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Ensamblaje enzimático de diversas estructuras lactónicas: una estrategia de funcionalización C-H intramolecular

Daniel J Wackelin¹, Runze Mao¹, Kathleen M Sicinski¹

¹Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.

Journal of the American Chemical Society

|January 2, 2024

Resumen

Los científicos diseñaron nuevas enzimas, las carbenotransferasas, que crean diversas lactonas a través de una nueva estrategia de enlace C-C, complementando los métodos de la naturaleza para los materiales y la medicina.

Área de la Ciencia:

Biocatálisis
Síntesis orgánica
Ingeniería de enzimas

Sus antecedentes:

Las lactonas son ésteres cíclicos versátiles cruciales en la ciencia de los materiales, la química medicinal y la industria.
La síntesis de lactona natural utiliza predominantemente una estrategia de desconexión de enlaces C-O.
Existe la necesidad de nuevas rutas sintéticas para acceder a diversas estructuras de lactona.

Objetivo del estudio:

Desarrollar enzimas de ingeniería de laboratorio para la síntesis de lactona utilizando una nueva estrategia de formación de enlaces C-C.
Ampliar la diversidad estructural de los andamios de lactona accesibles.
Para complementar las vías de biosíntesis naturales existentes para las lactonas.

Principales métodos:

Evolución dirigida de una variante del citocromo P450 ligada a la serina.
Ingeniería de enzimas de transferasa de carbenos para la inserción intramolecular de carbenos en enlaces C-H.
Síntesis de lactonas con anillos de diferentes tamaños y andamios complejos.

Principales resultados:

Las transferasas de carbenos diseñadas catalizan la formación de enlaces C-C para el ensamblaje de lactona.
La variante P411-LAS-5247 produce eficientemente lactonas de cinco miembros con un alto exceso enantiomérico.
Otras variantes (P411-LAS-5249, P411-LAS-5264) sintetizan lactonas de seis y siete miembros, superando la cepa de anillo.
La plataforma permite la síntesis de complejas estructuras de fusión, puente y espiro lactona.

Conclusiones:

Se ha establecido una nueva plataforma enzimática para la síntesis de lactona a través de la funcionalización C-H.
Este enfoque expande el espacio químico accesible de las lactonas más allá de las capacidades biosintéticas naturales.
Las enzimas diseñadas ofrecen una herramienta poderosa para crear diversas estructuras de lactona para diversas aplicaciones.

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