Pub Date : 2026-02-11DOI: 10.1038/s44160-026-00990-0
Ze-Xin Zhang, KaiChen Shu, Michael J. Tilby, Mark John P. Mandigma, Yiheng Guo, Jasper L. Tyler, Adam Noble, Varinder K. Aggarwal
Bioisosteric replacement of aromatic and heteroaromatic rings with bridged bicyclic hydrocarbons is an important strategy in drug discovery. Intramolecular [2+2] cycloadditions of unconjugated dienes can provide a route to such motifs but are governed by the ‘rule-of-five’, which dictates that five-membered rings are preferentially formed, limiting access to alternative ring sizes. Here we introduce a visible-light-mediated intramolecular [2 + 2] cycloaddition of aza-1,6-dienes that leverages radical stabilization strategies to enable the selective formation of bridged bicycles over typically favoured fused bicycles. This approach generates previously elusive 6-azabicyclo[3.1.1]heptanes with facile substitution at every position around the ring. Exit vector analysis and comparison of the physicochemical and pharmacological properties of a 6-azabicyclo[3.1.1]heptane analogue of a piperazine-based drug demonstrate the potential application of this scaffold in medicinal chemistry. The methodology enables access to new chemical space, with implications for drug discovery and beyond.
{"title":"Breaking the ‘rule-of-five’ to access bridged bicyclic heteroaromatic bioisosteres","authors":"Ze-Xin Zhang, KaiChen Shu, Michael J. Tilby, Mark John P. Mandigma, Yiheng Guo, Jasper L. Tyler, Adam Noble, Varinder K. Aggarwal","doi":"10.1038/s44160-026-00990-0","DOIUrl":"https://doi.org/10.1038/s44160-026-00990-0","url":null,"abstract":"Bioisosteric replacement of aromatic and heteroaromatic rings with bridged bicyclic hydrocarbons is an important strategy in drug discovery. Intramolecular [2+2] cycloadditions of unconjugated dienes can provide a route to such motifs but are governed by the ‘rule-of-five’, which dictates that five-membered rings are preferentially formed, limiting access to alternative ring sizes. Here we introduce a visible-light-mediated intramolecular [2 + 2] cycloaddition of aza-1,6-dienes that leverages radical stabilization strategies to enable the selective formation of bridged bicycles over typically favoured fused bicycles. This approach generates previously elusive 6-azabicyclo[3.1.1]heptanes with facile substitution at every position around the ring. Exit vector analysis and comparison of the physicochemical and pharmacological properties of a 6-azabicyclo[3.1.1]heptane analogue of a piperazine-based drug demonstrate the potential application of this scaffold in medicinal chemistry. The methodology enables access to new chemical space, with implications for drug discovery and beyond.","PeriodicalId":74251,"journal":{"name":"Nature synthesis","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-02DOI: 10.1038/s44160-025-00964-8
Hau Sun Sam Chan, Yingzi Li, Jack L. Sutro, Daniel S. Brown, Robert S. Paton, Jonathan W. Burton
Despite numerous studies of trialkyloxonium ions in the literature, investigations into the chemistry of allylic, benzylic, propargylic and allenylic oxonium ions are rare. Existing reports on well-characterized allylic and benzylic oxonium ions invariably construct these species based on constrained tricyclic oxatriquinane or oxatriquinacene scaffolds, with only limited studies reported on unconstrained benzylic oxonium ions. Here we report an investigation on a collection of allylic, benzylic and hitherto unknown propargylic and allenylic oxonium ions prepared on unconstrained scaffolds by a general, modular and unified strategy. Permutation of the substitution pattern of these oxonium ions allowed the extension of the strategy for the syntheses of various doubly substituted oxonium ions. Most of these oxonium ions could be characterized at room temperature by NMR spectroscopy, and a series of unexpected reactions and chemical behaviours pertinent to these species are briefly described.
{"title":"Synthesis and properties of allylic, benzylic, propargylic and allenylic oxonium ions","authors":"Hau Sun Sam Chan, Yingzi Li, Jack L. Sutro, Daniel S. Brown, Robert S. Paton, Jonathan W. Burton","doi":"10.1038/s44160-025-00964-8","DOIUrl":"https://doi.org/10.1038/s44160-025-00964-8","url":null,"abstract":"Despite numerous studies of trialkyloxonium ions in the literature, investigations into the chemistry of allylic, benzylic, propargylic and allenylic oxonium ions are rare. Existing reports on well-characterized allylic and benzylic oxonium ions invariably construct these species based on constrained tricyclic oxatriquinane or oxatriquinacene scaffolds, with only limited studies reported on unconstrained benzylic oxonium ions. Here we report an investigation on a collection of allylic, benzylic and hitherto unknown propargylic and allenylic oxonium ions prepared on unconstrained scaffolds by a general, modular and unified strategy. Permutation of the substitution pattern of these oxonium ions allowed the extension of the strategy for the syntheses of various doubly substituted oxonium ions. Most of these oxonium ions could be characterized at room temperature by NMR spectroscopy, and a series of unexpected reactions and chemical behaviours pertinent to these species are briefly described.","PeriodicalId":74251,"journal":{"name":"Nature synthesis","volume":"90 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-02DOI: 10.1038/s44160-025-00987-1
Dong Gao, Long-Zhou Qin, Zhong-Liang Li, Qiang-Shuai Gu, Xin-Yuan Liu
The pervasive occurrence of chiral quaternary all-carbon stereocentres has stimulated great efforts towards the construction of such motifs. Among them, transition-metal-catalysed asymmetric radical C(sp3)–C(sp3) cross-coupling of racemic tertiary alkyl electrophiles with alkyl-based nucleophiles constitutes an appealing strategy, though it has rarely been reported. The major challenge lies in the sluggish interaction of transition-metal–alkyl species and sterically hindered tertiary alkyl radicals, which complicates both chemo- and enantiocontrol. Here we demonstrate a practical copper-catalysed enantioconvergent C(sp3)–C(sp3) cross-coupling of racemic tertiary electrophiles with easily accessed and bench-stable cyclopropanols under mild reaction conditions. Key to success is the rational design of quinine-derived N,N,N-ligands to form coordinatively saturated copper intermediates with low steric congestion around the metal centre to accommodate tertiary alkyl radicals. This protocol provides a highly flexible platform for the rapid synthesis of enantioenriched C(sp3)-rich building blocks with sterically crowded stereocentres that hold substantial interest in organic synthesis and related disciplines.
{"title":"Copper-catalysed enantioconvergent radical C(sp3)–C(sp3) cross-coupling of tertiary electrophiles with cyclopropanols for quaternary carbon formation","authors":"Dong Gao, Long-Zhou Qin, Zhong-Liang Li, Qiang-Shuai Gu, Xin-Yuan Liu","doi":"10.1038/s44160-025-00987-1","DOIUrl":"https://doi.org/10.1038/s44160-025-00987-1","url":null,"abstract":"The pervasive occurrence of chiral quaternary all-carbon stereocentres has stimulated great efforts towards the construction of such motifs. Among them, transition-metal-catalysed asymmetric radical C(sp3)–C(sp3) cross-coupling of racemic tertiary alkyl electrophiles with alkyl-based nucleophiles constitutes an appealing strategy, though it has rarely been reported. The major challenge lies in the sluggish interaction of transition-metal–alkyl species and sterically hindered tertiary alkyl radicals, which complicates both chemo- and enantiocontrol. Here we demonstrate a practical copper-catalysed enantioconvergent C(sp3)–C(sp3) cross-coupling of racemic tertiary electrophiles with easily accessed and bench-stable cyclopropanols under mild reaction conditions. Key to success is the rational design of quinine-derived N,N,N-ligands to form coordinatively saturated copper intermediates with low steric congestion around the metal centre to accommodate tertiary alkyl radicals. This protocol provides a highly flexible platform for the rapid synthesis of enantioenriched C(sp3)-rich building blocks with sterically crowded stereocentres that hold substantial interest in organic synthesis and related disciplines.","PeriodicalId":74251,"journal":{"name":"Nature synthesis","volume":"44 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-02DOI: 10.1038/s44160-026-01002-x
Jet-Sing M. Lee
{"title":"Co-crystallizing stability into perovskite modules","authors":"Jet-Sing M. Lee","doi":"10.1038/s44160-026-01002-x","DOIUrl":"10.1038/s44160-026-01002-x","url":null,"abstract":"","PeriodicalId":74251,"journal":{"name":"Nature synthesis","volume":"5 2","pages":"153-153"},"PeriodicalIF":20.0,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146155305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-30DOI: 10.1038/s44160-025-00982-6
{"title":"Isolation of an isodiazomethyl anion as a nitrene synthon","authors":"","doi":"10.1038/s44160-025-00982-6","DOIUrl":"https://doi.org/10.1038/s44160-025-00982-6","url":null,"abstract":"","PeriodicalId":74251,"journal":{"name":"Nature synthesis","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-30DOI: 10.1038/s44160-025-00979-1
Jing Gong, Qian Wang, Jieping Zhu
In sharp contrast to 1,2-rearrangement, a concerted 1,3-alkyl shift is generally not feasible due to the antiaromatic 4π Hückel transition state and geometric strain. Existing stepwise approaches, which involve radical and organometallic intermediates, often lead to racemization of the migrating atom’s stereocentre and suffer from the highly competitive β-hydride elimination reaction. Theoretically, two consecutive 1,2-shifts could produce the same product as a direct 1,3-migration. Specifically, two scenarios are possible: two successive migrations of the same atom or sequential migrations of two different bonding atoms. Here we report the realization of this strategy by integrating a palladium-catalysed semi-pinacol rearrangement with a 1,2-C/Pd(IV) dyotropic rearrangement. We demonstrate that two distinct 1,3-shift products can be selectively obtained by controlling the conformation of the Pd(II) intermediate, which can in turn be modulated by the metal’s supporting ligand. A key feature of this methodology is that the absolute configuration of the migrating group is retained, an outcome unachievable with existing strategies.
与1,2-重排形成鲜明对比的是，由于反芳香的4π h ckel过渡态和几何应变，一致的1,3-烷基移位通常是不可行的。现有的分步方法，涉及自由基和有机金属中间体，往往导致迁移原子的立体中心外消旋，并遭受高度竞争的β-氢化物消除反应。理论上，两个连续的1,2班次可以产生与直接1,3迁移相同的产品。具体来说，有两种情况是可能的：同一原子的两次连续迁移或两个不同键合原子的连续迁移。在这里，我们通过整合钯催化的半蒎醇重排和1,2- c /Pd（IV）各向异性重排来实现这一策略。我们证明，通过控制Pd（II）中间体的构象，可以选择性地获得两种不同的1,3移位产物，而Pd（II）中间体的构象又可以被金属的支撑配体调节。该方法的一个关键特征是迁移群体的绝对配置被保留，这是现有策略无法实现的结果。
{"title":"Concerted 1,3-migration through regiodivergent consecutive 1,2-rearrangements using palladium catalysis","authors":"Jing Gong, Qian Wang, Jieping Zhu","doi":"10.1038/s44160-025-00979-1","DOIUrl":"https://doi.org/10.1038/s44160-025-00979-1","url":null,"abstract":"In sharp contrast to 1,2-rearrangement, a concerted 1,3-alkyl shift is generally not feasible due to the antiaromatic 4π Hückel transition state and geometric strain. Existing stepwise approaches, which involve radical and organometallic intermediates, often lead to racemization of the migrating atom’s stereocentre and suffer from the highly competitive β-hydride elimination reaction. Theoretically, two consecutive 1,2-shifts could produce the same product as a direct 1,3-migration. Specifically, two scenarios are possible: two successive migrations of the same atom or sequential migrations of two different bonding atoms. Here we report the realization of this strategy by integrating a palladium-catalysed semi-pinacol rearrangement with a 1,2-C/Pd(IV) dyotropic rearrangement. We demonstrate that two distinct 1,3-shift products can be selectively obtained by controlling the conformation of the Pd(II) intermediate, which can in turn be modulated by the metal’s supporting ligand. A key feature of this methodology is that the absolute configuration of the migrating group is retained, an outcome unachievable with existing strategies.","PeriodicalId":74251,"journal":{"name":"Nature synthesis","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-30DOI: 10.1038/s44160-025-00974-6
{"title":"Synthesis of fused pyridines through photothermal cascade activation of arylhydrazines","authors":"","doi":"10.1038/s44160-025-00974-6","DOIUrl":"https://doi.org/10.1038/s44160-025-00974-6","url":null,"abstract":"","PeriodicalId":74251,"journal":{"name":"Nature synthesis","volume":"232 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-30DOI: 10.1038/s44160-025-00976-4
Kun Li, Yin Zeng, Kai-Hang Li, Yifan Yang, Jinhui Shen, Huifeng Guo, Yingfei Tan, Jing-Jing Guo, Anhua Hu
The skeletal remodelling of benzene has been widely acknowledged as an attractive yet challenging approach for utilizing the extensive array of aromatic compounds. A primary challenge lies not only in overcoming the high activation barrier associated with the dearomatization step but also in achieving site-selective skeletal modifications within a single operational sequence. Here we present a photothermal cascade activation mode that unlocks the photoactivation reactivity of the transiently generated light-absorbing intermediate formed during interrupted Fischer indolization. Complementary to arene ring expansion methodologies, this protocol offers a practical ring contraction approach for the modular synthesis of fused pyridines with good functional group tolerance and predictable regioselectivity. This strategy is expected to broaden the chemical landscape for the design of innovative photochemical reactions.
{"title":"Photoinduced benzene ring contraction of arylhydrazines for the synthesis of fused pyridines","authors":"Kun Li, Yin Zeng, Kai-Hang Li, Yifan Yang, Jinhui Shen, Huifeng Guo, Yingfei Tan, Jing-Jing Guo, Anhua Hu","doi":"10.1038/s44160-025-00976-4","DOIUrl":"https://doi.org/10.1038/s44160-025-00976-4","url":null,"abstract":"The skeletal remodelling of benzene has been widely acknowledged as an attractive yet challenging approach for utilizing the extensive array of aromatic compounds. A primary challenge lies not only in overcoming the high activation barrier associated with the dearomatization step but also in achieving site-selective skeletal modifications within a single operational sequence. Here we present a photothermal cascade activation mode that unlocks the photoactivation reactivity of the transiently generated light-absorbing intermediate formed during interrupted Fischer indolization. Complementary to arene ring expansion methodologies, this protocol offers a practical ring contraction approach for the modular synthesis of fused pyridines with good functional group tolerance and predictable regioselectivity. This strategy is expected to broaden the chemical landscape for the design of innovative photochemical reactions.","PeriodicalId":74251,"journal":{"name":"Nature synthesis","volume":"82 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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