General method for asymmetric synthesis of alpha-methylsulfinyl ketones: Application to the synthesis of optically pure oxisuran and bioisosteres

The first asymmetric synthesis of oxisuran [1, (methylsulfinyl)methyl 8-pyridyl ketone], a synthetic immunosuppressive drug, is described. Both enantiomers were efficiently synthesized, in optically pure form, using DAG methodology for the key condensation step. Attempts to couple metal enolates of aryl methyl ketones with chiral sulfinyl compounds led to some epimerization at sulfur. This loss of chirality was circumvented by reacting the alpha-lithio derivatives of the N,N-dimethylhydrazones derived from these ketones with either the (R)- or the (S)-methanesulfinate of diacetone D-glucose, to yield the corresponding alpha-(methylsulfinyl)methylhydrazones, with complete inversion of chirality at sulfur. Hydrolysis of the resulting hydrazones with copper(II) chloride gave 1 in optically pure form. The generality of the method was demonstrated by the preparation of the optically active oxisuran analogs, 2-4, in which the pyridyl moiety was replaced by phenyl, furyl, and thienyl moieties, respectively. The optical purities of these products were determined by proton NMR spectroscopy, using chiral shift reagents, following conditions established by the study of racemic mixtures of the beta-keto sulfoxides.