Alkylation of penicillanates : aspects of the chemistry of penicillanate sulphonium salts

Abstract

Methyl (6S)-6-chloro-, (6S)-6-phthalimido-, and 6,6-dibromo-penicillanates (4)–(6) have been converted into sulphonium salts (7)–(12) using trimethyloxonium tetrafluoroborate, methyl fluorosulphonate, and triethyloxonium tetrafluoroborate. Methyl 6,6-dibromo-1-methylpenicillanate tetrafluoroborate (9) was assigned the 1α-configuration on the basis of an n.O.e. Experiment. Treatment of sulphonium salts (7)–(12) with sodium carbonate gives the corresponding methyl 2-[(2R)-2-alkylthio-4-oxoazetidin-1-yl)-3-methylbut-2-enoates (22)–(25) in high yield. Methanolysis of methyl (6S)-6-chloro-1-methylpenicillanate tetrafluoroborate (7)‡ gives a mixture of methyl (2S)-2-[(2S,3R)-3-chloro-2-methoxy-4-oxoazetidin-1-yl]-3-methyl-3-methylthiobutanoate (29), its C-2′ epimer (30), and methyl (2S)-2-[(2R)-2-chloro-3,3-dimethoxypropionamido]-3-methyl-3-methylthiobutanoate (32), whereas treatment with sodium carbonate in methanol gives methyl (2S)-2-(trans-2-chloro--cis-2-methoxycarbonylvinylamino)-3-methyl-3-methylthiobutanoate (36). Similar reactions were observed with ethanol. A sulphonium salt could not be isolated from the reaction between methyl (6R)-6-phthalimidopenicillanate (3) and trimethyloxonium tetrafluoroborate, but treatment of the mixture with anhydrous sodium carbonate gave a mixture of methyl 3-methyl-2-[(2R,3R)- and -[(2S,3R)-2-methylthio-4-oxo-3-phthalimidoazetidin-1-yl]but-2-enoates (39) and (46). Complex product mixtures were obtained from the reaction between methyl (6R)-6-phenylacetamidopenicillanate (2) and trimethyloxonium tetrafluoroborate.