2357

23

SYNTHESIS AND REDUCTION OF STEROID C-20 ALKYLIDENE CYANOACETATES P. Laboratory of A t h e n s ,

Tsitsa,

G.

Tsatsas

of P h a r m a c e u t i c a l Chemistry, University I0~ S o l o n o s street, Athens-14~, Greece and

Co

Sandris

Laboratory of O r g a n i c C h e m i s t r y , University, ~2 P a t i s s i o n street, Received 8-7-78 : ABSTRACT

National Technical Athens-147, Greece

The geometry of the c o n d e n s a t i o n products between ethyl cyanoaeetate and 20-ketosteroids (Sa-pregnane-20one, 3 ~ - h y d r o x y p r e g n - 5 - e n - 2 0 - o n e and 3~-acetoxypregn-5en-20-one) was established by N M R s p e c t r a . R e d u c t i o n of these steroid C-20 alkylidene cyanoaeetates w a s s h o w n to a f f o r d one of the two p o s s i b l e C - 2 0 e p i m e r s , w h i c h s e e m to c o r r e s p o n d to the 2 0 ~ - m e t h y l configuration. INTRODUCTION It nucleus

has

is

macologically itself

been

an

shown

ideal

the

Velluz for

~roups,

since

active

enhances

by

substrate

(I) the

that

the

pharmacological

the

steroid

attachment steroid

activity

of p h a r molecule

of

the

final

products. In

connection

derivatives

nucleus

I and

the

esters

attached.

starting f r o m me

the

of p r e g n a n e ,

of d i c a r b a m a t e ne

with

we

discuss

two

now

rated

by

yield

166-167 ° (major established was

shown

by

AND

Volume 33, Number 1

I with

product

as the

pregna-

of

shown

diol

in

[eometry

reduction

and

geometry

mp

as

to

Scheof

the

cyanoacetate

which

into

could

two

136-137 ° . The

~9

and

and

Wiley

(5)

8

T

o x D

~ B

ethyl

2,

crystallization

Jackman

the

DISCUSSION

of k e t o n e

product)

their

(2)

its

with

synthesis

synthesis

points:

2 and

the

active

3.

a solid

fractional

the

(!)

particular

RESULTS

fair

undertaken

report

cyanoacetate

Condensation

of p o t e n t i a l l y

of p r o p a n e - ] j 3 - d i o l We

pregnanyl-cyanoacetate

in

have

5Q-pregnane-20-one

alkylidene

~ave

study

2b

that

s

be

isomers, NMR

~-methyl

mp

spectra

respectively. a

sepa-

It

group

January, 1979

B

24

"x" ~', ! , o 1" ]m !

CH2~CN~CO2Et

NoBH4=

C02Et

E.o./.e, ~CH2OCONHPh

~CH20H

.'±

J,

7

.o..o.

of

geometrical

to

an

isomers,

downfield examined

ester

function

relative

to

the

bEpimeric

on

the

carbons

are

more

group

than

when

to

be

167 ° and the 2.31

true

(7,8)o

The

they in

are the

of

and

2°25

the

they

trans.

This

then

21-methyl

of

of

be

are

the

similar

We

which

21-methyl have

also

al

(6)

(~-methyl)

as

the

to

~-

the

ester

was

again

cyanoacetic

2a

es-

of

mp

]66-

and

2b

on

absorptions

at 6

respectively:

62.25ppm CH3 ~

was

condensation

isolated

of has

a mixture

singlets

CN C02Et

2b(m.p136-7°)

3~-hydroxypre~n-5-en-20-one oil

cis

isomers

2a (m.p166-7°J

two

of

assumption

assigned

CH3 z~z~C02Et ~CN

an

C-22.

absorbs et

protons

alkylidene

62.31ppm

A

ester

Hayashi

the

when

case

at

~-alkyloxy-~-alkyl-o-cyathat

stereochemistry

136-]37 ° must

basis

isomer. of

deshielded

mixture

unsaturated

other

assumption

4

I.

an

stereochemistry

noacrylates

found

in

the

oo..

5

Scheme

ters

v

5

aMixture

cis

~C02Et ~

of

were the

ethyl been

reported

~eometrical

observed

oily

cyanoaeetate

at

(9)

with to

isomers, 2. 16

condensation

and

give

since 2.92

products

ppm. 8

~

and

9

starting

with

,,x,.'~'n. ox

3~-hydroxypregn-5-en-20-one

cetoxypregn-5-en-20-Oneo have

the

21-methyl

2o30

ppm

(Sb

methyl mers

8a

and

~b).

The

showed

~a

Both

products

absorptions

and

singlets

25

w) m

(ca°

at

2o35

relative

a ~reater

70/30)o

were (~

and

intensities

proportion

The

38-a-

and again

of

found

2~)

and

of

these

the

stereochemistry

of

to

isothe

un-

452.30ppm CH3~,~¢~ CN

RO~_HI C02Et 9b {R-Acl

9a (R:Ac) saturated relative

esters sizes

~0

8a

the

smaller

of

and

the

2~

3,

of

-CN

steroid

dium

~ was

2b

and

ester

of

the

upon

and

to

-COOR

the

be

controlled

groups.

the

The

least

bulkier

unsaturated

by

the

isomers

interaction

cyclopentane

at

same

NMR

3.56

to

ppm

product of

].08

be

one

was

the

cps)

ppm of

2

and

of

ring

the

and

the

two

supported

by

the

with

so-

the

as

esters

2a~

saturated

-CH(CN)C00Et

(J:6.5

to

obtained,

isomeric of

proton

(J:3

at

(3,4)

spectrum

a-methine

a doublet appears

The

The

the

cyanoacetate

catalytically

reduction

mixture°

doublet

therefore

seems

present

with

(10).

(9,10),

as

2

molecule.

~ revealed

single

-CN

then

accomplished

their

protons

the

group

borohydride

expected

and

would

Reduction ester

~

O-21

cps). possible

The

as

a

methyl ester

C-20

e-

pimers0 This

conclusion

is

Briggs

0rgias

reported

by

luminium

amalgam

reduction was pair the

product

obtained of NMR

and of

(9)

unsaturated

of

ethyl

on

the

the

esters

observations

reduction

similar

to

with 2.

The

2-cyano-3-cyclohexylcrotonate

as

a mixture

of

diastez'eoisomers,

since

doublets

centered

at

3.34

appeared

spectrum.

The

a-

reduction

and

3.56

product,

ppm

a

ml, 1 4 3 - ] 4 5 ° , o f

in

B

26

have

the

same

products at let

stereochemistry

revealed

3.60

ppm

at

I .10

?]~I~OII)|

again

(J:3 ppm

cps)

as

the and

(J:6.5

o-methine

the

~,

compound

since

proton

21-methyl

as

a

protons

these doublet

as

a doub-

cps).

CN NoBH4 ~

8 9

~ ~ ' ~

C02Et

ROI v 10 (R=H) 11 (R-Ac)

An

attempt

reduction

to

products

the

outcome

of

nes

proposed

explain

could

be

nucleophilic

by

Cherest

the

stereo~hemistry

based

on

the

additions

to

, Felkin

and

of

these

interpretation open-chain

Prudent

(11),

of

ketothrough

CH3 CH3,~=~,A

CH3

_ ~

/

CH3 or

I

~

"CH2

\,)t"8 ) A" - CN or - C02Et

(A)

B- - C02Et or - CN

20a -CH3

81c", /

J"~CH3

I t u II13

IA- CH~...,f,..-~ ~

H- H

.....

---~A~../H2

H /~ "'B A (e)

the

unsaturated

0r~ias two

as

ester

a mixture

doublets

for

8 was of

the

,~'H

H

C-20

C-21

also

(c) considered

epimers

methyl

and

was

protons

at

by

Bri~s

found Io07

and

to

have

and

1.17

ppm. In the

oily

de.

The

order

to

unsaturated reduction

compare esters products

these

observations,

8

and

2 with

]0

(mp

] 5 2 - 1 5 4 °)

we

sodium and

reduced

borohydri]I

seem

to

S

the

lowest

tion

transition

should

then

be

!!- H o w e v e r ,

and

(12)

(see

steroid

transition

state

epimer,

lectivity

and

turated

esters

such

Degradation and

refluxing

cholanic

acid

corresponding of

the

spectrum

NMR

these

nification

of

tassium

hydroxide

of

ester

this

alcohol gave

~,

then

and

of

(12)was and

(4,

the

~ was

the

corresponding

sa-

not

the

by

hydroxi-

The

the

21-methyl again cps).

in

Sapo-

possible

with

However,

reaction

in

refluxing

resultin~ Q

the

dicarbamate

po-

amyl

product

(R=Et)

column

malonate yield

by

5~-nor-

~ive

(J:6

acetate

substituted 62~

to

ppm

methanol.

separated

in

potassium

Et)appeared

hydroxide of

206

cyano-

achieved

resulting

esters.

0.98

substituted

yielded

~ was

The

and

at

the

stereose-

correspondin~

with

ethyl

refluxing

be

the

esterified

R:Me

to

other

examination.

~lycol.

potassium

the

of

of

some

20-alkylidene

cyanoacetate

a doublet

could

case.

the

under

esterification

hydride

afforded

the

(12)

in

of

which

Reduction

aluminum

lead The

cyanoacetate

with

a mixture

lonate phyo

(Q)

(C) , w h i c h

the

natural

that

this

esters

the

seems

!Q

ester

the

in

R:H)

as

have

],

with

methyl

or

decarboxylation

methyl

protons

its

(B)

diethylene (4,

esters

correlated

and

it

configura-

apply

present

of

saturated

compounds

reduction

at

20a-methyl

be

R:H)

stereochemistry

is

saponification

the

~ could (4,

27

!1

The

to

these

as

should

the

D

configuration,

attendin~

acetates

in

acid

Since

20~-methyl

-methyl

de

ester

I

(A~

assigned

the

below)°

"t't I ~ O

state

5a-norcholanic

known

~

and

ma-

chromatogra-

~ with diol

6,

lithium which

7.

EXPERIMENTAL M.ps. were determined in c a p i l l a r y t u b e s a n d are uncorrected. IR spectra were obtained with a Perkin Elmer 137 s p e c t r o m e t e r as n u j o l m u l l s , u n l e s s o t h e r w i s e stated. Proton NMR spectra were recorded on a V a r i a n E M - 3 6 0 s p e c trometer; c h e m i c a l s h i f t s a r e ~ i v e n in p p m (6) d o w n f i e l d f r o m T M S as i n t e r n a l standard. 9a-pre6nane-20-one r e d b y the p a r t i a l 20-dione (I]).

Ethyl

(!). K e t o n e i, m p 1 3 0 - 1 3 1 ° , w a s p r e p a Clemmensen reduction of ~ a - p r e g n a n e - 9 ,

22-cyano-21~-nor-~a-chol-20(22)-en-2J-oate

(2).

A so-

28

~

.'.- ".=, ",-,. o

x

x.

,,,.

l u t i o n of 4 . 5 g of k e t o n e ! a n d 2°9 g of e t h y l c y a n o a c e t a te in 70 ml of a n h y d r o u s benzene containing 3.2 g of a m m o n i u m a c e t a t e a n d 7.2 ml of a c e t i c a c i d w a s r e f l u x e d f o r 30 hrs with continuous r e m o v a l of w a t e r v i a a D e a n - S t a r k trap. T h e m i x t u r e w a s a l l o w e d to c o o l a n d the b e n z e n e l a y e r w a s w a s h e d w i t h w a t e r , d r i e d ( N a _ S 0 . ) a n d the s o l v e n t w a s removed under reduced pressure. The oily residue was treated w i t h a s m a l l a m o u n t of m e t h a n o l g i v i n g 4 g (68%) of a colorless crystalline p r o d u c t , mp 9 5 - 1 0 2 °. This was recrystallized frq~omethanol to g i v e I. 7 g (29%) of 2a, mp 1 6 6 - 1 6 7 ° . ( a ) ~ ~ - 9 5 . 5 ° (c 1 5, C h f - M e O H

1:1).

IR ~ o o

(CN),

1724

(CO)~and

1570 /om

iC=C).

NMR

(CCI 4 0 . 7 0 , s, 18-Me; 0 . 8 o , s, 19-Me; 1.41, t J = 7 cps, e s t e r m e t h y l ; 2.31, s, 3H, 2 1 - M e ; 4 . 2 8 , q J = 7 cps, 2H, ester methylene. ( F o u n d : C, 7 8 . 5 7 ; H, 10.18; N, 3 . 4 8 . ~ 2 6 H NO requires: C, 7 8 . 5 3 ; H, 9 . 8 9 ; N, 3 . 5 3 % ) . 39Th~ mother liquors were concentrated to g i v e 1.3 g (22%) of a p r o d u c t m p 1 1 0 - 1 1 7 °, m i x t u r e of 2a a n d 2b. IR 2 2 0 0 , 1724 and 1570 /cm. N M R ( C C I h ) 2 . 2 5 a n d - 2 . 3 1 , two s, 3H, 2 1 - M e . ( F o u n d : C, 7 8 . 7 6 ; H, 9 ; 7 6 ; N, 3 . 4 8 % ) . Further recrystallization of the p r o d u c t m p 1 1 0 - 1 1 7 ° fro~2~ethanol g a v e a s m a l l a m o u n t of 2b, m p 1 3 6 - 1 3 7 °.

(a)i (CC~4)

- 400 2.25,

(c 2, Chf). s,

3H,

IR 2200,

21-Me.

1724:~nd

(Found:C,

78.35;

1570 /cm. H,

N~m

9.81%).

Ethyl 22-cyano-24-nor-~m-cholan-2~-oate (~). A s o l u t i o n of 41 m g (1.1 m m o l ) of N a B H 4 in 7 ml of T H F w a s c o o l e d to 0 ° under nitrogen and 0 . 7 5 g (I. 9 m m o l ) of c y a n o a c e t a t e 2a in 3 ml of T H F w a s a d d e d d r o p w i s e . The m i x t u r e w a s s t i r r e ~ f o r 2 h r s at 0 °, t h e n p o u r e d i n t o w a t e r a n d e x t r a c t e d with e t h e r . T h e e t h e r e a l e x t r a c t w a s w a s h e d w i t h w a t e r a n d sat u r a t e d N a C 1 , d r i e d ( N a 2 S 0 4 ) and the s o l v e n t e v a p o r a t e d . The solid residue was recrystallized from methanol to g i v e 0 . 4 g (53%) of ~, m p 1 7 1 - 1 7 3 ° . T h e s a m e p r o d M g ~ w a s o b t a i ned starting wi[h the mixture 2a a n d 2 b . ( a ) ~ ~ + 1 2 . 5 ° ( c 1, Chf). IR 2 2 4 0 (CN) a n d 1740 / c m - ( C 0 ) . - N M R ( C ~ C I $ ) 0 . 7 1 , s, 18-Me; 0 . 7 8 , s, 19-Me; 1.08, d J = 6 . 5 cps, 2 1 - M e , 1.32, t J = 7 cps, e s t e r m e t h y l ; 3 . 5 6 , d J = 3 cps, IH, 22-H; 4 . 2 2 , q J = 7 cps, 2H, e s t e r m e t h y l e n e . ( F o u n d : C, 7 8 . 0 6 ; H, 10.34; N, 3 . 5 6 . C 2 6 H 4 1 N O 2 r e q u i r e s : C, 7 8 . 1 5 ; H, 10.34; N , 3 . 5 1 % ) .

24-Nor->a-cholan-23-oic

acid

(4, R:H).

A mixture

of 0.8 g

of c y a n o a c e t a t e ~ in 12 ml of ~ i e t h y l e n e g l y c o l and 2 . 0 5 g of K O H in 17 ml of d i e t h y l e n e glycol was stirred under ref l u x f o r 30 hrs. T h e c o o l e d m i x t u r e w a s p o u r e d i n t o w a t e r , acidified w i t h conc. H C 1 a n d e x t r a c t e d w i t h e t h e r to g i v e , after recrystallization from methanol, 0 . 3 g (40%) of the a c i d , m p 1 6 8 - 1 7 0 °. (Lit (12, 14), m p ]70°). Methyl 24-nor-~a-cholan-23-oate (4, R = M e ) . 0 . 2 5 g of a c i d 4_ w a s e s t e r i f i e d by r e f l u x i n g f o r - 1 . 5 h r w i t h 30 ml of H C I in m e t h a n o l . T h e s o l v e n t w a s r e m o v e d a n d the s o l i d r e s i d u e was recrystallized from methanol to g i v e 0 . 1 5 g of m e t h y l e s t e r , m p 7 9 - 8 0 ° . (Lit (12), m p 7 9 , 5 ° ) . N M R ( C C 1 4 ) 0 . 7 1 , s, 18-Me; 0 . 8 ] , s, 19-Me; 0 . 9 8 , d J = 6 ops, 2 1 - M e ; 3 . 5 8 , s,

S

ester

~'l~

BOI

I)|

29

methyl.

Ethyl 24-nor-~a-cholan-23-oate (4, R = E t ) . 0 . 3 g of a c i d 4 ~R=H) w a s e s t e r i f i e d by r e f l u x i n g f o r I. 5 h r w i t h 10 ml ~f H C I in e t h a n o l . T h e s o l v e n t w a s r e m o v e d a n d the s o l i d residue was recrystallized fE~ methanol to g i v e 0 . 2 g of et h y l ester, mp 79-81 °. (a)i +20 ° (e I, Chf). IR 1725 /cm (CO). N M R ( C C 1 4 ) 0 . 7 1 , s, ~ 8 - M e ; 0 . 8 1 , s, 19-Me; 0 . 9 8 , d J=6 cps, 2 1 - M e ; 1.26, t J=7 cps, e s t e r m e t h y l ; 4 . 1 0 , q J = 7 cps, e s t e r m e t h y l e n e . ( F o u n d : C, 7 9 . 8 6 ; H, 10.98; C 2 5 H 4 2 0 2 requires: C, 8 0 . 1 6 ; H, 1 1 . 3 0 % ) . D i e t h y l 22-carboxy-24-nor-Sa-cholan-2~-oate (~). A m i x t u r e of 2.3 g of c y a n o a c e t a t e ~ in 150 ml of n - a m y l a l c o h o l a n d 7.6 g of K 0 H in 50 ml of n - a m y l a l c o h o l w a s s t i r r e d u n d e r r e f l u x f o r 30 hrs. T h e c o o l e d m i x t u r e w a s p o u r e d i n t o w a ter a n d w a s c o n c e n t r a t e d under reduced pressure. The a l k a line aqueous solution was washed with ether and acidified w i t h I0% HCI. The a c i d i c p r o d u c t (2.1 g, mp 1 6 3 - 1 6 9 ° ) w a s then extracted w i t h e t h e r al,d e s t e r i f i e d by r e f l u x i n g for 1.5 h r w i t h 70 ml of H C I in e t h a n o l . T h e s o l v e n t w a s r e m o ved under reduced pressure a n d the o i l y r e s i d u e w a s c h r o mato~raphed over alumina. Elution with petroleum e t h e r (b. p. 65 ° ) a f f o r d e d 0 . 5 g (23~) of e s t e r _4 ( R = E t ) , mp 8 0 - 8 1 ° ( M e 0 H ) . E l u t i o n w i t h a m i x t u r e of p e t r o l e u m ether - benzene ~ a f f o r d e d 0 . 7 g (27%) of e s t e r ~, m p 9 4 - 9 0 ° ( M e 0 H ) . (a)i +27 ° (c I, C h f ) . IR 1748 / c m (CO). ( F o u n d : C, 7 5 . 3 9 ; H, ~ 0 . 3 0 . C 2 8 H 4 6 0 4 requires: C, 7 5 . ~ 0 ; H, I 0 . ~ 8 ~ ) . 22-Hydroxymethyl-24-nor-~a-cholan-23-ol (6). A s o l u t i o n containing 1 g of e s t e r ~ in 50 ml of a n h y d r o u s ether was added d r o p w i s e u n d e r i c e - c o o l i n g to a s t i r r e d s l u r r y of 0 . 8 9 g of L A H in 35 ml of e t h e r . The m i x t u r e w a s s t i r r e d f o r 20 h r s at r.t. a n d the e x c e s s h y d r i d e w a s d e c o m p o s e d under ice-cooling by a d d i t i o n of e t h a n o l a n d 5 ~ N a O H s o l u tion. T h e i n o r g a n i c precipitate was filtered and washed successively with chloroform and methylene chloride. The combined organic extracts were dried and evaporated, and the r e s i d u e w a s r e e r y s t a l l i z e d f~ methanol to g i v e 0 . 5 g (62~) of d i o l 6, m p 2 2 0 - 2 2 2 9 ( a ) < = + 1 5 . 5 ° (e I, C h f ) . I R ( C H C I 3 ) 3 2 5 ° (~H) a n d 1100 / c m ( ~ - 0 ) . ( F o u n d : C, 7 9 . 2 9 ; H, 11.98. C 2 4 H 4 2 0 2 requires: C, 7 9 . 4 9 ; H, 1 1 . 6 8 ~ ) . Dicarbamate e s t e r of 2 2 - h y d r o x y m e t h y l - 2 4 - n o r - > a - c h o l a n - 2 ~ ol (~). A m i x t u r e of 0 . 5 g (1.4 m m o l ) of d i o l 6, 0 . 3 8 g ~.2-mmol) of p h e n y l i s o c y a n a t e and some drops-of pyridine w a s h e a t e d on a s t e a m - b a t h f o r I hr. T h e e x c e s s p h e n y l isocyanate w a s r e m o v e d u n d e r v a c u u m a n d the r e s i d u e w a s dissolved in b e n z e n e , w a s h e d w i t h w a t e r , d r i e d a n d the solvent evaporated to a f f o ~ o 0 . 7 7 g (93%) of c o l o r l e s s crystalline 7, mp 92 ° . ( a ) ~ +22 ° (c I, C h f ) . I N 3 2 5 0 (v

NH), 1698 (C~) a n d 1510 / c m ( 6 N H ) . 84 .. 76 68 ;~ ) . N, 4 . 85 . C38H52N204 r e q u i r e s : Ethyl

( F o u n d : C, C, 7 5 . 9 6 ;

7 5 . 9 8 ; H, H, 8 . 7 2 ; N,

3~-hydroxy-22-cyano-24-norchola-~,20(22)-dien-23-

~

30

oate ter g).

~]~OII)!

(8). The procedure described for the unsaturated 2 was f o l l o w e d u s i n g 3 ~ - h y d r o x y p r e g n - 5 - e n - 2 0 - o n e ~n oily r e s i d u e ( 5 . 6 g) was left a f t e r r e m o v a l

solvent.

IR 3440

(OH),

2230(CN),

1730

(CO)

and

es(4.5 of the

1580 / c m

(C=C). N M R (CC14) 0.75, s, 1 8 - M e ; I . 0 2 , s, 19-Me; 1.38 a n d 1.41 , two t J=7 cps, e s t e r m e t h y l ; 2 . 3 0 and 2.35, two s, 21-Me; 3 . 4 0 - 3 . 8 0 , b r o a d m, 3-H; 4.35, q J=7 cps, e s t e r m e thylene; 5.42, m, 6-H. E t h y l ~Tacetoxy-22-cyano-24-norchola-5~20(22)-dien-23oate ( The procedure described for the unsaturated ester 2 was f o l l o w e d u s i n g 3 ~ - a c e t o x y p r e g n - 5 - e n - 2 0 - o n e (4.5 g) o ~n oily r e s i d u e (5.4 g) w a s left a f t e r r e m o v a l of the solvent. IR 2225 (CN), 1750 and 1730 (CO), and 1575 / c m (C=C). N M R ( C C I ) 0.75, s, 18-Me; ].06, s, 19-Me; 1.38 and 1.41, two t j = 7 4 c p s , e s t e r m e t h y l ; 2.00, s, - 0 C O C H z ; 2.30 and 2.35, two s, 21-Me; 4 . 3 0 , q J:7 cps, e s t e r m e t M y l e n e ; 4 . 5 0 - 4 . 8 0 , b r o a d m, 3-H; 5.50, m, 6-H. E t h y l ~-hydroxy-22-cyano-24-norchol-~-en-23-oate (!9). The unsaturated c y a n o a c e t a t e 8 (1.5 g) w a s r e d u c e d as des c r i b e d for the preparation of the s a t u r a t e d e s t e r ~. Comp o u n d !9 w a @ _ ~ b t a i n e d in 5 3 ~ y i e l d (0.8 g), mp 1 5 2 - 7 5 4 ° (Me0a)7-(a)i ~ -440 (c ].5, Chf-MeOH I:]). I R 3 3 5 0 (0U), 2 2 5 5 ( C N ) a n ~ 1745 / c m (CO). N M R (CDCI3) 0.75, s, .18-Me; 1.02, s, 19-Me; 1.10, d J=6.5 cps, 21-Me; 1.33, t J=7 cps, e s t e r m e t h y l ; 3 . 3 0 - 3 . 7 0 , b r o a d m, IH,3-H; 3.60, d J=3 cps, IH, 22-H; 4.25, q J=7 cps, 2H, e s t e r m e t h y l e n e ; 5.18, m, IH, 6-H. (Found: C, 75.35; H, 9.28; N, 3.13. C 2 6 H 3 9 N 0 3 req u i r e s : C, 75.50; H, 9.50; N, 3 . 3 9 % ) . Ethyl 3~-acetoxy-22-cyano-24-norchol-5-en-23-oate (!!). The u n s a t u r a t e d cyanoacetate 9 (4.7 g) w a s r e d u c e d as des c r i b e d for the p r e p a r a t i o n o~ the s a t u r a t e d e s t e r ~, C o m p o u n d !! w a @ 2 @ b t a i n e d in 4 3 ~ y i e l d (2 ~!, mp 2 2 0 - 2 2 ~ °

(Me0H)?-(~)i - 2 5 . 5 ° (c 1 . 5 , Chf-MeOH . 1 ) . IR 2250 (CN), 1750 a n d 17~0 / c m (CO). NMR ( C D C 1 ) 0 . 7 5 , s , 18-Me; 1 . 0 3 , s , 19-Me; 1 . 1 0 , d J = 6 . 5 c p s , 21-M~; ] 3 3 , t J = 7 c p s , e s t e r m e t h y l ; 3 . 6 0 , d J = 3 c p s , 1H, 2 2 - H ; 4 . 2 5 , q J = 7 c p s , 2H, ester methylene; 4.35-4.75, b r o a d m, 1H, 3 - H ; 5 , 2 1 , m, 1H, 6 - H . ( F o u n d : C, 7 3 . 6 4 ; H, 9 , 0 0 ; N, 2 . 8 7 . C28H41N04 r e q u i r e s : C, 7 3 . 8 1 ; H, 9 . 0 7 ; N, 3 . 0 7 % ) . ACKNOWLEDGEMENTS The a u t h o r s are i n d e b t e d b o r a t o r i e s of C N R S (France) and elemental analyses.

to the m i c r o a n a l y t i c a l CIBA (Switzerland) for

lathe

REFERENCES I. V e l l u z L., B e r t i n 254, 42 (1962). 2.

D.

and

Mathieu

Similar reaction sequences have w i t h a 1 7 - k e t o (3) and a 3 - k e t o

J. , C.

R.

ACAD.

been applied (4) s t e r o i d .

SCI.

starting

~ - ~

3

B e r t i n D. (1962).

and

Nedelec

~, ~ o

L.,

Kontonassios D., S a n d r i s C H I M . FR. 622 ( 1 9 7 3 ) . 5

Jackman (1960).

L.

6

Hayashi

T.,

CHEM.

30,

M.

and

Hori

695

Wiley I°,

I ~

31

BULL. C.

R.

Baba

SOC.

and H.,

H.

CHIM.

Tsatsas J.

and

G.,

CHEM.

Midorikawa

Hayashi T., DULL. CHEM.

Igarashi M., Hayashi S. a n d SOC. JAPAN 3 8 , 2 0 6 3 ( 1 9 6 5 ) .

8

Schwarz

J.

9.

Briggs

L.

H.

SOC.

]555

BULL.

SOC.

2881,2886 H.,

J.

0RG.

(1965).

7

M.,

FR.

CHEM.

and

SOC.

0rgias

CHEM.

E.

F,,

Midorikawa

COMM. 2 1 2 J.

CHEM.

H.,

(1969).

SOC.

1885

(C)

(]97o). I0.

Marshall

2748

J.

A.

and

Carroll

R.

D0,

J.

0RG.

CHEM.

30,

(1965).

11.

Cherest M,,Felkin TERS 2 1 9 9 ( 1 9 6 8 ) .

12.

Chuang

C.

K.,

13.

Marker

R.

E.

H.

and

Prudent

N.,

JUSTUS L I E B I G S ANN. and

Lawson

E.

J.,

J.

TETRAHEDRON L E T -

CHEM.

AM.

500,

CHEM.

270(1933). SOC.

6_~1,

852 ( ] 9 3 9 ) . 14.

Heilbron I. M., CHEM. SOC. 1 4 1 0

S a m a n t K. (1933).

M. a n d

Simpson

J.

C.

E.,

J.