- A convenient synthesis of α-benzylacrylic acid
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A convenient and reliable two-stage synthesis of α-benzyl-acrylic acid from diethyl benzylmalonate in 72% yield and good purity is reported. The synthesis compares favourably with the other procedures tested.
- Issa,Andrews,Iskander,Reiss
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Read Online
- Palladium-Catalyzed Asymmetric Hydroesterification of α-Aryl Acrylic Acids to Chiral Substituted Succinates
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A palladium-catalyzed asymmetric hydroesterification of α-aryl acrylic acids with CO and alcohol was developed, preparing a variety of chiral α-substituted succinates in moderate yields with high ee values. The kinetic profile of the reaction progress revealed that the alkene substrate first underwent the hydroesterification followed by esterification with alcohol. The origin of the enantioselectivity was elucidated by density functional theory computation.
- Ji, Xiaolei,Shen, Chaoren,Tian, Xinxin,Dong, Kaiwu
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supporting information
p. 8645 - 8649
(2021/10/25)
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- Highly Selective Sub-Nanomolar Cathepsin S Inhibitors by Merging Fragment Binders with Nitrile Inhibitors
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Pharmacological inhibition of cathepsin S (CatS) allows for a specific modulation of the adaptive immune system and many major diseases. Here, we used NMR fragment screening and crystal structure-aided merging to synthesize novel, highly selective CatS inhibitors with picomolar enzymatic Ki values and nanomolar functional activity in human Raji cells. Noncovalent fragment hits revealed binding hotspots, while the covalent inhibitor structure-activity relationship enabled efficient potency optimization.
- Schade, Markus,Merla, Beatrix,Lesch, Bernhard,Wagener, Markus,Timmermanns, Simone,Pletinckx, Katrien,Hertrampf, Torsten
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supporting information
p. 11801 - 11808
(2020/11/26)
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- Macrolactam Synthesis via Ring-Closing Alkene-Alkene Cross-Coupling Reactions
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Reported herein is a practical method for macrolactam synthesis via a Rh(III)-catalyzed ring closing alkene-alkene cross-coupling reaction. The reaction proceeded via a Rh-catalyzed alkenyl sp2 C-H activation process, which allows access to macrocyclic molecules of different ring sizes. Macrolactams containing a conjugated diene framework could be easily prepared in high chemoselectivities and Z,E stereoselectivities.
- Goh, Jeffrey,Loh, Teck-Peng,Maraswami, Manikantha
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supporting information
p. 9724 - 9728
(2020/12/21)
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- A by 3 - phenyl -1 - methylacetylene preparation quickly disintegrating process method (by machine translation)
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A by 3 - phenyl - 1 - propyne preparation quickly disintegrating process method, which belongs to the technical field of pharmaceutical intermediates. In the preparation quickly disintegrating in the process, intermediate benzyl acrylic acid yield and purity of the most important, this method first using 3 - phenyl - 1 - propyne as the raw material, in the palladium catalyst Pd2 (Dba)3 And the ligand dppp with ethyl carbonate under the catalysis of the reaction to the one-step synthesis of benzyl acrylic acid, its advantage lies in atmospheric pressure to complete the addition reaction, functional group tolerance is good, high efficiency, high purity, the production process is greatly simplified, and to obtain the target product preparation process of yield and purity than the traditional process much higher. The method has the advantages of greatly improve the productivity, reduce the cost, improve the safety, energy saving and the like, in accordance with the green reaction of modern chemical production requirement. (by machine translation)
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Paragraph 0014-0016
(2019/07/10)
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- Ni-Catalyzed Enantioselective Reductive Diarylation of Activated Alkenes by Domino Cyclization/Cross-Coupling
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A Ni-catalyzed enantioselective reductive diarylation of activated alkenes by domino cyclizative/cross-coupling of two aryl bromides is developed. This reaction proceeds under very mild conditions and shows broad substrate scope, without requiring the use of preformed organometallic reagents. Moreover, this approach provides direct access to various bis-heterocycles bearing all-carbon quaternary centers in synthetically useful yields (up to 81%) with excellent enantioselectivity (>30 examples, 90-99% ee).
- Wang, Kuai,DIng, Zhengtian,Zhou, Zhijun,Kong, Wangqing
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supporting information
p. 12364 - 12368
(2018/10/05)
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- Direct Access to Versatile Electrophiles via Catalytic Oxidative Cyanation of Alkenes
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Nucleophilic attack on carbon-based electrophiles is a central reactivity paradigm in chemistry and biology. The steric and electronic properties of the electrophile dictate its reactivity with different nucleophiles of interest, allowing the opportunity to fine-tune electrophiles for use as coupling partners in multistep organic synthesis or for covalent modification of proteins in drug discovery. Reactions that directly transform inexpensive chemical feedstocks into versatile carbon electrophiles would therefore be highly enabling. Herein, we report the catalytic, regioselective oxidative cyanation of conjugated and nonconjugated alkenes using a homogeneous copper catalyst and a bystanding N-F oxidant to furnish branched alkenyl nitriles that are difficult to prepare using existing methods. We show that the alkenyl nitrile products serve as electrophilic reaction partners for both organic synthesis and the chemical proteomic discovery of covalent protein ligands.
- Gao, De-Wei,Vinogradova, Ekaterina V.,Nimmagadda, Sri Krishna,Medina, Jose M.,Xiao, Yiyang,Suciu, Radu M.,Cravatt, Benjamin F.,Engle, Keary M.
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supporting information
p. 8069 - 8073
(2018/06/22)
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- Compounding method for racecadotril intermediate
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The invention discloses a compounding method for a racecadotril intermediate. The compounding method comprises the following steps: causing ethyl phenylpropiolate, dimethylamine and trioxymethylene react with each other, treating with hydrochloric acid to obtain benzyl ethyl acrylate, and then hydrolyzing under an alkaline condition, thereby obtaining benzyl acrylic acid. According to the compounding method disclosed by the invention, benzyl chloride with higher toxicity is replaced by ethyl phenylpropiolate, the compounding route is shortened, the production efficiency is increased, and thus the compounding method is suitable for industrial production.
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Paragraph 0025; 0028; 0031
(2017/05/03)
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- Switchable C-H Functionalization of N-Tosyl Acrylamides with Acryloylsilanes
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A controllable Rh-catalyzed protocol to access alkylation and alkenylation-annulation of N-tosyl acrylamide with acryloyl silane is reported. In contrast to the directing group or catalyst-dependent divergent sp2 C-H alkylation/alkenylation, the intrinsic property of acryloylsilane allows the switchable reaction manifold, thereby affording either alkylation or annulation products with slight modification of the reaction conditions.
- Song, Shengjin,Lu, Ping,Liu, Huan,Cai, Sai-Hu,Feng, Chao,Loh, Teck-Peng
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supporting information
p. 2869 - 2872
(2017/06/13)
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- Diastereoselective synthesis of trans-3,5-disubstituted dihydrofuran-2(3H)-ones via SmI2-mediated reductive coupling of 2-alkylacrylates of N,N-diisopropyl-2-hydroxybenzamide with aldehydes
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Samarium(II) diiodide has been used to mediate reductive coupling reactions of aldehydes with a variety of substituted acrylates, in both achiral and chiral forms, for accessing substituted dihydrofuran-2(3H)-ones (γ-butyrolactones). Two major issues, concerning with self-dimerization of α-non-branched aliphatic aldehydes and low diastereoselectivity of the products, render limited application of the reductive coupling protocol in total synthesis of natural products. We report here on a novel type of substituted acrylates derived from the 2-amido arenols (HO-Aram) such as N,N-diisopropyl-2-hydroxybenzamide. The acrylates of HO-Aram enable: (a) preferential conjugate reduction of the acrylates than carbonyl reduction of aliphatic aldehydes, leading to diminished aldehyde self-dimerization; and (b) organization of an eight-membered ring among the amide carbonyl oxygen atom and samarium(III) to form a 7/8-bicyclic transition state, resulting in highly diastereoselective protonation of the samarium(III) enolate intermediate. Examples of synthesis of trans-3,5-disubstituted dihydrofuran-2(3H)-ones from 2-alkylacrylates of HO-Aram and aliphatic aldehydes are provided.
- Lai, Yecai,Sun, Lijie,Sit, Man Ki,Wang, Yan,Dai, Wei-Min
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p. 664 - 673
(2016/01/15)
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- Copper-catalyzed intermolecular chloro- and bromotrifluoromethylation of alkenes
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A highly practical copper-catalyzed intermolecular halotrifluoromethylation of alkenes has been developed under mild reaction conditions. A variety of Cl/Br-containing trifluoromethyl derivatives were directly synthesized from a wide range of alkenes, including electron-deficient and unactivated alkenes.
- Fu, Mingyang,Chen, Long,Jiang, Yongpeng,Jiang, Zhong-Xing,Yang, Zhigang
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supporting information
p. 348 - 351
(2016/02/19)
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- High-valent palladium-promoted formal Wagner-Meerwein rearrangement
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An oxy-palladation, formal Wagner-Meerwein rearrangement and fluorination cascade has been established for generating fluorinated oxazolidine-2,4-diones and oxazolidin-2-ones. The reaction has a broad substrate scope in which both aryl and alkyl groups can be utilized as efficient migrating groups. Experimental evidence suggests that the reaction is initiated by anti-oxy-palladation of the olefin, followed by oxidative generation of an alkyl PdIV intermediate and a concerted migration-fluorination.
- Wu, Hongmiao,Yang, Bin,Zhu, Lin,Lu, Ronghua,Li, Guigen,Lu, Hongjian
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supporting information
p. 5804 - 5807
(2016/11/29)
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- Preparation method of alpha, beta-unsaturated carboxylic acid compounds
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The invention provides a preparation method of alpha, beta-unsaturated carboxylic acid compounds. The method is characterized in that compounds represented by formula (I) react with formic acid in the presence of a nickel-containing catalyst, a phosphine ligand and an organic solvent to obtain the alpha, beta-unsaturated carboxylic acid compounds represented by formula (II), wherein R1 and R2 are respectively independently selected from H, C1-C30 alkyl groups, C1-C30 substituted alkyl groups, C1-C30 alkenyl groups, C1-C30 substituted alkenyl groups, C6-C30 aryl groups and C6-C30 substituted aryl groups. Compared with the prior art, the method adopting formic acid as a carboxylation reagent has the advantages of low price, safety, stability, low toxicity, high yield, simple operation, good economy, avoiding of use of precious metal catalysts and toxic gas carbon monoxide, meeting of requirements of environmentally friendly compounds, wide function group compatibility, high conversion rate and industrial synthesis values.
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Paragraph 0054; 0055; 0056; 0057; 0058; 0059; 0125-0129
(2016/10/07)
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- Rhodium(iii)-catalyzed C-H allylation of electron-deficient alkenes with allyl acetates
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Rhodium-catalyzed C-H allylation of acrylamides with allyl acetates is reported. The use of weakly coordinating directing group resulted in high reaction efficiency, broad functionality tolerance and excellent γ-selectivity, which opens a new synthetic pathway for the access of 1,4-diene skeletons.
- Feng, Chao,Feng, Daming,Loh, Teck-Peng
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supporting information
p. 342 - 345
(2015/01/09)
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- Palladium-Catalyzed Heck-type Domino Cyclization and Carboxylation to Synthesize Carboxylic Acids by Utilizing Chloroform as the Carbon Monoxide Source
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A palladium-catalyzed domino cyclization and carboxylation reaction for synthesis of a variety of carboxylic acids was developed, where chloroform was used as "carbon monoxide" source. The in situ generated neopentylpalladium species by Heck cyclization was efficiently trapped by dichlorocarbene to form a series of carboxylic acids. It was found that in this type of domino reaction CHCl3 is a convenient and safe alternation for CO gas.
- Liu, Xianglei,Li, Bin,Gu, Zhenhua
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p. 7547 - 7554
(2015/08/18)
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- Rhodium(III)-catalyzed olefinic C-H alkynylation of acrylamides using tosyl-imide as directing group
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The Rh(III)-catalyzed C-H alkynylation of acrylamide derivative is realized using a hypervalent alkynyl iodine reagent. The use of a weakly coordinating directing group proved to be of critical importance. This reaction displays broad functional group tolerance and high efficiency, which opens a new synthetic pathway to access functionalized 1,3-enyne skeletons.
- Feng, Chao,Feng, Daming,Luo, Yang,Loh, Teck-Peng
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supporting information
p. 5956 - 5959
(2015/01/08)
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- Synthesis of maculalactone A and derivatives for environmental fate tracking studies
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Maculalactone A (1) constitutes a promising antifouling agent, inhibiting the formation of biofilms in marine and freshwater systems. In this study, we developed a new route, based on a late-stage formation of the butenolide core, leading to the total synthesis of maculalactone A (three steps, overall yield of 45%) and delivering material on a gram scale. In addition, analogues of the title compound were assayed concerning their biological activity, utilizing Artemia franciscana and Thamnocephalus platyurus. The most active analogue was functionalized with a rhodamine B fluorophore and was utilized in an in vivo staining experiment in Artemia salina. Two different tissues were found to accumulate this maculalactone A derivative. This journal is
- Bader, Samuel L.,Luescher, Michael U.,Gademann, Karl
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supporting information
p. 199 - 206
(2015/02/19)
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- High-yielding sequential one-pot synthesis of chiral and achiral α-substituted acrylates via a metal-free reductive coupling reaction
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A general process for the high-yielding synthesis of substituted chiral and achiral α-substituted acrylates was achieved through the sequential one-pot combination of a metal-free reductive coupling reaction followed by an Eschenmoser methylenation. The proline catalyzed reaction of Meldrum's acid, aldehydes and Hantzsch ester followed by methylenation was successful with Eschenmoser's salt in the presence of an alcohol solvent. Herein, we have shown the high-yielding synthesis of privileged building blocks from chiral/achiral α-substituted acrylates and shown them to be very good intermediates in the pharmaceuticals and natural products synthesis. This journal is the Partner Organisations 2014.
- Ramachary, Dhevalapally B.,Venkaiah, Chintalapudi,Reddy, Y. Vijayendar
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supporting information
p. 5400 - 5406
(2014/07/21)
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- Microwave-assisted synthesis of the (E)-α-methylalkenoate framework from multifunctionalized allylic phosphonium salts
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A convenient and general microwave-assisted method for the synthesis of stereochemically defined α-methylalkenoic acids and esters from allylic phosphonium salts in a basic aqueous medium is described. A selective preparation of acids or esters was dependent on the base (NaOH or NaHCO 3) employed in the reaction and could be achieved with good to excellent yields under mild conditions in the absence of hydrides and reducing agents.
- Meier, Lidiane,Ferreira, Misael,Sa, Marcus M.
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experimental part
p. 179 - 186
(2012/07/14)
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- Enantioselective [3 + 2] cycloaddition of allenes to acrylates catalyzed by dipeptide-derived phosphines: Facile creation of functionalized cyclopentenes containing quaternary stereogenic centers
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A new family of dipeptide-based chiral phosphines was designed and prepared. d-Thr-l-tert-Leu-derived catalyst 4c promoted [3 + 2] cycloaddition of allenoates to α-substituted acrylates in a regiospecific and stereoselective manner, furnishing functionalized cyclopentenes with quaternary stereogenic centers in high yields and with excellent enantioselectivities.
- Han, Xiaoyu,Wang, Youqing,Zhong, Fangrui,Lu, Yixin
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supporting information; experimental part
p. 1726 - 1729
(2011/04/17)
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- Pd(II)-catalyzed intramolecular amidoarylation of alkenes with molecular oxygen as sole oxidant
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Stereoselective palladium-catalyzed synthesis of structurally versatile indoline derivatives, using molecular oxygen as the sole oxidant, is described. New C-N and C-C bonds form across an alkene in an intramolecular manner. The C-N bond-forming step proceeds via a syn-amidopalladation pathway. The moderate kinetic isotope effects (intramolecular KIE = 3.56) suggest that electrophilic aromatic substitution occurs in the arylation step.
- Yip, Kai-Tai,Yang, Dan
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supporting information; experimental part
p. 2134 - 2137
(2011/06/19)
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- Design and synthesis of non-cytotoxic tetrahydrothieno[3,2-c]pyridine derivatives exhibiting complement inhibition activity
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A series of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine derivatives have been synthesized and evaluated for their activity on the activation of human complement (classical pathway) and their intrinsic haemolytic activity. The in vitro assay results of these analogues for inhibition of complement activity reveals improved inhibitory activity for some of the analogues over existing tetrahydrothienopyridine derivatives like Ticlopidine and Clopidogrel. Significantly, these analogues did not exhibit any haemolytic activity and are non-cytotoxic to human cell lines.
- Master, Hoshang E.,Khan, Shabana I.,Poojari, Krishna A.
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- Peptide deformylase inhibitors of Mycobacterium tuberculosis: Synthesis, structural investigations, and biological results
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Bacterial peptide deformylase (PDF) belongs to a subfamily of metalloproteases catalyzing the removal of the N-terminal formyl group from newly synthesized proteins. We report the synthesis and biological activity of highly potent inhibitors of Mycobacterium tuberculosis (Mtb) PDF enzyme as well as the first X-ray crystal structure of Mtb PDF. Structure-activity relationship and crystallographic data clarified the structural requirements for high enzyme potency and cell based potency. Activities against single and multi-drug-resistant Mtb strains are also reported.
- Pichota, Arkadius,Duraiswamy, Jeyaraj,Yin, Zheng,Keller, Thomas H.,Alam, Jenefer,Liung, Sarah,Lee, Gladys,Ding, Mei,Wang, Gang,Chan, Wai Ling,Schreiber, Mark,Ma, Ida,Beer, David,Ngew, Xinyi,Mukherjee, Kakoli,Nanjundappa, Mahesh,Teo, Jeanette W.P.,Thayalan, Pamela,Yap, Amelia,Dick, Thomas,Meng, Wuyi,Xu, Mei,Koehn, James,Pan, Shi-Hao,Clark, Kirk,Xie, Xiaoling,Shoen, Carolyn,Cynamon, Michael
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scheme or table
p. 6568 - 6572
(2009/09/30)
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- Correlation of hydrolysis and desilylation of 2-[(trimethylsilyl)methyl] acrylate derivatives in aqueous alkali solutions
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Hydrolysis and desilylation reaction of 2-[(trimethylsilyl)methyl]acrylate (=2-[(trimethylsilyl)methyl] prop-2-enoate) derivatives were studied to evaluate the effect of the presence/absence of a further conjugating substituent (Schemes 3 and 4 and Tables 1 and 2). The substrates having a nonconjugating substituent at the acrylate moiety were stable to dilute alkali conditions, and afforded simple hydrolysis products under concentrated alkali conditions. In contrast, both hydrolysis and desilylation occurred from the substrates bearing conjugated substituents at the acrylate skeleton. The difference in reactivity can be explained in terms of the stabilization of the intermediate anion.
- Kuroda, Chiaki,Sunakawa, Takeshi,Muguruma, Yuichi
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scheme or table
p. 888 - 896
(2009/03/11)
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- Asymmetric synthesis of β2-amino acids: 2-substituted-3-aminopropanoic acids from N-acryloyl SuperQuat derivatives
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Conjugate addition of lithium dibenzylamide to (S)-N(3)-acryloyl-4- isopropyl-5,5-dimethyloxazolidin-2-one (derived from l-valine) and alkylation of the resultant lithium β-amino enolate provides, after deprotection, a range of (S)-2-alkyl-3-aminopropanoic acids in good yield and high ee. Alternatively, via a complementary pathway, conjugate addition of a range of secondary lithium amides to (S)-N(3)-(2′-alkylacryloyl)-4-isopropyl-5,5- dimethyloxazolidin-2-ones, diastereoselective protonation with 2-pyridone, and subsequent deprotection furnishes a range of (R)-2-alkyl- and (R)-2-aryl-3-aminopropanoic acids in good yield and high ee. Additionally, the boron-mediated aldol reaction of β-amino N-acyl oxazolidinones is a highly diastereoselective method for the synthesis of a range of β-amino- β′-hydroxy N-acyl oxazolidinones. The Royal Society of Chemistry.
- Beddow, James E.,Davies, Stephen G.,Ling, Kenneth B.,Roberts, Paul M.,Russell, Angela J.,Smith, Andrew D.,Thomson, James E.
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p. 2812 - 2825
(2008/03/12)
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- Discovery of potent HIV-1 protease inhibitors incorporating sulfoximine functionality
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Based on the unique property of sulfoximine and the homodimeric C2 structural symmetry of HIV-1 protease, a novel class of sulfoximine-based pseudosymmetric HIV-1 protease inhibitors was designed and synthesized. The sulfoximine moiety was demonstrated to be important for HIV-1 protease inhibitor potency. The most active stereoisomer (2S,2′S) displays a potency of 2.5 nM (IC50) against HIV-1 protease and an anti-HIV-1 activity of 408 nM (IC50). A possible mode of action is proposed.
- Lu, Ding,Vince, Robert
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p. 5614 - 5619
(2008/03/13)
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- Novel compounds that inhibit dipeptidyl peptidase (DPP-IV) and neprilysin (NEP) and/or angiotensin converting enzyme (ACE)
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This invention relates to novel compounds, compositions containing the compounds, that inhibit dipeptidyl peptidase (especially DPP-IV) and neprilysin (NEP, neutral endopeptidase) as well as dipeptidyl peptidase (especially DPP-IV) and angiotensin converting enzyme (ACE) and/or dipeptidyl Peptidase (especially DPP-IV) and vasopeptidases (especially ACE and NEP). These compounds and pharmaceutical compositions thereof are useful for the treatment as well as the prevention of type 2 diabetes mellitus.
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Page/Page column 8
(2010/10/20)
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- Structural studies of racecadotril and its process impurities by NMR and mass spectroscopy
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Three unknown impurities in racecadotril bulk drug at levels below 0.5% were detected by simple reverse phase isocratic high performance liquid chromatography (HPLC). Structures for these impurities were proposed by molecular ion information and their fragmentation pattern obtained by LC-MS and these impurities were confirmed by NMR spectroscopy. The impurities I, II and III were characterized as benzyl 2-methyl carboximido acetate, benzyl 2-phenyl ethyl carboximido acetate, and benzyl 2-(1-benzyl vinyl carboximido) acetate. These structures were further confirmed by co-injecting of synthetic standards of impurities with racecadotril. The mechanism of the formation of these process related impurities is discussed.
- Mallikarjun Reddy,Moses Babu,Sudhakar,Sharma,Sudershan Reddy,Vyas
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p. 994 - 998
(2007/10/03)
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- Substituted piperidine compounds and methods of their use
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Certain 4-aryl-piperidine compounds, including N-substituted 9β-substituted-5-(3-substituted-phenyl)morphans and N-substituted octahydro-4a-(3-hydroxyphenyl)-10a-methyl-benzo[g]isoquinolines, pharmaceutical compositions, and methods of their use, inter alia, as opioid antagonists are disclosed.
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Page/Page column 25-26
(2008/06/13)
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- N-formyl hydroxylamine containing compounds useful as ACE inhibitors and/or NEP inhibitors
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N-formyl hydroxylamines are provided which have the structure wherein R is H, alkyl, alkenyl, aryl-(CH2)p—, heteroaryl-(CH2)p— or cycloheteroalkyl-(CH2)p— R1is H or COR2where R2is alkyl, aryl-(CH2)p—, cycloheteroalkyl-(CH2)p—, heteroaryl-(CH2)p—, alkoxy or cycloalkyl-(CH2)p—, p is 0 to 8, and A is a dipeptide derived from an amino acid or is a conformationally restricted dipeptide mimic. The above compounds are useful in treating hypertension congestive heart failure, renal failure, and hepatic cirrhosis.
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Page column 15; 16
(2010/02/08)
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- HYDROXAMATE SULFONAMIDES AS CD23 SHEDDING INHIBITORS
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A class of piperidine and related heterocyclic derivatives, C-substituted by a substituted aryl or heteroaryl moiety, and N-substituted by an ethylsulfonyl group which in turn is substituted at the 2-position by a hydroxamic acid moiety and also by a range of alternative substituents, being potent inhibitors of CD23 shedding, are useful in the treatment and/or prevention of allergic, inflammatory and neoplastic diseases.
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- HYDROXAMATE SULFONAMIDES AS CD23 SHEDDING INHIBITORS
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A class of piperazine and related heterocyclic derivatives, substituted at the 4-position by a substituted aryl or heteroaryl moiety, and at the 1-position by an ethylsulfonyl group which in turn is substituted at the 2-position by a hydroxamic acid moiety and also by a range of alternative substituents, being potent inhibitors of CD23 shedding, are useful in the treatment and/or prevention of allergic, inflammatory and neoplastic diseases.
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- Synthesis of a novel series of 10-oxa-3-aza-tricyclo[5.2.1.0 1,5]dec-8-en-4-ones through an intramolecular Diels-Alder reaction
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The synthesis of a novel series of 10-oxa-3-aza-tricyclo[5.2.1.0 1,5]dec-8-en-4-ones through the use of the intramolecular Diels-Alder reaction is presented. The use of this reaction allows for the synthesis of functionalized polycyclic systems in a stereocontrolled manner.
- Milkiewicz, Karen L.,Neagu, Irina B.,Parks, Daniel J.,Lu, Tianbao
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p. 7341 - 7343
(2007/10/03)
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- Enantioselective synthesis of phosphinyl peptidomimetics via an asymmetric Michael reaction of phosphonic acids with acrylate derivatives
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Asymmetric Michael reaction of phosphinic or aminophosphinic acids with acrylate derivatives afforded phosphinyl dipeptidomimetics in excellent yields (>90 percent). Chiral induction of substituents at the α-position of acrylate derivatives of Evans oxazolidinone type auxiliaries was obtained in moderate to excellent diastereomeric and enantiomeric excesses (50-98 percent). Pure diastereomers and enantiomers of phosphinyl dipeptidomimetics 16-19 were also successfully separated by HPLC.
- Lui, Xuewei,Hu, Eric,Tian, Xinrong,Mazur, Adam,Ebetino, Frank H.
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p. 212 - 222
(2007/10/03)
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- N-formyl hydroxylamine derivatives as antibacterial agents
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Compounds of formula (I) are in the preparation of antibacterial agents, wherein: R1represents hydrogen, C1-C6alkyl or C1-C6alkyl substituted by one or more halogen atoms; R2represents a group R10(X)n—(ALK)— wherein R10represents hydrogen, a C1-C6alkyl, C2-C6alkenyl, C1-C6alkynyl, cycloalkyl, aryl, or heterocyclyl group, any of which may be unsubstituted or substituted by (C1-C6)alkyl, (C1-C6)alkoyy, hydroxy, mercapto, (C1-C6)alkylthio, amino, halo, trifluoromethyl, cyano, nitro, —COOH, —CONH2, —COORA, —NHCORA, —CONHRA, —NHRA, —NRARB, or —CONRARBwherein RAand RBare independently a (C1-C6)alkyl group, and ALK represents a straight or branched divalent C1-C6alkylene, C2-C6alkenylene, or C2-C6alkynylene radical, which may be interrupted by one or more non-adjacent —NH—, —O— or —S— linkages, X represents —NH—, —O— or —S—, and n is 0 or 1, R represents hydrogen or C1-C6alkyl, R3represents the characterising group or a natural or non-natural α amino acid in which any functional groups may be protected; and R4represents an ester or thioester group.
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- Cytostatic agents
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Compounds of formula (I) wherein R4 is an ester or thioester group and R, R1, R2 and R3 are as defined in the specification, inhibit proliferation of tumor cells.
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- Investigation of the enzymatic and nonenzymatic Cope rearrangement of carbaprephenate to carbachorismate
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The dimethyl esters of carbaprephenate and 4-epi-carbaprephenate were prepared by modification of published procedures. In methanol these compounds are converted quantitatively to isomeric 6-hydroxytricyclo[3.3.1.02.7]non-3-en-1,3-dimethyl esters via a two-step sequence involving an initial Cope rearrangement, followed by intramolecular Diels-Alder reaction of the dimethyl carbachorismate or 4-epi-carbachorismate intermediates. Carbaprephenate and its epimer were obtained by alkaline hydrolysis of the corresponding dimethyl esters. These compounds, in contrast to their ester precursors, undergo spontaneous acid-catalyzed decarboxylation in aqueous solution. Only at high pH does the Cope rearrangement compete with decarboxylation. At pH 12 and 90°C, carbaprephenate slowly rearranges to carbachorismate, which rapidly loses water to give 3-(2-carboxyallyl)benzoic acid as the major product. A small amount of the intramolecular Diels-Alder adduct derived from carbachorismate is also observed by NMR as a minor product. Carbaprephenate is not a substrate for the enzyme chorismate mutase from Bacillus subtilis (BsCM), nor does carbaprephenate inhibit the normal chorismate mutase activity of this enzyme, even when present in 200-fold excess over chorismate. Its low affinity for the enzyme-active site is presumably a consequence of placing a methylene group rather than an oxygen atom proximal to the essential cationic residue Arg90. Nevertheless, BsCM variants that lack this cation (R90G and R90A) do not accelerate the Cope rearrangement of carbaprephenate either, and a catalytic antibody 1F7, which exhibits modest chorismate mutase activity, is similarly inactive. Poor substrate binding and the relatively high barrier for the Cope compared to the Claisen rearrangement presumably account for the lack of detectable catalysis. Acceleration of this sigmatropic rearrangement apparently requires more than an active site that is complementary in shape to the reactive substrate conformer.
- Aemissegger, Andreas,Jaun, Bernhard,Hilvert, Donald
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p. 6725 - 6730
(2007/10/03)
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- Design and pharmacological activity of phosphinic acid based NAALADase inhibitors
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A novel series of phosphinic acid based inhibitors of the neuropeptidase NAALADase are described in this work. This series of compounds is the most potent series of inhibitors of the enzyme described to date. In addition, we have shown that these compounds are protective in animal models of neurodegeneration. Compound 34 significantly prevented neurodegeneration in a middle cerebral artery occlusion model of cerebral ischemia. In addition, in the chronic constrictive model of neuropathic pain, compound 34 significantly attenuated the hypersensitivity observed with saline-treated animals. These data suggest that NAALADase inhibition may provide a new approach for the treatment of both neurodegenerative disorders and peripheral neuropathies.
- Jackson,Tays,Maclin,Ko,Li,Vitharana,Tsukamoto,Stoermer,Lu,Wozniak,Slusher
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p. 4170 - 4175
(2007/10/03)
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- Synthesis of isopropylidene 5-alkyl-5-hydroxy-methylmalonates and their application to the preparation of 2-alkylacrylic acids
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Hydroxymethylated derivatives of isopropylidene 5-alkyl-malonates 3 were synthesized, via which 2-alkylacrylic acids 4 were prepared using isopropylidene 5-alkylmalonates 1 as starting materials.
- Chen,Li,Su
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p. 409 - 413
(2007/10/03)
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- Process for the synthesis of α-substituted acrylic acids and their application
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Process for the synthesis of a-substituted acrylic acids and their application. Process for the synthesis of a-substituted acrylic acids of general formula (I) and their application to the synthesis of N- (mercaptoacyl) aminoacid derivatives of formula (II). STR1
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- Thiol inhibitors of endothelin-converting enzyme
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Synthesis and structure activity relationships of a series of thiol inhibitors of the endothelin-converting enzyme (ECE) are presented. Optimisation of the stereochemistry as well as of the P'1 and P'2 residues led to inhibitors with similar potency to that of phosphoramidon.
- Deprez, Pierre,Guillaume, Jacques,Dumas, Jacques,Vevert, Jean-Paul
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p. 2317 - 2322
(2007/10/03)
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- ALKYLAMINOALKYL-TERMINATED SULFIDE/SULFONYL-CONTAINING PROPARGYL AMINO-DIOL COMPOUNDS FOR TREATMENT OF HYPERTENSION
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Compounds characterized generally as alkylaminoalkyl-terminated sulfide/sulfonyl-containing propargyl amino-diol derivatives are useful as renin inhibitors for the treatment of hypertension. Compounds of particular interest are those of Formula II: STR1 wherein q is two or three; wherein r is zero or two; wherein R 2 is selected from hydrido, methyl, ethyl and phenyl; wherein R 3 is selected from hydrido, cyclohexylmethyl, benzyl, fluorobenzyl, chlorobenzyl, fluoronaphthylmethyl and chloronaphthylmethyl; wherein R. sup.5 is propargyl or a propargyl containing moiety; wherein R. sup.7 is cyclohexylmethyl; wherein R 8 is selected from n-propyl, isobutyl, cyclopropyl, cyclopropylmethyl, allyl and vinyl; and wherein each of R. sup.12 and R 13 is a group independently selected from methyl, ethyl and isopropyl; or a pharmaceutically-acceptable salt thereof.
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- Mercaptoacyl amino acid inhibitors of atriopeptidase. 1. Structure- activity relationship studies of methionine and S-alkylcysteine derivatives
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A broad series of N-(3-mercaptoacyl) amino acid derivatives was evaluated for their ability to inhibit atriopeptidase (neutral endopeptidase, EC 3.4.24.11) in vitro and in vivo. Structural parameters studied were (i) the substituent on the 2-position of the 3-mercaptopropionyl moiety, (ii) the amino acid component, (iii) the S-terminal derivative, and (iv) the C- terminal derivative. Optimum activity was observed for derivatives of methionine and S-alkylcysteines. N-[3-Mercapto-2(S)-[(2- methylphenyl)methyl]-1-oxopropyl]-L-methionine was identified as a highly effective inhibitor of atriopeptidase meriting evaluation as a potential cardiovascular therapeutic agent.
- Neustadt,Smith,Nechuta,Bronnenkant,Haslanger,Watkins,Foster,Sybertz
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p. 2461 - 2476
(2007/10/02)
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- Conscripting the active-site zinc ion in carboxypeptidase A in inactivation chemistry by a new type of irreversible enzyme inactivator
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A new strategy for irreversible inactivation of the metalloenzyme carboxypeptidase A (CPA) involving a proposed activation of a carbon-iodide bond in an inactivator by the active-site zinc ion toward nucleophilic substitution is described. 2-Benzyl-3-iodopropanoic acid (compound 1) was designed to bind the active site of CPA. An energy-minimized complex of 1 in the active site of CPA reveals that the iodo moiety comes within the coordination sphere of the zinc ion. Such metal coordination was expected to facilitate the departure of the halide in an S(N)2-type reaction by the side-chain functions of either Glu-270 or Tyr-248. Compound 1 was shown to inactivate CPA in a time-dependent manner, a process which was active-site directed and irreversible; a rate enhancement of approximately 108 to 109-fold is estimated for the inactivation chemistry by 1 over model metal-activated S(N)2 type reactions. 2-Benzyl-4-iodobutanoic acid (compound 6), an analog of 1 with an extended structure by one methylene unit, was shown to serve solely as a poor competitive inhibitor for CPA (K(i) = 0.41 ± 0.07 mM) but not as an irreversible inactivator; a discussion of the kinetic behavior by the two compounds is provided. The results reported herein hold the promise of a novel chemistry for selective inactivation of metalloenzymes.
- Tanaka,Grapsas,Dakoji,Cho,Mobashery
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p. 7475 - 7480
(2007/10/02)
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- PHOSPHORUS CONTAINING COMPOUNDS AND USE AS HYPOTENSIVES
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Phosphorus containing compounds of the formula STR1 wherein X is a substituted or unsubstituted imino or amino acid and A is STR2 These compounds possess angiotensin converting enzyme activity and are thus useful as hypertensive agents.
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- Novel Synthesis of α-Substituted Acrylic Acids
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A facile three-step procedure has been developed for the synthesis of α-substituted acrylic acids.In the first step, a carboxylic acid having no α-substituents is condensed with 2-amino-2-methylpropanol (AMP) to form the corresponding oxazoline.The oxazoline reacts readily with paraformaldehyde to give an intermediate mixture of mono- and dimethylol derivatives which upon heating forms the α-methylene derivatives of the oxazoline.The latter, upon acid hydrolysis, yields the α-substituted acrylic acid generally in an overall yield of above 70percent and the acids are usually at least 95percent pure.
- Serota, S.,Simon, J. R.,Murray, E. B.,Linfield, W. M.
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p. 4147 - 4151
(2007/10/02)
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