3-Hydroxyazetidine Carboxylic Acids: Non-Proteinogenic Amino Acids for Medicinal Chemists

The formation from D-glucose of both enantiomers of 2,4-dideoxy-2,4-iminoribonic acid is the first chemical synthesis of unprotected 3-hydroxyazetidine carboxylic acids. The long-term stability of 3-hydroxyazetidine amides is established at acidic and neutral pH and implies their value as non-proteinogenic amino acid components of peptides, providing medicinal chemists with a new class of peptide isosteres. The structure of N,3-O-dibenzyl-2,4-dideoxy-2,4-imino-D-ribonic acid was established by X-ray crystallographic analysis. An N-methylazetidine amide derivative is a specific inhibitor of β-hexosaminidases at the micromolar level, and is only the second example of potent inhibition of any glycosidase by an amide of a sugar amino acid related to an iminosugar.