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Síntesis total de primera y segunda generación del tecoplanina aglicona

D L Boger¹, S H Kim, Y Mori

¹Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

Journal of the American Chemical Society

|July 18, 2001

Resumen

Los investigadores desarrollaron una síntesis total más eficiente para la teicoplanina aglicona, un componente clave de los antibióticos. Este método mejorado implica un cambio estratégico en el orden de cierre del anillo, mejorando la diastereoselectividad y el rendimiento general de esta molécula compleja.

Área de la Ciencia:

Química orgánica es la química orgánica.
Química Medicinal La Química Medicinal es el campo de la Química Medicinal.
Química sintética de la química sintética.

Sus antecedentes:

La teicoplanina aglicona es un complejo antibiótico glicopéptido de estructura núcleo.
La síntesis total de tales moléculas complejas presenta desafíos significativos en el estereocontrol y la eficiencia.
Las rutas sintéticas anteriores requerían numerosos pasos con rendimientos generales moderados.

Objetivo del estudio:

Para detallar la síntesis total de la primera generación de teicoplanin aglycon.
Para presentar una estrategia de síntesis total mejorada de segunda generación.
Para mejorar la eficiencia, la convergencia y la diastereoselectividad en la síntesis de aglicones de teicoplanina.

Principales métodos:

La síntesis de primera generación involucró el acoplamiento de un tripeptido EFG al sistema de anillos ABCD, seguido de macrociclaciones secuenciales DE y FG.
La síntesis de segunda generación alteró el orden, realizando la macrolactamización de FG antes de la macrociclación de DE y el acoplamiento de péptidos.
Las reacciones clave incluyeron la sustitución aromática nucleofílica de fenoxido por la formación de éter diarilo y la macrolactamización.

Principales resultados:

La síntesis de primera generación requirió 26 pasos con un rendimiento general del 1%.
La síntesis de segunda generación logró un rendimiento general del 2% en 22 pasos.
La macrolactamización FG revisada (95%) seguida de la macrociclización DE produjo el atropisómero natural con una diastereoselección >10:1 (76%).

Conclusiones:

La síntesis total de tecoplanina aglicona de segunda generación es significativamente más corta, más convergente y altamente diastereoselectiva.
La alteración de la secuencia de los pasos de macrociclado es crucial para mejorar la eficiencia y el resultado estereocímico.
Esta síntesis optimizada proporciona una ruta más accesible a la estructura del núcleo aglicónico de teicoplanina.

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