Convenient Route to Enantiopure Fmoc-Protected Morpholine-3-carboxylic Acid

Abstract

Enantiopure Fmoc-protected morpholine-3-carboxylic acid was synthesized from dimethoxyacetaldehyde and serine methyl ester through a short and practical synthetic route. The preparation consisted of a five-step process based on reductive amination, intramolecular acetalization, and concomitant elimination of the anomeric methoxy substituent, followed by hydrogenation of the double bond and final acidic ester hydrolysis. The optical purity of both enantiomers of the title amino acid was demonstrated by HPLC analysis of the corresponding amide derivatives obtained from coupling with chiral (S)-(-)-1-phenylethylamine. Moreover, the synthesis of a model tripeptide showed full compatibility of the title Fmoc-amino acid with solid-phase peptide synthesis, thus allowing the application of Fmoc-morpholine-3-carboxylic acid in peptidomimetic chemistry on the solid phase.