N-Heterocyclic Carbene Controlled Dehomologation of Aldoses
Carbohydrates constitute an important class of compounds in nature, fulfilling numerous roles in the biological context. Being a primary source and storage form of energy, they form structural biopolymers like cellulose or chitin and are important functional constituents of the cell surface in animals, plants and microorganisms. The genetic code is based on sugars and our blood group is determined by sugars for example. Most of the aforementioned carbohydrates are oligo- or polysaccharides, consisting of many sugar molecules, assembled in a specific manner. The repertoire to prepare these structures in the lab is getting ever more sophisticated, including progress in their automated synthesis. In this light, it seems surprising that many simple monosaccharides are still of limited commercial availability and at prohibitive prices, leading to repetitive unrewarding synthetic efforts or their rejection as starting materials. Due to their complex structure as poly-hydroxy ketones (ketoses) or aldehydes (aldoses), long synthetic routes are often required for seemingly simple transformation. More efficient methods for the interconversion of carbohydrates are required, a shortcoming this project aims to address.
In this light, the class of N-heterocyclic carbenes (NHCs) bear great potential as they exhibit very specific reactivity with aldehydes. Well-studied with simpler structures, this interaction has rarely been addressed in the complex context of sugars. The reported sacrificial use of aldoses undergoing uncontrolled degradation, triggered by NHCs, caught our attention.
We engaged in a preliminary study with the hypothesis that such degradation can be intercepted in order to obtain sugars with a reduced chain length (dehomologation). The feasibility of our approach was clearly confirmed setting the scene for the research outlined in this project. The systematic development of a new methodology for the efficient interconversion of carbohydrates based on the activation with NHCs is the ultimate goal. Mechanistic investigations to increase the understanding of the underlying chemical processes will be followed by thorough optimisation studies aiming at reliable protocols applicable for a variety of sugar structures. We strive to apply this new methodology in a pharmaceutically relevant context by to utilising the NHC-mediated dehomologation as the key step in a newly designed synthesis of fluorinated sugars, partial structures of modified nucleosides with known activities against viral infections and cancer. In a second stage, we will extend our study towards chiral versions of the optimised NHCs with the goal of interconverting sugars in just a single synthetic step.
We are convinced that based on our findings, further synthetic opportunities for us and others will be revealed based on the interaction of NHCs and sugars.
