- Chemoselective Electrosynthesis Using Rapid Alternating Polarity
-
Challenges in the selective manipulation of functional groups (chemoselectivity) in organic synthesis have historically been overcome either by using reagents/catalysts that tunably interact with a substrate or through modification to shield undesired sites of reactivity (protecting groups). Although electrochemistry offers precise redox control to achieve unique chemoselectivity, this approach often becomes challenging in the presence of multiple redox-active functionalities. Historically, electrosynthesis has been performed almost solely by using direct current (DC). In contrast, applying alternating current (AC) has been known to change reaction outcomes considerably on an analytical scale but has rarely been strategically exploited for use in complex preparative organic synthesis. Here we show how a square waveform employed to deliver electric current - rapid alternating polarity (rAP) - enables control over reaction outcomes in the chemoselective reduction of carbonyl compounds, one of the most widely used reaction manifolds. The reactivity observed cannot be recapitulated using DC electrolysis or chemical reagents. The synthetic value brought by this new method for controlling chemoselectivity is vividly demonstrated in the context of classical reactivity problems such as chiral auxiliary removal and cutting-edge medicinal chemistry topics such as the synthesis of PROTACs.
- Baran, Phil S.,Carlson, Ethan,Edwards, Jacob T.,Hayashi, Kyohei,Kawamata, Yu,Saito, Masato,Shaji, Shobin,Simmons, Bryan J.,Waldmann, Dirk,Zapf, Christoph W.
-
supporting information
p. 16580 - 16588
(2021/10/20)
-
- Benzil compound as well as preparation method and application thereof
-
The invention provides a benzil compound as well as a preparation method and application thereof, the structure of the benzil compound is shown as a formula I, wherein R1 is -(CH2) n-N (CX1Y1Z1) (CX2Y2Z2), n is an integer from 1 to 6, and X1, X2, Y1, Y2, Z1 and Z2 are independently selected from hydrogen or deuterium. The benzil compound provided by the invention is applied to detection of guanidine compounds, can remarkably improve the sensitivity, accuracy and stability of detection, can be used for identifying potential guanidine compounds in a to-be-detected sample, and is low in cost.
- -
-
Paragraph 0058; 0062
(2021/06/09)
-
- Multiplexed Analysis of Endogenous Guanidino Compounds via Isotope-Coded Doubly Charged Labeling: Application to Lung Cancer Tissues as a Case
-
Endogenous guanidino compounds (GCs), nitrogen-containing metabolites, have very important physiological activities and participate in biochemical processes. Therefore, accurately characterizing the distribution of endogenous GCs and monitoring their concentration variations are of great significance. In this work, a new derivatization reagent, 4,4′-bis[3-(dimethylamino)propyl]benzyl (BDMAPB), with isotope-coded reagents was designed and synthesized for doubly charged labeling of GCs. BDMAPB-derivatized GCs not only promote the MS signal but also form multicharged quasimolecular ions and abundant fragment ions. With this reagent, an isotope-coded doubly charged labeling (ICDCL) strategy was developed for endogenous GCs with high-resolution liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF MS). The core of this methodology is a 4-fold multiplexed set of [d0]-/[d4]-/[d8]-/[d12]-BDMAPB that yields isotope-coded derivatized GCs. Following a methodological assessment, good linear responses in the range of 25 nM to 1 μM with correlation coefficients over 0.99 were achieved. The limit of detection and the limit of quantitation were below 5 and 25 nM, respectively. The intra- and interday precisions were less than 18%, and the accuracy was in the range of 77.3–122.0%. The percentage recovery in tissues was in the range of 85.1–113.7%. The results indicate that the developed method facilitates long-term testing and ensures accuracy and reliability. Finally, the method was applied for the simultaneous analysis of endogenous GCs in four types of lung tissues (solid adenocarcinoma, solid squamous-cell carcinoma, ground-glass carcinoma, and paracancerous tissues) for absolute quantification, nontargeted screening, and metabolic difference analysis. It is strongly believed that ICDCL combined with isotope-coded BDMAPB will benefit the analysis and study of endogenous GCs.
- Liu, Li,Chen, Yan-Zhen,Zhang, Shu-Sheng,Chen, Xiu-Ping,Lin, Guo-Qiang,Yin, Hang,Feng, Chen-Guo,Zhang, Fang
-
p. 16862 - 16872
(2021/12/27)
-
- Niraparib intermediate, preparation method and application thereof, and synthesis method of niraparib
-
The invention relates to a compound alpha-(3-aminopropyl)-p-bromophenylacetic acid, a preparation method and application thereof, (S)-3-(4-bromophenyl)-piperidine-2-one, a preparation method and application thereof, and synthesis methods of (S)-3-(4-bromophenyl)-piperidine) p-toluenesulfonate, N-Boc-(3S)-(4-bromophenyl)piperidine and niraparib. 4-bromophenylacetate 5 is used as a raw material, a nucleophilic reaction is carried out on the raw material and a nitrogen source reagent 4 under the action of an alkali to generate a compound 6; the compound 6 is subjected to deprotection and hydrolysis to obtain an amino acid compound 7; and the amino acid compound 7 is subjected to chiral column separation or chemical resolution to obtain compounds 8 and 9; and the separated enantiomer 8 can besubjected to racemization and resolution conversion (or chiral column separation) to obtain a compound 9, and the process material cost is greatly reduced. After the compound 9 is obtained, a compound1 can be obtained through conventional condensation reaction ring closing, reduction and BOC loading. Splitting operation is advanced, and the enantiomer 8 is subjected to racemization recovery treatment and is repeatedly applied to different splitting batches to continuously obtain the product 9, so the process material cost is lower.
- -
-
Paragraph 0064; 0066-0067
(2020/09/08)
-
- Preparation method of N-(3-hydroxypropyl)phthalimide and catalyst for method
-
The invention relates to a method for preparing N-(3-hydroxypropyl)phthalimide and a catalyst used in the method, the method comprises making phthalimide and allyl alcohol react in a solvent in the presence of an iron-based catalyst, a sodium salt and a potassium salt in an inert atmosphere to obtain N-(3-hydroxypropyl)phthalimide. According to the method, phthalimide and allyl alcohol are used asraw materials, the cheap iron chelate catalyst Fe-PNP is used for replacing an expensive ruthenium catalyst, the product is directly obtained through a reverse Markov addition one-step method, and the method is simple in process, low in cost and high in yield and conversion rate.
- -
-
Paragraph 0041; 0045-0047; 0051-0064
(2020/05/30)
-
- INHIBITORS OF LEUCINE RICH REPEAT KINASE 2
-
The present invention relates to novel compounds that inhibit LRRK2 kinase activity, to processes for their preparation, to compositions containing them and to their use in the treatment of or prevention of diseases associated with or characterized by LRRK2 kinase activity, for example Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis (ALS).
- -
-
Page/Page column 159
(2019/02/02)
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- Chiral γ - amino alcohol compound preparation method
-
The invention discloses a preparation method of a chiral gamma-aminoalcohol compound. In the condition of a certain hydrogen pressure and a temperature, with the effects of solvents and a alkali, a ruthenium chiral catalyst is used for catalyzing a beta-amino ketone compound (I) for generating an asymmetric catalytic hydrogenation reaction, and the chiral gamma-aminoalcohol compound (II) is prepared. The preparation method of the present invention has the advantages of mild condition, low cost, few environment influences, good reaction yield, enantioselectivity and good application prospect.
- -
-
Paragraph 0123; 0124
(2018/11/26)
-
- Visible-Light-Mediated Aerobic Oxidation of Organoboron Compounds Using in Situ Generated Hydrogen Peroxide
-
A simple and general visible-light-mediated oxidation of organoboron compounds has been developed with rose bengal as the photocatalyst, substoichiometric Et3N as the electron donor, as well as air as the oxidant. This mild and metal-free protocol shows a broad substrate scope and provides a wide range of aliphatic alcohols and phenols in moderate to excellent yields. Notably, the robustness of this method is demonstrated on the stereospecific aerobic oxidation of organoboron compounds.
- Weng, Wei-Zhi,Liang, Hao,Zhang, Bo
-
supporting information
p. 4979 - 4983
(2018/08/24)
-
- Dual Rh?Ru Catalysts for Reductive Hydroformylation of Olefins to Alcohols
-
An active and selective dual catalytic system to promote domino hydroformylation–reduction reactions is described. Apart from terminal, di- and trisubstituted olefins, for the first time the less active internal C?C double bond of tetrasubstituted alkenes can also be utilized. As an example, 2,3-dimethylbut-2-ene is converted into the corresponding n-alcohol with high yield (90 %) as well as regio- and chemoselectivity (>97 %). Key for this development is the use of a combination of Rh complexes with bulky monophosphite ligands and the Ru-based Shvo's complex. A variety of aromatic and aliphatic alkenes can be directly used to obtain mainly linear alcohols.
- Rodrigues, Fábio M. S.,Kucmierczyk, Peter K.,Pineiro, Marta,Jackstell, Ralf,Franke, Robert,Pereira, Mariette M.,Beller, Matthias
-
p. 2310 - 2314
(2018/07/31)
-
- Direct Dehydroxytrifluoromethoxylation of Alcohols
-
The first example of a direct dehydroxytrifluoromethoxylation of alcohols has been developed. This method generated an alkyl fluoroformate in situ from alcohols, followed by nucleophilic trifluoromethoxylation with trifluoromethyl arylsulfonate (TFMS) as the trifluoromethoxylation reagent. The reaction is operationally simple and scalable, and it proceeds under mild reaction conditions to provide access to a wide range of trifluoromethyl ethers from alcohols. In addition, this method is suitable for the late-stage trifluoromethoxylation of complex small molecules.
- Jiang, Xiaohuan,Deng, Zhijie,Tang, Pingping
-
supporting information
p. 292 - 295
(2017/12/29)
-
- Delta-aminoalkylbenzofuranol ethers, and preparation method and application thereof
-
The invention relates to delta-aminoalkylbenzofuranol ethers represented by chemical structural formula I shown in the description, and an application thereof in the preparation of herbicides. In thechemical structural formula I, R is selected from C1-C2 alkyl groups, and n is selected from 2, 3 and 4.
- -
-
Paragraph 0042-0044
(2018/04/01)
-
- Exploring endoperoxides as a new entry for the synthesis of branched azasugars
-
A new class of nitrogen-containing endoperoxides were synthesised by a photochemical [4 + 2]-cycloaddition between a diene and singlet oxygen. The endoperoxides were dihydroxylated and protected to provide a series of endoperoxide building blocks for organic synthesis, with potential use as precursors for the synthesis of branched azasugars. Preliminary exploration of the chemistry of these building blocks provided access to a variety of derivatives including tetrahydrofurans, epoxides and protected amino-tetraols.
- Domeyer, Svenja,Bjerregaard, Mark,Johansson, Henrik,Pedersen, Daniel Sejer
-
supporting information
p. 644 - 647
(2017/06/20)
-
- Phthalimide-N-sulfonic acid, an efficient catalyst for the synthesis of various isoindoline-1,3-dione derivatives
-
An environmentally friendly method is described for the synthesis of various isoindoline-1,3-dione derivatives from the reaction of phthalic anhydride with aromatic/aliphatic amines in ethanol at 80 °C by phthalimide-N-sulfonic acid as an efficient heterogeneous acid catalyst. Some advantages include the metal-free and environmentally friendly protocol, simple operation and reusable processes, easy recovery, short reaction times, and high yields.
- Habibi, Davood,Pordanjani, Hossein Mohammadkhani
-
p. 2293 - 2299
(2017/10/05)
-
- X-ray crystal structures of Enterococcus faecalis thymidylate synthase with folate binding site inhibitors
-
Infections caused by Enterococcus faecalis (Ef) represent nowadays a relevant health problem. We selected Thymidylate synthase (TS) from this organism as a potential specific target for antibacterial therapy. We have previously demonstrated that species-specific inhibition of the protein can be achieved despite the relatively high structural similarity among bacterial TSs and human TS. We had previously obtained the EfTS crystal structure of the protein in complex with the metabolite 5-formyl-tetrahydrofolate (5-FTHF) suggesting the protein role as metabolite reservoir; however, protein–inhibitors complexes were still missing. In the present work we identified some inhibitors bearing the phthalimidic core from our in-house library and we performed crystallographic screening towards EfTS. We obtained two X-ray crystallographic structures: the first with a weak phthalimidic inhibitor bound in one subunit and 5-hydroxymethylene-6-hydrofolic acid (5-HMHF) in the other subunit; a second X-ray structure complex with methotrexate. The structural information achieved confirm the role of EfTS as an enzyme involved in the folate pool system and provide a structural basis for structure-based drug design.
- Catalano, Alessia,Luciani, Rosaria,Carocci, Alessia,Cortesi, Debora,Pozzi, Cecilia,Borsari, Chiara,Ferrari, Stefania,Mangani, Stefano
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p. 649 - 664
(2016/08/12)
-
- Mild deprotection of PMB ethers using tert-butyl bromide
-
A convenient and high yielding method for the cleavage and scavenging of p-methoxybenzyl protecting group of several alcohols using tert-butyl bromide in refluxing acetonitrile is described. Under these mild conditions other protecting groups such as acid sensitive allyl, benzyl, and Me3CPh2Si ethers, or isopropylidene acetals were unchanged. Interestingly, a selective alkoxy-PMB cleavage was observed in the presence of a PMB phenoxy ether.
- Rival, Nicolas,Albornoz Grados, Arantxa,Schiavo, Lucie,Colobert, Fran?oise,Hanquet, Gilles
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p. 6823 - 6826
(2015/11/27)
-
- A metal-free approach for transamidation of amides with amines in aqueous media
-
An efficient, environmentally benign and a mild protocol for transamidation of amides with a variety of amines in the presence of K2S2O8 using stoichiometric quantity in aqueous conditions has been established. This method works under conventional thermal conditions and in microwave irradiation as well. A series of amides have been prepared using this reaction and this is a greener protocol for transamidation, which offers a diverse kind of substrate scope with exclusive product formation (yields 90-98%).
- Srinivas, Mahesuni,Hudwekar, Abhinandan D.,Venkateswarlu, Vunnam,Reddy, G. Lakshma,Kumar, K. A. Aravinda,Vishwakarma, Ram A.,Sawant, Sanghapal D.
-
supporting information
p. 4775 - 4779
(2015/07/20)
-
- Complex columnar hexagonal polymorphism in supramolecular assemblies of a semifluorinated electron-accepting naphthalene bisimide
-
Simple synthetic methods for a strongly electron-accepting naphthalene bisimide (NBI) derivative functionalized with a new environmentally friendly chiral racemic semifluorinated alkyl group and with AB3 minidendrons containing the same semifluorinated group are reported. The semifluorinated dendron was attached to the imide groups of the NBI via one, two, and three (m = 1, 2, 3) methylenic units. The NBI-containing semifluorinated groups and the dendronized NBI with m = 1 and 2 self-organize into lamellar crystals. The dendronized NBI with m = 3 self-assembles into an unprecedentedly complex and ordered column that self-organizes in a columnar hexagonal periodic array. This array undergoes a continuous transition to a columnar hexagonal superlattice that does not display a first-order phase transition during analysis by differential scanning calorimetry at heating and cooling rates of 10 and 1 °C/min. These complex columnar hexagonal periodic arrays with intramolecular order could be elucidated only by a combination of powder and fiber X-ray diffraction studies and solid-state NMR experiments. The lamellar crystals self-organized from m = 1 and the two highly ordered columnar hexagonal periodic arrays of m = 3 are assembled via thermodynamically controlled processes. Since strongly electron-accepting derivatives are of great interest to replace fullerene acceptors in organic photovoltaics and for other supramolecular electronic materials, the multitechnique structural analysis methodology elaborated here must be taken into consideration in all related studies.
- Wu, Yu-Chun,Leowanawat, Pawaret,Sun, Hao-Jan,Partridge, Benjamin E.,Peterca, Mihai,Graf, Robert,Spiess, Hans W.,Zeng, Xiangbing,Ungar, Goran,Hsu, Chain-Shu,Heiney, Paul A.,Percec, Virgil
-
supporting information
p. 807 - 819
(2015/01/30)
-
- Versatile and sustainable synthesis of cyclic imides from dicarboxylic acids and amines by Nb2O5 as a base-tolerant heterogeneous lewis acid catalyst
-
Catalytic condensation of dicarboxylics acid and amines without excess amount of activating reagents is the most atom-efficient but unprecedented synthetic method of cyclic imides. Here we present the first general catalytic method, proceeding selectively and efficiently in the presence of a commercial Nb2O5 as a reusable and base-tolerant heterogeneous Lewis acid catalyst. The method is effective for the direct synthesis of pharmaceutically or industrially important cyclic imides, such as phensuximide, N-hydroxyphthalimide (NHPI), and unsubstituted cyclic imides from dicarboxylic acid or anhydrides with amines, hydroxylamine, or ammonia.
- Ali, Md. Ayub,Siddiki, S. M. A. Hakim,Kon, Kenichi,Hasegawa, Junya,Shimizu, Kenichi
-
supporting information
p. 14256 - 14260
(2015/01/09)
-
- From in vitro to in cellulo: Structure-activity relationship of (2-nitrophenyl)methanol derivatives as inhibitors of PqsD in Pseudomonas aeruginosa
-
Recent studies have shown that compounds based on a (2-nitrophenyl)methanol scaffold are promising inhibitors of PqsD, a key enzyme of signal molecule biosynthesis in the cell-to-cell communication of Pseudomonas aeruginosa. The most promising molecule displayed anti-biofilm activity and a tight-binding mode of action. Herein, we report on the convenient synthesis and biochemical evaluation of a comprehensive series of (2-nitrophenyl)methanol derivatives. The in vitro potency of these inhibitors against recombinant PqsD as well as the effect of selected compounds on the production of the signal molecules HHQ and PQS in P. aeruginosa were examined. The gathered data allowed the establishment of a structure-activity relationship, which was used to design fluorescent inhibitors, and finally, led to the discovery of (2-nitrophenyl)methanol derivatives with improved in cellulo efficacy providing new perspectives towards the application of PqsD inhibitors as anti-infectives. This journal is the Partner Organisations 2014.
- Storz, Michael P.,Allegretta, Giuseppe,Kirsch, Benjamin,Empting, Martin,Hartmann, Rolf W.
-
supporting information
p. 6094 - 6104
(2014/08/05)
-
- Reactions of difluorocarbene with organozinc reagents
-
Reactions of difluorocarbene with benzyl and alkylzinc halides leading to fluorinated organozinc species have been described. The generated α-difluorinated organozinc reagents are reasonably stable in solution and can be quenched with external electrophiles (iodine, bromine, proton), affording compounds containing the CF2 fragment.
- Levin, Vitalij V.,Zemtsov, Artem A.,Struchkova, Marina I.,Dilman, Alexander D.
-
supporting information
p. 917 - 919
(2013/03/28)
-
- Silver(I)-Catalyzed deprotection of p -methoxybenzyl ethers: A mild and chemoselective method
-
The p-methoxybenzyl protecting group (PMB) on various alcohols and an acid was efficiently and selectively cleaved by the action of a catalytic amount of silver(I) hexafluoroantimonate combined with 0.5 equiv of 1,3,5- trimethoxybenzene in dichloromethane at 40 °C.
- Kern, Nicolas,Dombray, Thomas,Blanc, Aurelien,Weibel, Jean-Marc,Pale, Patrick
-
p. 9227 - 9235,9
(2012/12/12)
-
- MODULATORS OF HISTONE METHYLTRANSFERASE, AND METHODS OF USE THEREOF
-
Disclosed are compounds, pharmaceutical compositions containing the compounds, and the uses of the compounds and compositions as modulators of histone methyltransferases, and for treating diseases influenced by modulation of histone methyltransferase activity.
- -
-
Page/Page column 245
(2012/06/30)
-
- ARYL CARBOXAMIDE DERIVATIVES AS SODIUM CHANNEL INHIBITORS FOR TREATMENT OF PAIN
-
The present invention provides compounds that are inhibitors of voltage-gated sodium channels (Nav), in particular Nav 1.7, and are therefore useful for the treatment of diseases treatable by inhibition of these channels, in particular, chronic pain disorders. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
- -
-
Page/Page column 110-111
(2011/09/19)
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- New N-(phenoxydecyl)phthalimide derivatives displaying potent inhibition activity towards α-glucosidase
-
Several members of a new family of non-sugar-type α-glucosidase inhibitors, bearing a phthalimide moiety connected to a variously substituted phenoxy ring by an alkyl chain, were synthesized and their activities were investigated. The efficacy of the inhibition activity appeared to be governed by the chain length of the substrate. Substrates possessing 10 carbons afforded the highest levels of activity, which were one to two orders of magnitude more potent than the known inhibitor 1-deoxynojirimycin (dNM). Furthermore, structure-activity relationship studies indicated a critical role of electron-withdrawing substituents at the phenoxy group for the activity. Derivatives bearing a chlorine atom along with a strong electron-withdrawing group, such as a nitro group, were the most potent of the series.
- Pascale, Rossana,Carocci, Alessia,Catalano, Alessia,Lentini, Giovanni,Spagnoletta, Anna,Cavalluzzi, Maria Maddalena,De Santis, Francesco,De Palma, Annalisa,Scalera, Vito,Franchini, Carlo
-
experimental part
p. 5903 - 5914
(2010/10/02)
-
- αvβ3 integrin-targeting Arg-Gly-Asp (RGD) peptidomimetics containing oligoethylene glycol (OEG) spacers
-
RGD peptides are used in biomaterials science for surface modifications with a view to elicit selective cellular responses. Our objective is to replace peptides by small peptidomimetics acting similarly. We designed novel molecules targeting αvβ3 integrin and featuring spacer-arms (for surface grafting), which do not disturb the biological activity, from (L) N-(3-(trifluoromethyl)benzenesulfonyl) tyrosine used as scaffold. Various Arg-mimics were fixed on the phenol function, and the ortho position was used for the coupling of OEG spacers. All peptidomimetics were active in the nM range in a binding test toward human αvβ 3 integrin (IC50 = 0.1 to 1.7 nM) and selective versus platelet integrin αIIbβ3. Selected compounds revealed excellent ability to inhibit bone cells adhesion on vitronectin. Modeling and docking studies were performed for comparing the most active RGD peptidomimetic to cilengitide, i.e., cyclo-[RGDfN(Me)V]-. Lastly, the adhesion of endothelial cells on a cultivation support grafted with RGD peptidomimetics was significantly improved. 2009 American Chemical Society.
- Rerat, Vincent,Dive, Georges,Cordi, Alex A.,Tucker, Gordon C.,Bareille, Reine,Amédée, Jo?lle,Bordenave, Laurence,Marchand-Brynaert, Jacqueline
-
supporting information; experimental part
p. 7029 - 7043
(2010/07/05)
-
- Asymmetric synthesis of highly substituted azapolycyclic compounds via 2-alkenyl sulfoximines: Potential scaffolds for peptide mimetics
-
The application of metalated, enantiomerically pure acyclic and cyclic 2-alkenyl sulfoximines for the synthesis of highly substituted aza(poly)cyclic ring systems is described. The method relies on a one-pot combination of a reagent-controlled allyl transfer reaction to α- or β-amino aldehydes, followed by a Michael-type cyclization of the intermediate vinyl sulfoximines generated in the first step. The sulfur-free target compounds are preferentially obtained by samarium iodide treatment of the sulfonimidoyl substituted heterocycles. In addition to this methodological work, initial results on the biological activity of selected examples are reported. Furthermore, a concept for the transformation of peptidic lead structures into non-peptide mimetics is described, and the relevance of the new approach to highly substituted azaheterocycles in this context is discussed.
- Reggelin, Michael,Junker, Bernd,Heinrich, Timo,Slavik, Stefan,Buehle, Philipp
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p. 4023 - 4034
(2007/10/03)
-
- Development of Irreversible Diphenyl Phosphonate Inhibitors for Urokinase Plasminogen Activator
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In this letter we report the synthesis and biochemical evaluation of selective, irreversible diphenyl phosphonate inhibitors for urokinase plasminogen activator (uPA). A diphenyl phosphonate group was introduced on the substratelike peptide Z-D-Ser-Ala-Arg, and modification of the guanidine side chain was investigated. A guanylated benzyl group appeared the most promising side chain modification. A kapp value in the 103 M -1 s-1 range for uPA was obtained, together with a selectivity index higher than 240 toward other trypsin-like proteases such as tPA, thrombin, plasmin, and FXa.
- Joossens,Van Der Veken,Lambeir,Augustyns,Haemers
-
p. 2411 - 2413
(2007/10/03)
-
- Free radical-mediated vinyl amination: A mild, general pyrrolidinyl enamine synthesis
-
The complete scope of free radical-mediated vinyl amination is described, using 5-exo-trig cyclizations of vinyl radicals to the nitrogen of azomethines. The focus is primarily on N,N-dialkyl enamines since their nucleophilicity renders them the most challenging enamines to synthesize using redox conditions. These studies establish several encouraging precedents for the broader application of this strategy.
- Nugent, Benjamin M.,Williams, Amie L.,Prabhakaran,Johnston, Jeffrey N.
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p. 8877 - 8888
(2007/10/03)
-
- Acid-mediated intramolecular cationic cyclization using an oxygen atom as internal nucleophile: Synthesis of substituted oxazolo-, oxazino- and oxazepinoisoindolinones
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Efficient assembly of substituted oxazolo-, oxazino-, and oxazepinoisoindolinones (5-7, 12-15 and 19) is described in three steps according to an acidic α-oxoamidoalkylation reaction from ready available phthalic anhydride by successive imidation, sodium borohydride reduction and intramolecular cationic cyclization involving N-acyliminium species. The relative stereochemistry accompanying these reactions was also discussed.
- Sikoraiová, Jana,Marchalín, ?tefan,Da?ch, Adam,Decroix, Bernard
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p. 4747 - 4751
(2007/10/03)
-
- Synthesis, CoMFA analysis, and receptor docking of 3,5-diacyl-2,4- dialkylpyridine derivatives as selective A3 adenosine receptor antagonists
-
3,5-Diacyl-2,4-dialkyl-6-phenylpyridine derivatives have been found to be selective antagonists at both human and rat A3 adenosine receptors (Li et al. J. Med. Chem. 1998, 41, 3186-3201). In the present study, ring- constrained, fluoro, hydroxy, and other derivatives in this series have been synthesized and tested for affinity at adenosine receptors in radioligand binding assays. K(i) values at recombinant human and rat A3 adenosine receptors were determined using [125I]AB-MECA (N6-(4-amino-3-iodobenzyl)- 5'-N-methylcarbamoyladenosine). Selectivity for A3 adenosine receptors was determined vs radioligand binding at rat brain A1 and A(2A) receptors, and structure-activity relationships at various positions of the pyridine ring (the 3- and 5-acyl substituents and the 2- and 4-alkyl substituents) were probed. At the 5-position inclusion of a β-fluoroethyl (7) or a γ- fluoropropyl ester (26) was favorable for human A3 receptor affinity, resulting in K(i) values of 4.2 and 9.7 nM, respectively, while the pentafluoropropyl analogue was clearly less potent at human A3 receptors. At the 2-, 3-, and 4-positions, fluoro or hydroxy substitution failed to enhance potency and selectivity at human A3 receptors. Several analogues were nearly equipotent at rat and human A3 receptors. To further define the pharmacophore conformationally, a lactam, a lactone, and thiolactones were tested in adenosine receptor binding. The most potent analogue in this group was compound 34, in which a thiolactone was formed between 3- and 4-positions and which had a K(i) value of 248 nM at human A3 receptors. Using affinity data and a general pharmacophore model for A3 adenosine receptor antagonists recently proposed, we applied comparative molecular field analysis (CoMFA) to obtain a three dimensional quantitative structure-activity relationship for pyridine derivatives, having good predictability (r2(pred) = 0.873) for compounds in the test set. A rhodopsin-based model of the human As receptor was built, and the pyridine reference ligand 2,3,4,5-tetraethyl-6-phenyl- pyridine-3-thiocarboxylate-5-carboxylate (MRS 1476) was docked in the putative ligand binding site. Interactions between receptor transmembrane domains and the steric and the electrostatic contour plots obtained from the CoMFA analysis were analyzed.
- Li, An-Hu,Moro, Stefano,Forsyth, Nancy,Melman, Neli,Ji, Xiao-Duo,Jacobson, Kenneth A.
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p. 706 - 721
(2007/10/03)
-
- COMPOUNDS AND METHODS FOR THE TREATMENT OF CARDIOVASCULAR, INFLAMMATORY AND IMMUNE DISORDERS
-
Enantiomerically enriched disubstituted tetrahydrofurans, tetrahydrothiophenes, pyrrolidines and cyclopentanes are disclosed that reduce the chemotaxis and respiratory burst leading to the formation of damaging oxygen radicals of polymorphonuclear leukocytes during an inflammatory or immune response. The compounds exhibit this biological activity by acting as PAF receptor antagonists, by inhibiting the enzyme 5-lipoxygenase, or by exhibiting dual activity, i.e., by acting as both a PAF receptor antagonist and inhibitor of 5-lipoxygenase. It has been determined that 5-lipoxygenase activity, oral availability, and stability in vivo (for example, glucuronidation rate) can vary significantly among the optical isomers of the disclosed compounds.
- -
-
-
- New carbamate supports for the preparation of 3'-amino-modified oligonucleotides
-
A novel approach for the preparation of oligonucleotides carrying amino groups at the 3'-end is described. Several CPG supports having aminoalkyl groups and 3'-amino-2',3'-dideoxynucleosides linked through base-labile carbamate linkages such as 2-(2- nitrophenyl)ethoxycarbonyl and fluorenylmethoxycarbonyl were prepared using two different strategies. These supports are compatible to the standard solid phase phosphite-triester methodology and yield oligonucleotides containing amino groups at the 3'-end. Several properties of the 3'-amino oligonucleotides, such as nuclease resistance, hybridization, and preparation of oligonucleotide conjugates are discussed.
- Avino, Anna,Garcia, Ramon Gueimil,Albericio, Fernando,Mann, Matthias,Wilm, Matthias,Neubauer, Gitte,Eritja, Ramon
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p. 1649 - 1658
(2007/10/03)
-
- Synthesis of L-ornithines stereospecifically deuterated at C-3
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(2S, 3S)-[2,3-2H2]-Ornithine and (2S, 3R)-[3-2H1]-ornithine were prepared with high stereoselectivity via asymmetric reduction catalysed by {bicyclo[2.2.1]hepta-2,5-diene}{(R)-1,2-bis(diphenylphosphino)propa ne}rhodium (I) trifluoromethanesulphonate [(R)-Rh-Prophos].
- Baldwin,Merritt,Schofield
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p. 3919 - 3920
(2007/10/02)
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- Photocyclization of N-Alkoxyalkylphthalimides with Favored δ-Hydrogen Abstraction: Syntheses of Oxazoloisoindoles and Oxazoloisoindole-1-spiro-1'-cycloalkane Ring System
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Photolysis of N-ω-alkoxyalkylphthalimides 1 gave the intramolecularly cyclized compounds, oxazoloisoindoles 2a-g, pyrroloisoindoles 6i-j, oxazolo-isoindole-1-spiro-1'-cycloalkanes 2k-n and 3,4-dihydro-2-benzazepine-1,5(2H)-dione 3, via δ-hydrogen abstraction and/or two-fold Norrish type II processes.Keywords: N-ω-alkoxyalkylphthalimide; photolysis; δ-hydrogen abstraction; two-fold Norrish type II process; multicyclic spiro system
- Sato, Yasuhiko,Nakai, Hideo,Wada, Masao,Ogiwara, Hiroshi,Mizoguchi, Tomishige,et al.
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p. 1639 - 1645
(2007/10/02)
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