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COMMUNICATIONS TO IHE EDITOR
Vol. 74
Of interest to the structure problem of these nionoepoxides, as well as their utilization for the synthesis of I, is the fact that acids in aqueous or polar media effect rearrangement to 7-ketones rather than 11-ketones. Thus the mono-epoxide f rom A7,9(11),22-ergostatrien-3 @-01; m.?. 188-1 89" ; [ a ]-34' ~ (CHC13); found: C, 81.23; H, 10.79; (obtained either by the direct action of perbenzoic acid or by alkaline hydrolysis of the 3-acetate) is converted by the action of 0.07 N sulfuric acid in aqueous-acetone a t 25-20' for ten to thirty minutes to A9(11)~z2-ergostadien-3~-ol-7-one (V) ; m.p. 153.5154.5'; [ a ] -53" ~ (CHCL); found: C , 82.10; DEPARTMENT OF BIOCHEMISTRY UNIVERSITYOF WISCONSIS MARKA. STAHMANNH, 10.40; end absorption above 220 mp; 3-acetate: VV'ISCONSIX ROBERT R. BECKER m.p. 176-177'; DI.[ MADISOX, -43.5' (CHC13); found: C, RECEIVED MARCH 17, 1952 78.89; H, 9.91.4 By the action of dilute sulfuric acid on the above mono-epoxide a t 50-70" for a few hours, or by treatment of V with alcoholic SYNTHESIS OF 11-KETO STEROIDS alkali a t room temperature, A8,2z-ergostadiene-3pSiu: 01-7-one (VI) is obtained; m.p. 179-180'; [alu In an earlier communication' we reported a syn- -43' (CHCls); Xmax 253 mp, E M 9970 (ale.); thesis of aZZopregnan-3p-ol-11,20-dione acetate (I) found: C, 82.11 H, 10.98. Acetylation of VI from ergosterol, stigmasterol, cholesterol and dios- yielded the 3-acetoxy derivative, m.p. 213-213.5' ; genin. In this communication we wish to present [ a ] ~ 59' (CHCl3); which had been obtained a second, more direct, method for the preparation previously in low yield by Stavely and Bollenbacks of the d o diketo pregnane (I) from these same raw from the oxidation of A7~22-ergostadien-3@-01 acematerials. Heusser and his co-workers3 have tate by chromic acid. Both V and VI yielded 2,4reported the isomerization of the mono-epoxide dinitrophenylhydrazones . acetate? derived from A7,9(11),22-ergostatrien-3-p-ol Complete details of this work will be published by the action of boron trifluoride etherate in ben- later in THISJOURNAL. zene solution a t room temperature to A*,"-ergo(4) Under similar conditions, 0.3N sulfuric acid in aqueous dioxane stadien-3p-01-11-one acetate (11)and we have indefor three minutes, 0. Jeger and his co-workers8 obtained A*'Z*-ergostapendently carried out the same reaction in 80% dien-3~,7(?),llu-triol-3-monoacetate.' The sensitivity of the triol to yield; m.p. 131.5134'; [LU]D + 1 l O o (CHCl3); acids suggests t h a t the time allowed for reaction is probably the most critical factor in determining the course of action. The @,r-unsatuXmax 234 my, E M 9140 (alc.); found: C, 79.19; H, 10.31. Saponification of I1 yielded AsbZs- rated ketone bas also been obtained by the action of dilute acids on the ergostadien-3/3-ol-ll-one(111); 1n.p. 171-173' ; triol. ( 5 ) H. E. Starely alid G. N. Uollenback, THISJ O U R N A L , 65, 1285 [ a ] D +135O (CHC13); Amax 254 mp, E M 8920 (1943). talc.); found: C, 81.54; H, 10.45. E. SCHOENEWALDT L. TURNBULL As expected, both I1 and 111are inert to reaction CONTRIBUTION FROM THE E. M. CHAMBERLIN with 2,4dinitrophenylhydrazine. Irrefutable RESEARCH LABORATORIES D. REINHOLD structure proof of these ketones as well as a new MERCKAND Co., INC. A. E. ERICKSOK and shorter path to I was provided by the reduction RAHWAY, W. V. RUYLE S . J. J. M. CHEMERDA oi the As-11-ketone (11) with lithium and liquid M. TISHLER ammonia in 85-90% yield to AZ2-ergostene-3~-olRECEIVED APRIL 25, 1952 11-one (IV), m.p. lG8-169.5O; [.ID f23' (CHCls). The identity of the lithium-ammonia reduction product of I1 was conclusively demonstrated by SAPOGENINS. XXI1I.l INTRODUCTION comparison with the product previously obtained STEROIDAL OF THE 11-KETO AND Ila-HYDROXY GROUPS INTO by the Wolff-Kishner reduction of A22-ergostene-3p- RING C UNSUBSTITUTED STEROIDS (PART 6 ) . NEW APPROACH TO 11-OXYGENATED STEROIDS ul-7,1I-dione acetate.' Similarly diosgenin acetate was converted via the Sir: iiionoepoxide to As-spirostene-3-p-01-11-one acetate Heusser and co-workers2 reported recently that (8-dehydro-11-keto tigogenin acetate) ; 1n.p. 235- mono-epoxides of certain steroidal A7,Q(11)-dienes 23S0; [ a ] D +57" (CHC13); Xmax 255 mp; E M upon treatment with boron trifluoride yield the 9000 (alc.); found: C, 73.62; H, 8.89; which was corresponding A*-1 1-ketones which would conlikewise reduced by lithium-liquid ammonia to the stitute a proof for the A7-9,11-oxidostructure of the previously described spirostan-3/3-ol-ll-one. ' starting mono-epoxides. The structure assign(1) E. M. Chamberlin, W. V. Ruyle, A. E, Erickson, J. M. Chemment of the unsaturated ketone rested essentially erda, L. M. Aliminosa, R. L. Erickson, G. E. Sita and M. Tishler, THIS on the non-reactivity of the carbonyl group and J O U R N A L , 1 3 , 2396 (1051). the substance's non-identity with the As-7-ketone. (2) I n accordance with the Swiss investigators,' we believe the monoepoxides prepared from allo-A."~(~')-steroidsare A'-gu,lla-epoxides, We should now like to report certain experiments in However, R. C. Anderson, R. Budzisrek, G. T. Newbold, R. Stevenson the sapogenin series which not only prove unand F. S.Spring regard the epoxide above to be a AgW)-7,8-epoxide:
proteins, forming the peptide bonds under such mild conditions that denaturation does not occur. We have utilized this method with other proteins and other amino acids with essentially similar results. It would seem to be applicable to many amino acid anhydrides and a wide variety of proteins. These studies, as well as an investigation of the relative reactivity of various groups of the protein which may be acylated by the anhydrides, are under investigation. The effects upon the biological activity of enzyme and virus proteins are also being studied.
Chcm. and Ind., 1035 (1950). Further discussion of this problem will be forthcoming in a later communication. ( 3 ) H. Heusser, K. Eichenberger, P, Kurath. H. R. Dallenhach and 0 . Jeger, Hclu. C h n . Acta, 34, 2106 (1951)
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(1) Paper X X I I , C. Djerassi, E. Batres, J. Romo and G. Rosenkranz, THISJ O U R N A L , 1 4 , June (1952). ( 2 ) H. Heusser. el u t . , Kcle. Chim. A c t o , 54, 2106 ( 1 9 5 1 ) ; 36, 295
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COMMUNICATIONS TO THE EDITOR
May 20, 1952
I
0 I1 (a) R = C H ~ C H ~ C ~ (b) R = H
2697
111
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equivocally the As-1 1-keto structure for the boron trifluoride rearrangement products but also open a new approach to cortisone and related 1l-oxygenated steroids. Esters of A7~~(11)-28-isoallospirostadien-3P-o13 upon treatment with 1.1 mole of perbenzoic or perphthalic acid afford in excellent yield the corresponding A'-9,1 l-oxido-22-isoallospirosten-3~-o14 (e.g. propionate (la), m.p. 22$-229', [o(]"D -91' (all rotations in chloroform), found: C, 74.39; H, 9.41). Kearrangement of Ia with boron trifluoride in benzene solution2 led to 70% of A8-22-isoallo~ spirosten-3P-01-11-one propionate (IIa) (m.p. 194196', [ a ] " D +42', xg2H 252 mp, log € 4.08, 1734 and 1656 cm.-l) found, C, 74.66; H, 9.35; (free alcohol IIb, m.p. 190-192', [ ~ ] ' O D +65', found: C, 75.56; H, 9.241, which upon reduction in ether-dioxane solution with ca. three moles of lithium in liquid ammonia followed by alkaline saponification furnished in good yield the %2-isoallospirostan-3~-ol-ll-one (111) (m.p. 223225', [ a I z 0-29', ~ identified by infrared comparison). Since this substance (as the acetate, m.p. 224-22'7') has already been converted to cortisone,6tgthe above steps open a new and convenient
x%t1
(3) G. Rosenkranz. J. Romo, E. Batres and C. Djerassi, J. Org, Chem., 16, 298 (1951). (4) G. Rosenkranz, J. Romo and C. Djerassi, U. S. Patent Application No. 191,942 (19.50). Such mono-epoxides in the sapogenin series have also been employed in ref. 5 , but no physical constants were reported. ( 5 ) E. M. Chamberlain, W. V. Ruyle, A . E. Erickson, J , M. Chemerda, L. M. Aliminosa, R. L. Erickson, G. E. Sita and M. Tishler, THIS JOURNAL, 73, 2398 (1951). (8) C. Djerassi, H.J. Ringold and G. Rosenkranz; ibid,, 73, 5513 (1951). (7) C. Djerassi, E. Batres, M. Velasco and G. Rosenkranz, ibid.,74, 1712 (1952). ( 8 ) J. M. Chermerda, E. M. Chamberlain, E. H . Wilson and M . Tishler, i b i d . , 73, 4052 (1951); G . Rosenkraiie, J , Pataki and C. Djerassi. ibid., 1 3 , 4055 (1951).
route to this important hormone. The use of larger amounts of lithium in the presence of alcoholg in the reduction stage led in good yield to the known 22-isoallospirostan-3~,11a-dio17(m.p. 21s220°, [ a I z 0 D -78') thus constituting a convenient synthesis of 11&-hydroxysteroids. In connection with the above described successful chemical reduction of the 8,g-double bond to the desired stereoisomer 111, i t is pertinent to mention that catalytic hydrogenation (5y0palladized charcoal, ethanol solution, room temperature, 40 hours) of the As-11-ketone I I a leads t o an 8-epi, 9-epi derivative, most likely S-epi(a)-g-epi( P)-22-isoallospirostan-3~-ol-ll-onepropionate (m.p. 21 1213O, changed to 224-227' upon rigorous drying, [CY]~OD -63', Xzil! 1730 and 1700 cm.-' found: C, 74.16; H, 9.61) which is not isomerized by alkali. Furthermore, i t was observed that the As-11-ketone IIa could be isomerized very readily a t C-14 on boiling with 5% ethanolic potassium hydroxide to produce 14-epi(/?)-A8-22-isoaIlospirosten-3P-ol11-one (m.p. 239-240°, [ ~ ] Z * D 113', xZ~H 252 mp, log E 4.09; found: C, 75.60; H, 9.42; propio90°, found: C, 74.18; nate, m.p. 217-219', [&]'OD H, 8.88). The details of a number of hydrogenation experiments leading to epi derivatives a t C-8, C-9 and C-14 together with the interrelationships established among the various series will be published shortly.
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RESEARCH LABORATORIES SYNTEX, S. A. LACUNAMAYRAN413
F. SONDHEIMER R. YASHIN G. ROSENKRANZ
MEXICOCITY 17, D. F. CARL RECEIVED MARCH 26, 1952
DJERASSI'O
______ (9) Cf.A. L . Wilds, Abstracts, p. 20M, American Chemical Society
Meeting, New York, September, 1961. (10) Department of Chemistry, Wayne University, Detroit Michigan.
1,
