[CONTRIBUTION FROM
THE
RESEARCH LABORATORIES OF SYNTEX, S. A.]
Steroidal Sapogenins. XXV1II.l The Reaction of Peracids with Enol Acetates of AS-7-Keto and A*-11-Keto Steroidal Sapogenins BY 0. MANCERA, L. MIRAMONTES, G. ROSENKRANZ, FRANZ SONDHEIMER AND CARLDJERASSI~ RECEIVED APRIL 15, 1953 A*-22a,5a-Spirosten-3P-ol-7-one acetate (I) upon conversion to the enol acetate followed by oxidation with perbenzoic acid leads to the corresponding lla-hydroxy derivative IIIa, which can be oxidized to A8-22a,5a-spirosten-3&ol-7, 11-dione (VI). A similar reaction sequence with the analogous A8-11-ketone (VII) affords the As-11-one-7-01IX, which can be either oxidized with sodium dichromate to the A8-7,11-dioneVI or isomerized with t-butoxide to the saturated 7,11-diketone V.
Recently, there was reported a method for the procedure to the sapogenin series. The structure conversion of As-7-ketones to the corresponding of the starting material I a was proved readily by 11a-hydroxy derivatives involving transformation catalytic hydrogenation to the known7 22aI5crinto the enol acetate and oxidation with perbenzoic spirostan-3P-ol-7-one (IVa), and the conversion of or monoperphthalic acid. 4 s illustrated in the I to the oily enol acetate I1 was carried out in the allopregnane3v4and cholanic acid seriesI4this pro- standard manner* with isopropenyl acetate. In cedure was applicable to steroids with both the contrast to the results obtained in the allopregnane 5a and 5/3 configuration. We should now like to series, oxidation with monoperphthalic acid was report on similar experiments in the sapogenin quite unsatisfactory, but oxidation with perbenzoic series. acid readily yielded the expected As-22aI5aThe starting material in the earlier study, As- spirostene-3PI11a-diol-7-one 3-monoacetate (IIIa) , allopregnen-3/3-01-7,2O-dione, was obtained3s5from further characterized by acetylation to the known the mother liquors of the performic acid oxidation6 3,ll-diacetate IIIbs and by oxidation to the of the corresponding A7*9(11)-diene.X similar yellowish A8-7,11-dione (VIa) .* investigation of the mother liquors from the perIt appeared of interest to examine the course of formic acid oxidation6of A7~9(11)-22a,5a-spirostadienthis reaction with the isomeric As-11-ketone, the 3P-01 acetate has now resulted in the isolation of preparation of which (in the form of its propionate As-22a,5~-spirosten-3,3-ol-7-one (Ia) and it has VII) has recently been described. l s 9 Conversion thus been possible to investigate the applicability to the enol acetate could lead either to the 11of the earlier described3,* enol acetate-peracid acet~xy-A~-~('l)-diene VI11 or to the isomeric homoannular A8(14),g(11)-diene, and some support for the latter possibility can be found in the observation that the As-11-ketone VI1 is readily isomerized a t C-14 by means of base.'zg However, : V 0 A c RG the oily enol acetate, obtained in the usual manner, possessed an ultraviolet absorption maximum a t 240 mp, thus excluding the homoannular structure and demonstrating that the enol acetate possessed the heteroannular diene system VIII. Reaction with perbenzoic or monoperphthalic acid proceeded in markedly lower yield and furnished an a$unsaturated ketone which was shown to possess structure IX, A8-22a,5a-spirostene-3/3,7-diol11-one 3-propionate, on the basis of the following reactions. ma R:H Oxidation with dichromate led to a yellow diketone b R CH,CO VIb with an ultraviolet absorption maximum at 270 mp, characteristic of As-7,l1-diones, while brief refluxing with potassium t-butoxide in t-butyl alcohol solutionlo resulted in isomerization t o the known1° 22a,5a-spirostan-3@-01-7,11-dione(V), as was to be expected on the basis of the known behavior of III.l0 It is of interest to note that while the isomerization of I11 to the saturated 7,11Ix diketone V cannot be accomplished with acid since dehydration occurs to a As(14)*16-dien-7-one,11 such (1) Paper XXVII, C. Djerassi, W. Frick, G. Rosenkranz and F.
-K
Sondheimer, THIS J O U R N A L , 7 6 , 3496 (1953). ( 2 ) Department of Chemistry, Wayne University, Detroit, Michigan. (3) C. Djerassi, 0. AIancera, G. Stork and G. Rosenkranz, THIS J O U R N A L , 73, 44913 (1951). (4) C. Djerassi, 0. Mancera, M. Velasco, G. Stork and G. Rosenkranz, ibid., 74, 3321 (1952). ( 5 ) C. Djerassi, 0. Mancera, J. Romo and G. Rosenkranz, i b i d . , 7 5 , 3505 (1953). (6) Cf. G. Stork, J . Romo, G. Rosenkranz and C. Djerassi, tbid., 73, 3616 (1951).
(7) R . E. Marker, R . B. Wagner, P. R . Ulshafer, E. L. Wittbecker, D. P. J. Goldsmith and C. H. Ruof, ibid., 69, 2178 (1947); R . E. Marker and J. Lopez, ibid., 69, 2401 (1947). (8) C. Djerassi, E. Batres, M . Velasco and G. Rosenkranz, ibid., 74, 1712 (1952). (9) F. Sondheimer. R . Yashin, G. Rosenkranz and C. Djerassi, ibid., 74, 2696 (1952). (10) J. Romo, G. Stork, G. Rosenkranz and C. Djerassi, ibid., 74, 2918 (1052). (11) A. J. Lemin, G. Rosenkranz and C. Djerassi, ibid., 7 6 , 1745 (1953).
Sept. 20, L!LX
PERACID WITII ENOLACETATESOF A*-'~-KETo STEROIDAL SAPOGENINS
4.429
Chromatography of the mother liquors on 100 g. of ethyl acetate washed alumina and elution with benzene-ether yielded an additional 0.96 g. with m.p. 172-177". The analytical sample of the monoacetate IIIa was obtained from Experimental12 252 acetone-hexane; m.p. 177-179', [aI2OD -32", . . log E 4.10. A8-22a,5a-Spirosten-3P-ol-7-one (Ia) .-The crude crystal- mu, Ami. Calcd. for CevHd~Oe: C, 71.57; H, 8.70. Found: line product (m.p. ca. 270') from the performic acid oxidations of A7~8(11)-22a,5a-spirostadien-3P-ol acetate13 was sa- C, 71.19; H, 8.81. ponified in the usual ~ n a n n e r ~and , ~ furnished A8-22a,5aAcetylation led to the 3,11-diacetate IIIb with m.p. 169spirostene-38, 1la-diol-7-one8 in yields of 70-90%. Accu- 171', identified with an authentic specimen8 by a mixture mulated mother liquors (125 g.) after removal of the crystal- melting point and infrared comparison. line saponification product were chromatographed on 2.5 kg. As-22a,5a-Spirosten-3P-ol-7, 11-&one Acetate (ma).-The of ethyl acetate washed alumina. The benzene-ether and above 3-monoacetate IIIa (3.3 9.) in 120 cc. of glacial acetic ether eluates afforded 43 g. 2f the desired unsaturated ke- acid was oxidized at room temperature for 2 hours with a tone Ia with m.p. 170-174 , while from the chloroformsolution of 0.49 g. of chromium trioxide in 25 cc. of 80% acetone eluates there was isolated 56 g. more of As-22a,5a- acetic acid. Dilution with water, filtration and recrystallispirostene-38,l la-dio1-7-0ne.~ The analytical sample of zation from chloroform-methanol yielded 2.8 g. of yellowish the A8-7-ketone Ia was obtained from chloroform-hexane; crystals of the unsaturated diketone VIa with m.p. 224-225" m.p. 172-174', [ a l Z 0-68', ~ Xg:H 252 mp, log e 4.03, (Kofler),I6 undepressed upon admixture with an authentic8 sample, 270 mp, log e 3.95; identity was further es"a,". 1660 cm.-l and free hydroxyl band. A n d . Calcd. for C27H4004: C, 75.66; H , 9.41. Found: tablished by infrared comparison. A8-22a,5~-SpiTostene-3~,7-dio1-1 1-one 3-Propionate (a). C, 75.32; H , 9.71. enol acetate VI11 was prepared exactly as described The acetate Ib, prepared in the usual manner (acetic an- -The hydride-pyridine, 1 hour, steam-bath), was recrystallized above for IIIa from 2.5 g. of AS-22a,&-spirosten-3~-ol-Il-one propionate (VII)l19; yield, 2.85 g. of pale yellow oil, from acetone-hexane, whereupon it exhibited m.p. 208240 mp, log e 4.16. The entire crude enol acetate VI11 was 210°, [ C Y ] ~ D-87', YE::', 1736 and 1656 em.-'. treated with 1.1equivalents of monoperphthalic acid in 25 cc. Anal. Calcd. for C29H4205: C, 74.01; H, 9.00. Found: of ether for 48 hours in the above described manner. The C, 73.75; H, 8.90. crude oily oxidation product possessed 248 mp, log E 22a,Sa-Spirostan-3p-ol-7-one(IVa).-A solution of 3.0 g. 3.93 and resisted attempts a t crystallization. It was chroof the unsaturated ketone Ia in 200 cc. of ethanol was hy- matographed on 125 g. of ethyl acetate washed alumina, and drogenated overnight at room temperature and atmospheric the benzene-ether eluates were combined and recrystallized pressure with 0.5 g. of 10% palladized charcoal. Filtration from acetone-hexane, yielding 0.32 g. of colorless crystals of the catalyst, evaporation of the filtrate to dryness and re- of the A8-ll-one-7-ol I X with m.p. 197-199' (Kofler), [ L Y ] ~ O D crystallization of the residue from chloroform-hexane af- +56', 252 mp, log e 4.09, ~ ' : : ;Y 1718, 1700 and 1656 forded 2.5 g. of 22a,5a-spirostan-3P-ol-7-one ( m a ) with m.p. 212-214", [ ~ ] * O D -110', no selectiveabsorption in the ultra- em.-'. Anal. Calcd. for C80H406: C, 71.97; H, 8.86. Found: violet,a~::z~ 1700 em.-' and free hydroxyl band; lit.' m.p. C, 71.88; H, 8.77. 214-215', no rotation given. A8-22a,5~-Spirosten-3p-ol-7, 11-dione 3-Propionate (VIb). Acetylation and recrystallization from chloroform-meth-To a solution of 0.25 g. of the above unsaturated keto1 I X anol furnished the acetate IVb with m.p. 208-210°, in 10 cc. of benzene was added dropwise with stirring a t 15' [OI]~D -100". a solution of 0.5 g. of sodium dichromate dihydrate in 10 cc. Anal. Calcd. for C29Har05: C, 73.69; H, 9.38. Found: of acetic acid and the mixture was allowed to stand overC, 73.40; H, 9.65. night. After dilution with water, addition of ether and Since the literature value' for this acetate is m.p. 218', an washing in the usual manner, the solvent was removed and authentic sample? was prepared by catalytic hydrogenation the residue was recrystallized twice from chloroform-meth(palladized charcoal in ethanol solution) of A5-22a-spirosten- anol yielding 0.19 g. of the yellowish unsaturated diketone 3P-ol-7-one acetate.14 The resulting product exhibited VIb with m.p. 20&207O, [a]%D -12', XEi:H 270 mp, log e m.p. 209-210°, undepressed upon admixture with a sample 3.96, $,Eclg 1730 and 1684 ern.-'. of IVb prepared as indicated above, [CY]~"D-104'. A8-22a,5~-Spirostene-3p, 1h-diol-7-one 3-Monoacetate Anal. Calcd. for C3oHaO6: C, 72.26; H, 8.49. Found: (IIIa).-A mixture of 6.0 g. of the unsaturated ketone Ib, C, 72.11; H, 8.62. 0.9 g. of p-toluenesulfonic acid, 20 cc. of isopropenyl acetate 22a,5a-Spirostan-3p-ol-7,11-dione (V). (a) With Potasand 100 cc. of benzene was concentrated by slow distillation sium t-Butoxide.-A solution of 0.5 g. of the unsaturated over a period of 4 hours to a volume of ca. 60 cc., 5 cc. of propionate IX and 0.5 g. of potassium in 60 cc. of t-butyl isopropenyl acetate having been added at the end of the alcohol was refluxed for 30 min., poured into water, acidified, second hour and an additional 3 cc. a t the end of the third concentrated under reduced pressure and extracted with hour. The solvent was removed in vacuo, the residue was ether. The ether residue was directly saponified with dissolved in ether, washed with sodium bicarbonate solution methanolic potassium hydroxide ( 1 hour, steam-bath) and and water, dried and evaporated, leaving an oil which pos- the product was isolated by dilution with water, filtration sessed an ultraviolet absorption maximum at 240 mp, log and recrystallization from acetone; yield 0.29 g., m.p. e 4.19. The oily enol acetate 11was kept a t room tempera272-275' (Kofler), undepressed upon admixture with an ture for 48 hours with 1.2 equivalents of perbenzoic acid in authentic sample,IO no selective absorption in the ultraviolet. 50 cc. of chloroform. After washing until neutral and evap(b) With Methanolic Hydrochloric Acid.-A solution of orating, the residue was crystallized from hexane-acetone 0.3 g. of the propionate I X in 30 cc. of methanol containing yielding 2.5 g. of colorless crystals with m.p. 170-174'. 0.6 cc. of concd. hydrochloric acid was refluxed for 5 hours, concentrated to one-half its volume, diluted with water and (12) Melting points are uncorrected except those marked "Kofler," extracted with ether. Chromatography of the ether exwhich were determined on the Kofler block. Rotations were measured tract on 12 g . of alumina and recrystallization of the benin chloroform, and ultraviolet absorption spectra in 95% ethanol soluzene-ether (6:4) eluates from acetone afforded 0.05 g . of the tion; infrared spectra were obtained with a Perkin-Elmer model 12 C saturated 7,ll-diketone V with m.p. 272-274', [ a l Z o-59". ~ single beam spectrophotometer. Grateful acknowledgment is made to The infrared spectrum was identical with that of samples Srta. Paquita Revaque for these measurements and to Srta. Amparo prepared according to (a) or from A8-22a,5a-spirostene-3@,Barba for the microanalyses. We are indebted to Srta. Carmen Ve1Icu-diol-7-0ne.'~ lasco and Srta. Mercedes Velasco for technical assistance. (13) G. Rosenkranz, J. Romo, E. Batres and C. Djerassi, J. Org. MEXICOCITY17, D. F.
conditions could be used, albeit in poor yield, for the transformation of the AB-11-one-7-01IX to the 7,ll-dione V.
Xz:H
Chem., 16, 298 (1950). (14) H. J. Ringold, G. Rosenkranz and C.Djerassi, THISJOURNAL, 74, 3318 (19.52).
(15) Repetition of the earlier reported (ref. 8) capillary melting point 213-214' on the Kofler block now gave a value of 223-225O.
