Work

Silver Oxide Promoted Synthesis of Alpha O-GalNAc Containing Glyco-Amino Acids: Synthesis of Core 2 Containing Glyco-Amino Acids for Solid Phase Synthesis of Glycopeptides

Year: 2024

Type: article

Abstract: O -GalNAc glycans on glycoproteins with eight different core structures sharing a common α-glycosidic linkage ( O -GalNAc-α-Ser/Thr) are critical in various physiological and pathological processes. Among the eight O -GalNAc glycan cores, core 2 characterized by a GlcNAcβ1–6(Galβ1–3)GalNAc structural motif plays a significant role in regulating diverse biological processes, such as immune response modulation, adhesive properties of selectins, and gastrointestinal tract protection. However, the large-quantity synthesis of core 2 containing glyco-amino acids for downstream solid-phase peptide synthesis is challenging. In this work, we successfully employed a silver oxide for coupling a 2-azido-galactosyl chloride donor with two acceptors, Fmoc-Ser/Thr-O t Bu, respectively, for the large-scale synthesis of the two important intermediates, α-GalN 3 –Fmoc-Ser/Thr-O t Bu, which can be further utilized for the large-scale synthesis of core 2 containing glyco-amino acids. The two intermediates, α-GalN 3 –Fmoc-Ser/Thr-O t Bu, were utilized for synthesizing core 2 containing Fmoc-Ser/Thr-COOH. The synthesis of core 2 containing Fmoc-Ser-COOH was achieved on a 1.95 g scale, while the synthesis of core 2 containing Fmoc-Thr-COOH was achieved on a 0.38 g scale. Additionally, the synthesis of the 2-azido-galactosyl chloride donor was optimized into a three-step process with only one column chromatography purification. Finally, core 2 containing Fmoc-Ser/Thr-COOH were applied for the synthesis of glycosylated CCR1 and CCR5 N-terminal peptides.

Source: The Journal of Organic Chemistry

DOI: 10.1021/acs.joc.4c01572