- Preparation method of duloxetine
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To the method, 1 - naphthol and 3 - (2 - thienyl) -2 - acrolein serve as starting materials, and (S)-3 - (1 - naphthyloxy) -3 - (2 - thienyl) propanal is obtained through addition reaction under the action of a catalyst. The raw materials are cheap and easily available, and 1 - fluoronaphthalene which is expensive is not needed. Sodium hydride and operation are tedious, the cost is low, the process operation is safe and convenient, the three wastes are small in generation amount, and green and environment-friendly. The reaction atom economy is high, the reaction selectivity of each step is high, the side reaction is small, the optical purity and yield of the target product are high, and the green industrial production is facilitated.
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- Synthesis of the C1-C27 Fragment of Stambomycin D Validates Modular Polyketide Synthase-Based Stereochemical Assignments
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The stambomycins are a family of bioactive macrolides isolated from Streptomyces ambofaciens. Aside from two stereocenters installed through cytochrome P450 oxidations, their stereochemistry has been predicted by sequence analysis of the polyketide synthase. We report a synthesis of the C1-C27 fragment of stambomycin D, the spectroscopic data of which correlates well with that of the natural product, further validating predictive sequence analysis as a powerful tool for stereochemical assignment of complex polyketide natural products.
- Anderson, Edward A.,Bernasconi, Alice,Blanco, Araceli,Challis, Gregory L.,Chintalapudi, Venkaiah,Gudmundsson, Haraldur G.,Lim, Jieyan,Song, Lijiang,Tran, Minh
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supporting information
p. 7439 - 7444
(2021/10/01)
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- Basicities and Nucleophilicities of Pyrrolidines and Imidazolidinones Used as Organocatalysts
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The Br?nsted basicities pKaH (i.e., pKa of the conjugate acids) of 32 pyrrolidines and imidazolidinones, commonly used in organocatalytic reactions, have been determined photometrically in acetonitrile solution using CH acids as indicators. Most investigated pyrrolidines have basicities in the range 16 aH aH aH 12.6) and the 2-imidazoliummethyl-substituted pyrrolidine A21 (pKaH 11.1) are outside the typical range for pyrrolidines with basicities comparable to those of imidazolidinones. Kinetics of the reactions of these 32 organocatalysts with benzhydrylium ions (Ar2CH+) and structurally related quinone methides, common reference electrophiles for quantifying nucleophilic reactivities, have been measured photometrically. Most reactions followed second-order kinetics, first order in amine and first order in electrophile. More complex kinetics were observed for the reactions of imidazolidinones and several pyrrolidines carrying bulky 2-substituents, due to reversibility of the initial attack of the amines at the electrophiles followed by rate-determining deprotonation of the intermediate ammonium ions. In the presence of 2,4,6-collidine or 2,6-di-tert-butyl-4-methyl-pyridine, the deprotonation of the initial adducts became faster, which allowed the rate of the attack of the amines at the electrophiles to be determined. The resulting second-order rate constants k2 followed the correlation log?k2(20 °C) = sN(N + E), where electrophiles are characterized by one parameter (E) and nucleophiles are characterized by the two solvent-dependent parameters N and sN. In this way, the organocatalysts A1-A32 were integrated in our comprehensive nucleophilicity scale, which compares n-, -, and σ-nucleophiles. The nucleophilic reactivities of the title compounds correlate only poorly with their Br?nsted basicities.
- An, Feng,Maji, Biplab,Min, Elizabeth,Ofial, Armin R.,Mayr, Herbert
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supporting information
p. 1526 - 1547
(2020/02/04)
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- Improved synthesis of (S)-N-Boc-5-oxaproline for protein synthesis with the α-ketoacid-hydroxylamine (KAHA) ligation
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We describe a new route for the synthesis of (S)-N-Boc-5-oxaproline. This building block is a key element for the chemical synthesis of proteins with the α-ketoacid-hydroxylamine (KAHA) ligation. The new synthetic pathway to the enantiopure oxaproline is
- Murar, Claudia E.,Harmand, Thibault J.,Bode, Jeffrey W.
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p. 4996 - 5001
(2017/09/21)
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- Importance of the Electron Correlation and Dispersion Corrections in Calculations Involving Enamines, Hemiaminals, and Aminals. Comparison of B3LYP, M06-2X, MP2, and CCSD Results with Experimental Data
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While B3LYP, M06-2X, and MP2 calculations predict the δG° values for exchange equilibria between enamines and ketones with similar acceptable accuracy, the M06-2X/6-311+G(d,p) and MP2/6-311+G(d,p) methods are required for enamine formation reactions (for example, for enamine 5a, arising from 3-methylbutanal and pyrrolidine). Stronger disagreement was observed when calculated energies of hemiaminals (N,O-acetals) and aminals (N,N-acetals) were compared with experimental equilibrium constants, which are reported here for the first time. Although it is known that the B3LYP method does not provide a good description of the London dispersion forces, while M06-2X and MP2 may overestimate them, it is shown here how large the gaps are and that at least single-point calculations at the CCSD(T)/6-31+G(d) level should be used for these reaction intermediates; CCSD(T)/6-31+G(d) and CCSD(T)/6-311+G(d,p) calculations afford δG° values in some cases quite close to MP2/6-311+G(d,p) while in others closer to M06-2X/6-311+G(d,p). The effect of solvents is similarly predicted by the SMD, CPCM, and IEFPCM approaches (with energy differences below 1 kcal/mol).
- Castro-Alvarez, Alejandro,Carneros, Héctor,Sánchez, Dani,Vilarrasa, Jaume
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p. 11977 - 11985
(2016/01/09)
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- Organocatalytic enantioselective α-hydroxymethylation of aldehydes: Mechanistic aspects and optimization
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Further studies of the direct enantioselective α-hydroxymethylation of aldehydes employing the α,α-diarylprolinol trimethylsilyl ether class of organocatalysts are described. This process has proven efficient for access to β-hydroxycarboxylic acids and δ-hydroxy-α,β-unsaturated esters from aldehydes in generally good yields, excellent enantioselectivity, and compatibility with a broad range of functional groups in the aldehyde. The goal of these studies was to identify the critical reaction variables that influence the yield and enantioselectivity of the α-hydroxymethylation process such as catalyst structure, pH of the medium, purity of the reactants and reagents particularly with respect to the presence of acidic impurities, and the nature of the buffer, along with the standard variables including solvent, time, temperature and mixing efficiency. The previously identified intermediate lactol has been further characterized and its reactivity examined. These studies have led to identification of the most critical variables translating directly into improved substrate scope, reproducibility, enantioselectivity, and yields.
- Boeckman, Robert K.,Biegasiewicz, Kyle F.,Tusch, Douglas J.,Miller, John R.
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p. 4030 - 4045
(2015/05/05)
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- Transfer of 1-alkenyl groups between secondary amines. Relative stability and reactivity of enamines from popular organocatalysts
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Enamines from 3-methylbutanal and several Pro- and Phe-derived secondary amines were prepared in DMSO-d6, CD3CN, and CDCl 3. For the first time, the relative thermodynamic stabilities of these and other enamines were compared, and rapid exchanges of 1-alkenyl groups were demonstrated. Competition experiments showed that the most favored enamines (without significant steric inhibition of resonance) react more rapidly with electrophiles.
- Carneros, Hector,Sanchez, Dani,Vilarrasa, Jaume
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p. 2900 - 2903
(2014/06/23)
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- KAHA ligations that form aspartyl aldehyde residues as synthetic handles for protein modification and purification
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Aldehydes are widely recognized as valuable synthetic handles for the chemoselective manipulation of peptides and proteins. In this report, we show that peptides and small proteins containing the aspartic acid semialdehyde (Asa) side chain can be easily p
- Murar, Claudia E.,Thuaud, Frdric,Bode, Jeffrey W.
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supporting information
p. 18140 - 18148
(2015/03/04)
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- Chiral aminophosphines as catalysts for enantioselective double-michael indoline syntheses
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The bisphosphine-catalyzed double-Michael addition of dinucleophiles to electron-deficient acetylenes is an efficient process for the synthesis of many nitrogencontaining heterocycles. Because the resulting heterocycles contain at least one stereogenic center, this double-Michael reaction would be even more useful if an asymmetric variant of the reaction were to be developed. Aminophosphines can also facilitate the double-Michael reaction and chiral amines are more readily available in Nature and synthetically; therefore, in this study we prepared several new chiral aminophosphines. When employed in the asymmetric double-Michael reaction between ortho-tosylamidophenyl malonate and 3-butyn-2-one, the chiral aminophosphines produced indolines in excellent yields with moderate asymmetric induction.
- Khong, San N.,Kwon, Ohyun
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p. 5626 - 5650
(2012/07/03)
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- Enantioselective michael addition to α,β-Unsaturated aldehydes: Combinatorial catalyst preparation and screening, reaction optimization and mechanistic studies
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Shortcut to chiral catalysts: An efficient combinatorial strategy based on back reaction screening by ESI-MS allows rapid evaluation of organocatalysis for the asymmetric Michael addition to α,β-unsaturated aldehydes (see scheme). An unexpected nonlinear effect has been observed in this reaction, resulting from a double nucleophilic-electrophilic activation mechanism involving two catalyst molecules "Chemical Equation Presented"
- Fleischer, Ivana,Pfaltz, Andreas
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supporting information; experimental part
p. 95 - 99
(2010/03/26)
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- SYNTHESIS OF TELCAGEPANT AND INTERMEDIATES THEREOF
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Disclosed is an efficient synthesis for the manufacture of the caprolactam intermediate (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one: Formula and salts thereof, and an efficient preparation of telcagepant using the caprolact
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Page/Page column 29
(2010/12/29)
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- Asymmetric synthesis of telcagepant, a CGRP receptor antagonist for the treatment of migraine
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A highly efficient, asymmetric synthesis of telcagepant (1), a CGRP receptor antagonist for the treatment of migraine, is described. This synthesis features the first application of iminium organocatalysis on an industrial scale. The key to the success of
- Xu, Feng,Zacuto, Michael,Yoshikawa, Naoki,Desmond, Richard,Hoerrner, Scott,Itoh, Tetsuji,Journet, Michel,Humphrey, Guy R.,Cowden, Cameron,Strotman, Neil,Devine, Paul
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supporting information; experimental part
p. 7829 - 7841
(2011/02/22)
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- Organocatalytic enantioselective synthesis of nitrogen-substituted dihydropyran-2-ones, a key synthetic intermediate of 1β-methylcarbapenems
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Organocatalytic enantioselective cycloadditions providing nitrogen-substituted dihydropyran-2-ones were developed in two catalytic systems. The (3R,4R)-product was a versatile intermediate in the synthesis of 1β-methylcarbapenem antibiotics.
- Kobayashi, Shoji,Kinoshita, Tatsuhiro,Uehara, Hisatoshi,Sudo, Tomoko,Ryu, Llhyong
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supporting information; experimental part
p. 3934 - 3937
(2009/12/05)
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- CONCISE BETA2-AMINO ACID SYNTHESIS VIA ORGANOCATALYTIC AMINOMETHYLATION
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The present invention provides a method for the synthesis of ?2-amino acids. The method also provides methods yielding a-substituted ?-amino aldehydes and ?-substituted γ-amino alcohols. The present method according to this invention allows for increased yield and easier purification using minimal chromatography or crystallization. The methods described herein are based on an aldehyde aminomethylation which involves a Mannich reaction between an aldehyde and a formaldehyde-derived N,O-acetal (iminium precursor) and a catalyst, such as, for example, L-proline or a pyrrolidine. The invention allows for large scale, commercial preparation of ?2-amino acids.
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Page/Page column 39
(2010/11/28)
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- Amine-catalyzed asymmetric epoxidation of α,β-unsaturated aldehydes
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The direct organocatalytic enantioselective epoxidation of α,β-unsaturated aldehydes with different peroxides is presented. Proline, chiral pyrrolidine derivatives, and amino acid-derived imidazolidinones catalyze the asymmetric epoxidation of α,β-unsatur
- Zhao, Gui-Ling,Ibrahem, Ismail,Sunden, Henrik,Cordova, Armando
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p. 1210 - 1224
(2008/09/17)
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- Direct organocatalytic asymmetric epoxidation of α,β-unsaturated aldehydes
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The organocatalytic asymmetric epoxidation of α,β-unsaturated aldehydes with peroxides or sodium percarbonate is presented. Chiral pyrrolidine derivatives, proline and amino acid derived imidazolidinones mediate the asymmetric epoxidation of α,β-unsaturat
- Sundén, Henrik,Ibrahem, Ismail,Córdova, Armando
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- Direct catalytic asymmetric anti-selective Mannich-type reactions
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The simple chiral pyrrolidine catalyzed asymmetric anti-selective Mannich-type reaction is presented; the reaction gives the corresponding amino acid derivatives with 10:1->19:1 dr and 97-99% ee. The Royal Society of Chemistry 2006.
- Ibrahem, Ismail,Cordova, Armando
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p. 1760 - 1762
(2008/09/16)
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- Diphenylprolinol silyl ethers as efficient organocatalysts for the asymmetric Michael reaction of aldehydes and nitroalkenes
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(Chemical Equation Presented) The direct, catalytic, asymmetric Michael addition of aldehydes to nitroolefins in the presence of a chiral diphenylprolinol silyl ether organocatalyst is described (see scheme). The desired 1,4-addition products were obtaine
- Hayashi, Yujiro,Gotoh, Hiroaki,Hayashi, Takaaki,Shoji, Mitsuru
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p. 4212 - 4215
(2007/10/03)
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- Enantioselective organocatalyzed α sulfenylation of aldehydes
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The facile elaboration of optically active α-sulfanyl-substituted aldehydes makes their direct preparation from unmodified aldehydes and 1-benzylsulfanyl-1,2,4-triazole particularly valuable. The substituted aldehydes are formed with excellent enantiosele
- Marigo, Mauro,Wabnitz, Tobias C.,Fielenbach, Doris,Jorgensen, Karl Anker
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p. 794 - 797
(2007/10/03)
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