Date of Award

5-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Committee Chair/Advisor

Byoungmoo Kim

Committee Member

Daniel C. Whitehead

Committee Member

Rhett C. Smith

Committee Member

Joseph S. Thrasher

Committee Member

Dev P. Arya

Abstract

The development of earth-abundant catalytic methodologies toward the valorization of stable carbonyl derivatives remains an urgent priority for both academia and industry alike. Functionalization of sp2 – sp2 carbon-heteroatom bonds has been a cornerstone of organic chemistry since its inception, but for the majority of that time, this has classically relied on aldehydes and imines due to their relative ease of modification. Unfortunately, aldehydes are prone to oxidation and decomposition, sometimes even when made and stored under inert conditions, and imines are even more so. Furthermore, making and/or (re)purifying aldehydes and imines requires additional synthetic steps, imposing costs of time, energy, and reagents.

As such, a growing push exists toward directly utilizing affordable, abundant, and bench-stable carboxylic acids and amides as feedstocks instead without intervening steps. Yet, the very stability of carboxylic acids and amides that makes them so abundant also renders them hard to use directly for complex molecule synthesis without first converting them to more reactive derivatives. Classical solutions have relied on strong activators with poor chemoselectivity that generate large amounts of waste, but in the past thirty years, precious metal catalysts and selective strong activators have made direct use of these feedstocks increasingly possible for the synthesis of complex natural products. In more recent years, several earth-abundant metals have also proven practical, though all of these systems possess cost, safety, and activation issues that render them difficult to scale beyond the laboratory bench.

To address these interwoven challenges, we have unlocked the multifaceted catalytic potential of titanium(IV) alkoxide, which when paired with the inexpensive diethoxymethylsilane (EtO)2MeSiH and a chiral aminoalcohol ligand, is capable of amidation, partial reduction, and cyanation all in the same sequence, achieving the first catalytic enantioselective Strecker reaction of carboxylic acids. This methodology was demonstrated on a variety of aromatic, aliphatic, and pharmaceutically-derived carboxylic acids, giving good yields and up to 98:2 er for the α-aminonitrile products. Following this success, the titanium-catalyzed amide reduction was further reoptimized to run on just a quarter of the catalyst loading, less than half the silane loading, and cleanly operate at 2 M concentration in a wide variety of organic solvents, demonstrating interoperability in THF, toluene, dioxane, and DCM. Additionally, this system even functions in MeCN despite the highly coordinating nature of this solvent, requiring only additional silane to cleanly complete the partial reduction to imine. We applied this reoptimized reduction toward the first asymmetric fluoroalkylation of amides, discovering an innovative use of the transimination reaction to obtain industrially-prized Ellman’s sulfinimines from amide precursors in one pot, and we were able to showcase this sequence to obtain chiral α‑fluoroalkyl amines in up to 70% isolated yield and > 20:1 dr Furthermore, this transformation has been extended beyond TMSCF3 and also works with slight modification for TMSCF2H and TMSC6F5.

Overall, titanium(IV) alkoxide-catalyzed amide partial reduction is proving itself a very robust platform while bringing catalytic amide partial reduction within practical industrial reach in a nontoxic, convenient, cost-effective manner, serving as a vital bridge between academic novelty and industrial reality.

Author ORCID Identifier

0009-0006-3990-3452

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