Enantioselective construction of pyrroloindolines catalyzed by chiral phosphoric acids: total synthesis of (-)-debromoflustramine B.
Enantioselective construction of pyrroloindolines catalyzed by chiral phosphoric acids: total synthesis of (-)-debromoflustramine B.
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DOI：
10.1002/anie.201203553
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发表时间：
2012-11
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通讯作者：
Zuhui Zhang;J. Antilla
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作者：
Zuhui Zhang;J. Antilla
结构.这些化合物的生物活性已经得到了很好的研究，其结果已经显示出几个有前途的应用，包括肌肉松弛剂，钾通道阻滞剂和抗癌剂。由于这个原因，这些天然产物的全合成受到了相当大的关注，并且已经由几个研究小组完成。然而，很少有采用催化不对称策略来形成关键的吡咯并吲哚啉子结构的例子。在吡咯并吲哚啉的C3位置上的手性，带有C-N键，虽然有些罕见，但在几种天然产物中发现，例如最近分离的生物碱（）-psychotrimine（图1）。Baran等人报道了通过吲哚-苯胺偶联策略全合成（±）-精神三胺。Gouverneur等人也报道了吲哚的有机催化对映选择性氟环化形成手性3-氟吡咯并吲哚啉，这是与吡咯并吲哚啉亚结构形成碳-杂原子键的有趣例子。然而，据我们所知，在催化不对称策略中与吡咯并吲哚啉基序形成C N键是未知的。开发一种通用的催化方法，以安装在一个对映选择性和控制的方法的碳-碳和碳-氮键可能是感兴趣的手性吡咯并吲哚啉的制备。手性磷酸已被证明是许多重要的不对称转化的有效催化剂。尽管有这些发展，但简单乙烯基酮作为合成有用的亲电试剂的活化不太为人所知，大概是由于预期活化较差。此外，没有手性磷酸催化的不对称亲电胺化的例子，这是一种潜在的有用的方法，用于形成具有这些类型的C N键的手性化合物。在此，我们已经规避了这些限制，并报告了手性磷酸催化的吡咯并吲哚啉的不对称形成的第一个例子，从而允许以良好的产率和高选择性获得吡咯并吲哚啉衍生物的碳-碳和碳-氮键。并将此方法用于（±）-去溴氟胺B的全合成。选择10-甲氧羰基色胺（1a）与甲基乙烯基酮（MVK）的反应作为模型反应以优化反应条件（表1）。令人惊讶的是，1a结合了两个MVK片段，以高产率形成2a作为单一的非对映异构体，据信其通过双迈克尔加成过程产生。如表1所示，在20 ℃下用4种分子筛（MS）在甲苯中筛选催化剂，表明在BINOL的3，3 ′位上带有2，4，6-三异丙基苯基的催化剂PA3在对映选择性方面是最好的催化剂（表1，条目1 - 3和条目8 - 10）。通过将温度降低到50 ℃，达到了91%的改进ee（条目4）。对于PA 4或PA 5，观察到相似的选择性，沿着具有略低的产率（条目3相对于条目5和6）。不饱和PA 3可用于提供具有86%ee和86%产率的产物（条目7）。通过改变溶剂进行进一步优化，证明甲苯比二氯甲烷、三氟甲苯和乙酸乙酯更合适（条目3对比条目11 - 13）。令人高兴的是，甲苯和苯的混合物在20 ℃下提供了93%ee的产物（表1，条目14）。然而，当反应在50 ° C下进行时，没有观察到进一步的改善（条目15）。当反应规模增加到1.0 mmol时，与图1的水平相同。代表性的吡咯并吲哚啉天然产物。
structures. The biological activities of these compounds have been well studied, the results of which have shown several promising applications, including muscle relaxants, potassium channel-blockers, and anti-cancer agents. For this reason, the total synthesis of these natural products has received considerable attention, and has been accomplished by several research groups. However, there are few examples employing catalytic asymmetric strategies to form the key pyrroloindoline substructure. Chirality at the C3 position of pyrroloindolines, bearing C N bonds, though somewhat rare, is found in several natural products, such as the recently isolated alkaloid ( )-psychotrimine (Figure 1). The total synthesis of ( )-psychotrimine by an elegant indole–aniline coupling strategy was reported by Baran et al. Also, Gouverneur et al. reported an organocatalyzed enantioselective fluorocyclization of indoles to form chiral 3-fluoropyrroloindolines, which is an interesting example of carbon–heteroatom bond formation with a pyrroloindoline substructure. However, to the best of our knowledge, the formation of a C N bond in a catalytic asymmetric strategy with a pyrroloindoline motif is not known. Development of a general catalytic method to install both carbon–carbon and carbon–nitrogen bonds in an enantioselective and controlled approach could be of interest for the preparation of chiral pyrroloindolines. Chiral phosphoric acids have proven to be efficient catalysts for many important asymmetric transformations. Despite these developments, the activation of a simple vinyl ketone as a synthetically useful electrophile is less well known, presumably owing to the expectation of poor activation. Also, there is no example of an asymmetric electrophilic amination catalyzed by chiral phosphoric acids, which is a potentially useful method for the formation of chiral compounds with these types of C N bonds. Herein, we have circumvented these limitations, and report the first example of the asymmetric formation of pyrroloindolines catalyzed by chiral phosphoric acids, thus allowing access to both the carbon–carbon and carbon–nitrogen bonds of pyrroloindoline derivatives with good yields and high selectivities. This method was then employed in the total synthesis of ( )-debromoflustramine B. The reaction of 10-carbomethoxytryptamine (1a) with methyl vinyl ketone (MVK) was selected as a model reaction to optimize the reaction conditions (Table 1). To our surprise, 1a, incorporates two MVK segments, forming 2a as a single diastereoisomer in high yield, which is believed to be generated through a double Michael addition processes. As shown in Table 1, catalyst screening in toluene at 20 8C with 4 molecular sieves (MS), indicates that catalyst PA3, which bears a 2,4,6-triisopropylphenyl group in the 3,3’ position of BINOL, is the best catalyst in terms of enantioselectivity (Table 1, entries 1–3, and entries 8–10). An improved ee of 91% was achieved by lowering the temperature to 50 8C (entry 4). With PA4 or PA5, similar selectivities were observed along with slightly lower yields (entry 3 vs. entries 5 and 6). Unsaturated PA3 could be used to deliver the product with 86 % ee and 86% yield (entry 7). Further optimization by variation of the solvent was conducted, with toluene proving to be more suitable than dichloromethane, trifluorotoluene, and ethyl acetate (entry 3 vs. entries 11–13). To our delight, a mixture of toluene and benzene furnished the product with 93% ee (Table 1, entry 14) at 20 8C. However, no further improvement was observed when the reaction was conducted at 50 8C (entry 15). When the reaction scale was increased to 1.0 mmol, the same level of Figure 1. Representative pyrroloindoline natural products.