Cyclization of cysteinylglycine sulfoxides under Pummerer reaction conditions

Abstract

A number of sulfoxides derived from 3-benzylthiopropionic acid, S-benzylcysteine, and S-phenylcystelne have been synthesized and exposed to typical Pummerer reaction conditions. Cyclization of the S-benzyl sulfoxides to six-membered or seven-membered heterocyclic rings (1,3-thiazin-4-ones and 1,3,6-oxathiazepines) is observed only in acetic anhydride solvent and only after conversion of the carboxyl group to an amide or peptide. Cyclization of S-phenylcysteinyl amides to β-lactams could not be achieved. The thiazolidine isomers of the six- and seven-membered rings have been synthesized and found not to be intermediates in the acetic anhydride reactions. The thiazolidines do rearrange to the six- and (or) seven-membered rings in anhydrous trifluoroacetic acid solvent. S-Benzylphthalimidocysteinylglycine sulfoxide, a 3:2 mixture of epimers at sulfur, affords a 3:2 mixture of isomeric thiazinones. A mechanism for these cyclizations is proposed, and it is suggested that the configuration at sulfur controls the configuration at the new asymmetric centre in the product.