Making the Longest Synthetic Oligosaccharides – First access to the synthetic 20- to 40-mer long heparanome

A paper from the Gardiner group in Chemical Science paper (DOI: 10.1039/C5SC02091C) describes a new advance in synthetic accessibility of long heparin-like glycosylaminoglycans (GAGs), providing a route to synthetic oligosaccharide structures much longer than previously available. 

The article was selected as a “hot” ChemSci article for July and is the subject of a highlight article in Chemistry World . The paper reports a new block strategy to access the longest examples of synthetic oligosaccharides yet reported, and substantially longer than any previously accessible synthetic GAGs. Heparanoid-like oligosaccharides have been synthetically-challenging due to component heterogeneity, inclusion of rare sugar, L-iduronic acid, and final sulfation targets. Previous access to sequences >12-mer has been rare. The group’s prior scalable iduronic acid synthesis underpins large scale access to modular components for GAG synthesis. This paper reports a tetrasaccharide-based iteration enabling syntheses of a +4 arithmetic series of heparin-related oligosaccharides from 16-mer through to the 40-mer. This more than doubles the length of any prior GAG-related backbone synthesis, and redefines the accessibility of synthetic assembly of GAGs in the longer heparanome space. It also reports the first ability to resolve all 12 anomeric signals of a 12-mer heparin oligosaccharide by NMR and extrapolation of these NMR methods to longer sequences confirms high anomeric integrity through-series. The work was supported by MRC and CRUK Project Grants.

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