Final Activity Report Summary - NCG (Native chemical glycosylation: A novel and efficient method for the synthesis of complex glycoconjugates)
We envisioned that the introduction of a glycosyl donor moiety in the proximity of a hydroxylated amino acid side-chain might lead to a novel and more efficient method for the convergent construction of O-linked glycopeptides. The rationale behind this strategy is based on the combination of two key features. First the ability to chemo- and siteselectively modify cysteine residues with electrophilic thiol-specific carbohydrate reagents yielding disulfide linked glycoconjugates. Secondly, that these glycosyl disulfides can be utilised as effective glycosyl donors in O-glycoside formation. Using this methodology, we were able to synthesise, in one-pot, O-linked glycopeptides in good overall yields from their corresponding disulfide linked glycopeptides. The retained cysteine residue can then be used for additional functionalisations or be reduced to an alanine residue. By emplyoing the acid-labile para-methoxybenzyl group as protective group, we were also able to access unprotected disulfide and O-linked glycopeptides.
During the proximity based glycan transfer outlined above, both inter- and intramolecular glycosylation can take place. We reasoned that forming a (di)sulfide linkage directly onto a hydroxylamino acid residue should lead to a sole intramolecular glycan transfer, which is highly beneficial in terms of stereochemistry and efficiency (yield). After some prelimiary results, this approach is being investigated in a collaboration with Dr H. H. Jensen (Aarhus University). It is believed that this methodology, along with the one outlined above, holds great potential in convergently constructing O-linked (in this case threonine) glycopeptides in a site- and chemoselective manner.