Synthesis and Study of Medicinally Important Molecules

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Project Summary/Abstract The goal of our research program is to innovate in both the strategy and methodology of organic synthesis, and apply them to solve problems of biological and medicinal importance and ultimately impact human health. Our program focuses on synthesis and study of both natural (Project 1A-C) and unnatural (Project 2) molecules with particular potential for the treatment of cancer, neurological disorders, and drug resistant infectious diseases. In project 1, we aim to synthesize lyconadin alkaloids (1A), bridged macrolides (1B), and polycyclic diterpene (1C) natural products and their analogs and identify compounds based on these privileged scaffolds for novel therapeutic development. In project 2, we aim to develop novel and practical amphoteric diamination methodologies including the enantioselective versions to provide new avenues toward N- heterocycles including piperazine, 1,4-diazepane, 1,4-diazocane, and related macrocyclic compounds with significantly increased substitution diversity on the carbon atoms. The selected natural molecules represent both the state of the art challenges for complex molecule synthesis as well as potential novel therapeutics for various human diseases. However, access of these natural products and their analogs are extremely difficult, which significantly hampered their biomedical development. The N-heterocycles are indispensable structural motifs in medicinal chemistry and exist in many lifesaving drug molecules. However, the substituents are generally limited on the nitrogen atoms and there is a significant lack of substitution diversity on the carbon atoms due to the limitations of the current synthetic methodologies. Our research program will address these gaps. The expected outcomes of this research will provide (i) new reactions and strategies in the toolbox of both medicinal chemists and synthetic chemists to prepare functional molecules, (ii) a collection of medicinally relevant molecules featuring structural novelty, complexity, and diversity for further and larger biological evaluations in academic institutions and pharmaceutical industries, and (iii) novel anticancer, anti- neurodegenerative and antimicrobial lead compounds with potentially novel mode of actions for in vivo and clinical evaluations.