A versatile synthetic approach toward diversity libraries using monosaccharide scaffolds

J Org Chem. 2010 Jan 1;75(1):197-203. doi: 10.1021/jo9021919.

Abstract

The pyranose scaffold is unique in its ability to position pharmacophore substituents in various ways in 3D space, and unique pharmacophore scanning libraries could be envisaged that focus on scanning topography rather than diversity in the type of substituents. Approaches have been described that make use of amine and acid functionalities on the pyranose scaffolds to append substituents, and this has enabled the generation of libraries of significant structural diversity. Our general aim was to generate libraries of pyranose-based drug-like mimetics, where the substituents are held close to the scaffold, in order to obtain molecules with better defined positions for the pharmacophore substituents. Here we describe the development of a versatile synthetic route toward peptide mimetics build on 2-amino pyranose scaffolds. The method allows introduction of a wide range of substituent types, it is regio- and stereospecific, and the later diversity steps are performed on solid phase. Further, the same process was applied on glucose and allose scaffolds, in the exemplified cases, and is likely adaptable to other pyranose building blocks. The methods developed in this work give access to molecules that position the three selected binding elements in various 3D orientations on a pyranose scaffold and have been applied for the production of a systematically diverse library of several hundred monosaccharide-based mimetics.

MeSH terms

  • Amines / chemistry*
  • Combinatorial Chemistry Techniques
  • Glycosylation
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Monosaccharides / chemical synthesis*
  • Monosaccharides / chemistry*
  • Peptides / chemical synthesis*
  • Peptides / chemistry*
  • Sugar Acids / chemical synthesis*
  • Sugar Acids / chemistry*

Substances

  • Amines
  • Monosaccharides
  • Peptides
  • Sugar Acids