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Estrategias estereoselectivas de ciclización e inversión piramidal para la síntesis de fosfolano P-quirogénico

¹Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. garrett.hoge@pfizer.com

Journal of the American Chemical Society

|August 12, 2004

Resumen

Los investigadores desarrollaron un nuevo método para sintetizar los fosfolanos quirales, cruciales para la catálisis asimétrica. Estos compuestos, en particular los isómeros "trans/trans", permiten una hidrogenación altamente enantioselectiva, un paso clave en la producción de productos farmacéuticos como la pregabalina.

Área de la Ciencia:

Química organometálica Química orgánica de los metales.
Catalización asimétrica por catálisis asimétrica.
Química orgánica sintética y orgánica.

Sus antecedentes:

Los fosfolanos p-quirogénicos son valiosos ligandos en la catálisis asimétrica.
Las rutas sintéticas existentes pueden carecer de estereoselectividad o eficiencia.
El desarrollo de nuevos ligandos quirales de fosfolano es crítico para avanzar en la síntesis enantioselectiva.

Objetivo del estudio:

Informar sobre un método novedoso y estereoselectivo para la preparación de mono- y bisfosfolanos P-quirogénicos.
Para demostrar la utilidad de estos fosfolanos como ligandos en la hidrogenación asimétrica.
Para sintetizar un intermediario clave para el producto farmacéutico pregabalina.

Principales métodos:

Ciclización estereoselectiva de sulfatos cíclicos con fosfinas primarias en presencia de una base.
Inversión piramidal inducida por el calor para convertir isómeros "cis" en isómeros "trans" termodinámicamente estables.
Complejación de un fosfolano "trans/trans" con rodio para la catálisis de hidrogenación asimétrica.

Principales resultados:

Síntesis exitosa de los fosfolanos P-quirogénicos "cis" y "trans".
Demostración de la epimerización inducida por calor para acceder a los isómeros "trans/trans" deseados.
Se logró una hidrogenación asimétrica altamente enantioselectiva de un precursor de sustrato utilizando un complejo rodio-fosfolano.

Conclusiones:

El método reportado proporciona un acceso eficiente a los valiosos fosfolanos P-quirogénicos.
Los ligandos fosfolanos desarrollados son efectivos en reacciones de hidrogenación asimétricas altamente enantioselectivas.
Este enfoque facilita la síntesis de importantes intermediarios farmacéuticos, como los precursores de la pregabalina.

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