Application and Development of New Radical Synthetic Methods

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This proposal focuses on the development of new technologies for the synthesis of molecules that are of interest to the pharmaceutical and agrochemical industries. A key goal is the development of new methods for fluorine incorporation into medicinal agents. While not common in natural organisms, fluorine is a valuable component of many bioactive molecules. Currently, over 20% of the top selling pharmaceutical agents contain fluorine. While fluorine is medicinally useful, it is often difficult to incorporate into molecules. The first and second portions of this proposal focus on new technologies for the synthesis of particularly challenging fluorinated motifs using organic free radicals. We will access the key radical intermediates using several different methods, including UV light. We will also investigate new technology using more environmentally-friendly and lower-energy visible light in combination with photoredox catalysis.       A second important application of fluorine is its medicinal use in positron emission tomography (PET). The 18F isotope is PET-active and is currently utilized in medicinal agents for a wide range of medicinal applications, including tumor imaging. There are a several technical challenges associated with using 18F: it has a short half-life (2 hours) and fluorine is challenging to incorporate into medicinal agents. New technology that can quickly add 18F to pharmaceuticals would, therefore, be of high impact to the medical community. We will utilize mechanistic insight recently obtained in my laboratory for the development of new 18F-incorporation technology exploiting both radical and ionic (fluoride) mechanisms.       The third portion of the research proposal focuses on new methods for the rapid synthesis of bioactive natural products. Natural products are of vital importance to the pharmaceutical industry as they often serve as the basis of new medicinal agents. To wit, nearly 50% of all anti-cancer compounds currently on the market either are natural products or are based upon them. Synthetically, one of the challenges in natural product synthesis is their rapid assembly to enable the synthesis of analogs. We plan to develop new radical and pericyclic methodologies for the synthesis of bioactive macrolides that will enable multiple bond forming processes in a single reaction.