Studies on lipase-catalyzed asymmetric synthesis of (S)-(hydroxymethyl)glutamic acid (HMG).

Hiromasa Yoshioka,Masato Oikawa

doi:10.1186/s40064-015-1503-8

Abstract

(S)-(Hydroxymethyl)glutamic acid was successfully synthesized in total 12 % yield over eight steps from tris(hydroxymethyl)aminomethane hydrochloride (Tris·HCl), employing lipase TL-induced enantioselective acetylation of a prochiral 1,3-diol as the key step.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-1503-8) contains supplementary material, which is available to authorized users.

Highlights

The metabotropic glutamate receptors play an important role in the modulation of synaptic transmission and neuronal excitability by glutamate, the main excitatory neurotransmitter, in the central nervous system (CNS) (Niswender and Conn 2010; Rondard and Pin 2015). mGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, and belong to family C receptors that typically contain the endogenous ligandbinding site at a large extracellular N-terminal domain. mGluRs are subdivided into three groups, group I, group II, and Group III
Group II mGluRs reduce cAMP accumulation resulting in neuroprotecting effect and are closely linked to construction of memory and learning (Kawasaki et al 2003). (Hydroxymethyl)glutamic acid (HMG) is one of the selective ligands for group II mGluRs. (R)-(hydroxymethyl)glutamic acid (HMG) is a selective agonist for mGluR3 (Miyaoka et al 2006), and the (S)-counterpart [(S)-HMG, Fig. 1] has been shown to act as a more potent agonist for mGluR3 and a weak antagonist for mGluR2, both belong to group II (Choudhury et al 2002)
In this paper, we demonstrated enantioselective synthesis of (S)-HMG (9) employing lipase-catalyzed asymmetric esterification of prochiral 1,3-diol 5

Summary

Introduction

The metabotropic glutamate receptors (mGluRs) play an important role in the modulation of synaptic transmission and neuronal excitability by glutamate, the main excitatory neurotransmitter, in the central nervous system (CNS) (Niswender and Conn 2010; Rondard and Pin 2015). mGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, and belong to family C receptors that typically contain the endogenous ligandbinding site at a large extracellular N-terminal domain. mGluRs are subdivided into three groups, group I (mGluRs 1 and 5), group II (mGluRs 2 and 3), and Group III (mGluRs 4, 6, 7, and 8). We have been interested in the synthesis of the neuronally active compounds, by the divergent route amenable to the structural analogs to discover novel compounds (Chiba et al 2015; Juknaitė et al 2013; Oikawa et al 2013; Sakai et al 2014; Sugeno et al 2014; Tanaka et al 2015). We report our synthetic study using lipase-mediated esterification of prochiral acyclic 1,3-diol as the key step. Such enzymatic strategy has been previously reported as noted above (Miyaoka et al 2006), in this study, we intended development of our own route to HMG and to the analogs. Enzymatic approach was expected to be applicable to the other biologically interesting natural products such as dysibetaine (Sakai et al 1999) and sphingofungin E (Horn et al 1992), by virtue of (1) the Yoshioka and Oikawa SpringerPlus (2015)4:726

Methods

Results

Conclusion