STRATEGIC USE OF FURAN IN THE SYNTHESIS OF MOLECULES OF BIOLOGICAL IMPORTANCE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our group?s primary focus has been the strategic use of furan in the synthesis of complex molecules of biological importance. We are currently exploring three target-driven methodologies and their application to natural product total synthesis. 1. Electrochemical Furan Annulations: The application of furans as flexible building blocks in synthesis has been an area of ongoing interest in my research group. We have developed a new method for the construction of annulated furans through a key electro-oxidative cyclization. The general strategy begins with a two step annulation reaction that involves a silyl promoted addition of a furyl substituted cuprate to an enone followed by an anodic oxidation to couple the nascent enol ether and the furan. Owing to the diversity of structures available from furan, these intermediates can serve as precursors to a variety on natural product skeletons. We are currently applying this methodology to the synthesis erincacine C and viridin. 2. Synthesis of Pyrans by Ring Opening Cross Metathesis: Another major focus of my program is on the application of ring-opening cross metathesis reactions to bridged bicyclic compounds (Scheme 2). The ready availability of oxabicyclo[3.2.1]octene derivatives from furan makes them powerful building blocks for heterocycle synthesis through ring-opening. Our strategy, utilizing alkene metathesis, links the ring opening with the generation of a new carbon-carbon bond to prepare differentially substituted pyrans. The majority of our studies thus far have focused on the intermolecular cross-metathesis. We have also demonstrated the intramolecular variant of this process that lead to spiro, linear and bridged fused systems depending on placement of the unsaturated tether. We are currently employing these pyran building blocks in the modular construction of the cytotoxic macrolide leucascandrolide. 3. Versatile oxabicyclic building blocks from cyclopropenes: Although oxabicyclo[3.2.1]octane building blocks are typically prepared by Noyori-type cycloadditions between furan and oxyallyl cations, it has been known for decades that analogous systems are available from direct condensation of furan and tetrahalocyclopropenes. While these reactions have been of mechanistic interest, they have remained virtually unexplored from a synthetic perspective. We have used these adducts as direct precursors to various oxabicyclic building blocks, several of which are now available in chiral form. These building blocks are being used as precursors for synthesis of showdomycin and colchicines.