Efforts Towards Steroid Natural Products Using a Sequential Diels-Alder Strategy
by
Jason Blair Crawford B. Sc., University o f Victoria, 1991
A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of
DOCTOR OF PHILOSOPHY
in the Department of Chemistry
We accept this dissertation as conforming to the required standard
Dr. Claude Sniffe Supervisor (Departement de Chimie, Universite de Sherbrooke)
Dr. G erk$A. Poulton, Departmental Member (Department of Chemistry)
Dr. Peter C. Wan, Departmental Member (Department o f Chemistry)
Dr. Paul Rom^jniuk, Outside Member (Department o f Biochemistry/Microbiology)
Dr. Edward Piers, External Examiner (Department o f Chemistry, University of British Columbia)
© Jason Blair Crawford, 1996 University o f Victoria
All rights reserved. This dissertation may not be reproduced in whole or in part, by photocopying or by other means, without the permission o f the author.
Supervisor; Dr, Claude Spino
ABSTRACT
A novel strategy has been developed for the generation of the
perhydrophenanthrene skeleton through the use o f sequential Diels-AJder reactions on a
1,3,7,9-tetraene. This strategy ailows for the generation o f the equivalent o f the steroidal
A/B/C ring-system, in an efficient and stereoselective manner. A similar strategy, also
involving sequential Diels-Alder cycloaddition reactions, was employed in the attempted
synthesis o f a steroid natural product.
Examiners:
Dr. Claude Spjkfo. Siio^rvisor (Departement de Chimie, Universite de Sherbrooke)
Dr. GeraldA. Poulton. Denartmental Member (Department o f Chemistry)
Dr, Peter C. Wan, Departmental Member (Department o f Chemistry)
Dr, Paul Roi^aniuk, Outside Member (Department o f Biochemistry/Microbiology)
Dr. Edward Piers, External Examiner (Department o f Chemistry, University o f British Columbia)
iiiTABLE OF CONTENTS:
Page#
Title Page i
Abstract ii
Table o f Contents iii
List o f Tables vi
List o f Figures vii
List o f Schemes ix
List of Spectra xi
Acknowledgements xiii
List o f Abbreviations xv
Chapter One: Introduction: Page #
1.1: Steroids: General Features, Functions and Historical Perspective 1
1.1.1; Cholesterol 1
1.1.2: Bile Salts 2
1.1.3: Cardiac Aglycones and Sapogenins 3
1.1.4: Sex Hormones and Corticosteroids 4
1.2: Biogenesis o f Steroids 6
1.3: Biological Activity and Clinical Uses of Androgenic Steroids 11
1.3.1: Biological Activity o f Androgens 11
1.3.2: Clinical Uses o f Androgens 13
1.4: Synthetic Strategies Towards Androgens and other Steroids 16
1.4,1 • Biomimetic Carbocation-Polyolefin Cyclization Approach 16
1.4.2: Aldol or Robinson Annulation Approach 20
1.4.3: Diels-Alder Approach 24
1.5: Project OutlineIV
33
Chapter Two: Results and Discussion: Page #
2.1: Retrosynthetic Analysi s 39
2.2: Model Diene Synthesis 41
2.3; Synthesis and Evaluation of Dienophiles 44
2.3.1: Carbomethoxybutadiene Studies 44
2.3.2: Acrolein Studies 48
2,3.3: Enyne Studies 54
2.4: Research Towards New Acyclic Bis-Dienes 68
2.5: Synthesis o f Bis-Dienes Incorporating the D-Ring 74
2.5.1: 2-Methyl-cyclopentane-1,3 -dione Studies 75
2.5.2: Studies Involving Cycloisomerization Reactions 78
2.5.2.1: Generation o f Cycloisomerization Precursor 78
2.5.22: Cycloisomerization Reaction 81
2.5.2.3: Attempts at the Generation o f the Second 90
Diene Fragment
2.6: Alternate Sequential Diels-Alder Strategy Using Cyclo- 99
Isomerization Product as ‘First’ Diene
2.6.1: Diels-Alder Reaction Between 118 and MVK 103
2.6.2: Subsequent Modification o f the Bicyclic Cycloadduct 106
2.6.3: Attempted IMDAC Using the Newly Generated Diene 119
2,7: Future Research 125
Chapter Three: Conclusions 128
Chapter Four: Experimental 129
References 182
Appendix 1: 195
A1.1: 2-Carbomethoxybutadiene as a Diene 195
A 1.1.1: Determination o f Enophilicity of 45 195
A 1.1.2: Reactivity o f Structural Analogs o f45 201
, Appendix 2: Spectra 205
viLIST OF TABLES:
Chapter Two: Paee #
Table 2-1: Preliminary Attempts at the Generation o f 118 from 111 83
via a Palladium Catalyzed Cycloisomerization
Table 2-2: Attempts at the Conversion o f 111 to 118 using 119 and 86
HOAc as a Catalytic System
Table 2-3: Optimization o f Cycloisomerization o f 111 Using 88
Pd(OAc)z/BBEDA as a Catalytic System
Table 2-4: Predicted Energetic and Dihedral Angle Values for 108
Cycloadducts 143 and 144
Table 2-5: Attempted Conditions for IMDAC o f 157 121
Appendix One: Paee #
Table A-l: Tlsermal Reaction o f 45 With Various Dienes 197
Table A-2: RT Reaction o f 45 With Various Dienes 198
Table A-3: Reaction o f 45 and 165 with Maleic Anhydride 199
Table A-4: Reactivity o f Amide Analogs o f 45 Diels-Alder 203
Reaction with 41
Appendix Two: Paee #
Table A-5: List o f Spectra 205
LIST OF FIGURES:vii
Chapter One: Page #
Figure 1-1: Cholesterol, Showing Conventional Carbon Numbering 1
and Ring Nomenclature
Figure 1-2: Digitonin: a steroidal glycoside 3
Figure 1-3: Prediction o f FMO Coefficients for Dienes and 27
Dienophiies
Figure 1-4: Possible Transition States for IMDAC of 25 35
Figure 1-5: Potential Steroidal A-Rings From a Common Synthetic 36
Intermediate
Figure 1-6: 5a-Dihydrotestosterone, a Potential Synthetic Target 38
Chapter Two: Paae #
Figure 2-1: Potential Dienophile Candidate Molecules 49
Figure 2-2: Transition States for IMDAC Reactions 53
Figure 2-3: Potential Steric Congestion Between Angular Methyl 54
Group and Pendant Diene in IMDAC exo Transition State
Figure 2-4: Structural and Functional Group Requirements o f Enyne 55
Bis-Dienophile
Figure 2-5: ORTEP Diagram of Major IMDAC Product 68 59
Figure 2-6: 'H NMR Spectrum (expansion) and 'H COSY Spectrum 65
of Major IMDAC Product 69
Figure 2-7: NMR Spectral Evidence for Proposed Structure o f 69a 65
Figure 2-8: Alternate Catalytic System 119 and Ligand 120 for 84
Cycloisomerization Reaction
Figure 2-9: Possible Facial Orientations for DAC of 118 with MVK 101
Figure 2-10: Portions o f the 'H -i3C Correlated Spectrum and 'H COSY 104
Spectrum o f Cycloadduct 143
Paae#
VM
Figure 2-11: Energy-Minimizt i Cycloadducts From Molecular 107
Modelling Calculations , -
Figure 2-12: Expected Transition State Geometry for IMDAC 121
Appendix One:
Figure A-l: Evans Chiral Auxilliary 203
ijcLIST OF SCHEMES:
Chapter One:
Scheme # Paee # Scheme # Pace ti-
Scheme 1-1 3 Scheme 1-13 23
f Scheme 1-2 5 Scheme 1-14 24
Scheme 1-3 6 Scheme 1-15 25
Scheme 1-4 7 Scheme 1-16 28
Scheme lr5 8 Scheme 1-17 29
Scheme 1-6 10 Scheme 1-18 30
Scheme 1-7 17 Scheme 1-19 31
Scheme 1-8 18 Scheme 1-20 32
Scheme 1-9 19 Scheme 1-21 32
Scheme 1-10 20 Scheme 1-22 34
Scheme 1-11 21 Scheme 1-23 37
Scheme 1-12 22
Chapter Two:
Scheme # Paee # Scheme # Paee H
Scheme 2-1 39 Scheme 2-11 57
Scheme 2-2 41 Scheme 2-12 58
Scheme 2-3 42 Scheme 2-13 60
Scheme 2-4 45 Scheme 2-14 62
Scheme 2-5 46 Scheme 2 -15 63
Scheme 2-6 47 Scheme 2-16 63
Scheme 2-7 50 Scheme 2-17 68
Scheme 2-8 51 Scheme 2-18 69
Scheme 2-9 52 Scheme 2-19 69
Scheme 2-10 56 Scheme 2-20 70
Chapter Two (continued):
Scheme # Paee # Scheme # Paee#
Scheme 2-21 71 Scheme 2-41 96
Scheme 2-22 71 Scheme 2-42 97
Scheme 2«23 72 Scheme 2-43 97
Scheme 2-24 73 Scheme 2-44 100
Scheme 2-25 74 Scheme 2-45 102
Scheme 2-26 75 Scheme 2-46 103
Scheme 2-27 76 Scheme 2-47 106
Scheme 2-28 77 Scheme 2-48 109
Scheme 2-29 78 Scheme 2-49 110
Scheme 2-30 77 Scheme 2-50 111
Scheme 2-31 79 Scheme 2-51 112
Scheme 2-32 80 Scheme 2-52 113
Scheme 2-33 82 Scheme 2-53 114
Scheme 2-34 87 Scheme 2-54 115
Scheme 2-35 90 Scheme 2-55 117
Scheme 2-36 91 Scheme 2-56 118
Scheme 2-37 92 Scheme 2-57 119
Scheme 2-38 93 Scheme 2-58 120
Scheme 2-39 94 Scheme 2-59 123
Scheme 2-40 95 Scheme 2-60 126
Appendix One:
Scheme # P aee# Scheme # Paee
Scheme A -1 195 Scheme A-4 200
Scheme A-2 197 Scheme A-5 202
Scheme A-3 199 Scheme A-6 202
xiLIST OF SPECTRA (contained in Appendix Two):
Snect'i' ... . Paso#
‘H NMR (250 MHz) and F:.,TR spectra o f 37 206
*H NMR (360 MHz) and 13C l4MR of 38 207
lH NMR (360 MHz) and 13C NMR of 40 208
'H NMR (360 MHz) and IR spectra of 41 209
13C NMR and DEPT spectra o f 41 210
'H NMR (90 MHz) and IR spectra of 44 211
’H NMR (360 MHz) and 13C NMR spectra o f 46 212
lH NMR (250 MHz) spectrum o f 47 213
lH NMR (360 MHz) and IR spectra of 55 214
‘H NMR (3C0 MHz) and IR spectra o f 56 215
'H NMR (250 MHz) spectrum o f 57 216
'H NMR (360 MHz) and IR spectra of 58 217
'H NMR (360 MHz) and IR spectra of 59 218
l3C NMR and DEPT spectra o f 59 219
‘H NMR (360 MHz) and IR spectra of 60 220
‘H NMR (360 MHz) and IR spectra of 61 221
‘H NMR (360 MHz) and IR spectra o f 63 222
*H NMR (360 MHz) and IR spectra of 65 223
‘H NMR (360 MHz) and IR spectra of 66 224
'H NMR (360 MHz) and IR spectra o f 67 225
‘H NMR (360 MHz) and IR spectra of 68 226
,3C NMR and DEPT spectra o f 68 227
]H NMR (360 MHz) and IR spectra o f 69 2.78
13C NMR and DEPT spectra of 69 229
NOESY (top) and COSY spectra o f 69 230
'H NMR (360 MHz) and IR spectra o f 107 23)
*H NMR (360 MHz) and IR spectra of 108 232
Spectra: Pane #
'H NMR (360 MHz) and IR spectra o f 109 233
’H NMR (360 MHz) and IR spectra o f 110 234
‘H NMR (360 MHz) and IR spectra o f 111 235
'H NMR (250 MHz) and 13C NMR spectra o f 112 236
’H NMR (300 MHz) and IR spectra o f 118 237
l3C NMR and DEPT spectra o f 118 238
’H NMR (300 MHz) and IR spectra o f 138 239
'H NMR (300 MHz) and IR spectra of 143 240
l3C NMR and DEPT spectra o f 143 241
‘H/i3C Correlated (top) and COSY spectra o f 143 242
'H NMR (300 MHz) and IR spectra of 144 243
'H NMR (300 MHz) and IR spectra o f 145 244
'H NMR (300 MHz) and IR spectra o f 146 245
1?C NMR and DEPT spectra of 146 246
'H NMR (300 MHz) and IR spectra o f 152 247
'H NMR (300 MHz) and IR spectra o f 157 248
xiiiACKNOWLEDGEMEN i S.
During the course o f my degree, I feel very fortunate to have had the unwavering
support o f my friends and family. I am confident that, without this support, the project
would have been much less productive and much less enjoyable. As such, I owe a great
deal of thanks to my parents, my brothers and sisters, and their families. Also, I wish to
thank my buddy Geoff, for making sure I didn’t take myself too seriously, and, o f course,
a particularly heartfelt thanks to Kathy, whose constant encouragement and caring support
was greatly appreciated.
At the University, I was also very fortunate to have had the opportunity, during the
course o f my research, to consult with many co-workers, professors, and other graduate
students, whose advice, in many cases was extremely helpful. I wish to thank the
following for their help and advice: Noah Tu, Gang Liu, Eric Fillion, Brian Eastman, Rob
Gossage, Rich Hooper, Dr. ^homas Fyles, and Dr. Peter Wan.
O f course, the degree required that I would have to obtain a wide variety o f
spectral data which, when I couldn’t obtain them myself, were provided by the following,
to whom I owe a great deal o f thanks: Mrs. Christine Greenwood (NMR, UVic), Dr,
Dave MacGillivray (MS, UVic), Mr. Lea Sohallig (MS, UVic), Dr. Norman Pothier
(NMR, Sherbrooke), Mr. Gaston Boulet (MS, Sherbrooke) and Mr. Marc Drouhin (X-
Ray, Sherbrooke).
I also owe a great deal o f thanks to Dr. Claude Spino. I feel very lucky to have
been associated with a supervisor whose enthusiasm for the project, and for organic
chemistry in general provided an atmosphere which allowed for a great deal o f enjoyable
learning to take place. I will forever be indebted to Claude for his unselfish sharing o f
knowledge and time, which allowed me to develop a much greater understanding and
appreciation o f synthetic organic chemistry than !’d anticipated when L started the project.
xivLastly, I ’d like to express my appreciation to the University o f Victoria for
providing me with funding for my degree. I feel very lucky and appreciative to have had
the benefit o f two particularly generous scholarships from the University. Also, I wish to
thank NSERC for funding Claude’s research, and thus largely allowing for such research
to take place at Canadian Universities.
LIST OF ABBREVIATIONS:xv
AcCl: Acetyl Chloride
AIBN: Azo-rso-Bis-Butyronitrile
BBEDA: Bis-(benzylidine)ethylenediamine
Bn: Benzyl
Bu: Butyl
CDAC: Cross Diels-Alder Cycloaddition
CoA: Coenzyme A
COSY: Homonuclear Shift Correlated Spectroscopy
DAC: Diels-Alder Cycloaddition
DHEA. Dehydroepiandrosterone
DEPT: Distortionless Enhancement by Polarization Transfer ( ‘H/I3C in this case)
An,n: Unsaturation Between Carbon # ’s n and n’
E: Ester
ee: Enantiomeric Excess
ERG: Electron Releasing Group
Et: Ethyl
EWG: Electron Withdrawing Group
FMO: Frontier Molecular Orbital
hGH: Human Growth Hormone
HMDS: Hexamethyldisilazane
HOMO: Highest Occupied Molecular Orbital
IMDAC: Intramolecular Diels-Alder Cycloaddition
IR: Infra Red
LAH: Lithium Aluminum Hydride
LDA: Lithium Diisopropylamide
LUMO: Lowest Unoccupied Molecular Orbital
Me; Methyl
MMPP: Monomagnesium Monoperphthalate
xviMs: Methanesulfonyl
MVK: Methyl Vinyl Ketone
nBuLi: n-Butyllithium
NBS: N-Brornosuccinimide
NMR: Nuclear Magnetic Resonance
nOe: Nuclear Overhauser Enhancement
NOESY: Homonuclear Nuclear Overhauser Enhancement Correlated Spectroscopy (2D)
Ph: Phenyl
Pr. Propyl
RT: Room Temperature
TBDMS: ter/-Butyldimethylsilyl
Tf; Trifluoromethanesulfonyl
THP: Tetrahydropyran
CHAPTER ONE: INTRODUCTION
1.1: General Features, Functions, and Historical Perspective:
Sterols are a diverse family o f modified triterpenoids which are present in most
eukaryotic cells. Originally, they were named as the collective group of solid alcohols
obtained from nor. saponifiable portions o f lipid extracts o f tissues': the name itself is
based on the Greek word steros, which means 'solid'. Structurally, a tetracyclic ring
skeleton (perhydrocyclopentenophenanthrene) is common to all steroids (see Figure 1-1),
and the wide ranging biological activities o f these molecules is a result of the differing
functionalities of the substituents on the rings and the varying degree of unsaturation of
the ring skeleton.
22 24 _
23
sH
HO
Figure 1-1: Cholesterol, Showing Conventional Carbon
Numbering and Ring Nomenclature
1.1.1: Cholesterol:
Cholesterol, the most abundant steroid in mammalian systems (approximately 2-3g
per kg body weight in humans), was first isolated in the early 1800's: the discovery
generally being accredited to Michel Eugene Chevreul in 1812.' Although, in North
2
American society, cholesterol is perhaps thought o f mainly as being a major cause o f heart
disease through the formation o f atheroscopic plaques (likely a result of a high-fat diet),
cholesterol is in fact an important and essential compound for survival. Through
integration into the phospholipid bilayer o f cell membranes (via hydrophobic association o f
the non-polar part o f the cholesterol molecule with the lipid chains and hydrogen bonding
of the cholesterol hydroxyl group to the fatty acid derived ester carbonyl group)
cholesterol plays an important role in the mediation o f membrane fluidity. By preventing
close, ordered association of the fatty acid acyl chains, cholesterol serves to prevent
crystallization of the membrane. And, through hydrogen bonding to the acyl chains,
cholesterol also hinders rapid movement o f the individual phospholipid groups. Thus,2
cholesterol prevents the membrane from becoming too fluid or too solid in nature.
1.1.2: Bile Salts:
Shortly after the discovery o f cholesterol, lithocholic acid, a steroidal bile acid, was
isolated from ox bile (in 1828 by Leopold Gmelin'). Lithocholic acid (Scheme 1-1), and
some twenty other structurally related steroid-based acids, are generally found in the body
as amide-acids that are formed through the condensation o f the C24 acid functionality o f
the parent steroid with the amino functionality o f an a-amino acid (often glycine or
taurine: see Scheme 1-1): o f course, in the intestine, they exist as the sodium salts o f the
respective acids. Through their amphipathic, detergent-like nature, they are capable of
emulsifying fats in the digestive tract into micelles, which enables transport through the2
small intestinal wall.
HO'Lithocholic acid
c o 2hH 2NCH 2C O 2H
Q^Gine) ^
HO'
Scheme 1-1
HOoC
Glycolithocholic acid
1.1.3: Cardiac Aglycones and Sapogenins:
The next major family o f steroids to be discovered were the cardiotonic glycosides.
Perhaps the most well known o f this group is digitonin, which is isolated from the purple
foxglove. It exists in nature as a steroidal glycoside: a condensation o f saccharide units
with the steroidal skeleton. In the case o f digitonin, a pentasaccharide chain is attached to
the oxygen on C3 (Figure 1-2). Although the structure o f the aglycone (without the
pentasaccharide) o f digitonin was not elucidated until 1935* the cardiotonic nature o f
digitonin was well known in the 19th century. In very small doses (0.1 mg per day),I 2
digitonin is an effective treatment o f congestive heart failure. ’ A related class o f
compounds, the sapogenins (so named because o f the soapy nature o f their aqueous
solutions) were also discovered at approximately the same time.'
HO-
(xylose)(galactose)5(glucos9)20 ' ^
Figure 1-2: Digitonin: a steroidal glycoside
4
1.1.4: Sex Hormones and Corticosteroids:
In the 1930's, a new class o f steroids were isolated: the se.: hormones, As was the
case with the cardiotonic glycosides, the knowledge of biologically active compounds
extracted from sexual organs (usually dog or bull testicles) preceded the isolation and
structural elucidation o f the compounds themselves by several decades. Perhaps the first
well documented case o f use o f steroid-based hormones was by Charles Edouard Brown-
Sequard, whom in 1889 made the bold claim that by injecting himself with liquid extract of
dog and guinea pig testicles he had reversed his own aging process: an increase in physical
strength and intellectual energy were two o f the claimed benefits.1 In 1911, A. Pezard
found that the comb o f a male capon grew in direct proportion to the injected dose of
animal testicular extract: perhaps the first documented case with verifiable scientific
results. Two decades later, in 1931, Adolf Butenandt isolated 15 mg of androsterone
from 15,000 litres o f male urine. Soon thereafter, in May, 1935, testosterone was also
isolated from urine by K.G. David, E. Laqueur and their colleagues. Perhaps more
interesting to the synthetic chemist were two subsequent syntheses, completed later in the
same year, o f testosterone from cholesterol by Butenandt (and co-workers) and by
Leopold Ruzicka and A. Wettstein: an achievement for which Butenandt and Ruzicka
received the Nobel Prize for Chemistry in 1939. At approximately the same time, estrone
and estradiol were isolated from ovaries o f cattle, and some o f the corticosteroids were
isolated from the adrenal cortex. Much later, the metabolic origin o f these steroid2 3
hormones *ou!d be traced back to cholesterol (see Scheme 1-2). ’
cholesterolHO
pregnenoloneHO
OH
testosterone progesterone
OHV , OH
estradiol
HO
corticosterone
Scheme 1-2
6
1.2: Biogenesis of Steroids:
Due to intense scientific interest in steroidal metabolism and biogenesis
(particularly cholesterol), a great deal is known about the biological origin o f steroids. In
fact, the genesis o f cholesterol and other steroids can be traced all the way back to the
individual acetate units ^ As shown in Scheme 1-3, the first step is the generation o f the
individual isopentenyl pyrophosphate units, which will later malm up the steroidal
skeleton. These units are biosynthesized from mevalonic acid, which, in turn, has acetyl-. . 2-4
coenzyme A as its origin.
A SCoA Acetyl CoA
OH v OH 9
OHm evalonic acid
H3O6P2Q H3O6P2O
pentenyl pyrophosphates
Scheme 1-3
As shown in Scheme 1-4, the next stage in the biogenesis o f steroids is the
condensation o f the five-carbon isoprenoid units into squalene. The newly formed
squalene molecule is referred to as a triterpene, as it is created from three ten-carbon
terpene units (which each consist o f two isoprene units), At this point the carbon skeleton
is large enough to create the steroidal skeleton, and in most animal systems, the
triterpenoids are the largest natural terpene-based molecules, As a side note, some forty-
carbon tetraterpenoids are generated in plants, which can lead to the highly coloured2,3
carotenoid family o f compounds.
H'
o p 2o 6h3 I o p2o 6h3isopentenyldimethylallyl
pyrophosphate pyrophosphate
i \^ O P 2 0 6H3
geranyl pyrophosphate
farnesyl pyrophosphate
squalene (C30)
Scheme 1-4
Following the generation o f squalene, an enzyme, squalene monooxygenase, serves
to epoxidize the C2-C3 bond o f the squalene. The molecule will then undergo a
stereospecific cyclization, undoubtedly utilizing another enzyme, which will provide a
mode of acid catalysis and a molecular geometry restriction, to give an intermediate
8
carbocation.2-* Note that, as shown in Scheme 1-5, the three six membered rings (A, B
and C respectively) are in a chair-boat-chair type array. The intermediate carbocation will
undergo a stereospecific rearrangement (made possible by the axial nature of the migrating
substituents) to give, as a product in animal systems, lanosterol. A similar cyclization2,3
occurs in plants and fungi to give stigmasterol and ergosterol respectively. Note that the
stereochemistry o f the cyclization and subsequent rearrangement is the cause o f the
stereochemical arrangement o f all the ring junctions and substituents. Following the2-4
generation o f lanosterol, several metabolic modifications take place to give cholesterol.
Squalene
squalene-2,3-epoxide
H* / Enzymatic Control
lanosterol
Scheme 1-5
9
As shown previously in Scheme 1-2, cholesterol (from lanosterol) is the biogenic
source (in animals) for the six major classes o f steroids: sterols, sapogenins, cardiac
aglycones, bile acids, adrenal steroids and sex hormones. This report will focus on the sex
hormones, and more specifically the androgenic male sex hormones. The conversion of
cholesterol to this class of compounds occurs mainly in the testis, but also occurs in lesser
amounts in the adrenal cortex and the ovaries. Cholesterol is first converted toM
pregnenolone, which is then converted to progesterone. From here, a variety of
androgens can be generated: the term androgen encompasses a group of male sex
hormones which are responsible (at least in part) for the development of secondary sexual
characteristics.
10
-C H 3C 02H H
17-a-hydroxy-progesterone
progesterone androstenedione
Handrosterone androstanedione testosterone
androstane-3a, 17|Vdiol androstane-17p-ol-3-one (dihydrotestosterone)
Scheme 1-6
As shown in Scheme 1-6, progesterone is hydroxylated at the Cl 7 position, which
can yield, after oxidation, androstenedione. From this point, testosterone, the most
abundant o f the human androgens, can be generated, Several other androstane-based
steroids can also be generated through subsequent metabolic modification of testosterone
(see Scheme 1-6).1,2,4
11
1.3: Biological Activity and Clinical Uses of Androgenic Steroids:
The androgenic steroids are responsible for two majOi types o f biological
activities: the androgenic effect (masculinization) and the anabolic effect.' As is well
known to the public, the use o f anabolic steroids (synthetic derivatives o f testosterone,
usually having an acyl chain attached to the oxygen on C l7) as performance enhancing
drugs provides athletes, both male and female, with a rapid degree o f muscular
development that may be accompanied by a variety of side effects. Recent estimates
suggest that the number o f people abusing anabolic steroids in the United States of
America may be close to one million.'
1.3.1: Biological Activity of Androgens:
The body, both male and female, naturally produces testosterone and other
androgens throughout life. These compounds are very effective, sometimes exerting their-9 5,6
desired effect at concentrations as low as 10 moles/litre. The natural level o f androgen
excretion is governed largely by peptide-based hormones which are excreted from the2
pituitary and hypothalamus glands (including human growth hormone and gonadotropin ).
When a certain level o f these hormones is detected by the extracellular receptors o f the
target organ, which, in this case would be the testis, ovaries or the adrenal cortex, a
cascade o f intracellular events occurs which provides for the synthesis o f greater levels o f
the androgens. In the case o f testosterone, the major site o f biosynthesis appears to be the
Leydig cells in the testis.5
The androgens themselves are then secreted into the bloodstream. Solubility o f
these lipid-based molecules in the aqueous extracellular environment is very low; as a
result, steroids are sometimes secreted to the bloodstream as sulfates or glucuronides.1
12
Another biologically operative mode o f solubilizing the androgens (and other steroids) in2 5 7 8
the bloodstream is through association with water-soluble plasma proteins.
Once the androgens reach the target organ, they must cross the cell membrane in
order 10 exert their desired effect. This can happen in three ways: attachment o f the 'free'
steroid to an extracellular receptor and subsequent incorporation into the cytoplasm,
diffusion o f the free steroid across the cell membrane, or 'ingestion' o f a lipoprotein5,8
complex which contains the steroid. Through either mode, the steroid is able to gain
access to the cytoplasm, which will contain a specific protein-based receptor for the
androgen. The next step after formation o f the steroid-receptor complex is migration of5 8
the complex to, and eventually through the nuclear membrane. ’ Once inside the nucleus,
the steroid-receptor complex is capable o f binding specific segments o f chromatin (DNA5 8
strands) which enhances the rate o f transcription o f certain genes. ’ Following the
transcription, the newly formed RNA, through a process o f translation, will generate new
proteins and enzymes which will exert their biological effects within the c e ll/8 Eventually,
the intranuclear steroid-receptor complex presumably dissociates or is biologically
degraded to terminate the increased rate o f transcription.
On a macroscopic level, the androgenic effects o f the steroids are those which
result in a development o f the reproductive tract and growth o f facial and body hair. The
anabolic effects o f these androgens are those which don't take place in the somatic and
reproductive tract tissue. Such effects are an acceleration in growth, with a concomitant
decrease in the level o f body fat, and also an enlargement o f the larynx and thickening o f
the vocal cords. Perhaps the most well known anabolic effect is the increase in muscle
bulk and strength.
13
Historically, the biological efficacy of various androgens was measured as a
function o f capon comb development as a function o f injected dose. Another similar
experiment measured the anabolic efficacy o f androgens by evaluating the increase in
nitrogen retention (detected through measurement o f concentrations in urine; increased
nitrogen retention being related to increased protein synthesis) as a function o f dose .
Through these tests, it was determined that testosterone was one o f the most effective
androgenic steroids.' At a later date, the blood plasma levels o f the various androgens
could be measured, and the following levels were found in the average adult male5
(expressed as pg per 100 mL): testosterone, 0.7; dehydroepiandrosterone, 0.5;
androstenedione, 0.1; 5a-dihydrotestosterone, 0.05. Through the use of radiolabelled
steroids in tissue binding studies, and subsequent recovery o f the intracellular steroids, it
was found that the major intracellular metabolite (and strongest binding steroid to theS 8
intracellular receptor) was 5a-dihydrotestosterone. ’
1.3.2: Clinical Uses of Androgens:
The clinical uses o f androgens (and anabolics) are quite varied, Since the
androgens are responsible for the development o f secondary sexual characteristics, they
have often been used as a puberty and growth stimulating factor in boys who are
experiencing a significant developmental delay.' Androgens are also used, in conjunction
with the proteinacious human growth hormone (hGH), to initiate growth in children who1.2,5
are hGH deficient. Another use o f the androgens has been for recuperative treatment of
chronic debilitating conditions such as those experienced by those who have recently been9
burned, had surgery, radiation therapy or chemotherapy.
As a result o f the pote. ’t effect o f the androgens on the reproductive tract, they
have been heavily studied as a mode o f contraception in both men and women. In fact,
14
most female oral contraceptives are based on varying ratios o f progesterone and
testosterone derivatives (with 17a-et.hynyl-19-nor-testosterone (norethindrone) being one. 1.4
o f the most widely used androgen derivatives). In males, testosterone has also been9
examined as a potential contraceptive. The hypothalamus gland reacts to high levels o f
plasma testosterone by reducing the release o f leutinizing hormone-releasing hormone,9
which, in turn, lowers the production o f sperm. Although such a contraceptive has not
yet become widely available, testing has been conducted on humans through the World9
Health Organization, the results o f which have shown that the treatment is effective.
Perhaps one o f the most interesting clinical potentials o f testosterone and other
androgens are as 'anti-aging' compounds. From the time that Brown-Sequard injected
himself with the testicular extracts and claimed their various benefits, people have been
enamoured with the idea o f the androgens' potential ability to retard (or, even more9
ambitiously, reverse) the effects o f aging. More recent experiments have used
testosterone derivatives, in some cases in the conjunction with hGH, in men over the age
o f 54 who had low to normal levels o f natural testosterone: the positive results included an9
increase in lean body mass and strength and a better spatial perception and word memory.
Another, more recent test carried out with eight men and eight women over the age o f 50
at the University o f California, San Diego, used dehydroepiandrosterone (DHEA), The
goal o f the experiment was to examine the effects o f restoring DHEA levels to peak levels
(usually experienced between the ages o f 25 and 30) on the patients.10 The reported mode
o f action o f tiiis steroid is to increase the amount o f insulin-like growth factor 1, which is
involved with the regulation o f cellular metabolism and the immune system. In males, the
steroid was also found to activate natural killer cells, which are involved in the immune
response. Although a well-controlled clinical study involving a large population has not
15
yet been conducted to verify the results, the sixteen patients in the preliminary study
reported an increase in physical and psychological well being.'0
Perhaps, most notoriously, androgenic and anabolic steroids are well known for
their anabolic effects. Athletes, and others, both male and female, have used anabolic
steroids to increase muscle mass and strength for enhanced appearance or performance
since the late 1940's.'° Unfortunately, the purchase and administration o f these steroids,
which are sometimes intended for livestock, are often conducted through an international
black market which exists largely due to the huge demand (roughly $1-billion US per year)
for such drugs. Unfortunately, these drugs are not without side effects. In women, the
excess testosterone (and metabolites) can lead to a degree o f masculinization (increased
amounts o f facial and body hair, deepening o f voice and increased clitoral size), In men,
the increased androgenic levels can lead to decreased sperm p ro d u c tio n .A n o th e r side
effect for men, which is well known amongst bodybuilders, is an enlargement o f the
nipples and an increase in amounts fatty tissue around the nipple (essentially the early
development o f a female-like breast): this is likely a result o f the effects the female sex
hormones estrogen and estradiol, which are two o f the metabolites o f testosterone,
Another side effect o f excess testosterone, for both men and women, is the development
o f pattern baldness on the scalp, which again is a result o f one o f the metabolites of5 8
testosterone; which, in this case is dihydrotestosterone. '
16
1.4: Synthetic Strategies Towards Androgens and Other Steroids:
With such a wide and varied degree o f biological activity (including those o f
clinical, and therefore economical importance), and with such a relatively complex
structure, the steroid family has long been a desired synthetic target for chemists. Early
experiments using exhaustive oxidative degradation were followed by selenium
dehydrogenation in the 1930's, which allowed for the structural elucidation o f many
steroids*. By the late 1940's, the stereochemistry o f the steroids had been largely
determined, which, along with the determination o f cyclohexane conformation (and axial
and equatorial substituents) in 1950,'* provided the necessary structural information to
allow for steroidal synthesis.
Many o f the first syntheses o f androgens were based on modifications o f existing
steroids (often cholesterol). These partial syntheses were mainly involved with functional
group manipulations, and didn't have to deal with the significant problem o f
stereoselective genera tion o f the carbocyclic ring skeleton.
Attempted total syntheses o f steroids soon followed, and could largely be broken
up into three basic classes (with various sub-classes) based on the strategy chosen for the
generation o f the carbocyclic skeleton: (1) those using a biomimetic, carbocation-based
'cascade'; (2) those using condensation reactions, such as the Aldol or the Robinson
Annulation; (3) tho ve using pericyclic reactions, such as the Diels-Alder reaction.
1.4.1: Biomimetic Carbocathn-Polyolefin Cyclization Approach:
Chemists have sought to mimic the biological cyclization o f squalene-2,3-oxide (to12-14
give lanosterol) for the past four decades. The biological cyclization, in which the
17
tetracyclic skeleton is generated 'in one step' in a stereoselective, and in biological systems
enantioselective manner provides a very attractive target to the synthetic organic chemist,
Unfortunately, there is one fundamental problem with this method if squalene epoxide is
used as a starting material. As shown in Scheme 1-7, in which the cyclization is shown in
a stepwise manner, a relatively unstable secondary carbocation is generated as an
intermediate. Without the stabilization which the biological enzyme presumably provides,
the cyclization cascade will not lead to lanosterol.
ctS <rvi c y 1
squalene or oxide
without e n z y m e ^ j^
lanosterol
2° carbocation at C-13
Scheme 1-7
In fact, the first attempted cyclizations o f squalene-2,3-oxide yielded a tricyclic
product which resulted from the formation of a tertiary carbocation at C14 rather than a12
secondary carbocation at C13. Thus, the 'C'-like ring will be five-membered, and the
fourth ring (the D-ring) won't form. This pathway, which gives two different tricyclic
alkenes (based on the elimination o f two different protons), is outlined in Scheme 1-8.
Unfortunately, experimentation with different Lewis acids, solvents, temperatures and
other variables was unsuccessful in altering the regiochemistry o f the cyclization in non-
18
enzymatic laboratory systems. As a side note, such a pathway has been successfully
utilized to generate natural products such as malabaricanediol.'3
Lewis
Acid L A O0 ^ R= C10H20
L.A.'
L A OHOHO
Scheme 1-8
In order to generate a steroid-like structure utilizing the carbocation-polyolefin
cascade type pathway, the difficulties associated with the secondary carbocation must
somehow be circumvented. The most obvious and common way that this is achieved is
through the use o f a starting material in which the five-membered ring (the D-ring) and
sometimes also the attached six membered ring (the C-ring) are already present. Two
examples o f such a strategy are provided in Scheme 1-9. The first uses a molecule in
which the five membered ring is present in the starting material (to give the isoeuphenol
type system)15, and the second uses a starting material in which the D-ring is also present
(to give the lanosterol-type system).'6 Note the variance in the B/C ring junction
stereochemistiy in the two examples resulting from the differing geometries o f cyclization.
19
R
DLewis Acid
HO
isoeuphenol system
Lewis Acid
HO'
lanosterol system
Scheme 1-9
Although these early biomimetic investigations did not lead immediately (as hoped)14
to lanosterol, a later study did in fact produce lanosterol from a biomimetic pathway in
which the C- and D-rings were present in the starting material (Scheme 1-10). It is
important to note, however that the cyclization did not yield lanosterol directly.
Following cyclization, the alkene was present between carbon atoms 7 and 8; therefore, a
short series o f alkene migrations were required to incorporate the alkene at the correct
location (at the B/C ring junction, carbons 8 and 9). Although the olefm-carbocation
cyclization route, owing to its potential simplicity, still remains a very attractive route to
the steroid skeleton, to date, synthetic chemists have unfortunately been unable to14
duplicate the economical effectiveness o f the single, natural 83-kDa enzyme by achieving
the conversion from squalene-2,3-oxide to lanosterol in a single step. Although research
in this area is still being conducted, many alternative routes have been developed which
allow for better, more predictable control o f the synthesis o f the steroidal skeleton.
20
Lewis Acid
AcO’
R
HO1 Lanosterol
Scheme 1-10
1.4.2: Aldol o r Robinson Annulation Approach:
The first total synthesis o f a steroid skeleton, conducted in 1951 by R.B.
Woodward,'7 did not use a biomimetic carbocation-olefin cyclization route. In fact, the
synthesis can be thought o f as a 'hybrid' route in that it uses both a Diels-Alder
reaction and two Robinson Annulation reactions to generate the tetracyclic molecule.
However, since the generation o f the A/B and the B/C ring junctions are a result o f the
Robinson Annulation reactions, the synthesis should provide an effective example o f the
condensation-type synthetic strategy towards the steroids.
As shown in Scheme 1-11, the synthesis commences with a Diels-Alder cyclization
(which will be discussed in more detail in section 1.4.3) between butadiene and
methoxyltolylquinone to give the bicyclic species 1. Subsequent epimerization o f the ring
junction stereochemistry with acid and lithium aluminum hydride reduction o f the dione
functionality yields the bicyclic ketone 2. Following removal o f the hydroxyl functionality
2i
18(with zinc and acid), and condensation (via a Robinson Annulation (see Scheme 1-12)),
the tricyclic ketone 3 is obtained. These three rings, from left to right, will constitute,
after suitable modification, the B,C, and D-rings o f the steroid.
heat
2 . LAH O
HO
2. ethyl vinyl Ketone
h 3c o0
Scheme 1-11
18The Robinson Annulation using ethyl vinyl ketone (or similar compounds) has
proven to be an efficient mode o f incorporating a six membered ring with a ketone
functionality (other methods will be discussed later). As shown in Scheme 1-12, the
reaction proceeds in two basic steps, the first being a 1,4-type addition (to generate 2a)
and the second being an Aldol condensation (to give 2b), Following dehydration (which
is often spontaneous), the a,p-unsaturated ketone 3 is generated, In this synthesis, the
newly-formed cyclohexenone ring will become the steroid B-ring. At this stage, two
major steps are required to generate the steroidal skeleton: incorporation of the A-ring,
and modification o f the D-ring to give a five, rather than a six-membered ring, The former
is achieved through the application o f another Robinson Annulation, As shown in Scheme
1-13, after modification o f 3 (oxidation o f the alkene on the D-ring and subsequent
22
protection o f the diol then hydrogenation o f the alkene on the C-ring) to give 4, the
enolate o f the ketone is reacted with an aniline derivative (in a three step sequence) to give
S, which serves the iiinction o f preventing enolization (and subsequent reaction) at that
site during the following Robinson Annulation. Thus, when 5 is treated with a base and
acrylonitrile, the reaction proceeds regiospecifically. Hydrolysis o f the nitrile functionality
(and the protected site a-to the B-ring ketone), and subsequent reaction o f the ethyl ester
(formed from the hydrolysis and subsequent esterification o f the nitrile) with
methylmagnesium bromide, allows for the Aldol reaction to occur and affords the
tetracyclic compound 6.
base 1,4-addition
“O' - o
aldol
Scheme 1-12
Note that the stereochemistry o f the newly formed ring junction is shown as a
single isomer: in the actual synthesis, the Robinson Annulation reactions yield both
isomers. The undesired isomers o f 6 and 3 were discarded, and only the compounds with
23
the correct stereochemistry were carried through to the next steps. This property o f the
Robinson Annulation is unfortunate, as it does not allow for a stereoselective formation of
the desired compounds. For a stereoselective synthesis, unless the 'wrong' stereoisomer
can be converted to the 'right' stereoisomer, the overall synthetic efficiency o f the pathway
will suffer since a significant fraction o f the material must be discarded at each Annulation
step.
NAr
base
H 1. hydrolysis , «|nd reduction ///
2. MeMgBr N3. base
Scheme 1-13
The last major sequence in the synthesis is involved with the conversion of the six-
membered ring at the upper right side to a five-membered steroidal D-ring, This was
achieved reasonably simply through the employment of periodic acid, which will deprotect
and oxidatively cleave the diol to give the dialdehyde 7 (thus opening the 'D' ring). As
seen in Scheme 1-14, the dialdehyde can then undergo an intramolecular Aldol reaction
(followed by a dehydration) to give 8. Oxidation o f the aldehyde, and esterification o f the
resulting acid will yield methyl-3-keto-A4'*1 l>16-etiocholatiienate, 9, as a final product.
24
As a side note, this compound was also used as a starting material for a later synthesis o f
cholesterol'9 and also lanosterol.20
base
0CHO
1. Oxidation
0
Scheme 1-14
1.4.3: Diels-Alder Approach:
The Diels-Alder reaction is a thermally induced [4+2]-cycloaddition between a 47t-
system (referred to as the diene) and a 27t-system (referred to as the dienophile).21 The
cycloaddition occurs in a concerted manner through a boat-like transition state to give a
cyclohexene ring as a product. Since the bond formation and bond breakage occur
simultaneously, the stereochemistry o f the substituents on the diene or dienophile are
reflected in the cycloadduct. Thus, if the geometry o f approach o f the dienophile (with
respect to the diene) can be predicted or controlled, then the stereochemistry o f the
cycloadduct can thus be predicted or controlled: as shown in Scheme 1-15, up to four
contiguous stereocenters may be generated. Fortunately, for the modem synthetic organic
chemist, a great deal o f research has been conducted with the Diels-Alder reaction, and as
a result it is, in fact, possible to predict (and, thus, with appropriate starting materials,
25
22control) the regiochemistry and stereochemistry o f the cycloaddition. In the case o f
steroids, or, for that matter, any product in which there are one or more cyclohexene (01
cyclohexane) rings present, the Diels-Alder reaction presents a very attractive route to
efficiently and predictably generate the carbocyclic skeleton.
diene dienophile cycloadduct
Scheme 1-15
The three main factors that must be considered when a Diels-Alder reaction is to
be employed in a synthesis are the relative reactivity of the diene/dienophile system, the22
regiochemistry of the addition, and the stereochemistiy of the addition. The first factor is23
perhaps best understood through the use o f Frontier Molecular Orbital Theory. ‘ Since
the ‘normal’ Diels-Alder reaction occurs as a result o f the interaction of the HOMO of the
diene with the LUMO o f the dienophile, it stands to reason that substituents which
minimize the energy gap between these two orbitals will cause the cycloaddition to
become more facile. Since the LUMO o f the dienophile will be higher in energy than the
HOMO o f the diene, the desired substituents should lower the energy o f the dienophile
LUMO while raising the energy o f the diene HOMO. Hence, electron-withdrawing
substituents (such as carbonyl groups or nitrites) 'activate' dienophiles, whereas electron
releasing substituents (alkoxy groups) 'activate' dienes.
26
The regiochemistry o f the cycloaddition can be predicted based on the location and22
the nature o f the substituents on both the diene and the dienophile. As discussed in the
previous paragraph, these substituents wiil affect the relative energies o f the molecular23
orbitals, but they will also affect the magnitude o f the frontier orbital coefficients. Since
the strongest interaction will occur between orbitals with the largest coefficients (and,
since these interactions involve the frontier orbitals), the relative location and electronic
effects o f the substituents will also control the regiochemistry o f the reaction. Although
the magnitude o f all the FMO coefficients in a molecule may be difficult to predict, one
can use a reasonably simple and reliable 'tool' to predict the regiochemistry o f the24
addition. The 'end' o f the diene (either carbon one or four o f the 1,3 diene) which has
the greatest orbital coefficient can be predicted, by simple resonance-like 'arrow-pushing'
from the most electron-rich substituent. As shown in Figure 1-3, the electron-releasing
group at carbon one will give the largest orbital coefficient at carbon four, and an ERG at
carbon two will give the largest FMO coefficient at carbon one. Similar arguments with
an electron-withdrawing group on the dienophile will show that carbon two is most
capable of'accepting' electrons, and will thus have the largest FMO coefficient.
27
ERG ERG
4C-4 has largest FMO coefficient
ERG. “
C-1 has largest FMO coefficient
EWG EWG
2 | j | - ' C-2 has largest FMO coefficient
EW 3=electron-withdrawing group (carbonyl, nitrile etc.) ERG=electron-releasing group (alkoxy, siloxy etc.)
Figure 1-3: Prediction o f FMO Coefficients for Dienes and Dienophiles
The stereochemistry o f the cycloaddition will be a result o f the orientation o f the
diene with respect to the dienophile. As shown in Scheme 1-16, the addition can proceed
through either an endo or an exo mode. Fortunately, for the organic chemist, the two
modes o f cycloaddition are often energetically quite different, thus one product is often
formed selectively or exclusively. In the case when the dienophile bears an unsaturated
substituent (such as a carbonyl), the substituent can undergo a stabilizing interaction with22
the Tt-system o f the diene. O f course, this so called secondary orbital interaction would
only occur when the substituent on the dienophile is oriented over the diene; thus, the
endo transition state would be expected to be energetically favoured. Other
rationalizations for the preference o f the endo-type addition have also been made using25
dipolar interactions and van der Waals interactions as arguments O f course, the degree
o f preference for the endo transition state will vary with different systems, but in many
cases the preference can be exploited in a synthetic strategy. As well, Lewis acid catalysts
28
can be employed to enhance the reactivity and the selectivity o f a given diene/dienophile
Since the steroidal skeleton contains three six-membered rings, a synthetic strategy
to generate one, two, or even all three o f the rings via Diels-Alder cycloaddition reactions
could potentially be developed. As shown in Scheme 1-17, an example o f three variations
on a basic intramolecular Diels-Alder strategy are shown, which can be used to generate
the A (to give 10b), B ( l ib ) , and C (12b) rings respectively. Note that, in each case, a
second ring, adjacent to the one formed via the Diels-Alder reaction, is also formed.
system.
cycloadductdienophile
cycloadduct
Scheme 1-16
29
-g $? *06?
c i ? —■
Scheme 1-17
In most Diels-Alder based strategies towards steroids, it is either the A- or B-ring
that is formed via the cycloaddition reaction. Perhaps the simplest example of such a
strategy is employed in the synthesis o f estrogen-based steroids. In such a system, the A-
ring is aromatic, which offers two advantages to the synthetic chemist: access to the
potential formation o f an orf&oquinone dimethide intermediate, an extremely reactive
diene, and secondly a relative degree o f simplicity since the A/B ring junction does not
contain any stereocenters. An example o f such a strategy is shown in the synthesis of27
estra-l,3,5(10)-trien-17-one (15). A thermally induced cheletropic elimination of sulfur
dioxide from the starting material 13 will generate the o-quinone dimethide diene. Note
that the intermediate dbne 14 contains only two stereocenters (which, in the synthesis are
racemic, but bear the indicated relative stereochemical relationship to each other). These
stereocenters control the approach o f the dienophile with respect to the diene, such that
the dienophile must be 'over* the diene (as drawn) during the cycloaddition. Thus, the
generation o f the newly formed stereocenters (B/C ring junction) is 'controlled' by the
30
relative stereochemistry o f the C/D ring junction: this process is generally known as
relative asymmetric induction. This aspect o f the Diels-Alder reaction is potentially very
powerful as it could allow for the generation o f a number o f stereocenters (which, if the
starting material were to be chiral, would also be chiral) from only a few 'directing'
centers.
O
Scheme 1-18
Such strategies to generate the B-ring o f a steroidal skeleton are not limited to the
estrogen/estrone type steroids. In fact, there are examples o f stereoselective transannular
Diels-Alder reactions (in macrocyclic systems such as 16) in which a transannular Diels-
Alder reaction is used to generate the B-ring, while, at the same time, also generating the28
A- and C-rings. As shown in Scheme 1-19, the stereochemistry at the ring junctions is
controlled by the approach o f the dienophile with respect to the diene and also by the
geometry (cis vs. tram ) o f the double bonds. In this case, the A/B/C junction
stereochemistry o f the product 17 is cis-anti-trans. Clearly, through changing the
stereochemistry o f the double bonds o f the diene and/or the dienophile, the
31
stereochemistry o f the junctions can be also changed. In fact, th t Deslongchamps group
has applied such a strategy to generate a variety o f polycyclic systems with good control29
over the ring junction stereochemistry.
18CPC
016
Scheme 1-19
Another example o f a stereocontrolled intramolecular Diels-Alder reaction, which,
in this case, was used to generate the A- (and B-) ring of a steroidal skeleton,30 is shown
in Scheme 1-20. This particular synthesis was conducted in an enantioselective manner;
thus the two newly formed stereocenters in 19 are chiral in nature. The Diels-Alder
reaction formed two isomeric products in a 4:1 ratio under the indicated conditions: the
major product having the stereochemistry shown in the scheme, and the minor product
having a cis A/B ring junction (with a P-hydrogen at carbon 5). Since both the diene and
the dienophile are not electronically activated (via appropriate substituents) in this system,
the cycloaddition requires a relatively high temperature and a long duration to occur
(220°C for 100 hours). In this case, the intermediate 19 was used to generate
testosterone and androsterone in an enantioselective manner.30
32
100 hours
Scheme 1-20
One final example3' o f the utility o f the Diels-Alder reactions in the generation o f
steroidal-type carbocyclic skeletons also illustrates a relatively new concept in synthetic
organic chemistry: the use o f tandem reactions. In this case, a radical cyclization reaction
is used on 20 to generate a five membered ring which contains an exocyclic diene (Scheme
1-21). This intermediate, 21, will, under the same reaction conditions, undergo an
intramolecular Diels-Alder reaction with the pendant dienophile, to give the tricyclic
species 22 as the product (thus generating the equivalent o f the steroidal B- and C-rings).
BuaSnH / AIBN
(E=C02C H 3)
Scheme 1-21
33
Although the product 22 does not contain the entire tetracyclic steroidal skeleton,
it could easily be employed as an intermediate in the synthesis o f various steroids or other
natural products. Effectively, in this reaction, the B, C, and D-rings are generated in one
step. Perhaps if such a strategy were to employ an intact A-ring with a defined junction
stereochemistry (where the B-ring will form), it would be possible to use this type of
strategy in a stereo- or enantioselective synthesis o f a steroidal skeleton.
34
1,5 Project Outline:
The goal o f this particular project is to develop a novel, efficient, versatile and
stereoselective method to generate the steroidal carbocyclic skeleton, and then employ the
method in a total synthesis o f a steroidal natural product. The basic strategy is to
construct the three six membered rings of the steroidal skeleton in a stereoselective
manner - giving a perhydrophenanthrene with the A/B/C stereochemistry being trans-anti
tram - using a tandem or a sequential Diels-Alder approach.
The basic outline o f the strategy is shown in Scheme 1-22. Ideally, both Diels-
Alder reactions could be conducted at the same time, in a tandem fashion. Such a strategy
provides an example o f an aspect o f the Diels-Alder reaction that is seldom employed in32
synthesis: the cross-Diels-Alder cycloaddiiion (CDAC), In such a reaction, two (or
more) dienes are reacted, with one acting as a dienophile and another as a diene. Clearly,
the substituents on the diene and dienophile must be chosen carefully to ensure that the
reactions occur in a chemoselective manner; in the first DAC in Scheme 1-22 (between 23
and 24), there are actually 18 possible cycloadducts.
HHE=electron-wfthdrawing group, Z=electron-releasing group
Scheme 1-22
35
One could predict, however, that the first DAC should occur between the most
electronically activated diene and dienophile, which, in Scheme 1-22, would be between
23 and 24 as indicated. In order for the A/B ring-junction stereochemistry to be tram in
nature, the first intermolecular DAC must be endo-selective. Following the first DAC, the
second intramolecular cycloaddition between the unactivated pendant diene and dienophile
should proceed in a selective manner to give 26 (see Figure 1-4). As shown in the figure,
the B-ring should, by energetic considerations, be in the most stable chair-like
conformation in the transition state. The pendant diene can then adopt two possible
conformations to enable the necessary formation o f the boat-like DAC geometry in the 'C-
ring. O f the two possible conformations, 25a should be more stable, and therefore
favoured, because it lacks the steric interaction between the diene and the axial 'E' group
in transition state 25b. Thus, one would predict, following the IMDAC, the
stereochemistry shown in 26.
25a
Figure 1-4: Possible Transition States for the IMDAC of 25
One rather attractive aspect o f this strategy, is that, with the appropriate 'Z'-
substituent on the diene (most likely trimethylsiloxy), it would be possible to generate,
from the cycloadduct, a number o f different A-rings present in steroid natural products
(see Figure 1-5). For example, hydrolysis o f the silyl enol ether would lead to the33
androstane-type A-ring directly. Oxidative desilylation would lead to the ot,p-
unsaturated ketone, which is present in the testosterone and progesterone-based systems.
36
And, finally, oxidative methods could be employed to the unsaturated ketone to yield the
aromatic A-ring present in estrogen and estrone-type steroids. This versatility o f the A-
ring intermediate should allow for the synthesis of a wide variety o f steroid natural
products from a common intermediate.
A-ring interm ediate Androstane-typeA-ring
T estosterone and Estrogen/estroneprogestin-type type A-ring
A-ring
Figure 1-5: Potential Steroidal A-Rings From a Common Synthetic ,
Intermediate.
As well, careful choice o f other substituents on the diene and dienophile could
lead, with synthetic control, to a number o f structural analogs (for example, 18, and 19-
nor steroids) o f the natural products which may have significant biological activity. In
fact, many commercial steroid based drugs are analogs o f natural products, so a potential
route to the synthesis o f these analogs could be o f significant pharmaceutical importance.
Following the synthesis o f the appropriate 'bis-diene' and 'bis-dienophile1, and
stereoselective generation o f the perhydrophenanthrene skeleton, a strategy to incorporate
37
the five-membered D-ring o f the stf .oidal skeleton would have to be developed. There
are two possible modes by which this could be achieved (as shown in Scheme 1-23);
incorporation o f the ring into the bis-diene (to give a structure such as 27 following the
Diels-Alder reactions), or addition o f the ring (to a structure such as 26) following the two
Diels-Alder reactions. Whichever mode is chosen, two major points must be addressed;
the stereochemistry o f the C/D ring junction, and the choice o f functionality at C l 7. The
C/D junction must be tram in nature, and in almost all steroids, there exists an angular
methyl group attached to C l3 (see structure 28 in Scheme 1-23). As well, several steroids
contain a defined stereocenter at C l7 (hydroxyl, or alkyl), so care must be taken in the
planning stage o f the total synthesis to ensure that the stereochemistry at Cl 7 will be in
accordance with that o f the rest o f the molecule.
Tricyclic Interm ediate Incorporated D-ring Defined Stereochem istryat C/D junction and Cl 7
Scheme 1-23
Once the five membered ring is incorporated, and the two cycloadditions are done,
a short number o f functional group manipulations would have to be accomplished to
complete the synthesis o f a steroidal natural product. Most likely, a product which
contains a saturated A-ring would be chosen as a synthetic target because o f its relatively
simple access via the above strategy. Thus, an androstane-type steroid - such as 5a-
dihydrotestosterone, shown in Figure 1-6 - would likely be the first natural product as a
synthetic target o f this strategy. Once such a total synthesis is achieved, the next step in
38
the project would be to attempt the total synthesis on an enantioselective level. At the
same time, it would also be possible to test the versatility o f the method through
attempting the synthesis o f a variety o f different Jeroid natural products. If adaptable to
enantioselective techniques, and versatile in its application, the strategy described
herein could be o f significant phaimaceutical (and chemical) interest, as it would allow
access to a wide variety o f structural analogs o f natural products for biological testing, and
even potential clinical use.
OH
0
Figure 1-6: 5a-Dihydrotestosterone, a Potential Synthetic Target
39
CHAPTER TWO:RESULTS AND DISCUSSION
2.1: Retrosvnthetic Analysis;
From the target molecule, dihydrotestosterone (29), the retrosynthetic analysis of
two synthetic strategies are shown in Scheme 2-1. The steroid should be available from
the products o f the two Diels-Alder cycloadditions (31 or 30). As shown in the diagram,
the stereochemistry o f the A/B/C ring junctions in 30 and 31 should be trans-anti-trans.
RO RO
OR
Scheme 2-1
40
In order to ensure the tram stereochemistry at the A/B ring junction, the first
DAC - between 32 or 33 and the 'bis-dienophile' - must be endo-selective in nature. Two
possible bis-dienes are shown in Scheme 2-1: one which incorporates an intact five-
membered ring (32), and another, 33, which is acyclic in nature, but which will allow for
the generation o f the D-ring following the DAC’s. The synthesis o f both bis-dienes would
be attempted. Synthesis o f 32 may be possible via an acyclic precursor 34 via application
o f recently developed palladium-catalyzed cycloisomerization techniques.34
From an experimental standpoint, we had to establish that the intermolecular DAC
occurs in an endo-selective (and regioselective) manner. Secondly, determination that the
two cycloadditions can be accomplished in a tandem or sequential manner to generate the
three six-membered rings must be made. Keeping this in mind, the syntheses were
approached with the following chronological goals: (1) Testing o f the reactivity and
selectivity o f various dienophiles using a simple model diene. (2) Generation o f a model
bis-diene and reaction with the previously evaluated dienophiles to generate a
perhydrophenanthrene (three fused six-membered rings) skeleton with the correct trans-
anti-tram stereochemistry o f the ring junctions. (3) Synthesis o f one or both bis-dienes
(32 and/or 33) (4) Stereoselective development of the C/D ring junction and generation
o f a steroidal natural product such as dihydrotestosterone (29).
i
412.2: Model Diene and Bis-Diene Synthesis:
In order to evaluate the endo-selectivity o f various dienophiles, a model diene was
required which, following a DAC, would generate a cycloadduct that would resemble the
A-ring o f a steroidal nucleus. Accordingly, 2-trimethylsiloxy-l,3-pentadiene 35 was
synthesized from 3-penten-2-one by treatment with LDA and quenching with TMSCl35
(Scheme 2-2). Two other model dienes were also made via trapping o f the enolate with
different electrophiles: TBDMSC1 and diethyl chlorophosphonate. However, the
trimethylsilyl enol ether was chosen as the preferred model due to its relatively easy
isolation (via distillation) and ease o f subsequent transformation.
1. LDA/THF
0 2. TMSCl J M S O35
Scheme 2-2
The next model compound that was required was one that would allow evaluation
o f both DAC reactions. Thus, a bis-diene that could react with a bis-dienophile to give the
perhydrophenanthrene skeleton was needed. The synthesis o f this bis-diene is outlined in37
Scheme 2-3. From the commercial vinylmagnesium bromide and acrolein, 1,4-
pentadien-3-ol (36) was generated in 87% yield. Following isolation o f the product by
distillation, the alcohol was reacted with triethyl orthoacetate in refluxing toluene,38
undergoing an orthoester Claisen rearrangement, to yield the ester 37 in a 73% yield
with the tra/w-stereochemistry at the internal alkene.
Note: 36 is also available commercially, but due to its high cost, the synthesis was conducted from the less expensive starting materials acrolein and vinylmagnesium bromide,
CH3C(OEt)3n-PrCO-iH,PhCH3, A
Swem
TMSCl
TMSO
Scheme 2-3
Generation o f the second diene unit was accomplished via reduction o f the ester 3739
to an aldehyde followed by a Homer-Wadsworth-Emmons reaction. Although the most
direct way to accomplish this was to reduce the ester with DIBAL-H, we found it more
efficient to instead reduce the ester 37 to the stable alcohol 38 (83 % yield), which could
be purified by distillation or chromatography, followed by oxidation to the aldehyde 394 0
using the Swem reaction conditions. The aldehyde was used directly, without
purification after work-up, in the subsequent Homer-Wadsworth-Emmons reaction to give
the ketone 40 in a 79% yield (from the alcohol 39). Treatment o f the ketone with LDA,
followed by trapping o f the kinetic enolate with TMSCl resulted in the formation o f the
second diene unit, and gave the bis-diene 41 in a 81% yield following distillation.
43
Fortunately, scale-up o f the model bis-diene synthesis (to give 5-10 gram
quantities o f 41) was reasonably easy, since only one chromatographic separation (to
purify 40) was necessary in the entire scheme: all other materials could be isolated in pure
form via distillation techniques.
44
2.3 Synthesis and Evaluation of Dienophiles:
As described previously in the introduction, the synthetic strategy requires a
dienophile that reacts in the first DAC in a regioselective, endo-selective manner with a
b’s-diene to generate what will eventually be the steroidal A-ring. The second requirement
o f the dienophile is that a second dienophile unit must be present (or be synthetically
available) in order to react with the second diene unit of the bis-diene to generate the
steroidal B and C-ring.
2.3.1: Carbom ethoxybutadiene Studies:
The simplest and most direct approach towards the generation o f the three six-
membered rings would be to react a bis-diene with a bis-dienophile. In such a strategy,
both the bis-diene and the bis-dienophile must be comprised o f units o f sufficiently
different reactivity such that the first DAC occurs in a regioselective manner: the
electronically activated diene reacting with the electronically activated dienophile. The
model bis diene 41 meets this requirement in that one o f the diene units is activated by a
trimethylsilyloxy group, while the other is electronically unactivated. For the bis-
dieneophile, the requirement is that one dienophile unit be electronically activated by an
electron withdrawing group (which, if carbonyl in nature, could also provide an endo-
dirccting effect), while the other dienophile group must be relatively unactivated.
Previous literature has described a molecule that could theoretically be a good
candidate for such a strategy: 2-carbomethoxy-1,3-butadiene 45.4,a Synthesis o f this
molecule's sulfolene precursor was reasonably simple, and was based on Belleau's
literature preparation4lb (see Scheme 2-4). The first two steps in the scheme are
essentially the same as that reported in literature: methyl aciylate and l,4-dithiane-2,5-diol
are condensed to give 42, which then undergoes a mesylation/elimination to give 43.
45Oxidation o f 43 was performed with MMPP rather than mCPBA to give the suholene
dioxide 44. The dienophile 45 can be generated in situ via a cheletropic elimination o f
sulfur dioxide from the sulfolene precursor 44 (Scheme 2-4).
j? .S . ,O H H0. .COjCHaH3C < r ' j j ♦ y EtaN / CHaCI; ^
S 42
CO2 CH3 C0 2CH3Et3N / MsCI / MMp p '
S 43 O . 44
CH2CI2 y EtOH / H2O
02C 0 2CH3
ft110°C
-S 0 2 45
Scheme 2-4
Theoretically, one would expect the electronically activated dienophile in 45 to
react with the electron-rich diene present in bis-diene 41. The rc-system o f the ester
should provide for some endo-selectivity, so the correct stereochemistry in the adduct
should be available. In fact, model studies which reacted 44 with a five to six-fold excess
o f diene 35 gave the desired product 46 (in a 76% yield as a mixture o f two isomers in a
2 :1 ratio, see Scheme 2-5).
Somewhat disconcertingly, a small amount (19 %) o f a side-product was formed,
which was identified as the dimer o f the dienophile 45: in which one molecule acts as a
diene and the other as a dienophile to give 47 (Scheme 2-5), Although the tendency o f the
molecule to dimerize in the absence o f any electron rich dienes was known41 (the sulfolene
precursor was shown in the laboratory to extrude sulfur dioxide over a 3-4 hour period in
46
the absence o f other dienes to give the dimer), the tendency towards dimerization in the
presence o f 35 was quite surprising. In fact, attempts to conduct the DAC with only one
equivalent o f diene 35 or using the diethylphosphate-based model diene (compound 35
with (Et0 )2 P(0 ) instead o f TMS; 3 .7 equivalents o f diene) resulted in the major product
being the dienophile dimer 47, which was isolated from the two reactions in yields o f42
76% and 69% respectively.
/ C° 2CH3 <^ .O T M So§ 2 44 f »
110°C
h3co2c
46 Hh3co2c
c o2ch3
47
Scheme 2-5
Although the tendency towards dimerization in the presence o f electron-rich dienes
was unexpected, the fact that the effect could be suppressed in part through the use o f an
excess o f diene did not rule out the possibility o f the bis-dienophile's potential synthetic
utility in the strategy. Unfortunately, however, all attempts at reacting the sulfolene with
the model bis-diene 41 were unsuccessful: the only cycloadduct isolated was that due to
dimerization o f the bis dienophile (see Scheme 2-6). In fact, even slow addition o f a
solution o f 44 via syringe pump to a refluxing solution o f bis-diene 41 in toluene - which
would generate the bis-dienophile in situ in such a way that the relative excess o f bis-diene
will be, at any given pcint, very high - did not lead to synthetically useful amounts o f the
desired cycloadduct 48.
47
These studies showed that the bis-dienophile 45 was in fact, capable o f reacting as
an activated diene as well as a dienophile. The fact that the dimer was the only
cycloadduct isolated in the reaction o f the bis-diene 41 with 45 shows that the bis-
dienophile is actually a more activated diene than the activated diene portion o f the bis-
diene (Scheme 2-6). Although this result was unexpected and interesting, it meant that the
bis-dienophile 45 would not be suitable for use in this particular synthetic strategy,
Another bis-dienophile would be required: one that would not dimerize.
The unexpected high diene-like reactivity o f 45 was examined in more detail in the
laboratory through the use o f competition studies: 45 was generated in the presence of
proposed rationalization o f the unexpected reactivity are contained in Appendix 1.
TMSO
H3COsole cycloadduct
TMSO
not formed
Scheme 2-6
various activated dienes and dienophiles in an attempt to determine the extent o f its diene-
like reactivity relative to other dienes. A discussion o f the resuits o f these studies, and a
48
2.3.2: Acrolein Studies:
Since the most prominent difficulty with 2-carbomethoxybutadiene as a dienophile
was its tendency towards dimerization, the next obvious choice for a dienophile would be
one in which this tendency was diminished or eliminated. One possible solution would be
to use a dienophile which contains only one alkene dienophile unit, but also contains
sufficient pendant functionality to allow the possibility o f the generation o f a second
alkene dienophile unit at a later stage in the synthesis. Ideally, the molecule should
possess an activated dienophile to allow for the first Diels-Alder reaction to be selective.
Several candidate molecules could potentially fit the above requirements, with
some possibilities shown in Figure 2-1. Sodium l,3-butadiene-2-carboxylate (49) could
be a potential candidate for use in relatively recently studied DAC reactions which can be43 44
conducted via micellar catalysis or through the use of lithium perchlorate solutions.
However, the tendency o f 49 towards dimerization is not known, and the silyl enol ether
functionality o f the bis diene 41 may not be stable to the DAC conditions required for a
carboxylate salt. Another potential candidate is 50, in which the alkene units are locked in
a tram oid configuration, thus making dimerization impossible. But, subsequent removal
o f the oxygen atom from the second dienophile fragment could prove to be difficult.
Perhaps more attractive is 51, in which the second dienophile unit could be constructed via
a Wittig reaction on the aldehyde. Unfortunately, 51 proved difficult to prepare and
handle, and potential problems could exist with respect to endo- vs exo-stereoselectivity.
Since acrolein (52) is readily available, is known to react as an activated dienophile in
Diels-Alder reactions, and also possesses a carbonyl group which can be converted into a
second dienophile unit, the choice was made to use it in tests as the next suitable
dienophile. Although acrolein would not allow for the incorporation o f an angular methyl
group at the A/B ring junction, the structural analog, methacrolein (53) could be used in
that case.
49
Figure 2-1: Potential Dienophile Candidate Molecules
45Through reaction o f the bis-diene 41 with acrolein in a sealed glass tube at
160°C for one hour, two cycloadducts, 54a and 54b, were isolated (see Scheme 2-7),
Although the first DAC proved to be not entirely regioselective, it was possible, through
diene to enable the isolation o f the adducts 54 in a 55% yield. Since the silyl enol ether
proved to be quite labile to silica gel column chromatography, it was more convenient to
hydrolyze the crude DAC reaction mixture before chromatography through treatment with
a catalytic amount o f concentrated HCl (one drop): reaction mixture vigorously stirred in
ethyl acetate with lg/mmol silica gel.
Characterization o f the flash-chromatographically inseparable ketone products 55a
and 55b (recovered in a 49% yield from the DAC starting materials) revealed that the
endo/exo selectivity was only 3.4:1 (by gc analysis). Although the configuration o f the
major isomer could not be concluded by nmr studies, it was assumed that the major
product was that which arose from the e/wfo-approach o f acrolein to the bis diene 41.
Although the selectivity was relatively low, the choice was made to attempt to complete
the perhydrophenanthrene synthesis using 55 as a synthetic intermediate in the hope that
the isomers would become chromatographically isolable at a later stage in the synthesis.
the minimization o f reaction time and careful control o f the relative ratios o f acrolein:bis
50
CHO
T52
TMSO TMSO'54a: oiH
0 H55a: aH55b: pH
Scheme 2-7
The next step in the synthetic scheme was to generate the second dienophile unit
from the pendant aldehyde in 55. Perhaps the simplest and most direct way to accomplish
this goal would be to generate the terminal alkene through a Wittig reaction.
Unfortunately, all attempts to accomplish this using methyl triphenylphosphonium bromide
(with n-BuLi as a base) were unsuccessful: only the starting material 55 was recovered.
Presumably, the possibility o f the enolization o f the aldehyde (in 55) as a side reaction was
responsible for this difficulty.
Two separate routes were then taken to attempt to generate two separate activated
dienophiles from the aldehyde in 55. The first route (Scheme 2-8) used the anion o f
phenyl methyl sulfone (generated by treatment o f phenyl methyl sulfone (56) with LDA or
n-BuLi) in an aldol-like reaction to give the alcohol 57. The sulfone itself was readily
available from the commercial sulfoxide through oxidation with MMPP. The product 57
was obtained as a mixture o f isomers resulting from the differing approaches o f the anion
to the aldehyde. Dehydration was then accomplished through in situ mesylation and
elimination to give the /ram-alkene 58 selectively ( J - l 5.3 Hz).
51
Since the newly-formed dienophile is electronically activated, the second DAC,
which is intramolecular in nature, could be performed in refluxing toluene (110°C) to give
two sets o f two inseparable isomers (59) in yields of 52% (ratio o f isomers 2.8:1) and
30% (ratio o f isomers 2.2:1 ) respectively. Unfortunately, the presence o f four isomers in
the product mixture means that the second Diels-Alder reaction is not selective in nature:
each of the two starting material isomers each gave two isomeric products. Since the ratio
o f starting material isomers was on the order of 2-3:1, the product mixture o f the second
Diels-Alder reaction indicates that the selectivity o f the reaction is also on the order o f 2-
3:1, This lack of selectivity in the DAC reactions required that a different synthetic
approach be used to generate the steroidal skeleton.
OH55 LDA or nBuLi
0 0
11(fC
Ph02S'i,,
MsCI / EtaN
Scheme 2-8
At this stage, the choice was made to try to generate a second activated dienophile
from 55 which would allow for a greater degree o f selectivity in subsequent IMDAC.
Reaction o f 55 with the anion o f methyl diethylphosphonoacetate proved to be a simple
and direct method o f accomplishing this goal. Since there was not a great deal of
selectivity for reaction o f the Wadsworth-Emmons reagent with the exocyclic aldehyde
52
over the A-ring ketone, the reaction was instead performed on the silyl enol ether 54, with
catalytic hydrolysis o f the enol ether afterwards (see Scheme 2-9). The newly-formed
alkene in 60 was formed with exclusive selectivity for the /ra/M-configuration (proven by
the 15.7 Hz coupling constant o f the alkene protons).
Attempts at the IMDAC using thermal methods (toluene reflux) unfortunately led
to a mixture o f four isomers: again showing the IMDAC proceeded with low selectivity.
As well, attempts at the IMDAC (Scheme 2-9) using dimethylaluminum chloride as a46
Lewis Acid catalyst (dichloromethane solvent, room temperature, 45 hours) yielded four
isomeric cycloadducts in a ratio o f 1:1.5:1.8:3.5 (by GC analysis). As was the case before,
these results show a low selectivity for the second Diels-Alder reaction.
C O X H
L i O1. (E t0)2PC H 2C 02C H 3
NaH, THF
2. HCI, SiO 2 . EtOAcTMSO
(CH3)2AICI, C H 2CI2 -----------------------
Scheme 2-9
A rationalization for the low selectivity o f the IMDAC reactions leading to 59 and
61 can be proposed by examining the transition states o f the reactions. As seen in Figure
2 -2 , the lack o f selectivity is a result o f the sterically less demanding exo-transition state
competing with the sterically congested e//do-transition state. Unfortunately, these
transition states must be very close in energy, which leads to the relatively low selectivity
53
in the reaction. Since the first DAC (intermolecular reaction between acrolein and the bis
diene 41) also did not give a very high selectivity for the desired isomer, the choice was
made to find another bis-dienophile.
Methacrolein might have been the most obvious choice at this point, since it might
well have resulted in a higher selectivity for the endo-product in the intermolecular DAC:
the presence of the methyl group on methacrolein (versus a hydrogen atom on acrolein)
would sterically congest, and therefore energetically destabilize the exo approach. Another
interesting aspect o f the methyl group is that it may be able to provide a destabilizing
effect in the IMDAC through steric interaction with the pendant diene (see Figure 2-3).
Thus, methacrolein might be able to increase the selectivity o f both DAC reactions.
However, methacrolein could only lead to steroids bearing an angular methyl group at the
A/B ring junction, which limits the versatility o f the approach. As well, methylcnation of
the pendant aldehyde was not accomplished in the acrolein studies, and presumably
methacrolein would show the same difficulty, so removal o f the sulfone or ester
functionalities (analogous to those in 59 and 61) would add a complicating element to a
steroid synthesis. For these reasons, methacrolein was not used in the DAC studies.
Endo T.S. Exo T.S.R=C0 2 CH3 or SC>2Ph
Figure 2-2. Transition States for IMDAC Reactions
54
R=CO^CH3 or SO ^h R'=CH3
Figure 2-3: Potential Steric Congestion Between Angular Methyl Group and Pendant
Diene in IMDAC exo Transition State
A more attractive bis-dienophile would be one which incorporates the versatile
angular ester group at the A/B ring junction as well as a reasonably large ‘masked’ second
dienophile unit which could provide for a high degree o f e/K/o-selectivity in the
intermolecular DAC.
2.3.3: Enyne Studies:
As stated in the previous study with acrolein, the ideal bis-dienophile would
incorporate an ester group to activate and provide a degree o f m/o-selectivity for the
‘first’ dienophile. As well, the ester group could provide a destabilizing effect o f the
undesired mode o f addition in the IMDAC (analogous to that described for methacrolein
in the exo mode o f addition). The other desired functionality in the bis-dienophile would
be a masked dienophile which can be readily converted to a terminal alkene and which
does not interfere with the intermolecular DAC. O f course, the bis-dienophile must also
not dimerize.
After careful consideration, the choice was made to attempt to synthesize an 1,3-
enyne as a bis-dienophile with the functionalities shown in Figure 2-4. The linear nature o f
the alkyne functionality would prevent dimerization from taking place, and the alkyne
55
could potentially be converted to a terminal alkene, in the presence o f alkenes such as the
pendant diene, through a variety o f reduction methods such as hydrogenation.47
R=alkylR -H or protecting group
Figure 2-4: Structural and Functional Group Requirements o f Enyne Bis-Dienophile
The synthesis o f the enyne bis-dienophile, methyl 2-[2-(trimethylsilyl)ethyn-l-yl]
acrylate (63) is shown in Scheme 2-10. From the commercial methyl acrylate,
bromination of the alkene followed by elimination o f hydrogen bromide leads to 62,
Initial attempts at adding acetylene through palladium catalyzed means48 to 62 resulted in
decomposition and some double addition (addition o f an acrylate unit to each ‘end’ o f the
acetylene). As a result, the choice was then made to use trimethylsilylacetylene, which is
easier to handle (liquid at room temperature) than acetylene, and cannot undergo a double
addition. After a variety o f attempts using different catalysts, solvents, and co-cataiysts,48
the bis-dienophile 63 was generated in a 76% yield using bis-(triphenylphosphine)
palladium(H) chloride as a catalyst, with copper(l) iodide as a co-catalyst.49
Unfortunately, the product 63 was always contaminated with the presence o f
approximately 2 0 % o f the starting material 62: all attempts at optimization o f reaction
conditions through the use o f excess trimethylsilylacetylene, larger amounts o f catalysts,
longer reaction times and higher temperatures failed to ameliorate this problem. The
product mixture o f 62 and 63 was also chromatographically inseparable, Interestingly, the
enyne 63 proved to be reasonably stable, unlike the bromoacrylate starting material, which
had a tendency towards polymerization. Presumably the TMS group provides some
degree o f stabilization o f the enyne
56
^ JM SH3C O £ ^ i.Brz/ccu H aC O sC ^B r = —TMS h 3C O £.
I ! 2. EfeN I I (Ph3P)2PdCl2 «2 Cut / Et3N
Scheme 2 - 1 0
Mechanistically, the palladium catalyzed addition o f the trimethylsilyl acetylene to
the bromoacrylate can be thought o f as a Heck-type reaction.50 The actual catalytic
species in the reaction is usually thought to be palladium(O). The formation o f this species
from ;he palladium(II) reagent is not particularly well understood, but some literature
reports51 indicate that the two chlorides may be reductively eliminated with the formation
o f a diyne side product (from two equivalents o f alkyne starting material): two
equivalents o f amine hydrochloride salt would be formed as well. Whatever the case may
be, once the active catalyst is made, the catalytic cycle serves to generate a stoichiometric
amount o f triethylamine hydrochloride as the reaction proceeds (which can be seen in the
reaction mixture as a precipitate).
With the newly-formed bis-dienophile 63 in-hand, the next test was to react the
molecule with the bis-diene 41 in the hope that the reaction would be regioselective. After
a few attempts to optimize conditions, the reaction was found to proceed in refluxing
toluene to give the desired product 65 as a mixture o f isomers in a ratio o f 5,8:1 (see
Scheme 2-11). Unfortunately, the bromoacrylate starting material that contaminated the
enyne reagent also underwent a DAC with the bis-diene. This side-product, along with
some polymeric material which presumably emanated from decomposition o f the enyne 63
required that several flash chromatographic treatments o f the adduct mixture be performed
to isolate pure material. During the course o f the chromatography, the acid-labile silyl
enol ether in 64 hydrolyzed to give the ketone 65, which was isolated in a yield o f 60%
57
(measured from 41). At this stage the designation o f the major isomer as being attributed
to that arising from the ester-m/o-cycloaddition geometry was presumptive (as shown in
Scheme 2-11), but one would expect that the enyne 63, with the large trimethylsilyl group
providing a steric impediment to the exo-approach, would show a greater e/it/o-preference
than acrolein, which gave an isomeric ratio o f 3.4:1 (as stated previously); therefore, the
assignment was not entirely arbitrary.
TMSOA__
TMSEndo T.S.
TMS
.TMS
TM SO
TM S
TM SO
Scheme 2 - 1 1
Since the enyne reacted in a regioselective manner with a stereoisomeric selectivity
almost twice as high as was achieved previously with acrolein, the choice was made to
continue the synthesis in the hope that the geometry o f what would become the A/B ring
junction could be determined unambiguously at a later point in the synthesis. Accordingly,
the first step would be to remove the trimethylsilyl protecting group on the alkyne. This
was accomplished in near quantitative yield using tetra-M-butylammonium fluoride in THF
to give 6 6 (See Scheme 2-12). Following the removal o f the silyl group, the terminal
alkyne was treated with a number o f hydrogenation catalysts including Pd/BaSO*
(poisoned with quinoline or pyridine) and Pd/CaCOj to attempt to yield triene 67,
Somewhat surprisingly, the internal double bond o f the pendant diene would always be
reduced as well as the terminal alkyne.
58
TMS
H2 / P d Catalysts
6665
Scheme 2-12
During the course o f the search for a method to reduce the terminal alkyne in a
regioselective manner, the IMDAC reaction o f the alkyne 6 6 was attempted. Although
the terminal alkyne is an unactivated dienophile (as was the diene), the reaction did
proceed in toluene at 170°C (over 48h) to give 6 8 as a mixture o f two isomeric52products, The ratio o f the adducts was 5:1, which was nearly identical to the ratio o f
isomers in 65. Since the starting material 6 6 was a mixture o f two isomers as well, the
IMDAC must have proceeded with nearly complete stereoselectivity. That is, each isomer
o f the starting material gave only one isomeric product. Presumably the difference in the
ratios shown in 65 and 6 8 are a result o f an incidental loss o f a fraction o f one o f the
isomers during a chromatographic step. As shown in Scheme 2-13, the ‘desired’ isomer
would arise from the transition state which has the least degree o f steric impediment
(shown for the presumptive major starting material isomer). By repeated chromatography
followed by recrystallization, it was possible to isolate the major isomer o f 6 8 in a pure
form, Careiiil crystal growth o f this isomer provided a sample for X-ray analysis (see
Figure 2-5) which provided proof o f the complete structure.
C16
0 3
02
C15
C14
C13
C12
C l 1 CIO
P> 0
Figure 2-5: ORTEP Diagram of Major IMDAC Product 6 8
60
The ORTEP diagram proves that the major isomeric cycloadduct o f the first DAC
(65) must have the hydrogen atom in the a-geometry .53 As well, the X-ray analysis
proves that the transition states shown in Scheme 2-13 for the major isomer are valid as
well. In this case, the IMDAC proceeds through only the favoured transition state, to
give, for the isomer o f 6 6 having the hydrogen atom in the a-geometiy, 6 8 as the sole
product (Scheme 2-13). The isomer o f 6 6 having the proton in the P-geometry also gave
only a single product, which presumably would differ from the isomer shown in Scheme 2 -
13 only at the configuration o f C5.
66
toluene / 17(fC
Favoured T.S. Unfavoured T.S.
Major Isomer
Scheme 2-13
By this stage, the enyne studies had proven to be vastly superior to any DAC
studies performed previously in the project. Not only was the first DAC much more
selective than those performed before with acrolein, but the second DAC was entirely
selective. And, to make matters better, the terminal alkyne did not bear any ‘excess’
functionality that would have to be removed at a later date. The only detrimental factor o f
6 8 is that, due to the unsaturation between C9 and C l l (steroid numbering), the
stereocenter at C9 is missing. By analogy, the alkene 67 should have the stereocenter
61
intact, and, if the IMDAC proceeds via the ‘favoured’ transition state shown in Scheme 2-
13, should bear the correct stereochemistry.
Interestingly, at the same time that the thermal IMDAC was being conducted,
attempts were made to conduct the IMDAC o f 6 6 through catalytic means, Literature has
shown that low valent rhodium complexes are capable of catalyzing unactivated IMDAC
reactions in which the dienophile is an alkyne.54 When commercial Wilkinson’s catalyst
((PhjPfoRhCl) was added to 6 6 (in trifluoroethanol at 55°C), a mixture of cycloadducts
was isolated, Somewhat surprisingly, the reaction was not selective. It appears that the
complexation of the catalyst to the starting material 6 6 provides a steric impediment to the
transition state which was favoured in Scheme 2-13. In fact, nearly equal amounts o f two
diastereomers (differing at the configuration at C8 (steroid numbering)) were isolated. A
rationalization for this result can be proposed by again examining possible transition state
structures. As shown in Scheme 2-14, it can be seen that the rhodium catalyst would, by
steric arguments, likely complex the alkyne functionality tram to the angular ester group,
By doing so, the ester ard the rhodium provide two competing steric groups between
which the pendant dienc must orient itself to undergo the IMDAC, The 1:1 mixture o f
diastereomers (6 8 a and 6 8 b) indicate that there is virtually no preference between the two
transition state structures shown.
Interestingly, a small amount o f a side product was also isolated from the reaction
which showed a bond migration in the C-ring such that the two double bonds were
conjugated. By 'H NMR analysis, it seemed that the disubstituted double bond was the
one that migrated (from C 13-C 14 to C12-C13),
66
(PhaPfcRhCI
CF3CH2OH
62.
> r
RhLnTransition States
1 :1 mixture
Scheme 2-14
After searching for an alternate method to reduce the alkyne, it was found that
activated zinc in refluxing ethanol55 would selectively reduce the alkyne in 6 6 without
reducing the diene to finally give 67 as the product (Scheme 2-15). At this point, the
molecule contained all the correct functionality to be able to undergo the IMDAC. Indeed,
the IMDAC did proceed, under identic?! conditions to those used in the synthesis o f 6 8 , to
give 69 as a mixture o f two isomeric products (Scheme 2-16). Again, each isomer of
starting material 67 gave a single isomeric product (which, in this case, were isolated in a
ratio o f 5.3:1). Unfortunately, in this case, crystals o f sufficient quality for X-ray analysis
could not be grown, so characterization o f the product was based on nmr analysis in
comparison with 6 8 , As the molecules have quite a similar structure, and since the
structure o f 6 8 was known in an unambiguous manner, the spectral comparisons should
prove valid.
0H 6 6
Z n /E tO H
reflux 72h
Scheme 2-15
Since the configuration o f the A/B ring junction in 6 8 and 69 must be the same
(since they arose from the common synthetic precursor 6 6 ), there are really only two
stereocenters whose relative configuration must be determined. By steroid numbering,
these would be C8 and C.9. One would expect that the favoured transition state geometry
for the IMDAC of 6 6 (Scheme 2-14) would also be valid for 67. Thus, the expected
major product o f the IMDAC of 67 would have the structure shown in Scheme 2-16
(69a). The ‘other’ possible product (69b) would result from the alternative transition
state structure,
Toluene/170°C
Transition State BTransition State A(favourable) (unfavourable)
H 69b69a
Scheme 2 -16
64
Through analysis o f the 'H NMR and COSY spectra o f 69 and 6 8 , most o f the
axial and equatorial hydrogen atoms could be independently assigned. By doing so, it
could be determined that the axial hydrogen atom on C7 in 69, which proved to be
separated quite clearly from other resonances in the spectrum (see Figure 2-6), showed
three large coupling constants (J=12,8 Hz), and one small one (4.3 Hz). This proton
would be expected to couple to the two protons (axial and equatorial) on C6, the
equatorial proton on C7 (geminal coupling) and finally to the proton on C8. Assuming
that the ‘B-ring’ is in a chair-like conformation (based on the proposed transition state for
the reaction), one would expect that the dihedral angle between the C7axja| proton and the
C6axja| proton would be close to 180°, which would give a large (12.8 Hz) coupling
constant as predicted by the Karplus equation56. Similarly, the coupling between the
C7aXja| proton and the C6c<Iuatoria| proton would give a small (4.3 Hz) coupling. This leaves
two relatively large coupling constants, which must be due to the geminal (C7aXja| /
C7oqua(oriai) coupling and the C7axja|/C8axia| coupling, Again, application o f the Karplus
equation predicts that the dihedral angle between the C8 proton and the C7aXjai proton
would be near 180°, Based on the two proposed transition states for the reaction (shown
in Scheme 2-16), this 180° dihedral angle seems the only likely orientation. This
configuration is also consistent with the proposed favoured transition state (cf. Figure 2-
7).
In order to further prove the conformation o f the C-ring (i.e. determination
whether the proton is up or down at C9), *H NOESY spectral analysis o f 69 was
necessary, From this spectrum, an nOe effect between Cl«,u*tori«i and one o f the hydrogens
on C l 1 could be seen. This effect requires that the two hydrogen atoms are in close
spatial proximity with one another (see Figure 2-7), which would only be possible if the
proton at C9 is in the a-configuration. Thus, it would appear that the proposed favoured
transition state is valid and 69a is the major product.
5.7
Figure 2-6: 'H NMR Spectrum (expansion) and *H COSY Spectrum o f Major IMDAC
Product 6 9 a
66
nO e
>ax
J=12.8Hz
Figure 2-7: NMR Spectral Evidence for Proposed Structure o f 69a
In both IMDAC reactions (leading to 6 8 and 69), it would appear that the angular
ester group plays a significant role in stereochemical control. Fortunately, in both cases,
the selectivity was for the isomer with the desired, steroid-like stereochemistry. Thus, one
of the main goals o f the project was achieved: an efficient and stereoselective route to the57perhydrophenanth.i ;?<* skeleton via a sequential Diels-Alder route.
What remains in the completion o f the synthesis o f a steroid natural product, at this
stage, is the incorporation o f the D-ring and elaboration o f the C/D ring junction,
Although structure 69a contains a functional group ‘handle’ (the double bond between
C13 and C l4) which could potentially be developed into such a structure (and, at a later
date, might be), the choice was instead made to develop a new bis-diene which contains an
intact D-ring (or tunctionality that could be developed into the D-ring). Thus, when the
sequential Diels-Alder reactions are performed, the structure would contain the D-ring,
with an unsaturation at the C/D ring junction.
67
The assumption, at this stage, is that it will be possible to conduct the sequential
Diels-Alder reactions on the ‘new’ bis-diene with the same degree of selectivity as
occurred with the bis-diene 41. Since the diene fragment which will be used to construct
the A-ring in both systems will likely be unchanged, the assumption o f similar reactivity
for this diene should be valid. However, the reactivity o f the ‘second’ diene (used in the
generation o f the C-ring) will be unkown; therefore, there are two major factors that must
be determined. The first is that the first (intermolecular) Diels-Alder reaction can occur in
a chemoselective manner. The second is that the second (intramolecular) Diels-Alder
reaction can occur with a high degree o f selectivity for the desired product.
68
2.4; Research Towards New Acyclic Bis-Dienes:
One potential approach towards the development o f the tetracyclic intermediate
would he conduct the sequential Diels-Alder reactions on an acyclic bis-diene such as
70. Such sn intermediate could then give, following the sequential Diels-Alder reactions
with enyne 63, a Structure such as 71 (see Scheme 2-17). Conversion of 71 to a
tetracyclic steroid-like molecule could then be accomplished through using t-hexyl borane
(to give 72) followed by treatment with carbon monoxide to give 73 .58
TMS Z ' S equen tia l DAC R eac tio n s
70TMSO
* PThb'
n
Scheme 2-17
O f course, such a strategy would depend on the successful generation o f the
acyclic bis-diene 70. A potential approach to such a structure is outlined in the
retrosynthetic analysis shown in Scheme 2-18. Since the diene fragment in 70 which
contains the silyl enol ether is identical to that found in the previously described model bis-
diene 41, the retrosynthetic analysis is shown from the alcohol precursor 74. Presumably,
the generation o f the second diene fragment from 74 would be possible using the same
reaction sequence used for the synthesis o f the model 41, The alcohol 74 should be
available from the protected alcohol 75, which, in turn, should be available via a
69
cheletropic elimination o f sulfur dioxide from the sulfolene precursor 76, Incorporation o f
the pendant arm (containing the protected alcohol) should be possible in a regioselective
manner59 through alkylation of the sulfolene dioxide 77, Generation o f the sulfolene
should be possible via reaction o f the two acyclic precursors, 78 and the commercial
i-erolein respectively.
HO THPO THPO
> ° ^ s 0 G ° = > ^ s h * f 11' ”77
Scheme 2-18
The first task in the approach o f the diene synthesis was the generation of 78, This
was achieved from acetone as shown in Scheme 2-19. The bromination of acetone*’0 was
carried out using bromine in water (catalyzed by acetic acid) to give, after distillation,
bromoacetone (79) in low yields (approximately 20-25%). Thiourea was then added to
the bromoacetone to give 80 as a product in 76% yield.61 Treatment or 80 with aqueous
sodium hydroxide gave the desired product 78 in an 80% yield.61
S
O btj^ hoac A nh2 nh2b
79 I 80nh2
.■SJfgU A / sh78
Scheme 2-19
70
Once 78 was generated, it was reacted without further purification with acrolein;
using triethylamine as a base as per the synthesis o f the previous thiophene 42.41
Surprisingly, the product isolated (in a yield o f 9% (mainly due to decomposition)) was
not the expected product 81, but rather was 82. As shown in Scheme 2-20, it appears that
an intramolecular proton exchange takes place following the Michael addition o f the thiol
to the acrolein. After this exchange occurs, a cyclization takes place to give the product
82. Since the yields o f the reaction were so low, and since the desired product was not
isolated, the choice was made to pursue a different route towards 81.
,X ^SH ♦ jj^H 78 II
0
e t3N
O'
Et3N / C H 2 CI2
O
'S ' 81not isolated
Scheme 2-20
v82
only cyclization product
work-up
0
Similar to the reaction o f 78 with acrolein, an attempt was made to react 78 with
methyl acrylate. As shown in Scheme 2-21, the desired product, 83, was isolated (i.e. the
intramolecular proton exchange did not appear to take place); however, the yield o f the
reaction was quite low (6 %). It seems that the thiol 78 is sensitive to the reaction
conditions and is prone to decomposition.
0 B-Nr •p
71
OOH
O C H 3 Et3 N / C H 2CI2 ' 'O C H 3
Scheme 2-21
In an attempt to increase the yields o f the thiophenes, a slightly different approach
was taken. Since the thiol 78 appeared to be the limiting factor, a replacement was chosen
for the molecule: methyl thioglycolate, a commercial product. Through condensation of
the glycolate 84 with methyl acrylate, the thiophene 85 was isolated in a 64% yield62
(Scheme 2-22). Attempts at adding a methyl group to the ketone in 85 using Grignard
reagents or methyllithium proved futile, with only starting material being recovered:
presumably enolization o f 85 is the problem. As a result, attempts to oxidize the sulliir
using MMPP (to try to modify the reactivity of 85) were made. In this case, the product
spontaneously aromatized to give 8 6 without oxidizing the sulfur. So, again, a different
method would be needed to introduce the methyl group.
OCH3 Et3N/CH2CI2 OCH
0MMPP or mCPBA
HO.
Scheme 2 - 2 2
The next method which was evaluated was to cnolize the ketone in 85 and then
trap the resulting enolate as a phosphate. This reaction proved to be quite easy to
perform, and gave the enol phosphate 87 in a 49% yield (Scheme 2-23). The next step,
72
then, was to attempt to add a methyl group in a Michael fashion, and, in the process
hopefully eliminate the phosphate to give the desired product 8 8 . Unfortunately, attempts
to do this using either methyllithium or dimethylcuprate reagents proved futile:
decomposition occurred in both cases.
1. LDAOCH3 2. CIP(0)<0Et)2 OCH
0
OCH
Scheme 2-23
Since the molecule 87 proved susceptible to decomposition during the attempted
addition o f the methyl group, attempts were then made to try to oxidize the sulfur atom
(again, to tiy to modify the reactivity o f the molecule), Direct oxidation o f 87 with MMPP
or mCPBA led to hydrolysis o f the enol phosphate and gave 8 6 as a product. Therefore, a
more circuitous route was pursued which would oxidize the sulfur atom, As per the
literature precedent,63 85 was protected with ethylene glycol to give 89 in a 67% yield
(Scheme 2-24). The protected thiophene was then oxidized with MMPP to give the
thiophene dioxide 90, which was then deprotected in aqueous acid to give 91 in an 81%
yield (two steps). Unfortunately, attempts at enolizing the ketone and trapping the enolate
with diethyl chlorophosphate (as before) to give 92 proved unsuccessful. The molecule
tended to decompose, even when weak bases such as triethylamine were used.
85
73
o 0 0
o c h 3° v - A o c h 3 Cf-A°cH3 Cx. , 85 HOOHj CHj OH W | ! MMp p 90
0 2
„ w V / o C H , T f ' ” ) - / ' 015" ,
0 2 § 2
Scheme 2-24
Unfortunately, the tendency towards decomposition in the conversion o f 91 to 92
placed yet another hurdle in the synthesis of the acyclic bis-diene At this time in the
project, the synthetic studies leading towards a diene which incorporates and intact five
membered ring, which were being performed concurrently with these studies, were
yielding more promising results, Thereto"’ the efforts towards the acyclic bis-diene were
abandoned in order to concentrate efforts on the dienes incorporating a D-ring
2.5: Synthesis of Bis-Dienes Incorporating the D-Ring:
74
Synthesis o f a diene which incorporates a five membered ring, such as 32, would
enable, after the sequential Diels-Alder reactions with the enyne 63 were performed,
generation of a tetracyclic structure similar to the steroidal carbocyclic skeleton. As
shown in Scheme 2-25, the sequential DAC reactions would lead to a tetracyclic
intermediate such as 94. O f course such a strategy would depend on the first DAC
(between 63 and 32) being regioselective as drawn.
OR ORTMS
.TMS
TMSO TMSO'
OR
Steroid Natural P roduct
TMSO
Scheme 2-25
Since the pendant diene in 32 is essentially identical to that found in bis-diene 41
(the portion that forms part o f the A-ring), the attempted synthesis o f 32 began at the
other ‘end’ o f the molecule. Attempts were made to first synthesize the cyclopentane-
based diene, to which the pendant diene would be incorporated.
75
2.5.1; 2-Methylcyclopentane-l,3-dione Studies:
The first attempts at the synthesis o f the D-ring diene involved commercial 2-
methylcyclopentane-l,3-dione (95) as a starting material. The general strategy o f :his
approach is shown in the retrosynthetic analysis in Scheme 2-26. The desired D-ring diene
98 could be synthetically available from the alkene precursor 97. This molecule, in turn,
would be available from 96 via an orthoester Claisen rearrangement (similar to that used in
the synthesis o f the bis diene 41). Generation of 96 was planned to proceed via a
Grignard reaction on one o f the ketone functionalities on the commercial starting mat erial
95.
EtO
i> Q
EtO
Scheme 2-26
As shown in Scheme 2-27, the synthetic approach was to monoprotect the diorif
(making use o f the enhanced acidity o f the proton a-to the two carbonyl groups (relative
to the ‘other’ protons a-to the carbonyls)) to allow for the reaction to be regioselective.
This protection, to give 99, proved to be quite facile: hexamethyldisilazane as a solvent
and silylating reagent, and imidazole as a base to give the silyi enol ether.64 Such a
protection would hopefully eliminate problems associated with selectivity o f the Grignard
reaction on the commercial dione (i.e. mono- and di-additions). Unfortunately, as shown
in Scheme 2-27, the product isolated from the Grignard reaction was not the desired
76
alkene 96, but instead was the diene 1 0 0 , It would appear that during the work up or
subsequent chromatography, the silyl enol ether was hydrolyzed and a spontaneous
dehydration took place; which, in retrospect, is not particularly surprising. Unfortunately,
attempts at changing work-up and purification steps failed to overcome this problem: it
appears that the silyl enol ether is particularly sensitive towards hydrolysis.
OTMSvinyl MgBrHMDS / imidazole HO
not isolated
Ospontaneousdehydration
100
Scheme 2-27
In order to try to eliminate the possibility o f the spontaneous dehydration, various
modifications at C2 in 95 were attempted. Unfortunately, attempts at conducting a
palladium-mediated oxidation33 of the commercial starting material 95 (to give 101) were
not successful (leading to decomposition). Similarly, attempts at bromination of 95
(attempting to brominate regioselectively at C2 to give 102) proved not to be
regioselective using either bromine in triethylamine, or NBS and AIBN65 in carbon
tetrachloride (see Scheme 2-28),
Since modification o f C2 proved to be quite difficult, the choice was made to try to
modify the protecting group, Monoprotection o f the diono 95 would likely prove to be
difficult, so, instead the silyl enol ether 99 was used. The strategy was to introduce a
protecting group on the unprotected ketone in 99. Then the silyl enol ether could he
77
hydrolyzed (which would likely occur during work-up or chromatography), leaving a
monoprotected product. Hopefully, the ‘new’ protecting group would prove to be
sufficiently robust to resist hydrolysis (and subsequent dehydration) during the Grignard
reaction.
Pd(OAc) 2
/ benzoquinone
XBr2 /Et3N or NBS / AIBN
102
Scheme 2-28
As shown in Scheme 2-29, attempts were made to introduce a cyclic ketal using
ethylene glycol. Unfortunately, all attempts at this were unsuccessful. Apparently the silyl
enol ether was hydrolyzed in all reaction conditions used (even when TMSCI was used as
a catalyst66) and only the di-protected ketone, 103, was isolated.
OTMS
Scheme 2-29
As a result o f these problems, and also as a result o f other studies, that were being
conducted at the same time as those with the diones, which were yielding more successful
results, this approach towards the D-ring diene was abandoned.
78
2.5.2: Studies Involving Cydoisomerization Reactions:
As a result o f recent studies, by B. Trost,34 o f palladium catalyzed
cydoisomerization reactions leading towards 1,3-dienes on five membered rings, the
choice was made to attempt a similar synthesis that might lead to a D-ring diene. As
shown in the retrosynthetic analysis in Scheme 2-30, the bis-diene 32 could be generated
from the precursor 104, The development of the five membered ring in 104 could then be
performed using the cydoisomerization methodology on the acyclic diyne 34.
OROR
H
TMSO 104OR
H,
34
Scheme 2-30
2.5.2.1: Generation of Cydoisom erization Precursor:
In order to test the methodology, a diyne such as 34 would have to be generated.
In the laboratory, this proved to be reasonably straightforward, Scheme 2-31 shows the
synthetic approach to the alcohol 110. From the commercial starting material 4-pentyn-l-
ol (105) a Swem oxidation40 provided the aldehyde 106. Other oxidation techniques were
also evaluated for this reaction, including the Dess-Martin periodinane67 and pyridinium
chlorochromate, but the Swem protocol provided the best yields, The aldehyde 106 was
then used, without further purification (no chromatography) in the next Grignard reaction
with vinyimagnesium bromide to give the alcohol 107 in a 73% yield (for 2 steps). The
79
conversion to the ester 108 (in 81% yield) was accomplished employing the same
procedure as that used in the synthesis o f the model bis-diene 41 (orthoester Claisen
rearrangement38). Reduction o f the ester to give the aldehyde 109 was accomplished
using DIBAL-H in diethyl ether, which proved to be a superior solvent for this reaction to
both THF and toluene, and gave the product in a 92% yield, After several attempts at
adding an acetylide anion to the aldehyde (using a commercial lithium acetylide - ethylene
diamine complex) in low yields, the choice was made to use ethynylmagnesium bromide
instead, which gave the desired alcohol 110 in a yield o f 87%, Overall, the synthesis of
110 from the commercial starting material 105 proved to be quite simple and easy to
reproduce, and could supply quantities o f 110 from 105 in a period o f only three or four
days.
D M SO /Oxalyl Chloride/
h - ^ - ^ o h105
M -----------CH2Cl2 106 ^
VinylMgBr-------------- ► H—= -
(EtO)3CCH3 /n -P fC 02H
107 Q|_| PhCH 3 / A
IIX DIBAL-H / Et2 0 n ............... .......... —-»•
108 0H—= = —
109
j-j EthynylMgBr / THF
O
H_ = = -----
110 OHScheme 2-31
80
After a few attempts at conducting the palladium catalyzed cydoisomerization
reaction using the alcohol 1 1 0 met with little success, the choice was made to either
protect the alcohol, or oxidize it (to the ketone) and protect it then. As shown in Scheme
2-32, both routes were pursued at the same time. The protection o f the alcohol 110 with
a TBDMS group proved to be quite facile, and gave the silyl ether 111 in high yields
(typically 90-95%). The oxidation o f the alcohol 110 with the Dess-Martin periodinane
(which was performed with and without pyridine as a buffer68 without significant
differences in yield). Protection o f the ketone 112 (recovered in a 78% yield) also
required ‘special’ conditions. The usual protection o f a ketone using ethylene glycol with
p-TsOH as a catalyst gave the product 113 (presumably through the generation o f an
aldehyde as an intermediate). In order to recover the desired product 114, TMSCI was
required as an acid catalyst (with ethylene glycol as a solvent) .66 In this case, the product
was recovered in a 55% yield.
OH/ TBDMSCI /
imidazoleDMF
110
PTBDMSH -H
111DMP / pyridine CH2CI2
HOCH2CH2OH / p-TsOH .
112 113
114Scheme 2-32
81
2.5.2.2: Cycloisiomerization Reaction:
With the two alternative cydoisomerization starting materials in hand, the quest
for the best conditions for the cydoisomerization reaction began. Based on the extensive
investigation o f the reaction by Trost,34,69 the reaction can be viewed, mechanistically, as
shown in Scl r.ne 2-33. The first part o f the reaction involves the complexation o f the
palladium catalyst to the enyne (in this case, 1 1 1 is shown as the starting material) to give
the intermediate 115. The pendant alkyne is thought to aid complexation and stabilize the
intermediate, 34 which is why the terminal alkyne was chosen as the functional group which
would later be converted irlo the ‘A-ring diene’. Following complexation, an oxidative
addition o f palladium can occur to give the bicyclic species 116. O f cou. se, if a Pd (0)
species were to be used as a catalyst, then the oxidative addition would lead to a palladium
(+2 ) intermediate rather than the Pd (M ) species (116) shown in the scheme.
At this point, the intermediate 116 can undergo two possible reductive eliminations
(with respect to palladium): each o f which will regenerate the catalytic palladium (+2 )
species (or, regenerate the Pd (0) species). The first elimination will give the 1,4-diene
117, and the second will give the desired 1,3-diene 118. With careful choice o f reaction
conditions (solvent choice, temperature, catalysts (and co-catalysts if necessary)) the goal
was to maximize the production o f 118 while minimizing the production o f 117. Although
the scheme shows the pathway for 1 1 1 as the only starting material, the pathway would be
cqu .lly valid if 114 was used as a starting material.
82
^OTBDMS pd+2
HHb
117
OTBDMSmigration
of Ha
Pd*2 catalyst
OTBDMS
115
OTBDMS
regeneration of
Pd(+4)
migration of Hb
Hb
Ha 116
regeneration of
Pd+Z catalyst
H.
OTBDMS
: 6
118•Ha
Scheme 2-33
Experimentally, the cydoisomerization reaction was approached using both i 11
and 114 as starting materials. The first goal was to obtain 118 (or the analog from 114) as
a product, and then worry about optimizing the conditions. Somewhat surprisingly, this
proved to be more difficult than originally anticipated. The first attempts used palladium
diacetate as a catalyst with 1 1 1 as a starting material, since it seemed to reasonably closely
match a system shown to react in literature.69 As shown in Table 2 - 1, a variety o f
catalyst/co-catalyst/solvent/temperature combinations were tried before any o f the desired
product 118 was isolated. It appears that the best solvent for the reaction is definitely
benzene (as shown by Reaction # 5 in the table yielding product). With respect to
83
catalysts, it seems that palladium diacetate by itself is too reactive, and leads to
decomposition in the reaction (as shown by the low recoveries o f starting material).
Table 2-1: Preliminary Attempts at the Generation o f 118 from 111 via a Palladium
Catalyzed Cycloisomerization
Rxn.
#
Pd Catalyst
(Co-Catalyst)
Mol %
Catalyst
(Co-
Catalyst)
Reaction
Conditions:
Solvent/Temp./
Time
% Con
version
to 118a
%Mass
Recov-
eryB
% Yield
o f 118
(from
l l l ) c
1 Pd(OAc) 2 5 THF/RT/18h 0 85 0
2 Pd(OAc) 2 5 THF/A/18h 0 18 0
3 Pd(OAc) 2 5 dichloroethane/
RT/4h
0 15 0
4 Pd(OAc)2 5 CHCl3/RT/3h 0 24 0
5 Pd(OAc) 2 5 C6H6/RT/3h - 1 0 2 2 - 2
6 Pd(OAc) 2 5 C6H6/A/3h 0 -5 0
7 Pd(OAc) 2
(Ph3P)
5(5 ) THF/RT/18h 0 89 0
8 Pd(OAc) 2
(Ph3P)
5(5) THF/A/18h 0 81 0
9 Pd(OAc) 2
(Ph3P)
5(5) C6H«/RT/3h 0 85 0
1 0 Pd(OAc) 2
Ph3P
5(5) C6H6/A/3h 0 71 0
* Refers to the % of 118 (of total contents) in the reaction mixture (remainder will be 111). Determined
by 'H NMR integrations.
b Refers to the mass of product mixture recovered after chromatography as a percentage with the amount
of starting material used. Note: Reactions performed on a 0.5 mmol scale in all cases.
c Yield of 118: Obtained from % Conversion x % Mass Recovery.
84
Reactions in which phosphiiie-based ligands were added as cc-catalysts in an
attempt to temper the reactivity o f the palladium catalyst proved to be unsuccessful,
When entries 5 and 6 are compared with entries 9 and 10 (Table 2-1), the phosphine co
catalyst only serves to ‘slow’ the reactivity o f the catalyst, and doesn’t appear to enhance
the formation o f 118 from the starting material: no desired product was isolated frnm
cycloisomerizatioh reactions in which the phosphine co-catalysts were used.
From an experi lenfal standpoint, the decomposition o f the starting material and/or
product was accompanied by a blackening o f the reaction mixture. Although it may be
possible that the TBDMS group in 111 may be responsible, at least in part, for this
behaviour, it seems unlikely since it was used as a protecting group in several
cycloisomerization reactions in the literature.34,69 Therefore, the choice was made to
search for other catalyst systems since the palladium diacetate’s reactivity could not be
modified sufficiently to give a good yield o f product. The next two catalytic systems tried
were the following: (dba)3Pd2«CHCl3 (119) with HO Ac as a co-reagent, and also
Pd(OAc)2 with BBGDA (120) as a co-catalyst (see Figure 2-8). The synthesis o f 119 was
based on the literature, 70 and proved to be reasonably simple. The BBEDA was generated
through a condensation o f benzaldehyde with ethylenediamina, which also proved to be
reasonably simple.
119
120
Figure 2-8: Alternate Catalytic System 119 and Ligand 120 For Cycloisomerization Reaction
85
The first attempts at the cycloisomerization reaction using 119 as a catalyst (with
HOAc as a co-reagent) were significantly more promising than the previous results using
palladium diacetate alone. Although the role o f the acetic acid, as a co-reagent with ti.J
Pd (0) catalyst 119, is at this stage unkown, its presence is essential to the catalytic
efficiency o f the reaction. Presumably, the acid serves to modify the rate at which the
unknown catalytic species (also Pd (0) based) is generated or regenerated. As shown in
Table 2-2, benzene again proved to be the best solvent for the reaction, with chloroform
and acetonitrile yielding no product (compare reaction # ’s 1 and 2 to 3).
The optimized set o f reaction conditions using this catalyst appears to be a three
hour reflux in benzene with 5 mol% catalyst and 2 0 mol% acetic acid. With such
conditions, the yield o f the reaction was typically about 60%. Unfortunately, the catalyst
119 seemed to be particularly sensitive to reaction conditions and, as a result, the
reproducibility o f the reaction with this catalyst was poor (yields varying by as much as
20% between reactions conducted under the ‘same’ conditions). Also disappointing was
the decrease in yield o f 118 with scale-up o f the reaction: most o f the reactions were
performed on a 0.5 mmol scale, but when the reaction was attempted on a 1.0 or 1.5
mmol scale, yields o f 118 typically decreased to 25-30%. Again, attempts to modify the
reactivity o f the catalytic system through the use o f triphenylphosphine as a co-catalyst
proved fruitless, as shown by reaction # 8 (Table 2-2), in which all the material
decomposed: perhaps the phosphine complexed the palladium, and the residual acetic acid
decomposed the starting material and/or product. Also, the use o f formic acid as a co
catalyst yielded poor results, as shown by reaction #9 not giving good yields o f product.
86
Table 2-2: Attempts at the Conversion o f I I 1 to 118 using 119
and HQAc as a Catalytic System
Rxn.
#
Pd Catalyst
(Co-Reagent)
Mol %
Catalyst
(Co-
Reagent)
Reaction
Conditions:
Solvent/Temp./
Time
% Con
version
to 118
%Mass
Recov
ery
% Yield
o f 118
(from 1 1 1 )
1 119 (HO Ac) 5(5) CH3CN/A/3h 0 75 0
2 119 (HOAc) 5(5) CHCl3/A/18h 0 80 0
3 119 (HOAc) 5(5) C6H6/RT/18h 0 82 0
4 119 (HOAc) 5(5) C6H6/A/3h 70 69 48
5 119 (HOAc) 5(10) C6H6/A/3h 40 80 32
6 119 (HOAc) 5(20) C6H6/A/3h 70 8 8 62
7 119 (HOAc) 10(40) C6H6/A/3h 65 42 34
8
,
119 (HOAc,
Ph3P)
10(20, 5) CsHfi/AAJh 0 0 0
9 119 (H 0 2CH) 5(20) CfiHe/A/Sh 1 0 89 9
(0.5 mmol Reaction Scale in all Cases)
The product mixture would be recovered from the reaction as a mixture o f 111
and 118. Through careful chromatography, the dark coloured catalyst residue (and
decomposition products) could be separated from the product and starting material.
Unfortunately, 11! and 118 were chromatographically inseparable, so the product was
characterized while contaminated with 111. By *H NMR integrations, 118 appears to be
the single product o f the reaction. The vinylic region o f the proton NMR shewed only
starting material 111 and product 118. The possibility that a 1,4-diene was made could be
immediately dismissed by simply counting the number o f resonances in the vinyl region o f
the proton nmr: the 1,3-diene gives three signals, and the 1,4-diene would be expected to
87
give four. At this stage, the assignment o f the stereochemistry o f the trisubstituted alkene
in 118 (Scheme 2-34) being the same as that shown was based on comparison o f the
chemical shift to similar compounds in literature.69
Based on these results, the ‘optimized’ set o f conditions used for the conversion o f
i l l to 118 were employed using 114 as a starting material. Somewhat surprisingly, the
yield of the reaction was poor (45%), and the conversion was low (~I0%). More
disappointing, however, was the fact that it seemed that more than one product was
formed in the reaction (potentially the 1,4-diene: Scheme 2-34). Although it may be
possible to optimize reaction conditions to attempt to increase the yield o f the
cycloisomerization reaction with 114 as a starting material, the studies with 111 as a
starting material showed that it might take a great deal o f effort (or luck). Therefore, the
choice was made to focus efforts on conducting the cycloisomerization reaction using only
111 as a starting material.
The next set o f cycloisomerization reactions attempted were those using palladium
diacetate with BBEDA (120) as a co-catalyst. As shown in Table 2-3, this catalytic
system did not increase the reaction yields: optimized conditions here (reaction #3) gave
OTBDMSH OTBDMS
H
H
111
Single Cycloisomerization Product, ~60% Yields
Mixture of Products, Low Yields
114
Scheme 2-34
88
yields of about the same as those with the 119/HOAc system (about 60%). However, the
Pd(OAc)2/BBEDA system did serve to increase the reproducibility o f the reaction (to give
yields for identical reactions within 5-10% o f each other). Also, the conversion o f the
reaction was typically higher (on the order o f 85-90%), so the product 118 could be
obtained in a more pure form. And, the reaction was less sensitive to scale-up. With
these conditions, the reaction could be carried out routinely on a 1.0 mmol scale (276 mg
o f starting material) without much difficulty. Unfortunately, scale-up above this amount
(to above about 1.5 mmol) led to decreased yields and lower conversions,
Table 2-3: Attempts to Optimize Cycloisomerization o f 111 Using
Pd(OAc)2 / BBEDA as a Catalytic System.
Rxn
#
Pd Catalyst
(Co-Catalyst)
Mol %
Catalyst
(Co-
Catalyst)
Reaction
Conditions:
Solvent/Temp./
Time
% Con
version
to 118
%Mass
Recov
ery
% Yield
o f 118
(from 111)
1 Pd(OAc) 2
(120)
5(5) C e H jm h 65 75 49
2 Pd(OAc) 2
(120)
1 0 ( 1 0 ) C6H6/A/3h 90 65 59
3 Pd(OAc) 2
(120)
15(15) C6H«/A/3h 90 52 47
4 Pd(OAc) 2
(120)
5(10) C6H6/A/3h 55 78 43
5 Pd(OAc) 2
(120)
1 0 (2 0 ) C«IVA/3h 58 67 39
Some interesting trends are shown in Table 2-3. It seems that an excess o f
BBEDA relative to the Pd serves to decrease the reactivity o f the catalyst (compare
89
reaction # ’s 1 to 4, and 2 to 5). Also, the mass recovery decreases with an increasing
amount o f catalyst. The 10% Pd(OAc)2/ 1 0 % BBEDA (reaction #3) strikes a good
compromise in that it gives a high maximal conversion (which does not appear to increase
with more than 10% catalyst) while still recovering a good mass balance. Perhaps a larger
amount o f catalyst (perhaps 2 0 % or more) could be used to try to increase the conversion
to over 90%, but the mass recovery would surely suffer. Also, the added financial
expense o f using twice as much palladium could be substantial (particularly if the reaction
were to be scaled-up). Also, the use o f more than 1 0 % catalyst led to the practical
experimental problem o f removing the catalyst from the product after the reaction.
Typically, if 15% catalyst were to be used, at least two flash columns would be required to
remove the brown-black catalyst residue (which tended to smear on silica gel) from the
product mixture.
Since the optimized cycloisomerization conditions were still showing sensitivity to
scale-up, and since the yields could still potentially be improved, two other starting
materials were evaluated using the optimized conditions (Pd(OAc) 2 / BBEDA) for the
reaction. The first was the unprotected alcohol 110, and the second was the benzyl
protected alcohol 1 2 1 (which was conveniently generated through reaction o f benzyl
bromide with alcohol 110). Surprisingly, neither starting material gave significant
amounts o f product. As shown in Scheme 2-35, the alcohol 110 decomposed in the
reaction medium (potentially polymerizing), and benzyl ether 1 2 1 proved to be unreactive.
These results show that the protecting group on the alcohol is important to the reaction.
Perhaps the palladium catalyst complexes to the oxygen atom in 1 1 0 and 121, which may
account for the unexpected reactivity: the steric bulk o f the TBDMS group in 111 would
likely make complexation to the oxygen atom by palladium unlikely or impossible. The
difference in reactivity between 1 1 0 and 1 2 1 must then be due to reactions which can
occur with the unprotected hydroxyl functionality in 1 1 0 : the benzyl ether in 1 2 1 would
not be expected to show the same reactivity.
90
OHH
110
Pd(OAc'/2 / BBEDA
C 6 H6 / A / 3 h
DECOMPOSITION With ~15% Recovery
of 1 1 0
OBnOBnH~Pd(OAc)2 / BBEDA HH
121 87% Recovery
Scheme 2-35
Overall, the Pd(OAc)2 / BBEDA system, using 111 as a starting material, gave the
most reproducible resuits with yields comparable to the 119/HOAc system (about 60%).
With such a system, it was reasonably easy in the laboratory to conduct two or three 1.0
mmol scale reactions side-by-side, and then combine the reaction contents before
chromatography when the reactions were complete. Thus, the choice was made to move
ahead in the project using the Pd(OAc)2 / BBEDA catalytic system exclusively for the
cycloisomerization reaction.
2.5.2.3: Attempts at the Generation o f the Second Diene Fragment:
With the cycloisomerization product 118 in hand, the next step in the project
would be to attempt to generate the second diene fragment (the portion that would
become part o f the A-ring in a steroidal system). Scheme 2-36 shows a ret£osynthetic
analysis to such an approach: the terminal alkyne in 118 would have to be converted to an
a,P-unsaturated ketone in which the alkene next to the carbonyl has a trans-
stereochemistry. Presumably such an approach would require some sort o f metallic
reagent be added to the alkyne in a stereoselective and regioselective manner, Once the
91
ketone 122 is _ merated, the formation o f 32 requires only that the kinetic enolate o f the
ketone be generated and trapped with TMSC1 (as per the synthesis o f 35 and 41).
TMSO
OTBDMS OTBDMS
122
H
113
Scheme 2-36
OTBDMS
Experimentally, the generation o f the second diene fragment was approached using
model compounds, such as 123 (Scheme 2-37), which was generated by the reaction o f
commercial 4-pcntyn-l-ol with TBDMSC1 (as per the synthesis o f 111). Since the model
compound contained both a silyl ether and a terminal alkyne (which are both present in
cycloisomerization product 118), it should serve as a good ‘guide’ to evaluate various
techniques to generate the ketone.
Several o f the early methodologies with 123 could be eliminated as ‘possibilities’
quite quickly, as they showed an undesired reactivity with 123. Two o f these techniques
are shown in Scheme 2-37. Addition o f DIBAL-H to the alkyne, followed by the
attempted replacement o f the aluminum with an iodine71 proved unsuccessful as the
TBDMS ether would be cleaved in the (acidic) work-up: also, this method gave an E-iodo
alkene (124) in yields o f only 52%. The second technique was the attempted addition o f
catecholborane to the alkyne, followed, again, by a replacement o f the boron by iodine.72
92
In ihis case, the TBDMS ether was again cleaved (likely in the basic work-up (2N
NaOH)), and, again, Me E-iodo alkene was not obtained in good yields (28%). From
these two studies, it can be readily determir j (• ?,t conditions which involve aqueous acids
or bases should be avoided due to the lability ci'the TBDMS group.
1. DiBAL-HOTBDMS
1. Catechol BoraneOTBDMS
2 . 12 / OH* 12428% yield
Scheme 2-37
Another method that was tried, again without much success, was the coupling of
the terminal alkyne in 123 with acetyl chloride. Literature73 has shown that it is possible
to couple a terminal alkyne with and an acid chloride (via generation o f an alkynyl cuprate
intermediate). Accordingly, the procedure was tried with 123, which gave the ketone 125
(Scheme 2-38) in low yields (44%). The next step in the synthesis would be to reduce the
alkyne in the presence o f the ketone (using DIBAL-H in HMPA/THF), which, again, has
shown to be possible, for similar systems, in the literature,74 Unfortunately, when
attempted on 125, this methodology led to decomposition o f the starting material and also
removal o f the protecting group (to give 126), No desired product, or reduced and
deprotccted product was recovered.
93
1. nBuLi/ Cul / Lil
0H
^ ^ ^ / O T B D M S123 2. CIC(0)CH3 1 2 5 ^ ^ - ' OTBDMS
044% Yield
HMPA / THF
DIBAL-H /DECOMPOSITION +
Scheme 2-38
A more lengthy approach was tried next to attempt to generate the desired ketone
(Scheme 2-39). The alkyne 123 was reacted with base (ethylmagnesium bromide proved
acetaldehyde to give the alkynol 127 (in a 65-70% yield) . 75 Two methods were then used
to attempt to reduce the alkynol to give the alkenol 128, The first, using lithium aluminum
of 50-55%. Unfortunately, attempts to increase the yields o f the reaction (which were low
partly due to low conversions) through the addition of excess LAH were unsuccessful, as
the TBDMS group would be partially to completely cleaved. Similarly, RED-A1
(NaAlHi(OCH2CH2OCH3)2) as a reducing agent7* gave low conversions, and when excess
PJED-A1 was added, partial to complete cleavage o f the O-Si bond occurred. An alternate
approach to the alkenol 128 through reacting DIBAL-H with the alkyne 123 followed by
reaction o f the aluminum complex with acetaldehyde79 failed to give the desired product:
alkene (129) was the only product (along with partial cleavage o f the O-Si bond,
accompanied by some decomposition). As a result o f these difficulties, other methods for
the conversion o f the terminal alkene to the unsaturated ketone were considered.
to be a superior base for this reaction to both nBuLi and LDA), and was then reacted with
hydride, 76 gave the desired alkenol (with the /ram-stereochemistry exclusively77) in yields
94
1. B ase (see text) OTBDMS ___________
123 2 . CH3CHO 127OTBDMS
LAH or RED-AI
OTBDMS123
1. DIBAL-H2 . CH3CHO
1. DIBAL-H2 . CH3CHO
- X -128 R=H or
TBDMS
R=H, TBDMS129
Scheme 2-39
The next method attempted with the model compound 123 was a stannylation
using tributyltin hydride.80 Through reaction of tributyltin hydride with 123 in a benzene
reflux (using AIBN as a radical initiator), the stannane 130 was isolated in a 94% yield as
a mixture o f two isomers (80% tram and 20% cis) by 'H NMR integrations (see Scheme
2-40). Attempts at conducting the stannylation using a magnesium-tin complex81 gave a
higher selectivity for the /ra/w-stannane at the expense of yield: product exclusively tram
by nmr and obtained in a 55% yield. The next step in the synthesis would be to couple the
stannane with acetyl chloride using a palladium catalyst.82 Luckily, the coupling worked
on the first attempt (a result well received after the experience with the cycloisomerization
reaction) to give the desired a,p-unsaturated ketone 131 in an 81% yield (with the same
isomeric distribution as that in 130). With these encouraging results, the next step would
be to attempt to conduct the same set o f reactions on the cycloisomerization product 118.
95
OTBDMS123
Bu3SnH / AIBN/ C6 H6 / A or
Bu3SnMgMe / THF
Bu3Sn130
(Ph3 P)4Pd / A cCI/CHCI3
OTBDMS
Scheme 2-40
Chronologically, the first set o f reactions that were attempted on the
cycloisomerization product 118 in an attempt to generate the unsaturated ketone 122 was
the coupling with acetaldehyde followed by aluminum hydride reduction of the alkynone.
Experimentally, the reaction o f 118 with ethylmagnesium bromide (the previously
determined ‘superior’ base for this reaction) followed by reaction with acetaldehyde gave
the desired product 132 in yields o f 35-40% (Scheme 2-41). The product mixture o f the
reaction would always contain some unreacted start‘ng material. Surprisingly, this was a
problem which addition o f excess base, longer reaction times or higher temperatures failed
to overcome: perhaps the acetylide anion was being quenched by forming an enolate o f the
acetaldehyde (which seems unlikely based on the results with the model compound).
However, the unreacted starting material could be recovered and recycled in the reaction.
Reduction o f the alkynol using LAH or RED-A1 gave the same difficulties as those
encountered with the model compound. Typically, the conversions o f starting material to
product (133) were poor (giving product yields o f 30-35%), and excess reducing agent (or
increased reaction temperatures) served only to deprotect the alcohol. In this case,
however, the alkene adjacent to the newly depr jtected alcohol would be reduced as well
and would give 134 as a product. Not surprisingly, attempts to react the terminal alkyne
96
in a regioselective manner using the DIBAL-H procedures described previously (with the
model compound) also did not give successful results.
Although oxidation o f 133 using the Dess-Martin Periodinane (and a pyridine
buffer) were able to provide very small amounts o f the desired ketone, the choice was
made to pursue other pathways in the hope that they would provide the desired product in
synthetically useful yields.
OTBDMS OTBDMS1. EtMgBr2. CH3CHO
H
118
OH
132
OTBDMS OH
LAH or RED-AI
133 134HO HO
Scheme 2-41
Since the stannylation followed by the palladium coupling, to give the unsaturated
ketone, worked so well on the model compound 123, the same sequence was
enthusiastically pursued using the cycloisomerization product 118 as a starting material.
However, the stannylation reaction proved to not be regioselective when using either
reagent (tributyltin hydride/AIBN or tributyltinMgMe) and it appeared that the tin reagent
would add to the diene before it would add to the terminal alkyne. Thus, the desired
stannane, 135, was not isolated (Scheme 2-42). It appears that even the addition o f the tin
reagents with respect to the diene itself did net appear to be selective, as a mixture o f
more than two products was always isolated from the reaction mixture.
97
OTBDMSOTBDMS
Bu3SnH / AIBN or
Bu3SnMgMe
Scheme 2-42
It appears that the diene in 118 was much more reactive than was initially
anticipated. When the diene 118 was first made, a preliminary ‘competition’ Diels-Alder
reaction test was conducted using one equivalent o f enyne 63, one equivalent o f A-ring
model diene 35 and one equivalent o f 118 in refluxing toluene. The crude nmr o f the
product mixture showed that there was still some 118 in the reaction mixture, and,
following chromatography o f the mixture, the expected product o f the DAC, 136, was
isolated (Scheme 2-43). Since the diene-like reactivity o f 118 appeared to be lower than
that o f 35, the high reactivity o f 118 towards other reagents was not expected.
OTBDMS
TMSO
1.0 equivalent 1.0 equivalent 1 . 0 equivalent
OTBDMS
Scheme 2-43
98
Since the conversion o f the terminal alkyne in 118 to the desired ketone was not
accomplished in synthetically acceptable yields, the choice was made to try a different
approach to the problem. One way to overcome the high reactivity o f the diene in 118
would be to react it with a dienophile in a DAC. This way, the diene is ‘eliminated’, and
hopefully, the other diene (and dienophile) necessary to generate the A-ring could then be
generated from the cycloadduct.
99
2.6: Alternate Seaential Diels-Alder Strategy Using Cycloisomerization
Product as * First* Diene:
The previously described sequential Diels-Alder strategy (between enyne 63 and
bis-diene 41) was based on the generation o f the A-ring first, and then the C-ring.
However, difficulties encountered in the attempted generation o f the second diene
fragment from the cycloisomerization product 118 did, unfortunately, not allow for this
approach to be evaluated for the ‘steroidal’ system.
Fortunately, a sequential Diels-Alder strategy towards a steroid natural product is
still possible using 118 as a starting material. The retrosynthetic analysis o f such an
approach is outlined in Scheme 2-44. The steroid precursor 30 should be available via an
IMDAC (and subsequent modification) o f the bicyclic precursor 137. There is some
literature precedent for the desired selectivity o f this type o f IMDAC, so the
stereochemistry indicated at the A/B ring junction in 30 should be synthetically available.83
The formation o f the bicyclic species 137 should be possible through modification o f the
cycloadduct 138. As suggested in the previous section, the cycloadduct could be
generated from a DAC o f the cycloisomerization product 118 with a suitable dienophile to
generate the C/D ring system o f a steroid natural product. In the scheme, the dienophile
is shown to be methyl vinyl ketone (MVK), which should be an appropriate dienophile
since it is electronically activated. Also, the carbonyl group o f MVK could be easily
converted into an alkene (as in 137) at a later stage in the synthesis.
The success o f the strategy outlined above would depend on two key points. The
first is that the intermolecular DAC between 118 and MVK occurs in a regioselective
manner (as shown in Scheme 2-44). The stereoselectivity is not crucial since the acidity o f
the proton a-to the carbonyl group could be exploited in an epimerization reaction (on
cycloadduct 138) to generate the desired stereochemistiy (if not generated in the DAC
100
itself). The second key point is that the dienophile and diene present in 137 must be
synthetically available from the cycloadduct 138. The generation o f a diene fragment from
the terminal alkyne in 118 proved to be extremely difficult due to the reactivity o f the
diene in 118: hopefully, this strategy will overcome this problem.
OR OR
137TMSO
OTBDMS OTBDMS
+
OMVK138 118
Scheme 2-44
Unfortunately, use o f this strategy means that the previously developed enyne/bis-
diene sequential DAC strategy, which proved to be an efficient and stereoselective
strategy to generate the perhydrophenanthrene skeleton, would have to be abandoned.
However, this alternate strategy has some merits o f its own. Perhaps the one factor that
stands out the most as being an attractive aspect o f this strategy is that it might be possible
to generate all the stereocenters o f a steroid natural product from the one stereocenter in
the cycloisomerization product 118. If the DAC between 118 and MVK occurs with a
degree o f facial selectivity (dienophile approaching on the opposite face to the OTBDMS
group), which seems likely due to the close proximity o f the bulky TBDMS ether
(compare geometries ‘A’ and ‘B’ in Figure 2-9), then the two new stereocenters generated
in the adduct 138 would bear the relative stereochemistry shown in Scheme 2-44 (after
101
epimerization). Likewise, the A/B ring junction would be developed with the relative
stereochemistry shown in Scheme 2-44.
0Geometry 'A' Geom etry 'B'
Expected DAC Facial Selectivity
Figure 2-9: Possible Facial Orientations for DAC of 118 with MVK (assuming
same regiochemistry and endo-selectivity).
The generation o f a steroid natural product, such as dihydrotestosterone, from a
structure such as 30 could also make use o f the ‘directing’ stereocenter on the D-ring to
stcreoselectively generate the C/D ring junction. As shown in Scheme 2-45, cleavage of
the silyl ether in 30 should give the alcohol 139, which can then be ‘protected’ with
another silyl group, 140, to give 141 as a product.84 At this stage, a radical cyclization can
take place, 85 which should give an intermediate such as 142, which, upon work-up with
base, 86 should give access to the natural product 29. The stereochemistry o f the angular
methyl group in the C/D ring junction will be determined by the stereocenter on the D-
ring. The stereochemical nature o f the C/D ring junction (c/s or trans) will hopefully give,
through experimental optimization, selectivity for the desired stereochemistry. If this
occurs, then the stereocenter on the D-ring o f 118 would be ‘responsible’ for the relative
stereochemistry o f all o f the six other stereocenters in 29. Thus, if 118 could be generated
OTBDMSOTBDMS
102
in a chiral form, the entire synthesis could be conducted in an enantioseleetive fashion
using the single stereocenter in 118 to ‘direct’ the synthesis.
OTBDMS
radical initiator /
hydridesource
t-BuOK / DMSODihydrotestosterone
Scheme 2-45
In the previous strategy (section 2.5), the Cl 7-alcohol (steroid numbering) would
have to somehow be introduced with the proper absolute configuration. A further
reqirement is that the intial, intermolccular Diels-Alder reactions (the first part o f the
sequential Diels-Alder strategy) would have to be conducted using an appropriate chiral
auxiliary to ensure correct absolute configuration at the A/B ring-junction.
103
Failure to synthetically ensure a specific configurational relationship between the
A/B ring junction and the stereocenter on the D-ring would necessarily give rise to
diastereomeric mixtures such as compounds 94 (Scheme 2-25, page 74). Since our initial
attempts were indeed performed on racemic mixtures o f C l 7-alcohols, we intended to
temporarily correct this problem by separating the diastereomeric cycloadducts and
recycling the ‘wrong’ one. Fortunately, the new synthetic route described in this section
circumvents this problem.
2.6.1: Diels Alder Reaction Between 118 and MVK:
The first attempts at conducting the DAC between 118 and MVK were conducted
at room temperature using benzene as a solvent.69 Luckily, the reaction did proceed, as
anticipated, to give a single cycloadduct 143 in a 79% yield (see Scheme 2-46). The
stereochemistry (and regiochemistry) o f the product was determined by various ‘H NMR
and ,3C NMR experiments: the assignment o f many proton signals could be made through
the use o f a 'H -I3C correlated spectrum. These assigned protons could then be further
analyzed using 'H COSY NMR techniques to confirm the stereochemistry shown in 143
(Figure 2-10). Unfortunately, the relative stereochemistry o f the substituents on the C-
ring to the stereocenter on the D-ring could not be established by NMR techniques.
However, in light o f the fact that only one cycloadduct was isolated from the reaction, it
seems unlikely that the dienophile would have approached the diene from only the same:
face as the TBDMS group. So, at this stage, the stereochemistry o f the D-ring center
relative to those on the C-ring remained speculative, but likely.
OTBDMS OTBDMS
MVK 0
CeHe/RT
143
H
Scheme 2-46
104
proton a-to carbonylmethine proton
jc-i-m nii-n
m ethine proton
proton a-to carbonyl
Figure 2-10: Portions o f the 'H -,3C Correlated Spectrum
and 'H COSY Spectrum of Cycloadduct 143.
105
A portion o f the 'H -,3C correlated spectrum, and the relevant portion o f the 'H
COSY spectrum are shown in Figure 2-10. As can be seen in the figure, the proton a-to
the carbonyl group and the adjacent methine proton couple to one another, which
confirms the regiochemistry o f the reaction. The magnitude o f the coupling constants
(and the fact that one would predict that the endo-isomer would predominate) provides
evidence for the stereochemical arrangement shown in Scheme 2-46.
As a side note, a tandem cycloisomerization/DAC reaction was attempted a few
times in an attempt to increase the yields o f the cycloisomerization reaction. As shown in
Scheme 2-47, the strategy was to ‘trap’ the newly formed (and reactive)
cycloisomerization product 118 as the cycloadduct 143 by adding MVK to the
cycloisomerization reaction mixture. The idea was that if 118 was trapped as an
‘unreactive’ cycloadduct, then the yield o f the reaction might rise since there would be
little to no chance for 118 to react further (and potentially decompose) with the catalyst,
Unfortunately, the MVK must have modified the reactivity o f the catalytic system, because
the presence of MVK caused the yields o f the cycloisomerization reaction (and subsequent
DAC) to be lowered. In particular, the conversion of starting material 11 1 to product
decreased from about 90% to 20%. In the tandem reactions, the recovery of starting
material 111 would be high, typically about 50%, and the yield o f cycloadduct 143 would
only be about 20%. So, although the tandem approach was faster (and also reduced a step
from the synthesis), it gave worse yields than the ‘two-step’ approach, so therefore was
abandoned. Interestingly, even at the elevated temperature o f the benzene reflux, there
was still only one cycloadduct isolated from the product mixture, so the preference for tht
formation o f the product 143 must be quite high in energetic terms.
106
OTBDMS
MVK O
Pd(OAc)2 /BBEDA
C6H6 / A / 3 h
ii
OTBDMS
H
OTBDMS
14320% Yield
OTBDMS
11150% Yield
Scheme 2-47
With the newly formed cycloadduct 143, the next steps in the synthetic strategy
would involve the development o f the diene and dienophile fragments necessary for the
second DAC to occur.
2.6.2: Subsequent Modification of Bicyclic Cycloadduct:
The first step that must be conducted u ith the cycloadduct 143 is the modification
o f the stereochemistry at the site adjacent to the carbonyl group In the cycloadduct, as
drawn, the two adjacent methine protons are both ‘up’, but in the steroid natural products,
the proton at C9 must be 'down’. Fortunately, it should be possible to perform an
epimerization reaction on 143 to generate the desired stereochemistry (as in 138, see
Scheme 2-44, page 1 0 0 ).
107
In this case, the preference for the two substituents on the six-membered ring (the
ketone and the pendant alkyne) to be in the energetically favourable fram-diequatorial
conformation should allow for the desired product to be isolated from the reaction. Also,
there is literature precedent for the success o f this type o f reaction on similar systems,x’’
'’ud preliminary analysis o f the system using Chem 3D molecular modelling software
indicates that there is, in fact, an energetic preference for the desired isomer 138 (see
figure 2-11 and Table 2-4). Although the software required that a t-butyl group be used
instead o f a TBDMS group for the calculations, the values in Table 2-4 should still be
usetui as a guide. As shown in the table, there should be approximately 0.5-0.6 kcal/mol
difference in steric energy between 143 and 138 (with 138 being more stable). Also, the
dihedral angle data shows that the proton resonance for H9 in 138 should be markedly
different, in coupling constant terms, from that in 143. In fact, one would expect the H9
proton in 138 to show two large, and one smaller coupling constants.
OR OR
138
R= TBDMS in com pounds, t-Bu for calculations R - CH2 CH2CCH
Figure 2-11: Energy-Minimized Cycloadducts
From Molecular Modelling Calculations
108
Table 2-4: Predicted Energetic And Dihedral Angle Values for
Cycloadducts 143 and 138
Structure
#
Steric Energy
(kcal/mol)
Dihedral Angle
H9-H8
Dihedral Angle
H 9-H llc
Dihedral Angle
H9-H11«
143 28.83 52.4° 56.2° 60.4°
138 28.29 170.3" 65.4° 176.9°
Note: Values obtained from Chem 3D
In order to carry out the epimerization reaction, conditions were required that
would be sufficiently basic to remove the proton (reversibly) a-to the ketone, but not so
basic as to potentially remove the TBDMS group or cause other undesired side reactions.
After a few attempts, the best reaction condition found was to use anhydrous potassium
carbonate in methanol (adding diethyl ether to help solubilize the starting material M3).
In this way, after stirring overnight (equilibrium appears to be reached after approximately
7-8 hours), the product mixture (recovered in an 84% yield) would consist o f a 7:1
mixture o f 138:143. Unfortunately, the two isomers did not appear to be separable by
flash chromatography (one ‘spot’ on TLC). Proof o f the formation o f 138 is given by two
pieces o f evidence: one is that the resonance of H9 ‘moved’ from 2.85ppm to 2.5ppm,
which is consistent with a ‘movement’ o f a proton from an equatorial to a more
electronically shielded axial position, and the second is that the H9 resonance appears as a
doublet o f triplets (J=2.8, 10.9 Hz), which, again is consistent with the geometry in 138
(and the values predicted by the molecular modelling software).
At this stage, the first major requirement o f this particular synthetic strategy was
met: the stereoselective generation o f the cycloadduct with the substituents having the
correct geometries. The success o f the entire strategy, however, would still depend on the
109
successful generation o f the ‘new’ diene and dienophile fragments from 138 and the
success o f the subsequent Diels-Alder cycloaddition.
Accordingly, the next step pursued in the synthesis was the generation o f the
dienophile fragment tfom the ketone in 138 Although the simplest way to achieve this
goal would be to react the ketone 138 with CH2PPh3, this was not achieved
experimentally: only starting material (and decomposition products) were isolated from
the reaction mixture. This occurred even if alternative bases, such as potassium tert-
butoxide87 or potassium tert-amyloxide, were used in an attempt to generate the ylide
from the commercial Wittig salt. Similar to the case with the reaction o f 55 with the same
reagent (section 2.3.2), enolization o f the ketone as a side reaction may be responsible for
this behaviour. Somewhat surprisingly, a recently developed methylenating reagent, the
Tebbe reagent (a titanium-aluminum methylidene complex) , 88 also failed to give good
yields o f the desired product 144. In this case, the problem was the difficulty encountered
in the removal o f the titanium and/or aluminum salts from the product mixture. If aqueous
acid or base was used to try to remove these salts, then partial cleavage o f the silyl ether
also occurred (Scheme 2-48).
138
OTBDMSPh3 P=CH2 or
- XH Cp2Ti(^AI^
Cl N144
OTBDMS
H
Scheme 2-48
Instead, what proved to be a successful method for the methylenation o f the
ketone was a two-step procedure84 using methyllithium first to add to the ketone, followed
by a dehydration (POCI3 in pyridine). With careful attention to the work-ups o f both
reactions, they would yield the alcohol intermediate 145 and then the desired alkene 144 in
110
yields o f 75% and 72% respectively (54% two-step yield, see Scheme 2-49). Another
potential route to the alkene 144 would involve the use o f the Peterson olefination89
(addition o f a silyl-substituted methylene anion to the ketone, followed by elimination o f a
silanol). However, due to the success o f the addition-dehydration sequence described
above, the Peterson olefination route was not attempted.
OTBDMS OTBDMSMeLi
HO138
7:1 a :p145
OTBDMS
POCI3 / pyridine
144
Scheme 2-49
At this stage, only the generation o f the second diene fragment from the terminal
alkyne remained before the IMDAC could be evaluated. Since 144 does not contain the
reactive diene unit that caused problems in reactions with 118, several methods for the
generation o f the ketone from the alkyne could be evaluated. However, experience gained
in the reactions with 118 (section 2 .5.2 .3) indicated that the stannylation followed by the
palladium catalyzed coupling to acetyl chloride would likely give an efficient and
stereoselective route to the desired product 146. As shown in Scheme 2-50, the plan was
to stannylate the alkyne in a stereoselective and regioselective manner (which, based on
the results with the model compound 123, should be possible) to give 147, which could
then be reacted with acetyl chloride (with an appropriate palladium catalyst) to give the
I l l
ketone 146. Since terminal alkynes are known to react quickly with tributyltin hydride,
there would be no expected side-reactivity with the isolated alkene (the dienophile).
144 .
OTBDM S
AcCI / 'Pd'OTBDMS
146
OTBDM S
147
Scheme 2-50
When this route was attempted in the laboratory, the reaction o f tributyltin hydride
with 144 did not give the desired product at all. In fact, it appears that some sort o f
radical cyclization occurred which gave a tricyclic species (potentially such as 148, see
Scheme 2-51) instead o f the desired product. In retrospect, this result was not particularly
surprising, as the generation o f a five-membered ring by a (5-exo-trig) radical cyclization is
a route which is commonly employed in synthetic strategies.90 However, this result meant
that, for this project, a different strategy would have to be used to generate the ketone 146
from the alkene 144. Ironically, the attempt to circumvent the undesired reactivity o f the
diene 118, by performing the DAC before generation o f the second diene fragment,
resulted in a molecule, 144, which also reacted in an undesired manner (albeit differently
than 118) with the tin reagent.
112
Since the previously evaluated alternative methods for the generation o f an a,P-
unsaturated ketone from a terminal alkyne (using the model compound 123) proved
lengthy, low yielding, or unsuccessful due to cleavage o f the silyl group (or other
undesired reactivity), the choice was made to search for a ‘new’ method to perform this
task rather than attempt to apply the ‘older’ methods. Although the sequence in which the
alkyne is reacted with acetaldehyde, followed by two reactions on the resulting alkynol
(reduction o f the alkyne followed by oxidation o f the alkenol) may give small amounts o f
the desired ketone 146, we still elected to attempt to find a shorter, more direct route to
the desired product.
144
OTBDM S
H
OTBDMSBu3SnH/A IEN
- X -CgHg / A
Bu3SnH / AIBN / CgHg / A
OTBDM S
148
147
Scheme 2-51
After a thorough search o f alternative strategies in literature,91 the choice was
made to attempt a hydrozirconation-based pathway. In such a strategy, Schwartz’s
reagent92 (CpaZrHCl) would be reacted with the terminal alkyne to give an
organozirconocene intermediate. As shown in Scheme 2-52, such an intermediate (149)
could then undergo a transnietallation reaction with aluminum93 or zinc94 to give an
organoaluminum or organozinc species (shown as ‘M ’ in 150). This species is thought to
113
be a more reactive nucleophile than the organozirconocene, and should be able to react
with an aldehyde (in this case, acetaldehyde), or perhaps even an acid chloride, to
eventually give the desired ketone 146.
OTBDMS OTBDMS
149144(7:1 a:(l, m ajor isom er shown) OTBDM S I . C H 3CHO
^ 2. Oxidation> orRAICI2 or Me2Zn
150OTBDM S
146
Scheme 2-52
Experimentally, the strategy was first approached using dimethyl zinc as the
transmetaliating reagent and ace" aldehyde as the electrophile.94 Also, to be certain that
144 wouldn’t give any ‘unexpected’ reactivity, the choice was made to attempt the
reaction, at least in a preliminary fashion, with 144 before attempting to optimize
conditions with the model compound 123. In these preliminary experiments, before the
reaction conditions were optimized for this particular system, the desired alkenol, 152,
would be isolated (in about 2 0 % yields), but also isolated was a reduced form o f the
starting material in about 55% yields (terminal alkene, 153, See Scheme 2-53). Also
isolated was some starting material 144, which can be rationalized by the starting material
not reacting with the Schwartz reagent. With regards to 153 however, there are two
114
potential reasons for the appearance o f this product. One is that the organozironocene
intermediate 149 was not undergoing a transmetallation reaction with the zinc (to give
151). This would mean that the organozirconocene would be carried through the reaction
until work-up, at which point the carbon-zirconium bond would be hydrolyzed to give
153: the organozirconocene 149 is known to be unreactive with clectrophiles such as
aldehydes.94 Another possibility is tnat the organozinc species 151 was not reacting with
the acetaldehyde. In this case, either an impurity in the acetaldehyde (water, acid, or
alcohol) was cleaving the carbon-zinc bond, or alternatively, the organozinc species did
not have enough time (or sufficient temperature) to react with the aldehyde. Attempts
were made to remedy both problems, in the hope that the yield of 152 could be increased,
and the yield o f l5 3 could be correspondingly decreased.
OTBDM S OTBDMS
CpzZrHCI
CH2CI2
^./ZrCfcC!
(7:1 a : p, major isom er shown) OTBDMS
CH3CHO
ZnM e
pT B D M S OTBDM S
Scheme 2-53
115
Since the hydrozirconation methodology showed the desired sort o f reactivity with
144, the optimization studies with the model compound 123 were pursued quite
enthusiastically. Unfortunately, all attempts at obtaining the desired ketone 131 directly
through reaction o f the organozinc intermediate 154 (made from model compound 123)
with acetyl chloride were unsuccessful in giving good yields. The reactions always
showed a great deal o f decomposition, and the ketone 131 was never isolated in yields
over 10% (Scheme 2-54). The case was much better, however, with the reaction o f the
organozinc intermediate with acetaldehyde. Increasing the amount o f Schwartz reagent in
the reaction (from 1.0 to 1.3 equivalents) was sufficient to ensure that all o f the starting
material would undergo the hydrozirconation reaction. Attempts to decrease the amount
o f terminal alkene in the product mixture, by adding more dimethyl zinc (up to 2 .0
equivalents), more acetaldehyde, using longer reaction times and higher temperatures (0 °C
instead o f -65°C), did manage to increase the yield o f the coupled products.
Unfortunately, the terminal alkene 156 was still always isolated in a yield o f about 30%.
Perhaps the organozinc intermediate 154 removes a proton from acetaldehyde to give 156
(and a zinc enolate).
TBDM SO 1.Cp2ZrHCI TBDM SO
ZnM e123 154
TBDM SO
OHTBDM SO TBDM SO
155TBDM SO 131
< 10% Yields166
Scheme 2-54
116
On a more positive note, as shown in the Scheme 2-54, there were two coupled
products isolated from the reaction: one being the expected alkenol 155, and the other
being the ketone 131. These products were isolated, after optimization o f the reaction
conditions, in yields o f 38% and 12% respectively (to give a 50% yield o f coupled
products). Confirmation o f the formation o f 131 in the reaction could readily be made by
oxidizing 155 with the Dess-Martin periodinane (with a pyridine buffer),6* which would
readily yield 131. This result, aside from being very welcome, was quite surprising, and
meant that some' sort o f in situ oxidation o f the alkenol must be taking place in the
reaction medium. If the reaction was monitored by TLC, one could clearly see that the
alkenol 155 would be formed first in the reaction, and over a period o f about 2-3 hours,
would be converted, at least in part, to the ketone 131. Unfortunately, attempts at
isolating 131 as the sole product from the reaction were unsuccessful; 155 would always
be isolated as well.
The direct formation o f the ketone in the reaction mixture was quite puzzling.
Upon initial inspection, there does not seem to be any suitable oxidizing agent in the
reaction. However, a review o f literature revealed that some zirconocene completes are
capable o f catalyzing an Oppenauer-type oxidation o f allylic alcohols.99 In order to have a
working catalytic system, the literature reports seem to indicate that either a Cp2ZrH2 or
Cp2Zr(OR) 2 species is required, along with an alkenol (to be oxidized) and a hydride
acceptor which can be reduced (which, in this case would be the excess acetaldehyde).
The zirconium species serves to catalytically oxidize the alkenol while reducing the
hydride acceptor (which would give ethanol from acetaldehyde in this reaction).
Since, in the system shown in Scheme 2-54, the ketone 131 was not isolated as the
sole product, the catalytic nature o f the oxidation might not be necessary. Also, this
system seems to lack the required type o f catalytic zirconium species indicated in
literature.93 As shown in the proposed mechanism (Scheme 2-55), a stoichiometric amount
117
o f ‘oxidizing agent’ (Cp2Zr(Me)Cl) is generated, which may well be sufficient to cause the
oxidation to occur. The scheme shows that the oxidation o f the zinc enolate may be
caused by the side-product o f the displacement o f the Schwartz reagent by the
dimethylzinc (earlier in the scheme). It may well also be possible that the Schwartz
reagent itself is responsible for the behaviour. But, seeing that an increase in the ‘excess’
o f the Schwartz reagent in the reaction failed to increase the yield o f ketone, this seems
unlikely.
TBDMSOTBDMSO
123
C l C \ C p 2 TBDMSO CH3 CHO
ZnMeCH; 154
TBDMSO C pN ,cp TBDMSO.MeZrv
131NZn
Scheme 2-55
Fortunately, the same sequence could also be applied to 144 to give the alkenol
152 in a 28% yield, and the enone 146 in a 35% yield (Scheme 2-56). Also, an oxidation
o f the recovered 152 using the Dess-Martin periodinane (with pyridine) 68 gave the enone
146 in a 78% yield. By combining the two enone fractions, the total yield o f the enone
from the alkene 144 was 56%, which was much higher than any yield obtained with this
system before. Unfortunately, further attempts at trying to increase the yield o f the enone
were unsuccessful. It appears that the formation o f the terminal alkene as a side reaction
(as was the case with the model compound) also prevents the yield o f the reaction from
being higher than 60%. Perhaps some optimization studies in the future will be able to
118
overcome this problem. But, at this stage, with the ketone 146 in hand, the choice was
made to move on in the synthesis.
The last stage in the synthesis before the IMDAC reaction would be the generation
o f the second diene fragment. Since this type o f reaction had been performed before using 1
the A-ring model diene 35, and the bis-diene 41, the generation of the silyl enol ether was
not expected to be a problem. However, the previous molecules used in the generation of
silyl enol ethers were relatively small and volatile, and could be purified by distillation, In
contrast, 146, and its silyl enol ether 157 (Scheme 2-57), are quite large molecules, and
attempted purification o f these via distillation techniques would likely lead to
decomposition. Unfortunately, silica gel chromatography is often impossible with silyl
enol ethers (due to their acid-sensitivity, they tend to hydrolyse on the column).
Therefore, a work-up and purification for the molecule would have to be very carefully
chosen.
OTBDMS 1. Cp2ZrHCI * 2. Me2Zn> 3. CH3CHO
D.M.PPyridine
OTBDMS
OTBDMS
146 ^ ^(major isomer shown)
Scheme 2-56
119
OTBDMS1.LDA2. TMSCI
OTM S
157
OTBDM S
146(major isom er shown)
Scheme 2-57
After trying several methods, the best one found for this system used a non-
aqueous work-up: removal o f the reaction solvents by rotary evaporation followed by
precipitation o f the amine salts through the addition o f pentane.96 Filtration o f the pentane
would remove the salts and leave the silyl enol ether in solution. Further purification o f
157 could be accomplished using silica gel chromatography with the following
modification: the silica gel used in the chromatography would have to be pre-treated with
1% triethylamine (v/v) in hexanes, and the column was ‘run’ using a mixture o f 15:1
hexanes: ethyl acetate with 0.5% triethylamine.34 This way, the silica gel was sufficiently
deactivated to allow for the silyl ether 157 to pass through undamaged. The pure silyl
enol ether was recovered in an 88% yield.
2.6.3: Attempted IMDAC Using Newly Generated Diene:
In order to successfully conduct the IMDAC of 157, a reactivity ‘window’ must be
found in which the temperature is sufficiently high to allow the reaction to occur, but not
so high as to decompose the product o f the reaction (or, just as importantly, decompose
the starting material). The determination o f such a temperature is usually based on trial*
and-error, using conditions found for similar systems (usually in literature) as a guideline
for initial ‘guesses’, In this case, two similar systems can be compared to the subject
system (157 to 158, as shown in Scheme 2-58). The first is the IMDAC used in the
sequential Diels-Alder strategy (67 to 69), which required sealed tube techniques: 170°C
120
in toluene for 48h.52,57 In this case, both the dienophile and the diene are unactivated, but
the dienophile is only disubstituted: the subject system contains a trisubstituted dienophile.
The second system (18 to 19) is quite similar to the subject system, having a trisubstituted
dienophile, but the diene is unactivated.30 This system also required sealed tube
techniques: 220°C for 100 hours. Although the subject system contains an electronically
activated diene that would be expected to decrease the temperature required for the
reaction to occur, the activation energy stabilization required by ‘activation' o f the diene
is much less profound than that caused by activation o f a dienophile.22 Hence, one would
expect that the temperature required for the IMDAC of the subject system to be fairly
similar to those o f the two comparison systems.
TM SO
OTBDM S
TM SO
OTBDMS
H3C 0 2C H3C 0 2C170°C / 48h
O ' 67 0 ^ ^ 69
OtBu
220°C / 100h
OtBu
Scheme 2-58
121
Once a suitable temperature for the reaction is found (or, alternatively, an
appropriate catalytic system is found), fh«n determination must be made that the
stereoselectivity o f the reaction is such that there is selectivity for the desired isomer. In
this case, there exists literature precedent (for similar a similar system30 (see 18 to 19 in
Scheme 2-58)) for a transition state, in the conversion o f 157 to 158, such as that shown
in Figure 2-12. As can be seen in the figure, the ‘expected’ transition state will give the
desired stereochemistry o f the A/B ring junction in the product 158: assuming, o f course,
that the B-ring adopts the expected most stable chair-like conformation in the transition
state.
OTBDM STM SO
Figure 2-12 Expected Transition State Geometry for IMDAC.
Armed with sufficient background information to enable some educated ‘guesses’
at reaction conditions for the IMDAC, the attempts at conducting the reaction in the
laboratory began. Starting from a reasonably low temperature (~140°C), the approach
was to increase the temperature o f the reaction, as necessary, until a reaction took place.
Table 2-5 Attempted Conditions for IMDAC o f 157.
Reaction Temperature Conditions Result
138°C m-xylene reflux / 16h no reaction
170°C toluene: sealed tube / 16h no reaction
200°C toluene: sealed tube / 16h reaction (see te. r i)
200°C toluene + methylene blue
(cat.); sealed tube / 16h
reaction (see text)
122As oan be seen in Table 2-5 the mixture appears to require approximately 200°C
before any reaction takes place. Unfortunately, the reaction that did take place was not
the desired IMDAC. From ’H and X'C NMR spectra of the crude product mixture, it was
immediately apparent that the dienophile was still present. Somewhat surprisingly, the
TBDMS ether in 157 appeared to have partially to completely hydrolyzed in the reaction,
not surprisingly, the TMS enol ether had also cleaved. Attempts at circumventing this
cleavage through the use o f silylation techniques37 on the sealed tube’s inner surfaces or
the addition o f a small amount o f methylene blue (suggested, in some cases,8 ’’97 to catalyze
DAC reactions) failed to fix the problem. In order for the IMDAC to occur, the diene
would have to be stable to temperatures (and conditio s) sufficient for the reaction to
occur. If the silyl enol ether cleaves prematurely, then clearly an IMDAC cannot take
place.
Purification o f the crude product mixture o f the IMDAC revealed that there were
two sets o f two products in the mixture. Since these compounds appeared to have a
TBDMS ether partly intact, they were treated with fluoride (nBu.iNF) in order to cleave
the silyl ether completely. After this was performed, it became evident that the less polar
set o f products appeared to likely be some sort o f decomposition product. The dienophile
unit appeared to be evident in one o f the compounds and not the other. The determination
that the desired IMDAC had not occurred could immediately be made by the lack o f the
expected methyl singlet at the A/B ring junction (C l9): in dihydrotestosterone, this
resonance would be expected to appear at 1.02 ppm in the 'H NMR and 11.5 ppm in the
l3C NMR (measured in C D C lj)98
The less polar materials, however, appeared to be a little mere interesting. One o f
these compounds appeared to have a methyl ketone intact, and two o f the alkene units in
the starting material 157 were missing. The alkene conjugated to the methyl ketone was
missing, as was the alkene at the C/D ring junction. One could postulate that an
123
intramolecular Michael addition could have occurred to give a product such as 159
(Scheme 2-59). At this stage, the identification remains speculative.
The other product isolated from the reaction seemed to also have the C/D ring
junction alkene missing and the original dienophile still present. In this case, however, a
‘new’ alkene was formed (by *H NMR signal at 5.5 5). It may be possible that an
alternate product, 160, could have been formed. At this stage, however, the structural
assignments remain tentative and will require future generation o f more material before a
definite conclusion can be made as to the structure o f the products.
O
MichaelAddition
OTBDM S
159P H
MichaelAdditionTM SO
157(major isom er shown)
160
Scheme 2-59
What is clear, however, is that the desired IMDAC product, 158, was not formed
in the reaction. Apparently, the temperature required for the DAC to occur would appear
to be higher than the starting material can tolerate without some sort o f decomposition or
side reactions occurring. Unfortunately, the presence o f products o f side reactions
necessitates that a different IMDAC starting material would have to be used if the IMDAC
were to be conducted with the traditional thermal means. One potential solution that
wasn’t tried, due to lack o f starting material 157, was a metal catalyzed route. In the
perhydrophenanthrene synthesis (Section 2.3.3), Wilkinson’s catalyst was employed in an
124
IMDAC reaction54 in which the dienophile was an alkyne. Although a slightly different
catalyst was suggested in literature for IMDAC systems in which the dienophile was an
alkene54 there is still a possibility that the IMDAC of 157 may occur through catalytic
means to obtain 158 as a product. The reduction in reaction temperature possible with
catalytic systems (RT vs 170°C when 66 was used as a starting material) may well prevent
the undesired side reactions from taking place. The only factor to determine (and
unfortunately this must be determined experimentally) is that the reaction, if it does take
place, is selective for the generation o f the desired stereochemistry at the A/B ring
junction.
1252.7: Future Research:
Unfortunately, the generation o f a tetracyclic steroidal skeleton via a sequential
Diels-Alder pathway is a goal that has, to date, eluded this project. However, the
alternate sequential Diels-Alder strategy (Section 2.6) is vety close to achieving this goal.
In fact, if the strategy had achieved the goal o f conducting the IMDAC with 157, then
there would only be three more steps to do to reach dihydrotestosterone (Scheme 2-45).
This, combined with the fourteen steps to synthetically reach 157, would enable a
stereoselective steroid synthesis in only seventeen steps. So, the paramount goal in the
project in the future will likely be the generation o f the tetracyclic steroidal skeleton from
the IMDAC. As suggested in section 2.6, perhaps the first strategy that should be
attempted would be the catalysis o f the reaction with low valent rhodium complexes.34
If the attempts at catalyzing the IMDAC are unsuccessful, then perhaps the best
strategy would be to electronically activate the dienophile in such a way that the
temperature required for the reaction to occur would be much lower than before (200°C).
Hopefully, this strategy will overcome the decomposition and side reactions that occurred
when the unactivated dienophile was used in the IMDAC. Perhaps the most sucessful way
to achieve such a goal might be through the use o f a palladium catalyzed reaction. I f it
were possible to generate the enol triflate (161) from the ketone in the cycloadduct 138,
then perhaps methyl chloroformate could be added via a palladium catalyzed Heck-type
reaction.49,30 As shown in Scheme 2-60, such a strategy would serve to activate the
dienophile, as seen in structure 162. Following generation o f the second diene unit, to
give 163, and subsequent IMDAC, the versatile ester group (described previously) would
be located at the A/B ring junction in 164. Also, as shown in the scheme, the ester group
might ‘aid’ the stereoselectivity o f the reaction through the endo-efleet that would only be
present with the desired transition state geometry.
126
OTBDMS1. Base2. TfjO
OTBDMS
CIC(0)0CHj
o H138
(major isomer)
TfO
OTDDMS
H Pd catalyst
OTBDMS
Generation of second diene unit
H3CO2C 162 h 3c o 2c
OTMS
OTBDMSTMSO
Expected Transition S tate Geometry
Scheme 2-60
164
OTBDMS
Another factor that makes the generation o f the tetracyclic skeleton through the
alternate sequential Diels-Alder strategy appealing is the fact that recent studies in the
Spino research group" have shown that the cycloisomerization starting material 111 can
be generated in a chiral form (93% ee) from a BINAL reduction100 o f the ketone 112.
Although, to date, this sequence would add two steps to the total synthesis, it may be
possible to add an acetylide equivalent to the aldehyde 109 in a chiral fashion through the
use o f a chiral boron reagent developed by Corey. 101 If possible, this sequence would not
add any steps to the sequence, and should allow for an extremely efficient and
enantioselective route to a number c l steroid natural products.
Another route that may be worthy o f consideration in the route towards steroid
natural products would be the continued development o f the enyne/bis-diene route
(section 2.5). Although development o f a second diene unit from the cycloisomerization
127product 118 was not achieved in synthetically useful yields, perhaps the hydrozirconation
methodology used in the alternate strategy could be applied. If this strategy enables a
good-yielding route to the second diene unit, then the sequential Diels-Alder reactions
could likely be applied to this system to generate 164 as a product: the A/B/C ring system
should be generated in a stereoselective fashion based on the results o f the enyne/model
bis diene studies (section 2.3.3).
Third in order o f priority would likely be the generation o f new acyclic bis-dienes.
Although this system proved difficult to generate, it would still be an interesting exercise
to determine if the sequential Diels-Alder reactions (using the enyne 63) could be
performed on such a system.
Finally, the last potential route developed in this project that might lead to
tetracyclic steroid-like systems would be the reaction of enyne 63 with mode! bis diene 41.
Although the tricyclic perhydrophenanthrene skeleton generated through this strategy (69:
see section 2.3 .3) contained an alkene that potentially could be used as a synthetic ‘handle’
for the generation o f the D-ring, regioselectivity may pose a probh. m. If the two ‘ends’ of
the alkene were to be made different from each other (electronically) through appropriate
modification of the bis-diene 41, then perhaps the D-ring could be added in a
regioselective manner.
128
CHAPTER THREE: CONCLUSIONS
A novel synthetic strategy has been developed for the generation of the
perhydrophenanthrene skeleton through sequential Diels-Alder reactions on a 1,3,7,9-
tetraene. This strategy allows for the efficient and stereoselective generation o f the
equivalent to the steroidal A/B/C ring system.
Although the above strategy could not be employed in the attempted synthesis o f a
steroid natural product (dihydrotestosterone), due to inability to overcome undesired
‘side’-reactivity during the generation o f the second, electronically activated diene
fragment, a similar strategy was developed which also employed sequential Diels-Alder
reactions. Unfortunately, the synthesis was not completed, using this alternate strategy,
due mainly to difficulties encountered in the second, intramolecular, Diels-Alder reaction,
which would have generated a tetracyclic skeleton. However, modification o f the
dienophile fragment (electronic activation) in the intramolecular Diels-Alder reaction may
well allow for this strategy to still be employed in the future for a successful total
synthesis (potentially in an enantioselective manner).
Although not directly related to the project, studies using carbomethoxybutadiene
(initially thought o f as a bis-dienophile) showed that the molecule is, in fact, an
electronically activated diene showing reactivity in [4+2] cycloadditions on the same order
as some well known highly reactive dienes. Even though the exact origin o f the reactivity
is not known, a series o f reactions has proven that the reactivity enhancement must be
electronic in nature.
129
CHAPTER FOUR:
EXPERIMENTAL
General Procedure:
All reactions were performed under an atmosphere o f argon or nitrogen (unless
otherwise stated). The solvents were distilled under a nitrogen atmosphere from sodium
before use (using benzophenone as an indicator), with the exception o f di- and
tetrachloromethane, amine-based solvents and dimethyl sulfoxide, which were distilled
without an indicat j r from calcium hydride. Glassware was generally assembled while still
hot from a 110-120°C oven, and was allowed to cool while being flushed with argon. All
reagents were used as received from the suppliers without further purification (unless
otherwise stated).
Solvent removal was generally performed via rotary evaporation, with a water
aspirator supplying vacuum, using a 40°C water bath temperature (unless higher
temperatures were required: toluene, for example required a 60°C water bath). Flash
column chromatography was done using Merck 60 silica gel: 230-400 mesh. Generally,
between 1-5 psi o f air pressure was supplied to the column to increase the speed o f
elution. Resolution o f the eluate fractions was done through thin layer chromatography
(aluminum or glass plates coated with 0.2 mm silica gel: EM separations Kieselgel 60 F234)
with resolution of'spots' via ultra-violet irradiation and also by chemical staining (vanillin
or phosphomolybdic acid-based stains). Preparative TLC was performed using the same
plates,
Nuclear magnetic resonance was performed using the following instruments:
Bruker AMX 360 (360 MHz 'H, 90.56 MHz ,3C), Broker AM 300 (300 MHz 'H , 75.5
130
MHz ,3C) and Briiker WM 250 (250 MHz ’H, 62.89 MHz l3C). Generally,
deuterochloroform was used as a solvent with the residual chloroform peak providing a
chemical shift reference (7.24 ppm for 'H, 77.0 ppm for 13C). Chemical shifts are
reported in ppm (8 ) and coupling in Hz, with the following abbreviations used for various
splitting patterns: s, singlet; d, doublet; t, triplet; q, quartet; qi, quintet; m, multipiet.
Infra-red analysis was done using sodium chloride solution cells, with chloroform
as a solvent, on the following instruments: Perkin Elmer Paragon 1000 FT-IR, Briiker
IFS-25 FT-IR or a Perkin-Elmer 1330 IR. Absorption descriptions are as follows: s,
strong; m, medium; w, weak; sh, sharp; br, broad. Low resolution mass spectra were
recorded on a Finnigan 3300 GC/MS with ionization provided by either 70 eV electron
impact, or methane (or ammonia) chemical ionization. High resolution mass spectra were
recorded on a Kratos Concept-H double focusing mass spectrometer using 70 eV electron
impact for ionization. Gas chromatography was performed on a Perkin-Elmer
AutoSystem Gas Chromatograph using a 15m, 0.25mm (inner diameter) DB-1 capillary
column and an FID detector. Melting points are uncorrected and were done on a Reichart
7905 Melting point apparatus using open capillary tubes.
EXPERIMENTAL PROCEDURES f IN NUMERICAL ORDER!:
l,4-Pentadien-3-ol (36).
OHTo a -78°C solution o f vinylmagnesium bromide (1.0 M solution in THF, 265 mL,
265 mmol) in THF (600 mL) was added acrolein (11.9 mL, 177 mmol) over a period o f
ten minutes. The resulting solution was then stirred at -78°C for 2.5 hours, at which point
a saturated solution o f ammonium chloride (200 mL) was added and the solution was
131
allowed to warm to room temperature. Following separation o f the organic and aqueous
layers (which may require the addition o f some IN HC1 and water to clarify the layers for
ease o f separation), the aqueous layer was extracted three times with diethyl ether. The
combined organic fractions were then dried over anhydrous magnesium sulfate and
filtered. Removal o f most o f the solvent was accomplished through distillation using a
Claisen head. When approximately 30 mL o f solution remained, it was transferred to a
micro-distillation apparatus (preferably with a 4-5 cm Vigreux column), and was
fractionally distilled. The product 36 was obtained as a colourless odiferous oil with a b.p.
o f 115-116°C in a yield o f 87%. The spectral data for the product was identical to that o f
the commercial material (Aldrich Chemical Company (Catalog #32,466-3)).
Ethyl (E)-hepta-4,6-dienoate (37).
O
V 'V \A < /\l,4-Pentadien-3-ol (14.9 g, 177 mmol), triethyl orthoacetate (227 mL, 1.24 mol)
and propionic acid (2.60 mL, 35 mmol) were refluxed in toluene overnight. Toluene was
then removed by rotary evaporation to yield a yellow oil which was subsequently distilled
under vacuum (0.1 mm Hg) to afford the product (b.p. 60-75°C), which was further
purified by a bulb-to-bulb (Kugelrohr) distillation to give a pale yellow oil in a 73% yield
(19.9g). The spectral data for the product is as follows: 'H NMR (250 MHz, CDCb): 8
6.26 (di, 1H, J=16.8, 10.2 Hz), 6.07 (m, 1H), 5.67 (m, 1H), 5.08 (dd, 1H, J=16.9, 1.6
Hz), 4.96 (dd, 1H, J=10.2, 1.6 Hz), 4.10 (q, 2H, J=7 ( Hz), 2.39 (m, 4H), 1.24 (t, 3H,
J=7.1 Hz). I3C NMR (62.89 MHz, CDC13): 8 172.3 (s), 138.6 (d), 132.6 (d), 131.9 (d),
115.6 (t), 60.2 (t), 33.8 (t), 27.2 (t), 14.1 (q); IR (CHCIj, c m 1) 3070 (w), 2970 (br), 1710
(br), 1590 (w), 1435 (w), 1365 (m), 1175 (br); LRMS (Cl) m/e (relative intensity): 169
(M+15, 31), 165 (M + ll, 32), 155 (M +l, 100), 119 (45), 109 (31), 81 (77), 67 (37);
132
HRMS calcd for C9H u0 2: 154.0994, found: 154.1007. Anal. Calcd for C9H M0 2: C,
70.11; H, 9.15, found: C, 70.02; H, 8.83.
(E)-Hepta-4,6-dien-l-ol (38).
Ethyl (E)-hepta-4,6-dienoate (37: 14g, 92 mmol, dissolved in 30mL THF) was
added to a stirred 0°C solution o f UAIH4 (3.5g, 92mmol) in 500mL THF. After stirring
for one hour, the reaction was quenched with distilled water, A solution of IN HC1 was
added to clarify the organic and aqueous layers. Following separation o f the aqueous and
organic layers, the aquous layer was extracted three times with diethyl ether. The
combined organic fractions were then dried over anhydrous M gS04 and concentrated by
rotary evaproation. The pure alcohol (8.54g, 83% yield) was obtained by Kugelrohr
distillation (product collected at 60-70°C at 0.1 mmHg). Spectral data is as follows: 'FI
NMR (250 MHz, CDCI3): 8 6.25 (dt, 1H, J=16.8, 10.2 Hz), 6,06 (m, 1H), 5,65 (dt, 1H,
J=16.8, 6.9 Hz), 5.06 (dd, 1H, J=16.9, 1.6 Hz), 4.93 (dd, 1H, J=10.2, 1.6 Hz), 3.59 (t,
2H, J=6.9 Hz), 2.11 (m, 3H), 1.63 (m, 2H). I3C NMR (90.56 MHz, CDCI3): 8 137.0 (d),
134.3 (d), 131.3 (d), 114.9 (t), 61.7 (t), 31.8 (t), 28.7 (t); IR (CHCI3, cm ') 3615 (s),
3470 (br), 3080 (m), 3000 (s), 2945 (s), 1645 (m), 1600 (m); LRMS m/e (relative
intensity): 113 (M+1,10), 99 (57), 95 (M-17, 100), 71 (32); HRMS calcd for C7H 120 :
112.0900, found: 112.0888. Anal. Calcd for C7H,20 : C, 74.94; H, 10,79, found: C,
75.01; H, 10.98.
133
(E)-Hepta-4,6-dienal (39).
Oxalyl chloride (7.28 mL, 78.S mmol) was added to a -60°C solution o f dimethyl
sulfoxide (5.92 mL, 78.5 mmol) in 500mL THF and the mixture was stirred for 15
minutes. Hepta-4,6-dien-l-ol (8.0g, 71.3 mmol) was then added slowly, and the mixture
was allowed to stir for a further 15 minutes. Triethylamine (31.7 mL, 215 mmol) was then
added, and the reaction was allowed to warm to room temperature and stir for 30 minutes.
The reaction was worked-up with IN HC1, the aqueous and organic phases were
separated, and the aqueous layer was extracted with diethyl ether. The combined organic
layers were then dried over anhydrous magnesium sulfate and concentrated by rotary
evaporation to afford crude hepta-4,6-dienal (39), which was used immediately, without
further purification, in the generation o f 40 (assuming, for calculation o f reagents in the
next reaction, that the aldehyde 39 was generated in quantitative yield).
(E, E)-Deca-3,7,9-trien-2-one (40).
Dimethyl-(2-oxopropyl)phosphonat« (11.6 mL, 83.4 mmol) was added to a 0°C
solution o f sodium hydride (3.34 g, 83.4 mmol) in 300mL THF, and the resulting mixture
was stirred for 60 minutes. The crude (E)-hepta-4,6-dienal (39: 78,5 mmol in 15mL THF)
134
was then added to the reaction via canula. After stirring for a further two hours, the
reaction was quenched with water (to aid clarification, IN HC1 was added as well). The
aqueous and organic layers were then separated, the aqueous layer extracted with diethyl
ether and the combined organic layers were dried over anhydrous magnesium sulfate.
Following concentration o f the organic layer by rotary evaporation, the residue was
chromatographed on silica gel (400g) using a 9:1 mixture o f hexanes:ethyl acetate as an
eluent. The product ketone was isolated in a 76% yield (8,98g, calculated from (E)-hepta-
4,6-dien-l-ol). Spectral data is as follows: 'H NMR (250 MHz, CDC13): 6 6.70 (dt, 1H,
J=16.0, 6.5 Hz), 6.24 (dt, 1H, J=16.7, 10.1 Hz), 6.02-5,90 (m, 2H), 5.59 (dt, 1H, J=16.1,
6.9 Hz), 5.08 (dd, 1H, J=16,7, 1.6 Hz), 4.92 (dd, 1H, J=10.1, 1.6 Hz), 2.25 (m, 4H), 2.15
(s, 3H). 13C NMR (62.89 MHz, CDClj). 6 198.5 (s), 147,2 (d), 136.9 (d), 132.9 (d),
131.7 (d), 115.7 (t), 32.0 (t), 31.0 (t), 26.9 (q); IR (CHC13, cm'1) 3090 (w), 3000 (si.
2930 (s), 1665 (s), 1625 (s), 1425 (br), 1360 (m); LRMS m/e (relative intensity): 151
(M +l, 12), 107 (15), 92 (13), 79 ( 1 0 ), 67 ( 1 0 0 ); HRMS ealed for C,„H140 : 150.10452,
found: 150.10578. Anal. Calcd for C,0HuO: C, 79.94; H, 9,40, found: C, 7 9 .8 8 ; H, 9.32.
(E,E)-2-Trimethy Isiloxy deca-1,3,7,9-tetraene (41).
TM SO
n-Butyllithium (2.0 mL, 4.4 mmol) was added to a -78"C solution o f
diisopropylamine (0.61 mL, 4.4 mmol) in 6 mL of tetrahydrofuran, The mixture was
stirred for 15 minutes, then deca-3,7,9-trien-2-one (40: 600 mg, 4,0 mmol) in 2mL of
THF was added over 5 minutes. After stirring the reaction at -78°C a further 25 minutes,
chlorotrimethylsilane (0.760 mL, 6.0 mmol) was quickly added. The solution was then
allowed to warm to room temperature and was stirred for 60 minutes. The reaction was
worked up with ice-cold distilled water, Addition o f a small amount o f diethyl ether aided
135
separation of the organic and aqueous layers. The aqueous layer was also extracted twice
with ether. The combined organic fractions were then dried over anhydrous magnesium
sulfate, filtered and concentrated by rotary evaporation. Purification was accomplished by
Kugelrohr distillation (collecting the product at 80-90°C at O.lmmHg) to yield a
colourless liquid in an 81% yield (720 mg). Spectral data is as follows: 'H NMR (250
MHz, CDC13): 5 6.28 (dt, 1H, J=16.0, 10.1 Hz), 5.98 (m, 3H), 5.68 (m, 1H), 5.08 (dd,
1H, J=16.7, 1.6 Hz), 4.94 (dd, 1H, J=-10.1f 1.6 Hz), 4.22 (s, 2H), 2.19 (m, 4H), 0.20 (s,
9H). 13C NMR (90.56 MHz, CDC13): 8 154.8 (s), 137.1 (d), 134.2 (d), 131.4 (d), 130.7
(d), 128,1 (d), 115.0 (t), 94.5 (t), 32.1 (t), 31.7 (t), 0 . 0 2 (q); IR (CHC13, c m 1) 3110 (m),
3080 (w), 3000-2880 (br, m), 1650 (m), 1590 (s), 1440,1410 (w), 1315 (s), 1250 (s),
1010 (s), 950 (m), 900 (m), 850 (s); LRMS m/e (relative intensity): 263 (M+41, 3),
251 (M+29, 14), 223 (M +l, 100), 207 (48), 155 (74), 133 (37); HRMS ealed for
C,oH22 0 Si: 222.1441, found: 223.15170 (M +l ealed 223.1519 for C ^ O S i ) .
3-Carbomethoxy-2,S-dihydrothiophene-l,1-dioxide (44).
To a solution o f 3-carbomethoxy-2,5-dihydrothiophene41b (43: 1.45g, 10 mmol) in
ethanol (9 mL) was added a solution o f MMPP (5.18g, 10.5 mmol) in water (10-12 mL
(minimum volume required for solubilization)). The resulting mixture was then heated to
50°C for two hours. After cooling to room temperature, the reaction was quenched with a
saturated solution o f sodium bicarbonate, and was extracted repeatedly with
dichloromethane. The combined organic fractions were then dried over anhydrous
magnesium sulfate and filtered. Removal o f solvent by rotary evaporation (and pumping
o f the colourless residue under vacuum) yielded the product 44 as a white crystalline solid
(mp 54-55°C: literature41* value: 58°C) in a yield o f 90% (745 mg). The spectral data for
136
the product is as follows: lH NMR (90 MHz, CDCI3): 8 6.95 (m, 1H), 3.90 (br s, 4H),
3.75 (s, 3H). IR (CHCb, c m 1): 3050 (w, br), 2960 (w, sh), 1720 (s), 1630 (m), 1440 (m),
1320 (s), 1270 (s), 1130 (m), 1070 (m), 1040 (m), 1000 (m), 910 (s).
3-Methyl-4-carbomethoxy-4-( 1 -ethenyl)cyclohexanone (46);
l,4-Bis-(carbomethoxy)-4-(l-ethenyl)cyclohex-l-ene (47).
c o 2c h
4746
To a solution o f 44 (124 mg, 0.70 mmol) in toluene (4 mL) was added (E)-2-
trimethylsiloxy-l,3-pentadiene35 (35: 655 mg, 4.20 mmol). The resulting solution was
then headed to reflux and stirred for 16 hours. The toluene was then removed under
reduced pressure (rotary evaporation) to give a yellow oil as a residue. In order to cleave
the silyl enol ether prior to chromatography, the residue was dissolved in ethyl acetate ( 8
mL) to which silica gel (1 mL) and concentrated hydrochloric acid (1-2 drops) were
added. After stirring for 90 minutes (monitored by tic), the hydrolysis appeared to be
complete. The mixture was then filtered over a small silica gel pad (approx, 5 mL silica
gel) using ethyl acetate to rinse. Concentration o f the filtrate gave a pale yellow oil which
was then purified by silica gel chromatography, using a 5:1 mixture o f ethyl
acetate:hexancs as an eluent. The desired product 46 was isolated in an 83% yield (156
mg) as a mixture o f two isomers in a 2:1 ratio, and the dimer o f the dienophile 47 was
isolated in a 12% yield (9 mg). Note: if 44 is refluxed alone in toluene (for 3 or more
hours), the dienophile dimer 47 is isolated in a 96% yield. The spectral data for the cross
cycloadduct 46 is as follows: 'H NMR (360 MHz, CDCI3): Major Isomer: 8 5,95 (dd, 1H,
137
J= ll , 17.6 Hz), 5.32 (d, 1H, J=11 Hz), 5.28 (d, 1H, J=17.6 Hz), 3.64 (s, 3H), 2.7-1.9 (m,
7H), 0.92 (d, 3H, J=7.5 Hz). Minor Isomer. 6 5.82 (dd, 1H, J = l l , 17.6 Hz), 5.24 (d, 1H,
J=11 Hz), 5.12 (d, 1H, J=17.6 Hz), 3.70 (s, 3H), 2.8-1.9 (m, 7H), 0.85 (d, 3H, J=7.1 Hz).
I3C NMR (90.56 MHz, CDCfe): Major Isomer: 6 210.5, 173.8, 139.0, 116.9, 52.3, 49.6,
38.5, 38.0,37.3, 27.5, 16.6. Minor Isomer: 6 210.4, 174.5, 137.9, 116.8, 52.0, 51.2, 45.7,
38.0, 37.0, 26.9, 15.4. LRMS (Cl) m/e (relative intensity): 196 (100), 180 (64). The
spectral data for the dienophile dimer 47 is as follows: lH NMR (250 MHz, CDCU): 6.9
(m, 1H), S.85 (dd, 1H, J=17.6, 11 Hz), 5.10 (d, 1H, J = l l Hz), 5.05 (d, 1H, J=17.6 Hz),
3.65 (s, 3H), 3.62 (s, 3H), 2.8-1.7 (m, 6 H).
(3S*, 4S*)-l-Trimethylsiloxy-4-formyl-3-((E)-l,3-hexadien-6-yI)cyclohex-l-ene (54);
(3S*, 4S*)-4-FormyI-3-((E)-l,3-hexadien-6-yl)cyclohexan-l-one (55).
TM SO
5554
3.4:1 mixture o f a : P, with P -H isomer being major isomer (named above),
(E,E)-2-Trimethylsiloxy-deca-l,3,7,9-tetraene (41: 2 2 2 mg, 1 .0 mmol), acrolein
(0,10 mL, 1.5 mmol) and hydroquinone (10 mg) were dissolved in 0.4 mL toluene and
placed in a glass tube which was subsequently sealed under vacuum (contents at liquid
nitrogen temperature). The sealed tube was then placed in a 160°C oven for 60 minutes.
The tube was then allowed to cool, opened at liquid nitrogen temperature and the contents
removed after warming slightly. Most o f the toluene and excess acrolein were removed by
rotary evaporation: a vacuum pump removed the last traces. Purification o f the Diels-
138
Alder adduct was accomplished by flash chromatography (3:1 hexanes: ethyl acetate on 25
g silica gel) to yield the silyl-enol ether 54 in 55% yield (which was often contaminated
with the ketone product 55 due to hydolysis in either the reaction itself or during
chromatography). Complete hydrolysis o f the ether was accomplished as follows: the silyl-
enol ether was dissolved in 5 mL o f ethyl acetate, to which 0.5 g silica gel and 2 drops o f
concentrated HC1 were added. The hydrolysis reached completion after 90 minutes, at
which point the mixture was filtered over approximately 1 0 g silica gel using ethyl acetate
as an eluent. After concentration o f the eluate by rotary evaporation, it was
chromatographed over 10 g silica gel using a 3:1 mixture o f hexanes:ethyl acetate as an
eluent. The product 55 was collected as a pale yellow viscous oil in a 49% yield (46 mg,
measured from 41). The two isomers formed in the reaction were found to be in a 3.4:1
ratio (by gas chromatography) which were inseparable by flash chromatography. The
spectral data for the isomeric mixture o f 55 is as follows: lH NMR (250 MHz, CDC13): 8
9.83 (d, <1H, J=2.1 Hz), 9.67 (d, <1H, J=2.1Hz); 6.25 (ddd, 1H, J=16.9, 10.2, 10.2Hz);
6.02 (dd, 1H, J=15.0, 10.2 Hz); 5.56 (dt, 1H, J=15.0, 7.0Hz); 5.06 (dd, 1H, J=16,9,
1.6Hz); 4.93 (dd, 1H, J=10.2, 1.6Hz); 2.88 (m, <1H); 2.20-2.55 (m, 6 H); 1.90-2.20 (m,
6 H); 1.30-1.60 (m, 2H). 13C NMR (90.56 MHz, CDCI3): 8 209.8 (s), 209.3 (s); 202.9
(d), 202.8 (d); 136.7 (d); 133.2 (d), 133.1 (d); 132.0 (d), 131.9 (d); 115.6 (t); 52.1 (d),
50.3 (d); 44.7 (t), 44. 2 (t); 38.9 (t), 38.8 (t); 37.2 (d), 36.1 (d); 33.4 (t), 30.3 (t); 29.9 (t),
29.1 (t); 23.7 (t), 22.9 (t); IR (CHCfe, cm'1) 3040 (w), 3000 (w), 2750 (w), 1730 (br, s),
1220 (br, m), 920 (m); LRMS m/e (relative intensity) 206 (M+, 25), 188 (13), 125 (20),
67 (100); HRMS calcd for C 13H,80 2 : 206.1307, found: 206.1301.
Methyl phenyl sulfone (56).
PhS02CH3
139In a minimum volume o f ethanol (approximately SmL) was dissolved methyl
phenyl sulfoxide (700 mg, 5 mmol). The solution was then added to a suspension o f
MMPP (1.70 g, 2.75 mmol) in 10 mL water. The mixture was then warmed to 50°C and
stirred for 90 minutes. The reaction was then quenched with a saturated solution o f
sodium bicarbonate, and extracted with ethyl acetate. The combined organic fractions
were then dried over anhydrous magnesium sulfate and filtered. Following removal o f the
solvent by rotary evaporation, the product was obtained as a white crystalline solid (mp
84-85°C) in a 97% yield (758mg). The spectral data for the product is as follows: 'H
NMR (250 MHz, CDC13): 8 7.90 (m, 2H), 7.60 (m, 3H), 3.08 (s, 3H); IR (CHC13, cm*1),
3023 (m), 1316 (m), 1216 (s), 1153 (m, sh), 952 (w, sh), 751 (s, br); LRMS m/e (relative
intensity): 197 (M+41, 2), 185 (M+29, 1), 157 (M +l, 100), 94 (1).
(3S*,4S*)-3-((E)-l,3-hexadien-6-yl)-4-(2-(phenylsulfonyl)-l-hydroxyethyI)
cydohexan-l-one (57).
OH
Major isomer: P-H (named above)
To a -78°C solution o f diisopropylamine (0.082 mL, 0.585 mmol) in 3 mL THF
was slowly added n-butyllithium (2.2 M in hexanes, 0.265 mL, 0.585 mmol). The solution
was allowed to stir at -78°C for 15 minutes, then methyl phenyl sulfone (56: 97 mg, 0.624
mmol, in lmL THF) was added over 5 minutes. The mixture was allowed to stir for 30
minutes, then a solution o f o f 4-formyl-3-((E)-l,3-hexadien-6-yl)cyclohexan-l-one (55:
108 mg, 0.39 mmol) in 1 mL THF was added. The mixture was then slowly warmed to
140
room temperature and stirred overnight. The reaction was quenched with saturated
ammonium chloride and extracted with ethyl acetate. The combined organic fractions
were then dried over anhydrous magnesium sulfate, filtered and concentrated. The residue
was then chromatographed over 12g silica gel using a 3:1 mixture o f hexanes:ethyl acetate
as an eluent. The silyl enol ether is partially hydrolyzed during chromatography to give a
44% yield o f product (74 mg) with the enol ether intact and 33% (47 mg) o f the product
in the keto form: in both cases, the product is a gummy yellow foam-like material. The
enol ether can be readily converted to the keto-product by treatment with a catalytic
amount o f concentrated HC1 (1 drop) in ethyl acetate containing silica gel (roughly lmL
per 100 mg product). The spectral data for the products are as follows: Silyl enol ether:
*H NMR (250 MHz, CDC13): 6 7.85 (m, 2H), 7.60 (m, 3H), 6.25 (m, 1H), 5.90 (m, 1H),
' 5.80-5.40 (m, 2H), 5.10-4.88 (m, 2H), 4.78 (m, 1H), 4.20 (br s, 1H), 4.05 (m, <1H), 3.85
(m, <1H), 3.60-3.00 (m, 3H), 2.10-1.10 (m, 8 H). Ketone product: 'H NMR (250 MHz,
CDCI3): 8 7.85 (m, 2H), 7.60 (m, 3H), 6.25 (m, 1H), 5.90 (m, 1H), 5.60 (m, <1H), 5.40
(m, <1H), 5.05 (d, 1H, J=16.9 Hz), 4.95 (dd, 1H, J=10.1 Hz), 4.30 (m, 1H), 3,60 (m,
1H), 3.20-3.00 (m, 2H), 2.60-0.90 (m, 10H).
(3SMS*)-3-((E)-l,3-Hexadien-6-yl)-4-((E)-2-(phenylsulfonyl)-ethen-l-yl)
cydohexan-l-one (58).
Major isomer: P~H (named above)
To a 0°C solution o f 3-((E)-l,3-hexadien-6-yl)-4-(2-(phenylsulfonyl)-l-
hydroxyethyl)cyclohexan-l-one (57: 75mg, 0.212mmol) in lOmL dry dichloromethane
141was added triethylamine (0 050mL, 0.346mmol) and methanesulfonyl chloride (0.020mL,
0.260mmol). The mixture was then allowed to warm slowly to room temperature and was
stirred overnight (16 hours). The reaction was then quenched with IN HC1 (5 mL) and
extracted with ethyl acetate. The combined organic fractions were then dried over
anhydrous magnesium sulfate, filtered, and concentrated by rotary evaporation.
Purification was accomplished by silica gel flash chromatography (1:1 hexanes: ethyl
acetate on Sg silica gel). The product was obtained as a viscous pale yellow oil which
contained an inseparable mixture o f isomers in a 49% yield (36 mg (37% of the starting
material recovered and used later (yield 73% based on starting material consumed)). The
spectral data for the 2:1 ratio o f isomers (by *H nmr integration) is as follows: 'H NMR
(360 MHz, CDCI3): (*denotes major isomer, ** denotes minor isomer; otherwise, both
isomers) 8 7.85 (m, 2H), 7.60 (m, 3H), 7.10 (dd, <1H*, J=15.3, 7.3 Hz), 6.80 (dd,
<1H**, J=14.9, 9.4 Hz), 6.39 (dd, 1H, J=15.1, 1.3 Hz), 6.21 (dt, 1H, J=16.9, 10.1 Hz),
5.92 (m, 1H), 5.48 (m, 1H), 5.05 (dd, 1H, J=16.9 ,1.2 Hz), 4.95 (dd, 1H, J=10.1, 1.2 Hz),
2.90 (m, 1H), 2.70-1.30 (m, 11H). 13C NMR (90.56 MHz, CDC13): 8 (both isomers) 209.3
(s), 209.1 (s), 149.0 (d), 145.5 (d), 140.2 (s), 140.1 (s), 136.7 (d), 133.4 (d), 133.3 (d),
133.2 (d), 132.2 (d), 131.7 (d), 131.6 (d), 129.3 (d), 127.4 (d), 115.5 (t), 45.1 (t), 44.1
(t), 44.0 (d), 41.3 (d), 40.0 (d), 39.8 (d), 39.6 (t), 38.2 (t), 33.8 (t), 30.6 (t), 30.3 (t), 29.5
(t), 28.5 (t), 27.6 (t); IR (CHC13, cm*1) 3020 (s, sh), 2936 (m), 1722 (s), 1446 (m, sh),
1362 (m, sh), 1310 (m), 1236 (s), 1144 (s) 1078 (m, sh), 1044 (m), 984 (m), 910 (m);
LRMS m/e (relative intensity): 385 (M+41, 12), 373 (M+29, 25), 345 (M +l, 100), 203
(77), 143 (39); HRMS calcd for C20H24O3S: 344.1447 found: 344.14315.
14-(Phenylsulfonyl)tricyclo[8.4.0.02’7]tetradec-l l-en-5-one (59).
142
3-((E)-1,3-Hexadien-6~yl)-4-((E)-2-(phenylsulfonyl)ethen- 1 -yl)cyclohexan- 1 -one
(58: 58mg, 0.168 mmol) was dissolved in 5mL of toluene and refluxed for 18 hours.
After cooling, the toluene was removed by rotary evaporation, and the residue was
chromatographed over 5g o f silica gel (flash chromatography) using 5:1 hexanes:ethyl
acetate as an eluent. The two isomers o f starting material each yielded two isomers
following cycloaddition. Thus, the product was obtained as two sets o f two inseparable
isomers (in yields o f 52% (30 mg (ratio o f isomers 2.8:1 by gc)) and 30% (17.4 mg (ratio
o f isomers 2.2:1 by gc)) respectively). Each set o f two isomers could be recrystallized
from an ethyl acetate/hexanes mixture. From the major starting material isomer, the
spectral data for the white crystalline solid (mp 198-202°C (dec)) is as follows: 'H NMR
(360 MHz, CDCb): 6 7.85 (m, 2H), 7.60 (m, 3H), 5.62 (m, 2H), 3.42 (m, 1H), 3.08 (m,
1H), 2.59-1.10 (m, 15H). 13C NMR (90.56 MHz, CDCI3): 8 (major isomer) 210,2, 138.8,
134.7, 133.6, 131.8, 129.3, 128.4, 126.0, 122.9, 60.0, 48.2, 42.9, 41.0, 38,5, 37.5, 31.1,
30.3, 30.0, 29.4, 20.6. (minor isomer) 210.4, 138.5, 133.6, 129.2, 129.1, 128.8, 127.4,
125.0, 124.0, 65.0, 64.8, 48.3, 44.1, 43.6, 41.3, 40.1, 34.1, 31,3, 30.9, 24.6; IR (CHCI3 ,
cm’1) 3000 (w), 2910 (m), 2850 (w), 1700 (s), 1440 (m), 1300 (m, sh), 1210 (m, br),
1140 (s), 1070 (m), 900 (w), 670 (m, br); LRMS m/e (relative intensity): 344 (4), 202
(100), 145 (6 ), 91 (12), 51 (11). HRMS calcd for C20H24O3 S: 344.1447, found:
344.1433. Anal. Calcd for C20H24O3S: C, 69.74, H, 7.02; O, 13,93; S, 9.31, found: C,
69.15; H, 6.96; O, 14.01.
The spectral data for the minor isomeric mixture (white crystalline solid, mp 196-
199°C (dec)) is as follows: lH NMR (360 MHz, CDCI3): 8 7.85 (m, 2H), 7.60 (m, 3H),
5.55 (m, 2H), 3.54 (m, 1H), 3.10 (m, 1H), 2.60-1.20 (m, 15H). I3C NMR (90.56 MHz,
CDCI3): 8 (major isomer) 211.7, 138.8, 134.2, 133.7, 131.7, 129.2, 128.5, 127.3, 1 2 2 ,1,
58.5, 44.4, 43.9, 39.3., 38.8, 37.3, 32.3, 29.4, 29.0, 27.3, 26.1. (minor isomer) 212.8,
138.7, 138.6, 133.7, 131.6, 129.3, 128.4, 125.0, 121.9,65.0,44.5,43.4, 42.9, 38.9, 38.4,
143
37.0, 33.5, 28.9, 26.9, 26.4; LRMS m/e (relative intensity): 344 (4), 203 (25), 202 (100),
143 (4), 104 (4), 91 (12), 51 (11); HRMS calcd for C20H24O3S: 344.1447, found:
344.1428.
(3S*,4S*)-3-((E)-l,3-Hexadien-6-yl)-4-((E)-2-(carbomethoxy)ethen-l-yl)cyclohexan-
1 -one (60).
Major isomer: P-H (named above)
To 5mL of anhydrous THF was added NaH (21mg, 0.52mmol (60% dispersion in
mineral oil)). The mixture was then cooled to 0°C (under argon) and methyl diethyl
phosphonoacetate (0.094mL, 0.49mmol) was slowly added. The reaction was then
allowed to stir for one hour, then l-trimethylsiloxy-4-formyl-3-((E)-l,3-hexadien-6-
yl)cyclohex-l-ene (54: 132mg, 0.47mmol) was slowly added. The mixture was then
allowed to stir for a further two hours at 0°C. The reaction was quenched with IN HC1
and extracted with ethyl acetate. The combined organic fractions were then combined and
dried over anhydrous magnesium sulfate, filtered, and concentrated by rotary evaporation.
Purification was accomplished by flash chromatography (3:1 hexanes:ethyl acetate on ISg
silica gel). A pale yellow viscous oil containing an inseparable mixture o f isomers (3:1
ratio) was obtained in a 61% yield (75 mg). The spectral data for the mixture is as follows:
*H NMR (360 MHz, CDCI3): ('"denotes major isomer, ** denotes minor isomer;
otherwise, both isomers) 8 7.06 (dd, <1H*, J=15.7,7.6 Hz), 6.74 (dd, <1H**, J=15.7, 8 .6
Hz), 6.2! (ddd, 1H, J=16.9, 10.1, 10.1 Hz), 5.92 (m, 2H), 5.53 (m, 1H), 5.03 (dd, 1H,
J=16.8, 1.2 Hz), 4.91 (dd, 1H, J=10.1, 1.2 Hz), 3.70 (s, <3H*), 3.69 (s, <3H*"), 2.70-
144
1.10 (m, 12H). 13C NMR (90.56 MHz, CDC13): 8 209.9 (s*), 209.8 (s**), 166.4 (s),
1172 (m, sh). LRMS m/e (relative intensity): 291 (M+29, 8 ), 263 (M +l, 100), 245 (4),
231 (5), 203 (18). HRMS calcd for C,6H220 3 262.1570, found: 262.1576.
!4-(Carbomethoxy)tricyclo[8.4.0.03'7]tetradec-l l-en-5-one (61).
To a solution o f o f 3-((E)-l,3-hexadien-6-yl)-4-(2-(carbomethoxy)ethen-l-yl)-
cyclohexan-l-one (60: 67 mg, 0.260 mmol) in dichloromethane ( 8 mL) was slowly added
dimethylaluminum chloride (1.0 M in toluene, 0.6L4 mL, 0.624 mmol) under an argon
atmosphere. The reaction was then allowed to stir for 45 hours at room temperature,
Approximately 2mL o f IN HC1 was then slowly added to the reaction mixture. Following
separation o f the organic and aqueous layers, the organic layer was extracted twice with
ethyl acetate. The combined organic fractions were then dried over anhydrous magnesium
sulfate and filtered. The solvent was removed by rotary evaporation, and the residue was
chromatographed over 7g silica gel using a 5:1 mixture o f hexanes:ethyl acetate as an
eluent. The product was obtained as four isomers (59.6mg, 89%); the major isomer was
separated from the other isomers as a viscous yellow liquid (26,6 mg, 40%) and was
characterized as follows: lH NMR (250 MHz, CDCI3): 8 5.65-5.50 (m, 1H), 5.45-5.35
150.5 (d**), 147.4 (d*), 136.7 (d), 133.6 (d), 131.6 (d*), 131.5 (d**), 122.7 (d*), 122.0
(d**), 115.3 (t), 51.5 (q), 45.2 (d**), 44.7 (d**), 44.1 (t*), 41.3 (d**), 40.2 (d*), 40,1
(d*), 39.9 (t*), 38.1 (t**), 33.9 (t**), 31.0 (t**), 30.8 (t*), 29.6 (t*), 28.7 (t**), 28.5
(t*); IR (CHClj, cm-') 3005 (m), 2920 (m), 1725 (s), 1661 (m, sh), 1423 (m, sh), 1260 (s),
(m, 1H), 3.60 (s, 3H), 2.43-2.20 (m, 3H), 2.05-1.15 (m, 14H), :JC NMR (90.56 MHz,
CDCfe): 8 177.7 (s), 171.0 (s), 132.4 (d), 123.6 (d), 51.5 (q), 45.5 (d), 41.9 (d), 41.7 (t),
145
37.1 (d), 36.1 (d), 35.3 (t), 31.9 (t), 31.2 (t), 28.3 (t), 26.5 (t), 26.3 (d); IR (CHC13, cm ')
3000 (m), 2920 (s), 1720 (s), 1429 (m, sh), 1371 (m, sh), 1327 (s), 1161 (m), 1044 (m);
LRMS m/e (relative intensity): 303 (M+41, 11), 291 (M+29, 21), 263 (M +l, 83), 261
(100), 249 (16), 203 (26), 201 (23). HRMS calcd for C ^ O j : 262.1570, found:
262.1581.
Methyl 2-bromoacrylate (62).
To a 0°C solution of methyl acrylate (10.80 mL, 120 mmol) in 500 mL o f distilled
carbon tetrachloride was slowly added (over 45 minutes) a solution o f bromine (6.54 mL,
127 mmol) in 50 mL o f carbon tetrachloride. The resulting brown solution was allowed to
slowly warm to room temperature and was then stirred for 24 hours. Then triethylamine
(27 mL, 192 mmol) was added to the solution and the mixture was allowed to stir a
further 4 hours. The reaction was then worked up with 1 N HC1 (50 mL) and extracted
with dichloromethane. The combined organic fractions were washed with brine, dried
over anhydrous magnesium sulfate and filtered. To the dried organic fractions was added
50mg o f recrystallized 4-methoxyphenol as a polymerization inhibitor. The volume o f the
organic solution was reduced to approximately 50 mL via distillation at atmospheric
pressure (using a Claisen head). The resulting solution was then purified via a fractional
distillation, using a 10 cm Vigreux column and a water aspirator. NOTE: approximately
lOmg o f 4-methoxyphenol was added to each receiver flask. The product was collected as
a very pale yellow viscous liquid (which has a boiling point (at water aspirator vacuum) of
88-90°C) in a yield o f 61% (12,0g), NOTE: over time, the neat bromoacrylate will tend to
polymerize to form a transparent plastic-like material. The spectral data for the product is
146as follows: *NMR (250 MHz, CDC13): 8 6.90 (d, 1H, J=lHz), 6.25 (d, 1H, J=lHz), 3.78
(s,3H).
Methyl 2-(2-(trimethylsilyl)ethyn-l-yl)acrylate (63).
S i(C H 3)3
To lOtnL o f distilled, argon-flushed triethylamine were added the following
compounds in order: 4-methoxyphenol (5 mg), copper(I) iodide (10 mg, 0.05 mmol), bis-
(triphenylphosphine) palladium(II) chloride (70 mg, 0.10 mmol), methyl 2-bromoacrylate
(62: 660 mg, 4 mmol), and finally trimethylsilylacetylene (0.680 mL, 5 mmol). Following
addition o f the trimethylsilylacetylene, the reaction mixture changed colour (over
approximately a 5 minute period) from yellow to a greenish-blue and eventually to a
reddish-brown. The flask was then wrapped in aluminum foil (to exclude light) and fitted
with a condenser (to prevent loss o f the volatile trimethylsilylacetylene), The mixture was
then allowed to stir for 20 hours. The resulting brown reaction mixture was then filtered,
washing the solid material with ethyl acetate. The filtrate was then concentrated by rotary
evapotation and the residue was chromatographed over 60g o f silica gel, using a 5:1
mixture o f hexanes:ethyl acetate as an eluent. The product was obtained in a 76% yield as
a yellow oil in about 80% purity (contaminated with the starting material 62). NOTE:
approximately 5 mg o f 4-methoxyphenol should be added to the neat product before
storage to prevent polymerization: it appears to be stable, however, if stored as a solution
in ethyl acetate. The spectral data for the product is as follows; 'H NMR (360 MHz,
CDCb) 8 6.57 (d, 1H, J=1.5 Hz), 6.09 (d, 1H, J=1.5 Hz), 3.78 (s, 3H), 0.20 (s, 9H). ,3C
NMR (90.56 MHz, CDCb) 8 164.3, 135.1, 123.8, 99.6, 97,9, 52.5, -0,4; IR (CHCIj,
147
cm'1) 3023 (m), 2961 (m), 2258 (w), 2157 (w), 2057 (w), 1731 (s), 1442 (m), 1379 (m),
1254 (s) LRMS m/e (relative intensity) 223 (M+41, 1), 211 (M+29, 4), 183 (M +l, 40),
167 (26), 89 (100), 79 (13). HRMS calcd for CgHuOzSi: 182.0763, found: 182.0768.
(3R*,4S*)-4-Carbomethoxy-3-((E)-l,3-hexadien-6-yl)-4-(2-(triinethylsilyl)ethyn-l-
yl)cydohexan-l-one (65).
TM S
Mixture o f isomers at C3: major isomer shown (and named)
Into 6 mL toluene were dissolved 2-trimethylsi!oxydeca-l,3,7,9-tetraene (41:
95mg, 0.43 mmol) and methyl 2-(2-(trimethylsilyl)ethyn-l-yl)acrylate (63: 8 8 mg, 0.43
mmol (76% pure by weight)). The mixture was then heated to reflux under argon and
stirred for 16 hours. The toluene was then removed by rotaiy evaporation and the residue
was chromatographed on lOg silica gel using 5:1 hexanes:ethyl acetate as an eluent. The
product was obtained as a mixture o f isomers (in a 5.8:1 ratio (average over 3 reactions))
as a yellow viscous oil in a yield o f 67% (96mg). The spectral data for the product is as
follows. ‘H NMR (250 MHz, CDCI,): S 6.24 (m, 1H), 6 . 0 0 (dd, 1H, J=15.1, 10.2 Hz),
5.55 (m, 1H), 5.06 (dd, J=16,9 ,1.6 Hz), 4.94 (dd, 1H, J=10.1 Hz), 3.75 (s, 3H), 2.95 (dd,
IH, J=14,0, 4.6 Hz), 2.75-1.80 (m, 11H), 1.60-1.10 (m, 2H), 0.15 (s, 9H). ,3C NMR
(62.89 MHz, CDCIj): (both isomers) S 209.7 (s), 208.7 (s), 171.2 (s), 136.9 (d), 133.6
(d), 133.3 (d), 131,9 (d), 115.4 (t), 115.3 (t), 104.8 (s), 89.5 (s), 52.9 (q), 52.7 (q), 49.7
(s), 46.9 (s), 43.5 (d), 43.0 (d), 42,5 (t), 41.3 (t), 37.5 (t), 37.3 (t), 35.2 (t), 32.2 (t), 30.3
(t), 30,0 (t), 29.7 (t), 29.2 (t), -0,1 (q); IR (CHCI,, cm’1) 3000 (m), 2950 (s), 2162 (w),
148
1722 (s), 1440 (m), 1250 (s), 1230-1200 (in, br), 840 (s); LRMS m/e (relative intensity):
373 (M+41, 5), 361 (M+29, 1 1 ), 333 (M +l, 63), 273 (31), 209 (22), 191 (100), HRMS
calcd for CwHaCfeSi: 332.1808, found: 332.1798.
(3R*,4S*)-4-Carboinethoxy-4-ethynyl-3-((E)-l,3-h»adien-6-yl)cyclohexan-l-one
(66).
H
Mixture o f isomers at C3: major isomer shown (and named)
To a 0°C solution o f tetra-n-butylammonium fluoride (1.0 M in THF, 0,33 mL,
0.33 mmol) in 4 mL THF was slowly added 4-carbomethoxy-3-((E)-l,3-hexadien-6-yl)-4-
{2-(trimethylsilyl)ethyn-l-yl}cyclohexan-i-one (65: 118 mg, 0,34 mmol (in 1 mL THF)),
The reaction was allowed to stir at 0°C for 90 minutes, at which point 2 mL o f a saturated
NaCl solution was added. The organic and aqueous layers were separated, then the
aqueous layer was extracted three times with ethyl acetate. The combined organic
fractions were then dried over magnesium sulfate and concentrated in vacuo. The residue
was then chromatographed over 1 2 g silica gel using a 6 :1 mixture o f hexanes: ethyl
acetate as an eluent. The product was obtained as a pale yellow viscous oil in a 98% yield
(92mg) as two isomers in a 5.5:1 ratio. The spectral data for the major isomer is as
follows: 'H NMR (360 MHz, CDCb): S 6.24 (dt, 1H, J=16.9, 10,1 Hz), 6,00 (dd, 1H,
J=15.0, 10,2 Hz), 5.55 (m, 1H), 5.06 (dd, 1H, J=16.9, 1.6 Hz), 4.93 (dd, 1H, J=10 2, 1.6
Hz), 3.76 (s, 3H), 2.83 (m, 1H), 2.70-1.90 (m, 9H), 1,60-1.15 (m, 2H). UC NMR (90.56
MHz, CDCfe): 6 209.5 (s), 171.0 (s), 136.7 (d), 133.0 (d), 131.9 (d), 115.5 (t), 83.2 (d),
72.7 (s), 52,9 (q), 45.9 (s), 43,4 (t), 41.2 (d), 37.3 (t), 30.4 (t), 29.8 (t), 29.5 (t). IR
149
(CHC13, cm'1) 3312 (s), 3011 (tn), 2948 (m), 2160 (w), 1731 (s), 1442 (m), 1241 (s).
LRMS m/e (relative intensity): 301 (M+41, 4), 289 (M+29, 14), 261 (M +l, 54), 229
(100), 201 (11), 151 (14), 89 (100). HRMS calcd for C,6H2o03: 260.1413, found:
260.1412.
(3/?*,4.V*)-4-Carbomethoxy-4-ethenyl-3-((E)-l,3-hexadien-6-yl)cycloliexan-l-one
(67).
H
Mixture o f isomers at C3: major isomer shown (and named)
To 2mL o f dry ethanol (under argon) was added acid dried zinc dust (163 mg, 2.5
mmol) and 1,2-dibromoethane (3 mL). The mixture was heated until a vigorous reaction
occurred (about 5 minutes o f gentle heating required), then the flask was allowed to cool
for 10 minutes. Another 3mL o f dibromoethane was added, and was then allowed to react
for a further 10 minutes. Then a solution o f CuBr and LiBr in THF was slowly added
(0,56 mL: 0,27 mmol CuBr, 0.66 mmol LiBr (solution was 1.07 M in CuBr and 2.07 M
in LiBr (133 mg/mL and 2 0 0 mg/mL respectively))) . The mixture was heated to reflux
and allowed to reflux for 2 0 minutes, during which time the reaction mixture changed
colour from grey to brown. The reaction mixture was then allowed to cool for 5 minutes,
then 4-carbomethoxy-4-ethynyl-3-((E)-l,3-hexadien-6-yl)cyclohexan-l-one (6 6 : 130 mg,
0.5 mmol) in lmL o f THF was added. The reaction was then heated to reflux, and
allowed to stir, at reflux, for 72 hours. The mixture was then allowed to cool, then 3mL
of a saturated ammonium chloride solution was added. The organic and aqueous layers
150
were separated, then the aqueous layer was extracted twice with diethyl ether. The
combined organic fractions were then dried over anhydrous magnesium sulfate and
concentrated by rotary evaporation. The residue was chromatographed over 13g o f silica
gel using a 9:1 mixture o f hexanes: ethyl acetate as an eluent. The product was isolated as
a viscous yellow oil in a 6 8 % yield ( 8 8 mg). The spectral data is as follows: ‘H NMR
(360MHz, CDCI3): 8 6.24 (dt, 1H, J=16.9, 10.1Hz), 6,00 (dd, 1H, J=15.0, 10.2 Hz), 5,92
(dd, 1H, J=17.6, 10.8 Hz), 5.56 (m, 1H), 5.35 (d, 1H, J=10.7 Hz), 5.19 (d, 1H, 17.6 Hz),
5.06 (dd, 1H, J=16.9, 10.6 Hz), 4.93 (dd, 1H, J=10.2, 1.6 Hz), 3.66 (s, 3H), 2.48-2.10
(m, 9H), ' ,38-1.20 (m, 2H). ,3C NMR (90.56 MHz, CDCI3): 8 210.4 (s), 173,8 (s), 139.0
(d), 136.9 (d), 133.6 (d), 131.7 (d), 117.1 (t), 115.3 (t), 52.1 (q), 51.9 (s), 42.9 (t), 41.2
(t), 37.3 (t), 30.2 (t), 30.1 (t), 28.1 (t). IR (CHCI3, cm'1) 3021 (m), 2937 (m, br), 1722 (s),
1429 (m), 1237 (m, br), 1002 (m). LRMS m/e (relative intensity) 303 (M+41, 6 ), 291
(M+29, 25), 277 (M+15, 5), 263 (M +l, 100), 261 (20), 235 (23), 231 (38), 229 (46), 203
(92), 175 (91). HRMS calcd for C 16H22O3: 262.1570, found: 262.1568.
(1R*, 7S*, 10S*)-l-Carbomethoxytricyclo[8.4.0.0:'7]tetradeca-2,5-dien-12-one (6 8 ).
HMajor isomer shown (and named): minor isomer is CIO epimer
4-Carbomethoxy-4-ethynyl-3 -((E)-1,3 -hexadien-6 -yl)cyclohexan-1 -one (6 6 : 140
mg, 0.54 mmol) and 2.0 mg o f methylene blue were dissolved in 3.0 mL o f toluene and
placed in a glass tube, which was then sealed under high vacuum (at liquid nitrogen
temperature). The tube was then placed in a 170°C oven for 48 hours. After cooling to
151
room temperature, the tube was cooled to liquid nitrogen temperature, opened, and the
contents removed. The toluene was removed by rotary evaporation, and the residue was
chromatographed over 15 g o f silica gel using a 9:1 mixture o f hexanes:ethyi acetate as an
eluent. The product was isolated as 2 isomers in a 5:1 ratio (by nmr) in an 64% yield:
51% (71 mg) o f the major isomer in a pure form (colourless crystalline solid (mp 139-
142°C) after recrystallization from a mixture o f hexanes and ethyl acetate) and 13% (18
mg) o f the minor isomer (which was contaminated with the major isomer). The spectral
data for the major isomer is as follows: *H NMR (360 MHz, CDCI?): 8 5.65-5.58 (m, 2H),
5.53 (ddt, 1H, J= 1.7, 3.4, 10.0 Hz), 3.68 (s, 3H), 2.98 (ddd, 1H, J=15.4, 13.6, 1.0 Hz),
2.75 (m, 2H), 2.60-2.38 (m, 3H), 2.28-2.08 (m, 3H), 1.90-1.65 (m, 3H), 1.49 (ddt, 1H,
J=13.4, 4.1, 2.4Hz), 1.21 (dq, 1H, J=4.3, 12.8 Hz). 13C NMR (90.56 MHz, CDC13): 8
210.4 (s), 173.7 (s), 138.2 (s), 128.8 (d), 122.4 (d), 117.7 (d), 52.0 (q), 51.7 (s), 46.0 (d),
45.0 (t), 38.6 (t), 35.6 (t), 34.9 (t), 32.4 (t), 29.2 (t), 27.0 (t). IR (CHClj, cm'1) 3031 (m),
2926 (m), 1718 (s), 1450 (m), 1433 (m). LRMS m e (relative intensity): 289 (M+29, 5),
261 (M +i, 32), 259 (24), 229 (17), 201 (94), 199 (100); HRMS calcd for C.eHzoOa:
260.1413, found: 262.1400. Anal. Calcd for Ci6H2o03: C, 73.81; H, 7.75, found: C,
74.03; H, 7.77.
(lR*,2S*,7R*,10S*)-l-Carbomethoxytricyclo[8.4.0.02'7|tetradec-5-en-12-one (69)
Major isomer shown (and named): minor isomer is C 10 epimer
152
4-Carbomethoxy-4-ethenyl-3-((E)-l,3-hexadien-6-yl)cyclohexan-l-one (67; 58
mg, 0.22 mmol) and 0.5mg o f methylene blue were dissolved in 2.0 mL o f toluene and
placed in a glass tube, which was then sealed under high vacuum (at liquid nitrogen
temperature). The tube was then placed in a 170°C overt for 48 hours. After cooling to
room temperature, the tube was cooled to liquid nitrogen temperature, opened, and the
contents removed. The toluene was removed by rotary evaporation, and the residue was
chromatographed over 6g o f silica gel using a 9:1 mixture o f hexanes; ethyl acetate as an
eluent. The product was isolated as 2 isomers in a 5.3:1 ratio (by nmr) in an 80% yield:
64% (37mg) o f the major isomer in a pure form and 16% (9mg) o f the minor isomer
(which was contaminated with the major isomer). The spectral data for the major isomer
is as follows: lH NMR (360 MHz, CDC13): 8 5.60 (m, IH), 5.37 (dd, 1H, 1=9.9, 1.9 Hz),
3.70 (s, 3H), 2.75 (ddd, 1H, J=13.3, 6.1, 2.6 Hz), 2.49 (dt, 1H, J=1.0, 14.1 Hz), 2.42-
1.15 (m, 14H), 1.10 (dq, 1H, J=4.3, 12.8 Hz). l3C NMR (90.56 MHz, CDClj): 8 210.5
(s), 173.5 (s), 131.9 (d), 126.0 (d), 51.2 (q), 50.2 (s), 49.0 (d), 45.7 (t), 39.0 (t), 36.5 (d),
34.5 (t), 32.9 (t), 29.1 (t), 26.5 (t), 23.8 (t). IR (CHC13, cm 1) 3000 (m), 2940 (m), 1722
(s), 1451 (m), 1437 (m), 1379 (s, sh), 1253 (s, br). LRMS m/e (relative intensity): 291
(M+29,. 11), 263 (M +l, 100), 260 (11), 231 (4), 203 (41). HRMS calcd for C ^ O j :
262.1570, found: 262.1569. Anal. Calcd for C ^ O j : C, 73.24; H, 8.46, found: C,
73.03; H, 8.40.
Propan-2-one-l-thieI (78):
OA ^ sh
To bromoacetone (prepared as per literature;60 685 mg, 5 mmol) in ethanol (2.5
mL) was added thiourea (380 mg, 5 mmol). The mixture was then refluxed for 3 hours,
and then allowed to cool. Following the addition of 10 mL o f IN HC1, the mixture was
153
extracted with ethyl acetate repeatedly. The combined organic fractions were then dried
over anhydrous magnesium sulfate and filtered. Removal o f the solvent by rotary
evaporation gave the urea salt 80, as a pale pink solid (810 mg, 76%), which was
immediately added to a solution o f IN NaOH (7.5 mL). After refiuxing for 2 hours, the
mixture was cooled, The reaction was then neutralized (to pH ~7.0) using IN HC1, and
extracted with ethyl acetate. The combined organic fractions were then dried over
anhydrous magnesium sulfate and filtered. Removal o f the solvent by rotary evaporation
afforded the product as a volatile, odiferous oil which darkened upon standing (258mg,
57% for 2 steps). As a result o f the instability, the product 78 was used immediately in a
crude form in subsequent reactions.
2-Acetyl-3-hydroxytetrahydrothiophene (82).
0
Acrolein (0.50 mL, 7.2 mmol) and propan-2-one-l-thiol (78. 258 mg, 2.87 mmol)
were added to dichloromethane (5 mL). To this solution was added triethylamine (0.80
mL, 5,7 mmol). The resulting mixture was then stirred for 2.5 hours. The reaction was
then quenched with IN HC1, and extracted with dichloromethane. The combined organic
fractions were then dried over anhydrous magnesium sulfate and filtered. Following
solvent removal by rotary evaporation, the resulting yellow oil was chromatographed over
silica gel, using a 1:1 mixture o f hexanes:ethyl acetate as an eluent. The product, 82, was
obtained as a pale yellow oil (solidifies in freezer) in a yield o f 9% (36 mg). The spectral
data is as follows: ‘H NMR (360 MHz, CDC13): 8 4.65 (dd, 1H, J=3.1, 4,0 Hz), 3.80 (d,
1H, J=3.1 Hz), 2.95-2.80 (m, 2H), 2.20 (s, 1H), 2.11 (s, 3H), 2.05 (m, 2H). I3C NMR
(90.56 MHz, CDCIj): 8 205.3 (s), 75.0 (d), 61.8 (d), 37.4 (t), 29.1 (t), 28.4 (q). LRMS
m/e (relative intensity): 146 (M+, 8 ), 128 (M -18,100).
154
3-Hydroxy-3-methyl-4-carbomethoxytetrahydrothiophene (83).
9 H co2ch3
Methyl acrylate (0.9 mL, 10 mmol) and propan-2-one-l-thiol (78: 360 mg, 4.0
mmol) were added to dichloromethane (10 mL). To this solution was added triethylamine
(1.1 mL, 8.0 mmol). The resulting mixture was then stirred for 2.5 hours. The reaction
was then quenched with IN HC1, and extracted with dichloromethane. The combined
organic fractions were then dried over anhydrous magnesium sulfate and filtered.
Following solvent removal by rotary evaporation, the resulting yellow oil was
chromatographed over silica gel, using a 1 :1 mixture o f hexanes:ethyl acetate as an eluent,
The product, 83, was obtained as a yellow oil in a yield o f 6 % (42 mg). The spectral data
is as follows: *H NMR (250 MHz, CDC13): 8 3.75 (br s, 1H), 3.65 (s, 3H), 2.80-2.60 (m,
5H), 2 ,2 1 (s, 3H). ,
2-M ethyl-3-trimethylsiloxycyclopent-2-en-l-one(99).
2-Methylcyclopentane-l,3-dione (700 mg, 6.3 mmol), and imidazole (25,5 mg,
0.38 mmol) were added to hexamethyldisilazane (5.0 mL, 24 mmol). The resulting
solution was then heated to reflux and stirred for 2 hours. After cooling, the residual
TMSO
155
HMDS was removed by distillation at atmospheric pressure (b.p. 1 2 S°C). The residue
was then purified by vacuum distillation to give the product 99 as a colourless oil (b.p. 78-
81° @ 0.5mmHg) in a yield o f 80% (920 mg). The spectral data is as follows: 'H NMR
(360 MHz, CDCI3): 8 2.40 (m, 2H), 2.30 (m, 2H), 1.45 (s, 3H), 0.22 (s, 9H). ,3C NMR
(90.56 MHz, CDCI3): 5 206.4 (s), 181.3 (s), 119.7 (s), 33.6 (t), 28.9 (t), 5.9 (q), 0.7 (q).
3-(I-Ethenyl)-2-methylcyclopent-2-en-l-one(100).
Vinylmagnesium bromide (1M in THF, 6.0 mL, 6.0 mmol) was slowly added to a
0°C solution o f silyl enol ether 99 (1,10 g, 6.0 mmol) in THF (50 mL). The resulting
solution was then stirred at 0°C for 4 hours. The reaction was then quenched with an
ammonium hydroxide/ammonium chloride/brine solution (made by adding sodium
hydroxide pellets to a saturated ammonium chloride solution until pH 7.0 is reached).
After extracting the mixture with diethyl ether, the combined organic fractions were dried
over anhydrous magnesium sulfate and filtered. After removal o f the solvent by rotary
evaporation, the residue was chromatographed over florisil, using diethyl ether as an
eluent. The product, 1 0 0 , was obtained as an off-white solid (mp SI°C) in a yield o f 91%
(665 mg). The spectral data is as follows: 'H NMR (360 MHz, CDCb): 8 6.85 (dd, 1H,
J=17.3, 10.7 Hz), 5.70 (d, 1H, J=17.3 Hz), 5.45 (d, 1H, J=10.7 Hz), 2.60 (m, 2H), 2.38
(m,2H), 1.73 (s,3H).
156
4-Pentynal (106).
no
To a -60°C solution o f dimethyl sulfoxide (1.56 mL, 22 mmol) in dichloromethane
(110 mL) was added oxalyl chloride (1.92 mL, 22 mmol ). The resulting mixture was
stirred for 15 minutes, then commercial 4-pentyn-l-o! (1.85 mL, 20 mmol) was added
over a two minute period. The resulting mixture was then stirred for a further 20 minutes,
at which point triethylamine (8.35 mL, 60 mmol) was added. The reaction mixture was
then allowed to warm to room temperature, and was stirred for 45 minutes. The mixture
was then filtered to remove the triethylamine hydrochloride salt and then the resulting
clear solution was quenched with IN HC1 (60 mL). The layers were then separated and
the aqueous layer was washed twice with dichloromethane. The combined organic layers
were then dried over anhydrous magnesium sulfate, filtered, concentrated by rotary
evaporation, and used in the next reaction without further purification.
Hept-l-en-6-yn-3-ol (107).
To a -78°C solution o f 4-pentynal (106: 20 mmol, 1.6 g) in diethyl ether (150 mL)
was added vinylmagnesium bromide (1.0 M solution in THF, 30 mmol, 30 mL). After
stirring at -78°C for two hours, the reaction was quenched with IN HC1 (50 mL). The
organic and aqueous layers were then separated, and the aqueous layer was washed twice
with diethyl ether. The combined organic layers were then dried over magnesium sulfate,
filtered, and concentrated by rotary evaporation. After chromatrography of the residue
over silica gel using a 3:1 mixture o f hexane:ethyl acetate as an eluent, the product was
obtained a a pale yellow oil in a yield o f 73% (1.61g, yield measured from the commercial
OH
157
pentynol). Spectral data as follows: *H NMR (300 MHz, CDCb): 8 5.81 (ddd, 1H,
J=17.2, 10.4, 6.1Hz), 5.22 (dt, 1H, J=17.2, 1.4 Hz), 5.08 (dt, 1H, J=10.4, 1.3 Hz), 4.22
(m, 2H), 2.25 (m, 2H), 2.16 (s,lH ), 1.94 (t, 1H, 1=2.1 Hz), 1.69 (dt, 2H, J=6 .6 , 6.7 Hz).
,3C NMR (75.5 MHz, CDCI3): 8 140.2(d), 115(t), 83.8(d), 71.6(d), 68.7(s), 35.1(t),
14.5(t). IR (CHCI3, cm'1) 3606 (m), 3298 (m, sh), 3018 (s), 2932 (m), 2403 (m), 1427
(m), 1215 (s, br). LRMS m/e (relative intensity): 109 (M-H, 20), 95(32). HRMS calcd
for C7H9O (M-H): 109.0653, found: 109.0657.
Ethyl (E)-non-4-en-8-ynoate (108).
To toluene (250 mL) was added : hept-l-en-6-yn-3-ol (107: 4.18 g, 38 mmol),
triethyl orthoacetate (35 mL, 190 mmol) and propionic acid (0.58 mL, 7.6 mmol). The
mixture was then heated to reflux and stirred for 16 hours. Following removal o f the
solvents and excess triethyl orthoacetate by rotary evaporation, the residue was
chromatographed over silica gel using a 3:1 mixture o f hexane:ethyl acetate as an eluent.
The product was isolated as a pale yellow oil in a yield o f 81% (5.5 lg>. The residue can,
if desired, also be purified by distillation under reduced pressure (bp 77°C @ 0 .1 mmHg).
The spectral data is as follows: 'H NMR (300MHz, CDCI3): 8 5.45 (m, 2H), 4.07 (q, 2H,
J=7.1 Hz), 2.31-2.28 (m, 4H), 2.18-2.15 (m,4H), 1.90 (t, 1H, J=2.5 Hz), 1.20 (t, 3H,
J=7,l Hz). ,3C NMR (75.5 MHz, CDCI3): 5 173.0(s), 129.6(d), 129.2(d), 83.8(d),
68.4(s), 60.1(t), 34.0(t), 31.3(t), 27.7(t), 18.6(t), 14.1(q). IR (CHCI3 , c m 1) 3307 (m, sh),
3028 (m, br), 2990-2850 (m), 1725 (s), 1224 (m), 1210 (m), 970 (m). LRMS m e
(relative intensity): 198 (M+18, 22), 181 (M+H, 100), 135 (32). HRMS calcd for
C ,.H 170 2 (M +1): 181.1228, found: 181.1231.
158
(E)-Non-4-en-8-ynal (109).
0
To a -78°C solution o f ethyl (E)-non-4-en-8-ynoate (108: 920 mg, 5.1 mmol) in
diethyl ether (50 mL) was added diisobutylaluminum hydride (DIBAL-H: 0.97M in
hexane, 6.3mL, 6.1 mmol). After the mixture was then stirred for 90 minutes, the
reaction was quenched with IN HC1 at -78°C. The mixture was then allowed to warm to
room temperature. Following separation o f the organic and aqueous layers, the aqueous
layer was washed twice with diethyl ether . The combined organic fractions were then
dried over anhydrous magnesium sulfate, filtered and the solvent was removed by rotary
evaporation. The residue was then chromatographed over silica gel using a 3; 1 mixture o f
hexanes:ethyl acetate as an eluent. The product was obtained as a colourless oil in a yield
o f 92% (640mg). Spectral data as follows: ‘H NMR (300 MHz, CDCI3): 8 9.75 (s,lH),
5.44 (m, 2H), 2.44 (t, 2H, J=7.2 Hz), 2.3-2.26 (m, 2H), 2.16-2.12 (m, 4H), 1.90 (t, 1H,
J—2.5 Hz). ,5C NMR (75.5 MHz, CDClj): 8 202.0(d), 129.4(d), 129.3(d), 83.7(d),
68.5(s), 43.2(t), 31.3(t), 24.9(t), 18.6(t). IR (CHCb, cm*1) 3307 (m, sh), 3026 (m), 2917
(m), 2117 (w), 1723 (s), 1442 (m), 969 (m). LRMS m/e (relative intensity): 135 (M-H, 6),
117 (19), 91 (67), 79 (100). HRMS calcd for C9H „ 0 (M-H): 135.0810, found: 135.0809,
159
(E)-Undec-6-ene-l,10-diyn-3-ol (110):
OH
To a 0°C solution o f (E)-non-4-en-8-ynal (109: 1.04g, 7.6 mmol) in THF (75 mL)
was added 0.5M ethynylmagnesium bromide in THF (16mL, 8.0mmol). The mixture was
then allowed to warm to room temperature and was stirred for 2 hours. The reaction was
then quenched with IN HC1. After separation o f the organic and aqueous layers, the
aqueous layer was washed twice with diethyl ether. The organic layers were then
combined, dried over anhydrous magnesium sulfate and filtered. Following removal o f the
solvent by rotary evaporation, the residue was chromatographed over silica gel using a
3:1 mixture o f hexanes:ethyl acetate as an eluent to afford the product as a colourless oil
in a yield o f 87% (1.07g), The spectral data is as follows: ‘H NMR (300 MHz, CDCIi): 8
5.55-5.43 (m, 2H), 4.37 (td, 1H, J=6.5, 2,1 Hz), 2.45 (d, 1H, J=2.2 Hz), 2.23-2.14 (m,
6H), 1.94 (t, 1H, J=2.4 Hz), 1.83-1.73 (m, 3H). 13C NMR (75.5 MHz, CDC13): 8
130.4(d), 129.2(d), 84.7(d), 84(d), 73(s), 68.6(s), 61.5(d), 37(t), 31.4(t), 27.9(t), 18.7(t).
IR (CHCb, cm’1) 3606 (m, br), 3307 (s, sh), 3030 (m), 2931 (m, br), 2117 (w), 1433 (m),
1248 (m, br), 970 (m). LRMS m/e (relative intensity): 161 (M-H, 2), 105 (81), 91 (100).
HRMS calcd for C „H ,30 (M-H): 161.0966, found: 161.0964.
(E)-3-(tert-Butyldimethylsiloxy)undec-6-ene-l,i0-diyne(lll):
160
— / \ S \ / \ / ' I
OTBDMS
To a solution o f undec-6(E)-ene-l,10-diyn-3-ol (110: 1.70g, 10.5 mmol) in DMF
(8 mL) was added imidazole (1.80g, 26.5 mmol) and t-butyldimethylchlorosilane (1.90g,
12.6 mmol). The resulting solution was then stirred at room temperature for 16 hours.
Hexanes (lOmL) was then added, and the resulting layers were separated (hexanes formed
the less-dense layer). Then 5 mL o f water was added to the DMF layer, and it was then
extracted three times with hexanes. The combined hexanes fractions were then dried over
anhydrous magnesium sulfate, concentrated by rotary evaporation, and chromatographed
over silica gel (150g) using a 15:1 mixture o f hexanes:ethyl acetate as an eluent. The
product was obtained as a colourless oil in a yield of 95% (2.76g). Spectral data is as
follows: 'H NMR (300 MHz, CDClj): 5 5.45 (m, 2H), 4.33 (dt, 1H, J=2,l, 6.5 Hz), 2.36
(d, 1H, J=2.1 Hz), 2.20 (m, 4H), 2.15-2,08 (m, 2H), 1.93 (t, 1H, J=2.2 Hz), 1.80-1.65
(m, 2H), 0.88 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H). ,3C NMR (75.5 MHz, CDCI3): 5 130.6
(d), 128.6 (d), 85.3 (d), 83.9 (d), 71.9 (s), 68.3 (s), 61.8 (d), 38.0 (t), 31.4 (t), 27.9 (t),
25.6 (q), 18,6 (t), 18.0 (s), -4.7 (q), -5.3 (q). IR (CHCI3, c m 1) 3307 (s, sh), 2960-2930
(m), 2857 (m), 2117 (w), 1472 (m), 1424 (m), 1094 (m, br). LRMS m/e (relative
intensity): 219 (M-C4H9, 4), 145 (21), 75 (100). HRMS calcd for C,3H,9OSi (M-C4H9):
219.1205, found: 219.1209.
161
(E)-Undec-6-ene-l,10-diyn-3-onc (112).
To a solution o f 110 (94 mg, 0.58 mmol) in dichloromethane (5 mL) was added
Dess-Martin periodinane67 (271 mg, 0.64 mmol). After stirring for 60 minutes, the
reaction was quenched with a solution o f 5% sodium bicarbonate and 5% sodium bisulfite
in water (~5 mL). The resulting mixture was then stirred vigorously for 30 minutes, or
until the aqueous and organic layers were transparent. The two layers were then
separated, and the aqueous layer was extracted three times with dichloromethane. The
combined organic fractions were then combined, dried over anhydrous magnesium sulfate,
filtered and concentrated by rotary evaporation. The residue was then chromatographed
over silica gel using a 5:1 mixture o f hexanes.ethyl acetate as an eluent to afford the
product as a pale yellow oil in a yield o f 78%, Spectral data is as follows: 'H NMR (360
MHz, CDC13): 8 5.45 (m, 2H), 3.21 (s, 1H), 2.65 (t, 2H, J=6.8 Hz), 2.40 (dt, 2H, J=6,9,
2.6 Hz), 2.20 (m, 4H), 1.91(t, 1H, 3=2.6 Hz). I3C NMR (92.6 MHz, CDC13); 8 186.6 (s),
129.8 (d), 128.9 (d), 83.3 (d), 81.3 (d), 76.6 (s), 68,6 (s), 45,0 (t), 31.4 (t), 26.5 (t), 18.6
0).
162
(E)-Undec-6-ene-l,10-diyn-3-one, ethylene ketal (114).
H
To a solution o f 112 (80 mg, 0.5 mmol) in ethylene glycol (3,0 mL) was added
TMSC1 (0,25 mL, 2.0 mmol). The resulting mixture was then stirred for 24 hours. After
the addition o f a saturated sodium bicarbonate solution (~3 mL) and diethyl ether (~5
mL), the organic and aqueous layers were separrted, and the aqueous layer was extracted
three times with ether. The combined organic fractions were then dried over anhydrous
magnesium sulfate, filtered, and concentrated by rotary evaporation to yield a yellow oil,
This residue was then chromatographed over silica gel using a 3:1 mixture of
hexanes.ethyl acetate as an eluent to afford the product 114 as a colourless oil in a yield o f
55% (56 mg). Spectral data is as follows: 'H NMR (360 MHz, CDCb), 8 5.50 (m, 2H),
4.10-3,90 (m, 4H), 2,45 (s, 1H), 2.25-2.10 (m, 8H), 1.90 (t, 1H, J=2.6 Hz). ,3C NMR
(92,6 MHz, CDCb): 8 130.5, 128,5, 102.5,84.0,81.4 ,71,9 ,68.4 ,64.6 ,38,7 ,31,5 ,26.8 ,
18.8.
163
l-(terf.ButyldimethylsiIoxy)-2-inethenyl-3-((E)-pent-l-en-5-yii-l-yl)cyclopeiitane
( 118).
OTBDMS
To a solution o f 3 -tert-butyldimethylsiloxy-undeca-6 -(E)-ene-1,10-diyne (111: 138
mg, 0.5 mmol) in benzene (5mL) was added palladium diacetate (11.2 mg, 0.05 mmol)
and BBEDA (11.8 mg, 0.05 mmol). The resulting solution was then heated to reflux for
three hours. After allowing the solution to cool, the solvent was removed by rotary
evaporation and the brown-black residue was chromatographed over silica gel (15g) using
a 15:1 mixture o f hexanes:ethyl acetate as an eluent. The product was obtained as a
yellow-brown oil in a yield c f 70% (100 mg, which was contaminated with -10% starting
material). The spectral data for the product is as follows: ‘H NMR (300 MHz, CDC13): 8
5,90 (m, 1H), 5.32 (d, 1H, J=2. Jz ) , 4.93 (d, 1H, J=2.1 Hz), 4.48 (ddt, 1H, J=9.0, 6.7,
2.4 Hz), 2.46 (m, 1H), 2.40-2.10 (m, 4H), 2.04-1.93 (m, 2H), 1.93 (t, !H, J=2.6 Hz),
1.58-1,40 (m, 1H), 0.90 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H). 13C NMR (75.5 MHz,
CDCb): 8 151.8 (s), 138.3 (s), 119.5 (d), 102.8 (t), 84.1 (s), 75.7 (d), 68.4 (d), 33.4 (t),
28.1 (t), 25.9 (q), 25,5 (t), 18.5 (t), 18.3 (s), -4.6 (q), -4.7 (q). IR (CHCb, cm'1) 3307 (m,
sh), 2960-2900 (s), 2850 (m), 2112 (w), 1602 (w), 1602 (m), 1471 (m), 1250 (s), 1116
(m, br). LRMS m/e (relative intensity): 219 (M-C4H9, 100), 189 (18), 145 (83). HRMS
calcdfor CullwQSi (M-C4H9): 219.1205, found: 219.1209.
164
(E)-Undec-6-en-l,10-diyn-3-ol, benzyl ether (121).
H
OCH2P h
To a 0°C solution o f alcohol 110 (486 mg, 3.0 mmol) in THF (30 mL) was slowly
added NaH (60% in mineral oil: 132 mg, 3.3 mmol). After warming the reaction to RT
and stirring for 30 minutes, benzyl bromide (538 mg, 3.15 mmol) in 2 mL THF was added
over 5 minutes. After stirring for a further 3 hours, the reaction was quenched with
saturated ammonium chloride, the organic and aqueous layers were separated, and the
aqueous layer was washed three times with diethyl ether. The combined organic fractions
were then dried over anhydrous magnesium sulfate, filtered and concentrated by ratary
evaporation. Chromatography o f the residue over silica gel, using a 10:1 mixture o f
hexanes:ethyl acetate as an eluent afforded the product 121 in an 85% yield (642 mg).
The spectral data is as follows: ‘H NMR (300 MHz, CDCb): 8 7.45-7.35 (m, 5H), 5.48
(m, 2H), 4.83 (d, 1H, J=11.7 Hz), 4.52 (d, 1H, j= l 1.7 Hz), 4.12 (dd, 1H, J=6.5, 2.1 Hz),
2.52 (d, 1H, J=2.1 Hz), 2.20 (m, 6 H), 1.96 (t, 1H, J-2.3 Hz), 1.85 (m, 2H). ,3C NMR
(75,5 MHz, CDCb): 8 137.8 (s), 130.4 (d), 129.0 (d), 128.2 (d), 127.9 (d), 127.6 (d),
84.0 (s), 82.7 (s), 73.8 (d), 70.4 (t), 68.5 (d), 67,5 (d), 35.2 (t), 31.4 (t), 28.0 (t), 18.7 (t).
l-(te/t-Butyldimethylsiloxy)-4-pentyne (123),
The procedure used for this reaction is identical to that used for the generation o f
111. In this case, product 123 was obtained from commercial 4-pentyn-l-ol in a yield o f
93% (purification by atmospheric pressure distillation (bp 105°C)). The spectral data is as
165
follows: 'H NMR (300 MHz, CDC13): 5 3.70 (t, 2H, J=6 .1 Hz), 2.28 (dt, 2H, J=2.7, 7.0
To a 0°C solution o f alkyne 123 (198 mg, 1.0 mmol) in hexanes (5 mL) was added
D1BAL-H (1.6 M in hexanes, 1.25 mL, 2.0 mmol). After stirring the reaction for one
hour, the solvent was removed under vacuum. The residue was then redissolved in THF
(5 mL) and cooled to -78°C. Iodine (390 mg, 3.0 mmol) in THF (2.0 mL) was then
added over 5 minutes via syringe. After stirring at -78°C for 2 0 minutes, the mixture was
warmed to RT and quenched vath IN HC1. Following separation o f the organic and
aqueous layers, the aqueous layer was washed three times with diethyl ether. The
combined organic fractions were then dried over anhydrous magnesium sulfate, filtered
and concentrated. Chromatography o f the residue afforded the product 124 in a 28%
yield (60 mg): *H NMR (300 MHz, CDCb): 8 6.45 (dt, 1H, J=14.5, 7.2 Hz), 5.97 (dt,
Hz), 1.94 (t, 1H, J=2.7 Hz), 1.73 (tt, 2H, J=7.0, 6.1 Hz), 0.88 (s, 9H), 0.05 (s, 6 H).
(E)-l-Iodo-l-penten-S-i?! (124).
1H, J=14,3, 1.2 Hz), 3.60 (t, 2H, J=6.7 Hz), 2.15 (dt, 2H, J=6.9 Hz, 7.2 l\z), 2.0 (br s,
1H), 1.56 (m, 2H).
l-(fcrf-ButySdimcthylsiloxy)hept-4-yn-6-ol (127):
/-s^O T B D M S
166
To a 0°C solution o f 123 (198 mg, 1.0 mmol) in THF (5 mL) was added
ethylmagnesium bromide (2 r'M in THF, 0.5 mL, 1.25 mmol). After stirring at 0°C for
one hour, acetaldehyde (0.112 mL, 2.0 mmol) was added. The mixture was then stirred
for 2 hours. The reaction was then quenched with a saturated ammonium chloride
solution and extracted with diethyl ether. The combined organic fractions were then dried
over anhydrous magnesium sulfate and concentrated by rotary evaporation. The residue
was then chromatographed over silica gel using a 5:1 mixture o f hexanes:ethyl acetate as
an eluent to afford the product 127 in a 65% yield (157 mg). The spectral data is as
follows: ‘H NMR (300 MHz, CDC13): 6 4.55 (m, 1H), 3.65 (t, 2H, J=6 .1 Hz), 2.36 (dt,
2H, J=2.0, 7.1 Hz), 1.70 (m, 3H), 1.42 (d, 3H, J=6 . 6 Hz), 0.88 (s, 9H), 0.05 (s, 6 H).
(E)-l-(terf-Butyldimethylsiloxy)hept-4-en-6-ol (128):
OTBD.MS
To a 0°C solution o f 127 (242 mg, 1.0 mmol) in THF (5 mL) was added lithium
aluminum hydride (50 mg, 1.25 mmol). The mixture was then allowed to warm to RT,
and was stirred for 16 hours. The reaction was then quenched with a saturated
ammonium chloride solution and extracted with diethyl ether. The combined organic
(factions were then dried over anhydrous magnesium sulfate and concentrated by rotary
evaporation. The residue was then chromatographed over silica gel using a 5:1 mixture o f
hexanes: ethyl acetate as an eluent to afford the product 128 in a 71% yield (141 mg:
isolated as a mixture o f ~80% 128 and ~20% 127), The spectral data for the product 128
is as follows: ‘H NMR (300 MHz, CDCIj): 6 5.65 (dt, 1H, J=15.4,6.4 Hz), 5.52 (dd, 1H,
,1=15.4,6.3 Hz), 4.50 (dq, 1H, J= 2 J , 6.4 Hz), 3,70 (t, 2H, J=6.9 Hz), 2.30 (dt, 2H, J«2.0,
7.1 Hz), 1.70 (m, 3H), 1.45 (d, 3H, J=6,4 Hz), 0.88 (s, 9H), 0.03 (s, 6 H).
1.67
(E)-l-Tributylstannyl-5-(fcrf-butyldimethylsiloxy)pent-l-ene(130):
B u 3S n s ^ ^ ^ ^ O T B D M S
Major isomer shown (and named): minor isomer is Z-alkene
To a solution o f alkyne 123 (198 mg, 1.0 mmol) in benzene ( 8 mL) was added
tributyltin hydride (0.350 mL, 1.3 mmol) and AIBN (50 mg, 0.3 mmol). The resulting
solution was then refluxed overnight. Following removal o f the solvent by rotary
evaporation, the residue was chromatographed over silica gel using a 15:1 mixture o f
hexanes:ethyl acetate as an eluent to afford the product 130 as a mixture o f two isomers
(~80% /ram-isomer with regiochemistry shown in above structure) in a yield o f 93% (543
mg). The spectral data for the product 130 (/ra/w-isomer) is as follows: ‘H NMR (300
MHz, CDCb): 5.94 (t, 1H, J=6.9 Hz), 5.92 (s, 1H), 3.61 (t, 2H, J=6 .8 Hz), 2.20 (m, 2H),
1.70-1.40 (m, 14 H), 1.0-0.8 (m, 15 H), 0.88 (s, 9H), 0.03 (s, 6 H).
(E)-l-(fe/f-Butyldimethylsiloxy)hept-4-en-6-one (131).
O
Major isom jr shown (and named): minor isomer is Z-alkene
To a solution o f 130 (244 mg, 0.5 mmol) in chloroform (3 mL) was added tetrakis
(triphenylphosphine)palladium (30 mg, 0.025 mmol), then acetyl chloride (46pL, 0.65
mmol). The resulting pale yellow solution was then stirred for 16 hours at room
168
temperature. After removal o f the solvent by rotary evaporation, the residue was
chromatographed over silica gel using a 9:1 mixture of hexanes ethyl acetate as an eluent
to give the product 131 as a colourless oil in a yield o f 81% (97 mg). The spectral data for
the product 131 is as follows: *H NMR (300 MHz, CDC13): 8 6.85 (dt, 1H, J=16.0, 6.9
Hz), 6.1 (dt, 1H, J=16.0, 1.4 Hz), 3.63 (t, 2H, J=6.4 Hz), 2.40 (m, 2H), 2.22 (s, 3H), 1.70
(m, 2H), 0.88 (s, 9H), 0.04 (s, 6 H). IR (CHC13, cm 1) 2950 (s), 1670 (s), 1625 (m, sh),
1471 (m), 1361 (s), 1100 (s, br), 837 (s). LRMS m/e (relative intensity) 227 (M-CH3, 5),
185 (M-C4H9, 100), 155 (18), 141 (44). HRMS calcd for C 12H230 2Si (M-CH3):
227.1467, found: 227.1467.
(lS*,4R*,5R*)-5-AcetyI-l-(ferr-butyldimethyIsiloxy)-4-(but-l-yn-4-yl)-4,5,6,7-‘
tctrahydroindan (143).
OTBDMS
To a solution o f diene (118) (310 mg, 1.12 mmol) in benzene (5 mL) was added
methyl vinyl ketone (190 pL, 2.24 mmol). The resulting mixture was then stirred at room
temperature for 16 hours, at which point another 2 equivalents o f methyl vinyl ketone
(190pL) was added. The reaction was stirred at room temperature for another 24 hours,
at which point the solvent was removed by rotary evaporation, and the resulting residue
was chromatographed over silica gel (30g) using a 9:1 mixture o f hexanes:ethyl acetate as
an eluent. The product was obtained as a pale yellow oil in a yield o f 79% (307 mg, 91%
based on consumed starting material: 14% starting material recovered). The spectral data
for the compound is as follows: *H NMR (300 MHz, CDCI3): 8 4,65 (m, 1H), 2,81 (ddd,
169
1H, J=11.0, 4,8, 3.1 Hz), 2.71 (dt, 1H, J=4.8, 7.3 Hz), 2.40-2.20 (m, 3H), 2.18 (s, 3H),
2.17-2.05 (m, 2H), 1.95 (t, 1H, J=2.6 Hz), 1.90-1.57 (m, 5H), 1.48 (q; 2H, J=7.3 Hz),
0.88 (s, 9H), 0.05 (s, 6 H). 13C NMR (75.5 MHz, CDC13): 6 210.8 (s), 139.3 (s), 137.5 (s),
83.8 (s), 79.5 (d), 69.0 (d), 51.7 (d), 36.3 (d), 33.7 (t), 32.7 (t), 29.3 (t), 28.9 (q), 25.9
(q), 22.3 (t), 20.3 (t), 18.3 (s), 17.4 ( t) , -4.5 (q), -4.8 (q). IR(CHC13, cm ') 3307 (m, sh),
3024 (m), 2950-2900 (s), 2856 (m, sh), 2110 (w), 1704 (s), 1471 (m), 1354 (m), 1256
(m), 1069 (m, br). LRMS m/e (relative intensity): 346 (M+, 61), 307 (41), 303 (38), 289
(100). Exact mass calcd for C2iH340 2 Si: 346.2328, found: 346.2324.
(lS*,4R*»5S*)-5-Acetyl-l-(f£rf-butyIdimethylsiloxy)-4-(l-butyn-4-yl)-4,5,6,7-
tetrahydroindan (138).
OTBDM S
Major isomer shown (and named): minor isomer is C5 epimer
To a solution o f ketone (143) (567 mg, 1.64 mmol) in anhydrous methanol (8 mL)
and diethyl ether (8 mL, required for solubilization) was added anhydrous potassium
carbonate (250 mg, 1.80 mmol). The resulting suspension was stirred rapidly at room
temperature for 16 hours. The reaction was then quenched with 5 mL o f saturated
ammonium chloride and 5 mL o f water. The organic and aqueous layers were then
separated, and the aqueous layer was extracted three times with diethyl ether, Following
combination o f the organic fractions and drying over anhydrous >.iagnesium sulfate, the
solution was filtered and concentrated by rotary evaporation. The residue was then
chromatographed over silica gel (50g) using a 9:1 mixture o f hexanes:ethyl acetate as an
170
eluent. The product was obtained as two inseparable isomers (product: starting material in
an approximately 7:1 ratio based on nmr integrations) as a pale yellow oil in a yield o f
84% (476 m g ). The spectral data for the major compound is as follows: ‘H NMR (300
MHz, CDCb): 6 4.70 (m, 1H), 2.73 (m, 1H), 2.49 (dt, 1H, J=10.9, 2.8 Hz), 2.40-2.20 (m,
3H), 2.18 (s, 3H), 2.17-1.80 (m, 3H), 1.70-1.48 (m, 7H), 0.87 (s, 9H), 0.04 (s, 6 H). l3C
NMR (75.5 MHz, CDCb): 8 211.5 (s), 138.3 (s), 137.7 (s), 84 4 (s), 79.1 (d), 6 8 . 6 (d),
52.6 (d), 36.3 (d), 33.5 (t), 31.1 (t), 30.7 (t), 28.4 (q), 25.9 (q), 25.7 (t), 22.1 (t), 18.3
(s), 15.3 (t), -4.4 (q), -4.7 (q). IR (CHCb, c m 1) 3316 (m, sh), 3013 (m), 2960-2900 (m),
2857 (m, sh), 2118 (w), 1707 (s), 1470 (m), 1361 (m), 1258 (m). LRMS m/e (relative
intensity): 346 (M+, 8 ), 307 (7), 289 (100). HRMS calcd for C2,H34 0 2Si: 346.2328,
found: 346.2324.
(lS*,4R*,5S*)-l-(te/Y-ButyldimethylsiIoiy)-5-(l-hydro:iy-l-methylethyl)-4-(but-l-
yn-4-yl)-4,5,6,7-tetrahydroindan (145).
OTBDMS
Major isomer shown: minor isomer is C5 epimer
To a 0°C solution o f ketone (138) (146mg, 0.42 mmol) in diethyl ether (5 mL) was
added methyllithium (1.4 M in ether, 0,75 mL, 1.05 mmol). The solution was then stirred
for 5 hours at 0°C. After quenching t he reaction with a 200 mM pH 7.0 phosphate buffer
(67 mM NaH2P 04, 133 mM Na2HPO.«), the solution was diluted with water and ether to
aid clarification. Following separation o f the aqueous and organic layers, the aqueous
layer was washed twice with ether. The combined organic fractions were then dried over
anhydrous magnesium sulfate and filtered. After removal o f the solvent by rotary
171
evaporation, the residue was chromatographed over silica gel (50g) using a 9:1 mixture o f
hexanes: ethyl acetate as an eluent. The product was obtained as a pale yellow viscous oil
in a yield o f 114 mg (75%). The spectral data for the compound is as follows: *H NMR
(300 MHz, CDCb): 8 4.62 (m, 1H), 2.40-2.10 (m, 8 H), 1.93 (t, 1H, J=2.4 Hz), 1.90-1.75
(m, 2H), 1.70-1.45 (m, 5H), 1.21 (s, 3H), 1.17 (s, 3H). 0.87 (s, 9H), 0.03 (s, 6 H). l3C
NMR (75.5 MHz, CDCb): 8 140.2 (s), 137.7 (s), 84.6 (s), 79.6 (d), 73.7 (s), 68.7 (d),
45.8 (d), 35.3 (d), 33.2 (t), 32.5 (t), 32,1 (t), 29.6 (q), 29.5 (t), 27.5 (q), 25.9 (q), 21.1 (t),
18.1 (q), 16,4 (t); -4.5 (q), -4.7 (q). IR (CHCb, c m 1) 3604 (m, br), 3307 (m, sh), 2956-
2860 (s, br), 2116 (w), 1472 (m, sh), 1365 (m, br), 1253 (m), 1062 (m, br). LRMS m/e
(relative intensity): 362 (M*, 7), 305 (42), 213 (63), 171 (80), 133 (100). HRMS calcd
for C22H3»0 2Si: 362.2641, found: 362.2633.
(1S \4R *, 5S*)-l-(terf-Butyldimethylsiloxy)-5-(l-niethylethenyl)-4-(but-l-yn-4-yl)-
4,5,6,7-tetrahydroindan (144).
OTBDM S
Major isomer shown (and named): minor isomer is C5 epimer
To a solution o f alcohol (145) (132 mg, 0.365 mmol) in pyridine (4 mL) was
added phosphorus oxychloride (POCb, 0.170 mL, 1.83 mmol). The resulting solution was
stirred at room temperature for six hours. The solution was then cooled to 0°C , and the
reaction was quenched through careful dropwise addition o f 1 mL o f water (caution:
reaction can be vigorously exothermic), followed by 3 mL o f a saturated sodium
bicarbonate solution. To aid clarification, ether and water were also added. Following
separation o f the aqueous and organic layers, the aqueous layer was washed three times
172
with ether. The combined organic fractions were then dried over anhydrous magnesium
sulfate, filtered and concentrated by rotary evaporation. The resulting yellow residue was
then chromatographed over lOg silica gel using a 9:1 mixture o f hexanes:ethyl acetate as
an eluent. The product was obtained as a viscous pale yellow oil (which solidifies at
temperatures below approximately 0°C) in a yield o f 90 mg (72%). Spectral data is as
follows: 'H NMR (300 MHz, CDCI3): 8 4.77 (d, 1H, J=1.5 Hz), 4.75 (d, 1H, J=1.5 Hz),
4.72 (m, 1H), 2.40-1.95 (m, 8 H), 1.93 (t, 1H, J=2.5 Hz), 1.75-1.65 (m, 6 H), 1.68 (s, 3H),
0.90 (s, 9H), 0.079 (s, 3H), 0.073 (s, 3H). ,3C NMR (75.5 MHz, CDCI3): 8 148.2 (s),
138.8 (s), 138.5 (s), 111.4 (t), 85.0 (s), 79.3 (d), 68.0 (d), 47.0 (d), 37.7 (d), 33.6 (t), 31.2
(t), 29.5 (t), 28.7 (t), 26.0 (q), 22.7 (t), 19.0 (q), 18.4 (s), 14.8 (t), -4.5 (q), -4.7 (q). 1R
(CHClj, c m 1) 3307 (m, sh), 2940-2860 (s, br), 2360 (m, sh), 1641 (w), 1471 (m, br),
1255 (m), 1056 (m, br). LRMS m/e (relative intensity): 344 (M+, 43), 287 (100), 211
(77). HRMS calcd for C22H36OSi: 344.2535, found: 344.2531.
(lS*,4R*,5S*)-l-(te/T-Butyldiinethylsiloxy)-5-(l-methylethenyl)-4-((E)-hex-3-en-2-
on-6-yl)-4,5,6,7-tetraliydrnindan (146); (1S*,4R*, 5S*)-l-(fert-Butyldimethylsiloxy)-
5-( 1 -inethyIetheny!)-4-((E)-2-hydroxyhex-3-en-6-yl)-4,5,6,7-tetrahyd. ..indan (152),
OTBDM S OTBDMS
146
OH
152
Major isomers shown (and named): minor isomers are €5 epimers
To a 0 °C solution o f 144 (70 mg, 0,203 mmol) in dichloromethane (1.5 mL) was
added zirconocene hydrochloride ( 6 8 mg, 0.265 mmol), The mixture was then stirred for
17330 minutes, at which point the solution was homogeneous and pale yellow in colour. The
mixture was then cooled to -78°C and dimethyl zinc (2.0 M in toluene, 0.203 mL, 0.406
mmol) was added over 2 minutes. After stirring for 10 minutes, the reaction mixture was
allowed to warm to 0°C, and was stirred for a further 45 minutes. Acetaldehyde (0.113
mL, 2.03 mmol) was then added, and the reaction was allowed to stir at 0°C for a further
two hours. The reaction was then quenched with saturated ammonium chloride.
Following separation o f the aqueous and organic layers, the aqueous layer was extracted
three times with dichloromethane. The combined organic layers were then dried over
anhydrous magnesium sulfate, filtered and concentrated by rotary evaporation.
Chromatography o f the residue over silica gel yielded the ketone product (146) in a 28%
yield (22 mg) and the alcohol product (152) in a 35% yield (28 mg). The alcohol product
could be readily converted to the ketone product as follows: pyridine (70pL, 0.87 mmol)
and Dess Martin periodinane (40.6 mg, 0.096 mmol) were stirred in dichloromethane (0.5
mL) for 15 minutes. The flask was then cooled to 0°C, and the alcohol (152) in 0.5 mL
dichloromethane was added via syringe. After stirring for 60 minutes, the reaction was
quenched with 1 mL o f a saturated sodium bisulfite solution and 1 mL o f a saturated
sodium bicarbonate solution. Addition o f dichloromethane and water (1 mL o f each), and
vigorous stirring for 20-30 minutes clarifies both layers, at which point they are separated.
After extraction o f the aqueous layer with dichloromethane, the combined organic
fractions were dried over anhydrous magnesium sulfate, filtered and concentrated by
rotary evaporation. Purification o f the residue is possible by silica gel flash
chromatography or preparative tic to give the ketone product (146) in a 78% yield (26
mg). The spectral data for the ketone (146) is as follows: *H NMR (300 MHz, CDCb): 5
6,72 (dt, 1H, J4*! 5.9, 7.0 Hz), 6.02 (dt, 1H, J=15.9, 1.0 Hz), 4.75 (d, 1H, J= l,6 Hz), 4.71
(d, 1H, 1=1.6 Hz), 4.70 (m, IH), 2.35-1.80 (m, 8H), 2.20 (s, 3H), 1.75-1.50 (m, 6H), 1.65
(s, 3H), 0,88 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H). ,3C NMR (75.5 MHz, CDCb); 5 198.5
(s), 148.6 (d), 148.2 (s), 138.9 (s), 138.5 (s), 131.1 (d), 111,2 (t), 79.3 (d), 46.9 (d), 38.0
(d), 33.7 (t), 31.3 (t), 28.8 (t), 28.6 (t), 28.4 (t), 26.7 (q), 26,0 (q), 25.6 (q), 22.7 (t)„ 18,5
(s), -4.5 (q), -4.7 (q). IR (CHCI3, cm'!) 2929 (s), 2856 (m), 1670 (m), 1471 (m), 1361
174
(m), 1256 (m, sh), 1056 (m, br). LRMS m/e (relative intensity): 388 (100), 331 (29), 305
(24), 303 (62). HRMS calcd for C24H4o02Si: 388,2797, found; 388.2793, Spectral data
for the alcohol product (152) is as follows: 'H NMR (300 MHz, CDCb): 8 5.55 (dt, 1H,.
J=15.4, 6.3 Hz), 5.44 (dd, 1H, J=15.4, 6.4 Hz), 4.74 (d, 1H, J=1.7 Hz), 4.71 (d, 1H,
J=1.7 Hz), 4.68 (m, 1H), 4.20 (qi, 1H, J=6.3 Hz), 2.3-1.8 (m, 9H), 1.70-1,50 (m, 4H),
1.65 (s, 3H), 1.48 (s, 2H), 1.21 (d, 3H, J=6.3 Hz), 0.88 (s, 9H), 0.06 (s, 3H), 0.05 (s,
3H). ,3C NMR (75.5 MHz, CDCb): 8 148.5 (d), 139.3 (s), 134.0 (s), 133.9 (s), 131.4
(d), 111.0 (t), 79.4 (d), 68.9 (d), 46.7 (d), 38.0 (d), 33,6 (t), 31,3 (t), 29.6 (t), 28.8 (t),
27.9 (t), 26.0 (q), 23.4 (t), 22.7 (q), 19.1 (q), 18.4 (s), -4.4 (q), -4.7 (q), IR (CHCb, cm-')
3611 (w, br), 2930 (s), 2856 (m), 1671 (w ) , 1642 (w), 1450 (m), 1375 (m), 1225 (m),
1056 (m, br). LRMS m e (relative intently): 390 (11), 372 (91), 303 (52), 291 (84), 173
(100), HRMS calcd for C24H420 2S i: 390.2954, found: 390.2947.
(IS*, 4R*, 5S*)-l-(ferf-Butyldiinethylsiloxy)-5-(l-methylethenyl)-4-((E)-2-
trimethylsiloxy-1,3-hexadien-6-yl)-4,5,6,7-tetrahydroindan (157).
OTBDM S
TM SO
Major isomer shown (and named): minor isomer is C5 epimer
To a -78°C solution o f 146 (12.5 mg, 0.032 mmol) in THF (1 mL) was added
LDA (0.5 M in THF, 78 ^L, 0,039 mmol (prepared as a stock solution just before
conducting the reaction from; 0.64 mL nBuLi (1.56 M in hexanes), 0,15 mL
diisopropylamine and 1.2 mL THF), The mixture was then stirred 45 minutes at -78°C,
then TMSC1 was added (0,5 M in THF, 104 |iL), The mixture was then allowed to warm
175
to room temperature and was stirred for 60 minutes. The solvent was then removed under
vacuum, and dry hexanes (2 mL) was added to the residue. The mixture was then filtered,
and the filtrate was concentrated under vacuum. Another 2 mL o f hexanes was added,
and the mixture was filtered again. Concentration o f the filtrate under vacuum yielded a
colourless transparent oil (if still cloudy, repeat hexane wash and filtration again).
Purification o f the residue was accomplished using silica gel chromatography in which the
silica was pretreated with 1% triethylamine in hexanes, and the eluent was a 15:1 mixture
o f hexanes:ethyl' acetate in which 0.5% triethylamine was added. The product was
obtained as a colourless transparent oil in a yield o f 87% (12.6 mg). Spectral data for the
product is as follows. 'H NMR (300 MHz, CDCb): 6 5.90 (dt, 1H, J=15.3,6.4 Hz), 5.85
(d, 1H, J=15.4 Hz), 4.76 (d, 1H, J=1.3 Hz), 4.73 (d, 1H, J-1.3 Hz), 4.75-4.60 (m, 1H),
4.19 (s, 2H), 2,4-2,0 (m, 8 H), 1.8-1.5 (m, 6 H), 1.7? (s, 3H), 0.88 (s, 9H), 0.21 (s, 9H),
0.07 (s, 3H), 0.05 (s, 3H). ,3C NMR (75.5 MHz, CDCb): 8 154.9 (s), 148.4 (s), 139.3
(s), 138,1 (s), 132,0 (d), 127.4 (d), 111.0 (t), 93.9 (t), 79.4 (d), 46.7 (d), 37.9 (d), 33.6
(t), 31.2 (t), 29.4 (t), 28.8 (t), 27.8 (t), 26.0 (q), 22.7 (t), 19.0 (s), 18.4 (q), 0.09 (q), -4.5
(q), -4,7 (q). IR (CHCI3, cm ') 2920 (s, sh), 2358 (m), 1597 (m), 1462 (m), 1320 (m, br),
1254 (m, sh), 1054 (m, br), 851 (s, sh). LRMS m/e (relative intensity): 460 (M+, 100),
417 (18), 329 (38), 303 (62). HRMS calcd for CzT^gOzSiz: 460.3193, found: 460.3184.
176
Attempted Diels-Alder Reaction of 157.
To a silylated thick-walled glass tube was added 157 (52 mg, 0.011 mmol) in
toluene (10 mL). Note: also some IMDAC attmepts, methylene blue (-0.5 mg) was also
added to the tube. The tube was then sealed under vacuum at liquid nitrogen temperature.
The tube was then placed in a 200°C oven for 16 hours. After cooling to RT, the base o f
the tube was immersed in liquid nitrogen until the contents solidified, at which point the
tube was opened. Following removal o f the solvents by rotary evaporation, the residue
was chromatographed over silica gel to yield 36 mg o f material which showed, by 'H
NMR to have the TBDMS bond partially cleaved. The material was then dissolved in
THF (1 mL) to which tetrabutylammonium fluoride (1M in THF, 50 pL, 0,05 mmol) was
added. After two hours, the reaction was quenched with brine, The organic and aqueous
layers were then separated, and the aqueous layer extracted three times with diethyl ether.
The combined organic layers were then dried over anhydrous magnesium sulfate, filtered
and concentrated. The residue was then chromatographed over silica gel to afford two
sets o f two compounds in yields o f 8 mg and 11 mg respectively (compound set ‘A’ and
‘B’), Compound set "A’ appeared to be some sort of decompositional product, but the
less polar compound set ‘B’ could be further purified to individually isolate the two
compounds. Spectral data for the major product in compound set ‘B’ (recoverd in a 7 mg
yield) is as follows: 'H NMR (300 MHz, CDCI3): 5 4.72 (d, 1H, J-1 ,6 Hz), 4,68 (d, 1H,
J=1.6 Hz), 3.82 (dd, IH, J=3,8, 4.2 Hz), 2,50-1.6 (m, -1 0 H), 2,20 (s, 3hw), 1,65 (s, 3H),
1.60 (s, 3H), 1.4-1.0 (m, 4 H). IR (CHCIj, cm ') 3614 (m), 2933 (s), 1705 (s), 1450 (w),
1429 (m, br), 1046 (m), 908 (m, sh). LRMS m/e (relative intensity) 274 (59), 256 (64),
215 (44), 91 (100).
177
2-Oxa-4-methoxy-4,5,6,7,8,9-hexahydroindan-1 ,3,6-trione (167):
0
To a solution o f Danishefsky’s Diene ( l-methoxy-3-trimet hylsiloxy-1,3-butadiene,
0.195 mL, 1.0 mmo!) in toluene (6 mL) was added maleic anhydride (98 mg, 1.0 mmol).
The resulting solution was then heated to reflux and was stirred overnight. After cooling
the reaction, IN HC1 (1 mL) was added, and the mixture was stirred for 20 minutes,
Following separation o f the organic and aqueous layers (and extraction o f the aqueous
phase with diethyl ether), the organic fractions were dried over anhydrous magnesium
sulfate, filtered and concentrated by rotary evaporation. The residue was then
chromatographed over silica gel, using a 1:1 mixture o f hexanes:ethyl acetate as an eluent.
The product was obtained as a pale yellow oil in a yield o f 95% (188 mg). Spectral data
for the product is as follows: *H NMR (250 MHz, CDC13): 5 4.25 (m, 1H), 3.8-3.5 (m,
2H), 3.30 (s, 3H), 3.0-2.7 (m, 3H), 2.3 (dd, 1H, J=13, 2.2 Hz). LRMS m/e (relative
intensity) 199 (M +l, 100), 167 (M-32, 82).
178
2-Oxa-5-carboniethoxy-4,7.8,9-tetrahydromdan-l,3-dione (168):
0h3co2c
.0
0To a solution o f 3-carbomethoxy-2,5-dihydrothiophene-l,l-dioxide4la (44: 176
mg, 1.0 mmol) in toluene (6 mL) was added maleic anhydride (98 mg, 1.0 mmol). The
resulting solution was then heated to reflux and was stirred overnight. After cooling, the
solvent was removed by rotary evaporation. The residue was then chromatographed over
silica gel, using a l l mixture o f hexanes:ethyl acetate as an eluent. The product was
obtained as a pale yellow oil in a yield o f 95% (200 mg). Spectral data for the product is
(dd, 1H, J=14, 2.5 Hz}, 2I S (m, 1H), 2.40 (m, 2H). LRMS m/e (relative intensity) 211
(63), 179 (100). HRMS calcd for C,oH100 5: 210.0596, found: 210.0593.
2,5-Dihydrothiophene-3-carboxylic acid (172):
To a solution o f IN NaOH (5 mL) was added 3-carbomethoxy-2,5-
dihydrothiophene4lb (43: 160 mg, 1.10 mmol). In order to partially solubilize the ester 43,
~1 mL o f methanol was added as well. The resulting mixture was then stirred at room
temperature overnight. After acidification o f the solution (to pH 2.0) with IN HC1, the
solution was extracted repeatedly with diethyl ether. After drying the ether extracts over
anhydrous magnesium sulfate, the solution was concentrated to give a white solid (172:
as follows: 'H NMR (250 MHz, CDCI3) 5 7.1 (m, 1H), 3.75 (s, 3H), 3.45 (im, 2H), 3.05
C02H
179
mp 97°C) in a yield o f 97% (139 mg). The spectral data is as follows: *H NMR (90 MHz,
CDCb) 8 12.5 (hr s, 1H), 7.0 (s, IK), 4.1-3.8 (br s, 4H). LRMS m/e (relative intensity)
130 (100), 85 (88), 44 (53). HRMS calcd for CjHsCbS: 130.0089, found: 130.0080.
Anal. Calcd for CsHeCbS: C, 46.28; H, 4.63, found. C, 46.15; H, 4.62.
2,5-Dihydrothiophene-l,l'dioxide-3-carboxam ides (173a-c):
O
u173a: R=
H3C^ \
s0 2
173b: R=NHiPr 173c: R-NEt2
Thionyl chloride (0.11 mL, 1.5 mmol) was added to a solution o f acid 172 (130
mg, 1 mmol) in dichloromethane (10 mL). The resulting mixture was then refluxed for 5
hours. After cooling to room temperature, the solvent was removed under vacuum, then
the residue was redissolved in THF (8 mL). After cooling the solution to 0°C, the various
amines could be added (1.3 mmol of: Evans Chiral Oxizolidinone, isopropylamine or
diethylamine). Note: addition o f -1 0 equivalents o f pyridine is useful in accelerating the
rate o f the reactions. The resulting solution was then stirred overnight at room
temperature. Saturated ammonium chloride (10 mL) was then added, the aqueous and
organic phases were separated, and the aqueous phase was extracted with diethyl ether
three times. The combined organic fractions were then dried over anhydrous magnesium
sulfate, filtered, and concentrated by rotary evaporation. The residue was then
chromatographed over silica gel using a 1:1 mixture o f hexanes:ethyl acetate as an eluent.
The product dihydrothiophene amides were recovered in 82, 89 and 78% yields
180
respectively. The sulfur atom was then oxidized using the following procedure:
dihydrcthiophene amides were dissolved in a minimum volume o f methanol (-1 mL), to
which a slurry o f MMPP (1.1 equivalent) in water (-1.5 mL) was added. The resulting
mixture was then stirred at 50°C for 2 hours. Water (3 mL) and dichloromethane (5 mL)
were then added. The aqueous and organic phases were then separated and the aqueous
phase was extracted three times with dichloromethane. The combined organic fractions
were then dried over anhydrous magnesium sulfate and concentrated by rotary
evaporation to give white crystalline solids 173a-c in yields o f 88, 91 and 83% (mp for
173c 202°C (dec.)). The spectral data for these compounds is as follows: 173a: 'H NMR
(250 MHz, CDCI3): 8 7 5-7.3 (m, 5H), 6.80 (m, 1H), 5.80 (m, 1H), 5.15 (m, 1H), 4.75
(qi, 1H, J=6.7 Hz), 4.15 (br s, 1H), 3.98 (m, 1H), 3.8-3.55 (m, 1H), 0.98 (d, 3H, J=6.7
Hz) IR (CHCI3, cm-') 3040 (m), 2950 (w), 1760 (s), 1680 (m), 1350 (s), 1200 (m), 1130
(m). LRMS m/e (relative intensity): 362 (M+41, 7), 350 (M+29, 15), 322 (M +l, 50), 279
(23), 214 (100). HRMS calcd for CisHisNCfc (M -S02). 257.1052, found: 257.1054.
Anal. Calcd for CI5H ,5N0 3 : C, 70.03; H, 5.84; N, 5.44. found: C, 70.12; H, 5.85; N,
5,38. Spectral data for 173b: *H NMR (250 MHz, CDCI3): 6.65 (m, 1H), 4.10 (br s, 1H),
3.95 (m, 2H), 3.80 (m, 2H), 1.82 (m, 1H), 1.3 (d, J=6.7 Hz, 6H). Anal. Calcd for
CgHnNOjS: C, 47.29; H, 6.40; N, 6.90. found: C, 47.31; H, 6.33; N, 6.85. Data for
173c: 'H NMR (250 MHz, CDCI3); 6.60 (m, 1H), 3.90 (m, 2H), 3.75 (m, 2H), 3.45 (q,
4H, J=6.4 Hz), 1.35 (t, 6H, J=6.4 Hz). Anal. Calcd for C9H,5N03S: C, 49.74; H, 6.78;
N, 6,27. ftn rd : C, 49.77; H, 6.91; N, 6.45.
181
Diels-Alder Reactions o f Sulfolenes 173:
COR
3 •0 2 TMSO
173a-cno°r
41
ROC COR
ROC
^ 175a-cT74a-c
To a solution o f model bis-diene 41 (222 mg, 1.0 mmol) in toluene ( 8 mL) was
added sulfolene 173 (1.0 mmol). The resulting mixture was then refluxed for 16 hours.
After cooling, the solvent was removed by rotary evaporation and the residue was
cliromatographed over silica gel using a 3:1 mixture o f hexanes:ethyl acetate as an eluent.
When 173a was used as a starting material, only dimer 175a was recovered (in a yield o f
83%). The spectral data is as follows for 175a: 'H NMR (250 MHz, CDCb): 8 7.4 (m,
10H), 6.2 (m, 2H), 5.8 (m, 2H), 5.15 (d, 1H, J=10.7 Hz), 5.00 (d, 1H, J=16.7 Hz), 4,95-
4.85 (m, 2H), 2.9 (m, 2H), 2.65-2.4 (m, 4H), 0.80 (m, 6 H). IR (CHC13, c m 1) 2950 (m,
br). 1750 (s), 1720 (m), 1660 (m), 1340 (m). 1200 (m, br). LRMS m/e (relative
intensity): 555 (M+41, 5), 543 (M+29, 9), 515 (M +l, 36), 353 (3), 338 (16), 310 (100).
HRMS calcd for C30H30N2O6 : 514.2105, found: 514.2105.
i f :
REFERENCES:
1. Historical Dates and General References Provided by: (a) Klyne, W. The Chemistry o f
Steroids J, Wiley & Sons, I960, New York, (b) Fieser, L.F.; Fieser, M .uteroids
Reinhold, New York, 1959 (chapters 1 and 2 and references contained therein).
(c) Klimstra, P.D. Androgenic and Anabolic Steroids in Intra-Science Chemistry
Reports 1969, 3(1) (pp 83-99). (d) Hoberman, J.M.; Yesalis, C.E. Scientific
American, 1995, 272 (2), 76.
2. For General References, see: (a) Stryer, L. Biochemistry 3rd Ed. W.H. Freeman
& Co., New York, 1988 (pp 554-571). (b) Lehninger, A.L.; Nelson, D.L.; Cox,
M.M.Princinples o f Biochemistry 2nd Ed. Worth, Toronto, 1993 (pp 674-680).
3. (a) Morrison, R.T.; Boyd, R.N. Organic Chemistry 5th Ed, Allyn and Bacon Inc.
Toronto, 1987 (pp 659-660). (b) Pine, S.H.^Organic Chemistry 5th Ed. McGraw
Hill Inc. Toronto, 1987 (pp875-880).
4. Torsell, K.B.G. Natural Product Chemistry J. Wiley & Sons, Toronto, 1983 (pp
198-215),
5. Schulster, D.; Burstein, D.; Cooke, B.A. Molecular Endocrinology o f Steroid
Hormones J. Wiley & Sons, Toronto, 1976 (pp 126-134).
6. Lehninger, A.L.; Nelson, D.L.; Cox, M M , Principles o f Biochemistry 2nd Ed. Worth
Publishing Co, Toronto, 1993 (pp 256).
183
7. Stryer, L. BiochemisUy 3rd Ed. W. H. Freeman & Co. New York, 1988 (pp 1000-
1001).
8. (a) Bruchovshy, N,; Lesser, B. Control o f Proliferative Growth in Androgen
Responsive Organs and Neoplasms, Chapter 1 in Cellular Mechanisms
Modulating Gonadal Hormone Action: Singhal, R.L.; Thomas, J.A. Eds.
University Press, Baltimore, 1976. (b) Mainwaring, W.I.P. The Mechanism o f
Action o f Androgens Springer Verlag. New York, 1977.
9. Hoberman, J.M.; Yesalis, C.E. The History o f Synthetic Testosterone, Scientific
American 1995, 272 (2), 76.
10. Yen, S.C. and coworkers, as cited in Chemical & Engineering News 1995, 73(26),
28 .
11. Barton, D.H.R. Experientia 1950, 6, 316.
12. van Tamelen, E.E.; Willet, J.; Schwartz, M.; Nadeau, R ../. Am. Chem. Soc. 1966,
88, 5937.
13. Sharpless, K.B. J. Am. Chem. Soc. 1970, 92, 6999,
14. Corey, E.J.; Lee, J.; Liu D.L. Tetrahedron Lett. 1994,35 (49), 9149,
184
15. (a) van Tamelen, E.E.; Milne, G.M.; Sufthess. M.I.; Rudler Chauvin, M.C. J. Am.
Chem. Soc. 1970, 92, 7202. (b) Anderson, R.J.; Achini, R.S. J. Am. Chem. Soc.
1970, 92, 7202.
16. van Tamelen, E.E.; Freed, J.H. ibid 1970, 92, 7204.
17. Woodward, R.B.; Sondheimer, F.; Taub, D.; Heusler, K.; McLamore, W.M. J. Am.
Chem. Soc. 1951, 73, 2404.
18. Cohen, N. Arc. Chem. Res. 1976, 9, 412 and references contained therein.
19. Woodward, R.B.; Sondheimer, F.; Taub, D. J. Am. Chem. Soc. 1951, 73, 3548.
20. Woodward, R.B.; Patchett, A,A.; Barton, D.H.R.; Ives, D.A.; Kelly, R.B. J. Am.
Chem. Soc. 1954, 76, 2852.
21. Wasserman, A. Diels-Alder Reactions, Elsevier, 1990, New York.
22. For reviews and texts, see: (a) Carruthers, W. Cycloaddition Reactions in Organic
Synthesis, Pergamon, 1990, Oxford (and references cited therein), (b) Pinder,
U.; Lutz, G ; Otto, C. Chem. Rev. 1993, 93, 741. (c) Houk, K.N.; Li, Y.;
Evanseck, J.D. Angew. Chem. Int. Ed. Engl. 1992, 3 1 ,682.
23. Fleming, I. Frontier Orbitals and Organic Chemical Reactions, Wiley Interscience,
1976, New York,
185
24. Carey, F.A.; Sundberg, R.J. Advanced Organic Chemistry (3rd Ed. Part B), Plenum,
1990, New York (pp287).
25. (a) Kobuke, Y.; Sugimoto, T.; Furukawa, J.; Funco, T. J. Amer. Chem. Soc. 1972,
94, 3633. (b) Williamson, K.L.; Hsu, Y-F. L. J. Amer. Chem. Soc. 1970, 92,
7385.
26. (a) Kiselev, V.D.; Konovalov, A.I. Russian Chem. Rev. 1989,58, 230, (b) Evans,
D.A.Science, 1988, 240, 420.
27. Nicolaou, K.C.; Barnette, W.E.; Ma, P. J. Org. Chem. 1980, 45, 1463.
28. Takahashi, T.; Shimizu, K.; Doi, T.; Tsuji, J.; Fukazawa, T. J. Amer. Chem. Soc.
1988 ,110, 2674.
29. (a) Deslongchamps, P. Aldrichimica Acta. 1991,2 4 ,43. (b) Ndibwami, A.;
Lamothe, S.; Guay, D.; Plante, R.; Soucy, P.; Goldstein, S.; Deslongchamps, P.
Can. J. Chem. 1993, 71 ,695.
30. Ihara, M,; Sudow, I.; Fukumoto, K.; Kametani, T. J. Chem. Soc. Perkin Trans. 1.
1986, 117.
31. Joumet, M.; Malacria, M. J. Org. Chem. 1994,5 9 ,6885.
186
32. For examples, see: (a) Johnstone, R A W .; Quan, P.M ../. Chem. Soc. 1963,935.
(b) Houk, K, N.; Luckus, L . J . Org. Chem. 1973, 38, 3836. (c) Belleville,
D.J.; Nathan, L.B. J. Am. Chem. Sjc . 1982,104, 2665.
33. Ito, Y ; Hirao, T.; Saegusa, T ../. Org. Chem. 19^8,43, 1011.
34. Trost, B.M.; Tanoury, G.J.; Lautens, M.; Chan, C.; MacPherson, D.T. J. Amer.
Chem. Soc. 1994,116, 4255.
35. Liu, H.J.; Ngooi, T.K.; Browne, E.N.C. Can. J. Chem. 1988, 66, 3143. House,
H.O.; Csuba, L.J.; Gall, M.; Olmstead, H .D .J. O rg Chem. 1969, 34, 2324.
36. Liu, H.J.; Feng, W.M. Synth. Commun. 1987,17(15), M i l .
37. (a) Preliminary studies towards the ketone :0 were conducted by John Bishop,
University o f Victoria Summer Student, May-August, 1991. (b)Spino, C.;
Crawford, J. Tetrahedron Lett. 1994, 35, 5559.
38. For a review o f the Claisen Rearrangement, see: Ziegler, F.E, Chem. Rev. 1988,88,
1423.
39. Berube, G.; Fallis, A,G, Can. .1. Chem. 1991, 69, 77.
40. Omura, K.; Swem, D, Tetrahedron 1978,34, 1651.
187
41. (a) McIntosh, J.M.; Sieler, R.A. J. Org. Chem. 1978,43, 4431, (b) Honek, J.F.;
Mancini, M.L.; Belleau, B. Synth. Comm. 1984,14 ,483.
42. Spino, C,, Crawford, J. Can. J. Chem. 1993, 7 1 ,1094.
43. (a) Rideout, D C .; Breslow, R. J. Am. Chem. Soc. 19S0,102, 7817. (b) Grieco,
P.A.; Gamer, P.; He, Z.M. Tetrahedron Lett. 1983, 24, 1897. (c) Otto, S.;
Blokzijl, W.; Engberts, J.B.F.N. J. Org. Chem. 1994, 59, 5372.
44. Larsen, S.D.; Grieco, P.A. J. Am. Chem. Soc. 198S, 107, 1768.
45. DeGraw, J.I.; Goodman, L.; Baker, B.R. J. Org. Chem. 1961, 26, 1156.
46. Evans, D.A.; Chapman, K.T.; Bisaha, J. Tetrahedron Lett. 1994, 2 5 ,4071.
47. (a) Pd/BaSOVquinoline/EtOH: Rama Rao, A.V.; Pulla Reddy, S.; Reddy, E.R. J. Org,
Chem. 1986,5 1 ,4158, (b) Pd/CaCOa/benzene: Chauhan, Y.S.; Chandraratna,
R.A.S.; Miller, D.A.; Kondrat, R.W.; ReischI, W,; Okamura, W ,H../. Am. Chem.
Soc. 1985,107, 1028. (c) Pd/BaSOVpyridine/MeOH: De Schong, P.; Kell, D.A.;
Sidler, D.R. J. Org. Chem. 1985,5 0 ,2309. (d) Pd/BaSO^quinoline/EtOAc:
Kerdesky, F.A.J.; Schmidt, S.P.; Brooks, D.W.; J. Org. Chem. 1983, 4 8 ,3516.
48. de Meijere, A.; Meyer, F.E Angew. Chem. Int. Ed, Engl. 1994,3 3 ,2379 (and
references contained therein).
188
49. (a“ leffery-Luong, T.; Linstrumelle, G. Synthesis, 1983, 32. (b) Takahashi, S.;
Kuroyama, Y.; Sonogashira, K.; Hagihara, N. Synthesis, 1980, 627.
50. Heck, R.F. Acc. Chem. Res. 1979,12, 146 (and references contained therein)
51. (a) Hayashi, T.; Kubo, A.; Ozawa, F. Pure Appl. Chem. 1992, 64, 421. (b)
Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Left. 1975, 4467.
52. (a) Taber, D.F.; Saleh, S.A. J. Am. Chem. Soc. 1980,102, 5085. (b) Wilson, SR.;
Mao, D.T. J. Am. Chem. Soc. 1976, 98, 6289. (c) lhara, M.I., Sudow, 1.;
Fukumoto, K.; Kametani, T. J. Chem. Soc. Perkin Trans. 1 1986, 117.
53. Atomic coordinates can be obtained from: The Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
54. Jolly, R.S.; Luedke, G.; Sheehan, D.; Livingstone, T. J. Am. Chem. Soc. 1990,112,
4965.
55. Aerssens, M.H.P.J.; van der Heiden, R.; Heus, M,; Brandsma, L. Synth. Comm. 1990,
20, 3421.
56. Abraham, R.J.; Fisher, J. Introduction to NMR Spectroscopy J, Wiley & Sons,
Toronto, 1988 (pp 45).
57. Spino, C,; Crawford, J.; Bishop, I. J, Org. Chem. 1995,60, 844,
189
58. (a) Brown, H.C.; Negishi, E,I. J. Chem. Soc. Chem. Comm. 1968, 594. (b) Brown,
H.C.; Negishi, E.l. J. Am. C krU »c. 1967, 89, 5477,
59. Unpublished results from the Spino Laboratory from Helen Mitchell, undergraduate
honours student (Chem. 499), University o f Victoria, 1994.
60. Levene, P. A, Org. Syn. Collective Volume 2. J. Wiley & Sons, New York,
1943, p. 88.
61. Urquharf, G.C.; Gates, J.W.; Connor, R. Org. Syn. Collective Volume 3. J.
Wiley & Sons, New York, 1955, p. 363.
62. Liu, H.J.; Ngooi, T.K. Can. J. Chem. 1982, 60, 437.
63. Chou, T.S.; Liu, H.M.; Chang, C.Y. Bull. Inst. Chem., Academia Sinica 1990, 3 7 ,21,
64. Torkelson, S.; Ainsworth, C. Synthesis 1976, 722.
65. Mehta, G.; Padma, S. J. Amer. Chem. Soc. 1987,109, 7230.
66. Chan, T.H.; Brook, M.A.; Chaly, T. Synthesis 1983,203.
67. Dess, D.B.; Martin, J.C. J. Am. Chem. Soc. 1991,113 ,7277,
68. Ireland, R.E.; Highsmith, T.K.; Gegnas, L.D.; Gleason, J.L ../. Org. Chem. 1992,57,
5071.
69. (a) Trost, B.M.; Lautens, M.; Chan, C.; Jebartnam, D.J.; Mueller, T ../. Am. Chem.
Soc. 1991,113, 636. (b) Trost, B.M.; Romero, D.L.; Rise, F. J. Am. Chem. Soc.
1994, 116, 4268. (c) Trost, B.M. Angew. Chem. Int. lul. Engl. 1995, 34, 259.
70. (a) Synthesis o f dba: Conard, C.R.; Dolliver, M.A. Org. Synth. Coll. Vol. 2. John
Wiley & Sons, New York, 1943, p. 167. (b) Synthesis o f catalyst: Ukai, T.;
Kawazura, K.; Ishii, Y. J. Organometallics. Chem. 1974, 65, 253.
71. Reich, H i.; Eisenhart, E.K.; Olson, R.E.; Kelly, M .J../. Am. Chem. Soc. 1986, 108,
7791.
72. Brown, H.C.; Hamaoka, T.; Ravindran, N. J. Am. Chem. Soc. 1973, 95, 5786,
73. Tsuda, T.; Yoshida, T.; Kawamoto, T.; Saegusa, T. J. Org. Chem. 1987, 52, 1624.
74. (a) Normant, J.F.; Bourgain, M. Tetrahedron Led. 1970, 2659. (b) Midland, M.M.;
Nguyen, N.H. J. Org. Chem. 1981,4 6 ,4108.
75. Marskens, K.; Minnikin, D.E.; Polgar, N. J. Chem. Soc. (C) 1966,2113,
76. Franzus, B.; Snyder, E.I. J. Am. Chem. Soc. 1965,8 7 ,3423.
191
77. Grant, B.; Djerassi, C. J. Org. Chem. 1974, 3 9 ,968.
78. (a) Molloy, B.B.; Hauser, K .L ../. Chem. Soc. Chem. Comm. 1968, 1017. (b) Johnson,
W.S.; Lyle, T.A.; Daub, G.W. J. Org. Chem. 1982, 47, 163
79. Zweifel, G.; Steele, R.B. J. Am. Chem. Soc. 1967,89, 2754.
80. Labradie, J.W.; Tueting, D.; Stifle, J.K. J. Org. Chem. 1983, 4 8 ,4634.
81. (a) Hibino, J.I.; Matsubara, S.; Morizawa, Y.; Oshima, K.; Nozaki, H. Tetrahedron
Lett. 1984, 25, 2151. (b) Idem J. Organometallic Chem. 198S, 2 8 5 ,163.
82. Stillc, J.K.; Groh, B.L. J. Am. Chem. Soc. 1987,109, 813.
83. Ihara, M.; Sudow, I.; Fukumoto, K.; Kametani, T. J. Chem. Soc. Perkin Trans. I
1986, 117.
84. Nishiyama, H.; Kitajima, T.; Matsumoto, M.; Itoh, K. J. Org. Chem. 1984, 49, 3281,
85. (a) Stork, G.; Kahn, M. J. Am. Chem. Soc. 198S, 107, 500. (b) Stork, G.; Mah, R.
Tetrahedron Lett. 1989,3 0 ,3609.
86. Stork, G.; Sofia, M.J. J. Am. Chem. Soc. 1986,108,6826.
87. Fitjer, L.; Quabeck, U. Synth. Comm. 1985, 855,
192
88. (a) Tebbe, F.N.; Parshall, G.W.; Reddy, G.S. J. Am. Chem. Soc. 1978, 100, 3611.
(b) Pine, S.H.; Shen, G.S.; Hoang, H. Synthesis, 1991, 165,
89. (a) Chan, T.H.; Chang, E. J. Org. Chem. 1974,39, 3264. (b) Peterson, D .J../. Org.
Chem. 1968, 33, 780.
90. For reviews, see: (a) Curran, D. P. Synthesis 1988, 417. (b) Curran, D.P. Synthesis
1988, 489.
91. For recent reviews, see: (a) Blagg, J. Contemporary Organic Synthesis 1995, 42.
Casson, S.; Kocienski, P. Contemporary Organic Synthesis 1995, 19.
92. Schwartz, J.; Labinger, J. A. Angew. Chem. Int. Ed. Engl. 1976,15, 333.
93. Carr, D.E ; Schwartz, J. J. Am. Chem. S 'e. 1979,101, 3521.
94. Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197.
95. Nakano, T.; Ishii, Y.; Ogawa, M. J. Org. Chem. 1987,5 2 ,4855. (b) Ishii, Y.;
Nakano, T.; Inada, A.; Kishigami, Y.; Sakurai, K.; Ogawa, M. J. Org. Chem.
1986,5 1 ,240.
96. Fleming, I.; Paterson, I. Synthesis, 1979, 736,
193
97. (a) Taber, D.F.; Saleh, S.A. J. Am. Chem. Soc. 1980,102, 5085. (b) Idem
Tetrahedron Lett. 1982, 23, 2361.
98. Mappus, E.; Renaud, M.; Rolland de Ravel, M.; Grenot, C.; Cuilleron, C.Y. Steroids
1992,57,122.
99. Unpublished results from Christian Beaulieu, summer research student, Universite de
Sherbrooke, 1995.
100. Noyori, R.; Tomino, Y.; Nishizawa, M. J. Am. Chem. Soc. 1984,106, 6709.
101. Corey, E.J.; Cimprich, A. J. Am. Chem. Soc. 1994,116, 3151,
102. Danishefsky, S.; Kitahara, T. J, Am. Chem. Soc. 1974, 96, 7807.
103. Studies conducted by Claude Spino at the University o f Victoria, 1992,
104. Baraldi, P.G.; Barco, A.; Benetti, S.; Manfredini. S.; Pollini, G.P.; Simoni, D.;
Zanirato, V. Tetrahedron 1988,4 4 ,6451.
105. (a) Townshend, R.E.; Ramunni, G.; Segal, G.; Hehre, W.J.; Salem, L, J. Am. Chem.
Soc. 1976,9 8 ,2190. (b) Bach, R.D.; McDougall, J.J.W.; Schlegel, H.B.; Wolber,
G.J. J. Org. Chem. 1989,5 4 ,2931.
106. Evans, D.A.; Bartoli, J.; Shih, T.L. J. Am. Chem. Soc. 1981,103,2127.
107. Preliminary studies with 173b and 173c in dimerization reactions, the results o f
which have not yet been published, were conducted by Gang Liu, Masters Student,
University o f Victoria, 1992, and Eva Boeringer, co-op student, University o f
Victoria, 1992.
195
APPENDIX ONE:
A l.l; 2-Carbomethoxvbutadiene as a Diene:
As stated in section 2.3.1, 2-carbomethoxy- 1,3-butadiene, 45, proved to react in
DAC reactions as a diene as well as a dienophile (when reacted with electron-rich dienes).
This behaviour prevented 45 from being used as a bis-dienophile in the sequential DAC
strategy. Since this behaviour was unexpected, and therefore interesting, various studies
were conducted to try to determine exactly how reactive 45 was as a diene, relative to
other dienes.
A l.l . i : Determination of the Enophilicity of 45:
Generally, the strategy o f these studies was to react 45 with dienes of varying
reactivity, and then evaluate the product mixture to determine exactly what happened in
the reaction. If 45 reacts only with itself (one molecule acting as a diene, the other as a
dienophile to give dimer 47), and not with the ‘other’ diene (to give the cross-
cycloadduct), then one can conclude that 45 is a more reactive diene than the ‘other’
diene. Conversely, if the cross-cycloadduct is obtained (between 45 and the ‘other’
diene), then the ‘other’ diene is more reactive than 45 as a diene (See Scheme A-l). By
conducting experiments o f this nature with a series o f ‘other’ dienes, the goal o f the study
was to place 45 in terms o f diene-like reactivity on a reactivity ‘scale’ relative to the well
known reactive dienes.
H3CO2C |C02 CH3 OR H3 C02CPhCHy
H3 CO2 C47: dimer
of 45cross cycloadduct with 'other1 diene
Scheme A -l
196
The earliest studies o f this sort were conducted using diene 35 (2-trimethylsiloxy-
1,3-pentadiene). When equivalent portions o f 45 and 35 were to be reacted together, then
the ratio o f the dimer:cross cycloadduct was 2:1. This tendency towards dimerization
could be reduced, in part, through the addition o f more 35: when five equivalents o f 35
were used, then the ratio dropped to 1:4. Unfortunately, the same was not true with the
model bis-diene 41 ((E,E)-2-trimethylsiloxydeca-l,3,7,9-tetraene): all attempts at
obtaining the cross cycloadduct were unsuccessful (see Table A-l). This result may be
explained, at least in part, by an increase in the steric bulk o f the alkyl substituent at C4 in
41 when compared to 35.
The next set o f experiments used the well known highly reactive Danishefsky’s
diene (165: l-methoxy-3-trimethylsiloxy-1,3-butadiene) in the competition study.
Somewhat surprisingly, these studies clearly showed that 45 was extremely reactive as a
diene, much more so than was originally anticipated. As shown in Table 1-A, when
equimolar amounts o f 45 and 165 were reacted, the ratio of dimer: cross cyloadduct was
1:2, which implies that 45 was competing with 165 for diene-like reactivity. Similar to the
case with the diene 35, increasing the equivalents o f 165 to five decreased the amount o f
dimer (ratio dropped to 1:9).
One potential rationalization for the results shown in Table A-l is that the //; situ
generation o f 45 from the sulfolene precursor 44 (via the previously described cheletropic
elimination o f sulfur dioxide) may occur in such a way that there are local concentration
differences. This rationalization assumes that 44 eliminates sulfur dioxide in such a way
that there are localized high concentrations o f 45, which would ‘enhance’ the formation o f
the dimer 47.
197
Table A-l: Thermal Reaction o f45 With Various Dienes
Rxn. # Diene (Equivalents)'1 Ratio o f 47: Cross
Cycloadductb
Combined Yield of
Adducts (%)c
1 35(1.0) 2:1 95
2 35 (5.0) 1:4 95
3 41 (1.0) >50:1 88
4 41 (5.0) >50:1 82
5 165(1.0) 1:2 89
6 165 (5.0) 1:9 80
“Relative to 45 being 1.0 equivalent.b47 is dimer of 45, Cross Cycloadduct is adduct of 45 with 35,41 or 165 respectively. “Yields measured after chromatography.Note: 45 generated in situ via thermal means from 44
Such an argument can be dismissed, however, based on two pieces o f evidence,
The first is that slow addition o f a solution o f 44, via syringe pump (which will guarantee
that there will always be a low concentration o f 45 relative to the ‘other’ diene), to a
refluxing solution o f dienes 35 or 41 did not prevent the formation o f 47. The other piece
o f evidence is that generation o f 45 via an alternate method, through the base-promoted
elimination o f HBr from precursor 166 (see Scheme A-2), did not serve to reverse the
product distributions (Table A-2).42’103 In fact, the room temperature generation o f 45
actually resulted in the formation o f a higher amount o f dimer than with the thermal route.
CO2 CH3 E N CO2 CH3
l e t Br CHzClj/RT 4 t
Scheme A-2
198
Table A-2: RT Reaction o f 45 With Various Dienes.
Rxn. # Diene (Equivalents)3 Ratio of 47:Cross
Cycloadductb
Combined Yield of
Adducts (%)c
1 35(1.0) 9:1 94
2 35 (5.0) 3:1 93
3 165(1.0) 3:1 80
"Relative to 45 being 1.0 equivalent.b47 is dimer of 45, Cross Cycloadduct is adduct of 45 with 35.41 or 165 respectively.°Yiclds measured after chromatography.Note: 45 generated in situ from 166
Another variation of the above competition study theme was carried out using an
electronically activated dienophile in the reaction mixture as well. In this case, maleic
anhydride was reacted with 45 and 165 individually to determine the extent o f the
reaction, As expected (shown in Table A-3), the maleic anhydride reacted with the
Danishefsky’s diene (165) in near quantitative yields to give the expected cycloadduct
167. The reaction o f 45 with maleic anhydride also yielded a near quantitative yield o f
cycloadduct in which 45 acted exclusively as a diene (no dimer was present) to give 168 as
a product (see Table A-3 and Scheme A-3). The competition experiment involved the use
o f one equivalent o f each reagent (45, 165 and maleic anhydride), and gave the product
distribution shown in the table. A point o f note is that the yield o f the dimer is measured
based on the quantity o f 45 consumed (i.e. 0.375 equivalents o f 47 were generated, which
required 0,75 equivalents o f 45). These results essentially confirm the other competition
studies: 45 is capable o f competing, in diene-like reactivity, with Danishefsky’s diene.
199
TM SO
165
h 3c o 2c x ^
X *45
0
.0
168 0O
Scheme A-3
Table A-3: Reaction o f 45 and 165 with Maleic Anhydride
Rxn. # Equivalents o f Reagents:
45,165, Maleic Anhydride
Product Yields (%):
47, 167, 168
1 0 ,1 ,1 0, 95 ,0
2 1 ,0 ,1 0, 0, 95
3 1,1 ,1 75, 20, 55
The high diene-like reactivity o f 45 is puzzling. One would expect, by FMO
arguments,23 to consider 45 to be an electronically activated dienophile. Usually,
‘activated’ dienes bear electron rich groups (such as Danishefsky’s diene). The fact that
45 tends to dimerize is unexpected in that, for the reaction to occur, an electronically
activated dienophile (electron-poor) is reacting with an electron-poor diene, even if other
electron-rich dienes are present.
At this stage, a number o f potential rationalizations can be put forward, The
possibility that the dimerization may occur via an electronic pathway can be dismissed due
to the regiochemistry o f the addition: a reaction involving a Micha il-like addition as the
first step in a cyclization pathway would require a different regiochemistry o f the product
200
than was obtained with 47. The possibility that the reaction may proceed through a
radical-type intermediate can also likely be dismissed due to the fact that the reaction can
be performed in the presence o f various radical quenching agents such as hydroquinone or
2,6-di-/e/7-butylphenol with no change in reactivity (for both the thermal and base-
catalyzed generation o f 45).
Two main possibilities remain to be considered to explain the reactivity o f the
dimerization. The first is that the reaction may be rapid due to steric reason That is, it
may be easier for 45 to dimerize, rather than react with one o f the ‘other’ dienes, simply
because there is lesser steric impediment to the dimerization than there is towards
formation o f the cross-cycloadduci. This argument can also be dismissed, due to the fact
that a structural analog o f 45, in which a thioether group is present (see compound 170,
which was generated from the precursor 169, as shown in Scheme A-4), also will
dimerize.42 In this case, the dimerization will take place at room temperature (in a neat
form) ever a period o f approximately 90 minutes, to give the cycloadduct 171, which has
a regiochemistry that is, again, consistent with that o f a concerted reaction. Clearly, if the
tendency o f 45 towards dimerization were to be only steric in nature, then one would
expect that the dimerization o f 170 would not proceed at all; which is clearly not the case.
By eliminating all other likely possibilities, one is left to conclude that the
dimerization reactivity o f 45 must be a result o f electronic factors. In fact, structural
C 0 2CH3CO2CH3(C 02CH3
CH2CI2/RT: 5-7 days
CH2CI2 MeS 4H3C 0 2C
169 170 171
Scheme A-4
201
analogs of 45, in which a different electron-withdrawing group is present at C2, also show
a tendency towards dimerization: the cyano atiislog shows comparable reactivity to 45.104
Although detailed calculations and kinetic measurements are still being conducted, a
potential rationalization can be developed. The reaction o f butadiene with ethylene has
been studied quite extensively, and it is proposed, that, in the transition state of the
reaction, there is a high double-bond character between C2 and C3 o f the butadiene.105 If
such a transition state were to be operative in the dimerization o f 45, then one would
expect that the 7i-electron withdrawing capability o f the ester group at C2 would serve to
stabilize the transition state through conjugation. Another potential factor to consider is
conjugation itself. A diene is a conjugated system, and, at some point in the reaction will
lose the conjugation to form the product. With an appropriate C2 substituent, this is not
true: the starting material 45 is conjugated with the ester, as is the product 47. This effect
may serve to lower the activation energy o f the reaction, which would serve to increase its
rate.
Al.1.2: Reactivity of S tructural Analogs of 45:
Since, in the previous section, it was determined that the diene-like character o f 45
was due to the C2 electron-withdrawing group, a few structural analogs o f 45 were
generated in an attempt to find molecule that would not dimerize, but would instead react
as an electronically activated dienophile. Clearly, if such a molecule could be found, then
it could potentially be used in the previously described Sequential Diels-Alder strategy
with a bis-diene (a tandem DAC may even be possible).
The general strategy towards this goal was to test the reactivity of various amide
analogs of 45. Accordingly, the experimental approach started with the generation o f the
carboxylic 172 acid from the ester 43, which proved to be facile (IN NaOH (with MeOH
added for solubilization)) and gave the acid in quantitative yields. The various amides
(173) could then be made through the addition o f the appropriate amines to the acid
202
chloride o f 172 (generated through the addition o f thionyl chloride), and subsequent
oxidation o f the sulfur atom (with MMPP). As seen in Scheme A-5, such a strategy could
allow access to a great deal o f structural analogs o f 45.
dC 0 2CH3 C 0 2H 1. (a) SOCI2 ,C 0 R1N NaOH f = ( (b) amine
S S 2. MMPP43 172
Scheme A-5
The testing o f the various amines as dienes or dienophiles were conducted through
the use o f the model bis-diene 41. The goal o f the reactions was to determine whether the
desired cross cycloadducts (reaction o f 173 with the electronically activated diene in 41 to
give 174) could be isolated instead o f the corresponding dimers (175: see Scheme A-6).
d0 2 TMSO
ROC COR
ROC110°C
^ 175
Scheme A-6
As expected, varying the C2 substituent had a profound effect on the reactivity of
the various analogs o f 45. As can be seen in '’'able A-4, the different amides show a
reactivity that is much lower than the ester 45, and the amides even show different
reactivity amongst themselves. For instance, the amide (173a), made from the E^ans
chiral auxiliary (176, see Figure A -l),106 showed a reasonably high diene-like character.
When reacted with the bis-diene 41, only dimer (175a) was isolated, and the reaction was
203
complete in 4-6 hours. In contrast, the isopropyiamide 173b also gave only dimer, but the
reaction was slower, requiring up to overnight reaction times for the reaction to be
complete. Going one step further to the diethylamide, 173c, there was no dimer and no
cross cycloadduct isolated from the reaction. The diene was apparently unreactive.107
Table A-4: Reactivity of Amide Analogs o f 45 in Reaction Shown in Scheme A-6.
Structure
#
R Dimer (175a-c) Cross Cycloadduct
(174a-c)
Reactivity (rel.
to 45=High)
173a 176 Yes No Moderate
173b NHiPr Yes No Low
173c NEt2 No No None
- IPh
176
Figure A -l: Evans Chiral Auxiliary
Unfortunately, attempts at tempering the reactivity o f the butadiene system to
enable the formation o f the cross cycloadduct with the bis-diene 41 while eliminating (or
reducing) the tendency towards dimerization were unsuccessful, Although some studies
are still being conducted, in the Spino laboratory, to determine if such a reactivity
‘window’ exists, to date, it has not been discovered.
However, such a strategy, if successful, could provide a very efficient route to the
perhydrophenanthrene skeleton, and even potentially to steroids, Particularly interesting is
the potential application o f chiral auxiliaries, such as the Evans auxiliary, shown in Figure
204
A-l. If the desired reactivity ‘window’ is found with such a system, then potential exists
for an enantioselective synthesis.
APPENDIX TWO: SPECTRASpectra Follow for the Following Compounds (as listed):
Compound#
'h n m r Infra-Red ,3c n m r !iC DEPT 2DNM R
37 X X
38 X X
40 X X
41 X X X X
44 X X
46 X X
47 X
55 X X
56 X X
57 X
58 X X
59 X X X X
60 X X
61. X X
63 X X
65 X X
66 X X
67 X X
68 X X X X
69 X X X X NOESY, COSY107 X X
108 X X
109 X X
n o X X
111 X X
112 X X
118 X X X X
138 X X
143 X X X X COSY, C-H Corr.144 X X
145 X X
146 X X X X
152 X X
157 X X
Table A-5: List o f Spectra
206
EtO
O fa J
1 8 1 * S •» 3 2 I o p p 'Y ,
* ‘ “ > , ‘ ■ 1 , 1 \ — — *— i - - - - - - - - - - - - 1- - - - - - - - - - - - - - - - - - - - - - - - - -» i »— 1— i t* * 0 <v> JIO f^O v i * . | V T>d (• ^ 0 * -w <U 'v . t c V» 7 0 it> ppm
'H NMR (250 MHz) and ,?C NMR spectra o f 37
8C jo w v n 3 £| pue (zh W 09C) WMN H,
fltl :n .31............il.W .L .1.,o at » » 09 CD) —
i u u M i iu im < u m i u i i t l i i t i u u i u m i i * » ^ K . . . .■ ■ lu l . l l i .u l , .
rrnr
.o h
LOZ
208
1JL JfU
5
l _ X _ lb 5
* Jlh 1 I™ i 8 7 <• 5 H 3 2 . 1 pj=m
| | | ) | 3>EPT-IB5
1
H
im n» )»• Pa I f 15a wo iSb »Jo / i a | o o 10 go 7 0 to SO 4o 3b z'p © /V"»
'H NMR (360 MHz) and WC NMR of 40
209
TMSO'
iiiiil 6c
‘H NMR (250 MHz) and IR spectra o f 41
I3C NMR and DEPT spectra o f 41
211co?ch3
‘H NMR (90 MHz) and IR spectra o f 44
212
■H*
'H NMR (360 MHz) and ,?C NMR spectra o f 46
213
'H NMR (250 MHz) spectrum of 47
214
jJULJLnIvI
m i m
*H NMR (360 MHz) and IR spectra o f 55
215
109.000
•4.000
0.000
21.000
0.000
M U iy lfN r tv l B u l# h « w
'H NMR (360 MHz) and 1R spectra o f 56
216
'H NMR (250 MHz) spectrum o f 57
217
S 0 2Ph
125.000
100.000
|
{ M.OMM
1129.N 400.0
C » i
'H NMR (360 MHz) and IR spectra o f 58
218
fillr.i:
mi i!anww
W A V f N U M tftf C M 1WAMMMNKM
lH N M R (360 MHz) and IR spectra o f 59
219
ISC
- r r^ ^ rw .m T t^ .M rr f tm n ^ m n ^ rT fT tT tt .T , „ | „ ,„ , ..............
,?C NMR and DEPT spectra of 59
220
US,000
ioo.no
IIM
o.ooo4009.00 1.00 1120.00
wmu
*H N M R (360 MHz) and IR spectra o f 60
221
u s .000
1M.000
71.000
IUO.OO
'H NMR (360 MHz) and IR spectra o f 61
222
TMS,
tOO .ON
o.ooe
N .O N
40.0N
IS.ON
4000.00 0.00 2500.00 1040.00 1120.N
wr*l400.0
'H NM R (360 MHz) and IR spectra o f 63
223
TMS
/ / /JJJL
T
125.000
100.000
ss75.000
24444
S 90.000
M
25.000
0.0004000.00
'H NM R (360 MHz) and IR spectra o f65
224
129,000
100,000
75.000
90.1
0.0002960.00 1120.00 400.0
c t - l
'H NM R (360 MHz) and 1R spectra o f 66
'H NMR (360 MHz) and IR spectra o f 67
226
68a
129.000
100.000
79.000
0.0004000.00 2900.00 1040.00 1120.00 400.0
c t - 1
'H NM R (360 MHz) and IR spectra o f 68
227
HjCOj C
H68a
160 140 120 100 60 60 20
m m i k ito , « 120 i;o k ................... & ......... ” T ................ i'o'
13C NM R and DEPT spectra o f 68
228
f r r r v r t f r r pH Tr TC
T T.et / <
t 25.000
'H NM R (360 MHz) and IR spectra o f 69
229
<9? too
,3C NMR and DEPT spectra o f 69
230
HjCOjC f h |
<Q)
or
Z.5 t (1 1 O
•a
03
M 1. » 3,5 1'.0
NOESY (top) and COSY spectra o f 69
231
OH
c«h son10001S002500 20003500 30004000
'H NMR (360 MHz) and IR spectra o f 107
232
OEt
100.co-
o.co15002500 10003500 3000 20004000
'H NM R (360 MHz) and IR spectra o f 108
233
100 . 00 -
0 . 00-4000 3500 15003000 2000 1000
'H NM R (360 MHz) and IR spectra o f 109
234
OH
0 . 00-35004000 3000 2500 1500 1000
‘H NMR (360 MHz) and IR spectra o f 110
/
235
'H NM R (360 M Hz) and IR spectra o f IU
236
¥* iW mu: : :e
‘H N M R (250 MHz) and ,3C NMR spectra o f 112
OTBOMS
'H NMR (300 MHz) and IR spectra o f 118
238
OTBDMS
100iso
y^ii)n«» ^ »v«i»fi. » y J i*J* # ^ W n !h w J «
loo t o150
l3C NM R and DEPT spectra o f 118
23P
OTBDMS
1 0 0 . 0 0 -
0 . 0 04000 3500 2500 20003000 1500 iooo
'H NM R (300 MHz) and IR spectra o f 138
240
OTBDMS
9 9 .0 6 -
40. 17-4000 3500 3000 2500 2000 1500 1000
'H NM R (300 M Hz) and IR spectra o f 143
241
OTBDMS
SOtoo
Iso looZoo
l*C NMR and DEPT spectra o f 143
242
OTBOMS
m /"• a * 6
ftI AD
'H /^C Correlated (top) and COSY spectra o f 143
243
OTBOMS
uu
— *'* .—y -----
i I i
37. 00-€•■* 5001500 1000200030004000
'H NMR (300 MHz) and IR spectra o f 144
244
OTBDMS
HO
A W d l l
Y T
0 ,001500 10002500 20003500 30004000
'H N M R (300 MHz) and IR spectra o f 145
245
OTBOMS
___ r___T » «I I
m w u n99.49-
10003000 2000 1500
'H NMR (300 MHz) and IR spectra o f 146
246
OTBOMS
♦. n * ti_ a L lti. • M. f i iUmb 1|i1|iJ I r ill'll ™ " I'WfP'P'~~T~-
Z.COI ■ ,i. ■ ,1.1 ,i ." .i.— i— r ’ n n — r
(5 0 ICO S o-r—r r
o p p m
13C NM R and DEPT spectra o f 146
247
OTBOMS
OH
mvAwi
10003500 3000 2500 20004000
'H NMR (300 MHz) and 1R spectra of 152
248
OTBOMS
OTMS
..................1 * i0 ppm
MaKMCUUC*
4000 3500 3000 2500 15002000
95 /1 2 /0 7 15s45 bh 070 X: 10 ica n a , 4 .0 c « - l
lH NM R (300 M Hz) and IR spectra o f 157
VITA
Surname: Crawford Given Names: Jason Blair
Place o f Birth: Victoria, British Columbia, Canada
Educational Institutions Attended:
University o f Victoria 1991 to 1996University o f Victoria 1986 to 1991
Degrees Awarded:
B.Sc. University o f Victoria 1991
Honours and Awards:
University o f Victoria Graduate Fellowship 1993 to 1995
Petch Scholarship 1993 to 1994
Publications:
Spino, C.; Crawford, J,; Bishop, J. Sequential Diels-Alder Reactions on a 1,3,7,9-Tetraene: An Efficient and Stereoselective Route to the Perhydrophenanthrene Skeleton. J. Org. Chem. 1995,6 0 ,844-851
Spino, C.; Crawford, J. An Expedient and Stereoselective Route to the Perhydrophenanthrene Skeleton via Sequential Diels-Alder Reactions, Tetrahedron Lett. 1994, 35, 5559-5562.
Spino, C.; Crawford, J. 2-Carbomethoxybutadiene: an Electronically Activated Diene in [4+2] Cycloadditions with Electron-Deficient Dienophiles. Can. ./. Chem. 1993, 71, 1094-1097.
Chambers, J.D.; Crawford, J.; Williams, H.W.R.; Dufresne, C.; Sheigetz, J.; Bernstein, M.A.; Lau, C.K. Reactions o f 2-phenyl-4-//-benzodioxaborin, a stable ortho-
quinone methide precursor. Can J. Chem. 1992, 70, 1717-1732,
PARTIAL COPYRIGHT LICENSE
I hereby grant the right to lend my thesis to users o f the University o f Victoria
Library, and to make single copies only for such users or in response to a request from the
Library or any other university, or similar institution, on its behalf or for one o f its users. I
further agree that permission for extensive copying o f this thesis for scholarly purposes
may be granted by me or a member o f the University designated by me. It is understood
that copying or publication o f this thesis for financial gain shall not be allowed without my
written permission.
Title o f Thesis: Efforts Towards Steroid Natural Products Using a Sequential Diels-Alder
Strategy
Author
Jason Blair Crawford
Date flto r d > 1 I