Use of a modified ring-switching strategy to synthesise the glutamate antagonist (2S)-2-amino-3-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)propionate and related compounds with two chiral centres

Abstract

(2S)-2-Amino-3-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)propionic acid 8, an isomer of the natural product willardiine 7, was synthesised by treatment of the pyroglutamate urea 19 with mild base followed by deprotection in a two-step modification of our ‘ring-switching’ approach to the synthesis of glutamate antagonists. Use of this two-step strategy has allowed us to synthesise L-alanine derivatives, which are β-substituted by a reduced pyrimidinedione which contains a second chiral centre. In one case, the antagonist activity at metabotropic glutamate receptors of two diastereoisomers showed little difference.