Enantioselective total synthesis of (+)-brefeldin A and 7-epi-brefeldin A.
Enantioselective total synthesis of (+)-brefeldin A and 7-epi-brefeldin A.
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DOI：
10.1021/jo049971d
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发表时间：
2004-04
期刊：
影响因子：
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通讯作者：
Yikang Wu;Xin Shen;Yong‐Qing Yang;Q. Hu;Jia‐Hui Huang
中科院分区：
文献类型：
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作者：
Yikang Wu;Xin Shen;Yong‐Qing Yang;Q. Hu;Jia‐Hui Huang
建立了一条收敛的不对称合成灯盏花素A(BFA)和7-表儿茶素-BFA的路线。在TiCl4和TMEDA存在下，利用手性辅助诱导的分子间不对称缩醛反应建立了关键的C-4/C-5手性中心。四甲基硫酮/TiCl4催化的分子间不对称缩醛反应的结果为现有的这类反应的范围和局限性增加了一些新的信息(到目前为止，这类反应基本上局限于与N-丙酰基四氮杂环硫酮的反应)。在此过程中，开发了一种利用廉价的TBSCl在以2，6-Lutidine为碱的DMF中保护易受攻击的羟醛羟基的方法，以取代原本不可避免的TBSOTf步骤。由于过多的空间位阻，辅助物的移除比大多数文献病例要困难得多。几乎不可能通过还原来裂解恶唑烷酮。噻唑硫酮助剂相对更容易去除。然而，文献中报道的几个简单去除噻唑硫酮辅助剂的反应仍然失败。在乙醚中用LiBH(4)在1当量甲醇存在下最有效地实现了对噻唑硫酮助剂的还原脱除(对文献中在较少阻碍的底物中脱除恶唑烷酮助剂的方法进行了修改)。除了辅助去除，醇的氧化成醛和二硫杂环戊烷保护基团的去保护在本上下文中也相当困难。在找到最终解决方案之前，对一系列方法进行了筛选。在各种条件下的分子内缩醛反应多次失败后，通过分子内Mukaiyama反应构建了五元环。关键中间体环戊酮49与DBU形成α，β-双键的烷氧基的消除速率与溶剂高度相关(在CH(2)Cl(2)中非常缓慢，但在MeOH中相当快)。较低的链(通过使用Jacobsen KHR合成来建立C-15手性)的引入是通过类似于文献中的先例的Michael加成实现的。以前没有注意到，使用3当量的铜-锂试剂55可以显著提高该Michael反应的产率。C-7羰基的还原显然比文献中的类似情况更困难。通过多种试剂在不同条件下的考察，确定了生成α-异构体的最佳试剂为(S)-2-甲基-2-甲基-硫代丁烷-硼氢化钠/BH(3)，生成β-异构体的最佳试剂为L选择剂。然后将α-和β-异构体分别进一步细化为(+)-灯盏花素A和7-表儿茶素-BFA。还观察到了BFA和7-epi-BFA之间意想不到但非常有趣的溶解度差异。
A convergent enantioselective route to brefeldin A (BFA) and 7-epi-BFA was developed. The key C-4/C-5 chiral centers were established by using chiral auxiliary induced intermolecular asymmetric aldolization in the presence of TiCl(4) and TMEDA. The results with the thiazolidinethione/TiCl(4) mediated intermolecular asymmetric aldolization added some new information about the scope and limitations to the existing knowledge of that type of reactions (which so far was essentially limited to the reactions with N-propionyl thiazolidinethiones). During the course a method for protecting the liable aldol hydroxyl groups by using inexpensive TBSCl in DMF with 2,6-lutidine as the base was developed to replace the otherwise unavoidable TBSOTf procedure. Due to the excessive steric hindrance, removal of the auxiliary was much more difficult than most literature cases. Cleavage of the oxazolidinone by reduction was almost impossible. The thiazolidinethione auxiliary was relatively easier to remove. However, several reactions reported for facile removal of thiazolidinethione auxiliaries in the literature still failed. Reductive removal of the thiazolidinethione auxiliary was most effectively realized with LiBH(4) in diethyl ether in the presence of 1 equiv of MeOH (a modification of a literature procedure for removal of oxazolidinone auxiliaries in less hindered substrates). Apart from the auxiliary removal, oxidation of the alcohol into aldehyde and the deprotection of the dithiolane protecting group were also rather difficult in the present context. A range of methods were screened before final solutions were found. The five-membered ring was constructed by employing an intramolecular Mukaiyama reaction after many attempts with the intramolecular aldolization under a variety of conditions failed. The rate of elimination of the alkoxyl to form the alpha,beta-double bond of the key intermediate cyclopentenone 49 with DBU was highly solvent dependent (very sluggish in CH(2)Cl(2) but rather fast in MeOH). Introduction of the lower chain (which was synthesized by using a Jacobsen KHR to establish the C-15 chirality) was achieved through a Michael addition similar to the precedents in the literature. It has not been noticed before that the yield of this Michael reaction could be dramatically raised by using 3 equiv of the copper-lithium reagent 55. Reduction of the C-7 carbonyl was apparently more difficult than similar cases in the literature. After examination of many reagents under various conditions, it was found that the best reagent for yielding the alpha-isomer was (S)-2-methyl-CBS-borolidine/BH(3) and that for the beta-isomer was L-Selectride. The alpha- and beta-isomers were then further elaborated into (+)-brefeldin A and 7-epi-BFA, respectively. An unexpected yet very interesting solubility difference between BFA and 7-epi-BFA was also observed.