Organophosphorus compounds VII: The absolute configuration of sarin and related anticholinesterases established by chemical correlation

The reaction of (+)-(i-PrO)MeP(O)SMe with phenylmagnesium bromide in tetrahydrofuran affords (+)-(i-PrO)MeP(O)Ph, representing the first example of a stereospecific synthesis of a phosphinate ester from a phosphonothiolate ester. Levorotatory (MeS)MeP(O)Ph is converted into (R)-(+)-n-PrMeP(O)Ph with inversion of configuration by reaction with n-propylmagnesium bromide. The two Grignard reactions are correlated by the conversion of (-)-(MeS)MeP(O)Ph into (+)-(i-PrO)MeP(O)Ph with potassium isopropoxide. The correlation of the configuration of (R)-(+)-n-PrMeP(O)Ph with that of (+)-(i-PrO)MeP(O)SMe by means of the fore-mentioned reactions determines the absolute configuration of (+)-(i-PrO)MeP(O)SH to be (s). Since the latter compound is a common precursor for the synthesis of several types of optically active anticholinesterases, the absolute configurations of these could also be deduced, e.g. (R)-(-)-isopropyl methylphosphonofluoridate (sarin).