Epoxy amino acids produced from allylglycines intramolecularly cyclised to yield four stereoisomers of 4-hydroxyproline derivatives

Derivatives of 2-amino-4-pentenoic acid (allylglycine) were efficiently resolved using Subtilisin or acylase. The side-chain unsaturated bond of the enantiomerically pure amino acid with tert -butoxycarbonyl (Boc) protection was smoothly epoxidized with m -chloroperbenzoic acid. When the Boc protection of the amino group was removed, the amino group intramolecularly attacked the side-chain epoxide, generating compounds with five-membered rings: the 4-hydroxyproline derivatives. Two diastereomeric products were formed through the cyclisation reaction, for example, (2 S ,4 S )-4-hydroxyproline benzyl ester ( cis - 8 ) and (2 S ,4 R )-4-hydroxyproline benzyl ester ( trans - 8 ) were formed from (2 S )-amino acid with a side-chain epoxide. Compound (2 S ,4 S )-4-hydroxyproline benzyl ester ( cis - 8 ) was transformed to a lactone ( cis- hydroxyproline lactone, 10 ) with the removal of benzyl alcohol. The cis -conformation was essential for the intramolecular ester exchange reaction; in fact, no lactone formation was observed for the trans isomer ( trans - 8 ). The separation of cis- hydroxyproline lactone and the trans- isomeric hydroxyproline benzyl ester was facile and clear, in contrast to the difficult separation of cis - and trans -hydroxyproline derivatives. Thus, two diastereomers of hydroxyproline derivatives for l -hydroxyproline and also for d -hydroxyproline were obtained, i.e. , four diastereomers of hydroxyproline derivatives. Intermolecular epoxide-opening generated stereoisomeric hydroxyprolines; cis -isomer formed lactone, being easily separable from trans -hydroxyproline ester.