Synthesis of 4-vinyl substituted β-lactams of the oxamazin family

4-Vinyl-substituted oxamazins 15,16, and 3 have been prepared. Key steps of the synthesis are: the preparation of protected α-amino-β-hydroxyacid 6 through ester enolate condensation of ethyl glycinate STABASE adduct 8 with CH-protected propiolaldehyde 9, the coupling of this acid with an appropriate protected hydroxylamine, the cyclization of resulting hydroxamate, and finally the acylation of the amino-group in 3 with ATMO side chain.     

β-lactams from esters and silylimines: A revaluation. Synthesis of N-unsubstituted 4-alkyl-β-lactams

The first preparation of enolizable silylimines is reported. The “in situ” trapping of these species with lithium enolates of esters gives rise in fairly good yields to N-unsubstituted 4-alkyl-β-lactams.     

Rearrangement of N-hydroxy β-lactams

A number of 4-carboalkoxy-N-hydroxy-2-azetidinones were converted to various derivatives which were shown to undergo novel rearrangements to substituted acryalamides. Under similar conditions 3,3-dimethyl-4-carboisopropoxy-N-hydroxy-2-azetidinone rearranged to a pyrimidine derivative.     

New method of preparing β-lactams

Summary A method has been devised for the synthesis of -lacrams from amides of -ha!ocarboxylic acids. Some new azetidinones with residues containing carboxyl groups on the nitrogen have been piepated. The method permits the conversion of $-amino acids trio difficulty accessible mixed (secondary) amino acids.This paper is publised under the regulations governing Brief Communications.     

Direct introduction of a benzoyloxy substituent at the C-4 position of β-lactams

The copper-promoted reaction of β-lactams with t-butyl perbenzoate results in benzoyloxylation of the azetidin-2-one ring at the C-4 position. There is no competing reaction at the C-3 position, but reaction at exocyclic carbon α to nitrogen competes with ring substitution.     

New method of preparing β-lactams

Summary A method has been devised for the synthesis of B-lactams from amides of -halocarboxylic acids, Some new azetidinones with residues containing carboxyl groups on the nitrogen have been prepared. The method permits the conversion of -amino acids into difficulty accessible mixed (secondary) amino acids.     

Argentic oxide mediated N-dearylation of β-lactams

A method is described for the N-dearylation of N-(4-methoxy- or 4-ethoxyphenyl)-2-azetidinones with argentic oxide. The yields are good-to-excellent and the reaction is simple, efficient, and fast.     

Synthesis and biology of N-thiolated β-lactams

N-Thiolated β-lactams are an interesting new family of bioactive agents having antibacterial, antifungal, and anticancer capabilities. Our interest in these β-lactams stems from their highly unusual structure–activity profiles and selectivity toward only a few genera of pathogenic bacteria, including Staphylococcus aureus, Bacillus anthracis, and Micrococcus. Here, we provide a complete outline on our work in the discovery and ongoing development of these compounds, starting from our initial, unexpected finding of antimicrobial activity for one of the lead compounds, to a more complete understanding of their chemical and biological mode of action and potential utility as antibacterial compounds.     

Synthesis of new nanocopolymer containing β-lactams

Several new monocyclic β-lactam monomers bearing the NO₂ group 2a–g were synthesized via a [2 + 2] ketene–imine cycloaddition reaction (Staudinger reaction). Calculation of coupling constant of H-3 and H-4, and the X-ray crystallography of β-lactam 2e confirmed the cis stereochemistry of these β-lactams. Then aminophenyl β-lactams were synthesized by the reduction of NO₂ to NH₂ group in the presence of Raney Ni and hydrazine hydrate. Treatment of these aminophenyl β-lactams with acryloyl chloride and sodium bicarbonate (NaHCO₃), afforded the monomers bearing the NHCOCH=CH₂ group. These acrylated β-lactam monomers were dissolved in a warm mixture of butyl acrylate and styrene and then were converted to the corresponding polyacrylate nano β-lactams by emulsion polymerization in water. A unique feature of this methodology is the ability to incorporate water-insoluble compounds directly into the nanoparticle framework. Structures of the synthesized compounds were confirmed by physical and spectral analyses. Dynamic light scattering analysis and transmission electron microscopy of the final emulsions show that the nanoparticles were about 50–70 nm in diameter.     

Kinetic resolution of β-lactams via enantioselective N-acylation

Enantioselective N-acylation of 4-aryl-β-lactams in the presence of acyl transfer catalyst Cl-PIQ provides an effective method for their non-enzymatic kinetic resolution.     

Stereoselective synthesis of N-phenylsulfonyl substituted spiro-β-lactams

A stereoselective synthesis of N-phenylsulfonyl substituted spiro-β-lactams obtained from the N-(phenylmethylene)benzenesulfonamide and the ketene valence tautomer of the bicyclic mesoionic compounds derived from 4-hydroxy substituted N-acyl-l-prolines in the presence of acetic anhydride as the dehydrating agent is presented. The reaction of (2S,4R)-4-acetyloxy or benzoyloxy-N-acyl-proline with the above imine afforded a mixture of two diastereoisomeric spiro-β-lactams with complete stereoselectivity for the spiro carbon.     

Stereoselective synthesis of constrained norbornane-derived spiro-β-lactams

New enantiopure polycyclic norbornane-derived spiro-β-lactams were synthesized by means of a Staudinger ketene–imine reaction between unsymmetrical bicyclic chiral ketenes, generated from differently substituted norbornane carboxylic acids, and (E)-N-benzyl-N-(phenylmethylene)amine, with high yields and moderate to good stereoselectivities. The diastereoisomeric results were rationalized taking into account the increasing steric encumbrance present on the norbornane skeleton and the stability of the products. The configurations of the newly formed stereocenters of spiro-β-lactams were assigned on the basis of 2D NMR experiments and X-ray analysis. Spiro-β-lactams were subjected to acid hydrolysis obtaining the corresponding norbornane-derived β-amino acids.     

Synthesis of β-lactams with π electron-withdrawing substituents

β-Lactams are crucial structural feature of β-lactam antibiotics and important intermediates in synthetic and pharmaceutical chemistry. Synthetic methods for β-lactams with π electron-withdrawing substituents, such as formyl (carbaldehyde), acyl, imino, carboxylic acids, carboxylates, carboxamides, cyano (carbonitriles), and nitro groups, on their 3- and/or 4-position(s) are presented in this review. The methods are divided mainly into intramolecular cyclizations, cycloaddition, and other methods, for example, Ugi-type reaction of β-keto acids, amines, and isonitriles, and modification of β-lactam derivatives. Cyclizations include cyclization of haloacetamidoacetates(malonates), intramolecular carbene insertion of α-diazoalkanamides, ring-opening cyclization of α,β-epoxyalkanamidoacetates, oxidative coupling of 3-oxoalkanamidoacetates, oxidative cyclization of N-p-hydroxyphenyl β-oxoalkanamides, intramolecular cyclization of aspartic acid derivatives or β-hydroxyalkanamides, and radical cyclization of N-vinyl β-oxoalkanamides. Cycloadditions incorporate Staudinger cycloaddition of ketenes and imines, cycloaddition of nitrones and alkynes, cycloaddition of nitrones and alkylidenecycopropanes and subsequent acidic rearrangement, and condensation of imines and enolates (ethers) of esters. The scope, limitation, and stereoselectivity are also discussed for some methods. Most of the β-lactam derivatives are key intermediates or precursors for preparation of β-lactam antibiotics and their analogs.     

Synthesis of some mono- and bis-spiro-β-lactams of benzylisatin

Some new mono- and bis-spiro-β-lactams of benzylisatin were prepared by Staudinger’s ketene-imine [2+2] cycloaddition reaction. The cycloadducts were characterized by spectral data including ¹H NMR, ¹³C NMR, IR and mass spectra. The configuration of benzylisatin and one of mono-spiro-β-lactams (5a) was established by X-ray crystal analysis.     

Rhodium-catalyzed coupling of α-lactams with indole derivatives

We report herein a method that allows for the formation of a C–N bond between the C–3 carbon of α-lactams and the nitrogen atom of indoles. A general procedure for the coupling of indoles and α-lactams in only 25 min with high yield is reported. The scope of the reaction was extended by the development of a method for the in situ generation of less stable phenyl-substituted α-lactams. The developed method provides an atom-economical method for the formation of substituted α-amino amides that are found in a variety of biologically-active compounds.     

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.