Pub Date : 2025-09-23DOI: 10.1016/j.tetlet.2025.155837
Boris A. Trofimov, Kseniya V. Belyaeva
The review covers the advances reached during the last five years in transition metal free functionalization and modification of nitrogen heterocycles with electrophilic acetylenes. The reactions are triggered and further driven by the initially formed 1,3(4)-dipole complexes (zwitterions), adducts of the nucleophilic attack of nitrogen heterocycles at the triple electrophilic carbon‑carbon bond of the acetylenes. The carbanionic sites of these zwitterions are usually captured by electrophiles such as second molecule of the acetylenes or other electrophilic CC and CO unsaturated compounds, as well as various CH, OH, NH, PH acids thereby raising molecular complexity (in the course of diverse cascade transformations) to a new higher level. The rich energy potential of the activated carbon‑carbon triple bond warrants mild reaction conditions and allows the functionalization to be performed without transition metal catalysts.
{"title":"Transition metal free functionalization of nitrogen heterocycles, triggered and driven by electrophilic acetylenes","authors":"Boris A. Trofimov, Kseniya V. Belyaeva","doi":"10.1016/j.tetlet.2025.155837","DOIUrl":"10.1016/j.tetlet.2025.155837","url":null,"abstract":"<div><div>The review covers the advances reached during the last five years in transition metal free functionalization and modification of nitrogen heterocycles with electrophilic acetylenes. The reactions are triggered and further driven by the initially formed 1,3(4)-dipole complexes (zwitterions), adducts of the nucleophilic attack of nitrogen heterocycles at the triple electrophilic carbon‑carbon bond of the acetylenes. The carbanionic sites of these zwitterions are usually captured by electrophiles such as second molecule of the acetylenes or other electrophilic C<img>C and C<img>O unsaturated compounds, as well as various CH<img>, OH<img>, NH<img>, PH<img> acids thereby raising molecular complexity (in the course of diverse cascade transformations) to a new higher level. The rich energy potential of the activated carbon‑carbon triple bond warrants mild reaction conditions and allows the functionalization to be performed without transition metal catalysts.</div></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":"173 ","pages":"Article 155837"},"PeriodicalIF":1.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145218393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The uniqueness of 4-membered ring systems has long been investigated for their potential applications in the field of chemistry and biology. Penicillin is a classic example of such a small ring system. These strained ring systems have opened new avenues in antibacterial drug discovery, though bacteria have gained resistance mechanisms over time. The inherent reactivity observed with these small ring systems as compared to larger ones could be due to the induced strain. The inclusion of heteroatoms like N, S or O, further enhances the reactivity due to increased polarity and electron distribution within the ring. In biology four membered rings constitute the core skeleton of various drug molecules including antibiotics, antivirals and kinases. It also has its role in energy materials and polymer chemistry. In spite of its importance in various fields, the necessity to highlight the scope and limitations of these small molecular ring systems in synthetic organic chemistry and chemical biology exists. Herein, a comprehensive review on the synthesis and potential applications of 4-membered heterocyclic systems - azetidine, thiazetidine and oxazetidine is given. The scope for these unique systems in various fields is also summarized.
{"title":"A comprehensive review of synthetic methods for four-membered strained ring systems: azetidine, thiazetidine and oxazetidine","authors":"Badruzzaman Choudhury , Barnali Maiti , M.M. Balamurali , Kaushik Chanda","doi":"10.1016/j.tetlet.2025.155833","DOIUrl":"10.1016/j.tetlet.2025.155833","url":null,"abstract":"<div><div>The uniqueness of 4-membered ring systems has long been investigated for their potential applications in the field of chemistry and biology. Penicillin is a classic example of such a small ring system. These strained ring systems have opened new avenues in antibacterial drug discovery, though bacteria have gained resistance mechanisms over time. The inherent reactivity observed with these small ring systems as compared to larger ones could be due to the induced strain. The inclusion of heteroatoms like N, S or O, further enhances the reactivity due to increased polarity and electron distribution within the ring. In biology four membered rings constitute the core skeleton of various drug molecules including antibiotics, antivirals and kinases. It also has its role in energy materials and polymer chemistry. In spite of its importance in various fields, the necessity to highlight the scope and limitations of these small molecular ring systems in synthetic organic chemistry and chemical biology exists. Herein, a comprehensive review on the synthesis and potential applications of 4-membered heterocyclic systems - azetidine, thiazetidine and oxazetidine is given. The scope for these unique systems in various fields is also summarized.</div></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":"173 ","pages":"Article 155833"},"PeriodicalIF":1.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145264126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-22DOI: 10.1016/j.tetlet.2025.155836
Yuanrong Shan , Takaki Kanbara , Junpei Kuwabara
The Povarov reaction, a classical [4+2] cycloaddition of imines and unsaturated compounds, provides a versatile synthetic platform for the synthesis of nitrogen-doped π-conjugated molecules. This review highlights the recent advances in the application of the Povarov reaction in the synthesis of aza-polycyclic aromatic hydrocarbons (aza-PAHs), which are important components of emerging organic optical and electronic materials. The modularity, one-pot multicomponent compatibility, and broad catalyst scope of the Povarov reaction afford structurally diverse aza-PAHs. Representative examples spanning small molecules, conjugated polymers, covalent organic frameworks (COFs), and molecular cages are discussed, with particular emphasis on their functional properties, including photoluminescence, sensing, circularly polarized luminescence, hole-blocking, and electron transport properties in organic light-emitting diodes. Mechanistic insights into regioselectivity and π-extension are also reviewed to facilitate the future design of aza-PAHs. The Povarov reaction is a powerful synthetic tool for the development of advanced aza-PAH-based materials for optical and electronic applications.
{"title":"Synthesis of aza-polycyclic aromatic hydrocarbons as organic optoelectronic materials via the Povarov reaction","authors":"Yuanrong Shan , Takaki Kanbara , Junpei Kuwabara","doi":"10.1016/j.tetlet.2025.155836","DOIUrl":"10.1016/j.tetlet.2025.155836","url":null,"abstract":"<div><div>The Povarov reaction, a classical [4+2] cycloaddition of imines and unsaturated compounds, provides a versatile synthetic platform for the synthesis of nitrogen-doped π-conjugated molecules. This review highlights the recent advances in the application of the Povarov reaction in the synthesis of aza-polycyclic aromatic hydrocarbons (aza-PAHs), which are important components of emerging organic optical and electronic materials. The modularity, one-pot multicomponent compatibility, and broad catalyst scope of the Povarov reaction afford structurally diverse aza-PAHs. Representative examples spanning small molecules, conjugated polymers, covalent organic frameworks (COFs), and molecular cages are discussed, with particular emphasis on their functional properties, including photoluminescence, sensing, circularly polarized luminescence, hole-blocking, and electron transport properties in organic light-emitting diodes. Mechanistic insights into regioselectivity and π-extension are also reviewed to facilitate the future design of aza-PAHs. The Povarov reaction is a powerful synthetic tool for the development of advanced aza-PAH-based materials for optical and electronic applications.</div></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":"173 ","pages":"Article 155836"},"PeriodicalIF":1.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145218392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A practical and sustainable protocol for the photocatalytic oxidation of benzylic CH bonds, particularly within polycyclic heteroaromatic (PHA) frameworks, has been developed. In contrast to many previously reported systems, which often rely on long reaction times, narrow-spectrum LEDs, additives, or specialized photoreactors or setups, this method employs inexpensive eosin Y under white LED illumination with molecular oxygen supplied via a balloon. The transformation proceeds under mild conditions without the need for transition metals, hazardous oxidants, or auxiliary additives, and operates via a radical mechanism supported by inhibition studies. The broad substrate tolerance and operational simplicity of this protocol facilitate efficient access to benzylic ketones. Its utility is exemplified in the synthesis of a variety of 6-aryl-8,9-dihydrobenzo[c]phenanthridin-10(7H)-one derivatives, where the substituent at the 6-position plays a critical role in determining product outcome. This method represents one of the few reported examples of late-stage CH functionalization in PHAs under photocatalytic conditions.
{"title":"Visible-Light-Induced Regioselective Benzylic CH Oxidation of Substituted 6-Aryl-7,8,9,10-tetrahydrobenzo[c]phenanthridine","authors":"Mukesh Kumar , Musfika Khatun , Simra Faraz , Satyajit Singh , Abu Taleb Khan","doi":"10.1016/j.tetlet.2025.155828","DOIUrl":"10.1016/j.tetlet.2025.155828","url":null,"abstract":"<div><div>A practical and sustainable protocol for the photocatalytic oxidation of benzylic C<img>H bonds, particularly within polycyclic heteroaromatic (PHA) frameworks, has been developed. In contrast to many previously reported systems, which often rely on long reaction times, narrow-spectrum LEDs, additives, or specialized photoreactors or setups, this method employs inexpensive eosin Y under white LED illumination with molecular oxygen supplied via a balloon. The transformation proceeds under mild conditions without the need for transition metals, hazardous oxidants, or auxiliary additives, and operates via a radical mechanism supported by inhibition studies. The broad substrate tolerance and operational simplicity of this protocol facilitate efficient access to benzylic ketones. Its utility is exemplified in the synthesis of a variety of 6-aryl-8,9-dihydrobenzo[<em>c</em>]phenanthridin-10(7<em>H</em>)-one derivatives, where the substituent at the 6-position plays a critical role in determining product outcome. This method represents one of the few reported examples of late-stage C<img>H functionalization in PHAs under photocatalytic conditions.</div></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":"171 ","pages":"Article 155828"},"PeriodicalIF":1.5,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-20DOI: 10.1016/j.tetlet.2025.155835
Kapil Chahal , Ravikumar Badhavath , K. Velangini Sunidhi Reddy , Kirti Vashishtha , K. Rajender Reddy
This method represents a significant advancement in the synthesis of Benzo[2,7]naphthyridines. The silver-catalyzed cyclization of ortho-alkynyl aldehydes and anthranilic acids proceeds under mild conditions with minimal catalyst loading, providing high yields and excellent regioselectivity. Control experiments and deuteration studies were performed to evaluate the reaction mechanism. The broad substrate scope and scalability make this protocol especially valuable for synthesizing diverse 2,7-naphthyridine derivatives, which are important scaffolds in medicinal chemistry and materials science.
{"title":"Silver-catalyzed regioselective synthesis of benzo[2,7] naphthyridines using ortho-alkynyl quinoline carbaldehyde and anthranilic acid derivatives","authors":"Kapil Chahal , Ravikumar Badhavath , K. Velangini Sunidhi Reddy , Kirti Vashishtha , K. Rajender Reddy","doi":"10.1016/j.tetlet.2025.155835","DOIUrl":"10.1016/j.tetlet.2025.155835","url":null,"abstract":"<div><div>This method represents a significant advancement in the synthesis of Benzo[2,7]naphthyridines. The silver-catalyzed cyclization of <em>ortho</em>-alkynyl aldehydes and anthranilic acids proceeds under mild conditions with minimal catalyst loading, providing high yields and excellent regioselectivity. Control experiments and deuteration studies were performed to evaluate the reaction mechanism. The broad substrate scope and scalability make this protocol especially valuable for synthesizing diverse 2,7-naphthyridine derivatives, which are important scaffolds in medicinal chemistry and materials science.</div></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":"173 ","pages":"Article 155835"},"PeriodicalIF":1.5,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145128258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-20DOI: 10.1016/j.tetlet.2025.155834
Xiu Liu , Hongjun Chen , Chenzhong Jin , Longzhi Zhu , Biquan Xiong
An efficient and atom-economical phosphoric acid-catalyzed amidation of para-quinone methides (p-QMs) with acetonitrile has been developed under mild conditions. Water serves as the sole source of both hydrogen and oxygen atoms, enabling 100 % atom economy in amide bond formation. The reaction exhibits excellent generality across a broad spectrum of electronically and sterically diverse p-QMs, facilitating efficient and highly regioselective synthesis of synthetically valuable N-diarylmethyl-substituted acetamides in good to excellent yields. Step-by-step control experiments and competitive deuterium-labeling KIE studies elucidated the reaction pathway and led to a plausible mechanism based on cumulative experimental evidences.
{"title":"Phosphoric acid-catalyzed regioselective amidation of para-quinone methides with acetonitrile","authors":"Xiu Liu , Hongjun Chen , Chenzhong Jin , Longzhi Zhu , Biquan Xiong","doi":"10.1016/j.tetlet.2025.155834","DOIUrl":"10.1016/j.tetlet.2025.155834","url":null,"abstract":"<div><div>An efficient and atom-economical phosphoric acid-catalyzed amidation of <em>para</em>-quinone methides (<em>p</em>-QMs) with acetonitrile has been developed under mild conditions. Water serves as the sole source of both hydrogen and oxygen atoms, enabling 100 % atom economy in amide bond formation. The reaction exhibits excellent generality across a broad spectrum of electronically and sterically diverse <em>p</em>-QMs, facilitating efficient and highly regioselective synthesis of synthetically valuable <em>N</em>-diarylmethyl-substituted acetamides in good to excellent yields. Step-by-step control experiments and competitive deuterium-labeling KIE studies elucidated the reaction pathway and led to a plausible mechanism based on cumulative experimental evidences.</div></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":"173 ","pages":"Article 155834"},"PeriodicalIF":1.5,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145157569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-18DOI: 10.1016/j.tetlet.2025.155830
Zhihua Chen , Jincheng Zhu , Mengxing Wang , Qinglin Wu , Yichun Xu , Lei Cui , Kewen Zheng
The widespread misuse of antibiotics has accelerated bacterial evolution, precipitating a global antimicrobial resistance (AMR) crisis. Photodynamic therapy (PDT) has recently emerged as a promising alternative due to its non-invasiveness, cost-effectiveness and broad-spectrum antimicrobial activity. Boron-dipyrromethene (BODIPY) derivatives constitute a promising class of organic photosensitizers with experimentally verified photodynamic activity. However, conventional BODIPY-based photosensitizers face significant limitations: their inherent hydrophobicity reduces reactive oxygen species (ROS) generation efficiency, diminishes antimicrobial coverage, and may paradoxically promote resistance development. Furthermore, their exclusive production of Type I PDT, without complementary Type II mechanisms, substantially restricts their therapeutic potential. Herein, a series of photosensitizers (PSs) with antibacterial properties was developed by leveraging electron push-pull systems coupled with heavy-atom effects. In addition to enhance the aqueous solubility of photosensitizers, three types were encapsulated into liposomes via the thin film hydration method. Benefiting from sufficient molecular rotors and high electronegativity of fluorine, the developed BDP-F Lips exhibit superior ROS generation capacity under laser irradiation, concurrently producing both Type I and Type II PDT, thereby demonstrating excellent antibacterial efficacy.
{"title":"Dual-type photodynamic therapy enabled by fluorinated BODIPY-liposome hybrids for enhanced antibacterial efficacy","authors":"Zhihua Chen , Jincheng Zhu , Mengxing Wang , Qinglin Wu , Yichun Xu , Lei Cui , Kewen Zheng","doi":"10.1016/j.tetlet.2025.155830","DOIUrl":"10.1016/j.tetlet.2025.155830","url":null,"abstract":"<div><div>The widespread misuse of antibiotics has accelerated bacterial evolution, precipitating a global antimicrobial resistance (AMR) crisis. Photodynamic therapy (PDT) has recently emerged as a promising alternative due to its non-invasiveness, cost-effectiveness and broad-spectrum antimicrobial activity. Boron-dipyrromethene (BODIPY) derivatives constitute a promising class of organic photosensitizers with experimentally verified photodynamic activity. However, conventional BODIPY-based photosensitizers face significant limitations: their inherent hydrophobicity reduces reactive oxygen species (ROS) generation efficiency, diminishes antimicrobial coverage, and may paradoxically promote resistance development. Furthermore, their exclusive production of Type I PDT, without complementary Type II mechanisms, substantially restricts their therapeutic potential. Herein, a series of photosensitizers (PSs) with antibacterial properties was developed by leveraging electron push-pull systems coupled with heavy-atom effects. In addition to enhance the aqueous solubility of photosensitizers, three types were encapsulated into liposomes via the thin film hydration method. Benefiting from sufficient molecular rotors and high electronegativity of fluorine, the developed BDP-F Lips exhibit superior ROS generation capacity under laser irradiation, concurrently producing both Type I and Type II PDT, thereby demonstrating excellent antibacterial efficacy.</div></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":"173 ","pages":"Article 155830"},"PeriodicalIF":1.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145128257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-18DOI: 10.1016/j.tetlet.2025.155824
T. Ravi Teja , Ch. Ajay , S. Karthik , B. Sridhar , B.V. Subba Reddy
A novel spiroannulation reaction between 4-arylquinazolinones and ynones has been developed to produce highly rigid spiroquinazolinone scaffolds through a [3+2] spirocyclization utilizing a catalytic amount of Ru(II) complex. This innovative strategy generates a broad spectrum of rigid spiro compounds in excellent yields with significant regioselectivity. Importantly, this process involves the CH functionalization of aryl (sp2)H bond followed by a nucleophilic addition of alkenyl ruthenium to imine functionality
{"title":"Ru(II)-catalyzed regioselective [3+2] spiroannulation of 4-arylquinazolin-2(1H)-ones with ynones","authors":"T. Ravi Teja , Ch. Ajay , S. Karthik , B. Sridhar , B.V. Subba Reddy","doi":"10.1016/j.tetlet.2025.155824","DOIUrl":"10.1016/j.tetlet.2025.155824","url":null,"abstract":"<div><div>A novel spiroannulation reaction between 4-arylquinazolinones and ynones has been developed to produce highly rigid spiroquinazolinone scaffolds through a [3+2] spirocyclization utilizing a catalytic amount of Ru(II) complex. This innovative strategy generates a broad spectrum of rigid spiro compounds in excellent yields with significant regioselectivity. Importantly, this process involves the C<img>H functionalization of aryl (sp2)<img>H bond followed by a nucleophilic addition of alkenyl ruthenium to imine functionality</div></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":"171 ","pages":"Article 155824"},"PeriodicalIF":1.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145105146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-18DOI: 10.1016/j.tetlet.2025.155832
Xing Guo , Yang Zhao , Yan Wang, Huiming Ge, Bo Zhang
In this study, we isolated and characterized two polyketides (1 and 2), along with reported depsidone derivative (3) from fermentation broth of the marine fish-derived endophytic fungus Colletotrichum sp. NF02092. The structures of 1 and 2 were deduced on the basis of comprehensive analysis of HRESIMS and NMR spectroscopic data. Both compounds are heterodimers formed by the fusion of the core structure isosulochrin with a xanthan (1) and a depsidone (2), respectively. However, neither 1 nor 2 exhibited significant antimicrobial activity or cytotoxic activities.
{"title":"Isosulochrin xanthone and isosulochrin depsidone heterodimers from the endophytic fungus Colletotrichum sp. NF02092","authors":"Xing Guo , Yang Zhao , Yan Wang, Huiming Ge, Bo Zhang","doi":"10.1016/j.tetlet.2025.155832","DOIUrl":"10.1016/j.tetlet.2025.155832","url":null,"abstract":"<div><div>In this study, we isolated and characterized two polyketides (<strong>1</strong> and <strong>2</strong>), along with reported depsidone derivative (<strong>3</strong>) from fermentation broth of the marine fish-derived endophytic fungus <em>Colletotrichum</em> sp. NF02092. The structures of <strong>1</strong> and <strong>2</strong> were deduced on the basis of comprehensive analysis of HRESIMS and NMR spectroscopic data. Both compounds are heterodimers formed by the fusion of the core structure isosulochrin with a xanthan (<strong>1</strong>) and a depsidone (<strong>2</strong>), respectively. However, neither <strong>1</strong> nor <strong>2</strong> exhibited significant antimicrobial activity or cytotoxic activities.</div></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":"171 ","pages":"Article 155832"},"PeriodicalIF":1.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145105227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-17DOI: 10.1016/j.tetlet.2025.155831
Lijuan Zhai, Lili He, Jingwen Ji, Yuanyu Gao, Jian Sun
Natural products kukoamine D and N1,N5,N14-tris(dihydrocaffeoyl)spermine, two hydrocaffeoylspermine alkaloids predominantly isolated from Solanaceae plants, exhibit diverse pharmacological activities. However, low natural contents and inefficient synthesis methods limit their applications. Commencing with tert-butyloxycarbonyl (Boc)-protected 1,4-butanediamine, we synthesized kukoamine D and N1,N5,N14-tris(dihydrocaffeoyl)spermine via an eight-step sequence, achieving overall yields of 29 % and 20 %, respectively. We used a one-pot two-step, nitrile reductive amination method using a nickel chloride (NiCl2·6H2O)/sodium borohydride (NaBH4) system, followed by active esters amidation. The synthesis is simple, cost effective, and scalable. This approach provides a practical route for the industrial production of structurally similar natural products, facilitating pharmacological studies and analog development.
{"title":"Efficient and improved synthesis of kukoamine D and N1,N5,N14-tris(dihydrocaffeoyl)spermine","authors":"Lijuan Zhai, Lili He, Jingwen Ji, Yuanyu Gao, Jian Sun","doi":"10.1016/j.tetlet.2025.155831","DOIUrl":"10.1016/j.tetlet.2025.155831","url":null,"abstract":"<div><div>Natural products kukoamine D and <em>N</em><sup><em>1</em></sup>,<em>N</em><sup><em>5</em></sup>,<em>N</em><sup><em>14</em></sup>-tris(dihydrocaffeoyl)spermine, two hydrocaffeoylspermine alkaloids predominantly isolated from <em>Solanaceae</em> plants, exhibit diverse pharmacological activities. However, low natural contents and inefficient synthesis methods limit their applications. Commencing with tert-butyloxycarbonyl (Boc)-protected 1,4-butanediamine, we synthesized kukoamine D and <em>N</em><sup><em>1</em></sup>,<em>N</em><sup><em>5</em></sup>,<em>N</em><sup><em>14</em></sup>-tris(dihydrocaffeoyl)spermine via an eight-step sequence, achieving overall yields of 29 % and 20 %, respectively. We used a one-pot two-step, nitrile reductive amination method using a nickel chloride (NiCl<sub>2</sub>·6H<sub>2</sub>O)/sodium borohydride (NaBH<sub>4</sub>) system, followed by active esters amidation. The synthesis is simple, cost effective, and scalable. This approach provides a practical route for the industrial production of structurally similar natural products, facilitating pharmacological studies and analog development.</div></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":"171 ","pages":"Article 155831"},"PeriodicalIF":1.5,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145109542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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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