Rigorous Conformational Analysis of Pyrrolidine Enamines with Relevance to Organocatalysis
Rigorous Conformational Analysis of Pyrrolidine Enamines with Relevance to Organocatalysis
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DOI：
10.1002/hlca.201700182
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发表时间：
2017-10-01
影响因子：
1.8
通讯作者：
Reiher, Markus
中科院分区：
文献类型：
--
作者：
Husch, Tamara;Seebach, Dieter;Reiher, Markus
有人认为，吡咯烷胺在Michael加成反应中的区域和立体选择性是由热力学控制而不是通过烯胺的不同构象偏好实现的。我们通过制定一种保证足够准确性的计算协议来评估这一提议。构象之间的微小能量差要求电子结构方法有很高的精度，此外，它还必须允许对大量构象进行计算可行的计算。我们的协议是基于密度泛函理论的，我们对照显式相关的耦合团簇理论进行了验证。结果与已有的实验数据相一致，但说明了为一种烯胺所确定的构象偏好不容易转移到其他类型的烯胺上。我们发现，要得到有意义的结论，适当的构象采样是不可避免的。最突出的是，对于醛和酮衍生的烯胺，S-顺和S-反式构象类似地稳定。吡咯烷衍生的烯胺在Michael加成反应中的区域和立体选择性一般不能用烯胺异构体和构象的显著稳定性差异来解释，这推翻了热力学控制假说。要阐明区域和立体选择性的起源，需要对Michael加成的基本步骤进行进一步的理论研究。
It has been suggested that the origin of regio- and stereoselectivity in Michael additions of pyrrolidine enamines is achieved by thermodynamic rather than kinetic control through distinct conformational preferences of the enamines. We assess this proposal by elaboration of a computational protocol that warrants sufficient accuracy. The small energy differences between the conformers necessitate a high accuracy of the electronic structure method which, in addition, must allow for computationally feasible calculations of a large number of conformers. Our protocol is based on density functional theory which we validated against explicitly correlated coupled cluster theory. The results are in agreement with the available experimental data, but illustrate that conformational preferences determined for one enamine are not readily transferable to other types of enamines. We found that an appropriate conformational sampling is inevitable to arrive at meaningful conclusions. Most prominently, s-cis and s-trans conformers are similarly stable for aldehyde- and ketone-derived enamines. The regio- and stereoselectivity in Michael additions of pyrrolidine-derived enamines can not be explained by pronounced stability differences of the enamine isomers and conformers in general, disproving the thermodynamic-control hypothesis. The elucidation of the origin of regio- and stereoselectivity requires further theoretical investigations of the elementary steps of Michael additions.