Nov. 5 , 1955
17-OH FROM 17a,21-DIHYDROXY-20-KETOPREGNANE DERIVATIVES [CONTRIBUTION FROM
THE
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RESEARCH LABORATORIES OF SYNTEX, S.A.]
Steroids. LXX.l Removal of the 17-Hydroxyl Group from 17c~,2 1-Dihydroxy-20-ketopregnaneDerivatives2 BY 0. MANCERA, G. ROSENKRANZ AND FRANZ SONDHEIMER RECEIVED MAY2, 1955
A convenient and simple two-step sequence for removing the 17a-hydroxy group from 17a,21-dihydroxy-20-ketopregnane derivatives is described, which involves formation of the 21,21-dibenzyloxy-20-ketone followed by catalytic hydrogenolysis. The method was first studied with A6-pregnene-3/3,17a,21-triol-20-one (I), which yielded allopregnane-3/3,21-diol-20-one (111), and has been used to prepare Reichstein’s Substance N (IXa) and R (IXb) from cortisone (IVa) and hydrocortisone (IVb), respectively. The conversion of Reichstein’s Substance S (IVc) to desoxycorticosterone (XII) shows that the A‘-3keto system may be left intact if it is protected by ketalization.
I n these laboratories certain naturally occur- smoothly in ca. 70% yield by treating the triol I ring 11-oxygenated pregnan-20-one-21-01 deriva- with dry hydrogen chloride in benzyl alcohol for 5 tives, especially allopregnane-3/3,21-diol-11,20-di- days a t room temperature. The structural asone (Reichstein’s substance N) (IXa) and allo- signment was based on the analogous dimethoxy pregnane-3/3,11/3,21-triol-20-one (Reichstein’s sub- acetals obtained by Mattox5with hydrogen chloride stance R) (IXb) were required. These compounds in methanol and was confirmed by the elementpreviously had been synthesized from corticoster- ary analysis, the comparatively low polarity and but in view of the ready commercial availa- the negative reaction with triphenyltetrazolium bility of cortisone (IVa) and hydrocortisone (IVb) i t chloride. The catalytic hydrogenolysis of the dibenzyl aceseemed highly desirable to convert these latter substances to I X a and IXb, respectively, through re- tal IIb was studied with a number of different catamoval of the 17a-hydroxy group and reduction of lysts. The best conditions were found to be hydroring A. The present paper describes the realiza- genation in ethanol solution over a 10% pallation of this objective. dium-charcoal catalyst a t room temperature and The removal of the 17a-hydroxy group from a atmospheric pressure, when ca. 4 moles of hydrogen 17a,21-dihydroxy-20-ketopregnane was studied was absorbed and allopregnane-3/3,21-diol-2O-one (I). 4 (111) (identified by comparison with an authentic first with A6-pregnene-3@,17a,21-triol-20-one A possible method seemed to be one involving re- sample) was produced in 64y0 yield. Catalytic action of I with methanol in the presence of anhy- hydrogenation of the 21,21-dibenzyloxy-20-ketone drous hydrogen chloride to give the 21,21-dimeth- system present in I I b therefore yields the 21-hyoxy-20-ketone (IIa) with the 17-hydroxy group droxy-20-ketone directly in one step (in the case eliminated, as described by Mattox5 in other series, studied the As-double bond was reduced as well) followed by hydrolysis to the 20-keto-2 1-aldehyde and a simple two-step method for removing the 17(or its hydrate) and reduction a t C-21. The hydroly- hydroxy grouping from 17a,21-dihydroxy-20-keof type IIa, how- tones had been found. sis of 21,21-dimethoxy-20-ketones ever, proved to be very complex6 and none of the The method was next applied to the synthesis 20-keto-21-alcohol I11 could be isolated after re- of Reichstein’s Substance N (IXa) from cortisone duction, despite the fact that both steps were car- (IVa). Treatment of the latter (or of its 21-aceried out under a variety of conditions. tate) with hydrogen chloride in a mixture of chloThe above difficulty was overcome by substitut- roform and benzyl alcohol for 2 days yielded the ing the 21,21-dibenzyl acetal I I b for the dimethyl dibenzyl acetal Va, which on hydrogenation over a acetal, since i t is known that benzyl ethers may be 10% .palladium-charcoal catalyst followed by acecleaved readily, e.g., through catalytic reduction. tylation and chromatographic purification produced The crystalline dibenzyl ether I I b was obtained the required allopregnane-3,11,2O-trione-21-ol acetate (VIa). The latter was identified with a sam(1) Paper L X I X , A. Zaffaroni, V. Troncoso and M Garcia, Chemistry &Industry, 534 (1955). ple prepared by oxidizing allopregnane-l1~,21-diol( 2 ) Presented in part a t t h e New York Meeting of the American 3,20-dione 21-acetate (dihydro-allocorticosterone Chemical Society, September, 1954. acetate) (VIb)7with chromium trioxide. It was ex(3) Synthesis of Substance R 21-monoacetate and 3,21-diacetate: J. Pataki, G. Rosenkranz and C. Djerassi, J. Bid. Chem., 196, 751 pected that the allo (5a)isomer would be produced (1952). Oxidation of Substance R diacetate t o Substance N diaceby reduction of the A4-double bond of Va, since it tate: T. Reichstein, Helu. Chim. Acta, 21, 1490 (1938). It is of interis known7 that 11-keto and lip-hydroxy-A4-3est t o mention t h a t an indirect path may be traced from cortisone acetate t o Substance N diacetate v i n allopregnane-38,11~,17~,20~,21-ketones on hydrogenation yield this isomer predompentol (Reichstein’s Substance A) 3,20,21-triacetate [C. Djerassi, inantly. G. Rosenkranz, J. Pataki and S. Kaufmann, J. Biol. Chem., 194, 115 Unfortunately the yield in the reduction step JOUR(1952); see also L. H. Sarett, M. Feurer and K. Folkers. THIS leading from Va to VIa was low, the over-all yield NAL, ‘73, 1777 (1951); P. L. Julian, E. W. Meyer, W. J. Karpel and W. Cole, ibid., ‘73, 1982 (1951); T. Reichstein and J. von Euw, Helu. of VIa from cortisone being only ca. 12%. This Chim. Acta, 2 4 , 247 E (1941)], 17-iso-allopregnane-38,11~,21-triolcould be improved by carrying out separately the 20-one (iso-R) 3,Zl-diacetate and 17-isoallopregnane-3~,2l-diolreduction of the A4-3-ketone system and that of 11,20-dione (iso-N) diacetate [C. W. Shoppee and T.Reichstein, ibid., 23, 729 (1940) 1. the 21J21-dibenzyloxy-20-ketonesystem. Thus, (4) J. Heer and K. Miescher, ibid., 34, 359 (1951). when cortisone acetate was f i s t reduced catalytiJOURNAL, 74, 4340 (1952). (5) V. R. Mattox, THIS (6) Cf H. Reich and T. Reichstein, Rclo. Chim. A d o , 22, 1124 (7) J. Pataki, G. Rosenkranz and c. Djerassi, J . Biol. Chcm., lS6, (1939).
751 (1952).
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0. MANCERA, G . ROSENKRANZ ,4ND F. CI 1201I
I-01. 77
SONDHEIMER
CII
I
C--0
C=O
1
,\l/-.;:,.O*
I
I
J CH20H
CH~OAC I
c=o
111
x
cally to dihydro-allocortisone acetate (VIIa) (72% yield)8 and the latter then converted to the dibenzyl acetal VIIIa, catalytically reduced and acetylated, allopregnan-21-01-3,11,2O-trione acetate (VIa) was obtained in 24% over-all yield. Finally preferential reduction of VIa a t C-3 through hydrogenation over a Raney nickel catalyst (as had been described for the corresponding l lp-hydroxy derivative VIb),’ followed by saponification with sodium carbonate, afforded Reichstein’s Substance N (IXa) in 52% yield. I n analogous fashion, for the synthesis of Reichstein’s Substance R (IXb), hydrocortisone (IVb) was transformed to the non-crystalline benzyl acetal Vb,9 which on hydrogenation over a lOyopalla( 8 ) C. Djerassi, G. Rosenkranz, J. Pataki and S . Kaufmann. J . B i d . Chem., 194, 115 (1952); E. Wilson and RI. Tishler, THISJ O V R 74, 1609 (1952). (9) It was found t h a t t h e reaction conditions employed (hydrogen chloride in chloroform and benzyl alcohol a t room temperature) did not cause appreciable dehydration of t h e 110-hydroxy group. The analogous transformation of hydrocortisone t o t h e dimethyl acetal corresponding t o Vb by means of hydrogen chloride in methanol a t room temperature now has been described by D. Taub, R. €1. Pettibone, N. L. Wendler and M. Tishler (ibid., 76, 4094 (1954)) and by S. A. Simpson, J. F. Tait. A. Wettstein, R . Neher, J. von Euw, 0. Schindler and T. Reichstein, H P ! ; , Chiin. A c : ~ Si’, , I l G 3 (1954)). NAL,
C-0
XI
XI1
diurn-charcoal catalyst followed by acetylatioii produced the known dihydro-allocorticosteronc acetate (VIb)’ in 16yoover-all yield. -1gain the yield could be improved to by first hydrogenating hydrocortisone acetate to the dihydro-allo compound VIIb‘ (Sly0)and then carrying out the benzyl acetal formation, catalytic hydrogenatioii and acetylation with this substance. The preferential reduction of VIb a t C-3 by means of hydrogen over Raney nickel has been described previously7 and saponification of the resulting Substance R 21-acetate with sodium carbonate furnished Substance I
