Grant: Discovery Grants Program - Individual

Organic synthesis is at the core of modern life, providing medicines, materials and crop-protection products which have enabled a profound improvement in the quality of life over the past century. Synthetic chemists build target molecules from simpler molecules through chemical transformations, including functional group interconversions, and the formation of carbon-carbon bonds. These synthetic sequences typically require multiple steps, and as complexity of targets grows, the generality of chemical transformations decreases, due to incompatibilities with functionality that is already present. The development of new transformations with different selectivities empowers synthetic chemistry, by expanding the scope of molecules that can be readily made. Control of chirality, or handedness of molecules, by selectively synthesizing one hand, or enantiomer, is particularly important for pharmaceuticals, since living systems are asymmetric, and different enantiomers of pharmaceuticals can have very different biological effects. My research group focuses on the discovery and development of chemical transformations catalysed by compounds of phosphorus, primarily diazaphospholenes. Recently we have achieved numerous firsts with diazaphospholene catalysis, including the first catalytic conjugate and imine reductions, the first example of asymmetric catalysis with diazaphospholenes, and improved examples of asymmetric catalysis with phosphenium cations. We were also among the first groups to show the synthetic utility of diazaphospholenes in free-radical chemistry, that is chemistry with intermediates containing unpaired electrons. Diazaphospholenes are attractive catalysts due to their simplicity, ease of synthesis, and compatibility with common functional groups such as amines, sulfides, and alkenes/alkynes that interfere with commonly used metal catalysts. The proposed research will explore new directions in diazaphospholene chemistry. In one direction, we will develop exquisitely selective asymmetric catalysts for reductive preparation of a broader range of substrates, including examples where asymmetric catalysis is rare. This will enable chemists to access a wider range of chiral materials than present, using diazaphospholenes. In another direction, we will expand our results in radical catalysis. By identifying undesirable side reactions, we are designing catalysts with increased steric bulk that are more resistant to decomposition. These catalysts will allow new strategies for the formation of carbon-carbon bonds from simple abundant starting materials to rapidly build molecular complexity. Diazaphospholenes combine radical initiation and trapping via hydrogen and halogen atom transfer in a single catalyst and have potential to greatly simplify the implementation of radical chemistry in synthesis. We demonstrate the potential of our methods through synthesis of relevant pharmaceutical fragments, and molecules of challenging complexity.