. The detailed examination of the fundamental chemical and biological properties of complex natural products provides critical insight to their mode of action and enables development of new approaches for treatment of human ailments. This research program aims to develop concise and efficient total chemical syntheses of structurally complex and biologically active natural products through the systematic invention, development, and application of new synthetic strategies and methodologies. The development of generalizable and highly chemo- and stereoselective transformations that enable rapid generation of molecular complexity, often inspired by biogenetic considerations, forms the basis of our approach. Of particular interest are versatile and unified approaches to families of natural products, which enable detailed chemical and biological studies. Critical to our approach is the synergistic development of new synthetic strategies that permit the stereocontrolled formation of multiple bonds and new synthetic methodologies for late-stage functionalization in complex settings. The targets are selected based on the complexity of the molecular architecture, abundance of opportunities for development of new chemical transformations, the potential for development of new generalizable strategies and methodologies, and the potential for multidisciplinary and collaborative biological investigations. This program studies the agelastatin alkaloids, their related functional derivatives, the aspidosperma indole alkaloids, including mehranine, fendleridine, and apodine subfamilies, in addition to complex dimeric aspidosperma alkaloids. These alkaloids inspire development of new and highly chemo- and stereoselective transformations relevant to assembly of complex alkaloids, and new synthetic methodology for late-stage derivatization of complex molecules. Our program provides direct access to samples of rare and precious compounds for structure validation, chemical study, and the pursuit of our collaborative biological evaluation and mechanistic studies concerning these alkaloids. The synthetic molecules accessed through this program behold great promise both as mechanistic tools and as new bioactive compounds, and are subject to systematic evaluation through our multidisciplinary collaborations concerning their translational potential for development as new treatments for human ailments.
The detailed examination of the fundamental chemical and biological mechanism of action of natural products is critical in the development of new treatments for various human ailments. This program's central objective is the discovery, development, and application of new strategies and methodologies for the chemical synthesis of bioactive complex natural alkaloids and designed functional derivatives to enable detailed chemical and biological studies. Whereas the immediate impact of this program is access to precious and rare samples of complex alkaloids, the broader impact of our program is the establishment of precedence for the application of new chemistries in the synthesis of other natural and rationally designed molecules with therapeutic potential.
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