- Azetidine-Containing Alkaloids Produced by a Quorum-Sensing Regulated Nonribosomal Peptide Synthetase Pathway in Pseudomonas aeruginosa
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Pseudomonas aeruginosa displays an impressive metabolic versatility, which ensures its survival in diverse environments. Reported herein is the identification of rare azetidine-containing alkaloids from P. aeruginosa PAO1, termed azetidomonamides, which are derived from a conserved, quorum-sensing regulated nonribosomal peptide synthetase (NRPS) pathway. Biosynthesis of the azetidine motif has been elucidated by gene inactivation, feeding experiments, and biochemical characterization in vitro, which involves a new S-adenosylmethionine-dependent enzyme to produce azetidine 2-carboxylic acid as an unusual building block of NRPS. The mutants of P. aeruginosa unable to produce azetidomonamides had an advantage in growth at high cell density in vitro and displayed rapid virulence in Galleria mellonella model, inferring functional roles of azetidomonamides in the host adaptation. This work opens the avenue to study the biological functions of azetidomonamides and related compounds in pathogenic and environmental bacteria.
- Hong, Zhilai,Bolard, Arnaud,Giraud, Caroline,Prévost, Sébastien,Genta-Jouve, Grégory,Deregnaucourt, Christiane,H?ussler, Susanne,Jeannot, Katy,Li, Yanyan
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- Multigram-scale and column chromatography-free synthesis of L-azetidine-2-carboxylic acid for the synthesis of nicotianamine and its derivatives
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Multigram-scale synthesis of L-azetidine-2-carboxylic acid from L-aspartic acid was achieved in 13 conventional synthetic steps, without the need for purification by silica-gel column chromatography and expensive reagents. Nicotianamine and its fluorescence-labeled derivatives could be obtained from this synthetic strategy.
- Takaishi, Tomohiro,Wakisaka, Kyosuke,Vavricka, Christopher J.,Kiyota, Hiromasa,Izumi, Minoru
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p. 2126 - 2134
(2019/04/04)
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- Synthesis of 2-carboxylated aza-ring derivatives through α-monohalogenation/ring-contraction of N-sulfonyl lactams
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2-Carboxylated aza-rings have been synthesized in two steps through a highly selective monohalogenation of N-sulfonylated lactams of various ring sizes (from 5- to 8-membered rings) followed by a ring contraction reaction. The selective monohalogenation of N-sulfonyl lactams has been achieved in modest to excellent yields (9 examples, 39–96%) using N-halogenosuccinimides via the in situ generation of trimethylsilyl ketene aminal derivatives. The so-obtained α-halogeno N-sulfonyl lactams were engaged in a ring opening/ring closing reaction in the presence of various alcohols or anilines under basic conditions affording 2-carboxylated aza-rings, such as azetidine, pyrrolidine or piperidine derivatives in high yields (24 examples, 61–99%).
- Sirindil, Fatih,Miaskiewicz, Solène,Kern, Nicolas,Lalaut, Arno,Felten, Anne-Sophie,Weibel, Jean-Marc,Pale, Patrick,Blanc, Aurélien
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p. 5096 - 5106
(2017/07/28)
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- Preparation of enantiopure 2-acylazetidines and their reactions with chloroformates
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Enantiopure 1-phenylethylazetidine-2-carboxylates and 2-acylazetidines were prepared and reacted with chloroformates to yield α-chloro-γ-amino butyric acid esters and ketones from ring opening reaction of azetidinium ion intermediate in a completely regio- and stereoselective manner.
- Ma, Sang-ho,Yoon, Doo Ha,Ha, Hyun-Joon,Lee, Won Koo
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p. 269 - 271
(2007/10/03)
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- Practical asymmetric preparation of azetidine-2-carboxylic acid
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Facile and straightforward syntheses of both enantiomers of azetidine-2-carboxylic acid are described. The syntheses depart from inexpensive chemicals and allow for the production, in five to six steps, of practical quantities of each enantiomer. Synthetic highlights include the construction of the azetidine ring using an intramolecular alkylation and the use of optically active α-methylbenzylamine as chiral auxiliary.
- Couty, Francois,Evano, Gwilherm,Vargas-Sanchez, Monica,Bouzas, Gloria
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p. 9028 - 9031
(2007/10/03)
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- Efficient route to (S)-azetidine-2-carboxylic acid
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A new and efficient route to (S)-azetidine-2-carboxylic acid (>99.9% ee) in five steps and total yield of 48% via malonic ester intermediates was established. As the key step, efficient four-membered ring formation (99%) was achieved from dimethyl (S)-(1′-methyl)benzylaminomalonate by treating with 1,2-dibromoethane (1.5 eq) and cesium carbonate (2 eq) in DMF. Krapcho dealkoxycarbonylation of dimethyl (1′S)-1-(1′-methyl) benzylazetidine-2,2-dicarboxylate, the product of this cyclization procedure, proceeded with preferential formation (2.7:1, 78% total yield) of the desired (2S,1′S)-monoester, with the help of a chiral auxiliary which was introduced on the nitrogen atom. The undesired (2R,1′S)-isomer could be converted to that with proper stereochemistry, by a deprotonation and subsequent reprotonation step. Finally, lipase-catalyzed preferential hydrolysis of the (2S,1′S)-monoester and subsequent deprotection provided enantiomerically pure (S)-azetidine-2-carboxylic acid in a 91% yield from the mixture of (2S,1′S)- and (2R,1′S)-isomers.
- Futamura, Yasuhiko,Kurokawa, Masayuki,Obata, Rika,Nishiyama, Shigeru,Sugai, Takeshi
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p. 1892 - 1897
(2008/02/03)
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- PROCESS FOR PRODUCING OPTICALLY ACTIVE AZETIDINE-2-CARBOXYLIC ACID
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The present invention provides an efficient, simple, and commercially advantageous process for producing optically active azetidine-2-carboxylic acid, which is an important material for medicines. The process includes the steps of halogenating an optically active N-protected 4-amino-2-hydroxybutyric acid following inversion of the configuration to produce an optically active N-protected 4-amino-2-halobutyryl halide; hydrolyzing the halide; deprotecting the amino group of the hydrolyzed product to produce an optically active 4-amino-2-halobutyric acid; cyclizing the product in an alkaline aqueous solution; and then protecting the amino group of the cyclized product to produce an optically active N-protected azetidine-2-carboxylic acid. The present invention also provides an optically active N-protected 4-amino-2-halobutyryl halide represented by general formula (2): (wherein P represents a protective group for the primary amino group; * indicates that the carbon atom is asymmetric; and each of X and Y independently represents a halogen atom), which is useful for producing the optically active azetidine-2-carboxylic acid.
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- Anti-heparin peptides
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The invention concerns a compound exhibiting an anti-heparin activity, of formula Z Bm ! (AXA)x Bn ! (AXA)y Bo (AXA)z Bp, the diagnostic reagents comprising it and the use of said compound in an in vitro diagnostic test of a medicine for anti-heparin activity.
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- Process for cyclizing optically active 4-amino-2-halogenobutyric acids
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The invention provides a process for producing optically active azetidine-2-carboxylic acid with good efficiency, expedience, and commercial advantage, which comprises cyclizing an optically active 4-amino-2-halogenobutyric acid in an optical yield of as high as 90% or more. It is a process for producing optically active azetidine-2-carboxylic acid of the general formula (2), in which * denotes an asymmetric carbon atom, which comprises cyclizing an optically active 4-amino-2-halogenobutyric acid of the general formula (1), in which X represents a halogen atom and * denotes an asymmetric carbon atom, in the presence of an oxide of an alkaline earth metal, a hydroxide of an alkaline earth metal excepting barium, or an organic amine.
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- Process
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There is provided a process for the production of a N-benzyl azetidine-2-carboxylic acid alkylphenyl, or alkyl, ester which process comprises the reaction of an optionally substituted alkylphenyl, or an optionally substituted alkyl, 2-bromo-4-chlorobutyrate with an optionally substituted benzylamine, which process may be used as part of an overall process for the production of azetidine-2-carboxylic acid.
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- Solid-Liquid Biphasic Hydroformylation of Olefins Catalyzed by Rhodium Carhonyl Complexes
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Some polymer-anchored alkenes have been hydroformylated by carrying out the reaction in a high-pressure reactor equipped with a suitably designed vial. The solid substrates are converted to the corresponding oxo-aldehydes in high yields. In all cases the regioselectivity was strongly shifted towards the linear aldehyde when the rhodium carbonyl complex was modified with xantphos (3:1 or 4:1 P/Rh molar ratio). Treatment with 5% of trifluoroacetine acid in dichloromethane at room temperature removed quantitatively the oxo-product from the polymer support, which can be purified and reused.
- Marchetti,Botteghi,Paganelli,Taddei
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p. 1229 - 1236
(2007/10/03)
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- PROCESS FOR PRODUCING OPTICALLY ACTIVE AZETIDINE-2-CARBOXYLIC ACIDS
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An optically active N-protected azetidine-2-carboxylic acid (5) can be produced by preparing an optically active 4-amino-2-halobutyric acid (3), ???by halogenating an optically active 3-hydroxy-2-pyrrolidinone (1) with inversion of configuration to prepare an optically active 3-halo-2-pyrrolidinone (2) followed by hydrolysis or, ???by halogenating an optically active 4-amino-2-hydroxybutyric acid ester (6) with inversion of configuration to prepare an optically active 4-amino-2-halobutyric acid ester (7) followed by hydrolysis or, ???by halogenating the compound (6) with inversion of configuration to prepare the compound (7), cyclizing the same to prepare the compound (2) followed by hydrolysis,???further cyclizing the compound (3) followed by treating the reaction product with an amino group-protecting agent.The optical purity of the thus-obtained compound (5) can be improved further by recrystallization.
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- Synthesis of chiral bicyclic azetidine derivatives
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(2S)-N-Benzoyl-2-azetidinecarboxylic acid was converted into several derivatives of (5R)-1-azabicycloheptane via lactamization of 3-((2R)-azetidine)propanoic acid, subsequent aldol reaction and reduction. The structures of three stereoisomers of (5R)-3-(hydroxy-(4-nitrophenyl)methyl)-1-azabicyclo[3.2.0]heptan-2-one were determined by X-ray crystallography.
- Barrett, Anthony G. M.,Dozzo, Paola,White, Andrew J. P.,Williams, David J.
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p. 7302 - 7314
(2007/10/03)
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- 3-Pyridyl enantiomers and their use as analgesics
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The present invention relates to a method of controlling pain in mammals, including humans, comprising administering to a mammal or patient in need of treatment thereof selected compounds of formula I: STR1 or a pharmaceutically acceptable salt thereof. The invention further relates to selected (R) and (S) compounds of formula I above which are useful as analgesics as well as neuronal cell death preventors and anti-inflammatories.
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- Bioresolution of N-acylazetidine-2-carboxylic acids
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PCT No. PCT/GB97/01916 Sec. 371 Date Dec. 15, 1998 Sec. 102(e) Date Dec. 15, 1998 PCT Filed Jul. 15, 1997 PCT Pub. No. WO98/02568 PCT Pub. Date Jan. 22, 1998Process for obtaining an enantiomerically enriched N-acylazetidine-2-carboxylic acid, wherein a racemic N-acylazetidine-2-carboxylic acid ester is contacted with an enzyme that displays enantiospecificity to form enantiomerically enriched N-acylazetidine-2-carboxylic acid.
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- Processes for producing azetidine-2-carboxylic acid and intermediates thereof
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PCT No. PCT/JP98/01895 Sec. 371 Date Dec. 30, 1999 Sec. 102(e) Date Dec. 30, 1999 PCT Filed Apr. 24, 1998 PCT Pub. No. WO98/47867 PCT Pub. Date Oct. 29, 1998The present invention has its object to provide a process for producing azetidine-2-carboxylic acid and an intermediate thereof, which is efficient and economical and suited for industrial practice. The present invention is related to a process for producing azetidine-2-carboxylic acid of the following formula (5), which comprises subjecting a 4-oxo-2-azetidinecarboxylic acid derivative represented by the general formula (1) to hydride reduction to give azetidine-2-methanol of the following formula (2), treating the same with an amino-protecting agent to give N-protected azetidine-2-methanol represented by the following general formula (3), treating this with an oxidizing agent to give N-protected azetidine-2-carboxylic acid represented by the following general formula (4) and, further, subjecting the amino-protecting group thereof to elimination.
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- Process for the production of enantiomerically-pure azetidine-2-carboxylic acid
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The invention relates to a process for the production of enantiomerically-pure AzeOH which comprises selective crystallisation of a diastereomerically-pure tartrate salt thereof, followed by liberation of the free amino acid, as well as the compounds L-azetidine-2-carboxylic acid-D-tartrate and D-azetidine-2-carboxylic acid-L-tartrate.
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- Process for producing optically active azetidine-2-carboxylic acid
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The present invention provides a process for preparing optically active azetidine-2-carboxylic acids using readily available reagents of relatively low price in the industry. Thus, there is provided optically active azetidine-2-carboxylic acid, and a process for producing the same by subjecting optically active N-(alkylbenzyl)azetidine-2-carboxylic acid represented by the formula (1): STR1 to hydrogenolysis in the presence of a catalyst.
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- Asymmetric synthesis of L-azetidine-2-carboxylic acid and 3-substituted congeners - Conformationally constrained analogs of phenylalanine, naphthylalanine, and leucine
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Enantiopure L-azetidine-2-carboxylic acid, the (3R)-phenyl, (3R)- naphthyl and (3S)-isopropyl analogs were prepared based on a zinc-mediated asymmetric addition of allylic halides to the camphor sultam derivative of glyoxylic acid O-benzyl oxime.
- Hanessian, Stephen,Bernstein, Naomy,Yang, Rui-Yang,Maguire, Robert
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p. 1437 - 1442
(2007/10/03)
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- Identification and initial structure-activity relationships of (R)-5- (2-azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors
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New members of a previously reported series of 3-pyridyl ether compounds are disclosed as novel, potent analgesic agents acting through neuronal nicotinic acetylcholine receptors. Both (R)-2-chloro-5-(2- azetidinylmethoxy)pyridine (ABT-594, 5) and its S-enantiomer (4) show potent analgesic activity in the mouse hot-plate assay following either intraperitoneal (ip) or oral (po) administration, as well as activity in the mouse abdominal constriction (writhing) assay, a model of persistent pain. Compared to the S-enantiomer and to the prototypical potent nicotinic analgesic agent (±)-epibatidine, 5 shows diminished activity in models of peripheral side effects. Structure-activity studies of analogues related to 4 and 5 suggest that the N-unsubstituted azetidine moiety and the 2-chloro substituent on the pyridine ring are important contributors to potent analgesic activity.
- Holladay, Mark W.,Wasicak, James T.,Lin, Nan-Horng,He, Yun,Ryther, Keith,Bannon, Anthony W.,Buckley, Michael J.,Kim, David J. B.,Decker, Michael W.,Anderson, David J.,Campbell, Jeffrey E.,Kuntzweiler, Theresa A.,Donnelly-Roberts, Diana L.,Piattoni-Kaplan, Marietta,Briggs, Clark A.,Williams, Michael,Arneric, Stephen P.
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p. 407 - 412
(2007/10/03)
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- Novel 3-pyridyl ethers with subnanomolar affinity for central neuronal nicotinic acetylcholine receptors
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Recent evidence indicating the therapeutic potential of cholinergic channel modulators for the treatment of central nervous system (CNS) disorders as well as the diversity of brain neuronal nicotinic acetylcholine receptors (nAChRs) have suggested an opportunity to develop subtype-selective nAChR ligands for the treatment of specific CNS disorders with reduced side effect liabilities. We report a novel series of 3-pyridyl ether compounds which possess subnanomolar affinity for brain nAChRs and differentially activate subtypes of neuronal nAChRs. The synthesis and structure-activity relationships for the leading members of the series are described, including A-85380 (4a), which possesses ca. 50 pM affinity for rat brain [3H]-(- )cytisine binding sites and 163% efficacy compared to nicotine to stimulate ion flux at human α4β2 nAChR subtype, and A-84543 (2a), which exhibits 84- fold selectivity to stimulate ion flux at human α4β2 nAChR subtype compared to human ganglionic type nAChRs. Computational studies indicate that a reasonable superposition of a low energy conformer of 4a with (S)-nicotine and (-)-epibatidine can be achieved.
- Abreo, Melwyn A.,Lin, Nan-Horng,Garvey, David S.,Gunn, David E.,Hettinger, Ann-Marie,Wasicak, James T.,Pavlik, Patricia A.,Martin, Yvonne C.,Donnelly-Roberts, Diana L.,Anderson, David J.,Sullivan, James P.,Williams, Michael,Arneric, Stephen P.,Holladay, Mark W.
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p. 817 - 825
(2007/10/03)
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- Enantioselective catalytic reductions of ketones with new four membered oxazaborolidines: Application to (S)-tetramisole
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Enantioselective catalytic reduction of ketones with both the enantiomers of new four membered oxazaborolidines is described.
- Rama Rao,Gurjar,Kaiwar
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p. 859 - 862
(2007/10/02)
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