Bifunctional Chiral Dehydroalanines for Peptide Coupling and Stereoselective S‑Michael Addition

A second generation of chiral bicyclic dehydroalanines easily accessible from serine has been developed. These scaffolds behaved as excellent S-Michael acceptors when tri-O-acetyl-2-acetamido-2-deoxy-1-thio-α-d-galactopyranose (abbreviated as GalNAc-α-SH) was used as a nucleophile. This addition proceeds with total chemo- and stereoselectivity, complete atom economy, quickly, and at room temperature, making it a true click reaction. The Michael adducts were easily transformed into S-(2-acetamido-2-deoxy-α-d-galactopyranosyl)-l- and -d-cysteines, which can be regarded as mimics of the Tn antigen derived from l-Ser (α-d-GalNAc-l-Ser) and d-Ser (α-d-GalNAc-d-Ser), respectively.