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 transformations will 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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Medicinal Chemistry Study Section (MCHA)
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Hagan, Ann A
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University of Michigan Ann Arbor
Schools of Arts and Sciences
Ann Arbor
United States
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Malapit, Christian A; Bour, James R; Brigham, Conor E et al. (2018) Base-free nickel-catalysed decarbonylative Suzuki-Miyaura coupling of acid fluorides. Nature 563:100-104
Cabrera, Pablo J; Lee, Melissa; Sanford, Melanie S (2018) Second-Generation Palladium Catalyst System for Transannular C-H Functionalization of Azabicycloalkanes. J Am Chem Soc 140:5599-5606
Shrestha, Anuska; Lee, Melissa; Dunn, Anna L et al. (2018) Palladium-Catalyzed C-H Bond Acetoxylation via Electrochemical Oxidation. Org Lett 20:204-207
Ichiishi, Naoko; Malapit, Christian A; Wo?niak, ?ukasz et al. (2018) Palladium- and Nickel-Catalyzed Decarbonylative C-S Coupling to Convert Thioesters to Thioethers. Org Lett 20:44-47
Malapit, Christian A; Ichiishi, Naoko; Sanford, Melanie S (2017) Pd-Catalyzed Decarbonylative Cross-Couplings of Aroyl Chlorides. Org Lett 19:4142-4145
Lee, Melissa; Sanford, Melanie S (2017) Remote C(sp3)-H Oxygenation of Protonated Aliphatic Amines with Potassium Persulfate. Org Lett 19:572-575
Mbofana, Curren T; Chong, Eugene; Lawniczak, James et al. (2016) Iron-Catalyzed Oxyfunctionalization of Aliphatic Amines at Remote Benzylic C-H Sites. Org Lett 18:4258-61
Topczewski, Joseph J; Cabrera, Pablo J; Saper, Noam I et al. (2016) Palladium-catalysed transannular C-H functionalization of alicyclic amines. Nature 531:220-224
Mossine, Andrew V; Brooks, Allen F; Makaravage, Katarina J et al. (2015) Synthesis of [18F]Arenes via the Copper-Mediated [18F]Fluorination of Boronic Acids. Org Lett 17:5780-3
Lee, Melissa; Sanford, Melanie S (2015) Platinum-Catalyzed, Terminal-Selective C(sp(3))-H Oxidation of Aliphatic Amines. J Am Chem Soc 137:12796-9

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