The value of chemical synthesis in health-related research is closely tied to the ability to efficiently generate medicinal agents from readily available materials. This MIRA application seeks to merge two productive NIGMS-funded projects centered on the development of innovative synthetic transformations of fundamental building blocks. The long-term goal of this program is to identify promising new modes of chemical reactivity to facilitate the rapid discovery and development of small molecules for biomedical applications. The overall objective of this application is to develop a diverse set of enabling transformations using either unactivated aliphatic C?H bonds or alkyl electrophiles. Site-selective transformations of aliphatic C?H bonds hold enormous promise in streamlining drug synthesis and expediting access to novel analogs of biologically relevant compounds via late-stage functionalization. Despite this potential, few intermolecular C?H functionalizations of preparative value exist. We seek to develop practical, intermolecular aliphatic C?H functionalizations that introduce diverse chemical functionality and proceed with high levels of site selectivity. This research is based on the hypothesis that radical-mediated intermolecular C?H functionalizations offer the potential for superior site selectivities and chemoselectivities as compared to alternative approaches, enabling the development of new, general C?H transformations. Our approach will involve the identification of new N- functionalized reagents as well as innovative pathways in photoredox catalysis to unlock a diverse set of valuable, currently inaccessible C?H transformations using heteroatom-centered radicals. Another major goal is to develop transition metal catalyzed processes for the stereoselective construction of C?C bonds that would otherwise be challenging to accomplish. With few exceptions, the use of unactivated alkyl halides in catalytic C?C bond-forming reactions involves reactive radical intermediates. This limitation prevents the use of alkyl halides in stereoselective C?C bond-forming reactions that would streamline drug synthesis and provide access to medicinally valuable, functionalized small molecules. We seek to establish new paradigms in metal catalysis that enable the stereoselective direct coupling of unactivated alkyl electrophiles and widely available chemical feedstocks. We hypothesize that two-electron activation of alkyl electrophiles will unlock a range of stereoselective C?C constructions. Our objectives include the development of stereospecific, carbonylative transformations and stereoselective carbocyclizations of unactivated alkyl electrophiles. The rationale of the proposed research is that the practical and selective reactions produced will facilitate access to diverse synthetically and medicinally valuable small molecules. Our proposed research is innovative because it involves underutilized modes of chemical reactivity to generate new, powerful bond- forming reactions. These contributions are significant because they will offer a range of transformations for the discovery and development of next generation, biologically active natural products and medicinal agents.
The proposed research is relevant to public health because it is expected to deliver new transformations that will increase the efficiency of drug synthesis and enable access to unique analogs of biologically important small molecules. Thus, we expect these synthetic tools to facilitate the development of next-generation small molecule therapeutics.
