Iridium-Catalyzed Regio- and Enantioselective Reverse Prenylation of Tryptamines and Other 3-Substituted Indoles

Prenylated indole alkaloids from bacteria, fungi, plants, and animals comprise a large structural diversity with a broad range of biological activities. A subclass of this alkaloid family are the C3a-reverse prenylated hexahydropyrrolo[2,3-b]indole (HPI) natural products that are in principle synthetically accessible via a metal-catalyzed allylic substitution. Here we report the first catalytic enantioselective reverse prenylation of achiral 3-substituted indoles that furnishes hexahydropyrrolo[2,3-b]indoles in a single step. The developed catalytic system utilizes a novel iridium-NHC-phosphoramidite catalyst and provides the C3-prenylated products with high yields and enantioselectivities as well as complete branched selectivity. This elaborate methodology closes a systematic gap in asymmetric allylic substitution chemistry and offers a convenient strategy for the synthesis of tryptamine-derived alkaloids as demonstrated in a short biomimetic total synthesis of (-)-flustramine A, a prototypical member of this class of natural products. Mechanistic investigations elucidate the catalyst's structure and reveal a chloride-induced allyl complex isomerization, which is dependent on the hemilabile phosphoramidite-olefin Carreira-type ligand.