Catalytic Asymmetric Synthesis of Either Enantiomer of the Calabar Alkaloids Physostigmine and Physovenine

Abstract

A potentially versatile asymmetric route to hexahydropyrrolo[2,3- b ]indoles having carbon substituents at C-3a (Scheme 1) is demonstrated through enantioselective total syntheses of the Calabar alkaloids (−)-physostigmine ( 2 ), (−)-physovenine ( 10 ), and their enantiomers. The synthesis of enantiopure (−)-physostigmine proceeds from commercially available 2-butyn-1-ol ( 11 ) and N -methyl- p -anisidine ( 15 ) in 15−20% overall yield by way of eight isolated and purified intermediates. The central step is catalytic asymmetric Heck cyclization of ( Z )-2-methyl-2-butenanilide 17 to form oxindole aldehyde ( S )- 19 in 84% yield and 95% ee.