C-3 β-lactam carbocation equivalents: versatile synthons for C-3 substituted β-lactams

An efficient and operationally simple strategy for the synthesis of differently C-3 monosubstituted (9) and disubstituted (10) monocyclic β-lactams is described. This involves reaction of β-lactam carbocation equivalents (8) with an active aromatic, aliphatic and heterocyclic substrates in the presence of a Lewis acid.     

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.     

N-activated β-lactams as versatile reagents for acyl carrier protein labeling

Acyl carrier proteins are critical components of fatty acid and polyketide biosynthesis. Their primary function is to shuttle intermediates between active sites via a covalently bound phosphopantetheine arm. Small molecules capable of acylating this prosthetic group will provide a simple and reversible means of introducing novel functionality onto carrier protein domains. A series of N-activated β-lactams are prepared to examine site-specific acylation of the phosphopantetheine-thiol. In general, β-lactams are found to be significantly more reactive than our previously studied β-lactones. Selectivity for the holo over apo-form of acyl carrier proteins is demonstrated indicating that only the phosphopantetheine-thiol is modified. Incorporation of an N-propargyloxycarbonyl group provides an alkyne handle for conjugation to fluorophores and affinity labels. The utility of these groups for mechanistic interrogation of a critical step in polyketide biosynthesis is examined through comparison to traditional probes. In all, we expect the probes described in this study to serve as valuable and versatile tools for mechanistic interrogation.     

N-Alkoxyl Templates for Diastereoselective Pyrrolidine Synthesis

Intramolecular cyclization of N-alkoxyl amines are studied for the stereoselective preparation of 2, 4-disubstituted pyrrolidine derivatives. Reduction of oximes under acidic conditions by NaBH3CN afforded the corresponding nucleophilic hydroxylamine derivatives,which subsequently cyclized via SN2‘ mechanism to give the desired N-alkoxyl pyrrolidines.     

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.     

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.     

Humicola lanuginosa lipase-catalyzed enantioselective resolution of β-hydroxy sulfides: versatile synthons for enantiopure β-hydroxy sulfoxides

Humicola lanuginosa lipase-catalyzed acylation of β-hydroxy sulfides provides both the (R)- and (S)-enantiomers in high enantiomeric purity. In two cases the resolved hydroxy sulfides were oxidized to give β-hydroxy sulfoxides in >99% e.e. The effect of substituents on enantioselectivity is discussed.     

Advanced procedure for the enzymatic ring opening of unsaturated alicyclic β-lactams

Enantiopure β-amino acids 1a–4a and β-lactams 1b–4b were prepared simultaneously through the lipolase-catalysed enantioselective ring opening of unsaturated racemic β-lactams (±)-1-(±)-4. High enantioselectivities (E>200) were observed when the reactions were performed with 1 equiv of water in iPr₂O at 70 °C. The resolved (1R,2S)-amino acids (yield⩾45%) and (1S,5R)-, (1S,6R)- and (1S,8R)-lactams (yield⩾47%) could be easily separated. The ring opening of lactam enantiomers 1b–4b with 18% HCl afforded the corresponding β-amino acid hydrochlorides 1c·HCl–4c·HCl (ee >95%).     

DMF-dimethyl sulfate as a new reagent for the synthesis of β-lactams

A number of 2-azetidinones were synthesized in good to excellent yields by a novel reaction between Schiff bases, substituted acetic acids and alkoxymethylene-N,N-dimethyliminium salts, the adduct formed from DMF and O-alkylating agents. The advantages of this new method are mild reaction conditions, low cost, avoiding the use of chlorinating agents and easy purification of the products. The best results were obtained when DMF and dimethyl sulfate were used at room temperature.     

Stereoselective synthesis of trans-3-functionalized-4-pyrazolo[5,1-b]thiazole-3-carboxylate substituted β-lactams: Potential synthons for diverse biologically active agents

Abstract

An efficient protocol for the stereoselective synthesis of pyrazolo[5,1-b]thiazole-3-carboxylate tethered β-lactam conjugates 8a–j from novel pyrazolo [5,1-b]thiazole-3-carboxylate substituted Schiff’s bases 6a–f is reported here. The reaction between various ketene precursors and novel Schiff’s bases 6a–f afforded exclusive formation of trans-β-lactams 8a–j. The substrate scope of this approach was investigated extensively by varying different groups (R, Z). All the novel compounds were characterized using various spectroscopic techniques, such as FT-IR, ¹H NMR, ¹³C NMR, elemental analysis, ¹³C NMR (DEPT-135), and mass spectrometry in representative cases. Single crystal X-ray crystallographic study of trans-ethyl 7-(1-(4-methoxyphenyl)-4-oxo-3-phenoxyazetidin-2-yl)-6-methyl-2-(methylthio)pyrazolo[5,1-b]thiazole-3-carboxylate 8a has confirmed the molecular structure and the stereochemical outcome. To the best of our knowledge, the synthesis of such types of Schiff’s bases and β-lactam conjugates has not been reported so far.     

Facile synthesis of novel α-methylene-pyrazole-carboxylate substituted imines and trans-β-lactams: Versatile synthons for diverse heterocyclic molecules

A simple, facile, and high yielding stereoselective approach for the integration of α-methylene-pyrazole-carboxylates at the β-lactam nucleus is described. These monocyclic β-lactams have been synthesized by treatment of 2-phenoxy/benzylthio/phenylthio ethanoic acids or acetoxyacetyl chloride/phthalimidoacetyl chloride 5a–e with novel α-methylene-pyrazole-carboxylate imines 4a–c using Et₃N and POCl₃ in refluxing toluene. All of the newly synthesized α-methylene-pyrazole carboxylate imines 4a–c and their β-lactam derivatives 6a–h have been fully characterized by spectroscopic techniques such as FTIR, NMR (¹H, ¹³C, and ¹³C DEPT-135), 2D-NMR (COSY and HSQC), and elemental analyses (CHN). The cycloaddition reaction was found to be highly stereoselective leading to the exclusive formation of trans-β-lactams 6a–h and trans configuration was assigned with respect to coupling constant values of C3-H and C4-H. The novel β-lactams 6a–h bearing α-methylene-pyrazole-carboxylate ring system will serve as useful synthons for highly functionalized acids, acetohydrazides/pyrazolones, alcohols, pyrazole carboxamides, peptides, and promising biologically active agents.     

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.     

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 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.     

Diastereoselective synthesis of novel 3-aryloxy/alkoxy-4-benzothiazolylpyrazolyl-β-lactams: Potential synthons for novel aminoacids/nanocopolymers

A fast, efficient, and diastereoselective synthesis of novel 3-oxo-4-benzothiazolylpyrazolyl-β-lactams is described. The reaction between 2-aryloxy/alkoxyacetic acid and novel benzothiazolylpyrazole-substituted imines afforded exclusive formation of trans-β-lactams. The scope of the reaction was investigated by varying different groups on substrates (R¹, R², R³, Z). All the novel compounds were characterized using various spectroscopic techniques such as FT-IR, ¹H NMR, ¹³C NMR, elemental analysis, and mass spectrometry in representative cases. No report has been listed in the literature for the synthesis of these types of β-lactam heterocycles so far.     

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.     

Synthetic route for the novel pyrimidine-substituted alkanoate,acetohydrazide, and imines: Synthon for β-lactams

A simple and efficient synthesis of novel pyrimidine-substituted alkanoate, acetohydrazide, and imines is described. The synthesis of novel ethyl 2-(2,6-dimethylpyrimidin-4-yloxy)acetate (EDMPyA) 2 was performed through S_N2 O-alkylation of 2,6-dimethyl-4-hydroxypyrimidine 1 with ethyl haloacetate. The compound EDMPyA 2 was subjected to nucleophilic substitution reaction with hydrazine hydrate to afford novel 2-(2,6-dimethylpyrimidin-4-yloxy)acetohydrazide (DMPyAH) 3. This DMPyAH 3 upon condensation with differently substituted carbonyl compounds (aldehydes/ketones) furnished DMPyAH imines (DMPyAH-I) 4a–d. These imines can be used for the preparation of unique β-lactams. The structure elucidation of all the newly synthesized compounds was performed using spectroscopy (FT-IR, ¹H and ¹³C NMR) and elemental analysis (C, H, N).