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1.
Bartolomê Vilanova Josefa Donoso Francisco Muoz Francisco García-Blanco 《Helvetica chimica acta》1996,79(7):1793-1802
The degradation of cefaclor ( 1 ), an oral cephalosporin antibiotic, was studied at 37° in a neutral aqueous medium by HPLC and 1H-NMR. Under these conditions, 1 underwent intramolecular aminolysis by the 7-side-chain NH2 group on the β-lactam moiety to give a piperazine-2,5-dione. The most prominent peak in the HPLC profile of a degradation solution from 1 was isolated by prep. HPLC. Mechanistically, the formation of this degradation product cis- 11 from 1 involves the contraction from a six-membered cephem ring to a five-membered ring, which presumably takes place via a common episulfonium ion intermediate 9 (see Scheme). Loss of the Cl-atom from 3-chloro-3-cephem is a general reaction subsequent to β-lactam ring opening. 相似文献
2.
Re-isolation of Pseudomonas tabaci strain NCPPB 2730 from its host, the tobacco plant, led to an activation of the bacteria in order to produce the β-lactam dipeptide tabtoxin (Wildfire toxin, 1 ). Incorporation of several 14C-labelled amino acids as well as L -[methyl-13C]methionine, L -[1,2-13C2]- and L -[3,4-13C2]aspartate, rac -[1,2-13C2]glycerol, and [1,2-13C2]acetate into isotabtoxion ( 2 ) demonstrated that the building blocks of tabtoxin ( 1 ) are L -threonine, L -aspartate, the Me group of L -methionine and a C2-unit derived from the C3-pool (Fig. 3). The Me group of L -methionine provides the carbonyl C-atom of the β-lactam moiety. These findings represent a novel pathway in β-lactam biosynthesis. Mechanistic aspects with respect to the β-lactam ring formation are discussed. A biradical 16 is proposed as an intermediate during the cyclization of a N-formyl-α-amino ketone 15 . 相似文献
3.
Several new monocyclic β-lactam monomers bearing the NO2 group 2a–g were synthesized via a [2 + 2] ketene–imine cycloaddition reaction (Staudinger reaction). Calculation of coupling constant of H-3 and H-4, and the X-ray crystallography of β-lactam 2e confirmed the cis stereochemistry of these β-lactams. Then aminophenyl β-lactams were synthesized by the reduction of NO2 to NH2 group in the presence of Raney Ni and hydrazine hydrate. Treatment of these aminophenyl β-lactams with acryloyl chloride and sodium bicarbonate (NaHCO3), afforded the monomers bearing the NHCOCH=CH2 group. These acrylated β-lactam monomers were dissolved in a warm mixture of butyl acrylate and styrene and then were converted to the corresponding polyacrylate nano β-lactams by emulsion polymerization in water. A unique feature of this methodology is the ability to incorporate water-insoluble compounds directly into the nanoparticle framework. Structures of the synthesized compounds were confirmed by physical and spectral analyses. Dynamic light scattering analysis and transmission electron microscopy of the final emulsions show that the nanoparticles were about 50–70 nm in diameter. 相似文献
4.
《合成通讯》2013,43(16):2499-2506
2,3-Dibromo-2-methyl-N-(1-adamantyl)propanamide (4), a precursor equally suited for the preparation of an α-lactam and a β-lactam, upon treatment with sodium tert-butoxide ether gives no α-lactam (5), but an excellent yield of the isomeric β-lactam, 1-(1-adamantyl)-3-bromo-3-methylazetidinone (6) as the only product. Repeating the experiment using a large excess of sodium tert-butoxide still leads to β-lactam 6 in 76.1% yield, but now accompanied by its dehydrobrominated derivative, β-lactam 7, in 17.4% yield, and no trace of α-lactam 5 相似文献
5.
The synthesis of some derivatives of the title compound VI is described. Bromination of diethyl (cis-3-azido-2-oxo-4-styrylazetidin-1-yl)(pyridin-2-yl)methylphosphonate ( 6 ) in MeOH gave tricyclic β-lactam 7 , while similar bromination of diethyl (cis-3-azido-2-oxo-4-vinylazetidin-1-yl)(pyridin-2-yl)methylphosphonate ( 9 ) afforded tri-cyclic β-lactam 10 . Mechanisms for these transformations are proposed (Schemes 1 and 2). 相似文献
6.
János Balogh 《Tetrahedron letters》2009,50(33):4727-1630
Novel 2-(1-ferrocenyl-methylidene)-malonic acid derivatives are obtained upon reacting ethyl diazoacetate, carbon monoxide and ferrocenylimines in the presence of Co2(CO)8 as catalyst under mild conditions. Presumably, the reaction involves three steps taking place in a domino fashion, (i) carbonylation of ethyl diazoacetate leading to a ketene derivative, (ii) [2+2] cycloaddition of the ketene with the ferrocenylimine present in the reaction mixture resulting in the formation of a β-lactam and (iii) N(1)-C(4) cleavage of the β-lactam ring. In most cases, 2-(1-ferrocenyl-methylidene)-malonic acid derivatives are obtained as a separable mixture of E- and Z-isomers in ratios depending on the structure of the imine component. 相似文献
7.
János Balogh László Párkányi Ferenc Ungváry 《Journal of organometallic chemistry》2011,696(7):1394-1630
The domino reaction of ethyl diazoacetate, carbon monoxide and ferrocenylimines was investigated in the presence of Co2(CO)8 as catalyst. In most cases the main products are 2-(1-ferrocenylmethylidene) malonates formed by an N(1)-C(4) cleavage of the primarily derived β-lactams. The latter compounds could only be isolated when the reaction was carried out at relatively low CO pressure, using an excess of ethyl diazoacetate. trans-N-(tert-Butyl)-3-ethoxycarbonyl-4-ferrocenyl-β-lactam proved to be the most stable one among these compounds and could be isolated in 55% yield. N-alkyl β-lactams were shown to undergo acidic cleavage leading to the E isomers of 2-(1-ferrocenylmethylidene) malonates as the main products. The structures of the two new compounds, (E)-2-ethoxycarbonyl-3-ferrocenyl-N-((R)-1-phenylethyl)-2-propenamide and trans-N-(tert-butyl)-3-ethoxycarbonyl-4-ferrocenyl-β-lactam were confirmed by X-ray crystallography. The relative thermodynamical stability of the products as well as the energetics of the acid-mediated cleavage of the β-lactam ring was elucidated with DFT calculations. 相似文献
8.
Fritz Kunz Jnos Rtey Duilio Arigoni Lin Tsai Thressa C. Stadtman 《Helvetica chimica acta》1978,61(3):1139-1145
Absolute configuration of the 3,5-diaminohexanoic acid produced in the β-lysine mutase reaction The (3S, 5S)-configuration of the 3,5-diaminohexanoic acid 3 produced by the coenzyme-B12-dependent β-lysine mutase from Clostridium sticklandii has been determined by two different methods: by comparison of the 1H-NMR.-spectrum of its δ-lactam with that of synthetic (±)-cis-and (±)-trans-4-amino-6-methyl-piperidones ( 1 and 2 ) and by chemical correlation with (+)-(6S)-6-methyl-piperidone-2 ( 9 ). 相似文献
9.
Alexander A. Kirichok Hennadii Tkachuk Yevhenii Kozyriev Oleh Shablykin Oleksandr Datsenko Dmitry Granat Tetyana Yegorova Yuliya P. Bas Vitalii Semirenko Iryna Pishel Vladimir Kubyshkin Dmytro Lesyk Oleksii Klymenko-Ulianov Pavel K. Mykhailiuk 《Angewandte Chemie (International ed. in English)》2023,62(51):e202311583
1-Azaspiro[3.3]heptanes were synthesized, characterized, and validated biologically as bioisosteres of piperidine. The key synthesis step was thermal [2+2] cycloaddition between endocyclic alkenes and the Graf isocyanate, ClO2S−NCO, to give spirocyclic β-lactams. Reduction of the β-lactam ring with alane produced 1-azaspiro[3.3]heptanes. Incorporation of this core into the anesthetic drug bupivacaine instead of the piperidine fragment resulted in a new patent-free analogue with high activity. 相似文献
10.
Metallo-β-lactamases (mβls) cause bacterial resistance toward a broad spectrum of β-lactam antibiotics by catalyzing the hydrolytic cleavage of the four-membered β-lactam ring, thus inactivating the drug. Minutiae of the mechanism of these enzymes are still not well understood, and reports about binding studies of the substrates to the enzymes as well as to synthetic model systems are rare. Here we report a new pyrazolate-based bioinspired dizinc complex (1) reminiscent of the active site of binuclear mβls. Since 1 does not mediate hydrolytic degradation of β-lactams, the binding of a series of common β-lactam antibiotics (benzylpenicillin, cephalotin, 6-aminopenicillanic acid, ampicillin) as well as the inhibitor sulbactam and the simplest β-lactam, 2-azetidinone, to the dizinc core of 1 could now be studied in detail by NMR and IR spectroscopy as well as mass spectrometry. X-ray crystallographic information was obtained for 1 and its complexes with 2-azetidinone (2) and sulbactam (3); the latter represents the first structurally characterized dizinc complex with a bound β-lactam drug. While 2-azetidinone was found deprotonated and bridging in the clamp of the two zinc ions in 2, in 3 and all other cases the substrates preferentially bind via their carboxylate group within the bimetallic pocket. The relevance of this binding mode for mβls and consequences for the design of functional model systems are discussed. 相似文献
11.
《Tetrahedron: Asymmetry》2007,18(20):2468-2472
Both enantiomers of fluorinated and non-fluorinated 4-phenyl-2-azetidinones are prepared in high enantiopurities (ee 99%) by a chemoenzymatic method, using a double resolution technique to N-hydroxymethylated β-lactams in the presence of Burkholderia cepacia lipase as the source of enantiopurity. N-Deprotections yield the β-lactam enantiomers from the corresponding hydroxymethylated counterparts using KMnO4 in a mixture of acetone and water. 相似文献
12.
The potential energy surface of the β-lactam + OH? reaction, related to the mode of action of β-lactam antibiotics, was investigated using the ab initio Hartree—Fock method with the STO-3G basis set. Three possible reaction paths for the BAC2 breaking of the amidic CN bond were obtained and discussed. The minimum-energy reaction path is characterized by the following processes: (1) the formation of a tetrahedral intermediate, ≈ 121 kcal mol?1 more stable than the reagents; (2) a barrier, ≈ 15 kcal mol?1 above the intermediate, which is mainly due to the partial breaking of the amidic bond; (3) the complete breaking of the amidic bond concerted with a proton transfer till the formation of the final product, ≈ 34 kcal mol?1 more stable than the intermediate. The evolution of some molecular orbitals and of the electron population along the reaction path was also discussed. 相似文献
13.
Development of a direct ELISA based on carboxy-terminal of penicillin-binding protein BlaR for the detection of β-lactam antibiotics in foods 总被引:1,自引:0,他引:1
Juan Peng Guyue Cheng Lingli Huang Yulian Wang Haihong Hao Dapeng Peng Zhenli Liu Zonghui Yuan 《Analytical and bioanalytical chemistry》2013,405(27):8925-8933
β-Lactam antibiotics, including penicillins and cephalosporins, are commonly used in veterinary medicine. Illegal use and abuse of β-lactams could cause allergy and selected bacterial resistance. BlaR-CTD, the carboxy-terminal of penicillin-recognizing protein BlaR from Bacillus licheniformis ATCC 14580, was utilized in this study to develop a receptor-based ELISA for detection and determination of β-lactam antibiotics in milk, beef, and chicken. This assay was based on directly competitive inhibition of binding of horseradish peroxidase-labeled ampicillin to the immobilized BlaR-CTD by β-lactams. The assay was developed as screening test with the option as semiquantitative assay, when the identity of a single type of residual β-lactam was known. The IC50 values of 15 β-lactam antibiotics, including benzylpenicillin, ampicillin, amoxicillin, dicloxacillin, oxacillin, nafcillin, cefapirin, cefoperazone, cefalotin, cefazolin, cefquinome, ceftriaxone, cefotaxime, cefalexin, ceftiofur and its metabolite desfuroylceftiofur were evaluated and ranged from 0.18 to 170.81 μg L?1. Simple sample extraction method was carried out with only phosphate-buffered saline, and the recoveries of selected β-lactam antibiotics in milk, beef, and chicken were in the range of 53.27 to 128.29 %, most ranging from 60 to 120 %. The inter-assay variability was below 30 %. Limits of detection in milk, beef, and chicken muscles with cefquinome matrix calibration were 2.10, 30.68, and 31.13 μg kg?1, respectively. This study firstly established a rapid, simple, and accurate method for simultaneous detection of 15 β-lactams in edible tissues, among which 11 β-lactams controlled by European Union could be detected below maximum residue limits. Figure
The receptor-based ELISA for blank sample (negative samples, left) and sample containing β-lactam antibiotics (positive samples, right) 相似文献
14.
Carlo Petrongolo Emilio Pescatori Graziella Ranghino Raimondo Scordamaglia 《Chemical physics》1980,45(2):291-304
The potential energy surface for the β-lactam amidic CN bond breaking in the 3-cephem + OH? reaction was investigated by using the ab initio Hartree—Fock method with a 9s6p/7s3p/3s basis set. The investigated reaction is a model of the reaction between an antibiotic cephalosporin and an enzymatic nucleophilic group, this last reaction being related to the mode of action of β-lactam antibiotics. The minimum-energy reaction path is characterized by a tetrahedral intermediate ≈ 116 kcal mol?1 more stable than the reagents, by a barrier which corresponds to the partial breaking of the amidic bond and is ≈ 7 kcal mol?1 above the intermediate and by a product ≈ 31 kcal mol?1 more stable than the intermediate. The analysis of the wavefunction along the reaction path and the comparison with the β-lactam + OH? reaction pointed out the role of electron-withdrawing groups on the height of the barrier and the role of intramolecular hydrogen bonds on the structure and energy of the product. The calculations suggest a model of the antibiotic activity of cephalosporins which is compared with previous qualitative pictures. 相似文献
15.
《Tetrahedron letters》1986,27(14):1545-1548
Structural modifications of 6-halopenicillanate Grignards result in increased “aldol” stereoselectivity. The intermediacy of tetrahedral penicillin carbanions in THF and β-lactam enolates in CH2Cl2/toluene is proposed. 相似文献
16.
Juan Frau Josefa Donoso Francisco Muoz Francisco Gracia-Blanco 《Helvetica chimica acta》1996,79(2):353-362
We used semi-empirical and ab initio calculations to investigate the nucleophilic attack of the OH? ion on the β-lactam carbonyl group. Both allowed us to detect reaction intermediates pertaining to proton-transfer reactions rather than the studied reaction. We also used the PM3 semi-empirical method to investigate the influence of the solvent on the process. The AMSOL method predicts the occurrence of a potential barrier of 20.7 kcal/mol due to the desolvation of the OH? ion in approaching the β-lactam carbonyl group. Using the supermolecular approach and a H2O solvation sphere of 20 molecules around the solute, the potential barrier is lowered to 17.5 kcal/mol, which is very close to the experimental value (16.7 kcal/mol). 相似文献
17.
Markus Grohmann 《Tetrahedron》2007,63(49):12172-12178
The intramolecular carbenoid C-H insertion of 2-diazoacetoacetamides, leading to γ- and/or β-lactams, is catalyzed effectively by dinuclear Ru(I,I) complexes of the type [Ru2(μ-L1)2(CO)4L22], where L1 is a bidentate bridging acetate, calix[4]arenedicarboxylate, saccharinate or 6-chloropyridin-2-olate ligand. By comparison with rhodium catalysts, namely dirhodium tetraacetate and dirhodium calix[4]arenedicarboxylate complexes, product yields are similarly high and the regioselectivity of the insertion reaction is the same. Surprisingly, even the ruthenium(0) cluster Ru3(CO)12 was found to be an effective catalyst for carbenoid C-H insertion of 2-diazoacetoacetamides and also of some diazoacetamides. In terms of diastereoselectivity, trans-isomers of β- and γ-lactams are obtained. However, the β-lactam obtained from diazomalonic ester amide 2 yields the cis-isomer stereoselectively, which slowly rearranges to the trans-isomer. 相似文献
18.
Semiempirical AM1, MINDO/3, and MNDO methods have been used in the study of the alkaline hydrolysis of β-lactam antibiotics through a base-catalyzed, acyl-cleavage, bimolecular mechanism. In this work, the hydroxyl ion has been chosen as nucleophilic agent and the azetidin-2-one ring like a model of β-lactam antibiotic. The MINDO/3 method does not predict correctly the energies of small rings. This, together with the fact that, like MNDO, it cannot detect the occurrence of hydrogen bonds, gives rise to uncertain estimates of energy barriers. The AM1 method can be considered the most suitable for studying the hydrolysis of β-lactam compounds. 相似文献
19.
Dr. Fanglong Zhao Dr. Zhiwen Liu Shuyuan Yang Ning Ding Dr. Xue Gao 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(43):19270-19276
Quinolactacins are novel fungal alkaloids that feature a quinolone-γ-lactam hybrid, which is a potential pharmacophore for the treatment of cancer and Alzheimer's disease. Herein, we report the identification of the quinolactacin A2 biosynthetic gene cluster and elucidate the enzymatic basis for the formation of the quinolone-γ-lactam structure. We reveal an unusual β-keto acid (N-methyl-2-aminobenzoylacetate) precursor that is derived from the primary metabolite l -kynurenine via methylation, oxidative decarboxylation, and amide hydrolysis reactions. In vitro assays reveal two single-module non-ribosomal peptide synthetases (NRPs) that incorporate the β-keto acid and l -isoleucine, followed by Dieckmann condensation, to form the quinolone-γ-lactam. Notably, the bioconversion from l -kynurenine to the β-keto acid is a unique strategy employed by nature to decouple R*-domain-containing NRPS from the polyketide synthase (PKS) machinery, expanding the paradigm for the biosynthesis of quinolone-γ-lactam natural products via Dieckmann condensation. 相似文献
20.
Construction of α-phosphonolactams via rhodium (II)-catalyzed intramolecular C?H insertion reactions
Yoshiharu Okada Toru Minami Masahiro Miyamoto Tsuneyuki Otaguro Sumiko Sawasaki Junji Ichikawa 《Heteroatom Chemistry》1995,6(3):195-210
The Rh(II)-catalyzed intramolecular C H insertion reactions of N,N-dialkyl-α-diazo-α-(diethylphosphono)acetamides 2a , f–j in CHCl3 or ClCH2CH2Cl were found to give monocyclic and bicyclic α-phosphono-β-lactams, 3a and 3f–j , in 43–67% yields via regiospecific α-C H insertion of the N-alkyl groups. Similar treatment of N-benzyl-N-isopropyl-α-diazo-α-(diethylphosphono)acetamide ( 2b ) and the corresponding N-isobutyl-N-methylacetamide 2d in ClCH2CH2Cl afforded mixtures of β-lactams 3b (35%) and and 3b ′ (16%), β-lactam 3d (47%), and γ-lactam 4d (10%), respectively, each of which is formed by the competitive C H insertion reaction between benzylic and isopropyl α-C H bonds and between methyl α-C H and methine β-C H bonds, respectively. For the formation of β-lactams, the selectivity in the rhodium-mediated C H insertion in ClCH2CH2Cl follows the order methyl > methine > benzylic α-C H bond on N-substituents. The N,N-dibutyl-α-diazo homologue 2c and Nα[α-diazo-α-(diethylphosphono)acetyl]-2-methylindoline ( 2k ) exclusively produced γ-lactams 4c (67%) and 4k (81%) via insertion into the methylene β-C H and methyl β-C H bonds. tert-Butyl N-[α-diazo-α-(dibenzylphosphono)acetyl]-piperidine-2-carboxylate ( 2m ) on similar treatment, followed by deprotection of the benzyl ester afforded the 7-phosphono carbacepham 6 in 32% overall yield. Similar Rh(II)-catalyzed cyclization of N-methyl-N[4-benzyloxy-α-(diethylphosphono)-phenyl(diethyl-phosphono)methyl]-α-diazo-acetamide ( 2n ) led to 1-[4′-benzylphenyl(diethylphosphono)methyl] -3-(diethyl-phosphono)azetidin-2-one ( 3n ) in 78% yicld. The phosphono group at C-7 of 3f was converted into the acetylamino group via a four-step reaction. Application of chiral rhodium(II) carboxylates 12a–c to the insertion reactions of 2b , c produced α-phosphono-β-and γ-lactams, 3b and 4c , in 6–24% ee and 25–29% ee, respectively. 相似文献