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This is to certify that the. 3,.-
. .’ 2‘“
thesis entitled " " i, "
MODIFICATION OF STEROID ENONES
m
a’-METHYLATION AND FUNCTIONAL METATHESIS
presented by

Kundanbhai M. Patel

has been accepted towards fulfillment
of the requirements for

_Eh..[l.___degree in JhemsigL

mm H. ELM/1 w
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ABSTRACT

MODIFICATION OF STEROID ENONES via
a'-METHYLATION AND FUNCTIONAL METATHESIS

BY

Kundanbhai M. Patel

Modification of steroids was accomplished by two dis-
tinct approaches: (1) a'eMethylation of a,B-unsaturated
and a,fi-epoxy ketosteroids; (2) A functional metathesis
of the a,5-unsaturated cyclohexanone systems.

Thus, a'-methylation of l'and 2 gave the monomethyl
derivatives g and g respectively using ZO-amide base. Com-

pound 2 gave the dimethyl derivatives g'in excellent yield,

c 3 CH3

0 o :

I

H

1, 2
CH3
CH3
0

 

(00

Kundanbhai M. Patel

whereas 3 gave g'in moderate yield. Also compounds 1 and g

     

CH3 CH3 CH3
CH.

O o ;
H
CH3 CH3

2 6

O
0
1 §,

were successfully methylated at the a'-position.
22Methyl-4B,SB-epoxy—B-ketosteroids (2) have been ob-
tained in good yield from the corresponding a,B-epoxyketones

(12). Similarly, isophorone oxide Ll gave 12,35 the major

product (Equation 1).

CH CH3 CH3
0 O I
C)
9,

Kundanbhai M. Patel

(3
1 - r
(1) . RzNLl, THFr’
HMPA
OCH
0 2. CHaI 3

11 70%
12

C) C)
OCH3 o

A new method for shifting the functional groups in

 

a,b-unsaturated ketones was developed (Equation 2). This

H202: O KOH. OCH3
2) NaOH, CH OH NHz-NH-TS,
CH30H reflux C2H50H?
1.5 hrs
OCH3H
CH3Li, ether
._.N_ TS

> 95% > 95%

 

procedure was applied to the steroidal enones 1 and g which
were thereby converted to lg and EQ, respectively, in high

yield.

CH3

Kundanbhai M. Patel

CH3

14

MODIFICATION OF STEROID ENONES

via

 

a'-METHYLATION AND FUNCTIONAL METATHESIS

BY

Kundanbhai M. Patel

A DISSERTATION

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

DOCTOR OF PHILOSOPHY

Department of Chemistry

1974

DEDICATION

To my parents, whose love, understanding and moral
support over the years have made this opportunity possible;
to my brothers and sisters, whose encouragement has made

these years good and worthwhile.

ii

ACKNOWLEDGMENTS

The author is deeply grateful to Professor William H.
Reusch for his continued interest, expert guidance and en-
couragement during the course of this work. For his
willingness to listen to "new" ideas and answer endless
questions and especially for the invaluable freedom he
afforded to investigate a number of different projects.

Appreciation is also extended to my friends and col-
leagues, both past and present, for informative "chalk
talks," for generating a cheerful environment, and for
their much valued friendship.

Finally, the author acknowledges financial support
from the National Science Foundation, The National Institutes
of Health and the Department of Chemistry, Michigan State

University.

iii

.d

 

TABLE OF CONTENTS

INTRODUCTION 0 I O O 0 O O O O O 0 O O O O O O .

RESULTS AND DISCUSSION . . . . . . . . . . . . .
A. NethYlation O O O O O O O O O O O O O O O

1.

4.

Direct a'-Methylation of Conjugated
KetosterOids O O C O O O C O O O O .

a-MethYIatiOD o o o o o o o o o o o o

Attempted y-Methylation of Conjugated
Ketosteroids . . . . . . . . . . . .

Direct a'-Methylation of a,B-Epoxy Ketones.

Page

10
10

10
24

26
28

B. Functional Metathesis of Conjugated Cyclohexanone
systems 0 O C O O I O O O O O O C O O C 0

EXPERIMENTAL O O O O O O O O O O O O O O O O O C

General
General

Procedure for the a'—Methylation of

a,B-Unsaturated Ketones . . . . . . . . . . .

(a)

(b)

(C)
(d)

(e)
(f)
(9)

ChOleSt-4 -en -3 "One (a) o o o o o o o
(i) Methylation with Methyl Iodide .

(ii) Methylation with Methyl-d3 Iodide

2-Methylcholest-4-en-3-one (12 or 11)
(i) Methylation with Methyl Iodide .

(ii) Methylation with Methyl-d3 Iodide

Methylation of 2i-Methyl-d3—cholest-4-en-

3 .0ne (’2’3") 0 o o o o o o o o o o o o

Methylation of 17B-tert-Buty1dimethylsiloxy-

androst—4-en-3-one (2E5 . . . . . . .

Methylation of Cholest-Z—en-3-one (£2)

Methylation of Isophorone (2g) . . .

Methylation of 4,4,6-Trimethylcyclohex-2-

enone (22) . . . . . . . . . . . . .

iv

30

41
41

42
43
43
43
43
43
43

44

44
44
45

45

TABLE OF CONTENTS (Cont.)
Page

Preparation of 17B-tert-Butyldimethylsiloxy-
andrOSt"4-en-3 "One (265 o o o o o o o o o o o o o 46

Preparation of 3-tert- -Butyldimethylsiloxy-

cholesta-Z, 4-diene (24) . . . . . . . . . . . . . 46
Preparation of 17B-Methoxy-2a-methylandrost-4—

en-3 -one (2'2) 0 o o o o o o o o o o o o o o o o o 47
Preparation of 3,5,5—Trimethyl-6—phenylsulfenylcyclo-
heX‘Z -en0ne (g) o o o o o o o o o o o o o o o o 48
Preparation of 4 ,4-Dimethylcholest-2-en-3-one (40) 49

Methylation of 176- tert—Butyldimethylsiloxy-5a-
androst-Z-en-4-one (3 3) . . . . . . . . . . . . 50

(a) Using One Equivalent of ngutyllithium . 50

(b) Using Two Equivalents of n-Butyllithium 51
Methylation of Cholest-4-en-3-one (9) Using
Triphenylmethyllithium as Base . . . . . . . . . 51
6B-Bromotestosterone Acetate . . . . . . . . . . 52
66-Bromo-17B-tert-butyldimethylsiloxyandrost-4-
en-3-one . . . . . . . . . . . . . . . . . . . . 52
Reaction of BB-Bromotestosterone Acetate (45)
with Lithium Dimethylcuprate . . . . . . . . . . 53
Methylation of Isophorone Oxide (49) . . . . . . 53

17B-tert-Butyldimethylsiloxy—4B,5B-epoxyandrostan-
3-One (54) o o o o o o o o o o o o o o o o o o o 55

Methylation of 17B-tert-Butyldimethylsiloxy-4B,56-

 

epoxyandrOStan-3 .0118 (a) o o o o o o o o o o o o 56
Methylation of 4B,56-Epoxycholestan-3-one . . . . 57
3,5,5-Trimethyl-2-methoxycyclohex-2-enone (5g) . 57
3,5,5-Trimethyl-2-methoxycyclohex-2-enone

Tosylhdrazone (52) . . . . . . . . . . . . . . . 58
Reaction of 3,5,5-Trimethyl-2-methoxycyclohex-2-

enone Tosylhydrazone (52) with Methyllithium . . 59
4,4,6-Trimethylcyclohex-2-enone (61) . . . . . . 60
Base Catalyzed Deuterium Exchange of 4,4,6-Tri-
methylcyclohex-Z-enone (61) . . . . . . . . . . . 60
4-Methoxytestosterone (63) . . . . . . . . . . . 61

17B-tert-Butyldimethylsiloxy-4-methoxyandrost-4—en-
3"One (64) o o o o o o o o o o o o o o o o o o o 61

175-tert-Butyldimethylsiloxy—4-methoxyandrost-4-
en-3-one Tosylhydrazone (62) . . . . . . . . . . 62

V

TABLE OF CONTENTS (Cont.)

Page

Reaction of 17B-tert-Butyldimethylsiloxy-4—methoxy-
androst-4-en-3-one Tosylhydrazone with Methyllithium 62

17B-tert-Butyldimethylsiloxy-Sa-androst-2-en-4-one
(38) . . . . . . . . . . . . . . . . . . . . 63

17fi-hydroxy-5a-androst-2-en-4-one (67) . . . . . . 64

Attempted Pyrolytic Aromatization of 17B-tert-
Butyldimethylsiloxy-4-methoxyandrosta-2, 4-diene (66) 64

17B-Hydroxy-5a-androst-1-en-3-one (12) . . . . . . 65
17BeHydroxy-1a,2a-epoxy-5a-androstan—3-one (21) . . 66
17BéHydroxy-2-methoxy-5a-androst-1-en-3-one (72). . 66

17B-tert-Butyldimethylsiloxy-2-methoxy-5a-androst-
1-en-3-one (73) . . . . . . . . . . . . . . . . . . 67

17B-tert-Butyldimethylsiloxy—2-methoxy-5a-androst-
1-en-3-one Tosylhydrazone (74) . . . . . . . . . . 68

Reaction of 17B-tert-Buty1dimethylsiloxy-Z-methoxy-
5a-androst-1-en—3-one Tosylhydrazone (74) with
Methyllithium . . . . . . . . . . . . . . . . . . . 69

17B-tert-Butyldimethylsiloxy—5a-androst-3-en-2-
one (zgj . . . . . . . . . . . . . . . . . . . . . 69

REFERENCES . . . . . . . . . . . . . . . . . . . . . . 71

APPENDIX: SPECTRA o o o o o o o o o o o o o o o o o o 75

vi

10.

11.

12.

13.

14.

LIST OF FIGURES

Infrared spectrum of 17fi—tert-butyldimethyl-
siloxy-Zg-methylandrost—4—en—3-one (21) . . .

Infrared spectrum of 4fi-methylcholest—2-en-
3-one (35) . . . . . . . . . . . . . . . . .

Infrared spectrum of 3,5,5,6-tetramethylcyclo-
hex-2 -en0ne (a) o o o o o o o o o o o o o 0

Infrared spectrum of 4,4,6,6-tetramethy1cyclo—
hex-2 -en0ne (a?) o o o o o o o o o o o o o 0

Infrared spectrum of 3-tert-butyldimethyl-
Siloxycholesta-2,4-diene (£2) . . . . . . . .

Infrared Spectrum of 17B-methoxy-2a-methyl-
andIOSt-4 -en-3 -0ne (12"?) o o o o o o o o o o 0

Infrared spectrum of 3,5,5-trimethyl-6-phenyl-
sulfenylcyclohex-Z-enone (32) . . . . . . . .

Infrared spectrum of 68-bromo-17B—tert-buty1-
dimethylsiloxyandrost-4-en-3-one . . . . . .

Infrared spectrum of 2,3-epoxy-3,5,5,6-tetra-
methylcyclohexanone (52) . . . . . . . . . .

Infrared Spectrum of 5,6-epoxy-3,3,5-trimethyl-
1-methoxycyclohexene (5;) . . . . . . . . . .

Infrared spectrum of 17B-tert-buty1dimethyl-
Siloxy-Zfi—methyl—4B,56-epoxyandrostan-3-one (g6)

Infrared Spectrum of 2fi-methyl-4B,58-epoxy—
cholestanone (51) . . . . . . . . . . . . . .

Infrared spectrum of 3,5,5-trimethyl-2-
methoxycyclohex-Z-enone tosylhydrazone (22) .

Infrared spectrum of 1,5,5-trimethy1-2-methoxy-
CYCIOheX-l 33-diene (fl) 0 o o o o o o o o o 0

vii

Page

75

77

78

79

80

81

82

83

84

85

86

87

88

LIST OF FIGURE (Cont.)
Figure Page

15. Infrared Spectrum of 4,4,6-trimethylcyclohex-
2 -e none (21") o o o o o o o o o o o o o o o o o 8 9

16. Infrared spectrum of 17B-tLrt-butyldimethyl-
Siloxy-4-methoxyandrost—4-en-3-one (64) . . . . 90

17. Infrared Spectrum of 17B-tert-buty1dimethyl-
Siloxy-4—methoxyandrost-4-en-3—one tosylhydra--
zone (Q) 0 O Q O O O C O C O O O O O O O O O O 91

18. Infrared spectrum of 17B—tert-butyldimethy1-
Siloxy-4-methoxyandrosta- -24 -diene (66) . . . . 92

19. Infrared spectrum of 17B-tert-butyldimethyl-
Siloxy-5a-androst-2-en-4—one (38) . . . . . . . 93

20. Infrared Spectrum of 17B—hydroxy-5a-androst-2-
en-4-One (it) o o o o o o o o o o o o o o o o o 94

21. Infrared spectrum of 176-tLrt4butyldimethy1-
siloxy-Z-methoxy-5a-androst-1-en-3-one (73) . . 95

22. Infrared spectrum of 17B-tert-butyldimethy1—
siloxy-2-methoxy-5a-androst—1-en-3-one
tosylhydrazone (14) . . . . . . . . . . . . . . 96

23. Infrared spectrum of 17B-tLrt-butyldimethyl-
siloxy-Z-methoxyandrosta-1, 3-diene (75) . . . . 97

24. Infrared spectrum of 17B-tLrt-butyldimethyl-
siloxy-Sa-androst-B-en-Z-one (76) . . . . . . . 98

25. 100 MHz Pmr spectrum of a mixture of 2a and 26-
methylcholest-4-en-3-one (12) with Eu(fod)3
reagent (CDC13) . . . . . . . . . . . . . . . 99

26. Pmr Spectrum of 17B-tLrt-butyldimethylsiloxy-
2gamethylandrost-4-en-3-one (22) (CDC13 ) . . . 100

27. Pmr spectrum of 4%-methy1cholest-2—en-3-one (35)
(cal-4) o o o o o o o o o o o o o o o o o o o o 101

28. Pmr spectrum of 3,5,5,6-tetramethylcyclohex—
Z-enone (a?) (CC14) o o o o o o o o o o o o o o 102

29. Pmr spectrum of 4,4,6,6-tetramethy1cyclohex—2-
enone (32) (CC14) . . . . . . . . . . . . . . . 103

viii

LIST OF FIGURES (Cont.)

Figure

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

Page
Pmr Spectrum of 3-tert-butyldimethylsiloxy-
cholesta-2,4-diene (22) (CDC13) . . . . . . . 104
Pmr Spectrum of 17B-methoxy-2a-methylandrost
4-en-3-one (26) (CDC13) . . . . . . . . . . . 105
Pmr Spectrum of 3,5,5-trimethyl-6-phenyl-
sulfenylcyclohex-Z-enone (32) (CC14) . . . . 106
Pmr Spectrum of 68—bromo-17B-tert-butyldimethyl-
Siloxyandrost-4-en-3-one (CDC13) . . . . . . 107
Pmr Spectrum of 2,3-epo -3,5,5,6-tetramethyl-
cyclohexanone (66) (Cle? . . . . . . . . . . 108
Pmr Spectrum of 5,6-epoxy-3,3,5-trimethy1-1-
methoxycyclohexene (61) (CC14) . . . . . . . 109

Pmr Spectrum of 17B-tert-butyldimethylsiloxy-Zg-
methyl-4B,58-epoxyandrost-3-one (66) (CDCls). 110

 

Pmr Spectrum of 2fi-methy1-4B,SB-epoxycholestan-
one (31) (CDC13) . . . . . . . . . . . . . . 111

Pmr Spectrum of 3,5,5-trimethyl-Z-methoxycyclo-
hex-Z—enone tosylhydrazone (66) (CDC13) . . . 112

Pmr Spectrum of 1,5,5-trimethyl-2-methoxycyclo-
hex-1,3-diene (66) (CDC13) . . . . . . . . . 113

Pmr spectrum of 4,4,6-trimethylcyclohex-Z-enone
(61) (cc14) . . . . . . . . . . . . . . . . . 114

Pmr Spectrum of 6-D-4,4,6-trimethy1cyclohex-2-
enone (CC14 ) o o o o o o o o o o o o o o o o 115

Pmr Spectrum of tert-butyldimethylsiloxy-4-
methoxyandrost-4-en-3-one (62) (CDC13) . . . 116

Pmr Spectrum of 17B-tert-butyldimethylsiloxy-4-
methoxyandrost-4-en-3-one tosylhydrazone (66)
(CDCls) o o. o o o o o o o o o o o o o o o o o 117

Pmr spectrum of 17B—tert-butyldimethylsiloxy-4-
methoxyandrosta-Z,4-diene (66) (CDC13) . . . 118

 

Pmr spectrum of 17B-tert-butyldimethylsiloxy-
5a-androst-2-en-4-one (66) (CDC13) . . . . . 119

ix

LIST or FIGURES (Cont.)

Figure

46.

47.

48.

49.

50.

51.

Page
Pmr spectrum of 17B-hydroxy-5a-androst-2-en-
4-0118 (fl) (CDC13 ) o o o o o o o o o o o o o 120
Pmr Spectrum of 17B-tert-butyldimethylsiloxy-Z-
methoxy-Sa-androst-l-en-3-one (ZE) (CDC13) . 121
Pmr spectrum of 17B-tert-butyldimethylsiloxy-2-
methoxy-Sa—androst-Z-en-3-one tosylhydrazone
(12) (freshly prepared solution CDC13) . . . 122

Pmr spectrum of 17B-tert-butyldimethylsiloxy-Z-
methoxy-Sa-androst-l-en-3-one tosylhydrazone
(22) (CDCl3 solution after standing for 24 hrs) 123

Pmr spectrum of 17B-tert-butyldimethylsiloxy—Z-
methoxyandrosta-l,3—diene (12) (CDC13) . . . 124

Pmr spectrum of 17B-tert-butyldimethylsiloxy-
5a-androst-3-en-2-one (76)(CDC13) . . . . . . 125

INTRODUCTION

The natural steroid hormones possess markedly different
biological properties associated with minor differences in
structures. Because of this, research activity has centered
on modification of the natural steroid, in an effort to
change and correlate the biological properties with struc-
tural differences.

Removal of the angular 19-methyl group increased the
anabolic activity of testosterone, while decreasing its
virilizing action.1 Researchers at Upjohn Co. have re-
ported2 that introduction of a 9a-fluorine atom into llfi-
hydroxy-17a-methyltestosterone caused a marked enhancement
of oral auflmflic activity, as well as lesser enhancement of
androgenic activity.

Another structural manipulation which has a similar
effect is the addition, rather than removal, of a methyl
group in certain selected loci. Thus, desirable physiologi-
cal effects have been obtained by introducting methyl sub-
stituentsa'4 at C-1, C-2, C-4, C-6, C-16, and C-17 (See 1).
A relevant example is 6a,21-dimethy1-17a-ethynyltestosterone,
which has been shown5 to be superior to the unmethylated
parent in terms of progestational activity. Likewise, 2a-
methyldihydrotestosterone propionate, 2,2-dimethy1-19-
norandrostane-3,17-dione, and 4,66-dimethy1testosterone

1

 

have very favorable anabolic/androgenic ratios; and the Zo-
ethynyl-A-norandrostane-Zfi,17B-diol is a strong antipro-
gestational agent.

The introduction of alkyl groups into steroids has
been generally achieved by the direct alkylation of enolate
anions derived from ketones and enones, by indirect alkyla-
tions such as addition of organometallic reagents to ketones
or epoxides, or by a Villsmeier formylation followed by
reduction.

The 4-en-3-one grouping g'is present in many important
steroid drugs; consequently, the methylation of conjugate
bases derived from this grouping is potentially an important
source of structurally modified drugs. The most likely
sites for such methylation reactions are the a' (C-2) posi-
tion, 11.3 the homoannular A2!4 -dienolate g, and the c C—4)
or 1 (C-6) positions yia_the A3'5-heteroannular dienolate 2'
(Scheme 1) .

It is clear from a variety of studies, that the conju-

gated dienolate anion 4’ which is thermodynamically more

'H
(0')

CH3

2.

Cross conjugated
dienolate

l

Electrophilic
attack at C-2

CH3

Scheme 1

(Gory)

CH3

4

~

Conjugated
dienolate

l

ElectrOphilic
attack at C-4
and/or C-6

4
stable than the cross-conjugated isomer g, undergoes alkyla-
tion at the C-4 carbon atom.3I7v8 Many of these reactions
have been reported to give mono and dialkylated non—conjugated

ketones (Equations 1 and 2).

 

 

 

CH3 CH3
(1)9 1)thuOK,EfBuOH
2) CH I .’
o 3 0
H3
CH3 CH3 CH3
(2)10 1)EfAmONa, ¢H
2) CH3I
o . O O
\ H3C \ ‘CHs H3C——\'\ CH3
CH3 CH3
CH2 CH2

Although 4-monoalkylation of steroidal 4-en-3-one is
usually poor, the best direct procedure for preparing such
derivatives is that described by Atwater.11 Moderate yields
of 4-methyltestosterone (44%) and 4-methy1-19-nortestosterone
(50%) were obtained, by adding methyliodide dr0pwise to a
refluxing basic solution of testosterone or 19-nortesto-
sterone over a period of 2.5 hours. Stork12 has described
recently 4-monoalkylation yia_metalloenamines. Thus cyclo-

hexylimine of testosterone benzoate was treated with three

5
equivalents of lithium diisopropylamide in tetrahydrofuran
followed by an excess ofrmfihyl iodide; gave, after hydrolysis,

4-methyltestosterone (56%) (Equation 3).

 

1 ' .
CH3 ) LIN THF CH3
( ) -5o°
3
.N 2)CH31, reflux
3)AcoNa,AcoH.

Examples of a' methylation of the cross-conjugated
dienolate anion g'are exceedingly rare. The 2a-methylation
of testosterone, through the action of sodium amide, has
been described in a patent issued to Schering Corporation13
(Equation 4). J

CH cs, CH3

1)NaNH2/liq.NH3: THF

1.,
o 2) CH3I o

 

(4)

”no yield given"

Recently, the Roussel group14 has described a novel method
for the synthesis of 2,2-dimethyl-A4-3—keto steroids. In
this procedure potassium Eggtfbutoxide was added at -70° to
a solution of 19-nortestosterone in tetrahydrofuran con-

taining excess methyliodide and hexamethylphosphorus triamide.

6
An initially formed cross-conjugated dienolate g'is appare
ently trapped by methylation before equilibration can occur

(Equation 5).

 

H CH3 H
H ---
(5) E-Buox, THF, HMPA 3C
0 CH3I, -70° 0
“good yield“

Direct alkylation at C-6 has apparently not been
achieved; however, the 6-methyl group has been introduced
in a large number of steroids by alternative sequences,
such as Grignard addition to a 5a,6a-epoxide;15‘23 or by
Villsmeier formylation24 of a A5 double bond.

From these methylation results, it seems reasonable to
assume that under equilibrating conditions, enolization of
a 4—en—3—one leads predominantly to the conjugated dienolate
derivative 4” which undergoes electrophilic attack at C-4.
In 1964 Malhotra and Ringold observed25 that the base
catalyzed deuterium exchange of testosterone with sodium
deuteroxide in diglyme led to the specific incorporation of
one atom of deuterium at C-2 (Equation 6). The correspond-
ing acid catalyzed enolization of testosterone in deuterio-
acetic acid gave a similar result. Furthermore, the reaction
of 2fi-deuterioandrost-4-en-3,17-dione with potassium 323$:

butoxide gave both 4,4-dimethylandrost—5-en-3,17—dione

CH3

(6) Neon/D20
O 5 Diglyme

and recovered starting material free of deuterium

(Equation 7).

CH3

1)E¢Bu0K,E¢Bu0H
—4>
2) CH3I

 

   

o 0'

 

‘
\
\

CH3 CH3

This study by Malhotra and Ringold suggests that a'-
proton abstraction may be preferred in the kinetically con-
trolled enolization of a,B-unsaturated ketone. On the basis
of this deuterium study it might be possible to generate
irreversibly the kinetically favored dienolate g'by using
a suitable strong base in an aprotic solvent. This has
been realized and will be discussed in this dissertation.

Desirable physiological effects also have been achieved
by altering the double bond and carbonyl locations in ring
A. Shifting26 the double bond of testosterone and 17a-
methyltestosterone from the 4,5- to 1,2- position enhanced
parental anabolic and, to some extent, androgenic activity.
The reduced analog, 17a-methyl-5a-androst-2en-1a,17fi-diol,

has a very high antiestrogenic response. Klimstra and

8

Counsell27 found that 17B-acetoxy-5a-androst-2en-4-one has
2.0 times the anabolic and 0.25 times the androgenic activity
of testosterone.

Some of these A ring conjugated enone derivatives can
be readily prepared from common enone systems by well known
transformations. For example, transformation of l-dehydro-
3-keto steroids to 2-dehydro-1-keto system was achieved by

using the Wharton transformation27 as shown in Equation 8.26

 

   

 

(8) H2 02 M12 NHZ
NaOH
0 CH3
fl

On the other hand, transformations of common enones into
the isomeric 2-en-4-one g and 3-en-—2-one g'has only been

accomplished in low yield.26

CH3 CH3
::;::1:::: , O:i::::‘:::: ,
0 H

2

go: my

CH3 CH3

 
   

200 m ...

f1
1

A new procedure for transforming enones Z'and g'into
é'and Q'is reported in this dissertation. We propose the
general name “functional metathesis" (metathesis from the

Greek metatithenai to transpose; Webster's 3rd International

 

Dictionary 1. a change of place or condition) for such

functional transformation.

RESULTS AND DISCUSSION

Two distinct approaches were used to develop structur-
ally modified steroids:
1) a'-Methylation of Conjugated Unsaturated Ketones,
and Epoxy Ketones.
2) Functional Methathesis of Conjugated Unsaturated

Ketones.

A. Methylation:

1. Direct a'-Methylation of Conjugated Ketosteroids

Addition of cholest-4-en-3—one g'to a 10% excess of
lithium isopropylcyclohexylamide in tetrahydrofuran at 0°
generated the kinetically favored A3o4-homoannular di-
enolate anion §'(Equation 9), which proved to be an import-

ant synthetic intermediate for effecting steroid modifica—

CH3
MN: ,THF

Li

tion.

CH3

(9)

 

OI'

11
Thus, reaction of dienolate anion §.with excess
methyl iodide for 2 hrs at room temperature gave a crystal-
line, sharp melting (mp 110-1110), epimeric mixture of a
and B 2-methylcholest-4-en-3-one 12'(Equation 10) in over
95% yield. Sodium methoxide catalyzed equilibration af-
forded the more stable 2a-methylcholest-4—en-3-one 11’

mp 122-24° (Lit 122-24°) .

 

CH CH
3 CH31, CH3 3
THF
<10.) —.
Li r.t.
2 hr 0
> 95%
s: 12 11

Thin layer chromatography (tlc) of 12,0“ silica gel,
and alumina (various activities) showed only one spot with
variety of eluting solvents. However, high-pressure liquid
chromatography (1c) of the mixture on a Zorbox (DuPont)
silica gel column fitted with a 254 nm detector showed two
peaks corresponding to 2d and ZB-methylcholest-4-en-3-one
in the ratio of 60:40 respectively. A similar conclusion
was reached independently by analyzing the 100 MHz nmr
spectrum29 of lg'with added Eu(fod)3 reagent.

The epimeric ratio of azfi epimers in 12 may be con-
trolled by steric hindrance to the approach of the alkyl-
ating agent and/or by stereoelectronic factors. In the

general case of enolate 1£'(Scheme 2), the energetically

12

 

 

.N memgom

qoeoxddv
Ierxoqenba

 

Hamo

qoeoxddv
Ierxv

 

x HMflx<
ya
I): /g

a

Hafinoumdvm

13
favorable transition states for alkylation will be the
chair-like transition state 1§'(leading to axial product
12) or the boat-like transition state 14 (leading to equa-
torial product 12) because these permit continuous orbital
overlap along the reaction coordinate. If steric hindrance
is present the predominant product will usually be that
resulting from introduction of the alkyl group from the
less hindered side.

Since steric hindrance effects appear to be small in
dienolate anion g, both a and B attack may occur but the
latter (axial) should be slightly favored. Another factor
that might account for the mixture of epimers in alkylation
product £Q_is a subsequent base catalyzed epimerization
occurring during the latter stages of the reaction or its
work-up. In this event more stable a-epimer 11 would pre-
dominate irrespective of the initial attack of methyl iodide
on the dienolate anion §;

To circumvent the problem of epimerization of the
B-monoalkylated product, investigations of 2,2-dialkylated
compounds were undertaken.

Reaction of dienolate anion g with benzyl bromide gave
monobenzyl (11) and dibenzyl (lg) derivatives in low yield
(Equation 11). Similarly, reaction of the dienolate anion
generated from lg'with benzyl bromide gave 2-benzyl-2-
methylcholest-4-en-3-one 12.(Equation 12). All attempts

to crystallize this material proved unsuccessful.

14

CH2
¢-CHK
(11) 3 ¢CHzBr. ¢CH2
~' THE

 

«.3o% ..30%
£1 £§

MB 3H
C33

LINN‘ THE CH
(12)
O 2. ¢CH2Br

12. 19

W

 

Because of the difficulties in crystallizing the benzyl
derivatives of cholestenone, another alkylating agent was
considered. Since methylation of 2-methylcholest-4-en-3-one
lg'gave 2,2-dimethylcholest-4-en-3-one gg’in over 95% yield
(Equation 13) and crystallization of this compound posed no
problem, methyl-d3 iodide seemed to be an ideal second

alkylating agent.

. CH3
CH CH3 LlN 3
0 2. CH31

» 95%

15
The reaction of 12 with lithium isopropylcyclohexyl-
amide in tetrahydrofuran at 00 followed by methylation with
methyl-d3 iodide at room temperature, gave a 40% yield of
a diastereomeric mixture of 2a-methyl-d3-2fi-methylcholest-
4-en-3-one gi'and ZB-methyl-d3-2a-methylcholest-4-en-3-
one gz'in a 40:60 ratio (Equation 14). The low yield is a

measure of the primary isotope effect in this reaction.

(14) 1o \XT‘.THF
“”' 2. CD31, overnightH3

r. t.

 

w W

This synthesis was repeated by reversing the order of
alkylating agents. Reaction of dienolate anion g'with
methyl-d3 iodide for 4 hrs at room temperature gave an
epimeric mixture of a and B 2-methylfd3~cholest-4-en-3-one
gg'in 75% yield (Equation 15). Subsequent alkylation with
methyl iodide, gave a 90% yield of a diastereomeric mixture

of 21 and 22 in a ratio of 60:40.

 

 

CH3 1. LIN CD CH8
,THF
(15) 9
0 2. CD31 0
75%
9 .22
23 same condition; 21 + 2

'> 90%

16

The diastereomeric mixtures of 21 and 22 also appeared
to be homogeneous on thin layer chromatography (silica gel
and alumina). The relative ratios of 21 and 22 in both
equations (14 and 15) were determined by nmr study.

The results of these dimethylation studies indicate
that the alkylation of dienolate anions related to g'is not
stereospecific. A similar result was noted earlier for an

a4ketonitri1e (Equation 16) by Beak and Chaffin.3°

1. t-BuOK,t-BuOH ‘
— fl — Hac
re ux $

2. CH3IIreflUX O

   

Other effects, such as electrophilicity of the alkyl-
ating agent, nucleophilicity of the dienolate base, the
nature of the associated cation, steric hindrance and in-
ductive effects of the non-reacting groups in the molecule,
size and reactivity of the alkylating agents, bond distor-
tion and torsional effects, and solvent effects on ion
aggregation, may have a significant influence on the relative
energies of stereochemically different transition states in
dienolate alkylation reactions.

Dienolate anion g'failed to react with Egrtfbutyldi-
methylchlorosilane in tetrahydrofuran; however, addition

of an equivalent amount of hexamethylphosphoric triamide

17
accelerated the reaction so that a homoannular 2,4-dienol

silyl ether 22 was obtained in 97% yield (Equation 17).

l CH3
Cle+-,HMPAI
I

 

’ l
LiO THF.at r.t. I SiO
I 24

(ca

The structural assignment of 22 was based on the ultra-

violet spectrum, x cyclohexane) 277 nm (e 4080); infra—

max(

red spectrum vm KBr) 1660 cm"1 [c=c (OSiMezBut)-C=C]: nmr

ax(
(CDCla) 6 4.9 (4-H), d 5.5 (2-H), 1.97 (d, J = 4 Hz, 1-H)
and an elemental analysis. Compound 2g is sensitive to
oxygen but can be stored for extended periods under an

inert atmosphere in the cold.

Diels-Alder cycloadditions and photochemical reactions
involving gg'should yield a variety of interesting modified
steroids.

The reaction of testosterone 22'(or its acetate deriva-
tive) with lithium isopropylcyclohexylamide is not efficient
in tetrahydrofuran, apparently because the dienolate—
alkoxide double salt is insoluble. However, Za-methyl-
17B-methoxyandrost-4-en-3-one gé'was obtained in 70% yield
(Equation 18) when testosterone zg'was treated with an
excess of lithium isopropylcyclohexylamide in a 1:1 mixture

of hexamethylphosphoric triamide-tetrahydrofuran containing

18
an equivalent amount of tetramethylethylene diamine. The
dimethylfggggfbutylsilyl ether derivative gg'of testosterone
is not subject to double salt formation; consequently, this

derivative was methylated in good yield (75%) (Equation 19).

°H Jo
CH3 .. 1. LiN
THF-HMPA
(18) O. a
O N<: (y)

 

 

24 C N<

CH31, r at.
3. NaOH, MeOH

(w 2.

 

 

, CH CH3
+ O.
O
75%
22. 22.

In order to demonstrate the remarkable regioselectivity
of a’-methylation, other substrates of varying structural
characteristics were also investigated. Methylation of
isophorone 2g under the same conditions described for cholest-

4-en-3—one 2, gave the a'-methylderivative 22 in high yield

19
(Equation 20). Methylation of pulegone £2 and 5,5-dimethyl-

cyclohex-Z-enone £1 gave similar results.31o32

Li 0
1. - THF. 0
(203‘ ’
O 2. CH31 0
CH3
29

28

"W m

0

3O 31

'W m

 

80%

Although the cross-conjugated dienolate anion from
isophorone reacted with methyl iodide to give a high yield
of 22, a similar reaction with diphenyl disulfide gave only

40-50% yield of the aLsulfide §£'(Equation 21).

Li

1. ,THF, 0°
(21) +
o 2. ¢>-S-S-¢ 0

Se»
28 gg 40-5095

 

20
In contrast to the facile a'—methylations of 2-methyl-
cholest-4-en-3-one 12'(Equation 13), and 4,4,6-trimethyl-
cyclohex-2-enone §§'(Equation 22) by the procedure described

here, compounds g5, 86, £1, and 88 were recovered unchanged

(22) f a
2. CH3I
80%

33 34

 

under equivalent reaction conditions. Indeed, compounds

gg'and 81 remained unchanged even after prolonged reflux

 

 

 

21
with a hexamethylphosphoric triamide-glyme solvent system.
The dienolate anion derived from gg'is of particular interest
due to its similarity to vitamin D precursors such as
ergosterol and 7-dehydrocholesterol.

4-Methylcholestében-3-one 32 was prepared from cholest-

2-en-3-one gg'in the usual manner (Equation 23).

LiN ::

 

 

CH3 1. ¥ , THF,0°
(23) 4
H
3"?" > 92%

:52,

Reaction of gg'with lithium diiSOpropylamide in re-
fluxing glyme containing one equivalent of HMPA, followed
by the addition of methyl iodide at reflux temperature gave

a moderate yield of 4,4-dimethylcholest-2—en-3-one 22'

(Equation 24).

1. nglyme,

CH3
HMPA
rib
reflux, 15 hrs. 0 .
11
C 3 3

 

2. CH3I, reflux
overnight

 

40

22
Under similar conditions, compound gg'gave a very small
amount (~v5%) of 42'(Equation 25), tentatively identified
by nmr and ir examination of the crude product and by the

results of thin layer chromatographic analysis.

%

   

 

LiN CH3
1. \\:', HMPA,
(25) 4
glyme, reflux 20 hrs.
H 2. CH31, reflux 0 CH3
overnight
38 41

w

The failure of the a'-methylation in the cases of 36,
31, 38, and to some extent with 32 can be rationalized in
one of two ways. Either the rate of formation of the di-
enolate anions is very slow, or the rate of reaction of
these dienolates with methyl iodide is slow, compared to
the reaction of the amine with methyl iodide. In the latter
event the dienolate anions would be protonated by the
tertiary-amine salt 44'(formed igfgitu by reaction of methyl
iodide with amine) before they would react with methyl
iodide (Scheme 3). The possibility that rapid O-methyla-
tion competes with the desired C-methylation was excluded
by tlc analysis of the crude reaction mixture under condi-

tions which resolved an authentic sample of O-methyl product.

CH3

CH3

4]

CH3I

23

Scheme 3.

+ R2 NH

CH31

gg

CH3
I

+ R-N + LiI
I

, R

CH3

. CH3

41

CH3I

23

C 3

- OLi

Scheme 3.

+ R2 NH

CH3I

CH3

R--N -H
R’/’+ I

43
42

AN

CH3

R

 

24

If the formation of these hindered dienolate anions
is in fact very slow, then the use of less bulky 2°-amide
bases might be helpful. On the other hand, if the dienolate
anions form readily but react slowly with methyl iodide,
then the regenerated amine must be removed in some way (34g,
by distillation) in order to prevent subsequent protonation.
of the intermediate base. These possibilities were distin-
guished by the addition of a second equivalent of butyl-
lithium following the initial treatment of the substrate
with the amide base. Methylation with excess methyl iodide
gave a slightly increased yield of 41 and recovered start-
ing material, suggesting that dienolate anion formation was

complete, but methylation was very slow.
2. arMethylation

The strong base trityllithium has frequently been used
to effect the irreversible formation of conjugate bases of
ketones and esters. However, when cholest-4-en-3-one (g)
was added to an excess of trityllithium in cold (0°) tetra-
hydrofuran solution and the resulting dienolate anion mix—
ture was quenched by reaction with methyl iodide, the major
product proved to be 4,4-dimethylcholest-5-en-3-one 42'
(Equation 26).

In a parallel study,32 the trityllithium promoted
methylation of pulegone again yielded products derived

from the more stable dienolate anion (Equation 27).

25

CH - + CH CH
3 1 . ¢3CL1 (XS), 3 CH3 3

THE, 0°
0 2. CH3I (XS) 0 o

 

 

2' CH3 CH3

75% 8%

:12, 10
CH3

— T
1 .¢3CL1 (xg), THF
0
(27) :p ‘
O 2. CH31 O O
I CH3 I
'\\
61% 20%

The predominance of a-methylation under conditions
that favored rate-controlled formation of the cross-conju-
gated dienolate ion was unexpected and inconsistent with
the results obtained using the 2°-amide bases.

These unexpected results can be rationalized by an
electron transfer followed by hydrogen abstraction (Equation

28) or radical coupling.

26

 

C 3 CH3
- fi-
¢3CL1 H-abstraction
(28) ——> a
O +. - 0
L10
2, +
<I>C °
1J0 ::: C::f:L Ocllc  |
.V H3 CH3

3. Attempted y-Methylation of Conjugated Ketosteroids

The synthesis of methyl steroids would be further en-
hanced if a simple method of effecting y-alkylation of the
fully conjugated dienolate anion g'could be found (Scheme 1
page 3). The corresponding dienol ethers are reported to
undergo Villsmeier formylation at the y-position;24
however, the introduction of methyl groups in this manner
is a lengthy procedure. Since radical bromination of conju-
gated enones has been shown to occur at y-carbon atom,83
the possibility of effecting a radical coupling of 22 with
metallo-methyl derivative such as lithium dimethylcuprate

seemed possible (Equation 29).

27

 

CH3 CH3
29
( g ether “’
0
Br CH3
4,2, 46

However, only testosterone acetate gz'was obtained
when 64bromotestosterone acetate 22 was added to a solution

of lithium dimethylcuprate in ether at -78° (Equation 30).

 

CH3 CH3
(CH3 ) 2CULi , ether I
‘30) _780 a
0 o
22L Br jgl

Presumably a reduction of zg'to the dienolate anion 2 has
taken place more rapidly than formation of dienolate radical.
A similar reduction of a-bromoéketones with lithium dimethyl-
cuprate have been observed by Posner and Sterling34 and
also by Bull and Tuinman.35

It may be possible to accomplish a y-methylation by
reacting dienolate anion 2g with lithium dimethylcuprate
(Equation 31), provided formation of 2g is faster than B,
elimination of bromine and provided 22 does not undergo any

alternative unimolecular transformations.

28

 

 

CH3 C 3
'-+
R N , , . '
(31) 2 LlOTHF’ 1 (CH3) 2CUL1,
0. -78 +-,- '1‘ngO
L10 2. H30
r Br
22. 48
CH3
0 .
H3
46

4. Direct a'-Methylation of a,B-Epoxy Ketones

a,B-Epoxy ketones33.37o88 may react with strong bases
by two distinct pathways: a nucleophilic displacement-
elimination process (Equation 32) and a Favorskii rearrange—

ment (Equation 33). Due to these modes of reaction the

C)

OCH3
(32) 50H 0 CHAOH . reflux ‘
O

O
80%

(33) . Efl‘B‘mK 2131130011)» A
re ux CO H
o '_| f‘ 2

80%

 

 

 

29
direct methylation of a,B-epoxy ketones has never been
observed. ISOphorone oxide gg'was selected as a model for
snxying a'-methylation reactions in these systems.

Addition of isophorone oxide 22 to an excess of lithium
isopropylcyclohexylamide in a 1:1 mixture of tetrahydro-
furan and hexamethylphosphoric triamide at 0°, followed by
methylation at room temperature gave 2,3-epoxy-3,5,5,6-
tetramethylcyclohexanone QQ,(Equation 34) as the major

product.

 

2,9. 70 10
29, 96 51 <26
0 O
Q + O
OCH3 '
5% 3%
52 53

With this result as a guide, a'-methylation of the di—
.methyl-tert4butylsilyl ether derivative of testosterone
epoxide Qé'and 46,5B-epoxycholestan-3-one ég’was effected in

900d yield under the same conditions (Equations 35 and 36).

30

3 Li CH CH3

 

 

1. , THF"
(35) HMPA ’
0 O
80%
2‘3. 22
CH3
CH .
3 CH3 CH3
36 Same
( ) 0 Conditions»
(3 O
74%
22 2?,

B. Functional Metathesis of Conjugated Cyclohexanone Systems

A new and efficient reaction sequence leading to shift
of functionality within certain a,B-unsaturated ketones was
sought because the previously described methylation studies
necessitated the preparation of the unnatural a,fi-unsaturated
ketosteroids g and Q, Since isophorone gg'is available at
low cost and its epoxidation is an established synthetic

method,”9 it was selected for a model study.

31

 

Isophorone 22 was epoxidized in methanol according to
the procedure of Wasson and House.39 Treatment of isophorone
oxide gg'with potassium hydroxide in absolute methanol gave
3,5,5-trimethyl-2-methoxycyclohex-2-enone gé'in 80% yield.
The tosylhydrazone derivative 22 of methoxy ketone §§ was
formed in an 85% yield by refluxing equivalent amounts of §§'
and tosyl hydrazine for 1.5 hrs in a small amount of absolute
ethanol (Scheme 4). Structure ég'was supported by its nmr
spectrum, featuring the characteristic AA' BB' pattern of the
four aromatic protons, doublets centered at 6 7.7 and 7.13 (J=
8 Hz), a broad one hydrogen singlet centered at 6 5.13 for NE,
a three proton singlet at 6 3.40 for methoxy methyl group and
a three proton singlet at 6 2.40 for the aromatic methyl group.
Although compound gg'failed to react when treated with
2.2 equivalents of methyllithium in ether at 0° for 2 hrs,
it was converted to Qg'in high yield after 3 hrs at room
temperature. The structural assignment of fig was based
on the ultraviolet spectrum lmax (ethanol) 267 nm (e
4138); infrared spectrum \nax (cc14) 1660 cm'1 (c :: c);

and nmr (CDCls) two sets of AB doublets at

H202.
NaOH,

32

 

 

28

w

CH3OH

C) KOH,
. CH3OH, reflux
4” £>
O

 

 

oCH3
C2H50H.
1. 5 hr, reflux.

30%
gs

 

OCH8
H3+o
THF

> 95%
gg

2,2,
OCH3 CH3Li,
H2 ether
"N"TS
:2:
llillfo
> 95%
1

Scheme 4

33

6 5.65 and 5.35 (J = 10 Hz, H>C=d< ) and 6 3.43 (s, -0C§3).
. H

Acid hydrolysis of 62 gave the a,B-unsaturated ketone 61 in
almost quantitative yield (Scheme 4). The nmr SpeCtrum of
compound 61 showed two vinylic hydrogen signals, a doublet
at 6 5.6 (J = 10 Hz) and a double doublet at 6 6.37 (J =

10 and 2 Hz) respectively. The cg; hydrogens at C-5 ap-
peared as a very unusual AB pattern (see Figure 40). The
complexity of this AB pattern was not improved by irradia-
tion of the C-6 hydrogen; however, substitution of deuterium
at C-6 resulted in a conventional AB pattern for the
methylene group.

The preparation of compounds of type 2 where the car—
bonyl group has been shifted from C-3 to the C-4 position
was accomplished starting with testosterone, 22, Epoxida-
tion40 of testosterone by alkaline peroxide in methanol gave
45. 55 -epoxytestosterone (62') in 75% yield. Treatment of
ngwith refluxing sodium hydroxide in aqueous methanol for
24 hrs, gave a 73% yield of 4-methoxytestosterone, 63} how-
ever, a greater than 95% conversion was achieved by using
sodium methoxide in absolute methanol. In this case the
17B-hydroxy group was protected as the Eggtfbutyldimethyl-
Silyl ether 62; Tosyl hydrazone formation from 64 required
only 15 min reflux in absolute ethanol (Scheme 5). The
hydrazone derivative 65 displayed an nmr Spectrum with the
characteristic AA' BB' pattern expected for this derivative

in the aromatic region.

34

m mamzom

     

0mo

,2 ,2 5

mo . no we
acmmo “n.3mmmms Rom Rum mm emm
o CCU
H nmoo u: m.H mmo. mm mm
2

.ms1m2uumz mo

XDHMQH
A .mOomuo
CHE gmfl sflgmmo -.mo.fl
0
m0

 

mm mm en
en»

nu: ma mom can
.mHONmUaEH. mZG

Hmao

   

 

 

¢*"

.vv“

Aayvl
'l.‘

..A.

v..ol

..,.

-u-I'

hi.

0‘0-
—

 

24"

 

35

Reaction of hydrazone gg'with methyllithium in ether at
room temperature appeared to be sluggish compared with the
corresponding reaction of hydrazone 52’ and reflux condi-
tions were necessary to convert gg'to the homoannular dienol
methoxy ether 62 (Scheme 5). The structure assigned to 66
was supported by its uv absorption band, xmax (cyclohexane)
276 nm (e 4369). I

The possibility that gg'might aromatize on heating,
by elimination of the C-10 methyl group, giving a modified
methoxy estradiol 6§'(Equation 37) was explored. However,
this compound failed to aromatize when heated at 2000 for

24 hrs in triethylene glycol dimethyl ether solution.‘1

 

CH3
triethylene glycol
(37) o dimethyl ether, ’
2000 for 24 hrs
OCH3
OCH3
66 68

m w

Hydrolysis of gg'with 5% hydrochloric acid in tetra-
hydrofuran for 15 min gave gg'in almost quantative yield.

Prolonged treatment with concentrated acid gave corre8ponding

alcohol 61.

Compounds 38 and 61 displayed a characteristic ABXY nmr

Pattern resulting from the pro-chiral methylene center at

<3"‘1- The two vinylic hydrogen atoms at C-2 and C-3 appeared

36
as a doublet of doublet of doublets centered at 6 6.67 (J =
9.6, 5.2 and 3.2 Hz) and at 6 5.87 (J = 9.6, 2.8 and 1.6 Hz)
respectively.

The synthesis of type 6'steroids proved to be somewhat
more lengthy than that of the type é'analogs, since prepara-
tion of 17B-hydroxy-5a-androst-1-en-3—one zg'required addi-
tional steps from testosterone. Thus, 17B-hydroxy-5a-
androst-3-one Qg'was obtained by reduction of testosterone
in liquid ammonia. Bromination of gg'with pyridinium
hydrobromide perbromide, followed by dehydrobromination
with lithium chloride and lithium carbonate in dimethyl
formamide (Equation 38) gave a mixture of 72/ 22, unreacted

62, l-dehydrotestosterone and 2-bromo-5a-androst-1-en-3-one.

CH3 CH3 1 . a... H CH3
(38) -—————t. 3
2 .NH C]. '3 2 'Lé'Cl ' z
0 4 O H L12C03 , O J
DMF,reflux
~ 50%
24 69 70

MI W NV

Although 12 can be purified by chromatography, a more
expedient method was used."2 Brief treatment (two to three
miJTutes) of the crude dehydrohalogenated mixture with excess
sOdium metabisulfite in aqueous methanol furnished the

Water soluble adduct of any unreacted

37
17fi-hydroxy-5a-androst-3-one £2, The less reactive un-
saturated derivatives were then separated by extraction.
Subsequent formation of the bisulfite addition product of
the unsaturated ketone led, after hydrolysis, to pure 1Q.

Epoxidation of 22 with 30% hydrogen peroxide and 10%

methanolic sodium hydroxide in methanol at 14-180 for

40 minutes, gave 17B-hydroxy-1a,2a-epoxyandrostan-3-one Z},
in 90% yield, mp 161-62o (lit43 161-62). Pelc, Hodkova and
Holubedk“‘reported a 41% yield of 2-methoxy-17B-hydroxy-
5a-androst-1-en-3-one zg'from treatment of Zl'with methanolic
sodium hydroxide. This conversion was improved to 78% by
refluxing Zl'in methanolic potassium hydroxide for five
hours. Treatment of zz'with Egrgfbutyldimethylchlorosilane
in dimethyl formamide, using imidazole as a catalyst, gave
98% of Z§'(Scheme 6).

An equiv-molar mixture of zg'and tosyl-hydrazine dis-
solved in a minimum amount of absolute ethanol and refluxed
for one minute, afforded a 97% yield of 22, A freshly pre-
pared sample of 22'showed only one isomer in its nmr spec-
trum; however, after standing for 24 hrs a mixture of syn
and anti isomers (ratio ca 1:1) was evident.

Treatment of 22 with methyllithium in ether gave the
eMpected dienol methoxy ether 22’, )‘max (cyclohexane) 275 nm
(€I 4538). Hydrolysis of dienol ether zg'gave the A3-2-keto-
steroid 16’ in high yield. The spectroscopic and analytical
evidence supporting 22. is presented in the experimental

section.

38

 

Hnmfl.onm
.mHonofle

3

05

ans mH mom m
.mma m
A .o+mm

mmo

mm

H ems m.

 

m msmnom

CHE on
.xDHMmH.Hm£uw
comm
mm
mu; m Rom
O .xsammu
u
moamo

«N
Rpm

'1' m

 

   

m9 Mb
. «SHNQH Rwa
3% CHE H
z .mOnmuu
.ma1mZIumZ
comm
nmo
|+Iflmo
_
mm
Cflfi OW.owHI¢H
_mo EU
momz
sflONm
«mo

39
Carbanion mechanisms have been previously proposed for
base induced tosylhydrazone decompositions,45a45.47 and

Scheme 7 is consistent with our results.

=N—N — TS C N—E
2am ' -TS
l -—- .3 ———~.-
13
n L
\C/NzNe 1 \CeL1@ \C/
-N2 H20
13 ——» n n
/ \ /C\ / \
Scheme 7

In conclusion, the scope of this new method for ef-
fecting a shift of functionality in (1.6—unsaturated ketones
appears to be limited only by alkyl substituents at the
iJlitial a- or a'- positions. The adverse effect of an a-
substituent is clearly due to the inability of such a sys-
tem to give an a-methoxy enone derivative, but the influence

of an a'-substituent is more subtle. A recent38 study in

u
. A '
('0 ?.
vvvu'

40
this laboratory has confirmed the existence of a'-substitu-
ents effect which favors Favorskii rearrangement of epoxy

ketones (Equations 39 and 40).

 

 

(39 KOH’ ‘ O \
-—————4> +
c) CH3OH' o .sCOZCHa +
H20 I I
50% 8%
OCH3
C " s
o o
OCH3
17% 13%
CH
KOH,
CH30H
(40) A '
o
C)

 

32% 30%

EXPERIMENTAL

General:

All reactions involving strong bases have been conducted
under dry nitrogen or argon, using solvents purified by
distillation from suitable drying agents. Magnetic stirring
devices were used in all cases. Organic extracts were al-
ways dried over anhydrous magnesium sulfate or potassium
carbonate before being concentrated or distilled. The pro-
gress of most reactions was followed by thin layer chromoto-
graphy (tlc). Visualization of the chromatograms was ef-
fected by ultraviolet light (uv) or spray reagents such as
5% p—anisaldehyde in ethanol and 30% sulfuric acid.

Analysis by glpc-was conducted with A-90-P3 or 1200
\JarianeAerograph instruments; preparative tlc was carried
CNJt on 2 mm silica gel F-254 or aluminum oxide F-254 ab-
sorbent on 20 x 20 cm glass plates. Melting points were
determined on either a Hoover-Thomas apparatus (capillary
tUbe) or on a Reichert hot-stage microscope and’are uncor-
1fected. Infrared spectra were recorded on a Perkin-Elmer
237B grating spectrophotometer. Nuclear magnetic resonance
(hunr) spectra were taken in deuterochloroform and CCl4

Sc>1utions with Varian A-60, T-60, and HA-100 high resolution

41

 

.nv'v

It 0

.
" '1
'Q.‘

,',..

‘v

)

 

(
I

r-:
1'!

I

.,‘

ll!

‘1'

 

42

spectrometers, and are calibrated in parts per million (6)
downfield from tetramethylsilane as an internal standard.
Ultraviolet spectra were recorded on a Unicam SP-800 spectro-
photometer. Mass spectra were obtained with Hitachi RMU 6
or LKB 9000 mass spectrometers. Optical rotations were
measured with a Perkin-Elmer 141 Polarimeter.

Microanalyses were performed by either Spang Micro-

analytical Labs, Ann Arbor, Michigan or Galbraith Labs,

Knoxville, Tennesse.

General Procedure for the a'-Methylation of QLfi-Unsaturated

Ketones:

To a cold solution of 1.30 mmol of isopropylcyclohexyl-
amine, in 0.5 ml of dry tetrahydrofuran (THF) was added
1.25 mmol of nfbutyllithium in hexane. After this mixture
was stirred at 0° for 15 min, 0.95 mmol of the a.6-unsatu-
rated ketone in 5 ml of THF was slowly added and the re-
sulting solution maintained at 00 for 90 minutes. Following
:rapid addition of 4.00 mmol of methyl iodide, the reaction
Inixture was allowed to warm to room temperature and held
tfliere for three hours before being mixed with water and

Enctracted with ether. The combined ether extracts were

Washed (twice each) with water and brine, dried and distilled

under reduced pressure.

43

(a) Cholest-4-en-3-one g;)
(i) Methylation with Methyl Iodide

The yield of crude 2z-methylcholest-4-en-3-one (151)
was 98%. Recrystallization from methanol afforded 95% of
pure 129 mp 110-1110; [a]D 33.760 (2.14 g per 100 ml chloro-
form).

This mixture of 2a and 26-methylcholest-4-en—3-one (12)
(150 mg) was treated with 50 mg of potassium hydroxide in
25 ml of methanol for 3 hrs at room temperature. The usual
work-up gave the 2a-methylcholest-4-en-3-one (11) in 98%
yield; mp 122-24o (lit 122-24); [a]D 89° (reported 94°).

(ii) Methylation with Methyl-d3 Iodide

The yield of crude 2f-methyl-d3-cholest-4-en-3-
one (23), was 75%:mp 98-1000; ir (KBr): C-D stretching

'band at 2222 cm_1.

(b) 2eMethylcholest-4-en-3-one (10 or 11)
M%

 

(i) Methylation with Methyl Iodide

The yield of crude 2,2—dimethylcholest-4-en-3-one
(gag)‘was 97%. Recrystallization from methanol afforded 93%

of pure ’22,; mp 94--95o (lit48 94-95).
(ii) Methylation with Methyl-da-Iodide

A mixture of diastereomeric, 2a-methyl-d3—ZB-

nuathylcholest-4-en-3-one (21) and ZB-methyl-da-Za-methyl-

A"
“.4-

an
'7.)

$.5-

- v-

.04

iv!

44
cholest-4-en-3-one (22) was obtained in 40% yield after
preparative tlc on a silica gel (cyclohexane—ethyl acetate
9:1 elutant); mp 80-820; ir (KBr) C-D stretching band at

2220 cm’1 .

(c) Methylation of 2§-Methyl-d3-cholest-4-en-3-one (23)

A mixture of diastereomers (21) and (22) was obtained

in 9095 yield; mp 86-870; ir (KBr) 2222 cm-1.

(d) Methylation of 17B-tert—Butyldimethylsiloxy-

androst-4-en-3-one (£2)

 

Column chromatography of the crude product on silica
9e21, eluting with 9:1 cyclohexane-ethyl acetate, afforded
75% of 17B-t_e£t_-butyldimethylsiloxy-Zfi-methylandrost-4-en—
3-one (21): mp 132—330; ir (KBr) 1670, 1616 cm-1; nmr (CC14)
<5 5.6 (s, 1H) 4-H, 5 3.5 (t, J = 8 Hz, 1n) 17-1-1, 5 1.13
(s. 3H) 19-H3, 5 1.10 (a, J = 8 Hz, 3102-313, 5 0.87 (s,
9H) ‘SiC(CH3)30 5 0.73 (s, 3H) 1841,, 5 0.0 (s, 3H) -Si(CH3)2;
mass spectrum, m/e (rel intensity) 416 (veryweak), 401. (< 5),
359 (100), 283 (19). ‘

Anal. Calcd. for C23H‘4028i: C, 74.94; H, 10.64;

Found: C, 74.93; H, 10.65.

(e) Methylation of Cholest-Z-en-3-one (22)

The yield of crude 4%-methy1cholest-2-en-3-one (32)
was 98%. Recrystallization from ethanol afforded 9296'of

Pure 22.: mp 76-770; ir (KBr) 1675 cm-1: nmr (0014) 6 6.98

45
(d, J - 10 Hz, 1H) 1-H, 0 5.75 (d, J = 10 Hz, 1H) 2-H;ms, m/e
(rel intensity) 398(41), 383(10), 342(32), 300(16), 285(18).
5221, Calcd. for C28H460: c, 84.36; H, 11.63;
Found: C, 84.39; H, 11.77.

(f) Methylation of Isophorone (28V)

Distillation of the crude product gave 81% of 3,5,5,6-
tetramethylcyclohex-Z-enone (2g): bp 60-62°/1mm; ir (061,)
1670, 1635, 1375 cm-1; nmr (c01,) 5 5.73 (m, 1H) =CH, 5 2.10
(m. 3H) ring CH2, 5 1.90 (s, 3H) =CCH3, 5 1.07 (s, 3H) 5-CH3,
0-97 (d, J '-' 6 Hz, 3H) 6-CH3, 00.90 (s, 3H) 5-CH3; mass Spec-
trum, m/e (rel intensity) 152(29), 137(20), 109(8), 82(100).

Anal. Calcd. for C10H130: C, 78.89; H, 10.59;

Found: C, 78.78; H, 10.60.
(g) Methylation of 4,4,6-Trimethylcyclohex-Z-enone(22)

Glpc analysis (4% QF-l, 120°) of the crude product
ShOwed it to be a mixture of 4,4,6,6-tetramethylcyclohex-2-
enone 14' (80%) and 3,3. (14%). An analytical sample of ’34,
obtained by preparative glpc, exhibited the following
Properties: ir (cc14), 1680 cm-1; nmr (cc1,) 5 6.32 (d,

J = 10 Hz, 1H) 3-H, 5 5.56 (d, J = 10 Hz, 1H) 2-H, 61.7
(3. 2H) ring CH2, 0 1.17 (s, 6H), 0 1.1 (s, 6H); mass spec-
trum, m/e (rel intensity) 152(8), 138(<5), 96(100), 81(50).
C, 78.89: H, 10.59:

Anal. CBICd. for C10H150:
Found: C, 78.88; H, 10.76.

46
Eeparation of 1 7B -tert—Butyldimethylsi loxyandrost-4-en-

i—one (gg):

Tatcsterme (24) (2.9 g, 10.06 mmol) was treated with 1.80 g
(11.95 mmol) of tert-buty1dimethylchlorosi1ane and 1.70 g

(24.97 mmol) of imidazole in 15 m1 DMF (dry) for 15 hours

at 35°. The reaction mixture was mixed with water and ex-

tracted several times with ether.

tracts were washed, dried and concentrated under reduced

The combined ether ex-

pressure. The yield of crude ggwas 4.0 g (98%) mp 131-350.

Crystallization from ether gave pure 2’6} mp 135-137°;
nmr (CDC13) 5 5.6 (s, 1H) 4-H,

ir (KBr) 1670, 1616 cm" .
3.46 (t, J = 8 Hz, 1H) 17—H,51.15 (s, 3H) 19-H3,60.85 (s,
9H) -SiC(CH3)3,00.72 (s, 3H) 18-H3,0.00 (s, 6H) -Si(CH3)2:
mass spectrum, m/e (rel intensity) 402 (very weak), 387
(<5), 345(100), 261(16).

Anal. Calcd. for C25H4202Si:
Found:

C, 74.57; H. 10.51;
C, 74.73: H, 10.36.

Preparation of 3—tert-Butyldimethylsiloxycholesta-2,4-

.diene (24 ) :

To a chilled (0°) solution of 1.01 mmol of lithium

isopropylcyclohexylamide (LiICA) in 1 m1 of THF was added
350 mg (0.91 mmol) of cholest-4-en-3—one (g) in 10 m1 THF-
After the reaction mixture was stirred at 0° for 30 min,
0 ~25 ml (1.42 mmol) portion of dry hexamethylphosphoric

triamide (HMPA) was added with stirring at 0°. This

47
reaction mixture was quenched by the addition of 165 mg
(1.09 mmol) of Eggtfbutyldimethylchlorosilane in 3 ml of
THF, and after it stood at 25° for three hours, the result-
ing mixture was poured into water and extracted with ether.
The combined ether extracts were washed, dried and concen-

trated under reduced pressure, yielding 475 mg of crude

product. The HMPA impurity remaining in the crude product

was removed by passing it through a short path alumina

column. The yield of pure 3—tert-—butyldimethylsiloxy-

Cholesta-2,4-diene (24) was 440 mg (97%); mp 115-16°; uv

Nnax (cyclohexane) 277 nm (e 4080): ix (00013) 1660 cm-1;
nmr 5 5.5 (bs, 1H) 4-H, 5 4.9 (m, 1H) 2.11, 5 1,97 (d, J

4 Hz, 2H) 1-H.

Anal. Calcd. for C33H580Si: C, 79.58; H, 11.64;

Found: C, 79.45; H, 11.57.

Preparation of 17B-Methoxy-2a-methylandrost-4-en-3-one (22):

To a chilled (0°) solution of 1.16 mmol of lithium ICA

in 2 ml THF was slowly added (10 min), a solution of 305 mg
(1 ~05 mmol) of testosterone (2,4) in 10 ml THF. Subsequently,
0'6 ml (3.04 mmol) of tetramethylethylenediamine was added,
f(XI-lowed by a 20 ml portion of dry HMPA: and after it was
s”litred for 90 min at 0°, the reaction mixture was quenched
by the rapid addition of excess methyl iodide. The reaction

was worked-up after it had stood 3 hr at 25°, by the addi-

tion of water and ether. The aqueous phase was extracted

several times with ether, and the combined ether extracts

48

were washed (twice each) with 5% hydrochloric acid, water

and brine and dried. Concentration of the ether extracts

yielded 315 mg of crude product, which was epimerized by
treatment with a solution of 200 mg of sodium hydroxide in

100 m1 methanol. Approximately 70% of the solvent was

evaporated at reduced pressure, and the concentrated solu-

tion was poured into water, and extracted with ether. The

combined ether extracts were washed, dried and concentrated
under reduced pressure, yielding 302 mg of crude product.
Preparative tlc on a 2 mm silica gel plate (20% ethyl

acetate in cyclohexane elutant) gave 200 mg (70%) of 176-

me thoxy -2a-methylandrost-4 -en-3 -one (25) . Recrystalliza-

tion from ether gave pure 2’5; mp 145-47: ir (KBr) 1670.

1o95 cm—l: nmr (cnc13) 5 5.6 (s, 1H) 4-H. 6 3.3 (s. 3H)

17—oc113, 0 3.2 (t, J=8 Hz, 1H) 17-H, 0 1.2 (s, 3H) 19-H3,
1.08 (d, J=6 Hz, 3H) 2-CH3, 5 0.80 (s, 3H) 18-H3: ms, m/e

(rel intesnity) 316(100), 301(8), 285(15), 260(29).

Found: C, 79.70; H, 10.10.

Preparation of 3 ,5,5-Trimethyl-6-phenylsulfonylcyclohex-2-

genome 02):

To a chilled (0°) solution of 8.00 mmol of lithium ICA

in 2 ml of THF was slowly added, a solution of 1.00 g
(7 -24 mmol) of isophorone (28') in 10 ml of THF and the re-
Sulting mixture was maintained at 0° for 90 minutes. In-

Verse quenching of this dienolate anion solution was

49

effected by adding it to a THF solution containing a 15%

excess of diphenyldisulfide. After this mixture was stirred

for 3 hours at room temperature, it was poured into water

and extracted with ether. The usual work-up gave 2.75 g

of crude product, which glpc analysis (4% QF-l at 150°)

showed to consist of: 3,5,5-trimethyl-6-phenylsulfony1-

cyclohex-Z-enone (3’2") (50%). isophorone and diphenyldisul—

fide. A pure sample of 32 was obtained by preparative glpc.

Identification of 3,2, rested on the following evidence:
11: (c014) 2950, 1670, 1635, 1245, 875, 685 cm-1; nmr
(CCl,,) 0 7.5 (brd. m, 5H) aromatic protons, 05.8 (brd. s,
1H) 2-H, 5 3.23 (s, 1H) 6—H,62.16aa187 (ABq, J=2o Hz, 2H)
ring CH3, 0 1.8 (s, 3H), 0 1.27 (s, 3H) and 0 1.1 (s, 3H)

5-CH3; mass spectrum, m/e (rel intensity) 246(49), 198(10),

164(100), 137(44), 110(44), 82(59).
Eeparation of 4,4-Dimethylcholest-2-en—3-one (22):

To a solution of 0.09 ml (0.63 mmol) of diisopropyl-

amine, in 1 ml of dry glyme was added 0.2ml of 2.21! n—butyl-

lithium (0.43 mmol) in hexane. After this solution was

stirred at 0° for 15 min, 150 mg (0.37 mmol) of 4i-methyl-
c1"lc>lest-2-en-3--one (3,5) in 5 m1 of glyme was slowly added
and the resulting solution was refluxed for 18 hr. Follow-
ing rapid addition of 0.5 ml (7.4 mol) of methyl iodide,
the resulting mixture was again refluxed for 10 hr; and

aEliter it cooled to room temperature, the reaction mixture

Was mixed with water and extracted several times with ether.

50
The combined ether extracts were washed and dried. Prepara-
tive tlc on a 2 mm silica gel plate (7% ethyl acetate in
cyclohexane elutant) gave 60 mg (40%) of 4,4—dimethylcholest-

2—en-3-one (42'); mp 88-91° (lit49 90-91).

Me thylation of 1 7B -tert-Buty ldimethy ls i loxy ~5a-andros t-2 -

3n -4-one (22‘) :

 

(a) Using One Equivalent of n—Butyllithium

To a chilled (0°) solution of 0.72 mmol of lithium
diisopropylamide in 0.5 ml of glyme was added 250 mg (0.62
mmol) of 17B-t_e_1_:_t_-butyldimethylsiloxy-5a-androst-2-en—4-
one (38) in 5 ml of glyme. A 0.25 ml (1.42 mmol) portion
of HMPA was then added and the reaction mixture was re-
fluxed for 10 hrs. After the reaction cooled to room
temperature, 0.5 ml (7.4 mmol) of methyl iodide was added,
and the resulting mixture was again refluxed for 5 hr.
Water and ether were added to this cooled reaction mixture,
and the aqueous phase was extracted several times with
ether. The combined ether extracts were washed and dried.
Analysis of the product mixture by high-pressure liquid
Chromatography (DUPONT 841 liquid chromatograph), using a
Silica gel column and eluting with 0.1% methanol in
methylene chloride, showed it to be composed of: starting
material (90%) and 17B-_t_e_r_t_-butyldimethylsiloxy-5E-methyl-
a1'ldrost-2--en-4-one (4,1,) (~6%). The structure gwas

tentatively assigned to the 5% product on the basis of the

Q'A‘

.. JU'

nv-un

Uni-I

n-~‘

-.u.
.

A',‘

'0‘“
.

4

A“

~.~

‘1‘
"1

(‘If

(1'

51

mass spectrum and nmr, ir and tlc analysis of the crude

product mixture .

(b) Using Two Equivalents of n-Butyllithium

The dienolate anion from 32was generated exactly the

same way as in (a). After the solution was cooled, a

second equivalent of g-butyllithium was added, and the

resulting solution was stirred for 10 min. An excess of

methyl iodide was then added, the reaction mixture was re-
fluxed for 5 hr; and, following the usual work-up, the

crude product was analyzed by high-pressure liquid chroma-

tography. The product mixture was thus shown to consist of

70% starting material, about 10% of 41' and three other minor

PrOducts.
Eithylation of Cholest-4-en-3-one ((9‘) Using Triphenylmethyl-
ifiium as Base:

To 1.670 g (6.9 mmol) of triphenylmethane in 5 ml of

dry THF, cooled to 0°, was added 2.6 ml (6.2 mmol) of £-

but-yllithium in hexane. The resulting red solution was

Waruled to room temperature and stirred for ninety minutes,
before being cooled to 0° again. A solution of 1.494 g
(3 ~88 mmol) of cholest-4-en-3-one (g) in 20 m1 THF was

Sleley added and the reaction mixture was maintained at 0°

for: 2 hr. Following rapid addition of 1 ml (9.8 mmol) of

methyl iodide, the resulting mixture was allowed to warm to

:00!!! temperature. After 4 hr of stirring, the reaction

52
mixture was mixed with water and extracted several times
with ether. The combined ether extracts were washed, dried,
and distilled under reduced pressure. The crude product
(3.30 g) was chromatographed on silica gel (170 g), elution
with cyclohexane-ethyl acetate (9:1) giving 1.62 g (75%)
‘4p4-dimethylcholest-5-en-3-one (42); mp 176-77° (lit8 176-77),
followed by 0.125 g (8%) 2-methylcholest-4-en-3-one (1’0).

GE-Bromotestosterone Acetate (22.) :

A solution of 1.10 g (3.33 mmol) of testosterone
acetate ’41, in 100 ml of carbon tetrachloride was refluxed
With a 0.596 g (3.35 mmol) of N-bromosuccinimide for 15 min,
While exposed to a strong incandescent light. After the
mixture cooled to room temperature and filtration of the
Succinimide, the solution was distilled under reduced pres-
sure. Crystallization from hexane gave 1.21 g (97.4%) of
6‘3 ~bromotestosterone acetate 42'; mp 146-1480 dec (lit 147-

148).

wromo-17B -_t_e_r_t-butyldime thy lsi loxyandros t—4-en-3 -one :

 

Bromination of 17B-_t£_r_t-butyldimethylsiloxyandrost-4-
en~3-one (26‘) in carbon tetrachloride solution with a molar
equivalent of N-bromosuccinimide by exposure to irradiation
fro!“ an incandescent light gave 95% of 6B-bromo-_t_e_1_r_§_—butyl-
dimethylsiloxyandrost-4-en-3-one. Crystallization from

1

ethe: gave pure material; mp 143-44; ir (CDC13) 1670 cm- 7

nrm: (cocla) 5 5.77 (s, 1H) 4-H, 5 4.87 (m, 1H) 6-H, <5 3.5

53
(t, J = 8 Hz, 1H) 17-H,51.5 (s, 3H) 19-H3,50.87 (s, 9H)
Si-C(CH3)3,60.77 (s, 3H) 18—H3,00.00 (s, 6H) Si-(CH3)2.
Anal, Calcd. for C25H4102818r: C, 62.35; H, 8.51;

Found: C, 61.91; H, 8.41.

Reaction of 6B-Bromotestosterone Acetate (45) with Lithium

 

Dimethylcuprate:

 

To a cold (-78°) solution of lithium dimethylcuprate
prepared from 0.979 g (3.36 mmol) of cuprous iodide and
8.40 mmol of methyllithium in 10 ml of ether, was added
0.412 g (1.00mmol) 63-bromotestosterone acetate(42) in 20 ml
ether. After the reaction mixture was stirred for 4 hr
at -78°, 2 ml of ammonium hydroxide (pH 8) solution was
added, and the product was isolated by pouring the reaction
mixture into 100 ml of saturated aqueous ammonium chloride,
extracting with ether, and drying. The crude product
(0.382 g) was chromatographed on silica gel (15% ethyl
acetate in cyclohexane elutant) and gave 310 mg testosterone

acetate (41) (93%); mp 138-40°.

Methylation of Isophorone Oxide (49)

 

To a chilled (0°) solution of 4.55 mmol of lithium
isopropylcyclohexylamide (LiICA) in 20 m1 of THF was added,
over a ten minute period,a solution of 0.54 g (3.57 mmol)
of iSOphorone oxide in 25 ml of THF. A 20 ml portion of dry
hexamethylphosphoric triamide (HMPA) was then added and,

following a ninety minute period of stirring at 0°, the

54

reaction mixture was quenched by the rapid addition of ex-
cess methyl iodide. After standing at 25° for three hours,
the resulting mixture was poured into ice water and ex-
tracted several times with ether. The combined ether
extract was washed (twice each) with 5% hydrochloric acid,
water and brine, dried and concentrated under reduced pres-
sure. Analysis of the product mixture by glpc (4% QF-l at
135°) showed it to be composed of: 2,3-epoxy-3,5,5,6-tetra-
methylcyclohexanone (52) (70%); 5,6-epoxy-2,3,5-trimethyl-
1-methoxycyclohexene (51) (10%); 5,6-epoxy-2,3,3,5-tetra-
methyl-1-methoxycyclohexene (52) (5%); 2,3-epoxy-3,5,5,6,6-
pentamethylcyclohexanone (53) (3%) and isophorone oxide (4%).

Pure samples of each component of this mixture were.

obtained by preparative glpc. Identification of each com-

pound rested on the following evidence:

2,3-epoxy-3,5,5,6-tetramethylcyclohexanone 52; ir (CC14)
1720 cm-1; nmr (C014) 6 3.0 (s, 1H) oxirane CH, 6 2.7 (q,
J = 7 Hz, 1H) ring CH, 5 2.1 and 1.6 (ABq, J = 14 Hz, 2H)
ring CH3, 5 1.40 (s, 3H), 5 0.96 (s, 3H), 5 0.86 (d, J =
7 Hz, 3H), 6 0.73 (s, 3H): mass spectrum, m/e (rel intensity)
168(20.8), 153(21.5), 139(37.5), 125(40.0), 97(99.8),
83(35.3), 70(99.4). I

Anal, Calcd. for C10H1502: C, 71.39; H, 9.59;

Found: C, 71.25; H, 9.65.

55
5,6éEpoxy-3,3,5-trimethyl-1—methoxycyclohexene (51); ir (CCl4)
1660, 1237, 1200 om“: nmr (001,) 5 4.33 (d, J =‘2.5 Hz, 1H)
=CH, 5 3.53 (s, 3H) OCH3, 5 2.86 (d, J = 2.5 Hz, 1H) oxirane
CH, 6 1.82 and 1.48 (ABq, J . 14 Hz, 1H) ring CH2, 6 1.36
(s, 3H), 6 1.06 (s, 3H), 6 1.00 (s, 3H): mass spectrum, m/e
(rel intensity) 168(44.6), 153(82.3), 137(10.6), 125(37.8),
112(66.7), 111(56.6), 95(21.8), 93(32.3), 77(20.7).

Anal. Calcd. for C10H160: C, 71.39; H, 9.59;
Found: C, 71.25; H, 9.63.

£5,6-Epoxy-2,3,3,5-tetramethyl-1-methoxycyclohexene (5g):

ir (ccl,) 1665, 1100 cm-1; nmr (cc1,) 5 3.43 (s, 3H) OCH3,
<5 2.86 (s, 1H) oxirane H, 6 1.53 (m, 2H) ring CH2, 6 1.3
(as, 6H), 6 0.90 (s, 6H); mass spectrum, m/e (rel intensity)

182(2), 123(5), 99(100).

2 . 3-Epoxy-3 , 5 , 5 , 6, 6-pentamethylcyclohexanone (55),- ir (CC14)
13710 om": nmr (ccl,) 5 2.93 (s, 1H) oxirane 0H, 5 2.18 and
1~.58 (ABq, J = 15 Hz, 2H) ring CH2, 6 1.40 (s, 3H), 6 1.10
(:3, 3H), 6 0.93 (6H): mass Spectrum, m/e (rel intensity)
1£32(5.8), 154(14.4), 139(20.5) 97(53.2), 84(99.4), 69(95.0).

137B-tert-Butyldimethylsiloxy-46,56-epoxyandrostan-3-one (52):

46,5B-Epoxytestosterone (2.36 9, mp 158-159°) was treated
‘flith 1.40 g (9.3 mmol) of Egggfbutyldimethylchlorosilane
and 1.32 g (19.41 mmol) of imidazole in 20 ml DMF (dry) for
15 hours at 35°. The usual work-up gave 2.750 g (85%) of

17B-tert4butyldimethylsiloxy-4B,56-epoxyandrostan-3-one (52):

56
mp 127-128°; ir (KBr) 1715 cm-1; nmr (c0c13) 5 3.57 (t, J -
8 Hz, 1H) 17-H, 5 2.97 (s, 1H) 4-H, 51.13 (s, 3H) 19-H3, 5
0.87 (s, 9H) -SiC(CH3)3,G.70 (s, 3H) 18-H3,60.00 (s, 6H)
-Si(CH3)2; mass spectrum, m/e (rel intensity) 418 (very
weak), 403(< 5), 361(82), 345(29), 285(15).
A33}, Calcd. for C25H42038i: C, 71.71; H, 10.11;

Found: C, 71.67; H, 10.12.

jgethylation of 17B-tert-Butyldimethylsiloxy-4B,5B-epoxy-
indrostan-3—one (53):

 

 

To a chilled (0°) solution of 2.95 mmol of lithium ICA
1J1 5 ml of THF was added 1.00 g (2.4 mmol) of 175‘EEEET
INJtyldimethylsiloxy-4B,56-epoxyandrostan-3-one in 15 ml of
{PEEK A 10 ml portion of HMPA was then added and, following
El ninety minute period of stirring at 0°, the reaction mix-
tlJre was quenched by the rapid addition of 16 mmol of methyl
irodide. After standing at room temperature for four hours,
tJne resulting mixture was poured into water and extracted
Vlith ether. The usual washing, drying and concentration of
lihe combined ether extract yielded 950 mg of a crystalline
E>roduct. Recrystallization from hexane gave an 80% yield
c>f 176-52557butyldimethylsiloxy-2fi-methyl-48,58-epoxy-
Eindrostan-3-one (55): mp. 131-133°; ir (KBr) 1710 cm-1;
nnm'(CDC13) 5 3.57 (m, 1H) 17-H, 5 2.97 (s, 1H) 4-H, 5 1.13

(s, 3H) 19-H3.5 1.08 (d, J = 7Hz, 3H) 2-CH3, 5 0.87 (s, 9H)

~SiC(CH3)3, 5 0.72 (s, 3H) 18-H3,6 0.00 (s, 6H) -Si(CH3)z;

57
mass spectrum, m/e (rel intensity) 432(very weak), 375(100),
359(30), 299(20). 7
5921, Calcd. for C23H4403Si: 'c, 72.16; H, 10.25;

Found: C, 72.30; H, 10.28.

Methylation of 4B,56-Epoxycholestan-3-one (55):

 

To a chilled (0°) solution of 1.09 mmol of lithium ICA
in 5 ml of THF was added 250 mg (0.62 mmol) of 46,58-epoxy-
cholestan-3-one in 15 ml THF. A.10 m1 portion of dry HMPA
was then added and, following a ninety minute period of
stirring at 0°, the reaction mixture was quenched by the
rapid addition of excess methyl iodide. After standing at
25° for three hours, the resulting mixture was poured into
water and extracted with ether. The combined ether ex-
tracts were washed, dried and concentrated under reduced
pressure, yielding 263 mg of crude product. Preparative
tlc on 2 mm silica gel plates (15% ethyl acetate in cyclo-
hexane elutant) gave 190 mg (74%) of 25-methyl-45,5B-epoxy—
cholestanone (51); mp 100-1010; ir (KBr) 1715 cm-1;
[aJD + 117.530 (0.015 g/lO ml CHCls).

523;, Calcd. for C28H4602: C, 81.10; H, 11.18;

Found: C, 81.01; H, 11.23.

3,5,5-Trimethyl-2-methoxycyclohex-2-enone (55):

 

To a solution of 6.00 g (91.07 mmol) of 85% potassium

hydroxide in 50 m1 of refluxing methanol was added, dropwise,

58
a solution of 7.83 g (50.84 mmol) isophorone oxide (25) in
25 ml methanol. After refluxing for ninety minutes, the
resulting mixture was poured into ice water and extracted
several times with ether. The combined ether extract was
washed, dried and concentrated under reduced pressure. The
yield of 3,5,5-trimethyl-2-methoxycyclohex-2-enone (55) was
7.00 g (80%): bp 135-1390/20 mm; ir (001,) 1678, 1640 cm-1;
nmr (CC14) 6 3.5 (s, 3H) OCH3, 6 2.15 (brd. s, 3H) 3-CH3,
6 1.78 (d,J=1Hz,2H) ring CH2,61.03 (s, 6H) 5-(CH3)2; mass
spectrum, m/e (rel intensity) 168(43), 153(14), 112(30),
84(35), 69(100). ‘

3,5,5-Trimethyl-2-methoxycyclohex-2-enone tosylhydrazone (55):

After substantial experimentation, the most successful
procedure for the formation of 55'proved to be the following.
A solution of 3.35 g (19.94 mmol) of 3,5,5-trimethyl-2-
methoxycyclohex-Z-enone (55) and 4.1 g (22.0 mmol) of ET
toluensulfonylhydrazine in a minimum amount of absolute
ethanol (5 ml) was refluxed for 1.5 hours in a Craig tube.
Acid was not used in order to prevent hydrolysis of the enol
ether prior to hydrazone formation. Cooling of the solution
afforded 5.69 g (85%) of crystalline product 55; mp 123-25°.
Recrystallization from 95% ethanol gave pure 55) mp 124-125°,
ir (KBr) 3560, 3510, 3200, 1635, 1590, 1327, 1160 cm-1;
nmr (0001,) 5 7.7 (d, J = 8 Hz, 2H) and 5 7.1 (d, J = 8 Hz,
2H) 4 aromatic protons, 6 5.13 (brd s, 1H) éNH, 6 3.4 (s,

3H) 00H,, 5 2.33 (s, an) aromatic -cH3, 5 2.1 (s, 2H) and

59
5 1.93 (brd s, 2H) ring CH2,61.7 (s, 3H) =CCH3,60.90 (s, 6H)
C(CH3)2; mass Spectrum, m/e (rel intensity) 336(17),
246(5), 181(99), 152(43), 137(99), 124(42), 92(100).
gpgl, Calcd. for 017H2,0,N28; 0, 60.68; H, 7.19; N, 8.32;

Found: C, 60.54, H, 7.24; N, 8.32.

Reaction of 3,5,5-Trimethyl-2-methoxycyclohex-2-enone
tosylhydrazone (55) with Methyllithium:

 

 

To a solution of L00 9 (2.97 mmol) 3,5,5-trimethyl-2-
methoxycyclohex-Z-enone tosylhydrazone (55) in 20 m1 of ether,
was added 3.5 ml (8.05 mmol) of 2.2M methyllithium. After
the reaction mixture was stirred for two hours, it was
quenched with 5% ammonium hydroxide solution and extracted
with ether. The combined ether extracts were washed, dried
and concentrated by distilling the solvent ether at atmos-
phere pressure. A yield of 0.450 g (99%) of 1,5,5-trimethyl-
2-methoxycyclohex-1,3-diene 55'was obtained. Glpc analysis
(4% QF-l, 110°) showed this material to be > 99% pure;
ir (001,) 1660, 1150 cm-1; uv xmax (ethanol) 267 nm (e 4138);
nmr (00013) 5 5.65 and 5 5.35 (ABq, J = 10 Hz, 2H) Hjc-CCH.
5 3.43 (s, 3H) -OCH3,61.97 (m, 2H) ring CH2, 5 1.63 (s, 3H)
=C-CH3, 6 0.97 (s, 6H) -C(CH3)3; mass spectrum, m/e (rel
intensity) 152(24), 137(76), 122(29), 96(69). '

Anal. Calcd. for ClOHIBO: C, 78.89; H, 10.59;
Found: C, 78.93; H, 10.68.

6O

4,4,6-Trimethylcyclohex-2-enone (51):

1,5,5-Trimethyl-2-methoxycyclohex-1,3-diene (55)
(450 mg) was treated with 5% hydrochloric acid in THF for
15 min. Dilution with water gave, after extraction with
ether and the usual work-up, 410 mg (98%) of 4,4,6-tri-
methylcyclohex-Z-enone (5L); ir (CC14) 1680, 1370 cm-1;
nmr (CC14) 6 6.37 (d.d, J = 10 Hz and 2H2, 1H) 3-H, 6 5.6
(d, J = 10 Hz, 1H) 2-H, 5 2.33 (octet, J = 6 Hz, 1H) 6-H,
6 1.70 (m, 2H) ring CH2, 6 1.17 (s, 3H) and 6 1.1 (s, 3H)
-C(CH3)2, 6 1.03 (d, J = 6H2, 3H) 6-CH3; mass Spectrum,
m/e (rel intensity) 138(17), 96(100), 82(36), 67(32).

gag}, Calcd. for C9H14O: c, 78.21; H, 10.21:

Found: C, 78.27; H, 10.21.

Base Catalyzed Deuterium Exchange of 4,4,6-Trimethylcyclo-

hex-Z-enone (5;):

 

To a chilled (0°) solution of 0.75 mmol of lithium ICA
in 0.5 m1 of THF was added, a solution of 100 mg (0.65 mmol)
of 4,4,6-trimethylcyclohex-Z-enone (55) in 5 ml of THF.

The reaction mixture was stirred at 0° for ninety minutes,
and then quenched by rapid addition of 0.5 ml of deuterium
oxide. After stirring for one hour, the reaction was
worked-up as usual. A pure sample of 6-D-4,4,6-trimethyl-
cyclohex-Z—enone was obtained by preparative glpc: nmr
(001,) 5 6.37 (d,d, J: 10 Hz and 2 Hz, 1H) 3—H, 5 5.6 (d,

J = 10 Hz, 1H) 2-H, 5 1.83 and 5 1.60 (ABq, J = 8 Hz, 2H)

61
ring CH2, 6 1.17 (s, 3H) and 6 1.1 (s, 3H) -C(CH3)2,61.03

(s. 3H) 6-CH3.

4-Methoxytestosterone (55):

 

A sample of 48,58-epoxytestosterone (55) (6.8 g, 22.4
mmol) containing a little of the a-isomer was dissolved in
125 ml of absolute methanol; 3.4 g (63.0 mmol) of sodium
methoxide was added and the mixture was heated under reflux
for 24 hours. After this solution cooled to room temperature,
it was diluted with water and extracted with chloroform.
Evaporation of the solvent gave 7.00 g (94%) of 4-methoxy-
testosterone (55), which was recrystallized from ethyl
acetate to give fine white needles; mp 218-220° (lit36C 218-

220).

17B-tert-Butyldimethylsiloxy-4-methoxyandrost-4-en-3-one(5g):

 

4-Methoxytestosterone (55) (800 mg, 2.48 mmol) was
treated with 450 mg (3.008 mmol) of Egggfbutyldimethyl~
chlorosilane and 420 mg (6.17 mmol) of imidazole in 10 ml
of DMF (dry) for 15 hours at 35°. The usual work—up gave
980 mg (93%) of 17B-Egggfbutyldimethylsiloxy-4-methoxy-
androst-4-en-3-one (52); mp 153-550; ir (KBr) 1680, 1605
cm-1: nmr (00013) 5 3.5 (s, 3H) 4-OCH3, 5 3.47 (t, J =
8 Hz, 1H) 17-H, 5 1.15 (a, 3n) 19-H3,60.87 (s, 9H) -Si-C(CH3)3,
5 0.71 (s, 3H) 18-H3, 5 0.00 (s, 6H) -Si-(CH3)2; mass
spectrum, m/e (rel intensity) 432(7), 375(90), 299(10),

267(15).

62
Anal. Calcd. for C26H4403Si: C, 72.17; H, 10.25;

Found: C, 72.26; H, 10.16.

17B-tert—Butyldimethylsiloxy-4-methoxyandrost-4-en-3-one

 

tosylhydrazone (£2):

 

A solution of 17B-Egrgfbutyldimethylsiloxy—4—methoxy-
androst—4-en-3-one (64) (1.54 g, 3.56 mmol) and 0.725 g
(3.89 mmol) of pftoluensulfonylhydrazine in 5 ml of absolute
ethanol was refluxed for 15 min in a Craig tube. Cooling
of the solution afforded 2.075 g (97%) of crystalline pro-
duct 62; mp 157-1580. Recrystallization from ether gave
pure 223 mp 160-162(d); ir (KBr) 3450, 3200, 2945, 1595 cm“;
nmr (c0c13) 5 7.73 (d, J = 8 Hz, 2H) and 5 7.13 (d, J =
8 Hz, 2H) 4-aromatic protons, 0 3.43 (s, 3H) 4-OCH3, 0 3.44
(t. J = 8 Hz, 1H) 17-H, 5 3.27 (s, 1H) NH, 5 2.33 (s, 3H)
aromatic -CH3, 5 0.97 (s, 3H) 19-H3, 5 0.83 (s, 9H)
-SiC(CH3)3, 5 0.70 (s, 3H) 18-H3, 5 0.00 (s, 6H) -Si(CH3)2.

gggi, Calcd. for C33H5204stsi: c, 65.95; H, 8.72;

N, 4.66:
Found: C, 65.75; H, 8.79;

N, 4.57.

Reaction of 17fi-tert-Butyldimethylsiloxy-4-methoxyandrost-
4-en-3-one tosylhydrazone (62) with Methyllithium:

‘

To a solution of 500 mg (0.83 mmol) of 17B-tert~butyl-
dimethylsiloxy-4-methoxyandrost-4-en—3-one tosylhydrazone

(fifii) in 30 m1 of ether, was added 1.0 ml (2.27 mmol) of

63

2.2M methyllithium. The resulting mixture was refluxed for
30 minutes, cooled to room temperature and quenched with
5% ammonium hydroxide solution. This mixture was extracted
with ether, and the combined ether extracts were washed and
dried. Evaporation of the ether solvent under reduced pres-
sure gave 365 mg (95%) of 17 -tg££fbutyldimethylsiloxy-4-
methoxyandrosta-Z,4-diene (66); mp 139-410; ir (KBr) 1650
cm-1; uv xmax (cyclohexane) 276 nm (e 4365); nmr (CDC13)
5 5.67 (m, 2H) 2-H and 3-H, 5 3.47 (m, 1H) 17-H, 5 3.42 (s,
3H) 4-OCH3, 5 0.90 (s, 3H) 19-H3, 5 0.87 (s, 9H) -Si-C(CH3)3,
50.70 (s, 3H) 18-H3, 5 0.00 (s, 6H) -Si-(CH3)2.: mass
Spectrum, m/e (rel intensity) 416(34), 401(70), 359(9),
283(14), 269(16). '

Anal, Calcd. for C23H4402Si: C, 74.94; H, 10.64;

Found: C, 74.86; H, 10.76.

17B-tert-Butyldimethylsiloxy-Sa- androst-Z—en-4-one (fig):

Treatment of 17B-Eggtfbutyldimethylsiloxy-4-methoxy-
androsta-2,4-diene (66) 155 mg with 5% hydrochloric acid
in THF for 15 min, gave, after dilution with water and ex-
traction with ether and the usual work-up, 140 mg (94%) of
17B-Egrtfbutyldimethylsiloxy-5a-androst-2—en-4-one (38);
mp 112-114°; ir (KBr) 1772 cm“; nmr (cnc13) 56.67 (d,d,d,
.1 = 3.2 Hz, 5.2Hz and 9.6 Hz, 1H) 2-H, 5 5.87 (d,d,d, J =
31.6 Hz, 2.8 Hz and 9.6 Hz, 1H) 3-H, 0 3.5 (t, J = 8 Hz, 1H)
17uqa, 5 0.87 (s, 9H) -SiC(CH3)3, 5 0.82 (s. 3H) 19-H3.

6 ().69 (s, 3H) 18-H3, 5 0.00 (s, 6H) -Si(CH3)2: mass

64
spectrum, m/e (rel intensity) 402 (very weak), 345(82),
269(67); [Q1370 = + 6.750 (0.0274 g/10 ml CHc13).
Agglp Calcd. for c25H4zozsi: C, 74.57; H, 10.51;

Found: C, 74.57; H, 10.45.

176-Hydroxy-5a-androst-2-en-4—one (61):

 

Prolonged treatment (24 hrs) of 17B—Egrtfbutyldimethyl-
siloxy-4-methoxyandrosta-2,4-diene (62) with 10% hydro-
chloric acid in THF gave 17B-hydroxy—5a-androst-2-en-4-one
(61); mp 174-750; ir (KBr) 1670 cm-1; nmr (CDC13) 6 6.67
(d,d,d, J - 3.2 Hz, 5.2 Hz and 9.6 Hz, 1H) 2H, 5 5.87 (d,d,d,
J = 1.6 Hz, 2.8 Hz and 9.6 Hz, 1H) 3-H, 5 3.5 (t, J - 8 Hz,
1H) 17-H, 5 0.83 (s, 3H) 19-H3, 5 0.70 (s, 3H)618-H3; mass
Spectrum, m/e (rel intensity) 288(54), 273(23), 255(11),
245(16). ‘ .

Anal, Calcd. for C19H2802: C, 79.12; H, 9.78;

Found: C, 78.90; H, 9.74.

Attempted Pyrolytic Aromatization of 17B-tert-Butyldimethyl-

siloxy-4-methoxyandrosta-2,4-diene (22):

 

A solution of 63 mg of 17B-Egrt-butyldimethylsiloxy-4-
methoxyandrosta-Z,4-diene (26) in 1 m1 of triethylene glycol
dimethyl ether was heated at 200° for 24 hr. The reaction
mixture was diluted with chloroform and extracted with
water. Concentration of dried chloroform solution gave 60
mg of product. The ir and nmr showed no indication of aroma-

tic protons, and all the analytical data indicated the pro-

duct was starting material.

65

17B+Hydroxy-5a-androst-1-en-3-one (22):

 

Pyridinium bromide perbromide (9.5 g) was added over a
5 minute period to a solution of 10.00 g 17B—hydroxy-5a-
androstane-3-one (62) (mp 184-1860) in 30 ml of acetic acid,
containing a trace of hydrogen bromide. After 15 minutes,
the solution was diluted with water and 10% sodium thio-
sulfate. The resultant precipitate was collected, washed
with 5% sodium bicarbonate and water, dissolved in methylene
chloride and dried. Removal of the solvent at reduced pres-
sure afforded 13.2 g of crude bromo compound, which was
dehydrobrominated by refluxing with lithium chloride (4.8 g)
and lithium carbonate (2.8 g) in dimethylformamide (100 ml)
for 4 hr under an inert atmosphere. Methylene chloride was
added to the cooled reaction mixture and the solution was
washed (twice each) with water, 10% hydrochloric acid, and
brine. The combined methylene chloride extracts were dried
and concentrated under reduced pressure, yielding 9.1 g of
crude product. The crude product was dissolved in methanol
(200 ml) and a solution of sodium metabisulfite (35 g) in
(170 ml) was added. The solution was stirred at1250 for
3 to 5 min, water (100 ml) added, and the mixture was im-
mediately extracted with methylene chloride (4 x 170 ml).
The combined extracts, when concentrated under reduced
pressure, yielded 8.09 g of an oil. This oil (8.09 g) was
dissolved in methanol (175 ml) and reacted with sodium meta-

bisulfite (27 g) in water (100 ml) for 90 min at reflux.

66

This cooled reaction mixture was diluted with 400 ml of
water and extracted with methylene chloride (4 x 70 ml).
The aqueous phase was then treated with sodium hydroxide

(5 g) and this solution was refluxed for 30 min. Extrac-
tion of the cooled solution with methylene chloride, fol-
lowed by the usual work-up gave 5.4 g (50%) of pure 175-
hydroxy-5a-androst-1-en-3-one (70); mp 156-159° (reported42

157-1590).

 

17B-Hydroxy-1a,2a-epoxy-5a-androstan-3-one czi):

To a cold (10°) solution of 17B-hydroxy-5a-androst-1-
en-3-one (22) (2.66 9; mp 152-53°) in 40 ml of methanol was
added 3 ml of 30% hydrogen peroxide, followed by 0.6 ml of
a 10% solution of sodium hydroxide in methanol. The tem-
perature of this reaction was maintained at 14 to 20°.
After 40 min, the reaction mixture was diluted with water,
extracted with ether and the combined ether extracts were
washed twice with water. Concentration of the dried ex-
tracts under reduced pressure yielded 2.62 g of crude pro-
duct. Crystallization from 90% methanol gave 2.41 g (90%)
of pure 17B-hydroxy-1a,2a-epoxy—5a-androstan-3-one (22);
mp 161-162 (lit43 161-162).

17B-Hydroxy-2-methoxy-5a-androst—1~en-3-one (22):

 

To a refluxing solution of 2.75 g (9.04 mmol) of 176-
hydroxy-la,2a-epoxy-5a-androstan-3-one (21) in 50 ml of

methanol was added 1.50 g (22.76 mmol) of 85% potassium

67

hydroxide in 20 ml of hot methanol. This reaction mixture
was refluxed for 5 hours, concentrated under reduced pres-
sure and then poured into ice water. The chloroform ex—
tract of this mixture gave 3.00 g of crude 28; This crude
product was chromatographed on alumina (110 g) and elution
with cyclohexane-ethyl acetate (8:2) gave 2.25 g (78%) of
17B-hydroxy-2-methoxy-5a-androst-1-en-3-one (12); mp
176-178° (lit44 178-79°). Crystallization from ethyl
acetate gave pure 22; mp 178-179°. The recovered starting

material was 400 mg.

17B-tert-Butyldimethylsiloxy-2-methoxy-50-androst-1-en-
3-one (13):

 

 

17B-Hydroxy-2-methoxy-5a-androst-1-en-3-one (22) (2.25 g,
7.07 mmol) was reacted with 1.1795 g (7.83 mmol) of 52:27
butyldimethylchlorosilane and 1.209 g (17.17 mmol) of imid—
azole in 30 ml of DMF (dry) for 15 hours at 35°. The usual
work-up gave 3.00 g (98%) of 17B-Egrgfbutyldimethylsiloxy-
2-methoxy-5a-androst-1-en-3-one (23); mp 103-104°, ir (KBr)
1680, 1602 cm-1; nmr (c0013) 5 5.92 (s, 1H). 6 3.48 (8:3H) OCHsv
5 3.46 (t, J = 8 Hz, 1H) 17-H, 5 1.00 (s, 3H) 19+H3, 5 0.85
(s, 3H)A-SiC(CH3)3, 5 0.70 (s, 3H) 18-H3, 5 0.00 (s, 6H)
-Si-(CH3)2. ' I

héggl, Calcd. for C23H44033i: C, 72.17; H, 10.25;

Found: C, 72.24; H, 10.22.

68

17B-tert-Butyldimethylsiloxy-2-methoxy-5a-androst—1-en-

 

3-one tosylhydrazone (14):

 

A solution of 17B-Eggtfbutyldimethylsiloxy-2-methoxy-
5a-androst-1-en-3-one (23) (1.6 g, 3.70 mmol) and 0.690 g
(3.70 mmol) of pftoluenesulfonylhydrazine in 3.2 ml absolute
ethanol was refluxed for 1 min in a Craig tube. Cooling
the reaction afforded 2.210 g (97%) of crystalline product
(22). Recrystallization from ethanol gave pure 22; mp
131-1330; ir (KBr) 3460, 3200, 2940, 1595 cm‘l; nmr (fresh
soln. of CDCla): 07.67 (d, J = 8 Hz, 2H) and 0 7.1 (d, J 3
8 Hz, 2H) 4 aromatic protons, 0 5.4 (s, 1H) 1-H, 0 3.43
(s, 3H) 2-0cna, 5 2.40 (t, J = 8 Hz, 1H) 17-H, 5 2.33 (4,
3H) aromatic -CH3, 5 0.87 (s, 9H) -SiC(CH3)3, 5 0.80 (s,
3H) 19-H3, 5 0.67 (s, 3H) 18-H3, 5 0.00 (s, 6H) -Si-(CH3)2:
nmr (after 24 hrs) 0 7.67 (d, J = 8 Hz, 1H), 0 7.6 (d, J =
8H2, 1H) and 0 7.1 (d, J = 8 Hz, 2H) 4 aromatic protons,

5 5.42 (s, 0.5 H) and 5 5.3 (s,(L5H)1-H, 5 3.47 (s, 1.5 H)
and 53.43 (s, 1.5 H) 2-00H3, 5 3.87 (s, 1H) -NH, 5 2.40

(t, J = 8 Hz, 1H) 17-H, 0 2.33 (s, 3H) aromatic -CH3, 0 0.87
(s, 9H) -SiC(CH3)3, 5 0.80 (s, 3H) 19-H3, 5 0.67 (s, 3H)
18-H3, 5 0.00 (s, 9H) -Si-(CH3)2.

Anal. Calcd. for C33H5204N288i: C, 65.95; H, 8.72;

N, 4.66:
Found: C, 65.70; H, 8.63;

N, 4.70.

69

Reaction of 17 -tert-Butyldimethylsiloxy-2-methoxy-5 -androst-

 

1- en-3-one tosylhydrazone (12) with Methyllithium:

 

To a solution of 760 mg (1.26 mmol) of 17B'EEEE-bUtYl‘
dimethylsiloxy-Z-methoxy-5a-androsta-1-en-3-one tosylhydra-
zone (Zé) in 10 ml ether, was added 2.0 ml (3.52 mmol) of
1.76M methyllithium. The resulting mixture was refluxed
for 50 minutes, cooled to room temperature and quenched with
5% ammonium hydroxide solution. This mixture was extracted
with ether, and the combined ether extracts were washed and
dried. Evaporation of the ether solvent under reduced
pressure gave 509 mg (96%) of 17B-Egrtfbutyldimethylsiloxy-
2-methoxyandrosta-1,3-diene (12) as an oil; ir (CHCla)
1650, 1600 cm-1; uv Amax (cyclohexane) 275 nm (e 4538); nmr
(CDc13) 5 5.28 (d, J = 6 Hz, 1H) 3-H, 5 5.18 (brd s, 1H)
12H, 5 4.67 (d,d, J = 6 Hz, and 1 Hz) 4-H, 5 3.47 (s, 3H)
2-0cna, 5 3.40 (m, 1H) 17-H, 5 0.92 (s, 3H) 19-H3, 5 0.85
(s, 9H) -SiC(CH3)3, 5 0.70 (s, 3H) 18-H3, 5 0.00 (s, 6H)
-Si(CH3)2.

Anal, Calcd. for C23H4402Si: C, 74.94; H, 10.64;

Found: C, 74.77; H, 10.60.

17B-tert-Butyldimethylsiloxy-5a-androst-3fen-2-one (12):

 

 

17B-tert-Butyldimethylsiloxy-2-methoxyandrosta-1,3-
diene (22) (165 mg) was treated with 5% hydrochloric acid
in THF f6r 15 min. Dilution with water gave, after extrac-

tion with chloroform and the usual work—up, 155 mg (97%) of

70
175-Egrtfbutyldimethylsiloxy-5a-androst-3-en-2-one (lg).
Crystallization from ether gave pure 16; mp 181-182°;'
ir (KBr) 1670 cm-1; nmr (c0c13) 5 6.42 (d,d, J - 2 Hz and
10 Hz, 1H) 4-H, 5 5.6 (d,d, J = 3 Hz and 10 Hz, 1H) 3-H,
5 3.45 (t, J = 8 Hz, 1H) 17-H, 5 2.53, and 5 1.97 (ABq,
J = 16 Hz, 2H) 1-CH2, 5 0.83 (s, 9H) -Si-C(CH3)3, 5 0.80
(s, 3H) 19-H3, 5 0.70 (s, 3H) 18-H3, 5 0.00 (s, 6H)
-s1(cna)z: [5137 - +28.82° (0.0251 g/10 ml CHC13).

Anal, Calcd. for C25H42025i: C, 74.57; H, 10.51;

Found: C, 74.57; H, 10.60.

REFERENCES

1.

REFERENCES

(a) L. E. Barnes, R. O. Stafford, M. E. Guild and
K. J. Olson, Proc. Soc. Exptl. Biol. Med., 87, 35
(1954). ’””
b) L. E. Barnes, R. O. Stafford, M. E. Guild, L. C.
Thole and K. J. Olson, Endocrinology, 55, 77 (1956).
(c) R. M. Dowben, Proc. Soc. Exptl. Biol. Med., 98,
644 (1958). '””
(d) F. J. Saunders and V. A. Drill, Metabolism Clin.
and Exptl., 7, 315 (1958); Proc. Soc. Exptl. Biol.
1135., 94, 646’ (1957

 

S. C. Lyster, G. H. Lund and R. O. Stafford, Endo-
crinology, 58, 781 (1956).

 

L. F. Fieser and M. Fieser, “Steroids", Reinhold,
New York, pg 563 and 692, 1959.

N. Applezweig,”Steroid Drugs:'Vol I, McGraw Hill, New
York, 1962.
Vol II, Holden Day, San Fransisco, 1964.

A. David, F. Hartley, D. R. Millson and R. Petrow,
J. Pharm. Pharmacol., g, 929 (1957).

H. 0. House, "Modern Synthetic Reactions," Second Edi-
tion, W. A. Benjamin, Inc., New York, 1972.

J. M. Conia, Rec. Chem. Prog£., 24, 43 (1963).

 

R. B. Woodward, A. A. Patchett, D. H. R. Barton,

D. A. J. Ives and R. B. Kelly, J. Amer. Chem. Soc.,
76, 2852 (1954). H. J. Ringold and s. K. Malfiotra,
$345., 84, 3402 (1962).

 

(a) w. J. Adams, D. K. Patel, v. Petrow, I. A. Stuart-
Webb and B. Sturglon, J. Chem. Soc., 1956, 4490.

(b) A. Bowers and H. J. Ringold, J. Amer. Chem. Soc.,
81, 424 (1959).
(3) H. J. Ringold and G. Rosenkranz, J. Org. Chem.,
2'2“, 602 (1957).

 

 

 

71

10.

11.
12.
13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

72
(a) C. Djerassi, J. Osiecki and E. J. Eisenbraum,
J. Amer. Chem. Soc., 83, 4433 (1961).
(b7_ M. R. Cox, H. P.~§och, W. B. Whalley, H. B.
Hursthouse and D. Rogers, Chem. Commun., 212 (1967)

 

N. W. Atwater, J. Amer. Chem. Soc., 22, 2847 (1960).

 

G. Stork, J. Benaim, J. Amer. Chem. Soc., 22, 5938 (1971).

 

 

O. Engelfried and M. Schenck, Chem. Abstr., 56, 11669a
1962 . 'vv

H. Laurent and R. Wiechert in "Organic Reactions in
Steroid Chemistry," edited by J. Fried and J. A.
Edwards, Van Nostrand Reinhold Co., New York, Vol II
1972. pP 86-99.

Y. Urushibara and M. Chuman, Bull. Chem. Soc. Jap.,
22, 69 (1949). C.A., 44, 1124'(1950).

 

H. J. Ringold, E. Batres and G. Rosenkranz, J. Org.
Chem., 22, 99 (1957).

M. Ackroyd, W. J. Adams, B. Ellis, V. Petrow and I. A.
Stuartdwebb, J. Chem. Soc., 1957, 4099.

 

O. S. Madaeva, M. I. Ushakov and N. F. Kosheleva, J.
Gen. Chem. USSR, 12, 213 (1940). C.A. 22, 7292 (1940).

 

J. A. Campbell, J. C. Babcock and J. A. H099. J. Amer.
Chem. Soc., 22, 4717 (1958).

 

H. J. Ringold, J. PerezRuelas, E. Batres and C.
Djerassi, J. Amer. Chem. Soc., 22, 3712 (1959).

 

D. Burn, B. Ellis, V. Petrow, I. A. Stuartdwebb and D. M.
Williamson, J. Chem. Soc., 1957 4092.

 

S. Bernstein, E. W. Cantrall and J. P. Dusza, J. Org.
Chem., 22, 269 (1961).

J. Iriarte and M. L. Franco, J. Org. Chem., 22, 2047
(1961).

M. Kato, H. Kosugi and A. Yoshikoshi, Chem. Comm., 185
(1920 .

S. K. Malhotra and H. J. Ringold, J. Amer. Chem. Soc.,
22, 1997 (1964).

R. E. Counsell, P. D. Klimstra and F. B. Colton, J. Org.
Chem., 21, 248 (1962).

P. D. Klimstra and R. E. Counsell, J. Med. Chem., 2,
48 (1965).

73

28. P. S. Wharton and D. H. Bohlen, J. Org. Chem., 26,
3615 (1961). "”

 

29. Author wishes to thank Dr. Kirk of Westfield College,
University of London for providing Nmr spectra.

30. P. Beak and T. L. Chaffin, J. Org, Chem., 22, 2275 (1970).

 

31. R. Lee, C. McAndrews, K. Patel and W. Reusch, Tetra-
hedron Lett., 965 (1973).

32. Ross Lee, Ph.D. Thesis, Michigan State University,
1973.

33.

 

a) C. Djerassi, Chem. Rev., 22, 271 (1948).
b D5 Awang and A. Vincent, J. Org, Chem., 37, 2625
1972 . ""

 

 

34. G. H. Posner and J. J. Sterling, J. Amer. Chem. Soc.,
22, 3076 (1973).

 

35. J. R. Bull and A. Tuinman, Tetrahedron Lett., 4349 (1973).

 

36. (a W. Tribs, Ber., 66, 610 1483 (1933).
b H. O. House-"5nd W? Gilmore, J. Amer. Chem. Soc.,
83, 3972 (1961).
c) B. Camerino, B. Patelli and R. Sciaky, Gazz. Chim.
Ital., 92, 709 (1962).
(d) G.“RK W. Cavill and C. D. Hall, Tetrahedron, 23
1119 (1967). ’VV

37. (a) W. Reusch and R. LeMahieu, J. Amer. Chem. Soc.,
85, 1669 (1963).
W. Reusch and R. LeMahieu, J. Org. Chem., 22,
2443 (1963).
c) W. Reusch and P. Mattison, Tetrahedron, 22, 1953
1967 .

g.)

 

38. R. W. Mouk, K. M. Patel and W. Reusch, Tetrahedron,
in press.

39. R. L. Wasson and H. 0. House, Org. Syn..2z, 58 (1957).

40. H. B. Henbest and W. R. Jackson, J. Chem. Soc., 1967
2459.

41. J. c. Loperfido, J. Org;_Chem., 22, 399 (1973).

42. R. E. Counsell, P. D. Klimstra and F. D. Colton,
J. 029. Chem., 21, 248 (1962).

 

43. W. M. Hoehn, J. Org, Chem., 22, 929 (1958).

 

44.

45.

46.

47.

48.

49.

74

B. Pele, J. Hodkova and J. Holubeck, Collect. Czech.
Chem. Commun., 22, 1367 (1966).

M. Fischer, 2. Pelah, D. H. Williams and C. Djerassi,
Ber., 22, 3236 (1965).

W. Kirmse, B. G. VonBfilow and H. SchePP. Ann., 22,
(a) R. H. Shapiro and M. J. Heath, J. Amer. Chem.
Soc., 22, 5734 (1967).

(b) R. H. Shapiro, Tetrahedron Lett., 345 (1968).

S. R. Pathak and G. H. Whitham, J. Chem. Soc., 1968,
193.

M. Avaro and J. Levisalles, Bull. Soc. Chim. Fr., 3173
(1969).

APPENDIX

SPECTRA

75

8 8 8

TRANSMITTANCEDB)

N
O

 

.3.)

3500 1 3000 2500 ‘ 2000 1500

TRANSMITTANCEHS)

 

1800 1500 1400 U 1200 1000 800

Figure 1. Infrared spectrum of 17B-tert-butyldimethylsiloxy-
-2fi-methylandrost-4-en-3-one (21).

76

A 0 O
O O O

TRANSMITTANCE(%)

M
O

 

o;__.

4000 3500“ H 3000 2500 V 2000 1500

IRANSMITTANCE(%)

 

1800 1500 1400 t 1200 1000 800

Figure 2. Infrared spectrum of 42-methylcholest-2-en-3-one
(35) .

77

 

 

 

 

 

 

 

 

 

 

 

 

 

 

100 — -—+-
_ -
80 X W... -
5..
z
<
E _ .__..- ._.<._ _
i
V)
240 -
<
K
p-
20
,.____..---___.!-_-. _
.z 00 3500
'IOO : ’ 1 -
80~ -
:3 '4‘ ‘ Q
860 -
z ; ,
:5 - -.
v:
z : . ;
£40 —< 1 7 5
< :
a .
’_ , .
2O ' ‘ " 5 I
' .
0L 1 . l 1 1 L j = ’
, c: 1300 1000 800

Figure 3. Infrared spectrum of 3,5,5,6-tetramethy1cyclohex-

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2-enone (22) .

MOO

IZ‘OO

 

78

  
   
    

0
O

TRANSMITTANCE(%)
A
O

 

 

 

 

rnANnMnTANCEmM
I.
O

 

 

 

~._—__

Q: 1 ~ . fiCd

Figure 4. Infrared spectrum of 4,4,6,6-tetramethylcyclohex-
2—enone (2g).

79

O
O

 
   
   

O
O

TRANSMITTANCEHS)
a
O

N
O

 

O . I i ' .
4000 3500 3000 2500 2000 ‘l 500

TRANSMITTANCEHS)

I“ .

 
   

; I .- 1. 1'. .
1800 1600 1400 '200 1000 800

Figure 5. Infrared spectrum of 3—tert-butyldimethylsiloxy-
cholesta-2,4-diene (22') .

80

 
   
   

TRANSMITTANCE (76)

3&0" 8 syn V.V’3&i ‘7‘ 29m “““‘3&m 1am

TRANSMITTANCE (73)

  
    

1400 ‘h‘1200 1000 800

   

5060 1800 '"M1000 ” "'
Figure 6. Infrared spectrum of 17Bmethoxy-2amethylandrost-
4-en—3-one (22) .

TRANSMITTANCE(%)

81

G
O

0
O

A
O

29

 

«m0

     
 

l.
1

TRANSMHTANCEWM

7:th
1

 

800

) C)
'1
J
I
_.
9
2,.
7

1800

Infrared spectrum of 3,5,5—trimethyl-6-pheny1

Figure 7.
sulfenylcyclohex-Z-enone (22).

82

m
0

 
 
 

O-
O

IRANSMITTANCEHS)
A
O

N
O

0
4000 3 500 .7000 2500 . 7000 I 500

YRANSMITTANCE(%)

 

2000 I 800 1600 1 400 1200 ‘ 1000 800

Figure 8. Infrared spectrum of 68-bromo-17B-tert-butyl-
dimethylsiloxyandrost-4-en-3-one.

83

 

SE

 

 

 

 

 

 

 

 

   
   

 

 

 

 

g 7”“““:‘“
56°“ ~05“
Z
.3 ___ _J
5
z40~ —— ——<
<
E

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

LU
o
z
<
E
E :
2.10 5 ‘
<
a:
- 2
E
20 g
o-__._._z.__-_. , .. , .._.__ -__--_. .__.__ _ ' i
2000 1800 1"m 1400 1200 1000 800

Figure 9. Infrared spectrum of 2,3-epoxy-3,5,5,6-tetramethyl-
cyclohexanone (22) .

84

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

100 -2-7-1-‘ 47 1 ;
é 1- ~
80 —— i
.2 ’- ’1”—
32 . _ . :
g“ —”-T_1 ;
< 7 i ‘
E ” ”’ ""f‘" 3
24 ~—— ———~—— - ... .
< O 5 , , .
m > I .
'— ~ 4’ - "a ':
2 3 1 !
20~— ._ __, ~ —~_—--——; g A —. I
i 1 a -77-
__ - -1 ___L_. .; . ! f ‘
1 g -
0' I l I 1 ‘ 4 ~ 1 : . ‘ J
4000 3500 3000 2500 2000 1500

“no :11 V 1N

 
   

TRAN$MHTANCE(%)

 

 

   

2000 1800 1600 1400 i200 1000 800

Ilicul H( Y 101 '

Figure 10. Infrared spectrum of 5,6-epoxy-3,3,5-trimethy1-1-
methoxycyclohexene (2,1,) .

85

TRANSMITI’ANCE (95)

3500 3000 2 500 2000

151011911. 4

0')
O
1

; 1 -
I

0
O

... _.__;1.. ..
I

111AN5M111ANCE198;

"00' ".1510 1.4:: " . 1010

 

I500

 

800

Figure 11. Infrared spectrum of 17B-tert-butyldimethylsiloxy-

2fi-methy145,5B-vepoxyandrostan—3-one (22) .

TRANSMITTANCE 1%)

86

 

35G)

 

 

 

O a:
O O
' 1

TRANSMITTANCE (76)
5
O

20‘

 

;: | 1
._ .1+_- 1- ‘-.
i ..
1 .'V
1 ‘ 1 l l I -...1”
1
er,_2";i .; ,_ .. ; L{r .11 lgi..1_

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O

 

11 : i’11'11,_g!11:1;;1

 

 

 

 

 

 

 

 

0
2000

1800 1600 1400 1200 1000 800

Figure 12. Infrared spectrum of 2E-methyl-4B,5B-epoxy-

cholestanone (21).

87

8

TRANSMITTANCEHS)
a
O

  
 

TRANSMIUANC‘Em)

1800 1600 1400 1200 1000 800

Figure 13. Infrared spectrum of 3,5,5-trimethy1-2-methoxy-
cyclohex-2-enone tosylhydrazone (22) .

88

§ 0 an
O O O

TRANSMITTANCEBG)

N
O

  
    

go

3500 3000 2500 2000 1500

TRANSMITTANCEOS)

2000 1800 ' 1500M ' 1400 1200 1000 800

Figure 14. Infrared spectrum of 1,5,5-trimethyl-2-methoxy-
cyclohex-1,3-diene (2g) .

89

S

1RANSMITTANCE(%)
;
C)

N
O

 

4000 3500 3000 2500 2000 1500

 
 
  

TRANSMIUANcem)

       

0..__. , ___ .-.- ,
2003 1800 1600 1400 1200 1000 800

Figure 15. Infrared spectrum of 4,4,6-trimethy1cyclohex-
2-enone (22).

90

TRANSMITTANCE (fl)

 

3500 3000 2500 2000 1500

 

 

 

 

 

 

 

 

 

 

11111)|.n u
1oo‘—~-«- --;- ' ~ '7 1' " “ r I
7 ‘ ' 1
l ' i ' . . f ' ' 3 1 . 1 ‘ ‘
. r ' . . - .._1._..
i i . 1 E 1 1 ' ; ' 5
; - ' 1 1 1 1 ' 7“
80L“: : — .... . I C I I 1 z .. _.
A ' . f i I *
39 1.-. _ i_ .__._- . ' - _ .1
5: ~ 1 I , .
u 1 ; ' 1’2"
2501‘ 7— --~ — ~4——,—
: 1 1. , l_.i_.
: L -.L -_-_ - ' 3, j__i_
E401 . ...‘. L.-.,.. ! , 1 I 1 Jr --»
g : ‘ -
1’ , .. 5 _ _ -51+ _ i 1
1’ I . f ‘ ' z 1 - J.
20}— —~—— ~-' - ,. 1 - w i
l I 2 . , . _ 1
O
i ..., . =
C’ ~ _ _J._. _ J ' . 1 I
' 5300

Figure 16. Infrared spectrum of 17B-tert-butyldimethyl
siloxy-4-methoxyandrost-4-en-3-one (24') .

91

TRANSMITMNCE 1%)

 

3 500 3000 2 500 2000 1500

 
 
 

TRANSMITTANCE(%)

1800 1/ 1' 1 1 1- 1 800

Figure 17. Infrared spectrum of 17B-tert-butyldimethyl-
siloxy-4—methoxyandrost-4-en—3-one tosylhydra-
zone (22).

92

O on
O O

TRANSMITTANCE(%)
5
O

20

 

 
 
  

TRANSMITIANCE(%)

     

~05

 

- J.__..

 

0 _mI .
2000 1800 1600 1400 I200 ' 1000 800

Figure 18. Infrared spectrum of 17B-tert-buty1dimethy1-
siloxy-4-methoxyandrosta-2,4-diene (fig).

 

93

  
  
  

0 on
O O

TRANSMITTANCE(%)
A
O

.....

20

AW“: ¥ V 1:11;!— ' V " ‘-V‘ '_)"I- '3an 1500

TRANSMITTANCE(%)

 

2000 1800 1600 I400 1200 1000 800

.utum 1

Figure 19. Infrared spectrum of 17B-tert-buty1dimethy1-
siloxy-5a-androst-2-en-4-one (gg).

94

 
 
 
 
  
        

0-
O

TRANSMIYI’ANCE(%)

N
O

------

3500 3000 2500 7 2000 1500

TRANSMITTANCEHS)

H
2‘.

(IL--... _ ...—4.-.. ‘_.-._. 4..-..-..1-..-..1_..._.'._

‘1 son 17m 1 «on 1 5:10 1000 800

Figure 20. Infrared spectrum of 17B-hydroxy-5a-androst-2-
en-4—one (£1).

S

TRANSMITIANCE(%)
A
O

N
1 O

 

4000 3500 3000 2500 2000 1500

 
  

TRANSMITLANCEHM

'.ll -

”00" 1800 1600 1400 I200 1000 800

Figure 21. Infrared spectrum of 17B-tert-buty1dimethyl-
siloxy-2-methoxy~5a-androst-1-en-3-one (2g) .

96

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

L

 

 

 

olvl 'll’t"'

 

m
.

 

 

«-.-.I

 

 

 

 

 

 

 

 

 

 

     

 

 

 

 

 

 

 

 

 

 

 

 

 

 

.IV'Q LI IIrIOOII¢MIl0I|II4
.
r ..
1 w 1 T
_ _
u M . .
b t.
_ 11+.
.

 

 

 

 

 

 

 

 

.. .s. .
LTTII 90; A (1.9.0 A ....o. 0.. ....q..... ....... 4 ............... . .
i . _. .» .. . , . w ,
1 1 -awfl;4: ...... h:. . i. ..w.“ H .
p 1. p F p h 1 L
m m. w w m. o
.émuzftzngp

15m)

2000

3500

'asdo

3000

4000

 

moo 1400 1200 1000 800

1800

m .0... w w m o
I Stuuzfitzngh

’.|"‘i' I (M

oh;

yldimethyl-

en-3-one

m-

Infrared spectrum of 17B-tert-but
siloxy-Z-methoxy-5a-andro

tosylhydrazone (74).

Figure 22.

Ml

S

IRANSMITTANCEHS)
;
o

N
O

4000

 
 
   

TRANSMITIANCEHS)

  
 

Figure 23.

2.

   

1800 1600 ._ '

97

 

3500 M '1i'11'1'r1w—W—“7500” ' 2000 1500

9 1400 I 200 1000 800
Infrared spectrum of 17B-tert-butyldimethy1-
siloxy-2-methoxyandrosta-1,3-diene (22).

98

 
   
  

8

IRANSMITTANCEHS)
3.
O

N
O

.3100 3500 1000 .. ‘ "-2500 if" I 2000 1500

TRANSMITTANCE(%)

0 , . .
2000 1800 H100 MOO I200 1000 800

Figure 24. Infrared spectrum of 17B-tert-butyldimethyl-
siloxy-Sa-androst-3-en-2-one (76).

99

 

 

 

F5.0o
011m—

 

 

 

 

 

 

;Jonuv 000300 20032.” :33 93 m
maoumtsmIVIumwaonoamnquImm 0cm Um no musuxflfi m we Esuuommm Hem um: ooa .mm was Hm

      

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100

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. Q6 0.“ ad 0.. it 0.0 :6 or

 

. d ‘ q .1 ‘ q ‘ ‘ - ‘1 1 ‘ q ._ d ‘ ‘ G - ‘l 1 Q q

 

 

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A--_ -A

 

q 11+ 1 q 1-‘4 . q ‘ ~ ‘0 I

27 1

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101

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