Stereodivergent Synthesis of Chiral Hydrobenzofuranpyrrolidines by Catalytic Asymmetric Dearomative Cyclization and Controlled Epimerization

Abstract

A rapid and straightforward way to access stereoisomeric sets of products bearing multiple stereogenic centers is still a significant challenge in asymmetric catalysis. We present herein our experimental studies on the stereodivergent synthesis of chiral hydrobenzofuran-fused pyrrolidines with three stereogenic centers via organocatalytic asymmetric dearomative cyclization and epimerization process. Chiral bifunctional thiourea catalyst could successfully promote the enantioselective dearomatization cyclization of 2-nitrobenzofurans with o-hydroxy aromatic aldimines, which enabled the synthesis of (3S,3aR,8bR)-hydrobenzofuran[3.2]pyrrolidines in 79-92% yields with >20:1 stereoselectivities and 93-99% enantio- selectivities. While catalytic amount of DBU could induce the direct intramolecular epimerization of (3S,3aR,8bR)-hydrobenzofuran[3.2] pyrrolidines to its diastereomers (3R,3aR,8bR)-hydrobenzofuran[3.2] pyrrolidines in 72-87% yields without loss of stereoselectivities. The mechanistic pathways of the epimerization process were investigated by a series of control experiments study. This work provides an alternative and forward solution for the stereodivergent preparation of functionalized pyrrolidines with potential bioactivities.