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Resolución catalizada por subtilisina de las N-acil arilsulfinamidas
Christopher K Savile1, Vladimir P Magloire, Romas J Kazlauskas
1Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, Québec, H3A 2K6, Canada.
Journal of the American Chemical Society
|February 17, 2005
Resumen
Este estudio introduce el primer método biocatalítico para producir sulfinamidas quirales, esenciales para la síntesis asimétrica de aminas. Una enzima específica, la subtilisina E, demostró una alta enantioselectividad en la resolución de estos compuestos, produciendo valiosos auxiliares quirales.
Área de la Ciencia:
- Química orgánica es la química orgánica.
- La biocatálisis por biocatálisis.
- Ingeniería de enzimas Ingeniería de enzimas Ingeniería de enzimas
Sus antecedentes:
- Las sulfinamidas poseen un estereocentro quiral de azufre, lo que las convierte en valiosas auxiliares quirales en la síntesis asimétrica.
- El desarrollo de métodos eficientes y enantioselectivos para su preparación es crucial para sintetizar aminas quirales.
Objetivo del estudio:
- Establecer la primera ruta biocatalítica para la síntesis de sulfinamidas enriquecidas enantioméricamente.
- Para investigar el alcance del sustrato y la enantioselectividad de la subtilisina E en la hidrólisis de la sulfinamida.
Principales métodos:
- Hidrólisis enzimática de varias arilsulfinamidas mediante el uso de subtilisina E.
- Resolución en escala de gramos de las sulfinamidas.
- La sobreexpresión de la subtilisina E en el Bacillus subtilis.
- Modelado molecular para dilucidar los determinantes de la unión al sustrato y la enantioselectividad.
Principales resultados:
- Subtilisin E hidrolizó selectivamente N-cloroacetil y N-dihydrocinnamoyl arylsulfinamides con alta enantioselectividad (E > 150).
- Las resoluciones en la escala de gramos arrojaron tres útiles auxiliares quirales de sulfinamida: (R) -p-toluenesulfinamida (95% ee), (R) -p-clorobenzenesulfinamida (97% ee) y (R) -2,4,6-trimetilbenzenesulfinamida (99% ee).
- El modelado molecular indicó que los grupos acilo específicos imitan la fenilalanina, lo que facilita la unión y las interacciones hidrofóbicas en la enantioselectividad de la unidad de bolsillo S1 '.
Conclusiones:
- La biocatálisis utilizando subtilisina E proporciona un método eficiente y altamente enantioselectivo para acceder a valiosos auxiliares de sulfinamida quiral.
- Los hallazgos ofrecen una ruta práctica para la preparación a gran escala de estos importantes componentes sintéticos.
- El modelado molecular ofrece información sobre las interacciones enzima-sustrato que rigen la enantioselectividad observada.
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