Stereoselective synthesis and characterization of novel trans-4-(thiophenyl)pyrazolyl-β-lactams and their C–3 functionalization

A stereoselective synthesis and C–3 functionalization of a long series of novel hybrid 4-(thiophenyl)pyrazolyl-β-lactams have been carried out. The divergent substrate scope and mechanistic insights were examined to delineate the generality of reaction that favored trans-β-lactams 4a-q almost exclusively in all cases. The C–3 functionalization was achieved by Lewis acid assisted nucleophilic substitution reaction of cis-3-chloro-β-lactams 6a-e to afford cis-3-monosubstituted-β-lactams 7a-e. The cis stereochemistry of β-lactams 7a-e was further established by stereospecific desulfurization with Raney-nickel, in representative cases (7a,b), leading to the formation of cis-β-lactams 8a,b. The structures and stereochemical assignments for synthesized β-lactams have been unambiguously confirmed using FT-IR, 1D NMR (¹H and ¹³C), 2D NMR (¹H–¹H COSY, ¹H–¹³C HSQC and ¹³C DEPT–135), elemental analysis (CHN), mass spectrometry (ESI-MS) and single crystal X-ray crystallography, in representative cases (4b,e). The cis and trans configuration of the hydrogen/chloro/nucleophile substituent at C–3 was assigned with respect C4–H of the β-lactam ring.     

Monocarboxylates of 3-Methylidene-β-lactams: Synthesis and unusual oxidative rearrangement into a spiro[azetidine-3,3′-pyrrolidine] derivative

Reaction of the 3-silylated β-lactams 1 with glycoxalates gives bis-lactam 3 , but the same reaction in the presence of 1 equiv. of Me₃SiCl leads to the formation of the disilylated adducts 5 . The latter is desilylated by (Bu₄N)F yielding the monocarboxylates 7 of 3-methylidene-β-lactams, which, with oxidizing agents, give the spiro compound 8 . The structure of 8 is established by spectroscopic data and a crystal-structure analysis.     

Synthesis of ethyl cis 2-[(Diethoxyphosphoryl)methyl]-7-oxo-3-phenyl-6-phthalimido-l-azabicyclo[3.2.0]hept-3-ene-2-carboxylate and Methyl cis-2-Bromo-3-methyl-8-oxo-7-phthalimido-4-oxa-1-azabicyclo[4.2.0]octane-2-carboxylate

The synthesis of a Δ¹-carbapenem and two β-lactams possessing a Br-atom at the N-substituting center not involved in the lactam ring and bearing the carboxyl group is described. The β-lactams having this kind of Br-substitution are more susceptible to nucleophilic attack than those having a conjugated double bond with the N-atom of the β-lactam ring. DBU is found to be an excellent reagent for the elimination of the silyloxy function. Moreover, a simple method for the addition of diethyl phosphite to an α, β-unsaturated double bond using a catalytic amount of NaH is described.     

含2-苯基-1,2,3-三唑基单环β-内酰胺类化合物的合成

寻找能口服、广谱的单环β-内酰胺类抗生素已经发展成为一个重要研究领域, 烯酮-亚胺环加成是最有效的合成方法之一. 在三乙胺与含2-苯基-1,2,3-三唑基的Schiff碱的苯溶液中逐滴加入邻苯二甲酰亚氨基乙酰氯或丙酰氯的苯溶液, 加热回流, 通过环加成反应得到含有2-苯基-1,2,3-三唑基和邻苯二甲酰亚胺基的单环β-内酰胺类化合物. 产物均为反式构型, 其结构由元素分析, IR, ¹H NMR, MS以及NOESY谱得到确证.     

Asymmetric synthesis of β-lactams. I. The reaction of dimethylketene silyl acetal with (S)-alkylidene(1-arylethyl)amines promoted by titanium tetrachloride

Asymmetric synthesis of β-lactams by means of the reaction of dimethylketene silyl acetal with (S)-alkylidene(1-arylethyl)amines in the presence of titanium tetrachloride was studied. The extent of the asymmetric induction was in the range of 44–78% (diastereomeric purity 72–89%) and the (S)-configuration was turned to be preferentially induced at the ⁴C position of the resulting β-lactams.     

Synthesis of β-Lactams by Palladium(0)-Catalyzed C(sp3)−H Carbamoylation

A general and user-friendly synthesis of β-lactams is reported that makes use of Pd⁰-catalyzed carbamoylation of C(sp³)−H bonds, and operates under stoichiometric carbon monoxide in a two-chamber reactor. This reaction is compatible with a range of primary, secondary and activated tertiary C−H bonds, in contrast to previous methods based on C(sp³)−H activation. In addition, the feasibility of an enantioselective version using a chiral phosphonite ligand is demonstrated. Finally, this method can be employed to synthesize valuable enantiopure free β-lactams and β-amino acids.     

SYNTHESIS AND BIOLOGICAL ACTIVITY OF SOME NEW 8-HYDROXYQUINOLINE SULPHONAMIDE DERIVATIVES

Abstract

Some new derivatives containing both 8-hydroxyquinoline and sulphonylamino β-lactams and thiazolidinones have been prepared. These compounds were synthesized from the corresponding 8-hydroxyquinoline sulphonylhydrazide (1) by converting it to hydrazones (2). The latter hydrazones (2) were easily transformed to β-lactams (3) and thiazolidinones (4) by cyclocondensation reaction with chloroacetyl chloride and/or mercaptoacetic acid. Some metal chelates with Fe³⁺. Co²⁺+, Ni²⁺, Cu²⁺ and Cd²⁺ have been prepared for some of the compounds and screened in vitro for their biological activity.     

3-Thiolated 2-azetidinones: synthesis and in vitro antibacterial and antifungal activities

A series of 3-thiolated β-lactams were synthesized by [2+2] ketene-imine cycloaddition reaction from S-substituted mercaptoacetic acids and Schiff bases. Then, some of the 3-methylthio β-lactams were converted to 3-(methylsulfinyl) β-lactams and 3-(methylsulfonyl) β-lactams using m-CPBA under different reaction conditions. All the compounds were characterized by spectral data and elemental analyses and were evaluated for their in vitro antibacterial and antifungal activities against pathogenic strains including Staphylococcus aureus (Methicillin resistant strain). The preliminary screening results indicated that some of these compounds demonstrated moderate to very good antibacterial and antifungal activities.     

A convenient route to α-amido-β-lactams

Dedicated to Professor John C. Sheehan on the occasion of his sixty-fifth birthday. A method for the synthesis of α-amido-β-lactams without the intermediacy of an α-amino-β-lactam is described. The appropriate β-keto ester is used for preparing a vinylamino β-lactam via a “Dane salt” by a previously reported method. Oxidation with ruthenium tetroxide and periodic acid of this product leads directly to the desired “V”, or “G” or analogous α-amido side chain.     

A facile synthesis of new β-lactams

Several new β-lactams have been synthesized in good yields, via the cyclization of 3-chloro-N-arylpropionamides in a mixture of N, N-dimethylformamide and anhydrous sodium carbonate under a nitrogen atmosphere.     

Novel synthesis of 3-pyrrole substituted β-lactams via microwave-induced bismuth nitrate-catalyzed reaction

Highly stereoselective synthesis of 3-pyrrole substituted β-lactams is accomplished. The first step involves the synthesis of 3-phthalimido substituted β-lactams following Staudinger cycloaddition reaction of acid chloride equivalent with imines. Synthesis of 3-amino β-lactams is achieved via the deprotection of phthalimido group with ethylenediamine. These 3-amino β-lactams are converted to a new series of N-substituted pyrroles at room temperature as well as using microwave-induced bismuth nitrate-catalyzed reaction with an excellent yield. Exclusive formation of trans pyrrole-substituted β-lactams is observed with N-chrysenyl system. The method is equally efficient for the synthesis of racemic as well as optically pure 3-pyrrole substituted β-lactams.     

Isomer differentiation and structural characterization of penem β-lactam antibiotics by mass-analyzed ion kinetic energy spectrometry

A number of clinically significant penem β-lactams, both free acids and sodium salts, were investigated by mass-analyzed ion kinetic energy spectrometry (MIKES) following fast atom bombardment (FAB) ionization. The collisionally activated dissociation (CAD) products of [M + H] ⁺ and [M + Na]⁺ ions are described. Carbon dioxide loss was observed for some of the free acids, whereas a daughter ion generated by β-lactam ring cleavage was characteristic of the sodiated species. Other fragments included successive cleavages and rearrangements of the substituent side-chain, permitting complete characterization of these chains. The fragmentation pattern for both protonated and sodiated species were more clearly established by CAD MIKES than by normal FAB mass spectral analyses. A notable feature of this technique was its ability to differentiate between pairs of regioisomeric penems on the basis of their fragmentation patterns. These compounds could not be differentiated in the usual mass spectra.     

Synthesis of monodisperse polyamides by living anionic polymerization of β-lactams in the mixture of N,N-dimethylacetamide and lithium chloride

Living anionic polymerization of two kinds of methyl-substituted β-lactams, 3,3-dimethyl-, and 4,4-dimethyl-2-azetidinones, was attained at 25°C in N,N-dimethylacetamide containing 5 wt % of lithium chloride and proceeded in a homogeneous phase quantitatively. The resulting polyamides were found to have a narrow molecular weight distribution from the gel permeation chromatography. The number average molecular weights estimated from the peak intensities in the ¹H-NMR spectra were almost equal to those calculated from the mol ratio of the consumed lactam to the corresponding N-benzoyl derivative used as an activator. In addition, the acyllactam-type growing chain ends were modified quantitatively by the reaction with benzylamine after the polymerization. © 1995 John Wiley & Sons, Inc.     

Development of a direct ELISA based on carboxy-terminal of penicillin-binding protein BlaR for the detection of β-lactam antibiotics in foods

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.

Ruthenium catalysts for carbenoid intramolecular C-H insertion of 2-diazoacetoacetamides and diazomalonic ester amides

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.     

Copper-Catalyzed Oxidative Benzylic C(sp3)−H Cyclization for the Synthesis of β-Lactams

β-Lactams are important structural motifs because of their ubiquity in natural products and pharmaceuticals. We report herein a Cu-catalyzed intramolecular oxidative C(sp³)−H amidation for the synthesis of β-lactams using tBuOOtBu. This method is based on Kharasch–Sosnovsky amidation and does not require prefunctionalization of C(sp³)−H bonds or the installation of a directing group, thereby allowing for the straightforward synthesis of β-lactams. Our intramolecular functionalization protocol can be extended to diverse benzylic C(sp³)−H bonds and shows excellent functional-group tolerance.     

Rate constants for the gas-phase reactions of OH radicals with β-dimethylstyrene and acetone. Mechanism of ββdimethylstyrene NOx – air photooxidation

The rate constants of gas-phase reactions of the hydroxyl radical with β-dimethylstyrene and acetone have been determined by a relative method at 298 K. The values obtained are β-dimethylstyrene (3.3 ± 0.5) × 10^?11 cm³/molecule·s and acetone (6.6 ± 0.9) × 10^?13 cm³/molecule·s. A simplified kinetic treatment of the experimental data shows that β-dimethylstyrene is stoichiometrically converted to benzaldehyde and acetone. In the photooxidation study of benzaldehyde, carbon dioxide was the only detected product. The ratio between carbon dioxide produced and benzaldehyde reacted was ≥1.     

Cycloadditions of ketenes with cyclic carbodiimides

The cycloaddition of ketenes with cyclic carbodiimides yields β-lactams in good to excellent yields. The cycloaddition of equal molar amounts of diphenyl-, phenylethyl- and phenylketenes with cyclic carbodiimides produced a 1:1 cycloaddition product, the expected β-lactams. However, the cycloaddition of a 2:1 molar ratio of diphenyl- and phenylketenes with 1,3-diazacycloocta-1,2-diene respectively, gave the 2:1 cycloadducts, the tricyclodi-β-lactams. The cycloaddition of methylchloro- and dichloroketenes yielded β-lactams that were very susceptible to hydrolysis to the N-substituted cycloureas. A trapping experiment suggests that these reactions proceed through a stabilized dipolar intermediate.     

Isomer differentiation via collision‐induced dissociation: The case of protonated α‐, β2‐ and β3‐phenylalanines and their derivatives

A combination of electrospray ionisation (ESI), multistage and high‐resolution mass spectrometry experiments is used to examine the gas‐phase fragmentation reactions of the three isomeric phenylalanine derivatives, α‐phenylalanine, β²‐phenylalanine and β³‐phenylalanine. Under collision‐induced dissociation (CID) conditions, each of the protonated phenylalanine isomers fragmented differently, allowing for differentiation. For example, protonated β³‐phenylalanine fragments almost exclusively via the loss of NH₃, only β²‐phenylalanine via the loss of H₂O, while α‐ and β²‐phenylalanine fragment mainly via the combined losses of H₂O + CO. Density functional theory (DFT) calculations were performed to examine the competition between NH₃ loss and the combined losses of H₂O and CO for each of the protonated phenylalanine isomers. Three potential NH₃ loss pathways were studied: (i) an aryl‐assisted neighbouring group; (ii) 1,2 hydride migration; and (iii) neighbouring group participation by the carboxyl group. Finally, we have shown that isomer differentiation is also possible when CID is performed on the protonated methyl ester and methyl amide derivatives of α‐, β²‐ and β³‐phenylalanines. Copyright © 2010 John Wiley & Sons, Ltd.     

Stereoselective synthesis and characterization of monocyclic cis-β-lactams containing 5-methyl-1,3,4-thiadiazole-2-thiol moiety

This article describes the stereoselective synthesis of monocyclic cis-β-lactams. The 2-(4-chlorophenoxy)-acetic acid or 2-phenoxy-acetic acid with a carboxylic acid activator 2-ethoxy carbonyl DCPN generate ketene in situ, which reacts with imines derived from substituted tetralone carbaldehyde yielded monocyclic cis-β-lactams having 5-methyl-1,3,4-thiadiazole-2-thiol moiety through [2+2] cyclo-addition reaction (Staudinger reaction). All structures of cis-β-lactams were elucidated by a spectral technique like FT-IR, ¹H and ¹³C NMR spectra, HRMS, and single X-ray crystallography. The cis configuration of the β-lactams was determined based on coupling constant (J) value using ¹H NMR for hydrogens H-3 and H-4 of the β-lactams ring. This work presents the synthesis of β-lactams more simply with high yields. The products were simply purified by crystallization technique.