Total Synthesis of (+)-Hinckdentine A: Harnessing Noncovalent Interactions for Organocatalytic Bromination

Abstract

Hinckdentine A, a marine-sponge-derived tribrominated indole alkaloid bearing a unique indolo[1,2-c]quinazoline skeleton, was completed in 12 steps featuring the construction of the Nα-quaternary carbon center by asymmetric azo-ene cyclization. A novel organocatalyst was developed to promote high-yielding tribromination, which represents a challenging process encountered in previous syntheses. Density functional theory calculations scrutinized viable substrates and deciphered the origin of the enhancement of C8 electrophilic bromination with a bifunctional organocatalyst. Moreover, the application of organocatalyst-enabled bromination on various substrates was demonstrated to highlight future late functionalizations of biologically intriguing targets.