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Enantioselective Synthesis of α‐Aryl‐β 2 ‐Amino‐Esters by Cooperative Isothiourea and Brønsted Acid Catalysis
Author(s) -
Zhao Feng,
Shu Chang,
Young Claire M.,
CarpenterWarren Cameron,
Slawin Alexandra M. Z.,
Smith Andrew D.
Publication year - 2021
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202016220
Subject(s) - enantioselective synthesis , chemistry , catalysis , iminium , yield (engineering) , brønsted–lowry acid–base theory , kinetic resolution , organocatalysis , aryl , ammonium , amino acid , medicinal chemistry , organic chemistry , combinatorial chemistry , biochemistry , materials science , alkyl , metallurgy
The synthesis of α‐aryl‐β 2 ‐amino esters through enantioselective aminomethylation of an arylacetic acid ester in high yields and enantioselectivity via cooperative isothiourea and Brønsted acid catalysis is demonstrated. The scope and limitations of this process are explored (25 examples, up to 94 % yield and 96:4 er), with applications to the synthesis of ( S )‐Venlafaxine⋅HCl and ( S )‐Nakinadine B. Mechanistic studies are consistent with a C(1)‐ammonium enolate pathway being followed rather than an alternative dynamic kinetic resolution process. Control studies indicate that (i) a linear effect between catalyst and product er is observed; (ii) an acyl ammonium ion can be used as a precatalyst; (iii) reversible isothiourea addition to an in situ generated iminium ion leads to an off‐cycle intermediate that can be used as a productive precatalyst.