: Chemical processes that enable fragment union between complex coupling partners define a subset of reactions that are exceptionally powerful. While they can help to define efficient pathways to complex molecules, they are also of central importance to combinatorial and medicinal chemistry. Despite the importance of such coupling reactions in chemical synthesis, it is surprising that only a handful of robust pathways are available for bimolecular C-C bond formation between highly functionalized coupling partners. The research program outlined in this proposal is focused on establishing a new approach to stereoselective chemical synthesis that derives from discovery and application of novel metallacycle-mediated bimolecular C- C bond forming reactions in natural product synthesis. Our first phase of funding for GM080266 was focused on methods development, and a great many reactions have been discovered/reported over the last five years. We are now in a position to develop these unique modes of reactivity in the context of target-oriented synthesis. This is a critical component of the scientific advance we aim to make, as reaction methods need to be vetted in complex settings to explore their true potential in impacting medicinally relevant pursuits. As such, we will pursue the application of our technology to the syntheses of a range of structurally diverse and rare natural products (alkaloids, fatty acids and polyketides) that are known to possess significant and medicinally relevant biological activities. Overall, the program proposed will result in: (1) confirming the utility of metallacycle-mediated cross- coupling technology in complex molecule synthesis, (2) the elucidation of a range of novel retrosynthetic strategies in target-oriented synthesis, and (3) the first, or the most concise, syntheses of a range of natural products including, the alkaloid 205B, ripostatin A, borrelidin and kendomycin. Therefore, our proposed studies will aim to advance the emerging modes of chemical reactivity supported by GM080266 from a foundation of reaction methodology to a powerful class of stereoselective fragment coupling reactions of profound utility in target-oriented synthesis. As such, successful development of this program will offer advances in stereoselective synthesis that have great potential to impact the search for medicinally relevant small molecules via enabling future scientific discovery at the interface of chemistry with biology and medicine. II.
: The manner in which complex molecules are synthesized greatly affects the role that organic chemistry plays in biology and medicine - a relationship that derives from the impact that chemical synthesis has on the availability of unique small molecules with medicinally relevant profiles. Chemical reactions that enable convergent coupling of complex partners are of central significance to organic synthesis, as they provide a means to both enhance efficiency in routes to intricate targets, and define workable schemes to establish SAR in medicinal chemistry. Described in this proposal is a scientific pursuit aimed at addressing the hypothesis that recently discovered fragment coupling reactions will have a profound and beneficial impact on the efficiency with which complex molecules are prepared - as evidenced by demonstrations in the context of rare natural products known to possess potent anticancer, antifungal, and antibiotic properties.
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