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The solvolysis of 9α, 11β-dichlorosteroids
233
TRH 8OLVOLYBIS OF ~,11fbDICHLOltOt3TRROID8
N. Murrlll, R. Grocela, W. Bebert, 0. anoj and H. L. Herzog Proaerrr Rc8carch and Development Department Sabering Corporation,Bloomfield, SVewJerrey Received June
2, 1966.
A convincing care for the ability of chlorine to give anohimerio a8sletance In displacement reactions has yet to be made
J.
.
We have now obrrerved a novel transformationof gar,llB-
dlchlororteroldsof the generic group I whloh provider some support for the idea that chlorine, in an appropriate molecular environment, may Indeed act ab a neighboring group. 0
1 ,OH
CH* OP,
I
0'
Ia+
c-0
oJ$?Rao o*Ra++ _)
I (R - R, =cE,,
II IWHS)
Compounds of formula I2, in aqueour solution at room temperature or at ~O'C, undergo spontaneous transformation Into the correepondlnggcX-chloro-ll@-hydroxy compound
(II),
accompanied by a progressive fall of pH from 8.5 to ea. 3.53.
STEROIDS
234
8:2
From 8 solution of pa,ll~-dichloro-17a,21-dihydroxy-16a134 methyl-A -pregnadlene-3,20-dione 21-disodium phosphate (800 mg.) in 40 ml. of distilled water at 60" for six hours there was isolated, by acidification to pH < 1 and filtration, 594 mg. of a crystalline precipitate which was substantially pa-chloro-11~,17a,21-trihydroxy-16a-methyl-A pregnadiene-3,20-dione
21-phosphate.
the following constants: (dioxane); hgigoH 280
mp.
A purified sample had
m.p. 173-175.1';
[al:* +l06O
237 rnp (en15,600) with a shoulder from 25O-
The structure
dephosphorylation
I,* -
of the product was proved by enzymatic
to the known chlorhydrin-21-01 and by
detailed comparison of the latter with an authentic samp1e4. There was no evidence in the solvolysls reaction mixture for the formation of any pa-chloro-lla-hydroxy
product, llp-chloro-
pa-hydroxy product or ll&chloro-gg-hydroxy The transformation
product.
of I into II (with retention of con-
figuration of ll-) can be explained by invoking the achloronium ion intermediate (III) formed by neighboring group displacement of 118-chloro by pa-chloro.
0’
Na+
‘0’
Na+
jj
CHeOP' I
Water acting as a
Aug. 1966
STEROIDS
235
base then completes the formation of II by S-attack at llin the expected manner', followed by 106s of a proton.
An
alternative possibility, that ionization at ll- ie not elgnificantly assisted by the group at 9-, but that the group at 9- blocks entry at llCX-, Is not excluded6. Experiments are now in progress to determine whether II (R = a-cxS),
as a possible intermediate in metabolism, is
Implicated In the antiinflammatory response which ia elicited when I (R 3:a-CHS) is administered to animal8 or man 7 .
1.
2.
According to L. S. Gould, Mechanism and Structure in Organic Chemistry, Henry Holt and Co., Eew York, 1959, p. 574, there has been "no evidence that a chloro group Cautiously renders appreciable anchimeric aesistance". expressed oppoeing views are given by B. Capon, and by W. Lwoweki, Quarterly Reviews, 18, 66 (1964) See also reference 6, Angew. Chem., 70, 485 (1958). footnote 48. 194 Prepared from ga,llS-dlchloro-17a,21-dlhydroxy-A pregnadiene-3,20-dione (and the 16a- and 16g-methyl homologs)7 by methanesulfonation at 21- and iodide displacement of mesylate ion by the methods of B. G. Christensen, R. F. Hirschmann and J. Putter, U.S.P. 2,932,657 (April 12, 1960) and phosphate replacement of the iodide by the method of J. Elks and 0. H. Phillips, u.s.P. 2,936,313 (day lo, 1960). The structures of the water-soluble phosphate salts were established by analysis and by enzymatic dephosphorylation with bacterial alkaline phosphatase (Eutritlonal Biochemicala, Cleveland, Ohio) to the starting materials.
3.
The extent of the pH change is a function of the degree of completeness of the reaction.
4.
H. Gerber, U.S.P. 3,086,032 (April 16, 1963).
5.
J. Fried and E. F. Sabo, J. Am. Chem. Sot., 79, 1130 (1957) l
236
STEROIDS
8:2
6.
Cf. H. C. Brown, K. J. Morgan and F. J. Chloupek, J. Am. Chem. Sot., 87, 2137 (1965). Our experimental findings offer no Support for a mechanism involving equilibrium between ionic species bearing a charge at 9- and at ll-, respectively.
7.
Cf. C. H. Robinson, L. Finckenor, E. P. Oliveto and D. Gould. J. Am. Chem. Sot., &, 2191 (1959); C. H. Robinson, L. E. Finckenor, R. Tiberi and E. P. Oliveto, J. Org. Chem., 26, 2863 (1961); L. H. Sarett, A. A. Patchett and S. L. Steelman, Progress in Drug Research, 2, 48 (1963); S. Tolksdorf, Inflammation and Diseases of Connective Tissue, L. C. Mills and J. H. Moyer, Eds., W. B. Saunders and Co., Philadelphia, 1961, p. 310; H. L. Herzog, R. IVeri, S. Symchowicz, I. I. A. Tabachnick and J. Black, Proceedings of the Second International Congress on Hormonal Steroids, in press.
TRH 8OLVOLYBIS OF ~,11fbDICHLOltOt3TRROID8
N. Murrlll, R. Grocela, W. Bebert, 0. anoj and H. L. Herzog Proaerrr Rc8carch and Development Department Sabering Corporation,Bloomfield, SVewJerrey Received June
2, 1966.
A convincing care for the ability of chlorine to give anohimerio a8sletance In displacement reactions has yet to be made
J.
.
We have now obrrerved a novel transformationof gar,llB-
dlchlororteroldsof the generic group I whloh provider some support for the idea that chlorine, in an appropriate molecular environment, may Indeed act ab a neighboring group. 0
1 ,OH
CH* OP,
I
0'
Ia+
c-0
oJ$?Rao o*Ra++ _)
I (R - R, =cE,,
II IWHS)
Compounds of formula I2, in aqueour solution at room temperature or at ~O'C, undergo spontaneous transformation Into the correepondlnggcX-chloro-ll@-hydroxy compound
(II),
accompanied by a progressive fall of pH from 8.5 to ea. 3.53.
STEROIDS
234
8:2
From 8 solution of pa,ll~-dichloro-17a,21-dihydroxy-16a134 methyl-A -pregnadlene-3,20-dione 21-disodium phosphate (800 mg.) in 40 ml. of distilled water at 60" for six hours there was isolated, by acidification to pH < 1 and filtration, 594 mg. of a crystalline precipitate which was substantially pa-chloro-11~,17a,21-trihydroxy-16a-methyl-A pregnadiene-3,20-dione
21-phosphate.
the following constants: (dioxane); hgigoH 280
mp.
A purified sample had
m.p. 173-175.1';
[al:* +l06O
237 rnp (en15,600) with a shoulder from 25O-
The structure
dephosphorylation
I,* -
of the product was proved by enzymatic
to the known chlorhydrin-21-01 and by
detailed comparison of the latter with an authentic samp1e4. There was no evidence in the solvolysls reaction mixture for the formation of any pa-chloro-lla-hydroxy
product, llp-chloro-
pa-hydroxy product or ll&chloro-gg-hydroxy The transformation
product.
of I into II (with retention of con-
figuration of ll-) can be explained by invoking the achloronium ion intermediate (III) formed by neighboring group displacement of 118-chloro by pa-chloro.
0’
Na+
‘0’
Na+
jj
CHeOP' I
Water acting as a
Aug. 1966
STEROIDS
235
base then completes the formation of II by S-attack at llin the expected manner', followed by 106s of a proton.
An
alternative possibility, that ionization at ll- ie not elgnificantly assisted by the group at 9-, but that the group at 9- blocks entry at llCX-, Is not excluded6. Experiments are now in progress to determine whether II (R = a-cxS),
as a possible intermediate in metabolism, is
Implicated In the antiinflammatory response which ia elicited when I (R 3:a-CHS) is administered to animal8 or man 7 .
1.
2.
According to L. S. Gould, Mechanism and Structure in Organic Chemistry, Henry Holt and Co., Eew York, 1959, p. 574, there has been "no evidence that a chloro group Cautiously renders appreciable anchimeric aesistance". expressed oppoeing views are given by B. Capon, and by W. Lwoweki, Quarterly Reviews, 18, 66 (1964) See also reference 6, Angew. Chem., 70, 485 (1958). footnote 48. 194 Prepared from ga,llS-dlchloro-17a,21-dlhydroxy-A pregnadiene-3,20-dione (and the 16a- and 16g-methyl homologs)7 by methanesulfonation at 21- and iodide displacement of mesylate ion by the methods of B. G. Christensen, R. F. Hirschmann and J. Putter, U.S.P. 2,932,657 (April 12, 1960) and phosphate replacement of the iodide by the method of J. Elks and 0. H. Phillips, u.s.P. 2,936,313 (day lo, 1960). The structures of the water-soluble phosphate salts were established by analysis and by enzymatic dephosphorylation with bacterial alkaline phosphatase (Eutritlonal Biochemicala, Cleveland, Ohio) to the starting materials.
3.
The extent of the pH change is a function of the degree of completeness of the reaction.
4.
H. Gerber, U.S.P. 3,086,032 (April 16, 1963).
5.
J. Fried and E. F. Sabo, J. Am. Chem. Sot., 79, 1130 (1957) l
236
STEROIDS
8:2
6.
Cf. H. C. Brown, K. J. Morgan and F. J. Chloupek, J. Am. Chem. Sot., 87, 2137 (1965). Our experimental findings offer no Support for a mechanism involving equilibrium between ionic species bearing a charge at 9- and at ll-, respectively.
7.
Cf. C. H. Robinson, L. Finckenor, E. P. Oliveto and D. Gould. J. Am. Chem. Sot., &, 2191 (1959); C. H. Robinson, L. E. Finckenor, R. Tiberi and E. P. Oliveto, J. Org. Chem., 26, 2863 (1961); L. H. Sarett, A. A. Patchett and S. L. Steelman, Progress in Drug Research, 2, 48 (1963); S. Tolksdorf, Inflammation and Diseases of Connective Tissue, L. C. Mills and J. H. Moyer, Eds., W. B. Saunders and Co., Philadelphia, 1961, p. 310; H. L. Herzog, R. IVeri, S. Symchowicz, I. I. A. Tabachnick and J. Black, Proceedings of the Second International Congress on Hormonal Steroids, in press.