Carbohydrates mediate a wide range of biological interactions, and understanding these processes benefits the development of new therapeutics. Isolating sufficient quantities of glycoconjugates from biological samples remains a significant challenge. With advances in chemical and enzymatic carbohydrate synthesis, the availability of complex carbohydrates is increasing and developing methods for stereoselective conjugation these polar head groups to proteins and lipids is critically important for pharmaceutical applications. The aim of this review is to provide an overview of commonly employed strategies for installing a functionalized linker at the anomeric position as well as examples of further transformations that have successfully led to glycoconjugation to vaccine constructs for biological evaluation as carbohydrate-based therapeutics.

This review describes how resonance in amides is greatly affected upon substitution at nitrogen by two electronegative atoms. Nitrogen becomes strongly pyramidal and resonance stabilisation, evaluated computationally, can be reduced to as little as 50% that of N,N-dimethylacetamide. However, this occurs without significant twisting about the amide bond, which is borne out both experimentally and theoretically. In certain configurations, reduced resonance and pronounced anomeric effects between heteroatom substituents are instrumental in driving the HERON (Heteroatom Rearrangement On Nitrogen)^† reaction, in which the more electronegative atom migrates from nitrogen to the carbonyl carbon in concert with heterolysis of the amide bond, to generate acyl derivatives and heteroatom-substituted nitrenes. In other cases the anomeric effect facilitates S­_N1 and S_N2 reactivity at the amide nitrogen.

In the case of type 2 diabetes, inhibitors of glycogen phosphorylase (GP) might prevent unwanted glycogenolysis under high glucose conditions and thus aim at the reduction of excessive glucose production by the liver. Anomeric spironucleosides, such as hydantocidin, present a rich synthetic chemistry and important biological function, e.g., inhibition of GP. Herein, the Suárez radical methodology is successfully applied to synthesize the first example of a 1,6-dioxa-4-azaspiro[4.5]decane system, not been previously constructed via a radical pathway, starting from 6-hydroxymethyl-b-D-glucopyranosyluracil. It is shown that in the rigid pyranosyl conformation the required [1,5]-radical translocation is a minor process. The stereochemistry of the spirocycles obtained was unequivocally determined based on the chemical shifts of key sugar protons in the ¹H NMR spectra. The two spirocycles were found to be modest inhibitors of RMGPb.