Enantioselective total synthesis of (1R,3S,4R,5R)-1-amino-4,5-dihydroxycyclopentane-1,3-dicarboxylic acid. A full-aldol access to carbaketose derivatives.

Abstract

The enantioselective synthesis of cyclopentanedicarboxylic amino acid 1, a novel rigid and functionalized L-glutamic acid analogue, has been achieved in 15 linear steps from silyloxypyrrole 3, utilizing L-glyceraldehyde 4 as the source of chirality. The key steps in the synthesis are three sequential aldol-based carbon-carbon bond-forming reactions: two crossed vinylogous aldol additions (2 + 3 --> 8 and 4 + 5 --> 10 + 11) and one intramolecular silylative aldolization (6 --> 7). En passant, the short syntheses of (2S)-2-hydroxymethylglutamic acid (16) and its (2R)-enantiomer ent-16, a potent metabotropic glutamate receptor agonist, have been achieved.