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.

通过常规[3+2]环加成实现甲亚胺叶立德（azomethine ylides）与各类亲偶极体（dipolarophiles）的催化不对称1,3-偶极环加成，已发展为构建吡咯烷环系的高效合成策略。然而，借助基于亚胺的极性反转策略（umpolung strategy）实现催化对映选择性区域反转[3+2]环加成，仍是一项极具挑战性的课题。本研究开发了铜催化的N-2,2,2-三氟乙基苯并[b]噻吩-2,3-二酮衍生酮亚胺的极性反转过程，可实现其与苯并[b]噻吩砜（benzo[b]thiophene sulfones）的区域反转对映选择性1,3-偶极环加成。该策略为构建含苯并噻吩酮、α-三氟甲基吡咯烷与苯并环丁砜结构单元的手性多环螺环化合物提供了高区域、非对映与对映选择性的合成路径，产物含有四个连续立体中心，整体反应性能优异：产率最高可达98%，所有案例的非对映选择性比均大于20:1，对映体过量值均大于99%。密度泛函理论（Density Functional Theory, DFT）计算研究阐明了该区域反转环加成反应的机理及立体选择性控制的根源。此外，通过放大实验与产物的多样衍生转化，验证了该合成方法的实用性与普适性。