J. F. Biellmann, W. S. Johnson
1965 Proceedings of the National Academy of Sciences of the United States of America  
Some time ago we undertook a study with the view to designing a general method for determining A-values of various groups. The idea in principle was to employ an equilibration technique of a 3a-substituted 6-keto steroid, I = II. Since it is known' that when R = H, the equilibrium lies largely, but not entirely, in favor of the 5a (A/B trans) isomer I (R = H), we felt that such a system would in principle be particularly suitable for the measurement of the A-values (defined as the freeenergy
more » ... ference between an equatorial and axial substituent) of fairly large R groups since the equilibrium I =. II would move toward the less abundant species II as the group size of R is increased. This expectation is a result of the fact that R assumes the stabilizing equatorial conformation in II and the destabilizing axial conformation in I. The present communication constitutes a report of the application of this principle to the determination of the A value of the methyl group. Recently, Neville Jones and Kine' have reported the measurement of A-values for OH, OCH3, OAc, and Cl by a similar technique, but with the 3-substituent in the 0-rather than the a-configuration. In this 303 system the equilibrium is pushed even further toward the side of the 5,3 (A/B trans) isomer, and the method can therefore not be employed for accurate determination of A-values of large groups. We elected to work in the cholestanone series. The previously known3 reference compounds I (R = H) and II (R = H) were prepared by a new approach: 6,3acetoxy-53-cholestan-3-one4 was reduced by the Caglioti procedure5 to 6f0-acetoxy-5f3-cholestane which, on saponification followed by oxidation with sodium dichromate in acetic acid, was converted into 5(3-cholestan-6-one (I, R = H), CD. in ethanol [0]294-29 -14058. Equilibration of this last substance under basic conditions yielded a mixture of the 5,f and 5a epimers from which the latter was easily separated because it was present in preponderance (see below), CD. in ethanol [0]296 -5377. The 3a-methylcholestan-6-ones, I (R = CHR) and II (R = CHO), were obtained as follows. The reaction of excess methylmagnesium iodide with 6,8-acetoxy-513-cholestan-3-one4 yielded a separable mixture of C-3 epimeric diols in approximately equal amounts: the 3a-hydroxy compound, m.p. 113.5-116°, [a]D + 200(c 1, CHCl3) [Found: C, 80.2; H, 11.9 ] and the 3,6-hydroxy isomer, m.p. 144-1450, [a]D + 230 (c 0.5, CHCl3) [Found: C, 80.2; H, 11.9]. The assignments of configurations at C-3 were made on the basis of infrared spectral properties in the hydroxyl stretch region and on the basis of the behavior 891 Downloaded by guest on March 9, 2020
doi:10.1073/pnas.53.5.891 pmid:16591275 pmcid:PMC301341 fatcat:7kcwpowr4ff7fgngwnvdbsh25q