Discovery and Development of Enabling Tools for the Synthesis and Late-Stage Modification of Natural Products and Pharmaceuticals

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The development of new methods to synthesize complex organic molecules continues to inspire discoveries in chemistry, biology and medicine. However, despite much effort, stereochemically rich heterocycles that are often found in biologically active natural products and drug leads still present a significant challenge for organic synthesis. Likewise, the available reactions for selectively modifying or functionalizing such complex molecules are significantly limited, which often prevents or obstructs efforts in medicinal chemistry. To address these issues, our group has developed a longstanding interest in the synthesis of heterocycles and the discovery of new tools to selectively functionalize these molecules. Here, we propose to explore the chemistry of an unusual class of molecules known as a-haloaldehydes that are often avoided due to their instabilities but represent ideal linchpins for heterocycle synthesis. Specifically, we will develop new processes to generate a-haloaldehydes and directly react them, thus circumventing their problematic instabilities. We will also more broadly explore the utility of this strategy for generating and reacting other unusual a-functionalized aldehydes and explore their application in the synthesis of structurally complex natural products. For example, we will exploit a-chloroaldehydes in the synthesis of the anticancer marine natural products salinosporamide C and phormidolide, and will demonstrate the versatility of this new process in an improved synthesis of the drug eribulin (breast cancer), which is considered the most complex drug to be made by total synthesis. To compliment our efforts in heterocycle synthesis, we will also develop new tools that will allow medicinal chemists to selectively modify and improve the properties of these molecules. Here, we will focus on the use of an inexpensive catalyst (decatungstate) that can be photo-activated by visible light to remove hydrogen atoms from complex molecules (including natural products and peptides). Specifically, we will identify and exploit reagents that can operate in combination with decatungstate to replace these hydrogen atoms with nitrogen-, oxygen- or carbon-based functional groups. We have also identified a unique class of molecules (dibenzensulfonamides) that are capable of selectively activating heterocycles, removing a hydrogen atom and replacing it with medicinally relevant functional groups (e.g., fluorine, trifluoromethylthio). Here, we will synthesize and investigate new dibenzensulfonamides for heterocycle functionalization and develop a platform technology for late-stage optimization of drug leads. Overall, this Program will provide enabling tools for the synthesis of heterocycles and natural products, and reagents and reactions for medicinal chemistry. This Program will also inspire new collaborations with academic and industry stakeholders and sustain a rich, multidisciplinary training environment for HQP.