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

The first synthesis of one of the 4 possible stereoisomers of 3,4-dihydroxy- -glutamic acid ((3S,4S)-DHGA Scheme 2 and 1), a natural product of unknown configuration, is described. The synthesis is based on the Lewis acid catalyzed reaction of benzyl alcohol with a -ribose-derived 2,3-aziridino-γ-lactone 4-benzyl carboxylate (Scheme 1 and Scheme 2). Preliminary pharmacological studies showed that (3S,4S)-Scheme 2 and 1 is an agonist of metabotropic glutamate receptors of type 1 (mGluR1) and a weak antagonist of mGluR4 but has no discernible activity with respect to mGluR2. This activity profile can be rationalized by fitting extended conformations of (3S,4S)-Scheme 2 and 1 in proposed models of each of these receptor subtypes. Scheme 2. Scheme 1.