Research Interests
Pushing strained compounds to their limits.
Strained Ring Functionalization
Strained rings are traditionally difficult to functionalize because of unwanted ring-opening reactions that produce more thermodynamically stable forms. A major goal of the Hill group is to develop new functionalization reactions of strained compounds that proceed without delterious ring-opening reacitons. Doing so will enable late-stage functionalizations of strained rings. In this set of projects we study how boron can functionalize C–F and C–H bonds in cyclopropenes through the intermediacy of aromatic ion intermediates.
Catalysis
The development of new reactions is critical for advances in many fields such as agrochemical, pharmaceutical, biological, and material sciences because doing so permits access to unique chemical space. In the Hill lab, we are interested in using dialkylhydrazones to obtain orphaned cyclopropanes. In this set of projects we study how transition metals and ligand combinations impact the stability of cyclopropylcarbinyl intermediates.
Reagent Development
Orphaned cyclopropanes are strained three membered rings that arise from the transfer of a non-stabilized carbene. Typically these are dialkylcarbenes, which provide dialkylcyclopropanes. These motifs are commonly found in drugs (e.g. nirmatrelvir) and pyrethroid agrochemicals (see below). A major challenge transfer non-stabilized carbenes to alkenes is the development of bench stable molecules that serve as carbene surrogates. In the Hill lab we have developed new sulfone reagents that transfer non-stabilized carbene groups to weakly activated alkenes.
Applications - Natural Product Synthesis. Toward Novel Pyrethroids
Isolated from plants, bacteria, marine sponges and other natural sources, complex secondary metabolites (natural products) oftentimes have important biological function (e.g., active in the central nervous system, anti-HIV, anticancer). As such, this chemical matter provides a unique starting point for the development of new pharmaceuticals. Additionally, these compounds are often used as tools for understanding biology, and their complex architectures are well-suited for investigating molecular reactivity in complex chemical environments.
The sequence of reactions by which a complex natural product is obtained is of paramount importance. Unique synthetic strategies can result in the development of innovative reaction methodologies, uncover new reactivity of small molecules, and begin to address shortages natural compounds used as leads for drug development. Total synthesis also provides a means to confirm the structure of natural products, which can be critical for understanding how they function. The Hill lab is interested synthesizing natural products containing orphaned cyclopropanes with the goal of using natural products as tools for understanding complex biology.