Synthesis of Enantioenriched Substituted (Hetero)Cycloalkanes by Convergent NiH Catalysis

Abstract

Enantioenriched alkyl-substituted cycloalkanes and azacyclic compounds constitute an essential class of compounds in pharmaceuticals, natural products and agrochemicals. Here we report an NiH-catalyzed asymmetric migratory hydroalkylation process for the efficient and selective construction of such compounds. Through a dynamic kinetic asymmetric transformation (DYKAT), easily accessible racemic and isomeric mixtures of cycloalkenes could be directly utilized as starting materials, convergently producing thermo-dynamically disfavored chiral 1,2-cis disubstituted cycloalkanes bearing vicinal stereocenters with high levels of regio-, diastereo- and enantioselectivity. Alternatively, N-heterocyclic alkenes can be employed, and deliver a variety of enantioenriched α-alkylated cyclic amines. The synthetic utility of this transformation is further demonstrated by the facile synthesis of two alkaloids, (+)-connine and (R)-pipecoline.

Nickel-Catalyzed Migratory Cross-Coupling Reactions: New Opportunities for Selective C–H Functionalization

“…Starting from stable and abundant alkenes and alkyl halides, NiH-catalyzed migratory hydroalkylation provides an attractive approach for constructing the most common but challenging C­(sp 3 )–C­(sp 3 ) bond at a distal, inert C­(sp 3 )–H position. , …”