Project Summary/Abstract: The ability to systematically construct highly functionalized molecules in a general and reliable manner is central to synthetic organic chemistry and key for drug discovery, development, and scale-up in both academia and, in particular, the pharmaceutical industry. Our proposed work includes palladium- catalyzed cross coupling methods for the formation of aromatic and heterocyclic carbon-nitrogen bonds, carbon-oxygen bonds and carbon-fluorine bonds. One aspect of the chemistry that we are proposing involves the design of improved ligands and methods for aromatic carbon-heteroatom bond formation. Our work in this area is used throughout academia and industry for the preparation of complex molecules and has become mainstay processes for synthetic chemists. As part of this, we have developed numerous new ligands and catalysts that are now commercially available and widely employed. The invention of new, more general, and more user-friendly techniques will not only allow access to important compounds but also the means to be able to efficiently and selectively modify them. This allows chemists to rationally make new derivatives, with decreased side effects and better properties. We are also working on copper-catalyzed methods for the highly regio-, diastereo-, and enantioselective synthesis of aliphatic amines, copper-catalyzed methods for the asymmetric formation of carbon-carbon bonds and dual copper- and palladium-catalyzed processes. A portion of this work aims to design new more economically, environmentally, and generally applicable methods for the formation of carbon-carbon bonds by using alkenes as pronucleophiles. We wish to develop chemistry that will allow us to replace standard, highly reactive reactants with more benign and useful ones. We will also carry out mechanistic studies to help understand the fundamental features of these transformations and to help guide us in advancing the efficiency and utility of this work. The substrates we are targeting are representative of common structural components found in pharmaceuticals, natural products, agrochemicals, and sensory materials. The availability of these new technologies will allow others to prepare a variety of highly- functionalized and structurally diverse compounds, many of which have previously been inaccessible, which will have a great impact in a range of areas that are directly important to human health.