Chemoenzymatic Synthesis of ortho-, meta-, and para-Substituted Derivatives of L-threo-3-Benzyloxyaspartate, An Important Glutamate Transporter Blocker

• Published in: ChemCatChem Vol. 7; no. 13; pp. 1931 - 1934
• Main Authors: de Villiers, Jandré, de Villiers, Marianne, Geertsema, Edzard M., Raj, Hans, Poelarends, Gerrit J.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 03.07.2015; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: Amino acids; biocatalysis; Communications; excitatory amino acid transporters; glutamate; inhibitors; threo-3-benzyloxyaspartate; inhibitors; threo-3-benzyloxyaspartate; excitatory amino acid transporters; biocatalysis; glutamate
• ISSN: 1867-3880; 1867-3899
• DOI: 10.1002/cctc.201500318

A simple, three‐step chemoenzymatic synthesis of L‐threo‐3‐benzyloxyaspartate (L‐TBOA), as well as L‐TBOA derivatives with F, CF3, and CH3 substituents at the aromatic ring, starting from dimethyl acetylenedicarboxylate was investigated. These chiral amino acids, which are extremely difficult to prepare by chemical synthesis, form an important class of inhibitors of excitatory amino acid transporters involved in the regulation of glutamatergic neurotransmission. In addition, a new chemical procedure for the synthesis of racemic mixtures of TBOA and its derivatives was explored. These chemically prepared racemates are valuable reference compounds in chiral‐phase HPLC to establish the enantiopurities of the corresponding chemoenzymatically prepared amino acids. EAAT it! The chemoenzymatic synthesis of L‐threo‐3‐benzyloxyaspartate (L‐TBOA), an important inhibitor of excitatory amino acid transporters (EAATs), and various derivatives of TBOA with substituents at the aromatic ring is described. This attractive chemoenzymatic method for the selective preparation of TBOA and its derivatives appears to be a simple and environmentally friendly alternative for existing multistep chemical synthesis methods.