Isothiourea-Catalyzed Enantioselective Addition of 4-Nitrophenyl Esters to Iminium Ions

Abstract

Isothioureas catalyze the enantioselective addition of 4-nitrophenyl esters to tetrahydroisoquinoline-derived iminium ions. 4-Nitrophenoxide, generated in situ from initial N-acylation of the isothiourea by the 4-nitrophenyl ester, is used to facilitate catalyst turnover in this reaction process. Optimization showed that 4-nitrophenyl esters give the best reactivity in this protocol over a range of alternative aryl esters, with the observed enantioselectivity markedly dependent on the nature of the iminium counterion. Highest yields and enantioselectivity were obtained using iminium bromide ions generated in situ via photoredox catalysis using BrCCl3 and Ru(bpy)3Cl2 (0.5 mol %) and commercially available tetramisole (5 mol %) as the Lewis base catalyst. The scope and limitations of this procedure was developed, giving the desired β-amino amide products in up to 96% yield, 79:21 diastereomeric ratio (dr), and ermajor (2R,1′S) 99.5:0.5.