Computational evidence for the enamine mechanism of intramolecular Aldol reactions catalyzed by proline
Computational evidence for the enamine mechanism of intramolecular Aldol reactions catalyzed by proline
复制标题
DOI：
10.1002/anie.200460916
复制
发表时间：
2004-01-01
影响因子：
16.6
通讯作者：
Houk, KN
中科院分区：
文献类型：
--
作者：
Clemente, FR;Houk, KN
1971年，Hajos和Parrish[1]以及Wiechert和他的同事[2]独立报道了第一个由Pro催化的对映选择性分子内羟醛环化反应的例子(方案1)。通过该反应很容易得到有用的合成中间体，如Wieland-Miescher酮(3b)。这一反应构成了对映选择性有机催化新兴领域的基石。近年来，利用手性有机催化已实现了多种C？C成键反应。[3]尽管该反应具有经典的地位，但其反应机理仍存在争议。在这里，我们对提出的各种反应机理提供了明确的理论评价；通过对反应中所有六个步骤的计算，我们展示了反应条件如何影响速率决定步骤和立体选择性。在他们的原始论文[1b]中，Hajos和Parrish提出了两个机制(方案2)：A，需要形成甲醇胺中间体，然后在该中心通过无环羰基的烯醇形式进行亲核取代；以及B，与烯胺中间体和C±C键形成，伴随着NHO氢转移和脯氨酸羧基的亲核辅助。Hajos仍然根据他对18O标记的水的实验[1C]来论证机制A，[1C]，在该实验中没有观察到18O在产品中的掺入。最近在严格控制的条件下重新调查了这些实验，他们发现效率(90%)
The first examples of enantioselective intramolecular aldol cyclizations catalyzed by proline (Scheme 1) were independently reported by Hajos and Parrish [1] and by Wiechert and co-workers [2] in 1971. Useful synthetic intermediates, such as the Wieland–Miescher ketone (3b) are easily obtained by this reaction. This reaction constitutes a cornerstone in the emergent field of enantioselective organocatalysis. A variety of CÀC bond-forming reactions have been achieved with chiral organocatalysis in recent years.[3]In spite of the classic status of this reaction, the mechanism remains controversial. Herein we provide definitive theoretical evaluation of the various mechanisms proposed for the reaction; by computation of all six steps in the reaction we show how the reaction conditions may influence the rate-determining step and the stereoselectivity. In their original paper,[1b] Hajos and Parrish proposed two mechanisms (Scheme 2): A, which requires the formation of a carbinolamine intermediate followed by nucleophilic substitution at this center by the enol form of the acyclic carbonyl; and B, with an enaminium intermediate and CÀC bondformation accompanied by NHO hydrogen transfer and nucleophilic assistance by the carboxylate group of proline. Hajos still argues for mechanism A,[1c] on the basis of his experiments with 18O-labeled water where no incorporation of 18O in the products was observed.[1b] However, List et al. have reinvestigated these experiments recently under carefully controlled conditions, and they found efficient (> 90%)