1712
CARL DJERASSI,
E.
BATRES, hf. VELASCO AND
most part those found to give the most active antispasmodics. Preliminary pharmacological studies indicate that some of these compounds are among the most
G. KOSENKRANZ
1701. i 4
potent antispasmodics, so far reported, having an activity approximately equal to that of atropine sulfate. These results are listed in Table I. KALAMAZOO, MICHIGAX
RECEIVED OCTOBER 25, 1951
s. A. ] Steroidal Sapogenins. XVL1" Introduction of the 11-Keto and 11&-Hydroxy Groups into Ring C Unsubstituted Steroids (Part 3).'" 11-Oxygenated Sapogenins [CONTRIBUTION FROM THE
RESEARCH LABORATORIES O F SYNTEX,
B Y CARL DJERASSI,' E. BATRES,' hf. \
T
~ AND ~
G.~ROSENKRANZ S ~ ~
The structure of 9a,lla-oxido-22-isoallospirostan-3~-ol-i-one acetate (IIa), the performic acid oxidation product of the corresponding A7is(11)-diene I, was proved by converting it via the 7-cycloethylenemercaptol to the known 90,l la-oxido-22laisoallospirostan-3 @-01acetate (IIc). Alkaline isomerization of the epoxyketone IIa led to Ae~s~-22-~soal~osp~rosten-~~,l diol-7-one (111), which after hydrogenation and Huang-Minlon reduction afforded 22-isoallospirostan-3p,1 la-diol (Vaj. Oxidation to the corresponding 3 , l I-dione (Vc), folloared by Raney nickel hydrogenation gave 22-isoallospirostan-3@-ol-11p-diol (Vfj. These exone (Vd), while lithium aluminum hydride treatment of the dione yielded 22-isoallospirostan-3~,ll periments complete the partial synthesis of the three possible C-11 oxygenated 22-isoallospirostan-3P-01s from the abundant plant sapogenin, diosgenin. Lithium aluminum hydride reduction of 9 a , l la-oxido-22-isoallospirostan-3 p-01-7-one acetate (IIa) affected only the 7-keto group and oxidation of the reduction product VIa followed by alkaline isomerization gave A8~s~-22-isoallospirosten-3,7-dione-lla-ol (VIIa), which was correlated with the original epxoyketone isomerization product IIIa by oxidation t o As~e~-22-isoallospirosten-3,7,1 1-trione (VIIc). Selective reduction of the 3-keto group of the latter proP-ol-7,ll-dione acetate (VIII), which could also be obtained by the Fieser dichromate oxidaduced A8(s)-22-isoallospirosten-3 tion of A7~9(11)-22-isoallospirostadien-3P-ol acetate ( Ij , Zinc dust reduction of the unsaturated diketone VI11 yielded 22isoallospirostan-3~-ol-7,1l-dione acetate ( I S ) .
C-11 oxygenated steroidal sapogenins represent oxido-22-isoallospirostan-3/3-ol-7-one acetate (IIa) almost ideal starting materials for the partial syn- and the structure of this key intermediate has now thesis of cortisone and related adrenal steroids, but been proved through correlation with the knownl0 until now no such representative in the sapo- Sa,11a-oxido-22-isoallospirostan-3/3-olacetate (IIc) genin series has been isolated from plant sources. by means of Raney nickel desulfurization of the 7The present paper is concerned with the partial cycloethylenemercaptol IIb. The subsequent synthesis of 11-keto (Vd), lla-hydroxy (Va) and transformations of this epoxyketone IIa, which 11,&hydroxy (Vf) 22-isoallospirostan-3 pols3 from serve as additional structure proof, proceeded the abundant, ring C unsubstituted sapogenin exactly as described2t8in the allopregnane series : A6-22-isospirosten-3p-01 (diosgenin). The publica- alkaline isomerization led to A8(g)-22-isoallospirotion of the physical constants of the three ll-oxy- sten-S6,11a-diol-7-one (IIIa), which was hydrogenated 22-isoallospirostan-3 6-01s (Va, d, f) should genated" to the saturated 3/3,11a-diol-7-one (IVaj facilitate the identification of such sapogenins in the and reduced by the Huang-Minlon12 procedure trJ event that they should be encountered subsequently the desired 22-isoallospirostan-3 /3,11 a-diol (Va) . in plant sources. Furthermore, the presently de- The spectral data of these intermediates, reported scribed experiments represent an alternate route in the experimental section, fully support the strucfrom diosgenin to cortisone, since 22-isoallospiro- ture assignments, while the a-configuration of the stan-3p-01-11-one (Vd), which has previously been C-11 hydroxyl group (in IIIa, IVa and Va), arid synthesized from 22-isoallospirostan-3 /3-01-12-one'~ ipso facto of the 9,ll-epoxide ring (in IIa, b, c)) (hecogenin) as well as from d i ~ s g e n i nhas , ~ already was demonstrated by the ease of acetylation (IIIb, IVb, Vb), characteristic13 of the l l a - but not the been transformedd-7 into cortisone. It has been reportedgearlier from this Laboratory 116-hydroxy series. t h a t performic acid oxidation of A7~9(11)-22-isoallo- 'The other two C-11 oxygenated 22-isoallospirospirostadien-3p-01 acetate (I)g affords ' J a , l l a - stan-36-ols (Vd, Vf) were prepared by unexceptional methods. The 3 6,11a-diol Va was oxidized ( l a ) Paper XV, C. Djerassi, H. J. Ririgold and G. Rosenkranz, to 22-isoallospirostan-3,1l-dione (Vc) and then T H I S JOURNAL, 1 3 , 5513 (1951). ( l b ) P a r t 2, C. Djerassi, 0. bcaucera, G . Stork and C . Rosenkranz, hydrogenated with Raney nickel catalyst at room ibid., 1 3 , 4496 (1951). temperature, conditions which are not sufficient (2) Department of Chemistry, Wayne University, Detroit, Michigan. to reduce the C-11 keto group, to yield 22-isoallo(3) For nomenclature of steroidal sapogenins see G . Rosenkranz spirostan-36-01-11-one (Vd), identical with a specia n d C. Djerassi, Nature, 166, 104 (1950). Cf.Report of Steroid Kornenclature Committee, Hclv. Chim. Acta, 34, 1680 (1951). men preparedla from 22-isoallospirosta1~-8/3-01-12(4) E. hf. Chamberlain, U '. V. Ruyle, A. E. Erickson, J. M. Chemone (hecogeninj. An alternate synthesis of this erda, L. M. Aliminosa, R. L. Erickson, G. E. Sita and M. Tishler, THIS 11-ketone Vd from diosgenin has already been reJOURNAL,1 3 , 2396 (1961). ( 5 ) G. Rosenkranz, J. Pataki a n d C. Djerassi, i b i d . , 1 3 , 4055 11951). (6) G. Rosenkranz, C. Djerassi, R . Yashiii a n d J. Pataki, J r n l u v e , 168, 28 (1951). ( i j J. M. Chemerda, E. I r l . Chamberlain, E . H . Wilson and M. Tishler, THISJ O G R K A L , 1 3 , 4063 (1931). ( 8 ) G. Stork, J . Romo. C Rosenkranz and C Djerassi, i b i d , 73, 3546 (1951). (9) T h e synthesis of this diene ( I ) from diosgenin has already been described [G. Rosenkranz. J. Romo. 1';. Batres a n d C I>jerassi, .I O r g . c ' / z t w , 16, 208 i l S S i ) ]
(10) C. Djerassi, €1. Martinez a n d G. Rosenkranz, ibid , 16, 1278 (l'tl.51). (1 1) T h e smooth hydrogenation (palladized charcoal catalyst, room
temperature, atmospheric pressure) is noteworthy if viewed in the light of the known resistance [cf. D. H. R . Barton and J. D. C o r , J . Chem. Soc., 214 (1949)l of I\8(9)-stenols toward reduction, and indicates t h a t i t may possibly proceed through a n enol form. ( 1 2 ) 3Iuang-Minlon, THISJ O C R N A L , 11, 3301 (1949) (13) \\'. 1'. Long .rud '1' 1' Ckillagher. J . Bioi. ( ' h e m , 162, 511 i194ti).
April 5, 1952
INTRODUCTION OF KETO AND ~ILU-HYDROXY GROUPS INTO RINGC STEROIDS 1713
111, a, R = H b, R = Ac C,
RZ = HZ
VI a, R~ =
/ OH “H
i
IV a, R = H b, R = AC
r
(OH
IX VII
cordeda4 As was to be anticipated on the basis of earlier work on the steric course of the lithium aluminum hydride reduction of 3-keto14 and 11keto15 steroids, similar treatment of the 3 , l l dione Vc led to 22-isoallospirostan-3 P,11 P-diol (Vf), thus completing the synthesis of the three desired C-11 oxygenated 22-isoallospirostan-3 p-01s. In addition to the above described alkaline isomerization of the epoxyketone IIa, there was also studied its reduction with lithium aluminum hydride and sodium borohydride. With both reagents, there was obtained the same substance Cz7H4206, to which is assigned the structure 9 a , l l a oxido-22-isoallospirostan-3~,7( P?)-diol (VIa) and which was oxidized to Qa,11a-oxido-22-isoallospirostan-3,7-dione (VIb), The presence of the intact oxide function16 in VIa and b was demon-
a,
R~ = ‘ \H
d, RS = , /OH; ‘XH /OAc e,
RP =
Rz‘= 0 ; Rp’ = 0
’\H
strated by the characteristic alkaline isomerization (cf. IIa-IIIa) of 9 a , l l a-oxido-22-isoallospirostan3,7-dione (VIb) (no ultraviolet absorption maxi11a-01-3~7-dione mum) t o A8(9~-22-isoallospirosten(VIIa) (ultraviolet absorption maximum a t 254 further characterized mp, typical of A8(9)-7-ketones), (14) C. %’. Shoppee a n d G. H. R. Summers, J. Chcm. Soc., 687 by formation of the lla-acetate VIIb. The (1950). structure proof was completed by chromium tri(15) L. H. Sarett, M. Feurer a n d K. Folkers, THISJ O U R N A L73, , oxide oxidation of the unsaturated 3,7-dione-11a1777 (1951); P. L. Julian, E. W. Meyer, W. J. Karpel and W. Cole, ibzd., 73, 1982 (1931); C. Djerassi. G. Rosenkranz, J. Pataki and St. 01 VIIa to As~9~-22-isoallospirosten-3,7,1 1-trione K a u f m a n n , J . Bid. Chem., 194, 115 (1932). (VIIc), identical with a sample prepared by oxida(16) Steroidal Sa,lla-onides are not attacked by lithium aluminum As(g)-22-isoallospirosten-3 p, 11a,diol-’i-one hydride (c,f. ref. 10, and L. F. Fieser a n d S. Rajagopalan, THIS,JOURNAL, tion of (IIIa). The unsaturated txione VIIc was hydro73, 118 (1931).
1714
CARLDJERASSI,E. BATRES,M. VELASCOAND G. KOSENKRANZ
Vol. $4
genated selectively a t C-3 to afford, after acetylation, A8(9~-22-isoallospirosten-3 p-ol-7,ll-dione acetate (VIII), which could also be obtained in 47, yield by the one-step dichromate oxidation" of ~7~3~11~-22-isoallospirostadien-3 p-01 acetate (I).g The synthesis of the L ~ ~ ( ~ ! - i , l l - d iVI11 o n e through LrII represents the fifth route1b~4*17~1s to such unsaturated diketones, which are reducible with zinc and acetic a ~ i d ~ to p ~the ~ *saturated '~ 7,11-diketones, the penultimate intermediates in a number of 11ketosteroid s y n t h e s e ~ . ~ The , ~ ~specific ~ ~ * ~applica~~~ tion of the zinc dust reduction to the sapogenin derivative VI11 is described in the experimental section and led in ca. 50% yield to 22-isoallospirostan-3P-ol-7,ll-dione acetate (1x1.
ethyl acetate was shaken in an atmosphere of hydrogen at room temperature and atmospheric pressure with 0.4 g. of 10% palladized charcoal catalyst (American Platinum Works, Kewark, N. J . ) for two hours, ,at which time the gas uptake corresponded to one mole. Filtration of the catalyst, evaporation of the filtrate to dryness and recrystallization from ethyl acetate afforded 1.27 g. of the saturated diol IVa with m.p. 236-237', [ C Y ] ~ D -137', A":;fl 170% cm.-l (saturated 7-ketone) and free hvdroxvl band. Anal. Calcd. for C2?HI?O5:C, 72.61; H , 9.48. Found: C, 72.91; H , 9.35. The diacetate IVb was reciystallized from ether-hexane; m.p. 225-227", [ a l u ) D -96.7 . Anal. Calcd. for C31H4607: C, 70.16; H , 8.74. Found: C, 70.21; H , 8.67. 22-Isoallospirostan-38,11Lu-diol(Va).-A solution of 4.0 g. of the above 3,11-diol-7-one IVa in 150 cc. of ethylene glycol and 8 cc. of hydrazine hydrate was refluxed for one hour, cooled in ice, 9.0 g. of potassium hydroxide in 12 cc. of water Experimental19 was added and the mixture was distilled until the tempcra9a, 1l~-Oxido-22-isoallospirostan-3 8-01-7-cycloethylene- ture of the vapor reached 190'. A reflux condenser was mercaptol 3-Acetate (IIb) .20-9a, 1la-Oxido-22-isoallospiroattached, the solution was refluxed for 4 hours, cooled, stan-38-01-7-one acetate (IIa)6(0.8 g.) was converted in 72% poured into ice-cold dilute hydrochloric acid solution and yield into the mercaptol I I b by IIauptmann's method,21 em- extracted with chloroform. The neutral and dry chloroploying 40 cc. of dry dioxane, 1 cc. of ethanedithiol, 8 g. of form extract WRS evaporated to dryness and the residue anhydrous sodium sulfate and 8 g. of anhydrous zinc chlo- crystallized from acetone; yield 2.27 g., n1.p. 214-216'. ride for 18 hours a t room temperature. The analytical Two additional recrystallizations from acetone furnished the sample crystallized from chloroform-methanol as colorless analytical sample, m.p. 217-2123', [ a ]2 0 ~ -69", which needles with m.p. 288-290, [ c Y ] ~-8G' ~ D (dioxane). showed no carbonyl baud in the infrared. -3nal. Calcd. for CatH460&: C, 66.lG; H, 8.23; S, Anal. Calcd. for C ~ T HC,~74.95; ~ ~ ~€1,: 10.26. Found: 11.37. Found: C, 613.19; H,8.50; S, 11.80. C, 74.82; H, 10.47. 9a,11~-Oxido-22-isoallospirostan-3p-01 Acetate (IIc) . 2 ~ The diacetate Vb exhibited m.p. 175-177', [ a I z o-84"; ~ The mercaptol (0.4 g.) was desulfurized by refluxing with 110 free hydroxyl band in the infrared. 300 cc. of ethanol aiid 10 g. of W-2 Raney nickel catalyst Anal. Calcd. for C31HlaOs: C, 72.06; 11, 9.36. Found: for three hours, filtering the catalyst and evaporating to C, 72.31; H , 9.49. dryness. Recrystallization from chloroform-methanol af(Vc).-The 3 p,lla-diol Va forded 0.21 g. of the oxide IIc with m.p. 246-250°, [ a ] * " ~ 22-Isoallospirostan-3,ll-dione -65.3', which gave no depression in m.p. upon admixture \vas oxidized with sodium dichromate dihydrate in benzeneacetic acid solution24and the product crystallized from etherwith an authentic (reported m.p. 248-252", hexane; m.p. 236-238", [ C Y ] %D - 19'. Theinfrared spectrum [a]20D-65"). (CIICla) showed a carbonyl band a t 1704 cm.-1 and was A.8~9)-22-Isoal~ospiosten-3~, 1la-diol-7-one (IIIa).-A suspension of 10 g. of the epoxyketone IIa8 in 2 1. of meth- identical in every respect with that of a specimen of the anol was refluxed for 30 minutes with 7 g. of potassium car- dione S'c prepared from 22-isoallospirostan-3~-0l-12-one.~~ Anal. Calcd. for C Z ; H ~ ~ OC~, :75.66; H , 9.41. Found: bonate and 400 cc. of water, whereupon a homogeneous C, 75.35; H, 9.24. solution was obtained. After concentrating to a volume of 1 l., diluting with ice-water and filtering, there mas isolated 22-Isoallospirostan-3p-ol-~~-one (Vd).-A solution of 9.2 g. of colorless crystals with m.p. 205-5213'. Kecrys- 0.3 g. of the 3,ll-dione Vc in 50 cc. of ethanol (distilled tallization from acetone raised the m.p. to 215-21 tio, [ a ]~ O D over Raney nickel) was shaken in an atmosphere of hydrogen -27",*: : A: 252 r n M , log t 4.08, A::,' 1656 cm.-l xnd free at room temperature and atmospheric pressure with a small spoon full of prereduced 'CV-4 Raney nickel catalystz2 for hydroxyl band. Anal. Calcd. for C?:I-I4,,Oj: C, 72.94; H, 9.07. Found: one-half hour. Filtration of the catalyst, evaporation of the filtrate to dryness and recrystallization from acetone furC, 73.08; H , 9.17. nished 0.26 g. of the hydroxyketone Vd with m.p. 223-225', The diacetate IIIb after recrystallization from hexane[CY]% -30°, 1702 ern.-' and free hydroxyl band. acetone showed 1n.p. 171-172", [&]'OD 4 " , AEi2H 251 mp, Anal. Calcd. for C27H4204: C, 75.30; H , 9.83. Found: log e 4.04, : , : :A 1736 (acetate) and 1676 (A8-7-ketone), C, 75.16; H, 10.01. no free hydroxyl band. The acetate VeZ3exhibited m.p. 222-223', [ O ~ ] ~-32' D Anal. Calcd. for CalH440i: C, 70.43; H, 8.39. Found: and proved to be identical (mixed m.p., infrared spectrum) C, 70.55; H , 8.51. with a sample prepared from 22-isoallospirostan-3p-ol-1222-Isoallospirostan-3 8,lla-diol-7-one IIVa) .--A solution OIlC.~~ of 1.9 8 . of thc un!,aturatcd tliol IITa i n 1 .if) c c . of ethaiiol or Z2-Isoallospirostan-3p,11@-diol (Vf).-The lithium nlu-__. .t i i i ~ i u i nhydridc reduction of the 3,l 1-dionc Yc (0.3 9.) wils H r r i i ~ i i i l\\'. l l u n n g , ihr,i , 73,2 3 ! J i ( l V 5 l ) .
