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Síntesis de diversidad utilizando glutarimidas como precursores de carbeno de rodio en la funcionalización y

William F Tracy¹, Jack C Sharland¹, Duc Ly¹

¹Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.

Journal of the American Chemical Society

|March 18, 2025

Resumen

Los nuevos métodos permiten la creación de fármacos moduladores de la ligasa Cereblon E3 estereoquímicamente diversos (CELMoD). La catálisis con dirodio facilita la funcionalización enantioselectiva, ampliando las opciones para el descubrimiento de fármacos dirigidos a la degradación de proteínas.

Área de la Ciencia:

Química medicinal
Síntesis orgánica
Descubrimiento de drogas

Sus antecedentes:

Los fármacos moduladores de la ligasa Cereblon E3 (CELMoD) se dirigen a las proteínas para su degradación a través del complejo de la ubiquitina ligasa CRL4CRBN E3.
La modificación de la estereoquímica y la regioquímica de los CELMoD afecta la actividad de degradación y la selectividad.
Son escasos los métodos eficaces para introducir fracciones enriquecidas con enantio en los CELMoD.

Objetivo del estudio:

Desarrollar un método novedoso para la preparación de compuestos diversos y estereoenriquecidos que contengan glutarimida.
Explorar la utilidad de la catálisis del dirodio en la síntesis de derivados de CELMoD.
Creación de productos intermedios para los degradantes moleculares de pegamento y los degradantes bifuncionales dirigidos por ligandos.

Principales métodos:

Derivación de núcleos clásicos de glutarimida que se unen al CRBN a los diazoacetatos de arilo.
Funcionalización enantioselectiva de C-H de los hidrocarburos mediante la catálisis del dirodio.
La enantioselección por ciclopropanación del estireno mediante la catálisis por dirodio.

Principales resultados:

Funcionalización exitosa de hidrocarburos por C-H de alto rendimiento y muy enantioselectiva.
Ciclopropanación exitosa de alto rendimiento y altamente enantioselectiva del estireno.
Generación de productos intermedios para pegamentos moleculares y degradantes dirigidos por ligandos bifuncionales.

Conclusiones:

La catálisis con dirodio es efectiva en un contexto de descubrimiento de fármacos para la síntesis de CELMoD.
Se ha establecido un nuevo método para la preparación de diversos compuestos estereoenriquecidos que contienen glutarimida.
Este enfoque facilita el desarrollo de nuevas terapias dirigidas a la degradación de proteínas.

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