Chemical synthesis study demonstrates cross-coupling of distinct bicyclo[1.1.0]butanes using scandium catalysis, offering a modular pathway to complex drug scaffolds.
Bicyclo[1.1.0]butanes (BCBs) are highly strained building blocks that enable the rapid construction of molecular complexity through strain-release reactivity. Utilizing the partial double bond character of the central bond in BCBs, herein, we report the Lewis acid catalyzed cross-coupling of electronically differentiated BCBs that provides efficient access to cyclobutene–cyclobutyl architectures with high diastereoselectivity. Using Sc(OTf)3 as the catalyst, the electron-deficient keto BCB acts as the enophile, while the relatively electron-rich ester BCB acts as the ene-component for the selective ene-type reaction. The protocol tolerates a broad range of substituents on both coupling partners, delivering sp3-rich scaffolds in moderate to good yields. The synthetic utility of the strategy was demonstrated through diverse downstream functionalizations. This strategy is likely to offer a modular platform for constructing structurally complex cyclobutanes relevant to medicinal chemistry.
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Sarkar et al. (2026) studied this question.
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