- Enantioselective Diels-Alder reaction with an α-chloronitroso dienophile derived from 5-O-acetyl-2,3-isopropylidenedioxy-D-ribose
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Crystalline 5-O-acetyl-2,3-isopropylidenedioxy-D-ribonolactone oxime (8) was synthesised from D-ribose in 40% overall yield. The chloronitroso dienophile 3b was obtained from 8 by oxidation with t-BuOCl and underwent asymmetric Diels-Alder reaction with cyclic and acyclic dienes 10-13 to give crystalline adducts 14a-17a in good yield and excellent enantiomeric excess (93-99%).
- Defoin,Joubert,Heuchel,Strehler,Streith
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Read Online
- Stabilization of vesicular and supported membranes by glycolipid oxime polymers
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We report herein new synthetic glycolipid dimers and polymers that provide unprecedented stability to both supported (SLBs) and vesicular lipid bilayers against dehydration and serum exposure. These novel physical properties will enable pharmaceutical delivery and development of SLB bioanalytical devices. The Royal Society of Chemistry.
- Ma, Mingming,Chatterjee, Soumitra,Zhang, Meng,Bong, Dennis
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Read Online
- Alternating Current Electrolysis as Efficient Tool for the Direct Electrochemical Oxidation of Hydroxamic Acids for Acyl Nitroso Diels–Alder Reactions
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The acyl nitroso Diels–Alder reaction of 1,3-dienes with electrochemically oxidised hydroxamic acids is described. By using alternating current electrolysis, their typical electro-induced decomposition could be suppressed in favour of the 1,2-oxazine cycloaddition products. The reaction was optimised using Design of Experiments (DoE) and a sensitivity test was conducted. A mixture of triethylamine/hexafluoroisopropanol served as supporting electrolyte in dichloromethane, thus giving products of high purity after evaporation of the volatiles without further purification. The optimised reaction conditions were applied to various 1,3-dienes and hydroxamic acids, giving up to 96 % isolated yield.
- F?hrmann, Jan,Hilt, Gerhard
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supporting information
p. 20313 - 20317
(2021/08/12)
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- Palladium-Catalyzed C-O Cross-Coupling as a Replacement for a Mitsunobu Reaction in the Development of an Androgen Receptor Antagonist
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A scalable and efficient synthesis of N-{trans-4-[(8-cyanoquinolin-4-yl)oxy]cyclohexyl}-3-fluorobenzamide (BAY 1161116), an androgen receptor antagonist, is reported. The original synthesis included a low-yielding Mitsunobu reaction and employed cis-aminocyclohexanol, which is accessible only via a troublesome synthesis, as a key building block. The novel synthetic pathway starts from readily available trans-aminocyclohexanol and features a palladium-catalyzed etherification reaction in place of the Mitsunobu reaction as the key step. This four-step synthesis can be performed reliably on a multikilogram scale, and purification of all intermediates as well as the final product can be achieved by simple extraction and crystallization procedures.
- Hager, Anastasia,Guimond, Nicolas,Grunenberg, Lars,Hanisch, Christine,Steiger, Sebastian,Preuss, Andre
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p. 654 - 660
(2021/03/15)
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- An Effective Method for the Synthesis of 1,3-Dihydro-2H-indazoles via N-N Bond Formation
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The [4+1] cycloaddition reaction of bifunctional amino reagents has been achieved with in situ formed aza-ortho-quinone methides. Specifically, N-(tosyloxy)carbamates were used as an N1 synthon and bifunctional amino reagents for this transformation, which provides a metal-free, catalyst-free, and oxidant-free strategy to form nitrogen-nitrogen bonds. (Figure presented.).
- Zhang, Xiaoke,Pan, Yang,Liang, Peng,Ma, Xiaofeng,Jiao, Wei,Shao, Huawu
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supporting information
p. 5552 - 5557
(2019/11/22)
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- Photo-auxiliary approach to control excited state reactivity: Cross [2+2]-photocycloaddition of oxazolidinone based hydrazides
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Chiral oxazolidinone based hydrazides undergo efficient cross [2 + 2]-photocycloaddition upon visible light illumination. Oxazolidinone functionality acted as an energy harvesting photo-auxiliary. The cross [2 + 2]-photocycloaddition proceeded efficiently from the excited state with moderate to excellent isolated yield of the photoproduct. The photo-auxiliary can be conveniently removed post-photoreaction, which highlights the versatility of this strategy.
- Ahuja, Sapna,Iyer, Akila,Kandappa, Sunil Kumar,Sivaguru, Jayaraman
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- Palladium-Catalyzed Synthesis of Indolines from Aroyloxycarbamates through a Tandem Decarboxylative Amination/Heck/Annulation Reaction
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A novel synthesis of functionalized indolines via a Pd-catalyzed tandem decarboxylative amination/Heck/annulation reaction has been developed. This process features operational simplicity, mild conditions, and the use of a readily available and environmentally friendly starting material, namely carboxylic acid. Furthermore, the reaction shows good functional group tolerance and chemical selectivity. (Figure presented.).
- Wang, Zheng,Li, Peihe,Fu, Hui,Dai, Qipu,Hu, Changwen
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p. 192 - 200
(2018/11/23)
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- FMOC PROTECTED (2S)-2-AMINO-8-[(1,1-DIMETHYLETHOXY)AMINO]-8-OXO-OCTANOIC ACID, (S)-2-AMINO-8-OXONONANOIC ACID AND (S)-2-AMINO-8-OXODECANOIC ACID FOR PEPTIDE SYNTHESIS
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The invention discloses Fmoc protected (2S)-2-amino-8-[(1,1- dimethylethoxy)amino]-8-oxo-octanoic acid, (S)-2-amino-8- oxononanoic acid and (S)-2-amino-8-oxodecanoic acid for use in peptide synthesis, such as solid phase synthesis, as well as the peptide H3K27 (Ac-Lys-Ala-Ala-Arg-Aox-Ser-Ala-NH2) prepared from Fmoc protected (2S)-2-amino-8-[(1,1-dimethylethoxy)amino]-8-oxo-octanoic acid (Aox). These three exemplary compounds as well as their unprotected forms are claimed in the form of four generic formulae. The first of these four formulae is (formula (I)) where -NPro is a protected amino group, such as an amino group protected with a base-labile protecting group, -L- is alkylene, heteroalkylene, arylene or aralkylene, -X- is a covalent bond, -N(H) - or -N(RN)-, where -RN is alkyl, -R2 is hydrogen or alkyl, -R3 is alkyl, such as C2-10 alkyl, or heterocyclyl, and -LAA- and -R1 are as defined in the claims.
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Page/Page column 42-43
(2019/12/04)
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- Base-Mediated Intramolecular Decarboxylative Synthesis of Alkylamines from Alkanoyloxycarbamates
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A general and effective method for the synthesis of alkylamine via intramolecular decarboxylation of alkanoyloxycarbamates is described. The alkanoyloxycarbamates are readily prepared with alkyl carboxylic acids and hydroxylamine. The reaction shows a broad range of substrates (primary and secondary alkyl) with functional tolerance, and the corresponding products were obtained in good yields under mild conditions.
- Li, Peihe,Ma, Nuannuan,Wang, Zheng,Dai, Qipu,Hu, Changwen
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p. 8233 - 8240
(2018/05/31)
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- Synthesis of indoles from aroyloxycarbamates with alkynes: Via decarboxylation/cyclization
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An efficient Pd-catalyzed decarboxylation/cyclization of aroyloxycarbamates to realize substituted indoles has been disclosed. Terminal alkynes as the coupling partners lead to site specific 2-substituted indoles through two pathways, while internal alkynes with aroyloxycarbamates can be transformed to 2,3-disubstituted indoles directly. This protocol is further demonstrated by the efficient synthesis of indoles as well as the success of employing inexpensive aryl acids as starting materials to construct C-N bonds by releasing CO2.
- Ma, Nuannuan,Li, Peihe,Wang, Zheng,Dai, Qipu,Hu, Changwen
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supporting information
p. 2421 - 2426
(2018/04/12)
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- Nondirected, cu-catalyzed sp3 C-H aminations with hydroxylamine-based amination reagents: Catalytic and mechanistic studies
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This work demonstrates the use of hydroxylamine-based amination reagents RSO2NH-OAc for the nondirected, Cu-catalyzed amination of benzylic C-H bonds. The amination reagents can be prepared on a gram scale, are benchtop stable, and provide benzylic C-H amination products with up to 86% yield. Mechanistic studies of the established reactivity with toluene as substrate reveal a ligand-promoted, Cu-catalyzed mechanism proceeding through Ph-CH2(NTsOAc) as a major intermediate. Stoichiometric reactivity of Ph-CH2(NTsOAc) to produce Ph-CH2-NHTs suggests a two-cycle, radical pathway for C-H amination, in which the decomposition of the employed diimine ligands plays an important role.
- Wang, Anqi,Venditto, Nicholas J.,Darcy, Julia W.,Emmert, Marion H.
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supporting information
p. 1259 - 1268
(2017/05/29)
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- Regioselective Synthesis of 2-Vinylanilines Using O-aroyloxycarba-mates by Sequential Decarboxylation/Amination/Heck Reaction
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A new sequential approach for 2-vinylanilines utilizing aryl carboxylic acids as stable, inexpensive and widely available arylating reagents is described. Employing a Pd-POVs catalyst system, this protocol is not only overcoming the restriction barrier of decarboxylative coupling to ortho-substituted substrates, but also provides site-special to create new C(sp2)-N and C(sp2)-C(sp2) bonds. Mechanistic experiments suggest the cleavage of C(sp2)-COOH gives priority to C(sp2)-X bond in this reaction.
- Li, Peihe,Ma, Nuannuan,Li, Jikun,Wang, Zheng,Dai, Qipu,Hu, Changwen
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p. 8251 - 8257
(2017/08/14)
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- Practical Synthetic Procedures for the Iron-Catalyzed Intermolecular Olefin Aminohydroxylation Using Functionalized Hydroxylamines
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A set of practical synthetic procedures for the iron-catalyzed intermolecular olefin aminohydroxylation reactions in gram scale is reported. In these transformations, a bench-stable functionalized hydroxylamine is applied as the amination reagent. This method is compatible with a broad range of synthetically valuable olefins including those that are incompatible with the existing aminohydroxylation methods. It also provides valuable amino alcohol building blocks with regio- and stereochemical arrays that are complementary to known methods.
- Zhu, Cheng-Liang,Lu, Deng-Fu,Sears, Jeffrey D.,Jia, Zhen-Xin,Xu, Hao
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p. 3031 - 3041
(2016/09/09)
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- Palladium-Catalyzed Decarboxylative Synthesis of Arylamines
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A novel approach has been developed for the synthesis of arylamines via the palladium-catalyzed intramolecular decarboxylative coupling (IDC) of aroyloxycarbamates, obtained in situ by reacting aryl carboxylic acids with hydroxycarbamates. The reaction offers facile access to structurally diverse arylamines with the site-specific formation of the C(sp2)-N bond under mild conditions.
- Dai, Qipu,Li, Peihe,Ma, Nuannuan,Hu, Changwen
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supporting information
p. 5560 - 5563
(2016/11/17)
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- Heartleaf houtluynia derivatives and their use in medicine
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The invention relates to houttuynia cordata derivatives or esters thereof, or an enantiomer or a diastereomer, stereomer, tautomer, hydate, solvate, predrug, or pharmaceutically acceptable salt. In addition, the invention further relates to a preparation method of the houttuynia cordata derivatives, and an application of the houttuynia cordata derivatives in a drug; and the invention further relates to a pharmaceutical composition of the compound, and applications in preparing an antibacterial and anti-virus drug especially used for treating various urinary system diseases, and the advantages are that the water solubility is good, the bioavailability is high, the purity is high, and the toxic and side effects and the stimulation effect due to low purity can be greatly reduced.
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Paragraph 0332; 0333
(2018/02/04)
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- Fluorescent flippers for mechanosensitive membrane probes
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In this report, "fluorescent flippers" are introduced to create planarizable push-pull probes with the mechanosensitivity and fluorescence lifetime needed for practical use in biology. Twisted push-pull scaffolds with large and bright dithienothiophenes and their S,S-dioxides as the first "fluorescent flippers" are shown to report on the lateral organization of lipid bilayers with quantum yields above 80% and lifetimes above 4 ns. Their planarization in liquid-ordered (Lo) and solid-ordered (So) membranes results in red shifts in excitation of up to +80 nm that can be transcribed into red shifts in emission of up to +140 nm by F?rster resonance energy transfer (FRET). These unique properties are compatible with multidomain imaging in giant unilamellar vesicles (GUVs) and cells by confocal laser scanning or fluorescence lifetime imaging microscopy. Controls indicate that strong push-pull macrodipoles are important, operational probes do not relocate in response to lateral membrane reorganization, and two flippers are indeed needed to "really swim," i.e., achieve high mechanosensitivity.
- Dal Molin, Marta,Verolet, Quentin,Colom, Adai,Letrun, Romain,Derivery, Emmanuel,Gonzalez-Gaitan, Marcos,Vauthey, Eric,Roux, Aurlien,Sakai, Naomi,Matile, Stefan
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supporting information
p. 568 - 571
(2015/01/30)
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- 2-catalyzed directed N -Boc amidation of arenes "on water"
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Rhodium(III) catalysis "on water" is effective for directed C-H amidation of arenes. The catalytic process is promoted by OH groups present on the hydrophobic water surface and is inefficient in all (most) common organic solvents investigated so far. In the presence of easily prepared tert-butyl 2,4-dinitrophenoxycarbamate, a new and stable nitrene source, the "on water" reaction can efficiently provide the desired N-Boc-aminated products with good functional group tolerance.
- Ali, Md Ashif,Yao, Xiayin,Sun, Hao,Lu, Hongjian
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supporting information
p. 1513 - 1516
(2015/03/30)
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- SUBSTITUTED BENZAMIDES AND THEIR USES
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Provided herein are Substituted Benzamides, compositions, and method of their manufacture and use.
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Paragraph 0643; 0644
(2015/12/01)
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- A dual inhibitor of matrix metalloproteinases and a disintegrin and metalloproteinases, [18F]FB-ML5, as a molecular probe for non-invasive MMP/ADAM-targeted imaging
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Background Numerous clinical studies have shown a correlation between increased matrix metalloproteinase (MMP)/a disintegrin and metalloproteinase (ADAM) activity and poor outcome of cancer. Various MMP inhibitors (MMPIs) have been developed for therapeutic purposes in oncology. In addition, molecular imaging of MMP/ADAM levels in vivo would allow the diagnosis of tumors. We selected the dual inhibitor of MMPs and ADAMs, ML5, which is a hydroxamate-based inhibitor with affinities for many MMPs and ADAMs. ML5 was radiolabelled with 18F and the newly obtained radiolabelled inhibitor was evaluated in vitro and in vivo. Materials and methods ML5 was radiolabelled by direct acylation with N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) for PET (positron emission tomography). The resulting radiotracer [18F]FB-ML5 was evaluated in vitro in human bronchial epithelium 16HBE cells and breast cancer MCF-7 cells. The non-radioactive probe FB-ML5 and native ML5 were tested in a fluorogenic inhibition assay against MMP-2, -9, -12 and ADAM-17. The in vivo kinetics of [18F]FB-ML5 were examined in a HT1080 tumor-bearing mouse model. Specificity of probe binding was examined by co-injection of 0 or 2.5 mg/kg ML5. Results ML5 and FB-ML5 showed high affinity for MMP-2, -9, -12 and ADAM-17; indeed IC50 values were respectively 7.4 ± 2.0, 19.5 ± 2.8, 2.0 ± 0.2 and 5.7 ± 2.2 nM and 12.5 ± 3.1, 31.5 ± 13.7, 138.0 ± 10.9 and 24.7 ± 2.8 nM. Radiochemical yield of HPLC-purified [18F]FB-ML5 was 13-16% (corrected for decay). Cellular binding of [18F]FB-ML5 was reduced by 36.6% and 27.5% in MCF-7 and 16HBE cells, respectively, after co-incubation with 10 μM of ML5. In microPET scans, HT1080 tumors exhibited a low and homogeneous uptake of the tracer. Tumors of mice injected with [18F]FB-ML5 showed a SUVmean of 0.145 ± 0.064 (n = 6) which decreased to 0.041 ± 0.027 (n = 6) after target blocking (p 18F. [18F]FB-ML5 demonstrated rather low binding in ADAM-17 overexpressing cell lines. [18F]FB-ML5 uptake showed significant reduction in the HT1080 tumor in vivo after co-injection of ML5. [18F]FB-ML5 may be suitable for the visualization/quantification of diseases overexpressing simultaneously MMPs and ADAMs.
- Matusiak, Nathalie,Castelli, Riccardo,Tuin, Adriaan W.,Overkleeft, Herman S.,Wisastra, Rosalina,Dekker, Frank J.,Prély, Laurette M.,Bischoff, Rainer P.M.,Van Waarde, Aren,Dierckx, Rudi A.J.O.,Elsinga, Philip H.
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p. 192 - 202
(2015/02/19)
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- Enantioselective aziridination of cyclic enals facilitated by the fluorine-iminium ion Gauche effect
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The enantioselective, organocatalytic aziridination of small, medium and macro-cyclic enals is reported using (S)-2-(fluorodiphenyl methyl)-pyrrolidine. Central to the reaction design is the reversible formation of a β-fluoroiminium ion intermediate, which is pre-organised on account of the fluorine-iminium ion gauche effect. This conformational effect positions the fluorine substituent synclinal-endo to the electropositive nitrogen centre thus benefiting from favourable stereoelectronic and electrostatic interactions (σC-H→σC-F*; F δ-···N+). Consequently, one of the shielding groups on the fluorine-bearing carbon atom is positioned above the π-system, forming the basis of an enantioinduction strategy. Treatment of this intermediate with a "nitrene" source furnished a series of novel, optically active aziridines (e.r. up to 99.5:0.5). Further derivatisation of the product aziridines gives facile access to various amino acid derivatives, including β-fluoroamino acids. Crystallographic analyses of both the aziridines and their derivatives are disclosed. Copyright
- Molnar, Istvan Gabor,Tanzer, Eva-Maria,Daniliuc, Constantin,Gilmour, Ryan
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supporting information
p. 794 - 800
(2014/01/23)
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- Iron(II)-catalyzed intermolecular amino-oxygenation of olefins through the N - O bond cleavage of functionalized hydroxylamines
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An iron-catalyzed diastereoselective intermolecular olefin amino-oxygenation reaction is reported, which proceeds via an iron-nitrenoid generated by the N - O bond cleavage of a functionalized hydroxylamine. In this reaction, a bench-stable hydroxylamine derivative is used as the amination reagent and oxidant. This method tolerates a range of synthetically valuable substrates that have been all incompatible with existing amino-oxygenation methods. It can also provide amino alcohol derivatives with regio- and stereochemical arrays complementary to known amino-oxygenation methods.
- Lu, Deng-Fu,Zhu, Cheng-Liang,Jia, Zhen-Xin,Xu, Hao
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supporting information
p. 13186 - 13189
(2015/03/30)
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- New and concise syntheses of the bicyclic oxamazin core using an intramolecular nitroso diels-alder reaction and ring-closing olefin metathesis
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Herein two new and concise synthetic approaches for making an unsaturated bicyclic oxamazin core are reported. The first involves the use of an intramolecular Diels-Alder reaction to form both of the fused rings in one step. The second approach incorporates ring-closing olefin metathesis in the final step to form the second fused ring of the core. The scope of the second approach was also expanded further to afford larger ringed bicyclic systems.
- Watson, Kyle D.,Carosso, Serena,Miller, Marvin J.
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p. 358 - 361
(2013/03/13)
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- Kinetics of action of a two-stage pro-inhibitor of serine β-lactamases
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β-Lactamase inhibitors are important in medicine in the protection of β-lactam antibiotics from β-lactamase-catalyzed destruction. The most effective inhibitors of serine β-lactamases covalently modify the enzyme active site. We have recently studied O-acyl and O-phosphyl hydroxamates as a new class of such inhibitors. In this paper, we describe our studies of the N-acyl derivatives of a cyclic O-acyl hydroxamic acid, 3H-benzo[d][1,2]oxazine- 1,4-dione, and, in particular, the N-tert-butoxycarbonyl derivative. This compound is not a β-lactamase inhibitor itself but undergoes spontaneous hydrolysis in aqueous solution, yielding an O-phthaloyl hydroxamic acid, which is a β-lactamase inhibitor. This compound spontaneously, but reversibly, cyclizes in solution to form phthalic anhydride, which is also a β-lactamase inhibitor. Both inhibitors react to form the same transiently stable phthaloyl-enzyme complex. Thus, we have a two-step cascade, beginning with a pro-inhibitor, in which each step leads to a different inhibitor, presumably with different enzyme specificities. The kinetics of these transformations have been elucidated in detail. The phthaloyl derivatives, where the free carboxylate is important for facile reaction with the enzyme, represent a new lead for serine β-lactamase inhibitors. Analogues can be conveniently constructed in situ by reaction of nucleophiles with phthalic anhydrides and then screened for activity. Active hits may then become new leads.
- Tilvawala, Ronak,Pratt
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p. 7060 - 7070
(2013/10/22)
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- SUBSTITUTED BENZAMIDES AND THEIR USES
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Provided herein are Substituted Benzamides, compositions, and method of their manufacture and use.
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Page/Page column 143
(2013/11/05)
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- [1,2,4]TRIAZOLOPYRIDINES AND THEIR USE AS PHOSPODIESTERASE INHIBITORS
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The present invention relates to novel [1,2,4]triazolopyridine compounds with phosphodiesterase inhibitory activity, as well as to their use as therapeutic agents in the treatment of inflammatory diseases and conditions.
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Page/Page column 13; 14
(2013/07/05)
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- Rh[III]-catalyzed direct C-H amination using N -chloroamines at room temperature
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An efficient Rh(III)-catalyzed direct C-H amination of N-pivaloyloxy benzamides with N-chloroamines proceeding at room temperature was achieved. The versatile directing group allows for selective mono- and diamination and can be readily converted to give valuable benzamide or aminoaniline derivatives. Mechanistic studies have been carried out to elucidate the reaction pathway.
- Grohmann, Christoph,Wang, Honggen,Glorius, Frank
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supporting information; experimental part
p. 656 - 659
(2012/03/08)
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- Mild rhodium(III)-catalyzed C-H activation and intermolecular annulation with allenes
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All(enes) great! A novel RhIII-catalyzed oxidative coupling with allenes under mild conditions provides heterocycles with exocyclic double bonds. This reaction features low catalyst loadings, high regio- and stereoselectivity, and excellent substrate scope. The products were derivatized and preliminary mechanistic studies were conducted. Copyright
- Wang, Honggen,Glorius, Frank
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supporting information; experimental part
p. 7318 - 7322
(2012/09/08)
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- IMPROVED AMINOHYDROXYLATION OF ALKENES
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The invention relates to a process for the aminohydroxylation of alkenes using N-oxycarbamate reagents, e.g. N-acyloxycarbamate, N-alkyloxycarbonyloxycarbamate and N-aralkoxycarbonyloxycarbamate reagents. The invention particularly relates to an intermolecular aminohydroxylation reaction that can be carried out in the absence of added base. The invention also relates to novel N-oxycarbamate reagents that are stable crystalline materials. The process of the invention is useful in the synthesis of compounds having a vicinal amino alcohol moiety, such as biologically active compounds.
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Page/Page column 41-42
(2012/01/06)
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- Alkyl 4-chlorobenzoyloxycarbamates as highly effective nitrogen source reagents for the base-free, intermolecular aminohydroxylation reaction
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Ethyl-(7), benzyl-(8), tert-butyl-(9), and fluorenylmethyl-4- chlorobenzoyloxycarbamates (10) have been prepared as storable and easy-to-prepare nitrogen sources for use in the intermolecular Sharpless aminohydroxylation reaction and its asymmetric variant. These reagents were found to be effective under base-free reaction conditions. The scope and limitations of these methods have been explored using a variety of alkenes, among which, trans-cinnamates, in particular, proved to be good substrates.
- Harris, Lawrence,Mee, Simon P. H.,Furneaux, Richard H.,Gainsford, Graeme J.,Luxenburger, Andreas
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experimental part
p. 358 - 372
(2011/04/17)
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- N-Boc-O-tosyl hydroxylamine as a safe and efficient nitrogen source for the N-amination of aryl and alkyl amines: Electrophylic amination
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β-Boc-protected aryl and alkyl hydrazines, useful intermediates for azapeptides and N-substituted pyrazoles, were synthesized by electrophylic amination methodology, using less energetic N-Boc-O-tosyl hydroxylamine as an efficient nitrogen source. Also we have demonstrated a two-step, chromatography-free synthesis of N-Boc-O-tosyl hydroxylamine. Georg Thieme Verlag Stuttgart - New York.
- Baburaj, Thankappan,Thambidurai, Sivalingam
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experimental part
p. 1993 - 1996
(2011/10/08)
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- Design, synthesis, and evaluation of duocarmycin O-amino phenol prodrugs subject to tunable reductive activation
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A series of N-acyl O-amino derivatives of seco-CBI-indole2 are reported and examined as prototypical members of a unique class of reductively activated (cleaved) prodrugs of the duocarmycin and CC-1065 family of antitumor agents. These prodrugs were designed to be potentially preferentially activated in hypoxic tumor environments which carry an intrinsically higher concentration of "reducing" nucleophiles (e.g., thiols) capable of activating such derivatives by nucleophilic cleavage of a weak N-O bond. A remarkable range of stabilities and a resulting direct correlation with in vitro/in vivo biological potencies was observed for these prodrugs, even enlisting subtle variations in the electronic and steric environment around the weak N-O bond. An in vivo evaluation of several of the prodrugs demonstrates that some approach the potency and exceed the efficacy of the free drug itself (CBI-indole 2), suggesting the prodrugs may offer an additional advantage related to a controlled or targeted release.
- Lajiness, James P.,Robertson, William M.,Dunwiddie, Irene,Broward, Melinda A.,Vielhauer, George A.,Weir, Scott J.,Boger, Dale L.
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experimental part
p. 7731 - 7738
(2011/02/24)
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- Synthesis, larvicidal activity, and SAR studies of new benzoylphenylureas containing oxime ether and oxime ester group
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A series of new structural benzoylphenylureas (BPUs) containing oxime ether and oxime ester group were designed and synthesized. The larvicidal activities against Oriental armyworm and mosquito of these benzoylphenylureas were evaluated and the result of bioassay displayed specific structure-activity relationship (SAR). Most of the compounds exhibited excellent larvicidal activities against Oriental armyworm and mosquito. Interestingly, some compounds showed different structure-activity relationship towards diamondback moth, beet armyworm, and corn borer although three tested insects all belong to the same insect order.
- Sun, Ranfeng,Li, Yongqiang,Lue, Maoyun,Xiong, Lixia,Wang, Qingmin
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scheme or table
p. 4693 - 4699
(2010/10/02)
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- The acyl nitroso Diels-Alder (ANDA) reaction of sorbate derivatives: An X-ray and 15N NMR study with an application to amino-acid synthesis
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We present a study of the acyl nitroso Diels-Alder (ANDA) reaction of sorbate esters and sorbic alcohol derivatives, using alkoxycarbonyl nitroso dienophiles. An optimisation of the reaction conditions for ethyl sorbate is first presented, and the product is used in an efficient synthesis of 5-methylornithine. Structure-reactivity trends in sorbic alcohol (E,E-2,4-hexadien-1-ol) and its acylated analogues are then discussed. We present single-crystal X-ray structural proof for key adducts in both series and present in detail a novel HMBC/HSQC (1H-15N) criterion for ready distinction of regioisomers arising from such ANDA reactions.
- Bollans, Lee,Bacsa, John,Iggo, Jonathan A.,Morris, Gareth A.,Stachulski, Andrew V.
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experimental part
p. 4531 - 4538
(2009/12/25)
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- Fischer synthesis of isomeric thienopyrrole LHRH antagonists
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As part of a structure-activity exploration into LHRH antagonists, structures containing the thieno[2,3-b]pyrrole core were identified as potent antagonists. This letter describes the employment of the Fischer synthesis to access this thienopyrrole and isomeric final compounds.
- Andrews, David M.,Arnould, Jean-Claude,Boutron, Pascal,Délouvrie, Bénédicte,Delvare, Christian,Foote, Kevin M.,Hamon, Annie,Harris, Craig S.,Lambert-van der Brempt, Christine,Lamorlette, Maryannick,Matusiak, Zbegniew M.
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experimental part
p. 5805 - 5816
(2009/12/24)
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- Syntheses and biological activity studies of novel sterol analogs from nitroso diels-alder reactions of ergosterol
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A serles of novel sterol analogs was prepared using nitroso Dlels-Alder reactions with ergosterol. Most cycloaddltlon reactions proceeded In an excellent reglo- and stereoselective fashion. Further N-O bond cleavage of cycloadducts generated compounds with biological activity In PC-3 and MCF-7 cancer cell lines
- Yang, Baiyuan,Miller, Patricia A.,Moellmann, Ute,Miller, Marvin J.
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body text
p. 2828 - 2831
(2009/12/06)
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- Design, synthesis, bioactivity, and structure-activity relationship (SAR) studies of novel benzoylphenylureas containing oxime ether group
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Novel benzoylphenylureas containing an oxime ether group were designed and synthesized by four schemes. These benzoylphenylureas were identified by 1H NMR spectroscopy and element analysis (or HRMS). The bioactivities of the new compounds were evaluated. These benzoylphenylureas exhibited excellent larvicidal activities against oriental armyworm, some of which were much better in comparison with the commercial Flucycloxuron. In particular, the larvicidal activities against oriental armyworm of compounds 1 and 23 were 5-10 times better than that of Flucycloxuron. Most of these benzoylphenyureas exhibited excellent larvicidal activities against mosquito. At the same time, some of these compounds have good plant growth regulatory activities as well.
- Sun, Ranfeng,Lue, Maoyun,Chen, Li,Li, Qingshan,Song, Haibin,Bi, Fuchun,Huang, Runqiu,Wang, Qingmin
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scheme or table
p. 11376 - 11391
(2010/04/02)
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- Semicarbazone-based inhibitors of cathepsin K, are they prodrugs for aldehyde inhibitors?
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Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and 13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.
- Adkison, Kim K.,Barrett, David G.,Deaton, David N.,Gampe, Robert T.,Hassell, Anne M.,Long, Stacey T.,McFadyen, Robert B.,Miller, Aaron B.,Miller, Larry R.,Payne, J. Alan,Shewchuk, Lisa M.,Wells-Knecht, Kevin J.,Willard Jr., Derril H.,Wright, Lois L.
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p. 978 - 983
(2007/10/03)
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- Copper-catalyzed allylic hydroxyamination and amination of alkenes with Boc-hydroxylamine
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Olefins react regioselectively with Boc-NHOH in the presence of Cu(I,II) salts to produce allyl-N(OH)(Boc) derivatives, apparently via the intermediacy of Boc-NO; yields and rates are dramatically improved by the addition of H 2O2. The corresponding allylamine derivatives, allyl-NH(Boc), are formed selectively from Boc-NHOH/olefin with CuBr/P(OEt) 3.
- Kalita, Biswajit,Nicholas, Kenneth M.
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p. 1451 - 1453
(2007/10/03)
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- Synthesis of 4-azacyclopent-2-enones and 5,5-dialkyl-4-azacyclopent-2- enones
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Three different methods are reported for the preparation of 4-azacyclo-2-enones 1, two of which allow the preparation of the compounds in optically active form. In addition, a facile route to 4-aza-5,5- dimethylcyclopent-2-enones 2 is disclosed.
- Dauvergne, Jér?me,Happe, Alan M.,Jadhav, Vasudev,Justice, David,Matos, Marie-Christine,McCormack, Peter J.,Pitts, Michael R.,Roberts, Stanley M.,Singh, Sanjay K.,Snape, Timothy J.,Whittall, John
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p. 2559 - 2567
(2007/10/03)
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- IMPROVEMENTS IN PHARMACEUTICALLY USEFUL COMPOUNDS
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A compound of formula (I) or (II): wherein A is hydrogen or CR1R2; Y and Z are each, independently, hydrogen or a halogen;X is -NR4R5, or R7; R1 is hydrogen, or a substituted or unsubstituted alkyl or alkenyl group containing 1-4 carbon atoms; when X is -NR4R5, R2 is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl aralkenyl, or aralkynyl group, that optionally includes at least one heteroatom in its carbon skeleton and contains 1-12 carbon atoms; when X is R7, R2 is an unsubstituted alkyl, alkenyl or alkynyl group, or a substituted or unsubstituted aryl, aralkyl aralkenyl, or aralkynyl group, that optionally includes at least one heteroatom in its carbon skeleton and contains 1-12 carbon atoms; R3 is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl aralkenyl, or aralkynyl group, that optionally includes at least one heteroatom in its carbon skeleton and contains 1-12 carbon atoms; R4 is hydrogen, a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl aralkenyl, or aralkynyl group, that optionally includes at least one heteroatom in its carbon skeleton and contains 1-12 carbon atoms, -COOR8, or -COR8; R5 is hydrogen, or a substituted or unsubstituted alkyl or alkenyl group containing 1-5 carbon atoms; R7 is an unsubstituted alkyl, alkenyl, or alkynyl group, that contains 1-4 carbon atoms; and, R8 is an unsubstituted or halo-substituted alkyl, aryl, or aralkyl group, that contains 1-12 carbon atoms.
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- ANTITHROMBOTIC ETHERS
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This application relates to a compound of formula I (or a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug thereof) as defined herein, pharmaceutical compositions thereof, and its use as an inhibitor of factor Xa and/or thrombin, as well as a process for its preparation and intermediates therefor (I).
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- Hydantoins and related heterocycles as inhibitors of matrix metalloproteinases and/or TNF-alpha converting enzyme (TACE)
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The present application describes novel hydantoin derivatives of formula (I): or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, R1, R2, R3, R4, R5, R6, R7, R11, and n are defined in the present specification, which are useful as inhibitors of matrix metalloproteinases (MMP), TNF-α converting enzyme (TACE), aggrecanase, or a combination thereof.
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- Asymmetric synthesis of potent glycosidase and very potent α-mannosidase inhibitors: 4-amino-4-deoxy-L-erythrose and 4-amino-4,5-dideoxy-L-ribose
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Pyrrolidine amino-sugars, cyclic iminoalditols as well as linear aminoalditols in 4-amino-L-erythrose and 4-amino-5-deoxy-L-ribose series were synthesised by asymmetric hetero-Diels-Alder reaction followed by chemical transformations. 4-Amino-4-deoxy-L-erythrose and 4-amino-4,5-dideoxy-L-ribose were potent β-D-glucosidase, α-D-mannosidase, α- and β-D-galactosidase inhibitors. We have shown that the ribose derivative was a very potent inhibitor of α-D-mannosidase.
- Behr, Jean-Bernard,Chevrier, Carine,Defoin, Albert,Tarnus, C.éline,Streith, Jacques
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p. 543 - 553
(2007/10/03)
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- Synthesis of an 1-azaglucose analogue with ring-oxygen retained
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Synthesis of the glucose analogue 4,5-dihydroxy-6-hydroxymethyl- tetrahydrooxazine (4) is reported for the first time.
- Bach, Peter,Bols, Mikael
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p. 3461 - 3464
(2007/10/03)
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- Diastereoselective synthesis of 3'-unsubstituted N-BOC- Aziridine from a readily available chiral α-β-unsaturated imide
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The conjugate addition of N-BOC-O-benzoyl hydroxylamine catalysed by sodium hydride to a chiral α,β-unsaturated imide gives a 3'-(BOC benzoyloxyaminopropanoyl) derivative. This undergoes cyclization upon treatment with sodium or lithium bases to give a 3'-unsubstituted N-BOC aziridine-2-imide in good yield and diastereoselectivity. When N-BOC-O-benzoyl hydroxylamine is deprotonated with stoichiometric lithium or sodium bases, the intermediate enolate resulting from the 1,4-addition spontaneously undergoes cyclization affording in a single step the N-BOC aziridine in higher yield.
- Cardillo, Giuliana,Gentilucci, Luca,Bastardas, Imma Ratera,Tolomelli, Alessandra
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p. 8217 - 8222
(2007/10/03)
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- Efficient functionalization of acylnitroso cycloadducts: Application to the syntheses of carbocyclic nucleoside precursors
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1,4-cis-disubstituted cyclopentene precursors of carbocyclic nucleosides were readily prepared utilizing acylnitroso hetero Diels-Alder reactions and Pd(0)-catalyzed alkylation reactions as the key steps. The chemistry was explored in both racemic and asymmetric fashion. The hydroxymethyl components of the carbocyclic nucleoside precursors were obtained from nitromethyl groups under oxidative Nef conditions and may be further elaborated into a variety of compounds of potential biological interest.
- Zhang, Deyi,Ghosh, Arun,Sueling, Carsten,Miller, Marvin J.
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p. 3799 - 3802
(2007/10/03)
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- Insecticidal 4,6-diamino-1,2-dihydro-1,3,5-triazine derivatives
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Insects, and particularly the larvae of Lepidoptera and Coleoptera, are controlled by application of 4,6-diamino-1,2-dihydro-dihydro-1,3,5-trazine derivatives, and agriculturally acceptable salts thereof, having the following structure; STR1 when they are admixed with a compatible agricultural vehicle; additionally, certain related novel heterocyclyl, phenyl, and naphthyl triazines and their substituted counterparts are also taught.
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- Synthesis of chiral isoxazolidin-5-ones and their applications to the synthesis of β-amino-alanines and β-(N-hydroxyamino)-alanines
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Herein we report a high-yielding synthesis of isoxazolidin-5-ones and their use to synthesise both β-amino-alanines and β-(N-hydroxyamino)-alanines.
- Baldwin, Jack E.,Adlington, Robert M.,Mellor, Lisa C.
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p. 5049 - 5066
(2007/10/02)
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- An Investigation of the Intramolecular Ene Reaction of N-Acyl Imines
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N-Acyl imines, produced by the flash vacuum thermolysis of hydroxamic acid derivatives, participate in the intramolecular ene reaction to give nitrogen heterocycles.The reaction is accelerated by carboxyl substituents on the carbon atom of the N-acyl imine, and the reaction is more succesful for the production of pyrrolidine rather than piperidine derivatives.
- Lin, Jyh-Ming,Koch, Kevin,Fowler, Frank W.
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p. 167 - 174
(2007/10/02)
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