First completely chemical synthesis of [(6S)-N5-formyltetrahydropteroyl]poly γ-L-glutamic acid derivatives

Abstract

The synthesis of (6S)-N5-formyl-5,6,7,8-tetrahydropteroyl-di-, -tri-, -tetra- and -penta-γ-L-glutamic acid derivatives 9a–d has been achieved for the first time through a three-step sequence of chemical reactions. The process involves converting [(6S)-N5-formyl-5,6,7,8-tetrahydropteroyl]- mono-L-glutamic acid 6 into the α-benzyl monoester 7, which is then coupled in four separate reactions to preformed polybenzyl esters of mono-, di-, tri-, and tetra-γ-L-glutamate. The resulting (6S)-N5-formyl-5,6,7,8-tetrahydropteroyl-di-, -tri-, -tetra- and -penta-γ-L-glutamate polybenzyl ester derivatives 8a–d are then subjected to hydrogenolysis, giving polyacids 9a–d. The overall yields for the individual sequences range from 37 to 49%. Importantly, enzymic and chiral chromatographic analyses of compounds 9a–d indicate that their stereochemical purity exceeds 99%.