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Síntesis totales de (+) - zampanolida y (+) - dactilolida explotando una estrategia unificada

Amos B Smith¹, Igor G Safonov, R Michael Corbett

¹Contribution from the Department of Chemistry, Monell Chemical Senses Center, and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104. smithab@sas.upenn.edu

Journal of the American Chemical Society

|September 13, 2002

Resumen

Los investigadores lograron las primeras síntesis totales de (+) -zampanolida y (+) -dactilolida, nuevos macrolidos que inhiben el crecimiento de las células tumorales. Estas síntesis utilizaron métodos estereocontrolados para las características estructurales clave, avanzando en la investigación del cáncer.

Área de la Ciencia:

Química orgánica es la química orgánica.
Química Medicinal La Química Medicinal es el campo de la Química Medicinal.
Síntesis Química La síntesis química es el proceso de síntesis química.

Sus antecedentes:

Zampanolide y dactylolide representan una nueva clase de macrólidos con propiedades demostradas de inhibición del crecimiento de células tumorales.
Las complejas estructuras de estos productos naturales presentan importantes desafíos sintéticos.

Objetivo del estudio:

Para lograr la primera síntesis total de (+) -zampanolida y (+) -dactilolida.
Desarrollar una estrategia sintética unificada para estos macrolides relacionados.
Para asignar las estereocímicas relativas y absolutas completas de los compuestos sintetizados.

Principales métodos:

Se empleó un esquema sintético unificado, con un reordenamiento modificado de Petasis-Ferrier para la construcción estereocontrolada de tetrahidropirano.
Se utilizó una estrategia convergente para ensamblar el núcleo macrocíclico.
Se utilizó una secuencia de reordenamiento / acilación de Curtius para zampanolide para instalar la fracción hemiaminal N-acil.

Principales resultados:

Se lograron con éxito las primeras síntesis totales de (+) - zampanolida y (+) - dactilolida.
La construcción estereocontrolada del tetrahidropirano cis-2,6-disubstituido fue un elemento clave de la estrategia sintética.
Se asignaron las estereocimias relativa y absoluta de ambos productos naturales, con una asignación tentativa para (+) - zampanolide.

Conclusiones:

La ruta sintética desarrollada proporciona acceso a nuevos inhibidores del crecimiento de las células tumorales.
La síntesis exitosa valida las asignaciones estereoquímicas propuestas y demuestra la utilidad de las metodologías sintéticas empleadas.
Este trabajo allana el camino para una mayor investigación sobre las actividades biológicas y los análogos estructurales de estos macrolidos.

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