Cooperative NHC/LA Catalysis for Stereoselective Strain-Release Difunctionalization of Bicyclo[1.1.0]butanes to 1,1,3,3-Tetrasubstituted Cyclobutanes

Abstract

The stereoselective synthesis of densely substituted cyclobutanes and the development of efficient strategies to access them have emerged as important frontiers in contemporary molecular synthesis, owing to their value as three-dimensional building blocks and bioisosteric motifs. Here we report a cooperative N-heterocyclic carbene (NHC)/Lewis acid catalytic strategy for the strain-release difunctionalization of bicyclo[1.1.0]butanes (BCBs) with α,β-unsaturated aldehydes, affording 1,1,3,3-tetrasubstituted cyclobutanes in up to 94% yield with excellent syn-diastereoselectivity across a broad substrate scope. Most reactions reach completion within 15 min at room temperature. Mechanistic studies, including isolation of a 2-oxabicyclo[2.1.1]hexane intermediate and its subsequent conversion to the cyclobutane product under the catalytic conditions, establish its involvement in the reaction pathway. The data support Lewis acid-assisted C–O σ-bond cleavage followed by NHC-mediated ring opening and rearrangement. Beyond the synthesis of substituted cyclobutanes, this transformation reveals an unconventional mode of NHC reactivity in an unusual oxygenated system and demonstrates how Lewis acid cooperation can redirect NHC reactivity to enable new reaction pathways.

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