Highly enantioselective syntheses of functionalized alpha-methylene-gamma-butyrolactones via Rh(I)-catalyzed intramolecular Alder ene reaction: application to formal synthesis of (+)-pilocarpine.

A highly enantioselective Rh(I)-catalyzed intramolecular Alder ene reaction has been developed. The desired products, 3-vinyl, vinyl acetate, and vinyl ether-substitued alpha-methylene-gamma-butyrolactones were formed in high yields. Aldehydes were produced with the formation of gamma-lactones when alcohols were substituted at allylic position in the substrates. All reactions with listed substrates proceeded in over 99% ee. A formal synthesis of (+)-pilocarpine is an excellent example to demonstrate the synthetic utility of this methodology.