- First asymmetric total synthesis of (+)-sparteine
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(Matrix presented) (+)-Sparteine The total synthesis of (+)-sparteine was accomplished from 2,5-norbornadione in 15 steps and 15.7% overall yield. The key steps were two ring-expansion reactions, one involving an intramolecular Schmidt reaction and one using a novel variant of the photo-Beckmann rearrangement.
- Smith, Brenton T.,Wendt, John A.,Aube, Jeffrey
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Read Online
- Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1
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Evidence suggests that specific mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2) are critical for the initiation and maintenance of certain tumor types and that inhibiting these mutant enzymes with small molecules may be therapeutically beneficial. In order to discover mutant allele-selective IDH1 inhibitors with chemical features distinct from existing probes, we screened a collection of small molecules derived from diversity-oriented synthesis. The assay identified compounds that inhibit the IDH1-R132H mutant allele commonly found in glioma. Here, we report the discovery of a potent (IC50 = 50 nM) series of IDH1-R132H inhibitors having 8-membered ring sulfonamides as exemplified by the compound BRD2879. The inhibitors suppress (R)-2-hydroxyglutarate production in cells without apparent toxicity. Although the solubility and pharmacokinetic properties of the specific inhibitor BRD2879 prevent its use in vivo, the scaffold presents a validated starting point for the synthesis of future IDH1-R132H inhibitors having improved pharmacological properties.
- Law, Jason M.,Stark, Sebastian C.,Liu, Ke,Liang, Norah E.,Hussain, Mahmud M.,Leiendecker, Matthias,Ito, Daisuke,Verho, Oscar,Stern, Andrew M.,Johnston, Stephen E.,Zhang, Yan-Ling,Dunn, Gavin P.,Shamji, Alykhan F.,Schreiber, Stuart L.
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- Rational Design of Orthogonal Multipolar Interactions with Fluorine in Protein-Ligand Complexes
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Multipolar interactions involving fluorine and the protein backbone have been frequently observed in protein-ligand complexes. Such fluorine-backbone interactions may substantially contribute to the high affinity of small molecule inhibitors. Here we found that introduction of trifluoromethyl groups into two different sites in the thienopyrimidine class of menin-MLL inhibitors considerably improved their inhibitory activity. In both cases, trifluoromethyl groups are engaged in short interactions with the backbone of menin. In order to understand the effect of fluorine, we synthesized a series of analogues by systematically changing the number of fluorine atoms, and we determined high-resolution crystal structures of the complexes with menin. We found that introduction of fluorine at favorable geometry for interactions with backbone carbonyls may improve the activity of menin-MLL inhibitors as much as 5- to 10-fold. In order to facilitate the design of multipolar fluorine-backbone interactions in protein-ligand complexes, we developed a computational algorithm named FMAP, which calculates fluorophilic sites in proximity to the protein backbone. We demonstrated that FMAP could be used to rationalize improvement in the activity of known protein inhibitors upon introduction of fluorine. Furthermore, FMAP may also represent a valuable tool for designing new fluorine substitutions and support ligand optimization in drug discovery projects. Analysis of the menin-MLL inhibitor complexes revealed that the backbone in secondary structures is particularly accessible to the interactions with fluorine. Considering that secondary structure elements are frequently exposed at protein interfaces, we postulate that multipolar fluorine-backbone interactions may represent a particularly attractive approach to improve inhibitors of protein-protein interactions.
- Pollock, Jonathan,Borkin, Dmitry,Lund, George,Purohit, Trupta,Dyguda-Kazimierowicz, Edyta,Grembecka, Jolanta,Cierpicki, Tomasz
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Read Online
- Cp*Rh(iii)/boron hybrid catalysis for directed C-H addition to β-substituted α,β-unsaturated carboxylic acids
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The C-H bond addition reaction of 2-phenylpyridine derivatives with α,β-unsaturated carboxylic acids catalyzed by Cp*Rh(iii)/BH3·SMe2is reported. Activation of C-H bonds with the rhodium catalyst and activation of α,β-unsaturated carboxylic acids with the boron catalyst cooperatively work, and a BINOL-urea hybrid ligand significantly improved the reactivity. With the optimized hybrid catalytic system, various β-disubstituted carboxylic acids were obtained under mild reaction conditions.
- Hirata, Yuki,Kojima, Masahiro,Matsunaga, Shigeki,Tanaka, Ryo,Yoshino, Tatsuhiko
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- C-H Alkylation of Aldehydes by Merging TBADT Hydrogen Atom Transfer with Nickel Catalysis
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Catalyst controlled site-selective C-H functionalization is a challenging but powerful tool in organic synthesis. Polarity-matched and sterically controlled hydrogen atom transfer (HAT) provides an excellent opportunity for site-selective functionalization. As such, the dual Ni/photoredox system was successfully employed to generate acyl radicals from aldehydes via selective formyl C-H activation and subsequently cross-coupled to generate ketones, a ubiquitous structural motif present in the vast majority of natural and bioactive molecules. However, only a handful of examples that are constrained to the use of aryl halides are developed. Given the wide availability of amines, we developed a cross-coupling reaction via C-N bond cleavage using the economic nickel and TBADT catalyst for the first time. A range of alkyl and aryl aldehydes were cross-coupled with benzylic and allylic pyridinium salts to afford ketones with a broad spectrum of functional group tolerance. High regioselectivity toward formyl C-H bonds even in the presence of α-methylene carbonyl or α-amino/oxy methylene was obtained.
- Murugesan, Vetrivelan,Ganguly, Anirban,Karthika, Ardra,Rasappan, Ramesh
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supporting information
p. 5389 - 5393
(2021/07/21)
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- Comparing the greenness and sustainability of three routes to an HIV protease inhibitor intermediate
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The greenness and sustainability of three different routes for the synthesis of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-ol (bis-furan alcohol), an advanced intermediate for a group of HIV protease inhibitors, including the FDA approved darunavir, used in antiretroviral (ARV) therapy, were compared. The method involved a comparison of (i) waste generated using theE-factor and relative to industrial benchmarks using the innovative Green Aspiration Level (iGAL) method, (ii) solvent usage on the basis of solvent intensity (SI) and properties according to the GSK solvent guide, and (iii) Green Motion scores according to the MANE methodology.
- Akakios, Stephanie Gina,Bode, Moira Leanne,Sheldon, Roger Arthur
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supporting information
p. 3334 - 3347
(2021/05/21)
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- Nickel-Catalyzed Decarboxylative Coupling of Redox-Active Esters with Aliphatic Aldehydes
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The addition of alkyl fragments to aliphatic aldehydes is a highly desirable transformation for fragment couplings, yet existing methods come with operational challenges related to the basicity and instability of the nucleophilic reagents commonly employed. We report herein that nickel catalysis using a readily available bioxazoline (BiOx) ligand can catalyze the reductive coupling of redox-active esters with aliphatic aldehydes using zinc metal as the reducing agent to deliver silyl-protected secondary alcohols. This protocol is operationally simple, proceeds under mild conditions, and tolerates a variety of functional groups. Initial mechanistic studies suggest a radical chain pathway. Additionally, alkyl tosylates and epoxides are suitable alkyl precursors to this transformation providing a versatile suite of catalytic reactions for the functionalization of aliphatic aldehydes.
- Xiao, Jichao,Li, Zhenning,Montgomery, John
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supporting information
p. 21234 - 21240
(2021/12/27)
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- METHODS OF USE FOR PYRIMIDINES AS FERROPORTIN INHIBITORS
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The subject matter described herein is directed to ferroportin inhibitor compounds of Formula (I) and pharmaceutical salts thereof, methods of preparing the compounds, pharmaceutical compositions comprising the compounds, and methods of administering the compounds for prophylaxis and/or treatment of diseases caused by a lack of hepcidin or iron metabolism disorders, particularly iron overload states, such as thalassemia, sickle cell disease and hemochromatosis, and also kidney injuries.
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Paragraph 745-748
(2021/11/06)
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- Synthesis of salicylate and salicylamide alcohols for the preparation of phosphorodiamidates and ifosfamide prodrugs
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Prodrugs are derivatives of drugs which gives parent drug or release drug when it breaks inside the body by the presence of suitable enzyme, and then exert desired pharmacological effect. For many years, prodrug strategy has been developed enormously to solve many unwanted drug properties. In drug discovery and development, prodrugs have well-known pharmacokinetic effects of pharmacologically nimble products. Almost 10% of drugs permitted whole world are classified as prodrugs, where the application of a prodrug method during initial stages of development is an emergent fashion. Phosphorodiamidates prodrugs are well known anticancer agents particularly against leucomia. To improve the selectivity of the chemotherapeutic agents and reduce systemic toxicity, I herein report different types of salicylate and salicylamide alcohols for the preparation of phosphorodiamidates and ifosfamide prodrugs.
- Pal, Ashutosh
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p. 295 - 301
(2021/05/19)
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- Manganese=Catalyzed Achmatowicz Rearrangement Using Green Oxidant H2O2
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Oxidation reactions have been extensively studied in the context of the transformations of biomass=derived furans. However, in contrast to the vast literature on utilizing the stoichiometric oxidants, such as m=CPBA and NBS, catalytic methods for the oxidative furan=recyclizations remain scarcely investigated. Given this, we report a means of manganese=catalyzed oxidations of furan with low loading, achieving the Achmatowicz rearrangement in the presence of hydrogen peroxide as an environmentally benign oxidant under mild conditions with wide functional group compatibility.
- Gao, Ziwei,Gou, Jing,Hao, Zhe,Hou, Jing,Li, Chaoqun,Li, Gaoqiang,Xing, Qingzhao,Yu, Binxun
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p. 9563 - 9586
(2021/07/20)
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- Predicting Octanol-Water Partition Coefficients of Fluorinated Drug-Like Molecules: A Combined Experimental and Theoretical Study
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In this paper, a dataset of 11 fluorinated compounds containing a variety of functional groups (amides, esters, indoles, and ethers) as well as mono, gem-difluoro, erythro-difluoro, and threo-difluoro patterns were synthesised and their octanol-water partition coefficients (log P) were measured using a shake-flask method. The resulting data was used to assess the performance of several popular empirical fragment-based methods as well as quantum chemical implicit solvent models (SMD and SM12). Overall, the empirical miLOGP, ALOGPS, and ALOGP methods performed the best with a mean absolute deviation (MAD) of ~0.25 log units, while the best performing implicit solvent model SMD has a slightly higher MAD of 0.36 log units. Based on the present work and previous studies, the miLOGP and ALOGP empirical methods are recommended for fast and moderately accurate prediction of log P for neutral organic solutes.
- Wu, Ying Min,Salas, Yuvixza Lizarme,Leung, Yun Cheuk,Hunter, Luke,Ho, Junming
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p. 677 - 685
(2020/05/26)
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- Efficient Generation and Synthetic Applications of Alkyl-Substituted Siloxycarbenes: Suppression of Norrish-Type Fragmentations of Alkanoylsilanes by Triplet Energy Transfer
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Acylsilanes have been known to undergo isomerization to siloxycarbenes under photoirradiation and the thus generated carbenes can be utilized for various synthetic reactions. But this carbene formation is not necessarily efficient with some alkanoylsilanes because Norrish-type fragmentations compete, which limit the synthetic utility of alkanoylsilanes as carbene precursors. In this study, generation of siloxycarbenes from alkanoylsilanes by visible-light-induced energy transfer was examined by using an Ir complex, [Ir{dF(CF3)ppy}2(dtbpy)]PF6, and was successfully applied to the C?C coupling reactions with boronic esters or aldehydes. This methodology efficiently suppressed undesired Norrish-type reactions and broadened synthetic utility of alkanoylsilanes.
- Abe, Manabu,Hagiwara, Chihiro,Ishida, Kento,Kusama, Hiroyuki,Yamazaki, Hokuto
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supporting information
p. 1249 - 1253
(2020/02/04)
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- Compounds and Their Use in Treating Cancer
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The specification generally relates to compounds of Formula (I): and pharmaceutically acceptable salts and prodrugs thereof, where R1, R4, R5, R6, R7, Linker, X, Y, A, G, D and E have any of the meanings defined herein. This specification also relates to the use of such compounds and pharmaceutically acceptable salts and prodrugs thereof in methods of treatment of the human or animal body, for example in prevention or treatment of cancer. This specification also relates to processes and intermediate compounds involved in the preparation of such compounds and to pharmaceutical compositions containing them.
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Paragraph 1331; 1332
(2019/07/10)
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- Tandem IBX-Promoted Primary Alcohol Oxidation/Opening of Intermediate β,γ-Diolcarbonate Aldehydes to (E)-γ-Hydroxy-α,β-enals
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A tandem IBX-promoted oxidation of primary alcohol to aldehyde and opening of intermediate β,γ-diolcarbonate aldehyde to (E)-γ-hydroxy-α,β-enal has been developed. Remarkably, the carbonate opening delivered exclusively (E)-olefin and no over-oxidation of γ-hydroxy was observed. The method developed has been extended to complete the stereoselective total synthesis of both (S)- and (R)-coriolides and d-xylo- and d-arabino-C-20 guggultetrols.
- Kumari, Anupama,Gholap, Sachin P.,Fernandes, Rodney A.
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p. 2278 - 2290
(2019/06/17)
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- Pipecolinic acid preparation process based on reverse dropping
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The invention discloses a pipecolinic acid preparation process based on reverse dropping and belongs to the technical field of medicines. By adopting the pipecolinic acid preparation process based onreverse dropping, S1-S2 and S3-S7 can be implemented simultaneously, so that the lasting time of the whole preparation process can be effectively shortened; meanwhile, by adopting a dropping mode in the preparation process, a conventional mode of dropping from top to bottom is changed into a mode of dropping from bottom to top, small water domes can be formed because of instantaneous impact resulted when a liquid to be dropped is fed into a reaction kettle, and are diffused outwards and upwards, liquid convection of the dropped liquid and a reactant can be enhanced because of the water domes,thus a good mixing effect is achieved, reactions can be accelerated to a certain extent, the preparation efficiency can be improved, and compared with the mode of dropping from top to bottom, the process is capable of effectively avoiding the phenomenon that the content of the reactant is changed to a certain extent as the liquid is splashed because of water impact and is adhered to an inner wall.
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Paragraph 0040; 0061; 0066
(2019/10/01)
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- Allylation of aldehydes by dual photoredox and nickel catalysis
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Here we report the application of dual nickel/photoredox catalysis to the allylation of aliphatic, aromatic and heteroaromatic aldehydes by using commercially available reagents. The process utilizes the combination of a Ni(ii) complex, [Ru(bpy)3]2+ as a photoredox catalyst, and allylacetate under blue LED irradiation, and allows the synthesis of a large variety of homoallylic alcohols.
- Gualandi, Andrea,Rodeghiero, Giacomo,Faraone, Adriana,Patuzzo, Filippo,Marchini, Marianna,Calogero, Francesco,Perciaccante, Rossana,Jansen, Thomas Paul,Ceroni, Paola,Cozzi, Pier Giorgio
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supporting information
p. 6838 - 6841
(2019/06/18)
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- Synthesis and glycosidase inhibition of broussonetine M and its analogues
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Cross-metathesis (CM) and Keck asymmetric allylation, which allows access to defined stereochemistry of a remote side chain hydroxyl group, are the key steps in a versatile synthesis of broussonetine M (3) from the D-arabinose-derived cyclic nitrone 14. By a similar strategy, ent-broussonetine M (ent-3) and six other stereoisomers have been synthesized, respectively, starting from L-arabino-nitrone (ent-14), L-lyxo-nitrone (ent-3-epi-14), and L-xylo-nitrone (2-epi-14) in five steps, in 26%–31% overall yield. The natural product broussonetine M (3) and 10’-epi-3 were potent inhibitors of β-glucosidase (IC50 = 6.3 μM and 0.8 μM, respectively) and β-galactosidase (IC50 = 2.3 μM and 0.2 μM, respectively); while their enantiomers, ent-3 and ent-10’-epi-3, were selective and potent inhibitors of rice α-glucosidase (IC50 = 1.2 μM and 1.3 μM, respectively) and rat intestinal maltase (IC50 = 0.29 μM and 18 μM, respectively). Both the configuration of the polyhydroxylated pyrrolidine ring and C-10’ hydroxyl on the alkyl side chain affect the specificity and potency of glycosidase inhibition.
- Wu, Qing-Kun,Kinami, Kyoko,Kato, Atsushi,Li, Yi-Xian,Jia, Yue-Mei,Fleet, George W.J.,Yu, Chu-Yi
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- Stereoselective synthesis of 5′-hydroxyzearalenone
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A first stereoselective total synthesis of 14-memebered β-resorcylic macrolactone 5′-hydroxyzearalenone (1) has been achieved. The key steps are Jocobsen hydrolytic kinetic resolution, Sharpless asymmetric dihydroxylation, Vilsmeier-Haack reaction, Mitsunobu esterification and ring-closing metathesis.
- Avuluri, Srilatha,Bujaranipalli, Sheshurao,Das, Saibal,Yadav
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p. 3547 - 3549
(2018/08/29)
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- Hydrogen Borrowing Catalysis with Secondary Alcohols: A New Route for the Generation of β-Branched Carbonyl Compounds
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A hydrogen borrowing reaction employing secondary alcohols and Ph? (Me5C6) ketones to give β-branched carbonyl products is described (21 examples). This new C-C bond forming process requires low loadings of [Cp?IrCl2]2, relatively low temperatures, and up to 2.0 equiv of the secondary alcohol. Substrate-induced diastereoselectivity was observed, and this represents the first example of a diastereoselective enolate hydrogen borrowing alkylation. By utilizing the Ph? group, the β-branched products could be straightforwardly cleaved to the corresponding esters or amides using a retro-Friedel-Crafts reaction. Finally, this protocol was applied to the synthesis of fragrance compound (±)-3-methyl-5-phenylpentanol.
- Akhtar, Wasim M.,Cheong, Choon Boon,Frost, James R.,Christensen, Kirsten E.,Stevenson, Neil G.,Donohoe, Timothy J.
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supporting information
p. 2577 - 2580
(2017/03/01)
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- BIPOLAR TETRAETHER LIPIDS
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Disclosed herein, inter alia, are compounds, compositions, and liposomes and methods of thereof.
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Paragraph 0450; 0453; 0454
(2017/03/21)
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- Total Synthesis of Brevisamide Using an Oxiranyl Anion Strategy
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A total synthesis of brevisamide, a marine monocyclic ether amide isolated from the dinoflagellate Karenia brevis, has been achieved in 18 steps starting from 4-(benzyloxy)butanol. The synthesis involves oxiranyl anion coupling between an epoxy sulfone and a triflate, intramolecular etherification of a hydroxy-bromoketone, diastereoselective introduction of the axial methyl group by hydroxyl-directed hydrogenation of an exocyclic olefin, and installation of an acetamide side chain by nucleophilic substitution of an N-acetyl carbamate. The dienal side chain is assembled using a Horner-Wadsworth-Emmons reaction to complete the synthesis.
- Sakai, Takeo,Fukuta, Ayumi,Nakamura, Kumiko,Nakano, Masato,Mori, Yuji
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p. 3799 - 3808
(2016/05/24)
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- Method for total synthesizing α-pyrone derivatives using by gold catalyst and α-pyrone derivatives having cytotoxicity against human cancer cell synthesized thereby
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The present invention relates to a method for total synthesis of an andalpha;-pyrone derivative comprises preparing a andbeta;-ketoester compound starting from butanol through the Witting olefin reaction, Swern oxidation reaction, Corey-Fuchs reaction and Claisen condensation, and subjecting the andbeta;-ketoester compound to 6-endo-dig intramolecular cyclization using a gold catalyst to form an andalpha;-pyrone ring and to carry out total synthesis of an andalpha;-pyrone derivative. The andalpha;-pyrone derivative obtained by the total synthesis method is (+)-violapyrone C having the same shape as the naturally occurring andalpha;-pyrone derivative and has cytotoxicity against at least 10 human cancer cell lines, and thus can be useful as an anti-cancer agent.(AA) Tautomer(BB) Bis(trifluoromethanesulfonyl)-imidate-(triphenylphosphine)gold(I)COPYRIGHT KIPO 2016
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Paragraph 0053; 0057
(2017/01/31)
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- Tandem vinylcyclopropane ring opening/Prins cyclization for the synthesis of 2,3-disubstituted tetrahydropyrans
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An efficient synthesis of 2,3-disubstituted tetrahydropyrans from aldehyde and cyclopropyl alkenol has been accomplished using HBF4·OEt2 as a promoter through a tandem vinylcyclopropane ring-opening/Prins cyclization. It is a convenient process to generate a structurally diverse and biologically relevant 2,3-disubstituted tetrahydropyrans in good yields with high selectivity.
- Reddy, B.V. Subba,Swathi,Bhadra, Manika Pal,Raju, M. Kanaka,Kunwar
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p. 1889 - 1891
(2016/04/19)
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- First stereoselective total synthesis of paecilomycin G
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The stereoselective total synthesis of resorcylic acid lactone, paecilomycin G (1) has been accomplished. The key steps involved are the Corey-Fuchs reaction, Sharpless asymmetric dihydroxylation, Jacobsen hydrolytic kinetic resolution, Stille coupling, Mitsunobu reaction, and Ring-closing metathesis (RCM) reaction.
- Bujaranipalli, Sheshurao,Das, Saibal
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supporting information
p. 2800 - 2802
(2016/06/09)
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- DIHYDROPYRIMIDIN-2-ONE COMPOUNDS AND MEDICAL USE THEREOF
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A compound of Formula [I] or a pharmaceutically acceptable salt thereof: wherein each symbol is defined as in the specification.
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Paragraph 0848-0850
(2016/08/07)
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- Stereoselective synthesis of dendrodolide-L
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An efficient stereoselective total synthesis of 12-membered macrolide dendrodolide L has been achieved. The key reactions involved are Keck asymmetric allylation, Jacobsen's hydrolytic kinetic resolution, Sharpless asymmetric epoxidation, Mitsunobu reaction and ring-closing metathesis reaction.
- Bujaranipalli, Sheshurao,Das, Saibal
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p. 254 - 260
(2017/03/01)
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- General, Simple, and Chemoselective Catalysts for the Isomerization of Allylic Alcohols: The Importance of the Halide Ligand
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Remarkably simple IrIIIcatalysts enable the isomerization of primary and sec-allylic alcohols under very mild reaction conditions. X-ray absorption spectroscopy (XAS) and mass spectrometry (MS) studies indicate that the catalysts, with the general formula [Cp*IrIII], require a halide ligand for catalytic activity, but no additives or additional ligands are needed.
- Erbing, Elis,Vázquez-Romero, Ana,Bermejo Gómez, Antonio,Platero-Prats, Ana E.,Carson, Fabian,Zou, Xiaodong,Tolstoy, P?ivi,Martín-Matute, Belén
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supporting information
p. 15659 - 15663
(2016/10/25)
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- Cyclohexane Rings Reduce Membrane Permeability to Small Ions in Archaea-Inspired Tetraether Lipids
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Extremophile archaeal organisms overcome problems of membrane permeability by producing lipids with structural elements that putatively improve membrane integrity compared to lipids from other life forms. Herein, we describe a series of lipids that mimic some key structural features of archaeal lipids, such as: 1) single tethering of lipid tails to create fully transmembrane tetraether lipids and 2) the incorporation of small rings into these tethered segments. We found that membranes formed from pure tetraether lipids leaked small ions at a rate that was about two orders of magnitude slower than common bilayer-forming lipids. Incorporation of cyclopentane rings into the tetraether lipids did not affect membrane leakage, whereas a cyclohexane ring reduced leakage by an additional 40 %. These results show that mimicking certain structural features of natural archaeal lipids results in improved membrane integrity, which may help overcome limitations of many current lipid-based technologies.
- Koyanagi, Takaoki,Leriche, Geoffray,Onofrei, David,Holland, Gregory P.,Mayer, Michael,Yang, Jerry
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supporting information
p. 1890 - 1893
(2016/02/03)
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- An enantioselective synthesis of (+)-hygroline and (+)-pseudohygroline via Keck allylation and CBS reduction
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Abstract An enantioselective synthesis of (+)-hygroline and (+)-pseudohygroline has been achieved in high optical purity (98% ee) from readily available 1,4-butanediol. The synthesis strategy employs a Keck allylation, CBS reduction, and Wacker oxidation.
- Bhoite, Shubhangi P.,Kamble, Rohit B.,Suryavanshi, Gurunath M.
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supporting information
p. 4704 - 4705
(2015/08/06)
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- A TEMPO-free copper-catalyzed aerobic oxidation of alcohols
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The copper-catalyzed aerobic oxidation of primary and secondary alcohols without an external N-oxide co-oxidant is described. The catalyst system is composed of a Cu/diamine complex inspired by the enzyme tyrosinase, along with dimethylaminopyridine (DMAP) or N-methylimidazole (NMI). The Cu catalyst system works without 2,2,6,6-tetramethyl-l-piperidinoxyl (TEMPO) at ambient pressure and temperature, and displays activity for un-activated secondary alcohols, which remain a challenging substrate for catalytic aerobic systems. Our work underscores the importance of finding alternative mechanistic pathways for alcohol oxidation, which complement Cu/TEMPO systems, and demonstrate, in this case, a preference for the oxidation of activated secondary over primary alcohols.
- Xu, Boran,Lumb, Jean-Philip,Arndtsen, Bruce A.
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supporting information
p. 4208 - 4211
(2015/04/14)
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- A formal total synthesis of (-)-brevisamide, a marine monocyclic ether amide
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A formal total synthesis of (-)-brevisamide, a monocyclic ether amide with architecturally unique structural features, has been achieved. The tetrahydropyran core part of the target was synthesized by the aldol reaction followed by ring-closing metathesis using the Grubbs second generation catalyst. After the stereochemistry at the carbon center bearing the hydroxy group was adjusted, the carbon-carbon double bond was stereoselectively reduced by catalytic hydrogenation. Finally, introduction of the amino group was followed by acetylation, which provided the desired advanced intermediate.
- Lee, Jungmee,Oh, Hong-Se,Kang, Han-Young
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supporting information
p. 1099 - 1102
(2015/02/19)
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- Influence of Alkoxy Groups on Rates of Acetal Hydrolysis and Tosylate Solvolysis: Electrostatic Stabilization of Developing Oxocarbenium Ion Intermediates and Neighboring-Group Participation to Form Oxonium Ions
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The hydrolysis of 4-alkoxy-substituted acetals was accelerated by about 20-fold compared to that of sterically comparable substrates that do not have an alkoxy group. Rate accelerations are largest when the two functional groups are linked by a flexible cyclic tether. When controlled for the inductive destabilization, an alkoxy group can accelerate acetal hydrolysis by up to 200-fold. The difference in rates of acetal hydrolysis between a substrate where the alkoxy group was tethered to the acetal group by a five-membered ring compared to one where it was tethered by an eight-membered ring was less than 100-fold, suggesting that fused-ring intermediates were not formed. By comparison, the difference in rates of solvolysis of structurally related tosylates were nearly 106-fold between the five- and eight-membered ring series. This observation implicates neighboring-group participation in the solvolysis of tosylates but not in the hydrolysis of acetals. The acceleration of acetal hydrolysis by an alkoxy group is better explained by electrostatic stabilization of intermediates that accumulate positive charge at the acetal carbon atom. (Chemical Presented).
- Garcia, Angie,Otte, Douglas A. L.,Salamant, Walter A.,Sanzone, Jillian R.,Woerpel
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p. 4470 - 4480
(2015/05/13)
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- Identification of novel ROS inducers: Quinone derivatives tethered to long hydrocarbon chains
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We performed the first synthesis of the 17-carbon chain-tethered quinone moiety 22 (SAN5201) of irisferin A, a natural product exhibiting anticancer activity, and its derivatives. We found that 22 is a potent ROS inducer and cytotoxic agent. Compound 25 (SAN7401), the hydroquinone form of 22, induced a significant release of intracellular ROS and apoptosis (EC50 = 1.3-2.6 μM) in cancer cell lines, including A549 and HCT-116. Compared with the activity of a well-known ROS inducer, piperlongumine, 22 and 25 showed stronger cytotoxicity and higher selectivity over noncancerous cells. Another hydroquinone tethering 12-carbon chain, 26 (SAN4601), generated reduced levels of ROS but showed more potent cytotoxicity (EC50 = 0.8-1.6 μM) in cancer cells, although it lacked selectivity over noncancerous cells, implying that the naturally occurring 17-carbon chain is also crucial for ROS production and a selective anticancer effect. Both 25 and 26 displayed strong, equipotent activities against vemurafenib-resistant SK-Mel2 melanoma cells and p53-deficient H1299 lung cancer cells as well, demonstrating their broad therapeutic potential as anticancer agents.
- Hong, Yeonsun,Sengupta, Sandip,Hur, Wooyoung,Sim, Taebo
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p. 3739 - 3750
(2015/05/27)
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- An expedient strategy towards an advanced pyrrolidine intermediate for the synthesis of pyrrolizidine alkaloids
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The asymmetric synthesis of a new pyrrolidine intermediate and a preceding amino triol derivative was accomplished using Crimmins' modified Evans aldol reaction as the key step. The synthetically useful pyrrolidine intermediate is expected to serve as the immediate precursor of biologically important pyrrolizidine alkaloids (-)-isoretronecanol and (-)-cremastrine. In addition, the amino triol subunit acts as a useful intermediate for the synthesis of oxocane heterocycles.
- Bera, Smritilekha,Mondal, Dhananjoy,Chatterjee, Bhaskar
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p. 1260 - 1262
(2015/09/22)
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- A convergent and stereoselective total synthesis of phomolides G and H
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A stereoselective total synthesis of phomolides G and H, a polyketide natural products is described. The synthesis involves organocatalytic enantioselective asymmetric epoxidation, C1-Wittig olefination, and ring-closing metathesis as key steps. The use of organocatalytic MacMillan asymmetric epoxidation for the construction of two chiral centers of phomolides G and H makes this approach more attractive. Georg Thieme Verlag Stuttgart New York.
- Subba Reddy,Sivaramakrishna Reddy,Phaneendra Reddy,Yadav
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p. 501 - 504
(2014/03/21)
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- Total synthesis and configurational validation of (+)-violapyrone C
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Gold(I)-catalyzed intramolecular 6-endo-dig cyclization of tert-butyl ynoates afforded α-pyrone cores of violapyrones. Moreover, this reaction was successfully applied to the stereospecific syntheses of (+)- and (-)-violapyrone C, which allowed the absolute configuration of natural (+)-violapyrone C to be assigned by comparison of the optical rotations. This first total synthesis, which proceeded in 22% yield over 10 steps from (S)-(-)-2-methylbutanol, features silver(I) oxide promoted monobenzylation of 1,4-butanediol, Wittig olefination, Claisen condensation, Corey-Fuchs reaction, and gold(I)-catalyzed α-pyrone synthesis. Copyright
- Lee, Jong Seok,Shin, Junho,Shin, Hee Jae,Lee, Hwa-Sun,Lee, Yeon-Ju,Lee, Hyi-Seung,Won, Hoshik
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supporting information
p. 4472 - 4476
(2014/08/05)
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- Design and synthesis of mimics of the T7-loop of FtsZ
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Mimics of the T7-loop of the bacterial cell division protein FtsZ have been designed and synthesized. The design is based on the X-ray cocrystal structure of P. aeruginosa FtsZ:SulA. Fast Rigid Exhaustive Docking (FRED) was employed to select compounds that can mimic the key interacting residues. Bicyclic oxazolidinones 1a-d were selected for further study and synthesized from a key bicyclic aziridine intermediate, which is synthesized from a readily available unsaturated aldehyde and amides derived from α-amino acids.
- Sorto, Nohemy A.,Painter, Phillip P.,Fettinger, James C.,Tantillo, Dean J.,Shaw, Jared T.
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supporting information
p. 2700 - 2703
(2013/07/19)
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- Total synthesis of attenols A and B
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A concise approach for the total synthesis of attenols A and B is described involving MacMillan's α-aminooxylation, Evan's asymmetric alkylation, Brown's allylation, and spiro-ketalization as key steps. This approach has successfully demonstrated the α-aminooxylation protocol for the construction of the anti-1,3-diol unit.
- Reddy, B.V. Subba,Reddy, B. Phaneendra,Swapnil,Yadav
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p. 5781 - 5784
(2013/10/01)
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- A formal stereoselective synthesis of (-)-brevisamide
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An efficient stereoselective formal synthesis of marine derived monocyclic ether (-)-brevisamide is reported. The key steps involved in this synthesis are syn-Aldol reaction, Sharpless asymmetric epoxidation, and stereoselective construction of tetrahydropyran ring by 6-endo-cyclization of suitably substituted hydroxy styrylepoxide.
- Yadav,Raju,Ravindar,Subba Reddy
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supporting information
p. 3227 - 3229
(2013/06/27)
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- Stereospecific asymmetric N-heterocyclic carbene (NHC)-catalyzed redox synthesis of trifluoromethyl dihydropyranones and mechanistic insights
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N-Heterocyclic carbene (NHC)-catalyzed redox asymmetric hetero-Diels-Alder reactions of α-aroyloxyaldehydes with β-trifluoromethyl enones generates synthetically useful dihydropyranones containing a stereogenic trifluoromethyl substituent in good yields (up to 81%) and excellent diastereoselectivity and enantioselectivity (up to >95:5 dr and >99% ee). The process is stereospecific, with use of either (E)- or (Z)-β- trifluoromethyl enones forming syn- or anti-dihydropyranone products, respectively. Mechanistic studies through in situ kinetic analysis of the reaction reveal key differences in reactivity between chiral NHC precursor 1 and an achiral NHC precursor.
- Davies, Alyn T.,Taylor, James E.,Douglas, James,Collett, Christopher J.,Morrill, Louis C.,Fallan, Charlene,Slawin, Alexandra M. Z.,Churchill, Gwydion,Smith, Andrew D.
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p. 9243 - 9257
(2013/10/08)
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- Total synthesis of the tubulin inhibitor WF-1360f based on macrocycle formation through ring-closing alkyne metathesis
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Key steps in this total synthesis of the antimitotic natural product WF-1360F (3) include the formation of the macrocycle through ring-closing alkyne metathesis and the subsequent conversion of the ensuing alkyne moiety into an E-configured double bond. As illustrated by the synthesis of 4, the macrocyclic vinyl iodide 2 can also serve as a common precursor for the synthesis of side-chain-modified rhizoxin analogues (see scheme; TIPS=triisopropylsilyl). Copyright
- Neuhaus, Christian M.,Liniger, Marc,Stieger, Martin,Altmann, Karl-Heinz
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supporting information
p. 5866 - 5870
(2013/07/05)
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- Synthesis and properties of monofluorinated dimyristoylphosphatidylcholine derivatives: Potential fluorinated probes for the study of membrane topology
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The synthesis of three monofluorinated dimyristoylphosphatidylcholine derivatives (F-DMPC), with the fluorine atom located on the acyl chain in position 2 of the glycerol (sn-2) is described. The synthetic strategy relies on the coupling of 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (lyso-PC) and three different fluorinated fatty acids. The latter were obtained from two different and complementary synthetic routes. Preliminary FTIR studies suggest that the presence of the fluorine atom does not significantly perturb the lipid conformational order and phase transition temperature and that these monofluorinated PC derivatives could be used as probes for the study of membrane topology, i.e. the location of drugs, peptides or proteins in membranes. The Royal Society of Chemistry 2012.
- Guimond-Tremblay, Jonathan,Gagnon, Marie-Claude,Pineault-Maltais, Jozy-Ann,Turcotte, Vanessa,Auger, Michele,Paquin, Jean-Franois
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supporting information; experimental part
p. 1145 - 1148
(2012/03/07)
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- COMPOUNDS
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The present invention features compounds of formula (I): and salts thereof, pharmaceutical compositions comprising said compounds, and uses of such compounds in treating or preventing viral infections, such as HCV infections, and diseases associated with such infections.
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Page/Page column 55
(2012/06/01)
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- Stereoselective total synthesis of stagonolide-C
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The highly stereoselective synthesis of a biologically active stagonolide-C has been described. The pivotal functionalities are derived from Barbier allylation, an epoxidation by m-CPBA, a chiral-auxiliary mediated acetate aldol addition, a 1,3-anti-reduction, a Sharpless kinetic resolution, a Yamaguchi macrolactonization, and ring-closing metathesis.
- Venkatesham, Akkaladevi,Nagaiah, Kommu
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p. 1186 - 1197,12
(2020/09/09)
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- Synthesis of the tetracyclic core of berkelic acid using gold(I)-catalyzed hydroarylation and oxidative radical cyclizations
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A synthetic approach to the tetracyclic core of berkelic acid is reported using gold(I)-catalyzed intramolecular hydroarylation and oxidative radical cyclizations to effect the key ring-forming steps. The carboxylic acid was introduced via a late-stage palladium-catalyzed carbonylation to afford the core tetracycle with the correct relative stereochemistry for the natural product.
- Brimble, Margaret A.,Haym, Isabell,Sperry, Jonathan,Furkert, Daniel P.
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p. 5820 - 5823
(2013/02/23)
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- A concise and diastereoselective synthesis of piperidine and indolizidine alkaloids via aza-Prins cyclization
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The synthesis of 2-substituted and 2,4-disubstituted piperidine alkaloids such as (±)-coniine, (±)-hydroxypipecolic acid, (±)-pipecolic acid, (±)-coniceine, and (±)-4-hydroxy-2- hydroxy-methyl piperidine have been accomplished in a highly diastereo-selective manner by employing aza-Prins cyclization as a key step to construct the piperidine core of these alkaloids. Georg Thieme Verlag Stuttgart · New York.
- Reddy, Basi V. Subba,Chaya, Dudhmal N.,Yadav, Jhillu S.,Gree, Rene
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experimental part
p. 297 - 303
(2012/03/26)
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- Dihydroxylation-based approach for the asymmetric syntheses of hydroxy-γ-butyrolactones
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A method of preparing enantiopure hydroxy-γ-butyrolactones containing multiple contiguous stereocenters in high yield with good diastereoselectivity has been developed. Osmium tetroxide mediated dihydroxylation of a range of β-alkenyl-β-hydroxy-N-acyloxazolidin-2-ones results in formation of triols that undergo spontaneous intramolecular 5-exo-trig cyclization reactions to provide hydroxy-γ-butyrolactones. The stereochemistry of these hydroxy-γ-butyrolactones has been established using NOE spectroscopy, which revealed that 1-substituted, 1,1-disubstituted, (E)-1,2-disubstituted, (Z)-1,2-disubstituted, and 1,1,2-trisubstituted alkenes undergo dihydroxylation with anti-diastereoselectivity, while 1,2,2-trisubstituted systems afford syn-diastereoisomers. The synthetic utility of this methodology has been demonstrated for the asymmetric synthesis of the natural product 2-deoxy-d-ribonolactone. Published 2011 by the American Chemical Society.
- Peed, Jennifer,Davies, Iwan R.,Peacock, Lucy R.,Taylor, James E.,Kociok-Koehn, Gabriele,Bull, Steven D.
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experimental part
p. 543 - 555
(2012/02/04)
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- Efficient and convenient method for workup of ozonolysis reaction using sodium hydrosulfite
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An efficient and convenient method is reported for reductive workup of the ozon-olysis reaction using sodium hydrosulfite. Comparisons were made between triethylamine and methyl sulfide for their use as a quenching reagent in the ozonolysis of a variety of alkenes. Taylor & Francis Group, LLC.
- Tyagi, Vipin,Gupta, Ashok Kumar
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experimental part
p. 843 - 848
(2012/02/01)
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- Preparation of (2E,4E)-2-(2-benzyloxyethyl)-5-(3-methoxy-4-chlorophenyl) penta-2,4-dienal as a key intermediate in the synthesis of strobilurin B
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(2E,4E)-2-(2-Benzyloxyethyl)-5-(4-chloro-3-methoxyphenyl)penta-2,4-dienal was obtained by the condensation of 4-benzyloxybutanal N-tert-butylimine with 4-chloro-3-methoxycinnamic aldehyde with ≥98% configurational purity and 40% yield. When 4-benzyloxy-2-triethylsilylbutanal imine was used, a 7: 3 mixture of the target (2E,4E)-dienal with its (2Z,4E)-isomer was obtained in 60% yield; the latter quantitatively isomerized to the thermodynamically preferable target (2E,4E)-dienal.
- Popovsky,Stepanov,Grigorieva
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p. 1616 - 1621
(2013/11/19)
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- Lewis acid-promoted addition of 1,3-bis(silyl)propenes to aldehydes: A route to 1,3-dienes
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The Lewis acid-promoted addition of 1,3-bis(silyl)-propenes to aldehydes to provide the corresponding (E)-1,3-dienes in excellent stereoselectivity and good to excellent yields is reported. The procedure is mild, base-free, and operationally straightforward.
- Borg, Tessie,Tuzina, Pavel,Somfai, Peter
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experimental part
p. 8070 - 8075
(2011/11/28)
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- Highly practical copper(I)/TEMPO catalyst system for chemoselective aerobic oxidation of primary alcohols
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Aerobic oxidation reactions have been the focus of considerable attention, but their use in mainstream organic chemistry has been constrained by limitations in their synthetic scope and by practical factors, such as the use of pure O2 as the oxidant or complex catalyst synthesis. Here, we report a new (bpy)CuI/TEMPO catalyst system that enables efficient and selective aerobic oxidation of a broad range of primary alcohols, including allylic, benzylic, and aliphatic derivatives, to the corresponding aldehydes using readily available reagents, at room temperature with ambient air as the oxidant. The catalyst system is compatible with a wide range of functional groups and the high selectivity for 1° alcohols enables selective oxidation of diols that lack protecting groups.
- Hoover, Jessica M.,Stahl, Shannon S.
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supporting information; experimental part
p. 16901 - 16910
(2011/12/04)
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