Abstract
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.
Highlights
A simple, three-step chemoenzymatic synthesis of l-threo-3benzyloxyaspartate (l-TBOA), as well as l-TBOA derivatives with F, CF3, and CH3 substituents at the aromatic ring, starting from dimethyl acetylenedicarboxylate was investigated
Studies on Excitatory amino acid transporters (EAATs), of which five subtypes (EAAT1–5) have been identified, have been largely dependent upon the development of selective and potent inhibitors that can be used to probe the physiological roles of these transporters in the regulation of glutamatergic neurotransmission or in the pathogenesis of neurological diseases.[1,3]
Aspartate derivatives with large aryl or aryloxy substituents at the C3 position form an important class of inhibitors of EAATs.[3,4]
Summary
A simple, three-step chemoenzymatic synthesis of l-threo-3benzyloxyaspartate (l-TBOA), as well as l-TBOA derivatives with F, CF3, and CH3 substituents at the aromatic ring, starting from dimethyl acetylenedicarboxylate was investigated. To further demonstrate the synthetic usefulness of the MAL mutants, a preparative-scale reaction using 0.01 mol % biocatalyst (the L384G mutant), ammonia (5 m), and 2 a (0.75 mmol, 50 mm) was performed at pH 9.0 and room temperature.
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