Title: Discovery of predictably selective C-H oxidations for complex molecule synthesis
Description: Selective functionalization of carbon-hydrogen (C-H) bonds is challenging, but holds the potential to dramatically transform synthetic strategy. The first chapter describes mild palladium-catalyzed methods for the allylic oxidation of monosubstituted olefins with high chemo-, regio- and stereoselectivities. Catalytic Pd(II) with dimethylsulfoxide (DMSO) and acetic acid (AcOH) promotes selective oxidation of monosubstituted olefins to furnish ( E )-linear allylic acetates in high regio- and stereoselectivity. Use of catalytic bis -sulfoxide ligand effects the coupling of carboxylic acids with monosubstituted olefins to regioselectively form branched allylic esters. Mechanistic studies of this system reveal that catalysis is achieved by different ligands promoting separate product-forming steps with a single metal. This concept is termed Serial Ligand Catalysis and establishes a novel strategy for effecting challenging catalytic chemical transformations. Discovery of new catalysts that are highly reactive and predictably selective is required for the utilization of unactivated sp3 C-H bond oxidation in organic synthesis. The second chapter describes an iron (Fe)-based small molecule catalyst that uses hydrogen peroxide (H 2 O 2 ) to oxidize a broad range of substrates, often via 3° C-H hydroxylation. Predictable selectivity is achieved solely on the basis of the electronic and steric properties of the C-H bonds, for non-directed oxidations, or through the use of carboxylic acid directing groups that furnish five-membered ring lactones.

We demonstrate that these three individual modes of selectivity enable the predictable oxidation of complex natural products and their derivatives at specific C-H bonds with preparatively useful yields. Methylene C-H bonds are some of the most difficult chemical bonds to selectively functionalize due to their inertness to most chemical reagents and abundance in organic structures. The third chapter describes the Fe-catalyzed oxidation of 2° C-H bonds in diverse natural product settings with predictable and high chemo- site- and even diastereoselectivities. Electronic, steric, and stereoelectronic factors, that effect selectivity with this catalyst, are demonstrated to be remarkably powerful control elements when operating in combination in complex molecules. This small molecule catalyst, serving as a tailoring enzyme functional mimic, displays site-selectivities complementary to those attained through enzymatic catalysis.