Chiral bisamidine catalysis: enantioselective alkylations and halolactonizations with applications to small molecule therapeutics

Abstract

Herein we demonstrate the development and application of chiral bis(amidines) as organocatalysts in novel enantioselective transformations. A chiral, Brønsted base-catalyzed asymmetric alkylation of nitroalkanes is described for the first time using bis(amidine) catalysis, delivering products with synthetically useful values of enantiomeric excess. Additionally, the first enantioselective synthesis of VNI, a potent CYP51 inhibitor, is divulged and highlighted by an enantioselective bromonitromethane aza-Henry addition to afford the desired intermediate with high enantioselectivity. Ultimately, gram quantities of VNI were synthesized to establish its efficacy in a murine model of chronic Chagas, a neglected tropical disease. Finally, the highly enantioselective iodolactonization of 1,1- and 1,2-disubstituted olefinic acids using chiral proton catalysis is reported, where steric and electronic modification of an achiral counterion offers a handle to control enantioselection.