- 29. Total synthesis of crenulatan diterpenes: Strategy and stereocontrolled construction of a bicyclic keto-lactone building block
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The bicyclic keto lactone 26 was synthesized for the purpose of developing a viable route to marine diterpenes of the crenulatan type. Following the efficient conversion of (S)-citronellol (5) to the allylated alcohol 9a, the α,β -unsaturated lactone 12 was efficiently accessed in preparation for stereocontrolled conjugate addition. The hydroxymethyl equivalent most suited to this task was (i-PrO)Me2SiCH2MgCl, which gave 13 predominantly in the presence of CuI and Me3SiCl. Once the OH group was deprotected (→14), it proved an easy matter to implement acid-catalyzed isomerization to lactone 15, oxidation of which gave the pivotal aldehyde 16. Condensation of 16 with PhSeCH2Li led via 21 to 22. Once the OH group was protected (→22b), it proved possible to effect aldolization with crotonaldehyde (→23). Exposure of 23 to acid gave the sub-target compound 25. Its subsequent oxidation and thermal activation resulted in sequential selenoxide elimination with Claisen rearrangement (→26). The structural features of 26 require that a chair-like transition state be adopted during the [3.3]sigmatropic event. With the clarification of these issues, a highly serviceable and more advanced assault on the crenulatans should prove capable of being mounted.
- He,Pinard,Paquette
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Read Online
- Stereospecificity of Pig Kidney and Pea Seedling Diamino Oxidases on 2-Methyl-1,4-diaminobutane
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Diamine oxidase from pea seedlings (PDAO) oxidizes both (R)- and (S)-2-methylputrescine at the less hindered C-4, whereas pig-kidney diamine oxidase (KDAO) shows a dependence on the stereochemistry of the substrate, since the (R)-isomer is oxidized at C-1 and the (S)-isomer at the less hindered amino group at C-4.
- Santaniello, Enzo,Manzocchi, Ada,Biondi, Pier Antonio,Secchi, Camillo,Simonic, Tatijana
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Read Online
- Oxidation of Primary Alcohols and Aldehydes to Carboxylic Acids via Hydrogen Atom Transfer
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The oxidation of primary alcohols and aldehydes to the corresponding carboxylic acids is a fundamental reaction in organic synthesis. In this paper, we report a new chemoselective process for the oxidation of primary alcohols and aldehydes. This metal-free reaction features a new oxidant, an easy to handle procedure, high isolated yields, and good to excellent functional group tolerance even in the presence of vulnerable secondary alcohols and tert-butanesulfinamides.
- Tan, Wen-Yun,Lu, Yi,Zhao, Jing-Feng,Chen, Wen,Zhang, Hongbin
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supporting information
p. 6648 - 6653
(2021/09/08)
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- Modulation of the Passive Permeability of Semipeptidic Macrocycles: N- And C-Methylations Fine-Tune Conformation and Properties
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Incorporating small modifications to peptidic macrocycles can have a major influence on their properties. For instance, N-methylation has been shown to impact permeability. A better understanding of the relationship between permeability and structure is of key importance as peptidic drugs are often associated with unfavorable pharmacokinetic profiles. Starting from a semipeptidic macrocycle backbone composed of a tripeptide tethered head-to-tail with an alkyl linker, we investigated two small changes: peptide-to-peptoid substitution and various methyl placements on the nonpeptidic linker. Implementing these changes in parallel, we created a collection of 36 compounds. Their permeability was then assessed in parallel artificial membrane permeability assay (PAMPA) and Caco-2 assays. Our results show a systematic improvement in permeability associated with one peptoid position in the cycle, while the influence of methyl substitution varies on a case-by-case basis. Using a combination of molecular dynamics simulations and NMR measurements, we offer hypotheses to explain such behavior.
- Boudreault, Pierre-Luc,Comeau, Christian,Derbali, Rabeb Mouna,Grandbois, Michel,Poulet, Sylvain,Ries, Benjamin,Riniker, Sereina,Sarret, Philippe,Stadelmann, Thomas,Tremblay, Jacob,C?té, Jér?me,Fr?hlich, Ulrike,Leclair, Grégoire,Marsault, éric
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p. 5365 - 5383
(2021/05/04)
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- Amides as bioisosteres of triazole-based geranylgeranyl diphosphate synthase inhibitors
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Geranylgeranyl diphosphate synthase (GGDPS) inhibitors are of potential therapeutic interest as a consequence of their activity against the bone marrow cancer multiple myeloma. A series of bisphosphonates linked to an isoprenoid tail through an amide linkage has been prepared and tested for the ability to inhibit GGDPS in enzyme and cell-based assays. The amides were designed as analogues to triazole-based GGDPS inhibitors. Several of the new compounds show GGDPS inhibitory activity in both enzyme and cell assays, with potency dependent on chain length and olefin stereochemistry.
- Goetz, Daniel B.,Holstein, Sarah A.,Varney, Michelle L.,Wiemer, David F.
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- PPAR AGONISTS, COMPOUNDS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE THEREOF
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Provided herein are compounds and compositions useful in increasing PPAR8 activity. The compounds and compositions provided herein are useful for the treatment of PPAR8 related diseases (e.g., muscular diseases, vascular disease, demyelinating disease, and metabolic diseases).
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Page/Page column 104-105
(2017/04/23)
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- A general approach to iridoids by applying a new Julia olefination and a tandem anion-radical-carbocation crossover reaction
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A unified, asymmetric approach to the total synthesis of naturally occurring iridoids is presented. The synthesis features a recently discovered ortho → α transmetalation of alkyl aryl sulfone carbanions, thus enabling Julia reactions, by which so far har
- ?ehová, Lucie,Dra?ínsky, Martin,Jahn, Ullrich
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supporting information
p. 9612 - 9621
(2016/10/22)
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- Rational Development of a Potent 15-Lipoxygenase-1 Inhibitor with in Vitro and ex Vivo Anti-inflammatory Properties
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Human 15-lipoxygenase-1 (h-15-LOX-1) is a mammalian lipoxygenase and plays an important role in several inflammatory lung diseases such as asthma, COPD, and chronic bronchitis. Novel potent inhibitors of h-15-LOX-1 are required to explore the role of this enzyme further and to enable drug discovery efforts. In this study, we applied an approach in which we screened a fragment collection that is focused on a diverse substitution pattern of nitrogen-containing heterocycles such as indoles, quinolones, pyrazoles, and others. We denoted this approach substitution-oriented fragment screening (SOS) because it focuses on the identification of novel substitution patterns rather than on novel scaffolds. This approach enabled the identification of hits with good potency and clear structure-activity relationships (SAR) for h-1-5-LOX-1 inhibition. Molecular modeling enabled the rationalization of the observed SAR and supported structure-based design for further optimization to obtain inhibitor 14d that binds with a Ki of 36 nM to the enzyme. In vitro and ex vivo biological evaluations of our best inhibitor demonstrate a significant increase of interleukin-10 (IL-10) gene expression, which indicates its anti-inflammatory properties.
- Eleftheriadis, Nikolaos,Neochoritis, Constantinos G.,Leus, Niek G. J.,Van Der Wouden, Petra E.,D?mling, Alexander,Dekker, Frank J.
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p. 7850 - 7862
(2015/10/20)
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- Straightforward synthesis of functionalized (E)-3-acylacrylic acids
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An experimentally simple, mild and straightforward synthetic route towards diversely functionalized (E)-3-acylacrylic acids is described, with Horner-Wadsworth-Emmons (HWE) reaction as the key step. The substrate scope and limitations of the HWE reaction were investigated with a range of β-ketophosphonates. Glyoxylic acid monohydrate was demonstrated to be fully compatible with the HWE reaction conditions, thus avoiding a troublesome hydrolysis of the corresponding 3-acylacrylates in the last step and providing a valuable synthetic shortcut.
- Sivák, Ivan,Václav, Jakub,Berke?, Du?an,Kolarovi?, Andrej
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supporting information
p. 8871 - 8875
(2015/11/02)
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- Enantioselective rearrangement coupled with water addition: Direct synthesis of enantiomerically pure saturated carboxylic acids from α,β-unsaturated aldehydes
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A novel type of organic synthesis enabling a direct one-pot transformation of α,β-unsaturated aldehydes into saturated carboxylic acids is described. As sole reagent water is required, which is integrated completely in the product. This tandem process proceeds under perfect atom economy, and consists of two coupled redox biotransformations without the need of external co-substrates for cofactor regeneration. The initial reduction of the C=C double bond of an α,β-unsaturated aldehyde is catalyzed by an NADPH-dependent ene reductase, leading to the formation of the saturated aldehyde and NADP+. The aldehyde intermediate is then oxidized to the corresponding carboxylic acid, thus regenerating NADPH for the next catalytic cycle. When using prochiral α,β-unsaturated aldehydes as substrates the corresponding carboxylic acids are formed enantioselectively with up to >99 % ee as demonstrated, e.g., for the transformation of citral to (S)-citronellic acid. Making a splash with citral: The direct one-pot transformation of α,β-unsaturated aldehydes to saturated carboxylic acids using only water proceeds with perfect atom economy. This tandem process involves two redox biotransformations without need of additional external co-substrates for cofactor regeneration. With, for example, citral as prochiral α,β-unsaturated aldehyde, transformation to (S)-citronellic acid proceeds with >99 % conversion and >99 % ee.
- Winkler, Till,Groeger, Harald,Hummel, Werner
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p. 961 - 964
(2014/05/06)
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- Enantioselectivity of the bioconversion of chiral citronellal during the inhibition of wheat seeds germination
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Citronellal is one of the most prominent monoterpenes present in many essential oils. Low persistence of essential oils as bioherbicides has often been addressed because of the high volatility of these compounds. Bioconversion of citronellal by wheat seeds releases less aggressive and injurious compounds as demonstrated by their diminished germination. We demonstrated that optically pure citronellal enantiomers were reduced to optically pure citronellol enantiomers with retention of the configuration both in isolated wheat embryos and endosperms. Our findings reveal the potential of essential oils as allelopathic agents providing an insight into their mechanism of action and persistence. Copyright
- Cavalieri, Andrea,Fischer, Ravit,Larkov, Olga,Dudai, Nativ
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p. 419 - 426
(2014/04/03)
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- Biotransformations of terpenes by fungi from amazonian Citrus plants
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The biotransformations of (RS)-linalool (1), (S)-citronellal (2), and sabinene (3) with fungi isolated from the epicarp of fruits of Citrus genus of the Amazonian forest (i.e., C. limon, C. aurantifolia, C. aurantium, and C. paradisiaca) are reported. The
- Moreno Rueda, Maria Gabriela,Guerrini, Alessandra,Giovannini, Pier Paolo,Medici, Alessandro,Grandini, Alessandro,Sacchetti, Gianni,Pedrini, Paola
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p. 1909 - 1919
(2013/11/06)
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- A piperidine chiron for the Veratrum alkaloids
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A Veratrum piperidine chiron was prepared over 11 steps (7.9% yield) from (-)-citronellal. Three methods for the installation of the propargylic side chain onto a cyclic enamide are presented.
- Taber, Douglass F.,Dematteo, Peter W.
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experimental part
p. 4235 - 4241
(2012/06/29)
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- Synthesis of All diastereomers of the piperidine - alkaloid substructure of cyclopamine
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"Chemical Equation Presented" All four diastereomers of the trisubstituted piperidine-alkaloids of the veratramine and jervine type were synthesized with complete stereocontrol starting from enantiopure citronellic acids. The flexible, high-yielding, and scalable route described here will facilitate convergent syntheses and give access to analogues of cyclopamine and other biologically active and diverse steroid alkaloids.
- Heretsch, Philipp,Rabe, Sebastian,Giannis, Athanasslos
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supporting information; experimental part
p. 5410 - 5412
(2010/02/28)
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- Traceless stereoinduction in the one-pot assembly of all three rings of hexahydrodibenzopyrans
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A one-pot method has been developed for the synthesis of all three rings of the hexahydrodibenzopyran ring system. This process involves a tandem sequence consisting of a benzannulation reaction of an alkenyl Fischer carbene complex and an alkyne followed by an elimination reaction that generates an o-quinone methide chromium tricarbonyl complex that is finally followed by an intramolecular heteroatom Diels-Alder cycloaddition. The stereoinduction for the overall process begins with the transfer of stereochemical information from the chiral center at the propargylic ether in the alkyne to the planar center of chirality in the in situ generated arene chromium tricarbonyl complexed intermediate and finally, after base-induced elimination to generate an o-quinone methide chromium tricarbonyl complexed intermediate, a transfer of chirality from the planar center of chirality in the o-quinone methide complex to the two new centers of chirality at positions 6a and 10a in the hexahydrodibenzopyran products upon intramolecular Diels-Alder reaction. The reactions of diastereomeric chiral propargyl ethers that contain an additional center of chirality can lead to high diastereoselectivity in the matched case and to low selectivity in the mismatched case. Copyright
- Korthals, Keith A.,Wulff, William D.
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p. 2898 - 2899
(2008/09/20)
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- Aplyronine A, a potent antitumor macrolide of marine origin, and the congeners aplyronines B and C: isolation, structures, and bioactivities
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Aplyronine A (2), a potent antitumor macrolide was isolated from the sea hare Aplysia kurodai together with the congeners aplyronines B (3) and C (4). The absolute stereostructure of aplyronine A (2) was determined by the instrumental analysis (mainly NMR and MS) and the enantioselective synthesis of the fragments obtained from chemical degradation of aplyronine A (2). The structures of aplyronines B (3) and C (4) were also elucidated. Cytotoxicity and antitumor activity of aplyronine A (2) were evaluated.
- Ojika, Makoto,Kigoshi, Hideo,Yoshida, Yoshifumi,Ishigaki, Takeshi,Nisiwaki, Masanori,Tsukada, Itaru,Arakawa, Masayuki,Ekimoto, Hisao,Yamada, Kiyoyuki
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p. 3138 - 3167
(2007/10/03)
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- Synthesis and stereochemistry of the four himachalene-type sesquiterpenes isolated from the flea beetle (Aphthona flava) as pheromone candidates
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Both the (1S,2R) and (1R,2S) isomers of 2,6,6-trimethylbicyclo[5.4.0]undec- 7-en-9-one (1) were synthesized by starting from (S)- and (R)-citronellal (5), respectively. The stereochemistry of (1R,2S)-(-)-1 was established by an X-ray analysis; it exhibits a CD spectrum similar to that of cholest-4-en-3-one, in agreement with its absolute configuration. The ketones (1S,2R)- and (1R,2S)-1 were converted into the en-antiomers of three other himachalene hydrocarbons, 2,2,6-trimethyl-10-methylenebicyclo[5.4.0]undec-1(11)-ene (2), 1,1,5,8-tetramethyl-1,2,3,4,5,6,5a-hepta hydro benzo [1,2-a]-[7]annulene (3), and 1,1,5,8-tetramethyl-1,2,3,4,5-pentahydrobenzo[a][7]annulene (ar-himachalene, 4). The stereochemistry of these himachalene-type sesquiterpenes isolated from flea beetles such as Aphthona flava and Phyllotreta cruciferae as their male-pheromone components was revised to (1S,2R)-1, (6R,7S)-2,(5R,5aS)-3, and (R)-4. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
- Muto, Shin-Etsu,Bando, Masahiko,Mori, Kenji
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p. 1946 - 1952
(2007/10/03)
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- Syntheses of optically active citronellol, citronellal, and citronellic acid by microbial oxidation and double coupling system in an interface bioreactor
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We have already reported that (RS)-Citronellol [(RS)-1] can be optically resolved via a transacetylation with acetyl coenzyme A [acetyl-CoA] by the aid of alcohol acetyltransferase [AATFase] in Pichia kluyveri IFO 1165, which we have referred to as a double coupling system (E value, 30 to 40). In this system, although (R)-1 is obtained at over 98% ee, (S)-Citronellyl acetate [(S)-2] is prepared at 70 to 80% ee. In this article, we report on the conversion of (R)-1 to (R)-Citronellal [(R)-3] and (R)-Citronellic acid [(R)-4] in high yield without racemization by the aid of Rhodococcus equi JCM 6817 and Geotrichum candidum JCM 01747, respectively. On the other hand, the low ee of (S)-1 (78% ee) prepared via the alkaline hydrolysis of (S)-2 is converted to optically active (S)-1 and (S)-4 in high yield with a repeated double coupling system with P. kluyveri IFO 1165 and via enantioselective oxidation with Candida viswanathii IFO 10321, respectively. Thus, five optically active terpenoids related to citronellol, except for (S)-3, were efficiently synthesized via microbial transformations in an interface bioreactor.
- Oda, Shinobu,Sugai, Takeshi,Ohta, Hiromichi
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p. 2819 - 2823
(2007/10/03)
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- Plant bioregulators, 2. Syntheses of (±)- and (+)-sorgolactone, the germination stimulant from Sorghum bicolor
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Syntheses of (±)-2a, the racemate of the structure proposed for sorgolactone, and its three racemic stereoisomers have been accomplished with confirmation of the stereostructures of the intermediate (±)-10 and the final product (±)-2a by X-ray analysis. Its optically active form, (3aR,8S,8bS,2'R)-(+)-2a, has also been prepared from (S)-(-)-citronellal by employing radical cyclization of 18 to 19 as the key step. Spectroscopic properties of the synthetic products are compared with those reported for natural sorgolactone. Bioassays using clover broomrape (Orobanche minor) seeds have revealed that all the stereoisomers strongly stimulate their germination.
- Matsui, Junichi,Bando, Masahiko,Kido, Masaru,Takeuchi, Yasutomo,Mori, Kenji
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p. 2183 - 2194
(2007/10/03)
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- Enantioselective oxidation of racemic citronellol with an interface bioreactor
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Microbial oxidation of racemic citronellol was done on the interface between a nutrient agar plate and decane (interface bioreactor). While Rhodococcus accumulated (R)-citronellal (21-80% e.e.), many yeasts accumulated (S)-citronellic acid (20-68% e.e.) as the oxidation product. For the production of (R)-citronellal and (S)-citronellic acid, Rhodococcus equi IFO 3730 and Hansenula anomala IFO 0147 were the best strains, respectively. While citronellol-oxidation in R. equi IFO 3730 was (S)-selective, citronellal-oxidation was (R)-selective. Although H. anomala had also both (S)-selective alcohol and aldehyde dehydrogenases (constitutive, NAD+-dependent), the equilibrium of the alcohol dehydrogenase shifted to reduction of citronellal. Geotrichum candidum JCM 01747 accumulated very high concentrations of citronellic acid (conversion yield 90% in 5 days or accumulation 65 mg/ml in 13 days) in spite of the strong toxicity of the acid, although the optical purity was low. For the alleviation of the toxicity of citronellol and accumulation of toxic citronellic acid, the interface bioreactor is superior to the organic-aqueous two-liquid-phase system (dispersion system).
- Oda, Shinobu,Kato, Akio,Matsudomi, Naotoshi,Ohta, Hiromichi
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- Synthetic Studies on the ophiobolane Sesterterpenes: Construction of an Optically Pure, Advanced Tricyclic Intermediate for the Synthesis of Ceroplasteric Acid
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Tropone has been transformed into an optically pure tricyclic system that could serve as an advanced intermediate in the synthesis of ceroplastic acid.The sequence features a stereoselective Ireland ester enolate Claisen rearrangement followed by an intra
- Rigby, James H.,McGuire, Timothy,Senanayake, Chrisantha,Khemani, Kishan
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p. 3449 - 3458
(2007/10/02)
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- Asymmetric Conjugate Addition to Unsaturated Chiral Amido Alcohols Using Grignard Reagents Co-ordinated with Tertiary Amines or DBU. Preparation of Optically Active 3-Substituted Carboxylic Acids and (S)-(-)-Citronellol
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Optically active 3-substituted carboxylic acids and (S)-(-)-citronellol have been obtained by diastereoselective conjugate addition of Grignard reagents co-ordinated with 1,8-diazabicyclo-undec-7-ene (DBU) to chiral amidoalcohols derived from (S)-proline.
- Soai, Kenso,Machida, Hideaki,Yokota, Noriko
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p. 1909 - 1914
(2007/10/02)
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- Asymmetric Hydrogenation of Unsaturated Carboxylic Acids Catalyzed by BINAP-Ruthenium(II) Complexes
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Homogeneous hydrogenation of α,β- or β,γ-unsaturated carboxylic acids in the presence of a catalytic amount of Ru(OCOCH3)2 affords the corresponding saturated products in high enantiomeric excesses and in quantitative yields.The new hydrogenation has been applied to the asymmetric synthesis of (S)-naproxen, a 1β-methylcarbapenem precursor, and some methylated γ- and δ-lactones
- Ohta, Tetsuo,Takaya, Hidemasa,Kitamura, Masato,Nagai, Katsunori,Noyori, Ryoji
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p. 3174 - 3176
(2007/10/02)
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- ASYMMETRIC 1,4-ADDITIONS OF COORDINATED MeCu.BF3 TO CHIRAL ENOATES: ENANTIOSELECTIVE SYNTHESES OF (S)-(-)-CITRONELLIC ACID
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nBu3P- or cyanide-stabilized RCu.BF3 (R=Me, 4-Me-3-pentenyl) undergo efficient 1,4-additions to neopentylether-shielded trans-enoates.Thus chiral β-substituted carboxylic acids e.g. (S)-citronellic acid were obtained in high e.e. (Schemes 2 and 4).
- Oppolzer, Wolfgang,Moretti, Robert,Godel, Thierry,Meunier, Anne,Loeher, Heinz
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p. 4971 - 4974
(2007/10/02)
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- Enantioselective Hydrogenations of a Terpenic Acrylic Acid Catalyzed by Rhodium Complexes of Chiral Diphosphines
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Hydrogenations of (E)-3,7-dimethylocta-2,6-dienoic acid ((E)-1) catalyzed by rhodium complexes of the chiral diphosphine (1R,2R)-biscyclobutane (5) in chloride-free methanol (23 deg C, 2-3 atm of H2) were rapid ( 300 turnovers per hour) and gave (S)-(-)-3,7-dimethyloct-6-enoic acid ((S)-(-)-3) in ca. 40-42percent ee.Under the same conditions, (Z)-1 was converted to (R)-(+)-3 in 45percent ee.The Rh-5-catalyzed hydrogenation of (E)-1 in chloride-free methanol was strongly promoted by triethylamine, with maximum rates of ca. 2500 turnovers per hour.The product ena ntiomeric excess was not changed by addition of triethylamine.A study of the amine-promoted hydrogenation of (E)-1 is reported.It is concluded that the carboxylate anion of (E)-1 complexes with rhodium more strongly than does the parent acid and that the resulting rhodium(I) substrate complex adds H2 more rapidly in the deprotonated form.
- Valentine, Donald,Sun, Ruen C.,Toth, Katherine
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p. 3703 - 3707
(2007/10/02)
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