Chemical processes that enable fragment union between functionalized 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 medicinal chemistry. Despite the importance of such reactions in chemical synthesis, it is surprising that only a handful of robust pathways are available for arguably the most relevant of such processes in natural product synthesis: intermolecular C-C bond formation between highly functionalized coupling partners. This research program is focused on establishing a new approach to stereoselective chemical synthesis that derives from design, discovery and development of new intermolecular C-C bond-forming reactions that proceed by metallacyclic intermediates, and establishing their utility in natural product synthesis Our initial phases of this program were heavily focused on methods development with recent efforts beginning to encompass the application of some of our coupling chemistry in natural product synthesis. Such latter study is critical for the evolution of new synthetic methods and the demonstration that they have a substantial impact on strategy and efficiency in a variety of target-oriented settings. To date, our efforts have established a foundation of new coupling technology that addresses structural motifs resident in a great variety of natural product targets (alkaloids, terpenes, and fatty acids), often doing so with exquisite levels of chemo-, regio-, and stereoselectivity. As our program moves forward, we are committed to: (1) confirming the utility of metallacycle-mediated cross-coupling technology in complex molecule synthesis, (2) the establishment of new retrosynthetic strategies in target-oriented synthesis that emerge from our chemical methods, and (3) the first, or the most concise, syntheses of a range of natural products. In this way, our proposed studies will advance new modes of chemical reactivity to firmly establish a foundation of reaction methodology that has the potential to have a profound impact on target-oriented synthesis (at the strategic level). As such, continued development of this program promises the delivery of science that will have a significant impact on mankind's search for medicinally relevant small molecules and will enable scientific discovery at the interface of chemistry with biology and medicine.
The manner in which complex molecules are synthesized defines 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. Our scientific pursuits are 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 a range of medicinally relevant properties (i.e. anticancer, antifungal, analgesic and antibiotic).
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