A catalytic asymmetric cross-coupling approach to the synthesis of cyclobutanes

Stereodefined four-membered rings are common motifs in bioactive molecules and versatile intermediates organic synthesis. However, the synthesis of complex, chiral cyclobutanes is a largely unsolved problem there need for general modular synthetic methods. Here we report series asymmetric cross-coupling reactions between cyclobutenes arylboronic acids which initiated by Rh-catalysed carbometallation. After initial carborhodation, Rh–cyclobutyl undergo chain-walking or C–H insertion so that overall variety additions such as reductive Heck reactions, 1,5-addition homoallylic substitution observed. The applicability these highly stereoselective transformations demonstrated concise syntheses drug candidates Belaperidone PF-04862853. We anticipate this approach will be widely adopted medicinal chemists. While carbometallation reported here exemplified with Rh acids, it likely to applicable other metals nucleophiles. Complex substituted but difficult make enantioselectively. Now, has been shown acids—initiated carbometallation—can provide access diverse range cyclobutanes.