The major challenges in the development of new therapeutic agents are the discovery and production of these substances. The active ingredients in most pharmaceuticals are complex small molecules that can be difficult and expensive to synthesize on scale. Because of this, new strategies for chemical synthesis are beneficial in providing alternative and efficient routes to these molecules from simple, abundant chemical feedstocks. The most ubiquitous yet diverse linkage in organic molecules is the carbon-hydrogen bond, and organic molecules also share the characteristic that their skeletal structure is predominantly composed of carbon- carbon linkages that affect the three-dimensional interactions with molecular receptors responsible for their precise biological activity. Hence, methods that harness selective carbon?hydrogen bond activation events and apply them directly toward controlled carbon?carbon bond-formation are transformative for the discovery and implementation of new small molecule therapeutics. This research combines two concepts in organic chemistry into a new mode of chemical synthesis that converts carbon-hydrogen bonds into carbon-carbon bonds in a stereocontrolled fashion. Transition metals, specifically rhodium, have long been known to selectively cleave unactivated carbon-hydrogen bonds but often form inert complexes in the process, thereby impeding catalysis. Photocatalysts are a powerful emerging tool that harness the energy of visible light and use it to promote reactivity in transition metal complexes.
The specific aims of this research are to use photocatalysts to induce new reactivity with rhodium complexes that activate carbon-hydrogen bonds by three distinct modes. Coupling this reactivity with the use of abundant alkenes will provide a convenient method for the efficient synthesis of the complex frameworks of biologically active molecules. The product of this research will be a new synthetic tool that enables the rapid discovery and production of biologically active small molecules. This will ultimately improve public health by facilitating the design and production of affordable medicines to diagnose, treat, and prevent human disease.
The current costs and challenges associated with the preparation of biologically active molecules poses a significant barrier to the development of new therapeutic agents. The proposed research provides a tool for the selective transformation of carbon-hydrogen bonds, the most ubiquitous linkage in organic chemistry, into more complex molecular structure in order to efficiently access such substances from simple, abundant chemical precursors. This tool will ultimately improve public health by enabling the rapid discovery and production of affordable medicines to diagnose, treat, and prevent human disease.
