Sterically Controlled Chemoselective Synthesis of Chiral [3.3.1]-Bridged N-Heterocycles via Organocatalytic Asymmetric Multicomponent Dearomatization

Abstract

Combining multicomponent reactions (MCRs) and catalytic asymmetric dearomatization (CADA) strategy in a tandem process to rapidly assemble valuable bridged N-heterocycles from indoles and other readily available materials remains extremely challenging with scarce reports. Herein, we report a chiral phosphoric acid (CPA) enabled multicomponent CADA reaction of indoles, affording chiral [3.3.1]-bridged N-heterocycles with high chemoselectivity in generally good to high efficiency (up to 99% yield), diastereo- (up to >50:1 dr), and enantioselectivity (up to 99% ee). Notably, it represents the catalytic asymmetric MCRs and CADA process to construct as many as six contiguous stereocenters, a skeleton previously inaccessible via such strategies. Importantly, the chemoselectivity is tunable simply by modulating the steric hindrance of substrates, as substantiated by control experiments and DFT calculations. Additionally, this multicomponent protocol enables highly efficient construction of a chiral tetracyclic bridged framework, four bonds, and two quaternary carbon chiral centers, exhibiting a broad substrate scope (>60 examples).