Synthesis of a tetraoxy-bis-nortaxadiene, en route to taxol, using a cascade radical cyclisation sequence

Concise syntheses of the substituted enynediones 28a, 33b and 36 starting from the cyclohexenealdehyde 18, corresponding to ring A in the taxanes, and the vinylstannane 24, are described. Treatment of 36 with Bu3SnH–AIBN did not lead to the oxy-substituted taxadiene 37 expected from a tandem radical macrocyclisation–radical transannulation sequence; instead, a mixture of unidentified products resulted. When the PMB ether 33b corresponding to the alcohol 36 was treated with Bu3SnH–AIBN under similar conditions, p-anisaldehyde was isolated, as a major by-product, but no evidence for the formation of a taxadiene could be observed. In contrast, the iododienynedione 41, i.e., deoxy 36, underwent a tandem radical macrocyclisation–transannulation sequence, when treated with Bu3SnH–AIBN, leading to the tetraoxy-bis-nortaxadiene 42 in 44% yield. Attempts to synthesise the alcohol 28b from the silyl ether 28a en route to the iodide 28c instead gave the substituted tetrahydrofuran 29 via an intramolecular oxy-Michael reaction.

Superoxide radical formation by pure complex I (NADH : Ubiquinone oxidoreductase) from Yarrowia lipolytica

Generation of reactive oxygen species (ROS) is increasingly recognized as an important cellular process involved in numerous physiological and pathophysiological processes. Complex I ( NADH: ubiquinone oxidoreductase) is considered as one of the major sources of ROS within mitochondria. Yet, the exact site and mechanism of superoxide production by this large membrane-bound multiprotein complex has remained controversial. Here we show that isolated complex 1 from Yarrowia lipolytica forms superoxide at a rate of 0.15% of the rate measured for catalytic turnover. Superoxide production is not inhibited by ubiquinone analogous inhibitors. Because mutant complex I lacking a detectable iron-sulfur cluster N2 exhibited the same rate of ROS production, this terminal redox center could be excluded as a source of electrons. From the effect of different ubiquinone derivatives and pH on this side reaction of complex I we concluded that oxygen accepts electrons from FMNH2 or FMN semiquinone either directly or via more hydrophilic ubiquinone derivatives.

Further evidence for double-strand breaks originating from a paired radical precursor from studies of oxygen fixation processes

By using a fast reaction technique which employs H2S gas as a fast-reacting chemical repair agent, it is possible to measure the competition kinetics between chemical repair reactions and oxygen fixation reactions in model DNA and cellular systems. In plasmid pBR322 DNA irradiated with electrons, we have compared the oxygen fixation reactions of the free radical precursors that lead to the production of single-strand (SSBs) and double-strand breaks (DSBs). For the oxygen-dependent fixation of radical damage leading to SSBs, a second-order rate constant of 2.3 x 10(8) dm(3) mol(-1) s(-1) was obtained compared to 8.9 x 10(7) dm(3) mol(-1) s(-1) for DSBs. The difference is in general agreement with predictions from a multiple-radical model where the precursor of a DSB originates from two radicals. The fixation of this precursor by oxygen will require both radicals to be fixed for the DSB to be formed, which will have slower kinetics than that of single free-radical precursors of SSBs. (C) 1999 by Radiation Research Society.

Asymmetric Total Synthesis of (+)-Inthomycin C Via O-Directed Free Radical Alkyne Hydrostannation with Ph3SnH and Catalytic Et3B: Reinstatement of the Zeeck-Taylor (3R)-Structure for (+)-Inthomycin C

A new pathway to (+)-inthomycin C is reported that exploits an O-directed free radical hydrostannation reaction on (−)-12 and a Stille cross-coupling as key steps. Significantly, the latter process was effected on 19 where a gauche-pentane repulsive interaction could interfere. Our stereochemical studies on the alkynol (−)-12 and the enyne (+)-7 confirm that Ryu and Hatakeyama’s (3S)-stereochemical revision of (+)-inthomycin C is invalid and that Zeeck and Taylor’s original (3R)-stereostructure for (+)-inthomycin C is correct.

Synthesis of the C(7)-C(22)-Sector of (+)-Acutiphycin Via O-Directed Double Free Radical Alkyne Hydrostannation with Ph3SnH/Et3B, Double I-Sn Exchange and Double Stille Coupling

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Herein a new double O-directed free radical hydrostannation reaction is reported on the structurally complex dialkyldiyne 11. Through our use of a conformation-restraining acetal to help prevent stereocenter-compromising 1,5-H-atom abstraction reactions by vinyl radical intermediates, the two vinylstannanes of 10 were concurrently constructed with high stereocontrol using Ph3SnH/Et3B/O2. Distannane 10 was thereafter elaborated into the bis-vinyl iodide 9 via O-silylation and double I–Sn exchange; double Stille coupling of 9, O-desilylation, and oxidation thereafter furnished 8.

A New Mechanism for Hydroxyl Radical Production in Irradiated Nanoparticle Solutions

The absolute yield of hydroxyl radicals per unit of deposited X-ray energy is determined for the first time for irradiated aqueous solutions containing metal nanoparticles based on a “reference” protocol. Measurements are made as a function of dose rate and nanoparticle concentration. Possible mechanisms for hydroxyl radical production are considered in turn: energy deposition in the nanoparticles followed by its transport into the surrounding environment is unable to account for observed yield whereas energy deposition in the water followed by a catalytic-like reaction at the water-nanoparticle interface can account for the total yield and its dependence on dose rate and nanoparticle concentration. This finding is important because current models used to account for nanoparticle enhancement to radiobiological damage only consider the primary interaction with the nanoparticle, not with the surrounding media. Nothing about the new mechanism appears to be specific to gold, the main requirements being the formation of a structured water layer in the vicinity of the nanoparticle possibly through the interaction of its charge and the water dipoles. The massive hydroxyl radical production is relevant to a number of application fields, particularly nanomedicine since the hydroxyl radical is responsible for the majority of radiation-induced DNA damage.