Intramolecular regioselective insertion into unactivated prochiral carbon-hydrogen bonds with diazoacetates of primary alcohols catalyzed by chiral dirhodium(II) carboxamidates. Highly enantioselective total synthesis of natural lignan lactones

Intramolecular insertion into unactivated prochiral C-H bonds of 3-aryl-1-propyl diazoacetates catalyzed by dirhodium(II) tetrakis[methyl 1-(3-phenyl propanoyl)imidazolidin-2-one-4(R or S)-carboxylate], Rh-2(4R-MPPIM)(4) or Rh-2(4S-MPPIM)(4), occurs in 91-96% ee and with virtually complete regiocontrol for the formation of beta-benzyl-gamma-butyrolactones. This methodology has been applied to the total synthesis of dibenzylbutyrolactone lignans (-)- and (+)-enterolactone, (-)- and (+)-hinokinin, and (+)-arctigenin from substituted cinnamic acids in 19-27% overall yields. Aryltetralin lignan (+)-isodeoxypodophyllotoxin was prepared from the reactant 3,4-(methylenedioxy)cinnamic acid in 36% yield overall, and the lactone precursor to (+)-isolauricerisinol was formed in 96.5% ee and 23% yield overall. Applications of the chiral Rh-2(MPPIM)4 catalysts to fully aliphatic systems resulting in the formation of beta-substituted-gamma-butyrolactones with high regiocontrol and with 93-96% ee have demonstrated the generality of this methodology. A model that provides accurate predictions of beta-substituted-gamma-butyrolactone absolute configurations in these asymmetric metal carbene transformations is described.