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MIRTH: Predicting Unseen Metabolite Measurements

MIRTH is in print at Genome Biology

Out of the thousands of metabolites in a given specimen, most metabolomics experiments measure only hundreds, with poor overlap across experimental platforms. Here, we describe Metabolite Imputation via Rank-Transformation and Harmonization (MIRTH), a method to impute unmeasured metabolite abundances by jointly modeling metabolite covariation across datasets which have heterogeneous coverage of metabolite features. MIRTH successfully recovers masked metabolite abundances both within single datasets and across multiple, independently profiled datasets. MIRTH demonstrates that latent information about otherwise unmeasured metabolites is embedded within existing metabolomics data, and can be used to generate novel hypotheses and simplify existing metabolomic workflows.

Understanding Fe-Catalyzed HIE

Chemistry Undergraduate Senior Thesis

C(sp2)-H activation-enabled catalysis for hydrogen isotope exchange (HIE) is desirable for the late-stage labelling of pharmaceuticals and other complex molecules with deuterium or tritium. Precious metal systems have long been fixtures of catalytic HIE, but their sustainability pitfalls, their ortho-selectivity, and their use of directing groups motivate the development of base-metal alternatives. Previous work from the Chirik group has detailed pyridine dicarbene iron (CNC(Fe)) complexes capable of performing HIE on a variety of aryl substrates, with reactivity complementary to that of existing precious-metal systems. However, their mechanism of C-H activation remains poorly understood. In this work, computational investigation via density function theory (DFT) supports a σ-complex assisted metathesis (σ-CAM) mechanism of C-H activation, consistent with other pathways in metal-catalyzed HIE. The computed pathway features a late transition state from a weakly-bound η2C-H-arene intermediate, leading to an η2-H2-coordinated intermediate typical of σ-CAM HIE. Furthermore, the analyses herein correctly predict the effect of ligand optimization on the rate of H/D exchange observed in prior work, opening the door to computationally informed ligand design. Though preliminary calculations suggest that the relative barriers to C-H activation of fluoroarenes do not account for the catalyst’s observed meta-to-fluorine regioselectivity, other factors, such as the relative energies of the ground states immediately adjacent to the transition states, may do so. Future work could fully untangle the thermodynamic and kinetic factors that lead to the system’s regioselectivity. Understanding the mechanism of the CNC(Fe) HIE catalyst may also inform the rational design of C-H activation-based (CNC)Fe catalysts for olefin hydrogenation and C-C cross coupling reactions.

Toward Process-Friendly Cu-Catalyzed Trifluoromethylation

Chemistry Junior Independent Work

Strategies for mild late-stage aryl trifluoromethylation, useful in pharmacochemical and agrochemical contexts, remain elusive. Transition metal catalyzed C-H trifluoromethylation displays poor regioselectivity without directing groups. C-X trifluoromethylation strategies are highly selective, but often employ expensive -CF3 reagents and stoichiometric metals. The trifluoromethylation of aryl boronic acids presents an alternative approach, leveraging work on highly selective C-H borylation methods. Cu-catalyzed electrophilic methods, which minimize the use of stoichiometric reagents and employ readily-available CF3+ reagents, are advantageous over nucleophilic or radical methods. In collaboration with Amgen, we propose a series of preliminary optimization steps and mechanistic studies that will inform high-throughput catalyst screening, toward improving the process-viability of these systems.