Innovative Transformations of Fundamental Synthetic Building Blocks

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

Project Summary: 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 continue our efforts 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 that 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 featuring widely available synthetic feedstocks. 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, synthetic capabilities remain limited to a narrow subset of possible C–H transformations. Moreover, site- and chemoselective derivatization of the functional group rich substrates most relevant to drug development remains a challenge. We seek to develop intermolecular aliphatic C–H functionalizations that open access to new chemical space with drug-like substrates and proceed with high levels of reagent-dictated site selectivity. This research is based on the hypothesis that radical-chain, intermolecular C–H functionalizations using tuned heteroatom-centered radicals can proceed with exceptional levels of efficiency and selectivity on complex, medicinally relevant substrates, enabling otherwise inaccessible C–H transformations. Our approach will leverage the reactivity of tuned heteroatom-centered radicals with a range of unique coupling partners to achieve new site- and chemoselective transformations. Another major goal is to develop new catalytic platforms of earth-abundant metals that enable valuable transformations of diverse synthetic feedstocks. Hydrocarbonylations of alkenes have demonstrated utility in the synthesis of medicinally relevant compounds, yet many attractive transformations remain inaccessible owing to limitations in catalysis. The development of catalytic C–C bond constructions that use easily-accessed alkyl electrophiles is another major challenge. We seek to establish new reactivity manifolds in earth-abundant metal catalysis which we hypothesize will enable solutions to these challenges. Our objectives include the development of both new hydrocarbonylations of alkenes that feature a range of common nucleophiles and catalytic C–C bond-forming couplings of unactivated alkyl chlorides. 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 develops several new 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.