Carbapenem and penem antibiotics. V. Synthesis and antibacterial activity of 2-functionalized-methyl 1-methylcarbapenems related to asparenomycins

The synthesis of 1 alpha- and/or 1 beta-methylcarbapenems, 2-unsubstituted and 2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl derivatives having a 1-(hydroxy)methylethylidene or cyclic carbonate side chain at the C-6 position, is described. The in vitro antibacterial activities of these compounds and their corresponding 1-unsubstituted carbapenems are compared.     

Synthetic study of carbapenem antibiotics I. (±)-2-cyclopropyl-6-(1′-hydroxyethyl)-1-carbapen-2-em-3-carboxylic acid

A synthetic scheme extensively utilizing silylation-desilylation reactions to achieve the total synthesis of 2,6-substituted carbapenem antibiotics from readily available azetidinones is reported. An epimeric pair of new 2,6-substituted carbapenems, (±)-2-cyclopropyl-6-(1′-hydroxyethyl)-1-carbapen-2-em-3-carboxylic acids were synthesized.     

The preparation and reactions of 2-azidocarbapenems

The preparation of 2-azasubstituted carbapenems is reported, wherein reactions of intermediate 2-azides provide the amine, 1,2,3-triazolines, 1,2,3- triazoles, and aziridines.     

Carbapenem and penem antibiotics. VII. Synthesis and antibacterial activity of 1 beta-methyl-2-(quaternary heteroaromatic-thiomethyl) carbapenems

The synthesis and antibacterial activity of a series of 1 beta-methylcarbapenems having quaternary heteroaromatic-thiomethyl groups at the C-2 position are described. Both 2-hydroxymethyl and 2-chloromethyl carbapenems (1 and 7) respectively served as the common key intermediates for the preparation of these compounds. Of these, the 4-pyridiniothiomethyl derivatives exhibited the best antibacterial properties and turned out to possess high in vivo efficacy as well.     

碳青霉烯类抗生素亲水作用色谱方法研究及其应用

建立了测定人尿液和自来水中4种碳青霉烯类抗生素(比阿培南、美罗培南、多利培南和厄他培南)的亲水作用色谱方法,所用流动相具有较好的质谱兼容性,可用于色谱-质谱联用。以XAmide为色谱柱,考察了乙腈比例、缓冲盐浓度和pH值对4种抗生素保留的影响,提出了可能的保留机理;所发展的方法对目标样品具有良好的线性响应:比阿培南、多利培南和厄他培南的线性范围为0.1~250 mg/L, R²=0.9999;美罗培南的线性范围为0.5~250 mg/L, R²=0.9998; 4种抗生素的定量限(LOQ)为0.1~0.5 mg/L。尿液样品和自来水样品在5 mg/L和25 mg/L两个水平的加标回收率分别为100.4%~111.9%和79.6%~107.4%,相对标准偏差(RSD)分别不大于1%和5%。该方法准确、灵敏、简便,可用于人尿液和自来水中多种碳青霉烯类抗生素的检测。     

Stereocontrolled total synthesis of the chiral building block (3S,4R)-3- [(R)-1-hydroxyethyl]-4-acetyloxy-azetidin-2-one: a useful synthon for the synthesis of (+)-thienamycin,carbapenems and penems.

A total stereocontrolled synthesis of ($\text{1}$), an intermediate in the synthesis of (+)-thienamycin, carbapenems and penems, based on a strategy that uses the S(-)hydroxy ethylbutyrate as chiral building block, is reported.     

Structures of OA-6129A,B1, B2 and C,new carbapenem antibiotics

The structures of carbapenems OA-6129A, B₁, B₂ and C were determined by spectroscopy and chemical transformation.     

Practicable synthesis of (1R,4R)-5-(ℓ-menthoxy)-2-azabicyclo[2.2.0]-hex-5-en-3-one and its derivatives: New building blocks for carbapenem nuclei

Enantioselective synthesis of (1R,4R)-2-azabicyclo[2.2.0]-hexane-3,5-dione and (1R, 4R,5S)-5-hydroxy-2-azabicyclo[2.2.0] hexan-3-one (new building blocks for carbapenems) from 4-(ℓ-menthoxy)-pyridin-2(1H)-one via photopyridone formation is reported.     

Synthesis of an optically active 4-acetoxyazetidinone intermediate for penems and carbapenems

The synthesis of the novel (3R,4R)-4-acetoxy-3-[(1S)-1-t- butyldimethylsilyloxymethyl-1-((1S)-1- phenylethylaminocarbonyl)]azetidin-2-one ( 1a ), a valuable key intermediate for penems and carbapenems bearing a 6-hydroxyacetamide side chain, and its diastereomer 1b , from dimethyl cis-2,3-oxirane dicarboxylate, is described. The allocation of absolute configurations to the diastereomers 1a and 1b ensued via single-crystal X-ray analysis of the isomer 1b.     

Trapping and characterization of a reaction intermediate in carbapenem hydrolysis by B. cereus metallo-beta-lactamase

Metallo-beta-lactamases hydrolyze most beta-lactam antibiotics. The lack of a successful inhibitor for them is related to the previous failure to characterize a reaction intermediate with a clinically useful substrate. Stopped-flow experiments together with rapid freeze-quench EPR and Raman spectroscopies were used to characterize the reaction of Co(II)-BcII with imipenem. These studies show that Co(II)-BcII is able to hydrolyze imipenem in both the mono- and dinuclear forms. In contrast to the situation met for penicillin, the species that accumulates during turnover is an enzyme-intermediate adduct in which the beta-lactam bond has already been cleaved. This intermediate is a metal-bound anionic species with a novel resonant structure that is stabilized by the metal ion at the DCH or Zn2 site. This species has been characterized based on its spectroscopic features. This represents a novel, previously unforeseen intermediate that is related to the chemical nature of carbapenems, as confirmed by the finding of a similar intermediate for meropenem. Since carbapenems are the only substrates cleaved by B1, B2, and B3 lactamases, identification of this intermediate could be exploited as a first step toward the design of transition-state-based inhibitors for all three classes of metallo-beta-lactamases.     

A New Mechanism for β‐Lactamases: Class D Enzymes Degrade 1β‐Methyl Carbapenems through Lactone Formation

β‐Lactamases threaten the clinical use of carbapenems, which are considered antibiotics of last resort. The classical mechanism of serine carbapenemase catalysis proceeds through hydrolysis of an acyl‐enzyme intermediate. We show that class D β‐lactamases also degrade clinically used 1β‐methyl‐substituted carbapenems through the unprecedented formation of a carbapenem‐derived β‐lactone. β‐Lactone formation results from nucleophilic attack of the carbapenem hydroxyethyl side chain on the ester carbonyl of the acyl‐enzyme intermediate. The carbapenem‐derived lactone products inhibit both serine β‐lactamases (particularly class D) and metallo‐β‐lactamases. These results define a new mechanism for the class D carbapenemases, in which a hydrolytic water molecule is not required.     

Double cyclization of aminophosphonoacetate derived β- hydroxyacids to bicyclic β-lactams

The carbon framework for carbapenems was constructed by an asymmetric aldol condensation and subsequent direct coupling of the resulting β-hydroxy acid equivalent with an aminophosphonoacetate. Cyclization to the monocyclic β-lactam 20 was followed by oxidative elaboration to the penultimate aldehyde 22 which was converted to carbapenem 23 by an intramolecular version of a Horner-Emmons cyclization.     

2-Polyfluoroalkylchromones. 8. 2-Trifluoromethyl- and 6-nitro-2-trifluoromethylchromones in reactions with amines

The reactions of 6-nitro-2-trifluoromethylchromone with benzylamine, ethanolamine, and aniline afforded 3-benzyl(2-hydroxyethyl,phenyl)amino-4,4,4-trifluoro-1-(2-hydroxy-5-nitrophenyl)but-2-en-1-ones, respectively, whereas the reactions with ethylenediamine and diethylenetriamine gave rise to 5-(2-hydroxy-5-nitrophenyl)-7-trifluoromethyl-2,3-dihydro-1H-1,4-diazepine and 5-(2-hydroxy-5-nitrophenyl)-7-trifluoromethyl-1,4,8-triazabicyclo[5.3.0]dec-4-ene, respectively. Morpholine added at the double bond of 2-trifluoromethyl- and 6-nitro-2-trifluoromethylchromones to form 2-morpholino-2-trifluoromethylchroman-4-one and its 6-nitro-substituted analog, respectively, whereas piperidine reacted only with 2-trifluoromethylchromone to yield 2-piperidino-2-trifluoromethylchroman-4-one.     

2'-C-branched ribonucleosides. 2. Synthesis of 2'-C-beta-trifluoromethyl pyrimidine ribonucleosides

[structure: see text]. The first synthesis of 2'-C-beta-trifluoromethyl pyrimidine ribonucleosides is described. 1,2,3,5-Tetra-O-benzoyl-2-C-beta-trifluoromethyl-alpha-D-ribofuranose (3) is prepared from 1,3,5-tri-O-benzoyl-alpha-D-ribofuranose (1) in three steps and converted to 3,5-di-O-benzoyl-2-C-beta-trifluoromethyl-alpha-D-1-ribofuranosyl bromide (5). The 1-bromo derivative (5) is found to be a powerful reaction intermediate for the synthesis of ribonucleosides. The reaction of silylated pyrimidines with (5) in the presence of HgO/HgBr2 affords exclusively the beta-anomers (6-8). Deprotection of (6-8) with ammonia in methanol yields the 2'-C-beta-trifluoromethyl nucleosides (9-11).     

1,2-Diacyl-1-arylhydrazines. 1. Derivatives of 2-hydroxy- and 2-halogenobenzoic acids

New 1,2-diacyl-1-arylhydrazines, containing a hydroxy group or a mobile halogen atom in the 1-acyl fragment, were obtained by the reaction of the arylhydrazones of acetyl and benzoyl chlorides with the salts of 2-hydroxy-, 2-acetoxy-, and 2-halogeno-3-nitrobenzoic acids. 1-(2-Hydroxybenzoyl)-1-aryl-2-acylhydrazines could not be converted into cyclic products. On heating in alkaline and acidic media elimination of the more hindered salicyloyl group and not dehydration occurred. When boiled in DMF in the presence of bases, 1-(2-halogeno-3-nitro-5-R-benzoyl)-1-aryl-2-acylhydrazines gave 2-aryl-5-R-7-nitroindazol-3-ones and not the expected 4,5-dihydrobenzo[f]-1,3,4-oxadiazepin-5-ones.A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan' Scientific Center, Russian Academy of Sciences, 420083 Kazan'. Translated fromIzvestiya Akademii Nauk, Seriya Khimicheskaya, No. 6, pp. 1424–1430, June, 1992.     

Pyrimidones. 2. Synthesis and reactions of 2-chloropyrimidines

The treatment of 1-alkyl-5-aryl and 1-alkyl-4,5-diaryl-2-(1H)pyrimidones with phosphorus oxychloride and phosphorus pentachloride resulted in chlorination and dealkylation to furnish 2-chloro-5-aryl (or 4,5-diaryl)-pyrimidines. These chlorpyrimidines were reacted with a variety of nitrogen, oxygen, sulfur, and carbon nucleophiles to produce the corresponding 2-substituted pyrimidines. In the case of phenyllithium, attack occurred at the 4-position of the pyrimidine ring yielding 11 . Triazolopyrimidine 9 was synthesized via the treatment of 2d with hydrazine followed by reaction with triethyl orthoformate.     

Hartree-Fock-Heitler-London method. 2. First and second row diatomic hydrides

The Hartree-Fock-Heitler-London, HF-HL, method is a new ab initio approach which variationally combines the Hartree-Fock, HF, and the Heitler-London, HL, approximations, yielding correct dissociation products. Furthermore, the new method accounts for nondynamical correlation and explicitly considers avoided crossing. With the HF-HL model we compute the ground-state potential energy curves for H2 [1Sigma+g], LiH [X 1Sigma+], BeH [2Sigma+], BH [1Sigma+], CH [2Pi], NH [3Sigma-], OH [2Pi], and FH [1Sigma+], obtaining in average 80% of the experimental binding energy with a correct representation of bond breaking. Inclusion of ionic configurations improves the computed binding energy. The computed dipole moment is in agreement with laboratory data. The dynamical and nondynamical correlation energies for atomic and molecular systems with 2-10 electrons are analyzed. For BeH the avoided crossing of the two lowest [2Sigma+] states is considered in detail. The HF-HL function is proposed as the zero-order reference wave function for molecular systems. To account for the dynamical correlation energy a post-HF-HL technique based on multiconfiguration expansions is presented. We have computed the potential energy curves for H2 [1Sigma+g], HeH [2Sigma+], LiH [X1Sigma+], LiH [A1Sigma+], and BeH [2Sigma+]. The corresponding computed binding energies are 109.26 (109.48), 0.01 (0.01), 57.68 (58.00), 24.19 (24.82), and 49.61 (49.83) kcal/mol, with the experimental values given in parentheses. The corresponding total energies are -1.1741, -3.4035, -8.0695, -7.9446, and -15.2452 hartrees, respectively, the best ab initio variational published calculations, H2 excluded.     

Synthetic studies of carbapenem and penem antibiotics. II. Synthesis of 3-acetyl-2-azetidinones by (2 + 2) cycloaddition of diketene and Schiff bases.

It was found that (2 + 2) cycloaddition reaction of diketene with Schiff bases was effectively promoted by imidazole as a catalyst to afford 3-acetyl-2-azetidinone derivatives 4. As an application of this new method, a practical asymmetric synthesis of 4 and its conversion into (3S,4S)-4-carboxy-1-(di-p-anisylmethyl)-3-[(R)-1-hydroxyethyl]-2- azetidinone, which is a key intermediate for the synthesis of carbapenem and penem antibiotics, were accomplished.     

Stereoselective synthesis of fluorine-containing analogues of anti-bacterial sanfetrinem and LK-157

The synthesis of (1′S,3R,4R)-4-acetoxy-3-(1′-trimethylsilyloxy-2′,2′,2′-trifluoroethyl)-2-azetidinone (10) precursor of modified carbapenems is described relying upon [Ru(C₆Me₆)(S,S)-(CH₂)₅NSO₂DPEN]-catalyzed asymmetric transfer hydrogenation under dynamic kinetic resolution using HCO₂H-Et₃N. This fluorine-containing precursor yielded the targeted trinems 1 and 2 via a stereoselective key step condensation with lithium (S)-6-methoxy-cyclohexenolate.     

Substituted 2-methyl- and 2-methyleneindolines. 2. Nitro- and amino-substituted 2-methyl- and 2-methylene-indolines

From 5- and 6-aminotetramethylindolines, 2-methyleneindolines have been synthesized; these compounds can be condensed with other heterocyclic systems. The nitration of 1,2,3,3-tetramethylindoline under different conditions was studied.For communication 1, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 919–923, July, 1989.