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‘ I

STUDIES TOWARD THE TOTAL SYNTHESIS OF TETRACYCLIC
TRITERPENES

By
Wuyi Wang

A DISSERTATION

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

DOCTOR OF PHILOSOPHY

Department of Chemistry

1987

ABSTRACT

STUDIES TOWARD THE TOTAL SYSNTHESIS OF TETRACYCLIC
TRITERF’ENES

By
Wuyi Wang

Studies of triterpene side chain synthesis, employing the model
compounds 12 and 13, and lanostane skeleton transformation from compound

18 are presented in two separate parts.

 

Bani: Oxidation of 12 with m-chloroperbenzoic acid gave epoxides 363
and 36b. These compounds proved acid-sensitive, and facile rearrangement to
39 even occurred on treatment with 1-diethylalumino-2,2,6,6-tetramethyl
piperidine.57 Smaller amide bases, such as lithium diethylamide, transformed
36a to the allylic alcohol 37, which was subsequently oxidized to enal 38.

lsomeric 36b was inert toward all the bases tested.

Wang,Wuyi

 

Oxidation of 12 with selenium dioxide gave p-alcohol 46. Borohydride
reduction of the corresponding ketone 48 led to the Ot-epimer 47. Each allylic
alcohol ( 46 and 47 ) reacted stereospecifically with phenylsulfenyl chloride to
give, respectively, diastereoisomeric sulfoxides 53 and 55. The latter yielded a
conjugate base that was methylated selectively to give sulfoxide 56.
Desulfuration of 56 with trimethylphosphite generated the ethylidene on-alcohol

57, and following PDC oxidation, E -enone 66.

 

 

An alternative synthesis, beginning with ethylidene derivative 13, yielded
enone 66 as a minor product. Treatment of 13 with selenium dioxide followed
by PDC- gave the isomeric Z-enone 67 as the major product. Reaction of 67
with lithium bis-4-methyl-3-pentenylcuprate proceeded by facial-selective
conjugate addition to give ketone 75, which on Wolf-Kishner reduction gave the
euphane CD-model 17. The E-isomer 66, under similar conditions gave only

an unresolved mixture.

 

CH30 ' 1.,

 

Bang: Methylation of 18 with methyl lithium or the corresponding

Grignard reagent yielded adducts 112 and 113. These alcohols were reduced

Wang,Wuyi

with DIBAL, followed by hydrolysis, to give 114, 115, 116 and 117 which were
then oxidized to 118 and 119.

 

1149 X'H oYBG‘I
1159 y-H ix.m

   

116, XsH :y30'l
117, y-H . x=(}l

Acid-catalyzed dehydration of 118 gave cyclic ether 124, which was
then reduced by lithium in ammonia to 125. The 0-4 epimer 119 gave complex
mixtures on dehydration; however, 119 was deoxygenated cleanly with zinc,

giving 120 and subsequently 121. Finally, addition of trimethylsilyl methyl

Wang,Wuyi

lithium to 18 generated epimers 128 and 129, which were subsequently

transformed to 1 30.

 

 

CH3O .,
0H cueswu-za

129

DEDICATION

This Dissertation ls Dedicated To My Parents

ACKNOWLEDGEMENTS

The author is deeply grateful to Professor William H. Reusch for
his guidance and encouragement during the course of this study, and for
his crucial proof reading of this manuscript.

The author would also like to thank his fellow students for their
friendship, assistance and helpful discussions.

Special appreciation is also extended to his wife, Jing Lin, for her
endless love, understanding and valuable supports.

Finally, the author appreciates financial support from Michigan

State University to make this research possible.

TABLE OF CONTENTS

INTRODUCTION ...................................................................................................... 1
SYNTHETIC STRATEGIES ................................................................................. 7
RESULTS AND DISCUSSION ............... ‘ ............................................................. 18
PART 1. STUDIES AND SYNTHESIS OF TRIT'ERPENE SIDE CHAIN
ONA MODEL SYSTEM .............................................................................................. 18
1.1 Base-Induced Epoxide Ring Opening as an Approach
to Side Chain Synthesis .............................................................................. 18
1.2 Studies of Sulfoxide-Sulfenate Rearrangements as a
Tool in Side Chain Synthesis .................................................................... 27

1.3 Conjugate Addition of Organocuprates to 17-
Ethylidene-l6-Ketones 66 and 67 as a Key Step for Side

Chain Synthesis ............................................................................................. 49
PART 2. CONSTRUCTION OF TETRACYCLIC FRAMEWORK OF
SENEXONOL AND LANOSTEROL .......................................................................... 6 3

2.1 Reduction of Ring-A Functionalities of 18 ................................. 63

2.2 Methylations at C-4 and Subsequent

Transformations ............................................................. ° ............................... 68
EXPERIMENTAL SECTION ................................................................................ 77

General .............................................................................................................. 77

Epoxidation of methoxy olefin 12 with unbuffered

peracid .............................................................................................................. 78

Epoxidation of 12 to give epoxides 36a and 36b ......................... 78

Reacition of epoxides 36a and 36b with diethyl

aluminum-2,2,6,6-tetramethyl piperidine to give 39 ................. 79

Lithium dimethyl amide induced epoxide ring opening of

36 ........................................................................................................................ 8O

Olefination of 43 to give 44 ................................................................... 8O

Epoxidation of 44 to epoxides 45a and 45b ................................... 81

Oxidation of allylic alcohol 37 to unsaturated aldehyde

38 ........................................................................................................................ 81

Selenium dioxide oxidation of 12 to allylic alcohol 46 and

unsaturated ketone 48 .............................................................................. 81

iv

Reduction of unsaturated ketone 48 to alcohol 47 ...................... 83

Preparation of R-sulfoxide'53 ................................................................ 83
Desulfuration of R-sulfoxide 53 under various

conditions ......................................................................................................... 84
Preparation of sulfenate ester 54 and S—sulfoxide 55 ................ 85
Preparation of methyl sulfoxide 56 ..................................................... 85
Proton and deuterium quenching of conjugate base of

56 ........................................................................................................................ 86
Desulfuration of S—sulfoxide 55 under various conditions ........ 86
Desulfuration of phenyl sulfenate 54 ................................................ 87
Treatment of alcohol 46 and alcohol 47 respectively with
trimethyl phosphite .................................................................................... 87
Desulfuration of methyl sulfoxide 56 ................................................. 87
Preparation of dimethyl sulfoxide 65 and rearranged
sulfoxide 64 .................................................................................................. 87
Preparation of methyl sulfoxide 62 from alcohol 58 ................. 88
Oxidation of 13 with 8e02 ....................................................................... 88
Oxidation of S7 and 58 to 66 and 67 ................................................ 89
Isomerization of 66 and 67 mixture under various

conditions ......................................................................................................... 90
Redution of enones 66 and 67 ............................................................. 90
Preparation of 70 ......................................................................................... 9 0
Preparation of 4-methyl-3-pentenyl lithium .................................. 91
Preparation of 75 ......................................................................................... 91
Reduction of 75 to 76 ................................................................................ 92
Deoxygenation of 75 to 17 ...................................................................... 93
Preparation of 80, 81 and 83 ................................................................ 94
Preparation of iso-heptyl triphenyl phosphonium

bromide 84 ..................................................................................................... 94
Olefination of 6 with isoheptyl triphenyl-phosphonium
bromide ............................................................................................................ 94
Oxidation of olefins 86 and 87 with Se02 ........................................ 95
Reduction of 18 with zinc ......................................................................... 96
Preparation of mesyl derivative 105 from 92 .............................. 96
Preparation of enediones 106 and 107 ............................................ 97
Stannic chloride catalyzed Diels-Alder reaction of enone

108 with diene 109 to give adduct 110 .......................................... 98
Preparation of alcohols 112 and 113 ................................................. 98
Preparation of diol 131 ............................................................................. 99
Preparation of epimeric diols 114 and 115 from 112 .............. 100
Oxidation of 114 and 115 ...................................................................... 101
Preparation of epimeric diols 116 and 117 from 113 .............. 101
Swem oxidation of 116 and 117 to 119 ........................................ 102

Zinc reduction of 119 to 120 ................................................................. 103

Hydrogenation of 120 to 121 ................................................................ 104

Preparation of ketal derivatives 122 and 123 from

diene 121 ........................................................................................................ 104

Acid-induced conversion of 118 to 124 ........................................... 105

Birch reduction of 118 and 124 ........................................................... 105

Preparation of trimethylsilylmethyl derivatives 128 and

129 .............................................................................................. ‘ ....................... l O 6

Eliminative desilylation of 128 ( or 129 ) to 130 ........................ 107
APPENDIX ................................................................................................................ 108
BIBLIOGRAPHY ..................................................................................................... 276

vi

LIST OF TABLES

1a. and 1b., Chemical Shifts of Angular Methyl Groups and

Epoxide Protons in Selected Steroids and Model Compounds ............. 23
2. Base-Induced Epoxide Ring Opening ...................................................... 25
3. Selected 1H NMR Data ............................................................................... 32
4. Alkylation of Sulfoxides ............................................................................... 47
5. Reaction of Halides with Metals ................................................................. 54
6. Metal Halogen Exchange ........................................................................... 55
7. Selected 13C NMR Chemical Shifts for Lanosterol, Euphol and

1 7 ........................................................................................................................ 281

vii

9‘5"!"

5‘

.‘O?°>’.°‘.‘"

ll.
12.
13.
14.
15.
16.
l7.
l8.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.

LIST OF FIGURES

Variation Chemical Shift for Protons in Alcohol 46 ............. 108
Variation Chemical Shift for Protons in Alcohol 47 ............. 109
Energy Diagram for Various Sulfoxides and

Sulfenates ............................................................................................... 42
Energy Diagram for Methyl Sulfoxides and

Sulfenates ............................................................................................... 46
Infrared spectrum of 37 .............................................................. 110
Infrared spectrum of 39 .............................................................. 1 l 1
Infrared spectrum of 132 ........................................................... 112
Infrared spectrum of 47 .............................................................. 113
Infrared spectrum of 48 .............................................................. 114
Infrared spectrum of 55 .............................................................. 115
Infrared spectrum of 56 .............................................................. 116
Infrared spectrum of 66 .............................................................. 117
Infrared spectrum of 67 .............................................................. 118
Infrared spectrum of 75 .............................................................. 119
Infrared spectrum of 80 .............................................................. 120
Infrared spectrum of 88 .............................................................. 121
Infrared spectrum of 89 .............................................................. 122
Infrared spectrum of 90 .............................................................. 123
Infrared spectrum of 91 .............................................................. 124
Infrared spectrum of 92 .............................................................. 125
Infrared spectrum of 93 .............................................................. 126
Infrared spectrum of 105 ........................................................... 127
Infrared spectrum of 106 ........................................................... 128
Infrared spectrum of 107 ........................................................... 129
Infrared spectrum of 112 ........................................................... 130
Infrared spectrum of 113 ........................................................... 131
Infrared spectrum of 131 ........................................................... 132
Infrared spectrum of 114 ........................................................... 133
Infrared spectrum of 115 ........................................................... 134
Infrared spectrum of 116 ........................................................... 135
Infrared spectrum of 117 ........................................................... 13 6
Infrared spectrum of 118 ........................................................... 137
Infrared spectrum of 119 ........................................................... 13 8
Infrared spectrum of 120 ........................................................... 139

viii

35.
36.
37.
38.
39.

41.
42.
43.

45.
46.
47.
48.
49.
50.
51.
52. ~
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.

65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.

Infrared spectrum of 121 ........................................................... 140
Infrared spectrum of 122 ........................................................... 141
Infrared spectrum of 128 ........................................................... 142
PMR spectrum of 36b ................................................................... 143
PMR spectrum of 36a and 36b ............................................... _ ..l 44
PMR spectrum of 37 ...................................................................... 145
PMR spectrum of 38 ...................................................................... 146
PMR spectrum of 39 ...................................................................... 147
PMR spectrum of 132 ................................................................... 148
PMR spectrum of 40 ...................................................................... 149
PMR spectrum of 43 ...................................................................... 150
PMR spectrum of 44 ...................................................................... 151
PMR spectrum of 45a and 45b ................................................. 152
PMR spectrum of 46 ...................................................................... 153
PMR spectrum of 47 ...................................................................... 154
PMR spectrum of 48 ...................................................................... 155
PMR spectrum of 53 ...................................................................... 156
PMR spectrum of 54 ...................................................................... 157
PMR spectrum of 55 ...................................................................... 158
PMR spectrum of 56 ...................................................................... 159
PMR spectrum of 57 ...................................................................... 160
PMR spectrum of 58 ...................................................................... 161
PMR spectrum of 58 and 60 ..................................................... 162
PMR spectrum of 56,61 and 62 ............................................... 163
PMR spectrum of 64 ...................................................................... 164
PMR spectrum of 65 ...................................................................... 165
PMR spectrum of 66 ...................................................................... 166
PMR spectrum of 67 ...................................................................... 167
PMR spectrum of 70 ...................................................................... 168
PMR spectrum of 72 ...................................................................... 169
PMR spectrum of 73 ...................................................................... 170
PMR spectrum of 74 ...................................................................... 171
PMR spectrum of 75 ...................................................................... 172
PMR spectrum of 76 ...................................................................... 173
PMR spectrum of 17 ...................................................................... 174
PMR spectrum of 81 ...................................................................... 175
PMR spectrum of 82 ...................................................................... 176
PMR spectrum of 83 ...................................................................... 177
PMR spectrum of 84 ...................................................................... 178
PMR spectrum of 88 ...................................................................... 179
PMR spectrum of 89 ...................................................................... 180
PMR spectrum of 90 ...................................................................... 181
PMR spectrum of 91 ...................................................................... 182

ix

78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.

91.
92.
93.
94.
95.
96.
97.
98.
99

100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.

PMR spectrum
PMR spectrum
PMR spectrum
PMR spectrum
PMR spectrum
PMR spectrum
PMR spectrum
PMR spectrum
PMR spectrum
PMR spectrum
PMR spectrum
PMR spectrum
PMR spectrum
PMR spectrum
PMR spectrum
PMR spectrum
PMR spectrum
PMR spectrum
PMR spectrum
PMR spectrum
PMR spectrum

PMR
PMR
PMR
PMR
PMR
PMR
CMR
CMR
CMR
CMR
CMR
CMR
CMR
CMR
CMR
CMR
CMR
CMR
CMR
CMR
CMR
CMR

spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum

of 92 ...................................................................... 183
of 93 ...................................................................... 184
of 105 ................................................................... 185
of 106 ................................................................... 186
of 107 ................................................................... 187
of 108 ................................................................... 188
of 110 ................................................................... 189
of 111 ................................................................... 190
of 112 ................................................................... 191
of 113 ................................................................... 192
of 131 ................................................................... 193
of 114 ................................................................... 194
of 115 ................................................................... 195
of 116 ................................................................... 196
of 117 ................................................................... 197
of 118 ................................................................... 198
of 119 ................................................................... 199
of 120 ................................................................... 200
of 121 ................................................................... 201
of 122 ................................................................... 202
of 123 ................................................................... 203
of 124 ................................................................... 204
of 125 ................................................................... 205
of 126 ................................................................... 206
of 127 .................................................................. 207
of 128 ................................................................... 208
of 130 ................................................................... 209
of 46 ...................................................................... 210
of 47 ...................................................................... 211
of 48 ..................................................................... .212
of 55 ...................................................................... 213
of 58 ...................................................................... 214
of 66 ...................................................................... 215
of 67 ...................................................................... 216
of 75 ..................................................................... 217
of 17 ...................................................................... 218
of 92 ...................................................................... 219
of 93 ...................................................................... 220
of 105 .................................................................. .221
of 106 ........................................... ' ........................ 2 22
of 112 ................................................................... 223
of 113 .................................................................. .224
of 131 ................................................................... 225

121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
152.
153.
154.
155.
156.
157.
158.
159.
1.60.
161'.
162.
163.

CMR spectrum of 114 ................................................................... 226
CMR spectrum of 115 ................................................................... 227
CMR spectrum of 116 ................................................................... 228
CMR spectrum of 117 ................................................................... 229
CMR spectrum of 118 ................................................................... 230
CMR spectrum of 119 ...................................................... . ............ 231
CMR spectrum of 120 ................................................................... 232
CMR spectrum of 121 ................................................................... 233
CMR spectrum of 122 ................................................................... 234
CMR spectrum of 128 ................................................................... 235
Mass spectrum of 37 ..................................................................... 236
Mass spectrum of 40 ..................................................................... 237
Mass spectrum of 43 ..................................................................... 238
Mass spectrum of 46 ..................................................................... 239
Mass spectrum of 47 ..................................................................... 240
Mass spectrum of 48 ..................................................................... 241
Mass spectrum of 55 .................................................................... .242
Mass spectrum of 56 ..... 243
Mass spectrum of 64 ..................................................................... 244
Mass spectrum of 66 ..................................................................... 245
Mass spectrum of 67 ..................................................................... 246
Mass spectrum of 76 ..................................................................... 247
Mass spectrum of 17 ..................................................................... 248
Mass spectrum of 17 (25 e.v) .................................................. 249
Mass spectrum of 88 .................................................................... .250
Mass spectrum of 89 ..................................................................... 251
Mass spectrum of 90 ..................................................................... 252
Mass spectrum of 91 ..................................................................... 253
Mass spectrum of 92 .................................................................... .254
Mass spectrum of 105 .................................................................. 255
Mass spectrum of 106 .................................................................. 256
Mass spectrum of 107 .................................................................. 257
Mass spectrum of 110 .................................................................. 258
Mass spectrum of 112 .................................................................. 259
Mass spectrum of 113 .................................................................. 260
Mass spectrum of 131 .................................................................. 261
Mass spectrum of 114 .................................................................. 262
Mass spectrum of 115 .................................................................. 263
Mass spectrum of 116 .................................................................. 264
Mass spectrum of 117 .................................................................. 265
Mass spectrum of 118 .................................................................. 266
Mass spectrum of 119 .................................................................. 267
Mass spectrum of 120 .................................................................. 268

xi

164.
165.
166.
167.
168.
169.
170.

Mass spectrum of 121 .................................................................. 269
Mass spectrum of 124 (25 e.v). .............................................. 270
Mass spectrum of 125 .................................................................. 271
Mass spectrum of 126 .................................................................. 272
Mass spectrum of 127 ................................................................. 273
Mass spectrum of 128 ........................................... ' ....................... 274
Mass spectrum of 130 .................................................................. 275

xii

INTRODUCTION

The tetracyclic triterpenes containing 30 carbons and having a common

perhydro-cyclopentenphenanthrene skeleton are found widely in nature.1

 

3 ,Polyporenic Acid D2b 4a

 

4'3 .3-Deoxosenexonol45a 4c ,Oxidosenexone45‘

Two important members of this group are lanosterol and euphol.
Lanosterol was isolated from wool wax3 and euphol from euphorbium resin and
several other Euphoribia species.4 More recently, cucurbitacins,5 an important
structurally related group, have been identified. 4

Different tetracyclic triterpenes show cytotoxic, cytostatic, antimicrobial,
and herbicidal activity. Numerous lanostane type compounds from
Neamatoloma fasciculare and N. membranacea6 have demonstrated growth
inhibitory properties on young plants. Lanostane bitter principles from
mushroom Ganoderma Iucidum7 have been used as folk medicine in Asia.
Euphane-like compound meliantriol8 has demonstrated antifeedant properties.
Both isocucurbitacin D and 3-epi-isocucurbitacin D, from Phormium tenax, show
tumor inhibitory properties against KB cell culture.9 Cucurbitacins from African
Euphorbiaceae10 killed HeLa cells, inhibited mitosis in AIIium sativum
meristems and its root growth. Cucurbitacin D and l, isolated from

Purshiatridenfa,11 inhibited seed germination.

Squalene
{W M
u OH+ ” n OH+u
Chair-Boat-Chair-Boat Chair-Chair-Chalr-Boat

 

Lanosterol Euphol

Scheme 1

In living organisms the tetracyclic triterpenes are enzymatically
synthesized from squalene. Under physiological conditions, squalene may
assume chair-boat-chair folding to give lanosterol or all chair folding to give
euphol12( Scheme 1 ). Lanosterol has been shown to lose three methyls to

give chlolesterol in biological systems13:14 ( Scheme 2 ):

Lanosterol

   

99 ~—*

1 \ X'
\

Cholesterol

Scheme 2
Compared to the vast work in the field of steroid syntheses, few total
syntheses of tetracyclic triterpenes have ever been reported. The first total
synthesis of a tetracyclic triterpene, specifically lanostenol, was accomplished

starting from cholesterol in 1953 by R. B. Woodward et al. (Scheme 3 ).15

 

Cholesterol

CaHn /

 

 

Lanosterol

 

Scheme 3

A key step in this synthesis is the stereoselective introduction of a methyl
group at C-14. This result may be rationalized by considering transition states

for electrOphilic attack on the enolate. The p-face of ring D is blocked chiefly by

6

the 13p angular methyl group and the side chain. Steric approach control
therefore favors approach of the methyl group from the OL-face.

A biomimetic acid induced polyene cyclization, work of van Tamelen
etal., led to syntheses of lanostenol as well as many other natural products,
demonstrating alternative efficient methods for organic synthesis.16-17

Over the past 30 years, many new triterpenes have been isolated. About
400 new triterpenes were identified during the period 1977-1981.18 However,
new total syntheses of tetracyclic triterpenes are surprisingly few. For example,
J.ApSimon's recent review19 on progress in triterpene synthesis covering the
past 12 years reported no total synthesis of a tetracyclic triterpene! It is possible
that the well developed field of steroid chemistry has obscured the necessity of
looking at the tetracyclic triterpenes as independent targets.

Although existing syntheses such as Woodward's and van Tamelen's
serve as good examples, the relatively well known methods and reagents used
therein are unlikely to lead to improved new approaches. In particular, van
Tamelen's approach is unlikely to be useful for the synthesis of euphanes
because of their facile rearrangement to corresponding isoeuphane systems.20
New general synthetic strategies and reagents are therefore needed to achieve

efficient total syntheses of these compounds.

SYNTHETIC STRATEGIES

We propose to approach the total synthesis of tetracyclic triterpenes in
two stages: 1. Side chain attachment. 2. Construction of the tetracyclic nucleus.

Methods of steroid side chain synthesis have been the subject of study
since the 1930's. As more and more biologically active compounds such as
ecdysones,21 various active metabolites of vitamin D,22 and marine sterols23
were isolated and characterized, research revealing the relationship between
biological activities and side chain structures increased. Therefore, new
approaches to side chain synthesis were developed as well. Recent progress in
this field has witnessed numerous ingenious designs and novel reagents.
Examples included applications of: ene reaction;24 oxy-Cope,25 Claisen26 and
WittigZ7 rearrangments; nucleophilic attack at p-allylpalladium complexes;28 1,4
additions of organocuprates to conjugated epoxides29 or conjugated
ketones;3° nucleophilic displacement of tosyl group;31 Birch reduction of
unsaturated ketones32 and addition of Grignard reagent to side chain
epoxides.33

It is necessary that any successful side chain synthesis have selective
control of configurations at C-17 and C-20. The configurations of 0-13, 0-14
and 0-17 of lanostane have a mirror image relationship with those of euphane.
The only difference lies at C-20. Therefore, controlled syntheses of C-20

epimers will give either lanostane side chains or euphane side chains.

   

Lanostane system Euphane system

Since side chain synthesis involves reactions on ring D, at sites relatively
remote to rings A and B, it is reasonable to assume that the influences to these
rings ( A and B ) is quite small. In other words, it should be possible to use a
bicyclic C,D ring model as a substrate to test new methods of the side chain
synthesis. In practice, our studies were carried out on compound 6 which was

made from compound 5 ( as shown in Scheme 4 ).34

    

O O
1.NaBH4 Side chain
I -..-> -—->
2.NaH, _ Elaboration
CH3I ~ ‘
CH30 6 CHaO

 

Scheme 4

As a model compound, 6 has obvious advantages. Both angular methyl
groups are in place and a ketone group at 0-17 ( triterpene numbering
system )35 is available for side chain development. Though steroidal 17-
ketones have been favorite starting materials for many side chain constructions,
the use of triterpene counterparts ( with a 14a angular methyl group in place )

has been explored little. The presence of 14-angular methyl group blocks the

9

or-face of ring D; as a result, methods for the syntheses of steroid side chains
become less predictable when applied to our model system.

A preliminary examination of model 6 for side chain synthesis was first
conducted by Dr. J. L. Martin“. The five membered ketone function was found
to be unreactive toward a variety of nucleophiles, such as stabilized ylides,
enolates and common organometallic reagents. This behavior was in part due
to facile enolization of the ketone by strong bases. Sodium acetylide reacted
with 6 to give the acetylide adduct 7, but treatment of 7 with formic acid failed to
effect a Rupe rearrangement36 as expected from a recorded steroid side chain

synthesis.37 Alkynyl ester 8 was obtained instead ( Scheme 5 ):

 

 

CH30

Scheme 5
Another useful reaction was the addition of crotyl magnesium bromide to
methoxy ketone 6. A cyclic transition state involving metal-oxygen coordination
is known~38 to facilitate allylic additions. Unfortunately, Lewis acid induced
dehydration of 10, derived from 9, caused rearrangement to the undesired

compound 11 ( Scheme 6 ):39

 

Scheme 6

    

cuao a CH30 ;1

Further studies were carried out by Dr. J. R. Gibson.39 Reaction of 6 with
unstabilized phosphorylidene ylides gave olefins 12 and 13. Starting from 13,
compound 14 was obtained through a four step sequence ( Scheme 7 ). When
14 was catalytically hydrogenated, a mixture of C-20 epimers ( 15 and 16 )

was formed, in agreement with examples in steroid side chain synthesis.40

 

CH50
15 and 16 Epimers ( 1:1 ) at C-20

Scheme 7

11

More recently, Krief ef al.33 used 17-keto steroids and lanostanes as
starting materials to demonstrate stereoselective side chain synthesis in which
reaction of Grignard reagents with the 20, 22-epoxides of a 17p-isopropenyl
derivative was a key step. When the same sequence was carried out on the
model compound 6 by Dr. H. Ok‘i1 in our laboratory, the euphane like side chain

substituted derivative 17 was obtained in good yield ( Scheme 8 ).

Koreeda-Krief's
Procedures

   

1. LiCHZSeCHa I
2. cuaosozf '

EtOC=CMgBr

fl

   

CHO
\ CHO

   

1. HzlPd/BaSO4
3. PTSA

 

12

In our approach to side chain synthesis, we proposed to introduce
functionality at C-16 concurrent with side chain construction. Many naturally
occurring triterpenes, such as tumulosic acid, echinodol, kulinone, and
holotoxin, have hydroxyl or carbonyl groups at this site.42 Birch reduction of 16-
keto-17-ethylidene derivative by Djerassi et al.,32 and oxy-Cope rearrangement
conducted by Koreeda et al.29 provided examples of such syntheses. Recent
work30 by Trost and Schmuff has established the usefulness of C-16
functionality in facilitating steroid side chain synthesis.

In this dissertation, our exploration of sulfenate-sulfoxide rearrangements
in side chain synthesis will be highlighted. Base induced epoxide ring opening
and 1, 4-addition of organocuprates26a to an axe enone derived from 13 will
also be discussed.

A second concern of this research program is construction of the
tetracyclic framework. A large number of such examples can be found in the
field of steroid synthesis. More than a dozen approaches43 are available. A
synthesis43 of tetracyclic compound 18 from bicyclic compound 6, using Diels-
Alder cycloaddition ( CD--ABCD, Scheme 9 ), provided an attractive

intermediate for lanostane total synthesis.

   

Scheme 9

13

A comparison of compound 18 with possible target molecules, such as
senexonol“5 and lanosterol, identifies the tasks remaining in such syntheses.
These are outlined below: 1. Functional group in ring A should be reduced and
altered; 2. Methyl group ( s ) should be introduced to C-4; and 3. Configurations
at C-5 and C—9 should be adjusted. With strong reducing agents such as lithium
aluminum hydride ( LAH ) or diisobutyl aluminum hydride ( DIBAL ), all the
ketone groups in 18 ( two ketones in ring A and one ketone in ring D ) will be
reduced. Selective reduction at C-4 can also be achieved, since the 4-ketone
group is more reactive than the 1- and'17-ketone groups ( ester like ketone and
five membered ketone‘l6 respectively ): I

The reduction with strong reducing agent, lithium aluminum hydride, of a
bicyclic compound, equivalent to rings A and B of model compound 18, was
precedent. In their cholesterol synthesis,“ R. B. Woodward et aI. exhaustively
reduced the bicyclic enedione system 19 to a diol, which on acidic hydrolysis
yielded the 4-acetoxyl enone 21. Cleavage of the acetoxyl group in 21 by zinc
in acetic anhydride, led to formation of enone 22 ( Scheme 10 ). Woodward's
method efficiently reduced ring A functionality, yet still reserved some important

functional group such as 3-ketone for further synthetic development in ring A.

14

0 OH
LiAlH4
CH30 ——> CH30
0 OH
19 20
1. H‘

2. Acetylation

Zn/AcOAc
<——
0 0
OAc

2 2 2 1
Scheme 10

On the basis of their structural resemblance, Dr. W. Munslow“8 carried
out the same sequence of reactions on 18, using similar reagents. As expected,

compound 23 and 24 were obtained, but in a low overall yield ( Scheme 11 ).

1. DIBAL

2. I430”

3. Ac20/Py.
4. Zn

 

   

Scheme 11

15

Related to the work of Woodward et al. was a modification reported by
Speziale et al.,49in which a 1-hydroxy-4-keto-2-methoxy-10-methyI-A2,6-
hexahydronaphthalene 203 was prepared first, by zinc reduction of the same
starting bicyclic compound 19 in acetic acid. From alcohol 203,‘ a camphor-10-
sulfonyl derivative 20b was made, which, after cleavage of the camphor
sulfonyloxy group with zinc and subsequent LAH reduction gave 22 in 55—60 %
overall yield. Indeed, Dr. L. Kolaczkowski's 5-epi-euphol synthesis“
demonstrated a successful application of this method to system 25 ( different
from 18 only in the relative configurations of the A, B and C, D ring fusions ) to
give 28 in good yield ( Scheme 12 ):

O
.. -99 “.0 :1: ..
c1130 -'-—>
R

20a. axon —-:_3 F130 or
b, RaCamphor _-. 2

sulfonyloxy Zn/HOAc
c, RsH <.__l.

 

1. Zn/AcOH/H20
2. MsCI/Py

 

 

1. DIBAL
2. 1130*

3. MeMCl CH30

   

Scheme 12

16

This result suggests that Speziale's stepwise reduction procedure may
provide a cure for the poor yield encountered when 23 was prepared
previously. We predicted that the difference between compounds 18 and 25 in
ring junctions should not seriously alter the chemistry at ring A.

If 24 could be obtained in good yield, Woodward's15 and Klyne's50 C-4
methylation methods, illustrated for lanosterol in the former work, should give
the homoannular diene 30. The derivative 31, after mercury salt catalyzed
dehydrogenation and Birch reduction, would give compound 32 ( see Scheme
13).

OAc

Mel/Base
24

 

   

1. Birch
2. Protection
OAc

1. Dehydrogenation
2. Birch Reduction
¢

 

   

Scheme 13

Alternatively after catalytic hydrogenation of 30,51 acid induced double

bond migration52 of 33 would give 34 (with proton at C-5 presumably being

17

on ), which after Birch reduction, should generate 35 as final product ( Scheme
14).

 

Scheme 14

In the second part of the dissertation, the tests of the available methods to
reduce ring A functionality of compound 18 will be described. In fact, selective
methyl group introduction at C-4 may be achieved53 prior to the reduction of
compound 18. Our study of methylation at C-4, featuring addition of

organometallic reagents or Peterson Olefination will also be discussed.

RESULTS AND DISCUSSION

PART 1. STUDIES AND SYNTHESIS OF TRITERPENE SIDE CHAINS ON A
MODEL SYSTEM

1.1_:-.‘_10. '1 er 111° 91111111: . .n ‘ 11 0.. h o .11:
5111mm

The first goal in our investigation was the preparation of compound 38, a
potentially useful intermediate for side chain attachment. An efficient plan for the

synthesis of 37 and its derived aldehyde is shown in Scheme 15 :

 

CH30
37

Scheme 15
Since the angular methyl groups in compound 12 block both sides of
ring 0,35 we anticipate that a mixture of two epoxides, 36a and 36b, would be
obtained in epoxidation. This lack of facial discrimination contrasts with steroid

analogues, which react chiefly at the or-face. The subsequent base treatment

18

19

should convert both epoxides to alcohol 37. Finally, controlled oxidation of this
alcohol with pyridinium dichromate ( PDC )54 would generate the desired
aldehyde 38.

In the event, epoxidation of 1 2 was first attempted with m-
chloroperbenzoic acid ( mCPBA ) in methylene chloride solution. The resulting
white crystalline product 40 displayed only one epoxide proton signal in its '
proton NMR spectrum, in contradiction to 36 for which two epoxy protons
should be observed. Furthermore, the mass spectrum gave a molecular ion at
226, suggesting that the initially formed epoxide might have rearranged into an
alcohol which was further oxidized. A possible mechanism is shown in Scheme
16 to account for the formation of compound 40:

mCPBA
12 -——~368 +36!) + PhCOOH‘.

 

Scheme 16

20

Accordingly, epoxidation of 12 generated the expected epoxide, 36, as
the initial product, and the latter on exposure to m-chlorobenzoic acid ( released
from mCPBA) underwent ring opening. During the ring opening step, a
positive charge gradually developed at C-17,35 inducing the angular methyl
group at 0-13 to migrate. The rearranged compound 39 was then oxidized by
excess peracid to give compound 40. This rationale was supported by a control
experiment in which an authentic sample of 36 ( its synthesis will be described
latter ) was treated with boron trifluoride etherate ( BF3-Et20 ) or p-toluene
sulfonic acid ( pTSA ) to yield 39, which was subsequently epoxidized into 40.
The possibility that compound 37 was also formed in these reactions was
eliminated by examination of the crude proton NMR spectrum.

Such acid-induced angular methyl group migration has been also
reported by others.39.55 Thus treatment of alcohol 10 with BF3 etherate gave
11 ( see page 10 ), and similar treatment of 1113,17p-dihydroxy-1701-pr0pynyl-
androstan-1,4-dien-3-one ( 41 ) with a Lewis acid gave the rearranged

compound 42 ( Eq. 1 ).

   
    

"I-CHa

to

 

Eq. 1

21

More suitable epoxidation conditions were then sought. Concurrent use
of a buffer during the reaction seemed advisable in order to keep the reaction
system slightly basic. The two-phase system ( methylene chloride / aqueous
sodium bicarbonate ) reported by Anderson and Veygeslu56 was employed,
since this procedure had been successful in preparing epoxides which would
othenlvise decompose. Indeed, when this procedure was carried out on 12,
epoxides 36a and 36b were obtained in 85% yield without contamination with
rearranged products. As expected, the ratio of 36a and 36b was 1:1. As a
comparison, the same epoxidation reaction with steroid 44 gave epoxide 45a

in eight-fold excess over its isomer 45b ( Scheme 17 ):

 

 

45b( minor)

Scheme 17

22

The structural assignments of epoxides 36a and 36b were made from
their proton NMR spectra by comparisons with known compounds such as 43
and 6. Angular methyl groups ( A| and Au ) in the model system ( 6 ) and steroid
analog ( 43 ) provided reference NMR signals against which signals from
methyls BI and Bu ( in 45a and 36a respectively ) and methyls Cl and Cu ( in
45b and 36b ) could be measured.

Hx Hy

  
  

(C1) H3C

g.‘O Series I

Series II

The molecules in series I and II, with equivalent configurations at 0-17
and C—20 ( ego-epoxides 453 and 36a ), should display a similar difference
in the chemical shifts of their angular methyl groups relative to those of the
reference molecules ( 43 and 6 ). In other words, the chemical shift difference
between 45a and 43 ( 53|—5Al I should be similar to that between 363 and 6
( San-5A" ). This correlation should also hold for SCI-SA] and 5Cll-5AII.

23

Furthermore, the chemical shift differences of the epoxide ring protons ( i.e., the
C-20 protons ) can also be used to identified the configurations (on or p ) of
these epoxides. Since the structures and corresponding NMR spectra of
compounds 43, 458, 45b and 6 are known, we can therefore assign structures
for 369 and 36b ( see Tables Ia and 1 b ).

Table 1a Chemical Shifts of Angular Methyl Groups in
Selected Steroids and Model Compounds

 

 

5A 58 5c 5A-58 5A-5c

 

 

St°'°ids 0.855 0.815 0.880 0.040 0025
(Series 1)
Triterpene
Models 1.150 1.113 1.200 0.087 0050
(Series 2)

 

 

Table 16 Chemical Shifts of Epoxide Protons in
Selected Steroids and Model Compounds

 

 

 

 

 

Q Epoxide p Epoxide
6x 5y 5 (x-y) 6x 6 y 6 (H)
Steroids 2.731 2.659 0.072 2.895 2.595 0.800
(Series 1) (d,j=5) (d,j=5) (d.i=5) (d.i=5)
Triterpene
. . . 7 . . .
Models 2635 2560 .003 2870 2650 0220
(Series 2) (d.j=5) (d.l=5) (d.i=5) (d.i=5)

 

 

 

24

Having obtained the desired epoxides 36a and 36b in good yield, we
next examined their base induced rearrangement. Such reactions have been
widely studied in recent years. A mechanistic study,57 using an isotope labeled
substrate, showed that the proton syn to the epoxy ring was selectively removed
by base through a cyclic transition state ( Scheme 18 ). This so-called syn
mechanism is also followed, to some degree, by other reactions such as base
eliminations of 4-butyl hexyl trimethyl ammonium chloride and 1-butyl hexyl

toluene-p-sulfonate.58

 

 

 

 

H01" H
LiN(Et)2 "
’
C(CH8I8
HO 0
Li N(Et)2
>
C(CHala
i‘
R
’Li— N_’
R o H
2% D
Scheme 18

In the present study, the epoxide mixture ( 368 and 36b ) was used

directly, since further chromatographic purification of this mixture caused

25

extensive rearrangement. A number of conditions were tested to effect these

rearrangements, and the results are listed in Table 2:

T116182 Base Induced Epoxide Ring Opening

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Run Base C° h Result
1 LDA/Ether 40 3l
2 LDA/Dioxane 45 38
3 LDA/THF -75 8 swung
Materials
4 LDA/HMPA 45 38
5 t-BuOK/t-BuOH 83 96
6 t-BuLi/THF -78 20
7 'CHQSOCH3 43 41 Unknown
DMSO Mixtures
8 /-fiK — — Starting
% Materials
—/- Other
9 /\ NMR: 0 6.5 39 +Compounds
368 360 37
IO EtzNLl/Etzo 40 IO IOX 50% 402
II I‘IBZNLI 0 I3
Et20 OX 50% 50%
12 /Mel 40 25 OX 50% 503

 

 

 

 

 

 

 

Most bases failed to open the epoxide ring of either 368 or 36b under

various conditions ( elevated temperature, extended reaction time, coordinating

 

26

or non-coordinating solvents ), and the starting materials were fully recovered.
Entry 9 is an interesting case. It was originally thought that Yamamoto's
reagent59 might be the reagent of choice because of its dual function. The
aluminum would coordinate with the oxygen atom of the epoxide ring, thus
weakening the O-C bond. At the same time, the piperidide base would serve to

abstract an or-proton.

 

The formation of compound 39 from reactions with Yamamoto reagent
indicated that this reagent was indeed a Lewis acid. The cyclic mechanism
suggested above for the direct elimination might be destabilized by steric
hindrance involving the bulky piperidide group. Consequently, rearrangement
dominated.

Having realized that steric hindrance was a major problem, we began to
search for smaller bases. When 36a and 36b were treated with lithium
diethylamide in refluxing ether, some of the expected allylic alcohol 37 was
formed. Encouraged by this result, we then examined a smaller base--lithium
dimethylamide. Unfortunately, only a slight improvement was realized. Added
lithium salts did not change the product ratio ( run 12 ). It was interesting that

only 368 rearranged, 36b remained unchanged.

27

 

According to previous discussions, the base induced epoxide eliminative
opening follows a syn mechanism. In compound 368, H (y) is syn to the
epoxide oxygen, and the dihedral angle < H (y)-C(16)-C(17)-O is rather small
( about 0° by a Molecular Mechanics calculation58 ). On the other hand, in
compound 36b, H (x) is syn to the epoxide, and the dihedral angle < H (x)-
C(16)-C(17)-O is much larger (about 80°, by the Molecular Mechanics
Calculation ). As a result, epoxide 36a opens more readily than does its epimer
epoxide 36b, since the smaller the dihedral angle the better the overlap of the

orbitals and the faster the reaction.

Continuing the studies of side chain synthesis, we began to look for new,

alternative approaches which would functionalize C-1635 as well as introduce

28

side chain segments selectively. Of particular interest was the possibility that C-
16 functionality could be used to control deveI0ping stereochemistry at C-20.
Beginning with compounds 12 or 13, we first looked for methods that would
functionalize allylic carbons.

Common reactions of this kind include bromination with N-
bromosuccinimide ( NBS )61 and oxidation with selenium dioxide ( SeOg ).62
The former reagent selectively brominates positions allylic to a C-C double
bond. In cases having more than one allylic site, the dominant product is usually
derived from the most stable allylic radical out of many competing radicals. As
precusors for side chain synthesis, bromides resulting from NBS reaction with
13 could be further converted into the corresponding alcohols, from which other
chemical transformations could be carried out. As an alternative, the
corresponding Grignard reagents might also be used in alkyl halide coupling
reactions. Unfortunately, the conventional procedures failed to generate the
derived allylic bromides from 13. Therefore, the bromination method was
ultimately abandoned, and selenium oxide reactions were studied in their
stead.

Selenium dioxide is a reliable and predictable reagent for allylic
oxidation reactions. Furthermore, Sharpless62 has developed a modification of
this reaction which uses a catalytic quantity of selenium dioxide together with a
stoichiometric amount of t-butylhydroperoxide. This procedure greatly reduced
the formation of undesired by-products and facilitated applications in organic
synthesis. _

Reactions of 17-alkylidene steroids with 8802 have been studied
recently. Following allylic oxidation, N. R. Schmuff and B. M.-Trost reported a
steroidal side chain synthesis,30 featuring 1,4-addition of an organocuprate

reagent to a 17, 20-unsaturated-16-ketone derivative ( Scheme 19 ):

29

 

I
to 99 .09
F

Moffatt
Oxidation

 

    

2. Wolf-Kishner
Deoxygenation 7 8

Scheme 19

The initial product from $902 treatment was the 0t alcohol which was

transformed to the unsaturated ketone 78 by Moffatt oxidation;63 and the
synthesis was finished by conjugate addition of an appropriate organometallic
reagent, followed by deoxygenation. The product was a steroid having the
”natural" R configuration at C-20.

The Schmuff and Trost' study of steroids serves as a good guide for our
work. In model compound 12, there is an extra methyl group at C-14, and the
selenium dioxide oxidation should reflect this structural difference. From an

inspection of Dreiding models, we anticipated that reactions at C-16 in

30

compound 12 should occur from the less hindered p-side of the five membered
ring. Of course, lack of a substituent at C-20 assured that the allylic reaction
occurred only at C-16. The homologous compound 13 is in fact a better choice
to reveal differences between steroids and our model systems. Reactions of this
compound will be discussed in the next section.

Accordingly, compound 12 was treated with 0.5 eq selenium dioxide and
4 eq t-butylperoxide in methylene chloride. As expected, the reaction occurred
only at C-16, and the product consisted of a single alcohol 46 and the derived

enone 48 ( shown in Eq. 2 ):

 

The 1H NMR spectrum of ketone 48 was characteristic. Two proton
singlets could be seen at 5 4.87 ppm and 5 5.75 ppm respectively, and the C-
15 methylation displayed an AB pattern centered at 5 2.23 ppm. The
assignment of compound 46 was not made until isomeric alcohol 47 was
obtained by sodium borohydride reduction64 of 48 ( Eq. 3 ), and these epimers

were compared by NMR.

31

   

————->
CeCI3.6HZO
90% CHsO
47
Only Product
Eq.3

With the help of molecular models, double resonance experiments, and
shift reagent experiments,65 structural assignments for alcohols 46 and 47

were made.

46 ,ZsOH, Y=H

47 ,Z=H, Y=OH

 

A key to assigning structures of 46 and 47 was the 1H NMR signal of the
C-16 carbinol proton. For example, alcohol 47 displayed a broad doublet at 5
4.78 ppm, characteristic of coupling with the adjacent protons H (f) and H (9).
Molecular models indicated that the dihedral angle between H (g) and 2 was
near 90 degrees, while that between H (i) and 2 was less than 30 degrees.
Therefore Z should appear as a doublet, in accordance with the observed data.
Long range coupling was also clearly demonstrated in the proton NMR

spectrum. Thus the H (f) signal appeared as a doublet of doublet of quartets,

32
due to a vicinal coupling with Z, a geminal coupling with H (g) and a long range
coupling with methyl group (b). When CH3 (6) was irradiated, H (f) collapsed to
a sharp doublet of doublets, confirming the long range coupling between H (b)

and H (i). Shift reagent experiments were also conducted with 47, and the
results supported the structural assignment ( Figure 1 and Figure 2 ). Thus, CH3

(0) shifted downfield to a greater extent than CH3 (a), and H (g) shifted to a

greater extent than H (i). In the same manner, the structure of 46 was assigned.

Detailed chemical shift data are listed in Table 3.

Table 3. Selected ‘H NMR Data

 

 

Compound Proton (5) Chemical Shift Multiplicity (J)

48 a I5) 1.25 ppm 8

YaZaO b (3) 0.92 d (JN .1112)
c (1) 4.87 s
d (1) 5.75 s
i (1) 2.88 d,q (8'9 .17, J” .1)
9(1) 1.77 d(J9=17)

45 e a 3 1.28 5

Y- l-I. )Z-OH 1, I3; 0.75 d (8” .1 Hz)
c (1) 4.78 d U“ -2)
d (1) 5.08 d u“ .1)
e (1) 4.59 1.1 (mi-'9 .7, J°°-d° 1.1.5)
1 (1) 2.12 d,d.q (J'9 -12, .1“ =7, .1” .1)
g (1) 1.6 - 1.9 Hidden

47 A3) a (3) 1.08 s

)7- OH, 2- b (8) 0.92 d U” =1Hzl
0(1) 4.74 d (1“ =2)
(1 (1) 4.95 d U“ -2)
e (1) 4.78 d,t (191.3, J°°'d° .. 2)
f (1) 2.85 d.t, (J'9 .18, .1"f .. 8, Jb'-1)
9(1) 1.20 d(J .18)

 

 

 

 

 

 

33

This convenient preparation of intermediates 46,47 and 48 next
prompted a study of possible applications of these compounds to side chain
synthesis. To this end we wanted to develop a synthesis in which the
stereochemistry at C-20 would be directed by the functional group at C-16. After
attachment of an appropriate side chain, the functionality at C-16 could be
retained ( many natural triterpenes have a carbonyl or a hydroxyl group at
C-16 ) or readily removed.

We first turned our attention to sulfoxide and sulfenate rearrangements66
because these [2,3j-sigmatropic shifts usually proceeded stereoselectively via a
suprafacial reaction path.67 Normally the rearrangement of a sulfenate ester,
prepared from the corresponding allylic alcohol, would give an equilibrium
strongly favoring the sulfoxide product. It is known, however, that steric
hindrance, electronegativity of substituent groups, and polarity of solvents can
influence this equilibrium. In the presence of a thiophile, such as trimethyl
phosphite, the sulfenate component may be trapped by desulfuration so that the

allylic alcohol is obtained:

0 [231-shift 1
- 1 3 1 (M80) P 3
S. 3
3.81 :— R' 0Y8, _. HO/\/\R1
R1

Evans and Andrews first demonstrated synthetic applications64 of this

rearrangement to the preparation of substituted allylic alcohols ( Scheme 20 ):

34

' n-BuLi
(VOH —>[ VOSPh] ——-> Ph'

PhSCl 49

Scheme 20

The starting alcohol was treated with n-butyl lithium, followed by addition
of phenyl sulfenyl chloride to give an allyl sulfenate ester which quickly
rearranged to the isomeric sulfoxide. On treatment with strong base, the
sulfoxide ( 49 ) was deprotonated at the ct-carbon and reacted with an alkyl
bromide to yield sulfoxide 50. Desulfuration of 50 with trimethyl phosphite then
produced the alkylated allylic alcohol 51. This reaction sequence proceeded in
the high overall yield.

Despite the potential importance of this method in organic synthesis, it

has limitations such as the formation of undesired y-substituted products
( Eq. 4 ).

35

O O O
I Rx I It
Ph’SW ——> Ph’SW 1‘ Ph’SN
R R
Eq.4

Evans has noted that the use of thiozoline and imidazol derivatives68
greatly enhanced the regioselectivity for ct-alkylation. The chelated lithium ion

served to localize the negative charge at the ct-position of the sulfoxide.

\/\ '9': -
V 1? ‘ct?

g

g It was also noted that only methyl iodide and allyl bromide gave facile
alkylation, the reaction with other halides being sluggish. Desulfuration of the
resulting sulfoxides, using phosphorous-containing thiophiles, such as trimethyl
phosphite and hexamethyl phosphorous triamide ( HMPT ), proved to be most
effective.

To incorporate this method in our synthetic plan, the allylic alcohols 46
and 47 need to be converted to corresponding sulfoxides, and then selectively

alkylated at the Ot-position ( i.e., at C-20 ). In practice, both 46 and 47 were

36

individually studied in the Evans/Mislow rearrangement. Our work with 46 is

undertaken first, and the results are summarized in Scheme 21:

1.n-BuLi

 

 

' 2.TMEDA

 

82%

 

 

 

   

Benzene
A
90%

90-95% (CH30)3P
MeOH
at RT.

or
46 Reflux

Scheme 21

37

The alkoxide anion prepared from 46 by low temperature reaction with
n-butyl lithium was treated with phenyl sulfenyl chloride, directly producing
sulfoxide 53 in excellent yield. Addition of tetramethylethylenediamine
(TMEDA ) proved necessary to achieve best results. This sulfoxide was stable
at room temperature, but decomposed slowly to alcohol 46 on exposure to air.
The proton NMR of pure 53 showed a characteristic AB system at 5 3.68 ppm
for the methylene protons adjacent to the sulfoxide group. Presumably the
sulfoxide 46 was formed from the intermediate sulfenate 52. Of two possible
transition state conformations for the conversion of 52 to 53, conformation A
should have lower energy ( exo-transition state ) than conformation B ( endo-
transition state ); the latter would be destabilized by steric hindrance between
the 14-angular methyl group and the phenyl group. Transition state A would

lead to a sulfoxide having an R configuration at the chiral sulfur.

 

A B
Lower energy Higher energy
conformation conformation

With the sulfoxide 53 in hand, we proceeded to study the following

reactions. 1. Desulfuration: conversion of [Ly-unsaturated sulfoxides to allylic

38

alcohols; 2. Epimerization: interconversion of sulfoxide isomers by a crossover
involving diastereomeric transition state, and 3. Alkylation: introduction of an
alkyl group on to the sulfoxide.

When compound 53 was treated with trimethyl phosphite either at room
temperature or in refluxing methanol; only alcohol 46 was recovered. This
result confirmed that in the interconversion of sulfoxide 53 and sulfenate ester
52, the favored axe-transition state has a lower energy than the endo-transition
state ( see conformations A and B ). Sulfoxide 53 was equilibrated to a 1:1
mixture of two isomeric sulfoxides ( 53 and 57 ) in refluxing benzene. Finally,
methylation of sulfoxide 53 with methyl iodide resulted in the recovery of allylic
alcohol 46. No methyl sulfoxide was isolated ( Scheme 21 ). The intermediate
sulfoxide anion may have rearranged to a vinyl anion ( Scheme 22 ), which
then abstracted a proton from diisopropyl amine to regenerate lithium
diisopropyl amide ( LDA ). The attack of the latter at sulfur would give lithium

alkoxide, which after work-up produced 46.

 

39

Although the methylation of sulfoxide 53 failed to work, this study
provided a useful basis for further investigation of isomeric alcohol 47, its
derived sulfoxide and related reactions. As it turned out, the reactions of 47

included several highly selective transformations as outlined in Scheme 23.

----OH

1.n-BuLi i
2.TMEDA. CHsO
47 3.CIS Ph

    

95%

 

3.Cl-l31
90%

(CHaO)3P \

in MeOH

    

 

Scheme 23

40

As in the case of alcohol 46, epimer 47 yielded an isomeric sulfoxide.
55, under the reaction conditions previously described. Of particular interest,
however, was the isolation of sulfenate 54. This intermediate was stable
enoUgh to survive a rapid chromatographic separation and was characterized
by 1H NMR. Thus 54 exhibited two vinyl singlets at 5 4.79 ppm and 5 5.17
ppm, compared with equivalent proton signals at 5 4.74 ppm and 5 4.95 ppm
in starting alcohol 47. The proton at C-16 in 54, displayed a well resolved
doublet at 5 4.70 ppm (J=8 Hz ); whereas in 47, it appeared as a doublet at 5
4.78 ppm ( J-8 Hz ), partially overlapping with the peak at 5 4.74 ppm.

The striking difference in stability between the sulfenate esters 52 and
54 can be explained in terms of steric hindrance. It has been noted that the five-
membered rings of our model compounds have a more hindered ct-side, in
contrast to steroid. A sulfenoxyl group located on the more relaxed p-side, as in
intermediate 52, is able to achieve the rearrangement transition state with little
steric distortion. Consequently, rearrangement to 53 may take place rapidly. In
contrast, the Ct -sulfenate 54 is inhibited by steric distortion of the
corresponding transition state, and the rearrangement to 55 is slower.

Sulfenate 54 is transformed to sulfoxide 55 over 24 hours of period at
room temperature. Of two possible transition states for the rearrangement to a
sulfoxide, C is clearly lower in energy than is D. If sulfoxide 55 isformed from
the lower energy conformation ( C ) it will necessarily have an S configuration

at the sulfur atom:

   

Lower energy Higher energy

41

Sulfoxide 55 gradually equilibrated to a 1:1 mixture of sulfoxides 55 and
53 on standing for several days. Desulfuration of 55 with trimethyl phosphite in
refluxing methyl alcohol ( at room temperature the reaction did not occur )
yielded alcohols 47 and 46 in ratio of a 3:1. This suggested that the reaction
path leading to these alcohols had quite high activation energies, but a
relatively small difference in energy.

Unlike isomer 53, the conjugate base of sulfoxide 55 cleanly reacted
with methyl iodide to give methyl sulfoxide 56 in high yield. The configuration of
the newly formed chiral center at C-20 was tentatively assigned as S, on the
assumption that attack from ct-face was favored. When sulfoxide 56 was
treated with methanolic trimethyl phosphite under reflux it was converted to
alcohols 57 ( major product ) and 58 ( minor product ) in a high ratio. These
compounds were easily separated, and on oxidation with pyridinium
dichromate, yielded the corresponding enone 66, with a little double bond
isomerization to the Z isomer 67 ( 5% ). When the mixture of enones 66 and 67
was reduced by sodium borohydride, p-facial attack ocurred and alcohols 57
and 59 were obtained. However, recovery of a substantial amount of starting
material ( 66 and 67 ) prevented this reaction from being of synthetic value
( Scheme 24 ).

  

01130

 

 

B7
NaBH .CeCl
+ ‘ 1 «.011+ 87 +66
0 59 57
g 4:2:9:1 (85%)
67 :63=(421)

Scheme 24

42

To summarize, an energy diagram encompassing sulfoxides 53 and 55,
sulfenates 52 and 54, and various transition state conformations is presented

in Figure 3.

 

 

 

 

 

I
CH30; CHSO 55

Figure 3
Energy Diagram for Various Sulfoxides and Sulfenates

43

Further studies of methylated sulfoxide 56 were then conducted. The
conjugate base of 56 ( generated by reaction with LDA ) was quenched in turn
with ammonium chloride, acetic acid, and deuterium oxide ( DZO ). The first two
quenchings gave back the original sulfoxide 56 and suggested that protonation
occurred from the top face of the anion. To explain these results conveniently,
the following equation was depicted. When X=H ( i.e., methylation experiment ),
the left planar conformation is more favored and in this case, methyl iodide

approaches the molecule from the bottom face to give sulfoxide 56.

      

Bottom Face X: H , CH3

On the other hand, when X=CH3 ( i.e., proton quenching experiments ),
the left conformer is destabilized by repulsion between X and C-12. By rotating
the methyl group upward, the methyl group moved farther away from C-12 to
assume the more favored conformation on the right. The loss of n-conjugation
with the double bond is not serious for et-sulfonyl or et-sulfoxide anions. The
alternative conformation in which the larger sulfoxide and methyl groups are
switched is destabilized by crowding of the sulfoxide group with the angular
methyl at C-13. Protonation ( or deuteration ) from the more accessible exo-face

regenerated 56.

44

 

 

 

62163 2561- 3:121.

Scheme 25

Additional studies of the sulfenate ester-sulfoxide rearrangement were
also conducted with methylated substrates related to 56 ( Scheme 25 ). From
alcohol 58 ( its preparation will be described later ) the sulfenate derivative 61
was prepared, and at room temperature this slowly isomerized to a mixture of
two sulfoxides ( 56 and 62 ) in the ratio indicated. Sulfoxide 62 was easily
distinguished by chemical shift difference in the proton signal at C-20: 62
exhibited a quartet at 5 3.09 ppm, whereas 56 gave a quartet at 5 3.47 ppm.
The formation of 56 may be the result of epimerization through a higher energy

ot-endo transition state ( Scheme 26 ):

:- O’§‘¢f r O_S‘<I>
31B \ _, .
: I1 I; \

 

 

E O : (pus-'8
I
_ 63 - 0
Scheme 26

A summarizing energy diagram of these methylsulfoxides, their
analogues sulfenates and the corresponding alcohols is shown in Figure 4.
Unlike the parent p-sulfenate ester 52, sulfenate ester 61 is isolable, implying
a higher energy transition state for the sigmatropic rearrangement. Absence of
sulfenate 63 suggested a lower activation energy for its rearrangement to
sulfoxide 56. The sulfenate 61 and the sulfoxide 56 are plotted at the same

energy based on their equal thermodynamic distribution.

46

 

 

Figure 4

Energy Diagram for Methyl Sulfoxides and Sulfenates

47

A brief investigation of additional alkylation of methyl sulfoxide 56 and sulfoxide

55 is described in Table 4.

Tabie4 Alkylation of Sulfoxides

 

Run SulfoxideI Condition Rx Result

 

45' at -45°;3h at 0°;

 

 

lit at -78°; 55 + 64
2 55 2h at 0-20°. 73
3 55 74. 10'. at -45° 74 65+55+56

Mel, l .Sh, at -45°. Mel

 

' . ' _ 0.
4 55 20 ,‘4S¢,30 , I0 , 74

0 Unknown Mix.
30',30 .

 

 

5 55 lh,-45°. N 5'5
8r
5 55 l.5h,-4s°. Mel 54 + 55 +55

 

 

 

 

 

 

 

73: \,\,Br 74: \/\/'

48

We first examined the reactivity of 56 toward alkylation with 4-
methylpentenyl bromide. When 56 was treated with lithium diisopropyl amide
and then the alkyl bromide for several hours at various temperatures, only 56
and some decomposed alcohol 57 were recovered ( run 1 ). Even sulfoxide 55
failed to be alkylated with 73. The starting sulfoxide 55 and a rearranged
isomer 64 ( shown below ) were recovered ( run 2 ). The results with reactive
halides such as 4-methyl pentenyl iodide, and allyl bromide were also
disappointing. Finally, product 65, the only dialkylation product, was obtained (

run 6 ) in a moderate yield.

 

CH30

65

In conclusion, we have explored the feasibility of using sulfoxide-
sulfenate rearrangement in triterpene side chain synthesis, and observed some
interesting results. In the next section, a study of conjugate addition of

organometallic reagents to enones 66 and 67 will be presented.

49
1,3 .. .- : 9.... . o .... . - : . - . '..=.. ..: ..: .. ...
EZ IISIIS'IGIISII'

Enone 67 was prepared from olefin 13 by a two-step sequence similar
to that we used to prepare'48 from 12. Thus, treatment of 13 with selenium
dioxide gave alcohols 57 and 58 as a 1:6 mixture in good yield. Large scale
reactions also produced a small amount ( 5 - 8 % ) of 59 and 60. The alcohol
mixture was then oxidized to enones 66 and 67 by the action of pyridinium

dichromate ( Scheme 27 ):

 

 

57

57 + 58 +59 +60 329—.-

80-90%

 

Sccheme 27

50

As expected, attack of the selenium reagent occurred mainly at the less
hindered p-face of the olefin substrate. The initial intermediate E either
rearranged directly to the major product ( 58 ) via intermediate F or, prior to the
rearrangement, assumed a less stable conformation G, which yielded the minor
product 57. The detection of trace amounts of alcohols 59 and 60 suggested
the possibility that some selenium dioxide also reacted at the ct-face of olefin
13 in the initial step ( Scheme 28 ).

 

 

Scheme 28

51

In the course of developing methods for enone preparation, we found30
that 66 slowly isomerized to 67 on exposure to air. Under reflux in benzene
with a trace of iodine, 66 equilibrated to a 1:1 mixture with 67. Curiously, 67
did not rearrange to 66 under the same conditions; however, on' base-treatment
in refluxing methanol it was converted to the same 1:1 mixture. These findings

enabled the yield of 67 to be raised to over 90% ( Scheme 29 ).

l2/PhH
Reflux, 95%

 

   

KOH/MeOH
Reflux, 95%

 

 

Scheme 29

We anticipated that the stereoselectivity for nucleophile attack at C-20
would be mainly controlled by the methyl group at C-13. Consequently,

conjugate addition of organometallic reagents to these enones ( 66 and 67 )

52

should occur from the less hindered 0t-face to give 68 and 75, respectively

( Scheme 30 ):

 

 

  

Scheme 30

To confirm this prediction, a cuprate reagent was prepared from n-
butyl lithium and cuprous bromide ( dimethyl sulfide complex ) and first
reacted with a solution of 67 ( chosen because of its convenient
preparation ). A single isomer 70 was obtained after work-up. The
product was believed to be the thermodynamically favored 17p-isomer,

because base treatment of it did not cause any change ( Eq. 4 ).

53

l
.. O (n-Bu)2CuLi
. _.

70-80%

 

 

Eq. 4
In order to apply this reaction to triterpene side chain syntheses we
needed to prepare lithium bis-( 4-methylpentenyl ) cuprate. The 4-methyl
pentenyl lithium, needed for making the cuprate, was eventually prepared from
the corresponding alkyl halides. Generally, organolithium compounds can be
generated by the reaction of alkylhalides with lithium metalfi9 by homogeneous
metal-halogen exchange70 by homogeneous metal-metal exchange71 ( Eqs. 5,

6 and 7, respectively).

2 Li + RX -—-> RLi + LiX Eq. 5
RX + R'Li -"""> RLi + R'X Eq. 6
Ph3$nR + PhLi ——’ RLi + Ph4Sn Eq. 7

The first method is used most frequently and seems particularly suited to
our needs. For best result, a small amount of sodium metal is usually added to
initiate the reaction. Applications of the second method are often for the
preparation of primary alkyl lithium reagents from a tertiary alkyl lithium and a

primary halide. Although metal-metal exchange is less commonly used, this

54

method finds unique value in preparing organolithiums from very active halides
' such as allyl bromide and benzylbromide by preventing potential
polymerizations. Recently, Luche at 31.72 reported that ultrasonic irradiation"3
improved the reaction of alkyl halides with metals. No initiators, such as l2 or
dibromoethane, were needed, and the yields of alkyllithium were greatly
improved with reduced reaction time periods. Nonetheless, opposite examples
also exist. For example, Boudjouk74 showed that ultrasound promoted coupling

of alkyl halides in presence of lithium.
We examined all three methods with different halides ( 72, 73, and 74)

for the preparation of organolithium reagents. In some cases ultrasonic
technique was used.
(CH3)2C=CHCH2CH2X + LI ——?(CH3)2C=CHCH2CH2LI

72 . X=Cl
73 o X=Bf'
74 . X=I
Tables Reaction of Halides with Metals

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Run Rx Metal (go) (5,) gm; Result

1 72 L1 -15 12 No ”it???"
2 72 Li -15 5 Yes NR.

3 73 L1 -IS 15 No 173 Pdt+ 73
4 73 Li r.t. 12 N0 NR.

5 73 Li r.t. 7 Yes Coupling
5 74 , L1 -15 15 No NR.

7 73 $843: -20 12 No 4OXPdt + 73
8 73 Mg r.t. 4-5 No 908

9 74 fig r.t. 4-5 No 902

 

 

55

The halides 72, 73 and 74 were prepared from 2-cyclopropyl
isopropanol by the procedure of McCormick75 and Balme.76 It was found that
lithium wire ( even with sodium present ) did not efficiently react with these
halides. A large quantity of unreacted lithium metal was usually recovered and
the ultrasound technique did not improve the yield of the desired product. In

some instances coupling products were formed ( runs 1-6, Table 5 ).

Table 6 Metal Halogen Exchange

 

 

 

 

 

 

 

 

Run Rx RLi T ( C° ) t ( h ) Result
1 7 3 - 78 4-5 NR.
2 73 - 45 4-5 N.R.

t-BuLl
3 74 - 78 4-5 NR.
4 74 - 55 4-5 N.R.

 

 

 

 

 

 

 

 

Attempts to effect metal halogen exchange with these halides" were
unsuccessful ( Table 6 ). As shown in the following scheme, transmetallation

reactions were also ineffective. The metal exchange did not go to completion
(Scheme 31 ).

>-‘\_/M°Br + ClSnd>3 —’ >=\_an¢3
10-15% 1 0

LI

MU + 048n ‘

( Poor Yield )

Scheme 31

56

Finally, when a dispersion of lithium-sodium alloy ( sodium content, 1 % )
was used, the desired 4-methyl-3-pentenyl lithium was generated in good
yield78( run 7, Table 5 ). The freshly made methylpentenyllithium was titrated by
a standard method.79 Alkylhalides 73 and 74 were also shown to give the
Grignard reagent in high yield ( runs 8,9 ).

When enone 67 was treated with freshly prepared alkylcuprate derived
from 73, a mixture of two compounds was obtained. Base treatment of this
mixture in refluxing methanol produced a single isomer as shown below

( Scheme 32 ).

 

   

1.( I
2. KOH/MeOH
59% CH30 75 Only Product
CH30 57 WW3,
V Complicated Mixture
u

I No S.M. left)

Scheme 32

Addition of the corresponding Grignard reagent to 67 was also studied,
but this reaction gave a complicated mixture of products. This mixture was not
simplified by base treatment. The similar poor selectivity with Grignard reagents

in conjugate additions has also been reported by others.32.80

57

We hoped that addition of organocuprates to 66 could be equally
selective, giving the C-20 epimer of compound 70 or 75. However, when this

enone was treated with lithium bisbutylcuprate, a mixture of products was

obtained. and base treatment of this mixture yielded four products as shown
below ( Scheme 33 ):

 

 

Scheme 33

Our results revealed an interesting difference in the behavior of 66 and
67 in conjugate addition reactions. These findings contrasted with those30
reported by Trost et al. for the addition of lithium isohexylcuprate to a similar
steroidal enone. Thus, compound 75 ( corresponding to our enone 67 ) gave a
mixture of C-20 isomers, whereas the same addition to steroidal enone 78
(corresponding to our enone 66 ) yielded only the single isomer 79, with a R

configuration at C-20 ( Scheme 34 ).

58

 

 

 

Scheme 34

Compound 75 was cleanly reduced by lithium aluminum hydride to a
single alcohol 76, which we assigned as the p-eplmer 76 by comparison of its

proton NMR spectrum with that of a steroidal analogue81 ( Eq. 8).

   
 

LAH/THF
——->

Quantitative

 

59

The preparation of 75 and 76 has provided a useful synthesis of
triterpene side chains with concurrent functionality at C-16. _
The carbonyl group at C-16 in compound 75 was finally removed by a

Wolf-Kishner reductive deoxygenation82 to give 17 in good yield ( Eq. 9 ):

   

 

> :
Eth lene GI col '
CH30 75 Y 80% V CH30 17

Eq. 9

The configuration at C-20 of product 17 was established. From previous
studies of triterpene 13C NMR spectra”, it is clear that significant chemical shift
differences are observed between equivalent lanostanes and euphanes,
especially for carbons 12, 16, 17, 20 and 22 ( A5 2 0.5 ppm ). Since
compound 17 constitutes a racemic model of the euphane side-chain, we .
expected to find a correlation of appropriate 13C NMR signals vis-a-vis those of
the lanostanes. The data in Table 784 show this to be the case (a comparative
value for C-12 is omitted, since the methoxy group in 17 causes a large
perturbation at this site ). Finally, 17 proved to be identical with the product from
Koreeda/Krief” side chain synthesis, as applied to 6.

The stereochemistry observed in the conjugation addition of
dialkylcuprate reagents to Z enone 68 suggested a means for achieving

opposite selectivity at C-20. If a compound like 90 could be prepared in good

60

yield, a corresponding conjugate addition with lithium dimethyl cuprate would
give a product having an R configuration at C-20. This would provide a

complementary method for construction of side chains ( Eq. 10 ).

 

   

Eq. 10

In the retro-synthetic strategy shown in Scheme 35, it is clear that a
method for preparing the E olefin 86 must be developed. In this case, the use of
a bulkier ylide, would require the Wittig reaction to be undertaken at a higher
temperature. Selenium dioxide oxidation of this olefin should be routine and is
expected to give the p-alcohol, which would be oxidized to enone 9O
( Scheme 35 ).

 

Scheme 35

61

The preparation of the phosphonium precursor to ylide 85 is described in
Scheme 36. Treatment of 3-methyl butanol with HBr gave bromide 80 in good
yield85 Condensation of 80 with malonic ester‘36 followed by acidic hydrolysis
produced acid 81, which was reduced by lithium aluminium hydride87 to
alcohol 82. Bromination of 82 yielded the desired bromide 83, which gave the

phosphonium salt 84 in 93% yield.

0 O
OH Br >

 

——>
H2304 3° 2. HWHZO/A
73% 79%
HBr
Wop. ——.—../k/\/\ 83
Ether OH H 284
83% 82%
93% PPI'I3 Br .
84
Scheme 36

Unfortunately, the reaction of ylide 85 with ketone was very sluggish.
Even after four days in refluxing toluene, only a 23% conversion to a mixture of
olefins 86 and 87 was realized. A substantial amount of the starting material

was recovered ( Eq. 11 ).

62

  
 

+ 7 (70%)

1 :1 (30%)

Eq.11

To test the facial selectivity of the selenium oxidation, we treated the
olefin mixture with selenium dioxide and t-butylperoxyl alcohol. A mixture of four
compounds was obtained. These products were separated, and were identified
as 88, 89, 90 and 91 on the basis of their NMR spectra ( Scheme 37 ).

 

$802

 

48%

   

Scheme 37

63

Finally, compound 90 was treated with lithium methyl cuprate and proved to be
unreactive. None of the desired adduct was detected and the starting enone

was fully recovered.

PART 2. CONSTRUCTION OF THE TETRACYCLIC FRAMEWORK OF
SENEXONOL AND LANOSTEROL

ZIBII' [B'-EE |' IT [IE

In the synthesis of senexonol or lanosterol from 18, the removal of
excess functionality from ring A must be effected at some stage. Speziale's
reduction procedure‘l9 gave good results when applied to the structurally
related compound 25. Treatment of 18 with zinc powder in acetic acid-water
gave two isomeric products, 92 and 93 (Scheme 38), in a ratio that
depended upon the acetic acid concentration. Glacial acetic acid gave a 1:1
mixture, whereas in dilute acid the formation of desired alcohol 92 was favored

(3:1 ratio in 1:1 acetic acid-water).

 

Zn

How/1120
95%
92 :93 = 3:1

 

01130

 

Scheme 38

64

Reduction of the double bond of a conjugated enedione is not
unprecedented. L. Sarett et al. observed88 that compound 94 was reduced to

give 95 as the only product ( Scheme 39 ).

 

CH3 CH3 0
CH30 CH3 CH30 CH3
Zn/HOAc
GD 4
94%
O O
Scheme 39

Other reducing agents such as sodium borohydride and sodium
acetylborohydride89 were also examined. Reduction of sodium borohydride
with 18 gave a mixture of three products, 92 and two other unidentified
compounds. On the other hand, only starting material was recovered, when
sodium acetyl borohydride was used.

Another method for reducing ring A functionality is the dissolving-metal
reaction, using alkali metal in liquid ammonia. Spencer etal. 90 have reported a

sequential Birch reduction of a diacetoxy enone system 96 ( Scheme 40 ).

65

 

OAc
AcO AcO OAC 0A3;
to on
——> . ——>
O -0 ' <24 ‘
CH3 CH3 CH3
96 97 I
Q. 1 to to
+— 4—— ,
-0 -0 0
CH3 CH3 CH3
99 98
100
Scheme 40

Direct Birch reduction of compound 18 is not feasible, because it would
likely cause the loss of the useful 3-methoxyl group. The derived enol ester 101
is a better candidate for this reduction.4‘lbrc If the initial protonation gives 102,
instead of 103, further reduction eventually should yield alcohol 104. Acid-
catalyzed hydrolysis of this alcohol would give desired products 23 or 24
(Scheme 41 ).

66

 

c1130

 

 

 

2Li
uo i
so
OAC“ Li/NH3
or Other
[H]
23 + 24 W

 

Scheme 41

67

Compound 101 was treated with lithium in liquid ammonia under various
conditions. In all cases either the starting material 18 or a complex mixture of
products was obtained.

At the same time that we were looking for better conditions to effect
reduction of ring A, we also investigated subsequent transformations with

alcohol 92. A previously developed sequence is shown in Scheme 42.

 

Scheme 42

Alcohol 92 was first converted to a mesylate derivative 105 in high yield.
Reduction of 105 with zinc in glyme gave two products in low yield, 106

(38%) and enone 107 ( 15% ). This result contrasted with earlier work

68

reported by our group. Thus, the io-epimer of 105 ( i.e., 26 ) was reductively
removed by zinc in glyme to give only enone 27 in high yield (p. 15).

ZZIIIIII' ID-l ISI II 1 l'

Eventually, one or two methyl groups must be introduced at C-4,
depending on whether the ultimate synthetic target is senexanol or lanosterol.
Previous work in our research group has probed the possibility of incorporating
these methyl groups in a dienophile capable of reacting with diene 109.
Dienophile 10891 reacted slowly with 109 under stannic chloride catalysis;
however, the yield of the desired product ( Eq. 9 ) was low, and substantial
aromatization occurred on heating. Direct methylation of enolate intermediates

was successful using tetracyclic substrates 133 and 134.414“b

OMEM OMEM

 

133 134

OMe

 

 

111

 

69

We began our investigation with a study of the addition of methyl
magnesium iodide to compound 18. Although it was reported“ that methyl
lithium did not give good results in this reaction, the addition of the
corresponding Grignard reagents was not investigated. We found that reaction
of methyl magnesium iodide with 18 proceeded to give the 4-methyl derivatives
112 and 113 ( 10:1 ) in good overall yield. Unexpectedly, we also found that
the addition with methyl lithium generated these derivatives in even better yield

but lower ratio ( Scheme 43):

Organometallics
>

 

TMEDA/T HF

   

MeMgl, 85%,112 :113 all=10:1
MeLi, 95%.1121113 =1:1

Scheme 43

70

The different selectivity observed here can be rationalized. Since the AB
ring junction is cis, the p-face of ring A should be more accessible than the ct-
face. Therefore a moderately reactive nucleophile such as methyl magnesium
attacks preferentially from the p-side. Methyl lithium, being more reactive,
attacks at both faces of ring A with little discrimination.

Following the preparation of 112 and 113, we proceeded to study
methods for removing the hydroxyl group from C-4. A simple approach to this
deoxygenation is treatment with refluxing acetic acid and zinc, as described by
Barton et al.92 in their steroid synthesis. Birch reduction is another possibility.
Derivatization of the C-4 hydroxyl in 112 and 113 with electron withdrawing
groups may be necessary to facilitate cleavage of the oxygen function.

Zinc dust reduction of 112 was attempted but proved to be ineffective.
Derivatization of both 112 and 113 with a number of reagents, such as acetyl
anhydride, acetyl chloride, and methyl sulfonyl chloride was also largely
unsuccessful. Furthermore, electrophile reagents such as methyl iodide and
acetic anhydride failed to quench the initially formed anion ( from addition of
methyl lithium to 18 ) to give the corresponding derivatives. In all cases, the
starting materials were recovered. Finally, lithium-ammonia reduction of
compounds 92, 112, and 113 were also conducted, and complex mixtures
were found in each case.

We next considered an alternative procedure, which involved initial
conversion of 112 and 113 to four products: 114,115,116 and 117.93
Oxidation of 114 and 115, or 116 and 117, gave 118 or 119 in good yields.

These results are shown in Scheme 44.

71

  
    

1 .DlBAL/CH2012

1 1 2 ——>
2.H*30/THF

0

'OH

74%
114". X=H .y=OI-I
115 1 YaH ,X=C}‘I
114:115=2n
x”Y

 
 
 

 

 

Swern
1.DIBAL/CH20I2 Oxidation
1 1 3 > —-—>
2.H*3O/THF 61%
O
81 % H0

1169 X'H 9Y'G"
1179 y-H ’X'O'.

116:117=3:1

Scheme 44

The configurations of C-17 for all four diols were determined by 1H NMR.
For example, C-14 angular methyl in 114 is syn to the 170t-hydroxyl group and
therefore shifted downfield to a greater degree than the 13-angular methyl. On
the contrary, the 13-angular methyl in 115, being syn to the 17p-hydroxy
group, should have greater downfield shift. As a result, compound 114 ( 40t,
170t-dihydroxyl derivative ) would display two methyl singlets ( in the proton
NMR ) with a larger A5CH3(13 )-5CH3(14) than that of epimer 115.

72

Once compounds 118 and 119 were prepared, they were treated with
zinc in refluxing acetic acid. Although 118 did not react, 119 gave the reduced
dienone 120 in high yield. By catalytic hydrogenation, 120 was converted
cleanly to 121 which was then protected by ketalization at C-3 to give the
potentially useful isomers 122 and 123 ( Scheme 45 ).

 

 

120

HzlPd,89%

 

 

     

122:123 =2:1

Scheme 45

73

Another approach, involving deoxygenation with concurrent formation of
a carbon double bond, was also considered. It has been reported94 that On-
hydroxy ketones are dehydrated by strong acid to give a afi-unstaturated
ketones. If compounds 118 and/or 119 could be transformed to the
corresponding enone in this way, we should be able to control the configuration
of C-5 by Birch reduction, thus moving closer toward the synthesis of senexonol
skeleton.45 Alternatively, a second methyl group might be attached at C-4
( using Woodward's method15 ) to generate the lanosterol skeleton. Care must
be taken in applying this method to compounds 118 or 119, because these
compounds may undergo acid-catalyzed rearrangements."5 Indeed, compound
119 was found to give involved products, possibly from the rearrangement, on
treatment with cone. H2504 at 0 °C, whereas under the same conditions, 118
gave a single product 124. This newly obtained product exhibited no C-7
olefinic signal in its proton NMR and showed a molecular ion at 328 ( m/e ) in
mass spectrum. These facts suggested that either the A-7,8 had migrated to the
8,9 position, or that intramolecular addition of the C-4 hydroxyl to 7,8-double
bond had occurred. Birch reduction of 124 gave only 125, which exhibited a
methyl doublet in its proton NMR ( suggesting hydrogenolysis of the C-0 bond
at C-4 ) and a molecular ion at mass 334. Considering this information, we have

proposed the following scheme.

74

 

( MT', 334 )

Scheme 46

Molecular models of 118 indicate that the hydroxy group at C-4 has an
ideal orientation for addition to the 7,8-double bond. The Birch reduction of the
resulting cyclic ether ( 124 ) cleaved the CO bond at C-4, leaving a hydroxyl
group at C-7. Interestingly, this C-O bond in 118 was not cleaved in the Birch
reduction, giving only the saturated diols 126 and 127 ( Scheme 47).

75

Li/NH3

 

50%

 

126:1 27 -6:1

Scheme 47
Finally, methylation for converting intermediate 18 to its 4-methylene
derivative was studied. Reactions of 18 with methylene triphenylphosphorane
did not proceed well.44b We found, however, that addition of trimethylsilylmethyl
lithium96 efficiently converted 18 to 128 and 129 ( 5:1 ) in excellent yield.
Furthermore, the silyl group in both 128 and 129 was readily removed by the
action of boron trifluoride, to yield 130 as the only product ( Scheme 48 ):

76

 

0” 'CHZSiMea
1 29

1281129 =5:1

Scheme 48

Selective methylene addition to the exocyclic methylene group in 130
should give a cyclopropyl derivative, which might then be cleaved to a

4,4-dimethyl compound by catalytic hydrogenation.97

EXPERIMENTAL SECTION

Unless otherwise indicated, all reactions were conducted under a dry
argon or nitrogen atmosphere, using solvents distilled from appropriate drying
agents. Reactions were generally monitored by thin layer chromatography
(silica gel 60 F254, E. Merck ), and analytical samples were prepared by Flash
Chromatography using 230-400 mesh silica gel. UV spectra were obtained on a
Perkin-Elmer spectrophotometer-HITACHI 200. IR spectra ( with sample in
CDC13 ) were obtained on Perkin-Elmer 237 B or on Perkin-Elmer 599 Infrared
spectrophotometers. 1H NMR spectra were taken in CDCI3 solution using either
a Varian T-60 ( 60 MHz ) or a Bruker Cryospec WM 250 ( 250 MHz )
spectrometer, and were calibrated in parts per million ( 5 ) from tetramethyl
silane. 13C NMR spectra were determined in deuterated chloroform with Bruker
Cryospec WM 250 ( 250 MHz ) instruments and calibrated in parts per million
from CDCI3. Double resonance experiments were made on the same Bruker
instruments using a directional coupler. Shifting reagent studies were
conducted with 2,2,6,6-tetramethyl heptanedionate eur0pium. Mass spectra
were obtained with a Finnigan model 4000 gas chromatography / mass
spectrometer system, and recorded as We vs relative intensity. High resolution
mass measurements were determined on a JEOL HX 100 spectrometer.
Ultrasound assisted experiments used a Branson 2200 laboratory cleaner, or
the High Intensity Ultrasonic Processor ( frequency 20 K Hz ) made by Sonic
and Materials Inc.. Elemental analyses were conducted by Spang

Microanalytical Laboratory. Melting points (°C, uncorrected ) were measured

77

78

on a Thomas Hoover Capillary Melting Point Apparatus or on a Reichert hot
stage. 1' ' ‘
Epoxidation of methoxy olefin 12 with unbuffered peracid. A 0.140 g
(0.72 mmol ) sample of 12 dissolved in 5 mL CH2Cl2 at 0 °C, was treated with
a solution of 100 mg MCPBA ( 85% ) in 5 mL CH2C12 for 30 h. To this. was
added 10 mL NazSOa ( 5% ) to reduce unreacted peracid. The organic layer
was separated, washed with water and brine, and dried over MgSO4. Removal
of the solvent gave a light brown oil, which was passed through a column of
silica gel ( Ether-Pet.Ether/ 2:1) to give 85 mg of white crystalline 40.
Characteristic properties of 40: mp, 70.5-71.5 °C; 1HNMR, 3.39 ( 1H, B of AB,
J=11 ), 3.28(3H, s), 3.26 ( 1H,Aof AB, J=11 ),3.17 ( 1H, s), 2.92 ( 1H,d, J=4 ),
0.99 ( 3H, s ), 0.91 (3H, s ); MS, 226 ( M+.).

Epoxidation of 12 to give epoxides 36a and 36b. To a flask containing
15 mL NaHC03 solution ( 0.5 M ), was added 194 mg ( 0.1 mmol ) of methoxy
olefin 12 in 15 mL methylene chloride. This was followed by addition of 0.22 g
MCPBA (85%) in 10 mL methylene chloride through a dropping funnel. After
the bi-layer mixture was stirred one day at r.t., 5 mL NagSO3 solution ( 5%) was
added to reduce excess peracid. The two layers were separated. The aqueous
layer was extracted with 10 mL CH2CI2. The combined organic layer was
washed three times with 0.5 M NaHC03 solution, and dried with K2003 (one
drop pyridine was added to maintain slightly basic condition ). A 155 mg mixture
of 36a and 36b, as a yellow oil, was obtained after removal of the solvent.
Flash chromatography of the mixture gave pure samples in 85% recovery.
Characteristic properties of 36a ( ct epoxide ): 1H NMR, 8.81 (3H, s ), 2.63
( 1H, d,J=5 ), 2.56 ( 1H, s), 1.13 ( 3H, s ),1.04(3H, s ).

79
Characteristic properties of 36b( 8 epoxide ): 1H NMR, 3.31 ( 3H, s ), 2.88
(1H, d, J=3), 2.66 ( 1H, d, J=5 ), 1.19 (3H, s ), 0.97 (3H, s ). Since the two
epoxides were acid sensitive, they were directly used for next reaction without

further purification.

Reaction of epoxides 36a and 36b with diethyl aluminum-2,2,6,6-
tetramethyl piperidide to give 39. To 1.48 mL n-BuLi ( 1.6 M in hexane )
was added 0.84 mL ( 2.4 mmol ) 2,2,6,6-tetramethyl piperidine followed 20 min.
later by addition of 1.55 mL Et2AlCl ( 1.48 M in benzene ). A solution of
epoxides 36a and 36b (0.115 g, 0.55 mmol ) in 5 mL of benzene was added
to this stirred mixture, and after a 4 h period, the reaction was quenched-by
addition of 2 mL aqueous methanol ( 1:1 ). The resulting mixture was
neutralized carefully and extracted with ether. The other layer was dried over
K2003. and after evaporation of the solvent gave a 0.113 g of a yellow oil.
Chromatographic separation yielded 38 mg of 39, and 46 mg of an unidentified
product. An acetate derivative, 132, of 39 was prepared by treatment with
acetic anhydride in pyridine ( 70 % yield ).

Characteristic properties of 39: IR, 3610, 1800, 1090, 1025, 827. 1H NMR, 5.87
( 1H, tr, J=3 ), 3.44 ( 1H, 8 of AB, J=13 ), 3.37 ( 1H, A of AB, J=13 ), 3.35 ( 3H,
s), 3.24 ( 1H, tr, J=3 ), 1.40 ( 1H, d, d, J1=8, J2=12 ), 1.25 ( 1H, d, d, J1=7,
J2=12 ), 1.05 ( 3H,s ), 1.00 (3H, s ).

Characteristic properties of 132: IR, 1720, 1600, 1452, 1370, 1250, 1083, 1025.
815. 1H NMR, 5.88 ( 1H, tr, J=4 ), 8.98 ( 1H, B of AB, J=11 ), 8.90 ( 1H, A of AB,
J=11 ), 3.35 ( 3H, s), 3.24 ( 1H, tr, J=3 ), 2.06 ( 3H, s), 1.00 (3H, s ), 1.43 ( 1H, d
of d, J1=7, J2=14 ), 1.24 (1H,d,d,J1=6,J2=11 ), 1.06 ( 8H, s ). As expected.
39 gave 40 upon epoxidation with MCPBA.

80

Lithium. dimethyl amide Induced epoxide ring opening of 36. Liquid
Me2NH (5.15 ml ) was treated with 3.0 mL n-BuLi ( 1.6 M in hexane ) at -78 °C
for five min. This mixture was then warmed to -5 °C and allowed to react with a
159 mg ( 0.76 mmol ) sample of epoxides ( 36a and 36b ) dissolved in 6 mL of
ether. The colorless solution turned slightly yellow and some precipitates was
observed. After the reaction mixture was stirred overnight at 0 °C, it was
quenched with water and extracted with ether. The ether extracts were washed,
dried over K2003 and evaporated to give a yellow oil ( 140 mg ), which was
shown to be a mixture of 87 and 36b ( 1:1 ) by 1H NMR. When this reaction
was conducted in refluxing ether, a similar ratio of 37 to 36b was observed.
Characteristic properties of 37: IR, 3600, 1630, 1460, 1375, 1200,1100, 1085,
880. 1H NMR: 5.50 ( 1H, s ). 4.17 ( 2H, s ), 8.84 ( 1H, s ), 8.88 ( 3H, s ), 2.70
(1H, d, J=16 ), 1.17 ( 3H, s ), 1.01 (8H, s ). 130 NMR: 152.8, 122.6, 83.2, 60.1,
57.7, 50.4, 48.3, 37.7, 30.9, 26.8, 24.7, 23.3, 226,175

Olefination of 43 to give 44. To 4.0 mmol orange colored triphenyl
phosphonium methylide ( generated from methyl triphenylphosphonium
bromide by treatment with potassium t-amylate in refluxing benzene solution )
was added 117 mg ( 0.35 mmol ) of ketone 43 in 5 mL hot benzene. This
mixture was refluxed for 22 h, then cooled and quenched with ice. The crude
product was mixed with water and extracted with ether. The ether extract was
dried over M9804, and after evaporation of the solvent gave 550 mg of a solid
residue. Chromatographic purification produced 101 mg of olefin 44.
Characteristic properties of 44: mp, 105-107 °C; 1H NMR, 4.70 ( 2H, br. s ), 3.99
(4H, s ), 2.51-1.00 ( 22H, m ), 0.89 ( 8H, s ), 0.81 (3H, s ).

81

Epoxidation of 44 to epoxides 458 and 45b. Two phase methylene
chloride-adheous sodium bicarbonate solvent mixture ( 10 mL each ) was
mixed with 90 mg ( 0.5 mmol ) of MCPBA, followed after 10 min by addition of
100 mg ( 0.30 mmol ) of olefin 44 in 4 mL methylene chloride. After being
stirred for 8 h, the reaction mixture was treated with N82S03 solution and
extracted with methylene chloride. Evaporation of the solvent gave 80 mg of a
mixture of 458 and 45b in ratio of 9:1.

Characteristic properties of 458: 1H NMR, 3.94 ( 4H, s ), 2.73 ( 1H, d, J=5 ), 2.66
(1H,d,J=5),1.90-1.10(22H,m),0.84(3H,s),0.82(3H,s).

Characteristic properties of 45b: 1H NMR, 3.94 ( 4H, s ), 2.90 ( 1H, d, J=5 ), 2.60
(1H, s, J=5), 1.90-1.10(22H, m ), 0.98(3H, s ), 0.88 ( 3H, s ).

Oxidation of allylic alcohol 37 to unsaturated aldehyde 38. To 0.160
g ( 0.48 mmol ) of PDC in 5 mL DMF at 0 °C , was added 74 mg (0.85 mmol ) of
allylic alcohol 87 in 4 mL DMF. This mixture was stirred for 12 h at 0 °C then
filtered. The filtrate was diluted with ether, which was then washed with water.
The other solution was dried over MgSO4. Removal of the solvent under
vacuum yielded 90% of unsaturated aldehyde 38.

Characteristic properties of 88: 1H NMR, 9.71 ( 1H, s ), 8.87 ( 1H,d, d,J1=2,
J2=4),3.33(1H,s),3.31 (8H, s ), 2.91 (1H, d, J=18 ),1.22 ( 8H, s ), 0.99 ( 3H,
d, J=1 ).

Selenium dioxide oxidation of 12 to allylic alcohol 46 and
unsaturated ketone 48. A mixture of 0.23 mL ( 4 eq ) 90%
t-butylhydroperoxide and 28.6 mg ( 0.5 eq ) S802 in 10 mL methylene chloride
was agitated for 30 min, before addition of a 100 mg ( 0.52 mmol ) sample of

methoxy olefin 12 in 5 mL CH20I2. The reaction mixture was stirred at r.t. for 22

82

h, then washed with NaOH ( 10%, 3x25 mL ), and brine ( 25 mL ). Evaporation
of the solv§nt yielded a lightly colored oil ( 118 mg ). 1H NMR ( 250 MHz )
indicated that the oil contained 46 ( 80% ) and 48 ( 20% ). Separation of the
mixture was carried out by means of chromatography.

Characteristic properties of 46: IR, 3602, 1470, 1375, 1315, 1200, 1135, 1085,
1020.880; 1H NMR, 5.08 ( 1H, d, J=1 ), 4.78 ( 1H, d, J=2 ), 4.59 ( 1H, d, d, tr,
J1=8, J2=7, J3=1 ), 8.81 (3H, s ), 8.20 (1 H, tr, J=3 ), 2.12 ( 1H, d, d, qua, «=9,
82.7,.13-41 ), 2.00 ( 1H, s, br ),1.82-1.42 ( 7H, m ), 0.75 ( 3H, d, J=1 ); 13C NMR,
163.8, 104.9, 83.1, 73.7, 57.8, 46.3, 45.6, 40.4, 29.1, 24.6, 24.2, 23217.3; MS,
210 ( 0.6 ), 192 ( 0.6 ), 177 ( 3 ), 160 ( 12 ), 145 ( 36 ), 71 (80 ), 41 (100 ).
Elemental analysis, Cal., C, 74.24; H, 10.54. Found, C,74.33; H, 10.50.
Characteristic properties of 48: IR, 2830, 1725, 1650, 1270, 1130, 1085, 890.;
1H NMR, 5.75(1H,s), 4.87(1H,s), 3.31 (3H,s), 3.28(1H,s), 2.88(1H, d,
q, J1=17, J2=1 ), 1.77 ( 1H, d, J=17 ), 1.80-1.95 ( 7H, m ), 1.25 ( 3H, s ), 0.92
(8H, d, J=1 ); 13c NMR, 207.8, 155.9, 110.0, 81.7, 57.5, 45.6, 44.8, 42.5, 28.2,
24.4, 22817.3; MS, 208(8), 193 (2 ), 176 ( 9.4 ), 165 (3), 161 ( 15), 148
(17 ), 135 (44 ), 107 ( 19 ), 71 (78 ), 55 ( 54), 41 ( 100 ). Elemental analysis,
Cal., C, 74.96, H, 9.68. Found, C, 74.74; H, 9.72.

The unsaturated ketone 48 could be also obtained by the following one-pot
reaction procedures: a 98 mg ( 0.51 mmol ) sample 12 in 10 mL methylene
Chloride was treated, in the same manner, with S802 and peroxy t-butanol.
After 24 h, 0.291 g ( 1.5 eq ) PDC was added. The heterogeneous mixture was
stirred for six h, and filtered through a short column of silica gel which was then
rinsed, for a few times, with ether. The filtrate was washed with N82803 ( 10% ),
NaOH ( 10% ), water, and brine, and dried over MgSO4. A 100 mg product
(lightly colored oil ) was obtained. 1H NMR spectrum showed the desired
product 48 to be 90% pure.

83

Reduction of unsaturated ketone 48 to alcohol 47. To a 82 mg ( 0.39
mmol ) salEple of enone 48, was added 146.9 mg ( 1 eq. ) CeCl3.7 H20 in 1
mL CH30H, followed by slow addition of NaBH4 ( 12 mg, 1 eq ). Hydrogen gas
evolved immediately. After 5 min, the mixture was poured into water and
extracted with ether. The organic layer was washed with water, brine and dried
over MgSO4. Removal of the solvent yielded a colorless oil ( 90% ) which, on
standing, solidified. 1H NMR showed it to be pure alcohol 47.

Characteristic properties of 47: mp, 71.0-72.5 °C; IR, 3605, 3070, 1450, 1370,
1250, 1195, 1075, 875; 1H NMR, 4.95 ( 1H, d, J=2 ), 4.78 ( 1H, d, J=8 ), 4.74
(1H, d, J=2 ), 3.29 ( 3H, s ), 3.23 ( 1H, s ), 2.65 ( 1H, d, d, qua, J1=13, J2=8,
J3=1 ), 1.27 (6H, m ), 1.20 ( 1H, d,J=13 ), 1.08 (3H, s ), 0.92 ( 3H, d,J=1 );130
NMR, 165.0, 101.3, 83.1, 72.2, 57.6, 47.4, 45.5, 40.6, 28.9, 24.6, 24.1, 23.2,
18.9; MS, 210 (1 ), 178(12 ), 163(31 ), 145(29 ), 121 (50 ), 107(39 ), 98
(35 ), 79 ( 36 ), 71 ( 100 ), 55 ( 57 ); Elemental analysis, Cal., C, 74.24; H,
10.54. Found, C, 74.27; H, 10.59.

Preparation of R-sulfoxlde 53. To1.5 eq n-BuLi ( in hexane ) diluted with 5
mL THF at -78 °C was added a 77 mg (0.87 mmol ) sample of alcohol 46 in 5
mL THF, followed, 15 min later, by slow addition of 0.1 mL TMEDA. The mixture
was stirred for another 5 min. then treated with 107 mg ( 0.74 mmol ) phenyl
sulfenyl Chloride in 5 mL THF. White particles ( LiCl ) deposited within a few
seconds. Temperature was raised to -45 °C at which the milky reaction mixture
was stirred for another 30 min. The reaction was quenched by addition of
NH4CI saturated solution, and extracted with ether. The ether extract was dried
over MgSO4. Removal of the solvent under vacuum gave 332 mg orange oil
which upon the flash chromatography ( eluent, ether—hexane ) yielded 84 mg

(82 % ) R-sulfoxide 53 as a colorless oil.

84
Characteristic properties of 15: 1H NMR, 7.52-7.68 ( 5H, m ), 5.48 ( 1H, s ), 3.59
(1H, d, B ofAB, J=13 ), 3.52 ( 1H, d, A of AB, J=13 ), 3.29 (3H, s ), 3.29 ( 1H, s ),
2.68 ( 1H, d, J=15 ), 1.15-1.81 (7H, m ), 1.09 ( 3H, s ), 0.98 ( 3H, s ); 13C NMR,
142.0, 131.1, 120.4, 129.0, 124.6, 124.2, 83.1, 57.7, 57.8, 49.3, 38.4, 26.4, 24.7,
23.1, 22.3, 17.5; MS, a weak molecular ion ( 318 ) was observed. Strong
fragment ions were found at 161, 149, 119, 105, 91, 77, 71 and 55.

Desulfuration of R-sulfoxlde 53 under various conditions. Condition
A: The R-sulfoxlde was stirred at r. t. with trimethyl phosphite in methanol for 12
h. 95% R-sulfoxide and 3% alcohol 46 were recovered.

Condition 8 : The R-sulfoxide was stirred at r. t. with trimethyl phosphite in
methanol for 2 days. Alcohol 46 was the only product (> 95% ) recovered. .
Condition C : The R-sulfoxide was refluxed in methanol for one day in presence
of trimethyl phosphite, and found to be transformed quantitatively to alcohol 46,

free of alcohol 47.

Preparation of sulfenate ester 54 8nd S-sulfoxlde 55. To 0.5 mL n-
BuLi ( 1.3 M, in hexane ) diluted with 5 mL THF at -78 °C, was added a 92 mg
(0.44 mmol ) sample of alcohol 47 in 5 mL THF, and after 20 min, 0.1 mL
TMEDA. This was followed by addition of 107 mg ( 0.74 mmol ) phenyl sulfenyl
chloride in 5 mL THF. White particles ( LiCI ) formed shortly. Temperature was
warmed up—to -45 °C, at which the reaction mixture was stirred for another h.
Saturated NH4CI solution was poured to quenched the reaction. The reaction
mixture was extracted with ether. The organic layer, without being washed with
water, was dried over MgSO4. A 322 mg orange colored oil was yielded. 1H
NMR spectrum showed it to be sulfenate ester 54. On standing at r.t. for 24 h,

54 transformed entirely into a crude product of 55 (free of R isomer, as judged

85

by 1H NMR ). Flash chromatography ( eluent, ether-hexane ) gave a 88 mg
analytical gmple of S-sulfoxide 55 as an oil .

Characteristic properties of 54: 1H NMR, 7.40-7.84 ( 5H, m ), 5.17 ( 1H, s ) , 4.79
(1H, s ), 4.70 ( 1H, d,J=8 ), 3.23(3H, s ), 3.18 ( 1H, s ), 2.57 ( 1H, d, d,J1=14,
J2=9),1.13-1.79(7H,m),1.01 (8H, s ), 0.91 (8H, s).

Characteristic properties of 55: IR, 1460, 1445, 1375, 1265, 1200, 1180, 1080,
1080. 880,690; 1H NMR,7.50-7.70 ( 5H, m ), 5.57 ( 1H, s ), 8.54 ( 1H, d, B of AB,
J=15 ), 3.40 ( 1H, d, A of AB, J=15 ), 3.31 (3H, s ), 2.70 ( 1H, d J=15 ), 1.60-1.90
(7H, m ), 1.18 ( 3H, s ), 1.08 ( 3H, s ); 130 NMR, 145.0, 142.8, 181.8, 181.2,
129.5, 124.7, 83.3, 59.2, 58.0, 50.5, 49.4, 38.5, 26.8, 24.9, 23.1, 22.4, 17.6; MS,
a molecular ion was not observed. Strong fragment ions were found at 1.61

(c1ngs ), 119, 105,91, 77, 71 and 55.

Preparation of methyl sulfoxide 56. A solution of 0.08 mL Et2NH ( in 3 mL
THF ) was treated with 1.2 eq n-BuLi. To this base was added, 15 min later, a 85
mg ( 0.27 mmol ) sample of S-sulfoxide 55 in 5 mL THF. The originally light
yellow solution turned orange immediately. The reaction mixture was stirred at
-78 °C for 10 min, warmed up to - 45 °C for '5 min, then re-cooled to -78 °C. To
this bright orange solution, was added 0.1 mL TMEDA, followed,10 min late, by
addition of 0.1 mL Mel ( 6 eq ) in 3 mL THF. The solution was stirred for 5 min
then warmed to -45 °C, and white particles were observed within 20 min. The
reaction was continued for another 1.5 h, then quenched by addition of NH4CI
saturated solution. The mixture was extracted with ether. Removal of the solvent
yielded 80 mg light yellow oil. 1H NMR speCtrum of the reaction mixture showed
56 as the only product, free of other isomers. .

Characteristic properties of 56: IR, 1460, 1448, 1375, 1265, 1200, 1090, 1035,
1025, 880, 790; 1H NMR, 7.46-7.57 ( 5H, m ), 5.36 ( 1H, s ). 3.47 ( 1H, qua,

It

86

J=8 ), 8.84( 1H, s ), 8.82 ( 8H, s ), 2.75 ( 1H, d, 8:15 ), 1.42-1.82 ( 7H, m ), 1.21
(3H, s ), 1.?2(8H,d, 8:8 ), 0.95 ( 3H, s ).

Proton and deuterium quenching of conjugated base of 56. A 68 mg
(0.20 mmol ) sample of methyl sulfoxide 56 in 10 mL THF was treated with 1.2
eq EtzNLi at -78 °C for 20 min. One part of this freshly made methyl sulfoxide
anion solution was poured through side arm of a flask to an ice-cold saturated
NH4CI solution ( kinetic quenching ). To the remaining anion solution warmed
to 0 °C was added slowly acetic acid ( thermodynamic quenching ). Products
from both ways of quenching proved to be the same as starting methyl sulfoxide
56. .
A 20 mg ( 0.06 mmol ) sample of methyl sulfoxide 56 was treated with 1.2 eq
Et2NLi at -78 °C, warmed to 0 °C, then quenched with D20. Deuterated methyl
sulfoxide ( 22 mg ) was recovered after workup 1H NMR showed that the

original methyl doublet ( 1.12 ppm, J=8 ) became a singlet.

Desulfuration of S-sulfoxlde 55 under various conditions. Condition
A: To a 30 mg ( 0.09 mmol ) sample of sulfoxide 55 in 8 mL methanol was
added via syringe 0.07 mL of distilled trimethyl phosphite. The resulted solution
was stirred for 11 h at room temperature. TLC showed that a considerable
amount of sulfoxide still existed. The temperature was raised up to the b.p. of
methanol, and the reaction stirred for 24 h. Removal of the solvent gave a
product residue ( 30 mg ) which was shown to be a mixture of two alcohols 46
and 47 in ratio of 1 : 2.

Condition B: The S-sulfoxide was stirred at r.t. for 2 days. No desulfuration was

observed. Starting sulfoxide 55 was fully recovered.

87

Desulfuration of phenyl sulfenate 54. The phenyl sulfenate 54 was
O
stirred in MeOH at r.t. with trimethyl phosphite ( 3 fold ) for 31 h. Alcohol 47

(70% ) was obtained as only isomer.

Treatment of alcohol 46 and alcohol 47 respectively with trimethyl
phosphite. Alcohol 46 was stirred in refluxing methanol with trimethyl
phosphite ( 1.5 eq ) for 14 h and same alcohol (46 ) was recovered; Alcohol 47
was treated with trimethyl phosphite ( 2.5 fold ) in refluxing methanol for one

day. Only 47 was recovered.

Desulfuration of methyl sulfoxide 56. A 80 mg ( 0.24 mmol ) sample. of
methyl sulfoxide 56 in 10 mL MeOH was stirred with 0.1 mL P( OMe )3 at r.t. folr
16 h, and the reaction progress was checked by NMR: about 50% sulfoxide 56
still remained. So the sulfoxide mixture was refluxed with 0.1 mL P( OMe )3 in
10 mL MeOH for 12 h and compounds 57 and 58 (13:1 ) were the only
products recovered. In another run the methyl sulfoxide 57 was directly refluxed
in methanol with trimethyl phosphite for 12 h, high transformation ( 100 % ) and

equally good selectivity was achieved.

Preparation of dimethyl sulfoxide 65 and rearranged sulfoxide 64.
In other at -78 °C the sulfoxide 55 was treated with 2.5 eq LDA for 15 min. and
0.19 mL of IT MEDA for 10 min. To this mixture was added 15 eq methyl iodide.
The temperature was raised to -45 °C and the mixture was stirred for 1 h. After
work-up procedures, a mixture ( 173 mg ), containing 56, 65 and 64 in ratio of

2:2:1, was recovered.

1.1

88
Characteristic properties of 84: 1H NMR, 7.63-7.48 ( 5H, m ), 5.85 ( 1H, tr, J=2 ),
3.31 (3H, 5), 2.98 ( 1H, m ), 2.81 (1H, qua, 8:9 ), 1.21 (3H, s ), 0.74 ( 8H, d,
8:1 ).
Characteristic properties of 65: 1H NMR, 7.65-7.45 ( 5H, m ), 4.73 ( 1H, tr, 8:7 ),
8.80 (3H, s ), 8.17 ( 1H, s ), 2.18 ( 1H, d, d, J1=12, J2=7 ), 1.78 ( 8H, s ), 1.71
(3H,s ), 1.81 (3H, s), 0.77(3H, s ).

Preparation of methyl sulfoxide 62 from alcohol 58. Alcohol 58 (66
mg, 0.29 mmol ), was treated with 3 eq LDA, 3 eq TMEDA and 4 eq phenyl
sulfenyl chloride ( see experimental part for preparation of sulfoxide 53 or 55 ).
After work-up procedures, a crude sulfenate ester 61 ( 96 mg ) was obtained-At
r.t. on standing, 61 slowly reached an equilibrium with 62 and 56 in a ratio of
1:3:1.

Characteristic properties of 51: 1H NMR, 7.20-7.70 ( 5H, m ), 5.28 ( 1H, d, qua,
J1=8, 82:2 ), 8.29 ( 8H, s ), 2.28 ( 1H, d, d, d, J1=13, 82:8, 83:1 ), 1.85 ( 3H, d,
8:8), 1.25 ( 3H, s ), 0.65 ( 3H, 0, 8:1 ).

Characteristic properties of 62: 1H NMR, 720-770 ( 5H, m ), 5.88 ( 1H, s ), 8.29
(3H, s ), 3.15 ( 1H, s ), 3.09 ( 1H, qua, 8:8 ), 2.74 ( 1H, d, d, 81:14, 82:8), 1.32
(3H,d,J=8), 0.97 (3H, s), 0.84 ( 3H, s).

Oxidation of 13 with $802. A mixture of 0.21 mL t-butylhydroperoxide ( 90
% ) and 26.4 mg ( 0.5 eq ) $902 in 10 mL methylene chloride was slowly
dripped to a 100 mg (0.45 mmol ) sample of 13 in 10 mL CH20I2. After being
stirred for 44 h at r.t., the resulting mixture was diluted with 20 mL CH20I2 and
washed with NaOH ( 10 % 3x25 mL ), H20 ( 25 mL ), brine ( 25 mL ) and dried
with MgSO4. A 0.110 g colorless oil was obtained. 1H NMR showed that 57

89

and 58 -(- 1:5 ) were the major products ( 6-8% 59 and 60 were isolated in
another nut).

Characteristic properties of 57: 1H NMR, 5.44 ( 1H, qua, d, J1=7, 82:2 ), 4.59
(1H, d, qua, J1=9, J2=2 ), 3.27 ( 3H, s ), 3.20 ( 1H, tr, J=3 ), 2.56 ( 1H, d, d, qua,
J1=14, 82:9, J3=1 ), 1.71 (3H, d, d, 81:7, 82:2 ), 1.50-2.10 ( 7H, m ), 1.14 ( 3H,
s), 0.99 ( 3H, d, J=1 ).

Characteristic properties of 58: 1H NMR, 5.16 ( 1H, qua, d, J1=7, J2=2 ); 4.80
(1H, tr, 8:7 ), 8.81 (3H, s ), 8.19 ( 1H, tr, 8:2 ), 2.12 ( 1H, d, d, J1=12, 82:7 ),
1.74 ( 3H, d, J=6 ), 1.24 ( 3H, s ), 0.71 (3H, d, J=1 ).

Characteristic properties ot 59: 1H NMR, 5.14 ( 1H, qua, o, J1=7, 82:2 ), 4.98
(1H, d, J=9 ), 3.30 ( 3H, s ), 2.60 ( 1H, m), 1.82 ( 3H, d, d, 8127, J2=2 ), 1.02
(3H, s ), 1.00 ( 3H, d, 8:1 ).

Characteristic properties ot 60: 1H NMR, 5.51 ( 1H, qua, d, J1=7, 82:1 ), 4.45

(1, tr, qua, J1=8, Jz=1 ), 3.30 ( 3H, s ), 1.74 ( 3H, d, J=6 ), 1.35 ( 3H, s ), 0.80
(3H, d, J=1 ).

Oxidation of 57 and 58 to 66 and 67. A 110 mg ( 0.5 mmol ) crude
sample of allylic alcohols( mainly 57 and 58, 1:6) in 15 mL methylene
chloride was treated with 290 mg PDC at r.t. for 5 h. The reaction mixture was
filtered through a column of silica gel. A mixture of 66 and 67 ( 86 mg ) was
obtained in a ratio of 1:4.

Characteristic properties of 66: lFi,1740-1720 ( d ), 1650, 1450, 1375, 1200,
1128, 1080, 875; 1H NMR, 8.89 ( 1H, qua, 8:7 ), 8.27 ( 3H, s ), 8.24 ( 1H, tr,
J=3 ), 2.80 ( 1H, d, qua, J1=17, Jz=2 ), 1.72 ( 1H, d, J=17 ), 1.75 ( 3H, d, J=8 ),
1.80-2.10 ( 6H, m), 1.28 ( 3H, s ), 0.92 ( 3H, a, 8:1 ); 13C NMR, 207.8, 147.5,
126.2, 82.0, 57.6, 46.5, 44.7, 42.9, 30.0, 25.0, 23.6, 22.4, 17.5; MS, 222 ( 3 ),
207(1),175(3),163(2),149(13),135(4),121(7),107(19),85(19).

h

90

71 ( 100 ),,55 ( 39 ). High resolution MS, Cal. 222.1697 for C14H2202; Found,
222.1618. 1’

Characteristic properties of 67: mp, 67—69 °C; IR,1708, 1640, 1435, 1190, 1075,
870; 1H NMR, 5.52 ( 1H, qua, J=7 ), 3.30 ( 3H, s), 3.24 ( 1H, tr, J=2 ), 2.84 ( 1H,
d, J=18 ), 2.07 ( 3H, d, J=7 ), 1.72 ( 1H, d, J=17 ), 1.45-1.95 ( 6H, m ), 1.21 (3H,
s ), 0.92 ( 3H, (1, 8:1 ); 13C NMR, 210.2, 148.0, 127.8, 82.1, 57.8, 46.6, 42.7,
28.6, 25.8, 24.4, 22.7; MS, 222 (5), 207 ( 8 ), 190 ( 1 ), 175 ( 11 ), 182 ( 2 ),
149 (21 ), 119 ( 10), 105 ( 15), 71 ( 100), 55 ( 27); High resolution MS, Cal.
222.161971 for C14H2202; Found, 222.1636,

Isomerization of 66 and 67 mixture under various conditions.
Treatment with iodine: A 25 mg sample of 66 was heated in refluxing benzene ,
in presence of l2 ( one piece ) for one day. The product was shown to be a
mixture of 66 and 67 in ratio of 1:1.

Treatment with base: A 25 mg sample of 67 was treated with KOH in refluxing

methanol over night to transform to a mixture of 66 and 67 in ratio of 1:1.

Reduction of enones 66 and 67, To 1.0 mL methanol solution of
CeCl3.H20 ( 149 mg ) was added a 86 mg ( 0.39 mmol ) sample of unsaturated
ketones 66 and 67 ( 1 : 4 ) and followed, after 5 min, addition of 12 mg of
NaBH4. H2 was evolved rapidly. The reaction mixture was stirred at r.t. for 10
min., then poured into water which was extracted with ether. A product mixture
(71 mg ) was obtained after work-up. The mixture was judged by 1H NMR to
be:67((45%),66(5°/o),59(20%),57(10%).

Preparation of 70. To 258 mg CuBr.Me2s (4 eq ) in 8 mL other at -78 °C,
was added slowly 1.03 mL ( 2.2 M, in hexane ) of n-BuLi to give a light yellow

91

precipitate, The reaction was warmed to -45 °C ( chlorobenzene/C02 cooling
bath ) andztirred for a few seconds when the initial yellow solid turned snow
white. This mixture turned brown then grayish within a period of 5 min. At this
point, a 62 mg ( 0.28 mmol ) sample of enone 67 in 3 mL THF was slowly
added. The mixture, turning dark quickly, was stirred at -45 °C for 30 min., then
warmed to -15 °C and stirred for another 30 min. The reaction was quenched
and the resulting mixture was extracted with ether. The organic layer was
diluted with ether and filtered through silica gel. Evaporation of the solvent gave
85 mg 70 as an oil. Base treatment of 70 with NaOMe/HOMe did not result in
new isomer. Flash chromatography gave 50 mg analytical sample.
Characteristic properties of 70: 1H NMR, 8.22 ( 3H, s ), 8.15 ( 1H, s ), 2.60 ( 1H,
d,J=18),1.09(3H,s),1.01(3H,d,J=6),1.00(3H,s);

Preparation of 4-methyl-3-pentenyl lithium. A 2.0 mL mineral oil slurry of
lithium powder ( 25 % v/v; sodium content, 1% ) was washed three times with
pentane and blown to dryness by argon. To this, was added 7 mL ether and
followed by addition of 20 drop of 5-bromo-2-methyi pentene 73 other solution
(prepared by mixing 7.0 g bromide with 35 mL ether). The material was stirred
for 10 min. and cooled to -20 °C, and rest of the bromide solution was dripped
slowly over 2 h. The cloudy, light yellow mixture was warmed to -15 °C and
stirred for another 2 h. Up to 20 mL ether was added and the resulting mixture
was stirred for an additional hour at 0 °C. The aliquot was taken to be titrated,
and found 0.22 M.

Preparation of 75. To 208 mg snow white CuBr.Me2s in 8 mL ether at -78
°C, was added 4.9 mL 4-methyl-3-pentenyl lithium. This mixture was stirred for 5

min. and then warmed to -45°C (controlled by amount of dry ice in the acetone

92

cooling bath ). The slight pink solution, turning slowly to light brown, was re-
cooled to 38 °C and treated with 50 mg ( 0.23 mmol ) enone 12 in 3 mL other.
This was again stirred, at -45 °C for 1.5 h and at -20 °C for 1 h, and quenched
by addition of saturated NH4Cl solution. The resulting mixture was extracted
with ether. The ether extracts were dried over MgSO4. The solvent was
removed to give 90 mg oil as a mixture of isomers. Base treatment
( KOH/HOMe ) 0f the mixture resulted in a single isomer 75. Analytical sample
.( 38 ) mg was chromatographicaily prepared.

Characteristic properties of 75: IR, 1725, 1449, 1870, 1080, 860; 1H NMR, 5.09
(1H, tr, 8:5 ), 3.30 ( 3H, s ), 8.22 ( 1H, s ), 2.87 ( 1H, d, 8:21 ), 2.20-2.88 ( 2H,
m), 2.10 ( 1H,d, 8:5 ), 1.25-1.90 ( 10H, m ), 1.89 ( 3H, s ), 1.61 (3H, s ), 1.15
(3H, s ), 1.09 ( 3H, d, 8:8 ), 1.07 ( 3H, d, 8:1 1; 13C NMR, 219.9, 180.8, 124.8,
83.2, 61.1, 57.7, 46.3, 44.3, 43.0. 37.1, 30.9, 30.1, 25.7, 25.5, 24.0, 22.6, 18.7,
18.2, 17.4.

Reduction of 75 to 76. A 16 mg ( 0.05 mmol ) sample of ketone 25 in 3 mL
THF was stirred with 0.5 mL ( 0.1 M ) LiAlH4 ( in THF ) at 0 °C for 40 min and
then the reaction was quenched with water. The mixture was diluted with both
water and ether. The ether extracts were combined, which were washed with
H20, brine, and dried over MgSO4. Evaporation of ether yielded 20 mg 76 as
the only product. Analytical sample ( 13 mg ) was obtained by
chromatographic purification ( eluent, ether/hexane ).

Characteristic properties of 76: 1H NMR: 5.09 ( 1H, s ), 4.48 ( 1H, d, o, J1=12,
82:7 ), 8.80 ( 3H, s ), 3.14.( 1H, s ), 1.88 ( 3H, s ), 1.80 ( 3H, s ), 1.17 ( 3H, s ),
1.01 (3H, d, J=7 ), 0.83(3H, 5); MS: 293 ( 9 ), 276 ( 1 ), 259 ( 1 ), 181 (23 ),
149( 100).

93

Deoxygenation 75 to 17. To 2.2 mL triethylene glycol solution of ketone 75
( 88 mg, 031 mmol ), was added 0.282 mL H2N4.H2C (80 % ), followed by
addition of 232 mg K2C03. The mixture was heated to 165 °C for 1.5 h. Then
water condenser was replaced by a distillation head. The mixture was heated to
220 °C for 10 min. At this time, water beads were formed on the inside of
distillation head which, after being cooled, was rinsed with hexane into the
reaction vessel to reduce possible loss of compound 17. The remaining
moisture ( hexane didn't remove the water beads ) on the distillation head was
rinsed out with MeOH. The one-piece distillation apparatus was put back to the
flask and the reaction mixture was heated to 220 °C for another 10 min. When
the water beads appeared on the inside of distillation head again, the reaction
mixture was cooled, and the apparatus rinsed with hexane and methanol in the
same way as described above. This process was repeated four or five times till
no water beads condensed upon heating to 220 °C. The water condenser, used
previously, was re-instailed. The reaction mixture was stirred for 10 h at
220-230 °C. The originally colorless solution turned dark brown. The cooled
mixture was partitioned between 15 mL hexane and 35 mL 4N HCl. The organic
layer was washed with water, NaHC03 ( 0.5 M ) and brine. The solvent was
removed to yield 38 mg light yellow oil. Analytical sample of 17 ( 25 mg ) was
prepared by passing the crude oil through silica gel with hexane as an eluent.
Characteristic properties of 17: 1H NMR, 5.09 ( 1H, tr, 8:8 ), 8.28 ( 3H, s ), 8.17
(1H, s), 1.87 ( 3H, s ), 1.60 ( 3H, s ), 1.00 ( 3H, s ), 0.86 ( 3H, s ), 0.85 ( 3H, d,
:5 ); 13C NMR, 130.8, 125.8, 85.5, 57.7, 51.0, 48.9, 48.9, 85.4, 34.8, 88.4,
30.0, 29.2, 26.9, 25.7, 24.8, 23.6, 23.2, 18.9, 17.8, 16.6; MS ( 25 ev ), 292 ( 1 ),
277 ( 4 ), 280 ( 20 ), 179 ( 28 ), 147 (58 ), 122 ( 100 ), 107 ( 52 ), 71 (80 ), 55
(11 ); High resolution MS, Calculated for Con350, 292.27660. Found,
292.2759.

94

Preparation of 3-methyl butyl bromide 80, 4-methyi pentyl bromide and
5-methyi.h.gxyl bromide 83 from the corresponding alcohols: see Org. Syn, Col.
ll, P246 and Laboratory Notebook lV, p.22, p.18, and p.26; Condensation of
80 with diethyl molanate: see Org. Syn, Col. II, R474 and Laboratory Notebook
IV, R23; Reduction of acid 81 to alcohol: see R. F. Nystrom and W. G. Brown,

MW

Preparation of lso-heptyl triphenyl phosphonium bromide 84. A
mixture of 44.0 g ( 0.168 mol ) triphenyl phosphine and 28.5 g ( 0.16 mol )
isoheptyl bromide 83 was refluxed in 50 mL benzene for 12-15 h, then cooled
slowly to 0 °C. The thick liquid solidified on standing over a period of 1 h. The
crude product was triturated in 265 mL ether-ethanol system ( 17:1 ) at r.t., and
filtered, to give 65.8 g ( 93.4% ) white crystal.

Characteristic properties of 84: mp, 226-227 °C; 1H NMR, 7.7-7.9 ( 15H, m l.
3.73 ( 2H, br. s ), 1.45 ( 1H, m, J=6 ), 0.80 ( 6H, d, J=6 ).

Olefination of 6 with isoheptyl triphenyl-phosphonium bromide. A
31.5 g (0.072 mol ) sample of isoheptyl triphenylphosphonium bromide 84
was treated with 68 mL 0.94 M potassium t-amylate in toluene at 80 °C for 40
min. and at 110 °C for 30 min. To this red-Colored mixture was added a 2.4 g
(0.012 moi ) sample of methoxy ketone 6 in 20 mL solvent. The reaction
mixture was stirred for four days, then cooled and checked by TLC. A large
amount of starting ketone 6 was still found. The dark solution was neutralized
with 48% HBr to recover some Wittig salt. The solid salt was separated out by
suction filtration and rinsed with ether. The filtrate was distilled under vacuum till

all toluene was removed. Chromatographic separation yielded 1.55 9 sample

95

which was.shown to be a mixture of triphenyl phosphine oxide and the olefins

86 and 87 {4:1 :1 ). A 1.26 9 starting ketone was also recovered.

Oxidation of olefins 86 and 87 with 8e02. The crude sample of the
olefins ( 1.55 g, 3.58 mmol ) was treated with Se02 ( see preparation of 46 ) for
3 days. Flash chromatography gave 88 ( 11 mg ), 89 ( 74 mg ), 90 ( 14 mg ),
and 91( 74 mg ). 147 mg starting ketone was also recovered. The total yield of
the ketones and alcohols was calculated to be 48%, based on starting olefin
content in the crude starting material.

Characteristic properties of 88, IR, 8595, 1450, 1870, 1175, 1000, 875; 1H
NMR, 5.08 ( 1H, tr, 8:7 ), 4.47 ( 1H, tr, 8:8 ), 8.81 (3H, s ), 8.20 ( 3H, s ), 2.80-
1.15 ( 17H, m ), 1.28 (3H, s ), 0.87 ( 6H, d, J=7 ), 0.72 ( 3H, s ); MS, 294, 276
(2),262(1 ),245(1 ),177(21),159(38),71 (100).

Characteristic properties of 89, lR, 8800, 1480, 1875, 1080, 875: 1H NMR, 5.91
( 1H, tr, J=8 ), 4.46 ( 1H, tr, J=8 ), 3.30 ( 3H, s ), 3.18 ( 1H, br. s ), 2.30-1.20 ( 17H,
m ), 1.35 (3H, s ), 0.88 ( 6H,d, 8:7 ), 0.79 (3H, s ); MS, 294, 278 (5 ), 282 ( 2)
245(8),229(8),187(10),177(20),159(38),135(17),121(23),71
(100 ).

Characteristic properties of 90, IR, 1715, 1649, 1460, 1120, 1075, 875; 1H
NMR, 5.4 ( 1H, tr, 8:8 ), 3.30 ( 8H, s ), 8.25 ( 1H, br. s ), 2.84 ( 1H, d, d, J1=18,
J2=1 ), 2.60 ( 2H, m), 1.72 ( 1H, d, J=18 ), 1.21 (3H, s), 0.94 ( 3H, d, J=1 ),
0.86(6H, d,J=7 ); MS, 292(18), 277(100 ), 261 (2), 245(13), 227(3), 217
(8),203(5),175(12),161(14),147(15),91(20),70(70),55(36),43
(70 ).

Characteristic properties of 91, lR, 1708, 1640, 1445, 1360, 1075, 870; 1H
NMR, 6.35 ( 1H, tr, J=8 ), 3.30 ( 3H, s ), 3.26 ( 1H, br. s), 2.85 ( 1H, d, J=17 ),
1.73 ( 1H, d, J=17 ), 1.30 (3H, s),0.95(3H, s), 0.86 ( 6H, d, J=6 ); MS, 292

96

(12), 27].( 23), 261,245(5), 235(1 ), 219(6), 207(10), 175(25), 161
(9),147(!6),105(15),91 (21 ),79(20),71 (100),55(31),43(58).

Reduction of 18 with Zn. A 400 mg ( 1.17 mmol ) sample of the off-white
solid 18 was stirred in a HOAc-H20 ( 2:1 ) system with 200 mg Zn powder
(3.13 mmol ). The trione 18 did not dissolve at beginning, but slowly went into
solution after 30 min. Following a period of two hours, t.l.c. test was done,
showing that the starting material was totally consumed. The solution was
filtered and the filtrate was extracted with ether. The organic solution was
washed, in turn, with water, saturated NaHC03 solution, brine, and dried over
MgSO4. A white solid ( 375 mg ) was obtained after evaporation of solvent.
Flash chromatography gave 214 mg 92 and 93 ( 3:1 ). . .
Characteristic properties of 92: mp, 289-290 °C; IR, 3600, 1735, 1668, 1620,
1462,1438,1225;1H NMR, 5.28 ( 1H, m ), 5.18 ( 1H, s ), 4.98 ( 1H, d, 8:4 ),
8.78 ( 3H, s ), 1.32(3H, s ), 1.30 ( 3H, s ), 1.03(3H, s ); 130 NMR, 218.2, 202.1,
170.5, 144.0, 117.4, 100.6, 77.2, 68.7, 56.1, 50.9, 48.6, 46.8, 46.4, 43.2, 34.3,
30.9, 25.4, 24.8, 24.5, 23.4, 21.8, 18.5; MS, 344 ( 27 ), 329 ( 6 ), 314 ( 21 ), 299
(11 ), 284(11 ), 257 ( 15), 215(60 ), 190(43), 43( 100 ).

Characteristic properties of 93: mp, 162-165 °C; lR, 1735-1725, 1605,
1250-1200, 910; 1H NMR, 5.29 ( 1H, s ), 4.28 ( 1H, d, d, J1=8, 82:10 i. 8.52 (
3H, s ), 1.32 ( 3H, s ), 1.28 (3H, s ), 1.02 ( 3H, s ); 13C NMR, 219.5, 208.0,
206.0, 144.8, 114.0, 77.7, 58.9, 56.5, 50.6, 50.5, 46.9, 44.5, 42.0, 34.2, 31.2,
26.9, 24.9, 24.1, 23.7, 17.8.

Preparation of mesyl derivative 105 from 92. To a solution of 150 mg
(0.44 mmol ) alcohol 92 in 10 mL pyridine at 0 °C, was added 0.1 mL ( 1.3

mmol) methanesulfonyi chloride. The mixture was stirred at 0 °C for 3.5 h, then

97

solvent was pumped out. The residue was diluted with methylene chloride,
which wasfivashed three times with water and once with brine. The organic
layer was dried over NazSO4. Evaporation of the solvent left 152 mg ( 89% )
light yellow solid. Analytical sample was prepared by recrystaliz‘ation from ethyl
acetate.

Characteristic properties of 105: mp, 147-150 °C; IR, 2900-3000, 1750, 1680,
1640, 1325-1400, 1225, 1180, 750; 1H NMR, 5.75 ( 1H, d, J=5 ), 5.22 ( 1H, m ),
5.15 ( 1H, s ), 3.69 ( 3H, s ), 8.09 ( 3H, s ), 1.80 ( 3H, s ), 0.94 ( 3H, s ); 13C NMR,
219.3, 200.5, 165.8, 144.3, 116.8, 102.6, 78.0, 56.6, 50.8, 49.3, 46.8, 42.9, 38.9,
34.4, 31.0, 25.6, 25.0, 24.8, 23.4, 22.0, 18.3; MS, 423 ( 2 ), 422 ( 4 ), 343, 326,
311,233(46),154(100),119(16),105(19).

Preparation of enediones 106 and 107. To a 190 mg ( 0.45 mmol )
sample of mesylate 105 in 12 mL glyme were added 450 mg Nal and 500 mg
Zn. This mixture was refluxed for 8 h. TLC showed three new spots but no
starting material. This mixture was cooled and filtered through a short column of
silica gel. The filtrate was diluted with other, then washed with water and brine.
The organic layer was dried with magnesium sulfate. Removal of the solvent
yielded 110 mg oil which slowly solidified on standing. Crystalization brought
about 54 mg ( 38 % ) pure product 106 and 20 mg 107.

Characteristic properties of 106: mp, 172-174 °C; lR, 3000-2850, 1750, 1670,
1825, 1875,-1210, 1190, 1175, 900, 800-700; 1H NMR, 5.20 ( 1H, s ), 5.10 ( 1H,
s ), 3.66 ( 3H, s ), 1.28 ( 3H, s ), 1.44 ( 3H, s ), 1.01 (3H, s ); 13C NMR, 220.2,
202.9, 172.7, 144.5, 117.0,100.6, 55.5, 50.8, 46.7, 46.6, 42.9, 39.9, 34.3, 33.0,
30.8, 30.1, 25.4, 24.8, 23.3, 22.0, 18.7; MS, 329 ( 3 ), 328 ( 2 ), 311 ( 6 ), 295,
284,267, 253, 215 ( 10), 139 ( 100).

98

Characteristic properties of 107: mp, 165-167 °C; IR, 1748, 1670, 1625, 1375
(doublet )21208, 1195, 1175, 908, 725; 1H NMR, 7.88 ( 1H, qua, J=3 ), 8.11
(1H,d, J=5), 5.42 (1H, br. s), 2.88 ( 1H, s), 2.75-1.5 ( 14H ), 1.24 (3H, s),
0.81 (3H,s), 0.79 (3H,s); MS, 284(28 ), 269(5), 189(56 ), 171 (12), 145
(52),188(88),119(40),105(54),91(78),77(55),85(88),55(100),
41 (90).

Stannic chloride catalyzed Dials-Alder reaction of enone 108 with
diene 109 to give adduct 110. To a sample of 94 mg ( 0.52 mmol ) methyl
carboxyiate enone 108 in 3 mL deuterated chloroform, was added 0.061 mL
freshly distilled stannic Chloride, followed by addition of 100 mg ( 0.53 mmol )
diene 109. The resulting mixture was stirred at r.t. for 4 h. TLC indicated that

most diene 109 still remained. The mixture was warmed to 50 °C and stirred for'

overnight. The reaction was quenched with water and 1.5 g product mixture was
recovered. Chromatographic separation of this mixture gave 110 ( 10 mg ) and
111 (90 mg).

Characteristic properties of 108:1H NMR, 7.8 ( 1H, d, J=3 ), 8.85 ( 1H, d, d,
J1=10, J2=3 ), 6.21 (1H, d, J=10 ), 3.88 ( 3H, s ), 1.37 ( 6H, s ).

Characteristic properties of 110: 1H NMR, 8.22 ( 1H, d, 8:10 ), 5.9 ( 1H, d,
8:10), 5.28 ( 1H, s), 8.74 (3H, s), 2.95 ( 1H, br.s ), 2.85-1.5 ( 11H ), 1.20 ( 3H,
s ), 1.15(3H, s),1.10 ( 3H, s), 1.00(3H, 3); MS, 370(5 ), 310 ( 13), 241 (3),
181(85),1__49(100),139(40),96(53).

Characteristic properties of 111: 1H NMR, 7.18 ( 1H, d, 8:8 ), 8.70 ( 1H, d, 8:8 ),
3.90 (3H, s), 2.38 ( 3H, s), 2.01 (3H, s ),

Preparation of alcohols 112 and 113. To a 50 mg ( 0.146 mmol ) sample
of trione 18 in 10 mL THF solution at -78 °C was added 3 eq methyl magnesium

bromide ( in ether). This mixture was stirred and slowly warmed to r.t. through a

18

99

period of 7 h, then poured into 10 mL sat. ammonium chloride. The organic
layer we; .diluted with methylene chloride, washed with water and brine, and
dried. Evaporation of the solvent yielded 55 mg crude product as a light yellow
solid. The mixture was shown by NMR to be 112 and 113 in ratio of 10:1. Flash
column chromatography gave 40 mg of 112 and 113 and an unknown ( non
u.v. sensitive ) product ( 8 mg ). The methylation of 18 with methyl lithium ( -78
°C, 1 day, 8 eq MeLi, 8 eq TMEDA, THF ) gave a 1:1 mixture of 112 and 118' in
90%-95% yield.

Characteristic properties of 112: mp, 210 °C; lR, 3585, 1735, 1660, 1620, 1450,
1223,1160,1100,900;1H NMR, 5.32 ( 1H, s ), 5.17 ( 1H, s ), 3.75 ( 3H, s), 1.74
(3H, s), 1.41 (3H, s ), 1.17(3H, s), 1.00 ( 3H, s); 13C NMR, 220.2, 202.4,
172.5, 143.0, 117.8, 99.9, 73.1, 55.0, 51.3, 50.6, 46.6, 42.6, 34.3, 30.7, 29.6:
26.7, 25.8, 24.8, 23.3, 19.0; MS, 297, 215, 187, 169 (60 ), 137 (100 ).
Characteristic properties of 113: mp, 235-237 °C; IR, 3583, 1735, 1660, 1618,
1480, 1225, 1170, 1050, 875; 1H NMR, 5.22 ( 1H, br. s ), 5.10 ( 1H, s ), 8.72
(3H, s ), 1.59 ( 3H, s ), 1.45 ( 3H, s ), 1.18 ( 3H, s ), 1.05 ( 8H, s ); 13c NMR,
220.3, 170.9, 144.1, 116.4, 99,9, 74.2, 56.0, 50.1, 48.9, 46.6, 42.9, 34.3, 30.8,
28.6, 26.0, 25.8, 25.6, 24.8, 23.3, 18.6; MS, 213, 187, 169 ( 57), 153 ( 15 ), 137
(100 ), 123(11 ), 105(11.5 ), 91 (6.8 ).

Preparation of dlol 131. To 10 mg ( 0.26 mmol ) lithium aluminium hydride
in 5 mL THE at 0 °C was added a 33 mg ( 0.092 mmol ) sample of alcohol 18 in
5 mL THF. The mixture was reacted for 4 h, then quenched with 3 mL water. The
water solution was extracted with ether. The ether extract was washed with
brine and dried with magnesium sulfate. Crude product 131 ( 29 mg, 87% )

was obtained.

100

Characteristic properties of 131: mp, 190-192 °C; IR, 3600, 3000-2850, 1670,
1820, 1460.,1230, 1220, 1100, 900; 1H NMR, 5.20 ( 1H, br. s ), 5.10 ( 1H, s ),
3.76 ( 1H, d, J=9 ), 3.70 ( 3H, s ), 1.69 ( 3H, s ), 1.39 ( 3H, s ), 1.27 ( 3H, s ), 0.78
(3H, s )‘; 13C NMR, 202.8, 172.8, 148.5, 118.5, 100.8, 79.8, 78.1, 56.0, 51.2,
49.6, 48.9, 46.5, 43.0, 35.1, 33.4, 29.8, 27.8, 26.6, 25.5, 25.4, 19.7; MS, 361,
848, 827, 299, 215, 189 ( 89 ), 137 ( 100 ), 105 ( 21 ), 48 ( 98 ).

Preparation of epimeric dlois 114 and 115 from 112. A 422 mg ( 1.2
mmol ) sample of dione 112 in 10 mL methylene chloride was treated with 12
mL solution ( 1.0 M ) of diisobutyl aluminium hydride ( DIBAL ) for 14 h. at 0-25
0C, then the mixture was poured to aqeous potassium sodium tartrate. The
colloidal residue was filtered. The filtrate was extraCted with methylene chloride. _
The filtering funnel was rinsed with 20 mL hot methanol which was combined
with the methylene chloride extract. The organic layer was washed with water,
brine and dried over magnesium sulfate. A 545 mg mixture ( sticky solid ) was
recovered after evaporation of the solvent. This solid was dissolved in a 50 mL
THF-H20 ( 4:1 ) system to which was added 6-8 drops conc. hydrochloric acid.
The solution was stirred overnight at r.t., then diluted with water and extracted
with methylene chloride. The organic layer was washed with water, brine and
dried over magnesium sulfate. Evaporation of the solvent yielded 424 mg crude
product ( solid foam ) which was subjected to chromatographic separation
(ether-hexane as an eluent ), giving 286 mg of both 114 and 115 in ratio of
2:1.

Characteristic properties of 114: mp, 134-135 °C; IR, 3605, 3510-3490, 3000-
2870, 1675, 1450, 1375, 1240, 1150-1100, 1040, 880, 820; 1H NMR, 6.99 ( 1H,
d, J=10 ), 5.94 ( 1H, d, J=10 ), 5.18 ( 1H, m ), 3.79 ( 1H, d, J=7 ), 1.47 ( 3H, s ),
1.35( 3H, s), 1.17 ( 3H, s), 0.78 ( 3H, s ); 13C NMR, 208.1, 158.8, 147.2,

101

125.8, 11.8.3, 79.6, 75.9, 50.2, 48.6, 47.1, 45.1, 42.1, 84.2, 88.4, 81.8, 26.5, 25.4,
25.1, 24.6,;233, 18.0; MS, 330, 812, 297, 287 ( 1 ), 289 (8 ), 241, 225, 209,
192, 174(8), 159 (18), 105(23 ), 48 (100 ).

Characteristic properties of 115: mp, 119-122 °C; lR, 3605, 3580-3460, 2900-
2880, 1880, 1450, 1375, 1080; 1H NMR, 6.61 (1H, d, d, J1=10, 82:1 ), 5.97
(1H, d, J=10 ), 5.27(1H, m ), 4.10 ( 1H, d, d,J1=9, 82:7 ), 3.76 ( 1H, m ), 1.52
(3H, s), 1.41 (8H, s), 0.86 ( 3H, s ), 0.74 (8H, s ), 13C NMR, 208.1, 153.7,
148.4, 125.7, 118.9, 80.1, 75.9, 50.1, 47.9, 44.8, 42.2, 82.4, 81.8, 30.8, 29.4,
25.2, 24.7, 28.4, 19.0, 17.7; MS, 330, 287, 289 ( 1 ), 215, 192 ( 10 ), 117 (9 ),
149(10),133(11),121(16),105(20),91(17),69(11),55(28),43
(100 ).

Oxidation of 114 and 115. To a 219 mg (0.66 mmol ) sample oi diol ( 114
and 115) in 20 mL methylene chloride was added 214 mg ( 1.5 eq. )

pyridinium chlorochromate ( PCC ). The brown mixture was stirred at r.t. for 5 h.

then filtered through a short column of silica gel. Removal of the solvent of the

filtrate gave a brown oil ( 188 mg ). Chromatographic separation gave 150 mg

(69% ) pure 118.

Characteristic properties of 118: mp, 141-143 °C; UV, kmax=234, 8:9.3x103;

IR, 3500-3480, 1735, 1680, 1115, 1085; 1H NMR, 6.45 ( 1H, d, J=10 ), 6.03,

(1H, d, J=10 ), 5.45 ( 1H, m ), 3.75 ( 1H, s), 1.58 ( 3H, s ), 1.45 ( 3H, s ), 0.92

(8H, s ), 087 ( 8H, s ); 130 NMR, 220.0, 202.8, 152.9, 148.8, 125.8, 120.8,

75.9, 51.0, 50.0, 45.9, 44.7, 41.9, 34.2, 31.6, 29.8, 25.1, 24.6, 24.2, 23.5, 22.5,

17.4; MS, 828 ( 1.5 ), 313, 895, 285(5), 267 (1 ), 227, 190 ( 18), 175 ( 18),

139(24), 121 (30 ), 105 ( 19 ),43(100 ).

Preparation of epimeric dlols 116 and 117 from 113. A 317 mg ( 0.885

mmol ) sample of 113 in 10 mL methylene chloride was treated with 9 mL

102

DIBAL (4 .0 M ) at 0 °C for 12 h. The mixture was then poured to saturated
potassiumgodium tartrate solution. The resulted colloidal mixture was filtered
by suction. The filtering funnel (containing the colloidal solid ) was rinsed with
hot methanol to same filtering flask. The filtrate was diluted. with water and
extracted with methylene chloride. Removal of the solvent gave a 467 mg sticky
solid. Acid hydrolysis of this product ( stirring in 25 mL THF-H20 system [ 4:1 ]
with 6 drops conc. HCI ) gave, after work-up procedures, a 317 mg solid
product. Chromatographic separation of the product yielded 135 mg 116 and
59 mg 117.

Characteristic properties of 116: mp, 198-1995 °C; IR, 3600, 3500-3470, 3020-
2830, 1670, 1665, 1600, 1450, 1380, 1240, 1200, 1100, 1040, 1000, 850, 830.;
1H NMR, 7.00 ( 1H, d, J=10 ), 5.97 ( 1H, d, J=10 ), 5.21 (1H, m ), 4.19 ( 1H, d,
8:8 ), 1.48 (3H, s ), 1.87 (3H, s), 1.18 ( 3H, s ), 0.80 ( 3H, s); 130 NMR, 200.5,
154.8, 147.3, 126.6, 117.8, 79.5, 76.6, 49.2, 48.2, 46.5, 42.6, 40.5, 34.7, 33.3,
27.6, 27.5, 27.4, 27.1, 25.1, 24.8, 18.5; MS, 330, 315, 297, 287, 269 ( 1 ), 218,
192(6),159(18),145(6),121(10),105(20),43(100).

Characteristic properties of 117: mp, 1915-1925 °C; IR, 3600, 3500-3450,
1670, 1855, 1450, 1880, 1080, 1040, 880; 1H NMR, 6.96 ( 1H, d, d, J1=10,
J2=2 ), 5.94 ( 1H, d, J=10 ), 5.15 ( 1H, m ), 4.12 ( 1H, d, d, J1=7, J2=6 ), 1.46
(3H, s ), 1.36 ( 8H, s), 1.00 (3H, s ), 0.88 ( 3H, s ); 13C NMR, 200.4, 154.6,
146.5, 126.7, 118.1, 80.4, 76.6, 48.5, 48.1, 44.1, 42.3, 40.5, 33.1, 30.7, 29.7,
27.7, 27.1,-26.8, 25.1, 19.9, 18.2; MS, 330, 287, 259, 241, 192 ( 9 ), 177 ( 4 ),
159(6),149(9),105(16),55(28),43(100).

Swern oxidation of 116 and 117 to 119. To a 10.3 mL methylene
Chloride solution of oxalyl chloride ( 0.44 M ) cooled at -78 °C, was added a

methylene chloride solution of dimethyl sulfoxide. The reaction mixture was

103

stirred forgo min. and turned cloudy. At this point, a 416 mg ( 1.26 mmol )
sample ofgliols in 20 mL methylene chloride was slowly added. The reaction
was quenched after 30 min. by addition of 2.0 mL triethyl amine (TEA ). A 470
mg crude product was recovered. Flash chromatography gave 300 mg ( 73 % )
pure product 119.

Characteristic properties of 119: mp, 199-201 °C; IR, 3580, 3460, 2980-2890,
1730, 1670-1650, 1450, 1410, 1380, 1110, 1080, 1030, 1000, 830; 1H NMR,
6.97 ( 1H, d, d, J1=10, Jz=2 ), 5.97 ( 1H, d, J=10 ), 5.34 ( 1H, m ), 1.48 ( 3H, s ),
1.88 ( 3H, s ), 1.03 ( 3H, s), 1.00 ( 8H, s ); 13C NMR, 219.3, 199.9, 158.8,
143.5, 126.7, 119.2, 76.2, 50.3, 47.9, 46.0, 42.3, 40.2, 34.0, 30.2, 27.4, 26.7,
26.4, 24.8, 24.2, 22.9, 17.8; MS, 828 ( 1 ), 818, 295, 285 (2), 267, 257, 227,
208, 175(12.7 ), 121 (16), 105(18), 91 (20 ), 55(22 ), 43(100 ). °

Zinc reduction of 119 to 120. A mixture of 93 mg ( 0.28 mmol ) sample of
119, 294 mg ( 4.6 mmol ) zinc and 25 mL galcial acetic acid was refluxed for 12
h when white particles ( ZnO ) was formed. The mixture was then chilled and
filtered, and the filtrate was diluted with water. The aqueous solution was
extracted with methylene chloride. The organic layer was washed with water,
sodium bicarbonate solution and brine, and dried over magnesium sulfate.
Evaporation of the solvent gave 108 mg white solid. Flash chromatography
yielded 78 mg ( 88% ) 120.

Characteristic properties of 120: mp, 149.5—150.5 °C; IR, 3020-2850, 1735,
1885, 1470, 1415, 1400, 1880, 820; 1H NMR, 8.88 ( 1H, d, d, J1=10, 82:2 ),
5,86 ( 1H, d, J=2 ), 5.38 ( 1H, m ), 3.10 ( 1H, d, q, 81:4, 82:7 ), 1.30 ( 3H, s ),
1.14 ( 3H, d, J=7 ), 1.04 ( 3H, s ), 1.00 ( 3H, s ): 13C NMR, 219.8, 201.8, 150.7,
143.2, 129.0, 120.6, 50.5, 46.2, 45.9, 42.5, 42.1, 39.7, 34.1, 30.4, 26.7, 25.7,
24.8, 28.8, 28.1, 17.9, 12.1; MS, 814 (1 ), 297 ( 2 ), 255 ( 2 ), 241 (2 ), 218 (2),

104

190(88), 175(88), 157(28), 188(40 ), 128 ( 100 ), 105(828), 91 (49 ), 79
(4e ). ‘ Z.

Hydrogenation of 120 to 121. To a 37 mg ( 0.12 mmol ) sample of
enedione 120 in 10 mL ethanol ( 95% ) was added 16 mg powder of Pd/C
(5% ). The black mixture was purged with H2 three times, and stirred under
hydrogen ( 1 atm ) for 2.8 h. The reaction mixture was filtered, and the filtrate
was evaporated to give white 33 mg ( 89% ) product of 121.

Characteristic properties of 121: mp, 160-163 °C; lR, 2980-2880, 1730, 1700,
1460, 1880.890; 1H NMR, 5.36 ( 1H, m ), 8.02 ( 1H, m), 1.85 ( 3H, s ), 1.08
(3H, s), 1.00 ( 8H, d, 8:7 ), 0.85 ( 3H, s ); 13c NMR, 219.5, 218.8, 142.2,
117.8, 50.5,47.8, 56.5, 44.5, 37.7, 35.5, 34.2, 30.7, 27.0, 26.2, 25.3, 24.7, 23.6.
28.2, 28.8, 11.7; MS, 315(7), 314(31 ), 299(7), 281 (8), 257(4), 230(6),
211(14),190(11),175(20),171(18),145(12),158(55),119(100).
105(57),91 (36), 79(23),67(24),55(64).

Preparation of ketai derivatives 122 and 123 from dlone 121. A
mixture of 31 mg ( 0.1 mmol ) of dione 20, 30 mL toluene, 3 mg of p-toluene
sulfonic acid (pTSA ), and 0.61 mL ( 8.8 mmol ) ethylene glycol was refluxed for
8 h, then chilled and diluted with methylene chloride. The organic layer was
washed with sodium bicarbonate, brine and dried with magnesium sulfate.
Evaporation of the solvent gave 39 mg product from which 19 mg ketai
derivative 122 and 10 mg 123 were isolated.

Characteristic properties of 122: IR, 2985-2850, 1735, 1480-1430, 1380, 1180,
1050, 930; 1H NMR, 5.39 ( 1H, s ), 4.05-3.73 ( 4H, br.s ), 1.08 ( 3H, s ), 1.05
(3H, s ), 0.95 ( 3H, s ), 0.87 ( 3H, d, 8:7 ); 130 NMR, 220.2, 140.4, 119.2,

105
111.2, 65.5., 63.7, 50.7, 46.4, 44.5, 44.4, 37.3, 35.2, 34.3, 31.6, 30.7, 26.7, 24.8,
23.6, 23.5.1330, 18.0.
Characteristic properties of 123: 1H NMR, 3.96 ( 4H, br. s ), 2.50-1.20 ( 18H ),
0.98 ( 3H, s ), 0.94 ( 3H, s ), 0.91 (3H, d, J=9 ).

Acid-Induced conversion of 118 to 124. To a 11 mg ( 0.03 mmol ) sample
of 118 at -5 °C was added 15 drops of conc. sulfuric acid. The original light

yellow compound turned brown quickly. This mixture was stirred at same

temperature for 7 min. then quenched with a piece of ice. The diluted aqueous ,

layer was extracted with methylene chloride. The organic extract was washed
with H20, brine and dried with magnesium sulfate. A 8.5 mg product ( 77% ) of
124 was obtained. Analytical sample was prepared by Flash chromatography. .
Characteristic properties of 124: mp, 138 °C; UV, Kmax = 234, €=2.3x103; 1H
NMR,'6.83 ( 1H, d, J=9 ), 6.08 ( 1H, d, J=9 ), 1.50 ( 3H, s ), 1.40 ( 3H, s ), 1.05(
3H, s), 1.00 (8H, s); MS, 829(1 ), 828 ( 10 ), 233(5), 207(25 ), 198(19),
148(92), 136 ( 100).

Birch reduction of 118 and 124. To a dry flask containing 45 mg Li ( 6.4
mmol ) at -78 °C, was condensed 15 mL ammonia ( dried by refluxed with
sodium for 30 min). The blue solution was stirred for 15 min. to allow Li fully
dissolved. This blue solution was splitted into two portions. To one of these
portions ( 7 mL ), was added a 15 mg ( 0.07 mmol ) sample of 118 in 10 mL
THF. To the remaining ammonia solution ( 5 mL ) was added a 9 mg ( 0.042
mmol ) sample of 124 in 5 mL THF. in these two flasks, the reactions were
carried out for 30 min. and then quenched with solid ammonium chloride. After
evaporation of ammonia, the residues in both flasks were treated separately,

with the same procedure shown below:

'4‘

106

The residue was diluted with water. The aqueous mixture was extracted with
methylenezhloride. The organic layer was washed with water, brine and dried
with magnesium sulfate. Removal of the solvent, a 9 mg mixture of 126 and
127 ( 6:1 ) was obtained from 118 and 9 mg product 125 from 124.
Chromatographic separation gave analytical samples of 125 ( 6 mg ), 126 ( 6
mg ) and 127 (1 mg ).

Characteristic properties of 125: 1H NMR, 4.17 ( 1H, d, d, J1=9, J2=6 ), 2.23
(3H, m ), 2.0-1.1 ( 17H, m), 1.04 ( 3H, d, J=8 ), 0.98 ( 3H, s), 0.95 ( 3H, s ), 0.83
(3H, s); MS, 334(2),319 (30 ), 274,262 ( 12.3), 247( 18),233, 215(8), 165
(41 ), 147(15),95(29),55(72.0),48( 100).

Characteristic properties of 126: 1H NMR, 5.22 ( 1H, m ), 4.09 ( 1H, d, d, J1‘=9,
J2=7 ), 1.64 ( 3H, s ), 1.39 (3H, s), 0.98 (3H, s),0.94 ( 3H,s); MS, 332,317,
299,281,271,159(12),149(16),133(8),119(12),105(21.5),91 (16.1 ),
69 ( 10.3), 55 ( 32.6 ), 43 ( 100 ).

Characteristic properties of 127:1H NMR, 5.26 ( 1H, m ), 3.81 ( 1H, d, J=8 ),
1.65 ( 3H, s ), 1.41 ( 3H, s ), 1.14( 3H, s ), 0.83 ( 3H,s ); MS, 332, 317,299
(2.0),289(5),271(10),153(3),213(2),105(21),55(30),43(100).

Preparation of trimethylsilylmethyl dervatlves 128 and 129. To a 331
mg (0.97 mmol ) sample oi 18 in 30 mi. THF at -35 °C was added 4.5 mL ( 1.0
M ) trimethylsilylmethyl lithium. The resulting yellow thick mixture was stirred for
5 h, then warmed to 0 °C, at which the reaction was carried out for another 5 h.
The reaction mixture was poured into ammonium chloride solution, and
extracted with methylene chloride. The organic extraction was washed with
water, brine and dried with magnesium sulfate. Evaporation of the solvent gave

519 mg light yellow oil which, on standing, solidified and was shown to be a

107

mixture of 128 and 129 in ratio of 5:1. Flash chromatography gave 353 mg ( 85
% ) both-silt! derivative.

Characteristic properties of 128: mp, 178.5—181 °C; lR, 3600, 2980, 1730, 1650,
1610, 1400, 1415, 1370, 1330, 1250, 1220, 1180, 1010, 990-, 840; 1H NMR,
5.23 ( 1H, m ), 5.00 ( 1H, s ), 3.63 ( 3H, s ), 2.50-1.70 ( 12H, m ), 1.46 ( 3H, s ),
1.84 ( 2H, s), 1.05 ( 8H, s ), 0.95 ( 3H, s), 0.06 ( 9H, s ); 13c NMR, 220.0,
202.0, 173.0, 143.0, 117.8, 99.4, 75.3, 55.8, 50.6, 50.1, 48.9, 46.5, 42.8, 34.2,
30.9, 30.6, 26.4, 25.9, 25.8, 24.7, 23.3, 19.0, 0.67; MS, 431 ( 8 ), 430 ( 13 ), 413,
'241 (99 ), 225, 209 ( 88 ), 198 ( 18 ), 151 (77 ), 137 ( 28 ), 121 ( 18 ), 119
(17),105(23),91(21),77(10),75(50),73(100).

Characteristic properties oi 129: 1H NMR, 5.18 ( 1H, s ), 4.96 ( 1H, s), other

peaks overlap with the corresponding peaks of 128.

Eliminative desilylation of 128 ( or 129 ) to 130. A 12 mg ( 0.028
mmol ) sample of silyl derivative 128 in 5 mL methylene Chloride was treated
with 0.1 mL boron triflouride etherate for 2 h. The mixture, diluted with
methylene chloride, was poured into water. The organic layer was washed with
0.5 M sodium bicarbonate, brine, and dried with magnesium sulfate.
Evaporation of the solvent gave a 9 mg ( 94% ) product of 130.

Characteristic properties of 130: mp, 176-178 °C; 1H NMR, 5.75 ( 1H, s ), 5.36
(1H,s), 5.21 (1H, m ), 5.12 ( 1H,s), 3.75(3H,s), 2.90-1.50 ( 12 H, m), 1.27
(3H,s), 1.18(3H,s), 1.03(3H,s); MS, 341,340(3), 325(7), 297(4), 281,
253,151 (100),121(8),105(6),91 (7),69(5),55.

APPENDIX

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CH30

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281

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84. TABLE 7:

Selected 13C NMR Chemical Shlfts for Lanosterol, Euphol and 17

War” Chemical Shiftc in: Lanosterol Eupml 11
16 30.7 29.7 29.2
17 50.3 49.6 48.9
20 36.7 35.3 34.9
22 36.2 35.7 35.4

a. Triterpene numbering; b. A comparative value for C-12 is omitted, since the
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from internal tetramethylsilane.

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282

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