{"title":"生物启发的天然产品全合成。","authors":"Lijun Chen, Peng Chen, Yanxing Jia","doi":"10.1021/acs.accounts.4c00654","DOIUrl":null,"url":null,"abstract":"<p><p>ConspectusCurrently, the frontier challenges in total synthesis pertain to increasing the synthetic efficiency and enabling the divergent synthesis of a number of natural products. Bioinspired synthesis has been well recognized as an effective approach to increasing synthetic efficiency. Especially, when bioinspired synthesis was applied at late-stage skeletal diversification to generate various natural products with distinct carbon skeletons, it held special promise for achieving both goals. In our laboratory, bioinspired synthesis has served as one of two long-standing principles for facilitating the efficient synthesis of natural products. In this Account, we summarize our endeavors and journeys in the bioinspired synthesis of natural products. We categorize our work into three parts based on the imitation of biosynthetic reactions and processes.(1) To mimic the key cyclization steps. Inspired by the biosynthetic process that formed the core skeleton, we developed new synthetic methods to enable the rapid and efficient construction of the core skeletons of the targeted molecules, ultimately leading to their concise total synthesis, for example, seven-step total synthesis of lamellarins D and H featuring three bioinspired oxidative coupling reactions, seven-step total synthesis of clavicipitic acid highlighted by a C-H activation/aminocyclization cascade reaction, eight-step total synthesis of phalarine via a bioinspired oxidative coupling, seven-step total synthesis of α-cyclopiazonic acid, and ten-step total synthesis of speradine C through a bioinspired cascade cyclization reaction initiated by the benzylic carbocation of indole. (2) To mimic the revised biosynthetic pathway proposed by us. In some cases, the proposed biosynthetic processes may be flawed, as they contradict some basic principles of chemistry. Thus, an alternative biosynthetic process must be proposed and investigated. We showcase the total synthesis of euphorikanin A through a bioinspired benzilic acid-type rearrangement and bipolarolides A and B via a bioinspired Prins reaction/ether formation cascade cyclization. (3) To mimic the skeletal diversification process. Nature usually synthesizes a multitude of products from a key common intermediate in a divergent manner. Biogenic skeletal diversification to generate various natural products with distinct carbon skeletons has also drawn our attention. Compared with single-target-oriented synthesis, skeletal-diversity-oriented synthesis of natural products remains underexplored due to its high synthetic challenges. We showcased the divergent total syntheses of ten <i>pallavicinia</i> diterpenoids with three distinct skeletons and six <i>grayanane</i> diterpenoids with three distinct skeletons, which were achieved with unprecedented ease and high efficiency by imitation of the proposed biogenic skeletal diversification process. These two successful projects can serve as inspiration for the application of the bioinspired skeletal diversification strategy to other skeletally diverse natural products.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"3524-3540"},"PeriodicalIF":16.4000,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Bioinspired Total Synthesis of Natural Products.\",\"authors\":\"Lijun Chen, Peng Chen, Yanxing Jia\",\"doi\":\"10.1021/acs.accounts.4c00654\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>ConspectusCurrently, the frontier challenges in total synthesis pertain to increasing the synthetic efficiency and enabling the divergent synthesis of a number of natural products. Bioinspired synthesis has been well recognized as an effective approach to increasing synthetic efficiency. Especially, when bioinspired synthesis was applied at late-stage skeletal diversification to generate various natural products with distinct carbon skeletons, it held special promise for achieving both goals. In our laboratory, bioinspired synthesis has served as one of two long-standing principles for facilitating the efficient synthesis of natural products. In this Account, we summarize our endeavors and journeys in the bioinspired synthesis of natural products. We categorize our work into three parts based on the imitation of biosynthetic reactions and processes.(1) To mimic the key cyclization steps. Inspired by the biosynthetic process that formed the core skeleton, we developed new synthetic methods to enable the rapid and efficient construction of the core skeletons of the targeted molecules, ultimately leading to their concise total synthesis, for example, seven-step total synthesis of lamellarins D and H featuring three bioinspired oxidative coupling reactions, seven-step total synthesis of clavicipitic acid highlighted by a C-H activation/aminocyclization cascade reaction, eight-step total synthesis of phalarine via a bioinspired oxidative coupling, seven-step total synthesis of α-cyclopiazonic acid, and ten-step total synthesis of speradine C through a bioinspired cascade cyclization reaction initiated by the benzylic carbocation of indole. (2) To mimic the revised biosynthetic pathway proposed by us. In some cases, the proposed biosynthetic processes may be flawed, as they contradict some basic principles of chemistry. Thus, an alternative biosynthetic process must be proposed and investigated. We showcase the total synthesis of euphorikanin A through a bioinspired benzilic acid-type rearrangement and bipolarolides A and B via a bioinspired Prins reaction/ether formation cascade cyclization. (3) To mimic the skeletal diversification process. Nature usually synthesizes a multitude of products from a key common intermediate in a divergent manner. Biogenic skeletal diversification to generate various natural products with distinct carbon skeletons has also drawn our attention. Compared with single-target-oriented synthesis, skeletal-diversity-oriented synthesis of natural products remains underexplored due to its high synthetic challenges. We showcased the divergent total syntheses of ten <i>pallavicinia</i> diterpenoids with three distinct skeletons and six <i>grayanane</i> diterpenoids with three distinct skeletons, which were achieved with unprecedented ease and high efficiency by imitation of the proposed biogenic skeletal diversification process. These two successful projects can serve as inspiration for the application of the bioinspired skeletal diversification strategy to other skeletally diverse natural products.</p>\",\"PeriodicalId\":1,\"journal\":{\"name\":\"Accounts of Chemical Research\",\"volume\":\" \",\"pages\":\"3524-3540\"},\"PeriodicalIF\":16.4000,\"publicationDate\":\"2024-12-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Accounts of Chemical Research\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.accounts.4c00654\",\"RegionNum\":1,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/11/27 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Accounts of Chemical Research","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1021/acs.accounts.4c00654","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/11/27 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
摘要
当前,全合成领域面临的前沿挑战是如何提高合成效率并实现多种天然产物的多元合成。生物启发合成已被公认为提高合成效率的有效方法。特别是当生物启发合成应用于后期骨架多样化,生成具有不同碳骨架的各种天然产物时,它特别有望实现这两个目标。在我们实验室,生物启发合成是促进天然产物高效合成的两大长期原则之一。在本报告中,我们总结了我们在生物启发合成天然产物方面的努力和历程。根据对生物合成反应和过程的模仿,我们将我们的工作分为三个部分:(1)模仿关键的环化步骤。受形成核心骨架的生物合成过程的启发,我们开发了新的合成方法,能够快速高效地构建目标分子的核心骨架,最终实现目标分子的简洁全合成,例如,以三个生物启发氧化偶联反应为特征的七步全合成片碱 D 和 H、通过 C-H 活化/氨基ocyclization 级联反应,七步全合成克拉维酸;通过生物启发氧化偶联反应,八步全合成法拉灵;七步全合成 α-环噻唑啉酸;通过吲哚的苄基碳位引发的生物启发级联环化反应,十步全合成斯佩拉定 C。(2)模仿我们提出的修正生物合成途径。在某些情况下,提出的生物合成过程可能存在缺陷,因为它们违背了一些基本的化学原理。因此,必须提出并研究替代的生物合成过程。我们展示了通过生物启发的苯二甲酸型重排全合成 euphorikanin A,以及通过生物启发的普林斯反应/醚形成级联环化全合成双极性内酯 A 和 B。(3) 模仿骨骼多样化过程。自然界通常会从一个关键的共同中间体以发散的方式合成多种产品。生物骨架多样化生成具有不同碳骨架的各种天然产物也引起了我们的关注。与面向单一目标的合成相比,面向骨架多样性的天然产物合成因其高合成挑战性而仍未得到充分探索。我们展示了具有三种不同骨架的十种帕拉维西尼亚二萜和具有三种不同骨架的六种格拉扬烷二萜的分歧全合成,通过模仿所提出的生物骨架多样化过程,以前所未有的简便和高效实现了合成。这两个成功的项目可以为将生物启发的骨架多样化策略应用于其他骨架多样化的天然产品提供灵感。
ConspectusCurrently, the frontier challenges in total synthesis pertain to increasing the synthetic efficiency and enabling the divergent synthesis of a number of natural products. Bioinspired synthesis has been well recognized as an effective approach to increasing synthetic efficiency. Especially, when bioinspired synthesis was applied at late-stage skeletal diversification to generate various natural products with distinct carbon skeletons, it held special promise for achieving both goals. In our laboratory, bioinspired synthesis has served as one of two long-standing principles for facilitating the efficient synthesis of natural products. In this Account, we summarize our endeavors and journeys in the bioinspired synthesis of natural products. We categorize our work into three parts based on the imitation of biosynthetic reactions and processes.(1) To mimic the key cyclization steps. Inspired by the biosynthetic process that formed the core skeleton, we developed new synthetic methods to enable the rapid and efficient construction of the core skeletons of the targeted molecules, ultimately leading to their concise total synthesis, for example, seven-step total synthesis of lamellarins D and H featuring three bioinspired oxidative coupling reactions, seven-step total synthesis of clavicipitic acid highlighted by a C-H activation/aminocyclization cascade reaction, eight-step total synthesis of phalarine via a bioinspired oxidative coupling, seven-step total synthesis of α-cyclopiazonic acid, and ten-step total synthesis of speradine C through a bioinspired cascade cyclization reaction initiated by the benzylic carbocation of indole. (2) To mimic the revised biosynthetic pathway proposed by us. In some cases, the proposed biosynthetic processes may be flawed, as they contradict some basic principles of chemistry. Thus, an alternative biosynthetic process must be proposed and investigated. We showcase the total synthesis of euphorikanin A through a bioinspired benzilic acid-type rearrangement and bipolarolides A and B via a bioinspired Prins reaction/ether formation cascade cyclization. (3) To mimic the skeletal diversification process. Nature usually synthesizes a multitude of products from a key common intermediate in a divergent manner. Biogenic skeletal diversification to generate various natural products with distinct carbon skeletons has also drawn our attention. Compared with single-target-oriented synthesis, skeletal-diversity-oriented synthesis of natural products remains underexplored due to its high synthetic challenges. We showcased the divergent total syntheses of ten pallavicinia diterpenoids with three distinct skeletons and six grayanane diterpenoids with three distinct skeletons, which were achieved with unprecedented ease and high efficiency by imitation of the proposed biogenic skeletal diversification process. These two successful projects can serve as inspiration for the application of the bioinspired skeletal diversification strategy to other skeletally diverse natural products.
期刊介绍:
Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance.
Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.