Theoretical Calculations of β-Lactam Antibiotics. Part VII. Influence of the solvent on the basic hydrolysis of the β-lactam ring

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).     

Alkaline hydrolysis of cephaloridine: An 1H?NMR study. Temperature dependence of the rate constants

A kinetic study on the basic hydrolysis of cephaloridine at pD= 10.5 was carried out by using the ¹H? NMR technique. Epimerization at H₇, a nucleophilic attack of hydroxyl ion on the β-lactam carbonyl group followed by the release of the pyridine molecule, and isomerization of the double bond at position 3 in the dihydrothiazine ring were the major reactions observed. Based on the results obtained, it should be emphasized that the presence of a pyridine group at 3′ results in a slightly increased formation constant for the exo methylene compound relative to other cephalosporins with different substituents at that position. The activation energy for the epimerization constant and the cleavage of the β-lactam ring at pD 10.5 was 21.2 kcal/mol. © 1993 John Wiley & Sons, Inc.     

The Degradation Mechanism of an Oral Cephalosporin: Cefaclor

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.     

The Driving Force for the Acylation of β-Lactam Antibiotics by L,D-Transpeptidase 2: Quantum Mechanics/Molecular Mechanics (QM/MM) Study

β-lactam antibiotics, which are used to treat infectious diseases, are currently the most widely used class of antibiotics. This study focused on the chemical reactivity of five- and six-membered ring systems attached to the β-lactam ring. The ring strain energy (RSE), force constant (FC) of amide (C−N), acylation transition states and second-order perturbation stabilization energies of 13 basic structural units of β-lactam derivatives were computed using the M06-2X and G3/B3LYP multistep method. In the ring strain calculations, an isodesmic reaction scheme was used to obtain the total energies. RSE is relatively greater in the five-(1a–2c) compared to the six-membered ring systems except for 4b, which gives a RSE that is comparable to five-membered ring lactams. These variations were also observed in the calculated inter-atomic amide bond distances (C−N), which is why the six-membered ring lactams C−N bond are more rigid than those with five-membered ring lactams. The calculated ΔG^# values from the acylation reaction of the lactams (involving the S−H group of the cysteine active residue from L,D transpeptidase 2) revealed a faster rate of C−N cleavage in the five-membered ring lactams especially in the 1–2 derivatives (17.58 kcal mol⁻¹). This observation is also reflected in the calculated amide bond force constant (1.26 mDyn/A) indicating a weaker bond strength, suggesting that electronic factors (electron delocalization) play more of a role on reactivity of the β-lactam ring, than ring strain.     

Studies on the Biosynthesis of Tabtoxin (Wildfire Toxin). Origin of the Carbonyl C-Atom of the β-Lactam Moiety from the C1-Pool

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 .     

Comparative studies on the concerted and two-step mechanism of ketene-methylenimine cycloaddition

The concerted reaction mechansim of the ketene-methylenimine cycloaddition reaction was reconfirmed by IRC calculation at HF/6-31G level.Other possible reaction schemes were also studied.The cis and gauch intermediate cannot be found on the potential energy surface,and the trans intermediate can only lead to a 6-membered ring product.Therefore,a two step mechanism to form β-lactam is excluded for the title reaction.     

Ab initio study of β-lactam antibiotics. II. Potential energy surface for the amidic CN bond breaking in the 3-cephem + OH− reaction and comparison with the β-lactam + OH− reaction

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.     

Stereomodulating effect of remote groups on the NADH-mimetic reduction of alkyl aroylformates with 1,4-dihydronicotinamide-β-lactam amides

Conformationally restricted NADH peptidomimetics 4a-e, characterized by the presence of a (1,4-dihydronicotinamide)-(β-lactam) moiety, have been synthesized and used to study the Mg²⁺ cation-promoted asymmetric reduction of alkyl aroylformates in acetonitrile. Increasing the bulkiness of peripheral substituents at the nitrogen atom of the β-lactam ring, at the 1,4-dihydronicotinamide moiety, or at the aroylformate ester group, was found to cause weak but clearly detectable variations of the enantiomeric excess of the reaction. A rational for these observations was consistent with a chelated NADH/Mg²⁺/ArCOCO₂R³ ternary complex model, according to DFT calculations computed at a B3LYP/6-31G^∗ theory level.     

Computational and Experimental Evidence of Two Competing Thermal Electrocyclization Pathways for Vinylheptafulvene

The thermal electrocyclic ring‐closure reaction of vinylheptafulvene (VHF) to form dihydroazulene (DHA) is elucidated herein by using DFT and ¹H NMR spectroscopy. Two different transition states were found computationally; one corresponds to a disrotatory pathway, which is allowed according to the Woodward–Hoffmann selection rules, whereas the other corresponds to a conrotatory pathway. The conrotatory pathway is found to be zwitterionic in the transition state, whereas the disrotatory transition state varies in zwitterionic character depending on solvent and substituents in the molecular framework. The conrotatory and disrotatory transition states are found to have similar energy and their relative stability varies with solvent polarity and functionalization at the C1 position. To support these findings, we chemically ring‐opened diastereomerically pure 1‐(benzothiazol‐2‐yl)‐DHA to give the VHF form, then subsequently thermally reconverted the VHF to DHA in a range of solvents with various polarities. We found that, depending on solvent polarity, different ratios of anti‐ and syn‐diastereoisomers of DHA were formed in a systematic manner, which supports the existence of two distinct thermal ring‐closure pathways for VHF.     

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.     

Theoretical study of ester enolate–imine condensation route to β-lactams

The condensation reaction of the enolate of methyl acetate with formaldimine to afford a β-lactam was studied using the MP2-FC/6-31+G* level of theory taking into account the electrostatic effect of the solvent by means of a self-consistent reaction field continuum model. The reaction is a stepwise process with three main steps: the formation of the C3(SINGLE BOND)C4 bond, the closure of the β-lactam ring, and the elimination of the methoxide ion. The formation of the C3(SINGLE BOND)C4 bond is rate determining and according to our calculations is not a reversible step. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 1826–1833, 1998     

Dihydrobenzopyran skeleton from β-lactams: a stereoselective ring opening–ring closure reaction sequence

Sodium borohydride treatment of the enantiomerically pure tricarbonyl(η⁶-arene) chromium(0) complexed β-lactam 7 promoted a stereoselective ring opening–ring closure reaction sequence leading to the novel dihydrobenzopyran derivative 9 in good yield.     

Inclusion of parabens in β-cyclodextrin: A solution NMR and X-ray structural investigation

A parallel study was conducted of the inclusion of alkyl parabens (guests) in the host β-cyclodextrin (β-CD). ¹H NMR data indicated an insertion of the guest phenyl ring into the β-CD cavity. The stoichiometry of each complex was 1:1, as determined by a continuous variation method that utilises the chemical shifts of the host protons. These chemical shifts were additionally used to determine the association constant yielding K values of 1631, 938, 460 and 2022 M^? 1 at 298 K for the methyl-, ethyl-, propyl- and butyl paraben solution state complexes, respectively. NOE experiments conducted on the methyl paraben solution complex indicated that the phenolic group of the guest was located at the secondary rim of the cyclodextrin cavity. Solid state structure analyses of the methyl and propyl paraben β-CD complexes were performed. Both complexes crystallised at ambient temperature in the space group C2, Z = 4 with a host to guest ratio of 1:1. Additionally, a second crystal structure between methyl paraben and β-CD is reported. This complex crystallised at 7^oC in the space group P1, Z = 2 with a 1:1 host–guest stoichiometry.

¹H NMR and solid state structure analyses were conducted on the inclusion of alkyl parabens in the host β-cyclodextrin. Both indicated an insertion of the guest phenyl ring into the β-CD cavity.     

Synthetic studies on chartelline C: stereoselective construction of the core skeleton

What a core-ker! The title synthesis was achieved using a route featuring an intramolecular Mitsunobu reaction of a nosyl amide, stereoselective construction of the β-lactam, and formation of an enamide moiety by selenoxide elimination. The stereochemistry of the alkylation for the formation of the β-lactam was controlled by a secondary hydroxy group on the ten-membered ring. SEM=2-(trimethylsilyl)ethoxymethyl; TBS=tert-butyldimethylsilyl.     

A 13C-NMR spectral study of cellulose and glucopyranose dissolved in the NH3/NH4SCN solvent system

The ¹³C-NMR chemical shifts of a cellulose with a DP_w of 23 dissolved in the NH₃/NH₄SCN solvent system were found to be very similar to those of cellulose dissolved in DMSO (cellulose oligomers), in the LiCl/DMAC system and in the N-methylmorpholine N-oxide/DMSO system. It was concluded from this that cellulose does not react with the NH₃/NH₄SCN solvent. It was found, however, that glucose reacts with the solvent at C-1 to form β-D -glucopyranosy-lamine. Separation of this compound from the solvent resulted in another compound which was determined to be β,β-di-D -glucopyranosylamine. The compounds β-D -glucopyranosylamine, N-acetyl-2,3,4,6-tetra-O-acetyl-β-D -glucopyranosylamine, β,β-di-D -glucopyranosylamine, α,β-di-D -glucopyranosylamine, 2,3,4,6,2′,3′,4′,6′-octa-O-acetyl-α,β-di-D -glucopyranosylamine were all synthesized and the ¹³C-NMR chemical shifts of these compounds are reported. It was also found that for the low-DP cellulose sample which was used the reducing end group existed and had reacted with the solvent to form an amine at C-1.     

HPLC and 1H-NMR Studies of Alkaline Hydrolysis of Some 7-(Oxyiminoacyl)cephalosporins

Alkaline hydrolysis (pH 10.5) of the three 7-(oxyiminoacyl)cephalosporins 1a–c (cefuroxime, ceftazidime, and ceftriaxone) was studied at 37° using HPLC and ¹H-NMR techniques. The 7-epicephalosporin 2 , the 3-methylidene compound 3 , and the 6-epimer 4 of the 3-methylidene compound 3 were identified for each cephalosporin as the major degradation products under the conditions used; ceftazidime ( 1b ) yielded also the Δ²-isomer 5b (Scheme 1). A kinetic scheme was developed to account for the production of these compounds, and the different kinetic constants involved in the process were calculated. The experimental results show that the presence of a pyridinio group at position C–C(3) favours the appearance of the Δ²-isomer, which was detected mainly in cephalosporins bearing an ester function at C(4). The presence of an oxyimino group at C? CONH? C(7) facilitates epimerization at C(7) (→ 2 ), whereas that of an electron-withdrawing group at C? C(3) results in a increased formation constant for the 3-methylidene compound 3 . The 3-methylidene compounds 3a–c produced by the three cephalosporins on cleavage of the β-lactam ring all underwent epimerization at C(6) to yield the corresponding 6-epimer 4 .     

Studies of amine-induced ring opening of some mesoionic xanthines

The ring-opening reactions of seven mesoionic thiazolo[3,2-a]pyrimidine-5,7-diones by a series of primary and secondary amines have been investigated. The rates of the ring fission of five N(8)-substituted mesoionic xanthines with benzylamine were measured and found to follow second order kinetics. The Hammett relationship is followed with ? value of + 0.48 in p-dioxane as solvent. The dependence of rates on temperatures has been studied for the N(8)-ethyl derivative; the energy of activation (Δ E* ) is 25.3 kcals mol^?1, the enthalpy of activation (Δ H* ) is 24.7 kcals mol^?1 and the entropy of activation (Δ S* ) is — 4.9 e.u. A slight increase in rate of reaction was observed when the solvent was changed from p-dioxane to dimethyl sulfoxide. In p-dioxane at constant mesoionic xanthine concentration, the rate constant for ring opening decreased with increasing benzylamine concentration. These results are consistent with a bimolecular nucleophilic mechanism proceeding by the rate-determining formation of a charged tetrahedral transition state.     

Theoretical calculations of β-lactam antibiotics. V. AM1 calculations of hydrolysis of cephalothin in gaseous phase and influence of the solvent

A comprehensive study on the gas-phase alkaline hydrolysis of cephalosporins by using the semiempirical AM1 method was carried out. Cephalothin was the model compound used on account of the presence of a good leaving group at C(3′). According to the results obtained, the hydrolysis process takes place via a twostep reaction mechanism that involves the formation of an intermediate with a fully open β-lactam ring that still preserves the acetate group. Likewise, the exo methylene end product is chiefly formed by nucleophilic attack on the β-lactam carbonyl group of cephalosporins containing a good leaving group at C(3′). On the other hand, the alternative mechanism involving hydrolysis of the ester function in the side chain at 3′ and subsequent hydrolysis of the resulting β-lactam yieds essentially the corresponding enamine. The presence of a first solvation layer consisting of five water molecules showed that, even though some potential barriers are slightly increased, the mechanism involved is identical to that of the gas-phase hydrolysis of this antibiotic. © John Wiley & Sons, Inc.     

Synthesis of N,4-diaryl substituted β-lactams via Kinugasa cycloaddition/rearrangement reaction

The methodology of construction of N,4-diaryl substituted β-lactam framework, based on the Kinugasa cycloaddition/rearrangement sequence is presented. The series of protected chiral propargyl alcohols was treated with diaryl nitrones to afford mainly the cis-I adduct, providing direct access to the highly-functionalized azetitidin-2-one derivatives with a well-defined stereochemistry. Under the optimized reaction conditions, the unprotected chiral propargylic alcohols were also found to be suitable precursors of β-lactams. The absolute configuration of adducts was determined by CD or HPLC-CD technique, which was shown to be reliable method of determination of the configuration at C-4 of 4-aryl-substituted azetidin-2-ones. Epimerization of the cis adduct to the respective trans isomer could be easily done by the oxidation of hydroxyl group next to the four-membered β-lactam ring to the ketone, followed by a base-mediated epimerization of the malonyl fragment.     

Exploring the transfer of hydrogen atom from kaempferol-based compounds to hydroxyl radical at ground state using PCM-DFT approach

Thermodynamic and kinetic studies of the hydrogen atom transfer (HAT) from hydroxyl (OH) groups of four kaempferol-based compounds, namely kaempferol, morin, morin-5^*-sulfonate and morin-7-O-sulfate to hydroxyl radical (·OH), have been carried out using density functional theory (DFT) methods at the CAM-B3LYP/6–311++G(d,p) level equipped with polarizable continuum model (PCM) of solvation. All HAT reactions in aqueous solution are exothermic and spontaneous. For most compounds, the most preferable OH group for HAT is situated at position C3 (O3-H3) on the pyrone ring. The reaction potential of such a reactive group is found to be highest in morin-7-O-sulfate. The rate constants for the HAT reactions at different OH groups of each compound have been determined based on the transition state theory. The presence of substituents leads to the variation in either the characteristic interactions at the reactive site or the charge distribution on transition-state geometries, hence significantly affecting the kinetics of HAT. The highest rate of HAT is resulted for the OH group at position C4^* (O4^*-H4^*) on the phenyl ring (ring B) of morin-5^*-sulfonate because a hydrogen bond between ·OH and the sulfonate group favors the formation of transition state. However, for most compounds under study, the HAT reaction at O3-H3 initiated by ·OH is highly favorable both thermodynamically and kinetically.