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.

This project investigated the chemistry being triggered from the interaction between N-heterocyclic carbenes (NHCs), a modern class of organocatalysts and aldoses, reducing sugars. We sought ways to influence the selectivity between two distinctly different reaction pathways, namely the controlled dehomolation (shortening) of the carbohydrate chain by one or more distinct carbon atoms up to an intercepting group, intended to prevent further uncontrolled degradation. Alternatively, a subsequent reaction, leading to elimination of this intercepting group and formation of a so called deoxy-lactone was observed. As a first result in the project, we have uncovered structural elements in the starting material influencing the direction of reactivity upon NHC activation and identified that the degree to which a sugar derivative (starting material or product) exists in its aldehyde form is a decisive element of control in this respect. This finding inspired us to find a way to measure these minute amounts of reactive species in equilibrium, which is described below. As a second direction of research, we have also screened and designed NHC-catalysts and found examples of catalysts derived divergence. This means, that starting materials without a strong bias to one or the other reaction outcome can result in either of the two possible products, depending on which catalyst it was reacted with. This finding has great potential but is not yet fully understood and more detailed studies to elucidate the reasons for it are currently ongoing (e.g. kinetic studies with NMR-spectroscopy on the initial reaction step between NHC catalysts and sugar derivatives). A second and more practical product of this project is a new assay, which was developed to measure the minute relative amount sugars exist in open chain content (OCC) form next to the dominating more stable ring-forms. We have identified this property as important feature for the reactivity of sugars as aldehyde species already several times in the past; that is why we sought ways to determine these minute, but distinctively different, proportions in an efficient way. We found a solution by utilizing the recently reported selective reaction between amino benzamidoximes (ABAOs) and aldehydes in a new kinetic photometric assay. This assay is operationally simple and only requires cheap standard analytical equipment (photometer) and chemicals to determine these small proportions (1% down to 100 ppm) in a very accurate fashion. It still produces comparable numbers to the established method for this purpose, yet with significantly reduced effort. This kinetic ABAO assay will be a practical tool for carbohydrate chemists and beyond to estimate and understand the reactivity of reducing sugars as aldehyde species.