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Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of α-Imino γ-Lactones and Alkylidene Pyrazolones
Published on: February 7, 2019
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Ligando habilitado Pd (II) - catalizado γ-C (sp) -H Lactamización de amidas nativas
Shuang Liu1, Zhe Zhuang1, Jennifer X Qiao2
1Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Journal of the American Chemical Society
|December 16, 2021
Resumen
Este estudio introduce un nuevo método catalizado por el paladio para sintetizar γ-lactamas directamente a partir de aminoácidos. Este enfoque eficiente ofrece una ruta simplificada a bloques de construcción farmacéuticos valiosos como los análogos de la lenalidomida.
Área de la Ciencia:
- Química orgánica
- Química medicinal
- Catálisis
Sus antecedentes:
- Las γ-lactamas son motivos estructurales cruciales en numerosos productos farmacéuticos, incluidos los medicamentos inmunomoduladores de imida (IMiD) y la familia de brivaracetam.
- Las rutas sintéticas actuales a menudo implican múltiples pasos, lo que limita la eficiencia y la accesibilidad de estos valiosos compuestos.
- La aminación intramolecular directa γ-C-H de las amidas presenta una alternativa atractiva para la construcción de núcleos γ-lactámicos a partir de precursores de aminoácidos abundantes.
Objetivo del estudio:
- Desarrollar un método nuevo y eficiente para la síntesis directa de γ-lactamas, isoindolinonas y 2-imidazolidinonas.
- Para explorar una γ-C(sp3)-H intramolecular catalizada por el paladio de amidas derivadas de aminoácidos.
- Establecer un protocolo práctico y respetuoso con el medio ambiente utilizando materiales de partida fácilmente disponibles.
Principales métodos:
- Utilizó una nueva reacción catalizada por 2-piridona habilitada por ligando de paladio.
- Empleó aminoácidos N-acil como grupos directores y socios de ciclización.
- Se utiliza el peróxido de hidrógeno tert-butilico (TBHP) como único oxidante en la reacción.
Principales resultados:
- Se han sintetizado exitosamente γ-lactamas, isoindolinonas y 2-imidazolidinonas a través de la lactamización Pd-C-sp3-H catalizada.
- Demostró el papel crucial de la sustitución de C6 en el ligando 2-piridona para la formación eficiente de lactamo.
- Mostró el amplio alcance del sustrato del protocolo desarrollado.
Conclusiones:
- El protocolo desarrollado proporciona una ruta conveniente y directa a valiosos motivos γ-lactámicos de los precursores de aminoácidos.
- La utilidad del método se validó a través de la síntesis en dos pasos de un análogo de lenalidomida y brivaracetam.
- Este enfoque ofrece una alternativa práctica y potencialmente más ecológica a las síntesis convencionales en múltiples etapas en química medicinal.
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