First enantiospecific synthesis of a 3,4-dihydroxy-L-glutamic acid [(3S,4S)-DHGA], a new mGluR1 agonist

The first synthesis of one of the 4 possible stereoisomers of 3,3-dihydroxy -L-glutamic acid ((3S,4S)-DHGA 3), a natural product of unknown configurati on, is described. The synthesis is based on the Lewis acid catalyzed reacti on of benzyl alcohol with a D-ribose-derived 2,3-aziridino-gamma-lactone 4- benzyl carboxylate (6). Preliminary pharmacological studies showed that (3S ,4S)-3 is an agonist of metabotropic glutamate receptors of type 1 (mGluR1) and a weak antagonist of mGluR4 but has no discernible activity with respe ct to mGluR2. This activity profile can be rationalized by fitting extended conformations of (3S,4S)-3 in proposed models of each of these receptor su btypes. (C) 2000 Elsevier Science Ltd. All rights reserved.