efforts towards steroid natural products using a

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 lr5 8 Scheme 1-17 29







Scheme 1-12 22

Chapter Two:

Scheme # Paee # Scheme # Paee H





Scheme 2-5 46 Scheme 2 -15 63






Chapter Two (continued):

Scheme # Paee # Scheme # Paee#



Scheme 2«23 72 Scheme 2-43 97


















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 (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



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 o f 63 222

*H NMR (360 MHz) and IR spectra of 65 223


'H NMR (360 MHz) and IR spectra o f 67 225


,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 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/i3C Correlated (top) and COSY spectra o f 143 242




1?C NMR and DEPT spectra of 146 246



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);


(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


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).


(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


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


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


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 :

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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


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


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

226

68a

129.000

100.000

79.000

0.0004000.00 2900.00 1040.00 1120.00 400.0

c t - 1


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


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


232

OEt

100.co-

o.co15002500 10003500 3000 20004000


233

100 . 00 -

0 . 00-4000 3500 15003000 2000 1000


234

OH

0 . 00-35004000 3000 2500 1500 1000


/

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


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


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


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


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,

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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

efforts towards steroid natural products using a

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