- Total syntheses of multiple cladiellin natural products by use of a completely general strategy
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The enantioselective total syntheses of 10 cladiellin natural products have been completed, starting from the known allylic alcohol (+)-14, which can be prepared in large quantities. The bridged tricyclic core of the cladiellins has been constructed via three ring-forming reactions: (i) an intramolecular reductive cyclization between an aldehyde and an unsaturated ester, mediated by samarium(II) iodide, to form a tetrahydropyranol; (ii) reaction of a metal carbenoid, generated from a diazo ketone, with an ether to produce an ylide-like intermediate that rearranges to produce E- or Z-oxabicyclo[6.2.1]-5-undecen-9- one; and (iii) a Diels-Alder cycloaddition reaction to construct the third ring found in the core structure of the cladiellins. The key ring-forming reaction, in which a diazo ketone is converted into a bridged bicyclic ether, can be tuned to give either of the isomeric oxabicyclo[6.2.1]-5-undecen-9-ones as the major product by switching from a copper to a rhodium catalyst and selecting the appropriate reaction conditions. The tricyclic products obtained from the three-step sequence involving the Diels-Alder cycloaddition reaction can be employed as advanced intermediates to prepare a wide range of cladiellin natural products.
- Clark, J. Stephen,Berger, Raphaelle,Hayes, Stewart T.,Senn, Hans Martin,Farrugia, Louis J.,Thomas, Lynne H.,Morrison, Angus J.,Gobbi, Luca
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- First total synthesis of 4-methylthio-3-butenyl glucosinolate
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The first total synthesis of 4-methylthio-3-butenyl glucosinolate (MTBG), a natural bioactive compound and a precursor of radish phototropism-regulating substances, was achieved from commercially available 1,4-butanediol. The glucosinolate framework was prepared by coupling of an oximyl chloride derivative and tetraacetyl thioglucose. A methylthio group was introduced to the framework by a Wittig reaction between triphenylphosphonium thiomethylmethylide and an aldehyde intermediate of glucosinolate. The synthetic route should facilitate preparation of various derivatives needed for probe synthesis based on MTBG.
- Yamazoe, Sayumi,Hasegawa, Koji,Shigemori, Hideyuki
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- Enantio and Stereoselective Synthesis of (5R,6S)-6-Acetoxy-hexadecanolide, a Mosquito Oviposition Attractant Pheromone
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The enantio and stereoselective synthesis of (5R,6S)-6-acetoxy-hexadecanolide is described via chemo, regio and stereoselective opening with LiI of a chiral epoxy alcohol precursor.
- Bonini, Carlo,Checconi, Massimo,Righi, Giuliana,Rossi, Leucio
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- Co2(CO)8-mediated endo mode cyclization of epoxy-alcohol: synthesis of 2-ethynyl-3-hydroxy-2-methyltetrahydropyran and 2-ethynyl-3-hydroxy-3-methyltetrahydropyran derivatives.
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Successive treatment of 4,5-epoxy-5-methyl-7-trimethylsilyl-6-heptyne-1-ol with Co2(CO)8 at 0 degrees C and a catalytic amount of BF3 x OEt2 at -78 degrees C gave the tetrahydropyran derivatives with the cobalt-complexed moiety. Similarly 4,5-epoxy-4-methyl-7-trimethylsilyl-6-heptyne-1-ol underwent ring closure under the above conditions to provide the corresponding tetrahydropyran derivatives. The preferential endo mode cyclization over the exo one was observed in these experiments.
- Mukai,Yamaguchi,Kim,Hanaoka
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- Synthesis of the originally proposed structure of palmerolide C
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A stereoselective synthesis of the proposed structure of palmerolide C (1), a cytotoxic marine macrolide isolated from the Antarctic tunicate Synoicum adareanum, utilizes a convergent carbonyl-based coupling strategy to construct the C1-C24 carbon skeleton (see scheme). Compound 1 was shown to be a diastereomer of palmerolide C, and the structural revision of the natural product is proposed. Copyright
- Florence, Gordon J.,Wlochal, Joanna
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p. 14250 - 14254,5
(2012)
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Read Online
- Unexpected dehydrogenation products in the furan series arising from ruthenium-catalyzed 4-oxo-1,6-enyne metathesis
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Metathesis of 4-oxo-1,6-enynes afforded the usual dihydrofuran products accompanied for the first time by unexpected side products identified as the corresponding furans. It probably arose from ruthenium-catalyzed dehydrogenation of dihydrofurans in the m
- Evanno, Laurent,Nay, Bastien,Bodo, Bernard
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- Synthesis of β-ketophosphonates from thioester intermediates: A stereocontrolled route to the C29-C35 fragment of the halichondramides
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An efficient synthesis of β-ketophosphonates from t-butyl thioesters using the lithium anion of either methane- or ethane-phosphonate is described. The elaboration of a range of substrates to intermediates in natural product syntheses via the Horner Wadsworth Emmons reaction is then discussed.
- Hulme, Alison N.,Howells, Garnet E.,Walker, Rachel H.
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- Building addressable libraries: The use of "safety-Catch" linkers on microelectrode arrays
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A "safety-catch" linker strategy has been used to site-selectively cleave and characterize molecules from a microelectrode array. The linkers are attached to the array by means of an ester and contain either a protected amine or protected alcohol nucleophile that can be released using acid generated at the microelectrodes.
- Bi, Bo,Maurer, Karl,Moeller, Kevin D.
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- Sigmatropic Rearrangement of Vinyl Aziridines: Expedient Synthesis of Cyclic Sulfoximines from Chiral Sulfinimines
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A novel rearrangement of 2-vinyl aziridine 2-carboxylates to unusual chiral cyclic sulfoximines is described herein. The method allows the synthesis of substituted cyclic sulfoximines in high yields with complete stereocontrol, and tolerates a wide substrate scope. A one-pot process starting directly from sulfinimines provides access to complex chiral sulfoximines in only two steps from commercially available aldehydes. A mechanistic hypothesis and synthetic application in the formal synthesis of trachelanthamidine, by transformation of a cyclic sulfoximine into a pyrroline, is also disclosed.
- Moragas, Toni,Liffey, Ryan M.,Regentová, Dominika,Ward, Jon-Paul S.,Dutton, Justine,Lewis, William,Churcher, Ian,Walton, Lesley,Souto, José A.,Stockman, Robert A.
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- SCALEABLE PREPARATION OF POLYKETIDES
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Disclosed herein, inter alia, are methods of making polyketide compounds.
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Paragraph 0253-0256; 0412-0415
(2021/02/12)
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- SUBSTITUTED STRAIGHT CHAIN SPIRO DERIVATIVES
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Provided herein are pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, pharmaceutical composition comprising such compounds, and their use as menin/MLL protein/protein interaction inhibitors, useful for treating diseases such as cancer, including but not limited to leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN); and diabetes.
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Page/Page column 95
(2021/06/26)
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- Micellar Catalysis for Sustainable Hydroformylation
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It is here reported a fully sustainable and generally applicable protocol for the regioselective hydroformylation of terminal alkenes, using cheap commercially available catalysts and ligands, in mild reaction conditions (70 °C, 9 bar, 40 min). The process can take advantages from both micellar catalysis and microwave irradiation to obtain the linear aldehydes as the major or sole regioisomers in good to high yields. The substrate scope is largely explored as well as the application of hydroformylation in tandem with intramolecular hemiacetalization thus demonstrating the compatibility with a broad variety of functional groups. The reaction is efficient even in large scale and the catalyst and micellar water phase can be reused at least 5 times without any impact in reaction yields. The efficiency and sustainability of this protocol is strictly related to the in situ transformation of the aldehyde into the corresponding Bertagnini's salt that precipitates in the reaction mixture avoiding organic solvent mediated purification steps to obtain the final aldehydes as pure compounds.
- Calamante, Massimo,Dei, Filippo,Maramai, Samuele,Migliorini, Francesca,Petricci, Elena
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p. 2794 - 2806
(2021/05/03)
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- Formal Synthesis of (-)-Haliclonin A: Stereoselective Construction of an Azabicyclo[3.3.1]nonane Ring System by a Tandem Radical Reaction
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A formal synthesis of (-)-haliclonin A, isolated from the marine sponge Haliclona sp. in Korea, is described. The key feature of the synthesis includes the highly stereoselective tandem radical reaction to construct the azabicyclo[3.3.1]nonane core and the enantioselective formation of an all-carbon quaternary center via the Pd-mediated deracemization.
- Komine, Keita,Urayama, Yasuhiro,Hosaka, Taku,Yamashita, Yuki,Fukuda, Hayato,Hatakeyama, Susumi,Ishihara, Jun
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supporting information
p. 5046 - 5050
(2020/07/04)
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- Catalytic Asymmetric Hydrogenation of Dehydroamino Acid Esters with Biscarbamate Protection and Its Application to the Synthesis of xCT Inhibitors
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Catalytic asymmetric hydrogenation of dehydroamino acid esters with biscarbamate protection was examined for the first time to prepare optically active amino acids. The new method was successfully applied to the synthesis of new cystine–glutamate exchanger inhibitors.
- Yasuno, Yoko,Mizutani, Iho,Sueuchi, Yuki,Wakabayashi, Yuuka,Yasuo, Nozomi,Shimamoto, Keiko,Shinada, Tetsuro
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supporting information
p. 5145 - 5148
(2019/03/17)
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- Site-Selective 1,1-Difunctionalization of Unactivated Alkenes Enabled by Cationic Palladium Catalysis
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A palladium(II)-catalyzed 1,1-difunctionalization of unactivated terminal and internal alkenes via addition of two nucleophiles was developed using a cationic palladium(II) complex. The palladacycle generated in situ as a result of a regioselective addition of a nucleophile to the alkene can readily undergo regioselective β-hydride elimination and migratory insertion with a cationic palladium catalyst. The resulting η3-π-allyl palladium(II) complex is the key intermediate that reacts with a second nucleophile to furnish the desired 1,1-difunctionalization of the alkene. Under the optimized reaction conditions, a wide range of indoles and anilines add to alkene units of 3-butenoic or 4-pentenoic acid derivatives to afford the synthetically useful γ,γ- or δ,δ-difunctionalized products with excellent regiocontrol. Furthermore, by employing internal hydroxyl or acid groups and external carbon nucleophiles, this transformation enables unsymmetric 1,1-difunctionalization to forge challenging and important oxo quaternary carbon centers. Combining experiments and DFT calculations on the mechanism of the reaction is investigated in detail.
- Jeon, Jinwon,Ryu, Ho,Lee, Changseok,Cho, Dasol,Baik, Mu-Hyun,Hong, Sungwoo
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- Site-Selective 1,1-Difunctionalization of Unactivated Alkenes Enabled by Cationic Palladium Catalysis
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A palladium(II)-catalyzed 1,1-difunctionalization of unactivated terminal and internal alkenes via addition of two nucleophiles was developed using a cationic palladium(II) complex. The palladacycle generated in situ as a result of a regioselective addition of a nucleophile to the alkene can readily undergo regioselective β-hydride elimination and migratory insertion with a cationic palladium catalyst. The resulting η 3-π-allyl palladium(II) complex is the key intermediate that reacts with a second nucleophile to furnish the desired 1,1-difunctionalization of the alkene. Under the optimized reaction conditions, a wide range of indoles and anilines add to alkene units of 3-butenoic or 4-pentenoic acid derivatives to afford the synthetically useful γ,γ-or ?,?-difunctionalized products with excellent regiocontrol. Furthermore, by employing internal hydroxyl or acid groups and external carbon nucleophiles, this transformation enables unsymmetric 1,1-difunctionalization to forge challenging and important oxo quaternary carbon centers. Combining experiments and DFT calculations on the mechanism of the reaction is investigated in detail.
- Jeon, Jinwon,Ryu, Ho,Lee, Changseok,Cho, Dasol,Baik, Mu-Hyun,Hong, Sungwoo
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p. 10048 - 10059
(2019/07/04)
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- Axial-to-Central Chirality Transfer for Construction of Quaternary Stereocenters via Dearomatization of BINOLs
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All-carbon quaternary stereocenters are versatile building blocks, and their asymmetric construction has attracted much attention. Herein, we disclose an axial-to-central chirality transfer strategy for the synthesis of chiral quaternary stereocenters via dearomatization of (S)-BINOLs. The reaction proceeded smoothly with a wide range of propargyl carbonates to afford chiral spiro-compounds in high yields with excellent enantioselectivities. In addition, the strategy was extended to kinetic resolution of rac-BINOLs albeit with moderate s value.
- Min, Xiao-Long,Xu, Xu-Ran,He, Ying
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supporting information
p. 9188 - 9193
(2019/11/14)
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- Chiral geminal disilyl alkane compound, synthesis method and applications thereof
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The present invention discloses a chiral geminal disilyl alkane compound, which is represented by a formula V, wherein * represents a chiral carbon atom in the formula V. The invention discloses a synthesis method of the chiral geminal disilyl alkane compound, wherein the synthesis method comprises: carrying out a reaction in the presence of a reducing agent by using alkyne represented by a formula I, dihydrosilane represented by a formula II and trihydrosilane represented by a formula III as raw materials and using Xantphos-CoBr2 and a chiral CoX2-OIP complex as catalysts under an inert gas to prepare the chiral geminal disilyl alkane compound represented by the formula V. According to the present invention, the method has characteristics of mild reaction condition, simple operation, highatomic economy, no requirement of the addition of any other toxic transition metals (such as ruthenium, rhodium, palladium and the like) salts, high yield and high enantioselectivity, and has great practical value in the synthesis of drugs and materials, wherein the yield is generally 50-85%, and the enantioselectivity is generally 93-99%. The formulas I, II, III and V are defined in the specification.
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Paragraph 0204; 0205; 0206; 0207; 0210
(2019/01/14)
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- Posaconazole derivative, pharmaceutical composition and use thereof
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The present disclosure provides a posaconazole derivative, a pharmaceutical composition and use thereof, which specifically include a compound represented by the following formula (I), a racemate, stereoisomer, tautomer, oxynitride, or a pharmaceutically acceptable salt thereof: The compounds of the present disclosure have strong antifungal activity, high safety, and good water solubility, without the need for the addition of a cosolvent (such as hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and the like) with potential safety risks. Furthermore, the formulation process of the compound could have less difficulty and less cost, and therefore can be used to prepare improved antifungal drugs.
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- Asymmetric Cycloetherification by Bifunctional Organocatalyst
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Attempts to obtain enantiomerically enriched tetrahydrofuran derivatives via an intramolecular oxy -Michael addition reaction of ?-hydroxyenone is discussed. Despite previous difficulties associated with the asymmetric induction of this reaction, which can proceed even without a catalyst, a highly efficient asymmetric induction was realized using a bifunctional organocatalyst derived from a cinchona alkaloid. The reaction could be extended to ζ-hydroxyenone to yield an optically active tetrahydropyran derivative with a high ee. In these reactions, it is important for the gentle acidic and basic sites in the bifunctional organocatalyst to be arranged properly within the molecular skeleton of the catalyst. The high performance asymmetric induction relied on the affinity of the catalyst for the substrate, which played an important role. A disubstituted tetrahydropyran synthesis could be effectively performed via kinetic resolution using ζ-hydroxyenone containing a secondary alcohol moiety using a chiral phosphoric acid catalyst.
- Asano, Keisuke,Matsubara, Seijiro
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supporting information
p. 4243 - 4253
(2018/07/03)
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- Scalable Synthesis of (-)-Rasfonin Enabled by a Convergent Enantioselective α-Hydroxymethylation Strategy
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A scalable synthesis of the potent antitumor agent, (-)-rasfonin, has been achieved. The synthetic strategy features a highly convergent approach based on a single protocol construction of both major fragments via catalytic enantioselective α-hydroxymethylation of simple aliphatic aldehydes. The route described has been successful in the generation of gram quantities of the natural product and serves as the first synthetic strategy to provide sufficient material to continue studies related to its mechanism of action and potential as a cancer therapeutic.
- Boeckman, Robert K.,Niziol, Justin M.,Biegasiewicz, Kyle F.
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supporting information
p. 5062 - 5065
(2018/08/24)
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- Pd(II)-Catalyzed [4 + 2] Heterocyclization Sequence for Polyheterocycle Generation
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A new Pd(II)-catalyzed cascade sequence for the formation of polyheterocycles, from simple starting materials, is reported. The sequence is applicable to both indole and pyrrole substrates, and a range of substituents are tolerated. The reaction is thought to proceed by a Pd(II)-catalyzed C-H activated Heck reaction followed by a second Pd(II)-catalyzed aza-Wacker reaction with two Cu(II)-mediated Pd(0) turnovers per sequence. The sequence can be considered a formal [4 + 2] heterocyclization.
- Glaisyer, Elizabeth L.,Watt, Michael S.,Booker-Milburn, Kevin I.
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supporting information
p. 5877 - 5880
(2018/09/25)
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- Gold-Catalyzed Oxidative Coupling of Alkynes toward the Synthesis of Cyclic Conjugated Diynes
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Gold-catalyzed oxidative coupling of alkynes was developed as an efficient approach for the synthesis of challenging cyclic conjugated diynes (CCD). Compared with the classic copper-promoted oxidative coupling reaction of alkynes, this gold-catalyzed process exhibited a faster reaction rate due to rapid reductive elimination from the Au(III) intermediate. This unique reactivity thus allowed a challenging diyne macrocyclization to take place with high efficiency. Condition screening revealed an [(n-Bu)4N]+[Cl-Au-Cl]? salt as the optimal pre-catalyst. Macrocycles with ring size between 13 and 28 atoms were prepared in moderate to good yields, which highlighted the broad substrate scope of this new strategy. Furthermore, the synthetic utilities of the CCDs for copper-free click chemistry have been demonstrated, showcasing the potential application of this strategy in biological systems. Macrocycles are important structural moieties in medicinal and biological research, and efficient methods for macrocyclization are always in high demand. With the unique conformation having six carbon atoms in a linear geometry, the cyclic conjugated diynes (CCD) present greater synthetic challenges and have been much less explored. Therefore, application of these unique macrocycles in biological studies is largely unexplored. Here, we describe the discovery of gold-catalyzed Glaser-Hay type oxidative coupling of terminal alkynes to achieve CCD under diluted conditions with broad substrate scope and great functional group compatibility. Taking advantage of the 14-member cyclic diyne, a copper-free click chemistry was achieved, which provided an effective alternative strategy for the traditional cyclooctyne-based azide-alkyne cycloaddition, suggesting a promising future for this method in tackling challenging problems in related biological and medicinal research. Gold-catalyzed oxidative coupling of alkynes was developed as an efficient approach for the synthesis of challenging cyclic conjugated diyne. Compared with copper-promoted oxidative coupling, this protocol allowed macrocyclization under dilute conditions with good overall reactivity and high functional group tolerance. The success in achieving copper-free click chemistry on cyclic conjugated diyne highlights its potential application in biological and medicinal research.
- Ye, Xiaohan,Peng, Haihui,Wei, Chiyu,Yuan, Teng,Wojtas, Lukasz,Shi, Xiaodong
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p. 1983 - 1993
(2018/10/02)
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- Total syntheses of surinone B, alatanones A–B, and trineurone A
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The total syntheses of four polyketides, surinone B (1), alatanones A–B (2–3), and trineurone A (4) were accomplished through an efficient and unified strategy via one-pot C-acylation reaction coupling 1,3-cyclohexadiones with EDC-activated acids under mild conditions. Alatanone A (2) was found to be a potent anti-microbial agent against Gram-positive and Gram-negative bacteria with MIC 31.25?μg/ml while alatanone B (3) was found to be a potent anti-fungal agent against Cladosporium cladosporioides with MIC 62.5?μg/ml compared to cycloheximide MIC 125?μg/ml. Our methodology allows performing kilogram scale of these scarce polyketides for the development of new antimicrobials.
- Gundoju, Narayana Rao,Bokam, Ramesh,Yalavarthi, Nageswara Rao,Buddana, Sudheer Kumar,Prakasham,Ponnapalli, Mangala Gowri
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- Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics
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The amide moiety of peptides can be replaced for example by a triazole moiety, which is considered to be bioisosteric. Therefore, the carbonyl moiety of an amino acid has to be replaced by an alkyne in order to provide a precursor of such peptidomimetics. As most amino acids have a chiral center at Cα, such amide bond surrogates need a chiral moiety. Here the asymmetric synthesis of a set of 24 N-sulfinyl propargylamines is presented. The condensation of various aldehydes with Ellman's chiral sulfinamide provides chiral N-sulfinylimines, which were reacted with (trimethylsilyl)ethynyllithium to afford diastereomerically pure N-sulfinyl propargylamines. Diverse functional groups present in the propargylic position resemble the side chain present at the Cα of amino acids. Whereas propargylamines with (cyclo)alkyl substituents can be prepared in a direct manner, residues with polar functional groups require suitable protective groups. The presence of particular functional groups in the side chain in some cases leads to remarkable side reactions of the alkyne moiety. Thus, electron-withdrawing substituents in the Cα-position facilitate a base induced rearrangement to α,β-unsaturated imines, while azide-substituted propargylamines form triazoles under surprisingly mild conditions. A panel of propargylamines bearing fluoro or chloro substituents, polar functional groups, or basic and acidic functional groups is accessible for the use as precursors of peptidomimetics.
- Wünsch, Matthias,Schr?der, David,Fr?hr, Tanja,Teichmann, Lisa,Hedwig, Sebastian,Janson, Nils,Belu, Clara,Simon, Jasmin,Heidemeyer, Shari,Holtkamp, Philipp,Rudlof, Jens,Klemme, Lennard,Hinzmann, Alessa,Neumann, Beate,Stammler, Hans-Georg,Sewald, Norbert
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supporting information
p. 2428 - 2441
(2017/12/06)
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- Backbone-Modified Bisdiazaphospholanes for Regioselective Rhodium-Catalyzed Hydroformylation of Alkenes
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A series of tetraaryl bisdiazaphospholane (BDP) ligands were prepared varying the phosphine bridge, backbone, and substituents in the 2- and 5-positions of the diazaphospholane ring. The parent acylhydrazine backbone was transformed to an alkylhydrazine via a borane reduction procedure. These reduced ligands contained an all sp3 hybridized ring mimicking the all sp3 phospholane of (R,R)-Ph-BPE, a highly selective ligand in asymmetric hydroformylation. The reduced bisdiazaphospholane (red-BDP) ligands were shown crystallographically to have an increased C-N-N-C torsion angle - this puckering resembles the structure of (R,R)-Ph-BPE and has a dramatic influence on regioselectivity in rhodium catalyzed hydroformylation. The red-BDPs demonstrated up to a 5-fold increase in selectivity for the branched aldehyde compared to the acylhydrazine parent ligands. This work demonstrates a facile procedure for increased branched selectivity from the highly active and accessible class of BDP ligands in hydroformylation.
- Wildt, Julia,Brezny, Anna C.,Landis, Clark R.
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p. 3142 - 3151
(2017/09/05)
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- Photochemical Approaches to the Bilobalide Core
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Bilobalide is a tetracyclic sesquiterpene containing three contiguous γ-lactone rings and an unusual tert-butyl group, which is found in the leaves of the ginkgo tree (Ginkgo biloba). Three different photochemical approaches towards bilobalide's unique sk
- Emsermann, Jens,Opatz, Till
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p. 3362 - 3372
(2017/06/29)
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- Intramolecular thermal stepwise [2 + 2] cycloadditions: Investigation of a stereoselective synthesis of [n.2.0]-bicyclolactones
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Fused cyclobutanes are found in a range of natural products and formation of these motifs in a straightforward and easy manner represents an interesting synthetic challenge. To this end we investigated an intramolecular variant of the thermal enamine [2 + 2] cyclisation, developing a diastereoselective intramolecular enamine [2 + 2] cyclisation furnishing δ lactone and lactam fused cyclobutenes in good yield and excellent diastereoselectivity.
- Throup, Adam,Patterson, Laurence H.,Sheldrake, Helen M.
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supporting information
p. 9554 - 9559
(2016/10/22)
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- BTK inhibitor and uses thereof
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The present invention provides a BTK inhibitor compound (having s structure represented by a formula (I)) and uses of the BTK inhibitor compound in medicines. According to the present invention, the compound and the pharmaceutical composition can be used for treatment of diffuse large B-cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia. The formula (I) is defined in the specification.
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Paragraph 0149; 0197-0198
(2017/01/09)
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- Tunable P-Chiral Bisdihydrobenzooxaphosphole Ligands for Enantioselective Hydroformylation
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Air-stable and tunable chiral bisdihydrobenzooxaphosphole ligands (BIBOPs) were employed in rhodium-catalyzed asymmetric hydroformylation of various terminal olefins with excellent conversions (>99%), moderate-to-excellent enantioselectivities (up to 95:5 er), and branched to linear ratios (b:l) of up to 400.
- Tan, Renchang,Zheng, Xin,Qu, Bo,Sader, C. Avery,Fandrick, Keith R.,Senanayake, Chris H.,Zhang, Xumu
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supporting information
p. 3346 - 3349
(2016/07/26)
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- Stereoselective Total Synthesis of Atractylodemayne A, a Conjugated 2(E),8(Z),10(E)-Triene-4,6-diyne
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The first total synthesis of the polyacetylene natural product atractylodemayne A is reported. Stereoselective construction of the conjugated 8(Z),10(E)-diene moiety was achieved through a tethered ring-closing metathesis approach, comprising a Ru-catalyz
- Schmidt, Bernd,Aud?rsch, Stephan
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p. 1162 - 1165
(2016/03/15)
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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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- Development of an efficient route toward meiogynin A-inspired dual inhibitors of Bcl-xL and Mcl-1 anti-apoptotic proteins
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The synthesis, on a large scale, with very good yield and er via an efficient strategy, of a chiral 4-substituted 2-cyclohexenone intermediate, was a milestone in the synthesis of seven analogues of meiogynin A, a natural sesquiterpenoid dimer. These comp
- Desrat, Sandy,Remeur, Camille,Roussi, Fanny
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p. 5520 - 5531
(2015/05/20)
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- Proline-Catalyzed Knoevenagel Condensation/[4+2] Cycloaddition Cascade Reaction: Application to Formal Synthesis of Averufin
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A remarkable proline-catalyzed method for the construction of biologically interesting oxygen-bridged tricyclic ketal skeletons was uncovered by starting from a variety of readily available cyclic 1,3-diketones and either 1,4- or 1,5-dicarbonyl substrates. The approach, which mimics a biosynthetic Knoevenagel condensation/[4+2] cycloaddition sequence, establishes a viable synthetic strategy for the efficient formal synthesis of averufin. A remarkable proline-catalyzed Knoevenagel condensation/[4+2] cycloaddition cascade reaction was uncovered for the construction of biologically interesting tricyclic ketal skeletons. This approach mimics a biosynthetic sequence and establishes a viable synthetic strategy for the efficient formal synthesis of averufin.
- Tan, Haibo,Chen, Xinzheng,Chen, Huiyu,Liu, Hongxin,Qiu, Shengxiang
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supporting information
p. 4956 - 4963
(2015/08/03)
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- Design, synthesis, and biological evaluation of simplified side chain hybrids of the potent actin binding polyketides rhizopodin and bistramide
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The natural products rhizopodin and bistramide belong to an elite class of highly potent actin binding agents. They show powerful antiproliferative activities against a range of tumor cell lines, with IC50 values in the low-nanomolar range. At the molecular level they disrupt the actin cytoskeleton by binding specifically to a few critical sites of G-actin, resulting in actin filament stabilization. The important biological properties of rhizopodin and bistramide, coupled with their unique and intriguing molecular architectures, render them attractive compounds for further development. However, this is severely hampered by the structural complexity of these metabolites. We initiated an interdisciplinary approach at the interface between molecular modeling, organic synthesis, and chemical biology to support further biological applications. We also wanted to expand structure-activity relationship studies with the goal of accessing simplified analogues with potent biological properties. We report computational analyses of actin-inhibitor interactions involving molecular docking, validated on known actin binding ligands, that show a close match between the crystal and modeled structures. Based on these results, the ligand shape was simplified, and more readily accessible rhizopodin-bistramide mimetics were designed. A flexible and modular strategy was applied for the synthesis of these compounds, enabling diverse access to dramatically simplified rhizopodin-bistramide hybrids. This novel analogue class was analyzed for its antiproliferative and actin binding properties.
- Herkommer, Daniel,Dreisigacker, Sandra,Sergeev, Galina,Sasse, Florenz,Gohlke, Holger,Menche, Dirk
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supporting information
p. 470 - 489
(2015/04/21)
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- Enantioselective Hydroformylation of 1-Alkenes with Commercial Ph-BPE Ligand
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A rhodium complex, in conjunction with commercially available Ph-BPE ligand, catalyzes the branch-selective asymmetric hydroformylation of 1-alkenes and rapidly generates α-chiral aldehydes. A wide range of terminal olefins including 1-dodecene were examined, and all delivered high enantioselectivity (up to 98:2 er) as well as good branch:linear ratios (up to 15:1). (Chemical Equation Presented).
- Yu, Zhiyong,Eno, Meredith S.,Annis, Alexandra H.,Morken, James P.
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p. 3264 - 3267
(2015/07/15)
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- Total Synthesis of the Nonenolide Xyolide Using a Regioselective Nucleophilic Epoxide Opening Approach
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The total synthesis of the nonenolide xyolide is described as a convergent synthesis in 16 steps from the commercially available starting material butane-1,4-diol. The key reactions involved are: Sharpless asymmetric epoxidation, Pinnick oxidation, acid-mediated nucleophilic regioselective epoxide ring opening, Steglich esterification, and ring-closing metathesis.
- Wadavrao, Sachin B.,Ghogare, Ramesh S.,Narsaiah, A. Venkat
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p. 2129 - 2137
(2015/07/15)
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- Synthesis of oxacyclic scaffolds via dual ruthenium hydride/Bronsted acid-catalyzed isomerization/cyclization of allylic ethers
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A ruthenium hydride/Bronsted acid-catalyzed tandem sequence is reported for the synthesis of 1,3,4,9-tetrahydropyrano[3,4-b]indoles (THPIs) and related oxacyclic scaffolds. The process was designed on the premise that readily available allylic ethers would undergo sequential isomerization, first to enol ethers (Ru catalysis), then to oxocarbenium ions (Bronsted acid catalysis) amenable to endo cyclization with tethered nucleophiles. This methodology provides not only an attractive alternative to the traditional oxa-Pictet-Spengler reaction for the synthesis of THPIs, but also convenient access to THPI congeners and other important oxacycles such as acetals.
- Ascic, Erhad,Ohm, Ragnhild G.,Petersen, Rico,Hansen, Mette R.,Hansen, Casper L.,Madsen, Daniel,Tanner, David,Nielsen, Thomas E.
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supporting information
p. 3297 - 3300
(2014/04/03)
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- Immobilized bisdiazaphospholane catalysts for asymmetric hydroformylation
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Condensation reactions of enantiopure bis-3,4-diazaphospholanes (BDPs) that are functionalized with carboxylic acids enable covalent attachment to bead and silica supports. Exposure of tethered BDPs to the hydroformylation catalyst precursor, Rh(acac)(CO)2, yields catalysts for immobilized asymmetric hydroformylation (iAHF) of prochiral alkenes. Compared with homogeneous catalysts, catalysts immobilized on Tentagel resins exhibit similarly high regioselectivity and enantioselectivity. When corrected for apparent catalyst loading, the activity of the immobilized catalysts approaches that of the homogeneous analogues. Excellent recyclability with trace levels of rhodium leaching are observed in batch and flow reactor conditions. Silica-bound catalysts exhibit poorer enantioselectivities.
- Adint, Tyler T.,Landis, Clark R.
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p. 7943 - 7953
(2014/06/23)
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- Easily accessible and highly tunable bisphosphine ligands for asymmetric hydroformylation of terminal and internal alkenes
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An efficient methodology for synthesizing a small library of easily tunable and sterically bulky ligands for asymmetric hydroformylation (AHF) has been reported. Five groups of alkene substrates have been tested with excellent conversions, moderate-to-excellent regio- and enantioselectivities. Among the best result of the reported literature, application of ligand 1 c in the highly selective AHF of the challenging substrate 2,5-dihydrofuran yielded almost one isomer in up to 99 % conversion along with enantiomeric excesses (ee) of up to 92 %. Highly enantioselective AHF of dihydropyrrole substrates is achieved using the same ligand, with up to 95 % ee and up to >1:50 β-isomer/α- isomer ratio. The simpler the better! An efficient method for the easy and tunable synthesis of a series of asymmetric hydroformylation (AHF) ligands from low-cost, commercially available starting materials has been reported. These ligands can give excellent conversions and moderate to excellent regio- and enantioselectivities for a broad range of mono- and disubstituted alkenes with a low catalyst loading (substrate-to-catalyst ratios (S/C) of 1000:1 to 3000:1).
- Xu, Kun,Zheng, Xin,Wang, Zhiyong,Zhang, Xumu
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p. 4357 - 4362
(2014/05/06)
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- Studies toward asymmetric synthesis of leiodelide A
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An enantioselective route for oxazoline 4, a key fragment toward the asymmetric synthesis of leiodelide A, is described. We synthesized northern subunit 6 through a Julia-Lythgoe olefination and subsequent Sharpless asymmetric dihydroxylation. Moreover, a highly diastereoselective method using well-established Evans' asymmetric aldol condensation was developed for preparation of southern fragment 5. The additional feature of this synthetic route is the formation of oxazoline 4 through DAST-promoted cyclization of the amidation product from subunits 5 and 6.
- Ren, Rong-Guo,Li, Ming,Si, Chang-Mei,Mao, Zhuo-Ya,Wei, Bang-Guo
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p. 6903 - 6906
(2015/02/02)
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- Stereoselective total synthesis of crucigasterins A, B and D through a common intermediate
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The first stereoselective total synthesis of the marine-derived antimicrobial amino-alcohols, crucigasterins A, B and D has been accomplished through a common intermediate starting from pent-3-en-1-ol. The method involves the Sharpless asymmetric aminohyd
- Kumar, Jayprakash Narayan,Das, Biswanath
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p. 3865 - 3867
(2013/07/19)
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- ANTI-CANCER POLYKETIDE COMPOUNDS
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Provided herein, inter alia, are anticancer polyketides. The uses of the polyketides described herein include treatment of cancer, for example, through regulation of the spliceosome and detection of spliceosome inhibition.
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Paragraph 0178
(2013/10/21)
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- Modular total synthesis of rhizopodin: A highly potent G-actin dimerizing macrolide
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A highly convergent total synthesis of the potent polyketide macrolide rhizopodin has been achieved in 29steps by employing a concise strategy that exploits the molecule′s C2 symmetry. Notable features of this convergent approach include a rapid assembly of the macrocycle through a site-directed sequential cross-coupling strategy and the bidirectional attachment of the side chains by means of Horner-Wadsworth-Emmons (HWE) coupling reactions. During the course of this endeavor, scalable routes for synthesis of three main building blocks of similar complexity were developed that allowed for their stereocontrolled construction. This modular route will be amenable to the development of syntheses of other analogues of rhizopodin.
- Kretschmer, Manuel,Dieckmann, Michael,Li, Pengfei,Rudolph, Sven,Herkommer, Daniel,Troendlin, Johannes,Menche, Dirk
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supporting information
p. 15993 - 16018
(2014/04/03)
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- The formal total synthesis of FR252921-An immunosuppressant
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The formal total synthesis of FR252921 is described. The key steps include the preparation of three fragments starting from 1,4-butanediol, (R)-malic acid, and prenol, respectively, followed by two consecutive peptide couplings of the three fragments. Other key steps involve an allene-type rearrangement or enyne isomerization to install the triene moiety, a Seebach methylation, a Julia olefination to construct the trisubstituted diene unit, and an enzymatic resolution strategy to generate the C-18 stereocenter.
- Yadav,Sengupta, Sandip
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p. 376 - 388
(2013/03/13)
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- Catalytic enantioselective formal Hetero-Diels-Alder reactions of enones with isatins to give spirooxindole tetrahydropyranones
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Organocatalytic formal hetero-Diels-Alder reactions of enones with isatins, which gave highly enantiomerically enriched functionalized spirooxindole tetrahydropyranones via an enamine-based mechanism, were developed. The catalyst systems were identified by a screen of combinations of amines, acids, and additives. With the identified catalyst systems, various spirooxindole tetrahydropyranones were synthesized in high yields with high diastereo- and enantioselectivities (see scheme). Copyright
- Cui, Hai-Lei,Tanaka, Fujie
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supporting information
p. 6213 - 6216
(2013/07/04)
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- Vicinal bisheterocyclizations of alkynes via nucleophilic interception of a catalytic platinum carbene
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A novel platinum-catalyzed double heterocyclization of propargylic ethers is described. The transformation exploits the intermediacy of a key α,β-unsaturated carbene. The reactivity of this carbene is such that systems can be developed which avoid a complicating 1,2-hydrogen migration, allowing remarkable versatility in the selective syntheses of oxygen- and nitrogen-containing vicinal bis-heterocyclic compounds.
- Allegretti, Paul A.,Ferreira, Eric M.
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supporting information
p. 17266 - 17269
(2014/01/06)
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- The stereochemical course of intramolecular michael reactions
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We present a general model for understanding the stereochemical course of intramolecular Michael reactions. We show that the addition of β- ketoester enolates to α,β-unsaturated esters and imides bearing adjacent stereocenters (X, Y = H, Me, OR) leads to high levels of asymmetric induction. Reinforcing and nonreinforcing stereochemical relationships are evaluated from the syn and anti reactant diastereomers. On the basis of synthetic, spectroscopic, and computational studies, we propose that the outcomes of these reactions can be rationalized by a dipole-minimized chair transition-state model.
- Kwan, Eugene E.,Scheerer, Onathan R.,Evans, David A.
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p. 175 - 203
(2013/04/10)
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- Copper-catalyzed arylative meyer-schuster rearrangement of propargylic alcohols to complex enones using diaryliodonium salts
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Free choice: A copper-catalyzed arylative Meyer-Schuster rearrangement is described. The reaction is compatible with a range of substituted propargylic alcohols and diaryliodonium salts and delivers complex trisubstituted enone products selectively as the
- Collins, Beatrice S. L.,Suero, Marcos G.,Gaunt, Matthew J.
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supporting information
p. 5799 - 5802
(2013/06/27)
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- Convergent access to bis-spiroacetals through a sila-Stetter-ketalization cascade
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An NHC-catalyzed sila-Stetter reaction between aliphatic acylsilanes and vinylketones bearing silyl ether substituents affords functionalized 1,4-diketones, which upon treatment under acidic conditions leads to the corresponding bis-spiroacetals. The two-step sequence may also be carried out in a one-pot operation leading to high yields of the desired bis-spiroacetals.
- Labarre-Laine, Jessica,Beniazza, Redouane,Desvergnes, Valerie,Landais, Yannick
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supporting information
p. 4706 - 4709
(2013/10/08)
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- Libraries of bisdiazaphospholanes and optimization of rhodium-catalyzed enantioselective hydroformylation
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Twelve chiral bis-3,4-diazaphospholane ligands and six alkene substrates (styrene, vinyl acetate, allyloxy-tert-butyldimethylsilane, (E)-1-phenyl-1,3- butadiene, 2,3-dihydrofuran, and 2,5-dihydrofuran) probe the influence of steric bulk on the activity and selectivity of asymmetric hydroformylation (AHF) catalysts. Reaction of an enantiopure bisdiazaphospholane tetraacyl fluoride with primary or secondary amines yields a small library of tetracarboxamides. For all six substrates, manipulation of reaction conditions and bisdiazaphospholane ligands enables state-of-the-art performance (90% or higher ee, good regioselectivity, and high turnover rates). For the nondihydrofuran substrates, the previously reported ligand, (S,S)-2, is generally most effective. However, optimal regio- and enantioselective hydroformylation of 2,3-dihydrofuran (up to 3.8:1 α-isomer/β-isomer ratio and 90% ee for the α-isomer) and 2,5-dihydrofuran (up to 1:30 α-isomer/β- isomer ratio and 95% ee for the β-isomer) arises from bisdiazaphospholanes containing tertiary carboxamides. Hydroformylation of either 2,3- or 2,5-dihydrofuran yields some of the β-formyl product. However, the absolute sense of stereochemistry is inverted. A stereoelectronic map rationalizes the opposing enantiopreferences
- Adint, Tyler T.,Wong, Gene W.,Landis, Clark R.
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p. 4231 - 4238
(2013/06/05)
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- Regio- and stereochemical studies on the nitroso-diels-alder reaction with 1,2-disubstituted dienes
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The regioselectivity of the nitroso-Diels-Alder reaction between unsymmetrical acyclic dienes and Boc-nitroso (Boc=tert-butoxycarbonyl) reagent or the Wightman chiral chloronitroso reagents has been studied. With the Boc-nitroso reagent, the selectivity is a consequence of steric effects at the C1-position in the diene and electronic effects at the C2-position in the diene. The combination of an unprotected hydroxyethyl side chain at C1 and an electron-withdrawing group at C2 allows complete regioselectivity in favour of the proximal isomer. The same isomer was obtained exclusively with the chiral nitroso reagent with high enantioselectivities. A model based on steric effects is proposed. Get selective! A combination of steric and electronic effects allows the design of 1,2-disubstituted dienes for highly regioselective nitroso-Diels-Alder reactions with either Boc-nitroso reagent or a chiral chloronitroso reagent. Enantiomerically enriched functionalized cycloadducts could be obtained by asymmetric and regioselective cycloadditions (see scheme; Boc=tert-butoxycarbonyl, TBS=tert-butyldimethylsilyl, Piv=pivaloyl). Copyright
- Galvani, Gilles,Lett, Robert,Kouklovsky, Cyrille
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p. 15604 - 15614
(2013/11/19)
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- Formal intramolecular (4 + 1)-cycloaddition of dialkoxycarbenes: Control of the stereoselectivity and a mechanistic portrait
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The stereoselective synthesis of 5-5, 6-5, and 7-5 fused O-heterocyclic compounds is reported. The key reaction is a formal intramolecular (4 + 1)-cycloaddition involving a dialkoxycarbene and an electron-deficient diene where the stereoselectivity is dependent on the length of the tether. An analysis of the stereochemical outcome of this reaction sheds light on its complex mechanistic picture. High-level calculations were used to support the proposed mechanistic portrait.
- Beaumier, Francis,Dupuis, Marianne,Spino, Claude,Legault, Claude Y.
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supporting information; experimental part
p. 5938 - 5953
(2012/05/07)
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- Total synthesis of rhizopodin
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Symmetry helps: The total synthesis of the potent actin-targeting C 2-symmetric myxobacterial macrolide rhizopodin (see scheme) is accomplished by the convergent assembly of three building blocks of similar complexity, a concise macrocyclization strategy, and a late-stage introduction of the labile side chains. Copyright
- Dieckmann, Michael,Kretschmer, Manuel,Li, Pengfei,Rudolph, Sven,Herkommer, Daniel,Menche, Dirk
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supporting information; experimental part
p. 5667 - 5670
(2012/07/13)
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- Structure of FD-895 revealed through total synthesis
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The total synthesis of FD-895 was completed through a strategy that featured the use of a tandem esterification ring-closing metathesis (RCM) process to construct the 12-membered macrolide and a modified Stille coupling to append the side chain. These stu
- Villa, Reymundo,Mandel, Alexander L.,Jones, Brian D.,La Clair, James J.,Burkart, Michael D.
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supporting information
p. 5396 - 5399
(2013/01/15)
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- Compositions Including 6-Aminohexanoic Acid Derivatives As HDAC Inhibitors
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This invention relates to compounds of Formula (I) wherein Cy1, L1, Y, R1, L2, and Ar2 are defined herein, for the treatment of cancers, inflammatory disorders, and neurological conditions.
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Page/Page column 48-49
(2012/04/23)
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