Current Research Interests:
Research Projects:

Kinetic Isotope Effects Upon Enantiotopic Groups - Understanding Asymmetric Reactions Asymmetric reactions play an ever-increasing role in the synthesis of natural products and in the production of pharmaceuticals and fine chemicals. Existing mechanistic methodologies, however, are largely insensitive to the symmetry breaking processes inherent to asymmetric reactions. One of the new mechanistic probes developed in our laboratory is a methodology for measuring deuterium kinetic isotope effects upon enantiotopic groups. Enantiotopic groups are equivalent by symmetry. As the molecule bearing the enantiotopic probes is approached by an asymmetric reactant, the enantiotopic groups are no longer equivalent by symmetry and experience disparate environments. The measurement of deuterium kinetic isotope effects upon enantiotopic groups provides a means of quantitatively measuring the influence of steric interactions upon the stereochemical course of a reaction. This methodology has been applied toward the DIP-Cl reduction of prochiral ketones and the Corey-Bakshi-Shibata Reaction. A computational method for computing steric deuterium isotope effects from model transition structures has also been developed and has been shown to provide far more reliable estimates than traditional calculations utilizing the harmonic approximation. Carbon-13 kinetic isotope effects upon enantiotopic groups have also been utilized in a study of the proline-catalyzed intramolecular aldol reaction. The findings of this study significantly revised over three decades of mechanistic thinking regarding this reaction.

Intramolecular Kinetic Isotope Effects upon Desymmetrizations - Mechanisms of Multi-channel Reactions The vast majority of mechanistic tools available for understanding organic reaction mechanisms depend upon clean, single-channel, high-yielding reactions. Our lab is utilizing intramolecular competition as a means of constructing transition state models for multiple reaction channels. Because intramolecular isotope effects are insensitive to reaction progress, relative kinetic isotope effects can be measured for all significant reaction channels. This approach to mechanistic inquiry is especially relevant to reaction classes that are in development, such as intramolecular hydroaminations and intermolecular proline-catalyzed aldol reactions. Using these techniques, we hope to gain quantitative understanding of the origin of mismatched pairs in diastereoselective reactions, the origins of stereoselection in intramolecular hydroaminations, and the limitations upon substrate range in the Corey-Bakshi-Shibata reaction.

Complete Mechanistic Analyses of Stereoselective Reactions Kinetic isotope effects and transition structure modeling provide snapshots of important points on the reaction pathway, namely the product- and rate-determining steps. Likewise, steady-state kinetics are important in understanding the molecularity of catalysts and reactants in the rate law. However, transient kinetics can also provide additional information, especially in reactions where an intermediate is formed prior to the rate-determining step. My laboratory is currently exploring transient kinetics in the intramolecular proline-catalyzed aldol reaction. These studies are illuminating hitherto unappreciated aspects of these interesting reactions.

Isotope Accounting - A General Method for Obtaining KIEs in Multi-channel Reactions Many of the techniques used in mechanistic inquiry suffer from what I call 'The Goldilocks Condition'. In order to apply structure-activity relationships, linear free energy relationships, perform kinetics, or kinetic isotope effect experiments, the reaction must typically be 'just right'. In other words, the reaction must be single-channel and typically high-yielding. Many useful reactions and reactions in development have multiple reaction channels and are not particularly high-yielding. My laboratory is developing a highly sensitive method for measuring kinetic isotope effects for reactions that have multiple reaction pathways or are not particularly high-yielding.

Rapid Measurement of Kinetic Isotope Effects Measurements of kinetic isotope effects typically require either the synthetic preparation of isotopologs or the precise measurement of isotopic ratios. My laboratory is currently developing a technique for the rapid measurement of kinetic isotope effects that utilizes a numerical mathematical transform to extrude kinetic isotope effect measurements from reaction progress curves. Rather than being highly model-dependent, these measurements can be utilized a priori to begin building mechanistic models.