Pub Date : 2024-07-05Epub Date: 2024-06-20DOI: 10.1021/acs.orglett.4c01750
Hui Lyu, Lukas Ernst, Yoko Nakamura, Yu Okamura, Tobias G Köllner, Katrin Luck, Benye Liu, Yu Chen, Ludger Beerhues, Jonathan Gershenzon, Christian Paetz
Here, we use transcriptomic data from seeds of Musella lasiocarpa to identify five enzymes involved in the formation of dihydrocurcuminoids. Characterization of the substrate specificities of the enzymes reveals two distinct dihydrocurcuminoid pathways leading to phenylphenalenones and linear diarylheptanoid derivatives, the major seed metabolites. Furthermore, we demonstrate the stepwise conversion of dihydrobisdemethoxycurcumin to the phenylphenalenone 4'-hydroxylachnanthocarpone by feeding intermediates to M. lasiocarpa root protein extract.
在本文中,我们利用麝香草(Musella lasiocarpa)种子的转录组数据,确定了参与形成二氢姜黄素的五种酶。对这些酶的底物特异性进行的表征揭示了两种不同的二氢卷烟素途径,它们导致了主要的种子代谢产物--苯基苯丙烯酮和线性二芳基庚烷衍生物。此外,我们还证明了通过将中间产物喂入 M. lasiocarpa 根蛋白提取物,二氢双去甲氧基姜黄素可以逐步转化为 4'-hydroxylachnanthocarpone 苯基菲烯酮。
{"title":"Phenylphenalenones and Linear Diarylheptanoid Derivatives Are Biosynthesized via Parallel Routes in <i>Musella lasiocarpa</i>, the Chinese Dwarf Banana.","authors":"Hui Lyu, Lukas Ernst, Yoko Nakamura, Yu Okamura, Tobias G Köllner, Katrin Luck, Benye Liu, Yu Chen, Ludger Beerhues, Jonathan Gershenzon, Christian Paetz","doi":"10.1021/acs.orglett.4c01750","DOIUrl":"10.1021/acs.orglett.4c01750","url":null,"abstract":"<p><p>Here, we use transcriptomic data from seeds of <i>Musella lasiocarpa</i> to identify five enzymes involved in the formation of dihydrocurcuminoids. Characterization of the substrate specificities of the enzymes reveals two distinct dihydrocurcuminoid pathways leading to phenylphenalenones and linear diarylheptanoid derivatives, the major seed metabolites. Furthermore, we demonstrate the stepwise conversion of dihydrobisdemethoxycurcumin to the phenylphenalenone 4'-hydroxylachnanthocarpone by feeding intermediates to <i>M. lasiocarpa</i> root protein extract.</p>","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-05Epub Date: 2024-06-20DOI: 10.1021/acs.joc.4c00399
Yugandhar Kothapalli, Chung K Chu, Uma S Singh
β-l-5-((E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) uracil (l-BHDU, 17) is a potent and selective inhibitor of the varicella-zoster virus (VZV). l-BHDU (17) has demonstrated excellent anti-VZV activity and is a preclinical candidate to treat chickenpox, shingles (herpes zoster), and herpes simplex virus 1 (HSV-1) infections. Its monophosphate prodrug (POM-l-BHDU-MP, 24) demonstrated an enhanced pharmacokinetic and antiviral profile. POM-l-BHDU-MP (24), in vivo, effectively reduced the VZV viral load and was effective for the topical treatment of VZV and HSV-1 infections. Therefore, a viable synthetic procedure for developing POM-l-BHDU-MP (24) is needed. In this article, an efficient approach for the synthesis of l-BHDU (17) from a readily available starting material is described in 7 steps. An efficient and practical methodology for both chiral pure l- & d-dioxolane 11 and 13 were developed via diastereomeric chiral amine salt formation. Neutralization of the amine carboxylate salt of l-dioxolane 10 provides enantiomerically pure l-dioxane 11 (ee ≥ 99%). Optically pure 11 was utilized to construct the final nucleoside l-BHDU (17) and its monophosphate ester prodrug (POM-l-BHDU-MP, 24). Notably, the reported process eliminates expensive chiral chromatography for the synthesis of chiral pure l- & d-dioxolane, which offers avenues for the development and structure-activity relationship studies of l- & d-dioxolane-derived nucleosides.
{"title":"Enantioselective Synthesis of β-l-5-[(<i>E</i>)-2-Bromovinyl)-1-((2<i>S</i>,4<i>S</i>)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) Uracil)] (l-BHDU) <i>via</i> Chiral Pure l-Dioxolane.","authors":"Yugandhar Kothapalli, Chung K Chu, Uma S Singh","doi":"10.1021/acs.joc.4c00399","DOIUrl":"10.1021/acs.joc.4c00399","url":null,"abstract":"<p><p>β-l-5-((<i>E</i>)-2-Bromovinyl)-1-((2<i>S</i>,4<i>S</i>)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) uracil (l-BHDU, <b>17</b>) is a potent and selective inhibitor of the varicella-zoster virus (VZV). l-BHDU (<b>17</b>) has demonstrated excellent <i>anti</i>-VZV activity and is a preclinical candidate to treat chickenpox, shingles (herpes zoster), and herpes simplex virus 1 (HSV-1) infections. Its monophosphate prodrug (POM-l-BHDU-MP, <b>24</b>) demonstrated an enhanced pharmacokinetic and antiviral profile. POM-l-BHDU-MP (<b>24</b>), <i>in vivo</i>, effectively reduced the VZV viral load and was effective for the topical treatment of VZV and HSV-1 infections. Therefore, a viable synthetic procedure for developing POM-l-BHDU-MP (<b>24</b>) is needed. In this article, an efficient approach for the synthesis of l-BHDU (<b>17</b>) from a readily available starting material is described in 7 steps. An efficient and practical methodology for both chiral pure l- & d-dioxolane <b>11</b> and <b>13</b> were developed <i>via</i> diastereomeric chiral amine salt formation. Neutralization of the amine carboxylate salt of l-dioxolane <b>10</b> provides enantiomerically pure l-dioxane <b>11</b> (ee ≥ 99%). Optically pure <b>11</b> was utilized to construct the final nucleoside l-BHDU (<b>17</b>) and its monophosphate ester prodrug (POM-l-BHDU-MP, <b>24</b>). Notably, the reported process eliminates expensive chiral chromatography for the synthesis of chiral pure l- & d-dioxolane, which offers avenues for the development and structure-activity relationship studies of l- & d-dioxolane-derived nucleosides.</p>","PeriodicalId":57,"journal":{"name":"The Journal of Organic Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430954","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 : 2024-07-05Epub Date: 2024-06-21DOI: 10.1021/acs.orglett.4c01924
Charles P Mikan, Joseph O Watson, Ryan Walton, Paul G Waddell, Jonathan P Knowles
Sequential oxidative cleavage and double-Mannich reactions enable the stereoselective conversion of simple norbornenes into complex alkaloid-like structures. The products undergo a wide range of derivatization reactions, including regioselective enol triflate formation/cross-coupling sequences and highly efficient conversion to an unusual tricyclic 8,5,5-fused lactam. Overall, the process represents a formal one-atom aza-ring expansion with concomitant bridging annulation, making it of interest for the broader derivatization of alkene feedstocks.
{"title":"Stereoselective Access to Diverse Alkaloid-Like Scaffolds via an Oxidation/Double-Mannich Reaction Sequence.","authors":"Charles P Mikan, Joseph O Watson, Ryan Walton, Paul G Waddell, Jonathan P Knowles","doi":"10.1021/acs.orglett.4c01924","DOIUrl":"10.1021/acs.orglett.4c01924","url":null,"abstract":"<p><p>Sequential oxidative cleavage and double-Mannich reactions enable the stereoselective conversion of simple norbornenes into complex alkaloid-like structures. The products undergo a wide range of derivatization reactions, including regioselective enol triflate formation/cross-coupling sequences and highly efficient conversion to an unusual tricyclic 8,5,5-fused lactam. Overall, the process represents a formal one-atom aza-ring expansion with concomitant bridging annulation, making it of interest for the broader derivatization of alkene feedstocks.</p>","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141436458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-05Epub Date: 2024-06-24DOI: 10.1021/acs.orglett.4c01538
Hongyan Liu, Bo Xu
We have gold-catalyzed C-N cross-couplings of aryl iodides with aliphatic nitriles. Although nitriles are usually challenging nitrogen cross-coupling partners, they could be activated by base-mediated deprotonation and isomerization. The method utilizes widely available substrates in moderate to good yields to provide various N-aryl compounds. In addition, a similar strategy could be extended to the cross-couplings of aryl iodides with silver cyanate. The protocol features high humidity/air tolerance and works inter- and intramolecularly.
{"title":"Gold-Catalyzed C-N Cross-Coupling Reactions of Aryl Iodides with Alkyl Nitriles or Silver Cyanate.","authors":"Hongyan Liu, Bo Xu","doi":"10.1021/acs.orglett.4c01538","DOIUrl":"10.1021/acs.orglett.4c01538","url":null,"abstract":"<p><p>We have gold-catalyzed C-N cross-couplings of aryl iodides with aliphatic nitriles. Although nitriles are usually challenging nitrogen cross-coupling partners, they could be activated by base-mediated deprotonation and isomerization. The method utilizes widely available substrates in moderate to good yields to provide various <i>N</i>-aryl compounds. In addition, a similar strategy could be extended to the cross-couplings of aryl iodides with silver cyanate. The protocol features high humidity/air tolerance and works inter- and intramolecularly.</p>","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141441749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-05Epub Date: 2024-06-24DOI: 10.1021/acs.orglett.4c01981
James W Pearson, Teh Ren Hou, Jelena Golijanin, Patricia I Stewart, Eun Seo Choi, Alexis L Gabbey, Michael S West, Sophie A L Rousseaux
An intermolecular nickel-catalyzed reductive 1,2-alkylarylation of acrylates with cyclopropylamine NHP esters and aryl iodides is reported. This operationally simple protocol provides direct access to 1-alkylcyclopropylamine scaffolds. The mild conditions are compatible with four-membered α-amino strained rings as well as five- and six-membered ring systems. The products undergo cyclization to access α-arylated spirocyclic γ-lactams─a motif present in several pharmaceuticals.
{"title":"Ni-Catalyzed Reductive 1,2-Alkylarylation of Alkenes for the Synthesis of Spirocyclic γ-Lactams.","authors":"James W Pearson, Teh Ren Hou, Jelena Golijanin, Patricia I Stewart, Eun Seo Choi, Alexis L Gabbey, Michael S West, Sophie A L Rousseaux","doi":"10.1021/acs.orglett.4c01981","DOIUrl":"10.1021/acs.orglett.4c01981","url":null,"abstract":"<p><p>An intermolecular nickel-catalyzed reductive 1,2-alkylarylation of acrylates with cyclopropylamine NHP esters and aryl iodides is reported. This operationally simple protocol provides direct access to 1-alkylcyclopropylamine scaffolds. The mild conditions are compatible with four-membered α-amino strained rings as well as five- and six-membered ring systems. The products undergo cyclization to access α-arylated spirocyclic γ-lactams─a motif present in several pharmaceuticals.</p>","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141445519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-05Epub Date: 2024-06-24DOI: 10.1021/acs.orglett.4c01894
Carter U Brzezinski, Andrew R LeBlanc, Madeline G Clerici, William M Wuest
The reduction of alkenes to their respective alkanes is one of the most important transformations in organic chemistry, given the abundance of natural and commercial olefins. Metal-catalyzed hydrogenation is the most common way to reduce alkenes; however, the use of H2 gas in combination with the precious metals required for these conditions can be impractical, dangerous, and expensive. More complex substrates often require extremely high pressures of H2, further emphasizing the safety concerns associated with these hydrogenation reactions. Here we report a safe, cheap, and practical photochemical alkene reduction using a readily available organophotocatalyst, catalytic thiol, and formate. These conditions reduce a variety of di-, tri-, and tetra-substituted alkenes in good yield as well as dearomatize pharmaceutically relevant heterocycles to generate sp3-rich isosteres of benzofurans and indoles. These formal-hydrogenation conditions tolerate a broad range of functionalities that would otherwise be sensitive to typical hydrogenations and are likely to be important for industry applications.
{"title":"Mild Photochemical Reduction of Alkenes and Heterocycles via Thiol-Mediated Formate Activation.","authors":"Carter U Brzezinski, Andrew R LeBlanc, Madeline G Clerici, William M Wuest","doi":"10.1021/acs.orglett.4c01894","DOIUrl":"10.1021/acs.orglett.4c01894","url":null,"abstract":"<p><p>The reduction of alkenes to their respective alkanes is one of the most important transformations in organic chemistry, given the abundance of natural and commercial olefins. Metal-catalyzed hydrogenation is the most common way to reduce alkenes; however, the use of H<sub>2</sub> gas in combination with the precious metals required for these conditions can be impractical, dangerous, and expensive. More complex substrates often require extremely high pressures of H<sub>2</sub>, further emphasizing the safety concerns associated with these hydrogenation reactions. Here we report a safe, cheap, and practical photochemical alkene reduction using a readily available organophotocatalyst, catalytic thiol, and formate. These conditions reduce a variety of di-, tri-, and tetra-substituted alkenes in good yield as well as dearomatize pharmaceutically relevant heterocycles to generate sp<sup>3</sup>-rich isosteres of benzofurans and indoles. These formal-hydrogenation conditions tolerate a broad range of functionalities that would otherwise be sensitive to typical hydrogenations and are likely to be important for industry applications.</p>","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141445518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-05Epub Date: 2024-06-24DOI: 10.1021/acs.jproteome.4c00430
Matthew S Fischer, Holden T Rogers, Emily A Chapman, Hsin-Ju Chan, Boris Krichel, Zhan Gao, Eli J Larson, Ying Ge
Native top-down mass spectrometry (nTDMS) allows characterization of protein structure and noncovalent interactions with simultaneous sequence mapping and proteoform characterization. The majority of nTDMS studies utilize purified recombinant proteins, with significant challenges hindering application to endogenous systems. To perform native top-down proteomics (nTDP), where endogenous proteins from complex biological systems are analyzed by nTDMS, it is essential to separate proteins under nondenaturing conditions. However, it remains difficult to achieve high resolution with MS-compatible online chromatography while preserving protein tertiary structure and noncovalent interactions. Herein, we report the use of online mixed-bed ion exchange chromatography (IEC) to enable separation of endogenous proteins from complex mixtures under nondenaturing conditions, preserving noncovalent interactions for nTDP analysis. We have successfully detected large proteins (>146 kDa) and identified endogenous metal-binding and oligomeric protein complexes in human heart tissue lysate. The use of a mixed-bed stationary phase allowed retention and elution of proteins over a wide range of isoelectric points without altering the sample or mobile phase pH. Overall, our method provides a simple online IEC-MS platform that can effectively separate proteins from complex mixtures under nondenaturing conditions and preserve higher-order structure for nTDP applications.
{"title":"Online Mixed-Bed Ion Exchange Chromatography for Native Top-Down Proteomics of Complex Mixtures.","authors":"Matthew S Fischer, Holden T Rogers, Emily A Chapman, Hsin-Ju Chan, Boris Krichel, Zhan Gao, Eli J Larson, Ying Ge","doi":"10.1021/acs.jproteome.4c00430","DOIUrl":"10.1021/acs.jproteome.4c00430","url":null,"abstract":"<p><p>Native top-down mass spectrometry (nTDMS) allows characterization of protein structure and noncovalent interactions with simultaneous sequence mapping and proteoform characterization. The majority of nTDMS studies utilize purified recombinant proteins, with significant challenges hindering application to endogenous systems. To perform native top-down proteomics (nTDP), where endogenous proteins from complex biological systems are analyzed by nTDMS, it is essential to separate proteins under nondenaturing conditions. However, it remains difficult to achieve high resolution with MS-compatible online chromatography while preserving protein tertiary structure and noncovalent interactions. Herein, we report the use of online mixed-bed ion exchange chromatography (IEC) to enable separation of endogenous proteins from complex mixtures under nondenaturing conditions, preserving noncovalent interactions for nTDP analysis. We have successfully detected large proteins (>146 kDa) and identified endogenous metal-binding and oligomeric protein complexes in human heart tissue lysate. The use of a mixed-bed stationary phase allowed retention and elution of proteins over a wide range of isoelectric points without altering the sample or mobile phase pH. Overall, our method provides a simple online IEC-MS platform that can effectively separate proteins from complex mixtures under nondenaturing conditions and preserve higher-order structure for nTDP applications.</p>","PeriodicalId":48,"journal":{"name":"Journal of Proteome Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141445575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-05Epub Date: 2024-06-26DOI: 10.1021/acs.orglett.4c01495
Jose R Montero Bastidas, Anshu Yadav, Seokjoo Lee, Behnaz Ghaffari, Milton R Smith, Robert E Maleczka
Ir-catalyzed arene C-H borylations (CHB) of anilines can be highly ortho selective by using a small B2eg2 (eg = ethane-1,2-diol) as the borylating reagent. Unfortunately, the products are prone to decomposition, and transesterification with pinacol is required prior to isolation. This work offers a solution by adjusting the size of the diboron reagent. Based on our evaluation, we conclude that B2bg2 (bg = butane-1,2-diol) achieves an optimal balance between CHB regioselectivity and stability for the borylated products.
{"title":"Balancing Reactivity, Regioselectivity, and Product Stability in Ir-Catalyzed Ortho-C-H Borylations of Anilines by Modulating the Diboron Partner.","authors":"Jose R Montero Bastidas, Anshu Yadav, Seokjoo Lee, Behnaz Ghaffari, Milton R Smith, Robert E Maleczka","doi":"10.1021/acs.orglett.4c01495","DOIUrl":"10.1021/acs.orglett.4c01495","url":null,"abstract":"<p><p>Ir-catalyzed arene C-H borylations (CHB) of anilines can be highly ortho selective by using a small B<sub>2</sub>eg<sub>2</sub> (eg = ethane-1,2-diol) as the borylating reagent. Unfortunately, the products are prone to decomposition, and transesterification with pinacol is required prior to isolation. This work offers a solution by adjusting the size of the diboron reagent. Based on our evaluation, we conclude that B<sub>2</sub>bg<sub>2</sub> (bg = butane-1,2-diol) achieves an optimal balance between CHB regioselectivity and stability for the borylated products.</p>","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-05Epub Date: 2024-06-12DOI: 10.1021/acs.joc.4c00652
Stephen Hanessian
A retrospective is presented highlighting the synthesis of selected "first-in-kind" natural products, their synthetic analogues, structure elucidations, and rationally designed bioactive synthetic compounds that were accomplished because of collaborations with past and present pharmaceutical and agrochemical companies. Medicinal chemistry projects involving structure-based design exploiting cocrystal structures of small molecules with biologically relevant enzymes, receptors, and bacterial ribosomes with synthetic small molecules leading to marketed products, clinical candidates, and novel drug prototypes were realized in collaboration. Personal reflections, historical insights, behind the scenes stories from various long-term projects are shared in this retrospective article.
{"title":"My 50-Plus Years of Academic Research Collaborations with Industry. A Retrospective.","authors":"Stephen Hanessian","doi":"10.1021/acs.joc.4c00652","DOIUrl":"10.1021/acs.joc.4c00652","url":null,"abstract":"<p><p>A retrospective is presented highlighting the synthesis of selected \"first-in-kind\" natural products, their synthetic analogues, structure elucidations, and rationally designed bioactive synthetic compounds that were accomplished because of collaborations with past and present pharmaceutical and agrochemical companies. Medicinal chemistry projects involving structure-based design exploiting cocrystal structures of small molecules with biologically relevant enzymes, receptors, and bacterial ribosomes with synthetic small molecules leading to marketed products, clinical candidates, and novel drug prototypes were realized in collaboration. Personal reflections, historical insights, behind the scenes stories from various long-term projects are shared in this retrospective article.</p>","PeriodicalId":57,"journal":{"name":"The Journal of Organic Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141304881","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 : 2024-07-05Epub Date: 2024-06-12DOI: 10.1021/acs.joc.3c02769
Sini K S, Arun S, Shinu V S
A novel and efficient fragment-based assembly of symmetrical bis-peptidotraizoles has been developed based on double Sharpless azide-alkyne click chemistry. A new Cu(II) catalyzed protocol with a wide substrate scope was developed for accessing the symmetrical alkylidene bis-azidoamide fragment that yields the products in very good yields at room temperature without employing column purifications. The propargylated β-acetamido ketone fragment was accessed using another Cu(II) catalyzed room temperature MCR protocol. A fast double-click reaction (2 h) of symmetrical alkylidene bis-azidoamides with propargylated β-acetamido ketone fragments leads to the formation of unusual symmetrical bis-peptidotriazoles.
{"title":"Fragment-Based Design and Synthesis of Symmetrical <i>bis</i>-Peptidotriazoles Using Alkylidene <i>bis</i>-Amide Formations and Subsequent Triazole Ligation with β-Acetamido Carbonyl Scaffolds.","authors":"Sini K S, Arun S, Shinu V S","doi":"10.1021/acs.joc.3c02769","DOIUrl":"10.1021/acs.joc.3c02769","url":null,"abstract":"<p><p>A novel and efficient fragment-based assembly of symmetrical <i>bis</i>-peptidotraizoles has been developed based on double Sharpless azide-alkyne click chemistry. A new Cu(II) catalyzed protocol with a wide substrate scope was developed for accessing the symmetrical alkylidene <i>bis-</i>azidoamide fragment that yields the products in very good yields at room temperature without employing column purifications. The propargylated β-acetamido ketone fragment was accessed using another Cu(II) catalyzed room temperature MCR protocol. A fast double-click reaction (2 h) of symmetrical alkylidene <i>bis-</i>azidoamides with propargylated β-acetamido ketone fragments leads to the formation of unusual symmetrical <i>bis</i>-peptidotriazoles.</p>","PeriodicalId":57,"journal":{"name":"The Journal of Organic Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141309639","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}