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Síntesis total de resiniferatoxina habilitada por el acoplamiento de tres componentes mediado por radicales y la

Satoshi Hashimoto¹, Shun-Ichiro Katoh¹, Takehiro Kato¹

¹Graduate School of Pharmaceutical Sciences, The University of Tokyo , Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

Journal of the American Chemical Society

|October 19, 2017

Resumen

Este estudio presenta una nueva estrategia basada en radicales para sintetizar la resiniferatoxina, un potente agonista del TRPV1. El nuevo método construye eficientemente su complejo núcleo tricíclico, ofreciendo un enfoque versátil para la síntesis de moléculas complejas.

Área de la Ciencia:

Química orgánica
Química sintética
Química medicinal

Sus antecedentes:

La resiniferatoxina (1) es un diterpenoide daphnano con potentes efectos agonistas sobre el TRPV1, un transductor clave del dolor y el calor.
El núcleo transcarbocíclico 5/7/6 densamente oxigenado de la resiniferatoxina presenta desafíos sintéticos significativos.
Las estrategias sintéticas actuales están limitadas en su capacidad para ensamblar eficientemente tales arquitecturas moleculares complejas.

Objetivo del estudio:

Desarrollar una nueva estrategia basada en radicales para la síntesis total de resiniferatoxina (1).
Demostrar la utilidad de las reacciones radicales en la construcción de enlaces impedidos dentro de sistemas carbocíclicos complejos.
Proporcionar un nuevo diseño estratégico para la síntesis orientada a objetivos en múltiples etapas de productos naturales complejos.

Principales métodos:

Se empleó una estrategia de tres componentes que incluía fragmentos de anillo A, estannano de alilo y anillo C.
La primera reacción radical generó un radical de cabeza de puente α-alcoxi para el acoplamiento secuencial de los anillos A y C.
Una segunda reacción radical logró la ciclización de anillos B de 7 miembros, la construcción de estereocentro y la instalación de olefinas.

Principales resultados:

Con éxito ensamblado el densamente oxigenado trans-fusionado 5/7/6-tricarbocycle de la resiniferatoxina.
La estrategia radical que se formó de manera eficiente obstaculizó el enlace C9,10 y extendió la cadena C4 estereoselectivamente.
La síntesis produjo resiniferatoxina a través de transformaciones quimioselectivas altamente optimizadas.

Conclusiones:

La estrategia desarrollada basada en radicales ofrece un enfoque eficiente y versátil para sintetizar la resiniferatoxina.
Esta metodología destaca las ventajas de las reacciones radicales para la construcción de carbociclos complejos sin daños en el grupo funcional.
La estrategia proporciona un nuevo paradigma para el diseño de síntesis de múltiples pasos dirigidas a moléculas complejas.

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