Kovember, 1963
which may have been initially formed was reduced further to the 2-hydroxymethyl compound. As noted previously, Knox and Velarde' mere unable to detect the formation of VI under their experimental conditions. As suggested by these workers, the differences in solubilities of the intermediary enolate salts and aluminum hydride complexes in the solvents employed is probably the best explanation for these observed differences in product formation and yield.
0
4L-V H
\ IIb. Vb
R'O+ \TI a, R = H b , R = CHS
737
ANABOLIC 2-nIETHYLENE-jff-ANDROSTANES
H
VI11 a, R = R1 = R2 = H b, R = H ; R1 = R2 = AC I X a, R = CHI; R1 = RZ = H b, R = CH,; R' = Ac; R2 = H
During the course of this investigation, the desired 2-methylene derivatives also were prepared by a less ambiguous route. The appropriate 2a-dimethylaminomethyl-3-ketosteroids (1711) 8 were reduced with either LXH or lithium tri-t-butoxyaluminum hydride to the corresponding 3P-ols (YIIIa, IXa) . The assignment of the P-configuration for the C-3 hydroxyl in these compounds was based on the appearance of an unresolved multiplet from 185 to 220 C.P.S.in the n.ii1.r. spectruni which is characteristic for C-3 axial protons. These amiiioalcohols were converted to their acetates (T'IIIb, IXb) and oxidized with perbenzoic acid. The resulting S-oxides were not isolated but immediately pyrolyzed in refluxing t-butyltoluene. This gave the desired 2-methylene-3/3-acetoxy derivatives (IIb, Vb) identical with the products described before. These results confirm the 3p-hydroxyl configuration for I1 and V which had been assigned previously by Kiiox and T-elarde' on the basis of mechanistic considerations and molecular rotation data. Biological Activity. O-Edwards and eo-workers previously reported that 2-methylene-170-methyltestosteroiie possessed 15% the androgenic and 50% the anstolic activity of 170-methyltestosterone. This reduction in biological activity produced by introduction of a 2-methylene group was even more dramatic in our cases. Whereas the 3P-hydroxy-50-androst-lciie derivatives were extremely potent myotrophic agcnts (Table I) the correspondiiig 2-methylene derivatives (IIb and T-b) displayed weak anabolic and androgenic8 activity. The low order of activity displayed by these 2-methylene derivatives has prompted interest in their evaluation as potential inhibitors of tumor growth. The results of these studies mill be reported elsewhere. (8) R . N a u l i , &I. ,J. Ringold. and C. Djerassi, J . A m . Chem. S o c . , 82, 5494 (1900).
(9) .J. N. Plioolery and 31. T. Rogers. ibid., 8 0 , ,5121 (1958). (10) FVe are grateful t o D r s . F. .J. Eaunders, H. L). Lennon. and E. IT. Xiittinp of o u r Endocrinology Dirision for furnishing us with this inforiliatiun.
TABLEI ANABOLIC AND ANDROGENIC ACTIVITIES"
Compound
1.m. adniin. llyo.Indrotrophic genic
Oral admin. RlyoAndrotrophlc genic
Testosterone propionate 100 100 5a-.4ndrost-l-ene-3p,lip-diol diacetate3 40 50 IIb
