Renewal of "Taming Fluorine: Metal-Organic Frameworks for the Heterogeneous Delivery of Fluorinated Building Blocks" - Project Summary The preparation of complex organic molecules is vital to the development of next-generation therapeutics. However, the synthesis of molecules bearing certain fluorinated and chlorinated functional groups, such as fluoroalkenes, remains challenging. A major barrier to installing these motifs within complex molecules is that many fluorinated and chlorinated building blocks are gases at room temperatures, which complicates high- throughput reaction optimization. In a similar vein, the signaling molecules hydrogen sulfide, nitric oxide, and carbon monoxide, possess therapeutic potential that is difficult to unlock due to their gaseous nature. Molecular donors for these molecules often result in the co-generation of toxic byproducts upon gasotransmitter release. We propose an interdisciplinary solution to these and other challenges relevant to medicinal chemistry: the use of porous materials, such as metal-organic frameworks (MOFs) and porous organic polymers (POPs). Supported by NIGMS, we have achieved several breakthroughs related to the synthesis and therapeutic delivery of bioactive molecules. First, we demonstrated the first example of fluorinated gas storage within MOFs, enabling their safe handling as solid reagents to streamline reaction development (publication in Science). Second, in a similar vein, we have shown that MOFs can be used to safely deliver hydrogen sulfide for the treatment of ischemia-reperfusion injury, which can occur during a heart attack or stroke. We have developed MOF-based catalysts for several industrially important reactions, including amide bond formation and halogen exchange. We have also employed electroactive molecules to achieve the selective electroreduction of (hetero)aryl halides without precious metal catalysts. We have also developed several methods for the synthesis of porous materials, including high-concentration solvothermal, mechanochemical, and ionothermal approaches. In the next research period, we will pursue three interconnected projects. First, we will employ our gas- releasing MOFs to develop several methods for the installation of vinyl fluorides and chlorides, as they are stable bioisosteres for ubiquitous amides in drug-like molecules. To achieve this goal, transition metal catalysis, electrosynthesis, and photoredox catalysis will be employed; the latter will require the development of new MOFs for gas storage that do not strongly absorb visible light. We will also develop novel methods for chemical ligation and stapling of peptides. We will also continue to add gases to our growing library of materials, further expanding the scope of synthetic transformations we can develop. Second, we will move beyond gas storage through weak non-covalent interactions to slow down gas release under ambient conditions and achieve stimuli-responsive gas release. We will demonstrate this concept using hydrogen sulfide delivery from MOFs before extending it to other biomedically relevant gases. Last, we will leverage the unique properties of isolated metal-halide sites in MOFs to design new catalysts for nucleophilic aromatic substitution and C-H functionalization reactions, leveraging confinement effects to tune reaction selectivity.
