Rapid chemoenzymatic route to glutamate transporter inhibitor l-TFB-TBOA and related amino acids

Abstract

The complex amino acid (L-threo)-3-[3-[4-(trifluoromethyl)benzoylamino]benzyloxy]aspartate (L-TFB-TBOA) and its derivatives are privileged compounds for studying the roles of excitatory amino acid transporters (EAATs) in regulation of glutamatergic neurotransmission, animal behavior, and in the pathogenesis of neurological diseases. The wide-spread use of L-TFB-TBOA stems from its high potency of EAAT inhibition and the lack of off-target binding to glutamate receptors. However, one of the main challenges in the evaluation of L-TFB-TBOA and its derivatives is the laborious synthesis of these compounds in stereoisomerically pure form. Here, we report an efficient and step-economic chemoenzymatic route that gives access to enantio- and diastereopure L-TFB-TBOA and its derivatives at multigram scale.