Organisch-Chemisches Institut der Westfälische Wilhelms-Universität Münster, Münster, Germany.
Acc Chem Res. 2011 Nov 15;44(11):1182-95. doi: 10.1021/ar2000716. Epub 2011 Jul 13.
Transition metal catalysis is a powerful means of effecting organic reactions, but it has some inherent drawbacks, such as the cost of the catalyst and the toxicity of the metals. Organocatalysis represents an attractive alternative and, in some cases, offers transformations unparalleled in metal catalysis. Unique transformations are a particular hallmark of N-heterocyclic carbene (NHC) organocatalysis, a versatile method for which a number of modes of action are known. The NHC-catalyzed umpolung (that is, the inversion of polarity) of electrophilic aldehydes, through formation of the nucleophilic Breslow intermediate, is probably the most important mode of action. In this Account, we discuss the reaction of Breslow intermediates with unconventional reaction partners. In two traditional umpolung reactions, the benzoin condensation and the Stetter reaction, some selectivity issues represent significant challenges, especially in intermolecular variants of these reactions. In intermolecular cross-benzoin reactions, high levels of selectivity were recently obtained, even in the hydroxymethylation of aldehydes with formaldehyde. The key to success was careful choice of the NHC catalyst and reaction conditions. Among asymmetric Stetter reactions, intermolecular versions have posed a long-standing challenge. Recently, the groups of Enders and Rovis reported the first selective and efficient systems. We have contributed to this field by developing an efficient intermolecular Stetter reaction for the formation of α-amino acid derivatives, with broad aldehyde scope and high enantiomeric excess. Moreover, tailor-made thiazolylidene catalysts allowed the unprecedented use of nonactivated olefins and alkynes as aldehyde coupling partners. The basis for this reactivity is a unique mode of NHC organocatalysis: dual activation. In a concerted but asynchronous transition state, the positively polarized proton of the Breslow intermediate activates the coupling partner (for example, an olefin), while the nucleophilic enamine moiety starts to attack the activated coupling partner. As a consequence of the concerted nature of this mechanism, excellent values for enantiomeric excess were obtained for many substrates in the intramolecular hydroacylation of alkenes. In addition, thiazolylidene catalysts have enabled the coupling of aldehydes with reactive species, for example, with arynes and with activated alkyl bromides. NHC catalysis should continue to flourish and lead to surprising developments. One remaining challenge is the asymmetric intermolecular hydroacylation of unactivated olefins. In this area, metal-based catalysts have shown promising early results, but they are far from being either general or practical. It will be interesting to see which class of catalyst, whether metal-based or NHC-based, eventually develops into the method of choice.
过渡金属催化是一种有效的有机反应手段，但它存在一些固有缺点，例如催化剂的成本和金属的毒性。有机催化代表了一种有吸引力的替代方法，在某些情况下，它提供了金属催化无法实现的转化。独特的转化是 N-杂环卡宾 (NHC) 有机催化的一个特别标志，这是一种多功能的方法，已知有多种作用模式。NHC 催化的极性反转（即极性的反转）通过形成亲核 Breslow 中间体，这可能是最重要的作用模式。在本综述中，我们讨论了 Breslow 中间体与非常规反应伙伴的反应。在两个传统的极性反转反应——苯偶姻缩合和 Stetter 反应中，一些选择性问题是重大挑战，尤其是在这些反应的分子间变体中。在分子间交叉苯偶姻反应中，最近在醛的羟甲基化中甚至获得了高选择性，其中甲醛是醛的一种。成功的关键是仔细选择 NHC 催化剂和反应条件。在不对称 Stetter 反应中，分子间变体一直是一个长期存在的挑战。最近，Enders 和 Rovis 小组报道了第一个具有选择性和高效的系统。我们通过开发一种有效的分子间 Stetter 反应来形成α-氨基酸衍生物，该反应具有广泛的醛范围和高对映体过量，为这个领域做出了贡献。此外，定制的噻唑啉基催化剂允许以前所未有的方式使用非活化的烯烃和炔烃作为醛的偶联伙伴。这种反应性的基础是一种独特的 NHC 有机催化模式：双重活化。在协同但异步的过渡态中，Breslow 中间体的带正电荷的质子激活偶联伙伴（例如烯烃），而亲核烯胺部分开始攻击活化的偶联伙伴。由于这种机制的协同性质，许多底物在烯烃的分子内氢酰化反应中获得了优异的对映体过量值。此外，噻唑啉基催化剂使醛与反应性物质（例如芳基和活化的烷基溴化物）偶联成为可能。NHC 催化应该继续蓬勃发展，并带来令人惊讶的发展。一个遗留的挑战是未活化烯烃的不对称分子间氢酰化。在这一领域，基于金属的催化剂显示出有希望的早期结果，但它们远未达到通用或实用的程度。最终是基于金属的催化剂还是基于 NHC 的催化剂成为首选方法，这将是一件很有趣的事情。
