JACS, 1995, 77, 4183
Transcript of JACS, 1995, 77, 4183
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8/19/2019 JACS, 1995, 77, 4183
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: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).
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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)