A P 4 S 10 ‐promoted [5 + 1] spiroannulation of 2‐(2‐nitrophenyl)‐indoles with cyclic ketones for the preparation of spirocyclic tetrahydrocarbolines has been described. The present approach afforded a series of structurally valuable spirocyclic tetrahydrocarbolines in moderate to good yields under metal‐free conditions. In this work, nitro reduction, C–N condensation, and spiroannulation were realized in one pot.
{"title":"P 4 S 10 ‐Promoted [5+1] Spiroannulation of 2‐(2‐Nitrophenyl)‐indoles with Cyclic Ketones to Access Spirocyclic Tetrahydrocarbolines","authors":"Qi Yin, Bin Tan, Jiao Liu, Xueao Wang, Yuhe Liu, Guo‐Jun Deng, Shanping Chen","doi":"10.1002/adsc.70244","DOIUrl":"https://doi.org/10.1002/adsc.70244","url":null,"abstract":"A P <jats:sub>4</jats:sub> S <jats:sub>10</jats:sub> ‐promoted [5 + 1] spiroannulation of 2‐(2‐nitrophenyl)‐indoles with cyclic ketones for the preparation of spirocyclic tetrahydrocarbolines has been described. The present approach afforded a series of structurally valuable spirocyclic tetrahydrocarbolines in moderate to good yields under metal‐free conditions. In this work, nitro reduction, C–N condensation, and spiroannulation were realized in one pot.","PeriodicalId":118,"journal":{"name":"Advanced Synthesis & Catalysis","volume":"48 4 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145593779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A general, chemoenzymatic one‐pot procedure for the transformation of alcohols or amines to the corresponding alkene products in aqueous media has been reported. The procedure is based on the laccase‐TEMPO‐mediated oxidations of substrates and subsequent Wittig reaction. In this way, a one‐pot sequence of two consecutive reactions has been developed, which has a number of advantages such as (a) no need of purification of the intermediate products, (b) application of water as green solvent and an enzyme‐laccase as natural catalyst, (c) application of molecular oxygen as final green oxidant, and (d) formation of water as a byproduct of the oxidation step.
报道了一种在水介质中将醇或胺转化为相应的烯烃产物的一般化学酶一锅程序。该程序是基于漆酶- TEMPO -介导的底物氧化和随后的Wittig反应。通过这种方式，一个由两个连续反应组成的一锅序列已经被开发出来，它具有许多优点，例如(a)不需要对中间产物进行纯化，(b)使用水作为绿色溶剂和酶-漆酶作为天然催化剂，(c)使用分子氧作为最终绿色氧化剂，以及(d)形成水作为氧化步骤的副产物。
{"title":"Chemoenzymatic Synthesis of Alkenes from Alcohols or Amines by One‐Pot Laccase‐Mediated Oxidations and Wittig Reaction in Water","authors":"Ignacy Janicki, Piotr Kiełbasiński","doi":"10.1002/adsc.70233","DOIUrl":"https://doi.org/10.1002/adsc.70233","url":null,"abstract":"A general, chemoenzymatic one‐pot procedure for the transformation of alcohols or amines to the corresponding alkene products in aqueous media has been reported. The procedure is based on the laccase‐TEMPO‐mediated oxidations of substrates and subsequent Wittig reaction. In this way, a one‐pot sequence of two consecutive reactions has been developed, which has a number of advantages such as (a) no need of purification of the intermediate products, (b) application of water as green solvent and an enzyme‐laccase as natural catalyst, (c) application of molecular oxygen as final green oxidant, and (d) formation of water as a byproduct of the oxidation step.","PeriodicalId":118,"journal":{"name":"Advanced Synthesis & Catalysis","volume":"89 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A mild and green photocatalytic strategy for synthesizing α ‐hydroxy ketones through N‐chlorosuccinimide (NCS)‐assisted decarboxylation of α ‐keto acids, followed by radical coupling and hydrogen atom transfer has been reported. The method operates at room temperature under visible light irradiation without metal catalysts, bases, or oxidants. A wide range of aromatic α ‐keto acids were smoothly converted into the expected products. The feasibility of scale‐up and sunlight‐driven reactions further highlighted its practicality. The ultraviolet–visible absorption spectra experiments ruled out the formation of electron donor–acceptor complexes, and Stern–Volmer experiments demonstrated the facilitative role of NCS in the photoinduced generation of acyl radical.
{"title":"Visible‐Light‐Induced Synthesis of α ‐Hydroxy Ketones From α ‐Keto Acids Under Mild Conditions","authors":"Wen‐Hui Yang, Ying Tong, Chen Li, Ming‐Qi Yang, Jia‐Yao Feng, Dong‐Qing Yang, Xi‐Ni Luo, Guo‐Ping Ge, Jun‐Qi Zhang, Wen‐Ting Wei","doi":"10.1002/adsc.70217","DOIUrl":"https://doi.org/10.1002/adsc.70217","url":null,"abstract":"A mild and green photocatalytic strategy for synthesizing <jats:italic>α</jats:italic> ‐hydroxy ketones through N‐chlorosuccinimide (NCS)‐assisted decarboxylation of <jats:italic>α</jats:italic> ‐keto acids, followed by radical coupling and hydrogen atom transfer has been reported. The method operates at room temperature under visible light irradiation without metal catalysts, bases, or oxidants. A wide range of aromatic <jats:italic>α</jats:italic> ‐keto acids were smoothly converted into the expected products. The feasibility of scale‐up and sunlight‐driven reactions further highlighted its practicality. The ultraviolet–visible absorption spectra experiments ruled out the formation of electron donor–acceptor complexes, and Stern–Volmer experiments demonstrated the facilitative role of NCS in the photoinduced generation of acyl radical.","PeriodicalId":118,"journal":{"name":"Advanced Synthesis & Catalysis","volume":"107 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Peng Guo, Guoliang Pu, Lin‐Yuan Zeng, Man Chen, Pan Wang, Jia Jia, Xuefei Li, Pan–Pan Zhou, Chun‐Yang He
α‐CF 3 ‐substituted alkenes are a class of highly important building blocks. Herein, a new phenol‐based catalytic system is developed that facilitates the elimination of trifluoromethylated alkyl bromides to produce trifluoromethylated alkenes‐a process previously deemed challenging. This method is distinguished by its mild reaction conditions, extensive substrate compatibility, and high chemo‐selectivity and regioselectivity. This facile elimination can be plausibly attributed to phenoxide anion–secondary trifluoromethylated alkyl bromides weak interactions.
{"title":"Phenoxide‐Catalyzed Synthesis of Trifluoromethylated Alkenes from Trifluoromethylated Alkyl Bromides","authors":"Peng Guo, Guoliang Pu, Lin‐Yuan Zeng, Man Chen, Pan Wang, Jia Jia, Xuefei Li, Pan–Pan Zhou, Chun‐Yang He","doi":"10.1002/adsc.70175","DOIUrl":"https://doi.org/10.1002/adsc.70175","url":null,"abstract":"α‐CF <jats:sub>3</jats:sub> ‐substituted alkenes are a class of highly important building blocks. Herein, a new phenol‐based catalytic system is developed that facilitates the elimination of trifluoromethylated alkyl bromides to produce trifluoromethylated alkenes‐a process previously deemed challenging. This method is distinguished by its mild reaction conditions, extensive substrate compatibility, and high chemo‐selectivity and regioselectivity. This facile elimination can be plausibly attributed to phenoxide anion–secondary trifluoromethylated alkyl bromides weak interactions.","PeriodicalId":118,"journal":{"name":"Advanced Synthesis & Catalysis","volume":"223 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yan Cao, Jing Wang, Wei Chen, Jianwei Wang, Linqi Wang, Xiaolong Wang, Jun Ying
A novel palladium‐catalyzed four‐component tandem sulfonylation and carbonylation of 1,6‐enynes has been developed for the rapid construction of succinimide, sulfone, and carbonyl motifs simultaneously. In the presence of very low palladium catalyst loading, the reaction of 1,6‐enynes with nucleophiles proceeded smoothly to afford a wide range of sulfone‐ and carbonyl‐containing succinimide derivatives with high yields and excellent selectivity. Notably, modifications of bioactive molecules were also demonstrated by using this method.
{"title":"Palladium‐Catalyzed Four‐Component Tandem Sulfonylation and Carbonylation of 1,6‐Enynes","authors":"Yan Cao, Jing Wang, Wei Chen, Jianwei Wang, Linqi Wang, Xiaolong Wang, Jun Ying","doi":"10.1002/adsc.70226","DOIUrl":"https://doi.org/10.1002/adsc.70226","url":null,"abstract":"A novel palladium‐catalyzed four‐component tandem sulfonylation and carbonylation of 1,6‐enynes has been developed for the rapid construction of succinimide, sulfone, and carbonyl motifs simultaneously. In the presence of very low palladium catalyst loading, the reaction of 1,6‐enynes with nucleophiles proceeded smoothly to afford a wide range of sulfone‐ and carbonyl‐containing succinimide derivatives with high yields and excellent selectivity. Notably, modifications of bioactive molecules were also demonstrated by using this method.","PeriodicalId":118,"journal":{"name":"Advanced Synthesis & Catalysis","volume":"1 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145567410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The global demand for amino acids continues to rise, yet traditional synthesis methods face environmental and safety challenges. To contribute to a sustainable future vision, we herein report a novel cofactor‐neutral in vitro multienzyme cascade that directly converts methanol, a renewable C1 feedstock, into glycine under mild conditions. A two‐step strategy achieves 82.2% methanol‐to‐glycolaldehyde and 86.0% glycolaldehyde‐to‐glycine conversion, respectively. At 500 mM methanol, it yields 18.8 mM glycine after 6 h, which represents a 26.8‐fold improvement over the one‐pot approach. These results demonstrate the potential of modular in vitro multienzyme catalysis for efficient C1‐to‐amino acid transformation and establish a foundation for the synthesis of many other complex nitrogen‐containing molecules.
全球对氨基酸的需求持续增长，但传统的合成方法面临环境和安全挑战。为了促进可持续的未来愿景，我们在此报道了一种新的辅助因子中性体外多酶级联，可在温和条件下直接将甲醇（一种可再生的C1原料）转化为甘氨酸。两步策略分别实现了82.2%的甲醇制乙醇醛和86.0%的乙醇醛制甘氨酸的转化率。在500 mM的甲醇条件下，6小时后产生18.8 mM的甘氨酸，这比单罐方法提高了26.8倍。这些结果证明了模块化体外多酶催化高效C1 - to -氨基酸转化的潜力，并为许多其他复杂含氮分子的合成奠定了基础。
{"title":"Glycine Synthesis From Methanol by a Cofactor‐Neutral In Vitro Multienzyme Cascade","authors":"Ranran Wu, Fei Li, Kaiyang Lian, Dingyu Liu, Huifeng Jiang, Zhiguang Zhu","doi":"10.1002/adsc.70238","DOIUrl":"https://doi.org/10.1002/adsc.70238","url":null,"abstract":"The global demand for amino acids continues to rise, yet traditional synthesis methods face environmental and safety challenges. To contribute to a sustainable future vision, we herein report a novel cofactor‐neutral in vitro multienzyme cascade that directly converts methanol, a renewable C1 feedstock, into glycine under mild conditions. A two‐step strategy achieves 82.2% methanol‐to‐glycolaldehyde and 86.0% glycolaldehyde‐to‐glycine conversion, respectively. At 500 mM methanol, it yields 18.8 mM glycine after 6 h, which represents a 26.8‐fold improvement over the one‐pot approach. These results demonstrate the potential of modular in vitro multienzyme catalysis for efficient C1‐to‐amino acid transformation and establish a foundation for the synthesis of many other complex nitrogen‐containing molecules.","PeriodicalId":118,"journal":{"name":"Advanced Synthesis & Catalysis","volume":"1 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tehmina Akram, Chuang Niu, Wen‐Jie Qiu, Guan‐Wu Wang
Skeletal editing has been achieved through triflic anhydride‐mediated O‐to‐N swapping reaction of 3,3‐diarylbenzofuranones with benzonitriles/benzyl/alkyl nitriles, successfully affording 3,3‐diarylisoindolinones. A possible reaction mechanism with triflic anhydride serving as a key mediator is proposed to explain this conversion. The present reaction features a broad substrate scope, excellent functional group tolerance and high yields, expanding the structural diversity of isoindolinones.
骨架编辑是通过三酸酐介导的3,3 -二芳基苯并呋喃酮与苯并腈/苄基/烷基腈的O - to - N交换反应实现的，成功地生成3,3 -二芳基异吲哚酮。提出了一种以三酸酐为主要介质的反应机理来解释这种转化。该反应具有底物范围广、官能团耐受性好、产率高等特点，扩大了异吲哚酮的结构多样性。
{"title":"An O‐to‐N Swapping Reaction via Triflic Anhydride‐Mediated Lactamization of 3,3‐Diarylbenzofuranones with Nitriles","authors":"Tehmina Akram, Chuang Niu, Wen‐Jie Qiu, Guan‐Wu Wang","doi":"10.1002/adsc.70230","DOIUrl":"https://doi.org/10.1002/adsc.70230","url":null,"abstract":"Skeletal editing has been achieved through triflic anhydride‐mediated O‐to‐N swapping reaction of 3,3‐diarylbenzofuranones with benzonitriles/benzyl/alkyl nitriles, successfully affording 3,3‐diarylisoindolinones. A possible reaction mechanism with triflic anhydride serving as a key mediator is proposed to explain this conversion. The present reaction features a broad substrate scope, excellent functional group tolerance and high yields, expanding the structural diversity of isoindolinones.","PeriodicalId":118,"journal":{"name":"Advanced Synthesis & Catalysis","volume":"103 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Audrey Gacogne, Julie Aguesseau‐Kondrotas, Samantha Chaise, Jean‐Marc Campagne, Aurélien Lebrun, Young Kee Kang, Muriel Amblard, Baptiste Legrand, Renata Marcia de Figueiredo, Ludovic T. Maillard
The structural optimization of ATC‐based foldamer catalysts for the enantioselective nitro‐Michael addition of ketones to nitroolefins is reported. Building on the previous work with heteroaromatic γ ‐peptides, the influence of the spatial arrangement and flexibility around the catalytic site is investigated. A series of modified sequences are designed to fine‐tune transition state preorganization while revisiting the contribution of an intramolecular proton donor function in ATC catalysts. These modifications lead to enhanced catalytic performance, with faster reaction rates and improved enantioselectivities under optimized conditions.
{"title":"Revisiting the Role of Intramolecular Proton Donation in ATC Foldamer Catalysts for Asymmetric Nitro‐Michael Reactions","authors":"Audrey Gacogne, Julie Aguesseau‐Kondrotas, Samantha Chaise, Jean‐Marc Campagne, Aurélien Lebrun, Young Kee Kang, Muriel Amblard, Baptiste Legrand, Renata Marcia de Figueiredo, Ludovic T. Maillard","doi":"10.1002/adsc.70156","DOIUrl":"https://doi.org/10.1002/adsc.70156","url":null,"abstract":"The structural optimization of ATC‐based foldamer catalysts for the enantioselective nitro‐Michael addition of ketones to nitroolefins is reported. Building on the previous work with heteroaromatic <jats:italic>γ</jats:italic> ‐peptides, the influence of the spatial arrangement and flexibility around the catalytic site is investigated. A series of modified sequences are designed to fine‐tune transition state preorganization while revisiting the contribution of an intramolecular proton donor function in ATC catalysts. These modifications lead to enhanced catalytic performance, with faster reaction rates and improved enantioselectivities under optimized conditions.","PeriodicalId":118,"journal":{"name":"Advanced Synthesis & Catalysis","volume":"41 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This work presents an efficient strategy for the dearomatization of 2,3‐disubstituted indoles to access chiral indole imine‐tetrasubstituted allene skeletons. The transformation is achieved through a chiral phosphoric acid‐catalyzed 1,6‐conjugate addition with alkyne 3‐methylene‐3H‐indoles, generated in situ from α ‐(3‐indolyl) propargylic alcohols. A series of chiral compounds possessing both axial and central chirality were synthesized in good to high yields with high asymmetric induction. Supported by control experiments, a plausible mechanism is proposed to elucidate the reaction pathway.
{"title":"Organocatalytic Enantioselective Dearomatization of 2,3‐Disubstituted Indoles with α ‐(3‐Indolyl)propargylic Alcohols","authors":"Hao Zhang, Zhenhua Song, Xiaohong Liu, Fang Fang, Pengfei Li, Wenjun Li","doi":"10.1002/adsc.70231","DOIUrl":"https://doi.org/10.1002/adsc.70231","url":null,"abstract":"This work presents an efficient strategy for the dearomatization of 2,3‐disubstituted indoles to access chiral indole imine‐tetrasubstituted allene skeletons. The transformation is achieved through a chiral phosphoric acid‐catalyzed 1,6‐conjugate addition with alkyne 3‐methylene‐3H‐indoles, generated in situ from <jats:italic>α</jats:italic> ‐(3‐indolyl) propargylic alcohols. A series of chiral compounds possessing both axial and central chirality were synthesized in good to high yields with high asymmetric induction. Supported by control experiments, a plausible mechanism is proposed to elucidate the reaction pathway.","PeriodicalId":118,"journal":{"name":"Advanced Synthesis & Catalysis","volume":"185 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aimen Al‐Hilfi, E. Alejandro Castellanos Franco, Connor J. Grady, Zinia Mohanta, Michael T. McMahon, Milana Bazayeva, Zhen Li, Kenneth M. Merz, Assaf A. Gilad
Magnetic resonance imaging (MRI) is a cornerstone of modern clinical diagnostics, often enhanced by contrast agents. Traditionally, these agents are chemically synthesized, which can involve complex, costly, and environmentally unfriendly processes. Here, we report a novel biocatalytic approach for the efficient, safe, and eco‐friendly synthesis of 5‐methyl‐5,6‐dihydrothymidine (5‐MDHT), a potent chemical exchange saturation transfer (CEST)‐MRI probe for imaging in vivo expression of the Herpes Simplex Virus Type‐1 Thymidine Kinase (HSV1‐TK) reporter gene. We demonstrate that 5‐MDHT can be biosynthesized via one‐ or two‐step enzymatic reactions using human purine nucleoside phosphorylase (hPNPase) and the SgvM VAV SAM‐dependent methyltransferase. hPNPase catalyzed the base‐exchange reaction with catalytic efficiencies ( kcat/KM ) between 138 and 316 s −1 ·M −1 , while SgvM VAV methylation of 5,6‐dihydrothymidine yielded 5‐MDHT with a catalytic efficiency of 26 s −1 ·M −1 . Molecular dynamics simulations supported the enzymatic binding and selectivity observed experimentally. The resulting 5‐MDHT was validated using CEST‐MRI, showing a distinct exchangeable imino proton signal at 5.3 ppm. These findings highlight the chemo‐ and regioselectivity of the biocatalysts and establish biocatalysis as a viable platform for producing clinically relevant MRI contrast agents.
{"title":"Biocatalytic Construction of a Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Nucleoside Probe: Synthesis and Evaluation of 5‐Methyl‐5,6‐Dihydrothymidine","authors":"Aimen Al‐Hilfi, E. Alejandro Castellanos Franco, Connor J. Grady, Zinia Mohanta, Michael T. McMahon, Milana Bazayeva, Zhen Li, Kenneth M. Merz, Assaf A. Gilad","doi":"10.1002/adsc.70200","DOIUrl":"https://doi.org/10.1002/adsc.70200","url":null,"abstract":"Magnetic resonance imaging (MRI) is a cornerstone of modern clinical diagnostics, often enhanced by contrast agents. Traditionally, these agents are chemically synthesized, which can involve complex, costly, and environmentally unfriendly processes. Here, we report a novel biocatalytic approach for the efficient, safe, and eco‐friendly synthesis of 5‐methyl‐5,6‐dihydrothymidine (5‐MDHT), a potent chemical exchange saturation transfer (CEST)‐MRI probe for imaging in vivo expression of the Herpes Simplex Virus Type‐1 Thymidine Kinase (HSV1‐TK) reporter gene. We demonstrate that 5‐MDHT can be biosynthesized via one‐ or two‐step enzymatic reactions using human purine nucleoside phosphorylase (hPNPase) and the SgvM <jats:sup>VAV</jats:sup> SAM‐dependent methyltransferase. hPNPase catalyzed the base‐exchange reaction with catalytic efficiencies ( <jats:italic>k</jats:italic> <jats:sub>cat</jats:sub> <jats:italic>/K</jats:italic> <jats:sub>M</jats:sub> ) between 138 and 316 s <jats:sup>−1</jats:sup> ·M <jats:sup>−1</jats:sup> , while SgvM <jats:sup>VAV</jats:sup> methylation of 5,6‐dihydrothymidine yielded 5‐MDHT with a catalytic efficiency of 26 s <jats:sup>−1</jats:sup> ·M <jats:sup>−1</jats:sup> . Molecular dynamics simulations supported the enzymatic binding and selectivity observed experimentally. The resulting 5‐MDHT was validated using CEST‐MRI, showing a distinct exchangeable imino proton signal at 5.3 ppm. These findings highlight the chemo‐ and regioselectivity of the biocatalysts and establish biocatalysis as a viable platform for producing clinically relevant MRI contrast agents.","PeriodicalId":118,"journal":{"name":"Advanced Synthesis & Catalysis","volume":"19 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145535937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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