A hexafluoroisopropanol (HFIP)-promoted hydrodifluoroalkylation of furans and vinyl ethers with difluorinated silyl enol ethers has been developed. Because of the inherent electron richer nature of furans and the poor nucleophilicity of difluorinated silyl enol ethers, the employment of simple furans as the substrates for nucleophilic dearomatization without a metal or stoichiometric chemical oxidizing reagent is challenging, especially considering the rearomatization driving force and ring fragmentation of the furan ring system. This protocol exploits the formation of oxocarbenium intermediate from furans using HFIP as a proton source to allow the nucleophilic addition of difluorinated silyl enol ethers, which provides an efficient synthetic strategy to install a gem-difluorinated group into heterocycles.
{"title":"Hexafluoroisopropanol (HFIP)-Promoted Hydrodifluoroalkylation of Furans and Vinyl Ethers Using Difluorinated Silyl Enol Ethers for the Synthesis of gem-Difluorinated Ethers","authors":"Xiaogang Zhou, Jing Zhang, Manman Sun, Hai-Qin Yang, Zhiming Wang, Jianguo Yang, Guo-Bo Huang","doi":"10.1021/acs.joc.4c02420","DOIUrl":"https://doi.org/10.1021/acs.joc.4c02420","url":null,"abstract":"A hexafluoroisopropanol (HFIP)-promoted hydrodifluoroalkylation of furans and vinyl ethers with difluorinated silyl enol ethers has been developed. Because of the inherent electron richer nature of furans and the poor nucleophilicity of difluorinated silyl enol ethers, the employment of simple furans as the substrates for nucleophilic dearomatization without a metal or stoichiometric chemical oxidizing reagent is challenging, especially considering the rearomatization driving force and ring fragmentation of the furan ring system. This protocol exploits the formation of oxocarbenium intermediate from furans using HFIP as a proton source to allow the nucleophilic addition of difluorinated silyl enol ethers, which provides an efficient synthetic strategy to install a <i>gem</i>-difluorinated group into heterocycles.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"236 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435533","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}
Michał Piotrowicz, Natasza Masłowska, Róża Dziewiątkowska, Anna Makal, Bogna Rudolf
The Friedel–Crafts acylation of ferrocene with amino acids carried out under mild conditions (metal-free catalytic system, room temperature, and a short reaction time of 1 h) has been reported. The acylating agent is generated in situ by N-protection of the amino group of the amino acid, followed by formation of mixed anhydride. This one-pot triflic-acid-promoted reaction provides N-trifluoroacetyl-protected amidoketones in good to excellent yields. Moreover, the trifluoroacetyl group can be easily removed or replaced with another protecting group under mild conditions in a one-pot procedure.
{"title":"Synthesis of Trifluoroacetamidoketones by Acylation of Ferrocene with In Situ Protected Amino Acids","authors":"Michał Piotrowicz, Natasza Masłowska, Róża Dziewiątkowska, Anna Makal, Bogna Rudolf","doi":"10.1021/acs.joc.4c02717","DOIUrl":"https://doi.org/10.1021/acs.joc.4c02717","url":null,"abstract":"The Friedel–Crafts acylation of ferrocene with amino acids carried out under mild conditions (metal-free catalytic system, room temperature, and a short reaction time of 1 h) has been reported. The acylating agent is generated in situ by N-protection of the amino group of the amino acid, followed by formation of mixed anhydride. This one-pot triflic-acid-promoted reaction provides <i>N</i>-trifluoroacetyl-protected amidoketones in good to excellent yields. Moreover, the trifluoroacetyl group can be easily removed or replaced with another protecting group under mild conditions in a one-pot procedure.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"88 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435536","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}
Márton Zwillinger, Petra Sőregi, Florian Sanchez, Céline Douat, Márton Csékei, Ivan Huc, András Kotschy
Aromatic oligoamides, with their intrinsic rigidity and well-defined conformations, are recognized for their potential in medical applications. Similar structures are present in several naturally occurring antibiotics and have been explored for their ability to bind to various proteins and B-DNA (canonical right-handed DNA helix). This study introduces a synthetic approach to produce quinoline amino acid monomers bearing diversified side chain combinations in positions 4, 5, and 6 of the quinoline ring, designed to enhance the side chain density on helical foldamers. By increasing the number of side chains on each monomer, we aim to mimic the dense side chain presentation of α-peptides, thus improving the potential for protein surface recognition. This synthetic strategy involves efficient functionalization through cross-coupling reactions, enabling the installation of diverse side chains at strategic positions on the quinoline ring. The process has been optimized for automated solid-phase synthesis, successfully producing a 20-unit oligoamide with good purity. This foldamer, featuring multiple cationic, anionic, polar, and hydrophobic side chains, demonstrates the potential for molecular recognition in drug discovery and therapeutic applications. The methodology described here represents a significant advancement in the construction of aromatic oligoamide foldamers, providing a robust platform for further exploration of biological systems.
{"title":"Development of Aromatic Foldamer Building Blocks Bearing Multiple Biogenic Side Chains","authors":"Márton Zwillinger, Petra Sőregi, Florian Sanchez, Céline Douat, Márton Csékei, Ivan Huc, András Kotschy","doi":"10.1021/acs.joc.4c02900","DOIUrl":"https://doi.org/10.1021/acs.joc.4c02900","url":null,"abstract":"Aromatic oligoamides, with their intrinsic rigidity and well-defined conformations, are recognized for their potential in medical applications. Similar structures are present in several naturally occurring antibiotics and have been explored for their ability to bind to various proteins and B-DNA (canonical right-handed DNA helix). This study introduces a synthetic approach to produce quinoline amino acid monomers bearing diversified side chain combinations in positions 4, 5, and 6 of the quinoline ring, designed to enhance the side chain density on helical foldamers. By increasing the number of side chains on each monomer, we aim to mimic the dense side chain presentation of α-peptides, thus improving the potential for protein surface recognition. This synthetic strategy involves efficient functionalization through cross-coupling reactions, enabling the installation of diverse side chains at strategic positions on the quinoline ring. The process has been optimized for automated solid-phase synthesis, successfully producing a 20-unit oligoamide with good purity. This foldamer, featuring multiple cationic, anionic, polar, and hydrophobic side chains, demonstrates the potential for molecular recognition in drug discovery and therapeutic applications. The methodology described here represents a significant advancement in the construction of aromatic oligoamide foldamers, providing a robust platform for further exploration of biological systems.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"13 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435534","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}
Moe Nakano, Kazuma Hiasa, Satoko Sato-Shimizu, Hajime Sato
Triterpenes represent a crucial class of natural compounds with diverse biological activities and structural complexity. Among the various skeletal modifications in triterpene biosynthesis, the formation of seven-membered rings through ring expansion reactions significantly contributes to their structural diversity and, consequently, their functional versatility. This study elucidates the detailed reaction mechanism of a key seven-membered ring formation via cyclopropane rearrangement in the biosynthesis of ilelic acid. Using density functional theory (DFT) calculations, we thoroughly investigated the biosynthetic pathway of ilelic acid, focusing on the critical ring expansion step. Our computational analysis reveals that the seven-membered ring formation proceeds through a cationic mechanism rather than a radical-mediated process. Notably, we found that the inherent instability of the secondary carbocation intermediate drives a concerted reaction pathway, avoiding the formation of high-energy intermediates. This mechanistic understanding not only sheds light on the biosynthesis of ilelic acid but also offers broader implications for comprehending similar transformations in other triterpene biosynthetic pathways. Our findings contribute to the fundamental understanding of triterpene skeletal diversity and pave the way for potential biomimetic approaches in the synthesis of complex seven-membered ring-containing terpenes. Furthermore, this work underscores the power of computational methods in unraveling intricate biosynthetic mechanisms.
{"title":"Seven-Membered Ring Formation in Triterpene Biosynthesis: A Key Cyclopropane Rearrangement in Ilelic Acid Biosynthesis","authors":"Moe Nakano, Kazuma Hiasa, Satoko Sato-Shimizu, Hajime Sato","doi":"10.1021/acs.joc.4c02541","DOIUrl":"https://doi.org/10.1021/acs.joc.4c02541","url":null,"abstract":"Triterpenes represent a crucial class of natural compounds with diverse biological activities and structural complexity. Among the various skeletal modifications in triterpene biosynthesis, the formation of seven-membered rings through ring expansion reactions significantly contributes to their structural diversity and, consequently, their functional versatility. This study elucidates the detailed reaction mechanism of a key seven-membered ring formation via cyclopropane rearrangement in the biosynthesis of ilelic acid. Using density functional theory (DFT) calculations, we thoroughly investigated the biosynthetic pathway of ilelic acid, focusing on the critical ring expansion step. Our computational analysis reveals that the seven-membered ring formation proceeds through a cationic mechanism rather than a radical-mediated process. Notably, we found that the inherent instability of the secondary carbocation intermediate drives a concerted reaction pathway, avoiding the formation of high-energy intermediates. This mechanistic understanding not only sheds light on the biosynthesis of ilelic acid but also offers broader implications for comprehending similar transformations in other triterpene biosynthetic pathways. Our findings contribute to the fundamental understanding of triterpene skeletal diversity and pave the way for potential biomimetic approaches in the synthesis of complex seven-membered ring-containing terpenes. Furthermore, this work underscores the power of computational methods in unraveling intricate biosynthetic mechanisms.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"12 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427365","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}
Wenjun Zhou, Liyuan Le, Youwen Chen, Wuxing Xie, Yi Chen, Shuang-Feng Yin, Renhua Qiu
This paper presents a novel NHC-BH3-promoted one-step synthesis of disulfides and stibine sulfides using odorless sulfonyl hydrazides. The protocol tolerates various functional groups as well as heterocyclic compounds. Mechanistic studies show that NHC-BH3 plays two roles: (1) reducing sulfonyl hydrazides into disulfides and (2) promoting the cross-coupling of chlorostibine with the disulfides. The synthesized stibine sulfides also exhibit satisfactory anticancer activity against 4T1 and MDA-MB-231 cancerous cells.
{"title":"NHC-BH3-Mediated Reduction of Sulfonyl Hydrazides into Disulfides and Further Cross-Coupling with Chlorostibine and Bioactivities","authors":"Wenjun Zhou, Liyuan Le, Youwen Chen, Wuxing Xie, Yi Chen, Shuang-Feng Yin, Renhua Qiu","doi":"10.1021/acs.joc.4c02638","DOIUrl":"https://doi.org/10.1021/acs.joc.4c02638","url":null,"abstract":"This paper presents a novel NHC-BH<sub>3</sub>-promoted one-step synthesis of disulfides and stibine sulfides using odorless sulfonyl hydrazides. The protocol tolerates various functional groups as well as heterocyclic compounds. Mechanistic studies show that NHC-BH<sub>3</sub> plays two roles: (1) reducing sulfonyl hydrazides into disulfides and (2) promoting the cross-coupling of chlorostibine with the disulfides. The synthesized stibine sulfides also exhibit satisfactory anticancer activity against 4T1 and MDA-MB-231 cancerous cells.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"19 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435535","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}
We herein describe the nickel-catalyzed C2–H alkylation of benzothiazoles with unactivated α-olefins by using the Ni(IPr*OMe)[P(OEt)3]Br2/Mg catalytic system in which a variety of linear alkylated benzothiazoles with high regioselectivity were formed under mild reaction conditions. This transformation showed good compatibility to unactivated α-olefins bearing various functional groups, such as esters, acetals, silyl ethers, amines, silanes, and boronate esters. Furthermore, this transformation is also suitable to other typical N-heteroarenes including thiazoles, benzimidazoles, quinazolones, uracils, pyridines, caffeines, and indoles. Thus, this work provides rapid access to diverse linear alkylated N-heteroarenes with good step and atom economy.
{"title":"Nickel-Catalyzed Linear-Selective C–H Alkylation of N-Heteroarenes with Unactivated α-Olefins","authors":"Yang Liu, Wen-Hui Jin, Rui-Peng Li, Hong-Mei Sun","doi":"10.1021/acs.joc.4c02939","DOIUrl":"https://doi.org/10.1021/acs.joc.4c02939","url":null,"abstract":"We herein describe the nickel-catalyzed C2–H alkylation of benzothiazoles with unactivated α-olefins by using the Ni(IPr<sup>*OMe</sup>)[P(OEt)<sub>3</sub>]Br<sub>2</sub>/Mg catalytic system in which a variety of linear alkylated benzothiazoles with high regioselectivity were formed under mild reaction conditions. This transformation showed good compatibility to unactivated α-olefins bearing various functional groups, such as esters, acetals, silyl ethers, amines, silanes, and boronate esters. Furthermore, this transformation is also suitable to other typical <i>N</i>-heteroarenes including thiazoles, benzimidazoles, quinazolones, uracils, pyridines, caffeines, and indoles. Thus, this work provides rapid access to diverse linear alkylated <i>N</i>-heteroarenes with good step and atom economy.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"85 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427283","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}
Bjarne Silkenath, Dennis Kläge, Philip Eppelin, Jörg S. Hartig, Valentin Wittmann
Carba-sugars─carbohydrate mimics in which the ring oxygen is replaced by a methylene group─are carbohydrate analogues of natural or synthetic origin that can have important biological functions. Especially, carba-aminosugars and glycosides containing carba-aminosugars are potent antibiotics. Furthermore, they have been shown to induce the self-cleavage reaction of the glmS riboswitch and thereby inhibit the ability of bacteria to synthesize glucosamine-6-phosphate, which is required to build up the bacterial cell wall. We report the synthesis of a library of 20 carba-glucosamine derivatives with various substituents at the carba-position including amines, alkyl, alkoxy, and aryloxy derivatives, fluorine derivatives, glycosylated derivatives, and a cyclopropane derivative. The compounds were obtained in an efficient way starting from late-stage synthetic intermediates of an earlier-developed synthesis of carba-substituted carba-glucosamines. All carba-glucosamine mimics were tested for their antibacterial properties against Bacillus subtilis, and some of them displayed promising activities in a filter disk assay.
{"title":"Diverse Library of 5a-Substituted Carba-Glucosamines","authors":"Bjarne Silkenath, Dennis Kläge, Philip Eppelin, Jörg S. Hartig, Valentin Wittmann","doi":"10.1021/acs.joc.4c02816","DOIUrl":"https://doi.org/10.1021/acs.joc.4c02816","url":null,"abstract":"Carba-sugars─carbohydrate mimics in which the ring oxygen is replaced by a methylene group─are carbohydrate analogues of natural or synthetic origin that can have important biological functions. Especially, carba-aminosugars and glycosides containing carba-aminosugars are potent antibiotics. Furthermore, they have been shown to induce the self-cleavage reaction of the <i>glmS</i> riboswitch and thereby inhibit the ability of bacteria to synthesize glucosamine-6-phosphate, which is required to build up the bacterial cell wall. We report the synthesis of a library of 20 carba-glucosamine derivatives with various substituents at the carba-position including amines, alkyl, alkoxy, and aryloxy derivatives, fluorine derivatives, glycosylated derivatives, and a cyclopropane derivative. The compounds were obtained in an efficient way starting from late-stage synthetic intermediates of an earlier-developed synthesis of carba-substituted carba-glucosamines. All carba-glucosamine mimics were tested for their antibacterial properties against <i>Bacillus subtilis</i>, and some of them displayed promising activities in a filter disk assay.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"21 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418403","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}
Pub Date : 2025-02-14Epub Date: 2025-01-30DOI: 10.1021/acs.joc.4c02393
Ting Zhao, Xuecai Tan, Ping Tang, Lin Xie, Yaowen Qin, Haiyue Cai, Huishan Zhao, Qin Huang, Sasa Wang
A regioselective [3 + 2] annulation of β,γ-alkynyl-α-ketimino esters with 1,3-dicarbonyls is disclosed. A series of Z-selective dihydrofurans bearing an exocyclic double bond and a quaternary carbon center are accessed without the usage of base. Control and deuterium-labeling experiments have been investigated to probe into the reaction mechanism. The catalyst and base-free nucleophilic addition highlights the transformation.
{"title":"Regioselective [3 + 2] Annulation of β,γ-Alkynyl-α-ketimino Esters with 1,3-Dicarbonyls: The Synthesis of Highly Functionalized Dihydrofurans.","authors":"Ting Zhao, Xuecai Tan, Ping Tang, Lin Xie, Yaowen Qin, Haiyue Cai, Huishan Zhao, Qin Huang, Sasa Wang","doi":"10.1021/acs.joc.4c02393","DOIUrl":"10.1021/acs.joc.4c02393","url":null,"abstract":"<p><p>A regioselective [3 + 2] annulation of β,γ-alkynyl-α-ketimino esters with 1,3-dicarbonyls is disclosed. A series of <i>Z</i>-selective dihydrofurans bearing an exocyclic double bond and a quaternary carbon center are accessed without the usage of base. Control and deuterium-labeling experiments have been investigated to probe into the reaction mechanism. The catalyst and base-free nucleophilic addition highlights the transformation.</p>","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":" ","pages":"2163-2171"},"PeriodicalIF":3.3,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062462","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 TBN-enabled tandem C-H bond oxidation/C-N bond cleavage/[3+2] cycloaddition of 1-nitromethyltetrahydroisoquinolines was realized, constructing a series of multifunctionalized isoxazole and isoxazoline skeletons in the presence of alkynes and alkenes, respectively. Various functional groups were smoothly tolerated, and the mechanistic study revealed that the construction of isoxazole and isoxazoline rings is mediated by the in situ generated nitrile oxides.
{"title":"<i>tert</i>-Butyl Nitrite (TBN)-Enabled Tandem C-H Bond Oxidation/C-N Bond Cleavage/[3+2] Cycloaddition of 1-Nitromethyltetrahydroisoquinoline Derivatives: Construction of Multifunctionalized Isoxazole and Isoxazoline Skeletons.","authors":"Yuhao Zhu, Jie Mao, Qiyuan Ma, Shuwei Zhang, Yu Yuan, Xiaodong Jia","doi":"10.1021/acs.joc.4c03048","DOIUrl":"10.1021/acs.joc.4c03048","url":null,"abstract":"<p><p>A TBN-enabled tandem C-H bond oxidation/C-N bond cleavage/[3+2] cycloaddition of 1-nitromethyltetrahydroisoquinolines was realized, constructing a series of multifunctionalized isoxazole and isoxazoline skeletons in the presence of alkynes and alkenes, respectively. Various functional groups were smoothly tolerated, and the mechanistic study revealed that the construction of isoxazole and isoxazoline rings is mediated by the in situ generated nitrile oxides.</p>","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":" ","pages":"2459-2471"},"PeriodicalIF":3.3,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070830","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}
Pub Date : 2025-02-14Epub Date: 2025-01-31DOI: 10.1021/acs.joc.4c02453
Yu Wang, Xin Zhang, Jia Zhou, Lijuan Song
The reaction mechanism and the enantioselectivity of the Brønsted acid/base (trans-stilbene diamine, simplified by BAM)-catalyzed CO2 fixation with homoallylic amine have been investigated using density functional theory (DFT) calculations. The proposed mechanism involves the initial activation of the amine by the Brønsted acid, followed by the nucleophilic attack of the amine on CO2 to form a carbamate intermediate. The Brønsted base subsequently deprotonates the carbamate intermediate to form the cyclic carbamate product, regenerating the Brønsted acid catalyst. The C-O cyclization is the enantio-determining step. The hydrogen bond network formed by the catalyst and substrate, similar to an enzyme pocket, plays a key role in stereoselectivity. In addition, the energy decomposition analysis (EDA) confirms that hydrogen bonding is driven by orbital and electrostatic attractions. The more Brønsted basic BAM catalyst (OMe at the quinoline 7-position) exhibits enhanced enantioselectivity.
利用密度泛函理论(DFT)计算研究了布氏酸/碱(反式二苯乙烯二胺,简写为 BAM)催化二氧化碳与均质烯丙基胺固定的反应机理和对映体选择性。提出的机理包括布氏酸对胺的初始活化,然后胺对 CO2 的亲核攻击形成氨基甲酸酯中间体。布氏碱随后对氨基甲酸酯中间体进行去质子化,形成环状氨基甲酸酯产物,从而再生布氏酸催化剂。C-O 环化是决定对映体的步骤。催化剂和底物形成的氢键网络类似于酶袋,对立体选择性起着关键作用。此外,能量分解分析(EDA)证实,氢键是由轨道和静电吸引驱动的。更具布氏碱性的 BAM 催化剂(喹啉 7 位上的 OMe)表现出更高的对映选择性。
{"title":"A Theoretical Study on the Mechanism of Bifunctional Brønsted Acid/Base-Catalyzed CO<sub>2</sub>-Fixation Reaction with Homoallylic Amine.","authors":"Yu Wang, Xin Zhang, Jia Zhou, Lijuan Song","doi":"10.1021/acs.joc.4c02453","DOIUrl":"10.1021/acs.joc.4c02453","url":null,"abstract":"<p><p>The reaction mechanism and the enantioselectivity of the Brønsted acid/base (<i>trans</i>-stilbene diamine, simplified by BAM)-catalyzed CO<sub>2</sub> fixation with homoallylic amine have been investigated using density functional theory (DFT) calculations. The proposed mechanism involves the initial activation of the amine by the Brønsted acid, followed by the nucleophilic attack of the amine on CO<sub>2</sub> to form a carbamate intermediate. The Brønsted base subsequently deprotonates the carbamate intermediate to form the cyclic carbamate product, regenerating the Brønsted acid catalyst. The C-O cyclization is the enantio-determining step. The hydrogen bond network formed by the catalyst and substrate, similar to an enzyme pocket, plays a key role in stereoselectivity. In addition, the energy decomposition analysis (EDA) confirms that hydrogen bonding is driven by orbital and electrostatic attractions. The more Brønsted basic BAM catalyst (OMe at the quinoline 7-position) exhibits enhanced enantioselectivity.</p>","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":" ","pages":"2172-2179"},"PeriodicalIF":3.3,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070833","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}