Thiol Esters from Steroid 17β-Carboxylic Acids: Carboxylate Activation and Internal Participation by 17α-Acylates

Article abstract of DOI:10.1021/jo00362a028

The chemistry of the steroid 17β-carboxylic acids derived from 16,17α-disubstituted corticosteroids was investigated with respect to thiol ester formation.Major quantities of 17-spiro byproducts were observed in the reactions of 16-methyl-17α-acyloxy acids, and the degree of 17-ester participation leading to these structures was dependent on the carboxylate activating group used and stereochemistry at C-16.Diethyl phosphate mixed anhydrides of these acids reacted with mercaptide salts to give mixtures of thiol esters with 17-spiro acylthio ortho esters, which predominated and were particularly stable in the case of 16β-methyl substrates; in addition, considerable reversion of 16α-methyl phosphate intermediates to starting acid was experienced.The use of diphenyl chlorophosphate as the activating agent greatly improved yields of thiol esters.Methanolysis of the phosphate adducts derived from 17α-acyloxy acids gave 17-spiro acyl ortho esters as the exclusive products.The reactions of 17α-acetoxy acids with 2-fluoro-N-methylpyridinium tosylate (FMPT) gave novel 17-spiro acyl fluoro ketals 32-35, whereas similar treatment of 17-hydroxy acids led to products of dehydration or of 18-methyl migration, including the novel 13,17-β-lactones 39 and 41.Activation with carbonyldiimidazole followed by addition of mercaptans allowed the preparation of thiol ester products from 17-hydroxy acids, but the method was restricted to use with these substrates.Neighbouring-group participation was not possible for the 16,17-acetonide acid 10, and activation with either cllorophosphate diesters or FMPT followed by reaction with methanethiolate gave high yields of methylthio ester 17.