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Arilación reductora asimétrica Ni-catalizada de las imidas α-sustituidas

Li-Ming Chen¹, Chungkeun Shin¹, Travis J DeLano¹

¹The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.

Journal of the American Chemical Society

|October 16, 2024

Resumen

Los investigadores desarrollaron un nuevo método para crear α-arilglutarimidas quirales utilizando el acoplamiento cruzado catalizado por níquel. Este enfoque sintetiza eficientemente moléculas importantes para el descubrimiento de fármacos y la degradación de proteínas dirigidas.

Área de la Ciencia:

Química orgánica
Química medicinal

Sus antecedentes:

Las imidas α-Aryl son unidades estructurales cruciales en los compuestos biológicamente activos.
Estos motivos se encuentran con frecuencia en las quimeras dirigidas a la proteólisis (PROTAC) para la degradación de proteínas dirigidas.

Objetivo del estudio:

Desarrollar una síntesis asimétrica para las α-arilglutarimidas enriquecidas con enantio.
Para establecer una nueva reacción de acoplamiento cruzado reductivo catalizado por Ni.

Principales métodos:

Utilizando una reacción de acoplamiento cruzado reductivo asimétrico catalizado por níquel.
Utilizando electrófilos de imida y haluros de (hetero) arilo como materiales de partida.
Optimización de las condiciones de reacción para el rendimiento y la enantioselectividad.

Principales resultados:

Síntesis exitosa de α-arilglutarimidas enriquecidas con enantio a partir de precursores simples.
Demostrado amplio alcance de sustrato, acoplamiento de haluros de arilo (hetero) ricos en electrones y deficientes en electrones.
Se obtienen buenos rendimientos y altas enantioselectividades.

Conclusiones:

El método desarrollado proporciona un acceso eficiente a los valiosos componentes quirales de la α-arilglutarimida.
Esta metodología es aplicable a la síntesis de moléculas complejas para aplicaciones farmacéuticas, incluidos los PROTAC.

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