June 5, 1960 [CONTRIBUTION FROM
4-SUBSTITUTED STEROIDS THE
2847
DIVISIONOF CHEMICAL RESEARCH, G. D. SEARLEAND Co., CHICAGO 80, ILL.]
4-Substituted Steroids1 BY NORMAN W. ATWATER RECEIVED NOVEMBER 19, 1959 A number of steroid analogs containing a hydrocarbon substituent at C-4 have been prepared by either or both of two methods. For one of these methods, direct alkylation of A4--3-keto-steroids,conditions are described which make it a useful preparative procedure. In the case of the second method, which involves treatment of an enol-lactone of a 5-oxo-3,5-secoA-nor acid with a Grignard reagent followed by base cyclization, the intermediate products of the Grignard reaction have been isolated and evidence is sresented bearing on their structure. Rearrangement reactions of some 4.4-dimethyl steroid analogs are described.
Since, a t the outset of this work, it had become apparent that profound changes in physiological activity resulted from the removal of C-19 from the steroid molecule, it seemed worthwhile to attempt introduction of hydrocarbon radicals on the steroid nucleus with the hope of effecting similar changes, The results of this work as well as the large amount of data which have been reported subsequently on the effects of methyl substitution a t C-43 and other positions4 demonstrate the validity of this general approach. This paper is concerned primarily with the synthesis of a number of 4-substituted androstane and 19-norandrostane derivatives which were prepared in the hope that they would possess high anabolic potency and favorable ratios of anabolic to androgenic activity. The well-explored scheme (I+-III+V-.VII~ IX) which has as its key step the reaction of a Grignard reagent with the enol-lactone of a 5oxo-3,5-seco-A-nor acid6 was chosen for the early experiments, but because of the number of steps involved and the low over-all yields a more direct method was sought. A modification of the dialkylation procedure of Woodward and co-workers6 was developed which gave fair yields of inonoalky-lated products which could be separated cleanly from the over-reacted and unreacted materials by chromatography. Identical samples of I X b and XIVb were produced by the two methods and the newly introduced substituent was definitely shown t o be a t C-4 by the ozonization of 4-methyltestosterone benzoate (IXg) to the same keto-acid IIIg (obtained in the tautomeric lactonol form7) that was obtained from testosterone benzoate (Ig). (1) N. W. Atwater. THISJOURNAL, 79, 5315 (1957).
(2) (a) A. L. Wilds and N. A. Nelson, ibid., 76, 5366 (1953); (b) L. G. Hershberger, E. G. Shipley and R. K. Meyer, Proc. Soc. Ex$. B i d . M e d . , 83, 175 (1953); (c) W.W.Tulner and R. Hertz, J. Clin. Eitdocrinol. a n d M e l o . , 12,916 (1952); (d) C. Djerassi, L. Miramontes, G. Rosenkranz and F. Sondheimer, THIS JOURNAL, 76, 4092 (1954). (3) (a) H . J. Ringold and G. Rosenkranz, J. Org. Chem., 22, 602 (1957); (b) F. Sondheimer and Y.Mazur, THISJOURNAL, 79, 2906
(1957). (4) J. A. Hogg, F . H. Lincoln, R . W. Jackson and W. P. Schneider, ibid., 7 7 , 6401 (1955); H. J. Ringold and G. Rosenkranz, J. Ors. Chem., 21, 1333 (1956); G.B. Spero, J. L. Thompson, B. J. Magerlein, A . R. Hanze, H C. Murray, 0. K. Sebek and J. A. Hogg, THZSJOTJRN A L , 78, 6213 (1956); J. A. Campbell, J. C. Babcock and J. A. Hogg, rbid., 80, 4717 (1988); G . E. Arth, D. B. R. Johnston, John Fried, W. W. Spooncer, D. R. Hoff and L. H . Sarett, ibid., 80, 3160 (1958). (8) (a) G. I. Fujimoto, ihid., 73, 1856 (1951); (b) R . D. H. Heard and P. Ziegler, ibid., 73, 4036 (1951); (c) R. B.Woodward, F. Sondheimer, D. Taub, K . Heusler and W. M. McLamore, ibid., 74, 4223 (1952). (6) R. B. Woodward, A. A. Patchett, D. H . R. Barton, D. A. J . Ives and R . B. Kelly, ibid., 76,2852(1954); J. Chem. Soc., 1131 (1957). 82, 2011 (7) (a) N. W, Atwater and J. W. Ralls, THISJOURNAL, (1960); (b) R. B. Turner, {bid., 72, 579 (1950).
4-Methylcholestenone (IXa),3b,8 4-methyltestosterone (IXb),3p9 4-ethyltestosterone (Xb),9 4phenyltestosterone (XIb) and 4-methyl-19-nortestosterone (XIVb) were prepared by the longer procedure.'O In three of these cases the intermediate products (VIIa, VIIg and VIIIg) of reaction of the Grignard reagent with the enol-lactone were isolated. These materials had spectral characteristics (infrared bands a t 2.82-2.92 and 5.87-5.88 p ) which were in better accord with a structure of the cyclized aldol type VII, VIII1l than with the alternate enol-hemiketal type XIXI* which has also been suggested. jb An attempt was also made to use this same general scheme of reactions to prepare A-nortestosterone. The appropriate enol-lactone XXV was prepared by acetyl chloride-acetic anhydride dehydration of the corresponding lactonol XXIV which was obtained in turn by ozonization of 2hydroxymethylenetestosterone (XXIII).l 3 However, when this enol-lactone was allowed to react with methylinagnesium bromide and the crude product refluxed in methanolic alkali a gum was obtained which showed none of the expected ultraviolet absorption. No attempt was made to identify the products.l 4 The direct procedure used to introduce a single alkyl group a t C-4 was essentially that employed in the synthesis of lanostenol from cholestenone6 with the exception that limited quantities of alkyl halide (1.00 to 1.26 moles) and bwe (1.5 moles) were used and the alkylating agent was added slowly to a refluxing solution of the steroid and base in t-butyl alcohol. It was found advantageous to conduct the reaction a t the boiling point of the solvent since a greater proportion of monoalkylated material was formed as compared with the reaction at room temperature. Thus 17a-methyltestosterone (IC)gave 15yoof the dialkylated material and 49% of the monoalkylation product in refluxing t-butyl alcohol while a t room temperature yields (8) G. D. Meakins and 0. R . Rodig, J. Chem. Soc., 4679 (1956). (9) B. Camerino, D.Cattapan, U.Valcavi and B. Patelli, Cues. chim. itol., 69, 674 (1959). (10) The author wishes t o acknowledge the work of Mr. Ivar Laos in preparing two of these substances. (11) S . A. Julia, A. Eschenmoser, H. Heusser and N. Tarkoy, R e l u . Chim. A d o . 36, 1885 (1953); K.D.Zwahlen, W. J. Horton and G. I. Fujimoto, THISJOURNAL. 79, 3131 (1957). (12) T h e carbon-carbon double bond stretching frequency of the enol-ether portion of this structure would be expected t o have its principal absorption a t wave lengths above 5.95 ~r(cf. G. D. Meakins. J. Chem. Soc., 4170 (1953)). (13) F. L. Weisenborn, D. C. Remy and T. L. Jacobs, THISJ O U R N A L .
76, 552 (1954). (14) T. L. Jacobs and N. Takahashi, ibid., 80, 4886 (1958).
2s4s
H0 IX, R K” = CHa XIX CHs, R ” = CzIIi X, K S I , R = CH3, R ” = CsHj SII,R = CH3, R ” = CH~CII:CH:! S l I I , R = CHs, R ” C4Hg XIV,R = H , R ” = CH,
“ XX, R R ” = CHB X X I , R = H, R ” = CH,
b, R’ = (OH ”H
C”, SXII
,OB2 g,
It’ =
\
‘.H
XVII; R = CH;; R” = CcH9 XVIII, R = H , R” = CH3 OH e, R‘ = / “C3H7
Ok1
-r/2
In no instance wcre products of oxygen alkylation at either position 3 or 17 noted, but unreacted starting material and the dialkylation product a t C-4 were always present in the crude reaction mixtures. The method. therefore, depended for success on a good procedure for separation. This was found in adsorption chromatography using silica gel as adsorbent and mixtures of benzene and ethyl acetate as elution solvents. The comDounds were eluted in order of decreasing degree
