W. Dean Harman

Antiparasitic Drug Nitazoxanide Inhibits the Pyruvate Oxidoreductases of Helicobacter pylori, Selected Anaerobic Bacteria and Parasites, and Campylobacter jejuni

ABSTRACT Nitazoxanide (NTZ) exhibits broad-spectrum activity against anaerobic bacteria and parasites and the ulcer-causing pathogen Helicobacter pylori. Here we show that NTZ is a noncompetitive inhibitor (Ki, 2 to 10 μM) of the pyruvate:ferredoxin/flavodoxin oxidoreductases (PFORs) of Trichomonas vaginalis, Entamoeba histolytica, Giardia intestinalis, Clostridium difficile, Clostridium perfringens, H. pylori, and Campylobacter jejuni and is weakly active against the pyruvate dehydrogenase of Escherichia coli. To further mechanistic studies, the PFOR operon of H. pylori was cloned and overexpressed in E. coli, and the multisubunit complex was purified by ion-exchange chromatography. Pyruvate-dependent PFOR activity with NTZ, as measured by a decrease in absorbance at 418 nm (spectral shift from 418 to 351 nm), unlike the reduction of viologen dyes, did not result in the accumulation of products (acetyl coenzyme A and CO2) and pyruvate was not consumed in the reaction. NTZ did not displace the thiamine pyrophosphate (TPP) cofactor of PFOR, and the 351-nm absorbing form of NTZ was inactive. Optical scans and 1H nuclear magnetic resonance analyses determined that the spectral shift (A418 to A351) of NTZ was due to protonation of the anion (NTZ−) of the 2-amino group of the thiazole ring which could be generated with the pure compound under acidic solutions (pKa = 6.18). We propose that NTZ− intercepts PFOR at an early step in the formation of the lactyl-TPP transition intermediate, resulting in the reversal of pyruvate binding prior to decarboxylation and in coordination with proton transfer to NTZ. Thus, NTZ might be the first example of an antimicrobial that targets the “activated cofactor” of an enzymatic reaction rather than its substrate or catalytic sites, a novel mechanism that may escape mutation-based drug resistance.

Dihapto binding of aromatic molecules by π-basic transition metal complexes: development of alternatives to the {Os(NH3)5}2+ fragment

Abstract Dihapto-coordination of aromatic ligands by electron-rich transition metals can effectively dearomatize the bound aromatic molecule. The pentaammineosmium(II) system forms thermally stable η 2 -complexes with a variety of arenes and aromatic heterocycles, and has been used for a variety of organic transformations on the bound aromatic fragments. The systematic variation of isoelectronic rhenium(I) systems has provided the necessary electronic and steric characteristics needed for a less expensive, chiral alternative to the {Os(NH 3 ) 5 } 2+ system. The {TpRe(CO)(PMe 3 )} system has been shown to form stable dihapto complexes with furan, thiophene and naphthalene. Accordingly, the {TpRe(CO)(PMe 3 )} fragment and analogous {TpRe(CO)(L)} fragments represent the first class of asymmetric surrogates to the pentaammineosmium(II) system.

Polarization of the Pyridine Ring: Highly Functionalized Piperidines from Tungsten−Pyridine Complex

The N-acetylpyridinium complex of {TpW(NO)(PMe3)} undergoes regio- and stereoselective reactions with a broad range of common organic nucleophiles, providing a family of 1,2-dihydropyridine (DHP) complexes of the form TpW(NO)(PMe3)(3,4-η(2)-DHP). The present study explores the elaboration of these systems into novel piperidines. The addition of an acid to the DHP complexes generates highly asymmetric π-allyl complexes that in turn react with a second nucleophile at either C3 or C5. The subsequent oxidative decomplexation of these materials yields several piperidinamides with unconventional substitution patterns.

[4 + 2] Cyclocondensation Reactions of Tungsten–Dihydropyridine Complexes and the Generation of Tri- and Tetrasubstituted Piperidines

A new method for the preparation of functionalized piperidines is described in which various dihydropyridine (DHP) complexes of {TpW(NO)(PMe(3))} that are derived from pyridine-borane undergo [4 + 2] cyclocondensation with enones, enals, nitrosobenzene, and several isocyanates to form [2.2.2] bicyclic species. In several cases the diazabicyclooctene products derived from DHP complexes and isocyanates can be further elaborated into novel syn-2,5-disubstituted and 2,3,6-trisubstituted piperidinamides.

Recent advances in osmium chemistry

Publisher Summary This chapter discusses the recent advances in osmium (Os) chemistry. The chapter explains the synthesis, properties, and chemistry of coordination complexes, focusing on the literature since the end of 1985. Analogous ruthenium (Ru) chemistry is also included to show the similarities and differences in the chemistry of these elements. Appropriate literature dealing with organometallic chemistry is referred relevant to the discussion on the coordination chemistry, because Os chemistry often transcends these traditional boundaries. Osmium complexes exist in every oxidation state from II– to VIII, but generally the coordination chemistry is restricted to oxidation states II through VIII. Most Os(IV) complexes are low spin and octahedral. Although they have two unpaired electrons, they often have anomalous magnetic properties at room temperature. This is because of quenching of the electron spin by the orbital spin, as a consequence of the large spin-orbit coupling constant. A large number of carbonyl complexes of Os have been prepared and characterized, but only CO complexes are discussed in the chapter, those with ligands that are normally associated with classical coordination chemistry. Reactions analogous to the protonation of π -acid ligand bound to Os ammine complexes have been observed with other electrophiles.

Efficient Synthesis of an η2-Pyridine Complex and a Preliminary Investigation of the Bound Heterocycle’s Reactivity

Pyridine borane is combined with TpW(NO)(PMe(3))(eta(2)-benzene) to form a complex of the heterocycle, which upon treatment with acetone and acid yields the pyridinium complex [TpW(NO)(PMe(3))(eta(2)-pyH(+))]OTf. Deprotonation in the presence of acetic anhydride delivers the N-acetylpyridinium complex as a 10:1 mixture of coordination diastereomers. This acylpyridinium resists reaction with water or oxygen but readily reacts with acetone, pyrrole, indole, or acrolein and a weak base to stereoselectively form 1,2-dihydropyridine complexes. Treatment of the indole-derived analogue with CuBr(2) results in liberation of 3-(pyridin-2-yl)-1H-indole.

Synthesis of 1-Oxadecalins from Anisole Promoted by Tungsten

The complex TpW(NO)(PMe3)(eta(2)-anisole) is combined with acrolein or methyl vinyl ketone and various nucleophiles to generate novel chromen complexes. These complexes may be further elaborated by protonation and nucleophilic addition to generate chroman analogues with increased saturation and stereocenters. Treatment with various oxidants effects the decomplexation of the chromen.

Stereoselective Umpolung Tandem Addition of Heteroatoms to Phenol

Upon coordination to {TpW(PMe3)(NO)}, phenol tautomerizes to a cyclohexadienone (a 2H-phenol). The uncoordinated, nonaromatic double bond of this ligand undergoes stepwise addition of electrophiles followed by nucleophiles to produce 4,5-disubstituted cyclohexenone complexes. The metal stabilizes the intermediate cationic ligand and sterically blocks one face of the ligand, resulting in a high degree of stereo- and regiocontrol. These substituted cyclohexenones are readily liberated from the metal by oxidative decomplexation.

Novel Cyclization Reactions for η2-Furan Complexes

Abstract A series of complexes has been prepared of the form [Os(NH3)5(4,5-η2-L)]2+ where L=furan and various 2-alkylated furans. Electrophilic addition to C(3) results in an unstable reaction intermediate, a 4,5-η2-3H-furanium species, that leads to several novel cyclization reactions with tethered nucleophiles to form new heterocycles.

Reversible β-hydride elimination of amine ligands forming stable cis-η2-iminium hydride OsII complexes

Abstract Octahedral tetraammineosmium(II) species are generated from their OsIII precursors containing an amine ligand cis to a labile alcohol or triflate. These compounds undergo reversible β-hydride eliminations resulting in the formation of cis-η2-iminium hydride complexes. Judging from NMR data, the η2-iminium group in these products lies parallel to the osmium-hydride bond with the iminium carbon eclipsing the hydride. Attempts to form η2-arene complexes of an OsII ammine system bearing a stereogenic carbon are also described.