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Azetidinas con centros cuaternarios de todo el carbono: fusión de catálisis de relevo con funcionalización de

Che-Ming Hsu¹, Heng-Bo Lin¹, Xin-Zhi Hou¹

¹Department of Chemistry, National Sun Yat-sen University, Kaohsiung 80424, Taiwan (R.O.C.).

Journal of the American Chemical Society

|August 17, 2023

Resumen

Un nuevo método catalizado por níquel sintetiza eficientemente azetidinas cuaternarias de todo carbono desafiantes utilizando una estrategia de relé de radicales polares. Este enfoque ofrece un amplio alcance y tolerancia funcional del grupo, ayudando al descubrimiento y optimización de fármacos.

Área de la Ciencia:

Química medicinal
Síntesis orgánica
Catálisis

Sus antecedentes:

Las azetidinas decoradas son cruciales en la química medicinal.
La síntesis eficiente de azetidinas complejas, particularmente aquellas con centros cuaternarios de todo carbono, sigue siendo un desafío significativo.

Objetivo del estudio:

Desarrollar una estrategia sintética fácil y eficiente para las azetidinas con centro cuaternario de carbono.
Explorar la aplicación de este método en la optimización de fármacos y la síntesis de moléculas biológicamente relevantes.

Principales métodos:

Se empleó una estrategia de relevo de radicales polares, utilizando la liberación de tensión en el anillo de 1-azabiciclo[1.1.0]butano benzoilado (ABB).
El acoplamiento cruzado Suzuki Csp2-Csp3 catalizado por níquel con ácidos borónicos se realizó en condiciones suaves.
Los estudios mecanicistas aclararon el papel de la catálisis del bromuro y el níquel en la vía de reacción.

Principales resultados:

Se sintetizó con éxito una amplia gama de azetidinas con centro cuaternario de carbono (> 50 ejemplos) con excelente tolerancia funcional del grupo.
Utilidad demostrada a escala de gramos y aplicación exitosa para modificar productos naturales, productos farmacéuticos y moléculas biológicamente relevantes.
Análogos sintetizados de los agonistas de la MC- 1R y de los inhibidores de la VAChT mediante la sustitución bioisostérica de piperidina por azetidina.

Conclusiones:

El método desarrollado proporciona una ruta eficiente hacia bloques de construcción valiosos de azetidina.
La estrategia pone de relieve el potencial del relé de radicales polares y la catálisis del níquel en la síntesis de moléculas complejas y el descubrimiento de fármacos.
El sistema catalítico también muestra utilidad en el acoplamiento cruzado Suzuki de bromuros alquilo terciarios.

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