Rapid phenolic O-glycosylation of small molecules and complex unprotected peptides in aqueous solvent

Nat Chem. 2018 Jun;10(6):644-652. doi: 10.1038/s41557-018-0041-8. Epub 2018 Apr 30.

Abstract

Glycosylated natural products and synthetic glycopeptides represent a significant and growing source of biochemical probes and therapeutic agents. However, methods that enable the aqueous glycosylation of endogenous amino acid functionality in peptides without the use of protecting groups are scarce. Here, we report a transformation that facilitates the efficient aqueous O-glycosylation of phenolic functionality in a wide range of small molecules, unprotected tyrosine, and tyrosine residues embedded within a range of complex, fully unprotected peptides. The transformation, which uses glycosyl fluoride donors and is promoted by Ca(OH)2, proceeds rapidly at room temperature in water, with good yields and selective formation of unique anomeric products depending on the stereochemistry of the glycosyl donor. High functional group tolerance is observed, and the phenol glycosylation occurs selectively in the presence of virtually all side chains of the proteinogenic amino acids with the singular exception of Cys. This method offers a highly selective, efficient, and operationally simple approach for the protecting-group-free synthesis of O-aryl glycosides and Tyr-O-glycosylated peptides in water.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acids / chemistry
  • Calcium Hydroxide / chemistry
  • Carbon-13 Magnetic Resonance Spectroscopy
  • Chromatography, High Pressure Liquid
  • Glycosylation
  • Peptides / chemistry*
  • Phenols / chemistry*
  • Proton Magnetic Resonance Spectroscopy
  • Small Molecule Libraries / chemistry*
  • Solvents / chemistry
  • Tandem Mass Spectrometry
  • Water / chemistry

Substances

  • Amino Acids
  • Peptides
  • Phenols
  • Small Molecule Libraries
  • Solvents
  • Water
  • Calcium Hydroxide