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Un enfoque modular y diastereoselectivo de ciclización 5 + 1 para las piperidinas N-{\displaystyle N-{{\displaystyle

Matthew A Larsen¹, Elisabeth T Hennessy¹, Madeleine C Deem²

¹Department of Discovery Chemistry , Merck & Co., Inc. , Boston , Massachusetts 02115 , United States.

Journal of the American Chemical Society

|December 28, 2019

Resumen

Un nuevo método de síntesis crea importantes piperidinas N- (hetero) arilo utilizando una aminación reductora diastereoselectiva y una reacción de aza-Michael. El agua mejora la reacción.

Área de la Ciencia:

Química orgánica
Química medicinal
Química sintética

Sus antecedentes:

Las piperidinas son andamios cruciales en muchos productos farmacéuticos.
La síntesis eficiente de derivados complejos de la piperidina sigue siendo un desafío.

Objetivo del estudio:

Desarrollar una síntesis general de novo para las piperidinas de N- (hetero) arilo de importancia farmacéutica.
Establecer un método robusto y diastereoselectivo para la construcción de complejos sistemas de anillos de piperidina polisubstituidos.

Principales métodos:

Utilizó una aminación reductora seguida de una secuencia de reacción de aza-Michael.
Se emplean nucleófilos de aminas heterocíclicas y electrófilos de carbonilo ampliamente disponibles.
Investigó el efecto del agua en la diastereoselectividad y empleó cálculos de DFT.

Principales resultados:

Logró la construcción rápida de complejos sistemas de anillos de piperidina poli-sustituidos.
Se ha demostrado una fuerte diastereoselectividad en la secuencia de reacción.
Se ha observado una mayor diastereoselectividad en presencia de agua.
Propuso un modelo estereoquímico que incluye intermedios de enol coordinados con agua.

Conclusiones:

El protocolo desarrollado ofrece una vía general y eficiente para las piperidinas de N- (hetero) arilo.
La diastereoselectividad de la reacción está significativamente influenciada por el agua, lo que proporciona información sobre el mecanismo.
Este método facilita la síntesis de fármacos candidatos complejos que contienen piperidina.

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