Studies related to penicillins. Part VIII. The rearrangement of penicillanic acid derivatives to 1,3-thiazines

Abstract

A mixture of methoxymethyl 6α-phthalimidopenicillanate (7) and 2-(3,6-dihydro-6-oxo-5-phthalimido-2H-1,3-thiazin-3-yl)-3-methylbut-2-enoic acid (17) is formed in the reaction of methoxymethyl 6β-phthalimidopenicillanate (1) with triethylamine. Methoxymethyl (3S)-2,3,4,7-tetrahydro-2,2-dimethyl-7-oxo-6-phthalimido-1,4-thiazepine-3-carboxylate (10) is shown to be a likely precursor of the acid (17). Methoxymethyl 6β-p-nitro-benzylideneaminopenicillanate (5) undergoes an analogous rearrangement under similar conditions.

The methyl ester (16) of the acid (17) is converted into the racemate of methyl (E)-β-[4(S)-methoxycarbonyl-5,5-dimethylthiazolidin-3-yl]-α-phthalimidoacrylate (22) in the presence of methanolic sodium methoxide. Iodine catalyses the isomerisation of the latter derivative to the racemate of the thermodynamically favoured (Z)-isomer (23), which may be prepared by diazomethane esterification of the acid derived from 4(S)-5,5-di-methylthiazolidine-4-carboxylic acid and methyl α-phthalimidomalonaldehydate.