Chemo-, regio- and enantioselective hydroformylation of trisubstituted cyclopropenes: access to chiral quaternary cyclopropanes

Abstract

Abstract Catalytic asymmetric synthesis of polysubstituted chiral cyclopropane presents a significant challenge in organic synthesis due to the difficulty in enantioselective control. Here we report a rhodium-catalyzed highly chemo-, regio- and enantioselective hydroformylation of trisubstituted cyclopropenes affording chiral quaternary cyclopropanes. Importantly, the easy made sterically bulky ligand L1 can effectively suppress hydrogenation and decomposition reactions and give quaternary cyclopropanes with high regio- and enantioselectivities for both aryl and alkyl functionalized substrates. Control experiments and computational studies reveal the sterically hindered well-defined chiral pocket instead of the substrates bearing electron-withdrawing diester groups is important for controlling the enantioselectivity and regioselectivity. Scale-up reaction and follow-up diverse transformations are also presented. Density Functional theory (DFT) computations suggest that the regio- and enantio-selectivities originate from the cyclopropene insertion to the Rh-H bond. The high regioselectivity is found to benefit from the presence of more efficient noncovalent interactions (NCIs) manifesting in the form of C–H···Cl, C–H···N, and l.p(Cl)···π contacts.