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Synthetic strategies toward the total synthesis of tetrapetalone A




Howell, Jennifer Marie, author
Wood, John L., advisor
Kennan, Alan J., committee member
Ferreira, Eric M., committee member
Prieto, Amy L., committee member
Brennan, Patrick J., committee member

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In 2003 Hirota and coworkers reported the isolation of tetrapetalone A (1) from the culture filtrate of Streptomyces sp. USF 4727, a Streptomyces strain isolated from a soil sample taken from Yada, Shizuoka City, Japan. The molecular structure of 1 was initially reported and then revised in a series of two papers which both appeared in 2003. In addition to the interesting molecular architecture, 1 demonstrated inhibition of soybean lipoxygenase (SBL) (IC50 of 190 μM) comparable to well-known human lipoxygenase and cyclooxygenase inhibitors. While no total synthesis has been reported to date, the groups of Porco, Hong and Sarpong have disclosed synthetic approaches toward the tetrapetalone core. Efforts in the Wood group to synthesize 1 are based on highly convergent synthetic strategies, the first of which was directed at constructing an advanced indanone coupling partner via a Stetter reaction. To this end, a route employing a diastereoselective Claisen rearrangement afforded a highly substituted Stetter reaction precursor but we were unable to realize the latter chemistry. We developed a synthetic route employing a Dieckmann condensation to furnish a highly functionalized tetramic acid. Coupling the tetramic acid with ortho substituted aryl halides under aryl amidation conditions proved futile. In an effort to promote an intramolecular aryl amidation we pursued an alternative coupling strategy, which relied on an extremely challenging ring closing metathesis. The desired ring closing metathesis product was not realized. Relay ring closing metathesis investigations provide confidence that the desired olefins will engage in metathesis chemistry. Current synthetic efforts are focused on a diastereoselective intramolecular Tsuji-Trost allylation to furnish a highly functionalized indanone, which has proven to be a competent coupling partner with allylamine under Pd(0)-catalyzed aryl amination conditions. Elaboration of this advanced indanone intermediate is expected to eventually provide a total synthesis of 1.


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