Front side neighbouring group participation in 16-hydroxymethyl-17-hydroxysteroids.

Press.Printed in Great Britain.

Tetrehedxen LetteraWo. 25, pp 2115 - 2118,1975. Per-

FRONT

SIDE

BEIGRBOURIBG

GROUP

PARTICIPATIOD

IH

16-HYDROXYMBTHYL-17-BYDROXYSTBROIDS.

Gy.Schneider

and

I.Weisz-Vincee

(Institute of Organic Chemistry, J6ssef Attila University, Seeged,

Rungary )

(Received in UK 14 April19751acceptedfor publicetion 8 my 1975)

GOLDWG

and associates recently found that

of vicinal diols show high

stereospecificity

bromide in acetic acid /l/.

cis- and trans-derivatives

in

reacting with hydrogen

Thus, _cis-cgclohexane-1,2-diol is converted in

good yield to trans-1-acetoxy-2-bromocyclohexane, while -l,2-diol gives trans-1,2-diacetoxy-cyclohexane.

The

trans-cyclohexane-

mechanism

of

this

process is knownas "front side neighbouring group participation", elucidated by

BOSCHAN and WINSTZIB /2/. More recently we found that the stereospecificity

hydrogen bromide in acetic acid can be extended to

of

1,2-diole with

1,3-diols

fused to the

steroid skeleton.

For example, 3P -acetoxy-16fi-hydroxymethylandrost+-en-17ac-01 (I a), containing cis-functions on the D ring, reacts with hydrogen bromide in acetic acid (2 mol. equivalent of HBr per mol. equivalent of steroid) at room temperature to yield 17u-diacetate

(IV); m.p. 186-87'; /w

Under similar conditions,

16a-bromomethylandrost-5-ene-3P,

/D -25 f 5' ( c=o.5

CHC13).

3p-acetoxy-16p-hydroxymethylandrost+-en-

-17oC-01 (V a), containing trans functions , gives exclusively the triacetate (V b); m.p. 126-28'; /d

/D -45

2 4' ( ~~0.5 CHC13).

i'ie assume that the firststep of the stereospecific transformation of (I a) is the formation of 3

r

-acetoxy-16MC-acetoxymethylandrost-5-en-17x-

2115

2116

No.

OR2 ;

R2x1 I

OR1 I

r

D

R1 X2(1)a; AC0

b;

OAc

OR2 z

H H AC I-!

1t

CH2 ,,a'

R1 (II >(a; CH3 b; CH3

OR2

c

fH2

R1 R2

HH

(X)a;

AC AC

OR*

b;

OR1 I CFi2

kc H

AC0

H AC

H AC

I CH2 :

R1 R2 H II

OAc

H > C2H5

OR1 I CH2

R1 R2 b;

R2

Br

OR1

(v ;a;

25

ti (YII)(a; b;

Br

(VIII)

CH3 CH 3

H C2H5

)

Aa.

2117

25

-01 (I b). This compound ie cyclised in acidic medium to the orthoester (II a), which is converted by HRr to the ambident 1,3-dioxene-2-ylium ion (III) and stabilizedin the form of

3p -acetoxy-16a-bromomethylandroet-

-5-en-17cc-acetate(IV). To prove this reaction mechanism, we prepared 3p-acetoxy-16&-acetoxymethylandrost-5-en-176-01 (I

b)

/3/,

and by transesterification

of (I t) with triethyl orthoacetatethe cyclic orthoeeter(II b); m.p. 152-56';/4 /D -72 +,4' ( ~50.5 CHC13). Both compoundswere transformedby HBr in acetic acid to the corremponding 16d.-bromomethylderivative (IV) in very good yield. In this process the configurationdid nor change, as the opening of the ring of the ambident cation (III) occurs at the sterically-favoured symmetric methylene group. On the other hand, (V a) cannot form an orthoesteror ambident cation and thus, under the experimental conditions applied, this compound gives only the triacetate of (V b) via proton-catalyaed acetylation. Quite similarly, 3p -acetoxy-16p-hydroxymethylandrost-5-en-17P-al

(VI a), containing functions in the p position, is transformed by HBr in acetic adid to 16~-bromomethylandrost-5-en-3~,17(j-diacetate 132-36'; /oC/D conditions

-46 + 3' ( ~0.5

3p-acetoxy-16b

CHC13). Under

similar

(IX); m.p.

experimental

-acetoxymethylsndrost-5-en-1713-01 (VI b) /3/,

the assumed intermediate, and the cyclic orthoester (VII b) (m.p. 130-32';

/d/D

-74 + 4O; c=o.5 CHC13) also give the correspondingbromomethyl

derivative (IX). 3P-Acetoxy-16cc-hydroxymethylandrost-5-en-l7~-ol (X a), with trans eubstituentson the D

ring, can not form an ambident cation and thus,

under the above experimentalconditions, results in the triacetate (X b); m.p. 108-10';/a/D

-107 2 4'.

We thank the Chemical Works of Gedeon Richter (Budapeet)for support of this work.

No. 25

2118

References

1.

B.T.Golding, D.R.Flall, S.Sakrikar,

2.

R.Boschan, S.Winstein,

3.

Gy.Schneider, I.Weisz-Vincze, A.Vma,

J.C.S.Perkin I., 1214

J.Am.Chem.Soc., 75, 4921 (1956).

Tetrahedron Letters, 3349 (13'72).

B.Kov&cs,

(1973).