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Isolating Free Carbenes, their Mixed Dimers and Organic Radicals

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Published on: April 19, 2019

Acceso general a los cubanos como bioisósteros del benceno

Mario P Wiesenfeldt¹, James A Rossi-Ashton¹, Ian B Perry¹

¹Merck Center for Catalysis at Princeton University, Princeton, NJ, USA.

|April 4, 2023

Resumen

Los investigadores desarrollaron nuevos métodos para sintetizar los bloques de construcción cubanos 1,3- y 1,2-disubstituidos. Esto permite el uso de cubano como un bioisóster versátil para todos los patrones de sustitución de benceno en el diseño de fármacos.

Área de la Ciencia:

Química medicinal
Síntesis orgánica
Descubrimiento de drogas

Sus antecedentes:

El reemplazo de los anillos de benceno por bioisósteros híbridos sp3 puede mejorar la farmacocinética del fármaco y mantener la actividad biológica.
Los marcos rígidos y tensos como el cubano ofrecen estabilidad metabólica debido a la alta fuerza de enlace C-H e imitan estrechamente la geometría del benceno.
Las limitaciones actuales restringen el uso de cubano a los reemplazos de benceno mono o para sustituidos debido a los desafíos sintéticos y la incompatibilidad de acoplamiento cruzado.

Objetivo del estudio:

Desarrollar vías sintéticas eficientes para los precursores cubanos 1,3- y 1,2-disubstituidos.
Para establecer protocolos de acoplamiento cruzado compatibles con el andamio cubano.
Permitir el uso integral del cubano como bioisóster para todos los patrones de sustitución del benceno en fármacos candidatos.

Principales métodos:

Síntesis de cubano 1,3-disubstituido utilizando un precursor de ciclobutadieno.
Carboxilación fotolítica de C-H para el acceso a los bloques de construcción de cubano 1,2-disubstituido.
Desarrollo de reacciones de acoplamiento cruzado catalizadas por cobre (C-N, C-C ((sp³), C-C ((sp²), C-CF₃) aprovechando la reactividad específica del cobre.

Principales resultados:

Se establecieron rutas convenientes para los principales productos intermedios cubanos 1,3- y 1,2-disubstituidos.
Se aplicaron con éxito nuevos métodos de acoplamiento cruzado al andamio cubano, superando las limitaciones anteriores.
La elaboración fácil de todos los isómeros cubanos en posibles candidatos a fármacos ahora es posible.

Conclusiones:

Las estrategias sintéticas desarrolladas y los protocolos de acoplamiento cruzado amplían significativamente la utilidad del cubano en la química medicinal.
El cubano ahora puede emplearse eficazmente como bioisóster para benceno orto-, meta- y para-sustituido.
Este avance facilita el diseño de fármacos candidatos con propiedades farmacocinéticas mejoradas a través del reemplazo ideal del anillo de benceno.

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