Multistep one-pot synthesis of enantioenriched polysubstituted cyclopenta[b]indoles.
Multistep one-pot synthesis of enantioenriched polysubstituted cyclopenta[b]indoles.
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DOI：
10.1002/anie.201107308
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发表时间：
2012-01
影响因子：
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通讯作者：
Biao Xu;Zhi‐Lei Guo;Wan‐Yan Jin;Zhi‐Ping Wang;Yungui Peng;Qixiang Guo
中科院分区：
文献类型：
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作者：
Biao Xu;Zhi‐Lei Guo;Wan‐Yan Jin;Zhi‐Ping Wang;Yungui Peng;Qixiang Guo
手性吲哚的不对称合成是有机合成领域的一个长期研究课题。吲哚骨架是杂环体系，存在于许多生物碱产品、药物和农用化学品中。[1]环戊二烯并[B]吲哚骨架可以在许多吲哚生物碱中发现，[2]但尚未被广泛报道。含有这种单元的化合物表现出广泛的生物活性。[3]例如，2-氨基环戊二烯并[B]吲哚，[4 a]环戊二烯并[B]吲哚取代的乙酸，[4 B]和一系列的yuehchukene类似物[5]已被成功地合成并用于药物化学。虽然已经开发了许多合成环戊二烯并[B]吲哚的方法，[6]其中只有少数是不对称的，特别是催化不对称方法。[7]据我们所知，只有一个例子，手性环戊二烯并[B]吲哚合成的不对称催化剂具有可接受的对映选择性。[8]因此，非常需要开发用于构建环戊并[B]吲哚单元的有效方法。作为我们研究小组对羰基化合物的催化不对称α-烷基化工作的继续，[9]我们合理地设计了一锅[10]三步反应，其中包括由伯胺取代的硫脲催化的醛的α-烷基化[11]和两个连续的Brønsted酸催化的吲哚的Friedel-Crafts反应，[12]以构建手性多取代的环戊二烯并[B]吲哚（方案1）。在此，我们报道了这些连续的有机催化反应，这些反应以高产率（高达85%）得到了结构多样的环戊二烯并[B]吲哚，并且具有优异的非对映选择性（高达> 99：1）和对映选择性（高达99%ee）。在第一阶段，我们研究了异丁醛4a与3-吲哚基甲醇3a在手性胺1和酸2催化下的α-烷基化反应（步骤1）。虽然在醛与二芳基甲醇化合物的类似α-烷基化反应中使用了几种基于胺的不对称催化方法，[11]但迄今为止，α，α-二取代
The development of asymmetric methodologies for the synthesis of chiral indoles has been a long-standing project in organic synthesis. Indole skeletons are heterocyclic systems and are present in numerous alkaloid products, pharmaceuticals, and agrochemicals.[1] Cyclopenta [b] indole skeletons can be found in a number of indole alkaloids,[2] but have not been extensively reported. Compounds that contain such a unit exhibit a wide range of biological activities.[3] For example, 2-aminocyclopenta [b] indoles,[4a] cyclopenta [b] indole-substituted acetic acids,[4b] and a series of yuehchukene analogues [5] have been successfully synthesized and used in medicinal chemistry. Although a number of methods have been developed for the synthesis of cyclopenta [b] indoles,[6] only few of them are asymmetric and especially catalytic asymmetric methods.[7] To the best of our knowledge, there is only one example of the synthesis of chiral cyclopenta [b] indoles by asymmetric catalysis with acceptable enantioselectivities.[8] The development of efficient methods for the construction of cyclopenta [b] indole units is therefore highly desirable. As a continuation of the work of our research group toward the catalytic asymmetric α-alkylation of carbonyl compounds,[9] we rationally designed a one-pot [10] three-step reaction, which consisted of the α-alkylation of an aldehyde, catalyzed by a primary-amine-substituted thiourea,[11] and two consecutive Brønsted acid catalyzed Friedel–Crafts reactions of an indole,[12] to construct chiral polysubstituted cyclopenta [b] indoles (Scheme1). Herein, we report these consecutive organocatalyzed reactions, which gave structurally diverse cyclopenta [b] indoles in high yields (up to 85%), and with excellent diastereoselectivities (up to> 99: 1) and enantioselectivities (up to 99% ee).The reactions shown in Scheme 1 were realized in three stages. In the first stage, we examined the α-alkylation of isobutylaldehyde 4a with 3-indolylmethanol 3a (step 1) under catalysis by chiral amines 1 and acids 2. Although several methods for the asymmetric amine-based catalysis have been used in similar α-alkylation reactions of aldehydes with diarylmethanol compounds,[11] to date α, α-disubstituted