Recent developments in stereoselective 1,2-cis glycosylation that have emerged during the past decade are surveyed herein.

Herein, we report a new class of glycosyl donors, benzoxazolyl imidates, for chemical glycosylation. The O-benzoxazolyl (OBox) leaving group was designed with an aim to compare the relative reactivity and stability of similarly structured S-benzoxazolyl (SBox) glycosides (thioimidates) developed in our lab and glycosyl trichloroacetimidates (TCAI, O-imidates) developed by Schmidt. Novel OBox donors can be activated under catalytic conditions and provided excellent yields in glycosylation. The OBox imidates were found to be more reactive than either SBox or TCAI donors. The high reactivity profile was confirmed in direct competitive experiments and was found beneficial for HPLC-assisted solid-phase synthesis.

This article describes 3,3-difluoroxindole (HOFox) – mediated glycosylation. The uniqueness of this approach is that both the in-situ synthesis of 3,3-difluoro-3Hindol-2-yl (OFox) glycosyl donors and activation thereof can be conducted in a regenerative fashion as is a typical reaction performed under nucleophilic catalysis. Only a catalytic amount of the OFox imidate donor and a Lewis acid activator are present in the reaction medium. The OFox imidate donor is constantly regenerated upon its consumption until all glycosyl acceptor has reacted.

The development of a useful methodology for simple, scalable, and transformative automation of oligosaccharide synthesis that easily interfaces with existing methods is reported. The automated synthesis can now be performed using accessible equipment where the reactants and reagents are delivered by the pump or the autosampler and the reactions can be monitored by the UV detector. The HPLC-based platform for automation is easy to setup and adapt to different systems and targets.

Previously we communicated 3,3-difluoroxindole (HOFox) – mediated glycosylations wherein 3,3-difluoro-3H-indol-2-yl (OFox) imidates were found to be key intermediates. Both the in situ synthesis from the corresponding glycosyl bromides and activation of the OFox imidates could be conducted in a regenerative fashion. Herein, we extend this study with the main focus on the synthesis of various OFox imidates and their investigation as glycosyl donors for chemical 1,2-cis and 1,2-trans glycosylation.

Comparative study of STICS using HPLC-assisted experimental set-up clearly demonstrated benefits of using longer spacer-anchoring systems. The use of mixed self-assembled monolayers helps to provide the required space for glycosylation reaction around the immobilized glycosyl acceptor. Both extension of the spacer length and using mixed self-assembled monolayers help to promote reaction and the beneficial effects may include moving the glycosyl acceptor further out into solution and providing additional conformational flexibility. It is possible that surface-immobilized glycosyl acceptors with a longer spacer (C8-O-C8)-lipoic acid have a higher tendency to mimic a solution-phase reaction environment than that of acceptors with shorter spacers.

Electrochemical impedance spectroscopy (EIS) is used to compare the apparent electron transfer rate constant (kapp) for a series of alkanethiol and of carbohydrate-terminated alkanethiol self-assembled monolayers (SAMs) on both flat gold and on nanoporous gold (np-Au). Using the surface area for np-Au determined by oxide stripping, the values of kapp for the alkanethiol modified np-Au are initially over two orders of magnitude smaller than the values found on flat Au. This result provides evidence that the diffusing redox probe Fe(CN)63−/4− only accesses a fraction of the np-Au surface after alkanethiol modification suggesting very limited wetting of the internal pores due to the hydrophobic nature of these surfaces. In contrast, for np-Au modified by carbohydrate-terminated (mannose or galactose) alkanethiols the values of kapp are about 10–40 fold smaller than on flat gold, suggesting more extensive access of the diffusing redox probe within the pores and better but still incomplete wetting, a result also found for modification of np-Au with mercaptododecanoic acid. A short chain PEG thiol derivative is found to result in a comparison of kapp values that suggests nearly complete wetting of the internal pores for this highly hydrophilic derivative. These results are of significance for the potential applications of SAM modified np-Au in electrochemical sensors, especially for those based on carbohydrate–protein recognition, or those of np-Au modified by SAMs with polar terminal groups.

In an attempt to refine a CAN-mediated synthesis of 1,3,4,6-tetra-O-acetyl-α-D-glucopyranose (2-OH glucose) we unexpectedly discovered that this reaction proceeds via the intermediacy of glycosyl nitrates. Improved mechanistic understanding of this reaction led to the development of a more versatile synthesis of 2-OH glucose from a variety of precursors. Also demonstrated is the conversion of 2-OH glucose into a variety of building blocks differentially protected at C-2, a position that is generally hard to protect regioselectively in the glucopyranose series.