Preparation of secopenicillanates; preparation of methyl 3-methyl-2-[(2R,3R)-2-methylthio-4-oxo-3-phthalimidoazetidin-1-yl]but-2-enoate

Abstract

Treatment of methyl (1R,6R)-1-oxo-6-phthalimidopenicillanate (4) with trimethyl phosphite gives a mixture of bis-{(2R,3R)-1-[(1R)-1-methoxycarbonyl-2-methylprop-2-enyl]-4-oxo-3-phthalimidoazetidin-2-yl} disulphide (12)(25–60%) and methyl (2R)-3-methyl-2-[(2R,3R)-2-methylthio-4-oxo-3-phthalimidoazetidin-l-yl]but-3-enoate (11)(15-35%). The latter compound was also prepared by heating methyl (1R,6R)-1-oxo-6-phthalimidopenicillanate sulphoxide in 2-methylpropane-1-thiol, under reflux, to give the unsymmetrical disulphide (21) which was cleaved by trimethyl phosphite to give the non-conjugated secopenicillanate (11). Conversion of the non-conjugated secopenicillanate (11) into methyl 3-methyl-2-[(2R,3R)-2-methylthio-4-oxo-3-phthalimido azetidin-1-yl]but-2-enoate (2) was achieved using a catalytic amount of diazabicyclononene (DBN) at room temperature. Prolonged treatment with DBN under reflux in benzene, gave a mixture of the conjugated secopenicillanate (2) and its 3′-epimer (22) in a ratio of 3 : 7.