Fen Han, Fenfen Xie, Mengyun Yin, Linhai Jing, Pan Han
Herein, a electroreductive carboxylation of benzylphosphonium salts was achieved by the cleavage of the C(sp3)-P bond, and various valuable arylacetic acids could be synthesized by this strategy. Also, based on control experiments and previous studies, a plausible reaction mechanism was proposed to explain the reaction process. The establishment of this procedure will provide a new paradigm for the functionalization of alkyl phosphonium salts.
{"title":"Electroreductive carboxylation of benzylphosphonium salts with CO<sub>2</sub> through the cleavage of the C(sp<sup>3</sup>)-P bond.","authors":"Fen Han, Fenfen Xie, Mengyun Yin, Linhai Jing, Pan Han","doi":"10.1039/d4ob00838c","DOIUrl":"https://doi.org/10.1039/d4ob00838c","url":null,"abstract":"<p><p>Herein, a electroreductive carboxylation of benzylphosphonium salts was achieved by the cleavage of the C(sp<sup>3</sup>)-P bond, and various valuable arylacetic acids could be synthesized by this strategy. Also, based on control experiments and previous studies, a plausible reaction mechanism was proposed to explain the reaction process. The establishment of this procedure will provide a new paradigm for the functionalization of alkyl phosphonium salts.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rodney A Fernandes, Sandhya S Yadav, Sanjita Moharana
We synthesized stereoselectively four stereoisomers of oxylipins (1a-d) by a convergent approach based on chiral catalysis. The synthetic approach involved sequential assembly of two key fragments - ene-diol and allyl alcohol - for an intended convergent cross-metathesis reaction to join these fragments. The key steps include Sharpless kinetic resolution, asymmetric dihydroxylation and Grubbs cross-metathesis. The characterization of the synthesized oxylipins revealed spectroscopic data that were consistent with previously reported values.
{"title":"Stereoselective convergent total synthesis of oxylipins.","authors":"Rodney A Fernandes, Sandhya S Yadav, Sanjita Moharana","doi":"10.1039/d4ob00282b","DOIUrl":"https://doi.org/10.1039/d4ob00282b","url":null,"abstract":"<p><p>We synthesized stereoselectively four stereoisomers of oxylipins (1a-d) by a convergent approach based on chiral catalysis. The synthetic approach involved sequential assembly of two key fragments - ene-diol and allyl alcohol - for an intended convergent cross-metathesis reaction to join these fragments. The key steps include Sharpless kinetic resolution, asymmetric dihydroxylation and Grubbs cross-metathesis. The characterization of the synthesized oxylipins revealed spectroscopic data that were consistent with previously reported values.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We describe the synthesis of two tetra-α aryl-extended calix[4]pyrroles (C[4]Ps) 4a-b bearing four terminal carboxylic groups in their meso-propyl chains defining the lower rims. The synthesized C[4]Ps became soluble (1-3 mM) in water at pD = 10. We probed the interaction of 4a towards tetra-methylammonium (G1) chloride in water using 1H NMR spectroscopy. The C[4]P 4a includes G1 in the shallow aromatic cavity defined by the pyrrole rings in cone conformation forming a 1 : 1 complex G1⊂4a. Pyridine-N-oxide (PNO) binding in the larger polar aromatic cavity of 4a results in the quantitative self-assembly of the supramolecular receptor PNO@4a featuring the pyrrole rings preorganized in cone conformation. The PNO@4a receptor displays improved binding properties towards G1 than the parent C[4]P 4a. We thermodynamically characterized (1H NMR titrations and ITC experiments) the 1 : 1 complexes of PNO@4a with a series of tetra-alkylammonium salts, including biologically relevant examples. The PNO@4a supramolecular receptor displays significant affinity (log K = 3-4) but lacks selectivity in water binding of methyl trialkyl ammonium cations. Cation-π and coulombic interactions are the main intermolecular forces stabilizing the complexes. We also performed DFT calculations to gain some insights into the complexes' structures.
{"title":"Enhanced binding of methyl alkylammonium cations through preorganization of a water-soluble calix[4]pyrrole.","authors":"Esteban Valencia, Pablo Ballester","doi":"10.1039/d4ob00843j","DOIUrl":"https://doi.org/10.1039/d4ob00843j","url":null,"abstract":"<p><p>We describe the synthesis of two tetra-α aryl-extended calix[4]pyrroles (C[4]Ps) 4a-b bearing four terminal carboxylic groups in their <i>meso</i>-propyl chains defining the lower rims. The synthesized C[4]Ps became soluble (1-3 mM) in water at pD = 10. We probed the interaction of 4a towards tetra-methylammonium (G1) chloride in water using <sup>1</sup>H NMR spectroscopy. The C[4]P 4a includes G1 in the shallow aromatic cavity defined by the pyrrole rings in cone conformation forming a 1 : 1 complex G1⊂4a. Pyridine-<i>N</i>-oxide (PNO) binding in the larger polar aromatic cavity of 4a results in the quantitative self-assembly of the supramolecular receptor PNO@4a featuring the pyrrole rings preorganized in cone conformation. The PNO@4a receptor displays improved binding properties towards G1 than the parent C[4]P 4a. We thermodynamically characterized (<sup>1</sup>H NMR titrations and ITC experiments) the 1 : 1 complexes of PNO@4a with a series of tetra-alkylammonium salts, including biologically relevant examples. The PNO@4a supramolecular receptor displays significant affinity (log <i>K</i> = 3-4) but lacks selectivity in water binding of methyl trialkyl ammonium cations. Cation-π and coulombic interactions are the main intermolecular forces stabilizing the complexes. We also performed DFT calculations to gain some insights into the complexes' structures.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stephen M Butler, Bilge Ercan, Jingyao You, Luke P Schulz, Katrina A Jolliffe
Phosphatidic acid and phosphatidylserine are anionic phospholipids with emerging signalling roles in cells. Determination of how phosphatidic acid and phosphatidylserine change location and quantity in cells over time requires selective fluorescent sensors that can distinguish these two anionic phospholipids. However, the design of such synthetic sensors that can selectively bind and respond to a single phospholipid within the complex membrane milieu remains challenging. In this work, we present a simple and robust strategy to control the selectivity of synthetic sensors for phosphatidic acid and phosphatidylserine. By changing the coordination metal of a dipicolylamine (DPA) ligand from Zn(II) to Ni(II) on the same synthetic sensor with a peptide backbone, we achieve a complete switch in selectivity from phosphatidic acid to phosphatidylserine in model lipid membranes. Furthermore, this strategy was largely unaffected by the choice and the position of the fluorophores. We envision that this strategy will provide a platform for the rational design of targeted synthetic phospholipid sensors to probe plasma and intracellular membranes.
{"title":"A change in metal cation switches selectivity of a phospholipid sensor from phosphatidic acid to phosphatidylserine.","authors":"Stephen M Butler, Bilge Ercan, Jingyao You, Luke P Schulz, Katrina A Jolliffe","doi":"10.1039/d4ob00418c","DOIUrl":"https://doi.org/10.1039/d4ob00418c","url":null,"abstract":"<p><p>Phosphatidic acid and phosphatidylserine are anionic phospholipids with emerging signalling roles in cells. Determination of how phosphatidic acid and phosphatidylserine change location and quantity in cells over time requires selective fluorescent sensors that can distinguish these two anionic phospholipids. However, the design of such synthetic sensors that can selectively bind and respond to a single phospholipid within the complex membrane milieu remains challenging. In this work, we present a simple and robust strategy to control the selectivity of synthetic sensors for phosphatidic acid and phosphatidylserine. By changing the coordination metal of a dipicolylamine (DPA) ligand from Zn(II) to Ni(II) on the same synthetic sensor with a peptide backbone, we achieve a complete switch in selectivity from phosphatidic acid to phosphatidylserine in model lipid membranes. Furthermore, this strategy was largely unaffected by the choice and the position of the fluorophores. We envision that this strategy will provide a platform for the rational design of targeted synthetic phospholipid sensors to probe plasma and intracellular membranes.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rhodium-catalyzed [3 + 2] annulation of diazoenals and N-alkyl imines resulted in N-alkyl-pyrrole-3-carbaldehyde derivatives. The reaction involves thermal 6π-electrocyclization and aromatization of a new class of enal-azomethine ylides (EAYs). The EAYs derived from dihydroisoquinoline and 2H-azirine gave fused-pyrrole and pyridine derivatives, respectively. The synthetic importance of pyrrole products has been demonstrated by one-step synthesis of the biologically relevant pyrrolo[3,2-c]quinoline scaffold as well as pyrrolo[2,1-a]isoquinoline which is a core structure of lamellarin alkaloids.
{"title":"Enal-azomethine ylides: application in the synthesis of functionalized pyrroles.","authors":"Pratap Kumar Mandal, Sandeep Patel, Sreenivas Katukojvala","doi":"10.1039/d4ob00859f","DOIUrl":"https://doi.org/10.1039/d4ob00859f","url":null,"abstract":"<p><p>Rhodium-catalyzed [3 + 2] annulation of diazoenals and <i>N</i>-alkyl imines resulted in <i>N</i>-alkyl-pyrrole-3-carbaldehyde derivatives. The reaction involves thermal 6π-electrocyclization and aromatization of a new class of enal-azomethine ylides (EAYs). The EAYs derived from dihydroisoquinoline and 2<i>H</i>-azirine gave fused-pyrrole and pyridine derivatives, respectively. The synthetic importance of pyrrole products has been demonstrated by one-step synthesis of the biologically relevant pyrrolo[3,2-<i>c</i>]quinoline scaffold as well as pyrrolo[2,1-<i>a</i>]isoquinoline which is a core structure of lamellarin alkaloids.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
An efficient method for the construction of 5-arylpyrazolo[1,5-a]pyrimidines using calcium carbide as a solid alkyne source instead of flammable and explosive gaseous acetylene, pyrazole-3-amine and (hetero)aromatic aldehydes as starting materials in the presence of a copper mediator is described. Meanwhile, 2-arylpyrimido[1,2-b]indazoles are also synthesized under similar conditions using indazole-3-amine as a substitute for pyrazole-3-amine as a starting material. The method has salient features such as the use of an inexpensive and easy-to-handle alkyne source, commercially available substrates, wide functional group tolerance, a low-cost mediator, and simple workup procedures. This protocol can also be extended to gram-scale synthesis.
{"title":"Construction of pyrazolo[1,5-<i>a</i>]pyrimidines and pyrimido[1,2-<i>b</i>]indazoles with calcium carbide as an alkyne source.","authors":"Xinjie You, Botao Wang, Fei Wen, Zheng Li","doi":"10.1039/d4ob00881b","DOIUrl":"https://doi.org/10.1039/d4ob00881b","url":null,"abstract":"<p><p>An efficient method for the construction of 5-arylpyrazolo[1,5-<i>a</i>]pyrimidines using calcium carbide as a solid alkyne source instead of flammable and explosive gaseous acetylene, pyrazole-3-amine and (hetero)aromatic aldehydes as starting materials in the presence of a copper mediator is described. Meanwhile, 2-arylpyrimido[1,2-<i>b</i>]indazoles are also synthesized under similar conditions using indazole-3-amine as a substitute for pyrazole-3-amine as a starting material. The method has salient features such as the use of an inexpensive and easy-to-handle alkyne source, commercially available substrates, wide functional group tolerance, a low-cost mediator, and simple workup procedures. This protocol can also be extended to gram-scale synthesis.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jun Yan, Pascal Retailleau, Christine Tran, Abdallah Hamze
We developed a transition metal-free methodology for the construction of pyrazoloquinazolinone derivatives. The strategy involves a one-pot reaction wherein the N-tosylhydrazone and its corresponding diazo derivative are generated in situ, followed by an intramolecular 1,3-dipolar cycloaddition-ring expansion to provide the pyrazolo-[1,5-c]quinazolinone motif. This approach enables straightforward access to a diverse range of highly functionalized N-heterocyclic compounds in good yields (up to 92%).
{"title":"Leveraging <i>in situ N</i>-tosylhydrazones as diazo surrogates for efficient access to pyrazolo-[1,5-<i>c</i>]quinazolinone derivatives.","authors":"Jun Yan, Pascal Retailleau, Christine Tran, Abdallah Hamze","doi":"10.1039/d4ob00950a","DOIUrl":"https://doi.org/10.1039/d4ob00950a","url":null,"abstract":"<p><p>We developed a transition metal-free methodology for the construction of pyrazoloquinazolinone derivatives. The strategy involves a one-pot reaction wherein the <i>N</i>-tosylhydrazone and its corresponding diazo derivative are generated <i>in situ</i>, followed by an intramolecular 1,3-dipolar cycloaddition-ring expansion to provide the pyrazolo-[1,5-<i>c</i>]quinazolinone motif. This approach enables straightforward access to a diverse range of highly functionalized N-heterocyclic compounds in good yields (up to 92%).</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The palladium-catalysed regioselective C-H chalcogenation of benzoxazines with disulfides and diselenides in air has been described. In this protocol, palladium acetate serves as the catalyst in conjunction with copper as an oxidizing agent. Through this approach, a wide array of sulfenylation and selenylation reactions of benzomorpholines have been effected, yielding results ranging from good to excellent. Thus, the established procedure demonstrates superb regioselectivity and a strong tolerance towards various functional groups and is suitable for gram-scale synthesis. Additionally, this synthetic approach offers a practical and convenient pathway for late-stage functionalization leading to the Rosenmund-von Braun reaction.
{"title":"Expedient, regioselective C-H chalcogenation of 3,4-dihydro-1,4-benzoxazines using a palladium-copper catalyst.","authors":"Ram Sunil Kumar Lalji, Monika, Mohit Gupta, Sandeep Kumar, Ray J Butcher, Brajendra Kumar Singh","doi":"10.1039/d4ob00524d","DOIUrl":"https://doi.org/10.1039/d4ob00524d","url":null,"abstract":"<p><p>The palladium-catalysed regioselective C-H chalcogenation of benzoxazines with disulfides and diselenides in air has been described. In this protocol, palladium acetate serves as the catalyst in conjunction with copper as an oxidizing agent. Through this approach, a wide array of sulfenylation and selenylation reactions of benzomorpholines have been effected, yielding results ranging from good to excellent. Thus, the established procedure demonstrates superb regioselectivity and a strong tolerance towards various functional groups and is suitable for gram-scale synthesis. Additionally, this synthetic approach offers a practical and convenient pathway for late-stage functionalization leading to the Rosenmund-von Braun reaction.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Subhashini V Subramaniam, Badal Singh, Natarajan Pradeep, Saravanan Peruncheralathan
We present the PIFA-mediated intramolecular N-arylation of 2-aminoquinoxalines at room temperature for the first time. This method provides a wide range of indolo[2,3-b]quinoxalines in good to excellent yields within a short time. The C-H bond functionalization occurs without the need for an inert atmosphere or additives. Additionally, a double C-H bond functionalization was observed, where the first reaction forms a C-N bond (N-arylation) and the second forms a C-O bond, yielding an acetal-functionalized product. Mechanistic investigations suggest that the C-H bond functionalization proceeds through an ionic mechanism, whereas acetal functionalization follows a radical pathway. This method extends to the derivation of indoloquinoxalines, including the target compound BIQMCz.
{"title":"PIFA-mediated intramolecular <i>N</i>-arylation of 2-aminoquinoxalines to afford indolo[2,3-<i>b</i>]quinoxaline derivatives.","authors":"Subhashini V Subramaniam, Badal Singh, Natarajan Pradeep, Saravanan Peruncheralathan","doi":"10.1039/d4ob00812j","DOIUrl":"https://doi.org/10.1039/d4ob00812j","url":null,"abstract":"<p><p>We present the PIFA-mediated intramolecular <i>N</i>-arylation of 2-aminoquinoxalines at room temperature for the first time. This method provides a wide range of indolo[2,3-<i>b</i>]quinoxalines in good to excellent yields within a short time. The C-H bond functionalization occurs without the need for an inert atmosphere or additives. Additionally, a double C-H bond functionalization was observed, where the first reaction forms a C-N bond (<i>N</i>-arylation) and the second forms a C-O bond, yielding an acetal-functionalized product. Mechanistic investigations suggest that the C-H bond functionalization proceeds through an ionic mechanism, whereas acetal functionalization follows a radical pathway. This method extends to the derivation of indoloquinoxalines, including the target compound BIQMCz.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A practical and efficient synthesis of the C8-C23 fragment of antarlides A-H, incorporating six stereocenters and a conjugated diene, is reported. A strategic combination of synthetic methods, including CBS reduction, Evans' aldol reaction, Keck-Maruoka allylation, and enzymatic resolution, enabled the selective introduction of these stereocenters. Furthermore, the pivotal coupling of key fragments is successfully executed through a Julia-Kocienski olefination reaction, connecting the C8-C14 and C15-C23 subunits.
{"title":"Stereo flexible synthesis of the C8-C23 fragment of antarlides, androgen receptor antagonists.","authors":"Palash Ghosh, Pralay Das, Prathama S Mainkar, Thenkrishnan Kumaraguru, Rudrakshula Madhavachary, Srivari Chandrasekhar","doi":"10.1039/d4ob00852a","DOIUrl":"https://doi.org/10.1039/d4ob00852a","url":null,"abstract":"<p><p>A practical and efficient synthesis of the C8-C23 fragment of antarlides A-H, incorporating six stereocenters and a conjugated diene, is reported. A strategic combination of synthetic methods, including CBS reduction, Evans' aldol reaction, Keck-Maruoka allylation, and enzymatic resolution, enabled the selective introduction of these stereocenters. Furthermore, the pivotal coupling of key fragments is successfully executed through a Julia-Kocienski olefination reaction, connecting the C8-C14 and C15-C23 subunits.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}