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.     

Nitrilimine cycloaddition to 4-(pyrazol-5-yl)carbonyl-2-azetidinone and 4-(pyrazol-4-yl)carbonyl-2-azetidinone

The higly stereoselective nitrilimine cycloaddition onto the novel 3(R*)-phenyl-4(S*)-cinnamoyl-2-azetidinone 2 gave 4-(4,5-dihydropyrazol-5-yl)carbonyl-2-azetidinone 5 as the major product and 4-(4,5-dihydropyrazol-4-yl)carbonyl-2-azetidinone 6 as the minor one. Ceric ammonium nitrate (CAN) oxidation of the cycloadducts gave the title compounds with good overall yield.     

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.     

Reaction of benzoyl and trichloroacetyl isocyanates with cyclic enamines

Conclusions Benzoyl isocyanate reacts with morpholinocyclohexene, morpholinocyclopentene, piperidinocyclohexene, and piperidinocyclopentene on the type of 1,4-cycloaddition, with the formation of 1,3-oxazin-4-one derivatives, while trichloroacetyl isocyanate reacts on the type of 1,2-cycloaddition, with the formation of 2-azetidinone derivatives, and only with morpholinocyclopentene does it react on the type of 1,4-cycloaddition.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 9, pp. 2086–2088, September, 1972.     

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.     

Cyclization reaction of n-propargyl epoxyamide to acetylenic 2-azetidinone,a precursor to thienamycin and related carbapenems

Base treatment of N-propargyl epoxyamide 5 afforded the acetylenic 3-(hydroxyethyl)-2-azetidinone 9a, which was subsequently transformed to phenyl thiolester 2, a versatile intermediate for the carbapenem synthesis.     

From theoretical calculations to the enantioselective synthesis of a 1,3,4-trisubstituted Gly-derived 2-azetidinone

Theoretical calculations on the transition states of the cyclization of 2S-chloropropionyl amino acid derivatives to the corresponding β-lactams have served to explain the high stereoselectivity of the reaction, and have been the driving force to extend the procedure to the preparation of a Gly-derived 1,3,4-trisubstituted 2-azetidinone in enantiopure form.     

Preparation of TiO2–ZrO2 mixed oxides with controlled acid–basic properties

Titania–zirconia mixed oxides with various ZrO₂ content in TiO₂ (10, 50 and 90 wt.%) were prepared by the sol–gel method. High specific surface areas (77–244 m²/g) were obtained. Acidity determined by NH₃-TPD and FTIR-pyridine adsorption showed that in mixed oxides the number of acid sites is dramatically increased; it varies from 173 μmol NH₃/g for TiO₂ to 1226–1456 μmol NH₃/g for the mixed oxides. FTIR-pyridine adsorption showed the presence of Lewis sites in the catalysts. Basic sites were identified by FTIR-CO₂ adsorption, suggesting the formation of mixed oxides with acid–basic properties. XRD spectra identified anatase in the TiO₂ rich region, amorphous material in the mixed oxide 50–50 TiO₂–ZrO₂ and tetragonal and monoclinic crystalline phases in the ZrO₂ rich region. Activity in the isopropanol decomposition showed a good correlation between the acid–basic properties and the selectivity to propene, acetone and isopropyl ether. The latter was found as a product which mainly depends of the acid sites density.     

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.     

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.     

Water-assisted alkaline hydrolysis of monobactams: a theoretical study

A theoretical study of the water-assisted alkaline hydrolysis of 2-azetidinone, 3-formylamino-2-azetidinone and 3-formylamino-2-azetidine-1-sulfonate ion is carried out at the B3LYP/6-31+G* level. The effect of bulk solvent is taken into account using the PCM solvation model while specific solvent effects are represented by the inclusion of an ancillary water molecule along the reaction profile. The calculated free energy barriers in solution are in reasonable agreement with experimental values. The observed substituent effects due to the presence of the 3-formylamino and the SO(3) groups attached to the beta-lactam ring are crucial factors determining the hydrolysis of monobactam antibiotics.     

Synthetic approaches to thienamycin: Carbon-carbon bond formation at C-4 of azetidin-2-ones

A mild and efficient method of β-lactam alkylation has been achieved using 4-acetoxy-2-azetidinone and a variety of silyl enol ethers.     

The Intramolecular Aldol Condensation Route to Fused Bi- and Tricyclic beta-Lactams(1)(,)(2)

Staüdinger cycloaddition of activated acid chlorides to 1,3-ketoaldimines, prepared in quantitative yields from 1,3-ketoaldehydes and amino esters, gave in excellent yields cis-2-azetidinones, 6-8, having the adequate functionality to obtain fused bi- and tricyclic beta-lactams. Reaction of compounds 6 with LHMDS at low temperature gave a single diastereomer of fused bicyclic compounds with a carbapenam or carbacefam skeleton. Treatment of diastereomeric cis-2-azetidinones, 7/8, in analogous conditions resulted either in the exclusive cyclization of one of the two diastereomers to form tricyclic [4.n.m] (n = 5, 6; m = 5, 6) compounds, or in the cyclization of both diastereomers to form tricyclic [4.n.7] (n = 5, 6) 2-azetidinones. In all cases the cyclization step was totally stereoselective. Alternatively, trans-carbapenams and one example of a tricyclic system having a trans-2-azetidinone ring have been obtained by using longer reaction times and higher temperatures. Epimerization at C3 of the 2-azetidinone nucleus occurs in these reaction conditions to obtain a single diastereomer of the final products. This approach to fused policyclic 2-azetidinones is one of the scarce syntheses of this kind of compound making use of the aldol condensation.     

Stereoselective synthesis of 3-(1-Hydroxyethyl)-2-azetidinonesfrom 3-hydroxybutyrates

Addition of dianions of 3-hydroxybutyrates to benzylideneaniline results in direct formation of $\text{trans}$$\text{S*}$-3-(l-hydroxyethyl)-1,4-diphenyl-2-azetidinone with 95% diastereoselectivity. Inversion of the configuration at Cα, gives the desired $\text{trans}$$\text{R*}$-2-azetidinone in high yield.     

Long-lived photoinduced charge separation in carbazole–pyrene–viologen system incorporated in Langmuir–Blodgett films of substituted diazacrown ethers

Diaza-18-crown-6 ethers appending two pyrenyl (Py) or two carbazolyl (Cz) groups were synthesized. These macrocyclic compounds form 1:1 host–guest complexes with methyl viologen chloride (MV²⁺), and these complexes were assembled into monolayers by Langmuir–Blodgett technique. The generated assembly involves the general structure of donor–sensitizer–acceptor (Cz–Py–MV²⁺) in space, although any of the photo- and redox-active components are not covalently bonded. Photoirradiation of the pyrenyl group resulted in the charge-separated pair Cz√⁺–Py–MV√⁺ which survived up to hours in a well anaerobic atmosphere. An electrode was fabricated by transferring the L–B film on an ITO glass. The photoinduced voltage of this electrode was measured with a saturated calomel reference electrode in hydroquinone (H₂Q) solution to be ca. 168 mV when the light intensity was 218 mW/cm². This electrode was also used as the light electrode to construct a photogalvanic cell with a platinum electrode as the dark electrode. Irradiation of the light electrode with visible light results in anodic photocurrent, and there is no net chemical change associated with the function of the cell which converts light to electricity.     

Metal-free diastereoselective synthesis of diaza-bicyclo[3.2.0]heptan-7-one and its transformation to functionalized proline esters

A metal-free diastereoselective synthesis of novel 4-halo-3,6-di-aryl-2,6-diaza-bicyclo[3.2.0]heptan-7-one by intramolecular endo-trig haloamination of 3-amino-2-azetidinone is reported. The amidiolytic ring opening of diaza-bicyclo[3.2.0]heptan-7-one with sodium methoxide provides an easy access to previously unknown 4-halo-3-aryl amino-pyrrolidine-2-carboxylic acid methyl esters in good yields.     

Transamidation reactions in the formation of macrocyclic lactams. A total synthesis of celacinnine

The macrocyclic spermidine alkaloid, celacinnine, has been synthesized by methods involving successive ring expansion reactions. One route starts with 4-phenyl-2-azetidinone; another, with piperidazine.     

Protecting group migration in the chemistry of 1-t-butyldimethylsilyl-4-hydroxymethyl-2-azetidinone

The alkoxide anion derived from 1-t-butyldimethylsilyl-4-hydroxymethyl-2-azetidinone (1) rearranged at −78°C into amide anion by N-O migration of the silyl protecting group. The occurrence of this intermediate was proved by quenching with benzyl bromide and phenethyl chloroformate, giving respectively N-benzyl (4) and N-(phenethyloxycarbonyl) (6) derivatives of 4-(t-butyldimethylsilyloxy)methyl-2-azetidinone.     

The application of BTEM to UV-vis and UV-vis CD spectroscopies: the reaction of Rh4(CO)12 with chiral and achiral ligands

Two different organometallic ligand substitution reactions were investigated: (1) an achiral reactive system consisting of Rh₄(CO)₁₂ + PPh₃  Rh₄(CO)₁₁PPh₃ + CO in n-hexane under argon; and (2) a chiral reactive system consisting of Rh₄(CO)₁₂ + (S)-BINAP  Rh₄(CO)₁₀BINAP + 2CO in cyclohexane under argon. These two reactions were run at ultra high dilution. In both multi-component reactive systems the concentrations of all the solutes were less than 40 ppm and many solute concentrations were just 1–10 ppm. In situ spectroscopic measurements were carried out using UV–vis (Ultraviolet–visible) spectroscopy and UV–vis CD spectroscopy on the reactive organometallic systems (1) and (2), respectively. The BTEM algorithm was applied to these spectroscopic data sets. The reconstructed UV–vis pure component spectra of Rh₄(CO)₁₂, Rh₄(CO)₁₁PPh₃ and Rh₄(CO)₁₀BINAP as well as the reconstructed UV–vis CD pure component spectra of Rh₄(CO)₁₀BINAP were successfully obtained from BTEM analyses. All these reconstructed pure component spectra are in good agreement with the experimental reference spectra. The concentration profiles of the present species were obtained by performing a least square fit with mass balance constraints for the reactions (1) and (2). The present results indicate that UV–vis and UV–vis-CD spectroscopies can be successfully combined with an appropriate chemometric technique in order to monitor reactive organometallic systems having UV and Vis chromophores.     

Formation of pyrrole derivatives through aminolysis of 2-azetidinone derivatives

A mixture of 3-(α,β-epoxyisopropyl)-1-phenyl-2-azetidinone and benzylamine was heated in a sealed tube at 120–130° yielding 4-anilinomethyl-1-benzyl-3-hydroxy-3-methyl-2-pyrrolidinone as a mixture of diastereoisomers. By this method, 4-anilinomethyl-3-hydroxy-3-methyl-1-phenyl-2-pyrrolidinone and 4-anilinomethyl-3-hydroxy-3-methyl-1-(3,4-dimethoxyphenethyl)-2-pyrrolidinone were obtained by using aniline and 3,4-dimethoxyphenethylamine, respectively, instead of benzylamine. The reaction of 4-formyl-1-phenyl-2-azetidinone with 3,4-dimethoxyphenethylamine afforded 4-anilino-1-(3,4-dimethoxyphenethyl)-2,3-dihydro-2-oxopyrrole. In a similar fashion, the 1-n-butyl and 1-isobutyl analogues were obtained by the use of n-butylamine and isobutylamine, respectively, instead of 3,4-dimethoxyphenethylamine.