Chemo-, Diastereo-, and Enantioselective (3+2) Cycloadditons of Bicyclobutanes with Enals Enabled by Synergistic Palladium and Organocatalysis

Abstract

Despite significant progress in catalytic asymmetric (3+X) cycloadditions of bicyclobutanes (BCBs) for constructing pharmaceutically valuable bicyclo[n.1.1]alkanes, current strategies are limited to using a single catalyst for the separate activation of BCBs or the "X" components. Herein, we report a new strategy that synergistically combines achiral Pd-catalysis for BCB activation with chiral iminium activation of α,β-unsaturated aldehydes, thereby overcoming existing limitations. These limitations include issues of chemo-, diastereo-, and enantioselectivity in the (3+2) cycloadditions of BCBs with enals for the synthesis of multisubstituted all-carbon bicyclo[2.1.1]hexanes (BCHs). Despite these challenges, up to 99% ee, >20 : 1 d.r., and 88% yield have been achieved. Moreover, the protocol demonstrates a wide range of substrates, high tolerance to various functional groups, scalable synthesis and versatile product functionalization, highlighting its practical value in constructing complex chiral BCH structures. Additionally, synergizing transition-metal catalysis and organocatalysis activation principles broadens the mechanistic and synthetic scope of the asymmetric cycloadditions of BCBs.

Keywords

Strained molecules / Cycloaddition / Palladium / Synergistic catalysis / Asymmetric catalysis / Chemoselectivity / Diastereoselectivity / Enantioselectivity

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