- Sparsomycin analogs. II. Synthesis and biological activities of 5-carboxy-6-methyluracil derivatives
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In order to study the structure-activity relationship of sparsomycin, an antitumor antibiotic, 26 sparsomycin-related compounds were synthesized and their antibacterial activities and lytic actions on Ehrlich ascites carcinoma cells were tested.
- Kanamoto,Nagai,Hase,et al.
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Read Online
- Enantioconvergent Cu-Catalyzed Radical C-N Coupling of Racemic Secondary Alkyl Halides to Access α-Chiral Primary Amines
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α-Chiral alkyl primary amines are virtually universal synthetic precursors for all other α-chiral N-containing compounds ubiquitous in biological, pharmaceutical, and material sciences. The enantioselective amination of common alkyl halides with ammonia is appealing for potential rapid access to α-chiral primary amines, but has hitherto remained rare due to the multifaceted difficulties in using ammonia and the underdeveloped C(sp3)-N coupling. Here we demonstrate sulfoximines as excellent ammonia surrogates for enantioconvergent radical C-N coupling with diverse racemic secondary alkyl halides (>60 examples) by copper catalysis under mild thermal conditions. The reaction efficiently provides highly enantioenrichedN-alkyl sulfoximines (up to 99% yield and >99% ee) featuring secondary benzyl, propargyl, α-carbonyl alkyl, and α-cyano alkyl stereocenters. In addition, we have converted the masked α-chiral primary amines thus obtained to various synthetic building blocks, ligands, and drugs possessing α-chiral N-functionalities, such as carbamate, carboxylamide, secondary and tertiary amine, and oxazoline, with commonly seen α-substitution patterns. These results shine light on the potential of enantioconvergent radical cross-coupling as a general chiral carbon-heteroatom formation strategy.
- Cheng, Jiang-Tao,Dong, Xiao-Yang,Gu, Qiang-Shuai,Li, Zhong-Liang,Liu, Juan,Liu, Xin-Yuan,Luan, Cheng,Wang, Fu-Li,Wang, Li-Lei,Yang, Ning-Yuan,Zhang, Yu-Feng
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p. 15413 - 15419
(2021/09/30)
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- Substituted macrocyclic tyrosine kinase inhibitor and application thereof
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The invention belongs to the technical field of medicines, and particularly relates to a substituted macrocyclic tyrosine kinase inhibitor compound, and pharmaceutically acceptable salts and stereoisomers thereof. More specifically, the tyrosine kinase is
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Paragraph 0206-0210
(2021/07/21)
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- A Mild, General, Metal-Free Method for Desulfurization of Thiols and Disulfides Induced by Visible-Light
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A visible-light-induced metal-free desulfurization method for thiols and disulfides has been explored. This radical desulfurization features mild conditions, robustness, and excellent functionality compatibility. It was successfully applied not only to the desulfurization of small molecules, but also to peptides.
- Qiu, Wenting,Shi, Shuai,Li, Ruining,Lin, Xianfeng,Rao, Liangming,Sun, Zhankui
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supporting information
p. 1255 - 1258
(2021/05/05)
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- Preparation method of carboxylic ester compound
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The invention relates to a preparation method of a carboxylic ester compound, which comprises the following steps: reacting carboxylic acid with methanol in air under the catalysis of nitrite to obtain an ester compound, the preparation method disclosed by the invention has the advantages of rich raw material sources, cheap and easily available catalyst, mild reaction conditions, simplicity and convenience in operation and the like, a series of fatty carboxylic acids can be modified with high yield, and particularly, the traditional esterification method is generally not suitable for esterification of drug molecules. By utilizing the method, a series of known drug molecules can be modified, so that a shortcut is provided for discovering new drug molecules.
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Paragraph 0044-0045
(2021/03/30)
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- Green Esterification of Carboxylic Acids Promoted by tert-Butyl Nitrite
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In this work, the green esterification of carboxylic acids promoted by tert-butyl nitrite has been well developed. This transformation is compatible with a broad range of substrates and exhibits excellent functional group tolerance. Various drugs and substituted amino acids are applicable to this reaction under near neutral conditions, with good to excellent yields.
- Cheng, Xionglve,Jiang, Gangzhong,Li, Xingxing,Tao, Suyan,Wan, Xiaobing,Zhao, Yanwei,Zheng, Yonggao
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supporting information
p. 2713 - 2718
(2021/06/25)
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- C-terminal 1-aminoethyltetrazole-containing oligopeptides as novel alanine racemase inhibitors
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In clinical culture media inoculated with patient samples, selective inhibition of commensal bacteria is essential for accurate diagnosis and effective treatment, as they can mask the presence of pathogenic bacteria. The alanine analogue, 1-aminoethyltetr
- Anderson, Rosaleen J.,Gray, Mark,Kondacs, Laszlo A.,Marrs, Emma C. L.,Orenga, Sylvain,Perry, John D.
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- ANTIBACTERIAL COMPOUND AND USES OF SAME
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A new compound exhibiting particularly advantageous antibacterial properties, and having the structural formula: L-pyroglutamyl-L-1-aminoethyltetrazole (or N-(1-(1H-tetrazol-5-yl)ethyl)-5-oxopyrrolidine-2-carboxamide). Also, the use of this compound in mi
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Paragraph 0048-0049
(2020/09/15)
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- Desulfurization method of organic compounds containing mercapto or disulfide bond
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The invention relates to a desulfurization method of organic compounds, in particular, organic compounds containing mercapto or a disulfide bond. The method comprises following steps: dissolving organic compounds containing mercapto or a disulfide bond by a solvent; adding a phosphine reagent and an initiator; and carrying out reactions in the presence of light to convert the substrate into corresponding desulfurization products. The organic compounds containing mercapto or a disulfide bond is R-SH or R-S-S-R; wherein R represents a primary carbon group, a secondary carbon group, a tertiary carbon group, an aryl group, or an acyl group. The reactions do not need any metal, and the reaction conditions are mild. Moreover, the desulfurization method has the advantages of high yield, wide substrate application range, and multiple suitable solvents, and is widely suitable for multiple kinds of mercapto-removing reactions and desulfurization reactions of disulfide.
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Paragraph 0026
(2019/10/01)
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- 2,4-Diamino-8-quinazoline carboxamides as novel, potent inhibitors of the NAD hydrolyzing enzyme CD38: Exploration of the 2-position structure-activity relationships
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Starting from 4-amino-8-quinoline carboxamide lead 1a and scaffold hopping to the chemically more tractable quinazoline, a systematic exploration of the 2-substituents of the quinazoline ring, utilizing structure activity relationships and conformational constraint, resulted in the identification of 39 novel CD38 inhibitors. Eight of these analogs were 10–100-fold more potent human CD38 inhibitors, including the single digit nanomolar inhibitor 1am. Several of these molecules also exhibited improved therapeutic indices relative to hERG activity. A representative analog 1r exhibited suitable pharmacokinetic parameters for in vivo animal studies, including moderate clearance and good oral bioavailability. These inhibitor compounds will aid in the exploration of the enzymatic functions of CD38, as well as furthering the study of the therapeutic implications of NAD enhancement in metabolic disease models.
- Deaton, David N.,Haffner, Curt D.,Henke, Brad R.,Jeune, Michael R.,Shearer, Barry G.,Stewart, Eugene L.,Stuart, J. Darren,Ulrich, John C.
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p. 2107 - 2150
(2018/03/28)
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- Method for selective removal of t-butyloxycarboryl from nitrogen
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The invention discloses a method for selective removal of t-butyloxycarboryl from nitrogen. According to the synthesis method, directed at a reaction substrate having t-butyloxycarboryl and another acyl protecting group on a molecular nitrogen atom, in the presence of a selectfluor reagent, reaction is carried out in a solution for selective removal of t-butyloxycarboryl and retention of another acyl protecting group. The synthesis method provided by the invention is novel and efficient, is not reported in literature, and can be widely used in total synthesis and drug intermediate synthesis.
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Paragraph 0024-0025; 0026-0028; 0044-0046
(2018/03/26)
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- Amidation of unactivated ester derivatives mediated by trifluoroethanol
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A catalytic amidation protocol mediated by 2,2,2-trifluoroethanol has been developed, facilitating the condensation of unactivated esters and amines, furnishing both secondary and tertiary amides. The complete scope and limitations of the method are described, along with modified conditions for challenging substrates such as acyclic secondary amines and chiral esters with retention of chiral integrity.
- McPherson, Christopher G.,Caldwell, Nicola,Jamieson, Craig,Simpson, Iain,Watson, Allan J. B.
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supporting information
p. 3507 - 3518
(2017/04/26)
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- N-Urethane protection of amines and amino acids in an ionic liquid
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An efficient, solvent-free protocol for the N-fluorenylmethoxycarbonylation and N-benzyloxycarbonylation of amines is described. The reaction of aliphatic and aromatic amines with FmocOSu and Cbz-Osu in [Bmim][BF4] at room temperature afforded the corresponding N-urethane derivatives in excellent yields and do not require any further purification. The method has been extended to the N-Fmoc and N-Cbz protection of amino acids. Absence of bases, very short reaction times, high yields, selectivity and ease of product separation are some advantages of this protocol.
- Di Gioia,Gagliardi,Leggio,Leotta,Romio,Liguori
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p. 63407 - 63420
(2015/08/11)
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- Catalytic, highly enantioselective, direct amination of enecarbamates
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Amination of enecarbamates with dibenzylazodicarboxylate and oxygenated nucleophiles in the presence of a catalytic amount of chiral phosphoric acid afforded optically active stable precursors of α-hydrazinoimines, which were reduced or oxidized, respectively, to vicinal diamines or α-amino acid precursors with excellent yield and enantioselectivity. This journal is
- Dumoulin, Audrey,Lalli, Claudia,Retailleau, Pascal,Masson, Géraldine
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supporting information
p. 5383 - 5386
(2015/03/30)
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- Synthesis and applications in Henry reactions of novel chiral thiazoline tridentate ligands
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Several novel chiral tridentate ligands containing thiazoline were efficiently synthesized from commercially available l=cysteine in high yield. These ligands were subsequently applied to the asymmetric Henry reaction of nitromethane and various aldehydes. It was found that the structures of the thiazoline ligands had a significant influence on the enantioselectivity. It was shown that the optimal catalyst for this reaction was a ligand complexed with CuCl, which was formed from chiral thiazoline with chiral aminoalcohol. At -20°C, with 10 mol% of this ligand, a product with (S)-configuration was isolated in 93% yield and 98% enantiomeric excess.
- Shi, Ye,Li, Yang,Sun, Jingbo,Lai, Qi,Wei, Chiyu,Gong, Zhiyong,Gu, Qiang,Song, Zhiguang
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p. 661 - 667
(2015/09/28)
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- Discovery of GS-9669, a thumb site II non-nucleoside inhibitor of NS5B for the treatment of genotype 1 chronic hepatitis C infection
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Investigation of thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guided by measurement of cell culture medium binding, revealed the structure-activity relationships for intrinsic cellular potency. The pharmacokinetic profile was enhanced through incorporation of heterocyclic ethers on the N-alkyl substituent. Hydroxyl groups were incorporated to modulate protein binding. Intrinsic potency was further improved through enantiospecific introduction of an olefin in the N-acyl motif, resulting in the discovery of the phase 2 clinical candidate GS-9669. The unexpected activity of this compound against the clinically relevant NS5B M423T mutant, relative to the wild type, was shown to arise from both the N-alkyl substituent and the N-acyl group.
- Lazerwith, Scott E.,Lew, Willard,Zhang, Jennifer,Morganelli, Philip,Liu, Qi,Canales, Eda,Clarke, Michael O.,Doerffler, Edward,Byun, Daniel,Mertzman, Michael,Ye, Hong,Chong, Lee,Xu, Lianhong,Appleby, Todd,Chen, Xiaowu,Fenaux, Martijn,Hashash, Ahmad,Leavitt, Stephanie A.,Mabery, Eric,Matles, Mike,Mwangi, Judy W.,Tian, Yang,Lee, Yu-Jen,Zhang, Jingyu,Zhu, Christine,Murray, Bernard P.,Watkins, William J.
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supporting information
p. 1893 - 1901
(2014/04/03)
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- Imino glycals via ruthenium-catalyzed RCM and isomerization
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N-Allyl-N-homoallylamines were converted in one step into cyclic enamides via a ruthenium-catalyzed assisted tandem catalytic ring-closing metathesis-isomerization sequence. The sequence relies on the in situ transformation of a metathesis active Ru-carbene into an isomerization active Ru-hydride by addition of hydroxide as a chemical trigger.
- Schmidt, Bernd,Hauke, Sylvia,Muehlenberg, Nino
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p. 1648 - 1658
(2014/06/23)
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- Autotandem catalysis: Synthesis of pyrroles by gold-catalyzed cascade reaction
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A novel synthesis of substituted pyrroles by a gold(I)-catalyzed cascade reaction has been developed. The reaction proceeded with an autotandem catalysis consisting of an initial addition of gold-acetylide to an acetal moiety and was followed by gold-catalyzed 5-endo-dig cyclization and aromatization. Gold catalysts play a dual role in activating nucleophilicity or electrophilicity of terminal acetylenes by forming gold-acetylides or by π-coordination. The formal (3 + 2) annulation of two components provided a variety of substituted pyrroles in a modular fashion.
- Ueda, Hirofumi,Yamaguchi, Minami,Kameya, Hiroshi,Sugimoto, Kenji,Tokuyama, Hidetoshi
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p. 4948 - 4951
(2015/04/27)
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- Unusual orthogonality in the cleavage process of closely related chelating protecting groups for carboxylic acids by using different metal ions
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Three structurally related relay protecting groups for carboxylic acids that are based on chelating amines have been developed. These protecting groups can easily be introduced by coupling the carboxylic acid and the corresponding amine in the presence of 2-(1Hbenzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU). In addition to being stable to a whole array of reaction conditions, these protecting groups are also stable under acidic and basic conditions, allowing them to be used in combination with the ester protection of carboxylic acids. The cleavage of these protecting groups is activated by the chelation of metal ions, involving an unusual coordination of the amide nitrogen. Despite their similarity, cleavage of these protecting groups is possible in both a stepwise and an orthogonal fashion by applying different metal salts.
- Mundinger, Stephan,Jakob, Uwe,Bannwarth, Willi
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supporting information
p. 1258 - 1262
(2014/04/03)
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- MaxPHOS ligand: PH/NH tautomerism and rhodium-catalyzed asymmetric hydrogenations
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MaxPHOS is an active and robust P-stereogenic ligand for asymmetric catalysis. The presence of an -NH- bridge between the two phosphine moieties allows the NH/PH tautomerism to take place. The neutral ligand, in which the NH form predominates, is an air-sensitive compound. However, protonation of MaxPHOS leads to the stable PH form of the ligand, in which the overall positive charge is distributed on both P centers. This protonation turns the MaxPHOS×HBF4 salt 3 into an air-stable compound both in the solid state and in solution. The salt 3 is also a convenient precursor for the preparation of rhodium(I) complexes by direct ligand exchange with the complex [Rh(acac)(cod)]. Finally, the corresponding rhodium(I)-MaxPHOS complex was tested in the asymmetric hydrogenation of a wide range of substrates. The complex proved to be a highly selective and robust system in these reactions.
- Cristobal-Lecina, Edgar,Etayo, Pablo,Doran, Sean,Reves, Marc,Martin-Gago, Pablo,Grabulosa, Arnald,Costantino, Andrea R.,Vidal-Ferran, Anton,Riera, Antoni,Verdaguer, Xavier
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p. 795 - 804
(2014/04/03)
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- Synthesis and biological evaluation of N-(2-fluorophenyl)-2β- deoxyfuconojirimycin acetamide as a potent inhibitor for α-L-fucosidases
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In this study we revealed that the addition of an N-phenylacetamide substituent to the C-1 position of 1-deoxyfuconojirimycin (DFJ) can lead to highly potent inhibitors of α-l-fucosidases. A structure-activity relationship study showed that a fluoro group on the phenyl ring greatly increased its potency and selectivity. In contrast the addition of two or three fluoro groups decreased their inhibition potency. Consequently, N-(2-fluorophenyl)-2β-DFJ acetamide (18j) was found to display very potent and selective inhibition of bovine kidney, rat epididymis, and human lysosome α-l-fucosidases, with IC50 value of 0.012, 0.044, and 0.0079 μM respectively. It is noteworthy that our designed N-phenyl-2β-DFJ acetamide derivative exhibited about 18-fold stronger effects on human lysosomal α-l-fucosidase than original DFJ and it occupied the active-site of this enzyme. We therefore expect that this compound may find applications in new therapeutic trials against genetic deficiency disorders.
- Kato, Atsushi,Okaki, Toru,Ifuku, Syohei,Sato, Kasumi,Hirokami, Yuki,Iwaki, Ren,Kamori, Akiko,Nakagawa, Shinpei,Adachi, Isao,Kiria, Peter G.,Onomura, Osamu,Minato, Daishiro,Sugimoto, Kenji,Matsuya, Yuji,Toyooka, Naoki
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p. 6565 - 6573
(2013/10/22)
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- Carica papaya lipase catalysed resolution of β-amino esters for the highly enantioselective synthesis of (S)-dapoxetine
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An efficient synthesis of the (S)-3-amino-3-phenylpropanoic acid enantiomer has been achieved by Carica papaya lipase (CPL) catalysed enantioselective alcoholysis of the corresponding racemic N-protected 2,2,2-trifluoroethyl esters in an organic solvent. A high enantioselectivity (E > 200) was achieved by two strategies that involved engineering of the substrates and optimization of the reaction conditions. Based on the resolution of a series of amino acids, it was found that the structure of the substrate has a profound effect on the CPL-catalysed resolution. The enantioselectivity and reaction rate were significantly enhanced by switching the conventional methyl ester to an activated trifluoroethyl ester. When considering steric effects, the substituted phenyl and amino groups should not both be large for the CPL-catalysed resolution. The mechanism of the CPL-catalysed enantioselective alcoholoysis of the amino acids is discussed to delineate the substrate requirements for CPL-catalysed resolution. Finally, the reaction was scaled up, and the products were separated and obtained in good yields (≥ 80 %). The (S)-3-amino-3- phenylpropanoic acid obtained was used as a key chiral intermediate in the synthesis of (S)-dapoxetine with very high enantiomeric excess (> 99 %). A carica papaya lipase catalysed resolution of N-protected β-phenylalanine esters has been developed. High enantioselectivity was achieved by two strategies that involved engineering of the substrates and optimization of the reaction conditions. After 50 % conversion, the products were separated and used as key chiral intermediates for the synthesis of (S)-dapoxetine with > 99 % ee. Copyright
- You, Pengyong,Qiu, Jian,Su, Erzheng,Wei, Dongzhi
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p. 557 - 565
(2013/03/13)
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- Protecting-group-free total synthesis of (-)-rhazinilam and (-)-rhazinicine using a gold-catalyzed cascade cyclization
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'Rhaz'zmatazz: A total synthesis of (-)-rhazinilam and the first asymmetric total synthesis of (-)-rhazinicine were accomplished by using constructing the indolizinone core through the gold-catalyzed cyclization of a fully elaborated linear ynamide. The scope and generality of this cascade reaction for the construction of highly substituted indolizinones were also investigated. Copyright
- Sugimoto, Kenji,Toyoshima, Kazuki,Nonaka, Shiori,Kotaki, Kenta,Ueda, Hirofumi,Tokuyama, Hidetoshi
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p. 7168 - 7171
(2013/07/26)
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- Synthesis and Antitubercular Activity of Novel Amino Acid Derivatives
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In this work, 17 new N-acylhydrazone derivatives of amino acids have been evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv. The compounds 8b, 8e, 8f, 9a-d, and 10c exhibited an important minimum inhibitory concentration activity between 12.5 and 50μg/mL, which can be compared with that of the tuberculostatic drug d-cycloserine (20μg/mL). In this work 17 new N-acylhydrazone derivatives of amino acids have been evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv. Eight compounds were non-cytotoxic and exhibited an important MIC activity between 12.5 and 50μg/mL, which can be compared with that of the tuberculostatic drug d-cycloserine (20μg/mL).
- Da Costa, Cristiane F.,Pinheiro, Alessandra C.,De Almeida, Mauro V.,Lourenco, Maria C.S.,De Souza, Marcus V.N.
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scheme or table
p. 216 - 222
(2012/04/23)
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- Modular P-OP ligands in rhodium-mediated asymmetric hydrogenation: A comparative catalysis study
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Highly efficient and enantioselective hydrogenation reactions for α-(acylamino)acrylates, itaconic acid derivatives and analogues, α-substituted enol ester derivatives, and α-arylenamides (25 substrates) catalyzed by chiral cationic rhodium complexes of a set of P-OP ligands have been developed. The catalytic systems derived from these P-OP ligands provided a straightforward access to enantiomerically enriched α-amino acid, carboxylic acid, amine, and alcohol derivatives that are valuable chiral building blocks. Excellent efficiencies (full conversion in all cases) and extremely high enantiomeric excesses (94-99% ee) were achieved for a wide range of α-substituted enol ester derivatives, regardless of the substitution pattern. The R-oxy group of the ligand (methoxy or triphenylmethoxy) strongly influences the enantioselectivity and catalytic activity. Greater steric bulk around the metal centre correlated to greater (or similar) enantioselectivity, but also to slower hydrogenation. Furthermore, the hydrogenation rates observed with the four model substrates follow the same trend, independently of the R-oxy group of the ligand: methyl 2-acetamidoacrylate>dimethyl itaconate>1-phenylvinyl acetate>N-(1- phenylvinyl)acetamide. A substrate-to-catalyst ratio (S/C) of up to 10,000:1 was sufficient for total hydrogenation of a model substrate of intermediate reactivity (dimethyl itaconate), and did not imply any loss in conversion or enantioselectivity. Copyright
- Nunez-Rico, Jose L.,Etayo, Pablo,Fernandez-Perez, Hector,Vidal-Ferran, Anton
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supporting information
p. 3025 - 3035
(2013/01/15)
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- The method of preparation of enantiomerically enriched products of condensation from racemic acids or acids of the low enentiomeric purity
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The method of obtaining enantiomerically enriched condensation products consists of subjecting a racemic acid or an acid of low enantiomeric purity to the action of a condensing reagent - a chiral N-triazinylammonium tetrafluoroborate (formula 1), a chira
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Page/Page column 5
(2012/03/08)
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- INHIBITORS OF FLAVIVIRIDAE VIRUSES
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Provided are compounds of Formula I: and pharmaceutically acceptable salts and esters thereof. The compounds, compositions, and methods provided are useful for the treatment of Flaviviridae virus infections, particularly hepatitis C infections.
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Page/Page column 56
(2011/02/18)
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- A favorable, narrow, δh Hansen-parameter domain for gelation of low-molecular-weight amino acid derivatives
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In recent years, the design of new low-molecular-weight gelators (LMWGs) has attracted considerable attention because of the interesting supramolecular architectures as well as industrial applications. In this context, the role of the organic solvent in d
- Curcio, Pasquale,Allix, Florent,Pickaert, Guillaume,Jamart-Gregoire, Brigitte
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scheme or table
p. 13603 - 13612
(2012/01/05)
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- Chiral rhodium complexes derived from electron-rich phosphine-phosphites as asymmetric hydrogenation catalysts
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Two new chiral cationic rhodium(I) complexes derived from electron-rich dicyclohexylphosphine-phosphite ligands were prepared from enantiopure Sharpless epoxy ethers. The best-performing catalyst system, which bears a less bulky methyl ether moiety, exhibited remarkably high enantioselectivity (up to 99% ee) and reactivity (up to >2500 TON) in asymmetric hydrogenation reactions of various functionalized alkenes (α-(acylamino)acrylates, itaconic acid derivatives, α-substituted enol esters and α-arylenamides). Our synthetic methodology has been successfully applied to the enantioselective synthesis of the antiepileptic drug (R)-lacosamide (Vimpat).
- Etayo, Pablo,Nunez-Rico, Jose L.,Vidal-Ferran, Anton
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experimental part
p. 6718 - 6725
(2012/02/05)
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- Discovery, biological evaluation, and structure-activity relationship of amidine based sphingosine kinase inhibitors
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Sphingosine 1-phosphate (S1P), a potent phospholipid growth and trophic factor, is synthesized in vivo by two sphingosine kinases. Thus these kinases have been proposed as important drug targets for treatment of hyperproliferative diseases and inflammation. We report here a new class of amidine-based sphingosine analogues that are competitive inhibitors of sphingosine kinases exhibiting varying degrees of enzyme selectivity. These inhibitors display KI values in the submicromolar range for both sphingosine kinases and, in cultured vascular smooth muscle cells, decrease S1P levels and initiate growth arrest.
- Mathews, Thomas P.,Kennedy, Andrew J.,Kharel, Yugesh,Kennedy, Perry C.,Nicoara, Oana,Sunkara, Manjula,Morris, Andrew J.,Wamhoff, Brian R.,Lynch, Kevin R.,MacDonald, Timothy L.
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scheme or table
p. 2766 - 2778
(2010/09/04)
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- Parallel synthesis of an oligomeric imidazole-4, 5-dicarboxamide library
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A library of oligomeric compounds was synthesized based on the imidazole-4, 5-dicarboxylic acid scaffold along with amino acid esters and chiral diamines derived from amino acids. The final compounds incorporate nonpolar amino acids (Leu, Phe, Trp), polar amino acids (Ser, Asp, Arg), and neutral amino acids (Gly, Ala), and were designed to be useful in screening for inhibitors of protein-protein interactions. Many of the protected and deprotected oligomers show evidence of conformational isomers persistent at room temperature in aqueous solution. A total of 317 final oligomers, out of 441 targeted compounds, were obtained in high analytical purity and of sufficient quantity to submit them for high-throughput screening as part of the NIH Roadmap.
- Xu, Zhigang,DiCesare, John C.,Baures, Paul W.
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supporting information; experimental part
p. 248 - 254
(2010/08/19)
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- Addition of allylzinc to a-amino acid-derived imines: Synthesis of diamino alcohols by Hydroboration
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Imines obtained by condensation of Z-pro- tected or Boc-protected α-amino aldehydes with α-amino tert-butyl esters or with O-silyl-protected amino alcohols were reacted with preformed allyl zinc yielding homoal- lylamines with yields around 50% and selectivities ranging from 50:50 to 90:10. Hydroboration of the terminal double bond furnished diamino alcohols with yields up to 97%. The configuration of the substrates was determined by X-ray-crystallographic analysis of a hydroboration product and comparison of physical data. Springer-Verlag 2010.
- Virlouvet, Mickael,Goesmann, Helmut,Feldmann, Claus,Podlech, Joachim
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scheme or table
p. 177 - 198
(2010/08/05)
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- Reagent-controlled diastereoselective synthesis of (2S,3R)- and (2R,3R)-2,3-diaminobutanoic acid derivatives using proline-catalyzed α-hydrazination reaction
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(2S,3R)- and (2R,3R)-2,3-Diaminobutanoic acid (Dab) derivatives were efficiently synthesized from Cbz-(R)-alanine using the proline-catalyzed diastereoselective α-hydrazination reaction and the SmI2-promoted reductive cleavage of the N-N bond a
- Makino, Kazuishi,Kubota, Sayaka,Hara, Sousuke,Sakaguchi, Masaru,Hamajima, Akinari,Hamada, Yasumasa
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experimental part
p. 9468 - 9473
(2009/12/28)
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- N- (2 { [1-PHENYL-1H-INDAZ0L-4-YL] AMINO} PROPYL) -SULFONAMIDE DERIVATIVES AS NON-STEROIDAL GLUCOCORTICOID RECEPTOR LIGANDS FOR THE TREATMENT OF INFLAMMATIONS
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The present invention provides compounds of formula (I): a process for their preparation, to pharmaceutical compositions comprising the compounds and the preparation of said compositions, to intermediates, and to use of the compounds for the manufacture o
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Page/Page column 64
(2009/07/17)
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- A mild and efficient chemoselective: N-benzyloxycarbonylation of amines using TBAB a catalyst under solvent-free conditions
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We describe a mild and efficient method for the chemoselective N-benzyloxycarbonylation of amines by treatment amines and aminoesters with benzyloxycarbonyl chloride (Cbz-Cl) in the presence of TBAB under solvent-free in excellent yields. The method is ge
- Babu, Kothamasu Suresh,Rao, Vidadala Rama Subba,Rao, Ravu Ranga,Babu, Sakhamuri Sivaram,Rao, Janaswami Madhusudana
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experimental part
p. 393 - 396
(2009/10/17)
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- Design, synthesis, and application of enantioselective coupling reagent with a traceless chiral auxiliary
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(Chemical Equation Presented) Stable chiral N-triazinylbrucinium tetrafluoroborate enantioselectively activates racemic carboxylic acids yielding enantiomerically enriched amides, esters, and dipeptides with er from 8:92 to 0.5:99.5. Due to the departure
- Kolesinska, Beata,Kaminski, Zbigniew J.
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supporting information; experimental part
p. 765 - 768
(2009/09/06)
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- Enzymatic synthesis of C-terminal arylamides of amino acids and peptides
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(Chemical Equation Presented) A mild and cost-efficient chemo-enzymatic method for the synthesis of C-terminal arylamides of amino acid and peptides is described. Using the industrial serine protease Alcalase under near-anhydrous conditions, C-terminal arylamides of N-Cbz-protected amino acids and peptides could be obtained from the corresponding C-terminal carboxylic acids, methyl (Me) or benzyl (Bn) esters, in high chemical and enantio- and diastereomeric purities. Yields ranged between 50% and 95% depending on the size of the aryl substituents and the presence of electron-withdrawing substituents. Complete α-C-terminal selectivity could be obtained even in the presence of various unprotected side-chain functionalities such as β/γ-carboxyl, hydroxyl, and guanidino groups. In addition, the use of the cysteine protease papain and the lipase Cal-B gave anilides in high yields. The chemo-enzymatic synthesis of arylamides proved to be completely free of racemization, in contrast to the state-of-the-art chemical methods.
- Nuijens, Timo,Cusan, Claudia,Kruijtzer, John A. W.,Rijkers, Dirk T. S.,Liskamp, Rob M. J.,Quaedflieg, Peter J. L. M.
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supporting information; experimental part
p. 5145 - 5150
(2009/12/06)
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- Resolution of non-proteinogenic amino acids via microbial lipase-catalyzed enantioselective transesterification
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A number of non-proteinogenic amino acids bearing aliphatic side chains were resolved with moderate to good enantioselectivities (E = 15-42) through the Burkholderia cepacia lipase-catalyzed enantioselective transesterification of the 2,2,2-trifluoroethyl esters of their N-benzyloxycarbonyl derivatives with methanol as a nucleophile in diisopropyl ether.
- Miyazawa, Toshifumi,Mio, Motoe,Watanabe, Yuko,Yamada, Takashi
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p. 219 - 224
(2008/09/20)
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- Method for synthesis of C2-symmetric diamino diol mediated by titanium complexes
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A method for synthesis of C2-symmetric diamino diol mediated by titanium complexes is provided. A substituted-L-phenylalaninal undergoes pinacol coupling to yield the corresponding C2-symmetric (1S,2R,3R,4S)-1,4-diamino 2,3-diol in the presence of Cp2TiCl2/ZnCl2 and zinc metal, mediated in good yield and highly selective. This titanium-catalyzed reaction yields diaminodiol, offering a convenient alternative method to the synthesis of C2-symmetric peptidic protease inhibitors. Consequently, the method allows to synthesize TL-3 via titanium complex in moderate yield.
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Page/Page column 2; 3
(2008/06/13)
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- A novel tert-butoxycarbonylation reagent: 1-tert-butoxy-2-tert-butoxycarbonyl-1,2-dihydroisoquinoline (BBDI)
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The use of 1-tert-butoxy-2-tert-butoxycarbonyl-1,2-dihydroisoquinoline (BBDI) as a tert-butoxycarbonylation reagent for acidic proton-containing substrates such as phenols, aromatic and aliphatic amines hydrochlorides, and aromatic carboxylic acids in the absence of a base is described. The reactions proceed chemoselectively in high yield under mild conditions.
- Saito, Yukako,Ouchi, Hidekazu,Takahata, Hiroki
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p. 11599 - 11607
(2007/10/03)
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- A novel 1-tert-butoxy-2-tert-butoxycarbonyl-1,2-dihydroisoquinoline (BBDI)-catalyzed esterification of N-protected amino acids with nearly equimolar amounts of alcohols in the presence of Boc2O
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A very mild, BBDI-catalyzed esterification using approximately equimolar amounts of N-protected amino acids and alcohols, in junction with Boc2O is described.
- Saito, Yukako,Watanabe, Tomokazu,Takahata, Hiroki
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p. 3099 - 3102
(2007/10/03)
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- A stereocontrolled route to protected isocyanates from alcohols
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Full details are given for a modified Mitsunobu approach to the formation of N-alkylated 1,2,4-dithiazolidine-3,5-diones 2 from a wide range of alcohols 10 with predominantly, inversion of configuration. The resulting products 2 can be regarded as protected isocyanates 6.
- Cane-Honeysett, Daniel J.,Dowle, Michael D.,Wood, Mark E.
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p. 2141 - 2148
(2007/10/03)
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- Resolution of non-protein amino acids via Carica papaya lipase-catalyzed enantioselective transesterification
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Carica papaya lipase-catalyzed transesterification of the 2,2,2-trifluoroethyl esters of N-benzyloxycarbonylated dl-amino acids carrying aliphatic side chains proceeded smoothly and, in almost all the cases, enantiospecifically (E = >200), affording the l-methyl esters and leaving the d-trifluoroethyl esters intact.
- Miyazawa, Toshifumi,Onishi, Kazuki,Murashima, Takashi,Yamada, Takashi,Tsai, Shau-Wei
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p. 2569 - 2573
(2007/10/03)
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- Synthesis and application of phosphinoferrocenylaminophosphine ligands for asymmetric catalysis
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(Chemical Equation Presented) A new class of bidentate ligands utilizing a phosphine-aminophosphine structure has been prepared on a ferrocenylethyl backbone in a straightforward and scalable fashion from acetylferrocene. The unique property of the α-ferrocenyl carbonium ion that allows the replacement of a variety of "leaving groups" with retention of configuration greatly facilitates the synthesis, and a number of ligands have been prepared by varying the nitrogen and phosphorus substituents on the aminophosphine. These readily prepared phosphinoferrocenylaminophosphines, known as BoPhoz ligands, show surprising hydrolytic and air stability, with no degradation after 3 years open to the air. The rhodium complexes of these ligands show exceedingly high enantioselectivities (generally > 95% ee) and activities often in excess of 50 000 catalyst turnovers per hour for the asymmetric hydrogenation of a wide variety of dehydro-α-amino acid and itaconic acid derivatives. They also show high activity and good to excellent enantioselectivity for the hydrogenation of a number of α-ketoesters.
- Boaz, Neil W.,Mackenzie, Elaine B.,Debenham, Sheryl D.,Large, Shannon E.,Ponasik Jr., James A.
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p. 1872 - 1880
(2007/10/03)
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- Simple and mild esterification of N-protected amino acids with nearly equimolar amounts of alcohols using 1-tert-butoxy-2-tert-butoxycarbonyl-1,2- dihydroisoquinoline
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A very mild, one-step esterification using nearly equimolar amounts of N-protected amino acids and alcohols, in conjunction with 1-tert-butoxy-2-tert- butoxycarbonyl-1,2-dihydroisoquinoline (BBDI) as a novel condensing reagent is described.
- Saito, Yukako,Yamaki, Toru,Kohashi, Fumiaki,Watanabe, Tomokazu,Ouchi, Hidekazu,Takahata, Hiroki
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p. 1277 - 1279
(2007/10/03)
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- Asymmetric hetero-Diels-Alder reactions of N-sulfinyl dienophiles using chiral bis(oxazoline)-copper(II) and -zinc(II) triflates
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Asymmetric hetero-Diels-Alder (HDA) reactions of N-sulfinyl dienophiles using bis(oxazoline)-copper(II) and -zinc(II) triflates are described. The cycloadditions with cyclic and acyclic 1,3-dienes have been studied. In most cases, good enantioselectivitie
- Bayer, Annette,Endeshaw, Molla Mellese,Gautun, Odd R.
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p. 7198 - 7205
(2007/10/03)
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- Concise total synthesis of (+)-carpamic acid
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We report herein an efficient enantioselective synthesis of (+)-carpamic acid, with nine steps as the longest linear sequence, the key strategy being based on a novel sequence of a cross-metathesis (CM) reaction and a subsequent cyclizing reductive amination to form the piperidine ring.
- Randl, Stefan,Blechert, Siegfried
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p. 1167 - 1169
(2007/10/03)
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- Simple, Mild, and Practical Esterification, Thioesterification, and Amide Formation Utilizing p-Toluenesulfonyl Chloride and N-Methylimidazole
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We have developed an efficient method for the esterification or thioesterification of equimolar amounts of carboxylic acids and alcohols or thiols using a novel reagent, p-toluenesulfonyl chloride (TsCl) together with N-methylimidazole. The present method is simple, mild, and reactive, uses readily available and economical reagents. The choice of amine is critical for the present method. The amine, N-methylimidazole, has two roles: (i) as an HCl scavenger for the initial smooth generation of mixed anhydrides between carboxylic acids and TsCl and (ii) successive formation of highly reactive ammonium intermediates from mixed anhydrides. This method could be applied to various types of carboxylic acids, alcohols, and thiols: a) several functionalities were tolerated; b) two N-Cbz amino acids were smoothly esterified without racemization; and c) the labile 1β-methylcarbapenem key intermediate and a pyrethroid insecticide, prallethrin, were successfully prepared. The related amide formation between carboxylic acids and primary or secondary amines was also performed. The proposed reaction mechanism involves a novel method for producing the reactive acylammonium intermediates. The production of these intermediates was rationally supported by a careful 1H NMR monitoring study.
- Wakasugi, Kazunori,Iida, Akira,Misaki, Tomonori,Nishii, Yoshinori,Tanabe, Yoo
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p. 1209 - 1214
(2007/10/03)
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- 1,2,4-Dithiazolidine-3,5-dione as an isocyanate equivalent in the Mitsunobu reaction
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1,2,4-Dithiazolidine-3,5-dione 1 can be used as a nitrogen nucleophile in a modified Mitsunobu procedure to give N-alkylated products 2 which can be converted via isocyanates, into amine derivatives, under very mild conditions.
- Wood, Mark E.,Cane-Honeysett, Daniel J.,Dowle, Michael D.
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p. 2046 - 2047
(2007/10/03)
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- Phosphinoferrocenylaminophosphines as novel and practical ligands for asymmetric catalysis
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(Matrix Presented) A new series of ligands with a novel phosphine-aminophosphine ligation design as depicted in structure 1 has been prepared on a ferrocenylethyl backbone. These BoPhoz ligands of structure 2 have afforded exceedingly high activity and enantioselectivity in the rhodium-catalyzed asymmetric hydrogenation of dehydro-α-amino acid derivatives, itaconic acids, and α-ketoesters. These air-stable ligands are readily prepared from cost-effective and non-pyrophoric intermediates.
- Boaz, Neil W.,Debenham, Sheryl D.,Mackenzie, Elaine B.,Large, Shannon E.
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p. 2421 - 2424
(2007/10/03)
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- Molecular discrimination of N-protected amino acid esters by a self-assembled cylindrical capsule: spectroscopic and computational studies.
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A self-assembled, cylindrical capsule was used to bind N-alpha-protected amino acid esters. The reversible encapsulation was studied using NMR spectroscopy in deuterated mesitylene solution and by computer-aided molecular modeling. BOC-L-alanine alkyl est
- Hayashida, Osamu,Sebo, Lubomir,Rebek Jr., Julius
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p. 8291 - 8298
(2007/10/03)
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