Copper-Catalyzed Enantioselective 1,3-Dipolar Cycloaddition Enabled by a Ketimine-Based Umpolung Strategy

Catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with various dipolarophiles has emerged as an efficient method for preparing pyrrolidine ring systems through normal [3 + 2] cycloadditions. However, achieving the catalytic enantioselective regio-reversed [3 + 2] cycloadditions via an imine-based umpolung strategy remains a formidable challenge. In this work, we present a copper-catalyzed umpolung of N-2,2,2-trifluoroethyl benzo[b]thiophene-2,3-dione-derived ketimines for the regio-reversed enantioselective 1,3-dipolar cycloaddition with benzo[b]thiophene sulfones. This strategy offers a highly regio-, diastereo-, and enantioselective approach for preparing chiral polycyclic spiro-compounds containing benzothiophenone, α-trifluoromethyl pyrrolidine, and benzosulfolane subunits, featuring four contiguous stereocenters with good results (up to 98% yield, all cases >20:1 dr and >99% ee). Density functional theory computational studies shed light on the reaction mechanism and the origin of the stereoselective control in this regio-reversed cycloaddition. The practicality and versatility of the methodology were also demonstrated by scale-up experiments and different transformations of the product.