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Hidrogenación asimétrica catalizada por Ru de los γ-lactamos α,β insaturados

Zhengdong Ding¹, Yicong Luo¹, Qianjia Yuan¹

¹Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.

Journal of the American Chemical Society

|September 2, 2024

Resumen

Un nuevo método de hidrogenación asimétrica catalizado por rutenio permite la síntesis eficiente de γ-lactamas quirales sustituidas por β. Este avance es crucial para la producción de fármacos antiepilépticos como el brivaracetam con alta enantioselectividad.

Área de la Ciencia:

Química orgánica
Catálisis
Síntesis asimétrica

Sus antecedentes:

Los γ-lactamas quirales son componentes importantes para los productos farmacéuticos.
El desarrollo de métodos sintéticos enantioselectivos eficientes es fundamental para el desarrollo de fármacos.

Objetivo del estudio:

Desarrollar una hidrogenación asimétrica altamente eficiente catalizada por rutenio de γ-lactamas α,β insaturadas.
Para lograr la síntesis enantioselectiva de γ-lactamas quirales sustituidas por β.

Principales métodos:

Se utilizó un ligando quiral C2-simétrico de rutenocenilfosfina-oxazolina para la catálisis de rutenio.
Mecanismos de reacción investigados mediante experimentos de control y estudios computacionales.

Principales resultados:

Se obtienen altos rendimientos (hasta el 99%) y excelentes enantioselectividades (hasta el 99% ee) para los γ-lactamas quirales sustituidos por β.
Se identificó un complejo catiónico Ru como la especie activa y la protonación de un complejo oxa-π-alilo-Ru como el paso determinante de la velocidad.
Demostró el papel crucial de PPh3 en el sistema catalítico.

Conclusiones:

Desarrolló un protocolo práctico de hidrogenación asimétrica para los γ-lactamas quirales.
El método es adecuado para la síntesis a escala industrial de intermediarios farmacéuticos clave, incluido el brivaracetam.
Este trabajo ofrece una vía valiosa para sintetizar compuestos bioactivos.

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