UC Berkeley

Bonds between carbon and hydrogen make up the backbone of almost all organic molecules. The functionalization of C–H bonds, that is, the direct conversion of a C–H bond into a bond to carbon or a heteroatom, has been investigated for more than half a century because of the potential of such reactions to unlock new synthetic pathways, increase atom economy, and convert hydrocarbon feedstocks into more valuable products. In the last decade, the functionalization of C–H bonds has been increasingly applied at a late stage in the synthesis of complex molecules. Most natural products and biologically active compounds contain a multitude of C–H bonds, therefore, these bonds are the most readily available starting point for the modification of these molecules. Selective reaction of one C–H bond among many is the central challenge in efforts to functionalize C–H bonds in complex targets.The work in this dissertation addresses the challenges in the selective functionalization of C–H bonds in complex molecules. First, a method to selectively functionalize methyl groups in terpenoids that is directed by an adjacent alcohol or ketone was developed based on an iridium-catalyzed silylation of C(sp3)–H bonds that was reported by our laboratory. This method was used to enable cleavage of the C–C bond to the methyl group and substitute it with a different functional group, eliminate it to form an alkene, or integrate the group into the skeleton of the terpenoid, enabling the diversification of these natural products starting from a normally inert group. Next, a method for the undirected oxidation of C(sp3)–H bonds in complex molecules with high efficiency was examined. A perfluorinated porphyrin complex of ruthenium was shown to catalyze the selective oxidation of tertiary and benzylic C–H bonds in various biologically active compounds with turnover numbers of up to 1000. In the final chapter, a method for the selective borylation of complex molecules containing multiple aryl or heteroaryl units was developed. Noncovalent interactions between an amide in the substrate and a recognition element on the ligand induce proximity between the amide and the iridium catalyst, which leads to selective functionalization of an aryl ring that is in close proximity to the amide over aryl or heteroaryl rings which are more electronically activated toward borylation. These studies have created opportunities for the application of transition metal catalysts to the synthesis and diversification of natural products and biologically active molecules by selective functionalization of C–H bonds.