Synthesis of Altrose Poly-amido-saccharides with β-N-(1→2)-d-amide Linkages: A Right-Handed Helical Conformation Engineered in at the Monomer Level

J Am Chem Soc. 2017 Oct 11;139(40):14217-14223. doi: 10.1021/jacs.7b07405. Epub 2017 Sep 27.

Abstract

The design and synthesis of amide-linked saccharide oligomers and polymers, which are predisposed to fold into specific ordered secondary structures, is of significant interest. Herein, right-handed helical poly amido-saccharides (PASs) with β-N-(1→2)-d-amide linkages are synthesized by the anionic ring-opening polymerization of an altrose β-lactam monomer (alt-lactam). The right-handed helical conformation is engineered into the polymers by preinstalling the β configuration of the lactam ring in the monomer via the stereospecific [2+2] cycloaddition of trichloroacetyl isocyanate with a d-glycal possessing a 3-benzyloxy group oriented to the α-face of the pyranose. The tert-butylacetyl chloride initiated polymerization of the alt-lactam proceeds smoothly to afford stereoregular polymers with narrow dispersities. Birch reduction of the benzylated polymers gives water-soluble altrose PASs (alt-PASs) in high yields without degradation of the polymer backbone. Circular dichroism analysis shows the alt-PASs adopt a right-handed helical conformation in aqueous solutions. This secondary conformation is stable over a wide range of different conditions, such as pH (2.0 to 12.0), temperature (5 to 75 °C), ionic salts (2.0 M LiCl, NaCl, and KCl), as well as in the presence of protein denaturants (4.0 M urea and guanidinium chloride). Cytotoxicity studies reveal that the alt-PASs are nontoxic to HEK, HeLa, and NIH3T3 cells. The results showcase the ability to direct solution conformation of polymers through monomer design. This approach is especially well-suited and straightforward for PASs as the helical conformations formed result from constraints imposed by the relatively rigid and sterically bulky repeating units.

MeSH terms

  • Amides / chemical synthesis*
  • Amides / chemistry
  • Amides / toxicity
  • Animals
  • Cell Survival / drug effects
  • Cycloaddition Reaction
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Lactams / chemical synthesis*
  • Lactams / chemistry
  • Lactams / toxicity
  • Mice
  • NIH 3T3 Cells
  • Polymerization
  • Polymers / chemical synthesis
  • Polymers / chemistry
  • Polymers / toxicity
  • Polysaccharides / chemical synthesis*
  • Polysaccharides / chemistry
  • Polysaccharides / toxicity

Substances

  • Amides
  • Lactams
  • Polymers
  • Polysaccharides