Hydrolysis of the known acetonide (I) with formic acid at 80 C afforded the trihydroxy compound (II) (1). Subsequent ketalization of (II) with butyraldehyde (III) in the presence of perchloric acid provided the butylidene ketal (IVa-b) as a 4:1 mixture of R/S epimers at C-20. Selective hydrogenation of the 1-2 double bond of (IVa-b) by iron pentacaarbonyl/sodium hydroxide gave (V). The carboxylate group of (V) was then activated as the mixed anhydride (VI) by reaction with diethyl chlorophosphate and Et3N. Condensation of anhydride (VI) with the sodium salt of N-hydroxypyridine-2-thione (VII) produced the pyridyl ester (VIII). Photolysis of ester (VIII) by irradiation with a tungsten lamp in the presence of dimethyl disulfide gave rise to the target methyl thioether as a diastereomeric mixture. The major (20R)-epimer was finally isolated by preparative HPLC.
In a related method, the dihydroxy steroid (IX) was converted to the 11-acetate ester (XI) via diacetylation with Ac2O and DMAP, followed by selective hydrolysis of the resultant 11,21-diacetate (X) under acidic conditions. Oxidative cleavage of the hydroxy ketone moiety of (XI) using periodic acid furnished the carboxylic acid (XII). The 1,2-double bond of (XII) was selectively reduced by hydrogenation in the presence of tris(triphenylphosphine)rhodium chloride to yield (XIII). Activation of (XIII) as the corresponding mixed anhydride with diethyl chlorophosphate, followed by coupling with N-hydroxy-2-thiopyridone (XIV), furnished the pyridyl ester (XV). Radical decarboxylation of (XV) in the presence of dimethyl disulfide gave rise to the methyl thioether (XVI). The acetate ester of (XVI) was finally hydrolyzed using LiOH in aqueous EtOH or, alternatively, K2CO3, NaOH or KOH in MeOH/H2O.