The transformative impact of catalytic cross-coupling methods on the assembly of organic molecules cannot be overstated, as evidenced by their widespread adoption for the synthesis of both pharamecuticals and small molecule products. A recently developed paradigm-shifting cross-coupling method that employs both photoredox and base-metal catalytic cycles working in concert has enabled the formation of carbon-carbon bonds that were inaccessible via traditional cross-couplings. These dual catalytic reactions proceed under exceedingly mild conditions (room temperature and near-neutral pH) and with excellent functional group tolerance, enabling the cross-coupling of various prefunctionalized alkyl and aryl halide partners. The goal of the proposed research is to utilize a photocatalyzed hydrogen atom transfer (HAT) process for the selective activation of alkyl C?H bonds at room temperature and their subsequent functionalization within a base-metal catalyzed cross-coupling cycle. Intra- and intermolecular HAT cycles will be explored, enabling both the directed functionalization of unactivated C?H bonds as well as the utilization of inexpensive commodity chemicals as coupling partners. The use of polarity reversal catalysts will further increase the diversity of C?H bonds that can be functionalized within this dual catalytic cross-coupling manifold. The ability to engage ubiquitous alkyl C?H bonds in cross-couplings will allow for the rapid and streamlined assembly of complex molecules under mild conditions from a virtually limitless pool of alkyl precursors, while simultaneously minimizing waste and improving the sustainability of the process.
Catalytic methods for the convergent assembly of carbon-carbon bonds have found widespread application for the synthesis of pharmaceutical compounds. However, these reactions have been largely limited to the formation two-dimension molecules. The proposed research aims to develop efficient and sustainable methods for the catalytic formation three-dimensional molecules from inexpensive and unfunctionalized substrates, facilitating the synthesis of novel molecular libraries for the discovery of new pharmaceuticals.
| Phelan, James P; Wiles, Rebecca J; Lang, Simon B et al. (2018) Rapid access to diverse, trifluoromethyl-substituted alkenes using complementary strategies. Chem Sci 9:3215-3220 |
| Phelan, James P; Lang, Simon B; Compton, Jordan S et al. (2018) Redox-Neutral Photocatalytic Cyclopropanation via Radical/Polar Crossover. J Am Chem Soc 140:8037-8047 |
| Milligan, John A; Phelan, James P; Polites, Viktor C et al. (2018) Radical/Polar Annulation Reactions (RPARs) Enable the Modular Construction of Cyclopropanes. Org Lett 20:6840-6844 |
