Synthetic molecular programming and substrate-dependent drug-discovery: From multi-component reactions to cyclic peptides

This dissertation is concerned with the utilization of multi-component reactions to ask new questions concerning the areas of drug discovery and drug development. A common thread throughout, is one particular multi-component reaction between carbonyl compounds, amines and boronic acids; this reaction is now generally referred to in the literature as the Petasis reaction. Chapter one places all this in perspective.; Chapter two introduces the idea of Synthetic Molecular Programming, which strives to make the process of drug production more efficient and powerful. A means for making programming in synthetic chemistry more pragmatic is also suggested. This chapter details efforts to put this theory into practice and describes programs which include tandem Petasis-Ugi and Petasis-Grigg sequences.; Chapter three describes the concept of Substrate-Dependent Drug-Discovery (SDDD). SDDD is a method for making the chemist's role in the drug discovery process more rational and efficient. It represents an approach for discovering therapeutics and their targets by making use of trends in typical discovery-assay data. These trends can be used to generate structural hypotheses about the unidentified target, which lead to the synthesis of new compounds to test these hypotheses in an iterative fashion. Practical efforts using this theory are also detailed.; Finally, Chapter four describes investigations of an amino amide forming instance of the Petasis reaction, which was used to produce cyclic peptides via the intramolecular ligation of two termini of a linear peptidomimetic. Application of this cyclic peptide methodology to produce molecules that could target protein-protein interactions is proposed.*; *Please refer to dissertation for diagrams.