Approaches to the chemical synthesis of the chlorosulfolipids.
Approaches to the chemical synthesis of the chlorosulfolipids.
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DOI：
10.1021/ar400246w
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发表时间：
2014-02-18
影响因子：
18.3
通讯作者：
Vanderwal, Christopher D.
中科院分区：
文献类型：
--
作者：
Chung, Won-Jin;Vanderwal, Christopher D.
自1969年最初发现氯化脂蛋白以来，化学合成社区在近四十年中在很大程度上忽略了这些化合物，也许是因为它们含有高密度的氯原子，这些原子表明这些分子和任何预测的合成中间体可能在2008年开始在文献中，包括我们自己的几个研究小组（包括我们自己的）的合成活动突然出现。从过去的几年开始，从叶绿素的化学合成开始工作。
我们在这一领域的工作始于在这些早期研究中立体选择性地产生丰富的二氯醇功能组。允许在几种氯磺酰脂中发现的Syn-DichloroalCholol立体关系的烯丙基醇衍生物。同时，我们调查了一种用于β-氯醛功能组排列的多个中间体A的方法，但是这种途径证明是棘手的。通过使用烯烃氧化反应引入所有极性官能团的途径。完成了Malhamensilipin A的对映选择性合成A。这项工作还导致了Danicleipin A的完整立体化学阐明和Malhamensilipin A的结构修订。
最后，随着Z选择性的烯烃交叉隔离，我们开发了第二代合成，该策略代替了表现不佳的Wittig烯烃，除了困扰我们的第一个方法之外，我们开发了一种可靠的方法。对高度敏感的α，β-二氯醛的映射和动力学分辨率的方法的方案，这些方案完全使乙烯基环氧化物的动力学分辨率。仅在八个步骤中合成对映体的Mytilipin a。
在这项工作的背景下，我们发现了许多高度立体选择反应，这些反应可能会提供新的，适用于无环立体控制的新课程，这项研究测试对多氯分子的稳定性进行应用，包括发现化学。
Since the initial discovery of the chlorosulfolipids in 1969, the chemical synthesis community largely ignored these compounds for nearly four decades, perhaps because they contain a high density of chlorine atoms that suggested that these molecules and any projected synthetic intermediates might be unstable. Beginning in 2008, a sudden flurry of synthesis activity by several research groups, including our own, appeared in the literature. In this Account, we highlight our work from the last several years on the chemical synthesis of the chlorosulfolipids. Our work in this area began with attempts to stereoselectively generate the abundant dichloroalcohol functional group arrangements in these natural targets. In these early studies, we learned that many polychlorinated intermediates were far more stable than anticipated. We also developed a method for the diastereoselective dichlorination of allylic alcohol derivatives that permitted access to the syn,syn-dichloroalcohol stereotriad found in several chlorosulfolipids. Concurrently, we investigated an approach to mytilipin A that included multiple intermediates bearing β-chloroaldehyde functional group arrangements, but this route proved intractable. However, we leveraged what we had learned from this approach into our first success in this area: we synthesized danicalipin A via a route that introduced all of the polar functional groups using alkene oxidation reactions. By adapting this relatively general strategy, we completed an enantioselective synthesis of malhamensilipin A. This body of work also resulted in the full stereochemical elucidation of danicalipin A and the structural revision of malhamensilipin A. Finally, with the advent of Z-selective alkene cross metathesis, we developed a second-generation synthesis that featured this strategy in place of a poorly performing Wittig olefination that plagued our first approach. In addition to this new convergent step, we developed a reliable protocol for diastereoselective addition to highly sensitive α,β-dichloroaldehydes and a method for kinetic resolution of complex vinyl epoxides. Altogether, these advances led to a synthesis of enantioenriched mytilipin A in only eight steps. In the context of this work, we discovered a number of highly stereoselective reactions that might offer new, broadly applicable lessons in acyclic stereocontrol. Moreover, this research testifies to the stability of polychlorinated molecules and should inspire confidence in the use of aliphatic chlorides in other applications, including in discovery chemistry.
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