Advancing Total Synthesis Through Skeletal Editing.

IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Accounts of Chemical Research Pub Date : 2025-05-06 Epub Date: 2025-04-10 DOI:10.1021/acs.accounts.5c00030
Reem Al-Ahmad, Mingji Dai
{"title":"Advancing Total Synthesis Through Skeletal Editing.","authors":"Reem Al-Ahmad, Mingji Dai","doi":"10.1021/acs.accounts.5c00030","DOIUrl":null,"url":null,"abstract":"<p><p>ConspectusTotal synthesis has long been a proving ground for advancing chemical thought, pushing chemists to develop strategies that not only replicate nature's complexity but often surpass it. The pursuit of efficiency, practicality, and elegance continues to challenge and reshape the guiding principles of total synthesis. In recent years, skeletal editing has emerged as a powerful strategy for reconfiguring skeletal frameworks in ways that were previously difficult to imagine. Unlike conventional chemical synthesis approaches, which primarily rely on the logic of bond construction reactions and functional group manipulations, skeletal editing introduces elements that allow for atom insertion, deletion, and exchange and skeletal rearrangement/reorganization by harnessing the potential energy and reactivity of certain structural motifs and morphing them into new electronic and spatial configurations. The logic of modern skeletal editing has been fueling the development of new editing methods and advancing the fields of total synthesis, medicinal chemistry, materials science, and others.In this Account, we detail our program using skeletal editing-based retrosynthetic logic to facilitate natural product synthesis. We first highlight two one-carbon insertion editing strategies utilizing the Ciamician-Dennstedt rearrangement and the Büchner-Curtius-Schlotterbeck ring expansion to streamline the total syntheses of complanadine and phleghenrine <i>Lycopodium</i> alkaloids. We next present our synthesis of crinipellin and gibberellin diterpenes by leveraging the facile synthesis and intrinsic strain of cyclobutanes as precursors to challenging cyclopentanes via cut-and-insert editing (crinipellins) or C-C bond migratory ring expansion (GA<sub>18</sub>). Toward the end, we describe our early efforts in orchestrating structural rearrangement and functional group pairing reactions to access seven monoterpene indole alkaloids and highlight the divergent potential of skeletal editing. Each of the five examples follows a build-edit-decorate workflow, inspired by Schreiber's build-couple-pair in diversity-oriented synthesis. In the build stage, key scaffolds are efficiently assembled from starting materials with matched reactivity. The edit stage morphs these scaffolds to the desired but more challenging ones encoded by the target molecules, reminiscent of Corey's application of rearrangement transforms as a topological strategy. The decorate stage introduces additional functional groups and adjusts oxidation states to complete the total synthesis, similar to the oxidase phase of Baran's two-phase synthesis. The essence of skeletal editing-based retrosynthetic analysis is to identify latent structural relationships between the readily assembled key scaffolds constructed in the build stage and the desired ones encoded by the target molecules as well as proper editing methods to transform the former into the latter with precision. The build-edit-decorate approach parallels the dynamism of biosynthesis, enabling rapid building of complexity with great efficiency and step economy, as analyzed by the spacial scores (SPS) of each case. Drawing on these principles, chemists can adopt skeletal editing-based retrosynthetic logic by identifying latent intermediates and employing and developing strategic editing methods to overcome synthetic bottlenecks.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"58 9","pages":"1392-1406"},"PeriodicalIF":16.4000,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12060283/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Accounts of Chemical Research","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1021/acs.accounts.5c00030","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/4/10 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0

Abstract

ConspectusTotal synthesis has long been a proving ground for advancing chemical thought, pushing chemists to develop strategies that not only replicate nature's complexity but often surpass it. The pursuit of efficiency, practicality, and elegance continues to challenge and reshape the guiding principles of total synthesis. In recent years, skeletal editing has emerged as a powerful strategy for reconfiguring skeletal frameworks in ways that were previously difficult to imagine. Unlike conventional chemical synthesis approaches, which primarily rely on the logic of bond construction reactions and functional group manipulations, skeletal editing introduces elements that allow for atom insertion, deletion, and exchange and skeletal rearrangement/reorganization by harnessing the potential energy and reactivity of certain structural motifs and morphing them into new electronic and spatial configurations. The logic of modern skeletal editing has been fueling the development of new editing methods and advancing the fields of total synthesis, medicinal chemistry, materials science, and others.In this Account, we detail our program using skeletal editing-based retrosynthetic logic to facilitate natural product synthesis. We first highlight two one-carbon insertion editing strategies utilizing the Ciamician-Dennstedt rearrangement and the Büchner-Curtius-Schlotterbeck ring expansion to streamline the total syntheses of complanadine and phleghenrine Lycopodium alkaloids. We next present our synthesis of crinipellin and gibberellin diterpenes by leveraging the facile synthesis and intrinsic strain of cyclobutanes as precursors to challenging cyclopentanes via cut-and-insert editing (crinipellins) or C-C bond migratory ring expansion (GA18). Toward the end, we describe our early efforts in orchestrating structural rearrangement and functional group pairing reactions to access seven monoterpene indole alkaloids and highlight the divergent potential of skeletal editing. Each of the five examples follows a build-edit-decorate workflow, inspired by Schreiber's build-couple-pair in diversity-oriented synthesis. In the build stage, key scaffolds are efficiently assembled from starting materials with matched reactivity. The edit stage morphs these scaffolds to the desired but more challenging ones encoded by the target molecules, reminiscent of Corey's application of rearrangement transforms as a topological strategy. The decorate stage introduces additional functional groups and adjusts oxidation states to complete the total synthesis, similar to the oxidase phase of Baran's two-phase synthesis. The essence of skeletal editing-based retrosynthetic analysis is to identify latent structural relationships between the readily assembled key scaffolds constructed in the build stage and the desired ones encoded by the target molecules as well as proper editing methods to transform the former into the latter with precision. The build-edit-decorate approach parallels the dynamism of biosynthesis, enabling rapid building of complexity with great efficiency and step economy, as analyzed by the spacial scores (SPS) of each case. Drawing on these principles, chemists can adopt skeletal editing-based retrosynthetic logic by identifying latent intermediates and employing and developing strategic editing methods to overcome synthetic bottlenecks.

通过骨骼编辑推进全面合成。
长期以来,连续合成一直是推进化学思想的试验场,促使化学家们开发出不仅复制自然复杂性,而且往往超越自然复杂性的策略。对效率、实用性和优雅的追求不断挑战和重塑全面综合的指导原则。近年来,骨骼编辑已经成为一种强大的策略,以以前难以想象的方式重新配置骨骼框架。传统的化学合成方法主要依赖于键构建反应和官能团操作的逻辑,而骨架编辑通过利用某些结构基序的势能和反应性并将其变形为新的电子和空间构型,引入了允许原子插入、删除和交换以及骨架重排/重组的元素。现代骨骼编辑的逻辑推动了新编辑方法的发展,推动了全合成、药物化学、材料科学等领域的发展。在本帐户中,我们详细介绍了我们的程序使用骨架编辑为基础的反合成逻辑,以促进天然产物的合成。我们首先强调了两种单碳插入编辑策略,利用Ciamician-Dennstedt重排和b chner- curtius - schlotterbeck环扩展来简化顺planadine和phleghenrine石松属生物碱的总合成。接下来,我们利用环丁烷的易合成和固有应变,通过剪切插入编辑(crinipellins)或C-C键迁移环扩展(GA18)作为挑战环戊烷的前体,合成了crinipellins和赤霉素二萜。最后,我们描述了我们在协调结构重排和官能团配对反应以获得七种单萜吲哚生物碱方面的早期努力,并强调了骨骼编辑的不同潜力。五个示例中的每一个都遵循构建-编辑-装饰工作流程,灵感来自Schreiber在面向多样性的合成中的构建-配对。在构建阶段,关键支架由具有匹配反应性的起始材料高效组装。编辑阶段将这些支架变形为目标分子编码的所需但更具挑战性的支架,这让人想起Corey将重排转换作为拓扑策略的应用。修饰阶段引入额外的官能团并调整氧化态以完成全合成,类似于Baran的两相合成的氧化酶阶段。基于骨骼编辑的反合成分析的本质是识别构建阶段构建的易组装关键支架与目标分子编码的所需支架之间的潜在结构关系,以及适当的编辑方法,将前者精确地转化为后者。构建-编辑-装饰方法与生物合成的动态相似,可以通过每种情况的空间分数(SPS)进行分析,以高效率和步骤经济的方式快速构建复杂性。根据这些原则,化学家可以通过识别潜在的中间体,采用和发展战略性的编辑方法来克服合成瓶颈,从而采用基于骨架编辑的反合成逻辑。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Accounts of Chemical Research
Accounts of Chemical Research 化学-化学综合
CiteScore
31.40
自引率
1.10%
发文量
312
审稿时长
2 months
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.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信