- The formation of a novel Pd/C-ethylenediamine complex catalyst: Chemoselective hydrogénation without deprotection of the o-benzyl and ZV-Cbz groups
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A Pd/C catalyst formed an isolable complex with ethylenediamine employed as the catalytic poison via one-to-one interaction between Pd metal and ethylenediamine, and this complex catalyst [Pd/ C(en)] chemoselectively hydrogenated a variety of reducible functionalities such as olefin, acetylene, nitro, benzyl ester, and azido in the presence of an O-benzyl or N-Cbz protective group. These findings reinforce the versatility potential of O-benzyl and N-Cbz as protective groups in organic synthesis, and the Pd/C(en) catalyst has been identified as a novel and chemoselective catalyst for the hydrogénation.
- Sajiki, Hironao,Hattori, Kazuyuki,Hirota, Kosaku
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- Asymmetric aldol reaction organocatalyzed by (S)-proline-containing dipeptides: Improved stereoinduction under solvent-free conditions
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The organocatalytic activity of the methyl ester of (S)-proline-(S)- phenylalanine, (S,S)-2, in the asymmetric aldol reaction between cyclohexanone and acetone with various aromatic aldehydes under solvent-free conditions in a ball mill has been evaluated. α,α-Dipeptide (S,S)-2 catalyzed the stereoselective formation of the expected aldol products, with higher diastereo-and enantioselectivity relative to similar reactions in solution, up to 91:9 anti:syn diastereomeric ratio and up to 95% enantiomeric excess.(Figure Presented)
- Hernandez, Jose G.,Juaristi, Eusebio
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- Synthesis, antitumor activity, and nephrotoxicity of the optical isomers of 2-aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato) platinum(II)
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The optical isomers of 2-aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato)platinum(II) (DWA2114, 1), which has potent antitumor activity against various tumors, were synthesized. They were examined for antitumor activity against Colon 26 carcinoma in a sc-iv system, and changes in urinary protein and sugar levels in drug-treated mice were used as an index of nephrotoxicity. In their effect on tumors, (+)-(S)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato) platinum(II) (6b) was more potent than the enantiomer 6a in that the effective dose of 6b was smaller than that of 6a; but, both drugs exhibited potent antitumor activity. On the other hand, a distinct difference between 6a and 6b was shown in their nephrotoxicity. Isomer 6b induced a great increase in urinary protein and sugar levels in mice, whereas 6a caused no increase in these levels.
- Morikawa,Honda,Endoh -i.,Matsumoto,Akamatsu -i.,Mitsui,Koizumi
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- Microwave spectroscopy of the twist C(β)-exo/C(γ)-endo conformation of prolinamide
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The rotational transitions of three isotopomers of prolinamide were measured with a Fourier-transform microwave spectrometer. A twist pyrrolidine ring conformation with C(β)-exo and C(γ)-endo reproduces the experimental moments of inertia. Stark-effect measurements of five [M] components were used to determine that the dipole moment of this conformation of prolinamide is 3.83(4) D. Kraitchman's method of isotopic substitution was used to determine an N-N distance of 2.684(2) A?.
- Kuhls, Kimberly A.,Centrone, Charla A.,Tubergen, Michael J.
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- 5-(Pyrrolidine-2-yl)tetrazole: Rationale for the increased reactivity of the tetrazole analogue of proline in organocatalyzed aldol reactions
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5-[(2S)-Pyrrolidine-2-yl]-1H-tetrazole (1), i.e. the tetrazolic acid analogue of proline, has been found to be significant more reactive than L-proline (2) in various organocatalyzed reactions. In the organocatalyzed direct asymmetric aldol reaction, acetone was reacted with aromatic and aliphatic aldehydes to afford the resulting β-hydroxy ketones in good yields and moderate to high enantiomeric excesses. The increased reactivity of 1, as compared to 2, has been rationalized through a combined computational and NMR spectroscopic study. It was found that catalyst 2 was almost completely engaged in oxazolidinone formation with the aldehyde whereas 1 did not take part in such parasitic equilibrium. This finding, together with the improved solubility of the tetrazole analogue, is proposed to account for the observed reactivity. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.
- Hartikka, Antti,Arvidsson, Per I.
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- Synthetic studies towards proline amide isosteres, potentially useful molecules for biological investigations
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2-Ethenylpyrrolidine derivative 8b was prepared from N-protected proline ethyl ester 6b. Bromofluorination of 8b wth NBS-Bu4NF/2HF gave a 1:1 regioisomeric mixture, 9b and 10b (X = Br). Dehydrobromination of 9b and 10b with t-BuOK produced a fluoroolefin 11 and a proline amide isostere model 12, respectively. Deprotection of the Z group in 12 was attempted by treatment with CF3COOH. Although formation of the useful molecule is pseudopeptide synthesis, 13, was observed as checked by NMR spectra, it seemed to decompose slowly during purification procedure to give a mixture of fluorine-free compounds.
- Takeuchi,Yamada,Suzuki,Koizumi
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- Organocatalytic activity of α,α-dipeptide derivatives of (S)-proline in the asymmetric aldol reaction in absence of solvent. Evidence for non-covalent π-π Interactions in the transition state
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The trend in the magnitude of stereoselectivities observed in the asymmetric aldol reaction between cyclohexanone and aromatic aldehydes with varying electron densities, catalyzed by dipeptidic organocatalyst (S,S)-1d, which contains an aromatic naphthyl substituent in the acyclic amino acid residue, is in line with expectation based on π-π stacking interactions between the aromatic ring on the organocatalyst and the aromatic aldehydes. Such non-covalent interactions are apparently enhanced under solvent-free mechanochemical activation in a ball mill.
- Machuca, Elizabeth,Juaristi, Eusebio
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- Rational design of asymmetric organocatalysts - Increased reactivity and solvent scope with a tetrazolic acid
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Replacement of the carboxylic acid functionality in the widely used organocatalyst proline with a tetrazolic acid leads to a catalyst with increased reactivity and solvent scope, as demonstrated in the direct catalytic asymmetric aldol reaction.
- Hartikka, Antti,Arvidsson, Per I.
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- Pipecolic esters as minimized templates for proteasome inhibition
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Allosteric regulators of clinically important enzymes are gaining popularity as alternatives to competitive inhibitors. This is also the case for the proteasome, a major intracellular protease and a target of anti-cancer drugs. All clinically used proteasome inhibitors bind to the active sites in catalytic chamber and display a competitive mechanism. Unfortunately, inevitable resistance associated with this type of inhibition drives the search for non-competitive agents. The multisubunit and multicatalytic “proteolytic machine” such as the proteasome is occasionally found to be affected by agents with other primary targets. For example the immunosuppressive agent rapamycin has been shown to allosterically inhibit the proteasome albeit at levels far higher than its mTOR related efficacy. As part of an ongoing program to search for novel proteasome-targeting pharmacophores, we identified the binding domain of rapamycin as required for proteasome inhibition even without the macrocyclic context of the parent compound. By subsequent structure-activity relationship studies, we generated a pipecolic ester derivative compound 3 representing a new class of proteasome inhibitors. Compound 3 affects the core proteasome activities and proliferation of cancer cells with low micromolar/high nanomolar efficacy. Molecular modeling, atomic force microscopy imaging and biochemical data suggest that compound 3 binds into one of intersubunit pockets in the proteasomal α ring and destabilizes the α face and the gate. The α face is used as a docking area for proteasome-regulating protein modules and the gate is critical for controlling access to the catalytic chamber. Thus, the pipecolic ester template elicits a new and attractive mechanism for proteasome inhibition distinct from classical competitive drugs.
- Giletto, Matthew B.,Osmulski, Pawel A.,Jones, Corey L.,Gaczynska, Maria E.,Tepe, Jetze J.
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- The Synthesis of 5,6,7,7a-Tetrahydro-1-methyl-3H-pyrrolizin-3-one by the Palladium-Catalyzed Cyclization of N-Bromoacetyl-2-vinylpyrrolidine
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N-Bromoacetyl-2-vinylpyrrolidine underwent cyclization to give a pyrrolizidine derivative in the presence of a base and a catalytic amount of palladium catalyst.
- Yang, Shyh-Chyun,Shea, Fang-Rong,Hung, Chung-Wei
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Read Online
- Efficient synthesis of methyl (S)-4-(1-methylpyrrolidin-2-YL)-3-oxobutanoate as the key intermediate for tropane alkaloid biosynthesis with optically acitve form
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Methyl (S)-4-(1-methylpyrrolidin-2-yl)-3-oxobutanoate has been synthesized for enzymatic studies on cyclization enzymes during cocaine biosynthesis in Erythroxylum coca plants. During the present new synthesis, L-proline was first protected with Cbz group and reduced to chiral amino alcohol, which were then followed by Swern oxidation, Wittig reaction and decarboxylative condensation. At the last step, N-methylamino acid precursor was treated with 1,1'-carbonyldiimidazole followed by reacting with methyl potassium malonate to give the 3-oxobutanoate in 54% overall yield. This new strategy has proven to avoid obvious racemization of the L-proline chiral center during the synthesis. In addition, six of the eight synthesis steps were performed via GAP chemistry/technology without the use of column chromatography for purification.
- Katakam, Nanda Kumar,Seifert, Cole W.,D'Auria, John,Li, Guigen
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p. 604 - 613
(2019/08/01)
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- PIPECOLIC ESTERS FOR INHIBITION OF THE PROTEASOME
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The present disclosure relates to chemical compounds that modulate proteasome activity, pharmaceutical compositions containing such compounds, and use of these compounds and compositions for the treatment of disorders of uncontrolled cellular proliferation such as, for example, a cancer. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
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Paragraph 00274; 00292
(2019/08/26)
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- PROCESS AND INTERMEDIATES FOR SYNTHESIS OF PEPTIDE COMPOUNDS
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Disclosed is a new process and intermediates for preparing dipyrrolidine peptide compounds such as, for example, rapastinel. Advantageously, the process may be industrially scalable and cost-effective and use less toxic reagents and/or solvents. Further, the process may be used to prepare peptide compounds having improved purity.
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Paragraph 0163; 0164
(2019/02/13)
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- Pharmaceutical combination of an atypical antipsychotic and an NMDA modulator for the treatment of schizophrenia,bipolar disorder, cognitive impairment and major depressive disorder
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This disclosure features combinations of NMDA modulators and atypical antipsychotics. The disclosure provides for example, methods of treating schizophrenia, bipolar disorder, and/or cognitive impairment disorder in a patient in need thereof, comprising administering e.g., rapastinel and an atypical antipsychotic.
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Paragraph 0095; 0113
(2018/10/11)
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- Application of metallide/palladium compound catalytic reduction system in debenzylation reaction and deuterization reaction
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The invention discloses an application of a metallide/palladium compound catalytic reduction system in debenzylation reaction and deuterization reaction of benzyl-containing compounds. The reaction comprises the following steps: under the protection of nitrogen, suspending a palladium compound and a metallide in a solvent, stirring for 5 minutes, adding the benzyl-containing compounds, carrying out a reaction for 0.5 to 48 h at the temperature of -30 DEG C to 150 DEG C, adding ice water to stop the reaction, adjusting the pH value to 3.5 with diluted hydrochloric acid, extracting the reactionsolution by a solvent, drying by distillation, purifying by column chromatography, and thus completing the reaction.
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Paragraph 0052
(2018/09/08)
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- 2-PYRROLIDINE PHENYLHYDRAZIDES ANTIBACTERIAL AGENTS
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2-Pyrrolidine phenylhydrazides antibacterial agents The present invention relates to 2-pyrrolidine phenylhydrazide compounds of formula (I), which are selective antibacterials specifically agalnstAcineto barter baumannii.The invention also relates to their therapeutic use as antibacterials, to a process for their preparation and to pharmaceutical compositions containing them.
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Page/Page column 64
(2018/02/28)
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- 3-(trimethylsilyl) pyrrolidine-2-carboxylic acid, its intermediate, preparation and application thereof
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The invention relates to 3-(trimethylsilyl) pyrrolidine-2-carboxylic acids, its intermediates , preparation and application thereof, the structural formula of the described 3-(trimethylsilyl) pyrrolidine-2-carboxylic acid is (the structural formula of the described 3-(trimethylsilyl) pyrrolidine-2-carboxylic acid is shown in the description). The preparation method uses chiral proline as raw material, and carries out C-H bond activation reaction with silanization reagent after protective group and adjuvant are introduced, then an intermediate is obtained after removing protective group; the intermediate can remove auxiliary groups under the acid action and the described 3-(trimethylsilyl) pyrrolidine-2-carboxylic acid can be obtained. 3-(trimethylsilyl) pyrrolidine-2-carboxylic acids are used in asymmetric catalytic reactions. The reaction condition of the 3-(trimethylsilyl) pyrrolidine-2-carboxylic acid is mild, with high chemical yield, which provides a new way for the synthesis of the silicon-containing structural analogue, and the prepared (2R, 3R)-3-(trimethylsilyl) pyrrolidine-2-carboxylic acid, (2S, 3S)-3-(trimethylsilyl) pyrrolidine-2-carboxylic acid can be used as chiral catalyst for asymmetric reaction, and has good application prospect.
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Paragraph 0049; 0050
(2018/10/19)
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- Application of metallide/palladium compound catalytic reduction system in reaction of removing allyl groups and deuteration reaction
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The invention discloses application of a metallide/palladium compound catalytic reduction system in reaction of removing allyl groups of a compound containing the allyl groups and deuteration reaction. The reaction comprises the following steps: under protection of nitrogen gas, suspending a palladium compound and a metallide in a solvent, stirring for 5 minutes, adding the compound containing theallyl groups, reacting for 0.5-36 hours at the temperature of minus 50-120 DEG C, adding ice water to stop reaction, regulating a pH value to 3.5 by using diluted hydrochloric acid, and carrying outsolvent extraction, drying by steaming and column-chromatography purification on reaction liquid to finish the reaction.
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Paragraph 0046
(2018/07/30)
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- PROCESSES FOR SYNTHESIS OF DIPYRROLIDINE PEPTIDE COMPOUNDS
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Disclosed is a new process for preparing dipyrrolidine peptide compounds such as, for example, GLYX-13. Advantageously, the process may be industrially scalable and cost-effective and use less toxic reagents and/or solvents. Further, the process may be used to prepare peptide compounds having improved purity.
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Page/Page column 0087-0091
(2017/12/27)
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- Cis-fused ring-containing β-lactam the synthetic method of the compound of
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The invention discloses a synthetic method of a beta-lactam compound with a cis condensed ring. Substituted or un-substituted pyrrole-2-formic acid, or substituted or un-substituted pyridine-2-formic acid or substituted or un-substituted indole-2-formic acid is used as a starting material, Pd(II) is adopted as a catalyst, and AgOAc or Ag2CO3 is used as an oxidant; a sp3C-H bond at a beta site of an amide substrate 2 (for example Scheme4) is activated through palladium catalysis; a key step of forming a C-N bond in a molecule to successfully construct a beta-lactam framework with the cis condensed ring is generated. According to the synthetic method disclosed by the invention, materials are simple and easily available, the price is cheap, the experiment operation is simple, the route is short and the yield is high; the synthetic method has very high atom economy, a little waste, environment friendliness, a wide scope of application of the substrate and good universality, and can be used for efficiently obtaining the beta-lactam compound with optical activity kept in a chiral manner.
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Paragraph 0057-0060
(2016/12/01)
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- Stereoselective synthesis of diazabicyclic β-lactams through intramolecular amination of unactivated C(sp3)-H bonds of carboxamides by palladium catalysis
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An efficient C(sp3)-H bond activation and intramolecular amination reaction via palladium catalysis at the β-position of carboxyamides to make β-lactams was described. The investigation of the substrate scope showed that the current reaction conditions favored activation of the β-methylene group. Short sequences were developed for preparation of various diazabicyclic β-lactam compounds with this method as the key step from chiral proline and piperidine derivatives.
- Zhang, Shi-Jin,Sun, Wen-Wu,Cao, Pei,Dong, Xiao-Ping,Liu, Ji-Kai,Wu, Bin
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p. 956 - 968
(2016/02/19)
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- Iminium Catalysis inside a Self-Assembled Supramolecular Capsule: Modulation of Enantiomeric Excess
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The noncovalent combination of a supramolecular host with iminium organocatalysis is described. Due to cation–π interactions the reactive iminium species is held inside the host and reacts in this confined environment. The products formed differ up to 92 % ee from the control experiments without added host. A model rationalizing the observed difference is presented.
- Br?uer, Thomas M.,Zhang, Qi,Tiefenbacher, Konrad
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supporting information
p. 7698 - 7701
(2016/07/07)
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- Transfer hydrogenation reactions catalyzed by chiral half-sandwich Ruthenium complexes derived from Proline
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Chiral ruthenium half-sandwich complexes were prepared using a chelating diamine made from proline with a phenyl, ethyl, or benzyl group, instead of hydrogen on one of the coordinating arms. Three of these complexes were obtained as single diastereoisomers and their configuration identified by X-ray crystallography. The complexes are recyclable catalysts for the reduction of ketones to chiral alcohols in water. A ruthenium hydride species is identified as the active species by NMR spectroscopy and isotopic labelling experiments. Maximum enantio-selectivity was attained when a phenyl group was directly attached to the primary amine on the diamine ligand derived from proline. [Figure not available: see fulltext.]
- Pandia Kumar, Arun Kumar,Samuelson, Ashoka G
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p. 1405 - 1415
(2016/09/19)
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- Ring-Strain Effects in Base-Induced Sommelet–Hauser Rearrangement: Application to Successive Stereocontrolled Transformations
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The base-induced Sommelet–Hauser (S–H) rearrangement of azetidine-2-carboxylic acid ester-derived ammonium salts into 2-aryl-substituted derivatives was demonstrated. The ring-strain of four-membered N-heterocycles enables efficient generation of the desired ylide intermediate and enhances the rate of the S–H rearrangement. The asymmetric version of the rearrangement was characterized by excellent levels of successive chirality transmissions. The regio- and stereo-controlled nucleophilic ring opening of the rearrangement products produced quaternary α-aryl amino acid esters with excellent enantiopurities.
- Tayama, Eiji,Watanabe, Kazutoshi,Matano, Yoshihiro
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supporting information
p. 3631 - 3641
(2016/07/29)
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- A N-benzyloxycarbonyl-L-prolinamide method for the preparation of
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The invention relates to a preparation method of N-carbobenzoxy-L-prolinamide. The preparation method is characterized by comprising following steps of (1) putting L-proline and alkali into a solvent and dropwise adding benzyl chloroformate; at the end of reaction, heating up till backflow, separating out water, cooling down to obtain liquid N-carbobenzoxy-L-proline; (2) dropwise adding sulfoxide chloride into the liquid N-carbobenzoxy-L-proline, heating up till backflow, distilling at reduced pressure to obtain N-carbobenzoxy-L-prolyl chloride solution; and (3) introducing ammonia gas into the N-carbobenzoxy-L-prolyl chloride solution, and at the end of reaction, concentrating at reduced pressure till drying the solvent, adding dichloromethane, cooling down, regulating pH value of the system to be 12-13, standing to separate liquid to obtain a water layer, decoloring, filtering to obtain distilled residue, crystallizing, filtering, washing by petroleum ether, drying to obtain the N-carbobenzoxy-L-prolinamide. The preparation method is simple, has high yield, can prepare the product with high purity and optical purity and no inorganic salt, and can be used for industrial production of N-carbobenzoxy-L-prolinamide in large scale.
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Paragraph 0024; 0028
(2018/02/04)
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- Structure-antiproliferative activity studies on l-proline- and homoproline-4-: N -pyrrolidine-3-thiosemicarbazone hybrids and their nickel(II), palladium(II) and copper(II) complexes
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Two water-soluble thiosemicarbazone-proline (H2L1) and thiosemicarbazone-homoproline hybrids (H2L2) were synthesised. By reaction of H2L1 with NiCl2·6H2O, PdCl2 and CuCl2·2H2O in ethanol, the series of square-planar complexes [Ni(H2L1)Cl]Cl·1.3H2O (1·1.3H2O), [Pd(H2L1)Cl]Cl·H2O (2·H2O) and [Cu(H2L1)Cl]Cl·0.7H2O (3·0.7H2O) was prepared, and starting from H2L2 and CuCl2·2H2O in methanol, the complex [Cu(H2L2)Cl2]·H2O (4·H2O) was obtained. The compounds have been characterised by elemental analysis, spectroscopic methods (IR, UV-vis and NMR spectroscopy), ESI mass spectrometry and single crystal X-ray crystallography (H2L1, 1, 2 and 4). As a solid, 1 is diamagnetic, while it is paramagnetic in methanolic solution. The effective magnetic moment of 3.26 B.M. at room temperature indicates the change in coordination geometry from square-planar to octahedral upon dissolution. The in vitro anticancer potency of ligand precursors H2L1 and H2L2 and metal complexes 1-4 was studied in three human cancer cell lines (A549, CH1 and SW480) and in noncancerous murine embryonal fibroblasts (NIH/3T3), and the mechanism of cell death was also assayed by flow cytometry. Clear-cut structure-activity relationships have been established. The metal ions exert marked effects in a divergent manner: copper(ii) increases, whereas nickel(ii) and palladium(ii) decrease the cytotoxicity of the hybrids. The antiproliferative activity of H2L1 and metal complexes 1-3 decreases in all three tumour cell lines in the following rank order: 3 > H2L1 > 1 > 2. The role of square-planar geometry in the underlying mechanism of cytotoxicity of the metal complexes studied seems to be negligible, while structural modifications at the terminal amino group of thiosemicarbazide and proline moieties are significant for enhancing the antiproliferative activity of both hybrids and copper(ii) complexes.
- Dobrova, Aliona,Platzer, Sonja,Bacher, Felix,Milunovic, Miljan N. M.,Dobrov, Anatolie,Spengler, Gabriella,Enyedy, éva A.,Novitchi, Ghenadie,Arion, Vladimir B.
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supporting information
p. 13427 - 13439
(2016/09/04)
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- A lanthanide(III) triflate mediated macrolactonization/solid-phase synthesis approach for depsipeptide synthesis
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The effect of dysprosium(III) triflate on macrolactonization reactions to form depsipeptides using MNBA (Shiina's reagent) is reported. Improved yields were obtained for the formation of 16-membered depsipeptides using lanthanide triflate additives. The use of a macrocyclization strategy permits the use of a semiautomated solid-phase synthesis approach for the rapid synthesis of analogues of the antibacterial A54556 acyldepsipeptides in only two physical operations, requiring only final product purification after cyclization.
- Goodreid, Jordan D.,Dos Santos Da Silveira, Eduardo,Batey, Robert A.
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supporting information
p. 2182 - 2185
(2015/05/13)
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- Light-enabled synthesis of anhydrides and amides
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Recently, we have demonstrated that the photogeneration of Vilsmeier-Haack reagents is possible using only dimethylformamide (DMF) and tetrabromomethane (CBr4) in the bromination of alcohols. Extending these findings to carboxylic acid substrates has produced a mild and facile approach to the in situ formation of symmetric anhydrides, which were conveniently converted to amide derivatives in a one-pot process. The efficient protocols discussed herein are marked by use of UVA LEDs (365 nm), which have reduced the reaction times and come with a low setup cost.
- Mccallum, Terry,Barriault, Louis
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supporting information
p. 2874 - 2878
(2015/03/30)
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- SPIRO-LACTAM NMDA RECEPTOR MODULATORS AND USES THEREOF
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Disclosed are compounds having enhanced potency in the modulation of NMDA receptor activity. Such compounds are contemplated for use in the treatment of conditions such as depression and related disorders. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
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Paragraph 00106; page 39
(2014/08/19)
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- SPIRO-LACTAM NMDA RECEPTOR MODULATORS AND USES THEREOF
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Disclosed are compounds having enhanced potency in the modulation of NMDA receptor activity. Such compounds are contemplated for use in the treatment of conditions such as depression and related disorders. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
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Paragraph 0111
(2014/08/19)
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- Glycosylation mediated - BAIL in aqueous solution
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The use of Br?nsted acid ionic liquid (BAIL) as a catalyst for the activation of unreactive and unprotected glycosyl donors has been demonstrated for the first time in aqueous solution.
- Delacroix, Sébastien,Bonnet, Jean-Pierre,Courty, Matthieu,Postel, Denis,Van Nhien, Albert Nguyen
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- The development of highly active acyclic chiral hydrazides for asymmetric iminium ion organocatalysis
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Double asymmetric induction has been employed as a tool to optimise pyrazolidinone-derived organocatalysts for the asymmetric iminium ion catalysed Diels-Alder reaction. Mechanistic studies revealed a superior hydrazide catalyst deriving from methanolysis of the chiral pyrazolidinone precursor. This catalyst displays unusually high endo diastereoselectivity and good enantioselectivity with a range of β-arylenals and cyclic dienes at catalyst loadings as low as 1 mol%.
- Gould, Eoin,Lebl, Tomas,Slawin, Alexandra M. Z.,Reid, Mark,Davies, Tony,Smith, Andrew D.
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p. 7877 - 7892
(2013/11/19)
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- Synthesis and evaluation of C8-substituted 4.5-spiro lactams as Glycogen Phosphorylase a inhibitors
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An effective synthesis of 4.5-spiro lactams 28/29, has been completed in nine steps with an overall yield of 5.8%. The 4.5-spiro lactams were made from 2-allyl-Cbz-Pro-OMe 21, which was converted into the corresponding alcohol 22 via a hindered borane reaction with (2-methylbutyl)2borane. Subsequent Swern oxidation of 22 gave novel aldehyde 23. Aldehyde 23 was treated under Bucherer-Bergs reaction conditions to give hydantoin 26, which was opened to the corresponding amino acid 30 using di-tert-butyl dicarbonate and DMAP followed by hydrolysis. Treatment of amino acid 30 with acidic methanol gave 4.5-spiro lactams 28/29. Only 4.5-spiro lactam 29 displayed moderate activity against GPa with an IC50 of 241 μM.
- Loughlin, Wendy A.,Schweiker, Stephanie S.,Jenkins, Ian D.,Henderson, Luke C.
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supporting information
p. 1576 - 1582
(2013/03/29)
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- BIARYL INHIBITORS OF THE SODIUM CHANNEL
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The invention relates to compounds useful in treating conditions associated with voltage- gated ion channel function, particularly conditions associated with sodium channel activity. More specifically, the invention concerns biaryl derivatives (e.g., compounds according to any of Formulas (I)-(XII) or Compounds (l)-(372) of Table 1) that are that are useful in treatment of conditions such as epilepsy, cancer, pain, migraine, Parkinson's Disease, mood disorders, schizophrenia, psychosis, tinnitus, amyotropic lateral sclerosis, glaucoma, ischaemia, spasticity disorders, obsessive compulsive disorder, restless leg syndrome and Tourette syndrome.
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Page/Page column 43; 44
(2013/09/12)
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- Hybrids of privileged structures benzothiazoles and pyrrolo[2,1-c] [1,4]benzodiazepin-5-one, and diversity-oriented synthesis of benzothiazoles
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Privileged structures like Benzothiazole and Pyrrolobenzodiazepine offer wonderful opportunity to explore in anti-cancer drug discovery as a mean to counter drug-resistance problem. BT-PBD hybrids and diverse BT derivatives have been synthesized and their in vitro cytotoxic activities were screened against five cancer cell lines have been discussed. The novel compounds showed promising results as compared with the marketed drug etoposide and could well be used in future anti-cancer drug development studies.
- Subhas Bose,Idrees, Mohd.,Todewale, Ismail K.,Jakka,Venkateswara Rao
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experimental part
p. 27 - 38
(2012/07/01)
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- Solvent-free asymmetric aldol reaction organocatalyzed by (S)-proline-containing thiodipeptides under ball-milling conditions
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An efficient, solvent-free ball-milling protocol for the asymmetric aldol reaction between cyclohexanone and cyclopentanone with various aromatic aldehydes using a novel series of (S)-proline-containing dipeptides and thiodipeptides 1a-f as organocatalysts is reported. In general, (S)-proline-containing thiodipeptides proved to be better organocatalysts relative to their analogous amides. In particular, thiodipeptide (S,S)-1d catalyzed the stereoselective formation of the expected aldol products with excellent diastereo- and enantioselectivity (up to 98:2 anti/syn dr and up to 96% ee). This observation may be ascribed to the increased N-H acidity of the thioamide segment that leads to stronger H-bonding interaction with the aldehyde carbonyl at the transition state and thus higher stereoinduction. Furthermore, thiodipeptide 1f proved to be an efficient organocatalyst for the aldol reaction of acetone with isatin and isatin derivatives (ee 56-86%).
- Hernández, José G.,García-López, Víctor,Juaristi, Eusebio
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scheme or table
p. 92 - 97
(2012/01/05)
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- A chiral amino-naphthalene-derived prolinamide catalyst for the enantioselective Michael addition of ketones to nitroolefins
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An enantioselective Michael addition of ketones to nitroolefins has been accomplished using a novel chiral aminonaphthalenederived prolinamides catalyst 1. The desired Michael adducts were obtained in high yields (up to 93%) as well as good diastereoselectivities (>99:1) and enantioselectivities (48%-99% ee).
- Yu, Chuanming,Zhang, Ke,Shi, Xiangjun
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scheme or table
p. 278 - 282
(2012/09/25)
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- Highly efficient bifunctional organocatalysts for the asymmetric Michael addition of ketones to nitroolefins
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A type of secondary-secondary-tertiary triamine bifunctional organocatalysts have been properly designed and synthesized. In our study, the designed catalyst (S)-N-(pyrrolidin-2-ylmethyl)pyridin-2-amine 5 has been shown to be highly efficient to promote the asymmetric Michael addition of ketones to nitroolefins at room temperature, which afforded the corresponding adducts in excellent diastereoselectivities (up to 99:1 dr) and enantioselectivities (up to >99% ee).
- Yu, Chuanming,Qiu, Jun,Zheng, Fei,Zhong, Weihui
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scheme or table
p. 3298 - 3302
(2011/06/28)
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- Amberlyst-15 catalyzed Cbz protection of amines under solvent-free conditions
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Amberlyst-15 can effectively catalyze Cbz protection of aliphatic and aromatic amines within 10-15 min under solvent-free conditions. The catalyst can be used repeatedly without loss of activity, and the reaction requires no workup and gives excellent yields. Taylor & Francis Group, LLC.
- Bora, Pranja P.,Vanlaldinpuia, Khiangte,Rokhum, Lalthazuala,Bez, Ghanashyam
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experimental part
p. 2674 - 2683
(2011/08/22)
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- Efficient ball-mill procedure in the 'green' asymmetric aldol reaction organocatalyzed by (S)-proline-containing dipeptides in the presence of water
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The organocatalytic activity of (S)-proline-based dipeptides 1a-c has been evaluated in the asymmetric aldol reaction between representative ketones with various aromatic aldehydes under solvent-free conditions in a ball mill. In particular, the methyl ester of (S)-proline-(S)-tryptophan, (S,S)-1c, proved to be an efficient organocatalyst, and the aldol reaction proceeded with good chemical yields and excellent diastereo- and enantioselectivity (up to 98:2 anti/syn dr and up to 98% ee), in the presence of water, and 5 mol % of benzoic acid as additive.
- Hernandez, Jose G.,Juaristi, Eusebio
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scheme or table
p. 6953 - 6959
(2011/10/02)
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- Papain-catalyzed peptide bond formation: Enzyme-specific activation with guanidinophenyl esters
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The substrate mimetics approach is a versatile method for small-scale enzymatic peptide-bond synthesis in aqueous systems. The protease-recognized amino acid side chain is incorporated in an ester leaving group, the substrate mimetic. This shift of the specific moiety enables the acceptance of amino acids and peptide sequences that are normally not recognized by the enzyme. The guanidinophenyl group (OGp), a known substrate mimetic for the serine proteases trypsin and chymotrypsin, has now been applied for the first time in combination with papain, a cheap and commercially available cysteine protease. To provide insight in the binding mode of various Z-XAA-OGp esters, computational docking studies were performed. The results strongly point at enzyme-specific activation of the OGp esters in papain through a novel mode of action, rather than their functioning as mimetics. Furthermore, the scope of a model dipeptide synthesis was investigated with respect to both the amino acid donor and the nucleophile. Molecular dynamics simulations were carried out to prioritize 22 natural and unnatural amino acid donors for synthesis. Experimental results correlate well with the predicted ranking and show that nearly all amino acids are accepted by papain.
- de Beer, Roseri J.A.C.,Zarzycka, Barbara,Amatdjais-Groenen, Helene I.V.,Jans, Sander C.B.,Nuijens, Timo,Quaedflieg, Peter J.L.M.,van Delft, Floris L.,Nabuurs, Sander B.,Rutjes, Floris P.J.T.
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experimental part
p. 2201 - 2207
(2012/05/05)
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- Organocerium additions to proline-derived hydrazones: Synthesis of enantiomerically enriched amines
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The addition of organocerium reagents (from both organolithium and organomagnesium precursors) to chiral aldehyde hydrazones prepared from 1-aminoproline derivatives has been studied. The additions proceed in good yield and high diastereoselectivity and with good nucleophile (Me, n-Bu, i-Pr, t-Bu, Ph, etc.) and substrate scope (alkyl, alkenyl and aryl). The resulting hydrazines can be converted to amines by N-N bond cleavage through hydrogenolysis (Raney nickel) or by acylation and cleavage with Li/NH 3. The influence of the side chain on the diastereoselectivity was investigated through variation of the substituents to include more coordinating atoms (oxygen and nitrogen) as well as the removal of coordinating atoms. The SAMEMP auxiliary bearing a 2-methoxyethoxymethyl group gave the highest diastereoselectivities. Remarkably, auxiliaries bearing simple methyl and isobutyl substituents gave high selectivities as well. Hypotheses for the origin of the selectivity are presented.
- Denmark, Scott E.,Edwards, James P.,Weber, Theodor,Piotrowski, David W.
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scheme or table
p. 1278 - 1302
(2010/11/02)
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- Synthesis of proline-derived dipeptides and their catalytic enantioselective direct aldol reactions: Catalyst, solvent, additive and temperature effects
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A series of dipeptides of l-proline-l-amino acid and l-proline-d-amino acid were synthesized to evaluate the catalytic effect for asymmetric direct aldol reactions. In the direct aldol reaction, a catalyst of l-proline-l-amino acid achieves better enantioselectivity than the corresponding l-proline-d-amino acid catalyst. Solubility of the dipeptide catalysts in the solvents is a key point for achieving a better yield of the direct aldol reaction, while hydrogen bonding of solvent does not play an important role in attaining better enantioselectivity and yield. Yield and enantioselectivity of the direct aldol reaction in water were improved by NMM and SDS additives, but the results that were done in plain DMSO were even better.
- Chen,Sung,Sung, Kuangsen
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scheme or table
p. 839 - 845
(2010/08/06)
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- A novel chiral aliphatic-aromatic diamine promoted direct, highly enantio- and diastereoselective Michael addition of cyclohexanone to nitroolefins under solvent-free conditions
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A series of new highly efficient chiral aliphatic-aromatic diamine catalysts have been designed and successfully applied to the asymmetric Michael addition of cyclohexanone with nitroolefins under solvent-free conditions without any acidic additives. The desired adducts were obtained in high yields with excellent enantio- and diastereoselectivities of syn products (up to >99% ee, >99:1 dr).
- Miao, Shifeng,Bai, Jinjin,Yang, Jin,Zhang, Yawen
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scheme or table
p. 855 - 862
(2010/11/17)
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- CONDENSED HETEROCYCLIC COMPOUNDS HAVING 5-HT6 RECEPTOR AFFINITY
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The present disclosure provides compounds having affinity for the 5-HT6 receptor which are of the formula (I) wherein R1, A, B, D, E, G, Q, Ar, n, m, and p are as defined herein. The disclosure also relates to methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
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Page/Page column 103-104
(2010/04/03)
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- Proline-threonine dipeptide as an organocatalyst for the direct asymmetric aldol reaction
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A new proline-threonine (H-Pro-Thr-OH) dipeptide has been demonstrated as an efficient organocatalyst for a direct asymmetric aldol reaction. It was found that this new peptide-based catalyst efficiently catalyzed the reaction between an aldehyde and acetone to provide β-hydroxy ketones in good yields with good enantioselectivities.
- Chandrasekhar, Srivari,Johny, Kancharla,Reddy, Chada Raji
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scheme or table
p. 1742 - 1745
(2009/12/26)
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- Direct electrochemical α-cyanation of N-protected cyclic amines
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α-Cyanation of N-protected cyclic amines was achieved using a direct electrochemical method. Unsubstituted N-protected cyclic amines were easily cyanated at the α-position using an undivided cell in high yields; moreover, α-cyanation of α′-substituted pyrrolidine and α′-,β′- or γ-substituted piperidines smoothly proceeded in high yield and with high to excellent diastereoselectivity. α-Substituted N-cyano-pyrrolidines and -piperidines were also cyanated at the more substituted position (the α-position) using a divided cell with high yield and high regioselectivity.
- Libendi, Samuel Shikuku,Demizu, Yosuke,Onomura, Osamu
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experimental part
p. 351 - 356
(2009/03/12)
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- Synthesis, characterisation and in vitro cytotoxicity studies of a series of chiral platinum(II) complexes based on the 2-aminomethylpyrrolidine ligand: X-ray crystal structure of [PtCl2(R-dimepyrr)] (R-dimepyrr = N-dimethyl-2(R)-aminomethylpyrrolidine)
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A series of platinum(II) complexes were synthesised based on the enantiomerically pure amino acid proline. Novel synthetic pathways were developed, adapted from standard peptide chemistry, to produce the 2-aminomethylpyrrolidine (pyrr) ligand and its derivatives with differing arrangements of methyl substituents at the exocyclic amine sites. The crystal structure of [PtCl2(R-dimepyrr)] (R-dimepyrr = N,N-dimethyl-2(R)-aminomethylpyrrolidine) is reported and the five-membered ligand ring has been shown to be in an envelope conformation. Cytotoxicity studies were carried out on the ovarian cancer A2780 tumour cell line and its cisplatin-resistant variant, A2780cisR. Remarkably good activity was seen for several of the drugs when compared to cisplatin despite the addition of substantial steric bulk to the amine groups, and there was a lack of cross-resistance with cisplatin seen for some compounds.
- Diakos, Connie I.,Zhang, Mei,Beale, Philip J.,Fenton, Ronald R.,Hambley, Trevor W.
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experimental part
p. 2807 - 2814
(2009/10/10)
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- Oxoammonium salt/NaClO2: An expedient, catalytic system for one-pot oxidation of primary alcohols to carboxylic acids with broad substrate applicability
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A facile, green, one-pot oxidation of primary alcohols to carboxylic acids with broad substrate applicability has been developed by employing an expedient catalytic system consisting of 1-Me-AZADO+X-/NaClO 2. The Royal Society of Chemistry.
- Shibuya, Masatoshi,Sato, Takahisa,Tomizawa, Masaki,Iwabuchi, Yoshiharu
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supporting information; experimental part
p. 1739 - 1741
(2009/08/08)
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- BENZOXAZOLE CARBOXAMIDE INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE (PARP)
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A compound having the structure set forth in Formula (I) or Formula (II): wherein the variables Y, R1, R2, R3, and R4 are as defined herein. Provided herein are inhibitors of poly(ADP-ribose)polymerase activity. Also described herein are pharmaceutical compositions that include at least one compound described herein and the use of a compound or pharmaceutical composition described herein to treat diseases, disorders and conditions that are ameliorated by the inhibition of PARP activity.
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Page/Page column 69
(2009/08/16)
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- Microwave-assisted carbamoylation of amines
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The influence of microwave irradiation on the reaction of various amines with benzyl chloroformate and di-tert-butyl dicarbonate was investigated. Microwave irradiation was successfully applied to the carbamoylation of several nonfunctionalized and functionalized amines, including amino acids and nucleobases, leading to satisfactory to high product conversion within very short reaction times. Copyright Taylor & Francis Group, LLC.
- Azzena, Ugo,Dettori, Giovanna,Pisano, Luisa,Pittalis, Mario
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p. 3623 - 3634
(2008/03/13)
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- Huperzine a prodrugs and uses thereof
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Disclosed are huperzine A prodrugs and method of synthesis thereof. The invention further relates to methods of treating, preventing or reversing neurodegenerative diseases, such as, Alzheimer's Disease and neuronal dysfunctions, such as, memory impairment using a pharmaceutical composition comprising a huperzine A prodrug as disclosed herein.
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Page/Page column 11-12
(2008/06/13)
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- A new and highly effective organometallic approach to 1,2-dehalogenations and related reactions
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We investigated the reductive elimination of several functionalized and non-functionalized vic-dibromides with 1,2-diphenyl-, 1,1,2,2-tetraphenyl- and 1-phenyl-2-(2-pyridyl)-1,2-disodioethane. The reaction, involving some of the less expensive organic and inorganic reagents, proceeds under mild conditions, and is tolerant of a variety of functional groups. Extension of this procedure to similar 1,2-disubstituted compounds was also investigated. Reductive eliminations run on stereochemical probe compounds strongly suggest that this reaction proceeds via a "single electron" reductive elimination reaction pathway.
- Azzena, Ugo,Pittalis, Mario,Dettori, Giovanna,Pisano, Luisa,Azara, Emanuela
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p. 3892 - 3900
(2008/03/12)
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- Synthesis of new β-lactam analogs and evaluation of their histone deacetylase (HDAC) activity
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A simple synthesis of the β-lactams 11-13 and 16-17 as novel histone deacetylase (HDAC) inhibitors is described. The key synthetic strategies involved the O-alkylation of 6-APA and the coupling reactions of freshly prepared N-carbobenzyloxy-L-prolines 5 and 6 and 6-aminopenicillanates 8-10 and 15 in high yields. It was found that all compounds show potent growth inhibitory activity on human tumor cell lines, the most potent compound 16 exhibiting an IC50 = 2.1 μM in vitro.
- Oh, Seikwan,Jung, Jae-Chul
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body text
p. 1459 - 1464
(2008/10/09)
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- Large nonlinear effect observed in the enantiomeric excess of proline in solution and that in the solid state
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(Chemical Equation Presented) A clue to the origin of chirality? A solution of proline with high enantiomeric excess (85-99% ee) was obtained from solid proline of only 10% ee through novel dissolution and crystallization processes (see scheme). This observation may be an explanation for the origin of chirality on Earth.
- Hayashi, Yujiro,Matsuzawa, Masayoshi,Yamaguchi, Junichiro,Yonehara, Sayaka,Matsumoto, Yasunobu,Shoji, Mitsuru,Hashizume, Daisuke,Koshino, Hiroyuki
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p. 4593 - 4597
(2007/10/03)
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- INDUCIBLE NITRIC OXIDE SYNTHASE DIMERIZATION INHIBITORS
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The present invention relates to compounds and methods useful as inhibitors of nitric oxide synthase. Certain compounds of the subject invention have the following structural formula: wherein T, X, and Y are independently selected from the group consisting of CR4, N, NR4, S, and O; U is selected from the group consisting of CR10 and N; V is selected from the group consisting of CR4 and N; W and W' are independently selected from the group consisting of CH2, CR7R8, NR9, O, N(O), S(O)q and C(O); n, m and p are independently an integer from 0 to 5; q is 0, 1, or 2; and other substituents are as defined herein. Other compounds of the subject invention have structural formulas as defined herein. Also disclosed herein are pharmaceutical compositions comprising the compounds of the subject invention
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Page/Page column 66
(2010/11/08)
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