Modern Synthetic Methods and their Application to the Synthesis of Bioactive Target Molecules

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The pursuit of more economical, and inexpensive ways to create carbon-carbon bonds has been a driving force behind many ground breaking synthetic chemistry discoveries. Advancements in this field of research are of paramount importance to the larger scientific community and also to the area of organic synthesis by providing more efficient alternative routes to target molecules. To this end, the proposed research focuses on the development of modern synthetic transformations for the formation of carbon-carbon bonds and their application in complex target oriented synthesis of biologically relevant molecules. Reactions involving C-H activation and functionalization chemistry are of particular interest to our group. Using frontline techniques developed within this area, we will explore multiple themes of research including tandem reactions involving C-H insertion chemistry and the utility of chiral thiols in radical reaction pathways. While synthetically powerful, C-H activation and functionalization chemistry is lacking in annulative and tandem processes involving C-H insertion and if successful, this proposed strategy will allow access to unique heterocyclic moieties potentially amenable to the synthesis of bioactive target molecules. Additionally, although radical reactions have a rich history in synthetic and polymer chemistry, many deficiencies have plagued their more widespread adoption including challenges in inducing stereoselective transformations. Very recently, significant strides have been made to overcome these drawbacks; however, stereoselective transformations is still in its infancy and I anticipate this will become a hot topic in the coming years. Overall, the method development aspect of this proposal will form the foundation of my research program and serve to push the frontier of C-H functionalization and radical reaction chemistry. In parallel with method development, the proposed research includes the preparation of biological screening collections of natural products and their derivatives, and will be completed in two ways. 1) Concise total synthesis of bioactive natural products through a planned approach, utilizing our reaction development platform. 2) Direct derivatization of bioactive molecules. Using readily available natural products, we can directly manipulate the parent compound and in 1-3 steps, create a library of unique molecules for each natural product. Benefits of this approach include the preparation of a collection of structurally complex molecules for biological screening, the possibility to develop new synthetic transformations (expanding my methods program), and student skill advancement in the areas of synthesis, isolation, and spectroscopic analyses. Ultimately, this area of research will foster the creativity, ingenuity and problem-solving skills required to be a successful organic chemist.