- Selective Isomerization via Transient Thermodynamic Control: Dynamic Epimerization of trans to cis Diols
-
Traditional approaches to stereoselective synthesis require high levels of enantio- and diastereocontrol in every step that forms a new stereocenter. Here, we report an alternative approach, in which the stereochemistry of organic substrates is selectivel
- Macmillan, David W. C.,Oswood, Christian J.
-
-
- Electrostatics Favor PNA : DNA Stability over Stereochemistry in Pyrrolidine-Based Cationic Dual-Backbone PNA Analogues
-
Modifications to the peptide nucleic acid (PNA) backbone has been well known to alter the thermodynamical parameters of PNA : DNA complexes to broaden their utility for different applications. Electrostatic interactions between a modified PNA having a positively charged backbone and the negatively charged DNA has been shown to enhance thermal stabilities of PNA : DNA complexes at various instances. On the other hand, chiral introduction in PNA backbone leads to stereochemical preference that affects binding properties. However, the interplay between electrostatics and stereochemistry has not been systematically studied so far. Herein, we report the synthesis and biophysical characterization of cationic PNA named dapPNA, first of its kind, having a dual PNA backbone constituting of a pyrrolidine ring having a β-substitution. One of the aims of this study was to investigate the role of electrostatics over stereochemical preferences. The results show that electrostatic attraction between cationic dapPNA and negatively charged DNA overcomes the unfavorable stereochemical effects and enhances stability of PNA : DNA complexes. Moreover, two different PNA backbones derived from a single PNA monomer expands the repertoire of pyrrolidine based PNA analogues.
- Sharma, Ashwani,More, Shahaji H.,Ganesh, Krishna N.
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p. 1146 - 1155
(2021/02/09)
-
- (3S,4S)-N-substituted-3,4-dihydroxypyrrolidines as ligands for the enantioselective Henry reaction
-
The enantioselective Henry reaction is a very important and useful carbon–carbon bond forming reaction. The execution of this reaction requires the use of efficient chiral catalysts. In this work, in situ formed complexes of N-substituted dihydroxypyrrolidines, chiral ligands derived from L-tartaric acid and amines, were evaluated as catalysts in the enantioselective Henry reaction. The results showed that the nature of the N-substituent on the ligand significantly influences the outcome of the reaction. Best results were obtained using a Cu (II) complex of (3S,4S)-N-benzyl-3,4-dihydroxypyrrolidine, in the presence of DIPEA, for the reaction of aromatic aldehydes with nitromethane, at room temperature, originating products with er up to 92:8 (R:S) and conversions up to 96%. The interaction between the pyrrolidine ligand and the copper ion, in isopropanol, was followed by UV-vis spectrophotometry, showing a 1:1 stoichiometry and a binding constant of 4.4. The results obtained will contribute to the design and development of more efficient chiral catalysts for this type of reaction.
- Rénio, Márcia R.R.,Sousa, Francisco J.P.M.,Tavares, Nélia C.T.,Valente, Artur J.M.,da Silva Serra, M. Elisa,Murtinho, Dina
-
-
- Synthesis of Three-Dimensional (Di)Azatricyclododecene Scaffold and Its Application to Peptidomimetics
-
A novel sp3 carbon-rich tricyclic 3D scaffold-based peptide mimetic compound library was constructed to target protein-protein interactions. Tricyclic framework 7 was synthesized from 9-azabicyclo[3,3,1]nonan-3-one (11) via a gold(I)-catalyzed Conia-ene reaction. The electron-donating group on the pendant alkyne of cyclization precursor 12 b–e was the key to forming 6-endo-dig cyclized product 7 with complete regioselectivity. Using the synthetic strategy for regioselective construction of bridged tricyclic framework 7, a diazatricyclododecene 3D-scaffold 8 a, which enables the introduction of substituents into the scaffold to mimic amino acid side chains, was designed and synthesized. The peptide mimetics 21 a–u were synthesized via step-by-step installation of three substituents on diazatricyclododecene scaffold 8 a. Compounds 21 a–h were synthesized as α-helix peptide mimics of hydrophobic ZZxxZ and ZxxZZ sequences (Z=Leu or Phe) and subjected to cell-based assays: antiproliferative activity, HIF-1 transcriptional activity which is considered to affect cancer malignancy, and antiviral activity against rabies virus. Compound 21 a showed the strongest inhibitory activity of HIF-1 transcriptional activity (IC50=4.1±0.8 μM), whereas compounds 21 a–g showed antiviral activity with IC50 values of 4.2–12.4 μM, suggesting that the 3D-scaffold 8 a has potential as a versatile peptide mimic skeleton.
- Katoh, Akira,Kouji, Hiroyuki,Morita, Taiki,Nakamura, Hiroyuki,Umedera, Kohei,Yamada, Kentaro,Yoshimori, Atsushi
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supporting information
p. 11888 - 11894
(2021/07/06)
-
- Preorganized helical chirality controlled homochiral self-assembly and circularly polarized luminescence of a quadruple-stranded Eu2 L 4 helicate
-
β-Diketones are one of the most widely used ligands for sensitizing the luminescence of lanthanide complexes due to their excellent sensitization abilities. However, the difficulties in introducing chiral groups to take part in the electronic transitions of conjugated systems limit their application in lanthanide circularly polarized luminescence (CPL) materials. In view of the inherent chirality of the helical structure, herein, a pair of homochiral quadruple-stranded helicates, Eu2L4, is assembled based on chiral bis-β-diketonate ligands, wherein the two point chirality centers in the spacer preorganize the helical conformation of the ligand (3S,4S)/(3R,4R)-3,4-bis(4,4′-bis(4,4,4-trifluoro-1,3-dioxobutyl)phenoxyl)-1-benzylpyrrolidine, LSS/LRR. X-ray crystallographic analyses reveal that the R,R configurations of the chiral carbons in the spacer induce the M helical sense of the ligand, while the S,S configurations induce the P helical sense. Through the comprehensive spectral characterization in combination with semiempirical geometry optimization using the Sparkle/RM1 model, it is confirmed that the preorganized ligands successfully control the homochirality of the helicates. Moreover, the mirror-image CD and CPL spectra and NMR measurements confirm the formation of enantiomeric pairs and their diastereopurities in solution. Detailed photophysical and chiroptical characterization studies reveal that the helicates not only exhibit intense circularly polarized luminescence (CPL) with |glum| values reaching 0.10, but also show a high luminescence quantum yield of 34%. This study effectively combines the helical chirality of the helicates with the excellent sensitization ability of the β-diketones, providing an effective strategy for the syntheses of chiral lanthanide CPL materials.
- Cheng, Zhenyu,Gao, Ting,Han, Guoying,Li, Hongfeng,Yan, Pengfei,Yao, Yuan,Zhou, Yanyan
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p. 3312 - 3320
(2020/03/23)
-
- Enantiospecific Synthesis of (3 R,4 R)-1-Benzyl-4-fluoropyrrolidin-3-amine Utilizing a Burgess-Type Transformation
-
Manufacture of an EGFR inhibitor required the asymmetric synthesis of a key 3,4-trans-substituted pyrrolidine suitable for pilot-plant scale. The initial synthetic route utilized reagents and intermediates that posed safety concerns due to their energetic potential and then required supercritical fluid chromatography to access the desired single enantiomer. Burgess-type reagents provide tremendous utility in organic synthesis but see limited use on large scales because of their high cost and instability. Nevertheless, extensive process development led to a scale-friendly process where in situ formation of a Boc-Burgess reagent enabled access to a chiral cyclic sulfamate from inexpensive materials. ReactIR monitoring was used to study intermediate stability and enabled processing on a multikilogram scale. The sulfamate was converted to trans-3-fluoro-4-aminopyrrolidine 1 with complete stereospecificity. Intermediate crystallinity offered purity control points where byproducts and impurities were rejected, avoiding the need for chromatography.
- Widlicka, Daniel W.,Gontcharov, Alexander,Mehta, Ruchi,Pedro, Dylan J.,North, Robert
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p. 1970 - 1978
(2019/08/22)
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- Investigation of stereoisomeric bisarylethenesulfonic acid esters for discovering potent and selective PTP1B inhibitors
-
Protein tyrosine phosphatase 1B (PTP1B) has been considered as a promising therapeutic target for type 2 diabetes mellitus (T2DM) and obesity due to its key regulating effects in insulin signaling and leptin receptor pathways. In this work, a series of cis- and trans-pyrrolidine bisarylethenesulfonic acid esters were prepared and their PTP1B inhibitory potency, selectivity and membrane permeability were evaluated. These novel stereoisomeric molecules especially trans-isomers exhibited remarkable inhibitory activity, significant selectivity as well as good membrane permeability (e.g. compound 28a, IC50 = 120, 1940 and 2670 nM against PTP1B, TCPTP and SHP2 respectively, and Papp = 1.74 × 10?6 cm/s). Molecular simulations indicated that trans-pyrrolidine bisarylethenesulfonic acid esters yielded the stronger binding affinity than their cis-isomers by constructing more interactions with non-catalytic sites of PTP1B. Further biological activity studies revealed that compound 28a could enhance insulin-stimulated glucose uptake and insulin-mediated insulin receptor β (IRβ) phosphorylation with no significant cytotoxicity.
- Xie, Fangzhou,Yang, Fengzhi,Liang, Yaoyao,Li, Liang,Xia, Yu,Jiang, Faqin,Liu, Wenlu,Qi, Yunyue,Chowdhury, Sharmin Reza,Xie, Dongsheng,Fu, Lei
-
p. 408 - 422
(2019/01/08)
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- Compound JK-03M having higher protein kinase G inhibitory activity or pharmaceutically acceptable salt thereof and preparation method thereof
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The invention discloses a compound which has higher protein kinase G inhibitory activity and is shown in a formula I or pharmaceutically acceptable salt thereof and a preparation method thereof. The compound JK-03M having the higher protein kinase G inhibitory activity comprises a pharmaceutical composition of a new compound and application of the new compound in treatment of pain, in particular to chronic pain. The formula (1) is shown in the description.
- -
-
Paragraph 0093; 0118; 0125-0127
(2018/11/03)
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- Novel PTP1B enzyme inhibitor, preparation method and applications thereof
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The present invention provides a novel PTP1B enzyme inhibitor, a preparation method and applications thereof, and particularly discloses a class of bis 2-substituted ethylene sulfonate compounds and a preparation method thereof, and uses of the bis 2-substituted ethylene sulfonate compounds as the PTP1B enzyme activity inhibitor. According to the present invention, the prepared novel compound has good PTP1B enzyme activity inhibition effect, and has the application value in preparation of drugs for treatment and prevention of diabetes and obesity.
- -
-
Paragraph 0083; 0186-0187
(2017/08/31)
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- Urea Derivatives of 2-Aryl-benzothiazol-5-amines: A New Class of Potential Drugs for Human African Trypanosomiasis
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A previous publication from this lab (Patrick, et al. Bioorg. Med. Chem. 2016, 24, 2451-2465) explored the antitrypanosomal activities of novel derivatives of 2-(2-benzamido)ethyl-4-phenylthiazole (1), which had been identified as a hit against Trypanosoma brucei, the causative agent of human African trypanosomiasis. While a number of these compounds, particularly the urea analogues, were quite potent, these molecules as a whole exhibited poor metabolic stability. The present work describes the synthesis of 65 new analogues arising from medicinal chemistry optimization at different sites on the molecule. The most promising compounds were the urea derivatives of 2-aryl-benzothiazol-5-amines. One such analogue, (S)-2-(3,4-difluorophenyl)-5-(3-fluoro-N-pyrrolidylamido)benzothiazole (57) was chosen for in vivo efficacy studies based upon in vitro activity, metabolic stability, and brain penetration. This compound attained 5/5 cures in murine models of both early and late stage human African trypanosomiasis, representing a new lead for the development of drugs to combat this neglected disease.
- Patrick, Donald A.,Gillespie, J. Robert,McQueen, Joshua,Hulverson, Matthew A.,Ranade, Ranae M.,Creason, Sharon A.,Herbst, Zackary M.,Gelb, Michael H.,Buckner, Frederick S.,Tidwell, Richard R.
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supporting information
p. 957 - 971
(2017/02/19)
-
- Synthesis and α-glucosidase inhibition activity of dihydroxy pyrrolidines
-
A new series of Deacetylsarmentamide A and B derivatives, amides and sulfonamides of 3,4-dihydroxypyrrolidines as α-glucosidase inhibitors were designed and synthesized. The biological screening test against α-glucosidase showed that some of these compounds have the positive inhibitory activity against α-glucosidase. Saturated aliphatic amides were more potent than the olefinic amides. Among all the compounds, 5o/6o having polar –NH2 group, 10f/11f having polar –OH group on phenyl ring displayed 3–4-fold more potent than the standard drugs. Acarbose, Voglibose and Miglitol were used as standard references. The promising compounds 6i, 5o, 6o, 10a, 11a, 10f and 11f have been identified. Molecular docking simulations were done for compounds to identify important binding modes responsible for inhibition activity of α-glucosidase.
- Kasturi, Sivaprasad,Surarapu, Sujatha,Uppalanchi, Srinivas,Anireddy, Jaya Shree,Dwivedi, Shubham,Anantaraju, Hasitha Shilpa,Perumal, Yogeeswari,Sigalapalli, Dilep Kumar,Babu, Bathini Nagendra,Ethiraj, Krishna S.
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supporting information
p. 2818 - 2823
(2017/05/29)
-
- Compounds with higher PKG (protein kinase G) inhibitory activity and preparation method of compounds
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The invention discloses compounds which have higher PKG (protein kinase G) inhibitory activity and are represented as a formula I, pharmaceutically acceptable salts, pharmaceutical composition containing the novel compounds, as well as an application of the novel compounds in treatment of pain, especially chronic pain. The invention further discloses a preparation method of the compounds and new intermediates. R1 and R2 are the same or different and are selected from a group comprising halogen (such as F or Cl), C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl; R3 is a terminal group and is selected from a group comprising H, halogen, alkyl, naphthenic base, alkenyl, alkynyl, aryl and heteroaryl; n is the number of repetitive units and is an integer in a range from 1 to 15.
- -
-
Paragraph 0148; 0149; 0159; 0151; 0152; 0153
(2016/10/08)
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- COMPOUND HAVING HIGHER INHIBITION OF PROTEIN KINASE G ACTIVITY AND PREPARATION METHOD THEREFOR
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Disclosed are a compound of Formula I having higher inhibition of protein kinase G (PKG) activity and pharmaceutically acceptable salts thereof. In Formula I, R1 and R2 are the same or different, each being independently chosen from the halogens, the C1-C6 alkoxyl group, the C1-C6 alkyl group, the C2-C6 alkenyl group, and the C2-C6 alkynyl group; R3 is chosen from H, the halogens, the substituted or unsubstituted C1-C6 alkyl group, C3-C6 cycloalkyl group, C2-C6 alkenyl group, and C2-C6 alkynyl group, aryl group, and heteroaryl group; and n is an integer between 0 and 15. Also disclosed is a pharmaceutical composition comprising said compound, the use of the compound in treating pains, in particular chronic pain, a preparation method for the compound, and a new intermediate.
- -
-
Paragraph 0071; 0072
(2016/12/12)
-
- PURINE DERIVATIVES
-
The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein Q, G, ring A, ring B, R1, R2, R3, R4, R5, R5a, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, and m are defined herein. The novel purine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. Additional embodiments relate to pharmaceutical compositions containing the compounds and to methods of using the compounds and compositions in the treatment of abnormal cell growth in mammals.
- -
-
Paragraph 0650; 0651
(2015/05/26)
-
- COFERONS AND METHODS OF MAKING AND USING THEM
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The present invention is directed to a monomer useful in preparing therapeutic compounds. The monomer includes one or more pharmacophores which potentially binds to a target molecule with a dissociation constant of less than 300 μM and a linker element connected to the pharmacophore. The linker element has a molecular weight less than 500 daltons, is connected, directly or indirectly through a connector, to the pharmacophore.
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-
Page/Page column 169; 170
(2012/12/13)
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- 1-((3S,4S)-4-Amino-1-(4-substituted-1,3,5-triazin-2-yl) pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one inhibitors of DPP-4 for the treatment of type 2 diabetes
-
A 3-amino-4-substituted pyrrolidine series of dipeptidyl peptidase IV (DPP-4) inhibitors was rapidly developed into a candidate series by identification of a polar valerolactam replacement for the lipophilic 2,4,5-trifluorophenyl pharmacophore. The additi
- Andrews, Kim M.,Beebe, David A.,Benbow, John W.,Boyer, David A.,Doran, Shawn D.,Hui, Yu,Liu, Shenping,McPherson, R. Kirk,Neagu, Constantin,Parker, Janice C.,Piotrowski, David W.,Schneider, Steven R.,Treadway, Judith L.,Vanvolkenberg, Maria A.,Zembrowski, William J.
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scheme or table
p. 1810 - 1814
(2011/05/11)
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- Synthesis of iminodiacetaldehyde derivatives as building blocks for pharmacologically active agents
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The preparation of iminodiacetaldehyde derivatives is reported via oxidative cleavage of 3,4-dihydroxypyrrolidines with sodium periodate. High yields of iminodiacetaldehydes are obtained starting from N-acyl-protected pyrrolidines, whereas the basic N-benzyl-protected derivative does not yield the expected dialdehyde. A cis-configured dihydroxypyrrolidine, prepared from 2,5-dihydropyrrole, reacts considerably faster with sodium periodate than the corresponding trans-configured derivatives which are obtained in three steps from (R,R)-tartaric acid. Georg Thieme Verlag Stuttgart.
- Fricke, Yvonne,Kopp, Nicole,Wuensch, Bernhard
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experimental part
p. 791 - 796
(2010/09/11)
-
- Exocyclic deoxyadenosine adducts of 1,2,3,4-diepoxybutane: Synthesis, structural elucidation, and mechanistic studies
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1,2,3,4-Diepoxybutane (DEB) is considered the ultimate carcinogenic metabolite of 1,3-butadiene, an important industrial chemical and environmental pollutant present in urban air. Although it preferentially modifies guanine within DNA, DEB induces a large number of A → T transversions, suggesting that it forms strongly mispairing lesions at adenine nucleobases. We now report the discovery of three potentially mispairing exocyclic adenine lesions of DEB: N6,N6-(2,3-dihydroxybutan-1,4-diyl)-2′- deoxyadenosine (compound 2), 1,N6-(2-hydroxy-3-hydroxymethylpropan-1, 3-diyl) -2′-deoxyadenosine (compound 3), and 1,N6-(1- hydroxymethyl-2-hydroxypropan-1,3-diyl)-2′-deoxyadenosine (compound 4). The structures and stereochemistry of the novel DEB-dA adducts were determined by a combination of UV and NMR spectroscopy, tandem mass spectrometry, and independent synthesis. We found that synthetic N6-(2-hydroxy-3,4- epoxybut-1-yl)-2′-deoxyadenosine (compound 1) representing the product of N6-adenine alkylation by DEB spontaneously cyclizes to form 3 under aqueous conditions or 2 under anhydrous conditions in the presence of an organic base. Compound 3 can be interconverted with 4 by a reversible unimolecular pericyclic reaction favoring 4 as a more thermodynamically stable product. Both 3 and 4 are present in double stranded DNA treated with DEB in vitro and in liver DNA of laboratory mice exposed to 1,3-butadiene by inhalation. We propose that in DNA under physiological conditions, DEB alkylates the N-1 position of adenine in DNA to form N1-(2-hydroxy-3,4-epoxybut-1-yl)-adenine adducts, which undergo an SN2-type intramolecular nucleophilic substitution and rearrangement to give 3 (minor) and 4 (major). Formation of exocyclic DEB-adenine lesions following exposure to 1,3-butadiene provides a possible mechanism of mutagenesis at the A:T base pairs.
- Seneviratne, Uthpala,Antsypovich, Sergey,Goggin, Melissa,Dorr, Danae Quirk,Guza, Rebecca,Moser, Adam,Thompson, Carrie,York, Darrin M.,Tretyakova, Natalia
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scheme or table
p. 118 - 133
(2011/02/16)
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- Enantioselective trimethylsilylcyanation of benzaldehyde using pyrrolidine-based chiral salen ligands
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The in situ formed Ti(IV) complexes of several pyrrolidine-based chiral salen ligands derived from natural (L)-tartaric acid were evaluated as catalysts in the enantioselective trimethylsilylcyanation of benzaldehyde. The catalysts were found to be very active, producing the corresponding product, O-trimethylsilylmandelonitrile, in high yields (>94%) and enantioselectivities of up to 88%.
- Serra, M. Elisa Silva,Murtinho, Dina,Goth, Albertino
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scheme or table
p. 64 - 69
(2010/08/07)
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- Novel L-tartaric acid derived pyrrolidinium cations for the synthesis of chiral ionic liquids
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Novel pyrrolidinium salts based on L-(+)-tartaric acid were designed and synthesized in very good yields with a simple and practical strategy. Twelve new chiral ionic potential task-specific catalysts, two of which are room-temperature chiral ionic liquids (RTCIL), were obtained, and their properties are discussed. Georg Thieme Verlag Stuttgart.
- Bonanni, Marco,Soldaini, Gianluca,Faggi, Cristina,Goti, Andrea,Cardona, Francesca
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experimental part
p. 747 - 750
(2009/07/25)
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- Synthesis of the new 7S-aminolentiginosine and derivatives
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The new 7S-aminolentiginosine has been synthesized by a diastereoselective 1,3-dipolar cycloaddition strategy starting from 3,4-dihydroxylat-ed pyrroline N-oxides derived from L-tartaric acid in thirteen steps. The intermediate 7S-azidolentigi-nosine unde
- Cordero, Franca M.,Bonanno, Paola,Neudeck, Sven,Vurchio, Carolina,Brandi, Alberto
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supporting information; experimental part
p. 1155 - 1161
(2009/12/05)
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- New route to N-alkylated trans-pyrrolidine diols from 2,2,3,3- tetramethoxybutane-protected dimethyl tartrate
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A short synthesis of some trans-pyrrolidine diols is described starting from (2R,3R,5R,6R)-5,6-dimethoxy-5,6-dimethyl[1,4]dioxane-2,3-dicarboxylic acid dimethyl ester 3. The key step was the occurrence of a tandem azide reduction/cyclization sequence on mono-azide intermediate 6 upon catalytic hydrogenation. This method afforded both (3R,4R)-(+)-1-benzyl-3,4- pyrrolidinediol 9a and (3R,4R)-(+)-1-allyl-3,4-pyrrolidinediol 9b starting from 3. Cytotoxicity tests were performed on compounds 9a and 9b using the brine shrimp bioassay, but each showed no activity, as were anti-oxidant tests using the stable free radical diphenylpicrylhydrazyl (DPPH). Copyright Taylor & Francis Group, LLC.
- Martins, J. Graca,Barrulas, P. Cambeiro,Marques, Carolina S.,Burke, Anthony J.
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p. 1365 - 1374
(2008/09/19)
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- AZA-BENZOFURANYL COMPOUNDS AND METHODS OF USE
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The invention relates to azabenzofuranyl compounds of Formula (I) with anti-cancer and/or anti-inflammatory activity and more specifically to azabenzofuranyl compounds which inhibit MEK kinase activity. The invention provides compositions and methods useful for inhibiting abnormal cell growth or treating a hyperproliferative disorder, or treating an inflammatory disease in a mammal. The invention also relates to methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.
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Page/Page column 122-123
(2008/06/13)
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- Asymmetric addition of diethylzinc to ketones promoted by tartaric acid derivatives
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The preparation of new sulfonamide ligands derived from L-tartaric acid and camphor sulfonyl chloride are described. The employment in the titanium tetraisopropoxide-promoted enantioselective addition of diethylzinc to ketones has been studied. The best enantiomeric excess is up to 99% with 7 mol% catalyst loading at room temperature. Copyright Taylor & Francis Group, LLC.
- Hui, Ailing,Zhang, Jintang,Wang, Zhiyong
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p. 2374 - 2384
(2008/09/21)
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- anti-Selective direct asymmetric Mannich reactions catalyzed by chiral pyrrolidine-based amino sulfonamides
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The novel pyrrolidine-based amino sulfonamides (R,R)-2, (S)-3, and (S)-4 were designed and synthesized as organocatalysts and successfully applied for the anti-selective direct asymmetric Mannich reaction.
- Kano, Taichi,Hato, Yoshio,Yamamoto, Akihiro,Maruoka, Keiji
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p. 1197 - 1203
(2008/09/18)
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- Synthesis of diastereomeric 3-hydroxy-4-pyrrolidinyl derivatives of nucleobases
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The work deals with the synthesis of hydroxypyrrolidine analogs of nucleosides. Starting from the optically pure l- or d-tartaric acid, we improved the synthesis of enantiomeric trans-3,4-dihydroxypyrrolidines and elaborated a procedure for the synthesis of all possible diastereoisomers of 3-hydroxy-4-pyrrolidinyl derivatives of both purine and pyrimidine nucleobases. The prepared compounds were tested for cytostatic and antiviral properties but no significant activity was found.
- Rejman, Dominik,Ko?alka, Petr,Budě?ínsky, Milo?,Pohl, Radek,Rosenberg, Ivan
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p. 1243 - 1253
(2007/10/03)
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- DIAMINE DERIVATIVES
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A compound represented by formula (1):Q1-Q2-To-N(R1) -Q3-N(R2)-T1-Q4 [wherein R1 and R2 are hydrogen atoms or the like; Q1 is a saturated or unsaturated, 5- or 6- membered cyclic hydrocarbon group which may be substituted, or the like; Q2 is a single bond or the like; Q3 represents the following group: (wherein Q5 is an alkylene group having 1 to 8 carbon atoms, or the like); and T0 and T1 are carbonyl groups or the like], a salt thereof, a solvate thereof, or an N-oxide thereof. The compound is useful as an agent for preventing and/or treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after artificial valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing.
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Page/Page column 162
(2008/06/13)
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- Diamine derivatives
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A compound represented by the general formula (1): Q1-Q2-T0-N(R1)-Q3-N(R2)-T1-Q4??(1) wherein R1 and R2 are hydrogen atoms or the like; Q1 is a saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon group which may be substituted, or the like; Q2 is a single bond or the like; Q3 is a group in which Q5 is an alkylene group having 1 to 8 carbon atoms, or the like; and T0 and T1 are carbonyl groups or the like; a salt thereof, a solvate thereof, or an N-oxide thereof. The compound is useful as an agent for preventing and/or treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing.
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-
-
- Fluoropyrrolidine amides as dipeptidyl peptidase IV inhibitors
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Amides derived from fluorinated pyrrolidines and 4-substituted cyclohexylglycine analogues have been prepared and evaluated as inhibitors of dipeptidyl dipeptidase IV (DP-IV). Analogues which incorporated (S)-3-fluoropyrrolidine showed good selectivity for DP-IV over quiescent cell proline dipeptidase (QPP). Compound 48 had good pharmacokinetic properties and was orally active in an oral glucose tolerance test in lean mice.
- Caldwell, Charles G.,Chen, Ping,He, Jiafang,Parmee, Emma R.,Leiting, Barbara,Marsilio, Frank,Patel, Reshma A.,Wu, Joseph K.,Eiermann, George J.,Petrov, Aleksandr,He, Huaibing,Lyons, Kathryn A.,Thornberry, Nancy A.,Weber, Ann E.
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p. 1265 - 1268
(2007/10/03)
-
- DIAMINE DERIVATIVES
-
A compound represented by the general formula (1):Q1-Q2-T0-N(R1)-Q3-N(R2)-T1-Q4 wherein R1 and R2 are hydrogen atoms or the like; Q1 is a saturated or unsaturated, 5- or 6- membered cyclic hydrocarbon group which may be substituted, or the like; Q2 is a single bond or the like; Q3 is a group in which Q5 is an alkylene group having 1 to 8 carbon atoms, or the like; and T0 and T1 are carbonyl groups or the like; a salt thereof, a solvate thereof, or an N-oxide thereof. The compound is useful as an agent for preventing and/or treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing.
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-
-
- Chiral hydride complexes
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Novel chiral boron and aluminum hydride complexes, compositions comprising the chiral hydride complexes, and methods for their synthesis and use are described. The novel chiral hydride complexes are of the formulas: PA1 MBH4-n-a (R*)n (R')a ; PA1 MBH2-b (R**) (R')b ; PA1 MBH(R***); PA1 MBH(R*) (R"); PA1 MAlH4-n-a (R*)n (R')a ; PA1 MAlH2-b (R**)(R')b ; PA1 MAlH(R***); and PA1 MAlH(R*) (R"), PAL wherein PA1 M is Na+, Li+ or K+ ; PA1 each R* is independently a monodentate chiral ligand; PA1 R** is a bidentate chiral ligand; PA1 R*** is a tridentate chiral ligand; PA1 R' is a monodentate achiral ligand; PA1 R" is a bidentate achiral ligand; PA1 n is 1-3; PA1 a is 0-2; and PA1 b is 0-1, PAL with the proviso that n+a3, and with the further proviso that when R** is S-BINOL, M is not Li+.
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- Combinatorial chemistry for ligand development in catalysis: Synthesis and catalysis screening of peptidosulfonamide tweezers on the solid phase
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On the basis of a pyrrolidine tweezer 1, a library of peptidosulfonamide tweezers (15a-e, 16a-e was synthesized on the solid phase. This library was screened in a simultaneous substrate screening procedure for the ability to enantioselectively catalyze the Ti(O-i-Pr)4-mediated addition of diethylzinc to aldehydes. One of the best solid-phase tweezer catalyst (i.e., 16d, giving an ee of 32% in solid-phase catalysis) was resynthesized in solution (compounds 20 and 21). The now homogeneous solution-phase catalysis showed even better enantioselectivity (i.e., up to 66%).
- Brouwer, Arwin J.,van Der Linden, Heiko J.,Liskamp, Rob M. J.
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p. 1750 - 1757
(2007/10/03)
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- Synthesis and biological evaluation of novel 1β-methylcarbapenems having a new moiety at C-2
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The synthesis and biological activity of the novel series of 1β- methylcarbapenems 1a-f, bearing a variety of 3'',4''-disubstituted pyrrolidinamides as substituents at C-2, are described. Of these carbapenems, diol 1a showed the most potent and well balanced antibacterial activity against Gram-positive and Gram-negative, 1a was also evaluated for pharmacokinetics and in vivo therapeutic efficacy in systemic infections.
- Kang, Yong Koo,Shin, Kye Jung,Yoo, Kyung Ho,Seo, Kyung Jae,Park, Seung Yong,Kim, Dong Jin,Park, Sang Woo
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p. 2385 - 2390
(2007/10/03)
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- Tweezers with different bite: Increasing the affinity of synthetic receptors by varying the hinge part
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With preservation of selectivity, the hinge part of tweezerlike synthetic receptor molecules can be varied to achieve a higher affinity. The synthetic peptidosulfonamide receptor (below left; R = Disperse Red 1) with the bis(aminomethyl)benzoic acid hinge selectively bound the tripeptide shown below on the right (K(a) = 4100 M-1). Combination of a diversity in the hinge part with that present in the tweezer arms will provide access to large and diverse synthetic receptor libraries.
- Loewik, Dennis W. P. M.,Weingarten, W. David,Broekema, Matthias,Brouwer, Arwin J.,Still, W. Clark,Liskamp, Rob M. J.
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p. 1846 - 1850
(2007/10/03)
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- Synthesis of C2 symmetric primary vicinal diamines. Double stereospecific Mitsunobu reaction of the heterocyclic diols derived from tartaric acid
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Homochiral 1-alkyl-3,4-dihydroxypyrrolidines, (S,S)- and (R,R)-5 were obtained by cyclization and reduction of both enantiomers of (+)- and (-)-tartaric acid, respectively. Also (S,S)-3,4-dihydroxytetrahydrofurane 6 was prepared from (+)-diethyl tartrate. All these heterocyclic vic-diols underwent twofold Mitsunobu reaction (Ph3P/DEA/HN3) followed by catalytic hydrogenation forming stereospecifically the corresponding primary vicinal diamines (R,R)-, (S,S)-2 and (R,R)-3. The absolute configuration of diamines 2, 3 was established by the exciton-coupling CD spectra of their N,N'-diphthaloyl derivatives.
- Skarzewski, Jacek,Gupta, Anil
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p. 1861 - 1867
(2007/10/03)
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- Synthesis of nitrones using the methyltrioxorhenium/hydrogen peroxide system
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Secondary amines are oxidized by the methyltrioxorhenium/hydrogen peroxide system to the corresponding nitrones in excellent yield. The results provide a further example of the parallel between the chemistry of this metal system and that of the dioxiranes.
- Murray, Robert W.,Iyanar, Kaliappan,Chen, Jianxin,Wearing, James T.
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p. 8099 - 8102
(2007/10/03)
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- Method of producing optically active pyrrolidines with high enantiomeric purity
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A method of producing optically active pyrrolidines of the general formula STR1 in which R1 is hydrogen or OH, R2 is a benzyl group which can have one or more alkyl-, alkoxy- and/or halogen substituents on the aromatic, and * is and/or can be an asymmetric center, by reducing the corresponding, enantiomerically pure pyrrolidinediones using activated alkali boron hydride.
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- FIRST EXAMPLE OF INTRAMOLECULAR 1,3-DIPOLAR CYCLOADDITION OF NON-STABILIZED AZOMETHINE YLIDE GENERATED FROM TERTIARY AMINE N-OXIDE
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The reaction of two optically active 1-alkyl-3,4-diallyloxypyrrolidine 1-oxides, (9) and (15), under basic conditions has been examined.The 1-benzyl derivative (9), on reaction with lithium diisopropylamide, furnished a single pyrrolidine derivative (11) by intramolecular 1,3-dipolar cycloaddition of an N-benzylidene azomethine ylide (10), while the 1-methyl derivative (15) reacted with tert-butyllithium in the presence of trimethylaluminum to afford only a single 7-azabicycloheptane derivative (19) by spontaneous intramolecular 1,3-dipolar cycloaddition of the endocyclic azomethane ylide (17).
- Takano, Seiichi,Sugihara, Yoshiaki,Ogasawara, Kunio
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p. 1519 - 1522
(2007/10/02)
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- Synthesis of (3S,4S)-3,4-dihydroxyprolines from L-tartaric acid
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Natural (2S,3S,4S)-3,4-dihydroxyproline (1) and the new (2R,3S,4S)-isomer (7) have been synthesized from L-tartaric acid via cyanosilylation of the cyclic Schiff base.
- Arakawa,Yoshifuji
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p. 2219 - 2224
(2007/10/02)
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- Enantioselective Catalysis, 4. Synthesis of N-Substituted (R,R)-3,4-Bis(diphenylphosphino)pyrrolidines. The Use of their Rhodium Complexes for the Asymmetric Hydrogenation of α-(Acylamino)acrylic Acid Derivatives
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A simple synthesis of (R,R)-3,4-bis(diphenylphosphino)pyrrolidine (6a) and some N-substituted derivatives 6b-m is described. 6l and 6m are optically active tetraphosphanes, composed of two (R,R)-3,4-bis(diphenylphosphino)pyrrolidine units and a dicarboxylic residue.The structure of the parent compound 6a was determined by X-ray diffraction.From the phosphanes 6a-m the cationic 1,5-cyclooctadiene-bisphosphane-rhodium complexes 7a-m were prepared.The complexes 7l and 7m are ligand bridged bis(rhodium) dications.The complexes 7a-m were used for the asymmetric catalytic hydrogenation of the α-(acylamino)acrylic acid derivatives 9a-l.Enantiomeric excesses up to 100percent were achieved.Between 1 and 70 at the optical yields do not depend on the hydrogen pressure.The substrate/catalyst ratio can be as high as 50000/1.
- Nagel, Ulrich,Kinzel, Elke,Andrade, Juan,Prescher, Guenter
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p. 3326 - 3343
(2007/10/02)
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- ASYMMETRIC HYDROGENATION OF DEHYDRODIPEPTIDES WITH RHODIUM(I)-CHIRAL DIPHOSPHINITES. SELECTIVE (S,S)- AND (R,R)-PRODUCT FORMATION BY DOUBLE ASYMMETRIC INDUCTION.
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In the hydrogenation of dehydrodipeptides, the effect of chiral center of the substrate ((S) or (R)) on the asymmetric induction was examined using the catalysts of Rh(I)-chiral diphosphinite containing pyrrolidine moiety (POP). The catalysts with POP's h
- Yatagai,Yamagishi,Hida
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p. 823 - 826
(2007/10/02)
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