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El control cinético, termodinámico y dinámico en el normal frente a la cruz [2 + 2] Cycloadditions de iones

Pan Zhang¹, Zhi-Xiang Yu¹

¹Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China.

Journal of the American Chemical Society

|April 19, 2023

Resumen

Este estudio explica por qué las reacciones cruzadas [2 + 2] son difíciles y revela cómo lograr esqueletos de biciclo [3.1.1] heptano. Los nuevos métodos permiten la síntesis de estos importantes componentes farmacéuticos.

Área de la Ciencia:

Química orgánica
Química computacional
Química medicinal

Sus antecedentes:

Las reacciones intramoleculares [2 + 2] generalmente producen bicicletas fusionadas, no el esqueleto de biciclo [3.1.1] heptano deseado.
El marco de biciclo[3.1.1]heptano es un bioisóster crucial en el desarrollo farmacéutico.
La comprensión del control regioquímico es clave para diseñar nuevas rutas sintéticas.

Objetivo del estudio:

Para racionalizar los resultados regioquímicos de las reacciones intramoleculares [2 + 2] de iones de ene-keteniminium.
Diseñar y permitir nuevas reacciones cruzadas [2 + 2] para sintetizar estructuras de biciclo[3.1.1]heptano.
Investigar las vías mecanicistas que rigen estas reacciones de cicloadición.

Principales métodos:

Investigaciones teóricas utilizando la teoría funcional de la densidad (DFT) y cálculos ab initio de alto nivel.
Simulaciones de dinámica molecular para analizar la dinámica de las reacciones y los paisajes energéticos.
Validación experimental de las predicciones teóricas y conocimientos mecanicistas.

Principales resultados:

Se han identificado patrones de control cinético, termodinámico y dinámico en la reacción [2 + 2].
Propuso un modelo de carbocatión que explica la influencia de la longitud del cable, los sustituyentes y la configuración de alceno.
Se predijeron con éxito y se lograron experimentalmente reacciones cruzadas [2 + 2] que producen productos de biciclo [3.1.1] heptano.

Conclusiones:

La colocación estratégica de los sustituyentes y el control de la configuración de alceno (trans) son críticos para las reacciones cruzadas [2 + 2].
El resultado de la reacción puede controlarse dinámicamente o cinéticamente en función del tipo de sustituto (alquilo vs. arilo).
El estudio proporciona un marco mecanicista robusto y una validación experimental para la síntesis de valiosos andamios de biciclo[3.1.1]heptano.

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