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Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of α-Imino γ-Lactones and Alkylidene Pyrazolones
Published on: February 7, 2019
Stereodivergencia en regioselectivas [4 + 2] cícloadiciones catalizadas por aminas de enonas cíclicas β-sustituidas y
Xin Feng1, Zhi Zhou, Rong Zhou
1Key Laboratory of Drug-Targeting and Drug Delivery System of the Ministry of Education, West China School of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, China.
Journal of the American Chemical Society
|November 16, 2012
Resumen
Las aminas primarias catalizan las reacciones conmutables de las enonas cíclicas. Dependiendo del sustrato, se producen adiciones de Michael o cicloadiciones [4 + 2], lo que produce estructuras cíclicas complejas con alta selectividad.
Área de la Ciencia:
- Química orgánica es la química orgánica.
- La catálisis de la catálisis.
- Síntesis asimétrica de síntesis.
Sus antecedentes:
- Las enonas cíclicas son versátiles bloques de construcción en la síntesis orgánica.
- La catálisis de dienamina ofrece una poderosa estrategia para activar sustratos.
- El control de las vías de reacción y la estereoselectividad sigue siendo un desafío clave.
Objetivo del estudio:
- Para investigar los patrones de reacción conmutables de las enonas cíclicas β-sustituidas utilizando la activación de la dienamina a base de aminas.
- Para lograr una alta diastereoselectividad y enantioselectividad en la formación de arquitecturas moleculares complejas.
- Para dilucidar el mecanismo de reacción, distinguiendo entre vías concertadas y paso a paso.
Principales métodos:
- Utilizó aminas primarias derivadas de la quinidina y la quinina naturales como catalizadores.
- Se emplean enonas cíclicas β-sustituidas con varios sustituyentes de malononitrilo (alquilideno, alilideno, alquinilidenoemalononitrilos).
- Investigó el papel de las interacciones de enlace de hidrógeno en el control de la diastereoselectividad.
- Intermedios de reacción aislados para sondear el camino mecanicista.
Principales resultados:
- Se observó adición de Michael viníloga γ-regioselectiva con adición de alquildenemalononitriles.
- Se logra la [4 + 2] cicloadición con alilideno o alquinilidenoemalononitriles, formando biciclo[2.2.2]octanos y estructuras análogas.
- Se ha demostrado de moderada a excelente diastereoselectividad y enantioselectividad.
- Se logró una alta diastereodivergencia mediante el empleo de sistemas catalíticos multifuncionales de aminas primarias y aditivos específicos (ácido salicílico).
- Se identificaron intermediarios de reacción, lo que sugiere un mecanismo de cascada Michael-Michael paso a paso sobre una vía concertada de Diels-Alder.
Conclusiones:
- Desarrolló un sistema catalítico para las vías de reacción conmutables de las enonas cíclicas a través de la activación de la dienamina.
- Se han sintetizado con éxito biciclo[2.2.2]octanos densamente sustituidos con alto estereocontrol.
- Proporcionó conocimientos mecanicistas que sugieren una vía de cascada gradual para la cicloadición observada [4 + 2].
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01:16[4+2] Cycloaddition of Conjugated Dienes: Diels–Alder Reaction
The Diels–Alder reaction is an example of a thermal pericyclic reaction between a conjugated diene and an alkene or alkyne, commonly referred to as a dienophile. The reaction involves a concerted movement of six π electrons, four from the diene and two from the dienophile, forming an unsaturated six-membered ring. As a result, these reactions are classified as [4+2] cycloadditions.
01:16Cycloaddition Reactions: Overview
Cycloadditions are one of the most valuable and effective synthesis routes to form cyclic compounds. These are concerted pericyclic reactions between two unsaturated compounds resulting in a cyclic product with two new σ bonds formed at the expense of π bonds. The [4 + 2] cycloaddition, known as the Diels–Alder reaction, is the most common. The other example is a [2 + 2] cycloaddition.
01:29Diels–Alder Reaction Forming Bridged Bicyclic Products: Stereochemistry
Diels–Alder reactions between cyclic dienes locked in an s-cis configuration and dienophiles yield bridged bicyclic products.
01:28Diels–Alder Reaction Forming Cyclic Products: Stereochemistry
The Diels–Alder reaction is one of the robust methods for synthesizing unsaturated six-membered rings. The reaction involves a concerted cyclic movement of six π electrons: four π electrons from the diene and two π electrons from the dienophile.
02:35Regioselectivity of Electrophilic Additions-Peroxide Effect
In the presence of organic peroxides, the addition of hydrogen bromide to an alkene yields the isomer that is not predicted by Markovnikov’s rule. For example, the addition of hydrogen bromide to 2-methylpropene in the presence of peroxides gives 1-bromo-2-methylpropane. This addition reaction proceeds via a free radical mechanism, which reverses the regioselectivity. The free radical reaction mechanism involves three stages: initiation, propagation, and termination.
02:36Regioselectivity and Stereochemistry of Hydroboration
A significant aspect of hydroboration–oxidation is the regio- and stereochemical outcome of the reaction.
Hydroboration proceeds in a concerted fashion with the attack of borane on the π bond, giving a cyclic four-centered transition state. The –BH2 group is bonded to the less substituted carbon and –H to the more substituted carbon. The concerted nature requires the simultaneous addition of –H and –BH2 across the same face of the alkene giving syn stereochemistry.
Hydroboration proceeds in a concerted fashion with the attack of borane on the π bond, giving a cyclic four-centered transition state. The –BH2 group is bonded to the less substituted carbon and –H to the more substituted carbon. The concerted nature requires the simultaneous addition of –H and –BH2 across the same face of the alkene giving syn stereochemistry.