Synthesis of highly functionalized chiral cyclopentanes by catalytic enantio- and diastereoselective double Michael addition reactions
Synthesis of highly functionalized chiral cyclopentanes by catalytic enantio- and diastereoselective double Michael addition reactions
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DOI：
10.1002/anie.200700485
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Wang, Wei
中科院分区：
文献类型：
--
作者：
Zu, Liansuo;Li, Hao;Wang, Wei
涉及CÀC键形成的反应被认为是有机合成中最重要的过程。级联反应涉及在一次操作中产生多个CÀC键和多个立体中心，由于其操作简单、原子经济、低能耗和化学废物最小化，在复杂分子结构的快速构建中是一种特别有吸引力的策略虽然在使用手性前体进行立体控制方面取得了重大进展，但催化对映和非对映选择性级联反应的发展已被证明是一项具有挑战性的任务特别是近年来基于手性小分子的有机催化不对称多米诺反应的发展受到了热烈的关注。[2-5]最近，我们和Córdova课题组同时描述了手性仲胺促进的对映选择性级联磺胺、氧-和aza-Michael/aldol/脱水反应（Scheme 1a）。[6,7]我们设想使用亲核碳原子代替杂原子S， O和N进行最初的Michael加成，可以生成两个新的CÀC键。此外，将醛基转变为α， β不饱和酯2作为亲电试剂，允许第二次共轭加成反应，将产生新的级联双共轭加成过程（方案1b）。[8,9]就我们所知，迄今为止还没有人描述过这样一个过程值得注意的是，级联过程将提供形成三个立体中心的产物，而不是一个，这在Michael/aldol/脱水序列（方案1a）中观察到。在此，我们希望报告一项研究的结果，该研究导致了一种新的有机催化非立体和对映选择性级联双迈克尔反应，其中两个CÀC键和三个连续的立体中心在一个锅转化中有效地产生，具有高度的相对和绝对立体化学控制。这种新的催化方法是合成有用的、高度功能化的手性环戊烷的一种简便方法催化级联双迈克尔加成反应的设计需要考虑几个因素。2中参与第二次共轭加成反应的α， β-不饱和体系的反应活性必须足够高，以允许分子内的Michael反应，但是
Reactions that involve the formation of CÀC bonds are considered the most important processes in organic synthesis. Cascade reactions that involve the production of multiple CÀC bonds and multiple stereogenic centers in a single manipulation are a particularly appealing strategy in the rapid construction of complex molecular architectures because of their operational simplicity, atom economy, low use of energy, and minimization of chemical waste.[1] While significant progress has been made in the use of chiral precursors for stereocontrol, the development of catalytic enantio-and diastereoselective cascade reactions has proven to be a challenging task.[1] Notably the recent development of organocatalytic asymmetric domino reactions based on chiral small molecules has been hotly pursued.[2–5] Recently, we and the research group of Córdova simultaneously described enantioselective cascade sulfa-, oxa-, and aza-Michael/aldol/dehydration reactions promoted by chiral secondary amines (Scheme 1a).[6, 7] We envisioned that the employment of a nucleophilic carbon atom instead of heteroatoms S, O, and N for the initial Michael addition could enable the generation of two new CÀC bonds. Furthermore, change of the aldehyde group to an α, βunsaturated ester 2 as the electrophile, which allows for a second conjugate addition reaction, would produce a new cascade double conjugate addition process (Scheme 1b).[8, 9] To the best of our knowledge, such a process has not been described to date.[10] Significantly, the cascade process would afford a product with the formation of three stereogenic centers rather than one, which was observed in the Michael/aldol/dehydration sequence (Scheme 1a). Herein we wish to report the results of an investigation that has led to a novel organocatalytic diastereo-and enantioselective cascade double Michael reaction, in which two CÀC bonds and three contiguous stereogenic centers are efficiently created in a one-pot transformation with a high control of relative and absolute stereochemistry. This new catalytic methodology serves as a facile approach to synthetically useful, highly functionalized chiral cyclopentanes.[11] The design of a catalytic cascade double Michael addition reaction required the consideration of several factors. The reactivity of the α, β-unsaturated system in 2 that participates in the second conjugate addition reaction must be high enough to allow for the intramolecular Michael reaction, but