Monosaccharide azides – challenges

I am not a carbohydrate chemist by training. I remember as an undergrad being very intimidated by the chair conformations, Fischer projections and the seemingly endless chiral centres, so I filed that knowledge away as “unlikely to use” and focussed on supramolecular chemistry. In recent times however, I couldn’t help but be drawn back to looking at these natural sources of chirality, particularly as a next direction to turn after my investigations to amino-acid derived triazolyl(pyridine) ligands. Sugars seemed a way to get chirality and solubility all in one go with the potential for biological interactions as a bonus.

oac-n3 sugar scheme

So, I began researching how to make various monosaccharide azides of the above form in a selective way, so that I could very the stereochemical properties at will when making families of compounds. It required a lot of searching to find everything I need, so I will present it here for anyone else who might be interested in making (in particular) tetra-acetylated glucose, galactose and mannose with an azide in the anomeric position, either α or β.

For glucose and galactose, buried in the German-language pages of a paper by Paulsen et al. from 1974 is a Lewis acid catalysed reaction, which selectively gives the β-azide derivative directly from reacting the penta-acetylated sugar (with mixed anomeric configuration) with tin(IV) chloride and trimethylsilyl-azide. This reaction has some nasty components and leaves you with a lot of tin-contaminated water to dispose of. I was delighted, therefore to find that the reaction can also be carried out rather straightforwardly from the commercially-available α-bromo tetra-acetylated compounds (for glucose and galactose) by simply heating overnight with sodium azide in a water-acetone mixture, a methodology that comes from that oft-overlooked source: Journal of Chemical Education (Norris and co-workers, 2012).

With mannose, things are a little trickier! It differs from glucose and galactose, by having the C-2 hydroxyl group in the axial position, and since this is adjacent to the reactive anomeric position, this will influence the outcome. Using tin(IV) chloride, as above, for instance, will yield the α-azide. This is a result of the reaction, as above, favour a 1,2-trans geometry. For the purposes of my research, however, I was really interested in using the β-azide to make a compound which differed from the glucose derivative in only one position. After a lot of hunting, I stumbled upon a two-step reaction in an article by Prof Paul Murphy from NUI Galway (Chem. Eur. J. 2013), which had originated with an early study from University of California. This approach generated an α-glycosyl-iodide in situ and reaction with tetrabutylammonium azide gave the desired β-azide product in good yields. Importantly, this gives β-azides in all cases and allowed me access to the building blocks I need to pursue my current project.