An Allenic Pauson-Khand Reaction, New Directions

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): The broadly defined objectives of our research program focus on the discovery and development of new methods to prepare organic compounds in a more rapid and stereoselective manner. Our program strives to validate these new methods by applying them to the synthesis of biologically relevant products. Our research program has been concerned specifically with an allenic transition metal catalyzed Pauson-Khand reaction that provides access to a-alkylidene and 4-alkylidene cyclopentenones, two classes of compounds that were previously accessible only via multi-step sequences. During the new funding period, we will continue our examination of the scope and limitations of the allenic Pauson-Khand reaction by preparing interesting and diversely functionalized ring systems. To further validate this method we will synthesize guanacastepene A. Guanacastepene A is a potent antibiotic that has shown remarkable activity against methicillin resistant S aureas and vancomycin resistant E faecalis. We will also synthesize other members of the guanacastepene family. Availability of guanacastepenes B through O has hampered biological assays, thus a rapid synthesis to these compounds is needed. We will synthesize suberosenone, a potent anticancer compound showing differential cytotoxicity against cancer cell lines. We will synthesize 15-deoxy-D12,14-PGJ2 using a newly developed silicon-tethered allenic Pauson-Khand reaction. 15-Deoxy-D12,14-PGJ2 is a ligand for the peroxisome proliferator activated receptor, which has been linked to a variety of disease states, including type 2 diabetes and obesity. We will investigate the generality of the newly discovered transannular ring closing Nicholas reaction for formation of vicinal quaternary centers. We expect that through these long-term investigations, that we will more thoroughly understand transition metal catalyzed carbon-carbon bond forming processes, with particular emphasis on allenes, an underrepresented moiety in the synthetic chemists' arsenal of functional groups.