Regiodivergent Asymmetric Hydroboration of Dimethylenecyclobutanes Enabled General Access to Chiral Cyclobutanes

The enantioselective borylation of strained carbocycles has emerged as a powerful platform for accessing chiral organoboron architectures. While borylated four-membered rings offer unique potential to combine ring strain with the synthetic versatility of the boron motif, the modular synthesis of chiral borylated cyclobutanes, particularly those bearing chiral tertiary boronate centers, remains a significant challenge due to inherent steric hindrance. Herein, we report an expedient route to strained conjugated dimethylenecyclobutanes (DMCs) via sequential Aldol and Wittig reactions and their application in a regiodivergent asymmetric hydroboration platform. Leveraging strain-release activation, we develop a regio-switchable asymmetric hydroboration of DMCs for constructing chiral tertiary cyclobutylboronates and cyclobutylmethylboronates. Mild copper-catalyzed enantioselective Markovnikov hydroboration of DMCs provides access to chiral tertiary cyclobutylboronates, whereas cobalt catalysis enables anti-Markovnikov hydroboration to afford chiral cyclobutylmethylboronates. These bifunctional cyclobutane linchpins, bearing both boronate and alkenyl handles, serve as versatile precursors to previously inaccessible chiral molecular scaffolds. Mechanistic experiments, in combination with computational studies, reveal a strong correlation between the distinct inductive and strain effects of DMCs and the selectivity observed during the initial copper hydride insertion. By addressing the key challenge in the synthesis of chiral borylated cyclobutanes, the asymmetric functionalization of DMCs holds significant promise for expanding the strained-ring chemical space in organic synthesis.