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Síntesis enantioselectiva divergente de (-) galantamina y (-) morfina
Barry M Trost1, Weiping Tang, F Dean Toste
1Department of Chemistry, Stanford University, Stanford, California 94305, USA. bmtrost@stanford.edu
Journal of the American Chemical Society
|October 20, 2005
Resumen
Una nueva estrategia sintética produce eficientemente opiáceos y alcaloides amarilídeos como la galantamina y la morfina. Este método utiliza la alquilación alilica asimétrica catalizada por el paladio (AAA) y otras reacciones clave para una síntesis simplificada.
Área de la Ciencia:
- Química orgánica es la química orgánica.
- Química sintética de la química sintética.
- Química Medicinal La Química Medicinal es un campo de estudio de la química medicinal.
Sus antecedentes:
- Los alcaloides opiáceos y de las Amaryllidaceae son importantes productos naturales con diversas actividades biológicas.
- Las rutas sintéticas existentes para estos alcaloides pueden ser largas y carecen de eficiencia.
- El desarrollo de nuevas estrategias sintéticas convergentes es crucial para acceder a estos valiosos compuestos.
Objetivo del estudio:
- Desarrollar una estrategia sintética eficiente y divergente para los alcaloides de opiáceos y Amaryllidaceae.
- Para establecer una síntesis estereoselectiva de galantamina y estructuras relacionadas.
- Explorar nuevas reacciones para la construcción de los esqueletos centrales de estas clases de alcaloides.
Principales métodos:
- La alquilación alilica asimétrica catalizada por el paladio (AAA) para establecer los estereocentros clave.
- Reacciones intramoleculares de Heck para la formación de anillos.
- Vinilación de cola y hidroaminación promovida por luz visible para la construcción de sistemas policíclicos complejos.
Principales resultados:
- Una síntesis en seis pasos de un intermediario tricíclico pivotal a partir de materiales de partida fácilmente disponibles.
- Conversión eficiente del intermediario en (-) galantamina en dos pasos adicionales.
- Construcción exitosa del cuarto anillo de esqueletos de codeína/morfina a través de la vinilación Heck.
- Una nueva hidroaminación promovida por la luz visible para el cierre final del anillo a la codeína y la posterior conversión a la morfina.
Conclusiones:
- La estrategia desarrollada proporciona una ruta eficiente y versátil a la galantamina, la codeína y la morfina.
- El uso de AAA catalizado por paladio es fundamental para el control de la estereoquímica al principio de la síntesis.
- Las reacciones empleadas ofrecen un poderoso kit de herramientas para la síntesis de alcaloides complejos.
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