Vibrational spectra of β-lactams—II. 1-Methyl-2-azetidinone and its deuterated compounds

The i.r. and Raman spectra of 1-methyl-2-azetidinone and its 3,3-d₂ and methyl-d₃ compounds have been recorded, and the observed bands have been assigned on the basis of the isotope effects and the normal coordinate analysis. Comparison of the CO and CN force constants between 2-azetidinone and 1-methyl-2-azetidinone indicates that, depending on amide resonance, these constants are related to each other. The solvent effects on the CO frequencies of four to seven-membered lactams have also been examined.     

Vibrational spectra of β-lactams—III. potassium 2-azetidinone-1-sulfonate and its isotopic compounds

The IR and Raman spectra of potassium 2-azetidinone-1-sulfonate and its three deuterated and two ¹⁵N-substituted compounds have been recorded, and the observed bands have been assigned on the basis of the isotope effects and the normal coordinate analysis. Comparison of the force constants for the amide group among 2-azetidinone, 1-methyl-2-azetidinone and potassium 2-azetidinone-1-sulfonate indicates that there is a correlation between these constants and the ease of hydrolysis which was determined by NMR spectroscopy, depending on the amide resonance.     

Modeling β-lactam interactions in aqueous solution through combined quantum mechanics–molecular mechanics methods

In this article, we have carried out a series of theoretical computations intended to analyze the interactions of β-lactam compounds in aqueous solution. The final aim is to rationalize the influence of the medium on β-lactam antibiotics reactivity. In particular, the hydrolysis reaction has been studied because of the considerable interest due to its relationship with resistance mechanisms developed by bacteria. The study is extended to the simplest β-lactam molecule, propiolactam or 2-azetidinone, and to the corresponding hydroxylated complex (resulting from the addition of a hydroxyl anion to the carbonyl group) that plays a crucial role in hydrolysis processes. Molecular Dynamics simulations have been carried out using a hybrid quantum mechanics–molecular mechanics potential: the solute is described using the density functional theory, whereas water solvent molecules are treated classically. This represents a sophisticated computational level which, compared to usual force-field simulations, has the advantage of allowing a detailed analysis of solute's electronic properties. The discussion of results is focused on the role played by solute–solvent hydrogen bonds and solvent fluctuations on solute's structure. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 1401–1411, 1999     

A theoretical investigation of the Co(CO)4--catalyzed carbonylative ring expansion of N-benzoyl-2-methylaziridine to beta-lactams: reaction mechanism and effect of substituent at the aziridine Calpha atom

The reaction mechanism of the Co(CO)4--catalyzed carbonylative ring expansion of N-benzoyl-2-methylaziridine to afford N-benzoyl-4-methyl-2-azetidinone and N-benzoyl-3-methyl-2-azetidinone was investigated by using the B3LYP density functional theory methodology in conjunction with the conductor polarizable continuum model/united atom Kohm-Sham method to take into account solvent effects. Computations predict that the most favorable reaction mechanism differs from the experimental proposals except for the nucleophilic ring-opening step, which is the rate-determining one. The regioselectivity and stereospecificity experimentally observed is explained in terms of the located reaction mechanism. The substitution of the methyl group at the carbon alpha of aziridine by the phenyl one gives rise to the obtaining of an only product that corresponds to the CO insertion into the C(substituted)-N bond in accordance with experimental findings. When the ethyl group replaces the methyl one the CO insertion occurs into the two C-N bonds, but the regioselectivity of the process is higher than that of the methyl substituent.     

Theoretical study of the conformational and electrostatic properties of C4-monosubstituted 2-azetidinones

The conformational preferences and electrostatic properties of 2-azetidinone, 4-(S)-methoxycarbonyl-2-azetidinone and 4-(R)-methyl-2-azetidinone have been studied in gas-phase, aqueous solution and CCl₄ solution using quantum mechanical methods. Gas-phase calculations were performed at the ab initio HF, MP2, and MP4 levels and solvent effects were investigated using a self-consistent reaction-field procedure adapted to the AM1 Hamiltonian. An almost planar arrangement was adopted by the-lactam ring in the three cases, whereas the alkoxycarbonyl side group was found to display a large conformational flexibility. The effects of the different solvents on the electrostatic properties of the three compounds were investigated by following the changes in both molecular electrostatic potentials and induced dipole moments. The resulting electrostatic parameters were used as static reactivity indices to predict the response of the systems to the attack of nucleophilic reagents. Theoretical results were compared with experimental data available on the structure and properties of-lactams. The validity of the method as a predicting tool was critically discussed.     

An ab initio study on the allene-isocyanic acid and ketene-vinylimine [2 + 2] cycloaddition reaction paths

The reaction paths of [2 + 2] cycloadditions of allene (H2C=C=CH2) to isocyanic acid (HN=C=O) and ketene (H2C=C=O) to vinylimine (H2C=C=NH), leading to all the possible 14 four-membered ring molecules, were investigated by the MP2/aug-cc-pVDZ method. In the two considered reactions, the 2-azetidinone (beta-lactam) ring compounds were predicted to be the most stable thermodynamically in the absence of an environment. Although 4-methylene-2-azetidinone is the most stable product of the ketene-vinylimine cycloaddition, its activation barrier is higher than that for 4-methylene-2-iminooxetane by ca. 6 kcal/mol. Therefore, the latter product can be obtained owing to kinetic control. The activation barriers in the allene-isocyanic acid reactions are quite high, 50-70 kcal/mol, whereas in the course of the ketene-vinylimine cycloaddition they are equal to ca. 30-55 kcal/mol. All the reactions studied were found to be concerted and mostly asynchronous. Simulation of the solvent environment (toluene, tetrahydrofuran, acetonitrile, and water) by using Tomasi's polarized continuum model with the integral equation formalism (IEF-PCM) method showed the allene-isocyanic reactions remained concerted, yet the activation barriers were somewhat higher than those in the gas phase, whereas the ketene-vinylimine reactions became stepwise. The larger the solvent dielectric constant, the lower the activation barriers found. The lowest-energy pathways in the gas phase and in solvent were confirmed by intrinsic reaction coordinate (IRC) calculations. The atoms in molecules (AIM) analysis of the electron density distribution in the transition-state (TS) structures allowed us to distinguish pericyclic from pseudopericyclic from nonplanar-pseudopericyclic types of reactions.     

Arthrobacter sp.: a lipase of choice for the kinetic resolution of racemic arylazetidinone precursors of taxanoid side chains

The native strain of Arthrobacter sp. (MTCC 5125) bearing a lipase has been found to be the most effective in the kinetic resolution of racemic arylazetidinones for producing cis-(3R,4S)-3-acetoxy-1-(4-methoxyphenyl)-4-phenyl-2-azetidinone, cis-(3R,4S)-3-acetoxy-1-(4-methoxyphenyl)-4-(2-furanyl)-2-azetidinone, cis-(3R,4S)-3-acetoxy-1-(4-methoxyphenyl)-4-(2-thienyl)-2-azetidinone, and cis-3-acetoxy-4-(t-butyl)-2-azetidinone products. The resolved compounds, which were obtained in high enantiopurity are important intermediates of amino acid side chains of paclitaxel as well as a new generation of taxanoids. The use of co-solvents dramatically improved the resolution efficacy of the lipase.     

Synthesis of 4-allenyl and 4-proparyl-2-azetidinone via Zn-mediated Barbier-type reaction and Pt-catalyzed intramolecular amidation to carbapenem skeletons

4-Propargyl-2-azetidinone and 4-allenyl-2-azetidinone derivatives can be facilely obtained from 4-acetoxy-2-azetidinone and propargyl bromides via zinc-mediated Barbier-type reaction. A new method has been developed to construct the carbapenem bicyclic nucleus by cyclization of 4-propargyl-2-azetidinone and 4-allenyl-2-azetidinone derivatives catalyzed by PtCl₂.     

Hydrolysis process of the second generation platinum-based anticancer drug cis-amminedichlorocyclohexylamineplatinum(II)

The hydrolysis process of the anticancer drug cis-amminedichlorocyclohexylamineplatinum(II) (JM118 or cis-[PtCl2(NH3)cyclohexylamine]) and the influence of solvent models therein have been studied using hybrid density functional theory (B3LYP). The aquation reactions leading to the activated drug forms a key step for the reaction with the target DNA. In this study, the stepwise hydrolysis, cis-[PtCl2(NH3)cyclohexylamine] + 2 H2O --> cis-[Pt(NH3)cyclohexylamine(OH2)2]2+ + 2 Cl- was explored, using three different models. Implicit solvent effects were incorporated through polarized continuum models. The stationary points on the potential energy surfaces for the first and second hydrolysis steps, proceeding via a general S(N)2 pathway, were fully optimized and characterized. It was found that the explicit solvent effects originating from the inclusion of extra water molecules into the system are significantly stronger than those arising from the bulk aqueous medium, especially for the second aquation step, emphasizing the use of appropriate models for these types of problems. In comparison with previous work on the parent compound cisplatin, a slower rate of hydrolysis is determined for the first (rate determining) reaction. The results furthermore imply that the doubly aquated form of JM118 will be the main DNA binding form of the drug. The results provide detailed energy profiles for the mechanism of hydrolysis of JM118, which may assist in understanding the reaction mechanism of the drug with the DNA target and in the design of novel Pt-containing anticancer drugs.     

Asymmetric synthesis of unusual fused tricyclic beta-lactam structures via aza-cycloadditions/ring closing metathesis

Conveniently substituted bis-beta-lactams, pyrrolidinyl-beta-lactams, and piperidinyl-beta-lactams undergo ring-closing methatesis using Grubbs' carbene, Cl(2)(Cy(3)P)(2)Ru=CHPh, to give medium-sized rings fused to bis-2-azetidinone, pyrrolidinyl-2-azetidinone, or piperidinyl-2-azetidinone systems. The diolefinic cyclization precursors can be obtained from optically pure 4-oxoazetidine-2-carbaldehydes bearing an extra alkene tether at position 1 or 3 of the beta-lactam ring via [2 + 2] cycloaddition of imino 2-azetidinones, N-metalated azometine ylide [3 + 2] cycloaddition, and subsequent N-acylation of the pyrrolidinyl nitrogen atom, or through aza-Diels-Alder cycloaddition of 2-azetidinone-tethered imines. Under standard reaction conditions, the combination of cycloaddition reactions of 2-azetidinone-tethered imines with ring-closing methatesis offers an asymmetric entry to a variety of unusual fused tricyclic 2-azetidinones bearing two bridgehead nitrogen atoms.     

Substituent and Isotope Effects on the Hydrolysis Rates of 2-Aryl-2-diazocarboxylic Esters

The overall kinetic solvent isotope effects on the acid catalyzed hydrolysis of a series of 2-aryl-2-diazocarboxylic esters ArCN₂COOCH₃, and one 2-aryl-2-diazocarboxamide C₆H₅CH₂CON (CH₃)₂ vary inversely with the reactivity of the substrate, between limits of 3.14 and 1.46. A linear Hammett plot for the hydrolysis rates of the a-diazocarboxylic esters indicates that there is no mechanistic change for the hydronium-ion-catalyzed reaction. The relation between hydrolysis rate and buffer acid concentration deviates from linearity for high values of the latter. It is shown on the basis of the solvent isotope effects for the non-linear region that this deviation does not stem from a mechanistic change caused by the buffer base component. The specific salt effects on the general acid-catalyzed reaction are discussed.     

An Asymmetric Synthesis of L-694,458, a Human Leukocyte Elastase Inhibitor, via Novel Enzyme Resolution of beta-Lactam Esters

A convergent synthesis of [S-(R,S)]-2-[4-[(4-methylpiperazin-1-yl)carbonyl]phenoxy]-3,3-diethyl-N-[1-[3,4-(methylenedioxy)phenyl]butyl]-4-oxo-1-azetidinecarboxamide (L-694,458, 1), a potent human leukocyte elastase inhibitor, was achieved via chiral synthesis of key intermediates: (S)-3,3-diethyl-4-[4'-[(N-methylpiperazin-1-yl)carbonylphenoxy]-2-azetidinone (2) and (R)-alpha-propylpiperonyl isocyanate (3). Synthesis of beta-lactam 2 was achieved by a novel enantioselective lipase hydrolysis of ester 5 to produce (S)-3,3-diethyl-4-(4'-carboxyphenoxy)-2-azetidinone (6) (60% yield, three cycles, 93% ee) with isolation, epimerization, and recycling of the undesired (R)-ester 5. Isocyanate 3 was prepared by chiral addition of Zn(n-Pr)(2) to piperonal (98% yield, 99.2% ee), azide displacement and reduction to (R)-alpha-propylpiperonylamine (11) (58% yield, 85% ee), crystallization as the D-pyroglutamic acid salt (92% yield, 98.2% ee), and isocyanate formation (98% yield) with phosgene.     

Hydrolysis Process of the Anticancer Agents Novel Non-classical trans-Platinum(Ⅱ) with Aliphatic Amines

The hydrolysis process of the anticancer agents novel non-classical trans- platinum(Ⅱ ) with aliphatic amines and the influence of solvent models therein have been studied by using hybrid density functional theory (B3LYP). In this study, the stepwise hydrolysis, trans- [PtCl2(Am)(isopropylamine)] + 2H2O → trans-[Pt(Am)(isopropylamine)(OH2)2]2+ + 2Cl-, was explored. Implicit solvent effects were incorporated through polarized continuum models. The stationary points on the potential energy surfaces for the first and second hydrolysis steps, proceeding via a general SN2 pathway, were fully optimized and characterized. It was found that the first hydrolysis reaction is easier than the second one and the hydrolysis of trans-[PtCl2- (isopropylamine)2] is the easiest in our studying systems. The result can assist in under-tanding the hydrolysis mechanism of trans-[PtCl2(Am)(isopropylamine)] and designing novel Pt-based anticancer drugs.     

Theoretical studies on the hydrolysis mechanism of N-(2-oxo-1,2-dihydro-pyrimidinyl) formamide

Density functional theory (B3LYP) and ab initio (MP2) methods with the 6-31G(d,p) basis set are used to study the mechanisms for the hydrolysis of N-(2-oxo-1,2-dihydro-pyrimidinyl) formamide (PFA) in the gas phase. The direct and the water-assisted hydrolysis processes are considered, involving one and two water molecules, respectively. Three different pathways are explored in each case. In the first pathway, the O atom of water first attacks at the C atom of amide while one H atom of water transfers toward the oxygen of amide, leading to an intermediate of tetrahedral coordinated carbon with two OH groups. In the subsequent step, the hydroxyl H atom transfers to the N atom of pyrimidine ring and the C-N covalent bond of amide dissociates simultaneously. In the second path, the O and one H of water attack at the C of amide and the N of pyrimidine ring, respectively, while the C-N bond of amide dissociates. In the third path, three processes occur simultaneously: the O of water attacks at the C of amide, one H atom attacks at the N of amide, and the C-N bond of amide is broken. It is shown that the second pathway is favored for the direct hydrolysis while the first pathway is favored for the water-assisted hydrolysis. It is also shown that the water-assisted hydrolysis is slightly more favorable than the direct hydrolysis. Moreover, solvent effects on five pathways are evaluated with Monte Carlo simulation (MC) and free energy perturbation methods. It is shown that the solvent water slightly reduces the energy barrier in each pathway. The first pathway in the water-assisted hydrolysis remains the most favorable when the solvent effects of bulk water are taken into account.     

硝酸氯冰溶胶水解反应过程的计算模拟

用二级微扰(MP2)和密度泛函理论(B3LYP),辅以不同的基组,对硝酸氯在冰表面上水解反应的机理进行了理论计算研究.根据关键部位化学键的松弛效应和关键原子的电荷分布,对冰表面催化的原因进行了深入分析.水分子一方面作为桥,辅助分子间质子发生迁移;另一方面作为连续介质,通过偶极相互作用加快硝酸氯的水解过程.     

Facile transformation of 2-azetidinones to unsaturated ketones: application to the formal synthesis of sphingosine and phytosphingosine

2-Azetidinones were smoothly transformed to unsaturated ketones through the ring opening of activated 2-azetidinone by phosphonate stabilized carbanion and subsequent Horner–Wadsworth–Emmons olefination of the resulting β-ketophosphonates with aldehydes. A formal synthesis of l-erythro-sphingosine and d-lyxo-phytosphingosine from readily available 2-azetidinone was established utilizing this methodology.     

Synthesis of ferrocene-substituted 2-azetidinones.

The photochemical reaction of alkoxychromium(0)carbene complexes and ferrocene mono- and disubstituted imines formed 2-azetidinones having one or two ferrocene moieties in good yields. Yields decrease when the carbene moiety bears an aminoferrocene moiety attached to the carbene carbon, while complex 9 having the ferrocene directly bonded to the carbene carbon was totally inert in these reactions. Access to beta-lactams with the ferrocene tethered to the C3 position through a methylene group was gained using the lithium enolate derived from ethyl 3-ferrocenylpropanoate. The reaction of this enolate produced two unexpected processes. Thus, 2-azetidinone 15 having an hydroxyl group at the C3 position was obtained together with the expected beta-lactam 14, by reaction of the lithium enolate of ethyl 3-ferrocenylpropenoate and imine 1. Additionally, unsaturated amide 17 was obtained by base-promoted Hoffmann-like breakage of the beta-lactam ring formed in the reaction of the same enolate and imine 2. Oxidation of the anion at the C3 of the 2-azetidinone ring on compound 14, as well as the sterically driven ring-breakage of the C3 anion derived from the nonisolated 2-azetidinone 18, should be responsible for this behavior.     

A theoretical study of rhodium(I) catalyzed carbonylative ring expansion of aziridines to beta-lactams: crucial activation of the breaking C-N bond by hyperconjugation

The regioselectivity and enantiospecificity of the [Rh(CO)2Cl]2-catalyzed carbonylative ring expansions of N-tert-butyl-2-phenylaziridine to yield 2-azetidinone and the lack of reactivity of N-tert-butyl-2-methylaziridine along this process were investigated at the B3LYP/6-31G(d) (LANL2DZ for Rh) theory level taking into account solvent effects. According to our results, the regioselectivity in the ring expansion of N-tert-butyl-2-phenylaziridine and the unreactivity of N-tert-butyl-2-methylaziridine experimentally observed are determined by the different degree of activation of the breaking C-N bond in the initial aziridine-Rh(CO)2Cl complex due to its hyperconjugation interaction with the substituent on the carbon atom. When a phenyl substituent is present its hyperconjugation interaction with the C(alpha)-N bond facilitates the insertion of the metal atom into this bond. On the other hand, when the substituent is a methyl group, a larger stability of the initial complex along with a lower stabilization through hyperconjugation of the TS for insertion of the Rh atom into the C(alpha)-N bond make the ring expansion of N-tert-butyl-2-methylaziridine unviable. The enantiospecificity experimentally observed is also reproduced by our calculations given that the stereogenic center is never perturbed to change its configuration.     

Binding of β-lactam antibiotics to a bioinspired dizinc complex reminiscent of the active site of metallo-β-lactamases

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.     

A theoretical analysis of the coordination modes of CuII with penicillins: activation of the beta-lactam C-N bond.

The interaction of CuII with 6-formylamino-3alpha-carboxypenam and 6-acetylamino-3alpha-carboxypenam was investigated by means of DFT calculations with the UB3LYP functional. Nine different modes of complexation between CuII and 6-formylamino-3alpha-carboxypenam were located. When two water molecules directly bonded to CuII are included in the calculations on 6-acetylamino-3alpha-carboxypenam as penicillin model, only six CuII(H2O)2-6-acetylamino-3alpha-carboxypenam complexes (1S-6S) are found. In solution the four most stable complexes obtained from our calculations, 6S, 1S, 2S, and 3S, exhibit CuII in square-planar coordination with at least one bond to the carboxylate group, in agreement with experimental evidence. Complexes 6S, 1S, and 3S were previously suggested by available experimental evidence. In three of the most stable complexes (6S, 2S, and 3S) the beta-lactam C-N bond is remarkably activated and displays C-N bond lengths similar to those found in some tetrahedral intermediates located for the hydrolysis of 2-azetidinones. This suggests that these kinds of complexes belong to the reaction coordinate for the degradation of beta-lactam antibiotics in the presence of CuII.