The discovery of new and efficient strategies for the construction of carbon-carbon bonds and the stereoselective synthesis of heteroatom functional groups is a primary challenge for organic chemists, as these processes are central to the ability to synthesize complex architectures prevalent in biologically active pharmaceuticals and agrochemicals. A modern approach to the efficient synthesis of useful target molecules takes advantage of metal catalysts that are capable of selective activation of an otherwise inert C-H bond, such that diverse reactivity can occur at the corresponding carbon center. This strategy circumvents the disadvantages of traditional approaches that rely on wasteful or costly functional group manipulations in order to generate reactive carbon centers. The research described in the attached proposal is focused on the development of cobalt catalyzed vinylic C-H addition reactions into imines. These processes will give rise to carbon-carbon bonds and chiral allylic amine products by convergent, intermolecular reactions between olefin-containing synthetic intermediates and electrophilic imine partners. The research approach will involve innovative substrate designs that employ electronically tuned directing groups for cobalt mediated vinylic C-H activation. In addition to enabling efficient C-H activation and vinylic addition into imines, these directing groups will provide convenient synthetic handles for the elaboration of the products into useful organic substructures, including 1,3-diamines, 1,4-diamines, 1,4-amino acids, pyrroles and ?-lactams. A second goal of the research approach will be the development of stereoselective cobalt catalyzed vinylic addition reactions into electronically activated chiral sulfinyl imine electrophilic partners. The ability to access enantioenriched branched allylic amine substructures will allow for the application of the reactions to the efficient synthesis of biologically relevant targets, including ?-aminobutyric aci, pyrrolidine, and tropane derivatives. Successful execution of the proposed research will highlight cobalt(III)-based catalysis as a promising area of study for the identification of new methods that replace and expand upon existing C-H functionalization technologies which rely on expensive second- and third-row metal catalysts. The information that will be gathered in this important area will likely spawn further research directions for the discovery and development of related cobalt catalyzed transformations.
The field of organic synthesis is challenged with the task of discovering new chemical reactions that allow access to complex and diverse molecular architectures. Modernized chemical processes must incur limited economic cost and environmental detriment in order to be deemed sustainable solutions for worldwide demands of products like pharmaceuticals. The research described in this proposal seeks to develop chemical reactivity that will provide cheap and environmentally benign strategies for the discovery and production of new drug therapies.
| Weinstein, Adam B; Ellman, Jonathan A (2016) Convergent Synthesis of Diverse Nitrogen Heterocycles via Rh(III)-Catalyzed C-H Conjugate Addition/Cyclization Reactions. Org Lett 18:3294-7 |
