The manufacture of pharmaceuticals relies heavily on the chemistry of carbonyl compounds, such as ketones and aldehydes. Reactions of enolizable carbonyl compounds generally occur at either the electrophilic carbonyl carbon or the ? carbon, whereas the ? position is notoriously difficult to functionalize directly. The goal of the proposed research is to develop a conceptually new reaction technology, which will serve as a general solution to the ?-functionalization of carbonyl compounds. The proposed reactions, including ?-carbonyl olefination (Specific Aim I) and trifluoromethylation (Specific Aim II), proceed via the synergistic combination of organocatalysis and photoredox catalysis. The proposed catalytic protocol would accomplish the coupling of nucleophilic ?-enaminyl radicals with various electrophilic radical species. Research will begin with a comprehensive screen of visible light-activated transition metal complexes as possible photoredox catalysts, in combination with single electron acceptor molecules and enamines. The substrate scope will be defined by investigating a wide range of ketones and aldehydes.
Specific Aim III of this proposal describes the invention of asymmetric ?-carbonyl olefination and trifluoromethylation reactions using chiral organocatalysts. The influence of organocatalyst structure on the efficiency of substrate binding and the overall reaction rate will be determined through a study of structurally related chiral amines. The expected outcomes of these studies include more efficient and general methods for the synthesis of ?-functionalized carbonyl compounds, such as enantioenriched chiral building blocks for the synthesis of chiral drugs. Ultimately, these studies will contribute to the improvement of public health by providing a means to enhance and accelerate the development of new pharmaceuticals.
Pharmaceuticals play an important role in the treatment of human diseases. The discovery of more potent and selective pharmaceuticals relies on the ability to screen multiple compounds in a cost-effective manner, which is facilitated by the development of efficient, scalable and operationally simple chemical transformations. This proposal aims to develop a general solution to the synthesis of pharmaceutically relevant building blocks, which would contribute to the improvement of public health by providing a means to enhance and accelerate the drug discovery process.
| Jeffrey, Jenna L; Petronijevi?, Filip R; MacMillan, David W C (2015) Selective Radical-Radical Cross-Couplings: Design of a Formal ?-Mannich Reaction. J Am Chem Soc 137:8404-7 |
| Jeffrey, Jenna L; Terrett, Jack A; MacMillan, David W C (2015) O-H hydrogen bonding promotes H-atom transfer from ? C-H bonds for C-alkylation of alcohols. Science 349:1532-6 |
