A practical synthesis of Nα-Fmoc protected l-threo-β-hydroxyaspartic acid derivatives for coupling via α- or β-carboxylic group

A simple and practical general synthetic protocol towards orthogonally protected t HyAsp derivatives fully compatible with Fmoc solid-phase peptide synthetic methodology is reported. Our approach includes enantioresolution of commercially available d , l - t HyAsp racemic mixture by co-crystallization with l -Lys, followed by ion exchange chromatography yielding enantiomerically pure l - t HyAsp and d - t HyAsp, and their selective orthogonal protection. In this way N α -Fmoc protected t HyAsp derivatives were prepared ready for couplings via either α - or β -carboxylic group onto the resins or the growing peptide chain. In addition, coupling of t HyAsp via β -carboxylic group onto amino resins allows preparation of peptides containing t HyAsn sequences, further increasing the synthetic utility of prepared t HyAsp derivatives. Graphical Abstract