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. B oth enantiomers were efficiently synthesized, in optically pure form, using DAG methodology for the key condensation step. Attempts to coupl e metal enolates of aryl methyl ketones with chiral sulfinyl compounds led to some epimerization at sulfur. This loss of chirality was circu mvented by reacting the alpha-lithio derivatives of the N,N-dimethylhy drazones derived from these ketones with either the (R)- or the (S)-me thanesulfinate of diacetone D-glucose, to yield the corresponding alph a-(methylsulfinyl)methylhydrazones, with complete inversion of chirali ty at sulfur. Hydrolysis of the resulting hydrazones with copper(II) c hloride gave 1 in optically pure form. The generality of the method wa s demonstrated by the preparation of the optically active oxisuran ana logs, 2-4, in which the pyridyl moiety was replaced by phenyl, furyl, and thienyl moieties, respectively. The optical purities of these prod ucts were determined by proton NMR spectroscopy, using chiral shift re agents, following conditions established by the study of racemic mixtu res of the beta-keto sulfoxides.