Synthetic Studies on Octalones

SYNTHETIC STUDIES ON OCTALONES

AND RELATED SYSTEMS

PAUL MURRAY WORSTER

B.Sc. (Hons.), University of British Columbia, 1967

A THESIS SUBMITTED IN PARTIAL FULFILMENT OF

THE REQUIREMENTS FOR THE DEGREE OF

DOCTOR OF PHILOSOPHY

in the Department

of CHEMISTRY

We accept this thesis as conforming to the

required standard

THE UNIVERSITY OF BRITISH COLUMBIA

December, 1975 In presenting this thesis in partial fulfilment of the requirements for

an advanced degree at the University of British Columbia, I agree that

the Library shall make it freely available for reference and study.

I further agree that permission for extensive copying of this thesis

for scholarly purposes may be granted by the Head of my Department or

by his representatives. It is understood that copying or publication

of this thesis for financial gain shall not be allowed without my

written permission.

Department of Cfl

The University of British Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 - ii -

ABSTRACT

This thesis describes a number of investigations that culminated in an improved series of practical preparations for substituted octalones. Starting with a study of acid and base catalyzed additions of methyl vinyl ketone to 2-methylcyclohexanone, the preparation of

4a-methyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone (234) was simplified and improved by a one pot reaction that sequentially employed both acid and base. The advantages of this efficient procedure were then demonstrated by the preparation of trans-4a,8-dimethy1-4,4a,5,6,7,8- hexahydro-2(3H)-naphthalenone (235) from 2,6-dimethylcyclohexanone and methyl vinyl ketone.

Several approaches to trans-8-acetoxy-4a-methyl-4,4a,5,6,7,8- hexahydro-2(3H)-naphthalenone (236) were then undertaken. An efficient two step conversion of octalone 234 to 8,8a-epoxy-2,2-ethylenedioxy-

4a-methyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone (284) was followed by an acid hydrolysis which afforded both 86,8aa-dihydroxy-4a3-methyl-

4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone (292) and the undesireable dione 4a-me thy1-3,4,4a,5,8,8a-hexahydro-1(2H),7(6H)-naph thalenedione

(294). The photosensitized oxygenation (^C^) of 4a-methyl-3,4,4a,5,6,7- hexahydro-2(lH)-naphthalenone (341), prepared in 96% from 234, was accomplished with Rose Bengal in pyridine or methanol and afforded

4a-methyl-3,4,4a,5-tetrahydro-l(2H),7(6H)-naphthalenedione (343), rather than the expected Y~peracetate, 4a-methyl-8-peracetoxy-4,4a,5,

6,7,8-hexahydro-2(3H)-naphthalenone (344), when acetylation of the product was attempted. Reduction of the intermediate Y~hyclroPeroxicle - iii -

(342) before acetylation afforded compound 236 in low yield. This work also resulted in the isolation of trans- and cis-4a-methyl-3,4,4a,

5,6,7,8,8a-decahydro-2(lH)-naphthalenone (349 and 350), the dione 294, and 4a-methyl-4,4a,5,6-tetrahydro-2(3H)-naphthalenone (353).

The octalone 237, 4a,8,8-trimethyl-4,4a,5,6,7,8-hexahydro-2(3H)- naphthalenone, was synthesized in an efficient seven step sequence that employed the n-butylthiomethylene blocking group. Octalone 234 was converted in two steps to its 3-n-butylthiomethylene derivative (375).

This compound was dialkylated with methyl iodide to afford 3-n-butylthiomethylene-1,1,4a-trimethyl-3,4,4a,5,6,7-hexahydro-2(IH)-naphthalenone

(376) and then unblocked by exhaustive hydrolysis to afford 1,1,4a- trimethyl-3,4,4a,5,6,7-hexahydro-2(lH)-naphthalenone (356). Successive

Wolff-Kishner reduction of 356 and allylic oxidation of the product, l,l,4a-trimethyl-l,2,3,4,4a,5,6,7-hexahydronaphthalene (357), with sodium chromate afforded the desired octalone 237.

Cis- and _trans-4a,5-dimethy1-4,4a,5,6,7,8-hexahydro-2(3H)- naphthalenone (238 and 239) were both prepared as pure compounds by

employing a sequence that originated from 2,3-dimethylcyclohexanone.

Alkylation of the n-butylthiomethylene derivative, 6-n-butylthiomethylene-

2,3-dimethylcyclohexanone (400), was studied to determine the stereo•

chemical effect of alkylating agent, solvent and base. Control of the

stereoselectivity was demonstrated to be primarily dependent on the

choice of alkali metal cation. The most practical means of producing the

cis-vicinyl dimethyl derivative, cis-2,3-dimethy1-2(2-ethoxycarbonyl-

ethyl)-6-ii-butylthiomethylenecyclohexanone (415), employed ethyl-3-

chloro- or bromopropionate as alkylating agent with potassium j^-butoxide - iv -

in _t-butanol whereas one of the most favourable means of obtaining the

trans-vicinyl dimethyl derivative, trans-2,3-dimethyl-2(2-ethoxycarbonyl- ethyl)-6-n-butylthiomethylenecyclohexanone (416) employed lithium _t- butoxide in t-butanol. Hydrolysis of 415 and 416 then yielded the keto acids cis- and trans-2,3-dimethy1-2(2-carboxyethyl)cyclohexanone ( 417 and 418). These compounds were readily dehydrated to their correspound- ing enol lactones, cis- and trans-4a,5-dimethyl-l-oxa-*3,4,4a,5,6,7- hexahydro-2(lH)-naphthalenone (419 and 420). Recrystallization of this mixture gave the cis-dimethyl enol lactone 419 in pure form. The more elusive trans isomer required successive silica chromatographies, hydrolysis of the impure trans enol lactone and crystallization of the pure trans keto acid (418) with subsequent dehydration to the enol lactone. Treatment of 419 and 420 with methyllithium at -25° yielded

cis- and trans-2,3-dimethy1-2(3-oxobutyl)cyclohexanone (440a and 440b) which, after base treatment, afforded 238 and 239. A study of the product distribution in the methyllithium reaction showed that stereo• isomerism played a hitherto unrecognized role. For example, an 84:16

ratio of enol lactones 419 and 420 yielded an octalone ratio of 95:5

(238:239).

Authentic octalone 239 was also prepared in an unambiguous manner by an eight step sequence from octalone 234. Dehydrogenation of 234

to 4a-methyl-5,6,7,8-tetrahydro-2(4aH)-naphthalenone (300) and conjugate

addition with lithium dimethylcuprate gave trans-4,4a-dimethy1-4,4a,5,

6,7,8-hexahydro-2(3H)-naphthalenone (381). Deconjugation of 381 gave

467, trans-4,4a-dimethyl-3,4,4a,5,6,7-hexahydro-2(lH)-naphthalenone, hydride reduction of 467 yielded 468, trans-4,4a-dimethyl-2-hydroxy- - V -

1,2,3,4,4a,5,6,7-octahydronaphthalene ., acetylation of 468 and subsequent allylic oxidation with chromic anhydride gave trans-4a,5-dimethyl-7- acetoxy-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone (470). Dehydro- acetylation of 470 produced the dienone 471, trans-4a,5-dimethyl-4,4a,

5,6-tetrahydro-2(3H)-naphthalenone, and selective hydrogenation gave octalone 239.

Androst-4-en-3-one (240) was prepared as the result of two studies on oxidation and reduction procedures. In the first study, 38-hydroxyandrost-5-en-17-one (473) was nearly quantitatively reduced via the

Wolff-Kishner reduction and then oxidized under a variety of conditions to 'octalone' 240. This work led to new insights into the mechanism of chromium trioxide oxidation in dimethylformamide with acid and in dichloromethane with nitrogen bases. Mechanistic explanations from studies on cholesterol oxidation and practical applications to other systems are given. In the second route to 'octalone' 240, testosterone

(472) was converted into a series of C-3 derivatives of androst-4-ene-

3,17-dione (562). These included the methoxy (602), ethylenedioxy (563),

trimethylenedioxy (619), ethylenedithio (598;), trimethylenedithio (600), and 2,2-dimethyltrimethylenedioxy (594) derivatives. The Wolff-Kishner reduction products from these compounds were studied and plausible mechanisms were formulated. 24Q - vii -

341 R = H

343 A-Enedione 467 R = CH3

375 Y = CHSBun 376 X = 0, Y=CHSBun

356 X=0, Y=H2

357 X = Y=H2

Et02C • cr^o

419 R^CHg, R2= H

420 R,= H, R2=CH3

468 X =H2,R = H 562

469 X =H2,R = C0CH3

470 X =0, R=C0CH3 - viii -

TABLE OF CONTENTS

Page

TITLE PAGE . . i

ABSTRACT . ii

TABLE OF CONTENTS . . . . . viii

LIST OF FIGURES, CHARTS, AND TABLES ...... x

ACKNOWLEDGEMENTS . , . * xii

INTRODUCTION ...... 1

I. General ...... 1

II. Approaches to Stereoselective Hydroazulene

Synthesis 12

III. Approaches to Stereoselective Spirane

Synthesis ...... 30

DISCUSSION ...... 49

I. General Development of the Reaction i

Sequence ...... 49

II. Synthesis of a,B-Unsaturated Hydronaphthalenone

Derivatives ...... 52

A. Octalone 234 (4a-Methyl-4,4a,5,6,7,8-

hexahydro-2(3H)-naphthalenone) ...... 56 - ix -

TABLE OF CONTENTS

DISCUSSION, II Continued. Page

B. Octalone 235 (4a,~8a-Dimethyl-4,4a,5,6,7,8-

hexahydro-2(3H)-naphthalenone) 62

C. Octalone 236 (8a-Acetoxy-4a-methyl-4,4a,5,

6,7,8-hexahydro-2(3H)-naphthalenone) ... 75

D. Octalone 232 (4a,8,8-Trimethyl-4,4a,5,6,7,8-

hexahydro-2(3H)-naphthalenone) 99

E. Octalone 238 and 239 (4a,5-Dimethyl-4,4a,5,

6,7,8-hexahydro-2(3H)-naphthalenone) . . . 108

F. 'Octalone' 240 (Androst-4-en-3-one)

Androstenone 240 from 38-Hydroxy-

androst-5-en-17-one (473) ...... 138

Androstenone 240 from

Testosterone (472) ... 199

EXPERIMENTAL 229

EXPERIMENTAL TABLE OF CONTENTS 302

BIBLIOGRAPHY 303

APPENDIX I 321

APPENDIX II 354 - x -

LIST OF FIGURES, CHARTS, AND TABLES

Page

CHART I SESQUITERPENE BIOSYNTHESIS 2

CHART II CYCLOPROPYL KETONES FROM INTRAMOLECULAR KETO-

CARBENE ADDITION TO SUBSTITUTED CYCLOHEXENES • • • 51

FIGURE I GAS CHROMATOGRAM OF OCTALONE 234 PREPARATION • • • 58

FIGURE II GAS CHROMATOGRAM OF OCTALONE j!35 PREPARATION • • • 65

TABLE I STEREOCHEMISTRY OF THE ALKYLATION PRODUCTS

OF THE BLOCKED KETONE 400 120

TABLE II PRODUCT DISTRIBUTION OBTAINED BY METHYLLITHIUM

TREATMENT OF ENOL LACTONES 127

TABLE Ilia CHROMIUM TRIOXIDE OXIDATION OF CHOLESTEROL

IN DIMETHYLFORMAMIDE 154, 163

TABLE Illb SNATZKE OXIDATIONS OF CHOLESTEROL OXIDATION

PRODUCTS 156

TABLE IVa CHROMIUM TRIOXIDE-PYRIDINE OXIDATION OF

CHOLESTEROL IN DICHLOROMETHANE ("COLLINS") ... 168 i

TABLE IVb PYRIDINE DEPENDENCE OF COLLINS OXIDATION

OF CHOLESTEROL 175

TABLE IVc INFLUENCE OF AMINE BASES ON THE COLLINS

OXIDATION OF CHOLESTEROL 180

TABLE V OXIDATION WITH CHROMIUM TRIOXIDE-NITROGEN

BASE REAGENTS , 169, 184 - xi -

LIST OF FIGURES, CHARTS, AND TABLES

Page

TABLE VI CHROMIUM TRIOXIDE-DIMETHYLPYRAZOLE OXIDATION

OF CHOLESTEROL IN DICHLOROMETHANE ("COREY") . 183

TABLE VII EFFECT OF pK^ ON "COLLINS" OXIDATION

OF CHOLESTEROL .... 188

TABLE VIII REDUCTION OF ANDROST-4-ENE-3,17-DIONE AND

ITS C-3 DERIVATIVES BY THE BARTON MODIFICATION

OF THE WOLFF-KISHNER REDUCTION 222

i - xii -

ACKNOWLEDGEMENTS

I wish to express my sincere thanks to Dr. Edward Piers for the patience shown, and the encouragement given, during the period of my graduate studies. His invaluable advice and enlightening discussions throughout the course of this research and the preparation of this thesis are a pleasure to acknowledge.

My experimental work has been the benificiary of many informal discussions and practical suggestions resulting from the general interest shown by all the present and past members of Dr.

Piers' research group. I would also like to acknowledge the help of various members of our closest neighbour, Dr. Kutney's group.

The work of Miss Beatrix Krizsan on the illustrations and Mrs Diane Gray on the typing has added immeasureably to the appearance of this thesis. The encouragement of my wife, Elizabeth, in the completion of this work was truly tested by her proof reading of the entire manuscript. The consideration' shown by many individuals during the course of the preparation of this thesis is only exceeded by Elizabeth's patience.

The financial support of the National Research Council of Canada (1968-1971) is gratefully acknowledged. - 1 -

STUDIES RELATED TO THE

TOTAL SYNTHESIS OF SESQUITERPENES

INTRODUCTION

I. General

The application of modern analytical techniques to naturally occurring oils and plant extracts has demonstrated the widespread occurrence of the terpenoid family of compounds in trees and shrubs.

Biologically, the derivation of these terpenoids commences with the common biochemical unit acetyl CoA and proceeds through mevalonic acid and the subsequently formed isoprene or polyisoprene pyrophosphate to

mono-(C10)-, sesqui-(C15)-, di-(C2Q)-, sester-(C25>-, or tri-(C3Q)- terpenes (1). The incomplete relationship between head-tb-tail linkages of isoprene units (4) (2) and the wide structural variations observed in the terpenoids isolated gave rise to the Biogenetic Isoprene Rule (3) by Ruzicka, Eschenmoser, Jeger, and Arigoni in 1955, postulating the possibility of rearrangement of the polyisoprene intermediates. As

the largest and most varied group of terpenoids, the sesquiterpenes

provided the most demanding tests of these concepts. The biogenetic

correlation of several sesquiterpenes was considered by Hendrickson in

1959 (4) and later reviewed comprehensively by Parker, Roberts and

Ramage in 1967 (5). Confirmation of the general biosynthetic route

for sesquiterpene formation from acetyl CoA (1_) and mevalonic acid (2)

through trans- or cis-farnesyl pyrophosphate (6,7_) has been completed, - 2 -

CHART I SESQUITERPENE BIOSYNTHESIS O II Acetyl CoAa CH,Co — SCoA OH 1

Mevalonic Acid

OPP Isopentyl Pyrophosphate Isoprene unit

Geranyl Pyrophosphate *- Monoterpenes OPP

Farnesyl Pyrophosphate Sesquiterpenes

OPP

aAcetyl Coenzyme A is NH2

O H CH3 O N II II

O—P —O OH I OH - 3 -

and this subject has been reviewed by Clayton (6). The postulated, and in some cases verified, relationship of trans- or cis-farnesyl pyro• phosphate to the different sesquiterpene classes completes a theoretical understanding of the biochemical origin of sesquiterpenes (5).

The biological role of sesquiterpenes is still little understood, although several classes appear to be essential to both plants and animals. Plant growth regulators include graphinone (8), a germination stimulant for lettuce seeds in the dark at a concentration of less than one p.p.m. (7), abscisic acid (abscisin II, dormin, 9), an inducer of dormancy in a number of plant species and a promoter of leaf abscision (8), and vernolepin (10), a more recently discovered growth inhibitor (9).^

The structures shown in this thesis do not necessarily depict the absolute configuration. When the absolute configuration is relevant and known, the sign of the optical rotation of the compound is placed before its name. On this basis j? and 9_ could be listed as (-)-graphinone and (+)-abscisic acid, although IUPAC nomenclature, such as S-(+)-abscisic acid, would be better. The total synthesis of sesquiterpenes, however, is usually racemic, providing a 1:1 mixture of both enantiomers. Abscisic acid, 9_, could then be used to represent both the naturally occurring (+)-abscisic acid and a racemic synthetic mixture, (+)-abscisic acid, where the other enantiomer is understood to be present, depending on the content of the discussion. For the most part of this thesis, relative configurations, rather than absolute, are emphasized. Sometimes absolute configurations are essential, as in the discussion of the absolute configurational homogeneity rule (Appendix I), where the occurrence in different species of a few (+) and (-) antipodal sesquiterpenes is an important biosynthetic feature. Sirenin (11), attracting sperm to the female gametes of the water mold

Allomyces at concentrations of 10 L® M (10), was the first plant sex hormone to be discovered. The Cochliobolus sativus (Helminthosporium sativum) fungus causes seedling blight and leaf spot through the toxin helminthosporal (12, R= -CHO) (11), while helminthosporol (12,

R= -CH^OH) (-12) is reported to have growth-promoting properties. The insect juvenile hormone activity of (+)-juvabione (13) and cecropia

juvenile hormone (C1QJ.H. = 14) has been recognized to have several lb — biological applications (13) as does the identification of degraded

farnesanes among the insect pheromones of butterflies (15, R = -COOH)

(14) and bees (2,3-dihydro-6-trans-farnesol) (15). - 5 -

The study of these and other biologically important sesquiterpenes has been somewhat restricted by their resistance to chemical isolation from the very complex mixtures that contain these compounds in minute amounts. The same difficulties are also apparent to a lesser extent in the discovery of acyclic, monocyclic, bicyclic, tricyclic, or tetracyclic sesquiterpene hydrocarbons, ketones, epoxides, alcohols, ethers, acids, or esters in essential oils of plants. However, in some

cases the compound isolated is not a naturally occurring sesquiterpene but an artifact of isolation. For example, neither helminthosporal

nor helminthosporol are present in the unpurified extract of

Helminthosporium sativum and only appear on heat, acid, or base

treatment of their corresponding acetals in the crude extract (11).

The Cannizzaro reaction, the disproportionation of an aldehyde to its

corresponding acid and alcohol, appears to be the most common side

reaction occurring during isolation. In the cedrane class of sesqui•

terpenes, jalaric acid B (16) is the precursor of epishellolic acid

(17) and epilaksholic acid (18), all three of which 'co-ocdur' (16),

while laccijalaric acid (19) would be expected to give laccishellolic

acid (20) and epilaccishellolic acid (21) (both isolated) and the

corresponding alcohols (not yet reported). The very recently reported - 6 -

(May, 1972) isolation of seven new cedrane derivatives (17) also suggests a Cannizzaro-derived alcohol 2_3 and acid 24 from 22^, while the alcohol

26 could originate in a similar manner from the aldehyde 25. The

22 R=-CHO , 25 R=-CHO

23 R=-CH2OH 26 R = -CH2OH 24 R = -COOH

isolation of valerenal (27) and valerenic acid (28) (18), or the

drimanes of general structure 29^, JiO and (19), from the same plant

suggests the possibility of a Cannizzaro reaction. It is somewhat cl suspicious too that only thujopsenol (32) (20 ) and hinokiic acid (33) - 7 -

CHO

30 31

(20 ) are known, and that only cyclocopacamphenol (34) (21 ) and cyclocopacamphenoic acid (35) (21b) are known, while their corresponding aldehydes have not been isolated. In addition, many of the naturally occurring sesquiterpene alcohols and acids occur as esters, but their successful isolation requires disruptive techniques. In the case of furoventalene (36), steam distillation is essential, but it is not known if thermal or solvolytic elimination is occurring (22). Also significant is the isolation of, the germacrane hedycaryol (37) by extraction of Hedycarya augustifolia leaves at room temperature, whereas the elemane artifact elemol (38) is produced by steam distillation (23). - 8 -

37 38

The complexity of the isolated multifunctional sesquiterpene can be exemplified by melampodin (39), a germacrane whose structure and configuration were reported in 1972 by one group using classical methods and an n.m.r. shift reagent (24), while a second group confirmed these findings by X-ray analysis (25) . The success of both careful isolation and structural elucidation techniques is demonstrated by the rapid growth in the number of different sesquiterpene carbon skeletons. These different types of sesquiterpenes were reviewed ten - 9 -

years ago by Sorm e_t al^. (26) when their survey listed twenty-eight classes, seven of which have subsequently t>een shown to be incorrect or non-existent. The collection of sesquiterpene data by Ourisson ejt al. in 1966 (27) gave over forty different sesquiterpene skeletal types, while the compilation completed during the course of this thesis 2 provided a list of almost ninety different sesquiterpene classes. The

rapid aging of this particular collection of literature information

suggests that more frequent reviews should be made.

It is this class growth, however, with the concomitant functional

variation of the class members that makes sesquiterpenes provide not

only demanding tests of biogenetic relationships, but also very

challenging problems to synthetic organic chemistry. The synthetic

work that mimics the biogenetic route has widespread interest, but

the classical concepts of strain and steric interactions are not

necessarily the dominant factors in biogenetic schemes, since here the

substrate will concur with the confirmational demands of the particular

enzyme involved. A successful total synthesis, therefore, generates a

requirement for a simple stereoselective sequence which fully corroborates

the structural and stereochemical assignments made to the particular

sesquiterpene. The rapid advances made in synthetic approaches to the

total synthesis of sesquiterpenes require that in this area also more 3 frequent and more extensive literature reviews by undertaken. 2 The different classes of sesquiterpenes have been listed in Appendix I to provide an up=to-date survey of the structural varieties known. Wherever possible, a recently discovered member of each class is given. Thus the excellent 1964 review by Mellor and Manavalli (28) requires updating to be relevant to this thesis. A literature survey of the generalized approaches to sesquiterpene synthesis is, therefore, presented in Appendix II. - 10 -

Synthetic strategies for sesquiterpene synthesis often require an efficient method of transforming decalinic compounds into less readily available ring systems. By necessity, this strategy often utilizes a study of nor-sesquiterpene model compounds to provide the

technical information required. The preparations of cyclodecadienes and cyclodecadiene derivatives are an example of this approach. As

discussed in the review of sesquiterpene synthetic approaches to be

found in Appendix II of this thesis, germacranes are difficult to

obtain synthetically and are readily isomerized to elemanes. The

recent use of heterolytic boronate fragmentation of a decalinic mesylate

(40,A = a-H, B = &-B0 H2, X = -S02CH3 (-Ms), R = H) (29) or the intra•

molecular elimination of a decalinic y-diol acetate (40, A = 3-0H, B =

H, X = -C0CH3 (-Ac), R = 1,1-(CH3)2) (30) has provided a method of

-.fir*

42 R'= CH= CH2

obtaining the desired internal cleavage product (41) rather than the

peripheral cleavage one (42). However the necessity of further studies

on model systems is emphasized by the very recently reported dependence

of this reaction on the presence of additional substituents. While

one trimethyldecalin compound (40^, A = a-H, B = B-BO^, X = -Ms, R =

1,1-(CH3)2) gave a single olefinic product, the expected cyclodecadiene

41, resulting from internal fragmentation, the corresponding trimethyl•

decalin with a 78-hydroxyl afforded only the elemene derivative 42_ - 11 -

(R' = CH^CHO), the peripheral cleavage product (31).

Before considering, specifically, the development of methods to convert decalinic compounds to hydroazulene or spirane systems, the stereorational approach developed by Heathcock e_t al. for guaiazulenic sesquiterpenes (32-34) should be considered. This group's synthetic strategy of (a) constructing an appropriately functionalized decalinic intermediate, (b) establishing the required relative stereochemistry of the eventual guaiazulene in the decalin through established conformational principles, and (c) rearranging solvolytically the decalinic intermediate to the desired hydroazulene actually represents the central theme of the work undertaken in this thesis. While the third part of the preceding strategy, the ring transformation process, is a solvolytic rearrangement in Heathcock's work and a photochemical reaction in the work described in this thesis, the attraction synthetically in both cases is the stereoselective conversion of readily available decalinic compounds to more unique ring systems. The completion of

Heathcock's work not only presented a comprehensively planned study

utilizing model decalinic systems, (32) but also resulted in the total

synthesis of two guaiazulenic sesquiterpenes, a-bulnesene (44, from 43) 4

and bulnesol (46 from 45) (33), While the latter work may, at present,

be of more interest to some, the very recently published full paper on

the study of the solvolytic product distributions from different model

decalinic tosylates under a variety of reaction conditions (34) offers

^ Other solvolytic syntheses of these compounds and the analogously prepared kessane are outlined in the 'eudesmane approach' in Appendix II. - 12 -

an invaluable source of information for both future mechanistic studies and future synthetic work.

II. Approaches to Stereoselective Hydroazulene Synthesis

Several preparations of hydroazulenes from cyclopentane, cyclo• heptane, cyclodecane, hydrindane, and hydronaphthalene derivatives have been reported, but only a few of these routes permit stereochemical control to be exerted. The utilization of preformed cyclopentane or cycloheptane precursors in an annelation method of synthesizing the 5/7 fused ring system, while pertinent to the preparation of azulenes (35), offers little opportunity to meet the stereochemical demands of sesquiterpene synthesis. Marshall and coworkers, in two separate studies, did find, however, that stereoselectively-formed hydroazulenes

could be obtained from cyclopentane (36) and cycloheptane (37)

derivatives. In the first instance, the trimethylhydrindanone 47_ was

converted to its oxime 4_8 and solvolytically fragmented to the nitriles

49 and 50_ in a 60:40 ratio by p_-toluenesulfonyl chloride in refluxing

pyridine (36). The cyclopentyl aldehyde _51, obtained by reduction of

the unsaturated nitrile 4_9_, was cyclized with stannic chloride in - 13 -

41 X=0 49 50 48 X = NOH

51 E = Electrophile 52

benzene (or silica gel) to afford the bicycio [5. 3. 0] decanol 52_

(4a-OH:48-OH is 89:11)5 in nearly quantitative yield. Marshall's second method (37) used an acid-catalyzed aldol condensation of the cycloheptyl dione 5_3 to produce the substituted bicycio[4. 3.1]decenone ester 54.

O02Et

52 54

While hydronaphthalene rind hydrindqne nomenclature provides the best description of the bicycio[4.4.0]decane (i.e. decalin and octalone) and bicycio[4.3.l]nonane systems, the IUPAC rules (39) have been followed for the other bicyclic systems considered in this thesis. In all cases where a numbered center is considered the appropriate position is labelled in the corresponding figure of the structure. - 14 -

This compound was used to provide both of the bridged alcohols 5_5

(a and b) by a reductive sequence. These compounds were solvolyzed

as their methylsulfonates by treatment with acetic acid-sodium acetate

to provide their respective hydroazulenes (56) in 80% yield.

a R'= H, R"= CH3

55 _b_ R'=CH3, R" = H Sfi.

The first study by Marshall's group, undertaken to develop a

synthetic route to the vetivane carbon skeleton, was not pursued

further after their discovery that vetivanes were spiremes (58) , not

vetihydroazulenes (57) (36). The second sequence was developed into a

57 52.

total stereoselective synthesis of (+)-bulnesol by solvolyzing the

acetoxymethyl-substituted bicyclo[4.3.l]decanol mesylate 59 (38) to

the bicyclo[5.3.0]decenyl derivative 60 and then elaborating the latter

While this first method could be considered as a conversion of a hydrindane to a hydroazulene (via a cyclopentyl derivative) Marshall later reported a more direct conversion method that will be considered subsequently. However see also Anderson's (36) recent publication. - 15 -

to (+)-bulnesol (46). However, in general, the requisite substituted

bicyclic precursors employed by these methods are difficult to prepare, and neither approach allows the stereochemical variations that are

synthetically desirable.^ A non-stereoselective,but relevant cyclopentyl -> hydroazulene sesquiterpene synthesis was recently reported for

(+)-guaiol (66) using a base-catalyzed ring cleavage of a bridged

system (41). The Michael addition product j53, obtained from 2-methyl-

cyclopentanone (61), was cyclized by sequential base and acid treatments

to the tricyclic 1,5-endione 64. This compound provided a 1:1 stereoisomer

The first total synthesis of patchouli alcohol (iii), a sesquiterpene biogenetically related to the guaianes, used homocamphor (i) in a

i if iii

sequence via ii^ that was unfortunately synthetically ambiguous although stereoselective (40). The synthesis utilized the rearrange• ment of a derivative of the hydroazulene ii, obtained in turn from a substituted 1 cycloheptanone' (i), to provide iii. - 16 -

mixture of the enone ester 65_ after ring cleavage with sodium methoxide.

Further elaboration of the ester 65_ yielded a mixture of isomers from which (+)-guaiol (66) was isolated.

The preparation of hydroazulenes from cyclodecanes has received

impetus from the biogenetic and chemical derivation of guaianes from

germacranes (42,43). The discovery by Hikino and colleagues (43 )

that epoxygermacrone (67), prepared from the corresponding germacrone

by stereoselective enzymatic epoxidation, was readily converted to

the guaiane procurcumenol (68) by treatment with p_-toluenesulfonic

acid is one of the more recently reported examples of such a conversion.

The previously known pyrolytic rearrangement of 69_ to 7_0 (43 ) and the

acid-catalyzed rearrangement of 69_ to a mixture of the diol 7_1 and the.

olefinic alcohol _72_ (43 ) are two others. In these three published

cases, the transannular cyclization to a bicyclo[5.3.0]decane system - 17 -

is the result of an anti-Markownikoff opening of the epoxide, with simultaneous or subsequent addition to the double bond. While these results imply that epoxides may be involved in guaiane biosynthesis, the previously discussed difficulty in preparing cyclodecene derivatives has made synthetic work arduous in this area. In spite of the stereo• chemical ambiguity of preparing hydroazulenes from cyclodecadiene derivatives, and in spite of Marshall's own earlier dismissal of this approach (38), Marshall and Huffman have recently disclosed their preliminary findings on a novel stereoselective approach to hydroazulenes from a cyclodecadiene. These workers employed their method of heterolytically fragmenting the boronate of a decalinic mesylate to provide the cyclodecadienyl alcohol 75_. The corresponding p_-nitrobenzoate derivative _76_ was then solvolyzed in aqueous dioxane to provide the - 18 -

H 75 R = H ZZ 78

76 R = rp— N02C6H4 CO- hydroazulenol 7_8 in 70% yield (44 ) . The high degrees of regio-

selectivity and stereoselectivity observed in the reaction were

explained in terms of a "sickle" transition state of the incipient

allylic cation 77. The crossed, versus aligned, orientation of the

transannular double bond systems presumably minimizes steric interactions,

thereby favouring the trans-fused product. The alternative, a stereo•

selective concerted (S^2') attack by the isolated double bond on the

allylic p_-nitrobenzoate, was recently excluded (44^) by the observation

that the allylic isomer of _76_ also provided 7_8_ stereoselectively by

solvolysis.

A preparation of hydroazulenes from hydrindanes was reported g independently and nearly simultaneously by two groups in 1971.

8 5 Previous work on the acetolysis of A -19-methanesulfonoxy steroids (45) and saturated bicyclic systems (46) provided literature precedence for this work. - 19 -

Scanio and Hill (47) found that the hydrindane 7_9 solvolyzed to the hydroazulenyl acetate £51, while the corresponding hydrindene j$0_ provided the hydronaphthyl acetate 82_. Marshall and Greene (48) prepared the hydroazulenic acetate 84_ stereoselectively by solvolyzing the hydrindanyl mesylate £!3_ in refluxing acetic acid-potassium acetate. In an

accompanying paper (49), Marshall and coworkers then elaborated the hydroazulene 84^ to guaiol (66). However, this work required a decalinic derivative, the protected alcohol j36_ prepared in six steps from 2-carbomethoxycyclohexanone (85), to provide the hydrindane aldehyde 87_ after ozonolysis, reductive workup, and aldol condensation.

Five additional steps were then needed to complete the preparation of the. required compound 83. - 20 -

COOCH3 3 Steps a85 86

5 83 Steps

CHO

The preparations of hydroazulenes from hydronaphthalenes have, to date, provided the most useful synthetic strategy available for the completion of sesquiterpene skeletons related to guaianes. There are three stereoselective routes available, one of which, the solvolysis of the 8a-methyl-l-hydronaphthene derivatives, includes the very recent work by Heathcock e_t aT. (34). The model trans-fused tosylates

88 and 90_ provided predominantly (80%) the hydroazulenes (89 and 91_ respectively) after solvolysis, while the corresponding cis-fused

compounds 9^2 and 95^ afforded unrearranged octalones in the case of 92

(93:94 is 74:13) and a mixture of octalvnifL; and hydronaphthalenes in

the case of 95_ (96^97_:98. ratio is 35:30:24). The importance of subtle

conformational influences by ring substituents in these solvolytic

rearrangements is apparent from the work by Yoshikoshi ejt al_. (50) on

similar compounds. The introduction of a 4a-methyl into 88^ led to an 85% - 21 -

TsO

yield of the hydroazulenone corresponding to 89_ as expected, but the

4a-methy1-6-keto-cis-tosylate provided 46% of 4a-CH3~93 and 38% of a hydroazulenone mixture of 3a-methyl-5-keto-97 and 3a-methyl-5-keto-98.

Application of this solvolytic preparative technique has led to the total stereoselective syntheses of (+)-a-bulnesene (44) and (+)- bulnesol (46) by Heathcock and Ratcliffe (33) and (+)-bulnesol (46) and (+)-kessane (103) by Yoshikoshi and coworkers (50,51). The efficiency - 22 -

OH MsO

104 of this aesthetically pleasing approach is demonstrated by the fact that Heathcock's syntheses, both of which required seventeen steps and proceeded via compound 100, provided 15-20% overall yield of sesquiterpene from the keto alcohol 9_9. An additional synthesis, the only known synthesis of a pseudoguaiane, should also be considered here. Hendrickson and coworkers in .1968 reported (52 ) their results obtained by solvolyzing the decalinic bromide 107, derived from a-santonin in six steps, with silver sulfate-sulfuric acid at room - 23 - temperature. The stereoelectronically favourable trans antiparallel orientation of migrating and leaving atoms in 107 afforded 75% yield

H Ref

106 107 Ra= H,Re = Br 1Q8 Ra = Br,Re = H of the unnatural pseudoguaianolide 109, while 108 with its axial bromine was recovered unchanged. Further synthetic work has not been reported for the natural pseudoguaianes similar to 109, probably because the natural compounds have been discovered to require a trans- 9 ring fusion and a cis-fused lactone.

The second stereoselective method of preparing hydroazulenes from decalins involves the facile conversion of vicinyl cis-glycol mono-

tosylates of bicyclo[4.4.0]decanes to bicyclo[5.3.0]decanes via the

Note added: A January 1973 publication reports the ozonolysis of 8,y-unsaturated naphthalenona derivatives (jL, R^=R2=H; or R^CH^, R2=H) provides hydroazulenedione derivatives (iii)- directly. However, the attempted conversion of iii to a pseudoguaianolide provided only the unnatural cis-ring junction and the preparation of R2=allyl in i^ failed (A^-2-one more stable) while regioselective alkylation at C-7 of the hydroazulenedione also failed (52b). - 24 -

pinacol type of rearrangement accomplished with potassium _t-butoxide or alumina (53) . The original work converted to octalin 110 into the perhydroazulenone 112 and further studies were then made of this ring

no 111 112

transformation sequence on steroidal compounds. Buchi and coworkers

later adopted this method for the total synthesis of (-)-aromadendrene

(118), the enantiomer of the naturally-occurring (+)-aromadendrene, by obtaining the key intermediate 114 in seven steps from (-)-perill-

aldehyde (113). The cis-glycol monotosylate 116, when allowed to remain

in contact with activated alumina or when treated with potassium

J^-butoxide in _t-butyl alcohol, rearranged to afford the perhydroazulenone

118 X= CH2 - 25 -

117 in 85% yield. A Wittig reaction with methylenetriphenylphosphorane gave the desired sesquiterpene 118 and, as such, provided unambiguous proof that the earlier assigned 1-epi structure was incorrect.

The third, and oldest, method of providing hydroazulenes from decalin derivatives utilizes the photochemical transformation of cross-

conjugated cyclohexadienones. The structural elucidation of "0_-

acetylisophotosantonic lactone", the photochemical rearrangement product

of a-santonin (106), occurred over a six year period after the total

synthesis of santonin and proved that the isolated hydroazulene had

the stereochemistry depicted in 119 (55). While investigations on the

106

generality of the reaction (56) and the mechanism of the rearrangement

were being pursured (57,58), the major product of santonin's photolysis

in acidic media was used for the synthesis of several guaiane

sesquiterpenes. 1-Epicyclocolorenone (120) (59), achillin (121) (60)

and desacetoxymatricarin (122) (61) were prepared directly from 119,

while geigerin acetate (125) (62) was elaborated from 8-epi-isophoto-

artemesolactone (124), a photoproduct obtained (56) by transforming

the cross-conjugated ketone chromophore of (-)-artemisin (123), a

naturally occurring eudesmolide that was itself later synthesized in

1969 (63). 12Q O O 121 122

O O

O O 123 124 125

These syntheses of guaianes from readily availble cross-conjugated

eudesmanes were, until recently, more attractive than a synthetic

sequence using a photochemical rearrangement as one of the terminal

steps. This was partly due to the 30% yield of isophotosantonic lactone

obtained originally with ultraviolet light on the aqueous acetic acid

solution of santonin (56). While the mechanistic and stereochemical

parameters of the photochemical rearrangement of cross-conjugated

cyclohexadienones will be discussed later, of the many studies reported

to date on this reaction, only two have attempted to systematically

maximize the yield of hydroazulene. Caine and DeBardeleben (64)

photolyzed the 2-formyl dienone 126 in aqueous acetic acid and, after

base-catalyzed deformylation of the crude photoproduct, obtained the

hydroazulenone 127 in 70% overall yield. Caine and his coworkers - 27 -

subsequently reported that the analogous photolysis with a 2-carboxy substituent (128) provided the model hydroazulene 129 directly and stereospecifically in 65% yield (65).

128 129

The work on these model systems was later found to be useful in the synthesis of a-bulnesene. Piers and Cheng (66) found that while the dienone 130, obtained from a-santonin, afforded 79% hydroazulene

131 and 10% spirane 132 upon photolysis, and while a-cyperone (133) could be converted to the hydroazulene 135 in 55% overall yield, the conversion of 7-epi-a-cyperone (136) provided only a 15% yield of the corresponding hydroazulene (138). The introduction of a 2-carboxy functionality into 137 (R = COOH) not only permitted the overall yield to be raised to 32%, but also simplified the photolysis mixture by the - 28 -

136 137 138

absence of the spirane analogous to 132. Further elaboration of the hydroazulenes 131, 135 and 138 provided 5-epi-a-bulnesene (139),

4-epi-a-bulnesene (140) and ct-bulnesene (44) , - 29 -

A second application of Caine's synthetic approach appeared very recently in the photosynthesis of the diterpene skeleton of grayano-

toxin-I (141) (67). The tetracyclic enone 142 and its C-14 epimer (*) were converted to the 2-formyl cross-conjugated dienone 144 and photolyzed in aqueous acetic acid to provide a 3:1 ratio of 144:145 in

12% yield. This intramolecular photochemical ether formation is

reminiscent of Yoshikoshi's solvolytic preparation of kessane (103) (51). - 30 -

III. Approaches to Stereoselective Spirane Synthesis

The synthesis of several monospiranes has been accomplished by introducing the required spiro center"^ into cyclopentane, cyclohexane, and fused bicyclic ring system derivatives. While few of these methods, unfortunately, are completely general,. some do permit stereochemical control to be exerted at several of the ring positions. The synthesis of the simpler spiranes, spiro[4.4]nonane and spiro[4.5]decane derivatives, have been reported over a period of nearly thirty years, but it is only in the last year or two that stereospecific spirane formation has become possible.

The methods reported by Cram and Steinberg in 1954 (69) are typical

of the early work. The symmetrical spiro[4.5]decan-6-one (147) was prepared by sulfuric acid treatment of cyclopentanone's reductive dimer

146

A 'spiro-union* is one formed by a single atom which is the only common atom to the two rings. A monospiro compound contains only one such union and is named by placing "spiro" before the name of the normal acyclic hydrocarbon of the same number of carbon atoms when the spirane consists of two acyclic rings. The number of carbon atoms linked to the spiro atom in each ring is indicated in ascending order in brackets and the ring atoms are numbered consecutively starting with the ring atom next to the spiro atom, first through the smaller ring (if present) and then through the spiro atom and around the second ring (68). - 31 -

product 146,' while the pyrolysis of the barium salt of the diacid 148,

a compound obtained from 147 by nitric acid oxidation, provided

spiro[4.4]nonanone (149). Successive intramolecular malonic ester

alkylations of the tetraester 150, followed by subsequent hydrolysis

and pyrolysis, afforded the related bifunctional spirane 151 in 9%

overall yield. Catalytic or hydride reduction of 151 provided a product

O COEt /

EtOC —(CH2)3—C

/ ^(CH2)3COEt EtOC II . ^ O O o 150 151

mixture of the cis-cis (152a), cis-trans (152b), and trans-trans (152c)

stereoisomers. The authors were then able to report the first known

OH OH S>€3 SXD OO 152 a 152 b HO 152c

preparation of individual spirane diastereomers when they successfully

applied chromatographic and fractional crystallization techniques to

the bis-p-nitrobenzoates of 152. Subsequent work by Cram and colleagues

(70) showed that the spiro ketol product 154 obtained from the

Dieckmann condensation of the substituted cyclopentanol 153, could

also be separated into its stereoisomers by chromatographing the two - 32 -

153 154 p_-nitrobenzoate diastereomers. The physical and chemical properties of the isolated diastereomers permitted the relative configurations of the two purified l-keto-6-hydroxy- and three purified 1,6-dihydroxy- spiro[4.4]nonanes to be elucidated. These dicyclopentane spirane systems were useful model systems for asymmetric induction studies.

The catalytic reduction of the dione 151 to compound 154, for example, afforded a 1:2 ratio of cis-ketol 154 to trans-ketol 154 in glacial

acetic acid while the reduction of 151 to 154 in 95% ethanol gave a

^ 6:1 ratio.

The successful resolution in 1968 of the trans, trans-diol 152c,

by Gerlach (71) using (-)-camphanic acid (155) , provided (-)-(lR,6R.)-

spiro [4.4]nonane-l,6-diol (=152c) which was then oxidized to (-)-(5S_)-

spiro[4.4]nonane-l,6-dione ((-)-151) by chromium tetroxide in acetone.

155 (—7—151 - 33 -

The chirality of the (-)-151 enantiomer was determined by chemical correlation work and, more recently, this enantiomer was used in an

X-ray analysis11 and in valence-force energy calculations (72) to show that the cyclopentane rings adopt a conformation intermediate between the envelope and half-chair form (but closer to the latter). Lightner et al. then used the preceding information to interpret (through the application of the Octant Rule) the results obtained by variable temperature circular dichroism of (-)-cis- and (-)-trans-6-methylspiro-

[4.4]nonan-l-one ((-)-157 and (-)-158) (73) and to calculate optical

O O ' O

(-)-156 (-)-157 (-)-l58

properties of (+)-151 for comparison with the experimentally observed

solvent and temperature dependent circular dichroism of the (+)-enantiomers

of 151 and 156 (74). This very recent work takes on synthetic significance

by the report (73) that the spirenone (-)-156, obtained from a Wittig

reaction with methylenetriphenylphosphorane on the (-)-dione ((-)-151),

was catalytically hydrogenated by a palladium-on-charcoal catalyst to

afford a 1:2 ratio of (-)-157 to (-)-158 in acetic acid and an 8:1

ratio in ethanol.

11 While the X-ray analysis uses the "correct" stereochemistry in its figures, the recent assertion (74) that this work confirms the absolute configuration is incorrect. The last sentence on page 2045 of reference 74 should read "...Altona e_t al. determined the conformation of...(151a)....by X-ray methods", not "configuration of,,, - 34 -

Before considering the cyclohexane derived spiranes, some comment 12 must be made on the remarkably stereoselective synthesis of g-acoratriene (161) published very recently (75). Kaiser ejt al_. (75) used a stannic chloride catalyzed cyclization of the tertiary allylic alcohol 160, derived in three steps from racemic dehydrolinalool 159, to afford g-acoratriene in approximately 50% yield. The isopropylidene

group appears to direct the cyclization of the end of the side chain

to the unhindered side of the cyclopentane ring because none of the

isomeric a-acoratriene (162) could be isolated. A short treatment of

162 163

While the reference cited considers this cyclization to be stereospecific, I consider stereoselective cyclization to be a more accurate description. - 35 -

161 with p_- toluene sulfonic acid in refluxing bezene afforded the 13 cedradiene 163. However, the attraction of this method for the synthesis of spiro-carbocyclic sesquiterpenes is diminished by the report that the corresponding cyclization of the isopropyl derivative

164 provided a 2:7 ratio of compounds 165 and 166. Little synthetic work has been done on the general preparation of model spiro[4.5]decanes

from cyclopentane derivatives, but recently trans-6-methylspiro[4.5]-

decan-l-one (170) was obtained stereospecifically by catalytic hydrogenation 13 This preparation of cedrane sesquiterpenes from spirane derivatives mimics the proposed biogenetic sequence and this approach usually provides a much shorter synthesis of bridged spiranes than a nonspirane approach. Details of both spirane and nonspirane sesquiterpene synthesis are discussed in Appendix II in the 'spirane approach'. The excellent work by Andersen and Syrdal in June 1972 and that of Tomila and Hirose earlier in the year showed that the chemical stimulation of the biogenesis of cedrene could be accomplished in the laboratory through the farnesane •+ bisabolane -* acorspirane -* cedrane sequence (76). The farnesane _i, nerolidol, was shown to be acid cyclized to a mixture of a- and B-bisabolene (ii), then isomerized to y-bisabolene (iii) to provide ions iv and v, the latter of which cyclized directly to afford 20% a-cedrene (vi) and ^15% epi-a-cedrene (vii). This direct method does not permit monospirane synthesis and is not a stereoselective synthesis for bridged spiranes.

v[ a-CH3

vii /3-CH3 IV of the Diels-Alder adduct 169 from trans-2-ethylidenecyclopentanone

(167) and 1,3-butadiene (168) (87).

167 168 169 17Q

The spiro[4.5]decanes derived from cyclohexane derivatives have been synthetic targets for many researchers, but only very limited stereochemical control has been obtained. For instance, an early example of such an application, the acyloin condensation of the diester 171, provided an inseparable mixture of four possible diastereomers of the spirane 172 (77). This difficulty was not present in the completely

171 172

A somewhat analogous Diels-Alder reaction was used successfully on a substituted cyclohexene and butadiene derivative in the synthesis of spiro sesquiterpene, a-chamigrene (190) (85). However, in this case asymmetrical centers are present in the spiro[5.5]undecane prepared. - 37 -

symmetrical spirane 175 that was obtained by an intramolecular C-

alkylation with 1-5 aryl neighbouring group participation in the 1959

pyrolysis of the sodium salt of 173 (78). The latter work has been

updated by two very recent publications. The first reported that aryl

displacement of the nitrogen from the diazo methyl carbonyl of 176

afforded 175 directly and in 65% yield (79) (versus 40% from 173), while

the second found that the diradical anion intermediate 178a, from the

lithium-ammonia reduction of 177, provided the related spirane 179 on

OH OH

CHN2

176 177

O II COH 177 ^

178 q 178b 179 - 38

workup in 60% overall yield (80). The spiro-dienones 181a and 181b were also prepared in 60% yield by a 1-5 aryl participation reaction

when the tosylates 180a and 180b were solvolyzed with potassium t-butoxide

in _t-butanol (81). While none of the above approaches would appear to R ,R

T90

180a R = H 181a R=H

18Qb R=CH3 181b R=CH^ provide a stereoselective route to spiro-carbocyclic sesquiterpenes, two

groups of researchers have reported, independently and nearly

simultaneously, a stereoselective synthesis for the spirane 184 from

aryl compounds. The first group utilized the base-catalyzed cyclization

of the a-bromo ester 182 (82a) while the second obtained the spirane

184 from the 6-bromo ester 183 (82^). These laboratory syntheses are

stereoselective^"^ only because, firstly, the spirane formation occurs on

a completely symmetrical cyclohexane and, secondly, the cross-conjugated

The resulting stereoselective synthesis of cedrol and cedrene by these two groups is discussed in Appendix II, 'the spirane approach'. - 39 -

spiro-ketone 184, obtained after base epimerization of the carbomethoxy

substituent, is only isolated as the trans-methyl, carbomethoxy

cyclopentyl spirenone.

While the preceding approach led successfully to the acorspirane

skeleton, a somewhat analogous approach to the vetispirane sesquiterpene,

8-vetivone (223), failed. Mukharji and Gupta (83) found that the

tetrahydropyranyl (THP) ether of the bromophenol 185 cyclized readily

to the expected spiro-dienone 186 but all attempts to introduce the

THPO

185 186

required C-10 methyl into 186 with lithium dimethylcuprate, or conjugate

hydrocyanation, were unsuccessful. It seems that the cyclopentyl moiety

of 186 hinders the approach to C-10 from either face of the cyclohexa-

dienone residue. Also the introduction of asymmetry into both of the

spiro[4.5]decane rings prevents this approach from being stereoselective

as both diastereomers of 186 are produced. This same problem is also

apparent in the very recently reported work by Pinder e_t al. (84) on a

reaction sequence affording the acorspirane skeleton. The cyclohexenone

derivative 187 was treated with sodium methoxide and underwent an

intramolecular Michael addition to provide both diastereomers of 188.

On the other hand, the cyclization of cis- and trans-monocyclofarnesol

(189) was a successful regioselective synthesis of (+)-a-chamigrene - 40 -

(190) (85), a spiro[5.5]undecane sesquiterpene, because of the absence of asymmetric centers in the cyclohexane portion of 189.

The first and, to this date, only method for the direct conversion of a general bicyclic [4.4.0] ring system to a spiro[4.5]decane is provided by the degradation of B-rotunol (191), a sesquiterpene from

Japanese nutgrass (86). The dehydration of this 5,10-cis-eudesmane readily afforded the cross-conjugated dienone spirane 192 when the C-5 hydroxyl and C-10 methyl were cis, but not when they were trans - 41 -

(ct-rotunol) . A direct method of providing spiranes from a fused bicyclo-

[5.4.0] system has also been discovered. Bicyclo[5.4.0]undec-l(7)-en-3- one (193) was found to undergo a [l,3]-sigmatropic photorearrangement via the singlet state to yield 6-methylenespiro[4.5]decan-l-one (194) (87).

O O 193 194 195

A photostationary state between 193 and 194 established a 2:3 equilibrium ratio of 193:194. The problems of stereoselectively synthesizing a substituted spirane by either of these methods would be substantial.

The synthetic difficulty in preparing cis-y-hydroxy octalones analogous to 191 (plus the lack of stereoselective reactions on 192) makes the first approach unattractive. The photochemical synthetic entry to medium ring spiro-molecules does not provide a method of introducing stereochemistry into the spirane. The fact that hydrogenation of 194 provides both diastereomers of 195 makes even the introduction of C-6 stereoisomers a serious problem (87).

Spiranes with configurational integrity have been obtained successfully

from bicyclic unsaturated hydronaphthalenones through the intermediacy

of tricyclic compounds. Mander et al. have recently reported (79,88)

several examples of intramolecular C-alkylations of diazo-ketones where

aryl 1-5 and aryl 1-6 neighbouring group participation led to spiro-dienone

formation in approximately 90% yield (196 -»• 197, 199 -> 200) . This work - 42 -

198a R = X = H 199 200

jo, R = CH3, X = H

C R = CH3, X=OH

was then extended to ir-bond participation by the benzylic displacement of the diazo methyl carbonyl's nitrogen from compounds of type 202 to afford high overall yields of the bridged spirane 203. Control of - 43 -

the relative stereochemistry between the carbonyl and other substituents of the starting compound, a rather straightforward problem, would permit the stereoselective synthesis of higher terpenoids to be

accomplished readily. As previously indicated by the lack of stereo•

chemical control in bicyclic spiranes, this approach would not be

useful for sesquiterpene synthesis.

The two-step conversion of the Wieland-Miescher ketone (204) to

the spirane dione 206 provides a unique method of obtaining the

simpler monospirane systems. A novel cyclization of the Wieland-Miescher

ketone was discovered to occur during the reduction of 204 in a lithium/

ammonia/ether solution'and quenching with ammonium chloride was found to

O 2Q4 2Q5 2Q6

afford an 80% yield of the cyclopropanol ketone 205 (X = H). A base-

catalyzed transformation of the sodium salt of 205 (X = Na) in a

hetereogeneous benzene-methanol medium provided, stereospecifically, the

spirodione 206 in 75% yield (89). Surprisingly, the use of a

homogeneous media (benzene-dimethylformamide) for the base-catalyzed

transformation provided the trans-indanedione, trans-l,6-dimethylbicyclo-

[4.3.0]nona-2,7-dione (208), stereospecifically (90). This

stereospecificity observed in both 206 and 208 has not been rationalized

yet, but the rearrangements are believed to be generally applicable for - 44 -

the two-step conversion of angularly substituted enediones analogous to

204. The synthetic advantage of configurational retention at C-6 of the spirane is obvious when it is remembered that most other methods afford diasteriomeric C-6 mixtures. The hindered environment of the cyclopentyl carbonyl of 206 also permits the cyclohexyl carbonyl to be removed regioselectively.

The oldest and most practical method of obtaining spiranes stereoselectively was discovered from the studies on santonin (106) photolysis.

Along with "isophotosantanoic lactone" (209), a second photoproduct,

luraisantonin, was obtained in low yield in protic media photolysis and it was assigned the structure 210 (91). When this reaction was

studied on the model hydronaphthalenone 211 (R2 = H, R^ = CH3) (57,92),

the analogous lumiproduct 213 was obtained in 65% yield as the single initial photoproduct if the photolysis was conducted in a neutral - 45 -

aprotic media such as dioxane. When irradiation in 45% acetic acid was used, the expected hydroazulenone 214 was obtained as the predominant product. However, photolysis of the corresponding unsubstituted

212 a 212 b 213

cross-conjugated dienone (211, = R^ = H) in acetic media afforded

a 1:1 mixture of the hydroazulenone (214, R2 = R^ = H) and a new

photoproduct, the hydroxyl spirenone 215 (R2 = R^ = H) (57). The

similar photoreaction with the 2-methyl substituted compound 211 (R2 =

CH^, R^ = H) was found to provide only the corresponding spirenone 215

as the major product. These stereospecifically formed hydroazulenone

and spirenone products have been interpreted mechanistically (58) to

be the result of nucleophilic attack by water at of 212a or 212b

respectively.

While only those hydroazulenones which are 2-alkyl substituted

can be converted to spirenpnes efficiently by the above approach, it - 46 - was discovered that the lumiproducts 213 can be cleaved solvolytically to provide a mixture of spiranes (93). The 2-alkyl substituted compound (213, R^ = CH^, = H) yielded a quantitative mixture of the three spiranes 215, 216, and 217 (88% of which was 216) in refluxing

45% acetic acid, while the unsubstituted lumiproduct 213 (R^ - R^ ~ H) afforded a 10:1 ratio of the three spiranes to the hydroazulenone 214

and the 4-alkyl substituted lumiproduct (214, R^ = H, R^ = CH3) provided a 1:2 ratio of the spirenone 216 to the related hydroazulenone

214. These substituent effects of the acid-catalyzed lumiproduct cleavages are reminiscent of those encountered above in the photochemical conversions of the corresponding parent dienones (211), but different product ratios and configurationally different compounds at C-10 are isolated from the light- and acid-initiated rearrangements. Kropp (93) interpreted the acid-catalyzed spirane product formation in terms of - 47 -

competitive C-9 proton loss (to 217), backside attack by water

(to 216), and frontside attack by water (to 215) during cleavage of the 4,10-bond of the protonated cyclopropyl ketone 218. The orbitals of the 4,10-bond are the only orbitals with the proper geometrical rearrangement for favourable overlap with the p_-orbitals of the C-3 carbonyl group..

Marshall and Johnson (94) exploited the above conversion method by transforming the known octalone 219 into the spirane 222 through the photochemical-acid treatment sequence. The trans-dimethyl relationship in the substituted hydronaphthalenones 219 and 220 became a cis relationship in the lumiproduct,^ establishing the carbonyl and

22QA*'4 the C-6 methyl as trans in compound 221. The rearrangement of the cyclopropyl ketone 221 in anhydrous acetic acid then cleaved the best overlapping cyclopropyl bond to provide a high yield of the spiro[4.5]decadienone 222. This reaction removed the asymmetry at C-10, but left the relative stereochemical relationship of the C-6 methyl and

C-3 carbonyl intact. Compound 222 was then elaborated to the sesquiterpene

A consideration of the mechanistic proposals for the configurational changes at C-10 is posponed until later. Formally, this reaction is a photochemical [o^-a + v^-a] cycloaddition reaction. - 48 -

8-vetivone (223) by standard chemical reactions. Compound 222 was also found by Marshall and Johnson to be catalytically hydrogenated in ethanol to yield a 3:1 mixture of the spiranes 224 and 225 > diastereomers

that could only be separated by gas chromatography.

222

222 - 49 -

DISCUSSION

I. General Development of the Reaction Sequence

As previously stated, our synthetic interests were oriented to the efficient stereospecific transformation of decalinic compounds into the less readily available hydroazulene and spirane systems. After surveying the literature on the guaiane sesquiterpene synthesis (Appendix

II) and the available perhydroazulene preparations, it was felt that a study on maximizing the hydroazulenone (C) yield from the photolysis of cross-conjugated cyclohexadienone derivatives (B) would be profitable.

A_ B. C_

To fulfill the objectives of this study, octalones of type A (R^ = = H,

CH^) would be required for conversion to the corresponding cross-conjugated

system B (R^ = R^ = H, CH3; R3 = H, CHO, COOH, COOR) so that photolysis of B_ could be studied in a variety of solvents. This approach to hydroazulene synthesis is fundamentally a yield study on the well-known photolysis of cross-conjugated ketones, with modifications originating - 50 -

with D. Caine (64,65), B (^ = R2 = H, R3 = COOH).

In contrast to the hydroazulene work, the investigation into

spirane synthesis grew from the question "Would the configuration of

the 8-center of an a,8-cyclopropyl ketone be retained, inverted, or

both on the reductive cleavage of _E to F?" Obviously, a series of simple

cyclopropyl ketones analogous to E, but with a bridgehead alkyl (R' = CH^)

substituent rather than hydrogen,.were necessary before this question

could be answered. The three general methods of preparing these

prerequisite systems include the copper-catalyzed decomposition of

olefinic diazo ketones, the photochemical rearrangement of the cyclic

ketone A, and the photolysis (with subsequent selective hydrogenation

' of D) of the cross-conjugated dienone IL While the unsaturated diazo

ketone 226 has been used to provide the simplest member of the E_ -series

(227) (95 ), the corresponding compounds with asymmetric centers in the

cyclohexene ring have been reported to afford mixtures containing both

diastereomers. Several examples of these intramolecular keto-carbene

insertions are presented in Chart II along with the total yield and the

ratio of diastereomers obtained. The availability of E from stereo•

selective photochemical reactions on either A or 13, therefore, naturally

led to the necessity of preparing several octalones of type A. While - 51 -

CHART II

CYCLOPROPYL KETONES FROM INTRAMOLECULAR KETO- CARBENE ADDITION TO SUBSTITUTED CYCLOHEXENES.

Product Compound (Literature Reference) Yield Diastereomer Ratio

226 (95°) 30 %

b 22 8 X2= H2(95 ) 44 229 : 230 = 1 : 9 228 X»= (-OCH ) (95b'c) 31, 40 229 : 230 = 1 :: 9 2 2 2

d 232: 233 = 3 : 5 231 R = CH(CH3)2(95 ) 78

e 232 : 233 = 1 : 1 231 ' R = C(=CH2)CH3(95 ) 24 - 52 -

spirane and hydroazulene synthesis are dealt with separately in the introduction, discussion, and experimental portions of this thesis, their common synthetic derivation from A in this work led to the inclusion of a single section on the preparation of a,3-unsaturated ketones followed by a section on the derivatives of cross-conjugated dienones.

II. Synthesis of a,8-Unsaturated Hydronaphthalenone Derivatives

The approach outlined above made the preparation of the seven a,8-unsaturated ketones 234 to 240, inclusive, the first synthetic objective of the work described in this thesis. These compounds are considered individually in order of increasing complexity because their preparation utilized widely different synthetic schemes. However, since

the compounds 234 to 240 were later all dehydrogenated to the corresponding

cross-conjugated systems, one synthetic generalization should be made.

The preparation of hydronaphthalene derivatives of type A from the

corresponding cyclohexanone can be achieved by one of two methods. The

first (Method I) is the addition of one methyl vinyl ketone equivalent

(M.V.K.E.)"^ to the 2-methylcyclohexanone derivative 241 with subsequent

ring closure to A while the second (Method II) is the addition of acetone

(or its derivative) to the corresponding 2-formyl-2-methylcyclohexanone

derivative (242) to provide 13 after ring closure and then A after

regioselective hydrogenation of 13. Because of the similarities of these

L^ MVKE includes methy]/vinyl ketone, l-diethylamino-3-butanone methiode, 1,3-dichlorobut-2-ene, l-iodo-3-benzylbutane with subsequent oxidation, l-bromo-butan-3-one ethylene ketal, 3,5-dimethyl-4-chloro- methylisoxazole, and ethyl 3-bromopropionate with subsequent methyl• lithium addition (96). The synthetic approaches to the octalone 236 provide several examples of these different reagents. - 53 -

24Q - 54 -

OHC

242 243 B

two schemes and the quantitative nature of the B_ —>• A conversion, the cross-conjugated systems prepared by the latter procedure are best discussed under the heading of the corresponding a,6-unsaturated ketone. In general, Method II is useful- for the simpler cross-conjugated dienones that are stereochemically unambiguous while Method I, with subsequent dehydrogenation, is essential for the preparation of highly substituted or specifically substituted compounds. The limitations of

Method II are illustrated by the 19% yield of B_ (R3 = COOH) reported for

the reaction of 242 (R^ = R2 = H) with the acetoacetic ester 243 (R^ =

COOEt) (97) and the 1:5 ratio of C-6 diastereomers of B (R± = 6-C(CH2)CH3; a:g = 5:1) obtained from condensing the C-4 isopropenyl substituted cyclohexanone 242 with acetone (243, R_ = H) (98). - 55 -

A. Octalone 234 (4a-Methyl-4,4a,5,6,7,8-hexahydro-2(3H)-

naphthalenone)

The well-known octalone 234 is normally prepared from 2-methylcyclohexanone using methyl vinyl ketone in place of the l-dimethylamino-3- butanone methiodide originally required in the Robinson annelation method since the latter reaction provides the octalone product in low yield and questionable purity (103). The procedure of Marshall and

Fanta (99) condenses 2-methylcyclohexanone and methyl vinyl ketone

at -10° in the presence of a catalytic amount of sodium ethoxide to

afford the crystalline ketol 247 in 55% yield. The stereoselective

formation of the cis-ketol is the result of kinetic control in the

OH 244 245 247 234

intramolecular aldol cyclization. Dehydration of this ketol with

potassium hydroxide then proceeds in ^90% yield to the desired octalone

234 (^ 50% overall). Heathcock et al. (100), in December 1971,

reported the corresponding acid-catalyzed Robinson annelation. In

this case, sulfuric acid is used as the catalyst for both forming and

dehydrating the ketol 247. Methyl vinyl ketone and 2-methylcyclohexanone

are refluxed for 16 hours in the presence of a catalytic amount of acid

to afford 49-55% yield of octalone 234 on workup.

To prepare the substantial amounts of octalone 234 required, the

procedure of Marshall and Fanta was adopted and then modified slightly - 56 -

during the course of repeating the reaction on six occasions. The two apparent problems were the excessive polymerization of methyl vinyl ketone observed during its dropwise addition to the reaction and the prohibitively large volumes of diethyl ether-hexane solution required

for the crystallization of the crude ketol 247. A Hershberg stirrer rod on a high torque stirring motor overcame the first problem and the

direct dehydration of the ketol in the reaction vessel with 10% aqueous potassium hydroxide solved the second. In this manner, the octalone

234 was prepared in 57% yield directly or 75% yield on the basis of

unrecovered 2-methylcyclohexanone.

When Heathcock et al. published their synthetic procedure for 18

octalone 234, its experimental simplicity encouraged us to apply it.

However, upon workup, all distillation fractions of the desired octalone

were found to be contaminated with 16% of a second component, 2-methyl-

2(3-oxobutyl)-cyclohexanone (246). A structural assignment was made on

the basis of the saturated carbonyl present in the infrared spectrum

(1710 cm ^) and the downfield acetyl methyl (T 7.80, singlet of three

protons) in the nuclear magnetic resonance spectrum. This impurity

was removed and octalone 234 produced by refluxing the initially obtained

material in an ethanolic potassium hydroxide solution to cyclize .compound

18 A private communication from Professor Heathcock indicated their procedure actually used 100 ml benzene in the reaction mixture for each 0.3 ml of sulfuric acid catalyst, a fact omitted from reference 100. Since benzene and methyl vinyl ketone have similar boiling points (81° versus 79-80°), it is not surprising that we have found the elimination of benzene makes very little difference to the reaction. The discussion on the preparation of octalone 234 and 235 by acid-catalyzed annelation was found to be unaffected by the presence or absence of benzene as shown by conducting the reactions both ways. - 57 -

246 3 249 248

246 and dehydrate the intermediate aldol product (247). At this point, a side-product that was shown to arise from the acid-catalyzed cyclization was isolated in the distillation forerun of octalone 234.

It was identified as 2,5-dimethylbicyclo[3.3.l]non-2-en-9-one, the bridged ketone 248 that has been obtained by Marshall and Schaeffer (107)

in 60% yield by hydrolyzing the vinyl chloride 249 with sulfuric acid at 0-20° for 2 h. In both instances, the intermediate dione 246

undergoes the alternative aldol condensation and dehydration to afford

248 instead of 234. The spectral data recorded for compound 248 is

in complete agreement with that reported (107), and the compound was

shown to be unaffected by the base treatment.

The above results suggested that the acid-catalyzed procedure should

incorporate a short period of treatment under basic conditions before

workup. Upon repeating the method of Heathcock et al. (100), a 0.5

molar ethanolic solution of sodium ethoxide was added before workup at

the end of the reaction period, and the basic solution was refluxed for

an hour under a nitrogen atmosphere. Workup then gave a 45% yield of

pure octalone, a 60% overall yield based on the 25% 2-methylcyclohexanone

recovered. Aliquot samples taken before and after the base treatment

- 59 -

were analyzed by gas chromatography to provide the data in Figure 1.

Ignoring the starting material, 2-methylcyclohexanone at R^ (R^ =

retention time is ^ 2 min), the product ratio of compound 248 (R,. ,.):

246 (Rg):234 (R1Q) is 7:14:75 under Heathcock's procedure (i.e. (a) in

Figure 1) becoming 7:0:87 after subsequent sodium ethoxide treatment

(i.e. (b) in Figure 1). Since Rj. _ is the bridged ketone 248, a

compound unaffected by the base treatment and therefore a useful

internal standard, the total dione 246 plus octalone 234 present in

(a) and the total octalone 234 present in (b) compare favourably as 89

versus 87. It was also noticed in more qualitative terms that

increasing the amount of acid catalyst decreased the R^/R^Q ratio

(246:234), but increased ^/^Q (248:234). In contrast to this acid-

catalyzed work where the bridged ketone 248 had to be removed by careful

distillation, Marshall and Fanta's experimentally more arduous base-

catalyzed procedure afforded octalone 234 free of impurities.

The preparation of the corresponding cross-conjugated cyclohexanone

(_B, R1 = R2 = R3 = H; 300) was reported in the 1950 work (104) of

Woodward and Singh using two methods. The sodium enolate of 2-methyl•

cyclohexanone was condensed with methyl ethinyl ketone in an extension

of the Robinson annelation to provide compound 300 in low yield (9%).

A 10 foot x 0.25 inch column packed with 20% SE-30 on 60/80 mesh Chromosorb W was employed at 155° with a flow-rate of 97 ml/min helium carrier gas. Chromatographic samples were washed with acid and base and then dried over anhydrous magnesium sulfate before use. - 60 -

The condensation of 2-formyl-2-methylcyclohexanone (241, = R2 = H) with acetone, adapted from the elegant method of Wilds and Djerassi

(105) for the synthesis of the tetracyclic ketone 251 from the tricycli ketone 250, afforded compound 300 in 62% yield.

Adopting the latter sequence, dry ethyl formate was added under

itrogen to a slurry of alcohol-free sodium methoxide in a benzene

olution of cyclohexanone to afford the desired 2-hydroxymethylene-

yclohexane (255) on workup (106). The solubility of the sodium sal - 61 -

of all hydroxymethylene derivatives (254) in water makes their isolation via aqueous base simple, but air oxidation and decomposition makes them difficult to store. Because of this instability, compound 255 was methylated by Claisen's method (106) immediately after its distilla•

tion. A mixture of the C-methylation and O-methylation products^ 256 and

257, were obtained by refluxing the freshly distilled 255 and methyl

iodide in an acetone slurry of potassium carbonate. A 3:1 ratio of

256:257 was obtained as determined by n.m.r. integration of the downfield

aldehyde proton of 256 at x 0.48 relative to the olefinic C-7 proton

of 257 at T 2.8. The methylated product mixture was then condensed

with acetone to afford the desired cross-conjugated system in 9%

overall yield from cyclohexanone.

The original work by Wilds and Djerassi revealed that the C-

methylated product was quite sensitive to cleavage with loss of the

formyl group. While sodium ethoxide and aluminum _t-butoxide caused

cleavage in the attempted condensation with acetone to provide 251,

piperidine with a slight excess of acetic acid gave yields of up to

40% of compound 251 (105). For the preparation of the cross-conjugated

dienone 300, the analogous reaction was found to afford, in our hands,

a 32% yield. The spectral data of this product fully corroborated

the structural assignment and the dienone's data is discussed with an

alternate synthesis that provided the pure dienone 300 in over 30%

overall yield from 2-methylcyclohexanone. - 62 -

B. Octalone 235 (4a,8-Dimethyl-4,4a,5,6,7,8-hexahydro-2(3H)-

naphthalenone)

In analogy with octalone 234, the 8a-methyl substituted octalone

235 has been prepared by condensing methyl vinyl ketone with 2,6- dimethylcyclohexanone. Unfortunately, Marshall and Fanta (99) found this method provided an impure product in low yield (< 20%). A year later, Marshall and Schaeffer (107) utilized the Wichterle reaction in a six-step sequence from 2,6-dimethylcyclohexanone to provide the desired trans-4a,8q-dimethyl octalone 235 in about 40% overall yield.

The cyclohexanone 258 was alkylated with 1,3-dichloro-cis-2-butene (259) and the Y~chlorocrotylcyclohexanone product (260) was brominated and dehydrobrominated to the cyclohexenone derivative 261. This product was

258 259 26Q 261

262 263 235 63 - then hydrolyzed to the unsaturated dione 262 which in turn was hydrogenated to the dione 263 and cyclized with base to afford the octalone 235. The introduction of the cyclohexene double bond was necessary because hydrolysis of the vinyl chlorine of 260 immediately caused the alternative acid-catalyzed aldol cyclization of the inter• mediate dione 263 and dehydration under the reaction conditions to 264.

Caine and Tuller (108) subsequently reported a sequence that used basic reaction conditions to obtain octalone 235 from compound 260.

Dehydrohalogenation of 260 with sodium amide in ammonia proceeded

quantitatively to the ketoacetylene 265 and isomerization of the triple

bond with sodium amide in refluxing toluene provided the terminal

acetylene 266 in 73% yield. Hydration with 2% sulfuric acid in methanol-

water and mercuric sulfate catalyst yielded 96% of the dione 263 which 4

i °v 264 265 266

cyclized in 73% yield to the octalone 235. The five steps of Caine

and Tuller's preparation afforded an overall 35% yield of 235 from

2,6-dimethylcyclohexanone.

From the preceding information, one would not expect to find that

Heathcock's acid-catalyzed Robinson annelation procedure (100) could 19

provide the desired octalone 235. In Figure 2, the gas chromatogram

(a) illustrates the very low yield of octalone 235 prepared by refluxing - 64 -

2,6-dimethylcyclohexanone and methyl vinyl ketone with a catalytic amount of sulfuric acid. The desired octalone has a retention time of approximately 14 minutes (R-j^) versus the bridged ketone (264) at

and 2,6-dimethylcyclohexanone (258) at R2« However, treatment for one hour with a refluxing 0.5 molar sodium ethoxide in ethanol solution caused a dramatic shift to a more favourable situation as illustrated by (b) in Figure 2. Upon workup, a considerable amount of 2,6-dimethyl• cyclohexanone was recovered (46-64%) and both the undesirable R^ component ( ^5% in pure form) and octalone 235 (20-25%) were cleanly separated by distillation. The octalone 235 afforded by this procedure was identical by an analytical infrared comparison with an authentic sample of octalone 235 prepared by an alternate unambiguous route described subsequently. However, since the yield of pure octalone 235

from this one-pot reaction is greater than 40% based on unrecovered

2,6-dime'thylcyclohexanone, the above procedure provides a very

attractive alternative to the six- and five-step literature sequence.

The impurity at R, c, being available in gram quantities on D.J workup, was readily purified and assigned the bridged ketone structure

264. The compound exhibited the spectral data previously reported

for this compound (107) and was very similar to that observed earlier

for the 1-desmethyl compound (248). In the n.m.r., the C-l tertiary

methyl (T 8.9) in 264 replaced the C-l one proton resonance (T 7.3) in

= 1 5 HZ J = 2 2 Hz and = 248, but the JC2(CH3)-C3H ' > C2 (C^-cV, ' ^H-C^

3.4 Hz were the same in both compounds. The infrared carbonyl (1720 cm--'-)

and double bond (1675 cm L) absorptions were identical and both ultraviolet

spectrums exhibited a weak 235 my shoulder on the strong end absorption

below 220 my.

- 66 -

The Rg and R^ components present in chromatogram (a) of

Figure 2 were isolated by preparative gas chromatography and demonstrated to have nearly superimposable analytical infrared spectrum showing a

1710 cm ^ carbonyl and an ultraviolet spectrum exhibiting end absorption below 220 my. Both n.m.r. spectrums showed an acetyl methyl (T 7.88 and 7.83 respectively), a methyl doublet with J = 6.4 Hz (x 9.01 in both spectra), a tertiary methyl (x 9.01 and 8.82 respectively), and eleven other protons based on the integration of the downfield acetyl methyl. Acid-catalyzed epimerization of either pure compound with concentrated hydrochloric acid resulted in the growth of the other's tertiary methyl and acetyl methyl in the n.m.r. spectrum until a 60:40 ratio was established, the same ratio as observed in Figure 2 (a). The substantial difference in retention times observed on the gas chromatograph are surprising since these two compounds are obviously the two methyl epimers of compound 263. The shorter retention time component was assigned the cis-2,6-dimethyl dione structure 263a and the longer retained component the trans-2,6-dimethyl structure 263b on the basis that the C-l carbonyl was exerting an anisotropic effect on the tertiary methyl. The equatorial C-2 methyl of 263a therefore became, - 67 - as expected, deshielded by 0.2 T in 263b when this methyl became 20 axially oriented to the adjacent carbonyl functionality (109).

Both isomers led co only the desired octalone 235 on sodium ethoxide

treatment since, independent of the isomer that cyclizes, the ketol 267 would be dehydrated and enolized in base to yield 268. This intermediate

is protonated under the reaction conditions to afford the thermodynamically more stable 8a-methyl octalone. The structure and stereochemistry

assigned to octalone 235 was confirmed by undertaking its synthesis by

another approach.

267 268 235

The cross-conjugated cyclohexanone (B, = Scx-CH^, R^ = H; 301)

was prepared by a literature procedure (111) that is completely analogous

to that discussed earlier for 300. Dry ethyl formate was added under

nitrogen to a slurry of alcohol-free sodium methoxide in a benzene

solution of 2-methylcyclohexanone. The isolated 2-hydroxymethylene-6-

methylcyclohexanone (270) from the workup was then immediately

methylated with methyl iodide in refluxing acetone solution containing

20 The preparation of 2,6-dimethyl-2(carbomethoxymethyl)cyclohexanone has been found to yield an epimeric ratio that indicates similar differences in the resonance of the tertiary methyl. A 55:45 ratio was assigned to the epimers analogous to 263a and 264b on the basis of aromatic solvent-induced shift studies in benzene on the mixture of isomers (110). - 68 -

a slurry of potassium carbonate. A 3:1 ratio of 271:272 was obtained

as determined by n.m.r. integration of the downfield aldehyde proton

of 271 at T 0.30 and 0.52 in relation to the olefinic C-7 proton of 272

at x 2.80. Of greater interest is the presence of the two aldehyde

isomers, 271a and 271b (271a:271b ratio is approximately 2:1), which were assigned their stereochemistry on the basis of the anisotropic

effect of the C-l carbonyl on the tertiary methyl group. The major

epimer 271a shows x 0.52 (singlet, IH, -CHO) and 8.78 (singlet, 3H,

tertiary methyl) signals in the n.m.r. while the other exhibits x 0.30

(singlet, IH, -CHO) and 8.63 (singlet, 3H, tertiary methyl) signals.

The methylated product mixture was condensed with acetone in a refluxing solution that contained piperidine and a slight excess of acetic acid.

The reaction was worked up to afford the desired cross-conjugated

system 301 in 23% overall yield from 2-methylcyclohexanone. Analytical - 69 - samples were obtained by crystallization from hexane and exhibited physical and spectral data which were in good agreement with that previously published (111).

The stereochemical relationship between the methyl groups of 301 has been proven by Bloom (112) to be trans. Therefore, selective hydrogenation of only the disubstituted double bond of 301 under neutral

conditions would provide authentic trans-4a,8-dimethyl octalone (235).

This selective reduction was accomplished in 99% yield by using a

benzene solution of the homogeneous hydrogenation catalyst tris(triphenyl-

phosphine)chlororhodium to hydrogenate the dienone 301 at atmospheric

pressure. This compound was identical in all respects to that prepared

by the acid-catalyzed Robinson annelation procedure.

The foregoing work provided a successful synthesis of the desired

8a-methyl octalone 235, but the procedure lacked generality since other

8a-substituted octalones (236 with its 8a-acetoxy for example) could

not be conveniently prepared this way. In view of the octalone 234

on hand and our desire to prepare a wider variety of hydronaphthalenones

substituted at the 8-position (8a-acetoxy or 8a-alkyl (^CH^)),

consideration was given to methods of introducing substituents y to a,8-

unsaturated ketones. The Vilsmeier reagent, phosphoryl chloride in

OAc

278a 278 b - 70 - dime thylformamide, has been used to prepare the octalone 278a and the steroid

278b from their corresponding y-desmethyl compounds (50,114 ). The conjugated

enone 273 was converted to its enol ether 274 (R' = CH3 or CR^CH^) and reacted with the Vilsmeier reagent to yield the salt 275 which, on hydride reduction (sodium borohydride or lithium aluminum hydride), afforded the amine 276. Further reduction with Raney nickel gave the enol ether 277 by hydrogenolysis and the desired y-methyl a,3-unsaturated

276 277 278

ketone 278 was obtained by acid hydrolysis. While the octalone 278a was prepared from its precursor 273 (R = 5B-0Ac) in 75% overall yield

(50), and while such intermediates as 275 have been used to obtain

other Y~substituents (formyl, hydroxymethyl and methylene (114^)),

another more general reaction sequence that had been utilized in steroid

chemistry appeared more attractive. - 71 -

Ketalization and epoxidation of a,6-unsaturated ketones (273) readily provide such 8,Y-epoxy steroidal ketals as 280 in high yield.

In 1958, Campbell e_t al. (115) reported the preparation of several

6a-methylandrostenones (278b, X = H, 6-OH for example) from their corresponding androst-4-en-3-ones (273) by cleaving the epoxide of 280 with methylmagnesium bromide, removing the ketal with aqueous acid and dehydrating and isomerizing to 278 with base. Zderic e_t al. (116) have introduced a phenyl group in an analogous manner to obtain an 80%

yield of the 66-phenyl derivative of progesterone (281, C-17B-C(OCH2CH20)CH3) by adding phenylmagnesium bromide to the corresponding epoxy ketal 280.

273 279

281 282 278 - 72 -

When the octalone 234 was ketalized with ethylene glycol in

toluene containing a catalytic amount of p-toluenesulfonic acid, a 73% yield of doubly distilled dioxolane 283 was obtained. Gas chromatography

and n.m.r. analysis indicated 6% of the octalone was still present, an

observation that has been reported previously (117). The dioxolane methylene protons at x 6.03 (singlet, 4H,-OCI^CH^O-) and the broadened

signal at x 4.63 (multiplet, IH, =CH-) confirmed that the desired

compound 283 had been prepared. Epoxidation of the latter with m-chloro-

perbenzoic acid in dichloromethane buffered with sodium bicarbonate

(118a) then afforded, after distillation, an 87% yield of a 40:60 mixture

of the two epoxy ketals (284). In view of the subsequently discovered

234 283 284 a 284 b

differences in reactivity of these two compounds, the major isomer,

having signals at x 8.92 (singlet, 3H, tertiary methyl) and x 7.04 g (multiplet, IH, C H) in the n.m.r., was assigned the cis-structure 284b

while the minor isomer, having signals at x 8.87 (singlet, 3H, tertiary g

methyl) and x 7.17 (multiplet, IH, C H), was designated as the trans-

isomer 284a. In support of these assignments, the decalins 285,

a b R = H (118 ) and 285, R = CH20H, C(CH3)20H (118 ) have been reported

to yield a 60:40 yield of the analogous epoxides 286a and 286b with

the 286, R = H compounds having n.m.r. methyl resonances at x 8.88 (286a) and T 8.94 (286b). While these 286, R = H isomers were reported to 21 be inseparable by gas chromatography, their rigorous structural proof have shown that the trans-isomer 286"a predominates (118 ). However,

Marshall e_t al. (117) found the hydroboration of the ketal 283 followed

285 286q 286b

by oxidation of the resulting organoborane with alkaline hydrogen peroxide

provided only the cis-fused hydroxy ketal. This result was expected

on the steric grounds that the axial oxygen of the ketal group in 283

blocked the a-face of the molecule. Therefore our observed 40:60 ratio

of a: 8 epoxidation of the ketal 283 is actually less stereoselective

with respect to the 8-isomer than might be expected (119).

When the epoxide mixture 284a+b was treated with methylmagnesium

bromide in tetrahydrofuran or hexamethylphosphoramide under a nitrogen

atmosphere at 35°, the a-epoxide 284a was rapidly cleaved, but the

8-isomer was recovered unchanged after periods of up to 60 hours. This

was not completely unexpected since Marshall e_t al. found that

refluxing a 60:40 mixture of 286a:286b (R = H) in anhydrous tetrahydro-

furan with methylmagnesium bromide for 32 hours cleaved the trans-isomer

In contrast, 284a and 284b were readily separated by g.l.c. using a 10 foot x 0.25 inch column packed with 20% SE 30 on 60/80 mesh Chromosorb W at 185°. - 74 -

286a nearly completely, but only cleaved two-thirds of the cis-isomer

(118). Their work also showed that while 85% of the trans-isomer could be accounted for by g.l.c. analysis of the product mixture, only 63% of the cis-isomer could be distinguished in such an analysis. The introduc• tion of the C-2 gem substituents in the ketal 284a must therefore make the a-face sufficiently sterically hindered to prevent the addition of the Grignard reagent.

In expectation that alkyllithiums would be better nucleophiles (120), methyllithium addition to the epoxides 284a+b in ethyl ether was tried at

0° for 12 hours, 20° for 12 hours and 35° for 24 hours. At 0° one-third of the ct-epoxide and all of the 8-epoxide were recovered unchanged, while at 20° and 35° none of the a and all of the 6 were recovered. When methyllithium was used in refluxing tetrahydrofuran for 2 hours, all the * a-epoxide, a substantial amount of the ketal and little, if any of the

0-epoxide were opened.

By coincidence, a timely publication appeared on the reaction of lithium dimethylcuprate and other organocopper reagents on cyclohexene oxide (122). The report indicated that lithium dialkylcuprates are more reactive towards epoxides than the corresponding alkyllithiums and possibly are superior to the alkyllithiums with respect to yields of the nucleophilic addition product. Since dialkylcuprates are known - 75 -

to be relatively inert to saturated carbonyls, let alone ketals (123), it was very disappointing to find that even the cx-epoxide was not cleaved over an 18 hour period at room temperature with a five-fold excess of lithium dimethylcuprate.

C. Octalone 236 (8a-Acetoxy-4a-methyl-4,4a, 5,6, 7,8-hexahydro-

2(3H)-naphthalenone)

The resistance of the a-epoxide to nucleophilic attack had been so well documented by the foregoing reactions that it was easy to be apprehensive about opening both 284a and 284b with hydroxylic nucleophiles. However, the perchloric acid hydrolysis work reported on the pregnenone derivatives 287 (124) was particularly informative because both the a- and B-epoxides were found to yield the identical diol 288

_ All the organometallic reactions were monitored by taking aliquot samples by syringe from the above reactions done under a nitrogen atmosphere. By these observations, it was discovered that the B-epoxide was more stable to the different organometallic reagents than was the ketal. Heathcock et. al. (121) have called attention to the fact that the dioxolane grouping can be removed by the following fragmentation mechanism.

1 ii

While this side reaction was a minor consideration with the above Grignard reactions, it was a serious problem with the organometallic reagents in reactions done above room temperature. A practical solution to this problem is demonstrated in subsequent work on the preparation of the steroid 240. - 76 -

22 under the same conditions. Since this diol had previously been acetylated to the monoacetate 289 and dehydrated with concomitant

^CH2OAc ...OH

OH 287a a-epoxide 288 287 b /3-epoxide epimerization of the C-6 acetoxy substituent to afford 290 (125), there was some literature precedence for treating 284a+b in a sequence utilizing aqueous perchloric acid in acetone, acetic anhydride in pyridine and anhydrous hydrogen chloride in chloroform to provide 236.

The addition of acid catalyst (HCIO^) allows hydration to be accomplished under much' milder conditions and at a much faster rate than in the absence of an acid catalyst. The expected opening of the oxirane in a trans-diaxial manner is demonstrated very clearly by the reported conversion with anhydrous hydrogen chloride of the 8-epoxide jL (partial steroidal structure) to the diaxial halohydrin 11 (A = OH, B = Cl), whereas the a-epoxide jL is diaxially opened to the halohydrin ii (A = Cl, B = OH) (120).

B ii - 77 -

284 g + b 292 236

When this sequence was applied to the epoxy ketal 284, the crude product of this sequence (obtained in 20% yield overall) was found to be a mixture of the dione 294 and an acetoxy-substituted octalone

(236?). Infrared and nuclear magnetic resonance spectra supported the structural assignments, but a considerable amount of material was lost in the aqueous layer of the workup of the perchloric acid hydrolysis reaction. While g.l.c. monitoring of the diol 292 preparation was not feasible because of the labile nature of 292, most of the ketal (284) was shown by g.l.c. to be removed after the first hour of the twenty-hour hydrolysis reaction. The dione 294 was rationalized to be the result of dehydration of the tertiary hydroxyl

(C-8a) of 292, enolization of 293 to remove the 1,3-diaxial interaction, - 78 -

292

293 294

and enolization to the dione 294 occurring much more readily than in

steroidal systems. The dione 294 was also prepared by a 20 min

steam bath treatment of the epoxy ketal 284 in acetone-6 N hydrochloric

acid (126,127).

However, since the isomerization of Y-hydroxy-a,8-unsaturated

ketones has been reported to occur much more slowly in base than acid

(127), some consideration was given to removing the ketal and opening 23

the epoxy ketone 291 with base. The previously reported examples of

catalyzed opening of 8,Y-epoxy ketones to afford Y~hydroxy-a,8- unsaturated ketones were accomplished with piperidine (115), pyridine b 3. b (129 ), and methanolic potassium hydroxide (129 ' ) on 3-keto steroids

^ The preparation of the 8,Y_epoxy ketone 291 by direct epoxidation of 341 (i.e. deconjugated octalone 234) (155) failed since the competing Baeyer-Villiger reaction (128) led to a crude reaction product mixture that was predominantly lactones iL and ii.

341 291 i ii- - 79 -

O O

291

having a B>Y_epoxy functionality. When the ketal of 284a+b was

removed with hydrochloric acid (.1 N 2 N) in dioxane or acetone,

some of the dione 294 was also produced, even after only short periods.

A one hour treatment of 284 with 1 ml of 1.5 N perchloric acid in

40 ml acetone was found to be best, but the subsequent treatment at

room temperature with acetic anhydride in pyridine was found to yield

a mixture of acetate-containing products. Several attempted

modifications led to the same mixture of four reaction products. The

work on this approach was therefore discontinued.

There is literature precedence for introducing the y-acetoxy

substituent through sequences that employ osmium tetroxide on the

corresponding g.y-olefin (130), peracid oxidation of the enol acetate

of the conjugated ketone (131^), y-bromination with N-bromosuccinimide

(297), or y-hydroxylation with selenium dioxide on a,8-unsaturated

O COOH Br COOH 296 297 1Q6 O - 80 - ketones (296), or hydroxylation of a,6-unsaturated ketones by molecular oxygen (133). This last method provided the 88-hydroxy- ketone 299 in approximately 50% yield by the autoxidation of 298 in the presence of alkali hydroxide, sodium isopropoxide, or other bases.

The autoxidation even occurred in aqueous piperidine, but at a much slower rate than it did in concentrated base. The influence of the

7a-substituent was demonstrated by the observation that the corresponding

76-compounds (307) provided only a small amount of 309 and none of the 25 expected 308. _ Santonin was synthesized via the sequence 296 -»• 297 106 (131) and A3-296 ->- 106 (131). The difficulty of preparing the desired octalone 237 directly from a cyclohexanone derivative was demonstrated by the destruction of the acetoxy substituent in the readily available compound i_ (132) when hydroxyme'thylation was attempted on this ct- acetoxy ketone. An approach analogous to this one was considered in one of the earlier santonin (106) syntheses (131a).

OAc OAc OAc

L ii 302

The stability of 299 to refluxing aqueous alcoholic potassium hydroxide (i.e. to isomerization to the corresponding 2,8-dione) was rationalized to be due to the deformation of ring B to a boat confirmation. The influence of C-7 stereochemistry was then related to the accessibility of the 8a-hydrogen atom in determining the mode of decomposition of the postulated C-8 hydroperoxide intermediate. - 81 -

298 R = /3-H 299 R = /3-H 2Q9_

3Q7 R = a — H 3Q8 R=a - H

While the basic conditions that were employed in the above reaction (to both generate the enolate and then to reduce by hydrolysis the hydroperoxide intermediate) precluded its being used in a sequence leading to the desired octalone 236, molecular oxygen has also been used in two neutral, but distinctly different, processes to prepare an isolatable y-hydroperoxide which, after mild reduction with sodium iodide or triphenylphosphine, affords the y-hydroxy-a,8- unsaturated ketone. The first of these oxygenation reactions uses the autoxidation of a 8,y-unsaturated ketone with ground state 3 - (triplet) oxygen ( I ) in a free radical process that probably involves 6 * the mesomeric radical 311 (133,135,142) while the second utilizes excited state (singlet) oxygen (^Z+ or *A )^ on a 8,Y-unsaturated

26 These two metastable singlet states differ in the electronic configuration of their degenerate highest occupied molecular (anti- bonding) orbitals. The -^Zg state (37 kcal) has one electron in each orbital while the ^Ag state (22 kcal) has both electrons in one orbital and the Statothee r vacant.

Relative Energy (Kcal) O f'2 37

Configuration of the highest occupied orbitals - 82 -

ketone in a concerted process that involves either a cis-"ene" (313a) or "perepoxide" (313b, peroxirane) transition state (136,143).

These two processes are easily confused since they both are 27

commonly accomplished photochemically and may give a product having

the same stereochemistry (312 = 314). For example, the report that

a chloroform solution of the norandrost-5,10-en-3-one 315 (X = -C=CH),

after exposure to fluorescent light under an oxygen atmosphere, yielded

40% of the 103-hydroperoxy compound 316 (147) was later followed by

a communication (136) that found the photosensitized irradiation of

A free radical oxygenation process (J02) can be accomplished with oxygen and base (133), oxygen and peroxides (146), or oxygen in an unsensitized photolysis (135) while the excited singlet state oxygenation process (IO2) requires photo-oxygenation in the presence of a sensitizing dye (139,140), positive halogen compounds (hypo• chlorites, etc.) with hydrogen peroxide (•'•Ag only) (137,141), or a radiofrequency (6.7 Mc) discharge in gaseous oxygen (138). - 83 -

315 (X = H) in pyridine afforded 45% of the corresponding 10B- hydroperoxy ketone 316. The first reaction requires a free radical chain process involving the generation of a mesomeric allylic radical by abstraction of the C-4 hydrogen while the second uses the photo- 1 28

excited singlet state oxygen ( 0^). For reasons that will be

considered below, it appears that the triplet and singlet hydroperoxyla-

tions usually give distinguishable products in a molecule where

diastereoisomers are possible when the oxygenated position is secondary

rather than tertiary.

HO X HO X

315 316

^8 The nature of the "L02 species (XAg or X£g> or both) has been discussed by CS. Foote and coworkers (141). This group suggested the -*-Ag state might be expected to react in two-electron, concerted processes while the ^-Eg state should resemble the ground state and would be expected to undergo radical-like reactions. Also the ^Ag , oxygen has a lifetime long enough to be consistent with the lifetime of the reactive complex while the ^Zg state would be expected to be rapidly quenched in solution. However in 1967, Kearns and coworkers (139,140) proposed that both -'•Eg and -^Ag oxygen molecules could be involved as reaction intermediates. They observed a product distribution (A -* B + C) that varied from 30:1 to 1:5 (B:C) as the triplet energy of the dye-sensitizer employed was raised above 38 kcal to 50 kcal. A similar variation was reported by Nickon and Mendelson in 1965 (148), but they proposed no mechanistic implications. Therefore, in the context of this thesis the symbol ^2 is used

without specifying -*-Ae or -'-Eg states. - 84 -

In an early example of the autoxidation process, Fieser et al.

(146) found that cholest-5-en-3-one in a hexane solution at 25° combined with molecular oxygen in the presence of dibenzoyl peroxide

(a radical initiator) to give 6(a plus 8)-hydroperoxide. A report was made in 1964 (147) that an attempted chromatography over silica gel of the 0 ,y-steroidal enone 317 yielded a mixture of the 6(ct plus 8)- hydroperoxides 318. Nickon and Mendelson then discovered in 1965 that cholest-5-en-3-one photo-oxygenation (without a sensitizer) and reduction of the photo-product with sodium iodide afforded a mixture of the 6(a plus B)-alcohols. A current (1973) re-examination of

OH OH

317 OOH

cholesterol autoxidation by L.L. Smith e_t al. (150 ) has resulted in the isolation of 68-hydroperoxycholest-4-en-3-one from samples of crystalline cholesterol stored at 70° in air for one month. The isolation of the 68- but not the 6a-isomer (probably formed via

A^-3-one) in this work suggests that autoxidation initially yields only the 68-hydroperoxide from triplet oxygen. Interestingly, Smith et al. (150^) also discovered that secondary allylic hydroperoxides can be readily epimerized (i.e. 319 320). Therefore, the earlier observed 6(a plus 8)-hydroperoxy mixtures could readily be rationalized - 85 -

AcO 319 3 2Q

as occurring from epimerization of the 68-isomer to remove the

1,3 diaxial interaction with the C-10 methyl. The report that enol

ethers (partial structure 321) are completely oxidized in 2 h at 30° 4

in direct sunlight by an autoxidation process to give 6-hydroxy-A -

3-ketones (322) (151) supports the above argument because the ratio

generally observed between the 68- and 6a-epimers was found to be

at least eight-ten to one.

OH 321 R = alkyl 322

The cholest-5-en-3-one is the only example of a photosensitized

oxygenation (^C^) studied to date where a B,Y-enone yields a

secondary hydroperoxy substituted product. However, oxygenations of

8,Y~enones with singlet oxygen should only be considered as an example

of the extension of the conversion of a monoolefin to an allylic

hydroperoxide in the much more extensively studied general hydroperoxy-

< - 86 - lations of olefins. The field of oxygenation of monoolefins has been recently reviewed elsewhere (142-145) and only a summary of the principles is considered here. Singlet oxygenation of the monoolefin

is always accompanied by the concommitant shift of the double bond without the intermediacy of free radicals. An analysis of the reaction

products often shows that a high degree of both regio-selectivity

and stereoselectivity is exhibited. In the case of (+)-limonene,

the presence of optically active (-)-cis-and (+)-trans-alcohols 324

and 325 along with other compounds in the reaction mixture (324-329)

was readily understood in terms of the concerted cis-attack by ^O^ 29 on the trisubstituted double bond and the allylic hydrogen. Taking

326 327 328 329

29 The mechanistic differences of autoxidation ( 02) were illustrated

when the 3o2 oxygenation of 323 was found to yield the racemates corresponding to 324 and 325 and none of the exocyclic (326, 327) products. - 87 - into account the conformational analysis of (+)-limonene and assuming that the transition state for the cyclic product-forming step resembles starting olefin more than it does the allylic hydroperoxide products,

the product distribution of 324 (5%):325 (10%):326 (21%):327

(20%):328 (34%):329 (10%) was readily.rationalized. Reaction on the favoured conformation of 323 (E 330) gave ^0^ the choice of several quasi-axial (a') and quasi-equatorial (e1) hydrogens. In the case of

(+)-limonene, as is generally found, the predominant product at each position always favoured the a' hydrogen abstraction.

331

Conformationally rigid steroidal olefins provide even better examples of stereoselectivity since pronounced steric interactions are also exhibited during singlet oxygenation. In cholesterol (331, R = OH) there are two equatorial/quasi-equatorial hydrogens, '4a-H/78-H, and two axial/quasi-axial hydrogens, 48-H/7a-H. Since a cyclic step involving the 48 axial hydrogen and C-0 bond formation at C-6 (i.e. 8-face reaction) would necessitate two 1,3-diaxial interactions with the C-10 methyl, the corresponding a-face reaction involving the 7ct-H and C-5 oxygenation is expected to predominate. Nickon and Bagli (149) not only found that the 5ct-hydroperoxide 332 was the exclusive product (from 331,

R = OH, OAc, or H), but also demonstrated the stereospecificity of the - 88 -

reaction by converting cholesterol-78-d to 332 (95%-7-d) and

cholesterol-7ct-d_ to 332 (8.5% 7-d_) . The inertness of the allylic equatorial steroidal hydrogens was also demonstrated by the fact that coprost-6-ene (333), containing a 58-quasi-equatorial hydrogen in the

(non-flexible) B ring did not undergo oxygenation. Steric blocking by the C-10 methyl of the pseudo-axial 88-H was also apparent in this work.

Since the preceding examples demonstrate that photo-oxygenation can be substantially blocked when the C-0 bond has to be introduced in a

1,3-diaxial relationship- to an alkyl substituent or when the allylic hydrogen is rigidly equatorial or quasi-equatorial (135), the report

that photosensitized oxygenation of cholest-5-en-3-one (334) yielded

the 68-hydroperoxide as the major product (134) was surprising. A

reinvestigation of the reaction by Nickon and Mendelson (135) concluded

that the expected product of ^0^ hydroperoxylation, 335, was produced to

the extent of ^35%. Their attempted isolation of the corresponding

5a-alcohol (obtained after reduction) by column chromatography resulted

in a 27% yield of the dehydrated compound cholest-4,6-diene-3-one.

However, the 6-hydroperoxycholest-4-en-3-one was isolated in 16% yield - 89 -

C H I 8 17

335 336

as the corresponding alcohol after reduction and was found to be a mixture of the 6a- and~6g-epimers. These C-6 oxygenated products were considered to be derived from the competing free-radical process 3 30

( 02)• However more recently, Nakanishi et al. (136) demonstrated

(without bothering to refer to earlier work) that a concerted cycloaddition at C-6 of cholest-5-en-3-one was occurring with excited singlet state oxygen. They employed stereospecifically deuterated 2

(90% 48- H) cholest-5-en-3-one (partial structure 337) and recovered

the hydroperoxide 339 labelled with deuterium at C-4 (85%). Although

' 337 338 339

Nickon and coworkers had previously found examples of conventional- type autoxidation competing with the expected photosensitized pathway, in reactions on steroidal olefins (152). In at least one case with -k^, a free-radical inhibitor (2 ,6-di-_t-butylphenol) has been used to suppress radical reactions with while reactions were being studied. This technique does not appear to have been used in any photosensitized studies. - 90 -

this 1968 communication does not give many details and the full paper has not yet appeared, autoxidation would be expected to abstract the quasi-axial 46-hydrogen (ring A in chair, see 331 where R is = 0) and almost certainly give some (all?) of the 68-hydroperoxide.

With some consideration of the interesting and controversial aspects of the preceding work, the y-acetylation of octalone 234 was undertaken by a sequence utilizing the photosensitized y-hydroperoxyla-

31 tion of the corresponding 6,y-enone 341. This unconjugated octalone

342 295 236

~5J" While oxygenation of the corresponding enol ethers of conjugated ketones (151) appears to be the best practical preparative autoxidation (-^02) method, photosensitized oxygenation appears to be the most

x useful 02 method. Also, while synthetically, photosensitized oxygena• tion has been used in sesquiterpene work only on olefins (J.A. Marshall and coworkers (118a,154)), the photosensitized y-hydroperoxylation reaction has been utilized in triterpene (ecdysone) synthesis (136). - 91 -

341, previously prepared from octalone 234 by Ringold and Malhotra

through an acid-quenched enolization procedure, was isolated in high

yield by following their method (155). The enolate anion of

octalone 234 was generated with potassium t^-butoxide in _t-butanol and

the corresponding anion 340 was treated with aqueous acetic acid.

As has been previously reported (155), the very high concentration of

enolate present is irreversibly protonated at C-l by the 10% aqueous

acetic acid to yield 341. However, while the original procedure was

written for mg quantities of octalone 234 (a typical example quoted

would require <200 mg octalone) with 10 equivalents of base for 1.5

hours to obtain 80% deconjugation (i.e. the ratio of 234:341 is 20:80), 32

a modified form of their procedure was found to deconjugate up to

96% of octalone 234 on large scale. No attempt was made to determine

the isolable yield of completely pure 8,Y~unsaturated ketone 341

because of the relative difficulty involved. The 96% pure compound

was readily identified as 341 by its spectral data. The deconjugation

of 234 to 341 was accompanied by the removal of >90% of the 240 my

ultraviolet absorption, a shift in the infrared of the carbonyl

absorption from 1670 to 1725 cm X,and the virtual removal of the T 4.29

(CXH) vinyl absorption of 234 with the subsequent appearance of a

quartet multiplet centered at T 4.60 in the n.m.r. In addition, the

32 Twenty grams (0.122 moles) of octalone was added to 14 g (0.36 moles) potassium (i.e. 3 equivalents) that had reacted with 250 ml _t-butanol In 100 ml of diglyme. After stirring under a nitrogen atmosphere for 5-7 h, 500 ml of 16% aqueous acetic acid was added. This homogeneous solution was diluted with 500 ml of 8% acetic acid and partitioned between petroleum ether:water. The organic layer was washed twice with water and aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated under reduced pressure. - 92 -

C°H of 341 would be expected to be coupled to the C-7 methylene and appear at % 4.6 x as it did in compound 283. Quite unexpectedly, it was found that compound 341 was not isomerized on the gas chromatograph to 234 and therefore the relative amount of deconjugation 19 could be measured very accurately on a 20% SE 30 column at 185° because 234 and 341 exhibited different retention times under these conditions. While even purified samples of 8>Y-enones have been found to undergo partial conjugation on standing at room temperature as well as the autoxidation reaction discussed earlier, the deconjugated octalone

341 could be stored at 0° (where it crystallized slowly) without these side reactions. Using the 8,Y-enone 341 now available, the cholest-5-en-3-one oxygenation procedure of irradiating an oxygenated pyridine solution 33

sensitized with Rose Bengal was followed (136). To monitor this

3~3

Rose Bengal (i) is 4,5,6,7-tetrachloro-2',4',51,71-tetraiiodofluores- cein potassium (or sodium) derivative potassium (or sodium) salt (142).

Nakanishi e_t al_. (136) used Rose Bengal in pyridine while Nickon ejt al. have used a mixture of hematoporphyrin and methylene blue in a pyridine solution (135). - 93 -

photolysis of 0.2 molar octalone in pyridine solution with a 275

35 watt sunlamp bulb, aliquots were removed and worked up for analysis.

Since the octalone 341 and y-hydroperoxide product 342 were not expected to be very stable, it was not surprising to find that g.l.c. analyzed samples contained mainly a mixture of octalone 234, derived from 341, and a longer retention time component that was identified as

the enedione 343, produced by thermal dehydration of 342. In an attempt to clarify the stereochemistry of the C-8 oxygenated product

344 j

CH3

342, the crude photolysis product was acetylated by treatment with (a) acetic anhydride in pyridine at room temperature or (b) acetyl chloride in methylene chloride added dropwise to a pyridine buffered methylene

chloride solution of crude product at 0°. In both cases, however, upon workup under neutral conditions at room temperature, no acetoxy- or hydroperoxy-substituted compounds were found to be present. The n.m.r.

34 and g.l.c. analysis confirmed that the enedione 343 was formed. 34 1 The enedione was readily identified by its very sharp downfield C TA resonance in the n.m.r. of the crude product 'acetate'. A g.l.c. isolated sample!9 showed the expected spectroscopic properties for 343: infrared (film), 1708, 1685 (conj. C=0) and 1603 (conj. C=C ) cm-1; n.m.r. x 3.77 (singlet, IH, C^-H), and x 8.75 (singlet, 3H, tertiary methyl); and ultraviolet AM§OH~249 my, e= 10,000 (Cholest-4-ene-3,6- dione was reported (157) to have X|j|8" 251.5 my, e = 10,600). When the Brackman e_t al. method (using a copper catalyzed autoxidation of a 8,Y-unsaturated ketone in a methanol solution of pyridine and triethylamine) (156) was employed to obtain another sample of the enedione 343 from the unconjugated enone 341, only a mixture of octalone 341 was recovered. However, as expected, this reaction was found to afford a good yield of cholest-4-ene-3,6-dione from cholest-5-en-3-one. - 94 - probably by an unexpected quantiative loss of acetic acid in the desired y-peracetoxy-substituted octalone 344. This reaction finds precedence in the dehydration of cholesterol 24-hydroperoxide by acetic anhydride and pyridine to give 38-acetoxycholest-5-en-24-one (150 ) and the very recently reported conversion of the 3-hydroxy-7- hydroperoxy steroid 345 to the corresponding 3-acetoxy-7-keto compound 346 (150^) when acetylation with acetic anhydride and pyridine was attempted.

AcO'

346

When the photosensitized oxygenation reactions in pyridine were 35 worked up, the crude product obtained was reduced with sodium iodide in ethanol (149), re-isolated as the alcohol, and acetylated with acetic anhydride in pyridine. The initial photolysis reaction was worked up after twelve hours of irradiation, carried through the above sequence and distilled (95° at 0.3 mm Hg) to afford a 10% overall yield of a 3:7 mixture of octalones 234:236. This was encouraging enough for such a short photolytic period that the 8,Y_enone 341 was irradiate35 d for 36 h, reduced and acetylated. However, after distilling A petroleum ether:water partition removed the water soluble Rose Bengal dye and the organic solvents were removed below 40° under reduced pressure after drying the organic layer over magnesium sulfate. The g.l.c. analysis was routinely done at 185° on a 20% SE 30 column.19 - 95 -

octalone 236 from a fraction eluted with 60-80% benzene in petroleum ether off a silica gel column, only a 15% overall yield of pure y-acetoxy enone 236 was available from octalone 234. Also, while the spectral properties observed for this compound; ultraviolet 242 my

(e = 15,400), infrared (film) 1760 (acetate carbonyl), 1670 (conj. carbonyl) and 1640 (conj. olefin) cm \ and n.m.r. x 4.28 (doublet, IH,

1 8 C ^), 4.60 (triplet, IH, C H), x 7.89 (singlet, 3H, 0=C-CH3) and x 8.94

(singlet, 3H, tertiary methyl), were those expected for 236 and were

consistant with those reported for yacetoxy-a,8-unsaturated steroidal

ketones, the subsequent elution of a much more polar conjugated ketone

containing an acetoxy substituent made collaborative evidence for

octalone 236 necessary. This was done by converting the first

acetate eluted from the silica gel column to the enedione 343. A

sample of this acetate, containing compound 248 as an internal standard,

was reduced with excess lithium aluminum hydride in ether for 1 h to

yield a 1:2 ratio of the allylic alcohols 347 and 348. A Collins

oxidation, accomplished with a methylene chloride solution of the chromium

trioxide-pyridine complex prepared in situ (158), then yielded a 1:2

ratio of the corresponding octalone 234 and enedione 343 in over 95%

yield based on the internal standard. The octalone 234 probably was

produced in this two-step sequence by hydrogenolysis of the acetate - 96 -

(236) during the hydride reduction,but the identification of the major product as enedione 343 left no doubt that the initially eluted acetate is indeed 8a-acetoxy-4a-methyl-4,4a,5,6,7,8-hexahydro-2(3H)-r naphthalenone (236).

I R 234 R = H 236 R = OAc

In addition to the unidentified very polar acetate, recovered octalone 234 (^12%), small amounts of the enedione 343 and the corresponding 2,8-diketone (294) were also eluted from the silica column. The isolation of an 8% yield of a mixture of two saturated ketones 349 and 350 was completely unexpected but could be rationalized 36 as the result of photoreduction of octalone 234. Equally surprising was the absence of substantial amounts of the dienone 353, expected to result from the photoproduct 351.

° Authentic samples of the trans-decalone (349), prepared by Birch reduction of octalone 234, and cis-decalone (350), prepared by hydrogenation of octalone 234 in 0.3 N NaOH in ethanol, (159), were used to demonstrate the presence of a 6:4 ratio of cis:trans decalones, the same ratio obtained when octalone 234 was hydrogenated in ethyl acetate under neutral conditions. While the closely related photoreduction of a,B-cyclopropyl ketones will be discussed subsequently, the above observed reduction of octalone 234 in oxygenated pyridine (and oxygenated methanol) solutions is unusual.(However see ref. 144). - 97 -

349 a-H 35J.R=0H 353 350 /3-H 352 R = H

Persevering, the photosensitized (Rose Bengal) oxygenation of the 37 unconjugated octalone 341 was studied in methanol. Results similar

to those obtained after 50 h irradiation in pyridine were observed by running the reaction for 86 h in methanol. However, in contrast

to the aliquots taken from the pyridine reaction, the methanol 35 aliquots were found by g.l.c. analysis after workup to be a mixture of the enedione 343, the octalone 341 and a small amount of octalone

234. Washing these samples with aqueous bicarbonate left them

unchanged while the use of 4 N hydrochloric converted 341 to 234 as

expected. When either the crude photolysis product obtained after

86 h or the corresponding sodium iodide reduction product were oxidized

with chromium trioxide-pyridine complex in methylene dichloride (185),

thJ/ e majoTher ratiproduco otf was foundeactivatiod to be nth toe enedion"""02 consumee 34d3 accompaniein product d formatioby n is denoted as 8 and is a function of the substrate and the solvent (142). Since the 6 values of many steroids have been observed to be much larger in alcohol solvents than in pyridine, most hydroperoxidations of olefins and all hydroperoxidations of 8,y-unsaturated ketones to date have been studied in pyridine. However, since Nickori and Mendelson (135) have reported using methanol in place of ethanol in the subsequent sodium iodide reduction of the crude hydroperoxide product to avoid the formation of iodoform,the use of methanol in the photosensitized oxygenation of 341 suggested itself in permitting the immediate reduction of the crude hydroperoxide products. - 98 -

octalone 234. However the infrared spectra demonstrated an unoxidizable alcohol (or hydroperoxide) was present, suggesting the presence of

352 (or 351). Further g.l.c analysis work showed the photolysis samples and oxidized or reduced hydroperoxide samples contained the

38 dienone 353 in a < 1:10 ratio to the enedione 343.

In conclusion, while the preparation of the y-hydroxy octalone 295 was contaminated by only small amounts of the B-hydroxy derivative, the product mixture and low yield obtained upon acetylation of 295 precluded employing this sequence synthetically. These unexpected and unsolved problems negated the original work planned for octalone 236 but the synthetic necessity for such an approach, and the novel features of the 39 reactions employed, made the results obtained worthy of discussion.

JO This analysis was performed with a 10 foot x 0.25 inch column packed with 20% FFAP on 60/80 mesh Chromosorb W at 220° and a flow-rate of 100 ml/min helium. Work on the dehydrogenation of octalone 234 had previously demonstrated that octalone 234 and 353 had the same retention time on the 20% SE 30 column used for routine analysis. The facile loss of the 8a substituent (hydroperoxy, hydroxy, peracetoxy, or acetoxy) prevented the isolation of these compounds. The dienone 353, in comparison with octalone 234, exhibited a T 4.22 absorption in the n.m.r.

In addition, octalone 236 was found to decompose slowly in solution (t-L/2 00 1 week) and more slowly when neat. While more than one product may be produced, the - acetate was not lost and g.l.c. behaviour and the very sharp c^H n.m.r. resonance suggested that dimerization at C-8 may be occurring. - 99 -

D. Octalone 237_ (4a,8,8-Trimethyl-4,4a,5,6,7,8-hexahydro-2(3H)-

naphthalenone).

A consideration of the possible approaches to octalone 237 suggests either elaboration of the gem-dimethyl substituted cyclohexanone

354 (R = CH^ or CN) to 237 or introduction of gem-methyls into 355

(R = CH,, H) by methylation followed by carbonyl transposition to

355 356

provide 237. While the former approach has been used to prepare the

octalone 362 (160) via a sodium ethoxide-catalyzed Michael addition

of methyl vinyl ketone to the activated gem-methylated cyclohexanone

derivative 360 (80% yield), it was also observed that the analogous

methyl compound (i.e. carboethoxy substituent replaced by methyl) did

not react. Also of interest, the four-step conversion of 2,2-dimethyl-

cyclohexanone (358) to the cyanoketone 363 in 76% overall yield was

followed by a reported 88% yield of the octalone 364 obtained by

condensing 363 with methyl vinyl ketone (161). A hydrogenation, - 100 -

ketalization, hydride and Wolff-Kishner reduction followed by ketal hydrolysis then afforded the trimethyl-trans-decalone 365 in 70% overall yield from 364.

The alternative approach of introducing the gem-dimethyl substituents into octalone 355 has already been used on two occasions in sesquiterpene synthesis. Compound 356, the initial product prepared by this route was then converted to octalone 237 by successive Wolff-Kishner - 101 - reduction and chromic acid oxidation reactions (162,163). The subsequent elaboration of 2_37 to (±)-widdrol (366) (162) and (±)-thujopsene (367)

(163) required only two and four additional steps respectively. In the first synthesis, Enzell (162) prepared the gem-dimethyl octalone 356 40 from the corresponding 1-methyl octalone derivative 355 (R = CH^) by

using Mukherjee and Dutta's procedure (164) of treating 355, R = CH^, with potassium _t-pentyloxide and methyl iodide, while in the second

synthesis, Dauben and Ashcraft (163) used octalone 355, R = H (= 234)

and followed the steroid reaction method reported by Woodward et^ al.

(165) for obtaining gem-dimethylation of cholest-4-en-3-one.

Since Dauben and Ashcraft's sequence appeared to provide the

highest overall yield of octalone 237 and since the prerequisite

40 This compound was derived from 2-methylcyclohexanone and 2-chloroethyl ethyl ketone in a manner analogous to the preparation of 355, R = H (i.e. 234) discussed earlier. See also reference 118. - 102 -

octalone 234 was already at hand, this last synthetic route was chosen.

Applying the "Woodward" methylation procedure, a one hour reflux of a

1:3:6:63 mole ratio of ketone:potassium _t-butoxide:methyl iodide:

_t-butanol to 30 g of the octalone 234 afforded a 92% yield of a colourless

oil. A g.l.c. analysis and preparation of analytical samples of

product showed that this oil was 89% of the trimethyl octalone (356),

7% of the tetramethyl octalone (369) and 3.5% of a mixture of the 42 starting (234) and monomethylated (355) compounds. The extent of ^ Woodward's ratio is actually 1:3:6:106, the ratio used by Dauben and Ashcroft to provide 77.4% yield of 95% pure 356. 19 42 This work required either both an SE 30 column at 175° and a similarly constructe* d 20% FFAP__ colum„ n at 200° or, whet n onli y smal1 l1 amounts of 234 were present, a 10 foot x 0.25 inch column packed with 20% Apiezon J on 60/80 mesh chromosorb W at 190°. When the alkylation was done with a 1:6:13:64 mole ratio at room temperature overnight (Stork et al. (166) procedure for the gem-dimethylation of i), a 94% yield of

OCH 3

crude product was obtained, but it contained 30% overmethylated material. From this and other overalkylation reactions, preparative g.l.c. work with the Apiezon J column resulted in the isolation of the previously unreported compound ijL, identified from its spectroscopic data. Compound's ii infrared and ultraviolet behaviour was very similar to that found for 356 and 369, but its n.m.r. absorptions were readily assigned to the pentamethyl octalone ii; n.m.r. T 4.47. (triplet, IH, C%, Jrj8H-c?H = ^'^

7 4 2 7.96 (broadened multiplet, 2H, C H2), 8.27 (singlet, 2H, C H2) and 8.73, 8.76, 8.82, 8.86 and 8.96 (singlets, 3H, tertiary methyls). Irradiation of the T 4.47 triplet simplified the T 7.96 multiplet to a triplet (J ^ 6 Hz) while irradiation at T 7.96 collapsed the T 4.47 triplet to a singlet. - 103 -

methylation was easily discovered by observing the infrared (1355, 1460 cm X region) and n.m.r. (x 8.7-9.2) spectra. The physical and chemical data obtained for the major product was in complete agreement with the data reported (162,163,167,168) for the compound 356. The n.m.r. differences between 234 and 356 were particularly useful evidence of the

356 369

shift of the site of unsaturation with the low field olefinic proton

singlet of 234 being replaced by a triplet (J = 3.7 Hz, AX^ system).

The methyl singlet observed at T 8.74 in 234 was replaced by singlets

at x 8.78 (6H) and 9.01 (3H). Although these signals have not been

definitely assigned, the x 8.78 absorption was tenatively identified

with the axial methyls at C-l and C-4a of 356. This is supported by

__ The unconjugated monomethylated octalone intermediate 368 is of mechanistic importance because it is methylated much more readily than 355 (160,167). For the stereochemistry of second methylation (a:B-methylation is 9:1) see reference 168. - 104 -

the recent report that the T 8.78 (6H) and 9.01 (3H) signals observed in chloroform are shifted to T 8.73 (6H) and 9.09 (3H) in benzene (168).

The minor (7%) product showed an additional methyl (doublet) absorption in the n.m.r. When the reaction sequence was continued on the mixture, this compound yielded 370 after carbonyl removal and 371 after allylic oxidation as an 8% impurity in the reaction mixture. The n.m.r. spectrum of 371 was especially definitive since it was superimposable

= on its 6-desmethyl counterpart when the T 9.08 methyl doublet (J^6cH

6 Hz) was ignored.

370 371

This overalkylation problem was found to be more serious when 100 g quantities of octalone 234 were alkylated with a 1:3:6:60 mole ratio of ketone:base:methyl iodide :jt-butanol. Reactions on this scale

(125 g octalone required 4 1. of dry _t-butanol) went in 92% yield, 44 but provided only 72% pure 356. When Marshall and Hochstetler (169) used a 1:2.2:9:19.4 mole ratio of ketone:base:methyl iodide :_t-butanol on octalone 234 at 10-20° for 2 hours, the 94% yield of colourless oil recovered by distillation was successfully fractionated on a spinning _ These large scale reactions were neutralized with hydrogen chloride rather than aqueous acid. It was discovered that the crude product must be washed with aqueous sodium thiosulfate before it is distilled to avoid excessive polymerization. Henceforth the work-up of all alkyl bromide or iodide alkylation always included treatment with thiosulfate to remove the free halogen liberated by air oxidation. - 105 -

band column under reduced pressure to give a 74% yield of 95% pure

356. Earlier, C. Enzell had used a spinning band column under reduced pressure to purify the octalin 357 and then he also used column chromatography of compound 237, while Dauben et^ a_l. (163) had waited and purified the trimethyl conjugated octalone 237 on a spinning band column under reduced pressure to afford 98% pure octalone. This latter group also used recrystallization of the semicarbazone of 237 and subsequent ketone regeneration with phthalic anhydride to raise the yield of pure 237.

An attempted purification of 356 via recrystallization of its semicarbazone (372) and then regeneration of the ketone with pyruvic acid (170) proved unsuccessful. While formylation of 356, base extraction of 373, and potassium carbonate hydrolysis to 356 removed the overmethylated compounds, this procedure (171) did not, of course, remove incompletely alkylated material. The spinning band purification technique was found to be more effective on the octalin mixture (357) than on the mixture corresponding to 356 or 237, but the time consumed by this method along with the tedious nature of spinning band separations led to the development of the modified route outlined below. - 106 -

The introduction of a blocking group allowed complete alkylation to be obtained without the problem of overalkylation.

The ri-butylthiomethylene blocking group was chosen because it is known that this group is readily introduced and removed, the enethiol ether does not deactivate the ketone by a conjugative or steric effect, and this functionality is stable to storage (172). Octalone 234 was treated in the usual manner with ethyl formate and methanol-free sodium methoxide in benzene to provide the corresponding base soluble hydroxymethylene compound 374 (64) in 90% yield. Reaction of 374 with n-butane^ thiol and p_-toluenesulfonic acid in benzene afforded the desired 3-n- butylthiomethylene derivative 375 in 91% yield. Alkylation of 375 with methyl iodide in _t-butanol (1:4.2:9.5:69 mole ratio of ketone:base: methyl iodide:_t-butanol) gave a 90% yield of the gem-dimethyl blocked octalone 376. The hydrolysis of the ri-butylthiomethylene functionality - 107 -

of 376 was successfully achieved with some difficulty, yielding 95% of 356 only after a ninety-hour treatment with potassium hydroxide in refluxing diethylene glycol. However, the 70% overall yield of pure

356 from 234 made this sequence very useful.

Adopting Dauben and Ashcraft's experimental procedure for the preparation of octalin 357 from 356, the method developed by Barton, Ives and Thomas (173) for the reduction of hindered ketones was used to obtain a 92% yield of pure octalin 357. Experimentally, this work involved the formation of the hydrazone derivative of 356 with a 170° refluxing solution of anhydrous hydrazine in a diethylene glycol-sodium glycolate solution. The hydrazone was then decomposed to 357 by raising the temperature to 210°. The much less dangerous^ method of Nagata et al.

(174,175), using hydrazine dihydrochloride, 95% hydrazine, and potassium hydroxide, was a less attractive method since it provided yields of

< 50% in our hands and excessive foaming was observed during the reaction.

An allylic oxidation of the octalin 357 with anhydrous sodium

chromate in acetic acid-acetic anhydride (162,163) then provided a 69% yield of the desired trimethyl octalone 237. This compound was identical

to samples prepared by the direct alkylation route from octalone 234 but, unlike the earlier products, this material was not contaminated with

45 The danger of preparing the required anhydrous hydrazine for the Barton e_t al. method was "observed" during the distillation of hydrazine hydrate from sodium hydroxide when a 500 ml anhydrous hydrazine generator "detonated" in a fume hood. The fact that the recommended procedure of preparing anhydrous hydrazine in a nitrogen atmosphere was being followed (176) illustrates the danger of having a leak in a positive pressure nitrogen system. - 108 - other octalones. In an attempt to improve the yield of the octalone

237, an allylic oxidation with chromium trioxide-pyridine complex in methylene chloride (177) was employed. In our hands, a less than 50% yield of octalone 237 with only a 5% recovery of olefin,coupled with

the large volume of methylene chloride used? made the reaction impractical for large scale work.

E. Octalone 238 and 239 (4a,5-Dimethyl-4,4a,5,6,7,8-hexahydro-

2(3H)-naphthalenone).

While a mixture of the vicinyl dimethyl octalones 238 and 239

can be readily prepared by several routes, the stereoselective synthesis

of either compound is a formidable obstacle. The introduction of cis

vicinyl dimethyls is of special importance because of the almost

universal occurrence of this relationship in eremophilane sesquiterpenes. 47

As described elsewhere, octalone 238 has been.used in the synthesis of

members of the bicyclic eremophilane (most recently (+)-eremophilenolide

(377) (179a)), tricyclic aristolane ((+)-aristolone (378) (179b)), and

tetracyclic ishwarane ((+)-ishwarane (379) (179 )) classes of __ Capsidiol (x), an antifungal compound whose structure was recently elucidated by Stothers et al. (178) is a possible exception. It was assigned a trans vicinyl dimethyl relationship based on IR n.m.r. spectroscopy and 13c n.m.r. data .OH supporting ring B being in a chair conformation.

OH i

See Appendix II, 'eremophilane approach'. - 109 - sesquiterpenes.

238/9 380/1

In the interests of brevity, the work on the vicinyl methyl octalones can be considered in terms of a non-annelation preparation or one involving the Robinson annelation approach to octalone 238/9 and the closely related octalone 380/1. The non-annelation work is exemplified by the cyclization of the triene 382 with anhydrous formic acid to provide only the cis vicinyl methyl compounds 383 and 384 in a

2:3 ratio in 67% yield (180a) while the Diels-Alder reaction of 385 and 386 was recently reported to yield only the trans vicinyl compound - 110 -

387 (180b).48 06 OCHO .-•OCHO

382 383 384

385 387

To date considerable success has been achieved in stereoselectively preparing substituted octalones related to 380/1. The Michael addition of trans-3-penten-2-one (388) to derivatives of activated cyclohexanones

(389 (181a,183b) 390 and 391 (181b)) was found to lead to the cis vicinyl

48 However, even more recently, a Diels-Alder reaction of the diene 1 with methyl acrylate (ii) was found to give the "masked" cis vicinyl methyl compound iii stereoselectively. Elaboration of iii to iv and the acid-catalyzed ring opening of the carbinol iy_'was then completed by the synthesis of (+)-nootkatone (v) (180°).

OCH, C02CH3

Y^OCH3

R JOT"

U LU R = CH ,R'=C00CH_,

iy R =-CH=CH2,R = C(CH3)2OH - Ill -

product 392 while 2-methylcyclohexa-l,3-dione (393 (181°) and 394 (181 )) yielded predominantly the trans vicinyl dione 395. However, a much

394 more general route to substituted octalones that are related to 380/1 became available when it was demonstrated that cross-conjugated octalones similar to 300 reacted with lithium dimethylcuprate to afford the

trans product stereoselectively (182 ) while 4-methyl substituted cross- conjugated ketones could be reduced stereoselectively to provide a cis vicinyl dimethyl compound such as 397 (98, 181^, 182^'°). In addition, XX) — 30Q 381 - 112 -

the independent demonstration by two groups in 1971 (183) that solvent parameters control the stereochemistry of the Robinson annelation reaction appears to supersede all other previous approaches. Trans-

3-penten-2-one and 2-methylcyclohexanone gave almost completely the cis dimethyl octalone 380 (> 95% cis) in dioxane while the trans (> 95%

381) was obtained with dimethyl .sulfoxide.

In contrast to the above, the methyl vinyl ketone annelation of

2,3-dimethylcyclohexanone has been reported by several groups to proceed

in only 15% yield to afford a 3:2 cis-.trans (238:239) ratio (179 ,184).

While Ourisson's group was able, by reduction and bromination of this mixture, to isolate 398 by crystallization and then dehydrohalogenate

398 399

to the octalone 399, the attention of other synthetic groups has turned

to stereoselectively alkylating derivatives of 2,3-dimethylcyclohexane.

After it was discovered that the alkylation of 2,3-dimethy1-6-n-butyl- - 113 -

thiomethylenecyclohexanone (400) with methallyl chloride produced a

4:1 mixture of the corresponding cis (403) and trans (404) derivatives

(185 ), the alkylation of 400 with ethyl 3-bromopropionate was found to

afford approximately a 9:1 mixture of cis (405) and trans (406)

compounds (184 ). Subsequently, the N-methylanilinomethylene derivative

of 2,3-dimethylcyclohexanone (401) was also alkylated with 3-bromopropionate

4Q0 X= SBun 405 X = SBu" 406 X = SBun

4Q1 X=N(CH3)C6H5 407 X = N(CHjC H, 408 X = N(CH JC H,. and found to provide the cis-407 and trans-408 in a ratio of >7:1 (184^).

Even when the order of introducing a substituent at C-2 was reversed by

introducing a methyl group into a 2-alkyl-3-methyl blocked cyclohexanone,

the cis vicinyl methyl product was found to predominate. An

illustration of this was the report that 402 afforded only the desired cis product 410 when the blocked, isoxazole-substituted cyclohexanone was alkylated with methyl iodide (185^). The high degree of selectivity observed for these cis vicinyl methyl products permitted 405 and 407 - 114 -

to be converted, through 417, to 238 while 410 gave 411 and then 412.

417 411 238 R = H

412 R = COCH3

The sequence that elaborated the n-butylthiomethylene blocked

2,3-dimethylcyclohexanone to octalone 238 is outlined on the following page. It was the initial experimentally explored route because it appeared to be the most efficient method available (186). At the outset, it was hoped that a method could be found to produce the trans dimethyl octalone (239) efficiently through some parameter variations in the alkylation step to enhance the relative yields of 418 and 420. In any event, it was expected that a better understanding of this reaction sequence would be obtained. For the purposes of discussion, this work will be considered in three parts - the conversion of 2,3- dimethylcyclohexanone, through its alkylated blocked derivative 415/6 and keto acids 417/8 to a mixture of enol lactones 419/420, the subsequent preparation of the corresponding individual enol lactones 419 and 420, - 115 -

4J4X = CH0H 415. 3/Q-CH3 4T7 3/3-CH3

400X = CHSBu 4J£.3a-CH3 41S.3a-CH3

and finally, the preparation of the vicinyl methyl octalones 238 and

239.

As discussed earlier, the introduction of a blocking group on the methylene a to a carbonyl permitted monoalkylation at the a' position when the a' position was trisubstituted and dialkylation when it was disubstituted. The previously demonstrated advantages of the iv-butylthiomethylene functionality in the preparation of octalone 237 led to the use of this blocking group for 2,3-dimethylcyclohexanone. The ketone 413, obtained by oxidizing the alcohol produced from hydrogenating 2,3-dimethylphenol, was treated in the usual manner with ethyl formate and sodium methoxide in benzene to provide the hydroxymethylene derivative 414 in 90% yield. Reaction of

414 with n-butanethiol and p_-toluenesulfonic acid in benzene afforded an 88% yield of 2,3-dimethyl-6-n-butylthiomethylenecyclohexanone (400). - 116 -

Enolate formation with potassium _t-butoxide and alkylation with ethyl-3- bromopropionate in _t-butanol (1:2.94:3.7:41 mole ratio of ketone: base: alkylation agent :t^-butanol) then gave a 94% yield of a mixture of

415 and 416. The concomittant hydrolysis of the n-butylthiomethylene and ethyl ester functionalities with base in refluxing aqueous diethylene glycol proceeded in 90% to afford a mixture of the keto acids 417 and 418. Enol lactone formation with sodium acetate in acetic anhydride then produced a 95% yield of a mixture of the correspond• ing enol lactones 419 and 420.

Under ideal circumstances, the ratio of cis:trans vicinyl methyl compounds resulting from the alkylation reaction would be measured directly on the alkylation product mixture (415/6), but unfortunately the gas chromatographic and proton nuclear magnetic resonance (n.m.r.) spectral data of this mixture were found to be unsuitable for such an analysis. While the individual keto acids showed small differences in the n.m.r. spectra and while the corresponding methyl esters of 417 and 418 could be resolved by gas chromatography, the individual enol lactones 419 and 420 were found to exhibit much more substantial a 49 differences in their n.m.r. (184 ) and g.l.c. behaviour. These differences were then exploited and used to measure the alkylation reaction's stereoselectivity by converting the various alkylation product

49 There was only a slight chemical shift difference in the downfield vinyl proton of the two enol lactones. The larger shift difference between the tertiary methyl of 419 and 420, along with the absence of non-methyl resonances between x 8.7-9.4, permitted an accurate measurement of the cis:trans ratio to be made using double n.m.r. integrals. These integrals were always taken on instrument scans of 100 hertz sweep width over the x 8.7-9.4 region. The cis enol lactone had methyl n.m.r. resonances at x 8.96 (singlet, 3H, tertiary methyl) and 9.04 (doublet, 3H, secondary methyl, J = 6.0 Hz). The trans one (420) showed x 8.78 (singlet, 3H, tertiary methyl) and 9.03 (doublet, 3H, secondary methyl, J = 6.4 Hz) resonances. - 117 - mixtures (415/6) to a mixture of enol lactones. However, the valid use of these "alkylation ratios" required the underlying assumption that the hydrolysis and lactonization steps did not differentiate between 415 and 416 or between 417 and 418. The latter portion of this assumption was proven to be correct when the individual cis- and trans-keto acids were found to give similar yields of enol lactones. The conversion of an enol lactone mixture to a mixture of keto acids and methyl esters and then back again to enol lactones was also shown to leave the cis:trans ratio unchanged.

The enol lactone mixture derived in 80% overall yield from the blocked ketone 400 via the above potassium _t-butoxide alkylation was analyzed by n.m.r. and a cis:trans vicinyl methyl ratio of 82:18 was observed.In considering literature precedents for shifting this ratio substantially, considerable recent work was found on the effect of base

(188) and solvent (189) on changing the regioselectivity of an alkylation

but very little could be found on the control of stereochemistry. As

expected, there were many examples of substantial steric hindrance on

one side of the molecule leading to attack on the less hindered side

(190 ) and one example of the a-substituent reversing the alkylation

stereochemistry when a 8-keto ester was replaced by a 8-keto nitrile

(190^), but for substituted cyclohexanones it appeared that the nature

of the enolate substituent was of general importance. When the enolate

Although a similar n.m.r. analysis (184 ) indicated a cis:trans ratio of approximately 9:1, the above would indicate that a ratio of approximately 8:2 or 4:1 would be a more accurate description. This ^ 4:1 ratio was the same as that previously reported for the alkylation of 400 with methallyl chloride (see 403/404) and confirms the observation made later that changing the halogen from Cl to Br does not affect the cis:trans ratio significantly. - 118 -

substituent was hydrogen, approximately equal amounts of "axial" and

"equatorial" products were formed as, for example, when 421, R = H gave a 422a:422e ratio of 45:55 (191a). An alkyl substituent usually led to

70-90% of the "axial" product with 421, R = CH, giving ^ 70% 422a while

423 yielded a 424a:424e ratio of 83:17 (191 ). In an analogous manner,

425 R = D 426a 426e 427 R = Alkyl 428a the simple octalone 425, which could be alkylated regioselectively by a reductive process, yielded a 40:60 mixture of the methyl decalones c

426a and 426e from methylation in tetrahydrofuran (191 ). The

introduction of a C-l alkyl group was found to permit a stereoselective axial alkylation to occur and has been explained in terms of a-side 1 2 attack contracting the C-l alkyl to C-8a methylene dihedral angle (A '

strain) in the alkylation transition state (191 ). In terms of changing

the product stereochemistry through the choice of reaction parameters,

the report that methylation of the 10-nor steroid, 429, switched from a - 119 -

ratio of 10:1 a-face alkylation:B-face alkylation in ^-butanol to a ratio of 3:7 in benzene (168) suggested that the choice of solvent could be very important.

Preliminary studies of the alkylation of the blocked ketone 400 showed that changing the mole ratio of a given base, alkylating agent and solvent resulted in little or no change in the cis:trans isomer ratio. This ratio was also independent of the extent of the reaction or the yield obtained. Table I summarizes some of the results produced when two gram amounts of ketone 400 were enolized with different bases in different solvents and alkylated with either ethyl-3-bromopropionate

(RBr) or ethyl-3-chloropropionate (RC1) and then converted to a mixture of enol lactones.By ignoring the runs in hexamethylphosphoric triamide (HMPT), the stereochemistry of the RBr alkylation in relative percentage of cis product can be expressed as potassium _t-butoxide (82 + 2), sodium _t-butoxide (75+1) and lithium _t-butoxide (51 + 1). * These runs paralleled each other in the sense that the mole ratio of ketone:base:alkylating agent:solvent was kept at 1:3.2:3.73:72. No effort was made to maximize the yields, but in the case of the LiOBut/ButOH/RBr reaction, extending the reaction time to 5 h from 1 h raised the yield from 30% to 80% overall. However, the g.l.c. analysis still showed 50.3:49.7 cis:trans ratio' in both cases. See experimental for other details on Table I. - 120 -

TABLE I. STEREOCHEMISTRY OF THE ALKYLATION PRODUCTS OF THE BLOCKED KETONE 400.

Base Solvent Alkylating Enol Lactone Ratio Employed System Agent 419 : 420

KOBu1 BifoH RBr 83:17

H II OH 81-19

H II THF 80=20

n II HMPT 90-10

NaOBu1 BiiOH RBr 75=25

LiOBu* BuOH RBr 50=50

M H OH 51 =49

II n THF 51 =49 11 HMPT 89-11

KOBu* BifOH RCl 86M4

LiOBu1 Bu*OH RCl 51 :49

The extension of this work to other bases showed that even a weak

potassium base like potassium carbonate in t-butanol provided a 84:16

ratio (albeit 10% overall yield) while sodium methoxide in tetrahydr

furan (THF) gave a 76:24 ratio. Therefore, while potassium hydroxide

in _t-butanol and sodium methoxide in _t-butanol, methanol, or benzene

did not provide any of the desired product because of side reactions,

and while lithium carbonate did not appear to cause any alkylation - 121 -

in _t-butanol, the stereochemistry of the alkylation of compound 400 appeared to be primarily dependent only on the alkali metal cation

(counterion) employed. The insignificance in the choice of alkylating agent was demonstrated by the observation that replacing the bromo-ester

(RBr) with the chloro-ester (RC1) caused no change with lithium t-butoxide in _t-butanol and only a minor difference with potassium _t-butoxide in

_t-butanol. The importance of solvent was illustrated by the large lithium base shift from ^50:50 to ^90:10 and the smaller potassium base 52 change from 82:18 to 90:10 when hexamethylphosphoric triamide was used in place of the other solvents. The relatively "free" nature of the enolate in HMPT makes the enolate's behaviour independent of its counterion and leads to an interpretation of the alkylation results in terms of the involvement of solvent-separated ions (431) or contact ion pairs

(432). The solvent-separated pair would be expected to be more reactive and could be represented as involving a mixture of the "half-chair"

431 432

Hexamethylphosphoric triamide (HMPT) is a polar, aprotic solvent whose relatively high basicity makes it an exceptionally good cation solvator and an exceptionally poor anion solvator (192) . Enolates in protic solvents (Buc0H) generally favour C-alkylation but polar aprotic solvents like HMPT enhance O-alkylation with the formation of enol ethers. The enol ether product of 400 would not interfer with the cis:trans C-alkylation measurements but would lower the overall yield. - 122 -

conformations 433a and 433b in the transition state. Lithium is known

to form more tightly associated ion pairs than sodium or potassium in most common protic or aprotic solvents (ButOH or 0H) (191^), but the

contact ion pair can be shown not to have a product-like transition

state. If a product-like transition state were involved with the lithium

contact ion pairs,the trans vicinyl methyl product resulting from the

alkylation of the more favourable conformation 435a would be expected to

dominate. Since this is clearly not the case for compound 400, and •

since reactant-like transition states have been found to be generally

appropriate for C-alkylation reactions elsewhere (191^), the involvement

of the rather planar transition state conformations 434a and 434b by the

aggregation of contact ion pairs is suggested. The involvement of 434a+b

in the transition state would lead to the observed 50:50 mixture of

H H

BuSHC

M H H 433a 433 b

BuSHC

434a 434 b - 123 -

BuSHC "H

BuSHC

435 b

cis:trans products. When the enolate of 400 was shifted from contact

ion pairs to solvent separated ions by HMPT or by the use of a potassium cation, the conformations 433a+b would become dominant. The alkylation

of 433a gives a 1,3-interaction with the C-4 hydrogen on the a-face

and a 1,2-eclipsing with the C-3 hydrogen on the B-face. If there is

any merit in House's recent proposal (191^) that the dihedral angle between the C-l carbon-oxygen-M+ and C-2 carbon-alkyl is not zero

(to avoid eclipsing in substituted enolates), the result would only lead

to enhancement (in 433a) of trans product formation or alternatively

enhancement of the population of conformer 433b because of the increase 1 2

in A ' strain (C-2, C-3 methyls) introduced into 433a. Conformation

433b, which could readily reduce the C-6 blocking group, the C-l

oxygen and C-2 methyl interaction by twisting the enolate double bond, would be subjected to predominantly B-face alkylation (cis-product) on

the basis of the steric factor introduced by the pseudoaxially oriented methyl. In any case, while these observed changes in stereochemistry with cation and solvent are of synthetic importance,the largest energy 53 difference between transition states is quite small. 53 In going from lithium enolates in ButOH (cis:trans is 1:1) to those in HMPT (cis:trans is 9:1), the energy difference between the cis and trans transition states changes from 0 in ButOH to ^1 kcal/mole in HMPT (AE «= RT ln cis/trans) (193) . - 124 -

In March 1973, Stork and Boeckman reported a much more dramatic dependence of nitrile alkylation stereochemistry dn the metal cation employed (194). The intramolecular alkylation of the nitrile 436 with its a-haloketal substituent (X = Br, I) gave 95% cis decalin 437 with potassium hexamethyldisilazane in benzene, while the lithium base in the same solvent provided 90% trans. The controlling factor of the

anion alkylation was considered.to be the requirement of a more closely held transition state for a lithium cation in benzene than for a potassium cation in achieving the proper alignment of the departing halide, the alkylating methylene, and.the trigonal nucleophilic centre. This work also reported that the use of the lithium base in tetrahydrofuran resulted in loosening of the ion pair by cation solvation so that a

20:80 ratio of cis-437 to trans-437 resulted. The lack of a similar solvent effect in Table I is puzzling.

Continuing the octalone preparation sequence, the cis enol lactone could be readily crystallized from a hexane solution of a 82:18 mixture of the cis and trans isomers 419 and 420. A recrystallization then afforded pure enol lactone 419. The more elusive trans isomer required successive silica chromatographies of the enol lactone mixture, hydrolysis of the impure trans enol lactone product, and crystallization of the pure trans keto acid (418) with subsequent dehydration to the enol lactone 420. Enol lactone 419 reacted with methyllithium at -25° in - 125 -

ethyl ether to provide intermediate 438a and the reaction was quenched with hydrochloric acid to afford 440a via 439a. An immediate base- catalyzed aldol condensation gave the desired octalone 238 in an overall direct yield from 419 of up to 78%. However, when the same experimental sequence was used on enol lactone 420^ only 30% octalone 239 was

238 *- or 239

419 3/3-CH3org 438_X = Li 440.

420 3a-CH3orb 439 X = H isolated. Considerably more unreacted trans enol lactone was recovered

(19.4%, as the trans keto acid) than had been the case of the cis enol lactone (8-9%, as the cis keto acid). The most reasonable explanation for these results suggested that the lithium adduct 438 was undergoing a spontaneous ring opening to 441 with a subsequent rapid addition of

438 a 3/3-CH3 44j_ 442

438b 3a-CH3 methyllithium to yield the "di-adduct" 442. In the case of the cis c c t t vicinyl methyl compounds, k^ > k^ while k^ = for the trans. In the distillation of octalone 239, a considerable amount of a slightly higher boiling material was isolated. The hydroxyl and carbonyl infrared absorptions and n.m.r. methyl resonances are in agreement with those - 126 - expected for compound 443. 54

LiO OH 443 444.

To gain a better understanding of the reaction, mixtures of enol

lactones 419 and 420 were used to prepare a mixture of the corresponding

octalones. The initial rate of attack of methyllithium on either enol

lactone to afford the methyl adduct 438 (k^) or the enolate 444 (k^,)

was shown to be the same for both the cis and trans enol lactone since

their isomer ratio was found to be unchanged in the recovered starting

material. For example, when the keto acid mixture recovered from a

reaction on a 59:41 ratio of cis:trans enol lactones was dehydrated,

the enol lactone product analyzed for a 59:41 ratio of cis:trans enol c t t c lactone. While k^ = k^ and k^ was obviously greater than k^, the

54 The relative weakness of the carbonyl absorbance compared to that of the hydroxyl in this keto alcohol (443, i) suggests that the hemiketal ii predominates. G.l.c.x^ work on this compound also provided a compound tentatively identified as iii. This ring-chain tautomerism has recently been reported (195) for 5-oxo-3,5--seco-A-norcholestan-3- ol, a compound analogous to i, R = H.

i R = CH3 R = CH3 IL R=CH3 iii - 127 -

t c

observed ratios of octalones isolated permitted an estimate of ^2^2 =

5 to 10 to be made."*"* Table II summarizes the results of optimizing the

yield of the cis octalone (runs 1-4) and the work comparing cis/trans

reactions (runs 5-9).

TABLE II.

PRODUCT DISTRIBUTION OBTAINED BY METHYLLITHIUM TREATMENT OF ENOL LACTONES.

Experimental Ratio of CH^Li Enol Lactone Octalone Octalone Recovered

Run to Enol Lactone 419 ; 420 Yield 238:239 Keto Acid

la 1.59 100=0 61% 100--o 18.3 %

2a 1.69 100--0 67.7 100=0 13.4%

3 1.82 100=0 78% 100=0 9%

4 1.93 • 100=0 60.4% 100=0 2.7%

5 1.78 100=0 73.7% 100=0 8.2%

6 1.88 0=100 31.3% OMOO 19.4 %

7 1.75 59=41 38.7% 92=8 12%

8 1.83 36--64 25.6% 72=28 13%

9 1.83 84=16 58% 95=5 8%

a1 3/4 h at -25°, otherwise 2h at-25°

55 t c Estimate based on approximating ^/k^ by the product of the observed trans/cis enol lactone ratio and the resulting cis/trans octalone ratio. - 128 -

To overcome the low yield of trans vicinyl dimethyl octalone resulting from the addition of methyllithium to the enol lactone 420, some consideration was given to using other possible methods. Corey and Chaykovsky (196) had used the methylsulfinyl carbanion with esters and lactones to obtain high yields of B-keto sulfoxides which were then desulfurized with aluminum amalgam to yield the corresponding methyl ketones. Attempts to use this method on the conversion of the enol lactone 420 to 440b were unsuccessful, but consideration of the modification of the trans keto acid 418 led to Stork and Clarke's work

(197) on the conversion of the keto acid 445 to the bicyclic enone 448 via the methyl ketone 447 in the synthesis of cedrol (450). In their work, attempts to use dimethylcadmium with the acid chloride 446 gave

449 450 - 129 -

only compound 449 by a process that was believed to be catalyzed by

magnesium bromide. However, excess diazomethane with the acid chloride

446 yielded the diazoketone (446, X = CH^) which was converted to the

chloromethyl ketone (446, X = C^Cl) and then reduced with zinc dust

in acetic acid to the methyl ketone 447. The remarkable 79% overall

yield of 447 obtained from the sodium salt of the keto acid 445 gave

this sequence some appeal but the recently reported reaction of acid

chlorides with methyl cuprates to yield methyl ketones appeared to be

an even more attractive and interesting alternative (198). Using

either a mixture of keto acids 417+418 or a mixture of the sodium salts

of 417+418 in a treatment with oxalyl chloride in benzene at 0° gave a

residue that was isolated under vacuum below room temperature and added

to a 2-fold excess of dimethylcuprate in ether at -78°. Subsequent

treatment with sodium methoxide in methanol provided, in both cases,

only a low yield of a mixture of the desired octalones and the correspond•

ing methyl esters of 417 and 418. Since there were two possible

alternative routes to be explored, further approaches through the keto

acid 418 to octalone 239 were not considered.

While the physical data obtained on the pure keto acids (417 and

418), their methyl esters, the enol lactones (419 and 420), and octalones

(238 and 239) have not been discussed, the observed spectroscopic data agreed well with that published (184) and, in general, the absorptions observed were those expected. The interesting exception was the proton magnetic resonance of the secondary methyl group that appears in all of these compounds. In the case of the cis octalone 238 and the trans keto acid 418 (or its corresponding methyl ester), virtual coupling - 130 -

(199)"^ is observed in both the 60 MHz and 100 MHz secondary methyl resonance, while the other compounds in the series show the expected methyl doublet. For example, the keto acid 418 exhibited an unresolved multiplet with line shape 451a in a 60 MHz spectrum and 451b in a 100 MHz

scan, while the corresponding cis keto acid 417 showed the normal line

shape depicted in 451c (60 MHz). A similar shift of line shape towards

the expected doublet (451c) was observed for the secondary methyl

of octalone 238 when a 100 MHz scan replaced the 60 MHz measurement.

In considering a general approach to octalone 238 and 239, the

close relationship of these compounds to the Wieland-Miescher ketone

(204) was evident. Since a sodium borohydride reduction of the C-5

carbonyl of the latter compound occurs regioselectively and stereo-

56 _/ Virtual coupling results from the chemical shift (6) of CJHCH3 and C^H_2 being smaller than their coupling constant (JQ5\{-C6^) • Since the chemical shift is proportional to the operating frequency and the coupling constant is independent of it, the 6/J ratio increases and hence the line shape simplifies in a higher field. Virtual coupling has been reported previously for octalone 238 and some of its derivatives (184a). While the trans-fused decalone and l-hydroxy-A^-octalin derived from 238 exhibit virtual coupling in their secondary methyl resonance, there was no such coupling evident in the cis-fused decalone obtained from 238 or in the trans-fused decalone obtained from 239. - 131 - selectively to afford 452 (199), the question arose concerning the possibility of reducing a Wieland-Miescher ketone derivative regioselectively and stereoselectively to octalone 238 or 239. Octalones 455 and 456 were prepared and their respective hydrogenations were studied as both of these compounds were also of some interest in several projected eremophilane syntheses. The Wieland-Miescher ketone (204, 202) was

204 452 455 Exocyclic 456 Endocyclic treated with 2,2-dimethoxypropane and a catalytic amount of p_-toluene^ sulfonic acid to yield in 93% the enol ether 453 (200). The presence of one methoxyl function and two vinyl protons by n.m.r. and a saturated carbonyl by infrared spectroscopy confirmed that a selective alkoxyl interchange had occurred. A Wittig reaction of methylenetriphenylphosphorane and compound 453 in dimethyl sulfoxide (201) then produced a 93% yield of the desired enol ether olefin 454, readily identified by the replacement

204 453 454 - 132 -

0 0 0' H 455 456 457/458

of the saturated carbonyl in the infrared with a two vinyl proton absorption at T 5.30 in the n.m.r. A short treatment of compound 454 with methanolic hydrochloric acid gave the exocyclic olefinic octalone

455 in 88%, while treatment of 454 with jD-toluenesulfonic acid in refluxing benzene or toluene yielded the endocyclic olefinic octalone

456 in 80%. When the above reactions were carried out with minimal workup of the intermediate steps, the Wieland-Miescher ketone afforded higher overall yields of 455 (95%) and 456 (64%).57 Both of these

"" A private communication (Geraghty, 186) indicated that an alternate route to compound 456 by addition of a methyl Grignard or methyllithium to the protected Wieland-Miescher ketone (i) and subsequent acid catalyzed dehydration proceeded in poor yield. In addition to considerable enolization of the carbonyl rather than the desired 1,2-addition of the methyl nucleophile, the bicyclic-6-hydroxy-a,8-enone precursor to 356, ii, once formed, has been shown recently to undergo a rearrangement in both acids and bases to iii (203).

0 OH - 133 - compounds had a conjugated ketone chromophore, with compound 455 exhibiting an exocyclic methylene in the n.m.r., while compound 456 indicated the presence of a vinyl methyl and vinyl proton. However, while tris(triphenylphosphine)chlororhodium catalyzed hydrogenations are regioselective for disubstituted double bonds in the presence of trisubstituted ones, such a hydrogenation of compound 454 yielded a

55:45 mixture of cis-238:trans-239 (after an acid catalyzed removal of the methyl ether), while a similar hydrogenation of compound 455 yielded a 75:25 ratio of 238:239 in 98%. An attempted regioselective hydrogenation of the unconjugated trisubstituted C-5 olefinic bond of compound 456 with palladium on charcoal in acidic ethanol failed to provide compounds 238-239, yielding instead a 50:50 mixture of the keto olefins 457 and 458,while hydrogenation of 455 under similar conditions 58 also led to preferential reduction of the conjugated double bond.

Since the attempted approaches to an efficient synthesis of pure octalone 239 were not successful, the stereoselectively available octalone 381 was transformed into octalone 239 by a route analogous to The reduction of 455 or 456 under dissolving metal (Birch) conditions gave the desired trans decalone derivatives and not the 204 -> 205 transformation indicated on page 43. The trans-fused derivative of 455 (i_, C9H3 at x 8.79 in the n.m.r.) was hydrogenated with ((j^P^Rhd to yield a 1:1 mixture of ii. to iii. Authentic compound ii_ (C^H^ at T 9.06) was obtained by a Birch reduction of octalone 238 while iii_ (C9H3 at x 8.83) was derived by a Birch reduction of octalone 239.

H IL ii - 134 - the one developed by Marshall and Brady in the synthesis of hinesol. In their work, the cross-conjugated dienone 459 was submitted to a conjugate addition of lithium dimethylcuprate to introduce a methyl into the 'A' ring. The enone 460 was then deconjugated to 461, the carbonyl reduced and the homoallylic alcohol product (462) acetylated and oxidized allylically to afford 464. A dehydroacetylation and selective hydrogenation

459 460 : 461 X =0 462 X = a-H,/3-0H 463 X = a-H,/3-0Ac

464 465 466

then completed the 'A' •> 'B' ring transposition of the enone functionality.

Using the cross-conjugated dienone 300 prepared as described earlier in this thesis, a stereospecific methylation was achieved with lithium 59 a dimethylcuprate to provide an 87% yield of compound 381 (182 ,204).

In the absence of large steric factors, cuprate additions are believed to proceed via a chair transition state rather than a boat. As proven elsewhere (182a,204,205a), a completelystereospecific axial methylation occurs when compound 300 is treated with LiCuCCH^^- Compound 459, on the other hand, was found to give a 1:3 ratio of 4a:48 methylation (205). - 135 -

300 381 467

The deconjugation of this ketone by base equilibration-acid quench

(potassium _t-butoxide/acetic acid) was accomplished by the procedure

developed earlier for the corresponding 4-desmethyl compound (234),

but in this case there was no measureable amount of octalone 381

present after workup (i.e. <1% 381 versus ^ 5% 234). The instability

of 8,y-octalones necessitated the immediate reduction of compound 467 with lithium aluminum hydride. The homoallylic alcohol product was

then acetylated with acetic anhydride and sodium acetate to afford a

76% overall yield of compound 469 from octalone 381. A tentative

468 R = H 4I0_ Hi. A- ene 469 R = OCCH* 239 II 6 0

assignment of a 2:1 ratio of the a: 8 7-acetoxy substituent could be made

on the basis of the n.m.r. absorptions of 469 , but these spectral

complications caused by the diastereomeric mixtures (of 468, 469 and

470) were removed by the subsequent dehydroacetylation. The homoallylic

acetate 469 was oxidized allylically in 80% yield with chromic anhydride

in acetic acid by a procedure analogous to the one utilized earlier on

a trimethyl octalin (357, the precursor to octalone 237). The - 136 -

dehydroacetylation of 470 with ethanolic hydrochloric acid (149) was

then accomplished cleanly in 86% yield to afford the desired dienone 471.

This compound showed the required spectroscopic data, unencumbered by

diastereoisomerism, having a conjugated dienone by infrared (1660, 1620,

1588 cm "S and three vinyl protons (x 3.85, 3.88, 4.22), a tertiary methyl

(x 8.75) and a doublet methyl (x 9.09) by n.m.r., but the observed MeOH extinction coeffieint of e = 31,300 associated with the X my 282 max ultraviolet absorption for 471 initially appeared to be unduly high.

While this observation is true in a comparison with the a,3-unsaturated and cross-conjugated ketones previously encountered (e = 10,000-15,000), the corresponding 5-desmethyl compound of 471 has been reported to have

a Et0H b xEt0H 28Q ^ (e = 19 400) (206 ) and A 278 my (e = 26,800) (206 ), while max max the analogous A^'^-3-keto steroids have been shown to exhibit XET^ 284 my ° max (e = 28,000) (206°,135) absorptions in the ultraviolet,

Spectroscopically, the chemical shift changes observed for the downfield protons in the n.m.r. are a useful feature of the above sequence, leaving no doubt that the enone functionality was transferred successfully. Of particular significance is the movement of the vinyl proton from a singlet at x 4.22 (381) to a multiplet at x 4.50 (467,

468, 469) and back to a singlet at x 4.15 (470) and 4.22 (471). The regioselective catalytic hydrogenation of the disubstituted unsaturation of 471 with tris(triphenylphosphine)chlororhodium proved this by yielding octalone 239 (113). However, this selective reduction with a homogeneous catalyst proceeded so very slowly that a switch was made to a palladium catalyst. By using 0.005 N potassium hydroxide in benzene- ethanol solution and pre-reducing the 5% palladium on carbon catalyst - 137 -

(207), the dienone 471 was reduced rapidly in 93% yield to octalone 239.

As expected, this compound was physically and spectroscopically identical with the one prepared earlier from enol lactone 420 but, in contrast to the rhodium catalyst where careful monitoring was not required, care was required to avoid hydrogenation of 239 by palladium on carbon to a mixture of decalones.

In conclusion therefore, while both cis and trans octalones 238 and 239 could be prepared in pure form from their respective enol lactones

(419 and 420), the novel selective destruction of the trans enol lactone in this route makes the sequence utilizing octalone 381 to prepare 239^ obviously superior in terms of overall efficiency of time and effort.

The n.m.r. spectra of octalesne 239 shows a complete absence of the T 8.88 methyl resonance from the corresponding cis octalone 238. This is surprising since there is one literature report- that the methyl cuprate addition to dieone 300 is not as stereospecific as indicated in footnote 59. Marshall and Warne (183^) found that the conjugate addition of lithium dimethyl copper to dienone 300 afforded a 95:5 mixture of octalones 381:380. Since the presence of IT cis octalone 238 could be detected in 239, this discrepancy requires an explanation. - 138 -

F. 'Octalone' 240 (Androst-4-en-3-one)

In considering the preparation of androst-4-en-3-one, two equally inexpensive commercially available compounds, testosterone (472) anci

36-hydroxyandrost-5-en-17-one (473), appeared to be useful as possible precursors. The conversion of either of these compounds into

240 would require the reductive removal of the C-17 oxygen functionality

472 240 473

necessitating C-3 carbonyl protection in the case of 472 and, in the 5 4 case of 473, subsequent C-3 oxidation with double bond (A -> A )

isomerism (228). Unforeseen difficulties with the reductive step in

the former sequence and with the oxidative step in the latter, resulted

in further experimental work being undertaken to elaborate these problems and to formulate general methods for minimizing them. Since

there is a great deal more literature precedence for elaborating 240

from 473, rather than from 472, this approach and its oxidation

problems will be considered first.

Androstenone 240 from 38-Hydroxyandrost-5-en-17-one (473)

Literature Precedence

Androst-4-en-3-one has been prepared previously, on two occasions, - 139 -

from compound 473 by a sequence utilizing the Wolff-Kishner reduction and Oppenauer oxidation reactions. Shoppee and Krueger (208), and then Fetizon and Golfier (209), reduced the carbonyl of 473 by the

Huang-Minion modification (210) of the Wolff-Kishner reduction. Both groups then subsequently employed the Oppenauer oxidation (211) of androst-5-en-38-ol (474) to afford approximately 70% androstenone 240 from 473. More recently, Habermehl and Haaf (212) used a five step

240

sequence to accomplish the same transformation. The steroid 38- acetoxyandrost-5-en-17-one (475) was reduced via Barton's vinyl iodide procedure for ketone removal (213). Formation of the hydrazone

476 was achieved under basic conditions with triethylamine as catalyst in a refluxing ethanol solution of hydrazine hydrate and the ketone

475. Oxidation with iodine in triethylamine-tetrahydrofuran solution

X I

475 X = 0,R = Ac 477 - 140 -

then provided the vinyl iodide 477 which furnished the desired compound

474 on Raney nickel reduction. However, the yield of less than 65% overall does not compare favourably with the 90% obtained by direct

Wolff-Kishner reduction (208). All three groups of workers (208,209,212) converted the B,y-unsaturated alcohol 474 to the a,B-unsaturated ketone 240 using the Oppenauer oxidation, even though a rival well-known literature alternative did exist.

Studies by L.F. Fieser on both partial (127) and exhaustive (214) dichromate oxidation of cholesterol in acetic acid-benzene solutions showed that a complex product mixture was produced. In this mixture, rather than the expected 3,y-unsaturated ketone 334 predominating, the enedione 480, cholest-4-ene-3,6-dione, was found to be the major 61 product. However, the dichromate oxidation of the C-3 alcohol in the corresponding protected 3,y-dibromo steroid 481 gave a nearly quantitative

(96%) yield of the dibromo ketone 482. Thus Fieser (216) was able to report the conversion of cholesterol (331) to cholestenone 478 in 81% overall yield for large scale experiments using the following sequence,

A diethyl ether solution of cholesterol was treated with an acetic acid solution of bromine and the crystalline dibromide 481 was oxidized with chromium trioxide in acetic acid to 482 and immediately debrominated with a slurry of powdered zinc in diethyl ether to afford the 3,y- 61 The stereospecific introduction of the thermodynamically less stable . 6B-oriented hydroxyl group into compound 334 to afford 479 was not rationalized but see thesis discussion on pages 81-90. The intermediacy of cholest-4-en-3-one (478) in this reaction was not possible because the unconjugated ketone 334 was not isomerized in acetic acid-benzene for periods up to 20 hours and the reaction mixture was found to be free of even trace amounts of the conjugated ketone 478 (215). - 141 -

482 X = 0

unsaturated ketone 334. Isomerization of this ketone to cholest-4- en-3-one (478) was accomplished either by chromatography or by treat• ment with mineral acid or base, with oxalic acid giving the best product. - 142 -

Normally the yields reported for the Fieser or Oppenauer procedures approximate 70%. Since both methods require special precautions and workup conditions and take a day to complete, an easier alternative was 4 desirable. Manganese dioxide oxidations of the A -3-ol allylie alcohols to conjugated ketones have been found to be quantitative in

15 minutes, but the corresponding A^-3-ols are oxidized by manganese 4 dioxide in refluxing solvents to a mixture of conjugated A -3-one and 4 6 A ' -dione products, with the latter predominating (217). In 1961, Rao (218) reported that Attenburrow's "active" manganese dioxide 4 afforded the conjugated A -3-one exclusively because of the rapid base isomerization of the 8,y-unsaturation to the relatively stable conjugated compound. This work found such a low conversion rate, 6% in eleven hours, that the method is not of synthetic interest at this time.

Three other pertinent literature procedures were available for the conversion of steroidal A^-3 -ol to the A^-3-one system. Djerassi and collaborators, in 1956 (219), were interested in preparing biologically important steroidal A^-3-ketones by direct oxidation of the A^-3-ol precursors. They found the Jones procedure (220) of titrating the alcohol 483 (a-d.) in an acetone solution with aqueous chromic-sulfuric acid oxidizing reagent afforded the unconjugated ketone 484 in high yield if the reaction was carried out at 10° for two minutes (reported

89% of 484 when R' = C0CH.J . - 143 -

483a R' = 0 (473) 484a R' = 0

b R' = 0C0C6H5 b R' = 0C0C6H5

c R' = COCH3 c. R' = COCH3

d. R' = COCH2OAc d. R' = C0CH20Ac e-R/ = H e R' H R 1 ' = CQH (331) f R' C8H_!H4) O If

Subsequently, in 1956, Snatzke found that cholesterol (311) was oxidized in. 79% yield to cholest-5-en-3-one (334) with a dimethylformamide solution of chromic acid (221,222 ). The sterol (0.5 mM) in dimethylformamide (15 ml) was treated first with chromium trioxide

(2 mM) and then concentrated sulfuric acid (1-3 drops) in dimethylformamide (10 ml). As with the Jones reagent, this work showed a-ketols and ketals were not cleaved despite the use of sulfuric - 144 -

acid. Also, allylic oxidation of A "'-sterols did not occur."*"

In 1966, Jones and Wigfield (223) found the optimum conditions for the A^-3-ol -»- A^-3-one transformation while establishing the best conditions for androst-5-ene-3,17-dione (484a) preparation. In their survey of available procedures, the Jones oxidation product was found to be contaminated with starting material (483a) and conjugated ketone while Fieser's dibromoketone intermediate underwent photolytic decompose ition leading to a lowered yield of pure compound 484a. Jones and

Wigfield utilized a modified form of Pfitzner and Moffat's procedure

(224,222^) to dehydrogenate the homoallylic alcohols 483a,e,f under the mild neutral conditions of N,N-dicyclohexylcarbodiimide (DCC) and pyridinium trifluoroacetate (PTFA). By using a 1:1 benzene:dimethyl

Surprisingly, no oxidation of the unusually reactive A" bond was reported in either case, but Djerassi and coworkers, in 1962, did find the Jones oxidation of 33-hydroxy-6,16a-dimethylpregn-5-en-r 20-one (i) for 3 minutes at 5° produced il, rather than iii. Allylic oxidation of iv was excluded from the reaction pathway when it was found to be stable to the oxidation conditions. Epoxidation of the olefinic linkage of iii was postulated, on acid cleavage, to generate a 5a,6$-diol which dehydrated to ri in the acidic medium. Other rapid epoxidations of tricyclic olefinic bonds with the Jones reagent were demonstrated (129^), - 145 -

sulfoxide solution at 50°, compounds ^83a,e^,f_ yielded 60-70% of the corresponding 484 with some of the methylthiomethoxy ether (483,

R = CH3-S-CH2-) as a byproduct.

The recently reported difficulties in the preparation of 6a- methylandrost-4-en-3-one (487) (225) from 38-hydroxy-6-methylandrost-

5-en-17-one (485) are also particularly informative. The Huang-Minion modification of the Wolff-Kishner reduction yielded 82% of the desired 8,y-unsaturated alcohol 486, but the subsequent Oppenauer

oxidation afforded only 40% 6a-methylandrost-4-en-3-one (487). In an attempt to oxidize the 8,y-unsaturated alcohol 486 directly to the corresponding ketone 488 for isomerization to the desired - 146 -

ketone 487, the very mild Sarett oxidation reagent (226 ) was

employed. A pyridine solution of compound 486 was allowed to stand at room temperature for forty hours in the presence of an excess of

dipyridine chromium trioxide reagent. Chromatographic separation

then afforded a 20% yield of the 63-hydroxy-6a-methylandrost-4-en-

3-one (489) . This result was completely unexpected since double bonds are not expected to be isomerized under these conditions and 63

the Sarett oxidation, as noted, was previously reported to be

essentially inert towards them. • Apparently the modest electron donating power of these bonds usually cannot compete with the

trivalent nitrogen for the chromic trioxide (226 ).

The isolation of products from the pyridine medium often presents

technical difficulties and Holum (226^), in 1961, studied acetone,

dimethyl sulfoxide, nitrobenzene, nitromethane, ethyl acetate, ethyl

bromide, chloroform and carbon disulfide as alternative dispersing

mediums to pyridine. Unfortunately, even the best solvent, acetone,

gave greatly reduced yields and it was not until Collins, Hess, and

Frank reported (227) in 1968 that the anhydrous dipyr.idine-chromium(VI)

oxide complex was moderately soluble in polar chlorohydrocarbons, that

a method for rapid alcohol oxidations in a basic medium became

The dipyridine-chromium(VI) oxide complex in pyridine was originally reported (226a) to be inert to double bonds and thiol ethers. Ketals are not cleaved and isolated double bonds are not isomerized since the medium is basic. Very prolonged exposure does lead to oxidation of allylic methylene positions, sometimes with concomitant migration of the unsaturation (177) but normally this reaction is of no consequence during alcohol oxidations (alcohol oxidations > 10^ faster). - 147 -

possible. Collins' coworkers isolated a 64% yield of cholest-5-en-

3-one (334) after cholesterol (331) was oxidized for thirty minutes at 10 with a 6:1 mole ratio of complex-to-alcohol in a dichloromethane solution. No cholest-4-en-3-one (478) was detected in the reaction mixture but cholest-4-ene-3,6-dione (480 in 10% yield) and

'cholest-4-en-3-ol-6-one' (490, 38-hydroxycholest-4-en-6-one, in 8%) were reported to be present.

Very recently, Jones and Gordon re-evaluated the synthetic routes to various C-17-substituted A^-3-keto steroids (229). In their hands the Pfitzner-Moffatt oxidation of the B,y-unsaturated alcohols did not go to completion without side reactions and the decomposition of the corresponding a,3-unsaturated ketones gave some oxygenated compounds. They found the use of dipyridine chromium trioxide in dichloromethane (Collins) provided the most satisfactory

This probably should be 10% cholest-4-ene-3,6-dione and 8% 6B-hydroxy-cholest-4-en-3-one (479) since these are "the major products obtained on direct chromic acid oxidation" (227). The dipyridine-chromium(VI) oxide complex is also called trioxobis- (pyridine)chromium). - 148 -

4 65 route to compounds free (< 1%) of their conjugated A -3-keto isomers.

Current Synthetic Work

Therefore, in the interest of. obtaining high overall yields of androstenone from the commercially available homoallylic alcohol precursor 473, Barton's Wolff-Kishner modifications (173) were used in place of those of Huang-Minion and chromium trioxide oxidation procedures — Jones, Collins, Snatzke — were explored as a replacement for the Oppenauer oxidation. Treatment of 38-hydroxyandrost-5-en-17- one with a 180° refluxing diethylene glycol solution of sodium glycolate and anhydrous hydrazine for 12 h, followed by 24 h at 210°, afforded the 8,y-unsaturated alcohol 474 in 98% yield after a short path 66 distillation. Oxidation of 474 with Jones (220), Collins (227), or Snatzke (221) reagents gave a product which was analyzable by g.l.c. 67 68 or n.m.r. The Jones oxidation method was quickly discarded because

65 This analysis, while undoubtedly true, is misleading. Although there is little double bond isomerization reported in their work, their results are based on the approximately < 50% yield of isolated crystallized compounds and their analysis therefore excluded the production of at least 20% impurities that we have shown to be in the reaction mixture. 66 When this was changed from 1.45 M base (60 ml) and 12 h @ 180°, 24 h @ 210° to 1.00 M (50 ml) and 6 h @ 180°, 18 h @ 210°; the yield from ketol 473 (5.0 g) dropped to 78%. Using 2.00 M (50 ml) and 6 h @ 180°, 18 h @ 210° yielded 98% 474. 67 As proven subsequently, compounds 474, 491 + 240, and 493 + 494 were eluted separately by g.l.c. (5' x k" 20% SE 30 columnly) with base line separation and their n.m.r. vinyl proton differences (3.82 x

for 493, 4.26 T for 492 and 240, and 4.64 x for 474 and 491) could then be exploited to measure the product ratios in mixtures. 68 The closely related two phase oxidation procedure by Brown et a_l. (230) was also unsuccessful. A stoichiometric amount of sodium dichromate and sulfuric acid in water led to an attack on the diethyl ether at room temperature while a 100% excess at 0° led, even after lh hours, to a mixture of starting material and compounds 240 + 493. Employing a 200% excess of aqueous chromic acid with an ether solution of alcohol 474 at 0° gave a 1:4 mixture of 240:493 after 2 hours. - 149 -

of the appearance of extraneous g.l.c. peaks, but both the Collins and Snatzke reactions were found to afford only two major components in ^ 3:1 ratio. If this mixture was carefully submitted to two short path distillations, the lower boiling dominant component was obtained as a 93% pure compound while the higher boiling component was 75% pure. Alumina chromatography separated both components sharply and provided analytical samples after a recrystallization from methanol. The major compound was identified as androst-4-en-3-one (240), having the same melting point and spectral properties as those reported for this compound (208,212) and being identical to a sample of 240 that was later prepared by an unambiguous route from testosterone (472). While n.m.r. analysis showed that no 240 was present in the initial - 150 -

Collins or Snatzke workup product, the corresponding 3,y-unsaturated ketone 491, the major reaction product, was cleanly isomerized on distillation and alumina chromatography to 240.

The more interesting minor component was shown by n.m.r. to be

a 7:3 mixture of the compounds 493 and 494. The endione 493 was purified by utilizing the base solubility of its yellow enolate (176b) and by crystallizing fine yellow needles of 493 from methanol solutions.

The structure of androst-4-ene-3,6-dione (493) was readily deduced

from its spectral data. The sharp C-4 vinyl proton at x 3.82 in the n.m.r. had a width at half peak height of 1.4 Hz, thereby demonstrating

the absence of allylic coupling. By way of comparison, androst-4-en-3-

one (240) had its vinyl proton at x 4.26 with a 3.4 Hz width at half peak height. Also the ultraviolet absorption for 493 exhibited X max 251 my (e = 10,600) with a shift to X 372 my in base, providing max 4 good agreement with values reported for other steroidal A -3,6-diones 69

(151,157,231). The structure for the dione 494 was then confirmed

to be androstane-3,6-dione by comparing it with the product obtained

from hydrogenating the enedione 493 over palladium on carbon.

If the 240:293/4 ratio that was initially obtained from the modified Collins procedure is considered as a measure of the degree of mono-oxidation to overoxidation (491:492), the 72:28 ratio observed 69 Confirmation of the structure proposed for the minor product was obtained by employing the procedure of Volger and Brackman (156a) to prepare 493. Compound 240 was deconjugated to 491 with KOBut/HOAc (157) and then oxidized to 493 with a copper-catalyzed autoxidation in a methanol-pyridine-trimethylamine solution. See also footnote 34, page 99. - 151 -

above is remarkably similar to the mono-oxidation:overoxidation product ratio reported for cholesterol by Collins ejt al. (227) — 64:18, better expressed as 78:22. When the androstenone experimental work was originally undertaken, it was thought that the desired C-3 alcohol oxidation could be done selectively. Therefore, these results were greeted with some surprise (disbelief) as both the acidic and basic conditions yielded the same product mixture. Since the little explored

Snatzke method offered several interesting parameter variations while the Collins offered less experimental scope for such work, additional Snatzke reactions were performed on a model B,y-unsaturated alcohol.

Snatzke Oxidations of Cholesterol

Fieser's method (216) of purifying commercial cholesterol via debromination of the dibromide 481 as well as his discussed procedure for preparing cholest-5-en-3-one (334) and cholest-4-en-3-one (478) were used. Authentic cholest-4-ene-3,6-dione (480) was prepared from cholest-5-en-3-one (334) by Brackman's method (156) of using a copper- catalyzed autoxidation. Volger and Brackman found B,y-unsaturated ketones could be readily oxidized with air by using cupric complexes in alkaline solution at 0° and their first reported example in 1965 was a 75% yield of 480 from 334. The dienolate anion (495) formation is the rate determining step and electron transfer to the cupric complex produces the dienoxy radical (496) which is trapped as the secondary 3 peroxy radical 497 by 0„ and reduced to a carbonyl by cuprous ion. - 152 -

£8H17

Usually, the required 8,Tf-unsaturated ketone is obtained by generating, with potassium _t-butoxide, the enolate of the corresponding conjugated ketone in _t-butanol and quenching it rapidly with acetic acid (155).

Without purification, the 8,Y-unsaturated ketone is then oxidized to the enedione with air and cupric acetate in a methanol solution of pyridine-triethylamine for thirty minutes. It was this latter method that was used to obtain an authentic sample of androst-4-ene-3,6-dione from androst-4-en-3-one in 50% yield. As noted earlier (footnote 34, +2 page 93) the Cu /O^ procedure sometimes fails completely and Brackman has reported the cholest-4-ene-3,6-dione product can be contaminated with 6(a and/or 8)-hydroxy-A -cholestenone. For these reasons, the crude enedione products were purified via extraction of their respective - 153 -

potassium enolates (499, 231 ) from petroleum ether with Claisen's alkali (aqueous potassium hydroxide in methanol) (231 ) before being recrystallized from methanol. R

0 42a

With the purified cholesterol and expected products in hand, a series of small scale modified Snatzke oxidations were analyzed and

tabulated. Table Ilia summarizes the results obtained and represents

the average result produced from multiple runs. In the standard oxidation, cholesterol (1.0 mmole) in a dimethylformamide solution

(50 ml) was treated for one hour at room temperature (23 ) in air with

chromium trioxide (4.0 mmoles) and sulfuric acid (1.8 mmole).

I - 154 -

Table Ilia Chromium Trioxide Oxidation of Cholesterol in Dimethylformamide

« c Reaction - Changes0 Yieldb Average Product Ratio 334 ;480 (% 331) 1 Standard Snatzke 88 % 73 : 27 (17%)

2 Nitrogen Atmosphere 89 % 80 : 20 (17%)

3 Reaction at 0° 60 : 40 (37%)

4 f|05 (2 mmoles) Added 73 % 57 : 43 (9%)

5 F|05(4 mmoles) Added 70 % 31 : 69 (9 %)

6 No H2S04 Used 82 % 76 :24 (79%)

7 H2S04(Q9 mmoles) 90 % 83 ; 17 (31%)

1 H2S04(1.8 mmoles) 88 % 73 : 27 (17%)

8 H2S04(4.5 mmoles) 75 % 40 : 60 (3%)

9 H2S04(9.0 mmoles) 69 % 1 : 99 (1 %)

10 H2S04(18.0mmoles) 53 % 1 : 99 (1 %)

Notes for details see Androstenone £4Q_ experimental, section (i) of (c). ^Quantitative measurement with internal standard.

CA measurement of cholesterol (331) recovered and the ratio of cholest- 5-en-3-one (334) to cholest-4-ene-3,6-dione (480). - 155 -

Table Illb illustrates the relative stability of the cholesterol oxidation products by substituting 1.0 mmole of cholest-

5-en-3-one (344) or cholest-4-en-3-one (478) or cholest-4-ene-3,6-dione

(480) for cholesterol (331) in a Snatzke reaction. These experiments are essential for an understanding of Table Ilia because they illustrate, that cholest-4-en-3-one is not found among the reaction products' after a workup under neutral conditions. Although the conjugated enone 478 was demonstrated to be inert to allylic oxidation and although the initial oxidation product of cholesterol, the unconjugated enone 334, was isomerized via its enol to 478 to the extent of 79% in the absence of chromium trioxide,the 76% cholest-5-en-3-one isomerized in the

"standard Snatzke" went primarily (> 85%) to cholest-4-ene-3,6-dione.

Under actual oxidation conditions this conversion becomes essentially quantitative and cholest-4-en-3-one is not found among the reaction products when neutral workup conditions are employed. Even when a two-fold excess of acid to oxidant was used in a Snatzke oxidation of cholesterol, no cholest-4-en-3-one was produced. The short lifetime of the enol to a strong oxidizing agent like chromic acid is completely understandable when one realizes that the enolate generated in the 2+ 2+ Cu /O^ reaction (495) is oxidized so quickly by Cu that the enolate cannot protonate at C-6 even though it is in methanol. Similar reasoning Table HI b Snatzke Oxidations of Cholesterol Oxidation Products^

Compound 'Oxidation Conditions (% Mass Recovery)0 478: 480 (% 334)

Cholest-5-en-3-one (334) Standard Snatzke (99%)b 14 ;: 86 (26%)

II b Standard without Cr03 (95%) 100: 0 (21 %)

II Inverse Snatzke (91 %)b 13: 87 (45 %)

Cholest-4-ene-3,6-dione (480) Standard(1.8 mmole H+) (82%) 76%c 0: . 100

II " (9 mmole H+) (80%) 66%c 0: 100

II " (18 mmole H+ ) (74%) 39%c 0: 100

Cholest-4-en-3-one (478) Standard(1.8mmoleH+) (83%) 83%° 95: 5

(9 mmole H+) (93%) 93% c 95:. 5

Notes Non-acidic material isolated after oxalic acid isomerization except for 334 •

Neutral workup employed ( NaHC03).

cQuantitative measurement with internal standard.

^For details see Androstenone experimental (c)(i). - 157 -

explains why Fieser's work on the chromic acid oxidation of cholesterol in acetic acid medium*'1 led only to the A^-3-one and A^-3,6-dione compounds. Table Illb also demonstrates that cholest-4-ene-3,6-dione

(480), unlike cholest-4-en-3-one, is oxidized to a considerable extent as the amount of acid is increased. The oxidation products of

480 were studied by Fieser and have been found to be a mixture of diacids and acid anhydrides (214).

As an aid in the product analysis for Table Ilia, and without introducing undue complications, the unconjugated enone product 334 was isomerized to the conjugated enone 478 with dilute acid. The use of acidic conditions in the oxidation workup was also particularly helpful in reducing emulsions in the aqueous:organic partition. The ratios of the nuclear magnetic resonances at x 4.21 (478), 3.82 (480) and 4.60 (331) were then taken from filtered samples to establish the product mole ratios of cholest-5-en-3-one to cholest-4-ene-3,6- dione and the percentage of unreacted cholesterol. An internal standard allowed a quantitative measurement to be made and, in most cases, there was a discrepancy of * 10% between the weight of the initially isolated non-acidic product and the weight assigned to 334, 480 and

331. This difference was mainly due to the non-inclusion of the very minor product 6-hydroxycholest-4-en-3-one, which is isomerized to cholestane-3,6-dione, as well as material loss during sample handling.

However, in the case of an inert compound like cholest-4-en-3-one, the mass recoveries and internal standard analysis gave identical results

(Table Illb). The reproduceability of individual experimental runs

(Standard Snatzke was 73 - 3% of 334 for 6 experiments) was certainly - 158 -

helped by the demonstration that the order of addition, the use of

magnetic stirring, the exclusion of water and the use of an air or

oxygen atmosphere were of no significance to the product mole ratio.

The only three variables found to be of any consequence were the

amount of acid used, the temperature employed, and the presence or

absence of an oxygen containing atmosphere. Decreasing the second

parameter and increasing the other two led to an undesired increase

in the enedione 480.

A comparison of these results with Snatzke's experimental (221)

reveals a fundamental "misunderstanding" in his original work. The

oxidation of cholesterol or any other alcohol cannot be done with a

"few drops" or catalytic amounts of sulfuric acid.7^ The Snatzke

oxidation, like all other acidic hexavalent chromium oxidations, fits

the following stoichiometric equation (236 ).

+ + 2Cr03+ 3R2CH0H+ 6H —^ 3R2C=0 + 2Cr? + 6H20 (a)

In agreement with this, the aliquots taken from a dimethylformamide

solution of anhydrous chromium trioxide and 3-hydroxyandrost-5-ene

Unfortunately this error has been transposed into English through citations of his work (226^) including a reference in the organic chemist's Bible, Fieser's Reagents for Organic Synthesis (234a). A second interesting error is the report in Augustine's book (222a) that cholesterol is oxidized to cholest-5-en-3-one in 79% yield while Fried and Edwards (235) report that 3-hydroxy-A^-system cannot be oxidized to the ketone satisfactorily by Snatzke's method. The sad part is that they both are citing the same original paper — Snatzke's. - 159 -

(474) were found to show that little oxidation had occurred until small

quantities of acid were introduced. As demonstrated by gas-liquid

chromatography, the reaction ceased as the acid was consumed.

However the oxidation went rapidly to completion after excess acid

had been added. The same sequence of results is reproduced in

Table Ilia when increasing amounts of sulfuric acid (0.9 mmole -> 1.8

mmole -> 4.5 mmole) are considered.

Important Parameters in the Snatzke Oxidation

While cholesterol oxidations have been studied for over a

century, it is the very extensive studies of isopropanol oxidation

that has led to mechanistic insights on the chromic acid oxidation.

The oxidation of isopropanol by chromium(VI) in aqueous acetic acid

has been shown to follow equation (b)

2 Rate of Oxidation- k1 [HCrO°] [(CH3)2CHOH] [H°] + kjHCrQj] [(CH^CHOH] [H*] (b)

requiring the two competing rate determining steps (e) and (f)

+ HCr04 R2CH0H + H® « [R2CH0-Cr03-H] + H20 (c)

R2CH0 -Cr03H + H* [R2CH0-Cr03H2] (d)

lv 2CH0-Cr03 [R H] R2C = 0 + Cr • (e)

,v [R2CH0-Cr03H2] R2C=0 + Cr (f ) - 160 -

in one of two possible transition states 500 or 501 (237 ).

o. o 0 R \Nf>°\S- 2 R2C= 0 a ox xo Base + Crlv

500 501 X = Hor H2

b c Stewart (237 ) and Wiberg (237 ) have discussed the relative merits

of the two mechanisms and since has been found to be about thirty

times k^, the aqueous chromic acid oxidation appears to be predominantly

second order in acid. The Jones oxidation has also been studied (238 )

and it has been found to follow first order kinetics in chromium(VI),

isopropanol and acidity. The authors favoured the cyclic transition

state 501 in this case because proton transfer to an external base in

a less polar solvent (acetone) should retard the reaction rate and

would not explain the observed rate enhancement.

The significant role of acid in chromate oxidations suggests that

the phosphorus pentoxide employed in Table Ilia is serving as a source

of phosphoric acid. The addition of the acid anhydride to a Snatzke

reaction ensures that the water generated in the rapid chromate

ester formation step will provide the acidic protons required to

catalyze the slower rate determining chromate ester decomposition.

When a lower reaction temperature was employed (0°), the rate of

chromate ester decomposition was retarded relative to the rate of

enolization of the 8,y-unsaturated ketone 334. Conversely, when the

reaction temperature was raised to 37°, the enone (334) to enedione

(480) product ratio became 84:16 in air (90:10 in nitrogen). - 161 -

Unfortunately, at 57°, this ratio had dropped to 70:30 (82:18 in nitrogen). Since two equivalents of acid are required to produce one mole of the enone 334 from cholesterol while six equivalents of acid are required to produce one mole of the enedione 480 by chromate oxidation of cholesterol, controlling the reaction temperature can be used to minimize the acid "catalyst" consumed in the allylic C-6 hydroxy oxidation.

To understand the product ratio change caused by going from oxidations in air to those in nitrogen requires Westheimer's (236) more complete analysis of the stoichiometric equation (a) outlined in (g), (h) and (i) below. In an acidic hexavalent chromium oxidation, V up to two-thirds of the alcohol oxidation is performed by a Cr species VI and one-third by a Cr species.

v, lv R2CH0H + Cr 03 R2C=0 + Cr 02 + H20 (g)

v H20 + Cr02 + Cr03 —>» 2Cr 03H (h)

+ ,u 2(Cr03H + R2CH0Ht3H R2C = 0 + Cr +- 3H20) (i )

+ 3+ 3R2CH0H + 2Cr03+6H 3R2C = 0 + 2Cr + 6H20 (a)

The result of going from an air to a nitrogen atmosphere in Table Ilia suggests that oxygen traps some of the active intermediate chromium species. Following this hypothesis, when the Snatzke is done under IV V nitrogen, the stronger oxidant Cr and its derivative Cr are left to perform oxidations. S ince these reactions are more rapid than the VI d parent Cr oxidations (236 ), this results in the sulfuric acid being - 162 -

consumed preferentially in C-3 oxidations rather than in oxidations subsequent to enolization of the B,y-enone 334. A related oxygen effect has been reported by Wiberg and Mill in their work on the oxidation of benzaldehyde to benzoic acid (239). When this reaction was carried out in air, benzaldehyde disappeared as though 8% more chromium trioxide was present than theoretically possible. Repeating the reaction under nitrogen reduced the oxidant to 90% of theoretical IV due to induced oxidation of the solvent by Cr

Unfortunately the above interpretation fails to explain why the amount of recovered cholesterol at a given reaction temperature is independent of whether the reaction was done in an air or nitrogen atmosphere. It does not explain why employing excess sulfuric acid

(4.5 mmole) gave a 40:60 ratio in air and a 60:40 ratio in nitrogen.

A simpler interpretation is that some autoxidation is occuring and the oxygen uptake is probably associated with a chromium trioxide inter• mediate (Cr^ -y Cr^^l) that facilitates the required one electron transfer step. Even so, the majority (y 2/3) of the oxygen introduced at C-6 originates with the chromium trioxide and not with the molecular oxygen.

Several additional observations were made of factors that have mechanistic rather than synthetic overtones. Using an extension of

Table Ilia below, the results are listed from the Snatzke oxidation of cholesterol with 1.8 mmole of sulfuric acid (the first two) and without sulfuric acid (the last six). The problem arises that in the absence of acid and under normal reaction circumstances about 20% of the cholesterol is oxidized. While hydration of hydroscopic chromium trioxide yields chromic acid, H„Cr0., it has already been demonstrated - 163 -

that adding water has no effect on the oxidation. Auto-oxidation of

cholesterol in the workup was shown not to be occurring since entries

six and twelve have the normal oxygen-nitrogen ratio changes and a

blank run with cholesterol was recovered unchanged. The surprising

feature is that while these reactions contain enough oxidant (4 mmoles)

to react with 6.0 mmole of alcohol, even leaving reaction six for

Table III a Chromium Trioxide Oxidation of Cholesterol in Dimethylformamide

Average Product Ratio Reaction - Changes 334 :480 (%331)

1 Standard Snatzke 73.:2 7 (17%)

11 Oxidant Doubled 63 :37 (6%)

6 NoH2S04 Used 76 : 24 (79%)

12 No H2S04>N2 Atmosphere 87 ; 13 (82 %)

+ 13 Volume Halved, NoH ,N2 86 ; 14 (69%)

14 No H+, Sodium Acetate (5.0 mmole) 0 •. 0 (100%)

15 Acetic Acid (17.5 mmole) 62 :38 (75%)

16 p-Toluenesulfonic Acid (2.0 mmole) 43 :57 (61 %)

twenty-four hours in air without added sulfuric acid left it essentially

unchanged (76:24 (74%) ratio after 24 hours). This "residual acidity"

of the anhydrous chromium trioxide is also evident in the results

produced by doubling the oxidant (run 11) and by halving the volume

of dimethylformamide employed (run 13). When commercial chromium - 164 -

trioxide was recrystallized from distilled water and dried under vacuum, results superimposeable with those found earlier were obtained. That is, run six changed from 76:24 (79%) with commercial chromium trioxide to 77:23 (80%) with recrystallized oxidant.

However, employing sodium acetate (5.0 mmole) as a weak base led to no oxidation occurring (run 14) and even the addition of water (55 mmole) or acetic acid (17.5 mmole) left this result unchanged. The addition of sulfuric acid (0.9 mmole) to the sodium acetate buffered solution resulted in ^ 40% of the cholesterol being oxidized. The most interesting aspect of employing sodium acetate was that in the absence of acid only about 20% of the starting material was initially

recovered by organic extraction of the quenched, slightly basic

aqueous reaction solution. If either acetic or hydrochloric acid were

used to acidify the aqueous layer, the recovery jumped to over 75%

isolated cholesterol. This is consistent with the intermediacy of the

monochromate ester. This ester is expected to be soluble in

bicarbonate and to undergo a very rapid hydrolysis in dilute acid

(242).

While the extra activity (acidity) of the chromium trioxide is

of no synthetic consequence it would influence rate studies and must

be subtracted from the observed oxidation results to permit comparisons,

Acetic acid (17.5 mmole) and p-toluenesulfonic acid (2.0 mmole)

actually caused only < 5% and ^ 15% oxidation respectively . (runs 15

and 16) while sulfuric acid (0.9 mmole)led to 50% of the cholesterol

being oxidized. In addition, the product ratios for the monoprotic

acetic and p_-toluenesulfonic acids were not as' favourable as that for - 165 -

the biprotic sulfuric. In retrospect, the sulfuric acid results seemed almost anomalous especially when 2.0 mmoles of nitric, perchloric,

or hydrochloric acid were found to give product ratios of 43:57 (63%),

59:41 (61%) and 65:35 (74%) respectively. To deal with this'wide reactivity variation of chromium trioxide with the acid employed, equations (c) to (f) in the Westheimer oxidation sequence must be replaced by (j) to (m).

e + HCr04 + HA + H HCr03A + H20 ( j )

R2CH0H + HCr03 A [R^CHO-CrC^-A] +• H20 ( k)

lv [R2CH0Cr02 A] R2C = 0 + Cr ( I)

+ ,v [R2CH0Cr02AH ] R2C= 0 + Cr (m)

Lee and Stewart have shown (241cl) that protonation of the acid

chromate ion in aqueous solutions is accompanied by incorporation of

the mineral acid anion into the chromium(VI) species. They have

suggested that the oxidation of isopropanol in moderately concentrated

aqueous solutions of the mineral acid (HA) then proceeds by a cyclic, + 71

unimolecular decomposition of the chromate ester, R?CH0Cr0?AH (503).

"The transfer of electrons toward the chromium occurs by formation of carbon-hydroxy-oxygen bonds in the transition state as well as carbon-oxygen-chromium bonds, i.e. partly occupied orbitals are used to bind the transferred hydrogen to both carbon and oxygen in the transition state. The developing carbonyl group in the electron- deficient transition state will be stabilized by electron-donating substituents...Protonation of the chromate portion of the ester also increases the reaction rate. The conversion of ester to transition state is thus aided by the combined polarizing effects of an electron- donating aromatic ring and an electron-withdrawing metal cation."(241 ). - 166 -

Since the transition state of chromate oxidations is known to be

electron deficient (241^), the incorporated conjugate base (A) will

2 Rp-C— 0V ,0 R — C-^0. OH R C =0 H //\ 0 A k .A 0 HgCrOfc/S ••0 A . 502 503

affect the oxidation rate markedly. In the Jones oxidation employing

chromic acid in acetone, Lee et al_. (238 ) have shown that electron

withdrawing ligands, like nitrate, enhance the rate while chloride,

an electron donating ligand, retards the oxidation. From our results

using dimethylformamide, the incorporation of the conjugate base must

also be essential for the oxidation and the particular base

incorporated must be of great significance in the Snatzke oxidation.

While Lee and Johnson in their study on the chromic acid oxidation

of isopropanol in trifluoroacetic acid (238^) could not distinguish

whether the conjugate.base group shifted the ester formation (equation

(k)) or ester decomposition (equation (1)) reactions, the results on

the oxidation of cholesterol give an indication that the ester

decomposition is being affected. It is difficult to see how such strong

acids as sulfuric and jD-toluenesulfonic could give such different

results in equation (k). It is quite possible however that electronic

considerations for bisulfate and tosylate would affect the rate of

decomposition of 502. This idea was strengthened when the results

with p_-toluenesulfonic acid were found to be unchanged by the addition - 167 -

o of 4 A molecular sieves to the reaction. Similarly, the addition of hydroscopic reagents (molecular sieves, magnesium sulfate, sodium sulfate, dicyclohexyl carbodiimide) to the reaction using sulfuric acid was shown to have no effect on the results. While the addition of bisulfate salts (potassium bisulfate hydrate) did shift these oxidations to completion and did suggest the intermediacy of a transition state like 504, having both the favourable hydrogen bonding and the

,-Ht. R 0" *0 I II II R-C-0-Cr-0-S==0 I 8+ll I

504 required protonation, the relative failure of phosphoric acid (1.0 mmole H^PO^ afforded 77:23 (84%) terminated further investigation of acid catalysts.

Collins Oxidations of Cholesterol

Fortunately the methods that were devised to explore the Snatzke reaction rapidly gave more general and significant results when applied to the Collins oxidation. Table IVa displays the average result produced from multiple runs by varying the oxidant mole ratio,

the temperature, and the atmosphere employed in a Collins reaction.

In a standard oxidation, cholesterol (1.0 mmole) in dichloromethane

solution (50 ml) was treated for thirty minutes at room temperature

(23 - 1°) with anhydrous chromium trioxide (2,4, or 6 mmoles) and

pyridine (12 mmoles). - 168 -

Table IVa Chromium irioxide-Pyridine Oxidation of Cholesterol in Dichloromethane ("Collins")

Oxidant/Alcohol Average Product Ratio Reaction-Changes Mole Ratiob 334=480 (%33J)

1 Standard 2 89 :11 (51%) 2 Standard 4 85 :15 (16%)

3 Standard 6 85 :15 («S3%)

4 Nitrogen Atmosphere 4 91 : 9 (37%)

5 Nitrogen Atmosphere 6 - 93 : 7 (9%)

6 Reaction at 0° 4 94 : 6 (29%)

7 Reaction at 0° 6 92 : 8 (9%)

8 Standard plus H20 (2.0• mmole) 4 84 ;16 (79%)

9 H00(2.0mmole) + R 0.(6.0mmole) 4 91 : 9 (41%)

Notes For details see Androstenone 240 experimental,section (ii) of (c).

bThis indicates the mole ratio of chromium trioxide to cholesterol.

c A measurement of cholesterol (331.) recovered and the ratio of cholest-

-5-en-3-one(334) to cho!est-4-ene-3,6-dione (480).

Table V demonstrates the relative stability of the cholesterol

oxidation products by substituting 1.0 mmole of cholest-5-en-3-one

(334) or cholest-4-en-3-one (478) or cholest-4-ene-3,6-dione (480)

for cholesterol (331) in a Collins reaction at room temperature

for one hour with a six-fold excess of oxidizing agent. These

experiments illustrate that pyridine alone does not isomerize the

unconjugated double bond of compound 334, that the conjugated ketone Table V Oxidations with Chromium Trioxide-Nitrogen Base Reagents.

Compound0* Oxidation Conditions (%Mass Recovery)0 478:480 (% 334)

Chotest-5-en-3-one (234J Standard Collins (70%)b(66)c 2:98 (15%)

II b Collins without Cr03 (99%) -: - (100%) II Standard Corey (77 %)b 5:95 (45%)

b Corey without Cr03 (94%) 100:0 (98%)

Cholest-4-ene-3,6-dione (42Q) Standard Collins (96%)(75%)c 0: 100 II Standard Corey (74%)(69%)c 0:100

Cholest-4-en-3-one (478) Standard Collins (92%)(85%)c 96: 4 II Standard Corey (85%)(78%)c 93:7

Notes U .Non-acidic material isolated after oxalicacid isomerization except for 334 •

b Neutral workup employed (NaHCO^.

c Quantitative measurement with internal standard.

^ For details see Androstenone experimental (c.) (ii.).. - 170 -

478 does not occur as a direct oxidation product of cholesterol and that cholest-4-ene-3,6-dione, the oxidation product of cholest-5- en-3-one, is itself oxidized further. These are essentially the same observations as those made in the Snatzke oxidations (Table Illb)

As an aid to tabulating Table IVa, the reaction mixtures were once again isomerized with oxalic acid to establish the product mole ratios of cholest-5-en-3-one to cholest-4-ene-3,6-dione and the percentage of unreacted cholesterol, The variables found to be the most significant were the mole ratio of oxidant to alcohol, the temperature and atmosphere employed, and the amount of acid or base present.

At this point, it is worthwhile to consider part of the original work by Collins, Hess, and Frank on the dipyridine-chromium(VI) oxide.

They reported (227)

O "Stoichiometric analysis of the oxidation of 2-butanol at 25 using 2:1, 4:1, and 6:1 mole ratios of complex to alcohol in 6% complex solutions provided 56%, 79% and 98% end point conversions to 2-butanone, respectively (vpc analysis). This low oxidation efficiency is undoubtedly due to the fact that reduced chromium products, as well as alcohol, react with the reagent — no active complex remained in solution following the oxidations even when the 6:1 ratio was used. Higher oxidizing efficiencies were obtained at a lower temperature and by using a suspension of phosphorus pentoxide in the reagent..."

The Table IVa results for cholesterol are in good agreement with the literature values for butanol as far as the oxidant mole ratios are concerned. That is, a 2:1, 4:1, and 6:1 mole ratio of complex to alcohol were found to provide a 49%, 84% and 97% end-point conversions of cholesterol. However the molecular oxygen dependence illustrated in Table IVa is the first example reported that the - 171 -

efficiency of the Collins reaction is dependent on an oxygen containing atmosphere. This observation has special significance because of the hygroscopic nature of the dipyridine-chromium(VT) oxide. The hydrated complex is chlorocarbon-insoluble and is quite unreactive as demonstrated by entry eight of Table IVa. The hydrophilic nature of the oxidant complex is the main reason that it is no longer isolated as suggested in the procedure of Collins e_t al. (227). The current procedure, suggested by Ratcliffe and Rodehorst (158), utilizes the in situ preparation of the complex to minimize the handling difficulties.

Two molar equivalents of pyridine in dichloromethane are added to one of anhydrous chromium trioxide and the magnetically stirred red solution is ready for use within ten minutes. Since the problem now becomes one of having a weighed amount of anhydrous chromium trioxide

(which is itself hygroscopic) suitable for the reaction, many reactions are conveniently done by heating the required amount of commercial reagent grade chromium trioxide under vacuum and then cooling in a nitrogen atmosphere. The pyridine and dichloromethane are added by syringe and, after a few minutes, the alcohol can be added as a 72 dichloromethane solution. Experiments show that for cholesterol a mole ratio of 8:1 of oxidant to alcohol, rather than the normal 6:1 ratio, is required for the oxidation to go to completion under a nitrogen atmosphere. "72 For example, Ratcliffe and Rodehorst (158) reported storing dichloro• methane solutions of the oxidant complex for up to 28 days under nitrogen without adverse reagent decomposition. Corey and Fleet (232) report doing their related oxidation work under an argon atmosphere. - 172 -

The literature observations quoted above on the higher oxidizing efficiency of the Collins oxidant at lower temperature and on the use of phosphorus pentoxide appear to be misleading. The oxidizing efficiency for a given mole ratio of oxidant to sterol obviously drops as the temperature is changed from 23 to 0 . That is, employing a

4:1 ratio of complex to alcohol changes the reaction from being 83%

o 6 complete at 23 to being 71% complete at 0 . On general principles, it would be very surprising if higher oxidizing efficiencies were obtained by lowering the temperature of the reaction. Nevertheless, since the Collins oxidation shows an even larger dependence on molecular oxygen than it does on temperature, the literature observations might have originated with oxygen deficient reactions. Lowering the temperature then would give an oxygen deficient reaction a better chance of completion because of the higher solubility of oxygen at lower temperatures and the longer lifetime of the oxidant complex under these conditions.

The use by Collins et ail. of a suspension of phosphorus pentoxide to give higher oxidizing efficiencies suggests the acid anhydride prevents or reverses hydrate formation of the oxidant complex. From

Table IVa, entry nine, it is clear that using even a nine-fold excess of phosphorus pentoxide only regenerates (dehydrates) about one-half

3H20 + P205 - 2H3P04 - 173 -

of the hydrated complex. As will be demonstrated subsequently, the most important aspect of adding phosphorus pentoxide is the addition of a good proton source, as phosphoric acid, rather than the employment of phosphoric pentoxide as an effective dehydrating reagent.

A discussion of acid parameter effects will follow that of the effect of bases, but first the favourable product shift to cholest-5-en-3-one in Table IVa should be considered. The decrease in cholest-4-ene-3,6- dione produced by using a nitrogen atmosphere suggests that about half this product originates from auto-oxidation, as was observed in the

Snatzke oxidation. The favourable minimization of enedione production at ice bath temperatures indicates that in the Collins oxidation, unlike in the Snatzke, the rate of enolization of the unconjugated ketone compared to the rate of oxidation of cholesterol is diminished by lowering the temperature. The latter observation provides experimental justification for the procedure of Jones and Gordon (229) who oxidized variously C-17 substituted A^-3-hydroxysteroids at 0° with dipyridine chromium trioxide complex. However their work gives no indication that enedione formation is suppressed at 0° and they are unaware that an eight or ten:one mole ratio of oxidant:sterol is required to permit the reaction to go to completion.

Other Parameters in the Collins Oxidation

The parameter work for Table IVa was so encouraging that a set of experiments was performed to establish the role of pyridine in the

Collins oxidation. The literature procedure of quenching the oxidation reaction with ether and then working it up was found to give anomalous - 174 -

results at low pyridine concentrations. The reason for this became evident when the results of performing a Collins' oxidation without any pyridine were considered. Using a 6:1 ratio of anhydrous chromium trioxide to cholesterol, without pyridine, gave a A^-3-one: 4

A -3,6-dione (% cholesterol) analysis of 81:19 (43%) when the reaction mixture was added to ethyl ether and filtered. When a similar reaction was added to ice-cold aqueous sodium bisulfite, dilute hydrochloric acid (3 N) or aqueous sodium bicarbonate, the product analyzed as

-:- (100%). Evidently, the lone pair electrons of oxygen in diethyl ether can serve the same function as those of the nitrogen in 73 pyridine, albeit several orders of magnitude less effectively. As a result of this finding, the reaction solutions in Table IVb were quenched by filtration into cold saturated solutions of sodium bicarbonate followed by washing the organic layer with water and dilute hydrochloric acid.

Table IVb gives a progression of end-point conversions similar to those observed in Table IVa when the 2:1, 4:1 and 6:1 mole ratio of complex (trioxobis(pyridine)chromium) to sterol are considered.

Also the mass recoveries on workup for Table IVb were even higher than

those observed for Table IVa, providing ^ 90% yields. However the results tabulated do not meet literature expectations when diminishing amounts of pyridine are considered. If the dipyridine complex is

73 . The point to be stressed is that while slight variations due to the workup procedure can be tolerated, anything that obliterates the effects of parameter variations, or parameter trends, is worse than useless. Fortunately, to this point, the trends discussed are are independent of the method of quenching the oxidation reaction. - 175 -

essential for oxidation, reducing the pyridine below a two molar

equivalent should cause a dramatic fall in the product yield. However,

Table IVb Pyridine Dependence of Collins Oxidation of Cholesterol

Reaction0- (Base /Oxidant Oxidant/Alcohol Average Product Ratio0 Mole Ratio) Mole Ratio b 334= 480 (%331)

1 Pyridine (6) 6 82 .18 (6%)

2 " (2) 6 86 :14 (2%)

3 " (1 ) 6 89 :11 (4%)

4 '* (0.5) 6 91 : 9 (14 %) — ; — 5 No Pyridine 6 (100%)

6 Pyridine (3) 4 87 -.13 (15%)

7 " (2) 4 91 : 9 (15%)

8 " (1) 4 92 :8 (17%) 9 " (6) 2 80 :20 (50%)

10 " (2) 2 84 :16 (50%)

Notes a For details see Androstenone 240 experimental,section (ii) of (c)

bThis indicates the mole ratio of chromium trioxide to cholesterol.

c A measurement of cholesterol (331) recovered and the ratio of cholest-

-5-en-3-one(334)to cholest-4-ene-3,6-dione (480). - 176 -

the listed results show there is little or no difference to employing one or two equivalents of pyridine. When a reaction containing a

1:1 ratio of pyridine:chromium trioxide is filtered before the addition of the sterol, the results were found to be unaffected. This particular reaction is consistent with the intermediacy of the monopyridine complex and the results of Table IVb are in agreement with a monopyridine, rather than a dipyridine, complex being responsible for the oxidation.7^

The hypothesis of a monopyridine complex was also strengthened by several other facts. The first of these was Collins' own analysis of the hydrated dipyridine chromium trioxide complex to be C^Yl^Cr^^Oj.

If the "diol" water displaces a pyridine from each dipyridine chromium(VI) complex (to form 505?), the transition state for the pyridine-chromium trioxide system and a secondary alcohol, RR'CHOH, probably resembles

506a. An alternative transition state 506b was less attractive because

R 505 506a

74 When 3B-hydroxyandrost-5-ene was oxidized with a 6:1 mole ratio of chromium trioxide to sterol and the reaction was monitored by g.l.c, similar results were observed. After thirty minutes without pyridine, no oxidation had occurred. After thirty minutes with one half equivalent pyridine for each millimole chromium(VI), and 88:12 (32%) analysis of A->-3-one: A^-3,6-dione (% Sterol) was obtained. Thirty minutes with a 1:1 mole ratio of pyridine:CrO, afforded an 89:11 (7%) analysis. - 177 -

0 0

Crv-ef H

I R' R 506b 508

strong bases, even those which do no co-ordinate chromium(VI), cause a substantial reduction in the amount of oxidation that occurs. If the hydroxyl proton was removed from 506b, the resultant dioxy dianion should abstract a proton faster in the depicted transition state.

In the case of transition state 506a a dioxy dianion would discourage the depicted cyclic concerted process because of its requirement for an electron deficient chromium (241^).

A second point worth consideration is the rate of oxidation. In

Table IVb there is an indication that as the amount of pyridine is increased either the yield of enedione product rises or the amount of recovered cholesterol increases. This amounts to the same thing, that is, that the rate of oxidation of cholesterol decreases as more and more pyridine is added. A more explicit demonstration of this was provided by performing Collins oxidations for short intervals and analyzing the reaction mixture. Below are the results obtained by dissolving cholesterol (1.0 mmole) in dichloromethane (5 ml) and a

second solvent (10 ml of "co-solvent"), cooling to 0° and adding the

sterol to the listed oxidant (6.0 mmoles) in dichloromethane (25 ml)

at 0°. The analyses were determined for three minute reaction periods - 178 -

and give the product ratio of cholest-5-en-3-one (334) to cholest-

4-ene-3,6-dione (480) with the percentage of unreacted cholesterol

(331) in parenthesis. The fourth reaction was included to show that acetic acid-chromium (VI) oxidations are much slower than dipyridine-

chromium(VI) oxidations in the presence of acetic acid.7^

"Co-solvent" " Oxidant" "Analysis"

Dichloromethane Cr03'(Pyridine)2 90:10 (35%)

Pyridine Cr03(Pyridine)2 100: - (98%)

Acetic Acid Cr03(Pyridine)2 93 : 7 (48%)

Acetic Acid Cr03 100; - (92%)

75 Several years before Collins et al. employed dichloromethane, Stensio and Wachmeister (243^) found that acetic acid was a useful solvent for the in situ generation of the complex 508. Oxidations in acetic acid could be easily performed on either a semimicro or preparative scale. An example of the latter was Theander's work in 1964 on the oxidation of i + (Sarett oxidation failed) (243c). However, since the general yields by Stensio's procedure of employing a 1:3.5 ratio of alcohol to oxidant tend to be 10-20% lower than Collins' method with its 1:6 mole ratio, acetic acid is rarely employed as a solvent. One possible useful exception is that Stensio found cholesterol was oxidized to cholest-4-ene-3,6-dione in 85% by his procedure (242a),

°s/y°\ iR = 0H,R' = H RA_7'X iiR,R'=0 R' 0-j- - 179 -

Obviously, pyridine dramatically slows the rate of oxidation

76 ' while acetic acid has little effect. Collins et ai. (227) have observed a similar, but smaller rate difference in the oxidation of

2-octanol in dichloromethane (Collins) compared to its oxidation in pyridine (Sarett) for a one hour period. The most readily available explanation of this behaviour employs the fact that the equilibrium

508 (n)

507 . 517 represented by (n) lies far to the right. If the alcohol to be oxidized only reacts with the monopyridine complex (507), the rate of oxidation could be severely retarded. However, even if the alcohol can react with the dipyridine complex 508, there is a second and much better reason for excess pyridine slowing down the oxidation.

When small quantities of an amine base were introduced to the

sterol being oxidized, the unexpected results listed in Table IVc were obtained. As the amount of triethylamine (pK + = 11.0) or

diisopropylamine (pKT3U+ = 11.0) (233^) was increased, the amount of Dei cholesterol recovered rose dramatically. By literature precedent,

Stronger acids may play a more significant role since protons are obviously important to the transition state 506a. Corey and Suggs (232^) have very recently demonstrated this point with pyridinium chlorochromate. This reagent, formed with chromium trioxide and pyridinium hydrochloride, has been found to be four times as efficient as the dipyridine complex. - 180 -

Table IVc Influence of Amine Bases on the Collins Oxidation of Cholesterol.

a Reaction—Base Oxidant/Alcohol Average Product Ratio (Base/Sterol Ratio) Mole Ratio 334 -.480 (%331)

1 Triethylamine (1) 6 90 -.10 (5 %) 2 Triethylamine (2) 6 93 : 7 (20%)

3 Triethylamine (3) 6 85 :15 (75%) 4 Triethylamine (5) 6 83 :17 (91 %)

5 Diisopropylamine (2) 6 91 : 9 (7%) 6 Diisopropylamine (4) 6 75 -.25 (63%)

7 1,8-bis-(dimethyl- (0.5) 6 95 : 5 (51%)

8 amino)naphthalene (10) 6 78 -.22 (75%)

Notes a For details see Androstenone 240 experimental .section (ii) of (c)

this trend is all wrong since Westheimer, in 1951, reported that i the oxidation of diisopropyl chromate to acetone was catalyzed

instantaneously by the introduction into the reaction medium of a 77 small amounts of pyridine or dimethylaniline (242 ).

The possible argument that the alkyl amines are forming a non-

reactive complex is untenable for several reasons. First, entry

To the best of our knowledge this effect of bases on the Collins oxidation has not been reported previously. A possible literature precedent does exist however. In the field of paint and lubricant engineering, organic chromate esters have been stabilized by amines to act as antioxidants. This work, done primarily in eastern Europe and Russia, has used such bases as guanidine, cyclohexylamine, dicyclohexylamine, isobutylamine and hexanediamine to reduce corrosion (245). - 181 -

three for triethylamine should lead to no more than 50% recovered cholesterol, instead of the 75% observed, if an equivalent amount of chromium trioxide was tied up by the base. Second, the hindered

base l,8-bis(dimethylamino)-naphthalene (pKBH+ = 12.3) (244) leads to an even more inexplicable result. How can one millimole of 78 this aryl base block the oxidation by almost six millimoles of chromium(VI)?

Consideration of the colour changes that were observed in all the reactions listed in Table IVc indicates that chromate ester formation is taking place. Evidence was later obtained from a related oxidation, Corey's method of employing dimethylpyrazole in place of pyridine, that chromate ester formation is almost complete even in those cases where enough amine is present to prevent any oxidation from occurring. In any case, it is very difficult to see how the very fast chromate ester formation step could be stopped by a base, especially by such a sterically restricted base as 1,8-bis(dimethylamino)naphthalene or

"proton sponge". However the postulated intermediate 506 is capable of being completely deprotonated as the concentration of free uncomplexed base rises. As the amount of proton sponge increases to about one equivalent of sterol, the equilibrium 506 -> 509 is shifted well to the right. As the amount of alkyl amine is increased to approximately five

78 Besides having a remarkable basicity, bis(dimethylamino)naphthalene, or "proton sponge", has been shown to be a very poor nucleophile. Alder et al. (244) recovered it unchanged after four days at reflux with ethyl iodide in acetonitrile. For the purpose of Table IVc, proton sponge, unlike the alkylamines, was demonstrated to be unable to form a complex with chromium trioxide. Therefore the above question should be rephrased to read "How does a very hindered base behave more effectively in blocking oxidation than one that can complex chromium(VI)?" - 182 -

f >3NH f

\=/ /V, / f \=/e/v / o o-c ' °o o-c / / \ , K3N / \ H R R" R R' 506 509 equivalents, this same shift occurs. It is therefore not surprising that a weaker base like pyridine can cause partial deprotonation that leads to noticeable product changes when approximately thirty or more excess equivalents of pyridine are employed. The preceding explanation indicates why the Sarett oxidation is both catalyzed and poisoned by pyridine and why the oxidation rates are observed to be very slow in the Sarett reaction.

An experiment particularly relevant to the topic of base-acid effects on the Collins oxidation was provided by g.l.c. monitoring of the oxidation of 33-hydroxyandrost-5-ene. When this sterol (1.0 mmole) was added to dipyridine-chromium(VI) oxide (6.0 mmoles) and proton sponge (0.3 mmoles), the oxidation gave a 1:1 mixture of starting material to cholest-5-en-3-one within fifteen minutes. This ratio remained unchanged until acetic acid (3.5 mmoles) was added.

Within thirty minutes, no sterol chould be detected and the usual product mixture of cholestenone and cholestenedione was obtained on workup. - 183 -

Corey Oxidations of Cholesterol

At this point, a short study of the general oxidative method

introduced by Corey and Fleet in 1973 should be considered. They

reported that a 1:1 complex of chromium trioxide — 3,5-dimethyl-

pyrazole in dichloromethane serves as a suitable reagent for oxidizing

alcohols to carbonyl compounds (232 ). In one of their examples, a

2.5:1 mole ratio of complex to 4-_t-butylcyclohexanol was found to

yield 98% 4-t-butylcyclohexanone after thirty minutes at room temperature.

This reagent was consequently employed on cholesterol and the results

were tabulated in Table VI. In the standard oxidation, cholesterol

Table VI Chromium Trioxide -Dimethylpyrazole Oxidation of Cholesterol in Dichloromethane ("Corey")

Oxidant/Alcohol Average Product Ratio Reaction-Changes Mole Ratio 334; 480 (%331)

1 Standard 3 50:50 (20%)

2 Standard 2 52 :48 (35%)

3 Standard .1 45 .55 (65%)

4 Reaction at 0° 3 60 :40 (37%) 5 Reaction under Nitrogen 3 59 :41 (26%)

6 Water(2mmole) Addition 3 50:50 (25%)

7 1,8-Bis(dimethylamino)naphthalene(05 mmole) 3 38 :62 (90%)

8 Triethylamine (1.0 mmole) 3 40 :60 (49%)

Notes a For details see Androstenone 240 experimental, section (ii) of (c). - 184 -

(1.0 mmole) in dichloromethane solution (50 ml) was treated for thirty

minutes at room temperature with the indicated amounts of oxidant

(1.0, 2.0, or 3.0 mmoles). The results indicate that the Corey

procedure is more comparable to the Snatzke oxidation than to the

Collins. There is no precipitation of chromium salts in the dimethyl-

pyrazole reaction and the addition of water has little effect on the

efficiency or outcome of the oxidation. Also while Table V, with its

synopsis .of the results of performing Collins and Corey reactions on

Table V Oxidations with Chromium Trioxide-Nitrogen Base Reagents.

Compound0" Oxidation Conditions (%Mass Recovery)0 478:480 (% 334)

Cholest-5-en-3-one (334) Standard Collins (70%)b(66)c 2 : 98 (15 %)

II b Collins without Cr03 (99%) -: - (100%)

II Standard Corey (77 %)b 5:95 (45%)

II Corey without CrOa (94%)b 100: 0 (98 %)

Cholest-4-ene-3,6-dione 14_8_Q.) Standard Collins (96%)(75%)c 0: 100

II Standard Corey (74%) (69%)c 0:100

Cholest-4-en-3-one (478) Standard Collins (92%)(85%)c 96: 4

II Standard Corey (85%)(78%)c 93:7

Notes Non-acidic materia! isolated after oxalic acid isomerization except for 334 .

b Neutral workup employed (NaHC03). c Quantitative measurement with internal standard. ^ For details see Androstenone experimental (c) (ii). - 185 -

cholest-5-en-3-one, cholest-4-en-3-one and cholest-4-ene-3,6-dione illustrates that dimethylpyrazole causes little isomerization of cholest-5-en-3-one, the Corey oxidative complex gives extensive oxidation of both cholest-5-en-3-one and cholest-4-ene-3,6-dione. Dimethyl• pyrazole is only a weak acid by equilibrium (o) below, but the oxidant complex , formulated as 512, should be a much better proton source for

the enolization of compound 334.

From the point of view of homoallylic alcohol oxidation, Corey's 79 ' procedure can be dismissed, since, from Table VI, the highly coloured product mixture tends to be a 1:1 ratio of enone to enedione plus substantial amounts of recovered sterol. However the results in

Table VI are very useful from a mechanistic viewpoint. Corey and Fleet postulated that the 3,5-dimethylpyrazole complex could be represented as 512. The oxidation was thought to proceed by the cyclic, intra• molecular course depicted in 513 after the oxidant complex 512 had combined with an alcohol to form the chromate ester complex 513 (232 ). 79 Other recent procedures can also be dismissed. Halogen attack on the double bond eliminates oxidations by bromine and silver salts (246a), 1-chlorobenzotriazole (246^), the dimethyl sulfoxide- chlorine complex (246c) and the dimethyl sulfide-chlorine complex (246^). Oxidations with sulfoxonium salts (246e), sulfur trioxide (246^) or chromic acid in dimethyl sulfoxide at 70° (240) do not appear to compare favourably with the Collins or Snatzke oxidations. - 186 -

,N—Cr—OH 513

512 R

This postulated oxidative mechanism appears untenable from the results

in Table VI. The addition of a base such as triethylamine should,

if anything, enhance the formulated oxidation, not restrict it. The

behaviour of 1,8-bis(dimethylamino)naphthalene also is unaccountable

on the basis of 513 representing the transition state. How can

one-half millimole of proton sponge prevent one millimole of sterol

from being oxidized by three millimoles of oxidant? If the controlling

factor of the oxidation is the electron deficiency of the chromium in

the chromate ester, the equilibrium represented by 514a and 514b may

514 a 514 b

be the crucial intermediate . There are several examples known of the

monohapto-pyrazole ligand exhibiting strong iminohydrogen bonding to

the counterion of transition metals (247). The oxidant complex 512

could serve as the proton source while the introduction of free bases

would buffer the reaction medium. The free amines would cause either - 187 -

minimization of the concentration of 514 or shorten its lifetime

sufficiently to prevent the depicted hydrogen shift in 515. In any

case, the Corey dipyrazole reaction, like Collins dipyridine oxidation, 80 has a proton dependence in the transition state.

RR C = 0

515

Interesting results were provided by g.l.c. monitoring of amine blocked Corey oxidations of 33-hydroxyandrost-5-ene. Using only short exposures to workup conditions, most of the sterol was recovered as its chromate complex rather than as the free alcohol when either a water quench or hydrochloric acid (3.0 N) quench was used. If saturated bicarbonate was used in the workup, the free sterol was recovered. Using an internal standard in the oxidation confirmed that at least 80% of the free sterol disappeared within the first five minutes. In the presence of an amine base, no reaction products were observed, even after seven days, although most of the free alcohol had disappeared with minutes of being added to the reaction. This suggests that alcohols rapidly form chromate esters, even in the

The cyclic transition state employing a planar concerted reaction is currently favoured (248) but the requirement that one of chromium's oxygens be protonated is ignored. Our transition state 515 differs from the suggested reaction in 513 in that the pyrazole nitrogen "protonates" the transition state rather than abstracts the carbinol hydrogen. - 188 -

presence of large amounts of amine, and that these esters can be

hydrolyzed on workup without any perceptible side reactions.

Consideration of the Collins and Corey oxidations in more

general terms leads directly to the concept of a monoamine-chromate

ester transition state. Since dimethylpyrazole (pK,,,,^ ^ 3) led to a Dn

product distribution so different to that of pyridine (pKg^+ = 5.25),

the effect of other pyridine analogues was considered. Table VII

lists the results of oxidizing cholesterol (1.0 mmole) with anhydrous

chromium trioxide (6.0 mmoles) and a pyridine derivative (6.0 mmoles)

for thirty minutes at room temperature. While the results show less

variation over a ApK.^4. of 2% units than was observed between pyridine

Table VII Effect of pKBH+ on "Collins" Oxidation of Cholesterol-

Average Product Ratio

0 Reaction-Bases Base's pKBH+ 334:480 (%331)

1 Quinoline (516) 5.00 85:15 (34%)

2 Pyridine (51Z) 5.25 88:12 (3%) 3 4-Methylpyridine (518) . 6.02 75 :25 (2%)

4 2,4-Drmethylpyridine (519) 6.99 79 ;21 (3%)

5 2,4,6-Trimethylpyridine (520) 7.43 80:20 ( 31%)

Notes0 For details see Androstenone 240 experimental, section (ii) of (c). - 189 -

and dimethylpyrazole, they demonstrate that the monopyridine complex

affords the most desirable product distribution. While the alkyl-

pyridine complexes always formed completely within thirty minutes, they

are not stable to storage. The trimethylpyridine complex lost ^50% of its

activity after a one day period, probably due to aldehyde formation

(256). The quinoline complex is formed much more slowly than the others

and it was stirred for three hours before being employed. It is worth

516

51Z R2= R6= R4= H

= = 518 R2 Rg H,R4-CH3 521

519 R2= R4=CH3,R6=H

520 R2= R4= R6= CH3

noting that N,N-dimethylaniline (521) (pKBH+ = 5.2) was found to be unable to complex chromium trioxide and to afford a -:- (100%) product analysis when it was employed under Table VII conditions.

While experimental work could, and should, be extended to other amine bases, the original objective of undertaking a study of the

Collins oxidation has been accomplished. Table VII completes the work on circumventing the production of the enedione product from the homoallylic alcohol. While this table represents the final parameter modications that were experimentally considered, it also leads directly into a short but worthwhile digression. Having come this far with chromium trioxide oxidations and the implications of the pK^+ of amines, possibly the best footnote to this discussion is a literature summary of some analogous work. - 190 -

Amino Alcohol Oxidations

If the original undertaking on the homoallylic alcohol oxidations has led to anything of general synthetic interest apart from a procedure for A^-3-keto steroid preparations, it is an explanation of the difficulty in oxidizing alkaloids. Often amino alcohol inter• mediates need to be converted to the corresponding carbonyl containing amino acids or alkaloids. The Oppenauer oxidation is usually chosen for this transformation, but its unreliability is demonstrated by its failure to oxidize the benzylic alcohol in the amine 522 (249). In the case of the Sarett oxidation, employing a 2.6:1 ratio of oxidant to alcohol gave approximately 50% 523 after one day. The employment of chromate oxidations is hindered by several misconceptions of the

522 R1 = H, R2= OH 524 H, Rg= OH, R = C0CH3

523.R1=R2= 0 525, R^R^O, R3=C0CH3 problems involved. The first of these is that the basic nitrogen ties up the chromium trioxide and thereby prevents oxidation. As demonstrated earlier by Table Vic, it is the basic nitrogens that are not complexed to chromium that result in the oxidation being retarded. In any case, the literature solution to this problem has been to employ the amide or lactam derivative of the original amino alchol in the chromium(VI) oxidation. Examples of this include the - 191 -

primary amine diol intermediate, protected as its amide 524, for the

Jones or Sarett oxidations in Wiesner's synthesis of the C-18

diterpene alkaloid 525 (250 ). The lactam functionality serves to

deactivate the di- and tri-substituted nitrogens in the work by

Salley (526 ->• 527) (250b), Augustine (528 ->• 529) (250b) and Wiesner

(530 -+ 531) (250d).

52& R1 = H,R2=0H 530 RT= H,R2=0H

529 R,= R2= 0 53L R1 = R2= 0

The rationale given for deactivating the nitrogen was not that it removed the basicity, but that "the lactam group protected the nitrogen from oxidation" (250^). This brings forward the second misconception of the relative rates of oxidation. Amines are converted to amides or lactams by chromic acid (251) and although this reaction has been - 192 -

known for some time, it has only recently been used synthetically.

In 1974, Corey and Balanson, in the total synthesis of (±)-porantherine

(532) (252), employed ten equivalents of Collins reagent in dichloro• methane for three days to afford 534 from 533 in 80%. Since an alcohol

532

533 R = CH3 534 R = CHO oxidation would be quantitative within ten minutes under these conditions, it is apparent that amine oxidations are many orders of magnitude slower than alcohol oxidations. Therefore, it is obvious that on the basis of kinetic rates, alcohols should be selectively oxidized in the presence of amines. The reason they are not is due to the "proton sponge" problem. When acetic acid was used earlier to overcome this difficulty, the oxidizing ability of the chromium trioxide reagent was found to be unimpaired by the presence of the amine.

In looking for literature confirmation of these ideas, the hexavalent chromium oxidations of the hydroxyl in the secondary a b amine 535 (253 ) and the tertiary amine 537 (253 ) were of some interest, but were not completely pertinent. Allylic and benzylic - 193 -

535 H,R2- OH 536 R2= 0 537 R1 = H, R2= OH

538 Rn = R2= 0 alcohols have a much lower activation energy for oxidation and their transition state requirements are quite different to those of 81 unactivated alcohols. However the elucidation of the salamander alkaloid cycloneosamandione (541) by Schbpf and Miiller (257a ) involved the reoxidation of the unactivated diol derivative, neosamandiol (539), with chromium trioxide. An 88% yield of cycloneosamandione was

In the case of the indole alcohols 535 and 537, a Sarett oxidation only required ten minutes to provide 76% and 82% yields respectively of the 2-acyl alkaloid 536, as its carbinolamine, and the N- acyl-indole 538. When the secondary amine of 535 was deactivated with the benzyl group (-CH^C^H,^) , the yield went to 90%.

The indole nitrogen has a very low basicity (pKgH+ for indole is ^-3) and when it protonates it is at C-3 and not at the indole nitrogen (254) . Therefore the oxidation of i_ to jii in 70% by the Collins method (255) is actually the oxidation of an allylic alcohol that contains a completely deactivated nitrogen base.

H 2 - 194 -

g^R^R^H 543 R1 = R2= H obtained by adding the theoretical amount of 0.2 N aqueous chromium

trioxide to a 3% sulfuric acid solution of 539 on a steam bath.

They also found the reoxidation of the corresponding C-16 alcohol

(540) to cycloneosamandione was essentially quantitative by this method. When Habermehl and Haaf later synthesized cycloneosamandione,

they imployed the same oxidation very successfully (257^). They also

reported (257 ) a quantitative oxidation in converting the model

compound 542 to 543 by this same procedure. The 19-oxo-3-aza

functionality cannot be isolated as such since it immediately forms

the cyclocompound with the carbinolamine group.

At this date, these publications appear to be the best (and

only?) literature examples of amino alcohol oxidations with chromium

trioxide where acid was used to overcome the detrimental pK.^4. effect

of the amine. - 195 -

Synthetic Applications

Putting mechanistic considerations aside and returning to the original synthetic objective, androst-5-en-38-ol (474) was oxidized for thirty minutes using an 8:1 mole ratio of oxidant to alcohol with monopyridine chromium(VI) oxide in dichloromethane at 0° in a nitrogen atmosphere. After a workup that included oxalic acid isomerization of the unconjugated ketone, the use of Claisen's alkali to remove any enedione, and a short path distillation, a 75% yield of androst-4-en-3-one (240) was obtained. This represents a 73% overall yield of the 'octalone' 240 from 38-hydroxyandrost-5-en-17-one.

If instead, the sterol 474 was oxidized for fifteen minutes with a 4:1 mole ratio of oxidant:alcohol using a 3:1 mole ratio of sulfuric acid to chromium trioxide (acidic "Snatzke"), a 65% yield of pure androst-4-ene-3,6-dione (493) was isolated. While this latter procedure has merit in preparing enediones, the limited availability 82 of the homoallylic alcohol precursors initially appeared to restrict the scope of the reaction. However, while the corresponding conjugated ketone was shown to be practically inert to the Collins and Snatzke oxidations, the B,Y_unsaturated ketone is oxidized by either procedure to the enedione (Tables Illb and V). Of more general significance, it was found that the dienol ethers of conjugated ketones, but not the corresponding dienol acetates,were very readily converted to their respective enediones by either the Collins reagent or the Snatzke 82 Tsui and Just (258) have reported that epoxidation of homoallylic alcohols followed by a Sarett oxidation also leads to enediones. Both isomers of 5B,6B-epoxycholestan-3-ol were converted to the same A^-3,6-dione by an overnight Sarett oxidation. - 196 -

reagent. For example, the Collins oxidation of 601, the methyl dienol ether of testosterone, did not give 602 but gave instead the

601, Rt= H R2= OH 0 544

602 Rr R2- 0 enetrione 544 as the major product. When compound 601 was oxidized

4 with the Snatzke reagent, it was found that the A -3,6-dione functionality was introduced even faster than the C-17 carbonyl and the enetrione

544 was again the major product.

455 Rlf R2=CH2 454 Ru R2= CH2 547 R1 , R2=CH2

238 R = H,R=CH3 546 R1=H,R2=CH3 548 R,=H,Ra=CH3

Extending this method,octalones 234, 455, and 238 were found to be converted quantitatively to their respective enol ethers (545, 454,

546) by treatment with 2,2-dimethoxypropane and p_-toluenesulfonic acid in dimethylformamide (200) for four hours. A Snatzke oxidation then - 197

afforded the enedione derivatives in good yield 83 Androst-4-en-3- one (240) and cholest-4-en-3-one (478) were also converted to their 4 respective A -3,6-dione derivatives (493 and 480) by this general procedure.

472 562

In addition to the oxidation of dienol ethers to enediones, the

Snatzke method also can be used to great advantage in the oxidation 84 of aliphatic alcohols. A Snatzke oxidation with a 3:1 mole ratio

83 One attractive application is to use 547 as an intermediate in the preparation of the sesquiterpene synthon JL. Taking 547 and sesquentially reducing the C-l double bond, isomerizing the other double bond with H (exo-C-5 -> C-6,7) and eliminating the saturated ketone would provide jL. Compound 455 was previously prepared in 95% overall yield by the sequence 240 453 -»- 454 455 (page 131).

84 This was not optimized but the corresponding oxidation by Collins method provided 98% of compound 562 from testosterone (472) using a 6:1 mole ratio of anhydrous oxidant to alcohol (optimized). - 198 -

of oxidant to alcohol afforded a 97% yield of the enedione 562 from

testosterone (472). The advantages of the underutilized Snatzke procedure are even more apparent in the oxidation of primary alcohols

to aldehydes. Using a 1:2:3 millimole ratio of alcohol:chromium

trioxide:sulfuric acid in dimethylformamide (15 ml), octadecanol

CH3(CH2)16R 549

(549, R = CH2OH) could be oxidized to octadecanal (549, R = CHO) in

over 90% yield. Commercial (hydrated) chromium trioxide was employed

but little stearic acid (549, R = COOH) was produced. The simplicity

of the Snatzke reaction is also attractive. After a thirty minute

reaction period at room temperature, the oxidation was quenched with

bicarbonate and partitioned between water and petroleum ether. The

dried organic layer was concentrated to afford the aldehyde as a white

solid. This corresponding Collins oxidation of octadecanol would

need three times as much oxidant and require anhydrous chromium trioxide. - 199 -

Androstenone 240 from Testosterone (472)

Literature Precedence

The simplest and most obvious way of transforming testosterone

to androst-4-en-3-one is to protect the C-3 carbonyl as its ethylene ketal, oxidize the C-17 hydroxyl to a carbonyl and then remove the

latter functionality via a Wolff Kishner reduction. This sequence appeared to be particularly attractive since we had previously performed these reactions individually on other compounds in a nearly quantitative manner. Also, the literature precedent for successfully

reducing keto ketals with hydrazine and base was excellent. Usually

either the method of Huang-Minion employing potassium hydroxide with

85% hydrazine hydrate (210), or that of Barton utilizing sodium

diethylene glycolate with anhydrous hydrazine (173), was followed. In

1962, Johnson and his coworkers (259) reported that the ethylene ketal

group was stable to the Huang-Minion conditions for the Wolff Kishner

reduction. They achieved a 71% yield of epimeric 551 from 550. Over

the years, a large number of substituted bicyclo[4.4.0]decanone ketals

have been reduced with hydrazine and then hydrolyzed on workup to

provide the corresponding decalones in 60-80% (260). In the steroid - 200 -

field, Nagata et al (261°) obtained an 88% yield of j>53 from 552 while Johnson et^ aL (261b) realized a more mediocre 63% 555 from 554.

However the most encouraging literature precedent was the removal of

C-17 hydroxyl by the sequence 556 through to 560. Jones and Zander

HO' 552 R = CH0 554 R =CH = NH

3 553 R=CH3 555 R=CH

R2R1

556 X=0 558 R,= R2= 0, X=-0CH2CH20-

559 R,= R2= H,X 2CH2 557 X=-0CH2CH20- =-0CH 0-

560 R,= R2= H,X=0

(262) successfully removed the 178-hydroxyl from both A-homo-5a- androstan-3- and -4-one by protecting the saturated carbonyl, introducing and then removing a C-17 carbonyl, and then regenerating the A-ring ketone. In the case of 3-keto alcohol 556, the ketal 557 was obtained in 86% by the Salmi procedure, the Moffat oxidation with dicyclohexyl- carbodumide provided 90% 558 ,the Huang-Minion reduction yielded 89% - 201 -

559 and an acid hydrolysis afforded 96% of the desired 3-keto steroid

560. The overall yield of A-homo-5a-androstan-3-one was 66% while an

analogous sequence gave 45% A-homo-5ot-androstan-4-one overall from

17 B-hydroxy-A-homo-5a-andros tan-4-one.

Curr ent Synthetic Work.

Therefore, while testosterone had not been previously utilized

as a precursor for androst-4-en-3-one, the required experimental

manipulation seemed almost trivial. The Salmi dioxolanation procedure uses a water separating apparatus (Dean-Stark) (263 ) to partition the

water-benzene azeotrope produced by refluxing a benzene solution of

p_-toluenesulf onic acid, ethylene glycol and ketone. When testosterone

(472) was subjected to this reaction, the product was found by n.m.r. 85

and infrared spectroscopy to be a mixture of the ketal 561 and

recovered starting material. Even after prolonged periods with refluxing Dean and Christiansen (263a) have postulated the sequence jL •+ v for unconjugated ketones being ketalized with ethylene glycol. They have demonstrated that the A^-3-ketal (iv) is isomerized by acid to its A -isomer. The A^-3-keto steroids usually, but not always (264), afford the unconjugated ketals when p-toluenesulfonic acid is employed. The A^-3,3-eth.ylenedioxy product is favoured by the employment of weaker organic acids (oxalic, (COOH)2 or adipic (0^)4 (COOH) 2) (263^) or small amounts of the much stronger p-toluenesulfonic acid (263a).

A4-3-ketal 4H + iv v - 202 -

benzene or toluene, the crude product contained 'v 20% testosterone.

The original work by Antonucci et al (265 ) reported ^ 50% yield of the ketal 561 after three and one-half hours in refluxing benzene and,

even twenty years ago, the saturated 3-keto steroids, which afforded 4

>85% dioxolanation, were contrasted to the A -3-keto steroids, which

afforded <65% conversions (266a).^^ Campbell et al (265^) utilized a

vacuum distillation of ethylene glycol from a 90° solution of testosterone

and catalyic p-toluenesulfonic acid in a large excess of ethylene

glycol to obtain a 75% yield of 561 that was 96% pure. Liston and Toft

(225) later employed this vacuum distillation method on 2a-methyl-

testosterone to obtain a 74% yield of the corresponding A^-3,3-ethylene-

dioxy derivative. Application of Campbell's procedure to our work

gave disappointing results but fortunately an even better literature

alternative was found. Dauben and cowo rkers (266 ) developed a method

of preparing ethylenedioxy derivatives by exchange dioxolanation. In

86 The contention that the oily byproducts of the conjugated ketones were the result of enol ether formation was investigated. Close scrutiny of the n.m.r. spectrum of the crude reaction product showed little enol ether was in the mixture. Enol ethers would be expected to survive the bicarbonate workup. - 203 -

this approach, the ethylene glycol portion of simple 2,2-dialkyl-

1,3-dioxolanes is transferred to the steroidal ketones by acid 87 catalysis in a refluxing inert solvent or excess reagent. Using this technique, they ketalized testosterone with 2-ethyl-2-methyl-l,3- dioxolane and obtained 75% yield of the ketal 561. Of much greater significance was their observation that exchange ketalization, unlike direct ketalization, could introduce the ethylenedioxy functionality selectively at C-3 without affecting the C-17 carbonyl. That is, that androst-4-ene-3,17-dione (562) could be directly converted to the desired monoketal 563 in 74% yield. Since this compound (563) could be much more readily crystallized from the enedione 562 than the ketal

561 could be from testosterone, and since the exchange ketalization was found to be a much cleaner reaction, Dauben's approach was followed.

Djerassi and Gorman (266b) extended Dauben's exchange dioxolanation reaction to 1,3-oxathiolanes (2,2-dimethyloxathiolane or cyclic ethylene hemithioketal of acetone, i_ Y=S) and 1,3-oxathianes (2,2-dimethyloxathiane or the cyclic trimethylene hemithioketal of acetone) and also demonstrated that cyclic thioketals would not undergo exchange. The generalized exchange reaction was formulated to proceed via the intermediacy of IJL, formed from the nonvolatile ketone R2C = 0 and the 2,2-dialkyl-l, 3-heterocycle i_. By Dauben's procedure, 2-butanone is usually distilled from the reaction while in Djerassi's work the equilibrium shift was accomplished by removing acetone.

R?C = 0

y R*CCH ii II 0 (Y = 0,S

R*= CH3,-CH2CH3) - 204 -

As discussed earlier, testosterone (472) could be oxidized almost quantitatively (98%) to the enedione 562 by a chromate oxidation with the Snatzke or Collins reagent. The exchange dioxolanation with j>- toluenesulfonic acid and purified 2-ethyl-2-methyl-l,3-dioxolane in refluxing toluene afforded the expected monoketal, free of bisketal and starting material, in 53% yield. Based on the enedione recovered by acid hydrolysis of the crystallization mother liquors, the yield rose to 88% or 86% overall from testosterone. This compound was idential to the one obtained by oxidizing testosterone ketal (561) with Collins reagent and exhibited the literature physical and spectral properties reported for 3,3-ethylenedioxyandrost-5-en-17-one (563).

The Wolff-Kishner reduction of compound 563 was accomplished using

Barton's procedure (173) with anhydrous hydrazine and sodium diethylene glycolate in refluxing diethylene glycol. The hydrazone was formed at 170° in the usual way and then decomposed by heating at 210° overnight (fourteen hours). After workup, a viscous oil was recovered

and shown to lack a carbonyl absorption in its infrared spectrum and

to have a diminished ethylenedioxy absorption in its n.m.r. spectrum. - 205 -

The removal of the ketal was accomplished by acid hydrolysis and the crude product was chromatographed on activity III alumina to afford androst-A-en-3-one (240). The yield, hoever, was a dismal 15%I The reaction was therefore repeated employing the Huang-Minion method (210) with 85% hydrazine hydrate and potassium hydroxide in refluxing diethylene glycol. The prerequisite hydrazine was formed over a two hour period and then the reaction temperature was raised to 195° and left refluxing for eight hours. After workup, acid hydrolysis, and column chromatography, androstenone 240 was isolated in 30% yield. The ethylene ketal, contrary to "literature precedent", was obviously being destroyed under both the Huang-Minion and Barton reaction conditions.

The other chromatographic fractions from both reactions were examined in an attempt to understand what was occurring. The material isolated from the column before ketone 240 was eluted was demons'trated by n.m.r., infrared, and mass spectroscopy to be an isomeric mixture of two or more mono-olefins. Hydrogenation with tris(triphenylphosphine)-

chlororhodium in benzene (113) or palladium on charcoal in perchloric-

acetic acid (207) failed to saturate this mixture. However allylic

oxidation with Collins reagent (177) did afford up to 60% androst-4-

en-3-one with a small amount of androst-4-ene-3,6-dione as a side

product. Since no other ketone products were observed, these results

suggested the mono-olefin mixture consisted of 3- and 4-androstenes.

Dauben et_ a_l (177) have demonstrated that allylic oxidations with

Collins reagent at allylic methine positions usually yield the isomeric

enone. - 206 -

After some difficulty, the olefin mixture was resolved by gas 19 liquid chromatography into a 2:1:1 ratio of three components. The first and major one was assigned the structure 564 from the following observations. The infrared spectrum of this compound, with olefinic bands at 3020 and 681 cm \ corresponds very closely to that reported for 58-cholest-3-ene (3015, 679 cm"1) (152) but not at all to those reported for 5a-cholest-3-ene (3012 and 671 cm ^), 5a-cholest-2-ene

(3017 and 664 cm"1), or cholest-4-ene (810 cm"1) (152,268). The n.m.r. spectra of 564 exhibits methyl singlets at x 9.04 and 9.29 and two downfield olefinic protons centered at x 4.34 and 4.67, the latter pair exhibiting a mutual coupling constant of 10 Hertz. Cholest-2-enes are known to show only a simplified olefinic multiplet while cholest-

3-enes have two unequivalent protons coupled by ^ 10 Hertz (268).

However, 5a-cholest-3-ene has been shown to have angular methyl resonances at x 9.26 and 9.34 (268), thereby eliminating 5a-androst-3- 88 ene from consideration. The structure proposed on the basis of spectroscopic evidence was confirmed by the reduction of 564 to

58-androstane and the oxidation to androst-4-en-3-one (240). The hydrogenation was performed over platinum oxide catalyst to yield the saturated hydrocarbon in 98%. This product's physical properties gg Few members of the androstene family of olefins have been reported but consideration of the cholestene analogues is helpful. For 19 18 example, 5a-androst-2-ene exhibits C H3 at x 9.23 and C H3 at 9.29 (270) while 5a-cholest-2-ene has its methyl resonances at 9.25 and 9.35 (268); androst-4-ene shows x 8.97 and 9.27 (see experimental) and cholest-4-ene is reported to be 9.01 and 9.33 (268). Therefore 5a-cholest-3-ene, with x 9.26 and 9.34 (268), compares too unfavourably with the first component (x 9.04 and 9.29) to consider assigning it the 5a-A^ structure. - 207 - correspond to 53-androstane' s, 565, with reported m.p. 78-79° and

C-19 methyl resonance at x 9.08 by n.m.r., rather than those of 5a- androstane, m.p. 50-52° and C-19 methyl appearing at T 9.21 (269,271).

The second component isolated by gas liquid chromatography had an olefinic infrared absorption at 810 cm with little or no absorption above 3000 cm \ and n.m.r. tertiary methyl resonances at

T8.97 and 9.27. This spectroscopic data bore such a close analogy to that reported for cholest-4-ene that an authentic sample of androst-

4-ene was immediately prepared from androst-4-en-3-one. Overnight treatment of ehohe 240 with 1,2-ethanedithiol and boron trifluoride etherate in acetic acid (272) gave a quantitative yield of 3,3- ethylenedithioandrost-4-ene (566). Desulfurization for twelve minutes

EL with Raney nickel in refluxing ethanol (273 ) afforded an 80% yield of the desired olefin 567. This compound had the same spectroscopic properties as the second component of the olefin mixture and enhanced the g.l.c. chromatogram of the second peak upon coinjection.

Hauptmann (274) has shown that no rearrangement of the double bond is involved in a sequence of the type 240 ->• 566 -> 567. - 208 -

240

The third component showed olefinic C-H bands at 3020 and 671 cm in its infrared spectrum and methyl singlet resonances at T 9.20 and

9.28 in its n.m.r. spectrum. As for 564, a close analogy could be made between 568 and cholest-3-ene, in this case 5a-cholest-3-ene.

When this third compound, 5a-androst-3-ene, was hydrogenated in ethyl acetate over platinum oxide, 5a-androstane (569) was the single product isolated in 95% yield (269). - 209 -

Literature Revisited

Determination of the structures of the Wolff-Kishner olefinic products permitted an assignment of a plausible reaction mechanism.

If a base catalyzed fragmentation of the dioxolane group occurred as depicted in the partial structure 570 (121), the resulting unconjugated ketone 571 would be isomerized rapidly into conjugation and then reduced via the Wolff-Kishner reduction to a mixture of olefins.

Conjugated ketones are known to give olefin isomers (275) and when androst-4-ene-3,17-dione (562) was subjected to treatment with hydrazine and base by Barton's procedure, a 95% recovery of a 2:1:1 mixture of 3 4 5 5B-A -, A - and 5a-A -androstenes was obtained.

Occasionally, the Wolff-Kishner reaction has been employed synthetically to prepare olefins. For example, Nickon et al (152) reduced cholest-4-en-3-one in this way to obtain a mixture of cholest-4- ene and 5a- and 5B-cholest-3-ene. Djerassi and Fishman (276) have also reported that a Wolff-Kishner reduction of the steroid 572 afforded three isomeric olefins. In their reduction of 25£-spirost-4-

en-3-one in an autoclave at 200° for 16 hours with absolute ethanol and sodium ethoxide, they observed that the product ratio of - 210 -

5B-A :A :5a-A was 2:1:1. However Djerassi and Fishman found this 89 ratio changed to 1:1:2 under the Huang-Minion conditions. In all these reactions, the olefin mixture is thought to result from the rapid and irreversible solvent protonation of the allylic carbanion 576.

The original hydrazone 573 is isomerized via the hydrazone anion (574) to the diimide anion 575 in the rate determining step followed by rapid product formation (275).

In working with the androstene isomers, we became aware of their susceptibility to auto-oxidation. In the literature work above, the isomer ratio for the small scale Huang-Minion experiment was determined on ^25% product recovery while the large scale autoclave product ratio was for >40% isolation. Nickon e_t al (152), without giving details, observed the product ratio changed when triethylene glycol was used in place of diethylene glycol. Szmant (275a) has stressed the importance of solvent on the course of the Wolff-Kishner reaction. In any event, our Wolff-Kishner reactions in diethylene glycol provided yields of up to 95% but g.l.c. showed only very minor ratio changes from 2:1:1. - 211 -

R"" R"" R,U,H , \ 6 \ R ON-N-H R N—NH2 \ / R C-N-Ne C=C ET w R' R" R" R'" R" R" 573 574 575

Mil

576 577 578

While there appears to be no precedent for the Wolff-Kishner

reaction affording olefinic products from the corresponding 8,Y-

unsaturated ethylene ketal, there are a number of literature reports

where these products must have' been overlooked. Liston and Howarth

(277 ) found the Wolff-Kishner (Huang-Minion) reduction of 579, the

116-hydroxy analogue of 3,3-ethylenedioxyandrost-5-en-17-one, yielded

55% of the desired product 580. Since the hydrazone reduction proceeds

nearly quantitatively, about 40% of the starting material (579) went

579 X = 0 581 X=0

580 X = H2 582 X= H2 - 212 -

3 4

unobserved into olefinic (A + A ) products. The magnitude of this

problem is even better represented in examples requiring the reduction

of an 11-oxo functionality. The Huang-Minion procedure fails

completely to reduce this sterically hindered carbonyl, but Barton's

modification using anhydrous hydrazine usually gives 90% yields.

However, when Nagata et al reduced the 3,17-bisketal 581 by Barton's

procedure, the 11-deoxo compound 582 was obtained in only 36% yield

(174). Although not reported as such, there is no doubt that most

of the 3,3-ethylenedioxy functionality was destroyed under the forcing

reaction conditions. Interestingly, Nagata (174,175,277^) developed an

alternative procedure using a mixture of hydrazine hydrate, hydrazine

hydrochloride and potassium hydroxide in triethylene glycol to overcome

Barton's requirement of using anhydrous hydrazine. This modification

afforded Nagata et al (174) a 52% yield of _582 from 581 and was also

found to provide a 40% yield of 584 from 583 (277^). It is reasonable

to expect a higher yield of 582 by Nagata's modifications, rather than

Barton's, because the base strength and base concentration are lower

in the former procedure. These same results have been interpreted as

showing that Nagata's procedure is more vigorous than Barton's (275^)

but actually it is quite the opposite. It is evident, however, that

considerable dioxolane fragmentation is occurring under both Nagata's 3 4

and Barton's reaction procedures, even though no A" or A olefinic products were isolated. - 213 -

a OR

o 583 X=CHO 561 R = H

584 X=CH3 585 R=S02C6H4CH3

586R=S02CH3

Before considering possible methods of overcoming the problem of protecting ketones during the Wolff-Kishner reduction, a slight digression is in order to deal with alternative methods of removing the

C-17 oxygen from testosterone and testosterone derivatives. Tosylates, mesylates and iodides are known to be reduced to the hydrocarbon by the action of lithium aluminum hydride in many cases (273^). Therefore, the ethylene ketal of testosterone was dissolved in dichloromethane and pyridine and treated with tosyl chloride to provide the tosylate

585 or with mesyl chloride to provide the mesylate 586. While the mesylate formation was complete at 0° in several hours, the tosylate preparation was incomplete after sixty hours at room temperature and required elevated temperatures to complete the ester formation.

Compounds 585 and 586 were then reduced with lithium aluminum hydride in refluxing tetrahydrofuran for twelve hours. Both the tosylate and mesylate were found to be completely removed. Reagent attack had occurred to give, not the desired carbon-oxygen fission at C-17, but complete oxygen-sulfur fission to regenerate compound 561. Acid - 214 -

hydrolysis of this product, followed by gas liquid chromatographic

analysis for androst-4-en-3-one, confirmed that little, if any, of

the desired reduction has occurred. Attempts to displace the mesylate

of 586 with iodide in hexamethylphosphoramide were unsuccessful (278).

587 X = NNHS02C6H4CH3

588 X=H2 589 X = NNHS02C6H4CH3

590 X=H2

The deoxygenation of the C-17 postion was also attempted by

reduction of the corresponding tosylhydrazone. Caglioti and Grasselli

(279) had reported that 17-oxo-steroids are reduced to the C-17 methylene compounds in 60-70% (587 -> 588) by sodium borohydride in

dioxane. The same reaction fails in methanol and gives the A^^-

androstene derivative with lithium aluminum (hydride. While their

postulated intermediacy of an alkyl diimide (RN=NH) makes this reaction

a similar, but milder, version of the Wolff-Kishner reaction,

unresolved difficulties with the preparation of the hindered C-17

hydrazone in the presence of 3,3-ethylenedioxy functionality (589)

resulted in abandonment of this approach. - 215 -

Protecting Group Modifications

Returning to the problem of ethylene ketal groups being labile to the Wolff-Kishner reduction, it was thought that the fragmentation of the 1,3-dioxolane could be circumvented by using a hetereocyclic ring that contained an additional carbon atom. For example, employing the 1,3-dioxane functionality in place of the 1,3-dioxolane should overcome the destruction of the masked carbonyl at C-3. There are two literature examples of the 1,3-dioxane functionality surviving a

Wolff-Kishner reduction. These compounds, 591 (259) and 592 (280), containing the 1,3-dioxane and 5,5-dimethyl-l,3-dioxane masked ketones

respectively, were employed in place of the corresponding ethylene ketal analogues only because the propanediols selectively ketalized

the desired carbonyls. However, work by Newman (281) on kinetic and

equilibrium studies for the formation and hydrolysis of cyclic ketals has demonstrated that ketones react very sluggishly with 1,3-propanediol

to give 1,3-dioxane derivatives. In contrast, ketones react with 2,2- dialkyl-1,3-propanediols even faster than they do with ethylene glycol.

For this reason, testosterone was ketalized with 2,2-dimethyl-l,3-

propanediol by the Salmi procedure using toluene as solvent and - 216 -

jD-toluenesulfonic acid as catalyst. Crystallization of the crude product from methanol, followed by recrystallization of the initial crops, afforded the desired steroidal dioxane 593. The yield, after

X ,

593 X=a-H,/3-0H 596 524. X=0 595 X=H2

allowing for a 76% recovery of testosterone by hydrolysis of the mother

90 liquors, was 87%. A Collins oxidation of the ketal alcohol 593 then 91

yielded 99% of the desired ketal ketone 594.

To check the relative stability of the different C-3 protected

ketones, Barton's modification of the Wolff-Kishner reduction was

employed under standardized conditions. That is, a twelve hour

hydrazone formation period at 180° with anhydrous hydrazine and sodium

diethylene glycolate (1.45 N) was followed by a twenty-four hour period

at 210° for the hydrazone decomposition. Under these conditions, the

3,3-ethylenedioxy derivative of androst-4-ene-3,17-dione and androst-4- 90 A chromatography of the mother liquors on thirty times their weight of activity III alumina did not permit separation of the ketal 593 from testosterone (472).

91 Exchange ketalization was also explored by preparing 2-ethyl-2,5,5- trimethyl-1,3-propanediol (596) from 2-butanone and dimethylpropanediol and reacting it with androst-4-ene-3,17-dione. Unfortunately, this exchange reaction failed, probably because of the steric limitations imposed by the gem-methyls of 596. - 217 - ene-3,17-dione itself provided 82% and 95% yields respectively of the

2:1:1 olefin mixture. However, when the dioxane 594 was refluxed under these conditions, a nearly quantitative yield of the" correspond• ing C-17 deoxy dioxane 595 was recovered with only a trace of olefin compounds in the product. Hydrolysis of this compound followed by product distillation then afforded up to 93% androst-4-en-3-one overall from compound 594. Since these forcing Wolff-Kishner conditions would remove a C-ll carbonyl, similar high yields of masked carbonyl compounds should be obtained by utilizing 1,3-dioxanes in place of the 1,3-dioxolanes that have always been employed to date.

In an attempt to find other C-3 carbonyl derivatives that would survive the Wolff-Kishner reduction of a C-17 carbonyl, the 3,3- ethylenedithio, 3,3-trimethylenedithio and 3-methoxy derivatives of androst-4-ene-3,17-dione were prepared. Testosterone was reacted with

1,2-ethanedithiol, 1,3-propanedithiol and 2,2-dimethoxypropane and an acid catalyst to afford 597, 599 or 601 in 99% yield. A Collins oxidation of 597 gave 89% 598 while the same reaction on 599 and 601 did not give the expected products 600 and 602. The oxidation of the enol ether to an enedione, in this case androst-4-ene-3,6,17-trione, has already been mentioned. The desired compound 602 could be readily prepared by first oxidizing testosterone to androst-4-ene-3,17-dione

(98%) and then selectively blocking the C-3 position with dimethoxypropane (200) in 99% yield. Until now, the physical constants of the

ketals and thioketals have been so straightforward that details were

left to the experimental section. An exception should be made in the - 218 -

598 X = 0,/=2 602 X=0

599 X = a-H,/3-OH,r=3 600 X=0,x=3 case of the Collins product from 599. While the thioketal alcohol 597 had a C-4 olefinic singlet at x 4.51 and the thioketal ketone 598 had one at x 4.50, the thioketal alcohol 599 exhibited a T 4.58 olefinic singlet that became a x 4.82 singlet in the oxidation product.

Also, the high resolution mass spectrum showed a mass unit increase of fourteen units when 599 was oxidized instead of the expected decrease of two mass units. Apparently one sulfur of the 1,3-dithiane ring in 600 is being oxidized selectively to give the sulfinyl derivative

603. Since the oxidation of thioketals with peracids and other oxidants followed by hydrolysis is a modern technique for regenerating a carbonyl (282), Collins reagent may be useful in selectively attacking dithianes in the presence of dithiolanes. In any case, by reducing the reaction time and oxidant mole ratio, the Collins oxidation of 599 provided compound 600 in 85% yield. The desired product 600 exhibited an olefinic singlet at x 4.56. - 219 -

Of the three protecting groups considered, only the cyclic ethylene thioketal has had its relative 'stability' to the Wolff-Kishner well documented. A 1,3-dithiolane masked carbonyl was considered by

Fieser in 1954 (272) to be expected to be stable to the Wolff-Kishner reduction. However Georgian .et _al, in 1959 reported (283) that complete desulfurization occurred under the Huang-Minion reduction conditions.

They also concluded that

"Although alkali was found not be necessary in some cases, it lowered the effective temperature of the reaction considerably... The sulfur was reduced completely to sulfide, no mercaptan being generated in the reaction. This fact plus the recognized stability of thioketals to alkali and the significantly lower reaction temperatures than those required in the Wolff-Kishner reduction vitiate an apparent relation• ship to the latter reaction."

They then suggested, along with other applications, that this method would serve uniquely well in overcoming the migration of carbon bond unsaturation in the reduction of a,8-unsaturated carbonyls. The publication by Georgian ert al_. subsequently realized synthetic importance in the work of Corey et^ aj_ (284 ) on the total synthesis of longifolene (607). In this synthesis, the Wolff-Kishner reduction of - 220 -

604 failed to yield 606 directly and the Raney nickel desulfurization

604 605 606 X=0

607 X= CH2 of the monoethylene thioketal 605 was unsuccessful. However, a combination of carbonyl reduction of 605 by lithium aluminum hydride and direct Wolff-Kishner reduction of the hydroxy thioketal was followed by a chromic acid oxidation to afford the desired (i)-longicamphenylone

(606). More recently, Becker and Loewenthal (284^) employed a

Huang-Minion reduction to remove a thioketal in the total synthesis of (±)-clovene (612). This "double" Wolff-Kishner, 609 -» 611, replaced the sequential desulf urization (609 610) and reduction

(610 •> 611) reactions. - 221 -

The trimethylene thioketal or 1,3-dithiane appears to have been used only once previously in connection with a Wol£f-Kishner reduction.

In 1969, Marshall and Roebke reported (285) that the ketone 613 afforded mainly polymeric material under the Huang-Minion modification of the Wolff-Kishner.

When the three androstenedione derivatives 598, 600 and 602 were subjected to the Wolff-Kishner reaction under standardized Barton 3 4 3 conditions, the familiar 2:1:1 mixture of 5B-A :A :5a-A androstenes was recovered from each reaction. The results of all the Barton

Wolff-Kishners are summarized in Table VIII. While the destruction of the 1,3-dithiolane was expected, the double bond isomerization was not. In a test for olefin isomerization under the Wolff-Kishner conditions, purified androst-4-ene was subjected to a Barton modified

Wolff-Kishner reduction. A 1:1 mixture of 5a- and 5B-androst-3-ene was also subjected to the same reaction. The recovery of unchanged olefins in both cases indicated bond isomerization was not occurring under the Wolff-Kishner reduction conditions. Treatment of these olefins with hydrochloric acid in acetone under the ketal hydrolysis conditions also afforded un-isomerized olefins. - 222 -

Table VIII Reduction of Androst-4-ene-3,17-dione and its C-3 Derivatives by the

Barton Modification of the Wolff-Kishner Reduction0

Compounds Reduced Yield Hydrolysis Product

Androst-4-ene-3,17-dione (562) 95 % Androstenes 3,3-Ethylenedioxy- androst-5-en-17-one (563) 82 % 3- Methoxyandrosta • 3,5-dien-l7-one (602) 79 % 3,3-Ethylenedithio- androst-4-en-17-one (598) 86 %

3,3-Trimethylenedithio- androst-4-en-17-one (600) 76 %

3,3- Trimethylenethiosulfinyl- androst-4-en-17-one (603) 78 % 3,3-(2,2-Dimethyltrimethylenedioxy)- androst-5-en-l7-one (594) 92 % Androstenone (240)

Note For details see Androstenone (240) experimental, section (d) (vi). k Androstenes were always in 2=1-1 ratio of 5/3-androst-3-ene:androst-4-ene: 5a-androst-3-ene, - 223 -

The destruction of the 1,3-dithiane indicates the dithiolane reaction does not necessarily proceed via a process analogous to the 92 dioxolane fragmentation (570 -»- 571). While the methyl dienol ether 92 Besides hydrogenolysis, there are three ketal or thioketal destruction processes known. The first one is the dioxolane fragmentation observed in the Wolff-Kishner reduction and reported previously by Heathcock as occurring through the action of alkyl lithium reagents on ethylene ketals (121). Ketone regeneration from ethylene hemithioketals by the action of Raney nickel in benzene has a closely related mechanism (286). The second process to give cleavage products is caused by the action of lewis acids and hydride reagents. Ethylene ketals have been reported to be cleaved by diborane during synthetic operations such as the hydroboration of JL, where 40% ketal cleavage occurred (117). Brown et^ al. have studied the lithium aluminum hydride-aluminum trichloride cleavage of many acetals and ketals (287a), including tetrahydropyranyl ethers (ii). Both 1,3- dioxolanes (y = 2) and 1,3-dioxanes (y = 3) undergo reductive cleavage via the oxocarbonium ion (iii) to afford hydroxy ethers.

6-(ci-y -oe a 0-R

il R=AlKyl ill

In 1974, this same intermediate (iii, y = 2) was used in an explanation of the reductive cleavage of acetals and ketals by borane (287^). The intermediate iii (y = 2,3 and 0~ replaced by S~) bears a close analogy with the intermediate postulated for the regeneration of ketones from hemithioketals by the action of Raney nickel in hydroxylic solvents (286). The third process involves an oxidative cleavage that is accomplished by a hydride transfer to the triphenylcarbonium (trityl) cation. Both ethylene ketals and ethylene hemithioketals were completely removed but ethylene thioketals were found to be inert because of the high energy required for thiocarbonyl formation (288). - 224 -

602 was unexpectedly hydrogenolyzed completely under the Barton modified Wolff-Kishner conditions, there is a report by Gates and

Tschudi (289) that extensive demethylation of 614 occurred under the

Huang-Minion procedure. Since there was a question as to whether it was

the base or the hydrazine that led to the removal of the C-3 protecting groups, compounds 563, 598 and 602 were subjected to a neutral Wolff-

Kishner reduction. In the absence of any base other than hydrazine, the ethylenedioxy functionality survived the Barton conditions while the ethylenedithio and dienol methyl ether were destroyed. However both the ethylenedioxy and ethylenedithio functionalities in 590 and

566 were destroyed under the Barton basic conditions in the absence of hydrazine. - 225 -

The Dioxane Fragmentation

It would be a mistake to leave the impression that only ethylene• dioxy derivatives of a,8-unsaturated 3-keto steroids are destroyed in the Wolff-Kishner reduction. It would also be a mistake to represent the base catalyzed fragmentation discussed earlier

(dioxolane fragmentation, 570 •> 571) as the only process destroying dioxolanes because some dioxane destruction has also been observed.

In pursuing the conversion of testosterone to androst-4-en-3-one

(240), it was found that the ketals of 1,3-propanediol, unlike those of 2,2-dimethylpropanediol, would undergo exchange ketalization. A

scheme involving exchange ketalization of testosterone with 2-ethyl-2- methyl-1,3-dioxane (616) and the subsequent oxidation (to 619),

reduction (to 620), hydrolysis and distillation was implemented. The 3 4 3

final product was found to be a 2:1:1 mixture of 58-A :A :5a-A

steroidal olefins. The trimethylenedioxy compounds 618 and 619 could

not be crystallized like their gem-methyl analogues but the bis ketal,

3,17-bis(trimethylenedioxy)androst-5-ene (621), obtained from androst-4-

ene-3,17-dione, was readily purified by crystallization. When this - 226 -

619 X=0 621

620 X= H2

compound was subjected to a Barton modified Wolff-Kishner both the

17-ketal and the 3-ketal were partially destroyed. The recovered material after acid hydrolysis showed the presence of androst-4-en-3- one (^20%); A\A^-androsten-17-ones (^30%); and A^,A^-androstenes

(usual 2:1:1 ratio) (^40%) with some androst-4-ene-3,17-dione ( 10%) 3 4 recovered. Authentic A ,A -androsten-17-ones were prepared by a Barton

Wolff-Kishner reduction of testosterone (472) in 95% yield followed by a subsequent Collins oxidation of 622 in 96%. A Wolff-Kishner 3 4 3 reduction of 623 yielded the usual 2:1:1 ratio of 5g-A :A :5a-A - androstenes.

472 622 X=a-H,/3-0H 623 X=0 - 227 -

A full understanding of the cleavage reactions would require the use of substituted diols and the use of reaction conditions, such as ethanol in an autoclave, that would allow the diol fragment of the

substituted dioxolane or dioxane to be isolated. Pending the outcome of this study, the fragmentation of the unsubstituted dioxane (trimethylenedioxy functionality) has been assigned as depicted in the partial structure 624 ->• 625. The introduction of gem-methyls at C-5 of the dioxane (2,2-dimethyltrimethylenedioxy functionality) prevents

this base catalyzed process from occurring. In any case, there is no

question that the stability of the ketals increases in the order

ethylene ketal < trimethylene ketal < 2,2-disubstituted trimethylene

ketal.

Any assessment of Wolff-Kishner reduction procedures should

emphasize that use of basic conditions during the hydrazone formation

period are unwise and unnecessary. In. addition, Barton's procedure,

as it now stands, is very unattractive. The distillation of excess

hydrazine-water back into the anhydrous hydrazine generator (173)

when the reaction temperature is raised from 180° to 210° is undesireable

because side products, and some of the desired product, may be lost. - 228 -

This may even be the reason fragmentation products have not been noticed previously. From a practical consideration of safety, the original Barton preparation of a 180° boiling solution of anhydrous hydrazine in basic diethylene glycol (173) is extremely hazardous.

A much better method of accomplishing the same reaction conditions is to add 8-10% anhydrous hydrazine, by volume, to a cold solution of the basic ethylene glycol solution along with the compound to o be reduced. A micro-distillation condenser can then be used to collect the small amount of excess hydrazine that distills as the temperature is raised to 180°. The downward distillation condenser is then rotated until it can serve as a reflux condenser for the twelve hour period of hydrazone formation. Rotation back to a downward distillation position permits the reaction temperature to be raised to 210°. After the hydrazone decomposition is complete, the liquid that distilled is included in the workup. This procedure has been found to be applicable to both large and small scale reactions. The necessary anhydrous hydrazine can be prepared much more safely by an azeotropic distillation with toluene off calcium oxide (174) than it can be by the recommended three hour reflux period over sodium hydroxide. - 229 -

EXPERIMENTAL

General

Melting points, which were determined on a Kofler block, and boiling points are uncorrected. Optical rotations were obtained at the sodium D line using a Perkin-Elmer Model 141 Automatic Polarimeter.

Ultraviolet spectra were, unless otherwise noted, measured in methanol solution with a Cary, Model 14, or Model 15, spectrophotometer.

Refractive indicies were taken on an Officine Galileo Refractometer.

Routine infrared spectra were recorded on a Perkin-Elmer Infracord

Model 137 or a Perkin-Elmer Model 710 spectrophotometer while analytical sample and comparison spectra were recorded on a Perkin-Elmer spectro• photometer, Model 457. Proton magnetic resonance (n.m.r.) spectra were, unless otherwise noted, recorded in deuterochloroform solution on Varian Associates spectrometer A-60, T-60 and/or HA-100, Xl-100.

Line positions are given in the Tiers T scale, with tetramethylsilane as internal standard; the multiplicity, integrated peak areas and proton assignments are indicated in parentheses. Gas-liquid chroma• tography (g.l.c.) was carried out on either an Aerograph Autoprep, - 230 -

Model 700, or a Varian Aerograph, Model 90-P. The following columns

(10 ft x 1/4 in, unless otherwise noted) were employed, with the inert supporting material being, in each case, 60/80 mesh Chromosorb

W (unless otherwise noted): column A (5 ft x 1/4 in), 20% SE-30; column B, 20% SE-30; column C (10 ft x 3/8 in), 30% SE-30; column

D, 20% FFAP; column E (10 ft x 3/8 in), 30% FFAP; column F, 20%

Apiezon J; column G, 8% FFAP (60/80 mesh Chromosorb G). The specific column used, along with the column temperature and carrier gas (helium) flow-rate (in ml/min) are indicated in parentheses. Column chroma• tography was performed using neutral silica gel (Camag or Macherey,

Nagel and Co.) or neutral alumina (Camag or Macherey, Nagel and Co.).

The alumina was deactivated to Act. Ill by the addition of 6% water by weight. High resolution mass spectra were recorded on an AEI, type MS-9, mass spectrometer by either Mr G. Gunn or Dr. G. Eigendorf.

Microanalyses were performed by Mr P. Borda, Microanalytical

Laboratory, University of British Columbia, Vancouver. - 231 -

4a-Methy1-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone (234)

(a) The octalone 234 was prepared by the procedure of Marshall and Fanta (99).

The Michael condensation reaction was done in a flame-dried reaction apparatus equipped with very efficient stirring (Fisher Stedi-Speed apparatus on low range, Hershberg stirring rod) under a nitrogen atmos• phere. External cooling with a thermostatically controlled constant temperature bath was provided by a 1:1 methanol:water (volume ratio) air-stirred bath solution maintained at -10° with an Eberbach apparatus.

A solution of 18 ml of 3 N ethanolic sodium ethoxide, prepared from 1.25 g of sodium and 20 ml of ethanol, was added to 294 g (2.62 moles) of

2-methylcyclohexanone in the reaction flask. Methyl vinyl ketone was distilled just before use and 180 g (2.57 moles) were added dropwise over a six hour interval with the reaction conditions being maintained at

-10° for an additional fourteen hours. Before the dehydration was started, a small sample was taken, dissolved in ether, filtered and evaporated to a small volume. A chloroform solution of the residue was washed with saturated sodium bicarbonate, dried over magnesium sulfate

and evaporated to a small volume again. Colourless crystals were

deposited from petroleum ether to provide 0.5 g of cis-10-methyl-2-

decalon-9-ol (247), m.p. 121.5-122° (lit. (101) m.p. 120.8-121.4°).

Infrared (KBr disc): 3350 (-0H); 1710 (C=0); 1050, 1035 cm"1 (C-0).

Nuclear magnetic resonance: x 8.87 (singlet, 3H, tertiary methyl),

x 7.94 (singlet, IH, -011, proton exchanged with D^O). The compound did

not have ultraviolet absorption in the region 350-220 mp but it did show

end absorption (C=0) below 220 my. - 232 -

A direct steam distillation of the condensation reaction mixture was accomplished by adding 1 1/3 1. of aqueous 10% potassium hydroxide to

the two liter reaction flask and distilling steam through the solution

for three hours. The cooled reaction vessel solution was saturated with

sodium chloride and extracted with diethyl ether after neutralization with 12 N hydrochloric acid. The steam distillate was worked up in an

analogous manner and the combined organic extracts were washed with brine and dried over anhydrous sodium sulfate and then evaporated under

reduced pressure to provide % 300 ml of a red oil. A distillation of

this extract gave 71.5 g (24%) of recovered 2-methylcyclohexanone

(35-40° at 1 mm Hg) and 240.8 g (57%) of a clear oil, b.p. 113-115°/0.75 mm.

A slow distillation of the latter fraction showed b.p. 73°/0.4 mm (lit.

(99) b.p. of octalone 234 is 70°/.3 mm and 82-83°/.7 mm) and a g.l.c.

preparation of an analytical sample (column C, 200°, 94) gave a colourless 20

liquid with the physical properties expected for compound 234: nD 1.5249 (lit. n25 1.5230 (99)). Ultraviolet X 239 my, e = 14,400 D max

(lit. 239 my, e = 14,400 (99)). Infrared (film): 1670 (conj. C=0),

1620 cm"1 (conj. C=C). N.m.r., x 4.29 (singlet, IH, -C'H) and x 8.74

(singlet, 3H, tertiary methyl). The 2,4-dinitrophenolhydrazone

prepared (102) showed m.p. 170.5° (lit. (103) m.p. 169°).

(b) The octalone 234 was also prepared by the acid-catalyzed Robinson

annelation procedure of Heathcock et al. (100). See (d) below as well.

A mixture of 56 g (0.5 moles) of 2-methylcyclohexanone, 44 g (0.63

moles) methyl vinyl ketone and 0.4 ml cone, sulfuric acid was refluxed

under nitrogen for 20 h. The cooled dark solution was diluted with 100

ml petroleum ether (30-60°) and washed twice with 50 ml portions of 5% - 233 - aqueous sodium hydroxide. After drying over anhydrous magnesium sulfate, the dark red solution was concentrated under reduced pressure and distilled to provide 15.7 g (28%) of recovered 2-methylcyclohexanone and

44.3 g (54%) of a yellow-tinted oil. Redistillation of the latter fraction at 130° on a water aspirator afforded 38.1 g (46%) of a colourless oil.

A g.l.c. analysis (column B, 185°, 86) of the distillation fractions showed the desired octalone (84%) was contaminated by a second component

(16%) which could not be removed by distillation. A g.l.c. isolated

(column C, 210°, 126) sample of this shorter retention time impurity exhibited infrared of 1710 cm \ a significant n.m.r. x 7.88 (singlet,

3H, CH^CO) and x 8.95 (singlet, 3H, tertiary methyl), and end absorption (< 210 mp) in the ultraviolet. A one hour reflux under a nitrogen atmosphere in a 400 ml ethanol solution of 5% potassium hydroxide removed the impurity. This reaction was worked up as in (c) below and yielded octalone identical to that reported in (a).

(c) A modified approach to the acid-catalyzed Robinson annelation procedure published by Heathcock et al. (100) was found to be the best.

Using the same reaction conditions and scale as in (b), the cooled dark reaction solution was diluted with 260 ml of 0.5 M sodium ethoxide in ethanol (3 g sodium used) and refluxed under nitrogen for a 1 h period and cooled. The. reaction was partitioned between 200 ml of petroleum ether (30-60°) and 300 ml water and the aqueous layer was washed with 100 ml petroleum ether. The combined organic extracts were washed in sequence by water, 2 N hydrochloric acid, water and brine and dried over anhydrous magnesium sulfate. The residue obtained by

concentrating the solution under reduced pressure was distilled to afford - 234 -

14.2 g (25%) of recovered 2-methylcyclohexanone and 36.3 g (44%) of colourless octalone 234, free of impurities. The forerun to the latter fraction yielded a 1:1 mixture of an impurity (248) and octalone 234.

A g.l.c. isolated sample (column B, 178°, 97) of this impurity showed

infrared (film) 1720 (C=0) and 1675 cm"1 (C=C); n.m.r. T 4.42 (a triplet 3 J = J = 1 5 Hz 7 3 of quartets, IH, vinyl C H, C3H_C4H 3.4 Hz, C3H„C10H - )> - 2 3 4 (multiplet, IH, t^H), 7.65 (multiplet, 2H, C H2), 8.33 (a triplet of

10 doublets, 3H, C H3, JG1Or _c4r = 2.2 Hz, JC10R _c3r = 1.5 Hz), and 3 *)_ 3 8.98 (singlet, 3H, C1:LH«); and ultraviolet with weak shoulder -3 absorption (235 my) on strong end absorption below 215 my (C=0). The

infrared and n.m.r. data agree with that reported for 2,5-dimethylbicyclo-

[3.3.l]non-2-en-9-one (107). This same impurity was isolated in part (b)

and found to be unaffected by treatment with base during a one hour

period.

(d) The procedure of Heathcock et al. (100) was repeated using 18 100 ml benzene per 0.3 ml sulfuric acid catalyst.

A mixture of 22.5 g (0.2 moles) of 2-methylcyclohexanone, 18.0 g

(0.25 moles) methyl vinyl ketone, 0.15 ml cone, sulfuric acid and 50 ml

of benzene was refluxed under a nitrogen atmosphere for 16 hours. The

cooled solution was diluted with 50 ml of petroleum ether and washed

with 50 ml of 5% aqueous potassium hydroxide. The dried, concentrated

solution was g.l.c. analyzed as before and shown to contain approximately

a 4:12:84 ratio of 248:246:234 products. After treatment with sodium

ethoxide in refluxing ethanol a 4:0:96 ratio of 248:246:234 was present.

The usual workup afforded 5.7 g (25%) recovered 2-methylcyclohexanone,

0.6 g of a mixture (248 plus 234) and 13.4 g (41%) of octalone 234. - 235 -

4a,8a-Dimethy1-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone (235).

(a) The acid-catalyzed Robinson annelation procedure used is analogous to the one developed for octalone 234 by modifying the method of Heathcock et al. (100). The procedure followed incorporated a short base treatment before workup.

A mixture of 72 g (0.57 moles) of 2,6-dimethylcyclohexanone, 52 g

(0.74 moles) methyl vinyl ketone and 0.4 ml cone, sulfuric acid was refluxed for 20 h. The cooled solution was diluted with 260 ml of 0.5 M sodium ethoxide in ethanol (3 g sodium used) and refluxed under nitrogen for a 1 h period and cooled. A petroleum ether (300 ml)-water (300 ml) partition yielded an organic layer that was washed with water and brine an dried over magnesium sulfate. The aqueous layer and insoluble red gum residue were discarded and the dried organic solution was concentrated under reduced pressure and distilled to yield 32.9 g (46%) of recovered

2,6-dimethylcyclohexanone (62-64° on water aspirator), 7.5 g of a mixture of the impurity (264) and the desired octalone (235), and 23.6 g (23%) of pure octalone 235. A redistillation (b.p. 146°, water aspirator) of the latter fraction afforded 20. 7 g (21%) of a colourless oil that

showed all the spectral properties reported for 235 (107) and that

exhibited an analytical infrared that was superimposable on the one

obtained from the octalone in (b) below.

A careful redistillation (110-120° on aspirator) of the mixture

fraction provided 4.6 g (5%) of 1,2,5-trimethylbicyclo[3.3.l]non-2-en-9-

one (264), an analytical sample of which was purified by gas chromatography

(column B, 185°, 97): infrared (film): 1710 (C=0) and 1675 cm"1 (C=C); 3 n.m.r. x 4.42 (a triplet of quartets, IH, vinyl C H_, ^Q^II-Q^^ = ^'^ HZ' - 236 -

.4, J„3„ = 1.5 Hz), 7.70 (multiplet, 2H, C*H.), 8.38 (a triplet of L li— L

n J doublets, 3H, c H3, C11H3_C4H3 = 2.2 Hz, JC11H3_C3H = 1-5 Hz), 8.90

10 12 (singlet, 3H, C H ), and 9.00 (singlet, 3H, C H3); and an ultraviolet

exhibiting a weak shoulder absorption (235 my) on strong end absorption below 220 my (C=0).

When the reaction was worked up before base treatment, slightly more

2,6-dimethylcyclohexanone was recovered (41.6 g, 58% recovery of

starting material) and there were four products (total = 100%) present;

the bridged ketone (20%), two unidentified components (43% and 31%

respectively), and octalone 235 (6%). After base treatment the products

(total = 100%) included the bridged ketone (23%), octalone ^35 (75%)

and miscellaneous (2%). The component having the g.l.c. retention time

of the bridged ketone before base treatment was identified as 264 by

analytical, infrared and found to be unaffected by sodium ethoxide in

refluxing ethanol. The two major unidentified components present before

the base treatment were isolated by preparative g.l.c. (column C, 190°,

154). The shorter retention time component respresenting ^40% of the

initial products exhibited infrared (film): 1710 (OO), 1460, 1370 and

X 1000 (medium absorption) cm ; n.m.r. T 7.88 (singlet, 3H, C0CH3), 9.01

(doublet, 3H, CH(CH3), J = 6.4 Hz), and 9.01 (singlet, 3H, tertiary

methyl); and an ultraviolet spectrum exhibiting a strong end absorption

below 220 my (C=0). The longer retention time component (^ 30%) showed

infrared (film): 1710 (C=0), 1460, 1370 and 1000 (strong, sharp absorption

1 peak) cm" ; n.m.r. x 7.83 (singlet, 3H, -C0CH3), 8.82 (singlet, 3H,

tertiary methyl), and 9.01 (doublet, 3H, CH(CH_3), J = 6.4 Hz); and an

ultraviolet with a strong end absorption below 220 my (C=0). Treatment of - 237 -

either pure component with cone, hydrochloric acid resulted in a 60:40

ratio of these two compounds being produced along with a small amount

of the bridged ketone 264 • (5% and 11% of the reaction mixture from the

first and second component respectively were 264). The recorded 60:40

ratio was obtained by n.m.r. and g.l.c. work and since the same ratio was observed in the initial reaction workup, these epimers of 2,6-

dimethyl-2(3-oxobutyl)cyclohexanone (263) were obviously at thermodynamic

equilibrium. 18

When the reaction was repeated incorporating 50 ml of benzene

into the reaction mixture of 25.2 g (0.2 moles) 2,6-dimethylcyclohexanone,

18.0 g (0.25 moles) methyl vinyl ketone, and 0.15 ml sulfuric acid,

the crude product mixture obtained on workup after 16 h reflux under

nitrogen showed a 15:46:32:7 ratio of 264 : 263a : 263b : 235 as determined

by the usual g.l.c. work. A one hour treatment with 130 ml of 0.5 M

sodium ethoxide in refluxing ethanol changed the ratio to 18:0:0:82.

Completion of the workup by distillation yielded 16.2 g (64%) recovered

2,6-dimethylcyclohexanone, 1.65 g of a mixture of 264 (predominantly) and

235, and 7.2 g (20%) octalone 235. (b) The following hydrogenation procedure on compound 301 is 1 4

analogous to one reported by Djerassi and Gutzwiller (113) for A ' _3-

keto steroids.

A solution of 4a,8a-dimethyl-5,6,7,8-tetrahydro-2(4aH)-napthalenone

(2.64 g, 15 mmoles) and tris(triphenylphosphine)chlororhodium (925 mg)

in benzene (300 ml) was subjected to hydrogenation at room temperature

and atmospheric pressure. Hydrogen uptake ceased after approximately 12 h.

The solvent was removed under reduced pressure and ether (200 ml) was - 238 - added to precipitate the catalyst. The filtrate obtained by suction filtration was passed through a short activity III Woelm neutral alumina column (150 g) with ether (800 ml) elution. After removal of the solvent under reduced pressure, the residue was distilled twice through a short path distillation apparatus, b.p. 120° at. 0.4mm(lit. (107) b.p. 90-99° at .3 mm), to afford 2.63 g (99%) of the desired compound 235 as a colourless oil. This compound was identical to that prepared in part

(a) above and showed infrared (film), 1670 (conj. C=0) and 1615 cm 1

(conj. C=C); n.m.r. T 4.20 (doublet, IH, (^H, J = 2.0 Hz), 8.74 (singlet,

8 3H, tertiary methyl), and 8.92 (doublet, 3H, C CH3, 6.4 Hz); ultraviolet

X 239 my, e = 15,500 (lit. (107) xEt0H 240 my, e = 15,600). max max

4a, 8,8-Trimethyl-4, 4a, 5,6, 7, 8-hexahydro-2 (311)-napthalenone (237)

This octalone was prepared by modifying the approach of Dauben and Ashcraft to 237 (163) by Ireland and Marshall's reported procedure

(172) for the methylation of n-butylthiomethylene blocked decalone and cyclohexanone compounds.

To an ice-cooled, stirred suspension of powdered sodium methoxide

(200 g, 3.70 moles) in 1000 ml of dry benzene, kept under an atmosphere of dry nitrogen, was added 125 g (0.76 moles) of 4a-methyl-4,4a,5,6,7,8- hexahydro-2(3H)-naphthalenone (octalone 234). The resulting mixture was stirred for 10 min, and then 168 g (2.26 moles) of ethyl formate was added. The mixture was stirred vigorously for 2 h and then allowed to stand at 0° for 12 h (172). Water was added, the mixture was transferred to a separatory funnel and the organic layer was extracted with four portions of 7% aqueous sodium hydroxide. The benzene layer was - 239 - concentrated under reduced pressure and distilled to afford 5.3 g of starting material (234). The combined aqueous layers were cooled in ice-, acidified with 4 N hydrochloric acid and thoroughly extracted with ether. These ethereal extracts were then washed with brine and

dried over anhydrous magnesium sulfate. Removal of the solvent,

followed by distillation of the residual oil under reduced pressure gave

129.9 g (90% yield without correcting for recovered starting material)

of the hy.droxymethylene derivative 374 as a transparent pale yellow

oil, b.p. 115-118° at 0.8-0.9 mm. Infrared (film): 1725, 1640, 1575

cm 1 with a broad absorption at 3500-2600 cm L; n.m.r. x 2.60 (singlet,

10 1 IH, C HOH), 4.16 (singlet, IH, C ^) and 8.90 (singlet, 3H, CH3);

ultraviolet: X 247 my, X (HCI added) 257, 300 my, and X (NaOH max max max added) 241, 357 my (lit. (65) XEtOH250 my and XEt0H + Na0H 240,360 my). max max A dry benzene solution (700 ml) of the hydroxymethylene derivative

374 (129.8 g, 0.675 moles) and n-butyl mercaptan (71.0 g, 0.79 moles)

was refluxed with a catalytic amount of p_-toluenesulfonic acid (500 mg)

in a nitrogen atmosphere under a Dean-Stark water separator for 16 h

(12.9 ml water collected). The cooled solution was washed with 200 ml

of 10% aqueous sodium bicarbonate, dried over magnesium sulfate, treated

with charcoal and concentrated under reduced pressure. A vacuum

distillation at 0.05 mm (b.p. 165-170°) afforded 162.6 g (91%) of the

desired thiol ether 37_5. Infrared (film): 1650, 1620, 1575 and 855 cm"1 9

J 4 13 = 2,2 HZ T 4 23 and n.m.r. x 2.58 (doublet, IH, CH, c9H_C H ^' '

= 1 Hz T 7 18 1 (triplet, IH, c\ JC1R_C8H )> - (triplet, 2H, S-C ^-, J =

A 7.1 Hz), x 7.43 (doublet, IH, C H\ J_4U _9tI = 15 Hz), x 7.72 (doublet of — L. rl— L ri

10 doublets, IH, cV', J = 15,2.2 Hz), x 8.88 (singlet, 3H, C H3) and

1A x 9.08 (triplet, 3H, C H3). - 240 -

The red coloured n-butylthiomethylene blocked octalone (375)

prepared above (162.5 g, 0.62 moles) was added to a magnetically stirred

solution of 282 g (2.55 moles) potassium _t-butoxide in 4000 ml of dry

_t-butanol at 60°. The deep purple solution was cooled in an ice bath

after 10 min and methyl iodide (825 g, 5.8 moles) was added. The

immediate production of potassium iodide was indicated by the formation

of a white suspension in the reaction flask. The solution was refluxed

for 2 hand then concentrated under reduced pressure to a volume of

approximately 600 ml. The partition of this solution between etherrwater

with subsequent washing of the organic layer with 4 N hydrochloric acid,

water, aqueous sodium bicarbonate and 5% sodium thiosulfate provided

the crude product. The magnesium sulfate dried ethereal solution was

concentrated under reduced pressure and the dark red residual oil was

vacuum distilled (165-175° at 0.05 mm) to afford 160.8 g (89.5%) of the

gem-methylated blocked octalone 376. Infrared (film): 1675, 1640 and

1565 cm n.m.r. T 2.48 (doublet of doublets, IH, C^H-S, JQII^ C^H' =

8 Hz 2.5 Hz, JcllH_c4H" = 1-2 Hz), 4.44 (triplet, IH, C H, JC8H_C7H2 = >>

7.17 (triplet, 2H, S-CH2~, J = 7.0 Hz), 7.62 (doublet of doublets, IH,

CAH', J = 15.0, 1.2 Hz), 7.80 (doublet of doublets, IH, C4H", J = 15.0,

12 16 2.5 Hz), 8.74 (singlet, 3H, C H3), 9.08 (triplet, 3H, C H3, J = 7 Hz),

and 8.84, 9.10 (singlets, 3H each C^CH^.

To remove the n-butylthiomethylene blocking group, an 800 ml di•

ethylene glycol solution of the above alkylated material (160.8 g) was

refluxed with 525 ml of 25% aqueous potassium hydroxide in a nitrogen atmo•

sphere for 90 hours. The reaction was monitored by infrared inspection for

the disappearance of the 1565 cm 1 absorption. The reaction was cooled,

diluted with 400 ml water and extracted several times with chloroform.

The organic layer was dried over anhydrous magnesium sulfate and - 241 - concentrated to a small volume under reduced pressure. A distillation of the dark red mobile oil residue (b.p. 79-85° at 1.1-1.25 mm) afforded

99.5 g of octalone 356, a 95% yield. A redistilled portion of this yellow-tinted oil provided a colourless sample, b.p. 106-109° at 3 mm

(lit. (164) b.p. 105-107° at 2 mm). A g.l.c. collected sample (column B and D, 200° + 175°, 90) showed the expected properties including a weak absorption in the ultraviolet centered at 275 my (e < 100) and strong end absorption below 220 my. Infrared (film): 1707 (strong, C=0), — 1 8 1650 (weak C=C) cm ; n.m.r. x 4.43 (triplet, IH, C H, J^8T1 ~7TJ =3.7 Hz), 3 1 7.5 (multiplet, 2H, CH^, 8.78 (singlet, 6H, tertiary methyls), and 9.00

(singlet, 3H, tertiary methyl). High resolution n.m.r. (HA 100) did not resolve the x 8.78 singlet but it did show a half-peak width of

0.6 Hz. The yellow 2,4-dinitrophenylhydrazone of octalone 356 had a m.p. 158-159° (lit. (163) 160.8-161.5°) and an ultraviolet absorption at 364 my (lit. (167) X 3 369.5 my). max

The Wolf f-Kishner reduction procedure, as modified by Barton e_t al.

(173) for sterically hindered carbonyl groups, was used to reduce 99.5 g

(0.52 moles) of the trimethyl octalone 356. Diethylene glycol (1500 ml) was dried with sodium and distilled into an all glass reaction vessel where it was reacted with 30 g of sodium under a nitrogen atmosphere.

Anhydrous hydrazine, prepared by refluxing hydrazine hydrate (200 ml) with an equal weight of sodium hydroxide (176a), was distilled into the reaction solution until the latter refluxed freely at 170°. The resulting solution was cooled and the ketone 356 was added. After eighteen hours refluxing under nitrogen with stirring at 170°, the reaction solution was distilled

until the temperature reached 210°. Care was taken to collect the - 242 - hydrazine-water mixture that distilled below 210°, and it was combined and worked up with the reaction solution after the latter had refluxed an additional 36 h (the reflux temperature had dropped from 210° to 190° by the end of this period). The cooled reaction solution was diluted with water, neutralized with hydrochloric acid (6 N) and extracted with ethyl ether. The combined organic extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a light yellow coloured liquid. The vacuum distillation

(76-82° at 4.4 mm) afforded 81.8 g (91.5%) of a clear colourless oil.

A g.l.c. prepared sample (column F, 160°, 90) from this already very pure product showed infrared (film): 1640 (weak, C=C), 1460, 795 cm 1 rn -1 1 (lit. (162)v 4 795, 1640 cm ); n.m.r. T 4.57 (triplet, IH, C H, max 2 J„l„ n2u = 3.8 Hz), 7.98 (poorly resolved multiplet, 2H, C H_), and L rl—L i.

8.83, 8.92, 8.96 (singlets, 3H, tertiary methyls).

Using a modified form of Dauben and Aschraft's (163) procedure,

81.5 g (0.46 moles) of the trimethyl octalin in 750 ml of glacial acetic acid and 407 ml of acetic anhydride was allowed to react for

30 h at 30-40° with 150 g (0.93 moles) anhydrous sodium chromate. The dark green reaction mixture was diluted with 1000 ml water, cooled in ice and neutralized with sodium hydroxide, and extracted with petroleum ether (38-47°). The organic layers were combined, washed twice with saturated aqueous sodium bicarbonate, and dried over magnesium sulfate.

Concentration under reduced pressure and distillation of the residue yielded only about 50 grams of product. A re-extraction of the neutralized dark green aqueous solution (24 h after the first) with ether followed by the usual workup provided an additional 19.0 g of crude product. A reduced pressure distillation on these combined fractions - 243 - yielded 60.3 g (68.8%) of the desired trimethyl octalone, b.p. 124-126° at 4.7 mm. A g.l.c. analysis (column B, 180°, 85) showed this product to-be free of both the original starting octalone 234 (unalkylated product) and "overmethylation" products, while a sample isolated by gas 19 25 chromatography showed n^ 1.5231 (lit. (162) n^ 1.5142); infrared (film):

1675 (strong, conj. C=0), 1600 (strong, conj. C=C) cm ^; n.m.r. x 4.04 1 3 (singlet, IH, C H), 7.53 (poorly resolved multiplet, 2H, C H2), 8.65,

8.81, 8.85 (singlets, 3H, tertiary methyls); and ultraviolet X 242 my, in 3.x e 13,700 (lit. (163) 242 my, e 13,700). The 2,4-dinitrophenylhydrazone prepared (102) had m.p. 199-201° (lit. (163) m.p. 201-202°).

4a,5-Cis- and 4a,5-trans-dimethyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone

(238 and 239)

(a) The above octalones were derived from 2,3-dimethylcyclohexanone

3. 3 by following the procedure of Piers, Britton and De Waal (184 ,185 , 186).

To facilitate the discussion, the following experimental is considered as (i) the synthesis of the enol lactone mixture 419 + 420, (ii) the purification of the enol lactone epimers and (iii) the preparation of the corresponding pure octalones.

(i) To an ice-cooled, stirred suspension of powdered methoxide

(157 g, 2.9 moles) in 1500 ml dry benzene, kept under an atmosphere of dry nitrogen, was added 142 g (1.13 mole) of 2,3-dimethylcyclohexanone

(413). The resulting mixture was stirred for 10 min, and then 150 g

(2.1 moles) of ethyl formate were added. The mixture was stirred vigorously for 2 h and then allowed to stand at 0° for 12 h (172). Water was added, the mixture was transferred to a separatory funnel and the organic layer - 244 - was extracted with four portions of 7% aqueous sodium hydroxide. The

benzene layer was concentrated under reduced pressure and distilled to

afford 6.4 g of starting material (413). The combined aqueous layers

were cooled in ice, acidified with 6 N hydrochloric acid and thoroughly

extracted with ether. These ether extracts were then washed with brine

and dried over anhydrous magnesium sulfate. Removal of the solvent,

followed by the distillation of the residual oil under reduced pressure

gave 156.0 g (90% yield without correcting for recovered starting

material) of the hydroxymethylene derivative 414 as a colourless oil,

b.p. 60-63° at 2 mm, nD 1.5135. Infrared (film), 3600-2400 (broad

absorption, hydrogen bonded -OH), 1640 (conj. carbonyl) and 1590 cm 1

(conj. double bond); n.m.r. T 1.42 (singlet, IH, C^HOH); and ultraviolet X 281 m , X (NaOH added) 316 mu. max max K

A dry benzene solution (750 ml) of the above hydroxymethylene

derivative 414 (117 g, 0.75 moles) and n-butyl mercaptan (84 g, 0.93 moles)

was refluxed with a catalytic amount of jj-toluenesulfonic acid (0.5 g)

in a nitrogen atmosphere under a Dean-Stark water separator for 16 h.

The cooled solution was washed with 100 ml of 10% aqueous sodium

bicarbonate, dried over magnesium sulfate, treated with charcoal and

concentrated under reduced pressure. A vacuum distillation afforded

150.8 g (88%) of the desired thiol ether 400, b.p. 116-118° at 0.3 mm, 20 -1 n^ 1.5368. Infrared (film), 1665 (conj. carbonyl) and 1550 cm (conj.

? J olefin); n.m.r. T 2.45 (triplet, IH, C H-S, C7H_C5H2 = 2.0 Hz) and 7.17

(triplet, 2H, S-CH„-, J = 7.0 Hz); and ultraviolet X 309 (e = 15,400). 2 max

The yellow-tinted n-butylthiomethylene blocked ketone prepared above

( 118 g, 0.52 moles) was added to a magnetically stirred solution of - 245 -

potassium t^-butoxide (60 g or 1.53 moles potassium) in 2000 ml of dry

^-butanol at 60° under a nitrogen atmosphere. The solution was cooled

in-an ice bath after 5 min and ethyl-3-bromopropionate (350 g, 1.93

moles) was added. The reaction was stirred for 30 min at room tempera•

ture and then the solution was concentrated to half volume under reduced

pressure and partitioned between ether and water. After three ether

washings, the combined organic layers were washed with 3 N hydrochloric

acid, water, aqueous bicarbonate, aqueous sodium thiosulfate (10%) and

brine. The magnesium sulfate dried solution was then concentrated under

reduced pressure and distilled to afford 160.5 g (94%) of the keto

esters 415/6. A redistilled sample showed b.p. 190-195° at 0.4 mm, 20

nD 1.5261; infrared (film) 1730 (ester carbonyl), 1650 (conj. carbonyl),

and 1540 cm"1 (conj. olefin); n.m.r. T 2.52 (triplet, IH, C7H) and 5.92

(quartet, 2H, -OCH^CH^, J = 7 Hz) in the low field portion of the spectrum; and ultraviolet X 311 (e = 14,900). max

The preceding alkylated material (160.5 g, 0.49 moles) was hydrolyzed

with a diethylene glycol (900 ml) and 25% aqueous potassium hydroxide

(150 g KOH/600 ml E^O) solution by refluxing in a nitrogen atmosphere

for 16 h. The cooled solution was diluted with water and extracted

twice with ether. The residue in the ether extracts was rehydrolyzed

for 18 h and re-extracted as above. The collected aqueous layers were

combined, cooled with ice, and acidified with 12 N hydrochloric acid.

Extractions with ether, the combined ether extracts being washed with

water and brine, led to the isolation of the crude keto acid products 417/8

from the magnesium sulfate dried and rotary evaporator concentrated

organic layer. A distillation of this dark oily residue (160-164° @ 0.5

mm) yielded 87.4 g (90%) of a mixture of the keto acids as a clear - 246 -

20 viscous oil, n^ .1.4868 and infrared (film) 3600-2400 (very broad, -OH of carboxyl), 1740, 1715 cm X. Additional data for the pure cis- and trans-vicinyl dimethyl keto acids is given in (ii) below.

A solution of the keto acid mixture (77.8 g, 0.39 moles) and anhydrous sodium acetate (16.5 g) in acetic anhydride (165 ml) was refluxed under a nitrogen atmosphere for 3 h. The acetic acid was removed under reduced pressure and the residual material was diluted with water.

The aqueous layer was extracted with ether and the ether layer was

dried over magnesium sulfate. Removal of the organic solvent was

followed by distillation of the crude product to give 67.1 g (95%) of

crystalline material, b.p. 108-110° at 0.5 mm. This material, as

judged by its n.m.r. spectrum, consisted of a mixture of the enol

lactones 419 and 420 in a ratio of 82:18 (83:17 in the first reaction

done on this scale and 82:18 in the second).

Alkylation Parameter Study

Standard Procedure: To 40 ml of anhydrous solvent under nitrogen

in a magnetically stirred round bottom flask, 28.0 millimoles of base

were added. The solution was warmed to 60° for 10-15 min, cooled to

room temperature and 2.0 g (8.85 millimoles) of the blocked ketone

400 were added in 20 ml of solvent. The solution was again warmed to

60°, cooled to room temperature after 10-15 min, and 6.0 g of ethyl

3-bromopropionate (or 4.55 g ethyl 3-chloropropionate) (33 millimoles)

were added. After 15 min the solution was heated to 60° for 45-90 min. - 247 -

Table I. Stereochemistry of the Alkylation Products of the Blocked

Ketone 400.

Base Solvent Alkylating 419:420 Ratio Overall Notes Employed System Agent by N.M.R. By G.L.C. Yield

K0But But0H RBr 81.4:18.6 84.4:15.6 53% 2 11 M' II 81 :19 20% 2 II THF n 80 :20 25% 2

it HMPT II 90 :10 20% 2

t II <10% K2C03 Bu 0H 84 :16

NaOBu1" But0H RBr 75 :25 40% 2 it 10% 3 NaOCH3 THF 76 :24

LiOBu1" But0H II 50.3:49.7 80% 1,4

II But0H " 51 :49 50.3:49.7 28% 4

II 52 :48 51 :49 25% 4

II THF 51 :49 51 :59 66% 4

II HMPT II 89 :11 7% 4

KOBu*1 But0H RC1 85 :15 86.5:13.5 45% 2

LiOBufc But0H RC1 53 :47 50.7:49.3 56% 4

Notes: 1. Reaction left at 60° for 5 h to ensure completion.

2. Base prepared under N2 and solvent removed under vacuum if solvent- free base required. 1 .2 g K or 0.8 g Na used

3. Methanol -free base used after storage in dessicator.

4. Base formed by adding 15 ml x 2 N LiBu11 to a stirred

t solution of Et20 (5 ml) and Bu0 H (5 ml) at-78° . Solvent then removed under vacuum and reaction solvent introduced via syringe. - 248 -

The isolated crude alkylation product was hydrolyzed with potassium hydroxide (5 g), water (20 ml) and ethylene glycol (20 ml) under nitrogen for 18 h. The usual workup (see large scale work) yielded a mixture of keto acids (418/7) after a short path distillation (135-

160° @ 0.5 mm). Treatment of this mixture with refluxing acetic anhydride (10 ml) and anhydrous sodium acetate (1 g) for 3 h gave, after the usual workup and short path distillation (100-120° at 0.5 mm Hg),

49 the samples that were analyzed by n.m.r. and g.l.c. The g.l.c. analysis could only be accomplished on a newly made 8% FFAP column

(column G, 190°, 130) where the trans compound (420) was eluted first

(16.5 min) and the cis compound (419) appeared shortly thereafter (17.6 min) .

(ii) Two crystallizations from hexane of the mixture (82:18) of the

cis and trans vicinyl dimethyl enol lactones (419 and 420) afforded the

cis enol lactone 419 in a pure state. This compound was recrystallized

from hexane to afford a white crystalline sample which exhibited m.p.

1 51-51.5°; infrared (CHC13), 1748 (lactone carbonyl) and 1680 cm"

= (enol unsaturation); and n.m.r. T 4.70 (triplet, IH, C^H, ^c6H_C5H

4.0 Hz), 7.2-7.5 (multiplet, 2H, -CH2C00-), 8.96 (singlet, 3H, tertiary

methyl) and 9.04 (doublet, 3H, secondary methyl, J = 6.0 Hz). Hydrolysis

of a sample of this material in tetrahydrofuran with aqueous sodium

hydroxide yielded the corresponding cis keto acid 417 as an oily solid.

Recrystallization from hexane-ether gave a white solid m.p. 40-41.5°;

1 infrared (CHC13) 3600-2400 (carbonyl-OH), 1710 cm" (both carbonyls

unresolved) with n.m.r.' x -0.80 (singlet (width @ h peak h. = 4 Hz), IH,

-COOH), 8.95 (singlet, 3H, tertiary methyl) and 9.04 (doublet, 3H, - 249 - secondary methyl, J = 6.2 Hz).

The isolation of gram amounts of pure trans vicinyl methyl enol lactone (420) started with a 1:1 mixture of cis:trans enol lactones prepared by allylating compound 400 with a lithium base and converting

the product to enol lactone or by repetitive seeding of the enol lactone

mixture with the cis compound (419). By further careful crystallizations

at -10° in hexane and suction filtration at 0°, a 30:70 cis-.trans mixture

of enol lactones could be isolated. Further enrichment was not practical,

but the trans isomer could not be induced to crystallize. Hydrolysis

of this (10 g enol lactone/20 ml 5% NaOH/10 mlTHF/2 h reflux under N2)

to a mixture of keto acids permitted the isolation of pure trans keto

acid 418 (2.3 g) by crystallizing from hexane. A more efficient way to

isolate the elusive trans isomer series in pure form was to chromatograph

the 419/420 mixture on one hundred times its weight of silica gel with

20% diethyl ether in petroleum ether. • The trans isomer (420) was eluted

first and two successive chromatographies afforded 95% pure trans enol

lactone. The final stage of purification was then hydrolysis and

purification of the trans keto acid 418 by a series of crystallizations

from hexane:ether. This white crystalline compound exhibited m.p. 62-63.5°;

1 infrared (CHC13) 3800-2500 (carboxyl -OH), 1710 cm" (both carbonyls) and

n.m.r. T -0.80 (singlet (w. @ \ p.h. = 3 Hz), IH, -COOH), 8.91 (singlet,

3H, tertiary methyl) and 9.00 (unresolved multiplet, 3H, secondary methyl).

Conversion of this trans keto acid 418 to its methyl ester with argenous

oxide and methyl iodide in methanol (97) gave a colourless oil (95%)

which exhibited infrared (film) 1735 (ester carbonyl), 1705 cm L

(cyclohexanone carbonyl) and n.m.r. resonances at x 6.31 (singlet, 3H, - 250 -

-OCH3), 8.93 (singlet, 3H, tertiary methyl), and 9.01 (unresolved multiplet, 3H, secondary methyl). The corresponding cis keto acid methyl ester showed the same major infrared absorptions (1735, 1705 cm X) and had n.m.r. signals at x 6.31 (singlet, 3H, -OCH^), 8.97 (singlet, 3H, tertiary methyl), and 9.05 (doublet, 3H, secondary methyl, J = 6.2 Hz).

A mixture of the two methyl esters could be recognized by the appearance of the cis ester's tertiary methyl at slightly higher field than that of the trans plus the fact that the trans ester was eluted from column G

(185°, 95) ahead of the cis compound.

The recrystallized trans keto acid purified above (3.96 g) was then converted to the trans enol lactone with sodium acetate in acetic anhydride, following the usual general procedure, to afford 3.36 g (93%) of a colourless oil (120° at 0.75 mm) having infrared (film) 1758 (enol lactone carbonyl) and 1680 cm X (enol unsaturation) and n.m.r. signals at x 4.69 (triplet, IH, C6H, J = 4.0 Hz), 7.2-7.5 (multiplet, 2H,

-CH2C00-), 8.78 (singlet, 3H, tertiary methyl) and 9.03 (doublet, 3H, secondary methyl, J = 6.4 Hz).

(iii) A solution of the crystalline cis enol lactone 419 (17.1 g,

0.096 moles) in 200 ml of anhydrous ether under nitrogen and magnetically stirred was maintained at -25° by means of an external carbon tetrachloride- dry ice slush bath. An ethereal solution of methyl lithium (75 ml of 2.36

M, 0.177 moles) was added dropwise over a 3 min period and the solution was held at -25° for 2 h. The reaction mixture was then quenched by pouring it slowly into excess 6 N hydrochloric acid and the crude product was isolated by extracting the aqueous layer three times with ether, washing the combined ethereal layers with water and concentrating the - 251 - organic residues under reduced pressure. These residues were then treated under a nitrogen atmosphere with a refluxing solution of potassium hydroxide (20 g) in water (100 ml) and methanol (1 1.) for

3 hours. The methanol was removed under reduced pressure and the residuals were subjected to ether/water partition. The combined ether extracts were dried over magnesium sulfate and, after concentration under reduced pressure, distilled to afford 13.2 g (78%) of the octalone 238, 20

b.p. 96-102° at 0.3 mm, nD 1.5155. Infrared (film), 1665 (conj. carbonyl) and 1615 cm 1 (conj. olefin); n.m.r. x 4.25 (broadened singlet (w. @ \ p. h. = 2.5 Hz), IH, C^H), 8.88 (singlet, 3H, tertiary methyl) and 9.C7

(unresolved multiplet, 3H, secondary methyl); and ultraviolet Xmax 239 my

(e = 15,500). A workup of the basic aqueous layer provided 1.7 g (9%)

of recovered keto acid 417.

When the above reaction was repeated on a smaller scale with 3.25 g

of cis enol lactone, 2.37 g (73.7%) cis vicinyl methyl dimethyl octalone

and 0.296 g (8.2%) cis keto acid (417) were isolated. However when the

reaction was repeated in a duplicate manner on 3.24 g of trans enol

lactone 420, only 1.004 g (31.3%) trans vicinyl dimethyl octalone 239

and 0.690 g (19.4%) trans keto acid (418) were recovered. The trans

octalone 239 exhibited infrared (film), 1665 (conj. carbonyl) and 1615 cm 1

(conj. olefin); n.m.r. x 4.17 (broadened singlet (w. @ \ p.h. = 4.0 Hz)

IH, C1H), 8.68 (singlet, 3H, tertiary methyl), and 9.05 (doublet, 3H,

secondary methyl); and ultraviolet X 241 my (e = 14,000). max

The following table summarizes all experiments performed using

methyllithium and the enol lactones at -25° for 1 3/4-2 h. The ratio

of the enol lactones 419:420 was determined by.n.m.r. as previously - 252 -

Table II. Product Distribution Obtained by Methyllithium Treatment

of Enol Lactones.

Wt. Enol Ratio of CH3Li Enol Lactone Octalone Octalone Recovered Lactone Used to Enol Lactone 419:420 Yield 238:239 Keto Acid (g) (%) (%)

20. 0a 1.59 100:0 61 100:0 18.3 31.5a 1.69 100:0 67.7 100:0 13.4 17. lb 1.82 100:0 78 100:0 9 28.4b 1.93 100:0 60.4 100:0 2.7 3.25b 1.78 100:0 73.7 100:0 8.2 3.24b 1.88 0:100 31.3 0:100 19.4 7.60b 1.75 59:41 38.7 92:8 12 6.20b 1.83 36:64 25.6 72:28,. 13 6.20b 1.83 84:16 58 95:5 8 a 1 3/4 h at -25°; b 2 h at -25°

described. The recovered keto acid was dehydrated with acetic anhydride and sodium acetate and, in all cases was found to have the same cis:trans composition as the starting mixture of enol lactone. The relative amounts of octalone 238 and 239 were determined by the relative integration of the T 4.25 and 4.17 vinyl resonances on a 100 hertz sweep width by a 60 M

Hz instrument. A sample consisting of a 92:8 ratio of cis-238:trans-239 by weight analyzed 93:7 spectroscopically. In those cases where low yields were obtained, a second product was isolated during the distillation of

the octalones under reduced pressure. This compound showed a slightly higher boiling point than the octalone and had to be redistilled to achieve good separation. A strong infrared absorption at 3500 cm 1 (OH) and weaker 1710 carbonyl (cyclohexanone) with additional methyl singlets in the - 253 -

n.m.r. were observed for this compound.

In summary, the experimental work showed a close agreement between b.p.'s and m.p.'s observed above and the values previously reported in the literature. In addition to the literature information on the O 3. cis enol lactone 419 (lit. m.p. 51.0-51.5 (184 ) versus observed 51.0-

51.5°) and octalone 238 (lit. b.p. 96-99° at 0.2 mm (184a) versus observed b.p. 96-102° at 0.3 mm), the data for the individually purified keto acids 417 (m.p. 40-41.5°) and 418 (m.p. 62-63.5°), the trans enol lactone 420 (b.p. 120° at 0.75 mm), and trans octalone 239 (b.p. 96-102° at 0.3 mm) can now be added. The analytical analyses of these compounds have previously been reported (184 ) with the exception of octalone 239 which analyzed correctly as indicated in part (c) below.

(b) - The above octalones were derived from the Wieland-Miescher ketone (204) by protecting the conjugated carbonyl and then elaborating

the C-5 carbonyl to a methyl group.

The Wieland-Miescher ketone (5.82 g, 33 mmoles) was dissolved in a

solution of 2,2-dimethoxypropane (50 ml), dimethylformamide (50 ml)

and methanol (2 ml) (200). p_-Toluenesulfonic acid (260 mg) was added

and the solution was refluxed under nitrogen for 4 h, cooled and

neutralized with solid sodium bicarbonate. Addition to ice water,

extraction with ether, and brine/magnesium sulfate drying of the

organic layer afforded a crude product. This product was subjected

to a short path distillation (115° at 0.75 mm Hg) to yield in 93% the - 254 - desired enol ether 453 (5.81 g, 30 mmoles) as a yellow oil, infrared

(film); 1710 (saturated carbonyl), 1660, 1630, 1240, 1175 cm"1 (dienol g

ether) and n.m.r. x 4.55 (broadened triplet, IH, C E), 4.77 (singlet,

IH, C1^), 6.41 (singlet, 3H, OCH ), and 8.77 (singlet, 3H, tertiary methyl).

A solution of methylsulfinyl carbanion was prepared by heating"

sodium hydride (20 mmoles as a 50% oil dispersion) in dimethyl

sulfoxide (50 ml) to 65-70° for 30 min under a nitrogen atmosphere (201).

Triphenylmethylphosphonium bromide (12 g, 34 mmoles) was added to this

basic solution after it was cooled to room temperature. The completion

of ylide formation from the bromide was then ensured by warming the

solution to 65° with a water bath for 30 min. The ketone 453 (1.91 g,

10.0 mmoles), in dimethyl sulfoxide (50 ml), was added after the

solution was cooled to room temperature and the magnetically stirred

reaction was left overnight (20 h) under a nitrogen atmosphere. A

petroleum ether:water partition of the reaction solution and an aqueous

bicarbonate, water, and brine wash of the petroleum ether layer provided

an anhydrous magnesium sulfate dried residue that was subjected to a

short path distillation (110° at 0.8 mm) to afford the olefinic enol

ether 454 (1.76 g, 9.3 mmoles) as a transparent yellow oil in 93% yield.

Infrared (film) showed 1660, 1630, 1245, 1220, 1175 and 890 cm"1 and

n.m.r. exhibited x 4.76 (triplet, IH, C H, J ^ 3.5 Hz), 4.87 (singlet,

IH, C1^), 5.30 (doublet, 2H, exocyclic methylene), 6.45 (singlet, 3H,

0CH3) and 8.81 (singlet, 3H, tertiary methyl).

A methanol solution (15 ml) of this enol ether (580 mg, 3.3 mmoles)

was treated with 2 N hydrochloric acid (1 ml) for 15 min, partitioned - 255 - between petroleum ether and water and the organic layer was washed, dried and subjected to the usual short path distillation (105° at 0.4 mm) to provide 464 mg (88%) of octalone 455. If instead of a methanolic hydrochloric acid solution, a benzene or toluene solution (50 ml) of the olefinic enol ether 454 (150 mg) and p_-toluenesulfonic acid (100 mg) was refluxed for 24 h, an 80% yield of pure octalone 456 (114 mg) was isolated after the workup and distillation. The former octalone

(455) showed infrared (film): 1670 (conj. carbonyl) and 1620 cm 1

(conj. olefin); n.m.r. T 4.25 (broadened singlet, IH, C^H), 5.18

(broadened singlet, 2H, =CH2), and 8.62 (singlet, 3H, tertiary methyl);

and ultraviolet A 238 my (e = 15,100) while the latter (456) max

exhibited infrared (film): 1670 (conj. carbonyl) and 1630 cm (conj.

olefin); n.m.r. T 4.22 (broadened singlet (w. @ 1/2 p.h. = 2.5 Hz), IH,

cho, 4.-53 (very broad singlet (w. @ 1/2 p.h. = 9.0 Hz), IH, C6H), 8.30

(doublet of doublets, 3H, vinyl methyl, J = 3.2, 1.5 Hz), and 8.64

(singlet, 3H, tertiary methyl); and ultraviolet A 237 (15,700). max Both compounds are C.-H-^O isomers and have a calculated analysis of 1Z lo

C, 81.77; H, 9.15. Compound 455 was found to analyze as C, 81.51; H,

9.17 while compound 456 analyzed as C, 81.61; H, 9.06.

When aliquots were taken from the p_-Ts0H isomerization reaction

after 1 h, only compound 455 was present, but after 12 h there was

a 30:70 mixture of 455:456 as measured by n.m.r. (exocyclic methylene

versus C-6 vinyl proton) or g.l.c. (column B, 180°, 97). Also when

the Wieland-Miescher ketone (6.0 g, 33.7 mmoles) was successively

treated with dimethoxypropane, the methylene ylide, and p_-TsOH,

using a minimal workup, a 64% overall yield (3.77 g) of pure compound - 256 -

456 was obtained. This yield could probably be increased since the

Wieland-Miescher ketone (10.1 g, 56.7 mmoles) was found to yield 95% compound 455 overall by the reaction of 204 with dimethoxypropane (5 h) and then with methylene ylide (30 h), using a 4 N hydrochloric acid wash of the organic layer in the final workup and two successive short path distillations. In general, the overall yields appear to be enhanced if the enol ether intermediates are kept away from oxygen and light.

The olefinic enol ether (496 mg of 454) was hydrogenated in benzene

(75 ml) with tris(triphenylphosphine)chlororhodium (220 mg) for 16 h and worked up in the usual way (113). The crude product was treated with methanolic hydrochloric acid, worked up and distilled (120° at

0.8 mm) to afford 418 mg (90%) of a 55:45 mixture of the cis and trans vicinyl dimethyl octalones 238 and 239. When the octalone 455

(230 mg) was hydrogenated in a similar manner with (c^P^RhCl, a 98% yield (228 mg) of a 75:25 mixture of 238:239 was obtained. Compound

456 would not reduce under these conditions,but hydrogenation with 5%

palladium on charcoal in ethanol (50 ml) containing hydrochloric acid

(0.4 ml) yielded a 1:1 mixture of 457:458. This mixture exhibited a

strong saturated carbonyl in the infrared (1715 cm ^) with the

unconjugated vinyl protons (overlapping broadened singlets at T 4.53

and 4.67) and tertiary methyls (T 8.81, 8.84) demonstrating the isomer

ratio by the chemical shift differences in the n.m.r. Compound 457

was prepared from compound 456 in an unambiguous manner by utilizing

the Birch reduction (Li/NH^) and distilling the oxidized (CrO^/

pyridine) crude product to yield an authentic sample of the trans-fused - 257 - ring system (457, T 4.67 vinyl proton and 8.84 methyl by n.m.r.).

When compound 455 was hydrogenated with palladium on charcoal, a 1:1 mixture of cis-fused:trans-fused dihydro-455 was isolated. The exocyclic methylene at T 5.10 and tertiary methyl at x 8.69 in the n.m.r. of the product mixture were assigned to the cis-fused isomer since a Birch reduction of compound 455 afforded only the trans-fused isomer having vinyl protons centered at x 5.30 and the tertiary methyl at T 8.79.

Also, when this latter Birch product was hydrogenated with (

(dihydro-238 having x 9.06 tertiary methyl by n.m.r. while dihydro-239

showed x 8.83) and confirmed by comparison with the Birch products of

octalone 238 and octalone 239.

(c). The 4a,5-trans-dimethy1-4,4a,5,6,7,8-hexahydro-2(3H)-naphthal-

enone (239) was prepared by the conjugate addition of lithium dimethyl-

cuprate to the cross-conjugated dienone 300 (182 , 204) and the subsequent

transposition of the conjugated carbonyl to the second ring by a

procedure analogous to one developed by Marshall and Brady (205).

A solution of lithium dimethylcuprate was prepared by adding 26 ml

of a 2.0 M ethereal solution of methyllithium (52 mmoles) to an ice

cold slurry of cuprous iodide (5.0 g, 26 mmoles) in anhydrous ether

(80 ml). The dienone 300 (2.00 g, 12.3 mmoles) was added dropwise

over 5 min to the resulting clear solution. The thick yellow solution

(polymeric methylcopper) produced was stirred at 0° for 1 h and the

reaction was quenched by addition to a rapidly stirred saturated aqueous - 258 - solution of ammonium chloride (200 ml). Concentrated ammonium hydroxide

(25 ml) was added to solubilize the precipitated copper salts and the partitioned ether layer was washed with water, dilute ammonium hydroxide, and brine. The organic layer was then dried over anhydrous magnesium sulfate, concentrated under reduced pressure and distilled

(short path apparatus, 110° at 0.6 mm) to yield 1.91 g (87%) of yellow tinted 381. Gas liquid chromatography (column B, 172°, 94) showed this crude product to be 98% pure and therefore suitable for direct use in the next reaction. A redistilled sample provided a colourless oil that exhibited infrared (film) of 1670 (conj. carbonyl) and 1620 cm 1

(conj. olefin); n.m.r. T 4.22 (broadened singlet (w. @ 1/2 p.h. = 2.8

Hz), IH, C^), 8.71 (singlet, 3H, tertiary methyl), and 9.00 (doublet,

3H, secondary methyl, J = 6.6 Hz); ultraviolet A 240 my (e = 14,200).

in 3.x

The procedure of Ringold and Malhotra (155) was adapted by adding, at room temperature, 8.08 g (45.4 mmoles) of compound 381 in 50 ml

2-methoxyethyl ether (diglyme) to a degassed potassium _t-butoxide solution formed from 9.0 g (225 mmoles) potassium and 250 ml _t-butanol under a nitrogen atmosphere. After standing overnight (14 h), the magnetically stirred basic solution was quenched by the addition of

250 ml of 20% acetic acid in water. This homogeneous solution was then diluted with 400 ml of 6% acetic acid in water and extracted twice in a separatory funnel with a 1:1 petroleum ether:ethyl ether solution.

The organic layer was washed three times with water (100 ml), three

times (carefully!) with saturated sodium bicarbonate (50 ml) and once with brine. After concentrating the magnesium sulfate dried solution under reduced pressure and removing the last traces of solvent on a vacuum pump, the crude product (467) showed an infrared (film) 1722 cm ^ - 259 -

(unconj. carbonyl) and n.m.r. T 4.50 (multiplet, IH, vinyl proton), 8.71

(singlet, 3H, tertiary methyl), and 9.11 (doublet, 3H, secondary methyl,

J = 6.6 Hz). This transparent red oil was used immediately in the next step.

To a suspension of lithium aluminum hydride (3.0 g) in anhydrous ether (250 ml) cooled to 0° was added dropwise a solution of the above crude unconjugated ketone in 100 ml of ether. After overnight stirring, the reaction was quenched by the addition of 15 ml of saturated sodium sulfate and dried one hour later by the addition of magnesium sulfate. The crude product showed, no carbonyl but did have a strong hydroxyl (3100-3600 cm ^) in the infrared and, after it was concentrated under reduced pressure, it was heated at reflux under nitrogen with 60 ml acetic anhydride and 5.0 g of sodium acetate for

3 h. This reaction mixture was processed by removal of the excess anhydride at reduced pressure (bath temperature 60°) and by partition between water:ether. The organic layer was dried and concentrated in

the usual manner and then distilled to afford 7.66 g (76% overall

from 381) of a colourless oil, the homoallylic acetate 469, b.p. 81°

at 0.35 mm. This product exhibited infrared (film) 1735 cm 1 (ester

carbonyl) and a single component by g.l.c. (column D), but its n.m.r.

demonstrated that two C-7 acetate epimers were present, both having

T 4.50 (multiplet, IH, ClE), 4.97 (multiplet, IH, C?H), and 9.03

(doublet, 3H, secondary methyl, J = 6.5 Hz) signals with the minor 3a

isomer assigned the x 7.98 (singlet, 3H, acetyl methyl) and the T 8.82

(singlet, 3H, tertiary methyl) absorptions while the ones at T 8.00

(singlet, 3H, acetyl methyl) and 8.88 (singlet, 3H, tertiary methyl)

were attributed to the 73-acetoxy derivative. - 260 -

A solution of the above acetate mixture (7.50 g, 33.8 mmoles) in glacial acetic acid (75 ml) and acetic anhydride (45 ml) was cooled to

0° and treated portionwise (4 x 5.0 g) with 20 g of anhydrous sodium chromate (163). The mixture was allowed to warm to 25-30° and stirred for 35 h. It was then poured into an ice cooled solution of 20% sodium hydroxide (300 ml) overlaid with ether (200 ml) and left stirring overnight. Workup via water:ether partition, magnesium sulfate drying of the organic layer and a short path distillation (126° at 0.3 mm) afforded 6.39 g (80%) of the crude keto acetate 470, infrared (film)

1740 (acetate carbonyl), 1680 (conj. carbonyl), and 1620 cm 1 (conj.

olefin) with n.m.r. T 4.15 (broadened singlet, IH, C^H), 4.85 (multiplet,

IH, C^H) and 8.00 (singlets, 3H, methyl of acetate). This very viscous

oil was used without further purification.

The keto acetate 470 was dehydroacetoxylated by treatment under

nitrogen with 1.8 ml of concentrated hydrochloric acid in 200 ml of

gently refluxing ethanol for 4 h (149). The cooled solution was then

concentrated under reduced pressure and subjected to an ether:water

partition. The combined dried organic layers were concentrated and

distilled under reduced pressure through a short-path micro distillation

apparatus to provide 4.12 g (86%) of the desired dienone (b.p. 107° at

0.4 mm). Infrared (film) 1660 (conj. carbonyl) and 1620, 1588 cm g

(conj. unsaturation); n.m.r. T 3.85 (singlet, IH, vinyl C H), 3.88

(doublet, IH, vinyl C7H, J = 3 Hz), 4.22 (singlet, IH, vinyl t^H), 8.75

(singlet, 3H, tertiary methyl) and 9.09 (doublet, 3H, secondary methyl,

J = 7.0 Hz); and ultraviolet A 282 (e = 31,300). max

The dienone 471 was hydrogenated with 5% palladium on carbon (54 mg)

in a solution containing benzene (35 ml), ethanol (14 ml) and 0.27 N - 261 - ethanolic potassium hydroxide (1 ml) (i.e. 50 ml of 0.005 N KOH). The catalyst was pre-reduced in 35 ml of solvent for 45 min, the compound

471 (266 mg, 1.5 mmole) was added in an additional 15 ml of solvent and the hydrogen uptake was monitored for the rapidly stirred solution.

After the theoretical amount of hydrogen had been absorbed (36 ml, 60 min), the reaction was stopped, the solution was washed with aqueous hydroxide (1 N) and brine. The magnesium sulfate dried organic layer was concentrated under reduced pressure and submitted to a short path distillation (115° at 0.45 mm) to afford 249 mg (93%) of a dihydro compound. A g.l.c. collected (column D, 200°, 100) sample of this compound provided infrared and n.m.r. spectra that were superimposable

on those obtained for compound 239. Mol. wt. calcd. for C10H100:

178.137. Found (high resolution mass spectrometry): 178.136.

In contrast to the above rapid reaction, the hydrogenation of

compound 471 with ((f^P^RhCl in benzene (113) proceeded slowly, giving

approximately a 1:6 ratio of 471:239 after two days.

Androst-4-en-3-one (240)

(a) Compound 240 was derived from 33~hydroxyandrost-5-en-17-one by

using Barton's Wolff-Kishner procedure (173) followed by either an

oxidation under mildly basic conditions (a modified Collins (158)) or

an oxidation under mildly acidic conditions (a Snatzke oxidation (221)).

The diethylene glycol solution required for the Wolff-Kishner

reduction of 3$-hydroxyandrost-5-en-17-one was prepared by reacting

sodium (2 g, 87 mmole) with diethylene glycol (60 ml) and then distilling

sufficient anhydrous hydrazine into this solution until it refluxed - 262 -

freely at 180°. The anhydrous hydrazine was generated by refluxing 95% hydrazine (25 ml) over sodium hydroxide (25 g) for 3 h. To the cooled

solution, 33-hydroxyandrost-5-en-17-one (5.0 g, 17.3 mmoles) was

added and the solution refluxed in the all glass apparatus for 12 h under protection from atmospheric moisture. The reaction temperature was raised to 210° by distilling excess hydrazine from the vessel.

After refluxing for an additional 24 h, the cooled solution was diluted with water (150 ml) and extracted with toluene (2 x 100 ml). The

organic layer was washed with water (4 x 15 ml), dried (anhydrous MgSO^)

and evaporated to a white crystalline solid. Distillation of this

material under reduced pressure afforded 4.67 g (98% yield) androst-5-

en-3g-ol (474), b.p. 165° at 0.3 mm, m.p. 133-136°. This material was free of carbonyl absorption by infrared and showed one peak by

g.l.c. (column B, 240°, 100). A methanol recrystallized sample exhibited

26 m.p. 134-136° and [a] -77° (c, 1.0 in CHC13) (lit. m.p. 135-136°

22 (208) and [a] -74° (c, 1.0 in dioxane) (223)); infrared (CHC13):

3610 and 3450 cm L (hydroxyl -OH); and n.m.r. x 4.64 (unresolved

multiplet (width @ 1/2 p.h. = 9 Hz), IH, olefinic C5H), 6.51 (very 3 broad signal, IH, C HOH), 8.97 (singlet, 3H, tertiary methyl) and 9.26 (singlet, 3H, tertiary methyl). Deuterium oxide exchanged one proton 3

(C HOH) singlet at T 8.20 in the n.m.r.

Anhydrous chromium trioxide (8.0 g, 80 mmoles) was added to

dimethylformamide (300 ml) and the magnetically stirred solution was

cooled to 0°. The 3,y-unsaturated sterol 474 (4.38 g, 16 mmoles) was

dissolved in dimethylformamide (100 ml) and added to the reaction

vessel with subsequent additions of sulfuric acid (3 x 0.5 ml) at 1/4 h

intervals. The oxidation was monitored by quenching reaction aliquots - 263 -

(1 ml) with an aqueous bicarbonate/chloroform partition and by analyzing the organic residue by g.l.c. (column A or B, 236°, 100). The reaction was" quenched after 1 1/4 h (30 min after the third addition of acid) by adding the dark solution to a well stirred solution of sodium bicarbonate. The benzene extractions were followed by the concentration of the organic layers under reduced pressure and a short path distillation

(160-210° @ 0.3 mm) to afford 3.78 (86% yield) of a yellow oil analyzing

8% starting material and 92% oxidation products. The g.l.c. separated oxidation components were in a ratio of 72:28 and this analysis was found to be unaffected by the reaction workup. When a modified Collins oxidation (158) replaced the above Snatzke reaction (221), androst-5- en-38-ol (2.7 g, 9.9 mmoles) was oxidized over 2 h with anhydrous chromium trioxide (9.0 g, 90 mmoles) in a solution of methylene chloride

(140 ml)-pyridine (25 ml), passed through an alumina column (30 g,

Act. I), concentrated and distilled to afford 2.2 g of the same 72:28 product mixture of 240:493+494.

While two successive careful distillations (165° @ 0.3 mm) could

give the major product in ^95% pure form, pure androstenone (2.49 g or

57% yield on the overall oxidation reaction) was obtained by eluting

the above Snatzke oxidation mixture from a 200 g Act. I alumina column with benzene containing up to 4% ether. The androst-4-en-3-one crystallized

on standing and a recrystallization from methanol afforded an analytical

25 sample m.p. 106-107° and [a] +104° (c, 1 in CHC13) (lit., m.p. 103-106°

(208) and [a] + 93±2.5° (dioxane) (209)); infrared (CHC13>: 1665

(conj. carbonyl) and 1616 cm 1 (conj. unsaturation); n.m.r. x 4.26 4 (broadened singlet (width @ 1/2 p.h. = 3.4 Hz), IH, C H), 8.81 and 9.24 - 264 -

(singlets, 3H, tertiary methyls); and ultraviolet A 242 my (e = 15,400) max

The ultraviolet absorption was unaffected by the addition of acid or base. Both the analytical sample and the chromatographed material from which it was derived were shown to be free of compounds 474 and

493+494 by g.l.c. (column A, 235°, 100).

The minor product 493 was found to predominate in the higher boiling fractions (up to 75% 493+494) of the oxidation product mixture but 493 was eluted separately from 240 off the alumina column by >5%

ether in benzene. Thus while g.l.c. and n.m.r. data showed none of

the androstenone was present, the n.m.r. demonstrated that a 7:3 ratio

of androst-4-ene-3,6-dione to androstane-3,6-dione was present. Using

Fieser's purification procedure (176^,231), 438 mg of this mixture were

dissolved in petroleum ether (30 ml), washed (6 x 10 ml) with

Claisen's alkali (35 g K0H/25ml H20/100 ml CH^H) , and neutralized

with hydrochloric acid at 0°. Extraction with petroleum ether,

drying, concentration, and short path distillation provided 364 mg of

a yellow oil that contained ^5% androstane-3,6-dione. Two crystalliza•

tions of the enedione from methanol gave an analytical sample of 493,

yellow-tinted crystals having m.p. 141.5-142.5° and [c*]^ -72° (c,

1 1 in CHCl^); infrared (CHC13): 1688 cm (broadened conj. carbonyl); 4

= n.m.r. x 3.82 (doublet (width @ h p.h. = 1.4 Hz), IH, C H, JC4H_C2H

0.7 Hz), 8.83 and 9.23 (singlets, 3H, tertiary methyls); and ultra-

OCT ,Me0H + NaOH 0-,„ „_.. viole• -i^t A i 251 my (/e = 10,600)in , A 372, 251 my max max

Anal. Calcd. for C.nH_,0o: C, 79.68; H. 9.15. Found: C, 79.48; 19 26 z H, 9.00. - 265 -

When compound 493 (74 mg, 0.26 mmoles) was hydrogenated in ethyl

acetate with 5% Pd/C (30 mg), the white solid (37 mg., 50%) that was

isolated after filtration, concentration, and distillation (205° @ 0.3

mm) was crystallized from methanol-hexane to afford an analytical sample

5 of 494, m.p. 134-136° and [a]^ -38° (c, 1.1 in CHC13). Infrared

1 (CHC13): 1718 cm (sat'd carbonyl); and n.m.r. T .9.02 and 9.24 (singlets,

3H, tertiary methyls).

C H 0 : 288 209 Mol. Wt. Calcd. for 19 28 2 • • Found (high resolution mass spectrometry): 288.211.

(b) Cholestenone analogues of the androstenone 240 series were

prepared. Cholesterol was purified via its dibromide derivative and

authentic samples of cholest-5-en-3-one and cholest-4-en-3-one were prepared by following the procedure of L.F. Fieser (216), while

cholest-4-ene-3,6-dione was prepared from the cholest-5-en-3-one using

Volger's method (156).

Commercial cholesterol, m.p. 137-139° (40 g, 0.1 mole), dissolved

in absolute ether (250 ml), was treated with bromine (17 g, 0.1 mole) and sodium acetate (1.0 g, 0.01 mole) in acetic acid (150 ml). The

resulting dibromide (481) filter cake was washed with acetic acid

(160 ml) and immediately debrominated by a mechanically stirred slurry

of zinc in ether (300 ml). The powdered zinc (12.0 g, 0.18 mole) was added in 1.5 g portions over 5 minutes and, after 20 minutes, the - 266 - inorganic products were removed by washing the organic solution several times with hydrochloric acid (3 N), water, and sodium hydroxide (6 N). The dried organic solution was concentrated under reduced pressure to a volume of 125 mis, diluted with methanol (125 ml) and concentrated again until the onset of crystallization. The first crop of crystals (30.4 g, 75%) provided analytically pure cholesterol

25 331, m.p. 147-148° and [a] -40° (c, 1.1 in CHC13) (lit. (233) 148.5° 20 -1 and [a] -31.6° (CHClj)); infrared (CHC13): 3625, 3450 cm

(hydroxyl OH); and n.m.r. x 4.60 (broadened singlet, IH, C H), 6.47 3 (very broad multiplet, IH, CH), 8.00 (singlet, IH, -OH), 8.99 (singlet,

19 21 3H, C H3), 9.07 (doublet, 3H, C H3, J = 5 Hz), 9.13 (doublet, 6H, 26 27 18 C H3 + C H3, J = 6 Hz) and 9.31 (singlet, 3H, C H3).

If the dibromide 481 was oxidized with sodium dichromate (20 g) in 55° acetic acid (1 i) in a mechanically stirred flask for 20 minutes and then cooled with an external ice bath, the dibromoketone 482 crystallized readily from solution. Dilution with water (100 ml), suction filtration, and methanol washing of the filter cake afforded a product that was immediately debrominated. Zinc (13 g, 0.19 mole) was added in portions to an ether (500 ml) and acetic acid (7 ml) solution of 482 and the exothermic reaction was cooled with an external ice bath. Pyridine was added to precipitate a white zinc salt and the filtered solution was washed with water and aqueous sodium bicarbonate several times. The solution was then dried and concentrated under reduced pressure so that a crystallization from a 1:1 ether:methanol solution (300 ml) provided the desired cholest-5-en-3-one (21.4 g,

25 54% overall) m.p. 120-122° and [a] -5° (c, 2.0 in CHC13) (lit. (216) - 267 -

25 m.p. 124-129° and [a] -2.5° (c, 2.03 in CHC13); infrared (CHClj) ;

1715 cm 1 (sat'd carbonyl); and n.m.r. T 4.63 (broadened singlet, IH,

C6H), 6.70, 7.23 (doublet, IH, C4H, J = 16 Hz), 8.81 (singlet, 3H,

*i Q O A O *7

C H3), 9.11 (doublet, 6H, C H3 + C H3), and 9.29 (singlet, 3H,

18 C H3).

Alternatively, cholest-5-en-3-one could be prepared directly

from commercial cholesterol in 55% yield by a Collins oxidation (158,

229). Commercial cholesterol (3.90 g, 10.1 mmole) in dichloromethane

(50 ml) was oxidized for 30 minutes by a solution of chromium

trioxide (6.0 g, 60 mmoles) and pyridine (10 ml, 124 mmole) in dichloro• methane (150 ml). The decanted solution was diluted with ether (150 ml), filtered through celite (5 g), washed with aqueous bicarbonate,

and dried over magnesium sulfate. Reduction of volume to i< 30 ml and

the addition of methanol (30 ml) provided cholest-5-en-3-one (2.15 g,

55%).

A solution of cholest-5-en-3-one (4.92 g, 12.8 mmoles), anhydrous

oxalic acid (0.5 g, 5.5 mmole) and 95% ethanol (40 ml) was heated on a

steam bath for 30 minutes and then allowed to stand for several hours at room temperature and then 0°. A suction filtration then yielded

3.51 g (71%) of cholest-4-en-3-one, m.p. 79.5-80.5° and [a]26 +82.9°

5 (c, 2.1 in CHC13) (lit. (216) m.p. 81-82° and [a]^ +92° (c, 2.01 in

1 CHC13)); infrared (CHC13): 1662 (conj. carbonyl) and 1618 cm" (conj. unsaturation); n.m.r. T 4.27 (broadened singlet (width @ \ p.h. = 3.4

A 19 26 Hz), IH, C H), 8.80 (singlet, 3H, C H3), 9.11 (doublet, 6H, C H3 + 27 18 C H0), and 9.27 (singlet, 3H, C H_); and ultraviolet X 242 mu 3 3 max (e = 15,700). - 268 -

A slurry of cholest-5-en-3-one (1.176 g, 3.06 mmole) in methanol

(120 ml) was added to a homogeneous methanol (35 ml) solution of

cupric acetate (120 mg, 0.6 mmole), pyridine (12 ml) and triethylamine

(3.0 ml) at 0°. Air was bubbled through the magnetically stirred

solution for 25 minutes and the reaction was then neutralized with

dilute nitric acid and extracted with petroleum ether (75 ml) (156 ).

This yellow organic layer was washed with dilute acid and extracted

with Claisen's alkali (6 x 10 ml), a methanol (50 ml) solution

containing potassium hydroxide (17.5 g) and water (12.5 ml) (231).

These basic extracts were immediately neutralized within a second

separatory funnel containing a mixture of water (20 ml), hydrochloric

acid (20 ml), ice (60 g) and ether (50 ml). The ethereal layer was

washed with water and bicarbonate before drying over magnesium sulfate

and concentrating under reduced pressure to afford 577 mg (46%) of the

yellow enedione. A recrystallization from methanol yielded analytical

25 cholest-4-ene-3,6-dione m.p. 124-125°, [a] -44° (c, 1.2 in CHC13)

(lit. (214) m.p. 124-125°, [a]D -40° (c, 2.43 in CHC13)); infrared

1 (CHC13): 1688 cm" (conj. carbonyl); n.m.r. T 3.82 (singlet (w. @ h 4 19 p.h. = 1.2 Hz), IH, C H), 8.83 (singlet, 3H, C H3), 9.13 (doublet, 26 27 18 6H, C H3 + C H3, J = 5.8 Hz), and 9.27 (singlet, 3H, C H3); and ultraviolet A 251 mp (e = 10,900). The base extracted petroleum max

ether layer was washed with brine, dried and concentrated to provide

475 mg (y 40%) of a yellow material that was shown to be free of

enedione and to contain only small amounts of cholest-5-en-3-one and

cholest-4-en-3-one. A cupric oxidation on 400 mg of cholest-5-en-3-one - 269 -

did lead to a 75% yield of base soluble material, but in this case

an n.m.r. showed the "enedione" to be quite impure.

in a study that employed either an acidic (Snatzke) (221,222) or

basic (Collins) (227,158) (Corey) (2323) medium. Pertinent results were then extended to 3B-hydroxyandrost-5-ene (474) and other

compounds.

(i) Snatzke Oxidations

The oxidation results in Table Ilia were obtained using purified

cholesterol in acidic dimethylformamide medium (221) and originated

from the following standard procedure. The sterol 331 (387 mg - 4 mg,

1.0 mmole) was dissolved in a magnetically stirred dimethylformamide

(30 ml) solution of anhydrous chromium trioxide (400 mg, 4.0 mmoles).

Ten minutes later, sulfuric acid (96%) (0.10 ml, 1.80 mmole) in dimethylformamide (20 ml) was added. After exactly one hour at room

temperature (23 ) and open to the atmosphere, an external ice bath was applied and aqueous sodium bicarbonate or sodium bisulfite(10 ml x

1 M) and ether (20 ml) were added to quench the reaction. An ether:water partition with a hydrochloric acid (4 N) wash of the organic 5 4

layer removed emulsions. To ensure the partial A •+ A bond

isomerization was complete, an acetone solution (20 ml) of the residue was either treated with (*) hydrochloric acid (4 N x 2 ml) or (**) aqueous oxalic acid (100 mg in 2 ml) on the steam bath for 15 minutes.

The isolated product mixture was then analyzed by n.m.r. using

enlarged double integrals of the downfield region. This work provided - 270 - a measurement of the cholest-5-en-3-one (334) to cholest-4-ene-3,6- dione (480) ratio plus the percentage recovered cholesterol (331) present in the original oxidation reaction mixture. Quantitative information was obtained by adding a weighed amount of purified cholesterol (331) to the product mixture and using double enlarged downfield (3.5-5.0 T) n.m.r. integrals to give actual yields.

Changes or deviations from the above are indicated by the column headed "changes". For example, reaction 12 employed a nitrogen atmosphere in place of air, reaction 20 used 800 mg of chromium trioxide instead of the standard 400 mg and reaction 25 included 600 mg phosphorus pentoxide as an additive.

Table Ilia Chromium Trioxide Oxidations of Cholesterol in

Dimethylformamide.

Experimental Variations from Standard Product P%.atio Procedure (% Recovery Cholesterol) Reaction - Changes - (% Mass Recovery)a 334:480 (% 331)

1 Standard''5 (97%) 73: 27 ( 8%) 2 II A (85%) 74: 26 (13%) ii 3 A (83%) 73: 27 (14%) 4 II * (56%) 71: 29 (25%) 5 " ** (83%) 70: 30 (26%) 6 " AA (98%)(88%) 74: 26 (16%) 7 No Stirring* (65%) 72: 28 (28%) 8 Inverse0 Addition* (99%)(99%) 71: 29 (28%) 9 Oxygen Atmosphere * (74%) 72: 28 (13%) 10 Water (0.10 ml) (97%)(77%)D 73: 27 (17%) Addition** 11 Water (0.5 ml) (77%) 73: 27 (19%) Addition* 12 Nitrogen Atmosphere* (88%) 81: 19 (12%) 13 II II A (90%) 83: 17 (20%) 14 II n (90%) 76: 24 (20%) 15 II II AA (99%)(89%) 78: 22 (14%) 16 Standard at 0°* (80%) 56: 44 (17%) 17 it II II AA (95%) 66: 34 (29%) - 271 -

Table Ilia cont.

ction - Changes - (% Mas s Recovery) 3_34: 480 (% 331)

18 Standard at 0°** (91%) 59: 41 (65%)

19 Double Cr03 (800 mg)* (90%) 60: 40 ( 0%) 20 II II II £ (87%) 66: 34 ( 8%) II II II £ 21 (85%)(86%)D 62: 38 (10%)

22 P205 (300 mg) Addition* (87%) 55: 45 ( 8%) 23 II II II (89%)(73%)D 59: 41 (10%) 24 11 (600 mg) 11 * (81%) 18: 83 ( 5%) 25 II II II *A (84%)(70%) 44: 56 (12%) 26 Increased H2SO4(0.25 ml)* (79%) 41: 59 ( 0%) 27 II . it II jf (78%) 35: 65 ( 3%) 28 II II II £JL (100%)(75%) 43: 57 ( 5%) 29 " (0.50 ml)*(88% ) , 0: 100 ( 0%) 30 II II it (95%)(66%); 0: 100 ( 0%) 31 " " " ft& (92%)(72%) 3: 97 ( 3%) 32 11 (1.0 ml)* (72%) 0: 100 ( 0%) 33 II II II (98%) (50%r 0: 100 ( 0%) 34 II II II *,U (80%) (55%)b 3: 97 ( 3%)

35 Decreased H2S04(0.05 ml)** (72%) 82: 18 (39%) 36 II II II AA (98%)(90%) '83: 17 (23%) 37 No Acid Employed** (94%) (83%)f> 76: 24 (76%) 38 II II II (96%)(81%) 76: 24 (82%)

39 No Acid, N2 Atmosphere** (99%) 88: 12 (74%) 40 II II II II (80%) 86: 14 (78%) + 41 No H ,N2,H20(0.5 ml)** (85%) 80: 20 (86%) + 42 No H ,N2,lgDMF (25 ml)** . (82%) 86: 14 •(69%) 43 No H+, Based** (21%) 0: 0 (100%) 44 No H+, Based** (23%) 0: 0 (100%) + d 45 No H ,Base ,H20 (1.0 ml)** (30%) 0: 0 (100%) 46 HOAc (1.0 ml), Based** (45%) 0: 0 (100%) 47 Acetic Acid Employed (1.0 ml)** (99%) 47: 53 (77%) 48 II II II g£ (95%) 76: 24 (72%) 49 p_-Toluenesulfonic Acid (344 mg)** (89%) 42: 58 (64%)

50 p_-Ts0H-H20 (380 mg)** (74%) 44: 56 (58%) 51 Standard Reaction at 37 ** (84%) 84: 16 (14%) 52 Standard at 37°,Nitrogen** (86%) 90: 10 (19%) 53 Standard at 57° ** (70%) 70: 30 (15%)

54 Standard at 57°, N2** (65%) 82: 18 (15%)

55 H2S04(0.25ml) at 23°,N2** (51%) 58: 42 ( 5%)

a 5 4 Notes Non-acidic material after A A isomerization. ° Quantitative measurement with internal standard.

C Sterol 331 in DMF (20 ml) added to H2S04-Cr03~DMF (30 ml) ^ Base is anhydrous sodium acetate (410 mg, 5.0 mmoles). - 272 -

The stability of the cholestenones and cholestenedione to the

Snatzke reaction conditions were also checked and tabulated in

Table Illb. The unsaturated ketones (1.0 mmole) were reacted with anhydrous chromium trioxide (4.0 mmoles) in dimethylformamide (50 ml) for one hour as outlined below.

Table Illb Snatzke Oxidations of Various Cholesten-3-ones at 23°C.

Compound Oxidation Conditions (% Mass Recovery) 478: 480( ;% 334)

Cholest-•5-en-3-one Standard Snatzke (99%)b 14: 86 (26%) n Standard without Cr03 (95%),° 100: 0 (21%) II Inverse Standard^ (91%) 13: 87 (45%) Cholest-•4-ene-3,6- Standard (0.1 ml H2SO4) (70%) 0: 100 dione ii " (0.25 ml H2S0,) (76%) 0: 100 ii (0.50 ml H2S04) (71%) 0: 100 ii (1.00 ml H2S04) (67%)(27%) 0: 100 II " (0.1 ml H2S04) (82%)(76%) 0: 100 II " (0.5 ml H2S04) (80%)(66%) 0: 100 II " (1.0 ml H2SO4) (74%)(39%) 0: 100

Cholest-•4-en-3-one Standard (0.1 ml H2SO4) (83%)(83%)c 95: 5 II (0.5 ml H2SO4) (93%)(93%) 95: 5

Notes Non-acidic material isolated after oxalic acid isomerization except for 334. ^ Neutral workup conditions employed (NaHC03). c Quantitative measurement with internal standard, the sterol d 334. Steroid J334 in DMF (20 ml) added to H2S04-Cr03-DMF (30 ml).

(ii) Basic Medium Oxidations

The results in Table IV were obtained by using purified cholesterol in a dichloromethane oxidation with dipyridine chromium (VI) oxide.

In the standard reaction, the sterol 331 (387 - 5 mg, 1.0 mmole) was dissolved in dichloromethane (20 ml) and added to the magnetically stirred red dichloromethane (30 ml) solution of anhydrous chromium - 273 - trioxide (600 mg, 6.0 mmoles; 400 mg, 4.0 mmoles; or 200 mg, 2.0 mmoles) and pyridine (1.0 ml, 12.4 mmole). After a thirty minute reaction period in a constant temperature bath (i 1°) at 23°, reactions 1 -> 27 were diluted with ethyl ether (50 ml), filtered through celite (3.0 g) and passed through an alumina bed (4.5 g of Act. Ill) . In the case of reactions 28->57, the reaction was filtered through celite (3.5 g) and washed with dichloromethane (25 ml) into a magnetically stirred ice-cold saturated solution of sodium bicarbonate (50 ml). After dilution with water (50 ml), the aqueous solution was drawn off and discarded and the organic layer was washed with water (50 ml) and 4 N hydrochloric acid

(50 ml) and filtered through sodium chloride/magnesium sulfate. The filtrate from each reaction was concentrated under reduced pressure and solvent traces were removed on high vacuum. This residue was then treated with oxalic acid (400 mg) in acetone (20 ml) in the steam bath for 15 minutes. An ether:water partition with bicarbonate wash yielded the non-acidic reaction products in the organic layer. The residue obtained by drying and concentrating this solution was then weighed and subjected to n.m.r. analysis.

Changes or deviations from the above are indicated in the column headed "changes". For example, reaction 10 employed a nitrogen atmosphere in place of air, reaction 20 used 3.0 ml pyridine instead of

1.0 ml, and reaction 48 used both water and phosphorus pentoxide as additives. - 274 -

Table IV Dipyridine-Chromium(VI) Oxide Oxidations of Cholesterol

in Dichloromethane. (Collins)

Experimental Variations in Standard Product Ratio (% Procedure Recovery Cholesterol) a (% Mass Recovery)^ 334:480 (% 331) Reaction - Changes - CrO^

1 Standard-2- (97%) 89:11 (52%) 2 Standard-2- (96%) 90:10 (50%) 3 Standard-4- (92%) 85:15 (16%) 4 Standard-4- (96%) 85:15 (16%) 5 Standard-6- (89%) 86:14 6 Standard-6- (87%) 83:17 (— 5% ) 7 Nitrogen Atmosphere-4- (92%) 88:12 (45%) 8 Nitrogen-4- (86%) 95:5 (30%) 9 Nitrogen-6- (89%) 94:6 (12%) 10 Nitrogen-6- (76%) 93:7 ( 6%) 11 Water(36 u£) Addition-4- (87%) 84:16 (79%)

12 H20(36 ufc) + P2O5(900 mg)-4- (91%) 91:9 (41%) 13 Standard at 0°-4- (89%) 91:9 (26%) 14 Standard at 0°-4- (71%) 96:4 (33%) 15 Standard at 0°-6- (86%) 89:11 (11%) 16 Standard at 0°-6- (80%) 95:5 ( 8%) 17 - No Pyridine-6- (70%) 81:19 (43%) 18 Pyridine (0.5m])-6- (74%) 89:11 (13%) 19' Pyridine (1.5 ml)-6- (85%) 87:13 ( 3%) 20 Pyridine (3.0 ml)-6- (89%) 88:12 (13%) 21 Pyridine (2/3 ml)-4- (89%) 85:15 (18%) 22 Pyridine (1/3 ml)-2- (83%) 92:8 (47%) 23 Sodium Acetate (409 mg)-4- (97%) 89:11 (18%) 24 Acetic Acid (1.0 ml)-6- (96%) 67:33 (14%) 25 Basec (0.5 mmole)-6- (78%) 95:5 (51%) 26 Based (2.0 mmole)-6- (93%) 93:7 (20%) 27 Based (5.0 mmole)-6- (75%) 83:17 (91%) 28 No Pyridine-6- (92%) (100%) 29 No Pyridine,HoAc (1 ml)-6- (83%) 95:—5 (48%) 30 Pyridine (0.25 ml)-6- (83%) 94:6 (14%) 31 .Pyridine (0.25 ml)-6- (95%) 88:12 (14%) 32 Pyridine (0.5 ml)-6- (89%) 88:12 ( 6%) 33 Pyridine (0.5 ml-6- (96%) 91:9 ( 2%) 34 Pyridine (1.0 ml)-6- (90%) 87:13 ( 2%) 35 Pyridine (1.0 ml)-6- (91%) 86:14 ( 2%) 36 Pyridine (3.0 ml)-6- - (92%) 84:16 ( 7%) 37 Pyridine (3.0 ml)-6- (88%) 79:21 ( 4%) 38 Pyridine (1/3 ml)-4- (94%) 93:7 (15%) 39 Pyridine (1/3 ml)-4- (91%) 91:9 (18%) 40 Pyridine (2/3 ml)-4- (89%) 92:8 (16%) - 275 -

Table IV cont.

Reaction - Changes - CrO a (% Mass Recovery)b 334:480 (% 331)

41 Pyridine (2/3 ml)-4- (90%) 91:9 (15%) 42 Pyridine (1.0 ml)-4- (88%) 87:13 (12%) 43 Pyridine (1.0 ml)-4- (90%) .88:12 (18%) 44 Pyridine (1/3 ml)-2- (91%) 84:16 (50%) 45 Pyridine (1/3 ml)-2- (93%) 83:17 (51%) 46 Pyridine (1.0 ml)-2- (88%) 81:19 (47%) 47 Pyridine (1.0 ml)-2- (97%) 80:20 (53%)

48 H20(36 y£) + P205(150 mg)-4- (79%) 58:42 (70%) 49 Basec (1.0 mmole)-6- (94%) 78:22 (75%) 50 Based (1.0 mmole)-6- (91%) 89:11 ( 4%) 51 .Based (1.0 mmole-6- (95%) 90:10 ( 6%) 52 Based (3.0 mmole)-6- (81%) 86:14 (79%) 53 Based (3.0 mmoles)-6- (87%) 85:15 (71%) 54 Basee (2.0 mmoles)-6- (81%) 89:11 ( 8%) 55 Basee (2.0 mmoles)-6- (92%) 93:7 ( 6%) 56 Basee (4.0 mmoles)-6- (77%) 88:12 (58%) 57 Basee (4.0 mmoles)-6- (81%) 62:38 (67%)

Notes This column lists mole ratio of chromium trioxide to cholesterol, i.e. Oxidant/Sterol ratio. b 5 4 c Non-acidic material after A ->• A isomerization. d Base is 1,8-bis(dimethylamino)naphthalene. Base is triethylamine. Base is diisopropylamine.

The stability of the cholestenones and cholestenedione to the Collins

(6:1 mole ratio) and Corey (3:1 mole ratio) reaction conditions were also checked and tabulated in Table V. The unsaturated ketones

(1.0 mole) were reacted with anhydrous chromium trioxide-nitrogen base complex for one hour as outlined below. - 276 -

Table V Oxidations with CrO *N Base Reagents at 23°.

Compound Oxidation Conditions (% Mass Recovery) 478: 480(% 334)

Cholest-5-en- Standard Collins (70%)b(66%)C 2: 98 (15%) -3-one (334) II Collins without CrO^ (99%)° (100%) II Standard Corey (77%),D —5: 95 (45%) ti b Corey without CrO^ (94%) 100: — (98%) Cholest-4-ene- Standard Collins (96%)(75%)° 0: 100 3,6-dione(480) it Standard Corey (74%)(69%)° 0: 100 Cholest-4-en- Standard Collins (92%) (85%)° 96: 4 3-one (478) it Standard Corey (85%)(78%)C 93: 7

Notes Non-acidic material isolated after oxalic acid isomerization except for 334. D Neutral workup conditions employed (NaHCO^)• c Quantitative measurement with internal standard, the. sterol 331.

The results in Table VI were obtained using cholesterol (387 + 5 mg, 1.0 mmole) in a dichloromethane solution with 3,5-dimethylpyrazole chromium(VI) oxide. In the standard reaction, the sterol 331 was dissolved in dichloromethane (25 ml) and added to a magnetically stirred red dichloromethane solution (25 ml) of anhydrous chromium trioxide (300 mg, 3.0 mmoles; 200 mg, 2.0 mmoles; or 100 mg, 1.0 mmole) and 3,5-dimethylpyrazole (288 mg, 3.0 mmoles; 192 mg, 2.0 mmoles; or

96 mg, 1.0 mmole). After thirty minutes at 23 - 1°, the reaction flask was cooled to 0° and filtered into sat'd sodium bicarbonate solution (50 ml). The filter cake was washed with dichloromethane

(25 ml) and the aqueous layer was discarded. After sequential washing - 277 - with water (50 ml), 4 N hydrochloric acid (50 ml) and 6 N hydrochloric acid, the organic layer was dried over sodium chloride-magnesium sulfate. The organic solvents were removed under reduced pressure after i-propanol (10 ml) had been added. The residue was isomerized

in the usual manner with an oxalic acid solution (25 ml). After

partition between petroleum ether:water, the organic material was

washed with water (10 ml) and dilute sodium bicarbonate and dried over

magnesium sulfate. The residue isolated by concentrating the organic

layer under reduced pressure was pumped down under vacuum to constant

weight, dissolved in deuterochloroform, filtered and analyzed by n.m.r

Entries in Table VI are tabulated in a manner analogous to Table IV.

Table VI 3,5-Bimethylpyrazole-Chromium(VI) Oxide Oxidations of

Cholesterol in Dichloromethane (Corey).

Product Ratio (% Recovery Cholesterol

1 a (X Mass Recovery) -

Reaction - Changes - Cr03 62:38 ( 7%) (78%) -3- 40:60 (29%) 1 Standard (91%) -3- 52:48 (35%) 2 Standard (86%) -2- 45:55 (65%) 3 Standard (80%) -1- 60:40 (37%) 4 Standard (82%) -3- 59:41 (26%) 5 0° Reaction (74%) -3- 51:49 (23%) 6 Nitrogen Atmos (95%) H2O Add'n (2 mmoles) -3- 49:50 (26%) 7 (87%) H2O Add'n (2 mmoles) -3- 38:62 (90%) 8 (78%) Basec (0.5 mmoles) -3- 40:60 (49%) 9 (78%) Base** (1.0 mmoles) -3- 10

. ~ " Tj cl-prnl where oxidant ^^K. Notcs • This. is. actuall.«u.lly m-lo Jj ^Sylpy^ole.

is 1:1 complex of Cr03 ana J,

K -^i aff-pr A -> A isomerization. b Non-acidic material after a c Base is 1,8-bis(dimethylamino)naphthalene.

d Base is triethylamine, - 278 -

The results in Table VII were obtained by adding a dichloromethane

(25 ml) solution of purified cholesterol (387 mg * 5 mg, 1.0 mmole) to a magnetically stirred solution of anhydrous chromium trioxide

(605 mg ± 5 mg, 6.0 mmole) and amine (6.0 mmole) in dichloromethane

(25 ml). After thirty minutes at room temperature, the reactions were quenched in the usual fashion with aqueous bicarbonate, worked

up for isomerization with oxalic acid and analyzed by n.m.r. for the

tabulation. Any variations in the procedure are indicated in the notes

to Table VII. •J

"Collins" Oxidations of Cholesterol Table VII Effect of pK^ on

r pmHuct Ratio with Amount of Product * x) (mg) (% Recovery Cholesterol; K Base - Base (Base P BH+) Reaction 89:11 (35%) 82:18 (33%) 1 Quinoline^ (5.00) (100%) 2 Quinoline ( 1%) 3 N,N-Dimethylaniline° (5.15) 86:14 ( 4%) 4 Pyridine^ (5.25) 89:11 ( 2%) 5 Pyridine , 73:27 ( 2%) 6 4-Methylpyridineb (6.02) 77:23 ( 2%) 7 4-Methylpyridine ^ 78:22 ( 5%) 8 2,4-Dimethylpyridine^ (6.99) 80:20 (32%) 9 2,4-Dimethylpyridine , 83:17 (83%) 10 2,4,6-Trimethylpyridined (7.43) 79:21 (29%) 11 2,4,6-Trimethylpyridine^ 77:23 12 2,4,6-Trimethylpyridine a b Notes Values taken from reference 233 . D Complex formation < 30 minutes. Complex formation over 3 hours. ^ Complex formation over 24 hour period. - 279 -

(iii) Application of Oxidation Studies

Androst-4-en-3-one. Androst-5-en-33~ol (474) (5.48 g, 20 mmoles) was dissolved in dichloromethane (200 ml) and oxidized with a magnet• ically stirred solution of pyridine (16.0 ml, 199 mmole), anhydrous

chromium trioxide (16.0 g, 160 mmoles) and dichloromethane (300 ml)

under a nitrogen atmosphere at 0°. After thirty minutes, the reaction

was quenched by the addition of ether (200 ml) and celite (20 g). The

solution was filtered through a column containing a bed of celite

(10 g) into a saturated solution of sodium bicarbonate (200 ml). After

washing the filtrate twice with water (2 x 200 ml), the organic layer

was washed with 1 N HCI (2 x 200 ml) and concentrated to a small volumne

under reduced pressure. The isomerization with oxalic acid (4.0 g)

in acetone (200 ml) was accomplished by heating on the steam bath for

fifteen minutes, diluting with water (200 ml) and extracting with

petroleum ether (200 ml). Washing this hydrocarbon extract with

Claisen's alkali (4 x 10 ml) (231) removed the enedione oxidation

product and drying over sodium chloride-magnesium sulfate removed

traces of water. Concentration under reduced pressure yielded a

residual oil that was distilled under vacuum (165° at 0.2 mm) to

afford 4.28 g (79%) of a white solid that analyzed 100:0 (6%) for

240:493 (% 474) by n.m.r. and g.l.c. (column A, 235°, 100).

Cholest-4-en-3-one. Cholesterol (7.76 g, 20 mmoles) oxidized as

per above to yield 6.24 (81%) crude product analyzing 98:2 (5%)

A 4 -3-one:A 4-3,6-dion e (% sterol). 280 -

Androst-4-ene-3,6-dione. Androst-5-en-3B-ol (280 mg, 1.0 mmole) was dissolved in dimethylformamide (20 ml), cooled on an ice bath and chromium trioxide (407 mg, 4.0 mmole) was added. After ten minutes, sulfuric acid (0.4 ml, 7.2 mmole) was added in dimethylformamide (10 ml) and the ice bath was removed. After fifteen minutes, the ice bath was replaced and isopropanol (1 ml), petroleum ether (20 ml) and dilute hydrochloric acid (20 ml x 1 N) were added. The aqueous layer was

discarded. The hydrocarbon extract was washed with Claisen's alkali

(6 x 10 ml) (231) and these basic extracts were immediately neutralized

in a separatory funnel containing dilute hydrochloric acid (20 ml x 6 N),

ice (30 g) and ether (30 ml). This second aqueous layer was discarded

and the ethereal layer was washed with sodium carbonate (5 ml of 5%)

containing 10% sodium chloride. The dried organic layer was concentrated

under reduced pressure and solvent traces were removed under vacuum to

afford 187 mg (64%) androst-4-ene-3,6-dione (493).

Employing the procedure of Volger and Brackman (156) on androst-4-

en-3-one yielded the enedione 493 in <50% over four reactions. The

physical properties observed were the. same as those found for androst-4-

ene-3,6-dione in part (a).

(d) Compound _240 was derived from testosterone by protecting the

C-3 carbonyl and then performing a Wolff-Kishner reduction on the C-17

carbonyl introduced by chromate oxidation. The preparation of the various

individual Wolff-Kishner precursors, C-3 protected testosterone

derivatives, is considered under the appropriate headings of (i) the

1,3-dioxolane (ethylene glycol ketal) (563), (ii) the methyl enol ether - 281

(602), (iii) the 1,3-dithiolane (1,2-ethanedithiol ketal) (598),

(iv) the substituted 1,3-dioxane (2,2-dimethyl-l,3-propanediol ketal)

(594), and (v) the 1,3-dithiane (1,3-propanedithiol ketal) (600) derivatives. The preparation of the bis-1,3-dioxane derivative (621)

of androst-4-ene-3,17-dione is given in (vi). The Wolff-Kishner

reductions are then considered part (vii).

(i) Testosterone (9.60 g, 33.3 mmoles of 472) was placed in a

Dean-Stark apparatus with ethylene glycol (50 ml, 894 mmoles), benzene

(300 ml) and p-toluenesulfonic acid monohydrate (200 mg) (263 ' ,265).

The solution was refluxed for 20 h in a nitrogen atmosphere and then

the cooled organic layer was washed with aqueous bicarbonate and dried

over anhydrous magnesium sulfate. The removal of the solvent under

reduced pressure left 10.4 g (97%) of crude ketal 561. The analysis

of the 472:561 ratio as 20:80 was accomplished through a measurement

4 6 of the relative vinyl C H (472) to vinyl C H (561) ratio exhibited in

the n.m.r. of the crude product. An analytical sample of 561 was

obtained by recrystallizing the crude product from methanol containing 25

a drop of pyridine. This material showed m.p. 178-179° and [a]^ -40.5°

a 2 (c, 1 in CHC13) lit. (266 ), m.p. 183-184° and [a] ^ -43.1 (CHClj);

infrared (CHCip: 3600 and 3450 cm"1 (hydroxyl); n.m.r. T 4.69 (multiplet.

1H, =C6H), 6.05 (singlet, 4H, OCH CH 0), 6.37 (triplet, IH, C1?H0H), 6.55

(singlet, IH, C17H0H), and 8.95, 9.23 (singlets, 3H, methyls).

Addition of deuterium oxide to n.m.r. sample removed the T 6.55

resonance. , . nsftt the above crude A-r^A Collins oxidation (158), Fmnloving a modified com"* , , was added to a .gno.iclly stirred,

ketal 561 (10.2 g, 31.7 »oleS) w-s - 282 - ice cooled solution of dichloromethane (400 ml), pyridine (80 ml,

1.0 mole) and anhydrous chromium trioxide (32 g, 320 mmoles). The reaction was left overnight (12 h) and then partitioned between water/

chloroform. The organic layer was washed several times with water,

dried with magnesium sulfate, treated with celite/charcoal, and

evaporated to dryness under reduced pressure. The crude ketal was an 4 6

20:80 ratio of 562:563 as evidenced by the C H:C H vinyl protons in

the n.m.r. (561 completely absent). An analytical sample of 563

was obtained by a crystallization from methanol containing a drop of

pyridine. The fine white needles of compound 563 had m.p. 194-196°

24 3 and [a] +15.8° (c, 1.0 in CHC13) (lit. (266 ), m.p. 197-198° and

[a] +15.4° (CHC13)); infrared (CHC13): 1735 cm" (sat'd carbonyl);

6 n.m.r. T 4.58 (multiplet, IH, C H), 6.03 (singlet, 4H, 0CH2CH 0), 8.93

and 9.10 (singlets, 3H, methyls).

As an alternative to the Salmi dioxolanation and chromate

oxidation route to 563, the chromate oxidation of testosterone with

selective dioxolanation at C-3 (266 ) was employed.

Testosterone (1.002 g, 3.5 mmoles) was added to a prepared

solution of anhydrous chromium trioxide (3.8 g, 38.0 mmoles) and

pyridine (10 ml, 124 mmoles) in dichloromethane (40 ml). After 2 h

the magnetically stirred solution was passed through a bed of alumina

(Act. I, 40 g) and the bed was washed with dichloromethane (100 ml)

and ethyl acetate (100 ml). Solvent removal under reduced pressure

with high vacuum removal of traces of solvent afforded 984 mg (98%)

of a white crystalline solid 562 having m.p. 156-158°. An analytical

sample was crystallized from hexane-chloroform and showed m.p. 169-171' - 283 -

26 and [a] +198° (c, 1.07 in CHC13> (lit. (267), m.p. 173-174° and

[

(conj. carbonyl), and 1620 cm 1 (conj. olefin); n.m.r. x 4.21

(broadened singlet, IH, cSl), 8.75 and 9.06 (singlets, 3H, methyls);

and ultraviolet X 239 (e = 16,400). max Treatment of compound 563 with dilute hydrochloric acid in acetone

also yielded 562 quantitatively.

The exchange dioxolanation was achieved using a toluene (15 ml)

solution of 562 (1.886 g, 6.6 mmoles), 2-methyl-2-ethyl-l,3-dioxolane

(20 g purified by distilling 25 g of butanone ketal from 0.5 g LiAlH^)

(266 ) , and p_-toluenesulf onic acid (20 mg) . The solution was maintained

at 110° for 7 h in a sand bath before the cooled reaction mixture was

diluted with water and extracted with ether. The organic extracts

were washed successively with 5% aqueous bicarbonate and water, and

then dried and concentrated in the usual manner. Crystallization of the

residual red oil from ether (much better than methanol) afforded two

crops of the 3-monodioxolane (1.17 g, 53% yield) while hydrolysis

(HCl/acetone) of the mother liquors and elution from alumina yielded

pure androst-4-ene-3,17-dione (744 mg, 40%). The recrystallized

monodioxolane provided experimental data superimposable on that

reported for 3,3-ethyienedioxyandrost-5-en-17-one (563).

(ii) Testosterone (2.00 g, 6.9 mmoles) was dissolved in 10 ml

dimethylformamide and 10 ml 2,2-dimethoxypropane. p_-Toluenesulfonic

acid monohydrate (40 mg) and methanol (0.4 ml) were added (200) and

the solution was refluxed under nitrogen with a Dean-Stark trap used - 284 - to remove 10 ml of solution over the first 2 h period. This was replaced with 10 ml of additional solvent mixture and the heating

was continued for 2 h longer. The cooled solution was neutralized

with sodium bicarbonate (500 mg), filtered, and concentrated under

reduced pressure to afford 601 as a viscous yellow oil. Infrared

(neat): 3450 (hydroxyl), 1660, 1635 cm 1 (enol ether); and n.m.r.

T 4.76 (multiplet, IH, C6H), 4.85 (singlet, IH, C4H), 6.40 (singlet,

3H, 0CH3), 9.00 and 9.20 (singlets, 3H, methyls). This material

was used immediately in a modified Collins oxidation (158) by adding

the enol ether 601 to a magnetically stirred solution of chromium

trioxide (7.0 g, 70 mmoles), pyridine (20 g, 248 mmoles) and dichloro•

methane (100 ml). After 2 h the dark solution was partitioned between

aqueous bicarbonate/ether and the organic layer was washed with water

and dried over magnesium sulfate. After concentration under reduced

pressure, the residue was passed through a bed of alumina (10 g of

Act. Ill) and eluted with ethyl acetate. The vinyl protons of the enol

ether were missing from the product's n.m.r. spectrum and a methanol-

hexane crystallization afforded only a compound subsequently identified

26 as 544, m.p. 217-219° and [a] +39.5°; infrared (CHC13): 1738 (sat'd

carbonyl), 1690 (conj. carbonyls) and 1603 cm 1 (conj. unsaturation);

n.m.r. T 3.78 (sharp singlet, IH, C H), 8.78 and 9.05 (singlets, 3H,

methyls); and ultraviolet X 248 my (e = 10,100). J max

C H : Moi. Wt. Calcd. for 19 24°3 300.173. Found (high resolution

mass spectrometry): 300.175. - 285 -

As an alternative approach to 602, the enedione 562 (2.68 g or

9.37 mmoles from (i)) was dissolved in a solution of 2,2-dimethoxypropane (15 ml) and dimethylformamide (15 ml) containing catalytic amounts of jj-toluenesulfonic acid (70 mg) and methanol (0.4 ml) and

refluxed under nitrogen for 4^ h (200). After cooling, the reaction

was neutralized with sodium bicarbonate (400 mg) and partitioned

between ice water and petroleum ether. The organic layer was washed

twice with water before drying over magnesium sulfate and concentrating

under reduced pressure to provide 602 nearly quantitatively (2.8 g,

99%). An analytical sample (1.4 g) was readily crystallized from

27 methanol and showed m.p. 169-172° and [a] -91.6° (c, 1.2 in CHC13)

(lit. (200), m.p. 141-163° and [a] -84.4°); infrared (CHCLj): 1735

(sat'd carbonyl), 1660 and 1630 cm 1 (enol ether); n.m.r.x 4.78 (multiplet,

6 4 IH, CH), 4.85 (singlet, IH, C H), 6.43 (singlet, 3H, 0CH3), 9.00 and

9.09 (singlets, 3H, methyls); and ultraviolet X 238 (e = 20,500) ° max

(lit. (200) e239 = 20,000).

Moi. Wt. Calcd. for Co_Hoo0o: 300.209. Found (high resolution ZU Zo Z ,

mass spectrometry):, 300.210.

(iii) Testosterone (2.83 g, 9.83 mmoles) and ethanedithiol

(1.0 g, 10.6 mmoles) were dissolved in 50 ml benzene and treated with

boron trifluoride etherate (0.5 ml). This solution was refluxed

overnight (12 h), cooled and neutralized with sodium bicarbonate and

then it was washed with aqueous sodium hydroxide and dried over

magnesium sulfate. The yellow tinted crude product (3.57 g, 99% of - 286 -

597), isolated by removing the solvent under reduced pressure, was found to be free of starting material (no carbonyl) and afforded an 26 analytical sample of a white solid; m.p. 103° and [a]n +120° (c, 1.0

1 in CHC13); infrared (CHCl-j): 3610 and 3460 (hydroxyl) and 1715 cm" 4

(olefinic thioketal); and n.m.r. x 4.51 (singlet, IH, C H), 6.38

17 (multiplet, IH, C H0H), 6.67 (multiplet, 4H, SCH2CH2S), 8.07 (singlet,

17 IH, C H0H, removed by D20 exchange), 8.97 and 9.24 (singlets, 3H, tertiary methyls).

c H 0S : 36 Mol. Wt. Calcd. for 2i 32 2 4«189. Found (high resolution mass spectrometry): 364.191.

The thioketal alcohol 597 (3.50 g, 9.6 mmoles) was oxidized with a dichloromethane solution (140 ml) of anhydrous chromium trioxide

(10 g, 100 mmoles) and pyridine (30 ml, 375 mmoles) for 2 h (158).

The organic layer obtained by partitioning the reaction mixture between aqueous sodium bicarbonate and chloroform was washed with bicarbonate and dried over magnesium sulfate. The tan-coloured solid that was isolated (3.147 g, 89%) after concentration of the organic solution under reduced pressure was recrystallized from methanol to afford an analytical sample of 598, m.p. 144-147° and [a]26 +176.8° (c, 1.15 in

1 CHC13); infrared (CHC13): 1735 (sat'd carbonyl) and 1715 cm" 4

(olefinic thioketal); and n.m.r. x 4.50 (singlet, IH, C H), 6.70

(multiplet, 4H, SCR^CR^S), 8.95 and 9.11 (singlets, 3H, tertiary methyls).

C H OS : 362 17 Found ni n Mol. Wt. Calcd. for 21 30 2 • ^' ( 8 resolution mass spectrometry): 362.173. - 287 -

(iv) Testosterone (4.46 g, 15.5 mmoles) and 2,2-dimethyl-l,3- propanediol (20.9 g, 201 mmoles) were dissolved in toluene (350 ml) containing _p_-toluenesulfonic acid (500 mg) and refluxed in a

Dean-Stark apparatus (263 ) under nitrogen for 60 h. The cooled solution was neutralized with sodium bicarbonate and washed six times with water. Drying and concentration of the organic solution led to the isolation of several crops of crystals from methanol. A recrystalliz• ation of this combined material and hydrochloric acid/acetone hydrolysis of the mother liquors afforded 1.20 g or 21% yield of 593 and 3.40 g (76%) recovered testosterone. The analytical ketal alcohol

23 593 showed m.p. 208-209° and [a] -44.3° (c, 1.0 in CHC13); infrared

1 (CHC13): 3610 and 3450 cm" (hydroxyl); and n.m.r. x 4.65 (multiplet,

IH, C6H), 6.37 (multiplet, IH, C17H0H), 6.47, 6.55 (singlets, 2H,

-0CH2-), and 8.96, 9.00, 9.08, 9.23 (singlets, 3H, tertiary methyls).

The x 8.37 (singlet, IH, C^^HOH) resonance was removed by the addition of deuterium oxide to the n.m.r. sample.

Moi. Wt. Calcd. for Co.Hoo0_: 374.282. Found (high resolution ^4 jo 5 mass spectrometry): 374.279.

Compound 593 (1.20 g, 3.21 mmoles) was added to a magnetically stirred slurry of anhydrous chromium trioxide (3.8 g, 38 mmoles) and pyridine (10 ml, 124 mmoles) in dichloromethane (40 ml). After 2 h,

the solution was passed through an alumina filter bed (25 g of Act. I) and the bed was washed with ethyl acetate (250 ml). Filtration and

concentration under reduced pressure afforded 1.18 g (99% yield) of

the white compound 594. An analytical sample obtained by a

recrystallization from methanol (+ 1 drop pyridine) showed m.p. 203-205° - 288 -

26 1 and [ct]D +10.2° (c, 1.05 in CHC13); infrared (CHC13>: 1735 cm (sat'd carbonyl); and n.m.r. T 4.62 (multiplet, IH, C^H), 6.46, 6.55 (singlets,

2H, -0CH2-), and 8.95, 8.98, 9.08, 9.10 (singlets, 3H, tertiary methyls).

Mol. Wt. Calcd. for Co/H.,0o: 372.266. Found (high resolution Z4 Jo 3 mass spectrometry): 372.267.

(v) Testosterone (2.83 g, 9.83 mmoles) and 1,3-dithiopropane (1.2 g, 11.1 mmole) were disolved in benzene (50 ml) containing p_-toluenesulfonic acid catalyst (50 mg) and the resulting solution was refluxed for 12 h in a Dean-Stark apparatus. The cooled solution was washed with sodium bicarbonate and dried and concentrated in the usual manner to afford 3.68 g (99%) of a yellow oil that showed no carbonyl absorption in the infrared. Alternatively, an acetic acid solution of testosterone and 1,3-dithiopropane was treated with boron trifluoride etherate and left standing overnight to yield 599 quantitatively (272). A crystallization from methanol yielded 559 as

26 a white powder, m.p. 117-119° and [a] +113° (c, 1.13 in CHC13);

1 infrared (CHC13): 3620, 3480 (hydroxyl) and 1646 cm" (olefinic

A thioketal); and n.m.r. T 4.58 (singlet, IH, C H), 6.37 (triplet, IH,

C17H0H, J = 8.0 Hz), 6.9-7.4 (multiplet, 4H, SCj^CH^j^S) , 8.06

17 (singlet, IH, C H0H, exchanged by D20), and 8.96, 9.25 (singlets, 3H, tertiary methyls).

Mol. Wt. Calcd. for C^H^OS^ 378.205. Found (high resolution mass spectrometry): 378.201. - 289 -

The thioketal alcohol 599 (3.55 g, 9.4 mmoles) was oxidized by the usual modified Collins procedure (158) of employing a magnetically stirred dichloromethane (150 ml) solution of anhydrous chromium trioxide (9.00 g, 90 mmoles) and pyridine (25 ml, 310 mmoles) for 2 h.

The reaction mixture was then passed though an alumina bed (100 g of

Act. Ill) and the elution was completed with ethyl acetate (300 ml).

Removal of the solvent under reduced pressure afforded 3.10 g (87%) of a yellow oil which was easily crystallized from methanol. A recrystallized analytical sample of 603 showed m.p. 163-164° and

26 17 [a] = +161° (c, 1.1 in CHC13); infrared (CHC13): 1740 (C carbonyl) and 1655 cm 1 (olefinic thioketal); and n.m.r. x 4.82 (singlet, IH, 4 C H) and 8.88, 9.10 (singlets, 3H, tertiary methyls).

C H S : 392 184 Moi. Wt. Calcd. for 22 32°2 2 • • Found (high resolution mass spectrometry): 392.186.

The thioketal alcohol 599 (1.30 g, 3.4 mmoles) was oxidized with anhydrous chromium trioxide (1.80 g, 18 mmole) and pyridine (5 ml,

62 mmole) in a magnetically stirred dichloromethane (50 ml) solution for 30 min. After the usual workup, 1.10 (85%) of a colourless oil was isolated. While this material (600) did not crystallize readily, it 26 provided a low melting solid, m.p. 69-73° and [ct]^ = +149° (c, 1.3 in 17 1 CHC13); infrared (CHC13): 1735 (C carbonyl) and 1645 cm" (olefinic 4 thioketal); and n.m.r. x 4.56 (singlet, IH, C H), and 8.95, 9.12

(singlets, 3H, tertiary methyls).

C H S : 376 189 Moi. Wt. Calcd. for 22 32° 2 • • Found (high resolution mass spectrometry): 376.191. - 290 -

(vi) 3,17-Bis(trimethylenedioxy)androst-5-ene (621)

An attempted Salmi dioxanation of androst-4-ene-3,17-dione with

1,3-propanediol and p_-toluenesulfonic acid in toluene failed to

permit the bis-ketal to be crystallized from the crude product.

An exchange dioxanation of androst-4-ene-3,17-dione and 2-methyl-

2-ethyl-1,3-dioxane was much superior. The dioxane 616 was prepared

from 1,3-propanediol and 2-butanone by the Salmi procedure (266 ).

The enedione 562 (2.53 g, 8.85 mmole) and dioxane 616 were dissolved in

toluene (30 ml) containing p_-toluenesulfonic acid (60 mg) and 1,3- propanediol (1 drop) and refluxed under nitrogen for thirty hours.

The cooled reaction solution was neutralized with bicarbonate, partitioned between water and petroleum ether and the organic layer was washed with water (6 x 10 ml). N.m.r. and infrared spectrum showed only trace of enone chromophore remained. Two recrystallizations from methanol yielded 447 mg of analytically pure bis-ketal 621, m.p. 181-183° and

26 1 [a] =-27.3° (c, 0.8 in CHC13); infrared (CHC13): 1110 cm" (C-O-C of ketal) and n.m.r. x 4.68 (singlet, IH, C6H), 6.11 (quartet, 8H, 19 18 0CH2-), 8.96 (singlet, 3H, C H3) and 9.19 (singlet, 3H, C H3).

Mol. Wt. Calcd. for C^H^O^: 402.277. Found (high resolution mass spectrometry): 402.273.

(vii) Wolff-Kishner Reductions

The following procedure, essentially Barton's method (173), was employed in the Table VIII reductions. The required anhydrous hydrazine was prepared by refluxing hydrazine hydrate over an equal weight of sodium hydroxide for 3 h. Then several 180° boiling solutions - 291 -

Table VIII The Wolff-Kishner Reduction of Androst-4-ene-3,17-dione

and its C-3 Derivatives

Exp. Compound Mmole Ketone Ml Solution Base Molarity Product (% Yield)

1 562 2.50 (1) 13 (5.2) 1.45 Olefins (76%)

23 562 44.2 (1) 220 (5.0) 1.00 Olefins (95%)

3b 563 31.8 (1) 150 (4.7) 1.45 Olefins (57%) +240 (15%)

4 563 1.21 (1) 30 (24.8) 1.45 Olefins (82%)

5 602 6.01 (1) 30 (5.0) 1.45 Olefins (69%)

6 602 1.67 (1) 40 (27.6) 1.45 Olefins (79%)

7 598 8.42 (1) 30 (3.6) 1.45 Olefins (86%)

8 594 4.19 (1) 40 (9.6) 1.09 240 (71%)

9 594 1.80 (1) 30 (16.7) 1.45 240

10 594 1.08 (1) 30 (27.8) 1.45 240 (93%)

11 594 0.66 (1) 30 (45.5) 1.45 240 (91%)

12 603 2.11 (1) 11 (5.2) 1.45 Olefins (78%)

13 600 3.27 (1) 17 (5.2) 1.45 Olefins (76%)

a Notes conditions were 7 hours at 180° and 15 In this reaction, hours at 210°.

b in this reaction, conditions were 12 hours at 170* and 14 hours at 210°. - 292 -

of sodium diethylene glycolate and anhydrous hydrazine in diethylene glycol were prepared in an all glass apparatus. The listed compounds were added, the mixtures were refluxed gently for 12 h and then the solutions were distilled until their temperature reached 210°.

After refluxing for an additional 24 h, each cooled solution and its collected distillate were subjected to a benzene:water partition.

The reaction product was isolated from the organic layer after it had been washed several times with water to ensure the removal of diethylene glycol. Subsequent ketal removal was achieved by heating a 1:1 acetone:6 N hydrochloric acid solution on the steam bath for several minutes. All of the products were readily analyzable by g.l.c.

(Column A, 208°j 95) and the yields reported apply only to distilled material.

As an example, in experiment 10, 1.08 mmoles of 594 were reduced with 30 ml of 1.45 M sodium glycolate at 180° for 12 h and 240° for 24 h

to provide a 93% yield of 240 after the usual workup, ketal removal, and short path distillation (165° @ 0.3 mm). The figures in brackets

indicate 27.8 mis of solution were used in experiment 10 for each mmole of ketone 594. When the Wolff-Kishner reduction of 594 was worked up under neutral conditions, a methanol crystallization 27

provided an analytical sample of 595 m.p. 174-175° and [a]D -57.5°

1 (c, 1.0 in CHC13); infrared (CHC13): 1100 cm" (C-0-); and n.m.r.

6 x 4.64 (multiplet, IH, C H), 6.46, 6.55 (singlets, 2H, 0CH2-) and

8.96, 8.99, 9.08 and .9.27 (singlets, 3H, tertiary methyls).

Moi. Wt. Calcd. for Co.Hoo0. is 358.287. Found (high resolution

i.H JO i. mass spectrum): 358.285. - 293 -

The hydrocarbon products were found, in each case, to be

separable into a 2:1:1 ratio of olefinic components by g.l.c. (column

B, 195°, 100). The hydrocarbon product mixtures all gave identical n.m.r. spectra and g.l.c. chromatograms and the mixture's analysis resulted in the assignment of a C^H^ mono-olefinic structure to

the three isomers.

Microanalysis for C^H^ is theoretically: C, 88.30; H, 11.70.

Found: C, 88.12; H, 11.77. Mol. Wt. Calcd. for C^H^ is 258.235.

Found (high resolution mass spectrometry): 258.234.

The first component eluted from the g.l.c. column was readily collected and identified as compound 564, exhibiting b.p. 130° @ 26

0.2 mm and [ct]D = +5.7° (c, 1.01 in CHC13); infrared (neat): 3020, -1 3 834, 681, and 623 cm (A olefin) (268) and n.m.r. x 4.34 (doublet 3

of multiplets, IH, C H, JC3H_C4R = 10.0 Hz), 4.67 (doublet of doublets, 4

= 10 HZ J 5 = 1,7 HZ) AND 9 04 9,29 IH, C H, JC3H_C4H '° > C,4H-C H ' ' ' (singlets, 3H, tertiary methyls).

Mol. Wt. Calcd. for CigH3Q: 258.235. Found (high resolution mass spectrometry): 258.234.

The second and third g.l.c. components consisted of two compounds that were only partially resolved (column B, new column only). The second component was identified by comparison with an authentic sample of androst-4-ene (567, see below) while the third was assigned as

5a-androst-3-ene (568, see below). The g.l.c. collected mixture of these components showed n.m.r. x 4.67 (IH), 8.97 and 9.27 (methyls) for 56_7 and x 4.52 (2H, multiplet), 9.20 and 9.27 (methyls) for 568 - 294 - while sufficient individual samples of the two compounds were collected to provide infrared spectra for 567 (865 and 810 cm l) and

568 (3020, 775 and 671 cm"1) (olefinic H's).

The major olefinic component (564, 100 mg, 0.39 mmole) was catalytically hydrogenated (Pt02» 50 mg) in ethyl acetate (10 ml) overnight (14 h) with magnetic stirring. Filtration through celite, concentration under reduced pressure, and short path distillation

(140° @ 0.3 mm) afforded 98 mg (98%) of a colourless oil which solified on standing, m.p. 71-7410. A recrystallized sample (565)

showed m.p. 77-79 °(EtOH) and [a]D +1.0° (c, 1.02 in CHC13) (lit. a 25 (271 ), m.p. 78-79° (acetone) and [cx]D + 2.0°); infrared (neat):

2925, 2860, 1454, 1382 cm"1; and n.m.r. T 9.08 and 9.31 (singlets,

H : 3H, tertiary methyls). Moi. Wt. Calcd. for C19 32 260.250. Found

(high resolution mass spectrometry): 260.248.

The mixture of three steroidal olefins (10.55 g, 40.9 mmole) was subjected to oxidation with anhydrous chromium trioxide (60.0 g,

600 mmole) and pyridine (120 g, 1.5 mole) in dichloromethane (500 ml) for 41 h. Celite (20 g) was added and the reaction mixture was filtered through Act. Ill alumina (100 g). The filtrate, along with ethyl acetate washings (300 ml), was concentrated under reduced pressure to provide ^ 10 g of a viscous oil which crystallized on standing. A crystallization from petroleum ether (30-60°) afforded pure androst-4-en-3-one(3.05 g) and a mother liquor which analyzed 27% steroidal olefins and 58% androst-4-en-3-one(Column A, 225°, 100).

Chromatography of the crude oxidation product on alumina (200 g,

Act. Ill) was followed by a short path distillation to provide - 295 - recovered olefins (1.18 g, 11% yield, eluted with up to 40% benzene in pet. ether) plus androst-4-en-3-one(2.64 g, total of 51% yield, eluted with 75-100% benzene plus ether wash (200 ml)). The olefin fraction showed a large reduction in the amount of 53-androst-3-ene

(564) recovered and virtual elimination of the androst-4-ene (567) component.

Monitoring the oxidation reaction demonstrated that these compounds were consumed much more readily than 5ot-androst-3-ene (568) . Some of the allylic oxidation reactions had the additional feature that androst-

4-ene-3,6-dione (up to 8% yield) was produced. In all experiments, the androstenone and androstenedione isolated were identical to samples of these compounds prepared in (a).

A collection of the third olefin by g.l.c. (new column B, 200°,

100), using the olefin mixture recovered from the allylic oxidation 29 above, provided compound 568, exhibiting b.p. 130° @ 0.2 mm and =

1 +44° (c, 1.22 in CHC13); infrared (neat): 3023, 771 and 671 cm" 3 3 4 (A olefin) (268) and n.m.r. T 4.52 (multiplet, 2H, C H-C H) and 9.20,

9.28 (singlets, 3H, tertiary methyls). This olefin (102 mg, 0.4 mmole) was catalytically hydrogenated (Pt02» 40 mg) in ethyl acetate (10 ml)

for 5 hours. Filtration through celite, concentration under reduced

pressure and short path distillation (140° (3 0.3 mm) afforded 98 mg (95%)

of a colourless oil (569) which could be crystallized from ethanol

m.p. 50-51° and [a]27 +0.4° (c, 1.1 in CHCl-j) (lit. (271), m.p. 50°

(acetone) and [ct]25 = +1.3°); infrared (neat): 2925, 2860, 1450 and

1380 cm 1; and n.m.r. T 9.20 and 9.30 (singlets, 3H, tertiary methyls). - 296 -

Moi. Wt. Calcd. for C19H32: 260.250. Found (high resolution mass spectroscopy): 260.247.

A series of Wolff-Kishner reductions under neutral (no base added) conditions were performed on 562, 563, 598 and 602. These keto steroids (1-2 mmoles) were treated with 10 ml of a 180° boiling mixture of anhydrous hydrazine in diethylene glycol for 12 h and then at 210° for 24 h. In all cases but 563, the vinyl proton (plus the blocking group) and the steroidal olefins 564, 567, and 568 were absent from the product mixture. Compound 563 was recovered unchanged in rings

A or B while the others appeared to give predominantly polymeric material.

The bis ketal 621, 3,17-bis(trimethylenedioxy)androst-5-ene (393 mg, 0.98 mmole) was treated with 14 ml of 1.45 N sodium glycol in diethylene glycol-anhydrous hydrazine. After twenty-four hours at

210°, the reaction was cooled and partitioned between water and petroleum ether. The residue from the organic layer was treated for fifteen minutes on the steam bath with 1:1 acetone:4 N hydrochloric acid solution and then reisolated by partition between water and petroleum ether. The dried and concentrated organic layer yielded 248 mg of residual oil which analyzed by g.l.c. (Column's A and B, 220°,

100) for androst-4-ene-3,6-dione (^10%), androst-3- and -4-en-17-ones

(30%), androst-4-en-3-one (^20%) and androst-3- and -4-enes (40%).

The androst-3- and -4-en-17-one (623) were identical to an authentic sample prepared from testosterone (see below). The androst-3- and -4- 3 4 3 enes were shown to separate into a 2:1:1 ratio of 5f3-A :A :5a-A androstenes (564, 567, 568). - 297 -

Authentic Samples of Possible Wolff-Kishner Products

4-Androsten-3-one Ethylenethioketal (566)

A 5.0 ml acetic acid solution of androstenone (278 mg, 1.0 mmole)

and ethanedithiol (400 mg, 4.3 mmoles) was treated with boron tri-

fluoride etherate (0.5 ml) and left standing overnight to yield 566

quantitatively (272). An ether-methanol crystallization afforded 26 white crystals, m.p. 112-115° and [a]D = +111° (c, 1.1 in CHC13);

infrared (CHCl^): 1643 cm 1 (olefinic thioketal); and n.m.r. x 4.52 L

(singlet, IH, C H), 6.66 (multiplet, 4H, SCR^CR^S), 8.97 and 9.28

(singlets, 3H, CH3).

c H S : Mol. Wt. Calcd. for 2i 32 2 348.194. Found (high resolution mass spectrometry): 348.193.

4-Androstene (567)

The thioketal 566 (273 mg, .0.78 mmole) was desulfurized with

Raney nickel prepared by following the procedure of Burgstahler (273 )

and digesting a 1:1 nickel:aluminum alloy (5 g) in aqueous sodium hydroxide (25 ml of 25% solution) at 75° for 1 h. The thioketal

showed limited solubility in ethanol and was therefore dispersed

in celite (1 g) with chloroform and added to a refluxing suspension

of the neutral Raney nickel in ethanol (40 ml). After twelve minutes,

the reaction was cooled, filtered through celite, concentrated under

reduced pressure and distilled (140° @ 0.4 mm) to provide 162 mg (80%)

of 567 as a clear oil. This oil solidified on standing to afford a white solid which, after being crystallized from ethanol, showed

26 m.p. 56-57° and [a] = +54° (c, 2.1 in CHC13) (lit. (290) m.p. 59-61°); - 298 -

infrared (neat): 865 and 810 cm L; and n.m.r. T 4.68 (broadened singlet,

IH, C H), 8.97 and 9.27 (singlets, 3H, tertiary methyls). This compound was identical to the second component observed in the mixture of steroidal olefins obtained by Wolff-Kishner reduction.

Moi. Wt. Calcd. for C^H^: 258.235. Found (high resolution mass spectrometry): 258.231.

5-Androsten-3-one Ethyleneketal (590)

Androstenone (327 mg, 1.20 mmoles), ethylene glycol (3 mis, 54 mmoles) and £-toluenesulfonic acid (17 mg) were dissolved in toluene

(30 ml) and the solution was refluxed under nitrogen for four hours.

The usual workup with bicarbonate gave a quantitative recovery of a

white crystalline solid which analyzed 88:12 for the ratio of ketal:

androstenone 240. This ratio was unchanged by extending the reflux

period to sixteen or twenty-four hours but the crude product became

more yellow coloured when the reaction times were extended. A

recrystallization of the initially isolated product from methanol

containing a drop of pyridine afforded an analytical sample (170 mg) of 22

the ketal 590 as long colourless needles, m.p. 150-151° and [<*]D =

1 -58.6° (c, 1.1 in CHC13); infrared (CHC13): 1100 cm" (ketal C-0),

and n.m.r. x 4.64 (broadened multiplet, w @ % ph = 5 Hertz, IH, C^H),

19 6.03 (singlet, 4H, -0CH2CH20-), 8.95 (singlet, 3H, C H3), and 9.26

(singlet, 3H, C H3).

H : Moi. Wt. Calcd. for C21 32°2 316.240. Found (high resolution

mass spectroscopy): 316.240. - 299 -

Treatment of the ketal 590 or the thioketal 566 with sodium glycolate in diethylene glycol (2.1 N) for sixteen hours above 200° destroyed both the ethylenedioxy and ethylenedithio functionalities.

3- and 4-Androsten-17-one (623)

Testosterone (2.90 g, 10.0 mmoles) was treated with 170° boiling anhydrous hydrazine-sodium glycolate-diethylene glycol (1.43 N, 50 ml) solution for twelve hours and then a further twenty-four hours at 210°.

The usual workup followed by a short path distillation (180° @ 0.3 mm of Hg) afforded 2.63 g (95% yield) of a mixture of 3- and 4-androsten-

1 17-ols (622); m.p. 114-118°, infrared (CHC13): 3625, 3450 cm"

(hydroxyl) and n.m.r. T 4.53 (olefinic protons), 6.40 (multiplet, IH,

C17H0H) and methyls at 8.97, 9.02 and 9.26.

A Collins oxidation of the above alcohol (2.46 g, 8.98 mmoles) was accomplished with anhydrous chromium trioxide (6.0 g, 60 mmoles)

and pyridine (7.5 mis) in dichloromethane (150 mis) for thirty minutes

at room temperature. The reaction was quenched with ether (150 ml),

filtered through alumina (50 g, Act. Ill), concentrated under reduced

pressure and distilled (165° @ 0.3 mm) to afford 2.35 g (96%) of the

desired ketone. Infrared (neat): 3020 (olefinic H) and 1740 cm 1

(cyclopentanone carbonyl): n.m.r. T 4.52 (multiplet, olefinic H),

8.96, 9.01, 9.13 (various tertiary methyls). Analysis by g.l.c.

(column A, 226°, 100) showed two components that were identical to

those appearing in the Wolff-Kishner reduction products of 3,17-bis-

(trimethylenedioxy)androst-5-ene. A Wolff-Kishner reduction on the - 300 - mixture of 3- and 4-androsten-17-one (490 mg, 1.80 mmole) afforded 3 4 3

399 mg (86% yield) of a 2:1:1 ratio of 5B-A :A :5ot-A -androstenes (Column B, 200°, 100). LEAF 301 OMITTED IN PAGE NUMBERING. - 302 -

EXPERIMENTAL TABLE OF CONTENTS Page Octalone 234

(a) Marshall's Procedure (99) 231 (b) Heathcock's Procedure without solvent (100) • • • 232 (c) Combined acid/base procedure ...... 233 (d) Heathcock's Procedure with benzene (100) .... 234

Octalone 235

(a) From 2,6-dimethylcyclohexanone 235 (b) From dienone 301 237

Octalone 237

Blocking with n-butylthiomethylene 238 Alkylation of blocked ketone _375 2^0 Hydrolysis of blocked ketone 376 2^0 Wolff-Kishner reduction of 356 2^1 Allylic chromate oxidation of 357 2^2

Octalone 238 + 239

(a) Procedure of Piers, Britton and De Waal (184 ,185 ,186) (i) Synthesis of enol lactone mixture 419 + 420 • 243 (ii) Purification of the enol lactone epimers • • 248 (iii)Octalone 238 and 239 preparation 250

(b) Preparation of 238 and 239 from the Wieland- Miescher ketone 253 (c) Preparation of octalone 239 from dienone 300 • • 257

'Octalone' 240

(a) Androstenone 240 from 3fi-hydroxyandrost-5-en- 17-one 261 (b) Cholestenone derivatives .... 265 (c) Cholesterol Oxidation Study (i) Snatzke oxidations 269 (ii) Collins and Corey oxidations 272 (iii)Synthetic applications 279 (d) Compound 240 from Testosterone (i)-(vi) Androst-4-ene-3,6-dione derivatives . . 280 (vii) Wolff-Kishner reduction study 290 Authentic samples of Wolff-Kishner Products. 297 - 303 -

BIBLIOGRAPHY

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2. L. Ruzicka, A. Eschenmoser,and H. Heusser. Experientia, 9, 357 (1953). 3. A. Eschenmoser, L. Ruzicka, 0. Jeger, and D. Arigoni- Helv. Chim. Acta, 1890 (1955). 4. J.B. Hendrickson. Tetrahedron, _7» 82 (1959).

5. W. Parker, J.S. Roberts,and R. Ramage. Quart. Rev., 21, 331 (1967).

6. R.B.' Clayton. Quart. Rev., 19, 168 (1965).

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258. P. Tsui and G. Just. Can. J. Chem., 51, 3502 (1973).

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262. J.B. Jones and J.M. Zander. Can. J. Chem., 46, 1913 (1968).

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3 265. R. Antonucci, S. Bernstein, R. Littell, S.J. Sax, and J.H. Williams. J. Org. Chem., 17, 1341 (1952). b J.A. Campbell, J.C. Babcock and J.H. Hogg. J. Amer. Chem. Soc, 80, 4717 (1958).

266. H.J. Dauben, Jr., B. Loken and H.J. Ringold. J. Amer. Chem. Soc., 76, 1359 (1954). b C. Djerassi and M. Gorman. J. Amer. Chem. Soc, 75, 3704 (1953).

267. Dictionary of Organic Compounds. G. Harris (Ed.). Oxford University Press, N.Y., 1965, p. 235.

268. G.M.L. Cragg, C.W. Davey, D.N. Hall, G.D. Meakins, (Mrs.) E.E. Richards, and T.L. Whateley. J. Chem. Soc. (C), 1266 (1966).

3 269. M. Fet izon, J.-C. Gramain, and I. Hanna. Bull. Soc Chim. Fr., 1388 (1971). b J.W. ApSimon, P.V. Demarco, D.W. Mathieson, W.G. Craig, A. Karin, L. Saunders and W.B. Whalley. Tetrahedron, 26, 119 (1970). c N.S. Bhacca and D.H. Williams. Applications of NMR Spectroscopy in Organic Chemistry, 2nd edition, Holden-Day, Inc., San Francisco, Calif., 1966, pp. 15-17.

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272. L.F. Fieser. J. Amer. Chem. Soc, 76, 1945 (1954).

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287. 3 R.K. Brown and H.A. Davis. Can. J. Chem., 51, 361 (1973); U.E. Diner and R.K. Brown. Ibid., 45, 1297 (1967). b B. Fleming and H.I. Bolker. Ibid., 52, 888 (1974).

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289. M. Gates and G. Tschudi. J. Amer. Chem. Soc, 78, 1380 (1956). See also M. Gates and W. Webb. Ibid., 80, 1186 (1958).

290. A.S. Meyer. Ecta Endocrinol. 25, 4892 (1965). - 321 -

APPENDIX I

Sesquiterpene Nomenclature

In reviewing the literature for general approaches to sesquiterpene

synthesis, it was advantageous to compile examples of the different

skeletal types. These sesquiterpene skeletal types have been listed

alphabetically in Table I and organized in Table II by their number of

carbocyclic rings, with further differentiation by listing in order of

increasing ring size, increasing number of quaternary carbons and

increasing length of the longest acyclic chain.

The multiplicity of skeletal types has been somewhat restricted by

including the nor-/homo-sesquiterpenes and the stereochemically distinguish•

able sub-classes of sesquiterpenes with their respective parent types.

Examples in Table III show that the very recently reported blumenols

(8) are nor-sesquiterpenes of the monocyclicfarnesane class, while the juvenile hormones (1_ and 2) are considered to be homo-sesquiterpenes of

the farnesane class (112). Table IV lists the sesquiterpene stereo• chemical sub-groups; for example, the four types of the parent cadinane class are the bulgaranes (16), muurolanes (17), amorphanes (18), and cadinanes (19). The names of enantiomers and diastereomers of the parent class have special importance in terms of the absolute configurational homogeneity rule (109).1 At present they represent a distinction that has only recently begun to receive extensive study in biosynthetic postulates and synthetic studies (113).

1 See footnoes to Table IV and reference 113. - 322 -

Table I

Names of Parent Sesquiterpene Classes

Name Table II Name Table II Listing Listing

Acorane See Cyclocopacamphene See Acorspirane Copacyclene Acorspirane 30 Cyclonerodane 1 Agarospirane See Cyclosativane See Vetispirane Copacyclene Alaskane See Daucane 45 Acorspirane Drimane 3A Allocedrane 83 Elemane 12. Allohimachalane 52 Eremophilane 52 Amorphane See Eudesmane 51 Cadinane Farnesane 2 Anisatane Ai Faurinane Aristolane See Fomannosane 22 Calarane Fukinane 39 Aromadendrane 65 Fumagillane 10 Artemane 3 Furopelargane 4 Bazzanane 59 Furoventalane 8 Bergamotane H Germacrane JI Bicyclofarnesane See Gorganane 49 Drimane Guaiane 4J. Bicyclogermacrane 21 Helminthosp o rane 11 Bisabolane 1 Himachalane 56 Bourbonane &£ Hirsutane 11 Bulgarane See Humbertane 6 Cadinane Humulane 18 Cadinane 41 Illudalane 32 Calacane 1 Illudane §1 Calarane £2 Iresane See Campherane 26 Drimane Carabrane 19 Ishwarane 89 Caryophyllane 24 Isopatchoulane ii Cedrane 77- Khusane See Chamigrane 53 Zizanane Clovane 82 Laurane 29 Copaane 11 Laurinterane 63 Copacamphorane 79 Longicyclene 88 Copacyclene 8^ Longifolane 80 Coriolane m Longipinane 72 Cubebane 61 Maaliane 66 Culmorane 81 Marasmane M Cuparane 36 Monocyclicfarnesane 13 Curcumane See Muurolane See Bisabolane Cadinane - 323 -

Table 1 (Continued)

Name Table II Name Table II Listing Listing

Myliane 86 Spirolaurane 38 Nardosinane 50 Spirovetivane See Nootkatane See Vetispirane Eremophilane Thujopsane 68 Oplopane 27 Tricothecane 2Z Patchoulane 84 Tri cyclove tivane See Picrotoxane 33 Zizanane Prezizanane 75 Valencane See Pseudoanisatane 34 Eremophilane Pseudoquaiane 46 Valerane 55 Psilostachyane 14 Valerenane 28 Rishitane 48 Vermeerane ct-Santalane 60 Verrucarane See 3-Santalane 25 Tricothecane Sativane 2k Vetispirane 31. Selinane See Vetivane See Eudesmane Vetispirane Sesquicarane 20 Widdrane 58 Seychellane 85 Xanthanane 11 Ylangane See Copaane Zierane 43 Zizanane 76 - 324 - TABLE II. SKELETAL TYPES OF NATURALLY OCCURING SESQUITERPENES

"Keto-lactone" (1)

Artemane* Artemone (3)

Cyclonerodane* Cyclonerodiol Oxide (5)

Non-farnesyl sesquiterpene which cannot be derived from farnesyl precurser. The proposed biogenetic scheme combines with a C isoprene unit ^Sesquiterpene sKeleton type proved by X-ray or unambiguous syn• thetic sequence. - 325 -

Humberrane Humbertiol (6)

7 Calacane* Ca!acone(7)

Furoventalane Furoventalene(8)

Fumagillane* Graphinone (10) - 326 - - 327 -

Carabrane Carabrone (19)

Sesquicarane* Sirenen (20) - 328 -

Bicyclogermacrane Bicyclogermacrene (21)

Caryophyllane* a-Multijugenol (24 )

CH2OH /3-Santalane* 0-Santalol (25) - 329 -

Campherane Campherenone (26)

Oplopane; Oplopanone (27)

Acorspirane1 a-Alaskene (30) (y -Acoradiene) - 330 -

Pseudoanisatane Pseudoanisatin (34)

Helminthosporane* Helminthosporal (35) - 331 -

Helicobasidin (36)

Br Spirolaurane Spirolaurenone (38)

Bakkenoiide - D (39a) (S-Fukinolide (39b))

Faurinane Faurinone (40) - 332 - - 333.-.

Cadinane Calamenene (47)

Nardosinane Nardosinone (50) - 334 -

OH OH

CH H 2° OH

Eudesmane Rupestrol (51)

Eremophilane* Furanoeremophilane -e/3, iO/3-diol (52)

Chamigrane*

OAc Drimane* Cinnamosmolide (54)

CH2OH

Valerane Kanokonol (55) - 335

Allohimachalane Allohimachalol (57)

a-Santalane* a-Santalol (60) - 336 -

Aromadendrane a-Gurjunene (65) - 337 -

H Maaliane {+)—y-Maaliene (66)

Calarane* Debilone(67) (Aristolane)

HOH2C

Thujopsane Thujopsenol (68)

Bourbonane /3-Bourbonane (69)

OC-CH(CH2)5CH3 O OH Coriolane* Coriolin C (70) - 338 -

Copaane (+)-a-Y!angene (71)

a-Longipinene (72)

Hirsutane* Isohirsutic Acid (Hirsutic Acid N) (73)

H 74

Sativane* Sativene (74)

Prezizanane Prezizaene (75) - 339 -

rsopatchoulane Scariodione (78)

Longifolane* Longifolon- 3a,7a-oxide (80) - 340 -

Clovane* Clovene(82) - 341 -

Myliol (86)

Copacyclene' Cyclocopacamphenol (87)

Longicyclene (+•)-Longicyclene (88)

Tsnwarane* Lshwarone (89) - 342 - TABLE III

EXAMPLES OF +(NUMBER OF CARBONS PRESENT HOMO-AND NOR- AND PARENT CLASS ) SESQUITERPENES

Q2CH3 C02CH3

Methyl 12- homojuvenate (90) Methyl-12,14-dihomojuvenare(91) +(16, Farnesane) + (17, Farnesane)

R = C02H Monarch Butterfly Pheromones (92) Geigerene (93) +(12, Farnesane) +(12, Elemane)

-op-O Theaspirone (94) Damascenone (95) + (13, Monocyclic farnesane) + (13,Monocyclic farnesane)

R=OH Volmifoliol (96) R = OH Blumenol B (97) ( Blumenol A ) R = H Blumenol C

+ (13,Monocyclicfarn esane) - 343 -

11 CHO

exo-Norbicycloekasantalal (99) R = H,R=CH Chamaecynone(IOO) 1 2 3 +(11,y9-Santalane) RfCH_R_=OH Hydroxyiso- 3 2 chamaecynone +(!4,Eudesmane) (101)

Nordrimenone (102) Mayurone (103)

+ + (14,Drimane) (14, Thujopsane)

O Khusitone (104) +(14,Cadinane) - 344 - TABLE IV

EXAMPLES OF SESQUITERPENE STEREOCHEMICAL SUB-CLASSES. ++( Sesquiterpene Parent Class)

Bulgarane Murrolane Amorphane Cadinane ++(Cadinanes) (71)

20 21

++(Copaane) (71)' Copaane Ylangane - 345 -

TABLE IV cont.

Eudesmane Vetiselinane (Eudesmane) (106)

Nootkatane (107)(Valencane (106)) Eremophilane "^(Eremophilane)

Vetispiranes (107) Agarospiranes 008) "^(.Vetispirane) - 346 -

^ (-)-a-Copaene and (+)-a-ylangene commonly co-occur in essential oils. Application of the absolute configurational homogeneity rule means that a biogenetic approach from a cyclodecadienyl cation precursor requires the same absolute configuration of the isopropyl group for both compounds (i.e. 2Q and 21_ can not be the absolute configuration of the corresponding parent sesquiterpenes) (109). This was confirmed when Ohta and Hirose (71) showed (-)-a-copaene and (+)-a-ylangene are related to 2Ji and the enantiomer of 27_ respectively.

J When a and g-alaskene were isolated in 1970, they were believed to be acoranes and as such were considered to be biogenetically derived from (-)-curcumene (i), another constituent of the leaf "oil. Earlier this year, a-alaskene was shown to be | not an acorane, but an alaskane (30). This is the first reported example of two co-occurring compounds that are formally double bond isomers, and yet are actually members of an enantiomer series. Recently, in June 1972, a biogenetic proposal was made to relate the farnesane-bisabolane-acorspirane-cedrane, zizanane series in terms of two distinct cyclizations of (-)-nerolidol phosphate (ii) to give the alaskane-cedrane parent systems or acroane-prezizanane- zizanane sesquiterpenes (110).

*• 24 (31) J»-75 *-76

(2 )-

RO 25 (31) »-77

R = PQ3h2

A biogenetic scheme which fails to satisfy the configurational homogeneity requirement is the use of the agarofuran iii, an antipodal eudesmane (51), for the origin of agarospirol. The same authors had

OH da-da j^oh OH

iii X OR

HO V - 347 - already shown agarospirol to be v, and obviously iv is a vetispirane and not the desired agarospirane (108). Somewhat surprisingly, this paper was reviewed without critiscism in an otherwise excellent report on sesquiterpene biogenesis (111). - 348 -

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95. E. Demole, P. Enggist, U. Sauberli, M. Stoll, and E. sz. Kovats. Helv. Chim. Acta, 53, 541 (1970).

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97. M.N. Galbraith and D.H.S. Horn. J. Chem. Soc. (D), 113 (1972).

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APPENDIX II

A Generalized Synthetic Approach to Sesquiterpene Classes

The proliferation of published material on the elucidation of new sesquiterpenes in the last decade has been paralleled by novel synthetic work confirming their structures. The extension of older synthetic approaches and the development of new ones have, unfortunately, dated such general sesquiterpene reviews as the one in 1964 by Mellor and Manavalli

(1). The literature summary that follows deals with the total stereo•

selective syntheses of sesquiterpenes in terms of the general strategies used to prepare the target molecules. The central role of decalinic

compounds in these syntheses makes the studies of decalinic transformations

carried out in this thesis particularly relevant in terms of providing

a synthetic stategy to several sesquiterpene classes. In recent years,

the importance of obtaining an efficient route with complete stereo•

chemical control has led to the organization of methods for systematically

'back-tracking' from the desired sesquiterpene target to a readily

available starting material (2,3). The application of computer-assisted

analysis methods to complex compounds goes a long way towards bringing the

approach to, or strategy selection for, the total synthesis of an

individual sesquiterpene in the realm of science rather than art.

Little consideration is given in the review that follows to the

interconversion of two or more sesquiterpene classes because of the

random nature of this work. While the reported conversion of (+)-B-

himachalene (1) to (+)-cuparene (2) gave little structural information (4),

the conversion of a bicyclogermacrane (3) through an elemane (4) to a - 355 -

maaliol (5_) of known absolute configuration was recently very useful in assigning the structure J3 (5). The recent successful conversion of germacrane sesquiterpenes into members of the cadinane (6), eudesmane

3. 4 5

(7), elemane (8), and guaiane (9) classes is very important biogenetically, but, unfortunately, of little general synthetic value because of the difficulty in synthesizing germacranes. The recent conversion of gurjunene (6_) to 10-epizierone (7) (10) permitted the stereochemistry of zierone to be deduced, and suggests that the 'eudesmane approach' could be used to synthesize zierone (8). Few, if any, sesquiterpene class interconversions can compare with the longifolane -> longiborane •*• himachalane -» longipinane sequence (9 12^ that was reported in 1972 (11). However the inter-relation of different sesquiterpenes cannot, without total - 356 -

1 a For example, the correlation in 1965 (12 ) of hinesol and B-vetivone as two sesquiterpenes having a hydroazulene skeleton permitted their respectively absolute configurations to be assigned (i.e., 203 and 197) on the basis of earlier work of Sorm et al. (12b). it was only the attempted total synthesis of this vetivane class two years later that led to the structural revision of these compounds, and proved they had a spirane ring skeleton, a spiro[4.5]decane (13). - 357 -

The Acyclic/Macrocyclic Olefin Approach

Successful synthetic entry into the farnesane class necessitates

the control of the stereochemistry at, and the functionality around,

the double bonds. Published synthetic work on members of the farnesane

class includes both acyclic compounds, i.e. farnesol (13) (14), nerolidol

(14) (15), 3-sinsensal (15) (16), and heterocyclic compounds, i.e. torreyal

(16, R = CH20H), neotorreyol (16, R = CHO), dendrolasin (16, R = CH3) (17)..

However, it is the large number of total syntheses of the Gecropia 2

juvenile hormones (C.. 7 JH, 17_; C ft JH, 18) that has led to methods that

There have been at least a dozen syntheses published on C^g JH since 1967, the year that Roller e_t al_. (19) completed the elucidation of the structure. The most recent synthetic work and reviews summarize the earlier ones (20). - 358 -

surmount the central problem of stereoselective and stereospecific olefin synthesis (18). The relevance of this work to the general synthesis of sesquiterpenes lies in its extension to the preparation of the sesquicarane, humulane, and caryophyllane classes, as well as other members of the farnesane class.4

The six reported syntheses of sesquicarene (19, R = R = CH^) (23)

3 have utilized 20_ (R = CH^ or H) or the corresponding diazoketone 1 2 equivalent. Sirenin, the water mould sperm attractant, (19, R = R =

CH^OH) has been synthesized by an analogous intramolecular diazo decomposition on an acyclic olefinic precursor by several different groups

(24). The g-diol fragmentation 21 •+ 22. is the crucial step in the synthesis of caryophyllene (ct-epimer of 22, X = CH„) (25), but this reaction

One recently stated set of definitions gives 1stereospecificity' as "the production of a major proportion of one diastereoisomer" while 'stereo• selectivity' "is dependence on the ability to separate readily a desired diastereoisomer produced in an admixture" (104). However, in this thesis the more explicit definitions of Zimmerman (21) have been applied. That is a 'stereospecific* reaction is "one in which there is some relationship between reactant and product configurations; the relationship may be retention of configuration, inversion, or any other by which one isomer of reactant goes to one isomer of product while the second isomer of reactant gives the other isomer of product. Stereospecificity is not necessarily complete. A 'stereoselective' reaction, according to these definitions, is one in which there is no relationship between the reactant and product configurations, both reactants giving the same product distribution, and where there is, nevertheless, a preferential formation of one of the possible stereoisomeric products due to some driving force."

4 The use of an a-cyclopropylcarbinol (Julia olefin synthesis) in an alternate approach to dendrolasin (16, R = CH3) (22) is an example of such an application. - 359 -

had previously been used twice in the first stereospecific sequence to provide juvenile hormone (18) (26). Humulene (25) was synthesized by the closure of the acyclic triene 2_3 with nickel carbonyl to 7A_ and subsequent photoisomerization to 25_ (27). Very unfortunately, an analogous

reaction on the decadiene dibromide 2^6 (28) resulted in the isolation of an elemane 27_, elemol, rather than the much more desirable germacrane member 28."*

1) Ni(C0)4r

r 2) CH3MgBr

Simplified elemanes like 27_ are usually artifacts of isolation (29). The eudesmane approach (following) provides synthetic entry to naturally occurring members of the elemane class. - 360 -

The combination of acyclic olefin synthesis and photolysis permitted

a simple total synthesis of (+)-a-bourbonene (32) (30 ). The 1,6-diene

29 was excited to the triplet state by ultraviolet radiation to yield the head-to-head cyclization product, the bicyclic diketone 30., which

32X = H2

6 cyclized in base to afford the enone 31_ stereoselectively."

The Eudesmane Approach7

Eudesmanes are probably the most commonly synthesized class of sesquiterpenes. Usually, the Robinson annelation procedure is utilized

to construct the eudesmane skeleton (31), although recently a stereo-

An earlier bourbonene synthesis photochemically added ii_ to i to afford both iii and iv, the latter of which afforded g-bourbonene (32) (30u).

II ill iv X=0

v. X = CH2

The 'eudesmane approach' includes members in the eudesmane, elemane, germacrane, guaiane, aromedendrane, pseudoguaiane, maaliane, and valerane classes. - 361 -

selective nonannelation sequence, 33_ ->• 3_4, was reported (32) that, as

1 such, represented the total synthesis of 8-eudesmol (35, R = CH2;

2 1 2 R = CH(CH3)2OH), cryptomeridiol (35, R = a-OH, g-CH3; R = CH(CH3)2OH),

1 2 and neointermedeol (35, R = a-CH3> B-OH; R = CH(=CH2)CH3). The short,

but impressive, seven-step total synthesis of (-)-a-santonin (37), reported

in 1956 (33), has encouraged the total synthesis of other eudesmanes

using santonin as a relay. In this way (+)-a-cyperone (38) and 4a-hydroxy-

isochamaecynone (39) were derived in eight steps (34) and eleven steps(35)

respectively from 37.8 In addition, the eudesmolide 40_ ((+)-arbusculin-B)

was synthesized from santonin in a five-step sequence reported in August

1972 to demonstrate a new way of preparing ot-methylene-y-butyrolactones (37).

Of much more general importance is the use of santonin to prepare

sesquiterpenes that are members of other classes. Both elemane (41, R = H)

More recently (+)-a-cyperone was prepared in a novel six-step sequence from a-santonin (36). - 362 - - 363 -

and elemol (41, R = OH) (38) and, more recently, a nor-elemane, geigerene (42) (39) were synthesized from santonin. Members of the germacrane class (dihydrocostunolide (43) (40 )), guaiane class (a- bulnesene (44) (41)), aromadendrane class ((-)-epicyclocolorenone (45)

(42)), pseudoguaiane class (pseudoguaianolide-A (46) (43)), and maaliane class (epimaalienone (47) (36)) have all been obtained through photo• chemical reactions on santonin or its derivatives. In an analogous manner other natural and synthetic eudesmanes have been transformed into other sesquiterpenes in these classes; for example (-)-epi-a-cyperone (48) to maaliol (49) (44) and 8-epi-artemisin acetate (50) to geigerin acetate

(51) (45).

The total synthesis of (-)-valeranone (53) (46**) did not originate

from an eudesmane, but from a compound (52) similar in stereochemistry 9

and functionality to an eudesmane-type of precursor. In a similar way,

9 Earlier unsuccessful attempts at the synthesis of the valeranone skeleton were also made via an 'eudesmane approach' (46D»C). - 364 -

2 Steps—*• — 5 Steps 0^ 0 CH30 52 53

Wharton e_t al. recently reported the total synthesis of (+)-hedycarol (55)

(47) via heterolytic boronate fragmentation of the 'eudesmane' tosylate

54. The 'eudesmane approach' is also evident in the short and general method of entry to the guaianes via solvolysis of the corresponding

54 55

eudesmane-type precursor (48). The solvolysis of the tosylate 56_ (49a) afforded the desired hydroazulene derivative 5_7 (R = CR^CH^) which, on treatment with methyllithium, gave (±)-bulnesol (57, R = C(CH.).OH).10

An earlier 18-step synthesis of bulnesol ,used the 'bridged bicyclic approach' (discussed subsequently) to prepare the bicyclic mesylate jL for solvolysis to the hydroazulene ii and elaboration to (+)-bulnesol (49b).

Na OAc HOAc

ll '2' - 365 -

Again in the synthesis of (±)-kessine (59) (50), it was solvolysis of an eudesmane type of mesylate (58) that provided the perhydroazulene - 366 -

skeleton. The 'eudesmane approach' was also used in the total synthesis of aromadendrene (61, X = CH^)(51) where the ring transformation was accomplished through a base-catalyzed pinacol rearrangement of the masked eudesmane 60_ to afford 61 (X = 0).

A total synthesis of (±)-guaiol (iii) (52) was reported in 1971 from the dione i^. This is certainly not the 'eudesmane approach', but then it is not stereoselective either! In the same year, a stereoselective

synthesis of a hydroazulenic precursor of guaiol was reported (v) (53). However, its subsequent conversion to guaiol lacked stereoselectivity when the isopropyl group was introduced.

iv - 3.67 -

-78e R

R< R*

3 1 2 1 A (R =R =H,R = H or CH3) &(R =R^H,R2=H orCH3)

1 3 1 2 C (R =CH3,R^HT R=COOCH3) D (R =ChL,R = H.R^COOCHJ

The recently reported studies on the photochemical conversion of 1 3 9,10-dimethyl-A ' -hexalins and related steroids to the corresponding 2 2 cyclodeca-l,3,5-trienes (A -> J5, R = a-H or ct-CH^ -*• trans bond and R = g-CH^ cis bond) (40^) relate to both the earlier mentioned preparation dihydrocostunolide 4J3 (a germacrane prepared from santonin) and the

recently reported total synthesis of (+)-occidentalol (62^ R = C(CH3)2OH)

This latter sequence converted (+)-carvone to the masked eudesmane 2 (-)-C (R = a-H) in 14 steps and then thermally cyclized the unstable

2 3 photoproduct D to provide (-)-C (R = g-H) and (+)-62 (R = C00CH3). 3 .

Methyllithium converted the latter product to (+)-62 (R = CCCH^OH), a compound identical to authentic (+)-occidentalol. - 368 -

The Eremophilane Approach

The 'eremophilane approach' can, in theory at least, be reduced to the stereochemical^ controlled conversion of the Wieland-Miescher ketone (63) to sesquiterpenes. While the conversion of the dione ()3_ to bk_ has not been reported, the ketone 6k_, or an equivalent cis vicinyl dimethyl ketone, has been synthesized by several groups (54-62), and used in the total synthesis of several members of the eremophilane

63 64 class. Examples are (±)-dehydrofukinone (65) (55), (±)-fukinone (66) (57,

63), (±)-tetrahydroeremophilone (67) (59), (±)-eremophilenolide (68) (64),

(+)-eremophilene (69) (65), (+)-valencene (70) (65), ct-vetivone (71) (66), and (+)-nootkatone (72) (62,67). Of more general significance has been the use of the ketone 64, or its equivalent, in the synthesis of the calarane class ((±)-aristolone (73) (68,69) and l(10)-aristolene (74) (70)) and, more recently, the ishwarane class ((+)-ishwarane (76) (71)).

The stereoselective total syntheses of (±)-longifolene (79) (72),

(+)-sativene (81, X = CH2) (73), and (±)-seychellene (83, X = CH2) (74) all originated from stereoselectively formed derivatives of the Wieland-

Miescher ketone (63). That is, the immediate precursor of the tricyclic

longifolane system was produced by the intramolecular Michael addition _ The 'eremophilane approach' includes the eremophilane, calarane, ishwarane, seychellane, longifolane, sativane, and copaane classes.

- 370 -

of the pinacol ring expansion product 7J3, derived from 7_7, while the tri• cyclic sativane and seychellane skeletons were derived by an intramolecular enolate-tosylate displacement in 80_ and JB2 respectively. The biogenetic route to a-copaene, a member of the copaane class, involves bond formation in a muurolane (84)(75), while the synthetic route utilizes the 'eremophilane approach' (85). The basic copaane ring skeleton was obtained by the ring closure of 85, a derivative of 63_ - 371 - obtained in eight steps, and then subsequently elaborated to copaene (86) (76a ) . Very recently, Corey et al. (76b ) have reported the synthesis of a-copaene (86), B-copaene (87), a-ylangene (88) and B-ylangene (89) by elaborating 92_, the only Diels-Alder product of 90 and 91_, to the keto

tosylate 93. (or 95) and utilizing the sodium methylsulfinylmethylide catalyzed cyclization to yield the copaane skeleton. The process depicted in 9J3 (or 95) was found to be less efficient than that indicated in 85. - 372 -

OTs

93 Endocyclic Unsaturation 94 Endocyclic 95 Exocyclic Unsaturation 96 Exocyclic

13 The Bridged Bicyclic Approach/

The conversion of a five- or six-membered monocarbocyclic diene or ketone to a bicyclic ring system with a bridge of one or more atoms

solves many structural and stereochemical problems for a wide diversity 14

of sesquiterpene classes. The first synthesis to use such an approach was the preparation of helminthosporal (101) by an acid-catalyst aldol

condensation of 99_ to 100 for subsequent elaboration to 101 (77). The

required dione 99_ was prepared by a Michael addition of methyl vinyl 13 Sesquiterpenes derived by the 'bridged bicyclic approach' include the helminthosporane, copacamphorane, copacyclene, culmorane, tricothecane laurane, $- and a-santalane, and bisabolane classes. 14 Earlier in 1963, a total synthesis of (+)-clovene (iii) was reported (78a»b) using the bicycio[3.3.l]-nonane precursor jL obtained from 2-methylcyclohexanone. This stereoselective preparation of (+)-clovene,

an artifact produced by mild acid treatment of the sesquiterpene, caryophyllene, is more elegant than later syntheses proceeding via a hydrindane precursor (79,80). - 373 -

101 ketone to 98, a derivative of (+)-carvomenthone (97). By an analogous base-catalyzed condensation of 103 to 104, the structures of the copacamphorane ((+)-copaborneol (106) (81)and copacyclene ((-)-cyclocopacamphene (107) (83)) classes were fully corroborated. Since the alkylation

103 104

A previously reported synthesis of copaborneol (106) (83) used a mixture of (+)-a-santalol and (-)-8-santalol as a relay to assign the constitution of the sesquiterpene alcohol 106. (Both 8- and a-santalane classes are generally synthesized by a 'bridged bicyclic approach'). - 374 -

of 102 to 103 was highly stereoselective, the subsequent elaboration of

104 to 106 (105, X = -

Y = -N-NH-Ts for 107) was unambiguous. The total synthesis of culmorin

(112)(84), a culmorane, was achieved by elaborating the diketone 110, obtained from a base-catalyzed intramolecular condensation of the keto ester 109. Since the alkylation of the tetrahydroeucarvone (108) was

regioselective for 109, and the bicyclo[4.2.ljnonane ring system of 110

directed reagent attack strongly by the steric interference of the four-

carbon bridge, the preparation of culmorin (112) by a Dieckmann condensation

of the diester 111 successfully completed this reaction sequence stereo•

specif ically.

The procedure of bridging a»a' to a ketone carbonyl was used in the

recent, very elegant total stereoselective synthesis of (±)-trichodermin

(113) (85), a tricothecane. The cyclohexenone derivative 114 was - 375 -

16 elaborated to the monocarbocyclic compounds 115 and 116 by standard reactions, and then reduced to the corresponding enol hemiacetal 117 which readily rearranged in acetic anhydride to afford only the

"trichothecane-like" product 118. The formation of the second carbocyclic ring (117 ->• 118) was stereochemical^ directed by the methyl of the cis-

fused system, and subsequent reactions on the ketone carbonyl (118 113) were, for the same reasons stereospecific.

The advantages of introducing a hetero atom bridge to control stereo•

chemistry in a bicarbocyclic system are best illustrated by considering

syntheses in several classes biogenetically related to tricothecane.

Interestingly, another preparation of 115 was reported in May 1972 as part of a total synthesis of 113. Both the choice of starting material and the synthetic route to 115 and 113 were different (86). - 376 -

For example, extension of the sequence used to synthesize several cuparanes

((±)-cuparene (119) (87,88) and B-cuparenone (122) (89)) to other classes where diastereomers are possible leads to ambiguity. That is, cyclizing the second ring on a side chain of the first, as in the four step (120 -v 122) synthesis of (±)-cuparenone (122) (89), does not present stereochemical problems, but closure of 123 to 124 in a total synthesis of a laurinterane, debromolaurinterol methyl ether (125) (90) is stereochemical^ ambiguous.

•3 Steps

122.X = 0 x 120 119 X = Hg

OCH .OCH,

124 X = 0

123 125 X = H2

However, the total syntheses of the laurane sesquiterpenes (±)-aplysin

(126, X = Br) and (+)-debromoaplysin (126, X = H) were achieved stereo•

selectively (91) by closing the intermediate 128 to 129 and elaborating

to 130. Upon hydrogenation, 130 afforded only 126, since only the convex

face of the molecule was open to the hydrogenating catalyst. This contrasts

sharply with the results obtained from an alternate sequence, where 131 was

cyclized to afford a 1:3 ratio of U6:127_ (91). - 377 -

Diels-Alder adducts have been used to advantage in the preparation of functionalized bridged bicyclic systems. The recently announced application of this method to the preparation of a nor-8-santalane, exo- norbicycloekasantalal (135, R = CHO) (92) is especially attractive. A reaction of ethyl tetrolate (133) with cyclopentadiene (132) gave the

Diels-Alder product 134 (R = C02Et), which was then modified by hydrogen• ation of the disubstituted olefin and a Claisen rearrangement (dihydro-134, - 378 -

R= -CH2OCH=CH2) to yield 135 completely stereoselectively. Essentially, this work completes the stereoselective synthesis of three natural $- santalanes; the norsantalane (136) (94), (±)-g-santalene (137 (95) and

I o (±)-g-santalol (138) (96).

132 133 134 R = C0Et 135 R = CHO

An earlier application of the Diels-Alder reaction afforded a mixture of (+)-g- and (+)-epi-B-santalene (137 and the * epimer) (93) using the sequence

Previously, the compound 135 (R=CH2CHO) had been prepared from norcamphor (iii) and converted to both 136 (94) and 138 (96).

III - 379 -.

The biogenetically related a-santalane skeleton was also recently prepared by a short sequence incorporating the Diels-Alder reaction.

Cyclopentadiene (132) and allenic acid (139) yielded the adducts 140 and

141, of which only 140 cyclized to the tricyclic skeleton 142 on treatment with formic acid (97). While this work only reported the subsequent 19 preparation of the monoterpene teresantaliol (143, R = Cl^OH) from 142, the sequence actually completes the total stereoselective synthesis of

19 The preparation of the naturally occurring sesquiterpene tricyclo-

ekasantalal (143 R = CH2CH2CH0) (94) would only require minor changes in the final steps of the reaction sequence. - 38.0 -

142 143 R = CH OH 144 2

20 both a-santalene (144, R = CH3) and cx-santalol (144, R = CR^OH).

Sesquiterpene synthesis by the 'bridged bicyclic approach1 is occasionally complicated by the introduction of asymmetry in the side chain. Thus, the Diels-Alder condensation of the dienone 145 with methyl vinyl ketone (146), although regioselective for 147, on elaboration to 148 introduced asymmetry (*) in the sequence to patchouli alcohol 21 (149) (101) Also in a racemic seychellene synthesis (102a), a

20 Corey e_t al. (98) prepared a-santalene from a-bromo-(+)-camphor (i) which was converted through 143 (R = CR^Br) to 144 (R = CH3), while santalol has also been prepared from 143

(R = CH2Br) (99,100).

21 The 'monoterpene approach' includes a synthesis that is stereoselective from homocamphor (146).

HO •• - 381 -

148 149

cyclohexadienone 150 was used to obtain the Diels-Alder adduct 151, but, 22 here too, there was ambiguity at the asymmetric carbon (*) introduced.

150 151

" The 'eudesmane approach' includes an earlier synthesis that was stereoselective. Another non-stereoselective seychellene synthesis was reported (102b) which, like the later patchouli alcohol synthesis considered above, elaborated the side chain of a Diels-Alder derived bicyclo[2.2.2]octene intermediate. Here too, there was stereochemical ambiguity at the asymmetric carbon after the tricyclic system was formed. - 382 -

A general synthetic route from enol acetates of monocyclic olefins gives both epimers of the corresponding bridged bicyclic ketones. The total synthesis of campherenone (155) was achieved through the intramolecular acid-catalyzed cyclization of the enol acetate 152 to afford a mixture of

153 and 154. The latter compound was subsequently converted to campherenone

(103).

1 2 152 154 R =CHj)R =(CH2)3Cl

The concept of the 'bridged bicyclic approach' can be best understood

by considering the work reported on a monocyclic class of sesquiterpenes,

the bisabolanes. The difficulty evident in the aforementioned syntheses

is the control of stereospecificity at prospective asymmetric centers on

conformationally mobile side-chains. The stereoselective synthesis of

(±)-juvabione (162), a bisabolane, solved a similar problem by making

intramolecular interactions of the diastereomers significant through the

intermediacy of a rigid bridged bicyclic skeleton (104). That is, the

Diels-Alder reaction of the diene 156 with the dienophile 157 gave the 23 readily separable Diels-Alder adducts 158 and 159. This permitted

purified 158 to be used in a quantitative a,B-fragmentation to 160,

23 cf. The non-stereoselective synthesis reported concurrently gave a mixture of juvabione (162) and its diastereomer, epi-juvabione, (i.e. double bond isomer of 162) indistinguishable from pure juvabione (162) by g.l.c, n.m.r., i.r. and mass spectra. - 383 -

OCH, ' 0 6-A 156 ]57 158 159

subsequent reduction and spontaneous ring closure to 161, and completion by stereospecific elaboration to 162. A particularly attractive feature of this sequence was its ready application to the preparation of many analogues of juvabione.2^

24 A synthesis of juvablone reported earlier (105) used the monoterpene jL as a starting material, but few analogs could be prepared, and overall yields were low. Work previous to this lacked stereoselectivity.

R-(+)-limonene - 384 -

The Triterpene Approach

The total synthesis of (+)-widdrol (166) (106) and the stereoselective total synthesis of (+)-thujopsane (167) (107) were achieved from the

26 octalone 163 through octalone 164 in five and eight steps respectively.

Alternatively, a second stereoselective synthesis of thujopsene photolyzed the sodium salt of the cis and trans isomers of 169, a compound derived from the monoterepene 168 (g-cyclocitral), to yield 167 in 4% yield (108), while more recently, the corresponding diazo ketone 170, also derived from

168, gave 165 stereoselectively (109). In 1972, (-)-daucene (176)

The 'triterpene approach' includes members of the widdrane, thujopsane, drimane, and daucane classes. The name was chosen because of the close analogy to stereoselective work reported earlier on the A/B rings of triterpenes.

The conversion equivalent to 163 -*• 164 had previously been reported for a steroidal system. - 385 -

was synthesized from R-(-)-limonene (171) as outlined 171 -> 176 (110), but since then the trimethyl keto alcohol 177 (derived from (+)-carvone,

171 X = 0) has been used in the total synthesis of (+)-daucene

(enantiomer of 176), (+)-carotol (178), and (-)-daucol (179) (111). - 386 -

177 178 179.

A simple sequence to the trimethyl perhydronaphthalene skeleton utilized the Diels-Alder reaction of the diene 180 with the dienophile 181 to afford the drimane 182, winterin (112). In addition, several

interesting drimanes have been obtained by the cyclization of farnesane derivatives (i.e. 183 184 (113)), but, while the reactions are stereospecific, only the 'triterpene approach', at the present, gives unambiguous structural information. - 387 -

The best example of the 'triterpene approach' is the stereoselective synthesis reported for (+)-andrographolide lactone (185) (114), (+)- isoiresin (186), and (±)-dihydroiresin (187) (115). The Robinson annelation of the dione 188 with the substituted methyl vinyl ketone (189) afforded the bicyclo enone 190. Alkylation of the monoketal derivative

193 - 388 -

27 191 was stereoselective, providing only the desired trans-4,10- dimethyl compound 192. Separate reductions of the C-3 carbonyl and

C-5 double bond were also selective, affording only the equatorial hydroxyl and the trans-ring fusion products. This permitted the keto diol 193 to be prepared with its relative stereochemistry known. The elaboration of the C-9 carbonyl then presented no stereochemical difficulties in the squence to andrographolide lactone, isoiresin, and dihydroiresin.

The Spirane Approach

There are a number of sesquiterpene classes which contain a carbocyclic skeleton centered around a spiro-carbon, a single carbon atom common to two simple rings in the molecule. Syntheses that prepare these spiro-carbocyclic sesquiterpenes by stereoselective transformations of decalinic or other fused ring systems into spiranes are considered here to be using the 'spirane approach'. The vetispirane, a bicyclic sesquiterpene class, and cedrane, a tricyclic sesquiterpene class, are representative of the spirane sesquiterpenes found in appendix I and, to

Compare this result with the cis-4,10-dimethyl compound obtained from the saturated keto ester (116).

28 At the present time the 'spirane approach' has only been used in the synthesis of vetispirane and cedrane classes. However, there are four classes of bicyclic spirane sesquiterpenes and ten other classes in appendix I that have such a ring junction. - 389 -

date, are the only ones whose members have been prepared via a 29

'spirane approach1.

The total synthesis of g-vetivone (197), a vetispirane reported by Marshall and Johnson (118), used the proven trans-dimethyl configurational relationship of the hydronaphthalenone 194 and the established

photochemical transformation relationship of cross-conjugated dienones and their cyclopropyl ketone products to provide a 'masked' spirane

195. This cyclopropyl ketone, on treatment with acid and selective hydrogenation of the conjugated double bond, afforded the desired keto spirene 196 in high yield. The latter compound, meeting the required

While they are not considered here, there are other sesquiterpenes which have the stereochemical problems associated with a spirane. The monocyclicfarnesane class usually involves a simplified 'triterpene approach' for the synthesis of its members. The C-6 substituent (R.1 = H or OH) and C-9 substituent (R2 = Et or OH) of 1 are introduced non- stereoselectively in all reported syntheses. In the preparation of theaspirone (ii) (117), an aroma constituent of tea oil, a 1:1 mixture of diastereomers at * were produced on the closure of ji (Rl = R2 = OH) to ii. Only one of these corresponds to the compound found in tea oil and the relative configuration has not yet been discovered. - 390 - stereochemical and functional demands for elaborations to 0-vetivone (197), represented a four-step solution to the problem of controlling spirane stereochemical requirements. Marshall and Brady then reported the total synthesis of hinesol (203)(119), a vetispirane, by a non-spirane approach. The tetralone 198 was elaborated over 31 steps to hinesol by constructing the cyclopentyl spirane ring (ring 'C') on a temporary ring ('B') that was later fragmented to give the desired isopropylol stereochemistry in hinesol

/3-vetivone - 391 -

(203). This synthesis was reminiscent of the strategy used in Stork and Clarke's earlier total stereoselective synthesis of cedrol (208) (120), where ring 'C was constructed with a cis-relationship to the secondary methyl, while Marshall and Brady's preparation of hinesol had the difficulty of introducing the secondary methyl trans to ring 'C'. Both synthetic sequences avoided bicyclic spirane systems and the associated

stereochemical problems only by using a long sequence (31 and 20 steps respectively).

The second 'spirane approach' synthesis was an alternate cedrol and

cedrane synthesis reported independently and nearly simultaneously,

by two groups. The first (121 ) elaborated the aryl ketone 209 to the

ot-bromo ester 210 and cyclized this to the spirane 211, while the

second (121^) obtained the <5-bromo ester 213 from 212 and used the

same based-catalyzed cyclization reaction to obtain the spirane. The

first group then converted the spirane to cedrene in a sequence of five - 392 -

steps through the intermediacy of the diol 214, while the second used eight reactions to provide a biogenetic-type cyclization of 215 to cedrene in the final step. Cedrol (208) was isolated from a short sequence using the intramolecular cyclization of the enol acetate 217, obtained from the spiral dienone 211 (121 ). Both laboratory syntheses were stereoselective only because, firstly, the spirane formation occurs on a completely symmetrical cyclohexenone and, secondly, the cross- conjugated spiro-dienone 211, obtained after base epimerization of the carbomethoxy substituent was isolated only as the trans-methyl, carbomethoxy cyclopentyl spirenone. - 393 -

However,two recently reported approaches to the vetispirane skeleton have shown that the formation of a spirane from a cyclohexenone derivative can be completely stereoselective. The compound 222, prepared by the reductive (lithium/ethyl amine) desulfurization/ debenzylation of 221, the coupling product of 219 and 220, was treated with aqueous acid and found to undergo intramolecular spiro-alkylation to yield only 224, 10-epi-g-vetivone, and none of the desired (±)-$- vetivone (197) (122 ). Thr other synthetic approach to g-vetivone was especially elegant in its simplicity. The alkylation of the kinetic enolate of 225 with 226 occurred initially through the allylic chloride of 226 and after a second kinetic enolization to 227, spirannelation - 394 -

0CH 0 S0 + 219

221X = S0,R = CH20 222X= R= H

222

223 224 197

was completed stereoselectively from the less hindered side. Treatment of 228 with methyllithium and aqueous acid then provided B-vetivone (197) (122b).

CH2CI OEt +

OEt CH2CH2Cl

225 226 227

228 197 - 395 -

Earlier work on agarospirane (229), a vetispirane, and acorone

(230), an acorspirane, are pertinent examples of the importance in obtaining stereochemical control. The partial synthesis of agarospirane, the first sesquiterpene to be isolated with a spiro-skeleton, used an acyloin condensation of the diester 232, derived from 2,6-dimethylcyclo• hexanone (231) to subsequently provide a mixture of four possible methyl

HO 229 230

epimers of the spiro-carbocyclic skeleton (233) (123). The strategy that

R.A. Raphael et al., used for the total synthesis of acorone (230) (124)

231; v 232 233

did not permit control of the relative stereochemistry in 235 between

the cyclohexyl methyl and the spirane center or between the spirane

center and the cyclopentyl methyl, although the cyclopentyl substituents

would, in any case, be trans after base epimerization (125). - 396 -

Another example of the synthetic difficulties caused by not using the stereoselective 'spirane approach' on a molecule containing a bridged spirane is provided by the three, very similar, total syntheses of a and 3-cubebene. All of the reaction sequences are stereochemically ambiguous in the generation of the spiral center because the acyclic chain can cyclize on the cyclohexyl olefin in two ways as shown below.

240 241 242 243 - 397 -

240 0 Mixture

Compounds 238 (126), 242 (127a) and the 245 mixture (127 ) were subsequently isolated after the cupric sulfate-catalyzed intramolecular cyclization on their respective olefinic precursors, and they were then elaborated to a- and 6-cubebene (246 and 247). An analogous synthetic problem is

~A H H ""\ H H 246 247 evident in the successful synthesis of (±)-epihinesol (255) reported in 1970 (128). Fortunately in this case, the copper-catalyzed internal cyclization of 249, obtained in 10 steps from 248, afforded 251 in a highly stereoselective manner (250:251 is 1:9). The chromatographically purified 251 was then carbomethoxylated to 252 and reacted with sodium' borohydride and methyl magnesium bromide to provide the 'masked' vetispirane skeleton 253. Treatment with aqueous acid freed the spirane 254 and further reduction afforded (+)-epihinesol (agarospirol). - 398 -

248 COCHN2

252 X = 0, R=-C02CH3 254 X = 0, A-ene

253 X = /3-QH. R = -C(OH)(CHj2 255 X = H2

The second portion of this thesis explores a general method of obtaining spirane skeletons stereoselectively from decalinic precursors in an effort to make these systems more readily available.

30 The Unalkylated Bridgehead Problem

There are several classes of sesquiterpenes which have dihydro-fused ring systems. The members of these classes have either bridgehead protons and/or olefinic bonds at both atoms of the ring fusion, and represent, as a group, the most difficult sesquiterpenes to synthesize. The _ This problem is present in the reported total stereoselective synthesis of members of the cadinane, rishitane, illudane, marasmane, coriolane and hirsutane classes. The same problem is also very evident in the work on the himachalane syntheses (129). - 399 - cadinane class is one of the largest groups of naturally occurring sesquiterpenes found in plants, but synthetically, for the aforementioned reasons, they are distinctly rare. Some recent synthetic work on model compounds has, however, provided useful information for future cadinane synthesis. In particular, the surprising discovery (130) that the Birch reduction of the 4a-isopropyl octalone (256) gave the unexpected cis-fused decalone (257) (cis/trans ratio is > 99:1), while the 43-isomer afforded the normal trans-fused product (trans/cis ratio is > 99:1), is especially pertinent. The reported preparation of the trans-dione 262 (131) from - 400 -

j£-anisoaldehyde (258) and methylisobutyl ketone (259) permitted the six

step synthesis of (+)-y^-cadinene (263) from compound 261 (132).

However, the successful preparation of a muurolane precursor (266) (133) 31

was followed by the discovery (134) that Wittig or organometallic

reagents caused epimerization and nucleophilic attack to afford only

(-) - cryptone

the trans-decalin. Thus a Wittig, hyd olysis, a Wittig sequence on the

ketone enol ether 266 afforded 267, (+ -e-cadinene (134), while a Wittig,

hydrolysis, methyllithium addition and dehydration sequence provided

268, (-)-Y9-cadinene (136).

267 268

Contrary to this publication's contention that this work represents the first example in the literature where both enolization and the usual nucleophilic attack upon the carbonyl occur ln the same synthetic step, Marshall e_t al. (135^, reported four years earlier similar cases of reversible enolate formation under Wittig reaction conditions. Another example has also appeared in Heathcock's work (47). - 401 -

Often, the synthetic work reported on decalins having unalkylated bridghead positions lacks stereoselectivity as in the final step in the reaction sequence used to prepare (+)-rishitinol (271) (137).

However, the work on the corresponding classes having cyclopentyl-fused ring systems has achieved a much greater degree of stereochemical control.

269 270 271

In most of these classes a gem dialkyl cyclopentyl derivative is the synthetic starting point for a sesquiterpene lacking alkylation at the bridgehead. The synthesis of illudin M (275) from the acyclic ketone 272 and substituted cyclopentenone 273 in twelve steps (138) showed both regioselectivity and stereoselectivity in an impressive piece of work on one of the simpler members of the illudane class. The eighteen step total synthesis of methyl isomarasmate (280) (139), in which the gem

272 273 274 275 - 402 -

dimethyl moiety was introduced as the cyclopropyl spirene 277, showed

the power of photochemistry with four photolysis reactions in the

sequence. The very recently reported total synthesis of the coriolane

276 277 278 279 HO C02CH3

Methyl — 8 Steps Marasmate

286, (±)-illudol, from the gem dimethyl cyclopentanone derivative 282

(140), was achieved stereoselectively by the reagent preference for the

convex face of the bicyclo-octane intermediate. Very recently, two

groups of workers, one American and the other Japanese, have reported

282 283 284 285 - 403 -

H OH I. •10 Steps 286

H HO approaches to the highly functionalized Hirsutic acid C (287) (141,142) skeleton culminating in the preparation of another hirsutane, Hirsutic acid N (isohirsuitic acid, 288) (143). The alkylation of the enamine

289 with the bromo-ketone 290 and subsequent aldol condensation provided both diastereoisomers of 291 (the ratio of desired:undesired is 3:2).

Hydrogenation and Claisen alkylation were stereoselective, affording only 292 and its * epimer. Chromatographically purified 292 then provided isohirsutic acid after sequential acid and base treatment.

H H 287 288

Br —2 Steps 0

H C02CH3 289 290 291 - 404 -

•2 Steps 3 Steps 288

32 The Monoterpene Approach

The formidable difficulty in constructing, stereoselectively, the desired carbocyclic skeleton required in some sesquiterpene classes has resulted in the use of monoterpenes and monoterpene derivatives as starting materials. In several classes discussed earlier in the

'bridged bicyclic approach' a suitably bridged, readily available monoterpene was originally used with a five carbon nucleophile to prepare a sesquiterpene. The developments made since have permitted direct total stereoselective syntheses of many of these classes, but

there are still several others whose stereochemical requirements have

8 Steps »• //

293 294 295

32 The 'monoterpene approach' includes those classes of sesquiterpenes whose only stereoselective syntheses have been completed from a

monoterpene, usually where the synthesis can be summarized as C1Q + C,. =

'15' - 405 -

been provided for through the use of suitable monoterpenes. The synthesis of (-)-q-cis-bergamotene (295) from (-)-g-pinene (293) (144), epizizanoic acid (298) from (+)-camphenecarboxylic acid (296) (145),

297 298 R = COOH

and patchouli alcohol (301) from (+)-camphor (299) (146) all made use

of the monoterpenes' structural features to provide a solution to some

of the stereochemical problems. The known photochemistry of citral

(302) led to the total stereoselective synthesis of (±)-furopelargone-A

(305) (147) by a short sequence incorporating the photolysis of 302 to - 406 -

the single diastereomer 303. The addition of five carbon atoms by a

Reformatzky condensation afforded 304, and subsequent elaboration

305 306 provided furopelargone-A (305). The known thermal cyclization of linalool (307) (148) to the cyclopentanol derivatives (308 plus diastereomers) was used to provide cyclonerodiol (306) (149) by oxidation of 308 and epimerization of 309 with a Grignard addition of a C-6 acyclic olefin

to 310. - 407 -

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141. P.T. Lansbury, N.Y. Wang, and J.E. Rhodes. Tetrahedron Letters, 1829 (1971); P.T. Lansbury and N. Nazarenko. Ibid., 1833 (1971).

142. F. Sakan, H. Hashimoto, A. Ichihara, H. Shirahama, and T. Matsumoto. Tetrahedron Letters, 3703 (1971).

143. P.T. Lansbury, N.Y. Wang and J.E. Rhodes. Tetrahedron Letters 2053 (1972).

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145. F. Kido, H. Uda, and A. Yoshikoshi. J. Chem. Soc. (D), 1335 (1969).

146. G. Buchi, W.D. MacLeod, Jr., and J. Padilla. 0. J. Amer. Chem. Soc, 86, 4438 (1964). - 415 -

147. G. Buchi and H. Wuest. J. Amer. Chem. Soc, 87, 1589 (1965).

148. H. Strickler, G. Ohloff and E. sz. Kovats. Helv. Chim. Acta, 50, 759 (1967).

149. S. Nozoe, M. Goi, and N. Morisaki. Tetrahedron Letters, 3701 (1971).