blay, 1963
3-PHEKYLPREGSANE-11~~O-DIONE
action of phenylmagnesium bromide on I11 gave two products which were separated readily by chromatography. I n addition t,o biphenyl, two isomeric compounds which gave correct analyses for the desired IT' were isolated. The first product t'o be eluted from the column was assigned the structure IVa on the basis of its polarity,*lesser yieldg and more positive rotation. lo Dioxolane removal with p-toluenesulfonic acid in acetone of either of the two isomers afforded a mixture of a dehydration product and the same alcohol. This alcohol was also obtained by the action of aqueous acetic acid at room temperature on IVa and hence was assigned the structure Ya. The isomeric alcohol (Vb) was obtained by treating IVb under identical conditions although a small amount of Va was also obtained. The olefin (T'I) was prepared by the methanesulfoiiyl chloride-pyridine dehydration of Tra and assigned the 3-dehydro structure on the basis of the greater stabilit'y of the 3-double bond in the pregnane series." The isolation of only one alcohol (T'a), as well as the uiisat'urat'ed compound (VI), under strongly acidic conditions and the isolation of T:a as well as Vb from the acetic acid reversal of IVb strongly suggest an easy dehydration of the equatorial hydroxyl in these 3-phenyl substituted compounds and rehydration to the thermodynamically more stable equatorial phenyl isomer (Va). Since dehydration of the axial hydroxyl and rehydration would give T'a also, nothing is learned about t'he relative ease of dehydration of axial and equatorial hydroxy groups in this series. Alternatively, the invocation of an intermediate benzylic carbonium ion would reasonably rat'ionalize the formation of these products. Further support for the structural assignments a t C-3 is based on the differential shielding experienced by the 19-methyl group (see Table I). Since increased or decreased shielding effects occur whenever groups face or lie within the plane of a nearby aromatic ring, respectively, one would expect the former condition to be (8) (a) B. Pelca, Coll. Czech. Chem. Comm., 25, 1624 (1960); (h) D. H. R. Barton, A. d a S. Campos-Neues, a n d R . C. Cookson, J . Chem. Soc., 3500 (1956); (e) J. A. Zderic, SI. E. C. Rivera, and D. C. L i n h , J . A m . Chem. Soc., 83, 6373 (1960). (9) Observation of molecular models would lead one t o expect t h a t the Grignard intermediate (ii) (see F. C. Whitmore, paper presented before t h e Atlantic City meeting of t h e American Chemical Society, September, 1941) would predominate over i by virtue of t h e bad interaction a i t h t h e ?a and Sa-hydrogens in i a n d hence IVh a o u l d he the major product. This interaction appears t o be greater t h a n t h a t of t h e 1 , 6 p hydrogens in ii.
I
303 TABLE 1'2
Compound
Va Vb 3~Hydroxypregnane-ll,20-dione
19-CHa
18-CHs
CHaCO
8 73 8 92 S 81
9 39 9 40 9 40
7 90 7 91 7 90
more nearly fulfilled by the 3P-phenyl in Vb (relative to 3a-hydroxypregnane-ll , 20-dione) . Conversely, the atypically low field position of the 19-methyl in T'a favors the 3a-phenyl assignment. Hydrogenation of T'I afforded a reaction product of wide melting point range, but only one product could be isolated by crystallization. The added hydrogen a t C-3 is assumed to have the p-configuration since T T I could be adsorbed on a large surface oiily 011 the p-side. Iieither T'a or Vb showed significant activity as an aldosterone antagonist at a dose of 10.7 mg. kg. rat in the DOCA-loaded, adrenalectomized rat.'j
+
1
11
&
C6H5 OH H
Vb
+
Va
Va
+ VI
IVb
I
i
ii
(10) A. K. Bose a n d B. G. Chatterjee, J . Org. Chem., 2S, 1425 (1958). However, it should be realized t h a t t h e unsaturation of t h e phenyl group adjacent t o the asymmetric center m a y have a profound effect on t h e rotation. thus vitiating these conclusions. (11) L. F. Fieser and RZ. Fieser, "Steroids," Reinhold Publishing Co., Xew York. N. Y., 1959, p. 276. The presence of the 3-phenyl group, however, might result in a different order of stability and so this assignment should be regarded a s tentative.
(12) The n.m.r. spectra were obtained with a Varian V-4300G high resolution spectrometer operating a t 60 megacycles. T h e chemical shifts are reported a s t a u (?) values. We would like t o thank Dr. N. R. Trenner and 11r. B. H. Arison for makina these determinations. (13) We are indebted t o Dr. M. Glitzer and his associates of t h e Merck Institute for Therapeutic Research, Rahu-ay, N. J., for these evaluations (unpublished procedure of Drs. Glitzer and S. L. Steelman).
