Chemists need more reliable, concise methods for accessing structural complexity. Decreasing the time to optimize the properties of a compound en route to the clinic requires reactions that are compatible with drug- like structures. Many state-of-the-art catalytic reactions based on the noble metals require highly specialized conditions and exotic ligands while remaining incompatible with common Lewis basic sites found in clinical candidates. In contrast, base metal catalysis, although vastly less developed, is ideally suited to overcome these issues through their rapid stepwise oxidative addition that enables facile Csp3-based cross couplings. Moreover, base metals offer long-term sustainability, low costs, and superior environmental profiles relative to their noble metal counterparts. Despite this potential, only small, isolated efforts exist to establish and explore the reactivity of base metals in cross-coupling processes. The goal of the laboratory is to develop and understand new synthetic strategies that enable the straightforward construction of complex molecules. The objective of this application is to invent different classes of base metal-catalyzed cross-coupling reactions that provide access to new reagents, pharmacophores, and SAR opportunities for medicinal chemistry. The rationale for developing the proposed chemistry is that it will offer new avenues for the late-stage functionalization of drug-like molecules as well as access to new chemical matter. With the benefit of robust preliminary data, the goals will be pursued under two specific aims: 1) manganese-catalyzed borylation of alkyl chlorides; and 2) 1,2-difunctionalization of alkenes. Under the first aim, novel manganese systems will be used to address key gaps in the synthesis of complex alkyl boronates from alkyl halides, leading to new boron- containing structures for drug discovery. Under the second aim, a new route to the 1,2-carboboration and 1,2- carboarylation of alkenes will offer unique regioselectivity and provide access to new fluorinated compounds, biologically active molecules, and opportunities in late-stage functionalization of drug-like molecules. Both of the proposed aims target transformations that are not currently possible. The conversion of ubiquitous functional groups (halides and alkenes) into complex functionality allows the direct synthesis of key pharmaceutical intermediates, drugs, and biological tool molecules.
The proposed research is relevant to public health because the discovery of new reactions that are compatible with drug-like architectures will shorten preclinical development time while increasing the success rate of drug discovery. Consequently, the proposed research is relevant to the NIH's mission to support research that lays the foundation for advances in disease treatment and prevention.
