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A major goal of our research program is to develop environmentally benign methods for carbon-carbon bond-formation for use in natural products synthesis. Transformations in which multiple bonds are made in a single reaction are of special interest in this context. With the funding we have enjoyed from the ACS Petroleum Research Fund this past year, we have been able to make significant progress along these lines in a number of important areas. In particular, we have uncovered several new and useful transformations of alkynyl ethers. A tandem carbon-carbon bond-forming process, involving [3,3]-sigmatropic rearrangement of substituted benzyl alkynyl ethers, followed by intramolecular 5-exo dig cyclization, gives rise to cis-disubstituted 2-indanones as major products.  The larger the benzylic substituent R₁ in the starting benzyl alkynyl ether, the greater the syn stereoselectivity (t-Bu>iPr>Me) of the reaction. A remarkable feature of this process is that the sigmatropic rearrangement, which involves the formation of a non-aromatic intermediate, takes place at the relatively low temperature of 60°C; similar aryl allyl ether Claisen rearrangements typically require temperatures in excess of 200°C to proceed! Furthermore, ester-substituted 2-indanones (R₂=CO­₂Et) may by transformed into substituted indenes in high yield by a two-step sequence involving enol triflate formation followed by palladium-catalyzed cross coupling reaction with organoindium reagents or boronic acids.

Another sigmatropic rearrangement process of alkynyl ethers we have been investigating involves the Claisen-like rearrangement of ester-derived silyl enol ethers; this reaction gives rise to allenyl ethers which isomerize to donor-acceptor dienes, which may subsequently engage a range of dienophiles in Diels-Alder reactions to form six-membered carbocycles. We are also currently exploring the ruthenium-alkylidene catalyzed metathesis reaction of ynol-ether alkenes, which would provide electron-rich dienes capable of undergoing Diels-Alder cycloadditions with suitable dienophiles. This sequential process may allow the formation of up to four fused rings in a one-pot process, resulting in a rapid increase of molecular complexity starting from simple acyclic precursors. We anticipate that easily prepared chiral ynol ethers may allow access to optically active polycyclic products of relevance in natural products synthesis. Finally, we have initiated the exploration of gold-catalyzed 6-endo-dig cyclization reactions of ketone-substituted alkynyl ethers, which would give rise, after treatment with an alkyllithium or Grignard reagent and hydrolytic quench, to beta-substituted cyclohexenones.

The research outlined above has had an important impact on the direction of our research program. With the encouraging results we have obtained, we are now solely focused on the application of these methodologies in the context of total synthesis. The undergraduate students who were involved in these projects have had their first laboratory research experience, and they have gained practical training in organic synthesis. One of the students is now considering a career in chemistry and is currently inquiring about graduate level research.