Synthesis of Unnatural α-Amino Acid Derivatives Bearing an Indole Side Chain via a Three-Component Cascade Reaction

Abstract A novel Mn(acac)3-mediated three-component cascade reaction involving o-alkenylaryl isocyanides, arylboronic acids, and amines has been established. This single-step strategy enables the concurrent assembly of both the privileged indole framework and the unnatural α-amino acid (UAA) scaffold within a single operation, providing efficient access to a broad range of structurally diverse, indole-tethered UAA derivatives. The transformation exhibits broad functional group tolerance and has been successfully applied to the late-stage modification of complex drug molecules. Mechanistic studies reveal that the cascade proceeds through a radical addition/cyclization/oxidation/nucleophilic addition pathway. The synthetic value of this protocol is further underscored by the straightforward conversion of the products into dipeptide-containing structures.