Abstract
The synthesis of α‐aryl‐β2‐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.
Highlights
Introduction bAmino acids are important functional groups in an abundance of natural products and medicinally relevant compounds
We proposed that enantioselective aminomethylation of C(1)-ammonium enolates, catalytically generated from chiral isothioureas and arylacetic acid esters, would provide ready access to enantioenriched a-aryl-b2amino esters
The effective enantioselective construction of a-aryl-b2amino ester 9 was realized via the benzotetramisole·HCl (BTM·HCl, 5 mol %) catalyzed Mannich addition of pentafluorophenyl ester pronucleophile 8 to hemiaminal ether iminium precursor 5 in THF at room temperature in the presence of 4 molecular sieves (MS)
Summary
Introduction bAmino acids are important functional groups in an abundance of natural products and medicinally relevant compounds. Subsequent addition of 2naphthyl substituted pentafluorophenyl ester 42, enantiopure (R)-BTM·HCl (15 mol %) and 5 allowed potential DKR of the b-amino ester under the reaction conditions to be assessed alongside the enantioselective aminomethylation of (Table 3 A).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
