A Mild Protecting-Group Free Strategy for Neoglycoconjugate Synthesis.

Abstract

The synthesis of neoglycoconjugates has paved the way for the discovery of novel probes that mimic natural glycoconjugates and can provide designed research tools and therapeutics. In some cases, the target protein may not be amenable to harsh conditions; therefore, semisynthetic or chemical methods must be chosen with care. Here, we present a simple and modular chemoselective coupling strategy between an unprotected sugar and an N,O-disubstituted hydroxylamine under mild acidic conditions. This strategy removes any need for protecting groups on the glycan. The terminal alkene group of the conjugate serves as an effective handle to allow facile conjugation to the protein of interest via thiol-ene coupling (TEC), with proteins bearing a cysteine or free thiol to prepare neoglycoconjugates. We demonstrate that the strategy is compatible with both N- and O-linked glycans using protecting-group free strategies and optimize the TEC conditions using a variety of photocatalysts. Finally, we test the method on an aggregation-prone protein, α-synuclein. We envision that this strategy could allow the construction of complex glycoconjugates for biological testing using isolated glycans, or for generation of conjugates where the protein of interest is sensitive to harsh conditions.