Catalytic Asymmetric Metallocyclopropanation Reactions Using Chloroform as a Carbyne Equivalent

Stereochemically complex, sp3-rich rings have attracted significant interest in drug discovery because of their ability to mitigate the physicochemical liabilities associated with flat aromatic rings. Cyclopropanes are attractive targets in this regard because they have unique three-dimensional structures and are resistant to metabolism. Numerous catalytic enantioselective alkene cyclopropanation reactions have been developed using carbene precursors. However, most of these methods use energetic reagents and are restricted to specific classes of resonance-stabilized carbenes. Here, we report a catalytic asymmetric cyclopropanation reaction using chloroform as a methylidyne equivalent and Zn as a stoichiometric reductant. The products are metallocyclopropanes that can be further functionalized in a telescoped process to yield halo-, aryl-, allyl-, alkynyl-, vinyl-, and other substituted cyclopropanes in highly enantioenriched form. A notable feature of the reaction is the high degree of cis diastereoselectivity, which is controlled by the large N-aryl substituent of the ligand. Application in the parallel synthesis of enantioenriched 1,2-diarylcyclopropanes bearing pharmaceutically relevant heterocycles is demonstrated.