G. ROSENKRANZ, M. VELASCO, C. DJERASSI AND F. SONDHEIMER
4430
[CONTRIBUTION FROM
THE
Vol. 75
RESEARCH LABORATORIES OF SYNTEX, SA.]
Steroidal Sapogenins. XXX.’ Synthesis and Side Chain Degradation of 22a,5P-Spirostan-3~~-ol-ll-one Acetate BY G. ROSENKRANZ, M. VELASCO,CARLDJERASSI~ AND FRANZ SONDHEIMER RECEIVEDAPRIL13. 1953 The chemical conversion of a ring C unsubstituted steroid (“diosgenin”) t o cortisone via intermediates of the desirable series is described. A7~0(11)-22a,5,9-Spirostadien-3a-ol acetate (I), obtainable from “diosgenin,” has been oxidized by Fieser’s sodium dichromate procedure to a mixture of A8-22a,5j3-spirosten-3a-ol-7, 11-dione acetate (11) and As(11)-22a,5~-spirosten-3a-ol-7-one acetate (111). The former on zinc reduction yielded the saturated diketone IV, from which the 7-ketone function was removed by conversion t o the ethylenethioketal V and nickel desulfurization. The resulting 22a,5j3-spirostan-3a-ol-ll-oneacetate (VI) on side chain degradation furnished A1*-pregnen-3a-ol-ll,20-dione acetate (VII) and thence on hydrogenation pregnan-3a-01-1 1,aO-dione acetate (VIII). The latter substance had previously been transformed to cortisone by Gallagher and co-workers.
56 (“normal”)
A number of methods for converting steroidal under the same conditions as had been used for the A7*g(11)-dienes to 11-oxygenated derivatives have corresponding 3P,5a-is0mer,~ no attempt being been shown to be applicable to the 5/3 (“normal”) made to characterize the intermediate “furosten” series, as exemplified with methyl A7b9(l1)-3a- and “diosone.” The A16-pregnen-3a-ol-11,20-dione aceto~ycholadienate.~The latter substance had acetate (VII) thus obtained was hydrogenated to been derived from a C.12 oxygenated steroid, pregnan-3a-01-11,20-dione acetate (VIII), the furcholic a ~ i d . ~With ~ - ~the recent synthesis in these ther transformations of which to cortisone had been (I) of the 22a- described previously by Gallagher and co-workers.’ laboratories of the 5/3-A7*9(11)-diene spirostane series4 from “diosgenin,” the way was Experimental8 opened, by use of any of the above mentioned A8-22a,58-Spirosten-3a-ol-7,1 1-dione Acetate (11) and oxygenation methods, to convert a ring C unAcetate (111) by Disubstituted steroid to cortisone chemically by way A8(11)-22a,58-Spirosten-3a-ol-7-one chromate Oxidation of A7,g(11)-22a,58-Spirostadien-3a-ol of intermediates with the desirable 5fl-configura- Acetate (I).-A solution of 17.5 g. of sodium dichromate tion. In this paper we wish to describe the realiza- dihydrate in 150 cc. of glacial acetic acid was added droption of this objective by use of the C-11 oxygen wise with stirring during cu. 30 minutes to 10 g. of Ar,g(ll)22a,5j3-spirostadien-3a-olacetate ( I ) 4dissolved in 150 cc. of introduction method described by Fieser, et al., benzene kept a t 15’. After being allowed to stand overin the cholanic acid series. night a t room temperature, the mixture was diluted with A7,9(11)-22a,5/3-Spir~~tadien-3a-ol acetate (I)4 on water, the aqueous layer washed well with ether, and the oxidation with sodium dichromate in benzene- combined organic extracts were washed with sodium carbonate solution and water, dried and evaporated. The acetic a ~ i d ~ furnished ~J’ two crystalline substances. residue was chromatographed on 500 g. of ethyl acetateOne was easily recognized as the As-7,11-dione I1 washed alumina, and the fractions eluted with benzene were by its yellow color and characteristic ultraviolet crystallized from chloroform-methanol. This yielded 1.2 acetate (111) maximum a t 272 mp. The other, containing only g. (12%) of A’(11J-22~,5@-spirosten-3a-ol-7-one m.p. 223-225 , -59’, v;$! 1736 (ester) and one additional oxygen atom, showed a saturated with 1700 cm.-’ (satd. ketone). carbonyl band in the infrared and no appreciable iinal. Calcd. for C29H~20e:C, 74.01; H, 9.00. Found: absorption in the ultraviolet. It was formulated C, 74.23; H, 9.20. as the AQ(”)-7-oneTI1 by analogy with a similar The mother liquors after the removal of 111 were concenin the cho- trated and crystallized from methanol. In this way 1.25 g. product obtained by Fieser, et uZ.,3a,b*c lanic acid series, and in view of its very ready isom- (12%) of the light yellow A8-22at,5@-spirosten-3a-ol-7,11acetate (11) with m.p. 146-148” was obtained. The erization with base to an a,P-unsaturated ketone, dione analytical sample was crystallized from chloroform-methpresumably the As-7-ketoneIX. anol and showed m.p. 151-153’, [ L Y ] ~ D D-14’, 272 mM, The A8-7,11-dione I1 on zinc reduction furnished loa e 3.93, v:$ 1736 and 1671 cm.-’. 2 n d . CGcd. for CzgH4006: C, 71.87; H, 8.32. Found: the corresponding saturated diketone IV, from which the superfluous C-7 oxygen function was C. 72.06: H, 8.47. Acetate (IV).-A soluremoved through conversion to the cycloethylene tion22a,5@-Spirostan-3a-ol-7,ll-dione of 14.8 g. of the A8-7,ll-dione I1 in 600 cc. of acetic mercaptal V and subsequent nickel desulfurization. acid was heated with stirring on the steam-bath (91’) with The resulting 22a,5P-spirostan-3a-ol-ll-one ace0 g. of zinc dust for 3 hours. The metal was removed bv tate (VI) was subjected to side chain degradation filtration, washed with hot acetic acid, and the filtrate waq 3apc
(1) Paper XXIX,C. Djerassi, A. J. Lemin, H. Martinez, G . Rosenkranz and F. Sondheimer, THISJOURNAL, 76, in press (1953). (2) Department of Chemistry, Wayne University, Detroit 1, Michigan. (3) (a) L. F. Fieser, J. E. Herz and W. Huang, THISJOURNAL, 73, 2397 (1951); (b) L. F. Fieser, J. C. Babcock, J. E. Herz, W. Huang and W. P. Schneider, ibid., 78, 4053 (1951); (c) L. F. Fieser, W. Huang a n d J. C. Babcock, ibid, 7 6 , llfi (1933); (d) L. F. Fieser, W. P. Schneider and W. Huang, chi?., 7 6 , 124 (1953); (e) H. Heusser, K. Efichenberger, P. Kurath, H . R . Dallenbach and 0. Jeger, Hela. Chim. Acta, 34, 2106 (1951); ( f ) C. Djerassi, 0. Mancera, M. Velasco, G. Stork and G. Rosenkranz, THISJ O U R X A L , 74, 3321 (1952). (4) R. Yashin, G. Rosenkranz and C. Djerassi, ibid., 73, 1654 (3851). ( 3 ) I,. F. Fieser and J . t.;. Herz, Ebid.. 76, 121 (1953).
diluted with water. The resulting saturated 7,tl-dione IV after crystallization from chloroform-pentane weighed 7 .B
(fi) C. Djerassi. E. Batres, J . Romo and G. Rosenkranz, ibid., 74, 3634 (1952); cf. E. lf.Chamberlain, W.V. Ruyle, A. E. Erickson, J. M. Chemerda, L. M . Aliminosa, R. I,. Brickson, G. E. Sita and M. Tishler. ibid., 73, 2396 (19.51). (7) T. H. Kritchevsky, D. I.. Garmaise and T. F. Gallagher, ibis!., 74, 483 (1932). (8) Melting points are uncorrected, except those marked (Kof.) which were determined on a Kofler micro hot-stage. Rotations were measured in chloroform and ultraviolet absorption spectra in 95q0 ethanol solution; infrared spectra were obtained with a Perkin-Elmer model 12C single beam spectrophotometer with sodium chloride prism. We are indebted to Srta. Paquita Revaque for these measurements aud to Srta. Amparo Rarba for the microanalyses.
Sept. 20, 1953
SYNTHESIS AND DEGRAD..ZTION O F 2 ~ a a , . j P - S P I R O S T A N - n a - o L - 1- O 1 N E XCETATE
I
44.31
/-
I11
I
,-
AcO'
V
VI
IV
IX
VI1
VI11
A1B-Pregnen-3a-ol-ll ,20-dione Acetate (VII).-A solution of 2.3 g. of 22a,5~-spirostan-3a-ol-ll-one acetate in 20 cc. of acetic anhydride was heated in a bomb tube a t ca. 180' for 8 hours, poured into water, extracted with ether, washed well with sodium carbonate solution and water, dried and evaporated. The resulting oily "furosten" was oxidized 22a,5p-Spirostan-3a-ol-l I-one-7-cycloethylenemercaptal with chromium trioxide and the oily "diosone" subjected Acetate (V).-A solution of 7.9 g. of the saturated 7,Il-di- to bicarbonate saponification exactly as described in the ketone IV in 100 cc. of glacial acetic acid containing 7.9 cc. degradation of A7-22a,5a-spirosten3p-ol acetate.B Crysof ethanedithiol and 4 cc. of a saturated solution of hydrogen tallization of the product from chloroform-hexane furnished bromide in acetic acid was allowed to stand at room temper- 0.43 g. of A18-pregnen-3a-ol-ll,20-dione acetate with m.p. ature (21') for 4 hours. The thioketal which had precipi- 197-198', 205-206" (Kof.), A, 236 and 312 mp, log e 4.12 tated was collected; the filtrate was diluted with water, ex- and 1.79, A:!1' 1736, 1718, 1700 and 1670 cm.-l. tracted with ethyl acetate, and the washed organic layer Anal. Calcd. for Ca3Ha204: C, 74.16; H , 8.66. Found: was dried, evaporated, and the residue crystallized from ether. This procedure yielded a total of 3.95 g. of the thio- C, 74.35; H, 8.43. Pregnan-3a-01-11 ,20-dione Acetate (VIII) .-The A16-dione ketal V with m.p. 275-278'. An additional 0.26 g. was obtained by chromatography of the mother liquors on ethyl VI1 (0.18 g.) in ethyl acetate (20 cc.) was hydrogenated over acetate-washed alumina. The analytical specimen was crys- 0.02 g. of 10% palladized charcoal a t room temperature and atmospheric pressure. Crystallization of the product from tallized from ether a n d h a d m p . 285-287', [ L Y ] ~ O D -23', u:$x acetone-hexane yielded 0.14 g. of the saturated dione VI11 1736 and 1710 cm.-l. with m.p. 133-134', [ a I M D +133', 1736, 1720 and Anal. Calcd. for C8lH&,&: C, 66.15; H, 8.24; S, 1700 cm.-l. A sample obtained by an independent routelo 11.39. Found: C, 66.16; H, 8.29; S, 10.97. showed m.p. 134-135', [CX]'~D+135', and identity was es22a,58-Spirostan-3a-ol-ll-one Acetate (VI).-A solution tablished by mixture melting point and infrared comparison. of 3.8 g. of the thioketal V dissolved in 3 1. of ethanol (preA8-22a,5p-Spirosten3a-ol-7-one (IX).-The A9(1*)-7-one viously distilled over Raney nickel) was boiled under reflux I11 (0.30 8.) dissolved in 25 cc. of methanol was heated under for 6 hours with ca. 50 g. of W-2 Raney nickel. The metal reflux for 1 hour with 0.30 g. of potassium hydroxide under was removed by filtration, and washed well with hot alcohol. an atmosphere of nitrogen. Water was added, the solid The filtrate was evaporated to dryness, dissolved in chloro- product was collected and crystallized from chloroformform, and washed with hydrochloric acid, sodium carbonate methanol. The A8-7-one weighed 0.21 g. and had m.p. 212and water. Drying, evaporation and crystallization of the 214', 22C-221' (Kof.), [ a I a o-77", ~ A,, 252 m p , log c 4.12, residue from ether furnished 2.1 g. of the 11-ketone VI with 1674 cm.+ and free hydroxyl band. m.pd 172-176'. The analytical sample showed m.p. 179181 , 186-187' (Kof.), [alp00 +6', ZJ;~ 1736 and 1714 (9) C. Djerassi,J. Romo and G . Rosenkranz, J . Org. Chcm., 16,754 cm.-l. (1951). A m l . Calcd. for C29HUOL: C, 73.69; H , 9.38. Found: (10) 0.Mancera. H. J. Ringold, C. Djerassi, 0.Rosenkranz and F. Sondheimer, THIS JOURNAL, 76, 1285:(1953). C,73.94; H,9.39. g. and had m.p. 174-176'. Further crystallization furnished the analytical sample, m.p. 185-186', no appreciable absorption in the ultraviolet, 1736 and 1718 cm.-l. Anal. Calcd. for C28Ha06: C, 71.57; H, 8.70. Found: C, 71.86; H , 8.76.
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