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

Abstract

Abstract 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).