The Recurring Roles of Chlorine in Synthetic and Biological Studies of the Lissoclimides.
The Recurring Roles of Chlorine in Synthetic and Biological Studies of the Lissoclimides.
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DOI：
10.1021/acs.accounts.0c00866
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发表时间：
2021-03-02
影响因子：
18.3
通讯作者：
Vanderwal CD
中科院分区：
文献类型：
--
作者：
Pak BS;Supantanapong N;Vanderwal CD
卤化的天然产物数以千计，但只有在极少数情况下，卤素赋予的进化优势才被理解。我们着手调查的细胞毒素，其中包括几个氯化的成员，因为我们长期以来的兴趣在氯化的次生代谢产物的合成利索克林家族。我们在这奋进取得的初步成功是从市售的倍半萜类香紫苏碱半合成氯异麦角胺（CL）。由于具有高度选择性、高效且看似仿生的C-H氯化作用，我们能够获得足够的CL用于合作研究，包括与真核核糖体的X射线共结晶学。通过这个实验，我们了解到CL的氯原子与核糖体E位点中的相邻核碱基进行了一种新的卤素-π分散相互作用。由于我们的半合成方法的局限性，我们建立了一个类似物导向的方法来访问众多的利索克林化合物，以提高我们对结构/活性关系的理解，并了解更多关于卤素-π相互作用。在这些研究过程中，我们制造了十几种类似利索环胺的化合物，其中最有趣的是含有非自然构型的含氯碳。为了证明这些化合物的保留效力似乎不适合利索克林结合口袋，我们开始意识到氯原子将参与这些相同的卤素-π相互作用，即使以扭转船构象变化的椅子为代价，这也允许化合物适合结合位点。最后，由于前两种方法都不能容易地获得最有效的天然lissoclimides，我们设计了一种合成方法，利用很少使用的末端环氧化物来引发多烯环化。在这种情况下，氯原子很早就被引入，并有助于控制关键步骤的立体化学结果。在这个项目的过程中，设计并执行了三种不同的合成方法，我们获得许多lissoclimides的能力推动了一系列合作生物学研究。此外，氯在合成和生物学的各个方面都发挥着重要作用。我们仍然受到启发，以了解更多关于这些化合物的作用机制，并深入研究在小分子/核酸结合的背景下潜在有价值的卤素-π分散相互作用。在这种情况下，我们的工作提供了一个例子，其中我们可能已经获得了一个基本的了解卤素的进化重要性卤化天然产品。
Halogenated natural products number in the thousands, but only in rare cases are the evolutionary advantages conferred by the halogens understood. We set out to investigate the lissoclimide family of cytotoxins, which includes several chlorinated members, because of our longstanding interest in the synthesis of chlorinated secondary metabolites. Our initial success in this endeavor was a semi-synthesis of chlorolissoclimide (CL) from the commercially available sesquiterpenoid sclareolide. Featuring a highly selective and efficient—and plausibly biomimetic—C–H chlorination, we were able to access enough CL for collaborative studies, including X-ray co-crystallography with the eukaryotic ribosome. Through this experiment, we learned that CL’s chlorine atom engages in a novel halogen-π dispersion interaction with a neighboring nucleobase in the ribosome E-site. Owing to the limitations of our semi-synthesis approach, we established an analogue-oriented approach to access numerous lissoclimide compounds to both improve our understanding of structure/activity relationships and to learn more about the halogen-π interaction. In the course of these studies, we made over a dozen lissoclimide-like compounds, the most interesting of which contained chlorine-bearing carbons with unnatural configurations. Rationalizing the retained potency of these compounds that appeared to be a poor fit for the lissoclimide binding pocket, we came to realize that the chlorine atoms would engage in these same halogen-π interactions even at the expense of a chair to twist-boat conformational change, which also permitted the compounds to fit in the binding site. Finally, because neither of the first two approaches could easily access the most potent natural lissoclimides, we designed a synthesis that took advantage of rarely used terminal epoxides to initiate polyene cyclizations. In this case, the chlorine atom was incorporated early, and helped control the stereochemical outcome of the key step. Over the course of this project, three different synthesis approaches were designed and executed, and our ability to access numerous lissoclimides fueled a range of collaborative biological studies. Further, chlorine played impactful roles throughout various aspects of both synthesis and biology. We remain inspired to learn more about the mechanism of action of these compounds, and to deeply investigate the potentially valuable halogen-π dispersion interaction in the context of small molecule/nucleic acid binding. In that context, our work offers an instance wherein we might have gained a rudimentary understanding of the evolutionary importance of the halogen in a halogenated natural product.
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