A NEW LEWIS ACID CATALYZED CLAISEN REARRANGEMENT

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DESCRIPTION: (Principal Investigator's Abstract) The objective of this research proposal is to invent catalytic synthetic methods that allow enantioselective access to structural and stereochemical motifs, which although common among anti-viral, anti-cancer, anti-bacterial and anti-inflammatory medicinal agents, connot be readily accessed using conventional methods. In this endeavor, we target processes that are readily applied within the related discipline of enantioselective catalysis and therefore will have a direct and immediate impact on the production of single enantiomer drugs with established biological importance. Our intent is to develop synthetic methods of broad utility and function that will ultimately provide new chemical tools for the diverse range of biomedical researchers that utilize molecule construction. As a consequence, this core research will prove valuable to a number of wide-ranging therapeutical areas. One of the most powerful tools for carbon-carbon bond formation in organic synthesis is the Claisen (3,3)-sigmatropic rearrangement. Remarkably, however, an enantioselective catalytic variant of this reaction has yet to be developed. This proposal outlines a new Lewis acid catalyzed Claisen rearrangement that is amenable to enantioselective catalysis and therefore the construction and modification of a diverse range of biologically important molecules and targets. The strategy is predicated on a new Lewis acid catalyzed Claisen rearrangement recently developed in our laboratory. We have already successfully demonstrated that this catalytic methodology is applicable to the construction of an unusually diverse spectrum of structural motifs. A major goal of this research is to utilize this powerful carbon-carbon bond forming methodology to expedite the synthesis of complex targets with important biological activity. One such example is the proposed general strategy towards the total syntheses of the briaranes, a marine metabolite family with extensive medicinal potential that have yet to be accessed through synthetic construction. This proposal outlines a new Lewis acid catalyzed tandem acyl-Claisen rearrangement that is broadly useful for the rapid construction of molecular complexity from simple reagents. This work will develop an innovative strategy for the one-step synthesis of stereochemically complex acyclic frameworks based upon a new tandem-Claisen reaction sequence. Having demonstrated the feasibility of this transformation, we hope to determine the scope and limitations of this catalytic tandem reaction methodology for the production of a range of functional, stereochemical and structural motifs. This methodology will be used in conjunction with our acyl-Claisen reaction for the highly expeditious synthesis of erythronolide B; a member of the erythromycin antibiotic class. This new chemical tool should prove valuable for the rapid construction of erythronolide analogues; an important area of research for treatment of resistant bacterial strains.