Sulfur-Free Penicillin Derivatives. V. Preparation, Hydrolysis, and Oxidative Rearrangement Of Fused Oxazoline–Azetidinones

Chlorinolysis of an anhydropenicillin affords a 2-(2′-chloro-3′S-amino, -acylamino or -phthalimido-4′-oxo)azetidinyl-3-methyl-2-butenoyl chloride, as a mixture of 2′R (cis) and 2′S (trans) epimers in which the 2′R epimer usually predominates. Hydrolysis of the acid chloride and treatment of the carboxylic acid with aqueous bicarbonate causes cyclization, in the case of a 3′-acylamino substituent, to a 2R-6-(1′-carboxy-2′-methyl-prop-1-enyl)-1-oxa-3,6-diaza-4S,5R-bicyclo[3,2,0]hept-2-ene-7-one. The mechanisms of these transformations are discussed, and alternative routes to such fused oxazoline–azetidinones are also presented.The oxazolines undergo ready hydrolysis to sulfonic acid salts of 2-(2′R-acyloxy-3′S-amino-4′-oxo)azetidinyl-3-methyl-2-butenoates upon treatment with the hydrate of a sulfonic acid in acetone solvent. Neutralization of these salts proceeds without O → N acyl transfer, because acylation yields a diacylated azetidinone in which the new acyl substituent is attached to nitrogen. Monobromination of the allylic methyl groups of these salts, followed by treatment with 2 molar-equiv. of triethylamine, leads to a deep-seated rearrangement, in high yield, to an oxazinone. The mechanism of this rearrangement and, in particular, the role of acylimines in this and related reactions, including the biosynthesis of penicillin, are discussed.