The detailed study of the chemistry and biology of complex natural products at a fundamental level provides critical insight to understanding their mode of action and enables development of new approaches for treatment of various human ailments. This research program focuses on the development of efficient and concise total chemical syntheses of structurally complex and biologically active natural products through the systematic discovery, development, and application of new synthetic strategies and methodologies. A key feature of the planned syntheses is the development of highly chemoselective and stereoselective transformations that enable the implementation of new generalizable synthetic strategies, often inspired by biogenetic consideration, for the rapid generation of molecular complexity. The development of concise and unified approaches to families of natural products, a continuing theme of this program, requires the concurrent development of new methodologies allowing advanced stage functionalization in complex settings. The targets are selected based on novelty of molecular architecture, paucity of prior synthetic studies, abundance of opportunities for development of new strategies and methodologies, possession of significant biological activity, and the potential for future chemical and biological studies. This program will focus on synthetic studies of the rich family of cyclotryptamine and diketopiperazine alkaloids. Of central interest is the directed, regioselective stereoselective, and efficient adjoining of cyclotryptamine substructures providing late stage unions to secure challenging quaternary stereocenters. With this program's particular focus on the potently bioactive epidithiodiketopiperazine, a concurrent effort is the development of new efficient methodologies to enable regioselective and stereoselective sulfidation of complex diketopiperazines. This program will continue to provide synthetic samples of rare and precious compounds for structure validation and detailed examination of their chemistry and biology. The well recognized biological activity of the entire family of compounds under investigation ensure that the many related intermediates and derivatives accessed through these efforts will also behold great promise both as mechanistic tools and as new bioactive compounds, and thus they will be subject to continuous evaluation through our multidisciplinary and collaborative engagements.
The study of the fundamental chemical and biological mechanism of action of natural products plays an important role in the development of new treatments for a variety of human ailments. This program aims to discover, develop, and apply new strategies and methodologies for preparation of bioactive and complex natural molecules and designed derivatives. While the immediate result is direct access to samples of extremely rare and precious compounds for structure validation, collaborative biological evaluation, and mechanistic studies, the longer term and broader impact of this program is the establishment of precedence for the application of these new chemistries to other targets and potential therapeutics both natural or rationally designed.
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