C-H Bond Functionalization in Organic Synthesis

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This proposal describes the development of general and highly selective Pd-catalyzed methods for converting unactivated arene and alkane C-H bonds to new functional groups X, where X = acetate, ether, amine, halide, cyanide, arene, alkene, or alkyne. These transformationswill find widespread application in SAR studies of pharmaceutical candidates as a result of their generality, functional group tolerance, and extremely high regio- and chemoselectivities. In addition, these methods provide versatile approaches to many other valuable structures, including alpha- and beta-functionalized ketones, 1,2- and 1,3-diols, diamines, and amino alcohols, and oxygen/nitrogen heterocycles, which all serve as important synthetic building blocks. Furthermore, many of these products represent key structural motifs of biologically active molecules, including polyketide natural products such as the epothilones (anti-cancer) and pseudomonic acid (antibacterial) and flavonoid (antibacterial, antioxidant, antimutagenic) derivatives. The proposed research will involve catalytically coupling alkane/arene C-H bond activation at Pd(ll) to subsequent functionalization with hypervalent iodine reagents or other oxidants. High reactivity and regioselectivity will be achieved by the use of organic substrates that contain appropriate chelating functional groups (for example oximes, heterocycles, ethers, amides and amines). The scope and functional group tolerance of these transformations will be explored, and asymmetric catalyst systems will be investigated. In addition, related tandem transformations will be developed in order to use the proposed methodology for the construction of structurally and stereochemically diverse molecules from simple building blocks such as arenes, alkanes, and olefins.