Syn/anti switching by specific heteroatom-titanium coordination in the Mannich-like synthesis of 2,3-diaryl-β-amino acid derivatives

A very efficient synthesis of 2,3-diaryl-β-amino acid derivatives is realized by a TiCl4/triethylamine-catalyzed Mannich-like reaction of arylacetic or arylthioacetic esters with arylimines. The presence on the arylacetic moiety of an ortho-heteroatom group able to coordinate to the titanium center is of dramatic importance for the outcome of the reaction and to tune the syn/anti diastereoselection. In particular, with o-F-, o-Cl-, and o-Br-arylacetates, the syn adduct was isolated as the largely prevalent isomer. When (-)-8-phenylmenthyl (2-fluorophenyl)acetate was used, the condensation with imines resulted in high diastereo- and enantioselectivity. In agreement with the stereochemical results and NMR studies, a conceivable reaction mechanism was proposed. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.