Thiourea-Catalyzed Highly Enantio- and Diastereoselective Additions of Oxindoles to Nitroolefins: Application to the Formal Synthesis of (+)-Physostigmine
Thiourea-Catalyzed Highly Enantio- and Diastereoselective Additions of Oxindoles to Nitroolefins: Application to the Formal Synthesis of (+)-Physostigmine
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DOI：
10.1021/ja903520c
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发表时间：
2009-07-01
影响因子：
15
通讯作者：
Barbas, Carlos F., III
中科院分区：
文献类型：
--
作者：
Bui, Tommy;Syed, Salahuddin;Barbas, Carlos F., III
吲哚及其吲哚衍生物是广泛存在于天然和生物活性分子中的常见结构基序。大多数不对称合成这些化合物的催化方法严重依赖于过渡金属催化剂的使用。相比之下，涉及有机催化的替代催化程序很少。在此，我们提出了一种概念新颖的有机催化方法来合成这些材料，使用硫脲催化的不对称1,4-氧吲哚衍生物加成到硝基烯烃上作为关键步骤。这些加成反应产生两个立体中心，其中一个是四元中心。对于氧化吲哚和硝基烯烃底物，这些反应的范围很广，并以高收率提供所需的产品，其对映性高达99%，非对映选择性高达>20:1。为了证明该方法的实用性，从1,4加成产物开始，经过3个步骤合成了(+)-芥子碱，总体产率很高，从而正式合成了(+)-芥子碱。
Oxindoles and their indoline derivatives are common structural motifs found in a wide array of natural and biologically active molecules. Most catalytic methods for the asymmetric syntheses of these compounds rely heavily on the use of transition-metal catalysts. In contrast, alternative catalytic procedures involving organocatalysis are scarce. Herein we disclose a conceptually novel organocatalytic approach to the syntheses of these materials using thiourea-catalyzed asymmetric 1,4-additions of oxindole derivatives to nitroolefins as a key step. These addition reactions create up to two stereogenic centers, one of which is a quaternary center. These reactions are broad in scope with respect to both the oxindole and nitroolefin substrates and provide the desired products in good yields with enantiosetectivities of up to 99% and diastereoselectivities of up to >20:1. To demonstrate the utility of this approach, (+)-esermethole was synthesized in good overall yield over 3 steps starting from the 1,4-addition product, thereby providing a formal synthesis of (+)-physostigmine.