The close examination and study of the fundamental chemical and biological properties of complex molecules, including natural products and related derivatives, significantly contributes to the development of therapeutics for the treatment of human ailments. Such studies provide key insight to understanding their mode of action and enable development of new treatments. This research program aims to discover and develop new and efficient strategies and methodologies for the enantioselective total synthesis of architecturally complex and biologically active alkaloids. The development of new synthetic strategies inspired by biogenetic considerations with broad applicability to complex molecule synthesis forms the basis of our approach. Of particular interest is development of new synthetic strategies allowing rapid generation of molecular complexity. These include cascade and tandem processes that permit the formation of multiple bonds with high levels of stereochemical control. Targets are selected on the basis of the complexity of the molecular architecture, the prospect of discovering new chemical transformations, the opportunities for development of new strategies and methodologies, the possession of significant biological activity, and the potential for future chemical and biological mechanistic studies. The oroidin family of alkaloids, represented by the agelastatins, is a rich and exciting setting for development of new synthetic methodology for rapid synthesis of imidazolone and aminoimidazole heterocycles, along with new cascade processes for construction of polycyclic frameworks seen in complex members of these alkaloids. Likewise, the aspidosperma alkaloids, represented by aspidophytine, offer outstanding architectures that inspire development of new and highly stereoselective cascade and tandem reactions for securing their skeletons, in addition to development of highly chemo- and stereoselective transformations relevant to assembly of more complex terpene-indole alkaloids. This program will result in a vast number of synthetic samples of rare and precious molecules. These will include both the final targets and the great many intermediates that are accessed in the context of our studies, all of which will enable exploration of their chemistry and biology. The compounds accessed in our studies will be subject to biological testing through our established collaborations both in direct bioactivity evaluation and also hold potential for use as chemical probes.
An important tool in the development of therapeutics for the treatment of human ailments is the fundamental chemical and biological study of complex bioactive compounds including natural products and related derivatives. Targets are selected on the basis of interesting molecular architectures, opportunities for methodological developments, mechanistic study, and the potential for future collaborative biological mechanistic studies and evaluation. The planned syntheses are designed to develop new complexity generating sequence of reactions, in particular multiple stereoselective bond-forming cascades, and to challenge existing synthetic methods in addition to inspire the development of new and broadly applicable methodologies for the synthesis of complex molecules.
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