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This is to certify that the
dissertation entitled

STUDIES TOWARD THE TOTAL SYNTHESIS OF TETRACYCLIC

TERPENES: (i) BUTYROSPERMOL AND (1:) EUPHOL

presented by

Hyun 0k 0k

has been accepted towards fulfillment
of the requirements for

Ph. D. degree in Chemistry

mi

Major p‘rofessor

Date May 28, 1986

MS U is an Affirmative Action/Equal Opportunity Institution 0- 12TH

 

 

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RETURNING MATERIALS:
Place in book drop to
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030617

 

STUDIES TOWARD THE TOTAL SYNTHESIS OF TETRACYCLIC
TRITERPENES: (i)BUTYROSPERMOL AND (i)EUPHOL

By

Hyun 0k OR

A DISSERTATION

Submitted to
Michigan State University
in partial fulfillment of the requirements

for the degree of
DOCTOR OF PHILOSOPHY
Department of Chemistry

1986

ABSTRACT .

STUDIES TOWARD THE TOTAL SYNTHESIS OF TETRACYCLIC
TERPENES: (i)BUTYROSPERMOL AND (i)EUPHOL

By

Hyun 0k 0k

Studies toward the total synthesis of tetracyclic
terpenes (i)butyrospermol and its double bond isomer
(i)euphol from the (i)5-epibutyrospermol ring system are
presented.

Conversion of 9 to 47 followed the procedures for (i)5-
epibutyrospermol. The introduction of a double bond at C-
4(5) and the subsequent gem-di-methylation generated p-ring
homodiene system 63, and then the dissolving metal reduction
of homodiene provided the trans-AB-ring fused tetracyclic
core 64. The conformation of this trans-AB—ring fusion came
after deprotection and functional group manipulation to give
69. Comparison of 69 with its C-5 epiner 49, prepared and
characterized in an earlier study, provided unequivical
evidence for these assignments.

With the tetracyclic core of butyrospernol 69 in hand,
the attachment of the CBHIS side-chain with control of the
configuration at 0-17 and C-20 was examined with model

ketone 12.

Stereoselective addition of methylthiomethyl lithium
led to the epoxide 80, and treatment with ethoxyethynyl
magnesium bromide, followed by reduction and then acid-
catalyzed rearrangement, produced the ¢,p-unsaturated
aldehyde EB. Subsequent reduction and Wittig olefination
provided the final model side-chain system. Configuration
at 0-17 and 0-20 was studied by comparing carbon-l3 chemical

shifts of equivalent natural products.

For my family, for their love,

support and understanding.

ii

ACKNOWLEDGEMENTS

The author wishes to express her deepest appreciation
to Professor William Reusch for his guidance and
encouragement throughout this study. Appreciation is
extended to Professor Steven P. Tanis for his helpful
suggestions and informative discussions.

Thanks are extended to my colleagues for their
friendship and many helpful discussions during the past
years. Many thanks also goes to Miss Tonya Acre for her
help in preparing this manuscript.

A special thanks goes to her husband, Dong, for his
endless love and understanding.

Finally, the author would like to thank Michigan State

University for a teaching assistantship and Mobay Company
for a summer term fellowship;

iii

TABLE OF CONTENTS

£212

LIST or FIGURES . . . . . . . . . . . . . . . . . . vi
INTRODUCTION. . . . . . . . . . . . . . . . . . . . 1
RESULTS AND DISCUSSION. . . . . . . . . . . . . . . 20
1. CONSTRUCTION OF THE TETRACYCLIC CORE . . . . 20

2. CONSTRUCTION or TRE Ce SIDE—CHAIN. . . . . . 53
EXPERIMENTAL. . . . . . . . . . . . . . . . . . . . 65
GENERAL. . . . . . . . . . . . . . . . . . . . . 65
PREPARATION OF TRIENONE 54 . . . . . . . . . . . 66
PREPARATION OF 4,4—DIMETHYLTRIENONE 63 . . . . . 68
PREPARATION OF A7»<8>, 3-ONE 64. . . . . . . . . 69
PREPARATION OF c—17 ALCOHOL 67 . . . . . . .'. . 71
PREPARATION OF C-3,17-DIKBTONE as. . . . . . . . 78
PREPARATION or 0-3 p—ALCOROL as. . . . . . . . . 74
PREPARATION OF COMPOUND 12 . . . . . . . . . . . 75
PREPARATION OF COMPOUND 78 . . . . . . . . . . . 76
PREPARATION or COMPOUND 79 . . . . . . . . . . . 77
PREPARATION OP COMPOUND 80 . . . . . . . . . . . 78
PREPARATION or COMPOUND 81 . . . . . . . . . . . 79
PREPARATION or COMPOUND 82 . . . . . . . . . . . 80

PREPARATION OF COMPOUND I! . . . . . . . . . . . 80

iv

Page
PREPARATION OF COMPOUND 85 . . . . . . . . . . . 81

PREPARATION OF COMPOUND 83 . . . . . . . . . . . 82

REFERENCES. . . . . . . . . . . . . . . . . . . . . 152

Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure

Figure

10
11
12
13
14
15
16
17
18
19
20
21

Carbon-13 Chemical Shifts of Euphenol

Carbon-13 Chemical Shifts of Compound 86

IR

IR

IR

IR

IR

IR

IR

IR

IR

IR

IR

IR

LIST OF FIGURES

Spectrum
Spectrum
Spectrum
Spectrum
SpectrUm
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum

Spectrum

of
of
of
of
of
of
of
of
of
of
of
of

Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound

Compound

540)
54(1)
53”)
64”)
64(s)
67(s)
66
60
81
66
86

Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum

Spectrum

of
of
of
of
of
of
of

vi

Compound
Compound
Compound
Compound
Compound
Compound

Compound

54(3)
54(1)
§§(l)
54(F)
64(1)
67”)
67(a)

Page
63

64
84
86
88
90
92
94
96
98

100

102

104

106

108

109

110

111

112

113

114

Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure

Figure

22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46

47

Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum

Spectrum

of
of
of
of
of
of
of

of

Compound
Compound
Compound
Compound
Compound
Compound
Compound

Compound

888588

18 NMR
1H NMR
1H NMR
1H NMR
1H NMR
1H NMR
1H NMR
13 NMR
IE NMR
18 NMR
1N NMR
18 NMR
1H NMR
1H NMR
18 NMR

1H NMR

130 NMR Spectrum of Compound 54([)

13C NMR Spectrum of Compound 54(s)

Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum

Spectrum

of
of
of
of
of
of
of
of
of
of
of
of
of
of
of

of

vii

Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound

Compound

Page
115

116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
I31
132
133
134
135
136
137
138
139

140

Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure

Figure

48
49
50
51
52
53
54
55
56
57
58

13C
130
13C
13C
130
130

13C

13C

13C

NMR

NMR

NMR

NMR

NMR

NMR

NMR

NMR

NMR

NMR

NMR

Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum

Spectrum

of
of
of
of
of
of
of
of
of
of

of

viii

Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound

Compound

G
p:

ER

Page
141

142
143
144
145
146
147
148
149
150

151

INTRODUCTION

The triterpenoids form the largest group among the
terpenoids. They are widely distributed in the plant
kingdom, either in the free state or as esters or
glycosides, although a few important members have been found
in the animal kingdom. These include squalene, first
isolated from shark liver oil, and a number of tetracyclic
compounds, including lanosterol (obtained from wool fat).

Among the tetracyclic terpenes having a penhydrocyclo-
pentanophenanthrene skeleton, the lanostanes, the euphanes
and the cucurbitanes all bear trans-oriented methyl groups
at 0—13 and 0-14. Representative structures of each group
are shown below.

In nature, the tetracyclic triterpenes are formed by
enzymatic cyclization of squalene followed by
rearrangement.1 Steroids are generated by subsequent loss of
methyl groups from lanostanes. A chair-boat-chair-boat
folding of squalene leads to the lanostane system, whereas a
chair-chair-chair-boat conformation leads to euphol and/or
'tirucallol derivatives. Non-enzymatic, acid-catalyzed

cyclization of appropriate polyene intermediates has also

 

Lanosterol Euphol

 

Butyroperniol CUCUFbltaCln 1

generated the lanostane skeleton. However, the euphane

skeleton cannot be obtained by such cation-induced polyene
cyclization due to its facile rearrangement to the

isoeuphane structure.

moamemoz<4
_n:_musc_e

H ”ocojm

 

 

 

 

lsoeuphol

Butyrospermol, isolated from the non-saponifiable
fraction of shes-nut oil from Butyrospermum Pat-lied, was
first characterized in pure form by Heibron, Jones and
Robins in 1949.2 Like so many other members of the Euphane

group, it is a secondary alcohol with one easily reduced

double bond, present in the side chain, and a second double
bond resistant to hydrogenation. Addition of bromine to the
side chain double bond of butyrospermol acetate, followed by
careful treatment with hydrogen chloride at 0°, and
regeneration of the side chain ethylenic linkage by reaction

with zinc gave euphenyl acetate. The acidic conditions

 

BUtyrospermol acetate Euphenyl acetate

required to convert dihydrobutyrospermol to euphol are
milder than those required to isomerize euphol to
isoeuphol.a

Chemical studies of the triterpenoids started in the
late nineteenth century, and 50 years have passed since the
initial structural work was reported by Ruzika, et.aLfi The
main structural difference between steroids and tetracyclic
triterpenes is the presence of three extra methyl groups,
two at C-4 and one at C-14, in the latter. Despite their
overall similarities, very little work has been accomplished

on the total synthesis of tetracyclic triterpenes, whereas

more than 100 steroid syntheses have been reported.5 To
date, two total syntheses of lanostane triterpenes have been
reported, one by R. B. Woodward’s group in 19545 and the
other by B. B. van Tamelen’s group in 1972.7 These two
syntheses show significantly different strategic approaches.
In the Woodward approach, cholesterol served as the starting
material, and the introduction of three additional methyl

groups was accomplished as shown in Scheme 1. 0n the other

 

Cholesterol

 

Dihydrolanosterol

Scheme I

_ _ oEocum

.3 n3 Bel-33:0». T. .3 0.9 .8233.

 

hand, van Tamelen’s synthesis applied a biomimetic strategy.
A polyene precursor was synthesized from (-)-limonene, and
the Lewis acid-induced cyclization of a derived epoxide gave
either parkeal or isotrucallol ‘ depending on the
configuration at C-3, as outlined in Scheme II. There are
no reported syntheses of the euphane ring system, and due to
its facile acid-induced rearrangement to the isoeuphane
system', a polyene cyclisation approach is unlikely to be
effective.

Recently, the 5-gpitEuphane ring system was synthesized
in this laboratory9 starting from the well-known Wieland-
Mieshler ketone, which was converted in two steps Ito

bicyclic diketone l.10 The synthesis of 1 is outlined in

 

 

 

 

OH 0
CH3 H2 CH3 1. KOH\MVK
’
5%Rh\A1203 2-
OH 0 Z 3
N
Li\NH3 KOH
----’r g,_
MeOH\H20

   

Scheme I I I

Scheme III. Using 1 as a starting material for the
tetracyclic triterpene synthesis offers certain advantages
since this compound contains the required trans dimethyl
functionality found in the CD rings of these natural
products. Furthermore, by using enantiomerically-pure
proline in the Aldol condensation step, either antipode of
the Wieland-Mieshler ketone can be obtainedll, permitting
the synthesis of enantiomerically pure, as well as racemic,
products.

There are several possible ways to prepare tetracyclic
compounds from CD intermediates. In the total syntheses of
steroids, bicyclic intermediates incorporating the C and D
rings have been Used to prepare both aromatic ’and
nonaromatic steroids.s The assembly strategies fall into
three fundamentally different categories. The first of
these comprises syntheses in which ring A is first added to
the initial CD fragment, followed by closure of ring D (A +
CD -—9 ACD --9 ADCD). In the second, the sequence of ring
formation is reversed: first ring D and then ring A (CD ---)
DCD -—-9 ADCD). Finally, the third method involves the
formation of ring D by Diels-Alder diene condensation with
the simultaneous introduction of ring A as a component part

of the dienophile (CD + A -——9 ABCD).

10

I. OA;:+QQ*-——9 ACD -——9 ABCD.

This strategy can be divided into many parts according
to the type of reaction used in the condensation of the A
fragment with the CD portion. The representative approaches
are first, reaction of an anionic ring A with a keto
function in the CD portion, as developed by Johnson in his

first estrone synthesis (Scheme IV).12 A second approach

0 O

O. 00
4- ———--~
,. D _

MeO ' OH

MeO

 

   

__... —-—> Estrone

Scheme IV
uses an anionic derivative of the CD portion to react with
A. Danishefsky, at. a!” were able to prepare D-

homosteroids by this route, which is outlined in Scheme v.13

 

 

 

D-Homosteroid

Scheme V

II. Q -—> DCD -—-—> ADCD.
Many examples of the CD ----> DCD —-) ADCD route are
found in the work of W. S. Johnson and his co-workers on the

synthesis of dUmAldosterone derivatives.1‘

12

Me N Etgl- OMe

NaOMe

   

MVK\NaOMe
F

 

 

Many Steps

a

 

 

 

The key step in this method is a Diels-Alder diene
condensation of 4—viny1indan with appropriate dienophiles;

this leads simultaneously to the formation of ring D and the

l3

introduction of ring A. Of the three approaches, this
cycloaddition is the most efficient way to form a
tetracyclic system due to the generally high regio- and
stereoselectivity of Dials-Alder reactions.

The reaction of 4-vinylindan 2 with bensoquinones lead

to moderate yields of adduct 3, and an equivalent reaction

0 O
cowl.
/
O
2 O 3

with toluquinone and methoxyquinone led to similar adducts
with a substituent at C-3.15 Similar reactions of saturated
analogs of diene 2 with benzoquinone and its methoxy
derivatives gave yields of about 202 of the cis-syn adducts
4 and 6, respectively.15

Recently, a common tetracyclic precursor for both
euphane and lanostane triterpenes has been synthesized in
this laboratory by a Diels-Alder cycloaddition reaction of
diene 6.17 This diene was prepared in 70% yield from
diketone 1 in two steps. It has been demonstrated that
cycloaddition reactions of 6, with a number of dienophiles
under both thermal and acid-catalyzed conditions, gave
excellent stereoselectivity. The reactions yielded p-endo

adducts exclusively, despite the steric congestion of the

 

. °=<:>=0 0 .0
‘!!IIHII’> 80IZ " [IIIIIIIIIl

 

 

O
OCH3
O O O
. t»
80 C, 48hr
CH3O
O
p S
endo transition state. The regioselectivity of the

cycloaddition of 6 with 2-methy1-5-methoxybenzoquinone can
be .controlled by selective Lewis-acid catalysis. Thus, an

efficient synthesis of the lanostane-like tetracyclic

O

CuSO45H20
a
Benzene

 

l + /\MgBr ————-s-

   

intermediate 7 was achieved as shown in Scheme VI.

Subsequent conversion of 7 to a euphane-like intermediate

15

was accomplished by photoisomerisation of enolacetate 8,

followed by hydrolysis.

CH
3 BF30Et

CH2C12,'17.

 

CH3O

 

NaOAc, DMAP

A620\Benzene

 

l.h0\CH3CN

 

«‘7
2.K2CO3VdeOH

   

Scheme VI

All the triterpenes mentioned earlier have a Cs side
chain at C-l7. These side chains are often alkyl in nature
but may incorporate a variety of functional groups, as in

the cases of cucurbitacins. There are many reported side-

16

chain syntheses for steroidsla, and they have been
documented in two excellent reviews.1°'3° However, it must
be noted that almost all of the studies referred to above
have been conducted in the absence of a Cis-s methyl
substituent.

A crucial aspect of side-chain synthesis is the control
of stereochemistry, especially at C-17 and C-20. A large
number of steroid side-chain syntheses use one of the
following substrates due to their availability from

naturally occuring compounds. Common reactions of the C-17

o :02 ..

carbonyl group include addition of hydrogen cyanides’l,

 

acetylides22 and Wittig reagents.23 The C-20 carboxylic acid
intermediate is usually transformed into an acid chloride21
or is transformed by direct addition of alkyl lithium
reagents.3‘ In reactions of the C-17 acetyl group, the
stereochemical outcome is dependent on conformational
preferences and will vary with different substituents. For
example, Grignard-reagent additions to 20-ketones35'2° and
20-aldehydes27 yield mixtures of isomers, whereas addition

of dimethyl sulfoxonium methylide is highly stereoselective

17

and gives the 20—R epoxide.‘a A ZO-R epoxide was also
obtained by stereoselective addition of methyl selenomethyl
lithium.39

Reusch and Gibson reported that Wittig ethylidenation
of a bicyclic (C/D) triterpenoid model, 10, gave the E

olefin 11.30 In contrast, the equivalent reaction of l7—keto

 

steroids gave predominantly the Z isomer. Rydroboration of
11, followed by oxidation, led to an epimeric mixture of 20-
ketones, which could be epimerized cleanly to the s-epimer
12. However, chain extension by Wittig olefination followed
by catalytic hydrogenation gave only fair configurational
control at C-20. The overall synthetic approach is outlined
in Scheme VII.

Recently, Koreda has described28 a 20-isocholesterol
side-chain synthesis involving reaction of isoamyl magnesium
bromide with epoxide 13. Rearrangement of the epoxide
proceeded by a completely stereoselective hydride shift to

an intermediate aldehyde. Krief also applied a similar

18

 

 

1.82H6
CZHSPBSBr __ 2.H202\NaOkI
NaH\DMSO '7 3 pcc '

   

 

 

‘2. H2\Pt02

 

Scheme VII

epoxide-rearrangement-addition reaction sequence for the
side-chain synthesis of 20-8 isolanosterol.2° Re obtained an

80/20 mixture of the ZOS/ZOR stereoisomers, as illustrated
in Scheme VIII.

 

 

Excess

WMgBr

 

 

 

19

I. LICHQSeCH3
2. CH30502F

 

   

 

  
  

 

l. EtOC CMgBr
2. LIAIH4
V
O
1. H2\Pd,BaSO4 \
H
i assess
THPO '
’
Scheme VIII

This dissertation describes an efficient means of
converting the 5-epi-euphane (cis A/B ring fusion)
tetracyclic ring skeleton to the correct A/B trans
configuration and stereoselective side-chain construction of

a bicyclic (C/D) triterpenoid model.

RESULTS AND DISCUSSION

A total synthesis of butyrospermol can be divided into
two sections: first, construction_ of the euphane-like
tetracyclic system and, second, the subsequent attachment of

the CB side chain.

I. Construction of the Tetracyclic Core.

Fused six-membered carbocyclic ring. systems may be
assembled in a number of- different ways, but the most
efficient of these is undoubtedly the Diels-Alder reaction.
Since its discovery in 192831, the Diels-Alder [4+2]
cycloaddition has been widely studied and is (valued as a
synthetic tool because of its normally high regio- and
stereoselectivity.

The stereochemistry of the adduct obtained in many
Diels-Alder reactions can be predicted on the basis of two
imperical rulesaz: the cis-principle and the endo-addition
rule. According to the cis-principle, the relative
configuration of substituents in both the dienophile and
diene is retained in the adducts. Thus, a dienophile with

trans substituents will give ‘an adduct in which their

20

21

configuration is retained; likewise, a cis substituted
dienophile will yield an adduct in which the substituents
are cis to each other. According to Alder’s endo-addition
rule, a dienophile and a diene approach each other in

parallel planes, and the most stable transition state arises

1+ COQCH3

I

H c02013
:> H COQCH3 4-» / H + / .C02CH3

 

 

 

c02013 H
COQCH3 H
H c0201, / C02043
fi__ _ H
H .
83,013

from that orientation in which there is a maximum overlap of
double bonds, including those of the activating groups of
the dienophile. The endo rule is not always obeyed and the
exo/endo composition in such cases often varies with the
structure of the dienophile and the reaction conditions.33
Construction of the Butyrospermol ring system by an A +
.CD --9 ADCD Diels-Alder strategy requires an appropriate
cisoide diene (CD ring portion), incorporating the trans C-

13 and C-14 methyl groups.

22

Diane 6 can be obtained from diketone l in two steps:
nucleophilic addition of a vinyl anion to the six-membered
ring carbonyl followed by dehydration of the resulting

tertiary allylic alcohol 14. It has been knowna‘ that the

   

reactivity of cyclohexanones in a nucleophilic addition
reaction is greater than that of cyclopentanones; and
Martin, Ten and Reusch have reported35 the selective
addition of a series of nucleophile to the six-membered ring
carbonyl of 1 without protecting the fiveemembered ring
carbonyl group. For example, sodium borohydride (NIBH4)
reduction, lithium phenylacetylide addition and vinyl
magnesium bromide addition all favored reaction at the six-
membered ring carbonyl site. For this synthesis, the
addition reaction of vinyl magnesium bromide with diketone 1
is best effected by using excess Grignard reagent in
toluene.3° This improves the yield of 14 from 602 (in THF)
to 758 since the change of the solvent enhances the 1,2

addition of Grignard reagents to easily enolizable ketones.

23

 

 

 

NaBH4
Db
/\MgBr
’
DCECLI
.-

 

 

HO CECG

. Dehydration of the vinyl alcohol 14 in refluxing xylene
containing a trace of iodine was troublesome due to the
acid-catalyzed rearrangement37 of the initially formed
cisoid diene 6 to the transoid isomer 15 under this
condition. Based'on an initial report by N. Cohen, et.
aLfi', Tan and Reusch found that boron trifluoride etherate
(RFs-Olta) in refluxing benzene-TRF solution serves to
dehydrate 14 to 6 without subsequent isomerisation in

75~808.39 Recently, Day and co-workers dehydrated the

24

 

Xylene

     

carbinol 16 in the presence of copper sulfate trihydrate in

refluxing xylene to give enyne 17 in very good yield.‘°

CUSO4'3H20

Xylene,A

 

   

16

Dehydration of vinyl alcohol 14 with copper sulfate
pentahydrate in refluxing benzene followed by Kugelrohr
distillation of the crude product gave essentially pure

diene 6 in over 908 yield on a multi—gram scale.

25

The Diels-Alder reaction of diene 6 with various
dienophiles has been studied intensively in this laboratory.
Ten and Reusch reported‘1 that, among four possible
diastereomeric structures for the Cycloaddition adducts
derived from the symmetrical dienophiles prbenzoquinone and
maleic anhydride s-endo 16, d-exo 19, p-endo 20, and fi-exo
20, where s and 3 refer to the bottom and top sides of the

diene as drawn here, the p—endo adducts were formed

   

O
18 19 2|
exclusively in both cases. The configurations of the

adducts were confirmed by pmr studies and x-ray diffraction
analysis of substituted quinone adducts.

An examination of molecular models of diene 6 shows
that the C-13 methyl group is tilted over the endocyclic
double bond whereas the C-14 methyl group is tilted back
away from it. The overall effect of this distortion is that
the top side (or p-face) of the diene is more accessable
than the bottom side (or s-face). Thus, p-addition should
be favored in the transition- state of the Dials-Alder

reaction (steric approach control).

26

Diels-Alder cycloaddition of an unsymmetrical diene
with an unsymmetrical dienophile may take place in two
orientations, which give two regioisomeric adducts.
However, in practice, formation of one of these isomers is

usually favored‘z, as shown below. This regioselectivity in

R R R
x x

+t ——»U+0

\ x

Major

K * IX —’RUX £1

Major

which the "ortho" or ”para” product is favored over the
”meta” has been rationalized by molecular-orbital
calculations.‘3

Derivatives of prbenzoquinone have been used as
dienophiles to construct the fused six-membered ring systems
found in many natural products. Their high degree of
functionality offers special interest and advantages in
subsequent transformations. Examples include the syntheses
of steroids3°t“, gibberellic acid‘s, reserpineu and

trichodermol", as outlined on the following page.

27

R
O O
\ to
+ —F ——m-
. .Q
0 O HO
Cholesterol
0 O
\\
+ ——>
OCH3
O OH HO 0
R0

0

:+> --sr-"
CH3O
COQH

o c02H

 

O

Gibberellic acid

    

CH3OQC

Reserpine OCH3

R 91.1. g1... 3%!

Trichodermol

28

When an unsymmetrically substituted prbensoquinone is
used as a dienophile in reactions with unsymmetrical dienes,

four possible regioisomers may be obtained as shown in

 

Scheme 1!.
0
R1 \
+ —-———.'
R2
0 R O R
+ +
R2 R1
0 0
Scheme IX
Several important observations have been made

concerning the directing effects of substituents on p-
benzoquinone.

They are:

(l) Electron-donating substituents on the quinone
deactivate the double bond to which they are attached.‘8 In
contrast, electron-withdrawing substituents further activate

quinone double bonds as dienophiles.‘9

I

CH3O ' CH3O
o

O

('3 III
I

(A

c02CH3 c02CH3

CH3O

(2) Substituents on quinone dienophile usually direct
the cycloaddition reaction to give ortho-adducts with 1-

substituted dienes‘fi'5° and para-products with 2-substituted

 

 

dienes.
O C02CH3 CO2CH3 ‘
+
O
O
+ m-

 

3O

(3) A methoxy substituent exerts a strong influence on
one of the two carbonyl groups of a quinone through a
vinylogous ester-like relationship. This interaction
results in a substantial perturbation of the double bond on
the other side of the substituted quinone, leading to strong

regioselectivity in the Dials-Alder reaction.“8

 

+ ——m-

CH3O CH 0
o CHQOAC 3

The regioselectivity of Diels-Alder reactions of diene
6 and unsymmetrically substituted prbenzoquinones has been
examined.“1 For example, the reactions of. 2-methoxy-5-
methyl-ptbenzoquinone 22 with 6 in refluxing xylene solution
gave adduct 23 exclusively. (However, the reaction of 2-'
methoxy-4-methyl-prbenzoquinone 2A with 6 under thermal

conditions gave poor regioselectivity and a poor yield of

CH3O CH3
Xylene CH3O

 

A

 

22

31

 

 

O
CH30 Xylene
6 + A
CH3
0
24

 

tetracyclic adducts 7 and 25. Both the yield and the
regioselectivity of this Diels-Alder reaction were greatly
improved by Lewis acid catalysis.51 The effect of two of the
most selective catalysts, BFs-OEtz and stannic chloride
(SnCla), is shown below.

This regioselectivity may be explained by a site-
specific coordination of the Lewis acid with one of the
carbonyl groups of 24 to give a reactive quinone:Lewis acid
complex. When a 1:1 ratio of quinone 24 to Lewis acid is
used, two types of mono-complexation may occur; and the
preferred complexation will depend on the nature of Lewis
acid. First, the Lewis acid may be stabilized by chelation

with the methoxy substituent, as in 26. Second, the Lewis

32

 

 

6 +24 Lewis acid.
CH3O
Catalyst used ratio( 7:25) yield (70)
Heat 2: l 34
5,104 <1 :>99 74
BF3-0Et2 lO ; 1 55

acid may coordinate to the more basic ester-like C—4

carbonyl group as in 27. Boron trifluoride etherate, which

LJX ‘wk
0 O
5 CH3 5 CH3
CH3O CH3O
‘1 o o
11A./4'

26 27

is normally tetracoordinate, prefers complex 27, and this
leads to activation at C-6 to yield the ortho- or para-

cycloadduct in the Diels-Alder reaction. On the other hand,

33

tin tetrachloride, which is able to expand its ligand shell
to hexacoordinate, prefers complex 26. The resultant
activation at C-5 gives the ggtgroriented cycloadducts.

No synthesis of a euphane triterpene or of the
characteristic tetracyclic core of this large family of
natural products has yet been achieved. Recently,
Kolaczkowski and Reusch reported9 an efficient means of

converting the lanostane-like configuration of 6 to a

euphane configuration 26 via photoisomerization.

 

 

It has been known52 that Usnic acid 29, a constituent
in several genera of licheues, racemized when heated in
acetic acid or on acetylation with acetic anhydride in the
presence of strong acid. This rare isomerization at a
quarternary center was explained by Stork in 1965 (see
Scheme X).53 Initial bond cleavage of 29 gives a diradical
30 and one of the resonance forms which can be drawn is the
conjugated diene ketene 31. Subsequent ring closure of 31

leads to racemic usnic acid.

34
OH O 0
H0 0 I OH
O
Usnic acid 29

OH H 0

 

   

Scheme x

Intramolecular photochemical reactions of saturated and
unsaturated ketones have been studied for decades. In 1960,
Barton and Quinkert reporteds‘ their investigations into the
photochemistry of cyclohexadienones, including the
photochemical racemization of usnic acid. Nineteen years
later, Quinkert and co-workers reported55 a detailed study
of solvent and excitation wavelength effects on the
isomerization of 2,4-androstadiene-l-one 32. They found
that irradiation of either 32 or 33 in the absence of
external nucleophiles gave a mixture of isomers 32 and 33.

The relative ratio of 32 and 33 in the photostationary state

35

 

 

34

proved to be the same in both cases. The expected ketene
intermediate 34iwas identified by spectroscopic studies and
by trapping experiments with cyclohexylamine. Thus, a
photoequilibrium is established between the two tetracyclic
dienones 32 and 33, and the photostationary ratio of 32 and
33 varies from 6.5:1 to 5.7:1, depending on the reaction
conditions. The naturally occurring C-lO p-methyl isomer 32
predominates. This result is not surprising since, in
isomer 32, the anti relationship of the C-10 methyl and C-9
proton allows the B-ring to adapt a stable chair
conformation; whereas, the C-9, C-lO syn relationship in
isomer 33 forces ring B into a less stable boat
conformation.

Reusch and Ten reported‘l that the C-4 carbonyl group

of Dials-Alder adduct 7 was enolizable and they trapped it

36

as the acetate 6‘by reaction with acetic anhydride. Mild
base ([200: in methanol) treatment of 6 gave back the
starting triketone 7 instead of the AB trans-fused 36,

indicating that the AD cis configuration was more stable.

AC20\DMAP\GH

7 a 8

 

<~

K2C03\MGOH

 

Bnol acetate 6 has a 9,10-syn configuration analogous to the
minor isomer 33 in the Quinkert study. We expected,
therefore, that 6‘would undergo photoisomerization to give
the desired euphane-like configuration 26 as the major
(product. However, in practice, two concerns remained
unanswered. First, the possible effect of the oxygen
functionality at C-3 and C-4 on the course of the
phOtoisomerization and, second, the presence of the C-17

carbonyl function.

37

Photochemical isomerization of keto-acetate 36 was
investigated in this laboratory.59 Iradiation of a solution
of 36 in ether solution with a 400 watt mercury lamp using a
pyrex filter causes isomerization to the cis-fused keto-

acetate 37. This Norish-type I cleavage-recombination

hV

 

   

reaction requires - higher energy light than the
photoisomerization of enolacetate 6. Thus, by using‘ a
saturated copper (II) sulfate filter to block wavelengths
below 365 nm, this undesired epimerization at C-13 can be
avoided.

Acting on the assumption that the substituents at C-3
and C-4 and A 7‘9) double bond would not perturb the
photochemical reaction seriously; a solution of enolacetate
6 in acetonitrile was irradiated under Quinkert’s
conditions. This photolysis generated a 5.5:1 mixture of
photoenol acetate isomer 26 and starting material 8,
respectively.9

Many cis-fused bicyclic Diels-Alder adducts with
quinones are known to be converted to the corresponding

trans-fused isomers on mild base treatment. For example,

38

the cycloaddition adduct 36 from the reaction of quinone 24
with pypenylene even isomerized to the trans compound 36 on

standing.35

CH3O

 

38

In more complex systems, isomerization proved to be
dependent upon the stability of the product. Valenta, 'et.
ah, reported“"57 that in the case of Diels-Alder adducts
40 and 41, 41 was converted smoothly to its trans isomer 43

under various conditions. These observations suggest that

 

   

39

 

4| 43

the anti-trans relationship at C-8, C-13 and C-14 in 42 is a
particularly stable configuration, whereas the syn-cis
relationship in 41 is more stable than the related syn-anti
configuration of 43. A similar observation was made for the

regioisomeric Diels-Alder adducts 7 and 26.39 These results

 

2S

 

are in accord with the work of W. S. Johnson53 on the
relative stabilities of perhydrophenanthrene isomers.
According to Johnson’s analysis, the trans-anti-trans isomer

has the lowest energy among the many stereoisomers of

4O

perhydrophenanthrene since this arrangement allows all the
D-ring bonds to assure equatorial orientation and all three

rings to adopt chair conformations.

~
.~‘.'

Trans-anti-trans
Dhenantnrene
All previous results indicated that the tetracyclic

enedione derived from 26 by base hydrolysis would have an
AD-trans relationship since an anti-relationship at C-9 and
C-10 exist in 26.

A series of reactions, outlined in Scheme XI, was then
carried out by Larry Kolaczkowski’, under the assumption
that the product from base-catalyzed solvolysis of 26 was
the AD trans-fused endione 44. The expected product was the
tetracyclic intermediate 46, a precursor to butyrospermol.
However, the actual product 46 resisted all attempts to
isomerize the 4‘79“) double bond to the more stable 6. 3")
location. Therefore, an X-ray crystallographic analysis was
conducted, and this demonstrated that the AB-ring fusion in
46 was cis, as shown throughout Scheme XI.

At this stage of our synthesis, modifications were

sought to convert the AB-cis 5-epi-butyrospermol tetracyclic

 

41

 

K2C03 l. Zn\AcOH f
281 ..m-
MeOH 2. MsCl\Pyridine

CH3O c1430

 

Ro 'H
44 ' 45 R=H

4K5 R= MB

1 Zn, Nal ,,Glyme A

o
l. DIBAL
t
2. H+,THF\H20

 

 

   

 

  

 

 

CH3O
9
l. MEMCl. Et(iPr)2N
OMEN O
2. 2tBUOK,THF,2CH3I
l.TiCl4\CH2C12
” ~4a>
2H2
3.PDC
4.NaBH4 ‘
0 H0'
48 49
Scheme XI
core to the desired AD-trans ring fusion. The most

attractive of these modifications was based on the work of

42

Pike, Summers and Klyne with lumistan43-one derivatives.5°
These workers reported that dried methylation of lumista-
4,7,22-triene-3-one 60, followed by dissolving metal
reduction of 61, gave AB-trans fused 4,4-dimethyl-5p-

1umista-7,22-diene-3-one 62 in excellent yield.

   

tBuOK\tBuOH,@I—l
CH3I

 

 

00

50

 

Li\Liq NH3

 

 

To effect transformation of 44 to a form suitable for
the introduction of a double bond at C-4, we followed the
sequence of Scheme XI to intermediate 46. This procedure
was patterned after one developed by Speziale, et. a130,
for the preparation of a key CD synthone in the Woodard

cholesterol synthesis.“b Thus,. zinc dust reduction of 44,

43

 

O O
2n,ACOH\H20
4
CH3O fi 01,0 3 R"
O HO

followed by mesylation and further reductive elimination,
gave the methoxy enone 9.

Selective reduction of one carbonyl function among
three carbonyl groups present in 44 was not a serious
concern since the C-1 carbonyl is ester-like in character,
due to donation of the electron density from the C-3 methoxy
group; and the C-17 carbonyl function was known to be
relatively unreactive due in part to severe steric
hinderance.

The conversion of alcohol 63 to enone 47*was carried
outby transforming the hydroxy function at C-4 to a good
leaving group, in this case, mesylate, followed by hydride
displacement and concurrent reduction of the remaining
carbonyl functions. Several methods for the selective
removal of mesylate in the presence of other sensitive
functionality have been reported.°1'|"c One of the mildest,
the method of FuJimoto and Tsatsuno°1¢, involves treatment
of mesylate with sodium iodide and zinc dust in refluxing
' glyme. Under these conditions, mesylate 46 was converted to
enedione 9 in good yield. Subsequent reduction of endione 9

with diisobutylaluminum hydride (DIDAL) gave, after careful

44

acid hydrolysis, a mixture of epimeric l7-alcohols 47 (s and
3) having the desired l-en-S-one function in ring A. These
epimers were separated initially to facilitate subsequent
structural assignment; however, this’ is not a necessary
operation in the synthesis.

Protection of the C-17 alcohols prior to the
introduction of a double bond at C-4 proved necessary. In
fact, Rolaczkowski and Reusch reported35 that the
introduction of the geminal dimethyl substituent at C-4 to
the compound 47, without protecting the C-17 hydroxyl
function, was troublesome. For this purpose, '-
methoxyethoxymethyl chloride (MBMCl), a reagent developed by

E. J.a Corey, eh.alfiz, proved to be effective.

OMEN

MEMCl,Et(iPr) N,CH Cl
47 2 2 2

 

 

The MEM-ether derivatives 63 (e and p) are ideally
suited for the introduction of a double bond at C-4 and
subsequent gem-dimethylation. Both enolization and
alkylation at C-2 is blocked by the A 1‘2) double bond, and
the reduced state of the C-17 carbonyl prevents enolization
at the C-17 ketone. Thus, the A “‘5> double bond was

introduced smoothly via selenylation‘3 of the enolate

45

generated by LDA, followed by oxidation (3202, ROAc/RzO),
and then elimination of the selenoxide to give trienone 64

(652 yield).

l. LDA
2.SeBr

3. H202,HOAC\H20

 

53’( and )

 

54

Our plan at this state was to introduce the gem-
dimethyl moiety at C-4, generating a B-ring homoannular
diene analogous to that of lumisterol.

Alkylation of s,fi-unsaturated ketones with sodium or
potassium salts of tertiary alcohols serving fee the base
normally gives the s,e—dialkyl-p,y-unsaturated ketone as the
major product.“ Woodward and co-workers developed6 this
method on their first total synthesis of lanosterol (Scheme
XII).'

Ringold, ah. ah, reporteda‘b that alkylation of the A
‘-3-keto steroid 66, even with a limited amount of base and
alkyl halide, led to the 4,4—dimethyl-A.5-3-one 66 as the

major product, together with 4-monomethyl-A“-3-one 67 as a

46

  
 

tBUOK\tBUOH

 

 

 

   

 

’
CH3I
O
Cholesterol
tBuOK\tBuOH
—.- —-> ’.
CH3I
820
——————a- -———a~
Dihydrolanosterol
Scheme Xll
minor product. This result can be explained by the

following scheme (Scheme XIII).

47

.. tBuOK .. CH3|
____p . ———’

o" 0
Q. H

55 K+ 56

tBuOK
Fas

   

Scheme XIII

The thermodynamically favored dienolate anion undergoes
kinetically controlled methylation at the e—position to give
4-monomethyl-p,y-unsaturated ketone 66. the e-proton in this
compound is more acidic than the y-proton in the starting
material 66 since it is activated by both a carbonyl group
and an ethylenic double bond. The resulting anion is again
methylated at the sbposition to give 4,4-dimethyl-A.5(°’-3-

one 66. If further alkylation does not occur, compound 66

48

isomerizes to the thermodynamically more stable e.)-
unsaturated ketone 67. Isolation of the dimethylated
compound 66 as the major product indicates that the second
alkylation step and/or tertiary carbanion formation proceeds
more rapidly than the first alkylation step and/or secondary
carbanion formation.

Methylation of cross-conjugated dienones in the
steroidal system have also been studied. V. Petrov, et.
ah, reported°5 that direct dimethylation of compound 66

failed to give any of the desired 4,4-dimethyl compound 66.

C8H17

  

59

 

A similar lack of reactivity is reported for these same
dienones in the deconjugation studies of Ringold and
Molhotra.“° A remarkable resistance to gem-dimethylation at
C-4 was also found for the cross-conjugated dienone 61 and

62 in this laboratory.°° Therefore, we were concerned that

tBuOK
CH3!

» NO reaction

 

49

tBuOK
CHSI

s- No reaction

 

the A 1“”-double bond might expert a negative influence on
the methylation reaction of 64. Fortunately, in the event,
a solution of trienone 64 is benzene was gem-dimethylated in
over 908 yield by the classical procedure of Woodward, et.

alfi

   

 

54» i-

 

/

An examination of the Drieding molecular models of
trienone 64 and cross-conjugated dienone 61 is helpful in
explaining the outcome of this methylation. Drieding models
show that a A 1-double bond causes the dienolate derivated
from a Ailv‘-diene-3-one 61 to twist about the C-4:C-5 bond
by 30° to 35°. This reduces the effective charge
delocalization available to this species. However, the

addition of a double bond at C-7, not only resists this

50

twisting, thus neutralising the adverse effect of the A 1-
double bond, but also extends the charge delocalization
(1'.e., gives a trienolate).

Treatment 'of 4,4-dimethyltrienone 63 with 20
equivalents of lithium in liquid ammonia solution containing
t-butyl alcohol (10 equivalents) yielded the AD trans-fused

A‘7<'>-3-one 64 in excellent yield. Without the t-butyl

   

Li\liq.NH3
tBuOH

63

 

 

alcohol, this reduction stopped after reduction of the C-1
double bond to give homodiene 66. The homodiene 66 was also
converted to 64 by treatment with lithium in liquid ammonia,
followed by oxidation of the resulting epimeric mixture of

C-3 alcohols 66.

51

The structure of 64 was assigned from its chemical and
spectral properties, and in part on the lumisterol analogy.
The infrared spectrum of 64 had a strong carbonyl absorption
at 1715 cm'l. The 250 MHz 16 NMR speCtrum showed a quartet-
like (1 = 3.3 Hz) signal at 6 5.22 for the vinyl proton at
C-7. In addition, there were four sharp singlets at 6 0.64,
1.02, 1.05 and 1.15 (overlap) for the five methyl groups.
The 13C NMR spectrum displayed the expected 26 signals,
including a saturated carbonyl peak at 6 216.45 and two
olefinic signals at 6 145.33 and 117.73.

Removal of the C-17 MRM group in 64 by reaction with
titanium tetrachloride (TiClc) in methylene chloride‘3
caused an unexpected problem. Even at ~78° for 1 minute,
TiClq, not only cleaved the MRM ether, but also rearranged
the ring system to give an unidentified product which showed
signals in the aromatic region of the 16 NMR.

It is well known“? that TiClA is a powerful Lewis acid
and the acidity of this Lewis acid can be tempered ‘by
replacing chloride by alkoxy groups, such as isopropoxy.
Realizing that TiCls is too strong an acid to be used in our
system, a series of modified TiCla catalysts were tried to
effect cleavage of the MRM ether without any undesired
rearrangement. Finally, the MEM protecting group was
cleaved cleanly with titanium diisopropyl dichloride (Ti(0-

iPr):Clz) to give the C-17 alcohols 67 in 908 yield.

52

Ti(OiPr) CI .01 Cl
64 2 2 2 2 *

 

 

The last two steps of this synthesis of the tetracyclic

core of butyrospermol were straight forward. Swern

 

68 69

oxidation°° of the epimeric alcohol mixture 67.gave diketone
66 (938). Finally, (taking advantage of the low reactivity
of the C-17 carbonyl group, treatment of 66 with sodium
borohydride (NaRRs) gave selective reduction of the C-3
carbonyl function, yielding the equatorial alcohol 66 (918).

With this compound in hand, we were able to achieve a
final conformation of its AD trans-ring fusion. Comparison
of chemical and spectral data of 66*with that of its C-5
epimer 46, prepared and characterized by X-ray
crystallography in an earlier study“, provided unequivocal

evidence for these assignments.

53
II. Construction of the Cg Side-chain.

With the butyrospermal tetracyclic core 66 in hand, our
next task was to attach the Cs side-chain stereoselectively.
Many excellent stereoselective side-chain syntheses for
steroids have been published1°v1°?2°, whereas for
triterpenes, only the epoxide rearrangement/addition

procedure described by Krief2° has been known.

.. NaEiH4
66 " " O
HC02 HOCO

  

 

BZO

 

Scheme XIV

54

As illustrated in Scheme XIV, reactions of the l7-keto
group in steroids can be highly stereoselective with the
effect diminishing as one proceeds along the flexible side-
chain to C-20 and C—22. Therefore, our task was to find an
appropriate synthetic pathway to control the stereochemistry
at C-20.

Compound 10, derived from bicyclic ketone 1, has been
used as a model compound for construction of the side-chain

for triterpenes in our laboratory. Examination of a

INaBH4
2.CH3O’Na
3.CH3I

  

 

 

CH3O
l l0

Drieding model of 10 indicates that its tr-I-configuration
induces a puckering of the five-membered ring, analogous to

the configuration of the butyrospermol tetracyclic core 66.

CH3O CH3

 

Gibson and Reusch reported30 that the Wittig reaction

of ketone 16 with ethylidene triphenyl phosphorane yielded

55

the synthetically useful olefin 11 in good yield. The

configuration of the double bond of 11 was assigned on the

C2H5p838r
NaCHQS(O)CH3,NaI

  

 

CH3O

11

basis of its proton NMR spectrum compared to the known
steroid analogs. It is interesting to note that the
olefination of 10 to 11 gave the E-olefin in contrast to
equivalent reactions with l7-keto steroids", where the ‘2-
isomer dominates. For the l7—keto steroids, the least-
hindered approach of nucleophilic reagent is from e-face21

(opposite side to the C-13 p-methyl group), which leads to

O /

6 - 6

the Z-isomer. For compound 10, molecular models reveal very

 

little difference in the steric environment of both the s-
and p-faces. However, the observed stereselectivity
reflected a lesser hindrance of the p-face despite the

similarities indicated by the molecular models.

56

 

     

H O
l I l. B2H6.THF ’ i. Swern
2. H202,NaOH 2. EtONa\
a EtOH E
CH3O , CH3O
20 ‘2

Rydroboration of 11 with diborane (6266) yielded alcohol
70 as a mixture of isomers, and subsequent oxidation
followed by epimerization with base gave a single isomer 12.
Gibson and Reusch assigned30 the ehconfiguration at C-l7 on

the basis of the proton NMR spectrum.

ECOEt

EtOCECMgBr » OH

.-

 

 

72 73

H l. LiAlH4

‘—

2. 2M H2SO4\ETHER

 

 

57

Recently, Krief, et. aL29, reported the first
stereoselective side-chain synthesis of unnatural 20-S
isolanosterol. The key step of this synthesis is a novel
stereospecific isomerization of the epOxide 72 to the
corresponding alcohol 73, using a technique developed by
Roreeda in his 20-isocholesterol side-chain synthesis.28

It has been known70'71'72 that epoxides react with
organometallics to give two different types of alcohols, 76
and 76, depending upon the nature of the reagents and the
reaction conditions. A direct nucleophilic ring opening of
the epoxide gives alcohol 75. On the other hand,
rearrangement of epoxides prior to organometallic attack

leads to alchol 76.

 

D
wi
O tr—a- R2 CH2R
R‘\c/__\ /H + R” "'7 OH 75
R2/ \H R1 R1 R
R2 H CH0 R2 H OHH

In Koreeda’s 20-isocholesterol side—chain syntheisza,
the reaction of isoamyl magnesium bromide with the epoxide
13 produced a rearranged alcohol. 77 with a 1008

stereoselective hydride shift during the transformation.

58

 

 

Similarly, Krief reported29 that the epoxide 72 gives a 92:8

(20Rz208) mixture of alcohols based largely on an
examination of the s,p-unsaturated aldehyde 74.

These results suggest a solution for our side-chain
synthesis with control of the configuration at C-20.
Dutyrospermol has the same C-20 configuration (R) as does
lanosterol. However, the relative configuration at C-l3, C-
17 and C-20 in these two natural products are different:
these are 13-R, l7-R and 20-R for lanosterol; 13-8, 17-8 and
20-R for butyrospermol. Therefore, assuming that the C-14
methyl substituent in butyrospermol core 66‘will not perturb
the stereoselectivities of the side-chain significantly, the
epoxide rearrangement/addition sequence described by Kriefé°
should offer the control needed for the butyrospermol
synthesis. Our application of this procedure was first
exercised on the model ketone 12.

There are many ways to form a one-carbon, extended
epoxide from a carbonyl compound.73 The most direct approach

is Corey’s dimethylsulfonium methylide73f; however, the

59

outcome of the stereoselectivity of the resulting epoxide is
doubtful. Recently, Tanis, et. 8L7“, described a
convenient method to prepare spiroepoxides with high

stereoselectivity using methylthiomethyl lithium.

 

l. LiCHQSCH3
2. CH3!
,
o 3. NaH\THF ""7
o
(90%, IS; I >

Treatment of 12 with methylthiomethyl lithium gave
alcohol 76 (988 yield, stereoselectivity 92:6 determined by
integration of proton NMR). Treatment of 76 with neat
methyl iodide provided sulfonium salt 79, which was used
without further purification. Ring closure of the hydroxy
sulfonium salt 79 with sodium hydride in TRF proceeded
smoothly to give the desired epoxide 66 as a single isomer
(determined by carbon NMR).

The configuration of the major product at C-12 (C-20
for tetracyclic analogs) in alcohol 76 was assigned in part
by examining the molecular models of 78 and in part on
Erief’s work.2° Molecular models show that the attack of a
nucleophile from the least-hindered side (away from the C-9
methyl group) of the carbonyl group will give the desired C-
12(S) thio alcohol (precursor of C-20(R) for the final

triterpene).

81111

00m

ind:
die:
Pro:
is,"
addj

Inn]

60

(11+
/\

Li(3112543113 ' Excess
m» ,,

CH3I

 

12

 

 

  

CH3O

80

The desired alcohol 61 'was obtained by reaction of
ethoxyethynyl magnesium bromide with epoxide 60 under the
conditions described by Krief29 (ether:benzene:3:l, 20°,
1h). The carbon NMR spectrum of alcohol 61 shows 19 signals
indicating that .61 twas obtained largely as a single
diastereomer. Thus, the Grignard reaction presumably
proceeded via an initial MgBrz-catalyzed, stereospecific
isomerization of epoxide 60 into aldehyde 64, followed by
addition of the Grignard reagent. Reduction of the
ynolether 61 by lithium aluminum hydride (LiAqu), followed

by acidic hydrolysis of the resulting y-hydroxy enolether 62

61

   
    

BngCEC—OEt
80 )-

 

 

CH3O

produced the ¢,p-unsaturated aldehyde 36 in 838 overall
yield. Aldehyde 33 was then reduced by catalytic

hydrogenation (palladium on charcoal). The Wittig reaction

Lewis Acid

80 hr
(MgBr2)

 

 

62
of the resulting saturated aldehyde 66*with isopropylidene

triphenyl phosphorane gave the final product 66 in 688

  

 

 

yield.
H O
H
83 pd\C’H2 (CH3)2C&Q3
EtOAc 3’
CH3O
85
The stereochemical outcome of this whole set of

reactions was studied at this stage by comparing carbon-13
chemical shifts of 66 to the chemical shifts of equivalent
natural products, reported by S. A. Knight.75 The chemical
shifts reported for euphenol (Figure l) and the assignments
proposed for 66 are shown in Figure 2. Based on these
assignments, we assume that compound 66 has a configuration
which is analogous to euphenol. However, a definitive
assignment may have to wait until the real tetracyclic

system is assembled.

. oa:o_a

Nmmm

 

63

Q:

mmN—

 

0mm
ow—

 

 

 

 

 

64

 

0N—

www.m—

 

GROW

00.0

N 839“.

 

www—

 

 

EXPERIMENTAL

Except where otherwise indicated, all reactions were
conducted under a dry argon or nitrogen atmosphere using
solvents distilled from appropriate drying agents. Small-
scale chromatographic separations were accomplished with the
use of 2 mm silica plates (Merck F-254, 20 x 20 cm). Larger
scale separations were effected by flash chromatography (40-
63 millimicron silica gel, Merck 9385. Melting points were
determined on either a Thomas-Hoover capillary melting point
apparatus or a Reichert hot-stage microscopic and are
uncorrected. Infrared (IR) spectra were recorded on a
Perkin-Elmer 237B grating spectrophotometer. Mass spectra
(M8) were obtained with a Finnigan 4000 GC/MS spectrometer.
Proton magnetic resonance spectra (PMR) were taken in
deuterochloroform solution using either a Varian T-60 or a
Bruker WM 250 speCtrometer and are calibrated in parts per
million (6) from tetramethylsilane (TMS) as an internal
standard. Carbon magnetic resonance spectra (CMR) were
recorded on a Druker WM 250 spectometer at 69.6 MHz using
deuterochloroform as solvent and are calibrated in parts per

million (6) from TMS as internal standard.

65

66

Microanalyses were performed by Spang Microanalytical
Labs, Eagle Harbor, Michigan. High resolution mass spectra
were performed by the Michigan State. University Department
of Biochemistry, Mass Spectroscopy Facility, East Lansing,

Michigan.

Trim-mmi64

To a solution of diisoproylamine (0.26 mL, 2 mmol) in
5mL TRF, cooled to -78°C in a dry ice-acetone bath, was
added n-butyllithium (1.1 mL, 1.55 M in hexane, 1.70 mmol)
over 2 minutes and the solution was stirred at -76°C for 30
minutes. A solution of enone 63 (610 mg, 1.57 mmol) in 5 mL
of TRF was added over 2 minutes and the resulting pale
yellow solution was stirred at -78°C for 30 minutes. To
this solution was added phenyl selenyl bromide (376 mg, 1.6
mmol) in 3 mL TRF in one portion. Stirring was continued
for an additional 2 h and the reaction mixture was slowly
warmed to 0°C and then 208 acetic acid (15 mL) was added
followed by addition of 308 hydrogen peroxide (63 mL). This
mixture was stirred .for l h at 0°C and warmed to room
temperature in a period of 30 minutes. The reaction was
quenched with 10 mL of water and extracted with ether (4
times). The combined organic layers were washed with water,
brine and dried with anhydrous magnesium sulfate. Removal

of the solvent gave a yellow oil which was chromatographed

ye
PM.
3H

311.

H
:1
cm
12E
53.
27.
11

CI'

Has

Che
PIIH
1.1

3.0

#3
*1
Cm;

128

67

(silica-ether) to give 515 I; (853) of trienone 54 es a
yellow oil. Characteristic properties of 54 p are:

P88 (00013) 250 882: 5 0.78 (s, 38), 1.20 (s, 38), 1.21 (s,
38), 1.3-2.4 (I, 88), 2.65 (I, 18), 3.05 (I, 28), 3.40 (s,
38), 3.56 (I, 28), 3.70 (I, 38), 4.62 (d, 18, J&6.782), 4.73
(d, 18, J56.782), 5.37 (q, 18, J23.382), 6.11 (t, 18,
JEl.882), 6.27 (dd, 18, Jhl.8,10.182), 7.0 (d, 18,
J&10.182).

088 (00013) 69.8 882: a 185.74, 165.87, 154.81, 145.28,
128.16, 123.67, 116.52, 94.58, 83.89, 74.94, 71.54, 66.48,
58.72, 49.42, 46.23, 44.35, 42.36, 34.89, 33.10, 32.91,
27.37, 24.71, 19.49, 16.70. 1

IR (0014): 3040, 2940, 2880, 2805, 1665, 1630, 1605, 1375
CI'l.

Mess spectruI (70eV): IVe’(re1. intens.) 386 (M’, 2), 371
(1), 310 (2), 265 (6), 159 (12), 89 (54), '59 (100).
Characteristic properties of 54 s are:

P88 (00613) 250 M82: 0 0.86 (s, 38), 1.09 (d, 38, J5182),
1.18 (s, 38), 1.5-2.0 (I, 78), 2.25 (I, 18), 2.65 (I, 18),
3.05 (I, 28), 3.40 (s, 38), 3.57 (I, 28), 3.70 (I, 28), 4.0
(dd, 18, .k6.4 and 9.082), 4.71 (s, 28), 5.35 (q, 18,
JE3.382), 6.11 (t, 18, J&1.882), 6.27 (dd, 18,
J&1.8,10.l82), 7.0 (d, 18, J&10.182).

CHE (CDCla) 69.8 M82: 5 185.45, 165.35, 154.47, 144.52,
128.05, 123.55, 116.57, 94.52, 84.65, 71.35, 66.30, 58.58,

48.07.
26.82.
11 (CCJ
1460, .
Hall a]

(2). 2!

1.4—8-
A
of dry
bottoue
condens
freshly
butanol
resulti
50°C.
added
50°C f0
cooled,
Iith u.
extFact
dried o
'Olvent

Crude D

68

48.07, 43.83, 43.38, 42.05, 33.06, 32.86, 29.70, 27.56,
26.82, 20.67, 19.03, 16.56.

I8 (001;): 3030, 2960, 2890, 2830, 1675, 1640, 1615, 1480,
1460, 1300 CI'l.

Mass spectruI (70eV): sVe’(re1. intens.) 386 (Ht, 1), 280

(2), 265 (2), 225 (1), 259 (6), 89 (43), 59 (100).

4y¥ifllldhfluuienuutflfl

A solution of trienone 54 (405 Ig, 1.05 IIol) in 50 IL
of dry benzene was prepared in a 100 IL three-necked round-
hottoIed flask equipped with an argon inlet, reflux
condenser, Iagnetic stirrer and an oil heating bath. A
freshly prepared solution of potassiuI t-butoxide in t-
butanol (6.3 IIol) was then added dropwise, and the
resulting dark brown solution was stirred and heated to
50°C. An excess of Iethyl iodide (2.980g, 21 IIole) was
added 10 Iinutes later, and this Iixture was Iaintained at
50°C for 3 h. The resulting bright-yellow solution was
cooled, quenched with 10 IL of water, and then extracted
with three 20 IL portions of ether. The coIbined ether
extracts were washed with water, then brine and finally
dried over anhydrous sodiuI sulfate. Evaporation of the
solvent yielded 417 Ig (963) of a dark brown oil. This

' crude product proved to be air and light sensitive and was,

69

therefore, used in the next step without further
purification. Characteristic properties of 58 p are:

PMR (0001.) 250 M82: 5 0.69 (s, 38), 1.11 (s, 38), 1.12 (s,
38), 1.23 (s, 38), 1.30 (s, 38), 0.80~2.70 (I, 98), 3.37 (s,
38), 3.55 (I, 28), 3.70 (I, 38), 4.60 (d, 18, J56.782), 4.71
(d, 18, Jh6.782), 5.65 (dd, 18, J&2.9,5.682), 5.91 (d, 18,
.k4.282), 5.96 (d, 18, J&10.382), 6.75 (d, 18, J&10.382).
0M8 (00013) 69.8 M82: 6 202.69, 153.83, 148.22, 144.69,
124.91, 119.33, 115.84, 94.79, 84.33, 71.76, 66.88, 85.92,
49.26, 47.79, 46.33, 44.35, 39.03, 34.18, 30.85, 30.28,
29.60, 27.08, 24.72, 21.80, 16.60, 15.12.

18 (0013): 3050, 2980, 2950, 2890, 2840, 1690, 1670, 1485,
1330 cn-I. ' -
Mass spectruI (70eV) sVe (rel. intens.) 414 (M’, 1), 389
(l), 330 (27), 279 (54), 190 (53), 175 (34), 159 (20), 149
(23), 133 (34), 119 (33), 55 (58), 43 (100).

d?"’, 3-oIe 64

To a 500 IL three-necked, round-bottoIed flask equipped
with an argon inlet adaptor, dry-ice condenser, and
Iechanical stirrer was added 200 IL of aIIonia (freshly
distilled froI sodiuI) at -78°C. LithiuI wire (171 Ig, 24.6
IIole) and 100 IL of dry THF were then added, and the
resulting dark blue solution was stirred at -78°C for 30
Iinutes. To this solution was added a solution of 4,4-

diIethyl trienone 84 (510 Ig, 1.231 IIol) in 50 IL of dry

THF, 1
stirri
adding
evapor
residu
was ex
organi
anhydr
504 1;
oil. !
PKR (CI
33). 1,
11, .h!
4.62 (1
£3.33:
Ii (cc;

1035 .

70

THE, followed by t—butyl alcohol (910 Ig, 12.3 IIol). After
stirring at -78°C for 5 h, the reaction was quenched by
adding 1g of aIIoniuI chloride, and the excess aIIonia was
evaporated into the hood under a streaI of argon. The
residue was treated with 50 IL of water, and this Iixture
was extracted by four 20 IL portions of ether. The coIbined
organic layers were washed with ether, brine and dried over
anhydrous sodiuI sulfate. ReIoval of the solvent yielded
504 Ig (98%) of 4,4—diIethy1 67(3), 3-one 84 as an off-white
oil. Characteristic properties of 84 p are:

PMR (00013) 250 M82: 6 0.84 (s, 38), 1.02 (s, 38), 1.05 (s,
an). 1.15 (s, an, overlap), 0.80-2.40 (n. 153), 2.76 (at,
18, J55.5,14.582), 3.39 (s, 38), 3.55 (I, 28), 3.70 (I, 38),
4.62 (d, 18, Jh6.782), 4.73 (d, 18, Jk6.782), 5.22 (q, 18,
J53.382).

IR (0014): 2960, 2940, 2880, 1710, 1450, 1380, 1370, 1260,
1035 CI'l.

Mass spectruI (70eV) aye (rel. intens.) 418 (M*, 4), 403
(1), 327 (10), 312 (5), 297 (26), 159 (5), 89 (100), 59
(89), 45 (13).

Characteristic properties of 64 a are:

PMR (00013) 250 M82: 6 0.93 (s, 38), 1.01 (s, 68, overlap),
1.05 (s, 38), 1.11 (s, 38), 0.80-2.45 (I, 158), 2.75 (dt,
18, JE5.5,14.582), 3.40 (s, 38), 3.58 (I, 28), 3.70 (I, 28),
4.22 (dd, 18, J56.4,9.082), 4.71 (s, 28), 5.30 (q, 18,

J53.382).

71

can (00013) 69.8 M82: 0 216.45, 145.33, 117.73, 94.87,
85.35, 71.72, 66.59, 58.90, 52.29, 48.28, 47.73, 43.84,
30.37, 35.06, 34.77, 33.42, 31.00, 30.41, 28.07, 27.13,
24.47, 24.20, 21.48, 21.26, 17.27, 12.65.~

IR (001.): 2960, 2900, 2830, 1730, 1480, 1460, 1395, 1375,
1210. 1130, 1050 cn-l.

Mass spectruI (70eV) aye (rel. intens.) 418 (M’, 1), 403
(1), 312 (1), 297 (7), 271 (2), 213 (1), 159 (a), 89 (100),
59 (79), 45 (a).

CFr7lflcdhfl.67

This procedure will be illustrated for a single 0-17 I-
epiIer 87. A solution of 17a~MBM ether 84 (240 Ig, 0.57
IIol) in 30 IL of dry Iethylene chloride was cooled to 0°C,
and a freshly prepared solution of titaniuI dichloro-
diisoproxide in Iethylene chloride (5.74 IIol)' was added
dropwise with stirring. The resulting pale yellow solution
was warIed to rooI teIperature and it slowly turned orange
as the reaction proceeded. This solution was stirred for 12
h at rooI teIperature; the starting Iaterial was no longer
evident by TLC analysis (silica-ether). The reaction was
then quenched by addition of 2 IL of concentrated aIIoniuI
hydroxide solution and then was diluted with 10 IL of water.
The aqueous phase was extracted twice with Iethylene
chloride, and the coIbined organic phases were washed with

water until the aqueous phase was neutral. ReIoval of the

72

solvent froI the dried extracts gave a yellow oil, which was
chroIatographed (silica-ether) to give 170.5 Ig (908) of the
17s-a1coho1 87 as an off-white solid. Characteristic
properties of 87 p are:

PMR (00013) 250 M82: 6 0.81 (s, 38), 1.03 (s, 38), 1.05 (s,
38), 1.12 (s, 38), 1.17 (s, 38), 0.8-2.40 (I, 158), 2.76
(dt, 18, J=5.5,14.582), 3.78 (dd, 18, J=1.7,7.482), 5.32 (q,
18, J53.382).

IR: 3600, 2960, 2860, 1700, 1445, 1380 CI'l.

Mass spectruI (70eV): 330 (M*, 19), 315 (100), 279 (40),
271 (6), 243 (12), 159 (13).

Characteristic properties of 87 s are:

PMR (00013) 250 M82: 0 0.91 (s, 38), 1.00 (s, 38), 1.01 (s,
38), 1.05 (s, 38), 1.11 (s, 38), 1.26 (s, 38), 1.74 (s, 38),
0.80—2.45 (I, 168), 2.76 (dt, 18, J55.5,14.582), 4.09 (dd,
18, J56.6,9.082), 5.30 (q, 18, J53.382).

0M8 (00013) 69.8 M82: 6 216.68, 145.47, 117.77, 80.60,
52.37, 48.31, 47.82, 44.01, 38.43, 35.13, 34.83, 33.52,
30.67, 29.71, 27.10, 24.52, 24.25, 21.54, 20.41, 17.24,
12.71.

IR (0014): 3640, 2970, 2940, 2880, 1740, 1465, 1390, 1275,
1120, 1045 cI‘l.

Mass spectruI (70eV) 330 (5), 315 (19), 297 (8), 243 (4),
149 (12), 145 (9), 119 (18), 105 (24), 57 (41), 43 (100).

73

03,rriflllhuI188

A solution of oxaryl chloride (0.1 IL, 1.14 IIol) in 5
IL of Iethylene chloride was placed in a 25 IL pear-shaped
flask equipped with an argon inlet, a Iagnetic stirred, and
cooled by a dry-ice/acetone bath. 0iIethy1 sulfoxide (0.2
IL, 3.2 IIol) was added slowly to the stirred oxaryl
chloride solution at -78°C, and after a 2 Iinute pause, a
solution of alcohol 87 (230 Ig, 0.7 IIol) in 2 IL of
Iethylene chloride was added. Stirring was continued for an
additional 15 Iinutes; triethylaIine (1 IL, 7.1 IIol) was
then added and the reaction Iixture was slowly warIed to
rooI teIperature. After Iixing with 10 IL of cold water,
the organic phase was separated and the aqueous phase was
extracted twice with ether. The coIbined organic phases
were washed with water, brine and dried over anhydrous
IagnesiuI sulfate. ReIoval of the solvent gave a yellow oil
which was chroIatographed (silica-hexane:ether:3:1) to give
210 Ig (918) of the 03,17-diketone 68 as a white solid.
PMR (00013) 250 M82: 0 0.98 (s, 38), 0.99 (s, 38), 1.04 (s,q
38), 1.07 (s, 38), 1.13 (s, 38), 0.80—2.40 (I, .148), 2.50
(ddd, 18, Jhl.8,9.6,19.482), 2.77 (dt, 18, JE5.5,14.582),
5.47 (q, 18, fi3.5,6.682).
0M8 (00013) 68.7 M82: 0 219.46, 216.19, 142.86, 119.17,
. 52.36, 48.52, 47.78, 46.17, 38.39, 35.19, 34.76, 34.21,
30.77, 29.65, 26.85, 24.56, 24.43, 24.19, 23.54, 21.58,
16.97, 12.66.

74

IR (0014): 2985, 2970, 1750, 1720, 1470, 1395, 1380, 1375
CI‘l.

Mass spectruI (70eV) aye (rel. intens.) 328 (M‘, 5), 313
(10), 295 (3), 271 (4), 257 (4), 241 (4), 175 (5), 149 (37),
129 (48), 119 (23), 83 (37), 69 (30), 55 (82), 41 (100).

CPapdflcdhfl.89

A solution of 03,17-diketone 88 (210 Ig, 0.66 IIol) in
15 IL of 952 aqueous ethanol was cooled to 0°C,‘ and 6 IL of
0.1M sodiuI borohydride in 38 aqueous sodiuI hydroxide was
added dropwise. This solution was stirred at 0°C, and the
reaction progress was Ionitored by TLC (silica—ether).
After 3 h, the soltuion was diluted with 20 IL of water and
extracted three 20 IL portions of ether. The coIbined ether
layers were washed with water, brine, and dried over
anhydrous sodiuI sulfate. ReIoval of the solvent yielded
189 Ig (918) of the 0-3p-alcohol 88 as an off-white solid.
PMR (00013) 250 M82: 6 0.78 (s, 38), 0.88 (s, 38), 0.94 (s,
38), 0.99 (s, 38), 1.05 (s, 38), 0.8-2.4 (I, 168), 2.50
(ddd, 18, J51.8,9.6,19.482), 3.26 (dd, 18, J54.4,10.882),
5.44 (q, 18, J53.382).
CMR (00013) 69.8 M82: 0 220.09, 142.58, 119.20, 78.94,
50.63, 48.90, 46.12, 38.89, 37.08, 35.05, 34.24, 31.12,
30.69, 29.62, 27.54, 26.67, 24.43, 23.73, 23.47, 16.77,
14.70, 12.91.

75

18 (0014): 3600, 2990, 1720, 1475, 1380 CI'1.

Mass spectruI (70eV) IVs (rel. intens.) 331 (7), 330 (M’,
27), 297 (42), 285 (4), 271 (4), 190 (32), 175 (17), 183
(10), 149 (25), 133 (15), 119 (19), 84 (100), 57 (79), 43
(89).

(banal-112

To a cooled (-78°0) stirred solution of oxaryl chloride
(1.22 IL, 13.95 IIol) in 30 IL dry Iethylene chloride was
added (5 Iinutes) a solution of diIethyl sulfoxide (1.5 IL,
2.1 IIol) in 5 IL of Iethylene chloride. This Iixture was
stirred for 5 Iinutes,‘ and a solution of alcohol 70 (1.05g,
4.65 IIol) was then added over a 10 Iinute period. Stirring
was continued for an additional 20 Iinutes at -78°C,
followed by addition of 10 IL of triethylaIine. The
reaction Iixture was warIed to rooI teIperature, diluted
with 50 IL of water and the organic phase was separated.
The aqueous layer was extracted with three 30 IL portions of
ether, and the coIbined organic layers were washed with
water, brine and dried over anhydrous sodiuI sulfate.
Evaporation of the solvent gave 980 Ig of a yellow oil as a
Iixture of ketones epiIeric at 0-17. This epiIeric Iixture,
in 30 IL of dry ethanol, was added to a freshly prepared
solution of sodiuI ethoxide (15 IIol) in ethanol (15 IL of a
l Iolar solution in ethanol). After stirring at rooI

teIperature for 3 h, the reaction Iixture was quenched with

76

water and extracted with ether (five tiIes). The coIbined
ether extracts were washed and dried; and evaporation of the
solvent, followed by flash chroIatography (silica-
hexane:ethy1acetate:4:1), yielded 843 Ig (80.33) of the 17-a
Iethyl ketone 12 as an off—white solid, I.p. 47—48°.
PMR (00013) 250 M82: 0 0.91 (s, 38), 0.92 (d, 38, JE182),
0.8-2.0 (I, 98), 2.08 (s, 38), 2.22-2.38 (I, 18), 2.75 (t,
18, JE8.382), 3.2 (I, 18), 3.27 (s, 38).

(klpoull784IIl79
To a chilled (0°C) solution of n-butyllithiuI (1.85 IL

of a 1.6M hexane solution, 2.96 IIol) in 2.6 IL of T8? was
added TMBDA (317 ul, 2.96 IIol). This Iixture was warIed to
rooI teIperature and stirred for 30 Iinutes. The resulting
pale yellow solution was cooled to 0°C and diIethylsulfide
(220 ul, 3.0 IIol) was added. The resulting yellow solution
was stirred for 3 h at rooI teIperature, cooled to -78°C in
a dry-ice/acetone bath, and then Iixed with a pre-cooled (-
78°C) solution of 17-s Iethyl ketone 12 (663 Ig, 2.96 IIol)
in 15 IL of T86. This Iixture was warIed to rooI
teIperature and then diluted with 50 IL of ether and 10 IL
of saturated aqueous aIIoniuI chloride. The organic phase
was separated, washed with water, brine and dried over
anhydrous sodiuI sulfate. ReIoval of the solvent gave the

crude adduct (698 Ig, 998) as a yellow oil which was used

II
I!
01

ex
ac
Ev
tr
id
f0

PM

He:
20'

10s

77

without further purification. The characteristic properties
of this C-21 alcohol 78 are:

PMR (00013) 250 M82: 0 0.90 (s, 38), 1.18 (s, 38), 1.31 (s,
38), 0.9-2.0 (I, 128), 2.15 (s, 38), 2.60 (s, 28), 3.19 (I,
18), 3.28 (s, 38).

IR (neat): 3500, 2970, 2940, 2910, 1470, 1430, 1380, 1090
cI'l.

Mass spectruI (70eV) aye (rel. intens.) 286 (M’, 1), 269
(1), 225 (16), 193 (12), 175 (16), 149 (48), 123 (30), 71
(100). 43 (87).

A portion of this alcohol (238 Ig, 1 IIol) was added to
excess Iethyl iodide (5 IL, 35 IIol) in 10 IL of dry
acetone, and the reaction Iixture was refluxed overnight.
Evaporation of the solvent gave a brown solid, which on
trituration with ether, yielded a white solid (310 Ig, 75%)

identified as sulfoniuI salt 79. Pure 79 displays the

following properties: I.p. 210 (Dec).
PMR (do-Acetone) 250 M82: 5 0.90 (s, 38), 1.19 (s, 38), 1.56
(s, 38), 0.90-2.0 (I, 128), 3.19 (I, 18), 3.21 (s, 38), 3.24
(s, 38), 3.28 (s, 38), 3.79 (d, 18, J51382), 3.98 (d, 18,
J51382).

Mass spectruI (70eV) IVe (rel. intens.) 255 (l), 225 (37),
207 (3), 193 (24), 175 (28), 149 (50), 142 (99), 127 (45),

109 (25), 71 (100).

78

(kIpoIII80

To a suspension of the sulfoniuI salt 79 (414 Ig, 1
IIol) in 20 IL of T8? was added 30 Ig (1.25 IIole) of sodiuI
hydride in one portion. After this Iixture was stirred at
rooI teIperature for 4 h, the starting Iaterial was no
longer evident by TLC analysis (silica-hexane:etherz3:1),
and the reaction was quenched with water and then extracted
with ether (three tiIes). The coIbined organic extracts
were washed with water, brine and dried over anhydrous
sodiuI sulfate. ReIoval of the solvent gave 230 Ig of crude
product, which on chroIatography (silica-hexane:ether:3:l),
yielded 215 Ig (903) of pure epoxide 80.
PMR (00013) 250 M82: 0 0.88 (s, 38), 1.11 (s, 38), 1.35 (s,
38), l.0-2.10 (I, 118), 2.30 (d, 18, JE5.2582), 2.49 (d, 18,
JE5.2582), 3.16 (I, 18), 3.28 (s, 38).
0M8 (00013) 69.8 M82: 6 85.00, 57.71, 56.24, 51.20, 49.89,
48.70, 44.83, 32.95, 28.95, 23.65, 23.13, 22.72, 20.05;
17.83, 17.60.
18 (0014): 3050, 2990, 2975, 2800, 2830, 1475, 1450, 1390,
1350, 1270, 1190, 1100 Cl'l.
Mass spectruI (70eV) sVe (rel. intens.) 238 (M’, 1), 223
(1), 206 (3), 191 (3), 175 (5), 147 (18), 122 (37), 107
(37), 98 (30), 71 (82), 43 (100).

79

Cain-Idln

To a cooled (0°C) solution of epoxide 80 (215 Ig, 0.90
IIol) in 20 IL of 3:1 (v/v) ether/benzene was added 3 IL of
a 1M solution of ethoxy ethynyl IagnesiuI broIide (3.0 IIol,
freshly prepared by reacting ethyl IagnesiuI broIide in
ether with ethoxyacetylene in benzene). The light brown
Iixture was warIed to rooI teIperature, and reaction
progress was Ionitored by TLC analysis (silica-
hexane:ether:3:1). After 2 h, the reaction was quenched
with 5 IL of saturated aqueous aIIoniuI chloride and
extracted with ether (four tiIes). The coIbined organic
layers were washed with water, brine and dried over
anhydrous IagnesiuI sulfate. Evaporation of the solvent
gave 247 Ig (898) of ynol ether 81 as a yellow oil.
PMR (00013) 250 M82: 5 0.89 (s, 38), 1.0 (s, 38), 1.01 (d,
an, $6.882), 1.37 (t, 311, 027.0112), 0.9-2.o (n, 133), 3.16
(I, 18), 3.28 (s, 38), 4.2 (q, 28, J57.082), 4.67 (d, 18,
J52.382).
0M8 (00013) 69.8 M82: 5 93.88, 85.35, 74.47, 63.97, 57.71,
48.83, 46.41, 43.69, 41.24, 39.52, 32.75, 29.26, 26.18,
23.77, 23.23, 17.77, 17.05, 14.37, 13.42.
18 (0014): 3620, 2955, 2895, 2850, 1685, 1460, 1380, 1260,

1115 CI’l.

80

Chaps-ullfltlullfi

. To a chilled (0°C) suspension of lithiuI aluIinuI
hydride (22.2 Ig, 0.584 IIol) in 30 IL of ether was added
(dropwise with stirring) a solution of ynol ether 81 (180
Ig, 0.584 IIol) in 5 IL of ether. The reaction Iixture was
warIed to rooI teIperature; and after stirring for 2 h,
excess hydride was destroyed by addition of 2 IL of 3N Na08
solution and diluted with 10 IL of water. Extraction with
ether followed by reIoval of solvent yielded 180 Ig (993) of
vinyl ether 82, a colorless oil which was used without
further purification. The characteristic properties of
vinyl ether 8! are:
PM! (00013) 250 M82: 6 0.88 (s, 38), 0.88 (d, 38,1 $6.882),
1.01 (s, 38), 1.28 (t, 38, J57.082), 0.9-2.0 (I, 138), 3.16
(I, 18), 3.28 (s, 38), 3.74 (q, 18, J57.082), 4.29 (dd, 18,
Jh2.3,7.982), 4.91 (dd, 18, JE7.9,12.682), 6.44 (d, 18,
J212.682).
CMR (00013) 69.8 M82: 6 148.11, 105.94, 85.27, 71.42, 64.68,
57.65, 48.76, 46.65, 43.74, 40.80, 32.69, 29.21, 26.03,
23.20, 17.72, 16.95, 14.62, 12.33.

This product was dissolved in 20 IL of 5:1 (v/v)
THE/water containing two drops of concentrated hydrochloric
acid. The resulting solution was stirred at rooa
teIperature and reaction progress was Ionitored by TLC.
After 3 h, the Iixture was diluted with water and then

extracted with ether. The coIbined ether extracts were

81

washed with saturated aqueous sodiuI bicarbonate, water,
brine and dried over sodiuI sulfate. Evaporation of the
solvent yielded a light yellow oil which was flash
chroIatographed (silica-hexane:ethylacetate:3:1) to give 130
Ig (84.48) of pure unsaturated aldehyde 8! as a white solid,
I.p. = 51-53°. .

PME (00013) 250 M82: 6 0.86 (s, 38), 0.96 (s, 38), 1.04 (d,
38, Jh6.982), 1.0-2.0 (I, ?8), 2.48 (I, 18), 3.16 (I, 18),
3.28 (s, 38), 6.06 (dd, 18, JE7.9,15.782), 6.70 (dd, 18,
J59.6,15.782), 9.49 (d, 18, J57.982).

0M8 (00013) 69.8 M82: 6 194.26, 165.03, 130.57, 84.92,
57.56, 51.55, 48.53, 43.88, 39.94, 32.47, 28.91, 26.13,
23.32, 23.02, 17.42. 16.99. '

IR (0014): 3020, 2980, 2960, 2880, 2820, 2740, 1695, 1635,
1455, 1380, 1190, 1095 Cl'l.

Mass spectruI (70eV) I/e (rel. intens.) 264 (M’, 10), 249
(l), 232 (12), 214 (5), 149 (51), 139 (20), 122 (100), 107
(61), 93 (39), 71 (91), 55 (60), 41 (53).

Ca-pnlddliandlli
The unsaturated aldehyde 88 (60 Ig, 0.227 IIol) was

reduced by hydrogen (1 atI.) in the presence of palladiuI on
charcoal suspended in 20 IL of ethyl acetate. The resulting
aldehyde 88 (60 Ig, 100*) exhibits the following

characteristic properties:

82

PME (00013) 250 M82: 6 0.84 (d, 38, J-‘=6.882), 0.86 (s, 38),
1.01 (s, 38), 1.0-2.0 (I, 158), 2.42 (I, 18), 3.16 (I, 18),
3.28 (s, 38), 9.76 (t, 18, JE1.982).
can (00013) 69.8 M82: 6 202.94, 85.22, 57.60, 50.76, 48.83,
43.82, 40.89, 34.37, 33.27, 29.07, 27.14, 26.83, 23.52,
23.04, 18.66, 17.70, 16.59.
IR (0014): 2940, 2880, 2820, 1710, 1470, 1380, 1090 CI'1.
Mass spectruI (70eV) IVe (rel. intens.) 266 (M’, 3), 251
(2), 234 (10), 219 (3), 201 (3), 179 (5), 154 (30), 122
(100), 107 (36), 71 (38), 55 (18).

To a suspension of isopropyl triphenylphosphine iodide
(994 Ig, 2.3 IIol) in 30 IL of dry toluene was added 2.2 IL
of a 1M solution of potassiuI t-aIylate (2.2 IIol).
Refluxing for 30 Iinutes gave a dark red solution, to which
was added a solution of the reduced aldehyde 85 (60 Ig,
0.227 VIIol) in 2 IL of toluene. After this Iixture was
stirred for 16 h under reflux, the starting Iaterial was no
longer evident by TLC analysis (silica-
hexane:ethylacetate:4:1). The cooled reaction Iixture was
diluted with 20 IL of water and extracted (three tiIes) with
pentane:ether (4:1). The coIbined organic phases were
washed with water, brine and dried over anhydrous IagnesiuI
sulfate. Evaporation of solvent followed by coluIn
dchroIatography yielded 58 Ig (883) of the product 88 as a

colorless oil.

83

PM]! (00013) 250 M82: 6 0.84 (d, 38, J=6.182), 0.85 (s, 38),
0.99 (s, 38), 0.9-2.10 (I, 168), 1.60 (s, 38), 1.68 (s, 38),
3.16 (I, 18), 3.27 (s, 38), 5.08 (t, 18, J57.082).

0M8 (00013) 69.8 M82: 5 130.75, 125.27, 85.48, 57.71, 51.04,
48.90, 43.90, 35.87, 34.85, 33.40, 29.69, 29.24, 26.96,
25.70, 24.79, 23.66, 23.26, 18.88, 17.84, 16.64.

18 (0014): 2920, 2885, 1470, 1380, 1095 ca'l.

Mass spectruI (CI) sVe (rel. intens.) 291 (M’, 1), 273 (2),

251 (24), 233 (100), 215 (39), 203 (12), 175 (9).

84

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Aavem vascmloo mo lauuoomm and: mu ouswwm
09 g .8 30 on» 8a 8a 03 mi
r»:—:.rhp:4wp:p::-»P>bp>>:h:rpbppbp»:>p:>.burp>-LPPH:.pith .
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110

 

 

 

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mo._ + convuamu moxmuxuo
.fifiatmmfll

111

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A§vvw vascaloo mo lauuomqm new: ma ouzuwm
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zauhummm mmc:

112

Auvcm vnzonloo mo lauuoomw mmmz m~ unauwm

 

 

 

 

 

  

 

 

  

 

 

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mm fix: ms 8. 8:— .cbs gowmm mmS.

113

A‘vpm vasonloo mo lauuuoqm now:

am

ouauwm

w v.

 

 

 

 

 

 

98 on SN on. as
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Ca mum 52 mm— a: mo—
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mam fix: wmco aw. ohm: “5.3 Empowum mmg

’
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4

mm

 

114

23!

232

 

 

 

Auvbm vaaonloo mo Iahuooam can: an ousuwh
ofi. n” 88 98 a!" £3 H‘ in 93 .3a wt
RE kw

2n 1
[can

i
. {.22
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mum on .8 g; a:
M'— Va . . . . . .

 

 

 

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115

L g n 4

 

 

GO m¢

 

o
.ou.nn .o.¢ 9. ago ..qu

:. 5). mg no. ‘82 .38

96 vasonloo mo lauuoonm and:

u;

 

on.

a;

mu ousuwu

 

3

mm

 

 

to I B.

. ”8312.0 .mg
on: + 8&«6— 83?:
55.8% $5.

 

 

 

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116

mu vcaoaaoo he aauuounm and:

8N uhfl kg «'N

 

 

 

 

 

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vw .wsz mmcu n0. «tutu .cfica

 

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92

060
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117

Nd canon-co mo lsuuoomm and: ¢N oysmflm

 

 

 

 

 

 

 

 

 

 

 

 

 

8. . 8 u).
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can mm
4 «a. .
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fl
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«3.22975 5.53
a. do .38 as + 8E5 835.

 

mv .th amen «_o manna .chca tachoumm mmc:

118

at vasomaoo mo lauuooam and:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

   

 

 

RM 22 .“~ 2"
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119

 

  

 

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8 venom-co mo lsuuoomm and: mm ousuwm .

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N..— + couNN.o~ mo\_~\_o
zauhowmw mma:

120

an venom-co no Ishuoonm and: 6N Gunman

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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U

121

 

 

 

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8 Egon-co no 573025 and:

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mm ouaufim
A”. !" we
a
um
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om
nm on
+
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regs.

m. I 2 mm. a» was

. 5 g: ”mg

33 + 8392 83:00
gown—m mm:

122

RN
EN

 

 

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now «mi wms

 

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van

mom

 

 

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on do 5.80
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gang 3%
83 + snow: 8x330
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123

.A§vvm venom-co ho lsuuownm :22 =~

n." G.N 86

_
>Hrrbrhrkkk

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124

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_

Auvvm venom-co mo azuaoomm mzz m”

an chaufla

 

 

m.“ B.“

 

 

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|LIPPLbb bk—[rb Pb rb PkLV—Ll

 

 

 

 

 

 

125

 

 

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A.vnu announce mo usuuoonm :22 a” an ousufim

 

 

 

 

 

 

126

A‘vqm vaaoa-oo mo naugocam as: a" an ousmflm

0.. o.~ own o.+ , o.m

FFF»_~L_F.LL+».»»~L»»»L. _»_+>»»»>_ka—rbpbh_FLbF—F»»»~.»FL

> 33...? ‘ t 5 is 7.
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127

Aavvm venom-co Mo asuuoumm :22 a” em muzmfim

ELL
m.N

 

 

 

 

 

 

m.“ N...

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B.r

m.: CLLa.m m‘m e.u

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128

Auvpm vaaomloo ho lsuuoomm ms: nu

 

 

 

 

 

 

 

 

 

 

 

 

 

on «human
as m n M; an nu nu Mn 9: ur tnnm.m mm
thrr_rrr rrr FFF rr r?» rrP» Thrrb»frkgrrr»_rrr »_»Lr?
3 \1 1: . <1 I‘ a J
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M
m
; ELL ELL ELL
h.N O.~ fl... n.m
L hi [ r lb!

 

 

 

 

 

129

. n

_

Avam vaaon-oo mo Isuuooam as: =_ mm unamwm

Hm a.” 0.... ELLQ.W QM”.

ppprhrb Frrf.rr»nPhhkp-rFrpph|rbrp+FrhhpPPFFFFPFP

 

 

 

 

 

 

 

 

:njéiwxégj A 4 4. f1

 

 

130

mu vasonloo mo lsuaoomm mzz a” 5m ousuflm

n.m

”I

 

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I

TIT

ft!
1 I4! « n._m v
4‘ 1 fi. 1 4‘
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NH vsaomlco mo Bauuommm :2: an

an ousufim

 

 

 

 

132

88 m a.

up vasomloo mo lsuuoomm :22 mg mm «Laugh

my an

mm an

Mn a: m: LLLs

. . . -
L_rpkr_rrPF PPrrerFrhr1r£hrrrb_rrrr erbrrrhl_PrPrr

1

fl :43

 

 

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133

am venomfioo mo Eauuommm :22 ad Vow chamwm

a.- _ m. 9.. m.. s.~ m.~ n.n n.n 8.: m.r cLLu.m m.m

'.

Fr—rrPPr—rPPr—rblrlpPrrPPFPrpr—rkhr~bpbPrPrPr~FPPP—rPFP_pbrr—P

4 _ Jgjgzgjfi

 

 

 

 

 

 

 

134

am vasomloo mo lahuoumm :22 z" ~¢ ohauwh

a a m. a." m._ a N. m.~ s n m n 8.: m r ELLa

L—rrkLPPrrLVrhlrr_rPPh—rrgrrbrrrp—PPPV_rrLI__FrPPHrPFL

 

 

 

 

 

 

“moumu

 

 

 

 

135

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I— Mg IN “N In

PIrPP_-Prr—rrrPP_Pbrr—Pr+rerrFPPPP—rhrPN

337a

 

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Nu vasomloo mo Iahuomnm :22 ad

«a «Laugh

(Lt
t um um an no up up H. m. n

. . _ . . _ .
Fr?» rrrrbpr b rffrwrr;.rkpp_.rrrk r??? rrrr_

 

 

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I.l “.0 I‘m a.“ ... “.0

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136

an vasomaou mo iauuoomm at: a” me chamwh

a I Dr
I. I. N n It I. _ p —rprr pup—rpprrrr
bP-rrr
pp rrr— rrrrrrrrrPflU- P .IP p P Fr? P pl? p p r F?
Prrrrrrrrrp FrplrrhlPP PPrFrr i

 

 

 

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”on." an? ‘ -— _ — .

"of.“ "OH? H ' N m N

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8 canon-co mo £3.50QO mzz ma ev Mun—mam

G.s m... B.~ m.— G.N .m.N. 8.”. W.n 8... Q.m W.n 8.B~

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.1, 31‘ A1.»

 

cm
AV

 

137

 

 

 

 

 

138

mu vasomloo mo lzuaoomm :22 I” .mv whamwh

3.9 m. 3., w.” e.~ w.~ e.n m.n 3.: w;. CLLnfm m m

er*»_rrlrr_rrrrb Llrlqrr_ hrrf_FFrf_r»rrL rfrr~r+EE

 

 

 

T

. _ .733 4 ....

 

 

 

 

 

 

 

 

 

 

 

139

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

“vam venom-co mo anguoomm mzz on“

 

we can»:

 

 

 

 

 

 

 

 

 

 

 

 

Alvin teach-co mo lauuuoam :22 0m” 5% «Lauwh

... I. in or. 9.11: km... awn. 7.. «Mn 60.— 9.5 5...
.

a Q .- — -
_r- p» _ PP L >p _> p »:—'> >--:>_>»>L::— rrt. L r? —r>?L .> h _ pL .. > L p — p ». L p

 

 

 

 

1; 2 L 3.. 3 J. .11 _ A .._

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

140

Vm

 

141

 

 

 

 

 

 

 

 

 

ALveu announce mo Isuuomnm :22 cm. me uuaufiu

..OO— . as

3:133:43}...ng

 

 

 

 

 

 

 

142

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Auvem canon-co mo nauauoam :22 on. me «unmfim

I. Ch I... n..... ”N” In.. It. Own fin” nun nu.” NH“
. o _ . . .

 

 

 

 

 

 

143

Aavbm vasomloo ma Izuuommm :22 and

an unauwm

 

 

3

main...

 

 

 

 

 

 

 

 

 

 

 

u u: an an 9. am nu up an an n. .....lq nu nu n... um. on. 0.“ can o
h .pb r“ b a w r» .> .. h L L» .t>p»>> .bbbbl {bi > > b» E» b . ' 5 VA} — —
L [bx
1.3.... 3L
..2 “3 E: q

 

144

J

 

 

 

a venom-30 mo lauaoomm :22 o:

 

Hm ousuflu

 

 

mu vasoa-oo mo nauaoomm mzz an. an opaufiu
I 8* On On Or am am 8h .0 EN .BHH 9:” nm. Hm. Rt“ 80‘ UM GEN MUM
E. _ ---_- . -_- _-:-_c .-L . _E. -_ .-,_ LE; MEL- LE. _ET-aLL L _ . . u . . .

 

 

 

 

 

 

 

 

145

00

 

146

am vaaomloo mo Inuuomam :22 co" mm chamwu

a S~ &N a!

.......l_..-; .-.-_xizilrz ..... Fli. _

Sm 8w SP SN am 8!. S

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

147

S Q ~
EFLrfiFiLtFr;

12.?5jj

 

 

 

EN

En 8.1

 

7

 

HQ UGq—OQIOO .HO I—uhHOOQm G22 00 a V0 Uhflmwh
Sm Gm NI: Gm fim S.
x—rr+>—yrer—LFVPPFPP—r1rFFrrb..—’? P-£P.rrr*1— irkufigrd
Tar/J 3321.)! , 7<, .«413?:.! fl.-.

 

 

 

 

Goumu

 

 

 

 

 

 

 

 

 

148

I n:

hP?”b’b”_’|.L7Lrb’b”—?”‘h””_’}’}b’}"—P’?FhlI’}_”>’h}-’}—'FD*P”}’—}DII-"u.—"”.I}.? —’ '

j

 

 

 

 

x" unschloo mo lzuuoomm :2: Dad

am an ar am am . an

.33....

 

 

 

 

 

 

 

 

 

 

GOIUHI

mm «Laugh

an In awfi enfi ar— am. an.

4‘

71:41}

 

 

’b'rtl
? b P br»>rhb>>>b>rh

— th»>>>b>>>?—b>»»

P ’h”” >

a}!!!

 

149

1nrfihuollluua-

-. ..
0".

v” vczomloo mo

8. BI- OOH 88m 80h 0.0" I.Ifl..

..: _ _ _ _ _ _ ..
p p». PPEPbpp Phhpbpbpp P>>>p->~ pphnbp-pb P~>>rpp>h—PFP>>-p’p—p~P~>>-P> EPhphpp tbpubnnp—ppppr hh—hnabppbbp uppbppppp

bib).-

8 0m”

DhPF—bpbbbPhFP—

asuuooam :22 on. we unamfim

a a: N. 8m” 8 nwu

. . —
P>>nh>erHPPphbhppb—pnpbbbpbP—rhrrr>>>>»> >>rbh>>>rvrrphpup hubbbPPr

 

 

 

3:] fl ... j.-

 

 

 

 

 

 

 

 

 

 

 

 

 

uu n
O.” I—
n“ 0.
Mama "
m. u"
worn a.
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“an" n.
"I.” u
nun" a»
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wn” u
ulmu a
nun ...
u .mu m .
unnn n
a , mu .

 

 

 

150

 

 

 

 

 

 

 

 

nu vasomloo mo Iauaommm :22 On"

 

 

 

um chaufiu

AEQN afim

 

 

 

151

mu vaaoaloo mo asuuownm :22 Dog mm ousmwm

ELL
8 P“ n“ 8? EM BU IF SO an 88— ‘- EN— BU— 8..— an
-trigiir» -_-»>L- I-m I-p--i—i-L>LIIT>ibi>L>ILt»-7

»_ iLL>>>—»t> pbt#&p>>bPPb> r—rkbbh’bb >_rt>hP>L>~ILFE$_>»>>L»>?L>

 

 

 

 

 

 

 

 

 

 

 

 

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10.

11.

12.

REFERENCES

a) Ourisson, G.; Crabbe, P.; Bodig, 0., "Tetracyclic
Triterpenes”, Holden Day, Inc., San Francisco,
1864.

b) de Nayo, P., "The Higher Terpenoids", Interscience
Publishers, Inc., New York, 159.

c) Geissnan, T. A.; Grout, D. 8., ”Organic Chenistry
of Secondary Plant Metabolism", Free-an, Cooper &
Company, 1939.

Beibron, S. 1.; Jones, R. R. 11.; Robins, P. A. J.
0b.. Soc. 1949, 444.

a) Barton, D. H. R. J. Chas. Soc. 151, 1444.
b) Seitz, K.; Jeger, 0. _Helv. (Ibis. Acts. 1949, 32,
1626.

Ruzicks, L. Merjentia 153, .9, 357.
Ruzicka, L. Proc. Chm. Soc. 1959, 341.

Blickenstoff, R.; Shosh, A.; Wolf, 6., "Total Synthesis
of Steroids", Acadelic Press, New York, 1974.

Woodward, R. D.; Patchett, A. A.; Barton, D. B. 8.;
Ives, D. A. J.; Kelly, R. B. J. As. Chen. Soc. M7,
7.9, 1131. -

van Tanelen, E. 8.; Anderson, R. J. J. Al. Chen. Soc.
1972, .94, 8225.

Barton, D. B. 8.; McGhie, J. F.; Pradhan, M. K.;
Knight, 8. A. J. Chen. Soc. 1“, 876.

Kolaczkowski, L.; Reusch, H. J. Org. Chen. 1“, 50,
4766. ' ,

Grin, K.; Venkataranani, S.; Reusch, W. J. As. Chen.
Soc. 1971, .95, 270.

Eder, D.; Sonar, 6.; Wiechert, R. Angew. Chas.
Internet. Edit. 1911, .10, 496.

Johnson, H. 8.; Banerjee, D. K.; Schneider, W. P.; Gutshe,
C. D. J. Al. Chen. Soc. 1”, 72, 1426; Johnson, W.

8.; Chinn, L. J. J. As. Chas. Soc. 151, 73, 4987;

Johnson, H. 8.; Banerjee, D. K.; Schneider, W. P.;
Gutshe, C. D.; Shelberg, W. 8.; Chinn, L. J. J. As.

Chen. Soc. 152, 74, 2832.

152

13.

14.

15.

16.

1'7.

18.

19.

20.

21.

22.

23.

24.

25.

153

Danishefsky, 8.; Cavanaugh, R. J. Al. Chas. Soc. 1”,
90, 520; Danishefsky, 8.; Nagal, A.; Peterson, D.
Chen. Cm. 1972, 374.

Johnson, N. 8.; Collins, J. C.; Pappo, 8.; Rubin, M. B.
J. As. Chen. Soc. 158, so, 2685; Johnson, N. 8.;
Collins, J. C.; Pappo, 8.; Rubin, M. D.; Krop, P. J.;
Johns, N. F.; Pike, J. 8.; Bart'nann, N. J. Al. Chen.
Soc. 1933, 85, 1409.

Corrall, C. Rev. Res]. Acad. Madrid157, 51, 103;
Lora-Tanayo, N.; Marin, J. Males Fix. Quiz. 1952, 48,
693; Lora-Talayo, N.; Alberola, A.; Corrall, C. AnaIes
Fis. Win. 1%7, 53, 63.

Martinez, M. 8. Rev. Reel. Acsd. Madrid 1932, 56', 383;
Alberola, A.; Lora-Ta-ayo, N.; del Rey, A.; Soto, J.
I..; Soto, M. Males F121. Quiz. 1-, 5.9, 1359.

Tou, J. 8.; Reusch, N. J. Org. Chen. 1m, 46, 5012.

a) Koreeda, N.; Schwartz, A. J. Org. Chen. 1m, 46,

1172.
b) Dauben, N.; Brookhart, T. J. AI. Chen. Soc. 1&1,
103, 237.

c) Marina, J.; Ahe, a. and. 1931, 103. 2907.
d) Takahashi, ’1‘.; Yanada, 8.; Tsuji, J. Ibid. m1,

103, 5259.

e) Midland, N.; Kwon, Y. Tetrahedron Lett. 1-, 23,
2077.

f) Schnuff, N.; Trost, B. J. Org. Chen. 1‘, 48,
1404.

Piatak, D.; Wicha, J. Chen. Rev. 1978, 78, 199.
Redpath, J.; Zeelen, F. Chen. Soc. Rev. 1-, 12, 75.
Oliveto, E. P. in "Organic Reactions in Steroid
Chenistry”, Vol. 2, Fried, J. and Edward, J. A., Bds.,
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