Complex of Ca(II) with Ceftriaxone: Synthesis, Structure, Spectral and Antibacterial Properties

The calcium complex of ceftriaxone was synthesized and characterized by elemental, atomic-emission analysis, TGA, IR spectroscopy and density functional theory calculations. The luminescence and antibacterial properties of the ceftriaxone disodium and calcium complex were investigated. Ca(II) complex was obtained in a crystalline form, cell parameters of the compound were determined. Ceftriaxone was coordinated to the calcium ion by the oxygen of the triazine cycle in the 6th position, the nitrogen of the amine group of the thiazole ring, and the oxygens of the lactam carbonyl and carboxylate groups. The complex of Ca(II) with ceftriaxone was screened for antibacterial activity against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, and the results were compared with the activity of ceftriaxone disodium salt

Syntheses and identification of cefotaxime-non-transition metal complexes

The coordination chemistry of the biologically active cefotaxime sodium and, in particular, the mode of its interaction with some metal ions of electronic configuration d0 (alkaline earth) and others, Zn(II), Pb(II), and Ce ions with the electronic configuration d10 has been investigated. Seven complexes were synthesized, isolated in the solid-state, and characterized by elemental analyses, conductivity measurements, IR and UV/VIS spectra, as well as thermal analyses. Based on the obtained experimental data and literature, the structural formulae to these complexes were suggested and formulated as [Mg(cef)2].2H2O (1), [Ca(cef)2].2H2O (2) [Sr(cef)2].2H2O (3), [Ba(cef)2].2H2O (4), [Zn(cef)2(H2O)2] (5), [Pb(cef)2(H2O)2].4H2O (6) and [Ce(cef)2(H2O)2].3H2O (7). The data obtained show that cefotaxime interacted with metal in a molar ratio of 2:1, respectively. Cefotaxime bonded to metal ions in the anionic form as a bidentate ligand through the lactam carbonyl (C=O) and the carboxylate group (COO-). Tetrahedral and octahedral shapes were proposed as the most likely geometries associated with a metal having such electronic configurations. The absorption bands observed in the electronic spectrum of free cefotaxime are also observed with some shifts in the spectra of its complexes, indicating their formation. The absorption bands of free cefotaxime and its complexes were assigned to electronic transitions. The thermal analyses date strongly support the structures proposed for the complexes and indicate the formation of the corresponding metal oxide as a final decomposition product.

Studies on the Enantioselective Synthesis of E-Ethylidene-bearing Spiro[indolizidine-1,3′-oxindole] Alkaloids

A synthetic route for the enantioselective construction of the tetracyclic spiro[indolizidine-1,3′-oxindole] framework present in a large number of oxindole alkaloids, with a cis H-3/H-15 stereochemistry, a functionalized two-carbon substituent at C-15, and an E-ethylidene substituent at C-20, is reported. The key steps of the synthesis are the generation of the tetracyclic spirooxindole ring system by stereoselective spirocyclization from a tryptophanol-derived oxazolopiperidone lactam, the removal of the hydroxymethyl group, and the stereoselective introduction of the E-ethylidene substituent by acetylation at the α-position of the lactam carbonyl, followed by hydride reduction and elimination. Following this route, the 21-oxo derivative of the enantiomer of the alkaloid 7(S)-geissoschizol oxindole has been prepared.

Pyroglutamic Acid and its Derivatives: The Privileged Precursors for the Asymmetric Synthesis of Bioactive Natural Products

Pyroglutamic acid is one of the privileged asymmetric precursors for the synthesis of a variety of molecules such as Angiotensin-Converting Enzyme (ACE) inhibitors, angiotensin II receptor subtypes (AT-1 receptor antagonists), as well as bioactive natural products. Starting with primary reports in 1980’s, last almost four decades has witnessed a rapid overgrowth of publications using pyroglutamic acid as a preferred asymmetric precursor and these have been well documented. Pyroglutamic acid has two differential carbonyl groups a lactam carbonyl and a carboxylic functionality along with an NH group, and all of these functionalities can be further derivatized/ transformed and in turn opened avenues for the synthesis of variety of molecules. Derived easily from glutamic acid by internal cyclization, pyroglutamic acid offers a cheap and very good source of chirality and has provided an important tool for the synthesis of natural products/intermediates to natural products. Herein, we wish to describe the exploitation of the chemistry of pyroglutamic acid and its derivatives in the asymmetric synthesis of natural products establishing its versatility as a privileged asymmetric precursor.

Biosynthetic Incorporation of Site-Specific Isotopes in βLactam Antibiotics Enables Biophysical Studies

A biophysical understanding of the mechanistic, chemical, and physical origins underlying antibiotic action and resistance is vital to the discovery of novel therapeutics and the development of strategies to combat the growing emergence of antibiotic resistance. The site-specific introduction of stable-isotope labels into chemically complex natural products is particularly important for techniques such as NMR, IR, mass spectrometry, imaging, and kinetic isotope effects. Towards this goal, we developed a biosynthetic strategy for the site-specific incorporation of ¹³C-labels into the canonical β-lactam carbonyl of penicillin G and cefotaxime, the latter via cephalosporin C. This was achieved through sulfur-replacement with 1-¹³C-L-cysteine, resulting in high isotope incorporations and mg-scale yields. Using ¹³C NMR and isotope-edited IR difference spectroscopy, we illustrate how these molecules can be used to interrogate interactions with their protein targets, e.g. TEM-1 β-lactamase. This method provides a feasible route to isotopically-labeled penicillin and cephalosporin precursors for future biophysical studies.

Biosynthetic Incorporation of Site-Specific Isotopes in βLactam Antibiotics Enables Biophysical Studies

A biophysical understanding of the mechanistic, chemical, and physical origins underlying antibiotic action and resistance is vital to the discovery of novel therapeutics and the development of strategies to combat the growing emergence of antibiotic resistance. The site-specific introduction of stable-isotope labels into chemically complex natural products is particularly important for techniques such as NMR, IR, mass spectrometry, imaging, and kinetic isotope effects. Towards this goal, we developed a biosynthetic strategy for the site-specific incorporation of ¹³C-labels into the canonical β-lactam carbonyl of penicillin G and cefotaxime, the latter via cephalosporin C. This was achieved through sulfur-replacement with 1-¹³C-L-cysteine, resulting in high isotope incorporations and mg-scale yields. Using ¹³C NMR and isotope-edited IR difference spectroscopy, we illustrate how these molecules can be used to interrogate interactions with their protein targets, e.g. TEM-1 β-lactamase. This method provides a feasible route to isotopically-labeled penicillin and cephalosporin precursors for future biophysical studies.

Fates of imine intermediates in radical cyclizations of N-sulfonylindoles and ene-sulfonamides

Two new fates of imine intermediates formed on radical cyclizations of ene-sulfonamides have been identified, reduction and hydration/fragmentation. Tin hydride-mediated cyclizations of 2-halo-N-(3-methyl-N-sulfonylindole)anilines provide spiro[indoline-3,3'-indolones] or spiro-3,3'-biindolines (derived from imine reduction), depending on the indole C2 substituent. Cyclizations of 2-haloanilide derivatives of 3-carboxy-N-sulfonyl-2,3-dihydropyrroles also presumably form spiro-imines as primary products. However, the lactam carbonyl group facilitates the ring-opening of these cyclic imines by a new pathway of hydration and retro-Claisen-type reaction, providing rearranged 2-(2'-formamidoethyl)oxindoles.

N-Alkyl pyrrolidone ether podands as versatile alkali metal ion chelants

The highly polar nature of lactam carbonyl groups makes them potent chelators of alkali metal ions as part of a flexible podand ligand.

Mixed-Ligand Nickel(II) Complexes Containing Sulfathiazole and Cephalosporin Antibiotics: Synthesis, Characterization, and Antibacterial Activity

Nickel(II) reacts with cephalosporins plus sulfathiazole (Hstz) to form the following mixed-ligand complexes of general formulae [Ni(L)(stz)(H2O)x]n (L1,4, x=1; L2,3, x=0; L = monoanion of cefazolin HL1, cephalothin HL2, cefotaxime HL3, ceftriaxone HL4) and [Ni(L5)(stz)]Cl (cefepime L5), which were characterized by physicochemical and spectroscopic methods. Their spectra indicated that cephalosporins are acting as multidentate chelating agents, via the lactam carbonyl and carboxylate and N-azomoieties. The complexes are insoluble in water and common organic solvents but soluble in DMSO, where the [Ni(L5)(stz)]Cl complex is 1 : 1 electrolyte. They probably have polymeric structures. They have been screened for antibacterial activity, and the results are compared with the activity of commercial cephalosporins.

The Takayama Synthesis of (-)-Cernuine

(-)-Cernuine 3 falls in the subset of the Lycopodium alkaloids that feature a bicyclic aminal core. There had not been a total synthesis of this class of alkaloids until the recent (Organic Lett. 2008, 10, 1987) work of Hiromitsu Takayama of Chiba University. The key step in this synthesis was a diastereoselective intramolecular reductive amination, converting 1 to 2. As is apparent from the 3-D projection, (-)-cernuine 3 has a tricyclic trans-anti-trans aminal core, with an appended six-membered ring, both branches of which are axial on the core. While the branch that is part of the aminal could be expected to equilibrate, the other branch had to be deliberately installed. The synthesis began with (+)-citronellal 4, each enantiomer of which is commercially available in bulk. After protection and ozonolysis, the first singly-aminated stereogenic center was installed by enantioselective, and therefore diastereoselective, addition of 5 to the azodicarboxylate 6, mediated by the organocatalyst 7. Reductive cleavage of the N-N bond followed by acetal methanolysis converted 8 to 9. Ionization followed by allyl silane addition then delivered 11, having the requisite axial alkyl branch. The next two tasks were the assembly of the second of the four rings of 3, and the construction of the second single-aminated stereogenic center. The ring was assembled by deprotection of 11 followed by acylation with acryloyl chloride, to give 12. Grubbs cyclization followed by hydrogenation then led to 13. Homologation of 13 to the aldehyde 14 set the stage for condensation with the camphor-derived tertiary amine 15, following the protocol developed by Kobayashi. Sequential imine formation, aza-Cope rearrangement, and hydrolysis led to 1 in 94% de. One could envision reduction of the lactam carbonyl of 1 to an aldehyde equivalent, that would then, under acidic conditions, condense to form the desired aminal 2. This approach was, however, not successful. As an alternative, conditions were developed to convert 1 to the amidine 16. Reduction then proceeded with the expected high diastereocontrol, to give the cis 1,3-fused aminal 2. This was not isolated, but was directly acylated with acryloyl chloride, to 17.