This proposal describes a plan for the total syntheses of nuphar dimmers based on biosynthetic rationale, and spurred by the development of new chemical methods for the construction of quinolizidine alkaloids. Impelled by the promising, yet incomplete biological knowledge regarding these compounds, the route will focus on practicality and scalabilty to facilitate pharmacological studies. Notably, the organisms of origin, the dried rhizomes of Nuphar japonicum DC and Nuphar pumilum (TIMM.) DC, have been prescribed for centuries in traditional Chinese and Japanese medicine, and can be eaten as part of a normal diet, suggesting their potential as cancer prophylaxes. Chemical methods will also be developed for the catalytic, asymmetric installation of terpenyl stereocenters; proof of principle will be demonstrated on these alkaloids and the terpene gnididione. The ultimate objective of this program will be a holistic approach to natural products chemistry, encompassing biogenetic elucidation, methods development and extension, total synthesis and analogue synthesis, and eventually pharmacological discovery. This work will naturally bolster industrial drug development and pharmacology, and will hopefully provide a model for the preliminary investigation of industrially inaccessible drugs, such as systemically benign, but complex natural products; or compounds that target neglected tropical diseases (NTDs).
Natural products continually provide impetus and inspiration for the development of new methods and broad advances in synthetic chemistry. However, the necessity of empirical discovery and chemical providence cannot be overstated, nor can the inescapable conclusion that chemical understanding remains in its infancy. Exploration of complex chemical systems provides a route to fundamental discoveries in chemistry that ultimately enable and hasten the industrial pipeline of new pharmaceuticals. Natural products synthesis in turn brings within reach molecules of increasing complexity and biological relevance, providing a foundation for the therapeutic sciences and a horizon to human pathology. ? ? ?
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