A paired electrocatalysis strategy for intermolecular oxidative cross-dehydrocoupling between styrenes and ethers or p-methylphenol derivatives using ketone as a mild oxidant is described. This approach enables the generation of Csp3 carbon-centered radicals through anodic oxidation, followed by reductive coupling of ketones at the cathode, ultimately yielding valuable oxidative alkylation products.
{"title":"Paired electrocatalysis enabled oxidative coupling of styrenes with alkyl radicals.","authors":"Dong Li, Ling Zhang, Daixi Li, Peng Yu, Tao Shen","doi":"10.1039/d4ob01605j","DOIUrl":"10.1039/d4ob01605j","url":null,"abstract":"<p><p>A paired electrocatalysis strategy for intermolecular oxidative cross-dehydrocoupling between styrenes and ethers or <i>p</i>-methylphenol derivatives using ketone as a mild oxidant is described. This approach enables the generation of Csp<sup>3</sup> carbon-centered radicals through anodic oxidation, followed by reductive coupling of ketones at the cathode, ultimately yielding valuable oxidative alkylation products.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589638","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}
Sunbum Kwon, Vasily Morozov, Lingfei Wang, Pradeep K Mandal, Stéphane Chaignepain, Céline Douat, Ivan Huc
A biotinylated helical aromatic oligoamide foldamer equivalent in size to a 24mer peptide was designed without any prejudice other than to display various polar and hydrophobic side chains at its surface. It was synthesized on solid phase, its P- and M-helical conformers were separated by HPLC on a chiral stationary phase, and the solid state structure of a non-biotinylated analogue was elucidated by X-ray crystallography. Pull-down experiments from a yeast cell lysate using the foldamer as a bait followed by proteomic analysis revealed potential protein binding partners. Three of these proteins were recombinantly expressed. Biolayer interferometry showed submicromolar binding demonstrating the potential of a given foldamer to have affinity for certain proteins in the absence of design considerations. Yet, binding selectivity was low in all three cases since both P- and M-conformers bound to the proteins with similar affinities.
除了在其表面显示各种极性和疏水侧链外,我们还设计了一种生物素化的螺旋芳香族寡酰胺折叠聚合物,其大小相当于 24 聚肽。该产品在固相上合成,其 P-和 M-螺旋构象在手性固定相上通过高效液相色谱进行分离,并通过 X 射线晶体学阐明了非生物素化类似物的固态结构。以折叠酶为诱饵从酵母细胞裂解物中进行拉取实验,然后进行蛋白质组分析,发现了潜在的蛋白质结合伙伴。其中三种蛋白质被重组表达。生物层干涉测量法显示了亚摩尔级的结合力,这表明在没有设计考虑的情况下,特定的折叠聚合体对某些蛋白质具有亲和力。然而,这三种情况下的结合选择性都很低,因为 P 型和 M 型折叠体与蛋白质的结合亲和力相似。
{"title":"Interrogating the potential of helical aromatic foldamers for protein recognition.","authors":"Sunbum Kwon, Vasily Morozov, Lingfei Wang, Pradeep K Mandal, Stéphane Chaignepain, Céline Douat, Ivan Huc","doi":"10.1039/d4ob01436g","DOIUrl":"https://doi.org/10.1039/d4ob01436g","url":null,"abstract":"<p><p>A biotinylated helical aromatic oligoamide foldamer equivalent in size to a 24mer peptide was designed without any prejudice other than to display various polar and hydrophobic side chains at its surface. It was synthesized on solid phase, its <i>P</i>- and <i>M</i>-helical conformers were separated by HPLC on a chiral stationary phase, and the solid state structure of a non-biotinylated analogue was elucidated by X-ray crystallography. Pull-down experiments from a yeast cell lysate using the foldamer as a bait followed by proteomic analysis revealed potential protein binding partners. Three of these proteins were recombinantly expressed. Biolayer interferometry showed submicromolar binding demonstrating the potential of a given foldamer to have affinity for certain proteins in the absence of design considerations. Yet, binding selectivity was low in all three cases since both <i>P</i>- and <i>M</i>-conformers bound to the proteins with similar affinities.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581304","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}
Ankush Banerjee, Tiffany A Brisco, Sneha Ray, Arani Datta, Xiaoyu Zhang, Zhen Zhang, Alexander A Busse, Hanspeter Niederstrasser, Krissty Sumida, Bruce A Posner, Dawn M Wetzel, Margaret A Phillips, Myles W Smith
We describe the development of a unified synthetic strategy for the preparation of all known 5/5-spirocyclic spiroindimicin (SPM) alkaloids, namely spiroindimicins B-G. The present synthetic route relies on four fundamental transformations: Grignard-based fragment coupling between halogenated pyrrolemetal and isatin partners, Suzuki coupling to generate a triaryl scaffold encompassing all requisite skeletal atoms of the natural products, Lewis acid-mediated spirocyclization to construct the 5/5-spirocyclic core, and chemoselective lactam reduction. The developed syntheses are step-economic (6-7 steps from commercial materials), scalable, and amenable to analogue synthesis. Preliminary investigations into a catalytic asymmetric spirocyclization towards an enantioselective SPM synthesis are also described. Further studies of the antiparasitic properties of this class have revealed promising activity against T. brucei for certain congeners. Together with our prior approach to the 6/5-family members, our work constitutes a synthetic solution to all known spiroindimicin natural products.
{"title":"Synthesis of the 5/5-spiroindimicin alkaloids: development of a general synthetic approach and biological investigations.","authors":"Ankush Banerjee, Tiffany A Brisco, Sneha Ray, Arani Datta, Xiaoyu Zhang, Zhen Zhang, Alexander A Busse, Hanspeter Niederstrasser, Krissty Sumida, Bruce A Posner, Dawn M Wetzel, Margaret A Phillips, Myles W Smith","doi":"10.1039/d4ob01552e","DOIUrl":"https://doi.org/10.1039/d4ob01552e","url":null,"abstract":"<p><p>We describe the development of a unified synthetic strategy for the preparation of all known 5/5-spirocyclic spiroindimicin (SPM) alkaloids, namely spiroindimicins B-G. The present synthetic route relies on four fundamental transformations: Grignard-based fragment coupling between halogenated pyrrolemetal and isatin partners, Suzuki coupling to generate a triaryl scaffold encompassing all requisite skeletal atoms of the natural products, Lewis acid-mediated spirocyclization to construct the 5/5-spirocyclic core, and chemoselective lactam reduction. The developed syntheses are step-economic (6-7 steps from commercial materials), scalable, and amenable to analogue synthesis. Preliminary investigations into a catalytic asymmetric spirocyclization towards an enantioselective SPM synthesis are also described. Further studies of the antiparasitic properties of this class have revealed promising activity against <i>T. brucei</i> for certain congeners. Together with our prior approach to the 6/5-family members, our work constitutes a synthetic solution to all known spiroindimicin natural products.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581308","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 novel synthetic method has been developed for generating thio(seleno)cyanato-substituted thiazolidine-2-imines via an electrochemical one-pot cascade reaction. This reaction employs isothiocyanates, N-2-en-1-amines, and KSCN (or KSeCN) under mild conditions, obviating the need for metals, chemical oxidants, and external electrolytes. The protocol is effective with unactivated alkenes and facilitates the synthesis of five- and six-membered thio(seleno)cyanato-substituted thiazolidine-2-imines. The versatility is demonstrated by its straightforward operation and scalability to gram-scale production, underscoring its potential for broader application.
{"title":"Electrochemical one-pot cascade synthesis of thio(seleno)cyanato-substituted thiazolidine-2-imines without external electrolyte.","authors":"Xiao Yu, Liqiang Hao, Xian Liu, Shengkui Jin, Yangchen Li, Yiping Liu, Yafei Ji","doi":"10.1039/d4ob01626b","DOIUrl":"https://doi.org/10.1039/d4ob01626b","url":null,"abstract":"<p><p>A novel synthetic method has been developed for generating thio(seleno)cyanato-substituted thiazolidine-2-imines <i>via</i> an electrochemical one-pot cascade reaction. This reaction employs isothiocyanates, <i>N</i>-2-en-1-amines, and KSCN (or KSeCN) under mild conditions, obviating the need for metals, chemical oxidants, and external electrolytes. The protocol is effective with unactivated alkenes and facilitates the synthesis of five- and six-membered thio(seleno)cyanato-substituted thiazolidine-2-imines. The versatility is demonstrated by its straightforward operation and scalability to gram-scale production, underscoring its potential for broader application.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575500","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}
Disulfide bonds are essential in protein folding, cellular redox balance, materials science, and drug development. Despite existing synthetic methods, the efficient and selective synthesis of unsymmetrical disulfides remains challenging. This review highlights innovative approaches in visible light photocatalysis, including decarboxylation, deoxydisulfidation of alcohols, and direct C-H disulfidation, showcasing broad substrate applicability and functional group tolerance under mild conditions. Additionally, it explores transition metal-catalyzed systems with copper, nickel, palladium, chromium, Iridium, Rhodium molybdenum, and scandium, offering effective strategies for unsymmetrical disulfide bond formation and late-stage functionalization of complex molecules through reductive coupling, selective oxidation, and novel insertion reactions.
{"title":"Recent advances in photocatalytic and transition metal-catalyzed synthesis of disulfide compounds.","authors":"Jia-Lin Tu","doi":"10.1039/d4ob01362j","DOIUrl":"https://doi.org/10.1039/d4ob01362j","url":null,"abstract":"<p><p>Disulfide bonds are essential in protein folding, cellular redox balance, materials science, and drug development. Despite existing synthetic methods, the efficient and selective synthesis of unsymmetrical disulfides remains challenging. This review highlights innovative approaches in visible light photocatalysis, including decarboxylation, deoxydisulfidation of alcohols, and direct C-H disulfidation, showcasing broad substrate applicability and functional group tolerance under mild conditions. Additionally, it explores transition metal-catalyzed systems with copper, nickel, palladium, chromium, Iridium, Rhodium molybdenum, and scandium, offering effective strategies for unsymmetrical disulfide bond formation and late-stage functionalization of complex molecules through reductive coupling, selective oxidation, and novel insertion reactions.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581306","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}
Tanmoy Sahoo, Dasari Vijaya Prasanna, B Sridhar, B V Subba Reddy
An efficient and operationally simple photochemical method has been demonstrated under transition metal-free, photocatalyst-free, and oxidant-free conditions. In recent times, diaryliodonium salts have become one of the most popular arylating sources under photoinduced conditions. Herein, we developed a visible light induced arylation of heterocycles using an EDA complex that is formed in situ from 2,6-lutidine and diaryliodonium triflate. Under light irradiation, the EDA complex generates the aryl radical that undergoes addition with 2-oxo-2H-chromene-3-carbonitriles via an SET process. This method serves as an effective tool to access biologically active and pharmaceutically relevant coumarin scaffolds.
在无过渡金属、无光催化剂和无氧化剂的条件下,一种高效且操作简单的光化学方法已经得到证实。近来,二芳基碘鎓盐已成为光诱导条件下最受欢迎的芳基化源之一。在此,我们开发了一种利用 2,6- 丁烷和三酸二亚碘鎓原位形成的 EDA 复合物进行可见光诱导的杂环芳基化反应。在光照射下,EDA 复合物生成芳基自由基,芳基自由基通过 SET 过程与 2-氧代-2H-铬-3-甲腈发生加成反应。这种方法是获得具有生物活性和医药相关性的香豆素支架的有效工具。
{"title":"Novel electron donor-acceptor (EDA) complex promoted arylation of 2-oxo-2<i>H</i>-chromene-3-carbonitriles under visible light irradiation.","authors":"Tanmoy Sahoo, Dasari Vijaya Prasanna, B Sridhar, B V Subba Reddy","doi":"10.1039/d4ob01493f","DOIUrl":"https://doi.org/10.1039/d4ob01493f","url":null,"abstract":"<p><p>An efficient and operationally simple photochemical method has been demonstrated under transition metal-free, photocatalyst-free, and oxidant-free conditions. In recent times, diaryliodonium salts have become one of the most popular arylating sources under photoinduced conditions. Herein, we developed a visible light induced arylation of heterocycles using an EDA complex that is formed <i>in situ</i> from 2,6-lutidine and diaryliodonium triflate. Under light irradiation, the EDA complex generates the aryl radical that undergoes addition with 2-oxo-2<i>H</i>-chromene-3-carbonitriles <i>via</i> an SET process. This method serves as an effective tool to access biologically active and pharmaceutically relevant coumarin scaffolds.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575503","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}
Many C-glycosides are found in natural products, drugs and small molecular probes. Herein, we report the synthesis of C-glycosides by the [Au]/[Ag]-catalysed activation of ethynylcyclohexyl glycosyl carbonate donors. This mild, catalytic, fast and high yielding protocol enables the synthesis of a diverse array of C-glycosides that were otherwise challenging to synthesize.
{"title":"[Au]/[Ag]-catalysed synthesis of non-hydrolysable <i>C</i>-glycosides.","authors":"Saptashwa Chakraborty, Daksh Telang, Bijoyananda Mishra, Srinivas Hotha","doi":"10.1039/d4ob01339e","DOIUrl":"https://doi.org/10.1039/d4ob01339e","url":null,"abstract":"<p><p>Many <i>C</i>-glycosides are found in natural products, drugs and small molecular probes. Herein, we report the synthesis of <i>C</i>-glycosides by the [Au]/[Ag]-catalysed activation of ethynylcyclohexyl glycosyl carbonate donors. This mild, catalytic, fast and high yielding protocol enables the synthesis of a diverse array of <i>C</i>-glycosides that were otherwise challenging to synthesize.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566523","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}
Pan Liu, Yang Geng, Dapeng Zou, Yangjie Wu, Yusheng Wu
A silver-mediated cascade trifluoromethylthiolation/cyclization of unactivated alkenes has been investigated. This strategy employs AgSCF3 as the trifluoromethylthiolating reagent to obtain a variety of useful trifluoromethylthiolated tricyclic imidazol derivatives in reasonable yields. Preliminary mechanistic studies indicate that the present reaction takes place via a radical process. This method is distinguished by its atom economy, wide functional group compatibility, operational simplicity and product diversity.
{"title":"Silver-mediated radical cascade trifluoromethylthiolation/cyclization of benzimidazole derivatives with AgSCF<sub>3</sub>.","authors":"Pan Liu, Yang Geng, Dapeng Zou, Yangjie Wu, Yusheng Wu","doi":"10.1039/d4ob01582g","DOIUrl":"https://doi.org/10.1039/d4ob01582g","url":null,"abstract":"<p><p>A silver-mediated cascade trifluoromethylthiolation/cyclization of unactivated alkenes has been investigated. This strategy employs AgSCF<sub>3</sub> as the trifluoromethylthiolating reagent to obtain a variety of useful trifluoromethylthiolated tricyclic imidazol derivatives in reasonable yields. Preliminary mechanistic studies indicate that the present reaction takes place <i>via</i> a radical process. This method is distinguished by its atom economy, wide functional group compatibility, operational simplicity and product diversity.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566564","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}
Guo-Biao Zhu, Chen Guo, Xue-Lian Ren, Ming-Zhe Li, Di-Ya Lu, Xi-Le Hu, He Huang, Tony D James, Xiao-Peng He
We have synthesized two sialic acid derivatives substituted with an ortho-nitrobenzyl alcohol (o-NBA) group that can undergo light-mediated conjugation with primary amines at their 5- or 9-carbon position. The o-NBA derivatives were shown to react with multiple lysine residues of human serum albumin (HSA) when exposed to 365 nm light irradiation within 10 min. The resulting sugar conjugates were characterized by mass spectroscopy and used for fluorescence-based cell imaging.
{"title":"Non-natural sialic acid derivatives with <i>o</i>-nitrobenzyl alcohol substituents for light-mediated protein conjugation and cell imaging.","authors":"Guo-Biao Zhu, Chen Guo, Xue-Lian Ren, Ming-Zhe Li, Di-Ya Lu, Xi-Le Hu, He Huang, Tony D James, Xiao-Peng He","doi":"10.1039/d4ob01563k","DOIUrl":"https://doi.org/10.1039/d4ob01563k","url":null,"abstract":"<p><p>We have synthesized two sialic acid derivatives substituted with an <i>ortho</i>-nitrobenzyl alcohol (o-NBA) group that can undergo light-mediated conjugation with primary amines at their 5- or 9-carbon position. The o-NBA derivatives were shown to react with multiple lysine residues of human serum albumin (HSA) when exposed to 365 nm light irradiation within 10 min. The resulting sugar conjugates were characterized by mass spectroscopy and used for fluorescence-based cell imaging.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566560","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}
Xingyuan Ye, Peng Bao, Yan Pan, Han Xiao, Qiuwen Li, Guangke He
A K2CO3-promoted tandem ring-opening/ring-closing of N-alkynyl-2-oxazolidinones has been described, affording 2-oxazolines in 42-99% yields without column chromatography isolation. This operationally simple reaction proceeds under ambient conditions without a transition-metal catalyst and an external oxidant and can be applied for the late-stage functionalization of biologically active compounds.
{"title":"Base-promoted tandem ring-opening/ring-closing of <i>N</i>-alkynyl-2-oxazolidinones enables facile synthesis of 2-oxazolines.","authors":"Xingyuan Ye, Peng Bao, Yan Pan, Han Xiao, Qiuwen Li, Guangke He","doi":"10.1039/d4ob01561d","DOIUrl":"10.1039/d4ob01561d","url":null,"abstract":"<p><p>A K<sub>2</sub>CO<sub>3</sub>-promoted tandem ring-opening/ring-closing of <i>N</i>-alkynyl-2-oxazolidinones has been described, affording 2-oxazolines in 42-99% yields without column chromatography isolation. This operationally simple reaction proceeds under ambient conditions without a transition-metal catalyst and an external oxidant and can be applied for the late-stage functionalization of biologically active compounds.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556614","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}