Enantioselective Synthesis of α‐Aryl‐β ² ‐Amino‐Esters by Cooperative Isothiourea and Brønsted Acid Catalysis

The synthesis of α-aryl-β2-amino esters through enantioselective aminomethylation an arylacetic acid ester in high yields and enantioselectivity via cooperative isothiourea Brønsted catalysis is demonstrated. scope limitations this process are explored (25 examples, up to 94 % yield 96:4 er), with applications the (S)-Venlafaxine⋅HCl (S)-Nakinadine B. Mechanistic studies consistent a C(1)-ammonium enolate pathway being followed rather than alternative dynamic kinetic resolution process. Control indicate that (i) linear effect between catalyst product er observed; (ii) acyl ammonium ion can be used as precatalyst; (iii) reversible addition situ generated iminium leads off-cycle intermediate productive precatalyst.