Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus C, Denmark.
Acc Chem Res. 2021 Apr 20;54(8):1830-1842. doi: 10.1021/acs.accounts.0c00851. Epub 2021 Mar 4.
Enamine and enol ethers are nucleophilic functional groups that are well known to most chemists. When enamine or enol ethers are present in natural products, they are nearly exclusively found as derivatives having a direct connection to electron-withdrawing groups for stabilization, and the resulting larger entities, such as enamides or enol acylates, can be further extended or modified in the framework of natural products. The restricted conformational space that is associated with even simple enamine and enol ether derivatives can be a strong determinant of the overall molecular structure, and the more polarized derivatives can endow some natural products with electrophilic properties and thus facilitate covalent interactions with biological targets.In this Account, I describe our efforts (published since 2016) to prepare natural products from several different classes that all feature enamine or enol ether derivatives as key functionalities. Our choice of targets has been guided by a desire to illuminate unknown biological mechanisms associated with the compounds or, alternatively, to improve upon known biological activities that appear to be promising from a biomedical perspective. In the present text, however, the exclusive focus will be on the syntheses.First, I will discuss the basic properties of the functional groups and briefly present a small collection of illustrative and inspirational examples from the literature for their construction in different complex settings. Next, I will provide an overview of our work on the macrocyclic APD-CLD natural products, rakicidin A and BE-43547A, involving the development of an efficient macrocyclization strategy and the development of methods to construct the hallmark APD group: a modified enamide. The synthesis of the meroterpenoid strongylophorine-26 is discussed next, where we developed an oxidative quinone methoxylation to build a vinylogous ester group in the final step of the synthesis and employed FeCl-mediated cascade reactions for the rapid assembly of the overall scaffold to enable a short semisynthesis from isocupressic acid. An efficient core scaffold assembly was also in focus in our synthesis of the alkaloid streptazone A with the signature enaminone system being assembled through a rhodium-catalyzed Pauson-Khand reaction. Sequential, site-selective redox manipulations were developed to arrive at strepatzone A and additional members of the natural product family. Finally, I discuss our work to prepare analogs of complex polyether ionophores featuring functionalized tetronic acids as cation-binding groups. A method for the construction of a suitably protected chloromethylidene-modified tetronate is presented which enabled its installation in the full structure through a C-acylation reaction. This work exemplifies how components of abundant polyether ionophores can be recycled and used to access new structures which may possess enhanced biological activities.
烯胺和烯醇醚是亲核官能团，大多数化学家都很熟悉。当烯胺或烯醇醚存在于天然产物中时，它们几乎都是作为与吸电子基团直接相连的衍生物存在，以稳定其结构，而由此产生的更大的实体，如烯酰胺或烯醇酰基化合物，可以在天然产物的框架内进一步扩展或修饰。即使是简单的烯胺和烯醇醚衍生物也会受到限制的构象空间的影响，这是整体分子结构的一个重要决定因素，而更具极性的衍生物可以赋予一些天然产物亲电性，并因此促进与生物靶标的共价相互作用。在本报告中，我描述了我们自 2016 年以来努力从具有烯胺或烯醇醚衍生物作为关键官能团的几个不同类别中制备天然产物的工作。我们选择目标的指导原则是阐明与化合物相关的未知生物学机制，或者改进从生物医学角度来看似乎有希望的已知生物学活性。然而，在本报告中，我们将重点仅放在合成上。首先，我将讨论官能团的基本性质，并简要介绍一些来自文献的说明性和启发性示例，说明它们在不同复杂环境中的构建。接下来，我将概述我们在大环 APD-CLD 天然产物，即 rakicidin A 和 BE-43547A 方面的工作，包括开发有效的大环化策略和构建标志性 APD 基团的方法：一个经过修饰的烯酰胺。接下来讨论了 Meroterpenoid Strongylophorine-26 的合成，我们开发了一种氧化醌甲氧基化反应，在合成的最后一步构建一个乙烯基酯基团，并使用 FeCl 介导的级联反应快速组装整体支架，使它能够从异贝壳杉酸进行短的半合成。我们还专注于生物碱 streptazone A 的核心支架组装，其标志性的烯胺系统通过 Rh 催化的 Pauson-Khand 反应组装。开发了顺序、选择性的氧化还原操作，以获得 strepatzone A 和天然产物家族的其他成员。最后，我讨论了我们制备具有功能化四氢酸作为阳离子结合基团的复杂聚醚离子载体类似物的工作。提出了一种构建适当保护的氯甲基化修饰的四氢酸盐的方法，通过 C-酰化反应可以将其安装在全结构中。这项工作例证了如何回收丰富的聚醚离子载体的组成部分，并用于获得可能具有增强的生物学活性的新结构。
