STRUCTURE OF STEROID D-RING LACTONES
July Yj, 1955 [CONTRIBUTION FROM
THE
3.559
RESEARCH LABORATORIES, CHEMICAL DIVISION,MERCK& CO., h C . 1
The Structure of Steroid D-Ring Lactones' BY
N. L. WENDLER,D. TAUB AND H. L. SLATES RECEIVED JANUARY 31, 1955
D-Ring lactones resulting from peracid oxidation of 17-keto steroids and 17a-keto D-homo steroids have been shown by unambiguous means to be the products of oxygen interpolation between carbon atoms 13,17 and 13,17a, respectively. The directional course of the Demianov rearrangement of 17-hydro~y-20-amino-norpregnanes was found to be independent of the configuration a t '21,. 0
In 1942, Westerfeld2 observed that estrone on treatment with alkaline hydrogen peroxide produced a lactone. Part structure A was assigned to this lactone in virtue of the fact that the corresponding hydroxy acid could be esterified by alcohol and acid, a fact considered to be less compatible with a tertiary acid derived from the alternative isomeric lactone part structure B. 0
/v A
d B
Since the time of these original observations numerous reports3 have appeared bearing on the structure of the lactones produced from peracid oxidation of 17-keto steroids. These reports unfortunately do not provide a completely unambiguous solution to the p r ~ b l e r n . ~It is the purpose of the present paper, therefore, to present unequivocal proof that these steroid D-ring lactones are indeed t o be formulated by the structural type A. Etiocholane-3a-01-11,17-dione6 (I) was converted by perbenzoic acid in good yield to a crystalline lactone, m.p. 216-220'. The latter, on treatment in refluxing methanol with less than one equivalent of sodium methoxide, gave a 90% yield of the crystalline a,@-unsaturatedketonic acid 111, m.p. 178-179', Amax 237 mp ( e 12,100). The production of an a,@-unsaturatedketonic acid establishes unequivocally that the original lactone possesses structure I1 with oxygen interpolated between CIS and C1, in a position for ready @elimination with base.6a In 1943, Goldberg and Wydler6 observed that hydrogenation of dehydroepiandrosterone acetate cyanohydrin followed by treatment with nitrous acid produced two ketones formulated as 17(1) Presented in part a t the American Chemical Society Meetingin-miniature, January 24, 1955, Newark, N.J. ( 2 ) W. W. Westerfeld, J . Bioi. Chem., 143, 177 (1942). (3) (a) R. P . Jacobsen, ibid., 171, 61 (1947); (b) H. Levy and R. P. Jacobsen, ibid., 171, 7 1 (1947); (c) R. P . Jacobsen. G. M. Picha and H. Levy, ibid., 1'71, 81 (1947); (d) M . Keller and J . Weiss, J. Ckem. Soc , 1247 (1951); (e) R. X. Jones, P. Humphries and K. Dohriner, T m a J O U R N A L , 7 2 , 956 (1950); (f) C. yon Seemann and G . A. Grant, ibid.,72,4073 (1950); (g) E. B. Hershberg, E. Schwenk and E. Stahl, Arch. Biochem., 19, 300 (1948); (h) G. Picha, THIS JOURNAL, '74, 703 (1952); (i) J. Fried, R. W. Thoma and A . Klingsberg, ibid., '7.5, 5764 (1953). (4) For a recent reference on this topic see: N. S. Leeds, D. K. Fukushima and T. F. Gallagher, ibid., 76,2265 (1954). ( 5 ) L. H. Sarett, J. BioI. Chem., 169, 601 (1946). (5a) The configuration a t Cia would not be expected t o be altered in the peracid reaction; c . f . T. F . Gallagher and T. H. Kritchevsky, T H I 3 JOURNAL,'78, 882 (1950); R. B. Turner, ibid., 1 9 , 878 (1950). (6) For a leading reference see M. W. Goldberg and 3: Wydler, Hclu. Chim. Acta, 26, 1142 (1943).
RO,' 11, R = H IIa, R = CH3C0
I{O.'
b J I11
and 17a-keto D-homo systems. The structural assignments were based on conversion of the 1 7 a - ~ homo ketone into 1-methylchrysene. Recently Heusser and his associates1 have intimated that the appearance of the two ketones was probably to be ascribed to the presence of two C17-stereoisomeric hydroxyamines which in turn arose from an original mixture of 17a- and 17p-cyanohydrins. As if to confirm this conclusion dehydroepiandrosterone acetate was converted to its cyanohydrin and the latter acetylated to give pure A5-3p,17@diacetoxy-17-isoetianic acid nitrile.' The latter compound on successive reduction with lithium aluminum hydride and treatment with nitrous acid was reported' to give the 17a-~-homo ketone exclusively.8 In the course of the present work we were able to establish that the Demianov rearrangement of 17hydroxy-20-amino-nor-pregnanes is independent of the configuration a t C1, and gives in each instance a mixture of 17- and 17a-ketones in a ratio of ca. 1 : 6. Thus etiocholane-3cr-ol-l1,1i-dione(I) was converted to 3a,170-diacetoxy-11-keto-17-isoetianic acid nitrile (IVa). Reduction of IVa with lithium aluminum hydride and subsequent rearrangement of the intermediate amine IVb with nitrous acid followed by oxidation a t C11 produced 10-1570 of ~-homoetiocholane-3a-ol-ll,17-dione acetate (VI), m.p. 203-205' and 85-9070 of D-homoetiocholane-3~-ol-l1,17a-dione acetate (VII), m.p. 164-165'. By an alternative approach pregnane3a,17a,21-triol-11,20-dione (V) was reduced with lithium aluminum hydride and the reduction product cleaved with periodic acid to the corresponding (&-aldehyde, the latter being isolated as its alkali(7) H. Heusser, P. T h . Herzig, A. Furst and P1. A . Plattner, ibid., 33, 1093 (1950). ( 8 ) F. Ramirez and S. Stafiej, THIS JOURXAI.,7 7 , 134 (19551, recently have advanced a mechanism which would accommodate dependence of the course of rearrangement on the configuration a t 0 7 .
H. L. WENDLER, D . TAUB A N D H. I,. SIATIFS
Xi00
soluble oxime Va. Hydrogenation of Va and nitrous acid rearrangement of the intermediate amine Vb followed by chromic acid oxidation a t C1,afforded the two ketones V I and VI1 in the identical ratio as had been experienced from IVb. The structure of the 17a-ketone VII, and convquently the 17-ketone VI as well, was established Ly converting VI1 to the 7-membered lactone VI11 with perbenzoic acid. Treatment of this lactone with refluxing base in the manner described for its 0-niembered counterpart 11 (see above) produced the a$-unsaturated ketonic acid IX, imp. 164I(iO', Amax 237.5 rnp ( E 12,500). Thus the preponderant 1G,17-bond migration involved in the Demianov rearrangements stands in marked contrast to the essentially exclusive 13,17-bond transposition of the peracid reaction. The mechanistic distinction between these two reactions is, therefore, not without an element of subtlety inasmuch as both are presumed to share the common feature of an electron-deficient center in the rearranging speciesg OR? 0
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A 'V I I .'V\/ \ ' I AcO. /A\
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R10" IV, R1 = Rz = H ; Ra CN IVa, R I = Rz = CH3CO; Ra = CN IVb, R1 = Rz = H ; R3 = CHaNHZ; 1lp-OH
t
11
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