Access to Unnatural Glycosyl Amino Acid Building Blocks via a One-Pot Ritter Reaction

Abstract

α-d-Galacto-2-deoxy-oct-3-ulopyranosonic acids, α-d-gluco-2-deoxy-oct-3-ulopyranosonic acids and α-l-galacto-2,8-dideoxy-oct-3-ulopyranosonic acids can be converted into unnatural glycosyl amino acids via a one-pot intramolecular Ritter reaction. Initially, a ketopyranoside-based acid condenses under Lewis acid-promoted conditions with a nitrile (benzonitrile or acetonitrile) and a partially protected diamino ester (Boc-DAB-Ot-Bu, Boc-Orn-Ot-Bu) to form unnatural glycosyl amino esters. The resulting glycosyl amino esters are useful building blocks for solid-phase glycopeptide synthesis. For example, the glycosyl amino acid derived by condensation of α-d-galacto-2-deoxy-oct-3-ulopyranosonic acid with benzonitrile and DAB was used to replace serine in the potent opioid peptide sequence H₂N-Tyr-d-Thr-Gly-Phe-Leu-Ser-CONH₂.

carbohydrates - glycopeptides - combinatorial chemistry - glycosyl amino acids - peptides

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Cyanoalanine and nitriles with branching at the β-position have previously been used without success in an intermolecular Ritter reaction (see ref. 29).