Diastereoselective synthesis of multi-substituted cyclobutanes via catalyst-controlled regiodivergent hydrophosphination of acyl bicyclobutanes.

Abstract

Although ring-opening reactions of bicyclo[1.1.0]butanes (BCBs) provide a reliable platform for synthesizing functionalized cyclobutanes, current methods frequently encounter challenges such as poor diastereoselectivity, regioselectivity issues, and a lack of α- and β'-selective transformations. Herein, we report a catalyst-controlled, regiodivergent α- and β'-selective hydrophosphination of acyl BCBs, which expands the chemical space of tertiary phosphines with multi-substituted cyclobutane backbones derived from identical starting materials. Utilizing a Cu(I) catalytic system, we achieve an α-selective nucleophilic addition to 1,3-disubstituted BCBs. This reaction exhibits a broad substrate scope under mild conditions, yielding valuable 1,1,3-functionalized cyclobutanes predominantly as single diastereoisomers. In contrast, the unusual β'-selective pathway facilitated by a Cu(II) catalytic system produces 1,2,3-trisubstituted variants with up to >20:1 d.r. The developed method holds promise for accessing structurally diverse cyclobutanes with potential applications in medicinal chemistry and the design of organophosphorus catalysts.