Mingkai Zhang, Matthew Chapman, Bhagyesh R. Sarode, Bingcong Xiong, Hao Liang, James K. Chen, Eranthie Weerapana, James P. Morken
{"title":"间苯异斯特的催化不对称合成","authors":"Mingkai Zhang, Matthew Chapman, Bhagyesh R. Sarode, Bingcong Xiong, Hao Liang, James K. Chen, Eranthie Weerapana, James P. Morken","doi":"10.1038/s41586-024-07865-4","DOIUrl":null,"url":null,"abstract":"Although aromatic rings are common elements in pharmaceutically active compounds, the presence of these motifs brings several liabilities with respect to the developability of a drug1. Nonoptimal potency, metabolic stability, solubility and lipophilicity in pharmaceutical compounds can be improved by replacing aromatic rings with non-aromatic isosteric motifs2. Moreover, whereas aromatic rings are planar and lack three-dimensionality, the binding pockets of most pharmaceutical targets are chiral. Thus, the stereochemical configuration of the isosteric replacements may offer an added opportunity to improve the affinity of derived ligands for target receptors. A notable impediment to this approach is the lack of simple and scalable catalytic enantioselective syntheses of candidate isosteres from readily available precursors. Here we present a previously unknown palladium-catalysed reaction that converts hydrocarbon-derived precursors to chiral boron-containing nortricyclanes and we show that the shape of these nortricyclanes makes them plausible isosteres for meta disubstituted aromatic rings. With chiral catalysts, the Pd-catalysed reaction can be accomplished in an enantioselective fashion and subsequent transformation of the boron group provides access to a broad array of structures. We also show that the incorporation of nortricyclanes into pharmaceutical motifs can result in improved biophysical properties along with stereochemistry-dependent activity. We anticipate that these features, coupled with the simple, inexpensive synthesis of the functionalized nortricyclane scaffold, will render this platform a useful foundation for the assembly of new biologically active agents. A palladium-catalysed reaction converts hydrocarbon-derived precursors to chiral boron-containing nortricyclanes, and the shape of these nortricyclanes makes them plausible isosteres for meta disubstituted aromatic rings.","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":50.5000,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Catalytic asymmetric synthesis of meta benzene isosteres\",\"authors\":\"Mingkai Zhang, Matthew Chapman, Bhagyesh R. Sarode, Bingcong Xiong, Hao Liang, James K. Chen, Eranthie Weerapana, James P. Morken\",\"doi\":\"10.1038/s41586-024-07865-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Although aromatic rings are common elements in pharmaceutically active compounds, the presence of these motifs brings several liabilities with respect to the developability of a drug1. Nonoptimal potency, metabolic stability, solubility and lipophilicity in pharmaceutical compounds can be improved by replacing aromatic rings with non-aromatic isosteric motifs2. Moreover, whereas aromatic rings are planar and lack three-dimensionality, the binding pockets of most pharmaceutical targets are chiral. Thus, the stereochemical configuration of the isosteric replacements may offer an added opportunity to improve the affinity of derived ligands for target receptors. A notable impediment to this approach is the lack of simple and scalable catalytic enantioselective syntheses of candidate isosteres from readily available precursors. Here we present a previously unknown palladium-catalysed reaction that converts hydrocarbon-derived precursors to chiral boron-containing nortricyclanes and we show that the shape of these nortricyclanes makes them plausible isosteres for meta disubstituted aromatic rings. With chiral catalysts, the Pd-catalysed reaction can be accomplished in an enantioselective fashion and subsequent transformation of the boron group provides access to a broad array of structures. We also show that the incorporation of nortricyclanes into pharmaceutical motifs can result in improved biophysical properties along with stereochemistry-dependent activity. We anticipate that these features, coupled with the simple, inexpensive synthesis of the functionalized nortricyclane scaffold, will render this platform a useful foundation for the assembly of new biologically active agents. A palladium-catalysed reaction converts hydrocarbon-derived precursors to chiral boron-containing nortricyclanes, and the shape of these nortricyclanes makes them plausible isosteres for meta disubstituted aromatic rings.\",\"PeriodicalId\":18787,\"journal\":{\"name\":\"Nature\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":50.5000,\"publicationDate\":\"2024-08-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://www.nature.com/articles/s41586-024-07865-4\",\"RegionNum\":1,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature","FirstCategoryId":"103","ListUrlMain":"https://www.nature.com/articles/s41586-024-07865-4","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
Catalytic asymmetric synthesis of meta benzene isosteres
Although aromatic rings are common elements in pharmaceutically active compounds, the presence of these motifs brings several liabilities with respect to the developability of a drug1. Nonoptimal potency, metabolic stability, solubility and lipophilicity in pharmaceutical compounds can be improved by replacing aromatic rings with non-aromatic isosteric motifs2. Moreover, whereas aromatic rings are planar and lack three-dimensionality, the binding pockets of most pharmaceutical targets are chiral. Thus, the stereochemical configuration of the isosteric replacements may offer an added opportunity to improve the affinity of derived ligands for target receptors. A notable impediment to this approach is the lack of simple and scalable catalytic enantioselective syntheses of candidate isosteres from readily available precursors. Here we present a previously unknown palladium-catalysed reaction that converts hydrocarbon-derived precursors to chiral boron-containing nortricyclanes and we show that the shape of these nortricyclanes makes them plausible isosteres for meta disubstituted aromatic rings. With chiral catalysts, the Pd-catalysed reaction can be accomplished in an enantioselective fashion and subsequent transformation of the boron group provides access to a broad array of structures. We also show that the incorporation of nortricyclanes into pharmaceutical motifs can result in improved biophysical properties along with stereochemistry-dependent activity. We anticipate that these features, coupled with the simple, inexpensive synthesis of the functionalized nortricyclane scaffold, will render this platform a useful foundation for the assembly of new biologically active agents. A palladium-catalysed reaction converts hydrocarbon-derived precursors to chiral boron-containing nortricyclanes, and the shape of these nortricyclanes makes them plausible isosteres for meta disubstituted aromatic rings.
期刊介绍:
Nature is a prestigious international journal that publishes peer-reviewed research in various scientific and technological fields. The selection of articles is based on criteria such as originality, importance, interdisciplinary relevance, timeliness, accessibility, elegance, and surprising conclusions. In addition to showcasing significant scientific advances, Nature delivers rapid, authoritative, insightful news, and interpretation of current and upcoming trends impacting science, scientists, and the broader public. The journal serves a dual purpose: firstly, to promptly share noteworthy scientific advances and foster discussions among scientists, and secondly, to ensure the swift dissemination of scientific results globally, emphasizing their significance for knowledge, culture, and daily life.