Electrocatalytic Asymmetric Nozaki–Hiyama–Kishi Decarboxylative Coupling: Scope, Applications, and Mechanism
Yang Gao, Baiyang Jiang, Nathan C. Friede, Arianne C. Hunter, Dylan G. Boucher, Shelley D. Minteer, Matthew S. Sigman, Sarah E. Reisman, Phil S. Baran
Abstract
The first general enantioselective alkyl-Nozaki–Hiyama–Kishi (NHK) coupling reactions are disclosed herein by employing a Cr-electrocatalytic decarboxylative approach. Using easily accessible aliphatic carboxylic acids (via redox-active esters) as alkyl nucleophile synthons, in combination with aldehydes and enabling additives, chiral secondary alcohols are produced in a good yield with high enantioselectivity under mild reductive electrolysis. This reaction, which cannot be mimicked using stoichiometric metal or organic reductants, tolerates a broad range of functional groups and is successfully applied to dramatically simplify the synthesis of multiple medicinally relevant structures and natural products. Mechanistic studies revealed that this asymmetric alkyl e-NHK reaction was enabled by using catalytic tetrakis(dimethylamino)ethylene, which acts as a key reductive mediator to mediate the electroreduction of the Cr III /chiral ligand complex.