Site-Selective Catalysts for Organic Synthesis

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DESCRIPTION (provided by applicant): Polyfunctional molecules play an important role in the chemotherapeutic treatment of disease. The field of organic synthesis resides in the vanguard of pharmaceutical science, delivering both the small molecules for screening against biological targets, and ultimately the efficient processes for drug synthesis on an industrial scale. A large fraction of drug candidate syntheses depends on the selective functionalization of unique reactive sites within molecules that contain many such sites. Thus, the risk of undesired side reactions is extreme. To date, the dominant strategy to handle this situation is the use of "protective groups." Protective groups are inherently inefficient. They require a step for installation, an additional step for removal, and neither of these steps generally occurs in 100% yield, with no waste, nor loss of time. Furthermore, from a fundamental standpoint, protective groups bely a host of unsolved problems in organic synthesis. Protective groups mask one reactive site, while allowing chemistry to occur at another. The more direct challenge in synthetic organic chemistry would be to achieve the desired reactivity, in the face of competing reactivity, without the inefficient application of such a mask. The development of tools - i.e., catalysts - that would allow the selective functionalization of very similar sites within polyfunctional molecules would constitute a major step forward. While the goal is, in some circles, viewed as intractable, we have initiated a program that has documented a potentially new strategy. The implications for both de novo syntheses of complex molecules are significant. Moreover, the implications of the protective group-free modification of pharmaceutically proven, structurally complex natural products is also highly exciting. The amazing biological activity of natural products has guided generations of synthetic organic chemists. Yet, notoriously, many pharmaceutical companies are de-emphasizing natural products discovery and drug development efforts. A major reason is the structural complexity that prevents both efficient synthesis, and straightforward analog generation. By taking aim at the direct, efficient and protecting group-free manipulation of natural products, we endeavor to introduce new tools that may assist in their exploration in both academic and industrial laboratories, enabling efficient access to novel and otherwise inaccessible biologically active analogs.