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.