Application of C-H Activation to Natural Product Synthesis

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DESCRIPTION (provided by applicant): Effective new strategies for organic synthesis are of great value to biomedical research. Even though it is often argued that any organic compound can be made, in reality the practical accessibility of a potential pharmaceutical target is a major consideration in drug design. Thus, new methodology has the potential of opening up new vistas of chemical structures as viable targets for exploration as pharmaceutical agents. Transition metal-catalyzed reactions have broadly impacted the methods used for the synthesis of pharmaceutical targets. C-H Activation is of considerable current interest because it has the potential of becoming a transforming strategic reaction. This proposal is centered around a recently discovered highly stereoselective rhodium-catalyzed C-H activation process, the combined C-H activation/Cope rearrangement. The hallmark of this C-C bond forming reaction is its remarkable stereoselectivity, with most reactions proceeding in >98% de and >96% ee. The exploration of the full scope of this chemistry will be the focus of this proposal. This C-H functionalization method offers exciting opportunities in organic synthesis but to achieve this, the methodology will need to be extended to a broader range of substrates. Once the foundation chemistry has been established the methodology will be applied to the synthesis of natural products of biomedical interest, the antitubercular agent elisabethin C and the potential anticancer agents sinulobatins B-D and harringtonolide.