Stereospecific synthesis of N-protected statine and its analogues via chiral tetramic acid

Abstract
The condensation of a chiral N-protected amino acid with Meldrum's acid in the presence of isopropenyl chloroformate (IPCF) and of 4-N,N-dimethylaminopyridine (DMAP) has been examined. The cyclisation of the reaction product, by heating in an organic solvent, gave the N-protected tetramic acid derivatives (4a–i) which, after reduction, afforded the corresponding threo-4-hydroxypyrrolidin-2- ones (5a–i). The regioselective alkaline or acid hydrolysis of the N-protected pyrrolidin-2-ones led to enantiomeric pure N- Boc-statine (6a) and its analogues (6b–i) in 40–60% yield from the N-protected amino acids. The corresponding statine methyl esters (7a–i) could also be synthesized in high yield.