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) tetrakismethyl 1-(3-phenyl propanoyl)imidazolidin-2-one-4(R or S)-carboxylate, Rh2(4R-MPPIM)4 or Rh2(4S-MPPIM)4, occurs in 91−96% ee and with virtually complete regiocontrol for the formation of β-benzyl-γ-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 Rh2(MPPIM)4 catalysts to fully aliphatic systems resulting in the formation of β-substituted-γ-butyrolactones with high regiocontrol and with 93−96% ee have demonstrated the generality of this methodology. A model that provides accurate predictions of β-substituted-γ-butyrolactone absolute configurations in these asymmetric metal carbene transformations is described.