Asymmetric synthesis and antimicrobial activity of some new mono and bicyclic beta-lactams

Reaction of the amino acid D-phenylalanine ethyl ester (4) with cinnamaldehyde gave chiral Schiff base 5, which underwent an asymmetric Staudinger [2+2] cycloaddition reaction with phthalimidoacetyl chloride to give the monocyclic beta-lactam 6 as a single stereoisomer. Ozonolysis of 6 followed by reduction with lithium aluminum tri(tert-butoxy) hydride afforded the hydroxymethyl beta-lactam 8. Treatment of 8 with methansulfonyl chloride gave the mesylated monocyclic beta-lactam 9, which was converted to the bicyclic beta-lactam 10 upon treatment with 1,8-diazabicyclo[5,4.0] undec-7-ene (DBU). Deprotection of the phthalimido group in beta-lactams 6 and 10 by methylhydrazine and subsequent acylation of the free amino beta-lactams with different acyl chlorides in the presence of pyridine afforded mono and bicyclic beta-lactams 14a-d and 15a-d respectively. The compounds prepared were tested against Escherichia coli, Staphilococcus citrus, Klebsiella pneumanie and Bacillus subtillis. Some of these compounds showed potential antimicrobial activities.     

Microwave-assisted decarboxylation of bicyclic 2-pyridone scaffolds and identification of Abeta-peptide aggregation inhibitors

A reagent-free microwave-assisted decarboxylation procedure for carboxylic acid functionalized bicyclic 2-pyridones has been developed. This new method, based on microwave heating at 220 degrees C for 600 seconds in N-methyl pyrrolidone (NMP), proved to be practical and very efficient, resulting in decarboxylated 2-pyridones in near-quantitative yields. The decarboxylated products and the intermediate 2-pyridones in the form of carboxylic acid methyl esters and carboxylic acids were screened for their effect on Abeta-peptide aggregation. Two out of the 21 2-pyridones described in this study inhibited amyloid formation of the Alzheimer Abeta(1-40) peptide. The effect was seen even at a 4 : 1 ratio of 2-pyridone and monomeric Abeta-peptide.     

Synthesis of pyrimidine derivatives of amino acids using pig liver esterase and pancreas lipase.

The parent methyl ester of the N-1 substituted 5-chloropyrimidinone is hydrolysed by pig liver esterase to the corresponding carboxylic acid. The acid chloride was made with PCl5 in toluene, and coupling with benzyl and methyl esters of selected L-amino acids to the corresponding amides was done in dichloromethane in the presence of triethylamine. The benzyl and methyl ester protecting groups were hydrolysed with pancreas lipase or esterase in a pH-stat to yield the corresponding carboxylic acids.     

Synthesis and cyclization reactions of 2-amino-3-[(methoxy-carbonyl)methylsulfonyl]pyrroles and thiophene

The title aminopyrroles and thiophene have been prepared by condensation of methyl (cyanomethyl-sulfonyl)acetate with various α-amino ketones or 2-mercaptoacetaldehyde, respectively. Subsequent cyclization of these compounds by reaction between the amine and activated methylene has led to various ester-substituted thiazine- and thiadiazine-based bicyclic derivatives. In addition, cyclization of the title compounds by intramolecular coupling of the amine and ester has led to the analogous bicyclic thiazin-3(2H)-ones. Attempted hydrolysis of the ester-substituted bicyclics to the corresponding carboxylic acids was unsuccessful.     

Preparation of beta- and gamma-lactams from carbamoyl radicals derived from oxime oxalate amides

A general synthetic route to oxime oxalate amides was developed and applied to the preparation of molecules incorporating N-benzyl-N-alkenyl amides linked with acetone oxime or benzaldoxime units. In addition, 2-substituted-thiazolidine-4-carboxylic acid methyl ester amides of oxalyl benzaldoxime were also prepared. It was shown by EPR spectroscopy that the oxalyl benzaldoxime amides dissociated to produce benziminyl and carbamoyl (aminoacyl) radicals when photolysed with 4-methoxyacetophenone as a photosensitizer. Carbamoyl radicals derived from N-alk-3-enyl oxime oxalate amides underwent ring closure to afford pyrrolidin-2-ones. The analogous N-alk-2-enyl precursors afforded azetidin-2-ones. Reactions of the cyclohexenyl and cinnamyl oxime oxalate amides afforded a bicyclic beta-lactam and a 3-benzyl-substituted beta-lactam respectively. Interestingly, both products were isolated as hydroxylated compounds. A thiazolidine-derived oxime oxalate amide containing an isobutenyl side chain also dissociated with production of the corresponding thiazolidinyl-carbamoyl radical, as shown by EPR spectroscopy. GC-MS evidence indicated that this radical cyclised to afford some of the corresponding penicillin derivative     

Simultaneous gas chromatographic determination of aliphatic C2−C20 n-carboxylic acids and their methyl esters using SE-30 and OV-351 quartz capillary columns

Summary Simultaneous determination of aliphatic C₂–C₂₀ carboxylic acids and their methyl esters was carried out using SE-30 and OV-351 quartz capillary columns with temperature programming. Complete resolution of all 36 components was achieved. On SE-30 the methyl ester and the corresponding free acid are eluted in turn, whereas on OV-351 acetic acid eluted after methyl octanoate, after which the C_n methyl ester and C_n-6 carboxylic acid (n>9) are eluted one after the other. A non-polar SE-30 column is better for long-chain acids giving sharp peaks without tailing, the analysis time of the mixture being less than 16 minutes. The weight response correction factors for compounds under optimum operating conditions are given.     

dM-Dim for carboxylic acid protection

The 1,3-dithian-2-yl-methyl (Dim) and its analogous groups including dimethyl-Dim (dM-Dim) can provide a new dimension of orthogonality for carboxylic acid protection. They can be deprotected under nearly neutral oxidative conditions. In this paper, the protection of carboxylic acid with dM-Dim, deprotection of dM-Dim ester with sodium periodate, stability of dM-Dim protected carboxylic acid under acidic and basic conditions, and selective deprotection of dM-Dim protected carboxylic acids in the presence of tertiary butyl and methyl esters are presented.     

2-Azabicyclo[2.2.1]heptane-3-carboxylic acid - A bicyclic proline

Diels-Alder reaction of cyclopentadiene and methyl N-carbobenzyloxy-2-iminoacetate generated in situ from methyl 2-chloro-N-carbobenzyloxyglycinate by triethylamine gave the N-carbobenzyloxy unsaturated bicyclic proline ester. This was converted in two steps to 2-azabicylo[2.2.1]heptane-3-carboxylic acid. In contrast to N-carbobenzyloxy-L-proline methyl ester, the corresponding bicyclic proline ester was resistant to hydrolysis catalyzed by carboxypeptidase Y.     

Synthesis and Evaluation of a Cyclophane Receptor for Acetic Acid

A bicyclic cyclophane ( 2 ) containing one pyridine nitrogen and four amide N-H groups oriented toward the interior of the cavity was synthesized. The binding constants of various carboxylic acids with 2 were measured by UV/Vis spectroscopy. Acetic acid bound to 2 with a K a of 980 - 90 M m 1 in chloroform while branched carboxylic acids showed significantly lower binding. The data indicate that acetic acid was bound within the cavity of 2 . Only one acetic acid binds to two control hosts, whereas 2 shows definitive 1:1 binding. The results suggest that selectivity in the binding of carboxylic acids can be achieved via size constraints dictated by the receptor cavity, and that the same size restrictions lead to only one carboxylic acid bound to the cyclophane. The crystal structure of 2 is reported.     

N,N-Dimethylchlorosulfitemethaniminium chloride (SOCl2-DMF) a versatile dehydrating reagent.

N,N-dimethylchlorosulfitemethaniminium chloride formed from thionyl chloride and dimethylformamide was found and efficient reagent for the synthesis of acyl azides from carboxylic acids and nitriles from oximes. It is also highly efficient for the direct synthesis of beta-lactams from carboxylic acids and imines avoiding the use of acid chlorides.     

Stereoselective synthesis of novel uracil polyoxin C conjugates as substrate analogues of chitin synthase

Stereoselective syntheses of both the natural (C5'- S) and unnatural (C5'- R) diastereoisomers of uracil polyoxin C methyl ester have been developed. The key stereocontrolled step involves nucleophilic addition of trimethylsilyl cyanide to the appropriate chiral sulfinimine derived from 2',3'-protected 5'-formyluridine and (S)-(-)-tert-butanesulfinamide or (R)-(+)-tert-butanesulfinamide, respectively. A variety of substrate mimics designed to function as inhibitors of chitin synthase have been synthesized by conjugation of the methyl ester of uracil polyoxin C (UPOC) with activated isoxazole carboxylic acids. Amide bond formation was accomplished via coupling of the amino functionality of UPOC methyl ester with a free isoxazole acid using HBTU or alternatively an isoxazole pentafluorophenyl ester. The substrate mimics incorporate features of the nucleoside-peptide antibiotics, the polyoxins and the nikkomycins, as well as features of the transition state structure expected during polymerization of the natural chitin synthase substrate uridine diphosphoryl-N-acetylglucosamine (UDP-GlcNAc), namely, a metal-binding site and glycosyl oxocarbenium ion mimic.     

SmI(2)-mediated cyclizations of derivatized beta-lactams for the highly diastereoselective construction of functionalized prolines

A series of C4-keto-functionalized 1-[(benzoyloxy)(ethoxycarbonyl)methyl]-2-azetidinones were prepared and studied for their tendency to undergo a Reformatsky-type cyclization to fused bicyclic or tricyclic beta-lactams with the single-electron reducing agent samarium diiodide. Whereas the azetidinone 21a underwent reductive cyclization, affording the potent antibiotic sanfetrinem's tricyclic [4.5.6] core structure as the major component, all other examples tested resulted in cyclization followed by an N to O acyl migration involving cleavage of the beta-lactam ring as the favored pathway. Highly functionalized proline derivatives were therefore accessed as single diastereomers through the reductive cyclization of benzoates 21b, 22, 23a,b, 24b, and 25-28. Pertinent for the success of these cyclizations was the addition of 1 equiv of tert-butyl alcohol, allowing for the protonation of the basic amide derivative obtained after the acyl migration step. The diastereoselectivities of these reactions deviate from those of similar cyclizations involving the corresponding lithium enolate. This divergence could be rationalized by the coordination of the metal ion of the samarium(III) enolate intermediate to the beta-lactam amide functionality in the cyclization step, which may not be possible for lithium enolates.     

Synthesis of cyclopentathiophenacetic acid derivatives. Reactivity of methyl 6-oxo-4,5-dihydro-6H-cyclopenta[b]thiophen-4-acetate

Oxodihydrocyclopentathiophenacetic acids 4 , 5 and 6 were synthesized from suitable 2- or 3-formylthiophenes. Reactivity of the carbonyl group or the carboxylic group of these bicyclic systems was investigated. The Beckmann rearrangement of methyl 6-oximino4,5-dihydro-6H-cyclopenta[b]thiophen-4-acetate 12 is an interesting route to methyl 7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-acetate ( 13 ).     

Energetic, structural, and antimicrobial analyses of beta-lactam side chain recognition by beta-lactamases

BACKGROUND: Penicillins and cephalosporins are among the most widely used and successful antibiotics. The emergence of resistance to these beta-lactams, most often through bacterial expression of beta-lactamases, threatens public health. To understand how beta-lactamases recognize their substrates, it would be helpful to know their binding energies. Unfortunately, these have been difficult to measure because beta-lactams form covalent adducts with beta-lactamases. This has complicated functional analyses and inhibitor design. RESULTS: To investigate the contribution to interaction energy of the key amide (R1) side chain of beta-lactam antibiotics, eight acylglycineboronic acids that bear the side chains of characteristic penicillins and cephalosporins, as well as four other analogs, were synthesized. These transition-state analogs form reversible adducts with serine beta-lactamases. Therefore, binding energies can be calculated directly from K(i) values. The K(i) values measured span four orders of magnitude against the Group I beta-lactamase AmpC and three orders of magnitude against the Group II beta-lactamase TEM-1. The acylglycineboronic acids have K(i) values as low as 20 nM against AmpC and as low as 390 nM against TEM-1. The inhibitors showed little activity against serine proteases, such as chymotrypsin. R1 side chains characteristic of beta-lactam inhibitors did not have better affinity for AmpC than did side chains characteristic of beta-lactam substrates. Two of the inhibitors reversed the resistance of pathogenic bacteria to beta-lactams in cell culture. Structures of two inhibitors in their complexes with AmpC were determined by X-ray crystallography to 1.90 A and 1.75 A resolution; these structures suggest interactions that are important to the affinity of the inhibitors. CONCLUSIONS: Acylglycineboronic acids allow us to begin to dissect interaction energies between beta-lactam side chains and beta-lactamases. Surprisingly, there is little correlation between the affinity contributed by R1 side chains and their occurrence in beta-lactam inhibitors or beta-lactam substrates of serine beta-lactamases. Nevertheless, presented in acylglycineboronic acids, these side chains can lead to inhibitors with high affinities and specificities. The structures of their complexes with AmpC give a molecular context to their affinities and may guide the design of anti-resistance compounds in this series.     

Lewis acid-promoted intermolecular carbonyl-ene reaction of enantiopure 4-oxoazetidine-2-carbaldehydes. Rapid entry to novel fused polycyclic beta-lactams

Lewis acid-promoted carbonyl-ene reaction of enantiomerically pure 4-oxoazetidine-2-carbaldehydes with various activated alkenes gives 4-[(1'-hydroxy)homoallyl]-beta-lactams with a very high level of syn diastereofacial selectivity. The above homoallylic alcohols are used for the diastereoselective preparation of fused bicyclic, tricyclic, and tetracyclic beta-lactams of nonconventional structure using tandem one-pot radical addition/cyclization or elimination-intramolecular Diels-Alder sequences. In addition, a novel domino process was discovered, the C4-N1 beta-lactam bond breakage/intramolecular Diels-Alder reaction.     

GC—MS analysis of carboxylic acids in petroleum after esterification with fluoroalcohols

The GC–MS characteristics of carboxylic acid esters prepared from fluorine-containing alcohols were compared to those of methyl esters. The GC retention of 2,2,2-trifluoroethyl (TFE) esters was less than, and 2,2,3,3,4,4,4-heptafluoro-1-butyl (HFB) esters was approximately equivalent to that of methyl esters. Mass spectra of TFE and HFB aliphatic esters show significantly more intense molecular and key fragment ions than those of methyl esters. Also, owing to their significantly higher molecular weights, TFE or HFB ester molecular ions and most fragment ions of interest occur at significantly higher m/z values than most potential interfering ions. Data for about 70 individual TFE and HFB esters are reported. Application of the methodology to a petroleum-derived carboxylic acid concentrate resulted in identification of straight chain, isoprenoid, methyl-substituted straight chain (2-, 3-, 5-,10-, 12-positions along chain), and dimethyl-substituted straight chain acids containing from 11 to 22 carbons. Benzoic acid and homologs with up to 3-carbons in alkyl substitutents were minor components in the sample. The procedure provided for forming TFE and HFB esters from free acids requires less time and effort than a previously reported method, while retaining its capability for achieving essentially quantitative conversion. Free hydroxyl groups in alcohols and phenols are converted to trifluoroacetate esters concurrently with formation of TFE/HFB carboxylic acid esters. The reaction products, including compounds with two functional groups (diacids, salicylic acid, etc.), chromatograph well on conventional nonpolar GC stationary phases.     

Mild and efficient boronic acid catalysis of Diels-Alder cycloadditions to 2-alkynoic acids

The concept of boronic acid catalysis (BAC) for the activation of unsaturated carboxylic acids is applied to the Diels-Alder cycloaddition between 2-alkynoic acids as dienophiles and various dienes. These [4+2] cycloadditions produce cyclohexadienyl carboxylic acids, which can be oxidized in situ to produce polysubstituted aromatic carboxylic acids. The boronic acid catalyst is suspected to provide activation by a LUMO-lowering effect of the unsaturated carboxylic acid likely via a covalent, monoacylated hemiboronic ester intermediate.     

Alkylation of Carboxylate Salts of Acidic Herbicides for Gas Chromatographic Analysis

Abstract

The methyl esters of 2-methoxy-3, 6-dichlorobenzoic acid and three phenoxyacetic acids were prepared by the admixture of an excess of both methyl iodide and anhydrous alkali-metal carbonate to a solution of the carboxylic acids in acetone. The reaction was completed within the shortest period of time when cesium carbonate was used, and the reaction mixture was injected without further work-up into a gas chromatograph fitted with a flame ionization detector. Further reduction of reaction time was achieved by heating the mixture to 50°C and by ultrasonic treatment; this technique is also suitable for esterification of microliter quantities and obviates the need for a microrefluxer. Butylesters of 2, 4-D and 2, 4, 5-T were prepared in an analogous manner. The methyl esters of 2, 4-D and 2, 4, 5-T, and the butyl ester of 2, 4-D were obtained in better than 90% yield.     

Triphenylphosphine dibromide and dimethylsulfide dibromide as versatile reagents for beta-lactam synthesis

Triphenylphosphine dibromide and dimethylsulfide dibromide are efficient reagents for the direct synthesis of beta-lactams from carboxylic acids and imines avoiding the use of acid halides as starting materials. Synthesis of 4-imino-beta-lactams are also briefly described. A potential synthesis of N-unsubstituted beta-lactams is made.     

Synthesis of acids in the polyacetylenic series

Summary Based on the methyl ester of hepta-4,6-diynoic acid, we synthesized several dicarboxylic and hydroxy carboxylic acids of the triacetylenic series, and also the dimethyl ester of tetradeca-4,6,8,10-tetrayn-1,14-dioic acid.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 3, pp. 544–546, March, 1965