State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences , 345 Lingling Lu, Shanghai 200032, China.
Acc Chem Res. 2014 Aug 19;47(8):2558-73. doi: 10.1021/ar500167f. Epub 2014 Jun 18.
Dearomatization reactions serve as powerful methods for the synthesis of highly functionalized, three-dimensional structures starting with simple planar aromatic compounds. Among processes of this type, catalytic asymmetric dearomatization (CADA) reactions are attractive owing to the large number of aromatic compounds that are readily available and the fact that they enable direct access to enantiopure polycycles and spirocycles, which frequently are key structural motifs in biologically active natural products and pharmaceuticals. However, as a consequence of their high stabilities, arenes only difficultly participate in dearomatization reactions that take place with high levels of enantioselectivity. Transition-metal-catalyzed asymmetric allylic substitution reactions have been demonstrated to be powerful methods for enantioselective formation of C-C and C-X (X = O, N, S, etc.) bonds. However, the scope of these processes has been explored mainly using soft carbon nucleophiles, some hard carbon nucleophiles such as enolates and preformed organometallic reagents, and heteroatom nucleophiles. Readily accessible aromatic compounds have been only rarely used directly as nucleophiles in these reactions. In this Account, we present the results of studies we have conducted aimed at the development of transition-metal-catalyzed asymmetric allylic dearomatization reactions. By utilizing this general process, we have devised methods for direct dearomatization of indoles, pyrroles, phenols, naphthols, pyridines, and pyrazines, which produce various highly functionalized structural motifs bearing all-carbon quaternary stereogenic centers in a straightforward manner. In mechanistic investigations of the dearomatization process, we found that the five-membered spiroindolenines serve as intermediates, which readily undergo stereospecific allylic migration to form corresponding tetrahydro-1H-carbazoles upon treatment with a catalytic amount of TsOH. It is worth noting that no notable loss of the enantiomeric excess of the spiroindolenine derivatives takes place during the rearrangement process as a consequence of the intervention of a "three-center-two-electron"-type transition state, a proposal that has gained support from the results of DFT calculations. Equally intriguing, upon tuning of the electronic nature of the tethers, pyrroles or indoles undergo unprecedented Ir or Ru catalyzed intramolecular allylic alkylation promoted dearomatization/migration reactions. The operation of this novel reaction pathway provides additional information leading to a greater mechanistic understanding of the transition-metal-catalyzed enantioselective intramolecular functionalizations of pyrroles and indoles. The combined results of this effort provide not only methods for the efficient synthesis of highly enantioenriched fused and spiro polycycles but also novel strategies in the field of asymmetric catalysis.
去芳构化反应是一种强大的方法，可用于从简单的平面芳香化合物合成高度官能化的三维结构。在这类反应中，催化不对称去芳构化（CADA）反应很有吸引力，因为大量的芳香化合物很容易获得，并且可以直接得到对映纯的多环和螺环化合物，这些化合物通常是生物活性天然产物和药物中的关键结构基序。然而，由于其高稳定性，芳烃很难参与具有高对映选择性的去芳构化反应。过渡金属催化的不对称烯丙基取代反应已被证明是对映选择性形成 C-C 和 C-X（X=O、N、S 等）键的有力方法。然而，这些过程的范围主要是使用软碳亲核试剂、一些硬碳亲核试剂（如烯醇盐和预形成的有机金属试剂）和杂原子亲核试剂来探索的。直接可利用的芳香族化合物很少直接用作这些反应中的亲核试剂。在本综述中，我们介绍了我们开展的旨在开发过渡金属催化的不对称烯丙基去芳构化反应的研究结果。通过利用这一通用过程，我们设计了直接去芳构化吲哚、吡咯、苯酚、萘酚、吡啶和吡嗪的方法，以直接的方式生成各种带有全碳季立体中心的高度官能化结构基序。在去芳构化过程的机理研究中，我们发现五员螺吲哚啉作为中间体，在与催化量的 TsOH 处理时，很容易经历立体特异性烯丙基迁移，形成相应的四氢-1H-咔唑。值得注意的是，由于“三中心-两电子”型过渡态的介入，螺吲哚啉衍生物在重排过程中不会显著损失对映过量，这一假设得到了密度泛函理论（DFT）计算结果的支持。同样有趣的是，通过调节连接基团的电子性质，吡咯或吲哚经历了前所未有的 Ir 或 Ru 催化的分子内烯丙基烷基化促进的去芳构化/迁移反应。这种新反应途径的操作提供了更多的信息，有助于更深入地了解过渡金属催化的吡咯和吲哚的对映选择性分子内官能化反应。这项工作的综合结果不仅提供了高效合成高度对映富集的稠合和螺环多环化合物的方法，而且为不对称催化领域提供了新的策略。
