Advancing Novel Catalytic Strategies to Solve Problems in Organic Synthesis

The topological and stereochemical complexity inherent in molecular scaffolds with high sp³ character imparts beneficial physical and biological properties relative to sp²-rich compounds, but also amplifies selectivity and reactivity challenges for their efficient synthesis. Modular strategies for the rapid and selective construction of stereodefined sp³-rich molecules would enable access to a broad range of chemical space and advance a significant frontier in organic synthesis. The Paradine group focuses on the discovery of selective catalytic methods for the efficient construction of sp³-rich molecules, with a specific focus on C‒C bond formation. A particular priority is placed on transformations that use simple starting materials and lead to a significant increase in molecular complexity. We are interested both in the development of catalytic synthetic methodologies that exert precise control over reaction outcomes (i.e. enantioselectivity, diastereoselectivity, site-selectivity, chemoselectivity), and fundamental studies that seek to understand the factors that contribute to highly selective transformations.

This research provides ample opportunities for applications to catalysis, total synthesis, medicinal chemistry, and other areas. Collaborations with colleagues across disciplines will be sought out to realize the full potential of our group’s research. Students in our group will gain expertise in organic synthesis and catalytic reaction discovery. In addition, students will learn diverse techniques in physical and mechanistic organic chemistry, spectroscopic characterization of organic compounds and transition metal complexes, computational chemistry, and the synthesis and investigation of transition metal complexes.

Catalytic Strategy #1: Ureas as an alternative ligand platform for Pd catalysis

We have found that compounds derived from urea are effective ligands for Pd catalysis. These ligands, which can be readily prepared from abundant, inexpensive amine precursors, are complementary to traditional ligands for Pd, and occupy a region of ligand space – small, organic ligands – that has been relatively unexplored for late transition metal catalysis.

Through urea-enabled heteroannulation of dienes and ambiphilic (bifunctional) reagents, we are making progress toward establishing a unified synthetic strategy to access diverse heterocyclic scaffolds. Through straightforward modifications to either coupling partner, we can rapidly access structural analogues of medicinally relevant heterocycles. Our methodology displays a high tolerance for sterically-demanding substrates and engages structurally and functionally diverse substrates. In addition to continuing to advance general methods for the convergent construction of heterocycles, we are exploring new olefin functionalization reactivity enabled by urea ligands.

Catalytic Strategy #2: Achieving ligand-controlled site-selectivity in olefin functionalization reactions

We found that an unconventional phosphine ligand, diadamantylbutylphosphine (CataCXium A), is capable of overriding substrate bias for carbopalladation to access complementary substitution patterns in diene heteroannulation. Exerting ligand control over diene carbofunctionalization reactions was unprecedented, and the ability to control site-selectivity in olefin functionalization reactions is generally challenging. Through multiparameter reaction analysis, we identified a predictive model for understanding the relationship between ligand structure and selectivity outcomes. We are currently looking to use this model as a starting point for generalizing this catalytic approach to other olefin functionalization reactions.

Catalytic Strategy #3: Cooperative coordination of ligand and substrate for Cu-catalyzed, oxidative radical addition reactions

We are working to develop a suite of general, oxidative methods for radical addition reactions to alkenes and arenes. We recently discovered a mild method for Cu-catalyzed, aerobic aminooxygenation of internal alkenes. Reaction investigations revealed that cooperative coordination of phenanthroline ligand and substrate to Cu resulted in rapid reduction from Cu(II) to Cu(I), thus promoting facile activation of O₂ to generate a potent single electron oxidant. We are currently expanding this methodology to different radical precursors and new reactivity.