- A novel highly effective chiral lithium amide for catalytic enantioselective deprotonation of meso-epoxides
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A highly enantioselective deprotonation of meso-epoxides was achieved by a catalytic amount of a new chiral lithium amide, derived from (2S,3aS,7aS)-2-(pyrrolidin-1-ylmethyl)octahydroindole, in the presence of excess lithium diisopropylamide to afford the corresponding allylic alcohol derivatives up to 94% ee.
- Asami, Masatoshi,Suga, Takashi,Honda, Kiyoshi,Inoue, Seiichi
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- Composition of the activated complex in the stereoselective deprotonation of cyclohexene oxide by a chiral lithium amide
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Chiral lithium amides are being developed for stereoselective synthesis of chiral allylic alcohols in high yields and with high enantiomeric excess. However, rational design of the amides for improved stereoselectivity by computational methods, for example, has not been possible due to lack of knowledge of the activated complexes involved in the reactions. Kinetic results are presented for the stereoselective deprotonation by lithium (S)-1- (2-pyrrolidinylmethyl)pyrrolidide (1-Li) of cyclohexene oxide 2, in diethyl ether (DEE), to form (S)-2-cyclohexen-1-ol (S)-3 in high enantiomeric excess. The results show that the rate limiting activated complex is composed of one lithium amide monomer and one molecule of 2 and presumably a solvent molecule. The diamine 1 is found to catalyze the deprotonation.
- Olsson, Roine I.,Ahlberg, Per
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- Investigation of site selectivity of the stereoselective deprotonation of cyclohexene oxide using kinetic resolution of isotopic enantiomers in natural abundance
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Stereoselective deprotonation of epoxides with lithium amides can occur by abstraction of protons from more than one site. The site selectivity of the deprotonation of cyclohexene oxide by several chiral and achiral lithium amides has been investigated. 2H NMR has been used to measure the relative abundances of the isotopomers of the epoxide containing one deuterium. An isotopic stereoisomer, with deuterium in the site undergoing abstraction, reacts slower than its enantiomer and other isotopomers having protium in the same site due to a kinetic isotope effect. This results in a kinetic resolution yielding a relative excess of the less reactive isotopic stereoisomer. Thus, the relative abundance of such an enantiomer increases when compared with those having protium at the site in question as the reaction proceeds. It can be concluded that deprotonation of cyclohexene oxide using some chiral- and non-chiral lithium amides occurs by βsyn-deprotonation.
- Diner, Peter,Pettersen, Daniel,Nilsson Lill, Sten O.,Ahlberg, Per
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- New catalysts for the base-promoted isomerization of epoxides to allylic alcohols. Broadened scope and near-perfect asymmetric induction
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Optically active (1S,3R,4R)-3-[N-(trans-2,5-dialkyl)pyrrolidinyl] methyl-2-azabicyclo-[2.2.1]heptanes were evaluated as catalysts for the enantioselective β-elimination of meso-epoxides. The (2R,5R)-dimethylpyrrolidinyl-substituted catalyst 4 exhibited ex
- Bertilsson, Sophie K.,Soedergren, Mikael J.,Andersson, Pher G.
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- Stereoselective synthesis of the a,e-ring bicyclic core of calyciphylline b-Type alkaloids
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A stereoselective synthesis of the bicyclic unit constituting the A and E rings of calyciphylline B-Type alkaloids is disclosed. The propionate ester of (1 R)-cyclohex-2-en-1-ol, obtained by enzymatic resolution, is subjected to an Ireland-Claisen rearrangement. Subsequent reduction of the acid, Mitsunobu reaction to introduce a nitrogen functionality, oxidative cleavage to a dialdehyde, and intramolecular aldol and aza-Michael reactions afford the bicyclic subunit.
- Kumar, Balagani Satish,Raghavan, Sadagopan
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- Catalytic Enantioselective Deprotonation of meso-Epoxides by the Use of Chiral Lithium Amide
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Catalytic enantioselective deprotonation of meso-compound is achieved for the first time by the combined use of a catalytic amount of chiral lithium amide, lithium (S)-2-(pyrrolidin-1-ylmethyl)pyrrolidide, and excess lithium diisopropylamide in the presence of 1,8-diazabicycloundec-7-ene.
- Asami, Masatoshi,Ishizaki, Tatsuya,Inoue, Seiichi
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- Synthesis of oxazolidinone from enantiomerically enriched allylic alcohols and determination of their molecular docking and biologic activities
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Enantioselective synthesis of functionalized cyclic allylic alcohols via kinetic resolution in transesterifcation with different lipase enzymes has been developed. The influence of the enzymes and temperature activity was studied. By determination of ideal reaction conditions, byproduct formation is minimized; this made it possible to prepare enantiomerically enriched allylic alcohols in high ee's and good yields. Enantiomerically enriched allylic alcohols were used for enantiomerically enriched oxazolidinone synthesis. Using benzoate as a leaving group means that 1 mol % of potassium osmate is necessary and can be obtained high yields 98%. Inhibitory activities of enantiomerically enriched oxazolidinones (8, 10 and 12) were tested against human carbonic anhydrase I and II isoenzymes (hCA I and hCA II), acetylcholinesterase (AChE), and α-glycosidase (α-Gly) enzymes. These enantiomerically enriched oxazolidinones derivatives had Ki values in the range of 11.6 ± 2.1–66.4 ± 22.7 nM for hCA I, 34.1 ± 6.7–45.2 ± 12.9 nM for hCA II, 16.5 ± 2.9 to 35.6 ± 13.9 for AChE, and 22.3 ± 6.0–70.9 ± 9.9 nM for α-glycosidase enzyme. Moreover, they had high binding affinity with ?5.767, ?6.568, ?9.014, and ?8.563 kcal/mol for hCA I, hCA II, AChE and α-glycosidase enzyme, respectively. These results strongly supported the promising nature of the enantiomerically enriched oxazolidinones as selective hCA, AChE, and α-glycosidase inhibitors. Overall, due to these derivatives’ inhibitory potential on the tested enzymes, they are promising drug candidates for the treatment of diseases like glaucoma, leukemia, epilepsy; Alzheimer's disease; type-2 diabetes mellitus that are associated with high enzymatic activity of CA, AChE, and α-glycosidase.
- Atmaca, Ufuk,Kaya, Rüya,Karaman, Halide Sedef,?elik, Murat,Gül?in, ?lhami
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- An intriguing effect of polymer-bound lithium amides in catalytic enantioselective rearrangement of meso-epoxides mediated by chiral lithium amides
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Polymer-bound lithium dialkylamides were prepared from the corresponding polymer-bound amines and butyllithium. The reagent was successfully employed as an in situ regenerating agent of a chiral lithium amide in a catalytic enantioselective rearrangement of meso-epoxides, and chiral allylic alcohols were obtained in up to 95% ee.
- Asami, Masatoshi,Seki, Atsushi
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- Asymmetric base-promoted epoxide rearrangement: Achiral lithium amides revisited
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The use of achiral bases other than lithium diisopropylamide (LDA) was investigated for the asymmetric (1S,3R,4R)-3-(pyrrolidinyl)methyl-2-azabicyclo[2.2.1]heptane catalyzed rearrangement of cyclohexene oxide to (1R)-cyclohex-2-en-1-ol. No significant imp
- Bertilsson, Sophie K,Andersson, Pher G
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- Catalytic enantioselective deprotonation of meso-epoxides utilising homochiral bis-lithium amide bases
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(R)-2-Cyclohexen-1 ol and (R)-2-cyclooctene-1-ol have been prepared in very good ee using R,R-homochiral bis-lithium amide bases derived from homochiral C2 symmetric diamines. (R)-2-Cyclohexen-1-ol has been synthesized in good ee utilising catalytic homochiral bis-lithium amide in the presence of n-butyl lithium.
- Tierney, Jason P.,Alexakis, Alexandre,Mangeney, Pierre
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- 69. Organic Reactions in the Solid State: The Reactivity of Guest Molecules in Tri-o-thymotide Clathrates
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Tri-o-thymotide (TOT) clathrates are enantiomorphous and enantioselective (chiral cages).It was shown that an external molecular reactant can diffuse in to the TOT host crystal lattice and reacts with the included molecule (guest) in characteristic ways, differing from those occurring in liquid solutions.Several aspects of the action of hydrogen halides (HCl, HBr) on the chemical behavior of included oxiranes were investigated for solid-gas and solid-liquid (aqueous) systems.Under well established experimental conditions, these reactions gave regiospecifically one target product and were asymmetric.The included substrate underwent first an acid-catalyzed allylic isomerization that is cage-specific and mostly quantitative.In sheer contrast, strong basic conditions were required to promote, in reduced yield, the analogous transformation in solution.The regiospecificity and enantioselectivity of several intra-crystalline conversions allowed the accurate determination of the absolute configuration of several guest molecules.Kinetic measurements were achived that disclosed some striking features of this new type of heterogeneous reactions.Tentative models for the cage stereoselective mechanisms are briefly discussed.
- Gerdil, Raymond,Barchietto, Giacomo
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- Lithium diisopinocampheylamide: A new and highly effective chiral catalyst in the enantioselective deprotonation of meso-epoxides
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α-Pinene based novel chiral lithium amides have been used for the catalytic enantioselective deprotonation of cyclohexene oxide. An enantiomeric excess of up to 95% for (R)-2-scyclohexen-1-ol was achieved with lithium (-)-N,N-diisopinocampheylamide. A systematic study shows that the isopinocampheyl moiety plays an important role in achieving high enantioselectivity.
- Malhotra, Sanjay V.
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- CHOLINE METABOLISM INHIBITORS
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The present disclosure relates to compounds, compositions and methods for inhibiting choline metabolism, e.g., conversion of choline to trimethylamine. Disclosed herein are compounds, compositions, and methods for inhibiting choline metabolism, e.g., conversion of choline to TMA. Also disclosed herein are compounds, methods and compositions for inhibiting choline metabolism by gut microbiota resulting in reduction in the formation of trimethylamine (TMA) and trimethylamine N-oxide (TMAO).
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Page/Page column 50; 102-104
(2020/07/05)
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- Guanidine–Copper Complex Catalyzed Allylic Borylation for the Enantioconvergent Synthesis of Tertiary Cyclic Allylboronates
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An enantioconvergent synthesis of chiral cyclic allylboronates from racemic allylic bromides was achieved by using a guanidine–copper catalyst. The allylboronates were obtained with high γ/α regioselectivities (up to 99:1) and enantioselectivities (up to 99 % ee), and could be further transformed into diverse functionalized allylic compounds without erosion of optical purity. Experimental and DFT mechanistic studies support an SN2′ borylation process catalyzed by a monodentate guanidine–copper(I) complex that proceeds through a special direct enantioconvergent transformation mechanism.
- Ge, Yicen,Cui, Xi-Yang,Tan, Siu Min,Jiang, Huan,Ren, Jingyun,Lee, Nicholas,Lee, Richmond,Tan, Choon-Hong
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supporting information
p. 2382 - 2386
(2019/02/01)
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- Enantioselective Hydrogenation of Ketones using Different Metal Complexes with a Chiral PNP Pincer Ligand
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The synthesis of different metal pincer complexes coordinating to the chiral PNP ligand bis(2-((2R,5R)-2,5-dimethyl-phospholanoethyl))amine is described in detail. The characterized complexes with Mn, Fe, Re and Ru as metal centers showed good activities regarding the reduction of several prochiral ketones. Comparing these catalysts, the non-noble metal complexes produced best selectivities not only for aromatic substrates, but also for different kinds of aliphatic ones leading to enantioselectivities up to 99% ee. Theoretical investigations elucidated the mechanism and rationalized the selectivity. (Figure presented.).
- Garbe, Marcel,Wei, Zhihong,Tannert, Bianca,Spannenberg, Anke,Jiao, Haijun,Bachmann, Stephan,Scalone, Michelangelo,Junge, Kathrin,Beller, Matthias
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supporting information
p. 1913 - 1920
(2019/03/13)
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- CHIRAL METAL COMPLEX COMPOUNDS
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The invention comprises novel chiral metal complex compounds of the formula (I) wherein M, PR2, R3 and R4 are outlined in the description, its stereoisomers, in the form as a neutral complex or a complex cation with a suitable counter ion. The chiral metal complex compounds can be used in asymmetric reactions, particularly in asymmetric reductions of ketones, imines or oximes.
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Page/Page column 18; 19; 22; 24; 28
(2018/11/10)
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- Manganese(I)-Catalyzed Enantioselective Hydrogenation of Ketones Using a Defined Chiral PNP Pincer Ligand
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A new chiral manganese PNP pincer complex is described. The asymmetric hydrogenation of several prochiral ketones with molecular hydrogen in the presence of this complex proceeds under mild conditions (30–40 °C, 4 h, 30 bar H2). Besides high catalytic activity for aromatic substrates, aliphatic ketones are hydrogenated with remarkable selectivity (e.r. up to 92:8). DFT calculations support an outer sphere hydrogenation mechanism as well as the experimentally determined stereochemistry.
- Garbe, Marcel,Junge, Kathrin,Walker, Svenja,Wei, Zhihong,Jiao, Haijun,Spannenberg, Anke,Bachmann, Stephan,Scalone, Michelangelo,Beller, Matthias
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supporting information
p. 11237 - 11241
(2017/09/02)
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- Caution in the Use of Nonlinear Effects as a Mechanistic Tool for Catalytic Enantioconvergent Reactions: Intrinsic Negative Nonlinear Effects in the Absence of Higher-Order Species
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Investigation of the dependence of product enantiometric excess (ee) on catalyst ee is a widely used tool to probe the mechanism of an enantioselective reaction; in particular, the observation of a nonlinear relationship is usually interpreted as an indication of the presence of one or more species that contain at least two units of the chiral entity. In this report, we demonstrate that catalytic enantioconvergent reactions can display an intrinsic negative nonlinear effect that originates purely from the kinetic characteristics of certain enantioconvergent processes and is independent of possible aggregation of the chiral entity. Specifically, this intrinsic negative nonlinear effect can arise when there is a kinetic resolution of the racemic starting material, and its magnitude is correlated with the selectivity factor and the conversion; the dependence on conversion provides a ready means to distinguish it from a more conventional nonlinear effect. We support our analysis with experimental data for two distinct enantioconvergent processes, one catalyzed by a chiral phosphine and the other by a chiral Pd/phosphine complex.
- Kalek, Marcin,Fu, Gregory C.
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supporting information
p. 4225 - 4229
(2017/03/27)
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- Characterization of the monolignol oxidoreductase AtBBE-like protein 15 L182V for biocatalytic applications
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Monolignol oxidoreductases from the berberine bridge enzyme-like (BBE-like) protein family (pfam 08031) catalyze the oxidation of monolignols to the corresponding aldehydes. In this report, we explore the potential of a monolignol oxidoreductase from Arabidopsis thaliana (AtBBE-like protein 15) as biocatalyst for oxidative reactions. For this study we employed a variant with enhanced reactivity towards oxygen, which was obtained by a single amino acid exchange (L182V). The pH and temperature optima of the purified AtBBE-like protein 15 L182V were determined as well as the tolerance toward organic co-solvents; furthermore the substrate scope was characterized. The enzyme has a temperature optimum of 50 °C and retains more than 50% activity between pH 5 and pH 10 within 5 min. The enzyme shows increased activity in the presence of various co-solvents (10–50% v/v), including acetonitrile, 2-propanol, 1,4-dioxane, and dimethyl sulfoxide. Primary benzylic and primary or secondary allylic alcohols were accepted as substrates. The enantioselectivity E in the oxidation of secondary alcohols was good to excellent (E>34 to?>200).
- Pils, Sabine,Schnabl, Kordula,Wallner, Silvia,Daniel, Bastian,Macheroux, Peter,Kljajic, Marko,Kupresanin, Nina,Breinbauer, Rolf,Fuchs, Michael,Rocha, Raquel,Schrittwieser, Joerg H.,Kroutil, Wolfgang
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- A recyclable Mn-porphyrin catalyst for enantioselective epoxidation of unfunctionalized olefins using molecular dioxygen
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A magnetically separable chiral catalyst, Fe3O4/tart/Mn(TCPP)Cl, was prepared by the synthesis and immobilization of manganese-tetra(4-carboxyphenyl)porphyrin, Mn(TCPP)Cl, onto the chiral surface of magnetite nanoparticles (Fe3O4/tart-NPs; tart = l-tartaric acid) through the carboxylate groups. The solid catalyst was characterized by a variety of methods including XRD, FE-SEM, FT-IR and UV-Vis spectroscopy. The catalytic activity was tested in the epoxidation reactions of prochiral olefins with molecular oxygen. The reactions were carried out in acetonitrile as solvent with molecular oxygen in the presence of isobutyraldehyde as the stoichiometric oxidant. The catalyst showed consistently high conversion, selectivity and enantioselectivity to epoxide formation in the oxidation of a variety of terminal, cyclic and aromatic olefins. The catalyst showed little deactivation with time and it is easily recovered by magnetic filtration and could be reused four times with little or no loss in activity and selectivity.
- Farokhi, Afsaneh,Hosseini-Monfared, Hassan
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p. 5032 - 5043
(2016/07/06)
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- Engineering Rieske Non-Heme Iron Oxygenases for the Asymmetric Dihydroxylation of Alkenes
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The asymmetric dihydroxylation of olefins is of special interest due to the facile transformation of the chiral diol products into valuable derivatives. Rieske non-heme iron oxygenases (ROs) represent promising biocatalysts for this reaction as they can be engineered to efficiently catalyze the selective mono- and dihydroxylation of various olefins. The introduction of a single point mutation improved selectivities (≥95 %) and conversions (>99 %) towards selected alkenes. By modifying the size of one active site amino acid side chain, we were able to modulate the regio- and stereoselectivity of these enzymes. For distinct substrates, mutants displayed altered regioselectivities or even favored opposite enantiomers compared to the wild-type ROs, offering a sustainable approach for the oxyfunctionalization of a wide variety of structurally different olefins. Modulation by mutation: Rieske non-heme iron oxygenases can be used as efficient biocatalysts for the selective oxyfunctionalization of various olefins yielding vicinal cis-diols and allylic alcohols. Introduction of a single amino acid substitution in the active sites of two selected oxygenases resulted in variants with improved stereoselectivities and product formations.
- Gally, Christine,Nestl, Bettina M.,Hauer, Bernhard
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supporting information
p. 12952 - 12956
(2015/11/02)
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- SULFONAMIDES DERIVED FROM TRICYCLYL-2-AMINOCYCLOALKANOLS AS ANTICANCER AGENTS
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A genus of arylsulfonamide derivatives of aminocycloalkanols is disclosed. The compounds are of the following genus (I):. The compounds induce FOXO1 transcription factor translocation to the nucleus by modulating PP2A and, as a consequence, exhibit anti-proliferative effects. They are useful in the treatment of a variety of disorders, including as a monotherapy in cancer treatment, or used in combination with other drugs to restore sensitivity to chemotherapy where resistance has developed.
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Paragraph 00142; 00143
(2015/10/05)
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- Facile synthesis of hybrid core-shell nanospheres for the asymmetric transfer hydrogenation of aromatic ketones
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The polymer-inorganic hybrid core-shell nanospheres with N-(para-toluenesulfonyl)-1,2-diphenylethylenediamine in the core and the poly(methyl acrylate) (PMA) polymer in the shell were prepared by using a sol-gel process. The surface properties of solid catalysts were modified by controlling PMA and the cetyltrimethylammonium bromide surfactant in the shell. The water contact angle results suggest that the presence of PMA and cetyltrimethylammonium bromide in the shell increases the surface hydrophobicity. In the Rh-catalyzed transfer hydrogenation of aromatic ketones in aqueous HCOONa, the solid catalyst with higher surface hydrophobicity demonstrates higher activity, which suggests that suitable surface properties increase the reaction rate by increasing the diffusion rates of hydrophobic substrates. Furthermore, this heterogeneous catalyst can be reused conveniently without loss of ee values. Clever condensation: A sol-gel process is used for the synthesis of polymer-inorganic hybrid core-shell composites with a mixture of poly(methyl acrylate)-organosilane (PMA SiO2) and tetraethoxysilane as a co-condensed silane source and the polystyrene-supported N-(para-toluenesulfonyl)-1,2-diphenylethylenediamine-type ligand as a polymer core. These core-shell materials demonstrate high reactivity and excellent ee values for the asymmetric transfer hydrogenation of aromatic ketones in aqueous HCOONa.
- Wei, Juan,Zhang, Xiaomin,Zhang, Xiaoming,Zhao, Yaopeng,Li, Ruixiang,Yang, Qihua
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p. 1368 - 1374
(2014/05/20)
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- Hydrogen: A good partner for rhodium-catalyzed hydrosilylation
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The influence of hydrogen pressure on the hydrosilylation of ketones catalyzed by [((S)-SYNPHOS)Rh(nbd)]OTf has been studied. We have notably demonstrated that hydrogen significantly affected the outcome of the reaction while not being consumed as stoichiometric reducing agent. In THF, diethyl ether or toluene, the hydrogen pressure exceedingly accelerated the hydrosilylation reaction and preserved or even improved the enantioselectivity of the process. In CH2Cl2, the rhodium catalyst also showed generally higher catalytic activity under hydrogen pressure. Most serendipitously, several ketones were found to give products of absolute opposite configuration upon performing the hydrosilylation under argon atmosphere or under hydrogen pressure. Copyright 2014 John Wiley & Sons, Ltd. We have shown that the performances of a rhodium complex associated with the atropisomeric diphosphine SYNPHOS as chiral ligand can be considerably upgraded under hydrogen pressure. Most serendipitously, several ketones were found to give the products of absolute opposite configuration upon performing the hydrosilylation under argon atmosphere or under H2 pressure. Copyright
- Balan, Cedric,Pop, Roxana,Comte, Virginie,Poinsot, Didier,Ratovelomanana-Vidal, Virginie,Gendre, Pierre Le
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p. 517 - 522
(2014/07/07)
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- Enzymatic preparation of (1S,2R)- and (1R,2S)-stereoisomers of 2-halocycloalkanols
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The stereoisomers of cis-2-halocycloalkanols were resolved by a kinetically controlled transesterification with vinyl acetate in the presence of lipases in organic media. High enantioselectivities (ee >98%) and good isolated yields were obtained for all substrates using the appropriate lipase. Burkholderia cepacia lipase was the most efficient enzyme for the resolution of these substrates. The enantiomeric purities of the compounds were defined by derivatization with Mosher's acid and the absolute configurations were determined by chemical correlation.
- Kolodiazhna, Olga O.,Kolodiazhna, Anastasy O.,Kolodiazhnyi, Oleg I.
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- Enzyme- and ruthenium-catalyzed dynamic kinetic resolution of functionalized cyclic allylic alcohols
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Enantioselective synthesis of functionalized cyclic allylic alcohols via dynamic kinetic resolution has been developed. Cyclopentadienylruthenium catalysts were used for the racemization, and lipase PS-IM or CALB was employed for the resolution. By optimization of the reaction conditions the formation of the enone byproduct was minimized, making it possible to prepare a range of optically active functionalized allylic alcohols in good yields and high ee's.
- Lihammar, Richard,Millet, Renaud,Baeckvall, Jan-E.
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p. 12114 - 12120
(2014/01/06)
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- Enzymatic resolution of stereoisomers of 2-iodocyclohexanol
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All four optically active stereoisomers of 2-iodocyclohexanol were synthesized. Their enantiomeric purity was determined upon derivatization with Mosher's acid, absolute configuration have been established by chemical correlation.
- Kolodiazhna,Kolodiazhna,Kolodiazhnyi
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p. 2175 - 2177
(2013/10/01)
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- Enantioselective zinc-catalyzed hydrosilylation of ketones using pybox or pybim ligands
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The combination of ZnEt2 and chiral pyridinebisoxazoline (pybox) or pyridinebisimidazoline (pybim) ligands catalyzed the asymmetric hydrosilylation of aryl, alkyl, cyclic, heterocyclic, and aliphatic ketones. Under mild conditions, high yields and good enantioselectivities were achieved. ESI measurements allowed for the characterization of the active catalyst. Zincing outside of the pybox: A ZnEt2/pybox catalyst promotes the hydrosilylation of carbonyl compounds under mild conditions to afford high yields and good ee values for a broad range of aryl, alkyl, cyclic, heterocyclic, and aliphatic ketones.
- Junge, Kathrin,Moeller, Konstanze,Wendt, Bianca,Das, Shoubhik,Goerdes, Dirk,Thurow, Kerstin,Beller, Matthias
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experimental part
p. 314 - 320
(2012/04/18)
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- Enzymatic allylic oxidations with a lyophilisate of the edible fungus Pleurotus sapidus
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Allylic oxidations belong to the most attractive synthetic transformations because they convert readily available and cheap starting materials into value-added products. In this study, we describe oxidative conversions of terpenoids and a number of related cycloalkenes with a lyophilisate of the edible fungus Pleurotus sapidus. The biocatalytic protocol is simple and the biocatalyst is readily available. The conversions of various cycloalkenes proceed cleanly in most cases to the corresponding enones. The substrate scope is remarkable and includes a number of mono- and sequiterpenes, functionalized terpenoids as well as simple cyclohexenes and benzylic substrates. Enzymatic allylic oxidations by Pleurotus sapidus are thus an excellent non-toxic alternative to metal-mediated oxidation procedures in academic labs and for industrial application in food technology, cosmetics or pharmaceutical research. The Royal Society of Chemistry 2012.
- Rickert, Aljona,Krombach, Verena,Hamers, Oliver,Zorn, Holger,Maison, Wolfgang
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experimental part
p. 639 - 644
(2012/04/23)
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- Pre-organization of the core structure of E-selectin antagonists
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A new class of N-acetyl-dglucosamine (GlcNAc) mimics for Eselectin antagonists was designed and synthesized. The mimic consists of a cyclohexane ring substituted with alkyl substituents adjacent to the linking position of the fucose moiety. Incorporation into E-selectin antagonists led to the test compounds 8 and the 2'-benzoylated analogues 21, which exhibit affinities in the low micromolar range. By using saturation transfer difference (STD)-NMR it could be shown that the increase in affinity does not result from an additional hydrophobic contact of the alkyl substituent with the target protein E-selectin, but rather from a steric effect stabilizing the antagonist in its bioactive conformation. The loss of affinity found for antagonists 10 and 35 containing a methyl substituent in a remote position (and therefore unable to support to the stabilization of the core) further supports this hypothesis. Finally, when a GlcNAc mimetic containing two methyl substituents (52 and 53) was used, in which one methyl was positioned adjacent to the fucose linking position and the other was in a remote position, the affinity was regained.
- Schwizer, Daniel,Patton, John T.,Cutting, Brian,Smiesko, Martin,Wagner, Beatrice,Kato, Ako,Weckerle, Celine,Binder, Florian P. C.,Rabbani, Said,Schwardt, Oliver,Magnani, John L.,Ernst, Beat
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supporting information; experimental part
p. 1342 - 1351
(2012/04/04)
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- Highly enantioselective and regioselective carbonyl reduction of cyclic α,β-unsaturated ketones using TarB-N02 and sodium borohydride
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Asymmetric 1,2-reduction of α,β-unsaturated ketones using TarB-NO2 and NaBH4 Is reported. Simple cycloalkenones give products In low enantiomeric excess. However, cycloalkenones with a-substituents, such as halides, alkyl, and aryl, have been enantioselectively reduced with this system to yield chiral allylic alcohols In enantiomeric excess up to 99%. The starting materials for TarB-N02 are inexpensive, and the boronlc acid can be easily recovered In high yield by a simple acid extraction.
- Kim, Jinsoo,Bruning, John,Park, Kevin E.,Lee, David J.,Singaram, Bakthan
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scheme or table
p. 4358 - 4361
(2009/12/24)
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- Methods of use of glycomimetics with replacements for hexoses and n-acetyl hexosamines
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Methods are provided for using a compound to treat, for example, endothelial dysfunction including vascular abnormalities. More specifically, methods are described for using an oligosaccharide compound or glycomimetic compound wherein a cyclohexane derivative is incorporated in either.
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- New pinene-derived pyridines as bidentate chiral ligands
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A synthesis of new bidentate pyridines 8a-d, 9, and 10 has been developed, starting from triflate 14, readily available from β-pinene 11. A copper complex of the pyridine-oxazoline ligands 8a has been found to catalyze asymmetric allylic oxidation of cyclic olefins 36a-c with good conversion rates and acceptable enantioselectivity (≤67% ee). The imidazolium salt 10 has been identified as a precursor of the corresponding N,N′-unsymmetrical N-heterocyclic carbene ligand, whose complex with palladium catalyzed the intramolecular amide enolate α-arylation leading to oxindole 45 in excellent yield but with low enantioselectivity.
- Malkov, Andrei V.,Stewart-Liddon, Angus J.P.,Teply, Filip,Kobr, Luká?,Muir, Kenneth W.,Haigh, David,Ko?ovsky, Pavel
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p. 4011 - 4025
(2008/09/20)
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- Glycomimetic replacements for hexoses and N-acetyl hexosamines
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Compounds and methods are provided for obtaining oligosaccharide mimics. More specifically, compounds and methods are described wherein oligosaccharide mimics are obtained by incorporating or substituting in a cyclohexane derivative.
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Page/Page column 20
(2008/12/06)
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- Biocatalytic reduction of a racemic selenocyclohexanone by Brazilian basidiomycetes
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An efficient synthesis of the chiral cyclic secondary alcohols, trans-2-(phenylseleno)cyclohexanol 1a and cis-2-(phenylseleno)cyclohexanol 1a, was obtained by enzymatic reduction of 2-(phenylseleno)cyclohexanone 1 using whole fungal cells. Five strains of white-rot basidiomycetes were examined; Irpex lacteus CCB 196, Pycnoporus sanguineus CCB 196, Trametes rigida CCB 285, Trametes versicolor CCB 202 and Trichaptum byssogenum CCB 203. Cells of T. rigida CCB 285 gave alcohols cis-(RS)-1a and trans-(SS)-1a in high enantiomeric excesses (ca. 99%).
- Piovan, Leandro,Capelari, Marina,Andrade, Leandro H.,Comasseto, Joao V.,Porto, Andre L.M.
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p. 1398 - 1402
(2008/02/11)
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- An enantiocontrolled approach for the synthesis of chiral 3,5-disubstituted 2(1H)-pyridinones
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An enantioselective route for the convergent synthesis of chiral, nonracemic 5-substituted 3-acyl-2(1H)-pyridinones is reported. Claisen rearrangement provides direct access to the α-branched 2-[4-(tert-butyldimethylsilanoxy)cyclohex-2-enyl]-3-hydroxypropionaldehyde as a key intermediate. The application of mild oxidation conditions facilitates the preparation of a series of 3,5-disubstituted 2(1H)-pyridinones.
- Williams, David R.,Kammler, David C.,Goundry, William R.F.
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p. 555 - 559
(2007/10/03)
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- Synthesis of 6-substituted 7-bomoazabicyclo[2.2.1]heptanes via nucleophilic addition to 3-bromo-1-azoniatricyclo[2.2.1.0]-heptane bromide
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We describe herein an efficient method for the preparation of a functionalised bicyclic framework (6-substituted 7-bromo-aza-bicyclo[2.2.1] heptane) through the selective opening of the aziridium 2 with organocuprates in up to 90% yield. These interesting chiral building blocks were then utilised as novel ligands in the rearrangement of epoxides to afford chiral allylic alcohols.
- Gayet, Arnaud,Andersson, Pher G.
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p. 1242 - 1246
(2007/10/03)
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- Palladium-catalyzed asymmetric synthesis of allylic alcohols from unsymmetrical and symmetrical racemic allylic carbonates featuring C-O-bond formation and dynamic kinetic resolution
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Described is the asymmetric synthesis of the allylic alcohols 11 (85% ee), 15 (99% ee), 17 (93% ee), 19 (61% ee), and 21 (69% ee) through a Pd-catalyzed reaction of the unsymmetrical carbonates rac-10, rac-12, rac-14, rac-16, rac-18, and rac-20, respectively, with KHCO3 and H2O in the presence of bisphosphane 6. Similarly the allylic alcohols 23 (99% ee) and 25 (97% ee) have been obtained from the symmetrical carbonates rac-22 and rac-24, respectively. Reaction of the meso-biscarbonate 26 with H2O and Pd(0)/6 afforded alcohol 27 (96% ee), which was converted to the PG building block 32. The unsaturated bisphosphane 33 showed in the synthesis of alcohols 36, 37, and 39 a similar high selectivity as 6. The formation of alcohols 11, 15, and 17 involves an efficient dynamic kinetic resolution.
- Gais, Hans-Joachim,Bondarev, Oleg,Hetzer, Ralf
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p. 6279 - 6283
(2007/10/03)
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- Enantioselective catalytic rearrangement of cyclohexene oxide with new homochiral bis-lithium amide bases
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Cyclohexene oxide can be rearranged with good levels of induction (up to 68% ee) with substoichiometric amounts of chiral bases derived from readily available diamines. The influence of the steric bulk of the amine substituents on the rearrangement enantioselectivity has also been studied.
- Equey, Olivier,Alexakis, Alexandre
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p. 1069 - 1072
(2007/10/03)
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- Palladium-catalyzed enantioselective allylic alkylation of thiocarboxylate ions: Asymmetri synthesis of allylic thioesters and memory effect/dynamic kinetic resolution of allylic esters
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The palladium-catalyzed allylic alkylation of KSAc and KSBz with racemic cyclic and acyclic allylic esters by using N,N'-(1R,2R)-1,2-cyclohexandiylbis[2-(diphenylphosphino)-benzamide] as ligand frequently gave the corresponding allylic thioesters with high ee values and yields. The reaction of the cyclic allylic carbonates with KSAc in the presence of H20 was accompanied by a partial palladium-catalyzed enantioselective "hydrolysis" of the substrates with formation of the corresponding enantioenriched allylic alcohols. The degree of the "hydrolysis" was strongly dependent on the solvent and the thiocarboxylate ion. Highly selective kinetic resolutions (KRs) were observed in the palladium-catalyzed reaction of the racemic cyclohexenyl and cycloheptenyl acetates with KSAc. While the KR of the cyclohexenyl acetate is characterized by a selectivity factor S = 72 ± 19, that of the cycloheptenyl acetate afforded (R)-cycloheptenyl acetate of ≥ 99% ee in 48% yield and (S)-cycloheptenyl thioacetate of 98% ee in 50% yield. The palladium-catalyzed reaction of the racemic cyclopentenyl acetate with KSAc showed a strong "memory effect" (ME), that is, both enantiomers reacted with different enantioselectivities. The ME was probed by studying the palladium-catalyzed reactions of both the matched acetate of ≥ 99% ee and the mismatched acetate of ≥ 99% ee with KSAc. The acetates not only reacted with different enantioselectivities and rates but also suffered an unexpected and concomitant palladium-catalyzed racemization in the presence of the chiral ligand. This led in the case of the mismatched acetate to a temporary dynamic kinetic resolution (DKR) that featured a racemization of the mismatched acetate by the chiral catalyst. Studies of the palladium-catalyzed reaction of the racemic cyclopentenyl acetate, carbonate, and naphthoate with KSAc in the presence of the chiral ligand also showed the ME to be strongly dependent on the nucleofuge. This also allowed the synthesis of (S)-cyclopentenyl thioacetate of 92% ee in high yield from the racemic cyclopentenyl naphthoate.
- Luessem, Bernhard J.,Gais, Hans-Joachim
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p. 4041 - 4052
(2007/10/03)
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- Solid-phase supported chiral lithium amides used in deprotonation reactions
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The lithium salt of polymer supported phenylethyl amine showed surprisingly high enantioselectivity in the asymmetric deprotonation reaction of cyclohexene oxide. The polymer supported chiral lithium amide base also proved to be more reactive compared to the free chiral lithium amide base. This is a new insight in the development and mechanism of chiral lithium amide bases used in asymmetric reactions.
- Johansson, Anna,Abrahamsson, Peter,Davidsson, Oejvind
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p. 1261 - 1266
(2007/10/03)
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- On the α-lithiation-rearrangement of N-toluensulfonyl aziridines: Mechanistic and synthetic aspects
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A detailed study of the rearrangement of five cycloalkene N-toluenesulfonyl (tosyl) aziridines using sec-butyllithium (with and without added ligands such as (-)-sparteine and TMEDA) has been carried out. Allylic sulfonamides were the main products from the cyclopentene and cyclohexene aziridines whereas bicyclic sulfonamides were obtained from the cycloheptene and cyclooctene aziridines. In most cases, p-toluenesulfonamide (TsNH 2) was produced as a by-product and a mechanistic explanation for its formation is forwarded. These reactions are believed to involve α-lithiation to a lithiated aziridine which can then partition through two pathways: (i) rearrangement to allylic or bicyclic sulfonamides via C-H insertion reactions or (ii) reductive alkylation to alkenes via attack by sec-butyllithium and subsequent elimination of TsNH2. In the (-)-sparteine reactions, the products were generated with 38-66% ee and the sense of asymmetric induction involved lithiation of the S-aziridine stereocentre. This is opposite to that observed with epoxides.
- O'Brien, Peter,Rosser, Clare M.,Caine, Darren
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p. 9779 - 9791
(2007/10/03)
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- Palladium-catalyzed deracemization of allylic carbonates in water with formation of allylic alcohols: Hydrogen carbonate ion as nucleophile in the palladium-catalyzed allylic substitution and kinetic resolution
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The palladium-catalyzed deracemization of racemic cyclic and acyclic allylic methyl carbonates in water in the presence of N,N′-(1R,2R)-1,2-cyclohexanediylbis[2-(diphenylphophino)benzamide] proceeds with high enantioselectivities to give the corresponding allylic alcohols in high yields. This deracemization involves a palladium-catalyzed allylic substitution with the in-situ-formed hydrogen carbonate ion and an irreversible decomposition of the intermediate allylic hydrogen carbonates, with formation of the corresponding allylic alcohols. The palladium-catalyzed reaction of racemic cyclic allylic acetates with potassium hydrogen carbonate in water in the presence of the chiral bisphosphane proceeds with a highly selective kinetic resolution to give the corresponding allylic alcohols and allylic acetates. Copyright
- Luessem, Bernhard J.,Gais, Hans-Joachim
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p. 6066 - 6067
(2007/10/03)
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- Highly selective palladium catalyzed kinetic resolution and enantioselective substitution of racemic allylic carbonates with sulfur nucleophiles: Asymmetric synthesis of allylic sulfides, allylic sulfones, and allylic alcohols
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We describe the highly selective palladium catalyzed kinetic resolutions of the racemic cyclic allylic carbonates rac-1a-c and racemic acyclic allylic carbonates rac-3aa and rac-3ba through reaction with tert-butylsulfinate, tolylsulfinate, phenylsulfinate anions and 2-pyrimidinethiol by using N,N′-(1R,2R)-1,2-cyclohexanediylbis[2-(di-phenylphosphino)-benzamide] (BPA) as ligand. Selectivities are expressed in yields and ee values of recovered substrate and product and in selectivity factors S. The reaction of the cyclohexenyl carbonate 1a (≥99% ee) with 2-pyrimidinethiol in the presence of BPA was shown to exhibit, under the conditions used, an overall pseudo-zero order kinetics in regard to the allylic substrate. Also described are the highly selective palladium catalyzed asymmetric syntheses of the cyclic and acyclic allylic tert-butylsulfones 2aa, 2b, 2c, 2d and 4 a - c, respectively, and of the cyclic and acyclic allylic 2-pyrimidyl-, 2-pyridyl-, and 4-chlorophenylsulfides 5aa, 5b, 5ab, 6aa - ac, 6ba and 6bb, respectively, from the corresponding racemic carbonates and sulfinate anions and thiols, respectively, in the presence of BPA. Synthesis of the E-configured allylic sulfides 6aa, 6ab, 6ac and 6bb was accompanied by the formation of minor amounts of the corresponding Z isomers. The analogous synthesis of allylic tert-butylsulfides from allylic carbonates and tert-butylthiol by using BPA could not be achieved. Reaction of the cyclopentenyl esters rac-1da and rac-1db with 2-pyrimidinethiol gave the allylic sulfide 5c having only a low ee value. Similar results were obtained in the case of the reaction of the cyclohexenyl carbonate rac-1a and of the acyclic carbonates rac-3aa and rac-3ba with 2-pyridinethiol and lead to the formation of the sulfides 5 ab, 6 ab, and 6 bb, respectively. The low ee values may be ascribed to the operating of a "memory effect", that is, both enantiomers of the substrate give the substitution product with different enantioselectivities. However, in the reaction of the racemic carbonate rac-1 a as well as of the highly enriched enantiomers la (≥99% ee) and ent-1a (≥99% ee) with 2-pyrimidinethiol the ee values of the substrates and the substitution product remained constant until complete conversion. Similar results were obtained in the reaction of the cyclic carbonates rac-1a, ent-1a (≥99% ee) and ent-1c (≥99% ee) with lithium tert-butylsulfinate. Thus, in the case of rac-1a and 2-pyrimidinthiol and tert-butylsulfinate anion as nucleophiles the enantioselectivity of the substitution step is, under the conditions used, independent of the chirality of the substrate; this shows that no "memory effect" is operating in this case. Hydrolysis of the carbonates ent-1a-c, ent-3aa and ent-3ba, which were obtained through kinetic resolution, afforded the enantiomerically highly enriched cyclic allylic alcohols 9a-c (≥99% ee) and acyclic allylic alcohols 10a (≥99% ee) and 10b (99% ee), respectively.
- Gais, Hans-Joachim,Jagusch, Thomas,Spalthoff, Nicole,Gerhards, Frank,Frank, Michael,Raabe, Gerhard
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p. 4202 - 4221
(2007/10/03)
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- Catalytic enantioselective rearrangement of meso-epoxides mediated by chiral lithium amides in the presence of excess cross-linked polymer-bound lithium amides
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Insoluble polymer-bound achiral lithium dialkylamides were prepared from the corresponding cross-linked polymer-bound amines and butyllithium. The polymer-bound achiral reagent was applied to a catalytic enantioselective rearrangement of meso-epoxides as an in situ regenerating agent of a chiral lithium amide. The efficiency of the catalytic system was improved, and chiral allylic alcohol derivatives were obtained in high enantiomeric excesses by using excess polymer-bound reagents and a sub-stoichiometric amount of chiral lithium amide, prepared from (2S,3aS,7aS)-2-(pyrrolidin-1-ylmethyl)octahydroindole. The reaction was successfully applied in the synthesis of (1S,4R)-4-benzoylamino-2-cyclopentenol, a useful chiral synthetic intermediate for carbocyclic nucleosides, in 97% ee.
- Seki, Atsushi,Asami, Masatoshi
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p. 4655 - 4663
(2007/10/03)
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- Kinetic and computational studies of the composition and structure of activated complexes in the asymmetric deprotonation of cyclohexene oxide by a norephedrine-derived chiral lithium amide
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Rational design of efficient chiral lithium amides for enantioselective deprotonations demands understanding of the origin of the selectivity. The mechanism of deprotonation of cyclohexene oxide 1 by lithium (1R,2S)-N-methyl-1-phenyl-2-pyrrolidinylpropanamide 3, which yields (S)-cyclohex-2-en-1-ol (S)-5 in 93% enantiomeric excess in tetrahydrofuran (THF), has been investigated. Kinetics have been used to show that the reaction is first order with respect to the reagents 1 and 3, respectively. NMR investigations of a 6Li and 15N labelled isotopologue of 3 have previously shown that 3 is mainly a dimer of the lithium amide monomer in THF in the initial state. On the basis of these results it is concluded that the rate-limiting activated complexes for the epoxide deprotonation are composed of two molecules of monomer of lithium amide 3 and one molecule of epoxide. Structures and energies of unsolvated and specific THF-solvated reagents and activated complexes have been calculated using PM3 and B3LYP/6-31+G(d). The results are currently being explored for the rational design of chiral lithium amides with improved stereoselectivities.
- Pettersen, Daniel,Amedjkouh, Mohamed,Nilsson Lill, Sten O.,Dahlen, Kristian,Ahlberg, Per
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p. 1654 - 1661
(2007/10/03)
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- Coordination of (β-N-sulfonylaminoalkyl)phosphines and their analogous arsines to PdII and PtII. Application of the Pd-complexes as chiral catalysts in asymmetric hydrosilylation of 1,3-dienes
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Optically active ligands 2 and 3 were synthesised from phenylglycine and the coordination of ligand 2 to PdCl2(CH3CN)2 and PtCl2(C6H5CN)2 was studied with 1H, 31P and 15N-1H-HMQC NMR spectroscopy. The results indicated P,O rather than P,N bidentate coordination. Both ligands were tested in the palladium catalysed hydrosilylation of cyclic 1,3-dienes. Asymmetric induction of up to 84% (≤25% yield), which is the hitherto highest reported ee value for asymmetric hydrosilylation of 1,3-dienes, was achieved as measured on the allylic alcohols formed after ethanolysis-oxidation of the initially formed allylic silanes.
- Gustafsson,Bergqvist,Frejd
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p. 1452 - 1457
(2007/10/03)
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- Enantioselective preparation of a novel chiral 1,2-diamine
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A short enantioselective preparation of (1S,2S)-trans-1,2-diamino-3-cyclohexene using a double [3,3]-sigmatropic rearrangement of an allylic bis(imidate) is described (Overman rearrangement). The starting chiral diol is conveniently obtained by enzymatic resolution.
- Demay, Stéphane,Kotschy, Andras,Knochel, Paul
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p. 863 - 866
(2007/10/03)
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- Allylic alcohols via catalytic asymmetric epoxide rearrangement
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Epoxides using chiral lithium amides, but other than for a small subset of meso-epoxides, insufficient reactivity and enantioselectivity hamper the existing methods. Furthermore, the chiral reagents are often required in large excess. This study presents a general and highly enantioselective process that, in addition, is based on catalytic amounts (5 mol %) of enantiopure (1S,3R,4R)-3-(1-pyrrolidinyl)methyl-2-azabicyclo[2.2.1]heptane and lithium diisopropylamide as the stoichiometric base. The influence of structural modification of the catalyst is studied in terms of activity, enantioselectivity, and aggregation behavior. The utility of the process is demonstrated by its application to a variety of epoxide derivatives (≥94% ee for 11 out of 14 examples), including the formal syntheses of, e.g., a prostaglandin core unit, epibatidine, carbovir, faranal, and lasiol. The system is readily extended to the resolution of racemic epoxides, which allows access to highly enantioenriched epoxides or allylic alcohols, even at conversions near 50%.
- Soedergren, Mikael J.,Bertilsson, Sophie K.,Andersson, Pher G.
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p. 6610 - 6618
(2007/10/03)
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- A highly enantioenriched, configurationally stable α-thioallyllithium compound and the stereochemical course of its electrophilic alkylation
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matrix presented The first highly enantioenriched, configurationally stable a-thioallyllithium compound (9) was generated by deprotonation of the S-cyclohex-2-enyl thiocarbamate 8. The methylation of 9 in both the α- and γ-positions proceeds antarafacially with a high degree of chirality transmission, as was elucidated by X-ray analysis of thiocarbamates 10 and 11. The optically active S-allyl thiocarbamate 8 was prepared by enantiospecific [3,3]sigmatropic rearrangement of the corresponding Oallyl thiocarbamate 7.
- Marr, Felix,Froehlich, Roland,Hoppe, Dieter
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p. 2081 - 2083
(2008/02/09)
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- A new chiral lithium amide based on (S)-2-[1-(3,3- dimethyl)pyrrolidinylmethyl]pyrrolidine-synthesis, NMR studies and use in the enantioselective deprotonation of cyclohexene oxide
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A new chiral lithium amide has been designed starting from (S)-proline. This new chiral lithium amide has been used for asymmetric deprotonation/ring opening of cyclohexene oxide to give (S)-2-cyclohexen-1-ol in 88% yield and 78% enantiomeric excess. NMR studies of the lithium amide and the ligand- substrate complex are also presented.
- Khan, Agha Zul-Qarnain,De Groot, Rimke W.,Arvidsson, Per I.,Davidsson, Oejvind
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p. 1223 - 1229
(2007/10/03)
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