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Chemoselective Preparation of 1-Iodoalkynes, 1,2-Diiodoalkenes, and 1,1,2-Triiodoalkenes Based on the Oxidative Iodination of Terminal Alkynes
Published on: September 12, 2018
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Hidrogenaciones estereoselectivas catalizadas por iridio simples y duales eficientes para el acceso a los
Kurt Püntener1, Anna-Lena Glass1, Leonardo Tensi2
1Department of Process Chemistry & Catalysis, F. Hoffmann-La Roche AG, 4070 Basel, Switzerland.
Journal of the American Chemical Society
|November 10, 2025
Resumen
Un nuevo sistema de doble catalizador que utiliza catalizadores de iridio logra una hidrogenación asimétrica altamente enantioselectiva para sintetizar productos farmacéuticos intermedios. Este método ofrece una mayor eficiencia y menores costes en comparación con los protocolos anteriores.
Área de la Ciencia:
- Síntesis orgánica
- Catálisis asimétrica
- Química medicinal
Sus antecedentes:
- La síntesis de productos farmacéuticos intermedios quirales a menudo se basa en procesos complejos de varios pasos.
- Los métodos existentes, como los que utilizan cetoreductasas, pueden ser ineficientes o costosos.
- Se necesitan técnicas de hidrogenación asimétrica más racionalizadas y rentables.
Objetivo del estudio:
- Desarrollar una novedosa metodología sintética de un solo recipiente para la hidrogenación asimétrica de un cetóester específico.
- Para crear un bloque de construcción de triol quiral clave, (2R,4R) -4-clorfenil) -butano-1,2,4-triol ((R,R) -7a), que es esencial para la síntesis de GDC-6599.
- Explorar la eficacia de un sistema de catalizador dual como una mejora sobre los enfoques de catalizador único o enzimáticos.
Principales métodos:
- Hidrogenación asimétrica del éster etílico del ácido 4- ((4-clorfenilo) 2-hidroxi-4-ceto-2-butírico.
- Se utilizó un catalizador de plomo (LC) compuesto por Ir/(S) -SpiroPAP y un catalizador auxiliar (AC) de Ir/(R,R) -Ms-DPEN.
- Se investigó una secuencia de reacción consecutiva de una sola olla comparando sistemas de LC y catalizadores duales.
Principales resultados:
- El sistema de catalizador dual mejoró significativamente la diastereoselectividad (relación trans/cis 18:1) y el rendimiento (77%) en comparación con el LC solo (7:1, 71%).
- El AC mejoró la enantioselectividad en la primera etapa de hidrogenación (96% ee), lo que condujo a una mayor ee general (90-94%).
- Los nuevos LC con ligandos PNN lograron una calidad comparable, el mayor rendimiento (81%) y un costo reducido.
Conclusiones:
- Un nuevo sistema dual catalítico se empleó con éxito por primera vez en la síntesis estereoselectiva de un intermediario farmacéutico.
- Esta metodología proporciona una ruta más eficiente, rentable y altamente selectiva al bloque de construcción del triol objetivo.
- El sistema desarrollado ofrece una alternativa prometedora a los protocolos existentes para sintetizar moléculas quirales complejas.
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