Aromatic stacking in Glycochemistry: can glycosidations be tamed?

Descripción del proyecto

Luna de miel para el control de las reacciones de glicosilación

Los glicanos, también conocidos como hidratos de carbono, sacáridos o azúcares, son predominantes en las células y desempeñan funciones esenciales en los procesos celulares. Son polímeros compuestos por diferentes combinaciones de monómeros o monosacáridos que forman complejas estructuras tridimensionales. Los glicanos también suelen estár unidos a otras moléculas que no son azúcares. Una de las principales formas para lograr este tipo de unión es mediante la glicosilación o la formación de enlaces glicosídicos. Los glicanos desempeñan un papel esencial en ámbitos relevantes, como la biomedicina, la energía y la biotecnología, por lo que en el proyecto SWEET-PI, financiado con fondos europeos, se investigarán rutas para lograr un mejor control sintético de los múltiples pasos y especies implicados en las reacciones de glicosilación.

Objetivo

Progress in chemical synthesis has provided access to a large variety of complex glycostructures, having a major impact in the expansion of Glycoscience. Central to carbohydrate chemistry is the glycosidation reaction, which involves the formation of a glycosidic bond between donor and acceptor molecules. It is commonly accepted that this process requires the formation of transient ionic species, whose stability, conformational properties and interactions determine to a large extend the reaction outcome. In principle, these elusive species are stabilized by means of inter- and intramolecular interactions, and in fact, this is a key feature for the activity of glycosidases and glycosyltransferases, typically requiring the participation of electron-rich functional groups, such as carboxylates. Interestingly, aromatic/carbohydrate interactions have too been detected and evaluated as supramolecular recognition motifs but, to the best of our knowledge, never at the reaction intermediate level, despite being frequently invoked to play a major role during enzymatic catalysis. Our hypothesis in this project revolves around the idea that stacking interactions involving electron-rich aromatic systems can be employed to stabilize the glycosyl oxocarbenium ion and to enhance the glycosyl acceptor reactivity; in the first case, these contacts might increase the life-time of the cationic intermediates, facilitating their detection and potentially allowing the modulation of the glycosidic donor in order to better control the stereochemical course of the reaction. Alternatively, CH/pi complexes involving the glycosyl acceptor could enhance the electron density of the reactive functional group, thus its nucleophilicity. This project aims to test both aspects of the carbohydrate/aromatic interaction employing a bioorganic approach based on the design, synthesis and systematic analysis of appropriate molecular models.