) -l469(7) 46(4) 1
C(22) 8033(8) 7093(8) -2031(7) 43(3) 1
C(23) 8526(8) 5732(8) -2537(8) 48(3) 1
C(24) 7122(8) -1170(6) 34(3) 1

9498(8)

 

U(eq) is defined as one third of the trace of the

orthogonalized Uij tensor.

273

Table A.1.3. Bond lengths [A] and angles [deg] for

 

246C-I
0(1)-C(15) 1.426(13)
0(1)-H(1) 0.8200
0(2)-C(23) 1.385(13)
0(2)-C(19) 1.467(13)
C(3)-C(16) 1.380(16)
C(3)-C(8) 1.377(14)
C(3)-C(13) 1.494(14)
C(4)-C(22) 1.508(15)
C(4)-C(9) 1.548(15)
C(4)-H(4A) 0.9700
C(4)-H(4B) 0.9700
0(5)-0(23) 1.366(16)
C(5)-C(22) 1.436(16)
C(5)-H(5) .0.9300
C(6)-C(12) 1.628(17)
C(6)-H(6A) 0.9600
C(6)-H(68) 0.9600
C(6)-H(6C) 0.9600
C(7)-C(15) 1.335(15)
C(7)-C(14) 1.407(15)
C(7)—C(13) 1.561(13)
C(8)-C(9) 1.435(16)
C(8)-C(24) 1.476(15)
C(9)-C(18) 1.328(16)
C(10)-C(20) 1.315(18)
C(10)-C(17) 1.42(2)
C(10)-H(10) 0.9300
C(11)-C(24) 1.334(16)
C(11)-C(17) 1.402(16)
C(11)-H(11) 0.9300
C(12)—C(16) 1.385(17)
C(12)-C(18) 1.453(17)
C(13)—H(13A) 0.9700
C(13)-H(133) 0.9700
C(14)-C(23)#1 1.438(15)
C(14)-H(14) 0.9300
C(15)-C(22)#1 1.371(15)
C(16)—H(16) 0.9300
C(17)-H(17) 0.9300
C(18)-H(18) 0.9300
C(19)-H(19A) 0.9600
C(19)-H(19B) 0.9600
C(19)-H(19C) 0.9600

274

C(20)-C(21)
C(20)-H(20)
C(21)-C(24)
C(21)—H(21)
C(22)—C(15)#1
C(23)—C(14)#1

C(15)-O(1)-H(1)
C(23)-0(2)-C(19)
C(16)-C(3)-C(8)
C(16)—C(3)-C(13)
C(8)-C(3)-C(l3)
C(22)-C(4)-C(9)
C(22)-C(4)-H(4A)
C(9)-C(4)-H(4A)
C(22)-C(4)-H(4B)
C(9)-C(4)-H(4B)
H(4A)-C(4)-H(4B)
C(23)-C(5)-C(22)
C(23)—C(5)—H(5)
C(22)-C(5)-H(5)
C(12)-C(6)-H(6A)
C(12)—C(6)-H(6B)
H(6A)-C(6)-H(6B)
C(12)—C(6)-H(6C)
H(6A)-C(6)—H(6C)
H(6B)-C(6)-H(6C)
C(15)-C(7)-C(14)
C(15)-C(7)-C(13)
C(14)—C(7)-C(13)
C(3)-C(8)—C(9)
C(3)-C(8)-C(24)
C(9)-C(8)-C(24)
C(18)-C(9)-C(8)
C(18)-C(9)-C(4)
C(8)-C(9)-C(4)
C(20)-C(10)-C(17)
C(20)-C(10)-H(10)
C(17)-C(10)-H(10)
C(24)-C(11)-C(17)
C(24)-C(11)-H(11)
C(17)-C(11)-H(11)
C(16)-C(12)-C(18)
C(16)-C(12)-C(6)
C(18)-C(12)-C(6)
C(3)—C(13)-C(7)
C(3)-C(13)-H(13A)
C(7)-C(13)-H(13A)

275

HHOHOH

117
124

110

.342(16)
.9300
.363(15)
.9300
.371(15)
.438(15)

.5
.0(10)
.0(11)
115.
120.

0(11)
9(11)

.8(9)
109.
109.
109.
109.
108.
119.
120.
120.
109.
109.
109.
109.
109.
109.
119.
121.
119.
116.
121.
122.
121.
116.
122.
121.
119.
119.
122.
118.
118.
118.
122.
118.
109.
109.
109.

(12)

mmmmmmmnwr—ammwm

 

C(3)—C(13)-H(13B) 109.8
C(7)-C(13)-H(13B) 109.7
H(13A)-C(13)-H(13B) 108.2
C(7)-C(14)-C(23)#l 118.1(12)
C(7)-C(14)-H(l4) 121.0
C(23)#1-C(14)—H(14) 121.0
C(7)-C(15)-C(22)#1 124.7(12)
C(7)-C(15)-0(1) , 120.5(10)
C(22)#l-C(15)-0(1) 114.8(10)
C(3)-C(16)-C(12) 118.4(13)
C(3)-C(16)—H(16) 120.8
C(12)-C(16)-H(16) 120.8
C(11)-C(17)-C(10) 115.5(15)
C(11)-C(17)—H(17) 122.2
C(10)-C(17)-H(17) 122.3
C(9)-C(18)-C(12) 120.7(12)
C(9)-C(18)-H(18) 119.7
C(12)-C(18)-H(18) 119.7
O(2)-C(19)-H(19A) 109.5
0(2)-C(19)-H(19B) 109.5
H(19A)-C(19)-H(19B) 109.5
O(2)-C(19)-H(19C) 109.4
H(19A)-C(l9)-H(19C) 109.5
H(19B)—C(19)-H(19C) 109.5
C(10)-C(20)-C(21) 119.6(14)
C(10)-C(20)-H(20) 120.2
C(21)-C(20)-H(20) 120.2
C(20)-C(21)-C(24) 122.9(13)
C(20)-C(21)-H(21) 118.6
C(24)-C(21)—H(21) 118.6
C(15)#1-C(22)-C(5) 117.8(11)
C(15)#1-C(22)-C(4) 123.3(11)
C(5)-C(22)-C(4) 118.8(11)
C(5)-C(23)-O(2) 125.2(12)
C(5)-C(23)-C(14)#1 121.0(12)
O(2)—C(23)-C(14)#1 113.8(12)
C(11)-C(24)-C(21) 118.0(13)
C(11)-C(24)-C(8) 122.4(12)
C(21)-C(24)-C(8) 119.5(12)

 

 

Symmetry transformations used to generate
equivalent atoms: #1 y,x,-z

276

(A‘Z x

Table A.1.4.
10‘3) for 246C-I

Anisotropic displacement parameters

 

 

011 022 033 023 013 012
0(1) 25(5) 56(6) 43(4) 11(5) 3(4) 5(4)
0(2) 67(6) 66(7) 44(5) -22(5) -15(5) 14(5)
0(3) 35(8) 32(8) 34(7) -5(6) -10(6) 5(7)
0(4) 73(10) 47(9) 19(7) -4(6) -11(7) 5(8)
0(5) 41(8) 50(9) 46(8) 14(7) -6(7) 7(7)
C(6) 56(10) 75(12) 76(11) -7(9) -20(11) -25(8)
0(7) 51(9) 39(8) 28(7) -3(6) 2(7) -4(7)
0(8) 29(7) 43(8) 27(6) -10(6) 7(6) 8(6)
0(9) 38(8) 36(8) 39(8) 13(7) -1(6) 6(7)
0(10) 121(15) 20(8) 45(9) -5(7) 36(10) -3(10)
0(11) 81(11) 35(9) 44(9) 0(7) -1(9) 5(9)
0(12) 57(10) 61(11) 61(10) 39(9) -29(8) 3(8)
0(13) 26(8) 50(8) 27(7) 6(6) -6(5) -9(7)
0(14) 40(9) 31(8) 64(9) 6(7) 0(8) 4(7)
0(15) 44(8) 23(7) 39(7) 0(6) 5(7) 11(6)
C(16) 55(10) 50(10) 45(9) -5(8) 0(8) 16(8)
0(17) 70(12) 69(12) 54(9) -10(9) 33(8) -13(10)
C(18) 47(9) 49(9) 30(7) -12(7) -4(7) 21(7)
0(19) 100(16) 80(14) 44(9) -27(10) -20(9) 15(11)
0(20) 51(9) 58(11) 39(8) 15(7) 3(8) 8(10)
0(21) 42(9) 65(11) 30(7) 0(7) -2(7) -2(8)
0(22) 55(9) 38(8) 37(8) -3(7) 4(7) 18(7)
C(23) 52(9) 45(9) 47(9) -4(8) 14(8) 0(8)
0(24) 37(8) 48(9) 17(6) -1(6) 0(6) 0(8)

 

the form: -2 pi‘2 [ h“2 a*“2 U11 + ...

The anisotropic displacement factor exponent takes

277

+ 2 h k a* 0* 012 1

 

Table A.1.5. Hydrogen coordinates ( x 1024), isotropic
displacement parameters (A22 2 1023), and occupancies for
246C-I

 

 

x y z U(eq) 000.
3(1) 7486 7983 382 250(130) 1
H(4A) 7274 7873 -2727 40(30) 1
H(4B) 7877 8384 -2134 50(40) 1
H(5) 7834 6570 -3186 340(140) 1
H(6A) 4619 6470 -344 150(80) 1
H(6B) 5360 5912 -702 700(400) 1
H(6C) 4711 6352 -1300 30(30) 1
H(10) 8150 11523 -1682 40(30) 1
H(ll) 8263 9116 -846 120(70) 1
H(13A) 5480 9539 270 50(40) 1
H(IBB) 6463 9705 185 0(20) 1
H(14) 5056 9199 1651 80(50) 1
H(16) 5157 7909 139 10(30) 1
H(17) 8980 10393 -1139 40(40) 1
H(18) 6338 6830 -1834 0(20) 1
H(19A) 8392 4728 -4269 80(50) 1
H(19B) 8509 5715 -4170 100(60) 1
H(19C) 7661 5278 -3883 80(50) 1
H(20) 6736 11395 -1801 0(20) 1
H(21) 6106 10127 -1567 160(80) 1

 

278

1

Fig A.3 Structure of 246C—II — 1,2 Alternate

279

 

Table A.2.1.

Crystal data and structure refinement

 

21<=k<=21,

[R(int)

for 246C-II
Identification code 3a-II
Empirical formula C44 H40 04
Formula weight 632.76
Temperature 293(2) K
Wavelength 0.71073 A
Crystal system monoclinic
Space group P2(1)/c
Unit cell dimensions a = 12.899(3) A
b = 16.405(3) A
c = 15.888(3) A
alpha = 90 deg.
beta = 97.61(3) deg.
gamma = 90 deg.
Volume 3332.3(12) A“3
Z 4
Density (calculated) 1.261 Mg/m“3
Absorption coefficient 0.079 mm‘-1
F(000) 1344

Crystal size

Theta range for data collection
Index ranges

-21<=1<=20

Reflections collected / unique
0.0892]
Completeness to theta
Refinement method

28.34

squares on F‘2

0.1228

0.1660

eoAA-3

Data / restraints / parameters
Goodness-of—fit on F‘Z

Final R indices [I>Zsigma(I)]
R indices (all data)

Extinction coefficient
Largest diff. peak and hole

280

0.45 x 0.40 x 0.35 mm
2.02 to 28.34 deg.
-16<=h<=17,

37057 / 7755

93.3%
Full-matrix least-

7755 / 0 / 537
0.858
R1 = 0.0551, wR2

R1 = 0.1379, WR2

0.0026(6)
0.239 and -0.225

 

 

Table A.2.2.

occupancies for 246C-II

Atomic coordinates ( x 10‘4), equivalent
isotropic displacement parameters (A‘Z x 1073), and

 

 

x y z U(eq) 000.
0(1) 5573(1) 844(1) 2(1) 33(1) 1
0(2) 9287(1) 1472(1) -1223(1) 34(1) 1
C(5) 7459(2) 1385(1) —1379(2) 25(1) 1
C(6) 8408(2) 1268(1) -863(2) 25(1) 1
C(8) 4836(2) 605(1) -l765(l) 22(1) 1
C(9) 6548(2) 947(1) -236(2) 24(1) 1
C(10) 6168(2) 886(2) 2005(2) 31(1) 1
C(11) 5477(2) 1379(1) -1602(2) 24(1) 1
C(12) 6622(2) 278(2) 1566(1) 27(1) 1
C(16) 6528(2) 1232(1) -1070(1) 22(1) 1
C(17) 7488(2) 800(1) 282(2) 25(1) 1
C(21) 7608(2) 473(2) 1188(2) 33(1) 1
C(22) 8416(2) 973(1) -50(2) 26(1) 1
C(23) 3863(2) 495(1) —1469(1) 24(1) 1
C(27) 3369(2) 1181(1) -1043(2) 26(1) 1
C(31) 5267(2) -28(2) -2187(1) 28(1) 1
C(34) 5233(2) 771(2) 2331(2) 32(1) 1
C(35) 10272(2) 1349(2) -721(2) 41(1) 1
C(40) 3292(2) 1178(2) —179(2) 32(1) 1
C(41) 4767(4) 1437(2) 2816(3) 52(1) 1
C(43) 2566(2) 2525(2) -266(2) 45(1) 1
C(45) 2895(2) 1845(2) 205(2) 41(1) 1
C(46) 2612(2) 2529(2) -1124(2) 44(1) 1
C(47) 3012(2) 1864(2) -1513(2) 35(1) 1
0(3) 340(1) 1519(1) 4828(1) 35(1) 1
0(4) -3130(1) 2181(1) 6399(1) 41(1) 1
C(7) 1971(2) 159(1) 5857(2) 26(1) 1
C(13) -572(2) 1649(1) 5169(2) 26(1) 1
C(14) —1547(2) 1713(1) 4675(2) 25(1) 1
C(15) —2412(2) 1893(1) 5082(2) 28(1) 1
C(18) 1158(2) -71(1) 6408(1) 24(1) 1
C(19) -2308(2) 1998(2) 5954(2) 31(1) 1
C(20) -1338(2) 1891(2) 6437(2) 31(1) 1
C(24) 1052(2) -903(1) 6611(1) 26(1) 1
C(25) 526(2) 502(1) 6757(1) 26(1) 1

281

C(26)
C(28)
C(29)
C(30)
0(32)
0(33)
C(36)
C(37)
C(38)
0(39)
0(42)
0(44)
0(51)

551(2)
-184(2)
2974(2)
1772(2)
-296(2)

330(2)
-469(2)

-1713(2)

3559(2)
3759(2)

-4146(2)
-1071(3)

2559(2)

1421(1)
235(2)
360(2)
114(2)

-576(2)

-1137(2)

1690(1)
1564(2)
422(2)
487(2)
2175(2)
-842(2)
242(2)

6573(2)
7284(2)
6221(2)
4973(2)
7492(2)
7146(2)
6054(2)
3725(2)
4854(2)
5723(2)
5927(2)
8075(2)
4479(2)

29(1)
28(1)
35(1)
32(1)
30(1)
29(1)
28(1)
30(1)
48(1)
48(1)
45(1)
42(1)
41(1)

HHHHHHHHt—IHHHH

 

U(eq) is defined as one third of the trace of the

orthogonalized Uij tensor.

282

 

 

Table 3.2.3.

Bond lengths [A] and angles [deg] for

 

246C-II
0(1)-0(9) 1.372(3)
0(1)-H(1) 0.86(3)
0(2)—C(6) 1.377(3)
0(2)-C(35) 1.422(3)
C(5)-C(16) 1.379(3)
C(5)—C(6) 1.393(3)
C(5)-H(5A) 0.9300
0(6)-0(22) 1.378(3)
C(8)-C(31) 1.391(3)
C(8)-C(23) 1.409(3)
C(8)-C(11) 1.519(3)
C(9)-C(17) 1.392(3)
C(9)-C(16) 1.403(3)
C(10)-C(34) 1.386(3)
C(10)-C(12) 1.390(3)
C(10)-H(10A) 0.9300
C(11)-C(16) 1.520(3)
C(11)-H(11A) 0.9700
C(11)—H(llB) 0.9700
0(12)-0(23)#1 1.413(3)
C(12)-C(21) 1.510(3)
C(17)-C(22) 1.400(3)
C(17)-C(21) 1.525(3)
C(21)-H(21A) 0.97(3)
C(21)-H(21B) 0.99(3)
C(22)-H(22A) 0.9300
0(23)-0(12)#1 1.413(3)
C(23)-C(27) 1.498(3)
C(27)-C(40) 1.389(3)
C(27)-C(47) 1.391(3)
C(31)-C(34)#1 1.384(3)
C(31)-H(31A) 0.9300
0(34)-0(31)#1 1.384(3)
C(34)-C(41) 1.507(4)
C(35)-H(35A) 0.99(3)
C(35)-H(35B) 0.99(3)
C(35)-H(35C) 1.05(3)
C(40)-C(45) 1.384(4)
C(40)-H(40A) 0.9300
C(41)-H(41A) 0.89(7)
C(41)-H(4lB) 0.99(7)
C(41)-H(41C) 1.09(11)

283

 

 

C(41)-H(41D)
C(41)-H(41E)
C(41)-H(41F)
C(43)—C(46)
C(43)-C(45)
C(43)-H(43A)
C(45)-H(45A)
C(46)-C(47)
C(46)-H(46A)
C(47)-H(47A)
0(3)—C(13)
0(3)-H(3A)
0(4)-C(19)
0(4)-C(42)
0(7)-0(29)
C(7)-C(30)
C(7)-C(18)~
C(13)-C(36)
C(13)-C(14)
C(14)-C(15)
C(14)-C(37)
C(15)-C(19)
C(15)-H(15A)
C(18)-C(25)
C(18)-0(24)
C(19)—C(20)
C(20)-C(36)
C(20)-H(20)
C(24)-C(33)
0(24)-0(37)#2
C(25)-C(28)
C(25)-C(26)
C(26)-C(36)
C(26)—H(26A)
C(26)—H(268)
C(28)-C(32)
C(28)-H(28A)
C(29)-C(39)
C(29)-H(29A)
C(30)-C(51)
C(30)-H(30A)
C(32)-C(33)
C(32)-C(44)
C(33)-H(33A)
0(37)-0(24)#2
C(37)-H(37A)
C(37)-H(37B)
C(38)-C(51)

284

HOOHOHHOHOHOHOOHHHI—IHOHHI—IHOHHHHHHHHHHOHOOHOOHHOHH

.05(5)
.04(5)
.99(7)
.373(4)
.378(4)
.9300
.9300
.386(4)
.9300
.9300
.375(3)
.8200
.383(3)
.420(3)
.385(3)
.396(3)
.500(3)
.397(3)
.396(3)
.392(3)
.515(3)
.386(3)
.9300
.405(3)
.414(3)
.390(4)
.384(3)
.97(3)
.396(3)
.519(3)
.391(3)
.536(3)
.522(3)
.9700
.9700
.382(3)
.9300
.381(4)
.9300
.379(4)
.9300
.385(3)
.514(4)
.9300
.519(3)
.9700
.9700
.379(4)

C(38)-C(39) 1.375(4)
C(38)-H(38A) 0.9300
C(39)-H(39A) 0.9300
C(42)-H(42A) 0.9600
C(42)-H(4ZB) 0.9600
C(42)-H(42C) 0.9600
C(44)-H(44A) 0.99(7)
C(44)-H(44B) 0.93(8)
C(44)-H(44C) 0.99(6)
C(44)-H(44D) 1.09(5)
C(44)—H(44E) 1.00(5)
C(44)-H(44F) 1.08(6)
C(51)—H(51A) 0.9300
C(9)—0(1)-H(1) 114(2)
C(6)-0(2)-C(35) 117.2(2)
0(16)-0(5)-0(6) 120.3(2)
C(16)—C(5)-H(SA) 119.8
C(6)-C(5)-H(5A) 119.8
C(22)-C(6)-0(2) 124.7(2)
C(22)-C(6)-C(5) 119.8(2)
0(2)-0(6)-0(5) 115.5(2)
C(31)-C(8)-C(23) 119.7(2)
C(31)-C(8)-C(11) 117.6(2)
C(23)-C(8)-C(11) 122.6(2)
0(1)-0(9)-0(17) 125.1(2)
0(1)-C(9)-C(16) 113.5(2)
C(17)-C(9)-C(16) 121.4(2)
C(34)-C(10)-C(12) 122.4(2)
C(34)-C(10)-H(10A) 118.8
C(12)-C(10)-H(10A) 118.8
C(8)-C(11)-C(16) 112.79(18)
C(8)-C(11)-H(11A) 109.0
C(16)-C(11)-H(11A) 109.0
C(8)-C(11)-H(llB) 109.0
C(16)-C(11)-H(llB) 109.0
H(11A)-C(ll)-H(llB) 107.8
0(10)-0(12)-0(23)#1 119.2(2)
0(10)-0(12)-0(21) 118.7(2)
0(23)#1-0(12)-0(21) 122.1(2)
C(5)-C(16)-C(9) 119.3(2)
C(5)-C(16)-C(11) 121.9(2)
0(9)-0(16)-0(11) 118.8(2)
0(9)-0(17)-0(22) 117.7(2)
0(9)-0(17)-0(21) 126.1(2)
0(22)-0(17)-0(21) 116.3(2)
0(12)-0(21)-0(17) 117.7(2)
C(12)-C(21)-H(21A) 107.8(15)

285

C(17)-C(21)-H(21A) 108.0(15)

C(12)-C(21)-H(21B) 108.6(15)
0(17)-0(21)-H(21B) 108.5(15)
H(21A)—0(21)-H(218) 106(2)
C(6)-C(22)-C(17) 121.5(2)
C(6)-C(22)-H(22A) 119.2
C(17)-C(22)-H(22A) 119.2
C(8)-C(23)-C(12)#1 118.6(2)
C(8)-C(23)-C(27) 120.4(2)
0(12)#1-0(23)-0(27) 120.9(2)
0(40)-0(27)-0(47) 118.1(2)
0(40)-0(27)-0(23) 122.3(2)
0(47)-0(27)-0(23) 119.6(2)
C(34)#1-C(31)-C(8) 122.0(2)
C(34)#1-C(31)-H(31A) 119.0
C(8)—C(31)-H(31A) 119.0
0(31)#1-0(34)-0(10) 117.8(2)
0(31)#1-0(34)—0(41) 120.9(3)
0(10)-0(34)-0(41) 121.2(3)
0(2)-C(35)-H(35A) 110.6(17)
0(2)-C(35)-H(35B) 104.3(16)
H(35A)-C(35)—H(3SB) 112(2)
0(2)—C(35)-H(35C) 111.8(17)
H(35A)-C(35)-H(35C) 111(2)
H(358)-0(35)-H(350) 108(2)
0(45)-0(40)-0(27) 120.7(3)
C(45)-C(40)-H(40A) 119.6
C(27)-C(40)-H(40A) 119.6
C(34)-C(41)-H(41A) 110(4)
C(34)-C(41)-H(4lB) 114(4)
H(41A)-C(41)-H(4lB) 101(6)
C(34)-C(41)-H(41C) 111(5)
H(41A)—C(41)-H(41C) 114(7)
H(4lB)—C(41)-H(41C) 107(6)
C(34)-C(41)-H(41D) 112(2)
H(41A)-C(41)-H(41D) 138(5)
H(4lB)-C(41)-H(41D) 61(4)
H(4lC)-C(41)-H(41D) 50(6)
C(34)-C(41)-H(41E) 110(3)
H(41A)-C(41)-H(41E) 67(4)
H(4lB)-C(41)-H(41E) 135(5)
H(41C)-C(41)-H(41E) 51(6)
H(41D)-C(41)-H(41E) 98(4)
C(34)-C(41)-H(41F) 111(4)
H(41A)-C(41)-H(41F) 50(5)
H(4lB)-C(41)-H(41F) 54(4)
H(41C)-C(4l)-H(41F) 138(6)
H(41D)-C(41)-H(41F) 111(5)

286

H(41E)-C(41)-H(41F) 113(5)

C(46)-C(43)-C(45) 119.5(3)
C(46)—C(43)-H(43A) 120.3
C(45)-C(43)-H(43A) 120.3
0(43)-0(45)-0(40) 120.5(3)
C(43)-C(45)-H(45A) 119.8
C(40)—C(45)-H(45A) 119.8
C(43)-C(46)-C(47) 120.4(3)
C(43)-C(46)-H(46A) 119.8
C(47)-C(46)-H(46A) 119.8
0(46)-0(47)-0(27) 120.8(3)
C(46)-C(47)-H(47A) 119.6
C(27)-C(47)-H(47A) 119.6
C(13)-0(3)—H(3A) 109.5
0(19)-0(4)-0(42) 116.5(2)
0(29)-0(7)-0(30) 118.0(2)
C(29)-C(7)—C(18) 120.2(2)
C(30)-C(7)-C(18) 121.6(2)
0(3)-C(13)-C(36) 115.5(2)
0(3)-0(13)-0(14) 123.0(2)
C(36)—C(13)-C(14) 121.5(2)
C(15)-C(14)-C(13) 118.2(2)
0(15)-0(14)-0(37) 118.7(2)
0(13)-0(14)-0(37) 123.1(2)
0(19)-0(15)-0(14) 120.9(2)
C(19)-C(15)-H(15A) 119.5
C(14)-C(15)-H(15A) 119.5
C(25)-C(18)-C(24) 118.5(2)
C(25)-C(18)—C(7) 123.3(2)
0(24)-0(18)-0(7) 118.1(2)
0(4)-0(19)-0(20) 116.1(2)
0(4)-0(19)—0(15) 124.0(2)
0(20)-0(19)-0(15) 119.8(2)
C(36)-C(20)-C(19) 120.7(2)
C(36)-C(20)-H(20) 121.1(15)
C(19)-C(20)-H(20) 118.1(15)
C(33)-C(24)-C(18) 119.8(2)
0(33)-0(24)-0(37)#2 118.0(2)
C(18)-C(24)-C(37)#2 122.2(2)
C(28)-C(25)-C(18) 119.2(2)
0(28)-0(25)-0(26) 117.1(2)
C(18)—C(25)-C(26) 123.6(2)
C(36)—C(26)-C(25) 110.42(19)
C(36)-C(26)-H(26A) 109.6
C(25)-C(26)-H(26A) 109.6
C(36)-C(26)-H(26B) 109.6
C(25)—C(26)-H(26B) 109.6
H(26A)-0(26)-H(268) 108.1

287

0(32)-0(28)-0(25)
C(32)-C(28)-H(28A)
0(25)-0(28)-H(28A)
0(39)-0(29)-0(7)
C(39)-C(29)-H(29A)
C(7)-C(29)-H(29A)
0(51)-0(30)-0(7)
C(51)-C(30)-H(30A)
C(7)-C(30)-H(30A)
C(28)-C(32)-C(33)
C(28)-C(32)—C(44)
0(33)-0(32)-0(44)
C(32)-0(33)-0(24)
C(32)-C(33)-H(33A)
C(24)-C(33)-H(33A)
C(20)-C(36)-C(13)
0(20)-0(36)-0(26)
C(13)-C(36)-C(26)
0(14)-0(37)-0(24)#2
C(14)-C(37)-H(37A)
C(24)#2-C(37)—H(37A)
C(14)-C(37)-H(37B)
C(24)#2-C(37)-H(37B)
H(37A)-C(37)-H(37B)
C(51)-C(38)-C(39)
C(51)-C(38)-H(38A)
C(39)-C(38)-H(38A)
C(38)-C(39)-C(29)
C(38)—C(39)-H(39A)
C(29)-C(39)-H(39A)
0(4)-C(42)-H(42A)
0(4)-C(42)-H(4ZB)
H(42A)-C(42)-H(42B)
0(4)-C(42)-H(42C)
H(42A)-C(42)—H(42C)
H(428)-0(42)-H(420)
C(32)-C(44)-H(44A)
C(32)-C(44)-H(44B)
H(44A)-C(44)-H(44B)
C(32)-C(44)-H(44C)
H(44A)-C(44)-H(44C)
H(44B)-C(44)—H(44C)
C(32)-C(44)-H(44D)
H(44A)-C(44)-H(44D)
H(44B)-C(44)-H(44D)
H(44C)-C(44)-H(44D)
C(32)-C(44)-H(44E)
H(44A)-C(44)-H(44E)

288

123.
118.
118.
120.
119.
119.
120.
119.
119.
117.
121.
121.
122.
119.
119.
118.
121.
119.
117.
108.
108.
108.
108.
107.
119.
120.
120.
120.
119.
119.
109.
109.
109.
109.
109.
109.
113(
107(
106(
112(
102(
117(
109(
138(

57(

65(
112(

53(

A
w
v

WWWWWMQQO‘LAUNWCOOO
A
w
v

4)
4)
6)
3)
5)
6)
2)
4)
5)
4)
3)
4)

 

H(44B)-C(44)—H(44E) 55(5)

H(44C)-C(44)-H(44E) 135(4)
H(44D)-C(44)-H(44E) 108(4)
C(32)-C(44)-H(44F) 108(3)
H(44A)-C(44)-H(44F) 54(4)
H(44B)-C(44)-H(44F) 144(5)
H(44C)-C(44)-H(44F) 52(4)
H(44D)-C(44)-H(44F) 115(4)
H(44E)-C(44)-H(44F) 105(4)
0(38)-0(51)-0(30) 120.3(3)
C(38)-C(51)-H(51A) 119.8
C(30)-C(51)-H(51A) 119.8

 

Symmetry transformations used to generate
equivalent atoms: #1 -x+1,-y,-z #2 -x,-y,-z+1

289

Table A.2.4.

Anisotropic displacement parameters
(A22 x 1023) for 246C-II

 

 

011 022 033 023 013 012
0(1) 21(1) 52(1) 25(1) 10(1) 3(1) -5(1)
0(2) 24(1) 45(1) 35(1) -2(1) 12(1) -4(1)
0(5) 30(1) 24(1) 22(1) -1(1) 6(1) -4(1)
C(6) 24(1) 22(1) 31(1) -6(1) 10(1) -3(1)
C(8) 24(1) 24(1) 18(1) 4(1) -3(1) -1(1)
0(9) 23(1) 22(1) 27(1) 0(1) 5(1) -5(1)
0(10) 40(2) 26(1) 24(1) 2(1) -1(1) -9(1)
0(11) 26(1) 24(1) 22(1) 4(1) 3(1) 0(1)
0(12) 29(1) 32(1) 18(1) 6(1) -3(1) -2(1)
0(16) 24(1) 18(1) 24(1) 0(1) 4(1) -3(1)
0(17) 28(1) 21(1) 26(1) 0(1) 3(1) —4(1)
0(21) 27(1) 40(2) 29(1) 8(1) -4(1) -8(1)
0(22) 22(1) 26(1) 31(1) -1(1) 2(1) 0(1)
0(23) 24(1) 28(1) 19(1) 2(1) -1(1) 0(1)
0(27) 18(1) 29(1) 32(1) 1(1) 2(1) 0(1)
0(31) 31(1) 30(1) 24(1) 1(1) 6(1) 0(1)
0(34) 42(2) 30(1) 25(1) -1(1) 2(1) -2(1)
0(35) 22(2) 56(2) 45(2) —2(2) 8(1) -5(1)
0(40) 29(1) 35(2) 34(2) 0(1) 5(1) 1(1)
0(41) 74(3) 37(2) 50(2) 14(2) 23(2) 7(2)
0(43) 29(2) 40(2) 68(2) -9(2) 15(1) 3(1)
0(45) 34(2) 48(2) 42(2) -8(1) 11(1) 1(1)
C(46) 32(2) 32(2) 69(2) 10(1) 9(1) 6(1)
0(47) 28(1) 39(2) 40(2) 9(1) 7(1) 1(1)
0(3) 26(1) 52(1) 28(1) -3(1) 5(1) —1(1)
0(4) 36(1) 50(1) 38(1) -1(1) 12(1) 11(1)
0(7) 28(1) 24(1) 26(1) 2(1) 3(1) 1(1)
0(13) 27(1) 21(1) 31(1) 0(1) 6(1) -2(1)
0(14) 31(1) 19(1) 26(1) 2(1) 6(1) 2(1)
0(15) 30(1) 25(1) 29(1) 2(1) 3(1) 3(1)
C(18) 24(1) 29(1) 19(1) -2(1) -2(1) -2(1)
0(19) 34(2) 26(1) 35(2) —1(1) 12(1) 5(1)
0(20) 40(2) 26(1) 27(1) -3(1) 7(1) 2(1)
0(24) 27(1) 28(1) 22(1) 0(1) 1(1) 1(1)
0(25) 26(1) 28(1) 22(1) -1(1) -3(1) -1(1)
0(26) 33(1) 26(1) 28(1) -7(1) 1(1) -3(1)

290

C(28)
0(29)
0(30)
0(32)
0(33)
0(36)
0(37)
0(38)
0(39)
0(42)
0(44)
0(51)

29(1)
31(2)
38(2)
27(1)
31(1)
33(1)
33(2)
44(2)
26(2)
37(2)
41(2)
60(2)

32(1)
41(2)
27(1)
38(2)
29(1)
22(1)
28(1)
50(2)
63(2)
54(2)
50(2)
36(2)

24(1)
32(2)
30(1)
24(1)
28(1)
31(1)
28(1)
53(2)
54(2)
48(2)
38(2)
30(2)

-2(1)
10(1)
-1(1)
-2(1)
4(1)
-3(1)
4(1)
22(2)
25(2)
-3(2)
0(2)
5(1)

2(1)
0(1)
4(1)
3(1)
1(1)
3(1)
3(1)
23(2)
4(1)
16(1)
14(2)
14(1)

4(1)
-2(1)
-2(1)
-3(1)
-2(1)
-1(1)

3(1)

9(1)
-4(1)

2(1)
-3(2)

6(1)

 

the form: -2 pi“2 [ h‘2 a*‘2 U11 + ...

The anisotropic displacement factor exponent takes

291

+ 2 h k a* b* 012 1

Table A.2.5.

occupancies for 246C-II

Hydrogen coordinates ( x 10‘4),
isotropic displacement parameters (A‘Z x 10‘3), and

 

 

x y z U(eq) 000.
3(1) 5570(30) 650(20) 510(20) 72(11) 1
H(SA) 7454 1566 -1934 29(7) 1
H(10A) 6503 1387 2082 29(7) 1
H(11A) 5084 1770 -1314 26(6) 1
H(1lB) 5592 1615 -2143 27(6) 1
H(22A) 9054 887 286 29(7) 1
H(31A) 5910 51 -2378 27(6) 1
H(35A) 10330(20) 1690(18) -204(19) 51(9) 1
H(3SB) 10790(20) 1507(16) -1099(17) 41(8) 1
H(35C) 10400(20) 730(20) -562(19) 63(10) 1
H(40A) 3510 722 145 45(8) 1
H(41A) 5200(50) 1860(40) 2890(50) 44(19) 0.50
H(41E) 4700(70) 1300(40) 3410(50) 60(20) 0.50
H(41C) 3990(90) 1600(70) 2510(70) 120(40) 0.50
H(41D) 4030(40) 1280(30) 2970(30) 15(12) 0.50
H(41E) 4540(50) 1920(30) 2420(30) 21(13) 0.50
H(41F) 5250(50) 1600(50) 3330(50) 46(19) 0.50
H(43A) 2314 2977 -4 54(9) 1
H(45A) 2851 1835 784 46(8) 1
H(46A) 2374 2981 -1447 55(9) 1
H(47A) 3042 1875 -2094 28(7) 1
H(3A) 213 1503 4309 63(11) 1
H(15A) -3068 1942 4763 28(7) 1
H(ZO) -1296(19) 1933(15) 7050(17) 34(7) 1
H(26A) 656 1720 7104 18(6) 1
H(ZGB) 1132 1542 6262 33(7) 1
H(28A) -603 619 7506 35(7) 1
H(29A) 3120 410 6808 39(8) 1
H(30A) 1099 -5 4714 27(7) 1
H(33A) 267 -1687 7275 32(7) 1
H(37A) -1581 2071 3444 24(6) 1
H(37B) -2443 1428 3561 36(7) 1
H(38A) 4093 499 4522 55(9) 1
H(39A) 4429 617 5978 44(8) 1
H(42A) -4653 2313 6295 49(8) 1

292

H(428)
H(42C)
H(44A)
H(44B)
H(44C)
H(44D)
H(44E)
H(44F)
H(SlA)
H(21A)
H(218)

-4295
-4177
-1640(60)
—720(60)
-1460(50)
-800(30)
-1140(40)
-1840(40)
2415
8000(20)
8050(20)

1642
2567
—450(40)
—860(50)
-1330(40)
-1410(30)
-430(30)
-870(40)
207
868(16)
-23(17)

5693
5476
8100(50)
8620(50)
7860(40)

8380(30)

8530(30)
7710(30)
3891

1553(16)
1217(16)

71(11)
61(10)
53(19)
60(20)
48(17)
11(11)
11(11)
29(14)
38(8)

34(7)

41(8)

1

0.50
0.50
0.50
0.50
0.50
0.50
1

1

 

293

Reference:

10.

11.

12.

Zinke, A.; Ziegler, E. Chem. Ber. 1944, 77, 264

Gutsche, C.D.; Dhawan, B.; No, K.H.; Muthukrishnan, R. J. Am. Chem. Soc.
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B0hmer, V.; Marschollek, P.; Zetta, L. .1. Org. Chem. 1987, 52, 3200-3205
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