Application of Chiral Liquid Chromatography in Photocatalytic Asymmetric Synthesis of β-N-Hydroxyamino Alcohols

光催化有机合成反应是现代合成化学的研究热点。由于可见光本身固有的清洁、温和、经济等特点，可见光诱导的光催化氧化还原反应已引起合成化学家们广泛的研究兴趣，近年来也取得了一些突破性进展。 光催化硝酮与醛（酮）的不对称交叉偶联反应合成光活性β-羟胺醇是一种创新的合成反应体系探索，具有一定的挑战性。由于产物β-羟胺醇含有双手性中心，因此，寻求合适的光催化合成条件、筛选设计能有效控制反应的化学选择性和立体选择性的金属试剂和手性配体催化剂是创立这一新的合成反应体系的关键。因此，发展高效快速检测光活性产物的分析方法至关重要。但β-羟胺醇产物含有四个立体异构体，也给产物分离纯化及其光学纯度的准确测定带来了困...Catalytic synthesis using light is a hot research topic of modern synthetic chemistry. Due to the intrinsic clean and economic characteristics of the visible light, the reaction using the visible light has attracted the interests of many synthetic chemists. Some breakthrough progresses have been achieved in recent years. The photocatalytic asymmetric cross-coupling reaction of nitrons with aldehy...学位：理学硕士院系专业：化学化工学院_分析化学学号：2052013115156

Stereodivergent routes in organic synthesis: carbohydrates, amino acids, alkaloids and terpenes

The natural occurrence of enantiomers and diastereomers is often encountered. In addition, the synthesis of these stereoisomers is important for structure determination and for the study of structure–activity relationships. Stereodivergent routes simplify the access to these molecules starting from a common material. This review is focused on the synthesis of carbohydrates, amino acids, alkaloids and terpenes using this efficient strategy. In the case of carbohydrates, such as monosaccharides, carbasugars, aminosugars and azasugars, carbohydrates are usually employed as common starting materials. As a very common strategy, configurations of hydroxy groups are inverted by SN2 methods playing with protection and deprotection processes. For the synthesis of acyclic α-AAs, diastereoselective methods using mainly Garner's aldehyde have been described. Diastereodivergent routes allowed the synthesis of β-hydroxy- and β-amino-α-amino acids, as well as of β- and γ-amino acids. Heterocyclic and cyclic amino phosphonic acids were synthesized using diastereodivergent routes. Alkaloids containing five- and six-membered saturated azaheterocycles needed multistep stereodivergent routes and other alkaloids, such as enantiomers of balanol, vincamine, anatoxin and codeine, and diastereomeric isochaetominines C and galanthamines. In the terpene field, sesquiterpenes β-santalene, α-curcumene and α-cuparenone and the diterpene scopadulcic acid A have been synthesized using enantiodivergent routes.We thank the Spanish Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, EU) (projects CTQ2016-76782-P, CTQ2016-81797-REDC, and CTQ2017-85093-P), the Generalitat Valenciana (PROMETEOII/2014/017) and the University of Alicante for financial support

Structure Determination of Bioactive Metabolites from Marine-Derived Fungi and Simultaneous Analysis of Herbal Medicines by HPLC-DAD-ELSD-MS

학위논문 (박사)-- 서울대학교 대학원 : 약학과 천연물과학전공, 2015. 8. Shin Jongheon.Part A. Structure Determination of Bioactive Metabolites from Marine-Derived Fungi Marine natural products have been proven to be a prolific source of novel therapeutic agents that have demonstrated significant activities in various pathological conditions including cancer, viral infection, inflammation, analgesia, and immune modulation. The marine-derived fungi is one of the three dominated phylogenetic groups, have shown great diversity of their secondary metabolites and a wide range novel secondary metabolites have been isolated since 1980s. Marine-derived fungi alone have produced more than 400 novel compounds, of which several have exhibited potent and diverse bioactivities. The purpose of this study is to investigate new marine natural products from marine-derived fungi and study their biological activities. During the course of searching for bioactive metabolites from marine-derived fungi, two strains Penicillium sp. and Aspergillus sp. were selected for chemical investigation based on LC-ESIMS analysis and bioassay screening of the crude extracts. Secondary metabolites from the selected fungi were isolated and structure determination based on 1D, 2D NMR, and IR, UV, OR and MS. As a result, 9 novel compounds and 9 known compounds were structurally determined using integrated spectroscopic analysis and chemical approaches. These compounds belonged to various structural classes: meroterpenoids, alkaloids, anthroquinones, and lipopeptides. The biological activities of the isolated compounds were studied on various bioactivity tests: cytotoxicity, antimicrobial activities, inhibition against the enzymes isocitrate lyase (ICL), sortase A (SrtA) and Na+/K+-ATPase, and quinone reductase. Structure-activity relationships were also deduced. Part B. Simultaneous Analysis of Herbal Medicines by HPLC-DAD-ELSD-MS Traditional herbal medicines have been practiced to maintain health and treat diseases especially in the Asia communities for more than 2,000 years. Increment of worldwide attention and concomitant pharmaceutical research has made it essential to carry out the quality control measurement for the herbal medicines. However, serious hindrance has been attributed to the lack of recognition and regulation of professions, qualified practitioners, quality-controlled herbal medicines, and evidence-based clinical studies. Thus it is urgently needed to establish a comprehensive qualified evaluation method that could accurately reflect the quality of herbal medicines. The purpose of this study is developing simultaneous analysis methods of bioactive compounds in herbal medicines. Two herbal medicines, which are Kalopanacis Cortex and Semen Ziziphus jujuba were subjected to the current study. In herbal medicines, it is hard to consider that single or a few compounds would determine the overall pharmacological activities. Rather, it is more likely that multiple compounds act simultaneously and attribute to the therapeutic function of the herbal medicine. For this reason, most bioactive metabolite in the selected herbal medicines were analyzed and determined. In particular, three phenolics and nine hedergenin saponins were selected for the analysis of Kalopanacis Cortex. Moreover, one alkaloid, five flavonoid saponins and three jujuboside saponins from Semen Ziziphus jujuba were also analyzed. The methods based on HPLC-DAD-ELSD-MS was established for the quantitative and qualitative analysis of a selected folk medicine. Various validation parameters, such as linearity, limit of detection, limit of quantification, recovery, accuracy, and precision, were successfully obtained. In addition, the efficiencies of diverse extraction methods were compared for the development of a standard analytic method. The verified methods were successfully applied to the quantitative determination of representative metabolites in commercial samples from Korea, Myanmar and China.Abstract in English I List of Contents VI List of Tables VIII List of Figures XI Part A. Structure Determination of Bioactive Metabolites from Marine-Derived Fungi 1 I. Introduction 2 II. Penicillipyrones A and B, Meroterpenoids from a Marine-Derived Penicillium sp. Fungus. 13 III. Alkaloidal Metabolites from a Marine-Derived Aspergillus sp. Fungus 32 IV. Asperphenins A and B, as anticancer agents from a Marine-Derived Aspergillus sp. Fungus 64 V. Conclusion 102 Part B. Simultaneous Analysis of Herbal Medicines by HPLC-DAD-ELSD-MS 103 I. Introduction 104 II. Quantification and Identification of Bioactive Metabolites from Kalopanacis Cortex by HPLC with Evaporative Light Scattering Detection and ESI Quadrupole TOF MS 107 III. Simultaneous Analysis of Bioactive Metabolites from Semen Ziziphus jujuba by HPLC-DAD-ELSD-MS/MS 138 IV. Conclusion 162 Summary 163 References 170 Appendix A : NMR Spectroscopic Data 184 Appendix B : Supporting Information 196 Publication List 212 Acknowledgements 214Docto

One-step preparation of enantiopure L- or D-amino acid benzyl esters avoiding the use of banned solvents

The enantiomers of amino acid benzyl esters are very important synthetic intermediates. Many of them are currently prepared by treatment with benzyl alcohol and p-toluenesulfonic acid in refluxing benzene or carbon tetrachloride, to azeotropically remove water, and then precipitated as tosylate salt by adding diethyl ether. Here, we report a very efficient preparation of eight l- or d-amino acid benzyl esters (Ala, Phe, Tyr, Phg, Val, Leu, Lys, Ser), in which these highly hazardous solvents are dismissed using cyclohexane as a water azeotroping solvent and ethyl acetate to precipitate the tosylate salt. With some work-up modifications and lower yield, the procedure can be applied also to methionine. Chiral HPLC analysis shows that all the benzyl esters, including the highly racemizable ones such as those of phenylglycine, tyrosine and methionine, are formed enantiomerically pure under these new reaction conditions thus validating the solvents replacement. Contrariwise, toluene cannot be used in place of benzene or carbon tetrachloride because leading to partially or totally racemized amino acid benzyl esters depending on the polar effect of the amino acid \u3b1-side chain as expressed by Taft\u2019s substituent constant (\u3c3*)

Metabolomic tools to assess the chemistry and bioactivity of endophytic aspergillus strain

Endophytic fungi associated with medicinal plants are a potential source of novel chemistry and biology that may find applications as pharmaceutical and agrochemical drugs. In this study, a combination of metabolomics and bioactivity-guided approaches were employed to isolate anticancer secondary metabolites from an endophytic Aspergillus aculeatus. The endophyte was isolated from the Egyptian medicinal plant Terminalia laxiflora and identified using molecular biological methods. Metabolomics and dereplication studies were accomplished by utilizing the MZmine software coupled with the universal Dictionary of Natural Products database. Metabolic profiling, with aid of multivariate data analysis, was performed at different stages of the growth curve to choose the optimised method suitable for up-scaling. The optimised culture method yielded a crude extract abundant with biologically-active secondary metabolites. Crude extracts were fractionated using different high-throughput chromatographic techniques. Purified compounds were identified by HRESI-MS, 1D and 2D-NMR. This study introduced a new method of dereplication utilising both high-resolution mass spectrometry and NMR spectroscopy. The metabolites were putatively identified by applying a chemotaxonomic filter. We also present a short review on the diverse chemistry of terrestrial endophytic strains of Aspergillus, which has become a part of our dereplication work and this will be of wide interest to those working in this field. This article is protected by copyright. All rights reserved

Synthèses totales stéréodivergentes et énantiosélectives d'alcaloïdes de type chaetominine, cyclisations en cascade de radicaux azaphiliques pour la synthèse d'hétéroaromatiques de type imidazole et vers des analogues de l'unité 2-carboxyl-6-hydroxyoctahydroindole (CHOI)

Nitrogen-containing compounds have a great interest as this element is found in natural products and drugs, thus the development of efficient methods for their preparation is highly desirable. First, a stereodivergent and enantioselective method has been developed for the total syntheses of chaetominine-type alkaloids including the proposed structures of (-)-pseudofischerine, (-)-aniquinazoline D and (-)-isochaetominine, (-)-isochaetominines A–C, (+)-14-epi-isochaetominine C, as well as the four hitherto unknown stereoisomers of isochaetominine C. The structures of natural (-)-pseudofischerine and (-)-aniquinazoline D have been revised as (-)-isochaetominine C and the structure of the natural (-)-isochaetominine have been revised to (-)-11-epi-chaetominine based on our synthetic efforts. Next, an azaphilic radical cascade cyclization reaction has been developed leading to the efficient synthesis of imidazo-fused heteroaromatics from easily available N-heteroaryl-O-propargyl carbamates. The organocatalyzed electrochemical synthesis has a broad scope, tolerates many common functional groups, and proceeds under mild conditions without the need of transition-metal catalysis or chemical oxidant. Finally, two approaches toward analogs of the CHOI unit have been developed. The key steps of the synthetic route were based on Pd-catalyzed C-allylation and N-allylation, which converted a cyclic bis-allylic substrate into a hexahydroindole scaffold. Depending on the strategy applied, the position of alkene moiety of the resulting hexahydroindole can be obtained at different positions. One-carbon homologation followed by epoxidation or syn-dihydroxylation of the resulting bicyclic intermediates afforded the desired CHOI analogues.Les composés azotés ont un grand intérêt car cet élément se retrouve dans la plupart des produits naturels et pharmaceutiques, de sorte que le développement de méthodes efficaces pour leur préparation est hautement souhaitable. Tout d'abord, une méthode stéréodivergente et énantiosélective a été développée pour la synthèse totale des alcaloïdes de type chaetominine, y compris les structures proposées de la (-)-pseudofischerine, de l’(-)-aniquinazoline D et de l’(-)-isochaetominine, de l’(-)-isochaetominines A-C, de la (+)-14-epi-isochaetominine C, ainsi que les quatre stéréoisomères jusqu'ici inconnus de l'isochaetominine C. A la lumière de nos travaux de synthèse, les structures de la (-)-pseudofischerine naturelle et l’(-)-aniquinazoline D ont été révisées comme l’(-)-isochaetominine C, et la structure de l’(-)-isochaetominine naturelle a été révisée comme la (-)-11-epi-chaetominine. Ensuite, une réaction de cyclisation en cascade de radicaux azaphiles a été développée conduisant à une synthèse efficace d'hétéroaromatiques de type imidazo-accolés à partir de carbamates N-hétéroaryl-O-propargyliques facilement disponibles. La synthèse électrochimique organocatalysée est généralisable, tolère de nombreux groupes fonctionnels, et se déroule dans des conditions douces sans besoin de catalyse par les métaux de transition, ni d'oxydants. Enfin, deux approches à des analogues de l'unité CHOI ont été développées. Les étapes clés de la de synthèse sont basées sur la C-allylation et la N-allylation palladocatalysées, qui permettent la transformation d’un substrat bis-allylique cyclique en un hexahydroindole. En fonction de la stratégie appliquée, la position de la fonction alcène de l'hexahydroindole peut se retrouver sur des positions différentes du squelette. L’homologation d’un atome de carbone suivie d'une époxydation ou d'une syn-dihydroxylation des intermédiaires bicycliques résultants fournissent les analogues CHOI désirés

Synthèses totales stéréodivergentes et énantiosélectives d'alcaloïdes de type chaetominine, cyclisations en cascade de radicaux azaphiliques pour la synthèse d'hétéroaromatiques de type imidazole et vers des analogues de l'unité 2-carboxyl-6-hydroxyoctahydroindole (CHOI)

Les composés azotés ont un grand intérêt car cet élément se retrouve dans la plupart des produits naturels et pharmaceutiques, de sorte que le développement de méthodes efficaces pour leur préparation est hautement souhaitable. Tout d'abord, une méthode stéréodivergente et énantiosélective a été développée pour la synthèse totale des alcaloïdes de type chaetominine, y compris les structures proposées de la (-)-pseudofischerine, de l’(-)-aniquinazoline D et de l’(-)-isochaetominine, de l’(-)-isochaetominines A-C, de la (+)-14-epi-isochaetominine C, ainsi que les quatre stéréoisomères jusqu'ici inconnus de l'isochaetominine C. A la lumière de nos travaux de synthèse, les structures de la (-)-pseudofischerine naturelle et l’(-)-aniquinazoline D ont été révisées comme l’(-)-isochaetominine C, et la structure de l’(-)-isochaetominine naturelle a été révisée comme la (-)-11-epi-chaetominine. Ensuite, une réaction de cyclisation en cascade de radicaux azaphiles a été développée conduisant à une synthèse efficace d'hétéroaromatiques de type imidazo-accolés à partir de carbamates N-hétéroaryl-O-propargyliques facilement disponibles. La synthèse électrochimique organocatalysée est généralisable, tolère de nombreux groupes fonctionnels, et se déroule dans des conditions douces sans besoin de catalyse par les métaux de transition, ni d'oxydants. Enfin, deux approches à des analogues de l'unité CHOI ont été développées. Les étapes clés de la de synthèse sont basées sur la C-allylation et la N-allylation palladocatalysées, qui permettent la transformation d’un substrat bis-allylique cyclique en un hexahydroindole. En fonction de la stratégie appliquée, la position de la fonction alcène de l'hexahydroindole peut se retrouver sur des positions différentes du squelette. L’homologation d’un atome de carbone suivie d'une époxydation ou d'une syn-dihydroxylation des intermédiaires bicycliques résultants fournissent les analogues CHOI désirés.Nitrogen-containing compounds have a great interest as this element is found in natural products and drugs, thus the development of efficient methods for their preparation is highly desirable. First, a stereodivergent and enantioselective method has been developed for the total syntheses of chaetominine-type alkaloids including the proposed structures of (-)-pseudofischerine, (-)-aniquinazoline D and (-)-isochaetominine, (-)-isochaetominines A–C, (+)-14-epi-isochaetominine C, as well as the four hitherto unknown stereoisomers of isochaetominine C. The structures of natural (-)-pseudofischerine and (-)-aniquinazoline D have been revised as (-)-isochaetominine C and the structure of the natural (-)-isochaetominine have been revised to (-)-11-epi-chaetominine based on our synthetic efforts. Next, an azaphilic radical cascade cyclization reaction has been developed leading to the efficient synthesis of imidazo-fused heteroaromatics from easily available N-heteroaryl-O-propargyl carbamates. The organocatalyzed electrochemical synthesis has a broad scope, tolerates many common functional groups, and proceeds under mild conditions without the need of transition-metal catalysis or chemical oxidant. Finally, two approaches toward analogs of the CHOI unit have been developed. The key steps of the synthetic route were based on Pd-catalyzed C-allylation and N-allylation, which converted a cyclic bis-allylic substrate into a hexahydroindole scaffold. Depending on the strategy applied, the position of alkene moiety of the resulting hexahydroindole can be obtained at different positions. One-carbon homologation followed by epoxidation or syn-dihydroxylation of the resulting bicyclic intermediates afforded the desired CHOI analogues