SYNTHESIS OF AMPHIDINOLIDE P USING RUTHENIUM CATALYSIS

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This research proposal describes experiments that will expand the scope of the ruthenium catalyzed addition of alkenes to alkynes. The facile synthesis of certain 1,4-unconjugated dienes distinguishes this ruthenium based methodology, providing an alternative to multistep olefination protocols. Reactions are performed in polar protic solvents (DMF/H2O mixtures or methanol) at elevated temperatures (100 degrees C), in contrast to other carbon-carbon bond forming reactions which require low temperature and an anhydrous environment. These reaction conditions do not disturb other functionality, such as esters and alcohols, which simplifies protecting group strategies. The cytotoxic agent amphidinolide P offers an excellent opportunity to explore this chemistry. Retrosynthesis of this macrolide reveals a 1,4-diene. Disconnection of this diene reveals an enyne or a 1,3-diene as substrates for the ruthenium catalyzed transformation. These two functional groups have not been previously utilized in this coupling method. The first part of the proposal studies the effect of functionality on the selectivity of the ruthenium catalyzed process. The characteristics of new substrates in this powerful carbon-carbon bond forming reaction will be explored. Choice of functionality on the coupling partners will determine the best reaction conditions to be used in the second part of the proposal, which deals with the synthesis of amphidinolide P. The proposal allows for the synthesis of a cytotoxic agent with a novel structure, and provides an opportunity to explore the utility of a relatively new carbon-carbon bond forming reaction. The knowledge gained from this study will be useful in later syntheses, and will lead to a better understanding of this ruthenium coupling chemistry.