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

Abstract

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.

Synthesis of the enantiomers of XYLNAc and LYXNAc: comparison of β-N-acetylhexosaminidase inhibition by the 8 stereoisomers of 2-N-acetylamino-1,2,4-trideoxy-1,4-iminopentitols

“…22,23 The D-galacto-analogue DGJNAc 7 24 a is the only known potent inhibitor of α-GalNAcases but is also a good inhibitor of HexNAcases. 25 Both the amides of hydroxylated pipecolic 8 26 and azetidine 9 27 carboxylic acids are potent inhibitors of HexNAcases. ADMDP (1-acetamido-1,2,5-trideoxy-2,5-imino-D-mannitol) 10 28,29 is a rare example of a potent pyrrolidine HexNAcase inhibitor.…”

Ligands and Receptors with Broad Binding Capabilities Have Common Structural Characteristics: An Antibiotic Design Perspective

“…Several of them contain reactive double bonds; thus in practice their saturated versions should be used. The effect of such (e.g., azetidine-like) four-membered rings on toxicity is less clear; azetidine-based inhibitors of herpesvirus proteases are known and being developed, and azetidines have been suggested for use as peptidomimetics in medicinal chemistry . However, exactly due to its incorporation into proteins (as a substitute of proline), azetidine-2-carboxylic acid is known to be toxic.…”

Synthesis of Chiral Tetrasubstituted Azetidines from Donor–Acceptor Azetines via Asymmetric Copper(I)‐Catalyzed Imido‐Ylide [3+1]‐Cycloaddition with Metallo‐Enolcarbenes

“…Diol or polyol products from reduction of azetine‐2‐carboxylates or ‐carboxylic acids form derivatives that are a common structural unit in penaresidins A and B (Figure ) and other naturally occurring or synthetic azetidine iminosugars—a class of compounds with potent glycosidase inhibitory activities also suitable for incorporation into peptides . Chiral azetidine‐carboxylates 4 or ‐carboxylic acids 5 appear to be suitable substrates for the synthesis of azetidine iminosugar derivatives.…”