Stereoselective synthesis of mexiletine and structural analogs with chiral tert-butanesulfinamide

Journal: 
Tetrahedron Letters
Publication Year: 
2015
Authors: 
Daniel A. Ryan
Karl J. Ololotowicz
Mark Mercola
John R. Cashman
PubMed link: 
Public Summary: 
An asymmetric synthesis of mexiletine and structural analogs was developed using chiral tert-butanesulfinamide to convert precursor ketones to chiral amines. Starting from a-aryloxy ketones, a two-step condensation–reduction procedure provided chiral N-tert-butanesulfinyl amines as immediate precursors to mexiletine or structural analogs. Reduction of the intermediate N-tert-butanesulfinyl imine showed substrate- and reagent-derived stereoselectivity. Following removal of the chiral auxiliary, mexiletine and structural analogs were obtained in high enantiopurity using this approach.
Scientific Abstract: 
An asymmetric synthesis of mexiletine and structural analogs was developed using chiral tert-butanesulfinamide to convert precursor ketones to chiral amines. Starting from α-aryloxy ketones, a two-step condensation–reduction procedure provided chiral N-tert-butanesulfinyl amines as immediate precursors to mexiletine or structural analogs. Reduction of the intermediate N-tert-butanesulfinyl imine showed substrate- and reagent-derived stereoselectivity. Following removal of the chiral auxiliary, mexiletine and structural analogs were obtained in high enantiopurity using this approach.