Unexpected Z-stereoselectivity in the Ramberg-Bäcklund reaction of diarylsulfones leading to cis-stilbenes: the effect of aryl substituents and application in the synthesis of the integrastatin nucleus.

With certain substituent patterns, benzyl benzyl sulfone systems have been found to give unexpectedly high Z-stereoselectivity (up to E:Z = 1:16) in the Meyers variant of the Ramberg-Bäcklund reaction. A range of sulfones, bearing various aryl substituents, were explored to rationalize this unprecedented selectivity for Z-stilbene systems. This high level of double bond stereocontrol has also been utilized in the synthesis of integrastatin nucleus, the core of two highly bioactive anti-HIV compounds.

EPR evidence for the involvement of free radicals in the iron-catalysed decomposition of qinghaosu (artemisinin) and some derivatives; antimalarial action of some polycyclic endoperoxides.

EPR experiments confirm that reaction of qinghaosu and some related endoperoxides with Fe2+ in aqueous acetonitrile leads to the production of carbon-centred radicals derived by rapid rearrangement of first-formed cyclic alkoxyl radicals. Signals obtained from qinghaosu itself with spin-traps DMPO and DBNBS are assigned to the adducts (15) and (16), a finding which accounts for the formation of the major products (11) and (14).

Lipid peroxidation-dependent chemiluminescence from the cyclization of alkylperoxyl radicals to dioxetane radical intermediates.

This work reveals a novel mechanism for triplet carbonyl formation (and hence chemiluminescence) during lipid peroxidation, whose chemiluminescence has been attributed to both triplet carbonyls and singlet oxygen. As a model for polyunsaturated fatty acid hydroperoxides, we have synthesized 3-hydroperoxy-2,3-dimethyl-1-butene by photooxygenation of tetramethylethylene. One-electron oxidation of this hydroperoxide with heme proteins and peroxynitrite to the corresponding alkylperoxyl radical results in chemiluminescence, both direct and 9,10-dibromoanthracene-2-sulfonate-sensitized, the latter attributed to the formation of triplet acetone. It is postulated that triplet acetone results from the cyclization of the alkylperoxyl radical to a dioxetane radical intermediate followed by its thermolysis. This is supported by EPR spin-trapping experiments in which discrimination between carbon-centered radicals derived from the alkyloxyl and alkylperoxyl radicals is achieved through the use of one-electron oxidants and reductants, e.g., FeII- and TiIII.

Use of isotopically labelled spin-traps to determine definitively the presence or absence of non-radical addition artefacts in EPR spin-trapping systems.

EPR spin-trapping, although a powerful, sensitive technique for the study of free radicals, can be susceptible to artefacts; one of the most intractable to determine has been the non-radical addition of a substrate to a spin-trap followed by oxidation of the product to an EPR-detectable nitroxide. This work details how differentially isotopically labelled spin-traps (either nitroso or nitrone) may be used to determine the presence (or absence) of such artefacts, and provide a semi-quantitative measure of the extent of their contribution to the total EPR spectra in spin-trapping reactions. Artefactual 'ene' addition of the nitroso spin-trap 3,5-dibromo-4-nitroso-benzenesulphonic acid (DBNBS) to tryptophan followed by oxidation to EPR-detectable products has been confirmed, as has its nucleophilic addition to the thiol of glutathione to give non-EPR detectable products. The nitrone α-phenyl-N-tert-butylnitrone (PBN) exhibited no such reactivity.

A kinetic and ESR investigation of iron(II) oxalate oxidation by hydrogen peroxide and dioxygen as a source of hydroxyl radicals.

The reaction of Fe(II) oxalate with hydrogen peroxide and dioxygen was studied for oxalate concentrations up to 20 mM and pH 2-5, under which conditions mono- and bis-oxalate complexes (Fe[II](ox) and Fe[II](ox)2[2-]) and uncomplexed Fe2+ must be considered. The reaction of Fe(II) oxalate with hydrogen peroxide (Fe2+ + H2O2 --> Fe3+ + .OH + OH-) was monitored in continuous flow by ESR with t-butanol as a radical trap. The reaction is much faster than for uncomplexed Fe2+ and a rate constant, k = 1 x 10(4) M(-1) s(-1) is deduced for Fe(II)(ox). The reaction of Fe(II) oxalate with dioxygen is strongly pH dependent in a manner which indicates that the reactive species is Fe(II)(ox)2(2-), for which an apparent second order rate constant, k = 3.6 M(-1) s(-1), is deduced. Taken together, these results provide a mechanism for hydroxyl radical production in aqueous systems containing Fe(II) complexed by oxalate. Further ESR studies with DMPO as spin trap reveal that reaction of Fe(II) oxalate with hydrogen peroxide can also lead to formation of the carboxylate radical anion (CO2-), an assignment confirmed by photolysis of Fe(II) oxalate in the presence of DMPO.

An E.S.R. investigation of the reactive intermediate generated in the reaction between FeII and H2O2 in aqueous solution. Direct evidence for the formation of the hydroxyl radical.

The technique of E.S.R. spectroscopy, when employed in conjunction with a continuous flow system, provides direct evidence for the nature of free radicals formed from organic substrates in the presence of FeII and H2O2 in aqueous solution. It is shown, both via the identification of hydroxyl-radical adducts to alkenes and via the observed site-selectivity of radical attack, that the hydroxyl radical is formed as the reactive intermediate in the presence of various chelators (e.g. EDTA, DTPA). This approach also allows the rate constants for the FeII-H2O2 reaction in the presence of the different chelates to be determined; values obtained are in reasonable agreement with most of those measured by other methods. Examples of radical oxidation (by FeIII) and reduction (by FeII) are revealed.