8/19/2019 JACS, 1995, 77, 4183

1/2

:lug.

3, 1935

COX~IUNICATIONS

O THE

EDITOR

4183

TABLE

PRODUCTSF REACTION

F

ALLYLIC LCOHOLSITH THIONYLHLORIDE

Alcohol Reac tion conditions Pro duc t composition

CHKHClCH=CHz SOCl2,

no

solvent 33 CHaCHClCH=CHs

6770

CH&H=CHCHICl

CHaCH=CHCHzOH SOC12, no solvent 71% CHoCHClCH=CH*

CHaCH=CHCHzOH SOC12 in Et20 99% CHsCHClCH=CHt

CHaCHOHCH=CHz SOClz

in

Et20 100% CHsCH=CHCHzCl

(

- trans-

CHsCH=CHCHOHCHa SOCl, in EtzO CHsCH=CHCHClCHs

CsHsCH=CHCHzOH

0.1

M R O H +

0.1

MSOCl, in Et20

100

CeHsCHClCH=CHz

CsHbCH=CHCH*OH

60% CsHrCHClCH=CHz

40

CeHsCH=CHCHzCl

297 0 CH,CH=CCH CHzCl

100% ( -1 tram-

1

1 ROH + 1 M SOCL in Et20

show a-phenylallyl chloride is the product. This

thermodynamically less stable secondary chloride is

rearranged only very slowly in the reaction solut ion.

Our present evidence is still insufficient to decide

whether the SNi' mechanismZ nvolves a one-stage

concerted process or ionization to an intimate,

rigidly oriented carbonium chlorosulfinate ion pairI6

followed by internal returne

of

the chloride com-

ponent of t he chlorosulfinate anion to give re-

arranged chloride.

It

is very clear that the SNi'

mechanisms does not involve a carbonium chloride

ion pair of the ty pe employed by Cram' in his

preferred mechanism for the action of thionyl

chloride on the 3-phenyl-2-bu tanols.

A

carbonium

chloride ion pair

in

the a ,y-dimethylallyl system

would lead to a trans-chloride which is 100

racemic instead

of

the inverted chloride actually

observed. Fur the r, a carbonium chloride ion pair

would not lead to the specific structural results

obtained with the butenols a nd cinnamyl alcohol.

The dominant role of the SNi' reaction is soine-

times difficult to preserve. In the case of cinnamyl

alcohol, even the use of

1

M concentrations of

reactants changes the polarity of the medium and re-

sult s in the product ion of a mixture of 60 cinnamyl

chloride and

40%

a-phenylallyl chloride from the

reaction itself since a-phenylallyl chloride is stable

under the condit ions used.

5) E.

Kosower, Ph.D. Thesis, U.C.L.A.,

1952,

page

97.

(6) W. G. Young, S. Winstein and H. L. Goering,

THIS

OURNAL ,

(7) D.

J.

Cram,

ibid., 75, 332 1953).

73 ,

1958 1951).

FREDERICK

. CASERIO

GERALD . DENNIS

ROBERT . DEWOLFE

WILLIAMG. YOUNG

DEPARTMENTF CHEMISTRY

UNIVERSITYF CALIFORNIA

Los ANGELES, ALIFORNIA

RECEIVEDPRIL28, 1955

7-NORBORNENYL AND 7-NORBORNYL CATIONS

Sir:

We wish to record the synthesis of ant i-7-nor-

bornenol (I) and 7-norborneol (11),and

a

ratio of

10

in the solvolytic reactivities

of

the

corresponding

toluenesulfonates.

unti-7-Norborneno1, m.p. 117-118°, was ob-

tained: (i) as its acetate

by

reaction

of

ethylene

with acetoxycyclopentadiene, generated

in

situ

from

acetoxydicyclopentadiene,

a t looo , and (ii)

by selective hydrolysis of th e unsaturated dibromide

1)

Dissertations (Harvard): P Wilder, Jr.

l 9 5 0 ) ,

R. E. Vanelli

1950), C

J . Norton

1955).

(111),one of the products of addition of bromine to

bicycloheptadiene (IV), followed by zinc debromi-

nation of th e resulting bromohydrin.

I11 I V

7-Norborneol, m.p. 150-151°, was obtained by

cata lyti c hydrogenation of anfi-7-norbornenol

(I) .

The first order rat e constants kl) or acetolysis of

the corresponding p-toluenesulfonates in acetic acid

(0.1 M in potassium acetate, containing 1% Ac20),

and other pertinent dat a, are

,OTs

v

V I

m.p. 60.5-61.0 m.p. 54.7-55.7

ki(205 ) 8.40

X

sec.-l

23.3 0.3 kcal./mole AH* 35 .7 0.6 kcal./mole

5.7

2.0

e.u. A S -3.5

1.7

e.u.

0.04

X

sec.-l

K1(25')

6.36

X

10-'6

sec.-l

The striking situation brought to light by the

new measurements is emphasized by the following

reactivities at 25

~TOLUENESULFON

TE

anli-7-Norbornenyl 104

exo-5-Norbornenyl2 103

Cyclohexyl*

1

endo-5-Norbornenylz 10-1

7-Norborny13 10-7

It is clear that the geometry

of

the norbornyl

system is uniquely unfavorable for stabilization of a

cationic center a t (2.7.

We attribute t he high reactivity of the unti-7-

norbornenyl derivatives to powerful anchimeric

assistance to ionization

at

C.7, involving the

2,3

*-electron cloud

(VI

arrow).

It

will be noted that

a homoallylic system4 s present, which is geometri-

cally unique in th at a vacant orbital on C.7 can

overlap the p orbital systems

of

the double bond

2) S.

Winstein,

H. M.

Walborsky and

K.

Schreiber.

THIS

OURNAL,

72, 5795 1950); H. L.

Schmid an d K. Schreiber, unpublished work.

(3)

Qualitative mention of low reactivity

for

7-norbornyl chloride

and syn-7-norbornenyl chloride has been m ade by

J. D.

Roberts,

P.

0 .

Johnson and

R. A.

Carbon,

ibid., 76 , 5fiR5 1954).

( 4 ) hl

Simonctta and

S

Winstein, ibrd

,

76, 18

(19.51).

8/19/2019 JACS, 1995, 77, 4183

2/2

4184 C O M h l U N I C A T I O N S

TO

T H E

EDITOR

Vol. 77

symmetrically. The 7-norbornenyl cation may be

represented by ( V I ) .

It

reacts with solvent

V I

stereospecifically; complete retention of con-

figuration was observed in the hydrolysis of th e

dibromide

(111)

to t he alcohol, and in the acetolysis

of 7-norbornenyl toluenesulfonate ( V ) .

DEPARTMENTF CHEMISTRY

USIVERSITY F CALIFORNIA S WINSTEIN

Los AXGELES

24, CALIFORNIA

I\l SHATAVSKY

COSVERSEMEMORIALABORATORY

C S O R T O N

d - -

HARVARD

~ I V E R S I T Y

R.

B \ \ 'OODWARD

CAMBRIDGE,

hlASSACHUSE rTS

RECEIVED

U L Y

13,

1955

MICROBIOLOGICAL TRANSFORMATION OF STER-

OIDS. I. A'~ DIENE-3-KETOSTEROIDS

Sit,:

It has become a problem

of

to

devise efficient techniques for the introduction of

AI-unsaturation in cortisone

(Ij3

and cortisol

(11)

since it has been shown that A',4-pregnadiene-

17a,21-diol-3,11,20-trione111)

and A1m4-pregna-

diene-1

p ,

17a,21-triol-3,20-dione (IV) are consider-

ably more potent anti-inflammatory agents than

the natural corticosteroids. We wish to report

that I may be converted t o 111 and

I1

may be con-

verted to I V by the action of Corynebacter ium

s implex (X.T.C.C. (5946). Either I or 11, dissolved

in methanol, was added to shake flasks containing

a 24-hour culture of C . simplex in a nutrient medium

of 0.155 Difco yeast extract buffered a t PH 7.

The mixture was shaken at

28'

for

;3-24

hours.

Extraction of t he resultant broth with chloroform,

followed by evaporation to a residue and crys-

tallization from acetone, afforded excellent yields

of

I11

or IV, respectively. Compounds I11 and

IV, obtained in this way, were identical in every

respect with samples prepared by purely chemical

means. By similar microbiological procedures

we have also prepared

A1,~-pregnadiene-l'7cr,21-

diol-3,20-dione

17)

[m.p. 246-249' dec., [ a I z 5 D

+

76' (CHC13),hz::ht*hanol244 mp

(t

= 15,900),

3.03

p

(OH),

3 80 p

(20-carboiiyl),

6.0, ( i . l f i

and

6.22

p

(~14,-dietie-:3-orie),ound: C,

7:l..j(j; H,

8.401,

A1*-'-pregnadiene-l

$,2l

-diol-3,20-dione (VI)

imp.

2 7. 230.3°

dec.,

[CYI'l'D

+173O (methanol),

2-13

mp E =

1-1,300),

A 2.88 and

2.9i

p

(OH), 535

p

(?O-carbonyl), 6.07,

6.20

and

0.25 p

(A1,4-diene-3-one), ound: C, 73.49; H, S.12],

I). J .

Bunim, bl.

SI.

echet and A. J . Bollet, J . 4nz

.bled . ~ S S O L . ,

167 311 (1955).

2) H .

L.

Herzog,

A.

Xohile,

S.

Tolksdorf, XY. Charney, E.

BI

Hershberg,

P. L.

Perlman and hf.

M.

Pechet,

Sc i ence ,

121, 176 (1955).

( 3 )

E.

Vischer,

C.

hleystre and

A.

Wettstein,

HeZu Chim

Acta,

38.

855 ( 1 9 5 5 ) ,

have reported the prepa ration of 111 and

V

by the

action of usarium so la n i on cortisone and Reichstein's Compound S

respectively, and the preparation of VI and

VI1

by the action of

Caloneclria

decora on corticos terone and desoxycorticosterone (followed

by acetylation in the latter case).

4)

H. L. Herzog. C. C

Payne. hl.

A .

Jevnik. D

Gould, E.

I..

Shapiro, E. P. Oliveto and

E. B.

Hershherg, THIS

OURNAI

,

i n

press

( i j

.J. I i r i ~ d ,

. I V ,

Thnmn and

A

R l i n g s h e r p . > h i d ,

5

5 7 G i

1

AI 4-pregnadiene-2 -ol-3,20-dione 2

1

acetate (VII)6

(m.p.

202-204', [ a ] ~

143' (chloroform),

+152'

(ethanol) Xzi:hanol

43

mp

( E =

15,800, Xzzp'

2.93 p

(OH), 5.72 and 5.&0

p

(20-carbonyl, 21-acetate

interaction), 6.01, 6.16 and 6.23 p (A1s4-diene-3-one)

S.06 p

(C-0-C

of acetate), found: C, 74.46;

H,

8.241,

and 9a-fluoro-A s4-pregnadiene-1

?

17a,21-

triol-3,20-dione (IX) [m.p. 265-269' dec. , [ c ~ ] * ~ D

+111 (ethanolj, X~~: l ano1 -39

inp E = 14,800),

found:

C,

64.22;

H,

'7.31.

Calcd. for

C21H2iOjF.-

CH,O: C

(j4.37;

H,

7.611.

In addition to the recently noted, enhanced

glucocorticoid activity of the 21-acetate of IX'

we wish to report that IX and its 21-acetate

possess intense mineralocorticoid action,8

oi

the

order of the parent fluorinated steroid, 9a-fluoro-4-

pregnene-1 1B

7a,%l-triol-3,20-dione.

In subsequent reports we will describe in greater

deta il the chemistry and microbiology of these and

related transformations, a nd th e biochemical studies

of the previously undescribed A'-unsaturated

derivatives of the known natural and synthetic

steroid hormones.

(6) Ci.R. L.

Clarke, K. Dobriner,

.4.

Slooradian and C.

? i f .

Martini,

i b i d . ,

77, 661 (1955).

( 7 )

R.

F.

Hirschmann, R. Miller,

K .

E .

Reyler ,

L. H. Sarett and

11 Tishler, ibid.,77, 3166 (185n).

(8)

11, R .

Cook, Jr . , and F. Elmadjian, J . d i i i Phoi~i i i .

As.roC..

Sci. Ed.; XLII,

329

(1953) .

9) J.

Fried and

E.

F

Saho,

THISOURNAL , 76 , 1455 (1954).

A . S O B I L E

BIOLOGICALESEARCH

ABORATORIES I V , CHARNEY

SCHERINGORPORATION

P.

L.

PERLMAX

H . L. HERZOG

CHEMICALESEARCHABORATORIES C. C.

PAYNE

SCHERING

ORPORATION

11.E. TULLY

BLOOMFIELD, . J.

31 . JEVNIK

E . R HERSHBERC

RECEIVEDLrL'i 11,

1955

ISOLATION FROM URINE AND SYNTHESIS OF

TETRAHYDROCORTISONE GLUCURONOSIDE

S i r

:

I t

is generally agreed that 3a,l7cr,2l-trihydroiy-

pregnane-11,20-dione (tetrahydrocortisone) is the

most abundant adrenocortical steroid metabolite

excreted by man, and that it is present in urine

largely as a glucuronoside. Because of the general

interest in this conjugate and the recent evidence

that its synthesis can be accomplished

in

vitro' we

wish t o report its recovery froin urine in a relativelj.

pure state and the synthesis and characterization

of

its tetraacetyl methyl ester.

Eight 230-mg. doses

of

free tetrahydrocortisone

in aqueous alcohol were given orally to a man a t half

hourly intervals. Th e urine which was collected

during this period and the twelve-hour interval

that followed was acidified and extracted with

butanol. Th e butanol extract was washed with

water, neutralized with aqueous sodium carbonate

and concentrated n vacuo The crude product

which separated weighed

2.92

g. and contained

1 45

g. of t he desired sodium glucuronosidate as

determined by analysis based on the method o f

Porter and Silber.' Four hundred milligrams

of

(1) kl. 1.

Isselhacher and

1.

Axelrod,

Tins J O U R N A L , 7 7 1070 flRbd)

I ? C

c

P , l r fP r

i n 4 li

€

.?l lhrr Erai C l w n : ,

185.

201 1'130)