[ C O N T R I B L T I O h FROM THE DANIEL
SIEFF RESEARCH INSTITUTE,THE
I v E I Z M A A S I S 5 T I l U r t UF S C I L A L E ]
Synthesis of 4-Methylated Steroids' BY FRAXZ SOI~DHEIMER AXD YEIIUDA XIZT'R RECEIVED DECEMBER 18, 1950 T r v o neth hods of synthesis of 4-methyl-A4-cholesten-3-one (Xa) are described. The first involves the reaction of the enol l x t o n e \'Id with ethylmagnesium bromide, followed by treatment with base The second, which proceeds only in poor yield, involves the direct monomethylation of A4-cholesten-3-one (IVa). The first method is applied to the synthesis of 4methyltestosterone (Xb) and 4-methylprogesterone (Xd). 4-Methyltestosterone acetate ( X c ) is dehydrogenated with acetate (XIc), which on dienone-phenol rearrangement arid saponifiselenium dioxide t o 4-methyl-I-dehydrotestosterone cation produces 1,4-dimethylestradioI ( X I I b ) . This rearrangement is a n exact parallel in the steroid series t o the santonindesmotroposantonin rearrangement.
The possibility that a substance isolated in these laboratories from grapefruit oil was a 4-methylated steroid first aroused our interest in this class of compound. Such substituted steroids, in particular the d-methyl-A4-3-ketones (type X), were unknown, although in the bicyclic series the analogous 3-keto4,9-dimethyl-A4-octahydronaphthalene(I) and substituted derivatives are well known. Thus, the sesquiterpenes a - ~ y p e r o n eand ~ ~ c a r i s ~ o n econ~~ tain the system I, and other derivatives have been
low (conditions which have been used with the methyl Grignard r e a g e r ~ t ~ ~ was , ~ ~ unsatisfactory. ,*) However, when an excess of ethylmagnesium bromide was used in refluxing ether-benzene, the required 4-methyl-A4-cholesten-3-one (Xa) was obtained in 65(% yield after base cyclization.$ The structure of X a was confirmed by the infrared spectrum which indicated the presence of an o,Punsaturated ketone and especially by the ultraviolet 251 nip, log E 4.18) is in spectrum. The latter (A, good agreement with the value (A,, 252 mp) to bc expected of an a,p,p-trisubstituted a$-unsaturated ketone with one exocyclic double bond.l0 Other substances containing the same chromophoric system as X a have been shown to exhibit similar absorption (Amax 2-18--251 mp, log E 4.13-4.21).2.334,6b I I1 I11 The substance produced by the reaction of A4described in connection with studies related to the cholesten-3-one with the ethyl Grignard reagent, synthesis of santonin (11). 4 4-Methylated steroidal which on base treatment furnishes the 4methylA4-3-ketoneshave furthermore become of consider- A4-3-ketone Xa, is presumably the unsaturated able interest recently in view of the announcement hemiketal VIIa or the corresponding diketone ((If. that certain steroidal A4-3-ketones methylated a t ref. Tb). No attempt a t isolation of this intermethe C-2 position possess higher biological activi- diate was made in view of the known lability of thc corresponding methyl However, two ties than the unmethylated hormones.5 further substances were produced by the Grignard The preparation of a 4-methyl-A4-3-ketone was first investigated in the cholesterol series. Two reaction and could be isolated after the base treatsuccessful routes were found, both proceeding from ment. The more polar of the two was a comparaAd-cholesten-3-one (IVa) itself. The first utilized tively high melting substance, saturated to tetrathe enol lactone VIa, readily prepared from IVa nitromethane, exhibiting an associated hydroxyl through ozonolysis to the keto-acid Va, followed by band at 3.05 p , but no carbon>-1bands in the infraheating with sodium acetate and acetic anhydride.6 red. The empirical formula appeared to be CUI t is known that the enol lactone on reaction with H&, and we believe this compound to be the heniimethylmagnesium iodide, followed by base cycli- ketal VIIIa derived from VIa by reaction with two zation of the product, regenerates A4-cholesten- equivalents of the Grignard reagent. It has pre;
