Straightforward synthesis of 7 alpha-methoxy-1-oxacephems from penicillins

A straightforward and industrially feasible synthesis of 7 beta-acylamino-7 alpha-methoxy-3-[(1-methyl-1H-tetrazol-5-ylthio)methyl]-1-oxa-3-cephem-4-carboxylic acid (35) from penicillins is described. Reaction of 6 alpha-acylaminopenicillanate S-oxides with triphenylphosphine gave epioxazolines (16) which were transformed into allylic alcohols (28) via allylic chlorides (22) and iodides (27). Intramolecular etherification of 28 gave 7 alpha-acylamino-3-exomethylene-1-oxacepham-4 alpha-carboxylate (30), a versatile key intermediate. 7 alpha-Methoxylation of 30, followed by substitution with sodium 1-methyl-1H-tetrazol-5-ylthiolate at C3 and side chain cleavage, afforded the methoxyamine (33), the desired 1-oxa-3-cephem nucleus, which on acylation and subsequent deprotection gave 35 (6059-S free acid, where the acyl is p-hydroxyphenylmalonyl).