Monocyclic Β-lactams Research Articles

Chemical Methods for the Construction of Spirocyclic β-Lactams and Their Biological Importance

AbstractSpirocyclic β-lactams are a family of natural and synthetic chemicals with different biological activities, including antibacterial properties, and interact with critical physiological targets such as T-type calcium channels and acetyl-CoA cholesterol acyltransferase. Their unique chemical structure, combining a spiro ring system with a β-lactam group, offers promising opportunities for the targeted discovery of medications in medicinal chemistry. Spirocyclic β-lactams have the potential to be adaptable frameworks for developing novel therapeutic medicines with particular three-dimensional pharmacophoric characteristics and increased biological efficacy. Numerous methods are employed for the synthesis of spirocyclic β-lactams, such as cyclization, functional group modifications, asymmetric synthesis utilizing chiral catalysts and biomimetic approaches. In this short review, two distinct approaches describing recent syntheses of spirocyclic β-lactams (from 2021 to 2024) are discussed. The first is based on constructing the β-lactam ring, while the other entails transforming monocyclic β-lactams into spirocyclic structures. These methods include detailed reaction processes and descriptions of the biological functions of the target spirocycles. The applications of spirocyclic β-lactams in medicinal chemistry highlight their role in the synthesis of structurally diverse compounds with significant therapeutic potential, demonstrating creative chemical methods for building complex molecular structures.1 Introduction2 β-Lactam Ring Synthesis3 Non-β-Lactam Ring Synthesis4 Miscellaneous Examples5 Conclusion and Outlook

Improved synthesis and evaluation of preclinical pharmacodynamic parameters of a new monocyclic β-lactam DPI-2016

Monocyclic β-lactams are stable to a number of β-lactamases and are the focus of researchers for the development of antibacterial drugs, particularly against Enterobacterales. We recently synthesized and reported the bactericidal activity of diverse series of aztreonam appended with amidine moieties as siderophores. One of the derivatives exhibiting the highest MIC value in vitro was selected for further preclinical studies. The compound DPI-2016 was reassessed for its synthetic routes and methods that were improved to find the maximum final yields aimed at large-scale synthesis. In addition, the results of the pharmacological studies were determined with reference to aztreonam. It has been found that the compound DPI-2016 showed comparable or slightly improved ADMET as well as pharmacokinetic parameters to aztreonam. It is estimated that the compound could be a potential lead for further clinical evaluation.

Assessment of Safety Signals for Aztreonam in Different Age Groups: National and International Drug Safety Monitoring

Aztreonam is the only approved monocyclic β-lactam antibiotic for human use that is active against Gram-negative aerobes, primarily Pseudomonas аeruginosa. Aztreonam has been used for more than 35 years, and aztreonam lysine has been on the market for 15 years. Although the medicinal products show clinical and microbiological efficacy in severe infections and are significant for cystic fibrosis patients, little information is published on their safety. In the meantime, new data have accumulated.The aim of the study was to analyse the data on adverse reactions in patients of different age groups receiving aztreonam, collected in the safety monitoring databases VigiBase and Pharmacovigilance.Materials and methods: the data on adverse reactions associated with aztreonam, in any dosage form, from the individual case reports submitted to VigiBase (the database of the Uppsala Monitoring Centre) before 15.09.2021 and to Pharmacovigilance (the database for spontaneous reports in the Automated Information System of the Federal Service for Surveillance in Healthcare of the Russian Federation) before 05.10.2021.Results: the analysis of adverse reactions during the use of aztreonam for approved indications showed differences in frequency, types and severity of the adverse reactions amongst the age groups. The most common adverse reaction with aztreonam was cystic fibrosis referred to in 1828 reports (12.0%). It was recorded more often in patients aged 18–44 years (39.2%).Conclusions: the data obtained allowed the authors to identify a new safety signal for aztreonam, namely an increased risk of inefficacy or insufficient efficacy in cystic fibrosis considered an adverse reaction in the individual reports from the databases of spontaneous reports. Confirmation of the signal requires further monitoring.

Synthesis and Antibacterial Activities of Amidine Substituted Monocyclic β-Lactams.

Mononcyclic β-lactams are regarded as the most resistant class of β-lactams against a series of β-lactamases, although they possess limited antibacterial activity. Aztreonam, being the first clinically approved monobactam, needs broad-spectrum efficacy through structural modification. We strive to synthesize a number of monocyclic β-lactams by varying the substituents at N1, C3, and C4 positions of azetidinone ring and study the antimicrobial effect on variable bacterial strains. Seven new monobactam derivatives 23a-g, containing substituted-amidine moieties linked to the azetidinone ring via thiazole linker, were synthesized through multistep synthesis. The final compounds were investigated for their in vitro antibacterial activities using the broth microdilution method against ten bacterial strains of clinical interest. The minimum inhibitory concentrations (MICs) of newly synthesized derivatives were compared with aztreonam, ceftazidime, and meropenem, existing clinical antibiotics. All compounds 23a-g showed higher antibacterial activities (MIC 0.25 μg/mL to 64 μg/mL) against tested strains as compared to aztreonam (MIC 16 μg/mL to >64 μg/mL) and ceftazidime (MIC >64 μg/mL). However, all compounds, except 23d, exhibited lower antibacterial activity against all tested bacterial strains compared to meropenem. Compound 23d showed comparable or improved antibacterial activity (MIC 0.25 μg/mL to 2 μg/mL) to meropenem (MIC 1 μg/mL to 2 μg/mL) in the case of seven bacterial species. Therefore, compound 23d may be a valuable lead target for further investigations against multi-drug resistant Gram-negative bacteria.

Exploring the Molecular Basis of Substrate and Product Selectivities of Nocardicin Bifunctional Thioesterase.

D-amino acid introduction in peptides can enrich their biological activities and pharmacological properties as potential drugs. This achievement of stereochemical inversion usually owes to an epimerase or racemase. Interestingly, a unique bifunctional thioesterase (NocTE), which is incorporated in nonribosomal peptide synthetase (NRPS) NocA-NocB assembly line for the biosynthesis of monocyclic β-lactam antibiotic nocardicin A, can control the generation of D-products with high stereochemical purity. However, the molecular basis of NocTE selectivity on substrates and products is still unclear. Herein, we constructed a series of systems with different peptides varying in stereochemistry, length, and composition to investigate the substrate selectivity. The studies on binding affinities and loading conformations elucidated the important roles of peptide length and β-lactam ring in substrate selectivity. Through energy decomposition and interaction analyses, some key residues involved in substrate selectivity were captured. On the other hand, natural product undergoing epimerization was found to be liberated from the active pocket more easily in comparison with its diastereomer (epi-nocardicin G), explaining the superiority of nocardicin G. These results provide detailed molecular insights into the exquisite control of substrate and product scopes for NocTE, and encourage to diversification of substrates and final products for NRPS assembly line. The molecular insights into substrate and product selectivities of unique bifunctional thioesterase NocTE were illustrated via several molecular simulations and free energy calculations, contributing to expanding substrate and product scopes of nonribosomal peptide synthetases.

Conjugation of Aztreonam, a Synthetic Monocyclic β-Lactam Antibiotic, to a Siderophore Mimetic Significantly Expands Activity Against Gram-Negative Bacteria.

Monocyclic β-lactams with antibiotic activity were first synthesized more than 40 years ago. Extensive early structure-activity relationship (SAR) studies, especially in the 1980s, emphasized the need for heteroatom activation of monocyclic β-lactams and led to studies of oxamazins, monobactams, monosulfactams, and monocarbams with various side chains and peripheral substitution that revealed potent activity against select strains of Gram-negative bacteria. Aztreonam, still the only clinically used monobactam, has notable activity against many Gram-negative bacteria but limited activity against some of the most problematic multidrug resistant (MDR) strains of Pseudomonas aeruginosa and Acinetobacter baumannii. Herein, we report that extension of the side chain of aztreonam is tolerated and especially that coupling of the side chain free acid with a bis-catechol siderophore mimetic significantly improves activity against the MDR strains of Gram-negative bacteria that are of most significant concern.

Substituted-Amidine Functionalized Monocyclic β-Lactams: Synthesis and In Vitro Antibacterial Profile

Background. Owing to the intrinsic stability against common β-lactamases and metallo-lactamases, monobactams gathered special attention in antibiotic drug development. However, so far, aztreonam is the only monobactam approved by FDA for clinical use. We designed new derivatives of aztreonam to enhance its antibacterial efficacy. Methods. We synthesized a series of monocyclic β-lactams by modifying mainly at the C3 position of azetidinone ring. NH2 group at C3 of azetidinone was attached to thiazole and thiadiazole which in turn was linked to nitrogenous heterocyclic rings via amidine moieties. We then investigated the in vitro antibacterial activities of synthesized compounds against ten bacterial strains of clinical interest in comparison to aztreonam and ceftazidime. Results. All compounds showed improved antibacterial activities against tested strains compared to reference drugs. Compounds 14d and 14e were most potent and showed the highest potency against all bacterial strains, with MIC values ranging from 0.25 µg/mL to 8 µg/mL, as compared to aztreonam (MIC 16 µg/mL to >64 µg/mL) and ceftazidime (MIC >64 µg/mL). These compounds (14d and 14e) may be valuable lead targets against multidrug-resistant Gram-negative bacteria.

MC-100093, a Novel β-Lactam Glutamate Transporter-1 Enhancer Devoid of Antimicrobial Properties, Attenuates Cocaine Relapse in Rats.

Cocaine use disorder currently lacks Food and Drug Administration-approved treatments. In rodents, the glutamate transporter-1 (GLT-1) is downregulated in the nucleus accumbens after cocaine self-administration, and increasing the expression and function of GLT-1 reduces the reinstatement of cocaine seeking. The β-lactam antibiotic ceftriaxone upregulates GLT-1 and attenuates cue- and cocaine-induced cocaine seeking without affecting motivation for natural rewards. Although ceftriaxone shows promise for treating cocaine use disorder, it possesses characteristics that limit successful translation from bench to bedside, including poor brain penetration, a lack of oral bioavailability, and a risk of bacterial resistance when used chronically. Thus, we aimed to develop novel molecules that retained the GLT-1-enhancing effects of ceftriaxone but displayed superior drug-like properties. Here, we describe a new monocyclic β-lactam, MC-100093, as a potent upregulator of GLT-1 that is orally bioavailable and devoid of antimicrobial properties. MC-100093 was synthesized and tested in vitro and in vivo to determine physiochemical, pharmacokinetic, and pharmacodynamic properties. Next, adult male rats underwent cocaine self-administration and extinction training. During extinction training, rats received one of four doses of MC-100093 for 6-8 days prior to a single cue-primed reinstatement test. Separate cohorts of rats were used to assess nucleus accumbens GLT-1 expression and MC-100093 effects on sucrose self-administration. We found that 50 mg/kg MC-100093 attenuated cue-primed reinstatement of cocaine seeking while upregulating GLT-1 expression in the nucleus accumbens core. This dose did not produce sedation, nor did it decrease sucrose consumption or body weight. Thus, MC-100093 represents a potential treatment to reduce cocaine relapse. SIGNIFICANCE STATEMENT: Increasing GLT-1 activity reliably reduces drug-seeking across classes of drugs; however, existing GLT1-enhancers have side effects and lack oral bioavailability. To address this issue, novel GLT-1 enhancers were synthesized, and the compound with the most favorable pharmacokinetic and pharmacodynamic properties, MC-100093, was selected for further testing. MC-100093 attenuated cued cocaine seeking without reducing food seeking or locomotion and upregulated GLT-1 expression in the nucleus accumbens.

N-Thio-β-lactams targeting L,D-transpeptidase-2, with activity against drug-resistant strains of Mycobacterium tuberculosis

Effective treatment of tuberculosis is frequently hindered by the emerging antimicrobial resistance of Mycobacterium tuberculosis. The present study evaluates monocyclic β-lactam compounds targeting the mycobacterial cell wall remodeling. Novel N-thio-β-lactams were designed, synthesized, and characterized on the L,D-transpeptidase-2, a validated target in M. tuberculosis. The candidates were evaluated in biochemical assays identifying five compounds presenting target-specific kinetic constants equal or superior to meropenem, a carbapenem currently considered for tuberculosis therapy. Mass spectrometry in line with the crystal structures of five target-ligand complexes revealed that the N-thio-β-lactams act via an unconventional mode of adduct formation, transferring the thio-residues from the lactam ring to the active-site cysteine of LdtMt2. The resulting stable adducts lead to a long-term inactivation of the target protein. Finally, the candidates were evaluated invitro against a drug-susceptible and multidrug-resistant clinical isolates of M. tuberculosis, confirming the antimycobacterial effect of these novel compounds.

Strontium substituted hydroxyapatite with β-lactam integrin agonists to enhance mesenchymal cells adhesion and to promote bone regeneration

Multi-functionalization of calcium phosphates to get delivery systems of therapeutic agents is gaining increasing relevance for the development of functional biomaterials aimed to solve problems related to disorders of the muscolo-skeletal system. In this regard, we functionalized Strontium substituted hydroxyapatite (SrHA) with some β-lactam integrin agonists to develop materials with enhanced properties in promoting cell adhesion and activation of intracellular signaling as well as in counteracting abnormal bone resorption. For this purpose, we selected two monocyclic β-lactams on the basis of their activities towards specific integrins on promoting cell adhesion and signalling. The amount of β-lactams loaded on SrHA could be modulated on changing the polarity of the loading solution, from 3.5–24 wt% for compound 1 and from 3.2–8.4 wt% for compound 2. Studies on the release of the β-lactams from the functionalized SrHA in aqueous medium showed an initial burst followed by a steady-release that ensures a small but constant amount of the compounds over time. The new composites were fully characterized. Co-culture of human primary mesenchymal stem cells (hMSC) and human primary osteoclast (OC) demonstrated that the presence of β-lactams on SrHA favors hMSC adhesion and viability, as well as differentiation towards osteoblastic lineage. Moreover, the β-lactams were found to enhance the inhibitory role of Strontium on osteoclast viability and differentiation.

Monocyclic β-Lactam: A Review on Synthesis and Potential Biological Activities of a Multitarget Core.

A monocyclic ring in their structure characterizes monobactams, a subclass of β-lactam antibiotics. Many of these compounds have a bactericidal mechanism of action and acts as penicillin and cephalosporins, interfering with bacterial cell wall biosynthesis. The synthesis of novel β-lactams is an emerging area of organic synthesis research due to the problem of increasing bacterial resistance to existing β -lactam antibiotics, and, in this way, new compounds have been presented with several structural modifications, aiming to improve biological activities. Among the biological activities studied, the most outstanding are antibacterial, antitubercular, anticholesterolemic, anticancer, antiinflammatory, antiviral, and anti-enzymatic, among others. This review explores the vast number of works related to monocyclic β-lactams, compounds of great importance in scientific research.

Studies towards synthesis and Lewis acid catalysed functionalization of 3-(4′-substitutedphenylthio)-azetidin-2-ones

Medicinal chemistry of heterocycles especially β-lactams have been an important discovery in today’s mankind. β-Lactam nucleus is structural feature and core of the biological activity of one of most successful classes of therapeutics to date characterized by a broad spectrum of activity and low toxicity. It constitutes classes of drugs that includes the antibiotics like penicillins, cephalosporins, clavulanic acid, monobactams and also shows wide range of important biological activities such as anti-cancer, anti-inflammatory and anti-malarial. The monocyclic β-lactams and their hetero-substituted conjugates are also applied for the synthesis of many classes of compounds which include taxol derivatives, alkaloids and amino acids. Antimicrobial resistance is one of the major and growing concerns in hospital and community acquired infections and new anti-microbial agents are therefore urgently required. So now, the organic chemists have focussed on the modification of existing molecules for the synthesis of new compounds having diverse pharmacological activities with broad spectrum activity. Monocyclic β-lactams are stable to hydrolysis by β-lactamases in comparison to other β-lactams and thus are attractive platform for searching anti-bacterial agents. The discovery of differently substituted 3-alkyl/aryl β-lactams having significant anti-microbial activities have given insight that substitution at C-3 and C-4 of β-lactam ring affects the biological activity of the ring. So, keeping this in mind and synthetic utility of β-lactams here we have made an attempt towards the feasibility and efficiency of 3-(p-substituted-phenylthio)-β-lactams towards Lewis acid functionalization reactions. In our previous works, we have explored the synthetic utility of cis-3-chloro-3-phenyl/benzyl/methylthio-β-lactams as suitable substrate for the Lewis acid catalysed nucleophilic substitution. The current work is designed to explore the effect of electronic changes at phenylthio group at C-3 on the products profile in the Lewis acid catalysed nucleophilic substitution reactions. The synthetic utility 3-(4′-substitutedphenylthio)-azetidin-2-ones towards Lewis acid catalyzed C-3 functionalization reactions have been studied.

Synthesis, docking and evaluation of in vitro anti-inflammatory activity of novel morpholine capped β-lactam derivatives

This study reports the synthesis and biological investigation of three series of novel monocyclic β-lactam derivatives bearing a morpholine ring substituent on the nitrogen. The resulting β-lactam adducts were synthesized via Staudinger's [2 + 2]-ketene-imine cycloaddition reaction. New synthesized products were fully characterized by spectral data and elemental analyses, and then evaluated for anti-inflammatory activity toward human inducible nitric oxide synthase (iNOS) and cytotoxicity toward HepG2 cell line. The compounds 3e, 3h, 3k, 5c, 5f, 6c, 6d and 6f showed higher activity with anti-inflammatory ratio values of 38, 62, 51, 72, 51, 35, 55 and 99, respectively, in comparison to the reference compound dexamethasone having an anti-inflammatory ratio value of 32. Hence, these compounds can be considered as potent iNOS inhibitors. They also exhibited IC50 values of 0.48 ± 0.04 mM, 0.51 ± 0.01 mM, 0.22 ± 0.02 mM, 0.12 ± 0.00 mM, 0.25 ± 0.05 mM, 0.82 ± 0.07 mM, 0.44 ± 0.04 mM and 0.60 ± 0.04 mM, respectively, in comparison with doxorubicin (IC50 < 0.01 mM) against HepG2 cells, biocompatibility and nontoxic behavior. In silico prediction of drug-likeness characteristic indicated that the compounds are compliant with the Lipinski and Veber rules. Molecular docking experiments showed a good correlation between the experimental activity and the calculated binding affinity to human inducible nitric oxide synthase, the enzymatic target for the anti-inflammatory response.

Synthesis and Penicillin-binding Protein Inhibitory Assessment of Dipeptidic 4-Phenyl-β-lactams from α-Amino Acid-derived Imines.

Monocyclic β-lactams revive the research field on antibiotics, which are threatened by the emergence of resistant bacteria. A six-step synthetic route was developed, providing easy access to new 3-amino-1-carboxymethyl-4-phenyl-β-lactams, of which the penicillin-binding protein (PBP) inhibitory potency was demonstrated biochemically.

α-Unsaturated 3-Amino-1-carboxymethyl-β-lactams as Bacterial PBP Inhibitors: Synthesis and Biochemical Assessment.

Innovative monocyclic β-lactam entities create opportunities in the battle against resistant bacteria because of their PBP acylation potential, intrinsically high β-lactamase stability and compact scaffold. α-Benzylidene-substituted 3-amino-1-carboxymethyl-β-lactams were recently shown to be potent PBP inhibitors and constitute eligible anchor points for synthetic elaboration of the chemical space around the central β-lactam ring. The present study discloses a 12-step synthesis of ten α-arylmethylidenecarboxylates using a microwave-assisted Wittig olefination as the crucial reaction step. The library was designed aiming at enhanced β-lactam electrophilicity and extended electron flow after enzymatic attack. Additionally, increased β-lactamase stability and intermolecular target interaction were envisioned by tackling both the substitution pattern of the aromatic ring and the β-lactam C4-position. The significance of α-unsaturation was validated and the R39/PBP3 inhibitory potency shown to be augmented the most through decoration of the aromatic ring with electron-withdrawing groups. Furthermore, ring cleavage by representative β-lactamases was ruled out, providing new insights in the SAR landscape of monocyclic β-lactams as eligible PBP or β-lactamase inhibitors.

Characteristics of and germicidal efficacy at different temperatures against Vibrio parahaemolyticus

Objective To study the biological characteristics of, antibiotic resistance in and germicidal efficacy at different temperatures against Vibrio parahaemolyticus (V.parahaemolyticus) strains isolated from different sources in order to provide reference for clinical treatment and prevention. Methods Stool samples from patients with diarrhea and small seafood product specimens from markets were collected and analyzed with biochemical identification method, serotyping analysis, drug susceptibility test and germicidal efficacy test at different temperatures. Results There were 107 V. parahaemolyticus strains isolated from 1 166 stool samples of patients with foodborne diarrhea with a positive rate of 9.18% and 42 from 72 seafood product samples with a positive rate of 58.30%. V. parahaemolyticus strains isolated from the foodborne diarrhea cases were divided into eight serogroups and among them, O3 and O4 were the predominant serogroups, accounting for 49.53% and 34.58%, respectively. Most of the O antigens in small seafood products belonged to serogroups of O4, O1 and O3, and four strains of O3∶K6 were isolated. Results of the drug susceptibility test showed that both of the clinical isolates and marine product isolates were highly resistant to ampicillin and the drug resistance rates were 94.39% and 88.10%, respectively. Antibiotic-sensitive strains to monocyclic β-lactams, aminoglycosides, quinolones, carbapenems, tetracyclines and sulfonamides accounted for over 90.00% or even nearly 100.00%. There were 17 (15.89%) clinical strains and three (7.14%) marine product isolates resistant to three or more kinds of antibiotics. At 80℃, the bactericidal rate for marine product isolates was 85.71% in 60 s and reached 100.00% in 90 s. At 90℃ and 100℃, these isolates could be completely killed in 40 s and 30 s. It took 120 s, 90 s and 50 s to kill clinical isolates at 80℃, 90℃ and 100℃, respectively. Conclusions This study systematically analyzed and compared the drug-resistant phenotypes of and the bactericidal efficacy at different temperatures on V. parahaemolyticus strains isolated from clinical samples and marine products. It would provide reference for preventing and controlling the spread of V. parahaemolyticus and hospital infection and for studying treatment strategies. Key words: Vibrio parahaemolyticus; Antibiotic susceptibility; Germicidal efficacy; Temperature

Facile synthesis of novel benzothiazolylpyrazolyl anchored 3-thio/seleno/chloro-β-lactams: Synthetic intermediates for novel 3-sulfenyl/sulfonyl, C-3 functionalized monocyclic and spirocyclic β-lactams

Efficient synthesis of a new series of 3-phenyl/benzylthio-4-benzothiazolylpyrazolyl-β-lactams is described. Treatment of 2-phenylthio/benzylthioacetic acid with benzothiazolylpyrazolyl substituted Schiff’s bases furnished trans-β-lactams exclusively. Newly synthesized substituted Schiff’s bases and β-lactams were identified using FT-IR, 1H NMR, 13C NMR and elemental analysis (CHN). The trans configuration was assigned with respect to coupling constant values of C3-H and C4-H. The novel β-lactams will be the potential synthetic intermediates to access 3-sulfenyl/sulfonyl, C-3 functionalized monocyclic and spirocyclic β-lactams of medicinal interest. The present manuscript provides first report on β-lactams linked to bulky group benzothiazolylpyrazolyl.

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

ABSTRACTA 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.

Stereoselective synthesis, spectroscopic and X-ray crystallographic characterization of novel trans- and cis-3-methylseleno substituted monocyclic β-lactams: Potential synthons for C-3 functionalized/bicyclic/halospiroseleno-β-lactams of medicinal interest

Abstract New series of trans- and cis-3-methylseleno substituted β-lactams (4, 5) have been prepared from 2-methylselenoethanoic acid (2). The four-membered β-lactam ring was introduced by the condensation reaction between ketene retrieved from 2-methylselenoethanoic acid (2) and suitably substituted imines (3a-f) in the presence of triethylamine using POCl3 in refluxing toluene. The structural and stereochemical analysis of novel trans- and cis-3-methylseleno substituted β-lactams were carried out using IR, NMR (1H and 13C), 2D-NMR (1H–1H COSY, 1H–13C HSQC), elemental analysis (CHN) and mass spectrometry (EIMS). Further, the structures of trans-1-(4′-methoxyphenyl)-3-methylseleno-4-(4′-chlorophenyl)azetidin-2-one (4b), trans-1-(4′-methoxyphenyl)-3-methylseleno-4-(4′-methylphenyl)azetidin-2-one (4c), trans- and cis-1-(4′-methoxyphenyl)-3-methylseleno-4-styrylazetidin-2-ones (4e and 5e) were established by single crystal X-ray crystallographic studies. The cis or trans configuration of the hydrogen at C-3 was assigned with respect to C4-H.

Process Development for the Synthesis of Monocyclic β-Lactam Core 17

Process development and multikilogram synthesis of the monocyclic β-lactam core 17 for a novel pyridone-conjugated monobactam antibiotic is described. Starting with commercially available 2-(2,2-diethoxyethyl)isoindoline-1,3-dione, the five-step synthesis features several telescoped operations and direct isolations to provide significant improvement in throughput and reduced solvent usage over initial scale-up campaigns. A particular highlight in this effort includes the development of an efficient Staudinger ketene–imine [2 + 2] cycloaddition reaction of N-Boc-glycine ketene 12 and imine 9 to form racemic β-lactam 13 in good isolated yield (66%) and purity (97%). Another key feature in the synthesis involves a classical resolution of racemic amine 15 to afford single enantiomer salt 17 in excellent isolated yield (45%) with high enantiomeric excess (98%).