Synthesis of Novel Glycopeptidomimetics Containing O- and N-Glycosylated α-Aminooxy Acids by Fragment Coupling on Solid Support

Abstract

New glycosylated peptidomimetics possessing O- and N-glycosylated α-aminooxy acids were efficiently synthesized by fragment coupling on solid support. The N-terminal glycosylated tripeptide mimics prepared in solution were coupled to the C-terminal dipeptides attached to the resin under O-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU)/1-hydroxy-7-azabenzotriazole (HOAt)/N-ethylmorpholin (NEM) conditions.

Key words

α-aminooxy acids - carbohydrates - coupling - glycopeptidomimetics - solid-phase synthesis

References

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7

Initially, we made attempt to prepare O-glycosylated pentamers with an acetyl group at the N-terminus. The coupling of Ac-Leu-Ala-OH to ^N-O Ser(OAc)₄-OBn with HOBt-Bop-DIEA produced the desired LLL-trimer and an epimerized LDL-trimer in almost equal ratio and in low yield (20% and 15% yields, respectively). Although scrambling of the stereocenter was remarkably reduced using HATU-HOAt-NEM, these conditions gave only 27% of the desired trimer. Therefore, we replaced the acetyl group with benzoyl group at the N-terminus to improve the coupling yield.

10

The epimerized glycosylated pentamers during fragment coupling were produced in < 2% yield based on HPLC analysis.