April 5 , 1958
COMMUNICATIONS TO THE EDITOR
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copolymer" character presumably is responsible for the variation in X-ray and physical property data observed with type I11 poly- (methyl methacrylate). The exact nature of the crystals themselves is under more intensive investigation.
the lower range expected for a stable carbinolamine ether.' (2) The infrared spectrum showed no absorption in the hydroxyl region. (3) The 16-acetate group survived prolonged treatment with methanol and triethylamine, an indication of the T. G. Fox absence of an axial hydroxyl a t C20 t o facilitate B. S. GARRETT methanolysis.4 (4) Chromic anhydride-pyridine RESEARCH LABORATORIES W. E. GOODE oxidation of IIIa afforded a neutral product (m.p. ROHMAND HAASCOMPANY SERGE GRATCH 263-264' dec., [a]D f54" diox., 6.07 p , J. F. KINCAID PHILADELPHIA, PA. ALDENLEESPELL -NCO-, found, C, 60.59; H, 7.17)) evidently the J. D. STROUPE formamido ketone IVa. Acid hydrolysis afforded one mole equivalent of formic acid. Alkaline hyRECEIVED FEBRUARY 8, 1958 drolysis of the corresponding formamido ketone IVb (m.p. 288" dec., [a]D +52" py., &A:: 6.07 THE CONFIGURATION OF CEVINE p ; found, C,60.98;H, 7.08) derived from cevine Sir: gave the desacetyl-formamido-ketone IVc (m.p. The configurations of nine (C3, Cq, Cg, CS,(210, 259-260' dec., [CY]D 4-22' py., found, c, 61.66; CIZ,C14, C1,,C26) of the fourteen asymmetric cen- H, 7.24). In addition to the amide band, the inters of cevine were established almost simultane- frared spectrum of this substance exhibited normal ously with the climactic structure elucidation in ketone absorption a t 5.85 p , 1954-55.1-3 Recent work in our laboratory made The alternative formulations V and VI for the possible assignment of configuration at CM and CZO oxide and formamido ketone were excluded on the and provides support for previously considered' basis of the following evidence. (1) The fonnconfigurational a$signments a t CS and C I ~ .Evi~ amido ketone IVb derived from cevine readily dence is presented herewith for assignment of con- formed a semicarbazone (m.p. 273-274" dec.; figuration a t the remaining asymmetric center found, C, 57.91; H, 6.80, N, 6.93). ( 2 ) The ((222) of cevine which now can be represented comformamido ketone IVa showed active methylene pletely by formula I. It is highly probable that group reactivity in the Zimmermann tests and upon closely related alkaloids, such as zygadenine and treatment in alkaline solution with furfural. (3) germine, also have this basic configuration. The corresponding formamido ketone (m.p. 253Oxidation of veracevine D-orthoacetate triace- 255" dec., [ a ] -83" ~ diox.; found, D, 60.96; H, tate (IIa)5 (pKa' 7.4) with ;N-bromosuccinimide6 7.10) from cevagenine-C-orthoacetate diacetate5 yielded a dehydro compound (m.p. 280-282' dec., was, like the parent alkaloid, stable to lead tetra[ a ] +33" ~ diox.; found, C, 63.51; H, 7.35; Ac, acetate. This behavior is characteristic of a rigid trans diaxial glycol system a t C17,C20, a situation clearly not satisfied by VI. The bridged /3-oriented oxide structure of I I I a and b requires that the hydrogen a t C52 be aoriented. T h a t the stereochemical integrity of the molecule was preserved during the oxide formation was demonstrated by catalytic hydrogenation of I I I a over platinum in acetic acid. Two moleequivalents of hydrogen was absorbed to give a substance identical with the product of hydrogenation (one mole-equivalent uptake) of IIa, namely veracevine-D-dihydroorthoacetate triacetate (m.p. 299300' dec., [ a ] -4-21' ~ diox.; found, C, 63.53; H, 7.85; Ac, 19.98).'s9 (7) H. Bloom a n d L. H Briggs, J. Chem. Soc ,3591 (1952) ( 8 ) W. Z i m m e r m a a a , Z . physiol. Chem., 233, 257 (1935); D.H . R.
+b ,__ --0
Re
I1 I11 a (R1 = B-OAc,R2 = 0.4~; R 3 = At) b (R1 = or-OAc, R * = OAc; R3 = Ac) c (R' = a-OH, R2 = OH; R 3 = H)
IV
25.52), evidently the bridged oxide I I I a for the following reasons. (1) The QKa' (found, 3.8) was in (1) D.H . R. Barton, C. J. W. Brooks a n d P. De Mayo, J. Chem. SOC., 3950 (1954). (2) F. Gautschi, 0. Jeger, V. Prelog a n d R. B. Woodward, Helo. Chim. A d a , 38, 296 (1955). (3) S. M . Kupchan, THISJOURNAL, 77,686 (1955). (4) S.M.Kupchan a n d W. S. Johnson, ibid., 78,3864 (1956). ( 5 ) S. M .K u p c h a n , D. Lavie, C. V. Deliwala a n d B. Y.A. Andoh, ibid.. 1 6 , 5519 (1953). (6) C f . 0. E.E d w a r d s , F. H. Clarke a n d B. Douglas, Can. J . Ckcm., 32, 235 (1954).
Barton a n d P. d e Mayo, J. Chem. SOC.,887 (1954). (9) T h i s work was supported in p a r t b y a g r a n t (H-2275 ('22)) from t h e National H e a r t I n s t i t u t e of t h e National Institute,a of Health.
DEPARTMENTS OF CHEMISTRY S. MORRISKUPCHAN PHARMACEUTICAL CHEMISTRY S. JOHNSON WILLIAM UNIVERSITY OF WISCONSIN MADISON, WISCONSIN S. RAJAGOPALAN RECEIVED JANUARY 27. 1958
AND
1601-CHLORO- AND 16a-IODOESTRONE METHYL ETHER, NEW AND POTENT LIPID-SHIFTING AGENTS
Sir: The problem of finding estrogen-like substances capable of altering blood lipid composition, and which a t the same time are not feminizing, is important in clinical treatment of atherosclerosis. A
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COMMUNICATIONS TO THE EDITOR
striking separation of properties has now been demonstrated in certain C-16 halogenated estrone derivatives. Some of these show lipid-shifting to feminizing ratios about one hundred times that of estrone as, for example, 16a-chloroestrone methyl ether (I) and 16a-iodoestrone methyl ether (11). The enol acetate of estrone methyl ether' in carbon tetrachloride was treated with chlorine and potassium carbonate to give I, m.p. 177-179'; [ a ] D +161';? (Anal. Calcd. for ClgH&lOn: c, 71.57; H , 7 . 2 7 ; C1, 11.12. Found: C, 71.53; H, 7.59; C1, 11.17). To establish the configuration of the chlorine atom I was reduced with lithium aluminum hydride, yielding 16a-chloroestradiol 3-methyl ether (III), m.p. 112-114'; [ Q ] D +72.5'; (Anal. Calcd. for C1gH25C102:C, 71.12; H , 7.85. Found: C, 71.40; H , 7.71) and 16wchloroepiestradiol %methyl ether (IT.'), m.p. 162-164'; [a111 $68.4'; (Anal. Found: C, 71.39; H, 7.80). Chromic acid oxidation converted both 111 and I V again into the ketone I. Treatment with alcoholic S-methoxy-potassium hydroxide rearranged the cis chlorohydrin, 117, to estrone 3-methyl ether; similar treatment converted I11 into 16@,17@-epoxy-1,3,5(10)-estratriene, m.p. 116-117', [ D I D +115" (Anal. Calcd. for C19H2402:C, 80.24; H , 8.51. Found: C, 80.04; H, 8.75) whose structure was confirmed by reduction with lithium aluminum hydride to 3-methoxy-16,B-hydroxy- 1>3,,? (10)-estratriene, m.p. 105-107', identical with an anthentic sainp1e.l Iodination5 of the enol acetate yielded 11, m.p. 161-166'; [ a ] +913; ~ (Anal. Calcd. for C19H231 0 2 : C, 55.62; H , 5.63; I, 30.93. Found: C, 55.71; H, 6.04; I, 30.27) and 169-iodoestrone 3methyl ether (VI), m.p. 163-166'; [ a ] D +ITS'; (Found: C, 53.43; H, 5.73; I, 30.38). Configurational assignments for I1 and 11- were made relative to molecular rotational differences given for the 16-bromoandrostan-17-ones.
observed in a 3-day test with cholesterol-fed cockerels.' Uterine growth in intact, immature mice was used to estimate feminizing a c t i ~ i t y . ~Potencies in these tests relative to the estrone standard are shown in the table. The ratio X/B is a measure of the separation of the two kinds of activityg and presumably will give some indication of therapeutic efficiency. The more potent members of this series are active on oral administration. (7) D L C(ir,k. K . A . Edjiren a n d D. J . S a u n d c r s . E i i f l o o in press ( 8 ) K . A . Edgren, P Y O CSOC. . E i p t i . B i d . J i c d , 9 2 , .jl>
