Direct, highly enantioselective pyrrolidine sulfonamide catalyzed Michael addition of aldehydes to nitrostyrenes.
Direct, highly enantioselective pyrrolidine sulfonamide catalyzed Michael addition of aldehydes to nitrostyrenes.
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DOI：
10.1002/anie.200461959
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发表时间：
2005-02
影响因子：
--
通讯作者：
Wei Wang-;Jian Wang;Hao Li
中科院分区：
文献类型：
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作者：
Wei Wang-;Jian Wang;Hao Li
迈克尔加成反应无疑是有机合成中最常用的生成C12 C键的方法之一。[1]因此，这并不奇怪，对映选择性催化协议的发展，这基石反应受到了极大的关注。[2]近年来，通过使用手性有机催化剂来实现该方法的不对称版本的努力已经被深入探索。[3]已经描述了用于不对称Michael反应的L-脯氨酸和其他基于吡咯烷的催化体系，但通常仅观察到中等的对映选择性。[4，5]因此，设计和开发新的和有效的手性有机催化剂以在迈克尔共轭加成中实现高水平的对映体和/或非对映体选择性仍然是合成有机化学中的主要挑战。[6-9]最近，Kotsuki和他的同事描述了一种手性吡咯烷-吡啶催化剂，该催化剂促进酮与硝基苯乙烯的高度对映和非对映选择性Michael加成反应。[10]然而，差的对映体选择性（ca. 22%ee）。本文中，我们描述了手性吡咯烷磺酰胺1，其催化醛与硝基苯乙烯的Michael共轭加成，具有高水平的对映体-（89- 99%ee）和非对映体选择性（！20：1 dr）。作为旨在开发用于不对称有机转化的新型有机催化剂的计划的一部分，我们最近观察到吡咯烷磺酰胺1作为α-氨氧基化和Mannich型反应的有效催化剂。[11这些方法以异常高水平的对映体和/或非对映体选择性发生。此外，该催化剂对醛和酮的α-亚磺酰基化反应也表现出很高的活性。[13]基于这些观察，我们设想（S）-吡咯烷磺酰胺1将与醛反应以形成手性烯胺，其可以在与硝基烯烃的反应中充当迈克尔供体。此外，模型检查表明，该过程将通过优先烯胺加成到硝基烯烃的较少受阻的Si面而发生[Eq.①]。因此，预期高水平的对映体和/或非对映体选择性。此外，具有酸性磺酰胺[14]和碱性吡咯烷基团的催化剂1的双官能性质，即使在不存在酸性添加剂的情况下，也可以预期导致高催化活性。本文描述了使用1促进高度对映体和非对映体选择性迈克尔加成反应的研究结果，初步研究了在室温下，在各种溶剂中，在20mol%的吡咯烷磺酰胺1存在下，异丁醛与反式-β-硝基苯乙烯的反应。如表1所示，反应产率在测试的溶剂中显著变化。一般来说，反应在极性溶剂中进行得更快。例如，在二甲基亚砜（DMSO）、异丙醇（iPrOH）、N，N-二甲基甲酰胺（DMF）和MeCN（表1，条目1-5）中，获得高产率（64-93%），而在极性较低的THF和1，4-二氧六环中的反应非常缓慢（表1，条目7和8）。有趣的是，无论使用何种溶剂，反应都具有高度的对映选择性（63- 83%ee）。使用iPrOH导致最高ee值（83%），当反应温度降低至0 ℃时，其进一步增加至90%ee，而反应速率没有显著降低（表1，条目3）。
The Michael addition reaction is without question one of the most general and versatile methods for formation of CÀC bonds in organic synthesis.[1] Thus, it is not surprising that the development of enantioselective catalytic protocols for this cornerstone reaction has received much attention.[2] Efforts aimed at achieving asymmetric versions of the process by using chiral organocatalysts have been explored intensively in recent years.[3] L-Proline and other pyrrolidine-based catalytic systems for asymmetric Michael reactions have been described, but only moderate enantioselectivities are typically observed.[4, 5] As a result, the design and development of new and efficient chiral organocatalysts to achieve high levels of enantio-and/or diastereoselectivity in Michael conjugate additions remain a major challenge in synthetic organic chemistry.[6–9] Recently, Kotsuki and his co-workers described a chiral pyrrolidine–pyridine catalyst that promoted highly enantio-and diastereoselective Michael addition reactions of ketones with nitrostyrenes.[10] However, poor enantioselectivity (ca. 22% ee) resulted when an aldehyde was used as the substrate. Herein, we describe the chiral pyrrolidine sulfonamide 1, which catalyzes the Michael conjugate additions of aldehydes to nitrostyrenes with high levels of enantio-(89–99% ee) and diastereoselectivity (! 20: 1 dr). As part of a program aimed at developing new organocatalysts for asymmetric organic transformations, we recently observed that the pyrrolidine sulfonamide 1 serves as an efficient catalyst for α-aminoxylation and Mannich-type reactions.[11, 12] These processes take place with exceptionally high levels of enantio-and/or diastereoselectivity. Moreover, the catalyst also shows high activity for α-sulfenylation reactions of aldehydes and ketones.[13] Based on these observations, we envisioned that the (S)-pyrrolidine sulfonamide 1 would react with an aldehyde to form a chiral enamine, which could serve as a Michael donor in reactions with nitroolefins. In addition, a model inspection suggested that the process would take place by the preferential enamine addition to the less hindered Si face of the nitroolefin [Eq.(1)]. Consequently, high levels of enantio-and/or diastereoselectivity are expected. In addition, the bifunctional nature of catalyst 1, which possesses an acidic sulfonamide [14] and a basic pyrrolidine group, could be expected to lead to high catalytic activities even in the absence of an acidic additive. Herein, we describe the results of the studies using 1 to promote highly enantio-and diastereoselective Michael addition reactions.The reaction of isobutyraldehyde with trans-β-nitrostyrene in the presence of the pyrrolidine sulfonamide 1 (20mol%) in various solvents at room temperature was investigated initially. As evident in Table 1, the reaction yields varied significantly in the solvents tested. In general, the reaction proceeded more rapidly in polar solvents. For example, in dimethyl sulfoxide (DMSO), isopropyl alcohol (iPrOH), N, N-dimethylformamide (DMF), and MeCN (Table 1, entries 1–5), high yields (64–93%) were obtained, whereas reactions in less polar THF and 1, 4-dioxane were very sluggish (Table 1, entries 7 and 8). Interestingly, regardless of the solvents used, the reactions were highly enantioselective (63–83% ee). The use of iPrOH led to the highest ee value (83%), which was further increased to 90% ee when the reaction temperature was lowered to 08C without a significant reduction in the reaction rate (Table 1, entry 3).