Descripción del proyecto
Nuevos métodos de síntesis de moléculas quirales podrían aumentar la sostenibilidad del descubrimiento de medicamentos
Más de la mitad de los fármacos que se usan hoy en día son compuestos quirales. A pesar de los inmensos avances que se han realizado en la catálisis durante las últimas décadas, la complejidad quiral de las quimiotecas en el descubrimiento de fármacos no ha seguido la misma tendencia ascendente. Los procesos eficientes que acceden directamente a andamios quirales privilegiados son muy necesarios en la industria farmacéutica. Las reacciones de acoplamiento cruzado de los enlaces C-H de alquenos y arenos eluden los pasos de «concesión» tomados por otras reacciones de acoplamiento cruzado utilizadas en la industria farmacéutica, minimizando así el coste, el esfuerzo y los residuos. El proyecto financiado con fondos europeos ChiCC desarrollará catalizadores adecuados para estas reacciones de acoplamiento que fomentan las formaciones de enlaces C-C asimétricos, centrándose en disminuir el número de pasos. Los científicos también utilizarán reacciones con una elevada eficiencia atómica, lo que es fundamental para la sostenibilidad de los procesos químicos.
Objetivo
Over 60% of the world’s top selling small molecule drug compounds are chiral and, of these, approximately 80% are marketed as single enantiomers. Surprisingly, and despite the tremendous advances made in catalysis over the past several decades, the average “chiral complexity” of drug discovery libraries has actually decreased, while, at the same time the “chiral complexity” of marketed drugs has increased. Consequently, there is now an urgent need to provide efficient processes that access directly privileged chiral “3D” building blocks. It is our philosophy that catalysis holds the key here and new processes should be based upon atom and step economical platforms that exert control over both absolute and relative stereochemistry. Palladium catalysed cross-coupling reactions of aryl (pseudo)halides with organo-nucleophiles (esp. the Suzuki coupling) have become mainstays of the pharmaceutical industry. Here, multiple “concession” steps are usually required to prepare the reaction partners, thereby detracting from atom and step economy. Further, these processes predominantly provide planar “2D” structures and are not well suited to the production of chiral “3D” building blocks. Consequently, methods that allow feedstock precursors (e.g. alkenes and aryl C-H bonds) to be combined directly in enantioselective or enantiospecific C-C bond formations are highly desirable. Cross-couplings of this type would circumvent “concession” steps, thereby minimising cost, effort and waste; however, such processes are highly challenging because of issues associated with regio- and stereocontrol. Recently, we developed prototype catalyst systems that can address this. In the proposed ERC project, these exciting preliminary results will be developed into a wider family of processes where asymmetric C-C bond formations are achieved directly by C-H activation. The new methods, which fulfil modern reaction ideals of atom and step economy, will likely find broad use in applied settings.
Ámbito científico
Programa(s)
Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
L69 7ZX Liverpool
Reino Unido