Upgrading alcohols with bio-oxidation and chemo-catalysis in single-flask processes
Biocatalysis provides exquisite chemo-, regio-, and stereo-control, built-in co-factor regeneration, and can upgrade renewable feedstocks through multi-step transformations, all while avoiding high temperatures, organic solvents, and metal catalysts. Despite these marked advantages over conventional synthesis, biocatalysis is handicapped by a narrow range of transformations and limited scope of accessible products. Enzymes are selective in what substrates they accommodate, microbes have mass transfer and toxicity limitations, and many quintessential organic transformations are scarce in nature. These and other factors limit the product scope that can be accessed through biosynthetic means alone. To expand product scope, recent efforts have sought to augment bioprocesses with chemo-catalytic transformations in single-flask processes. In this vein, our group targets alcohol substrates for upgrading with biocompatible chemistry. Alcohols are attractive targets for their easy access from renewable feedstocks yet scarce opportunities for upgrading in water. Since alcohols are relatively inert towards traditional synthesis under biocompatible conditions, our single-flask processes start with bio-catalyzed oxidation of the alcohol substrate to a synthetically-flexible aldehyde. We then derivatize the aldehyde with abiotic catalysis to furnish upgraded products in one-pot. This complementary approach expands beyond the product scope of biocatalysis while maintaining its many benefits. This thesis details our recent work towards upgrading alcohols with one-pot bio/chemo-catalytic cascades. It begins with a comprehensive literature review on aqueous micellar catalysis, organized into sections by co-catalyst. In this review, we introduce a novel framework for understanding the mechanisms of micellar catalysis, discuss synergies between co-catalysts and micelles, and highlight strategies for leveraging micellar catalysis. The next chapter covers our synthesis and evaluation of a prospective and, ultimately, ineffective micellar catalyst for biocompatible aldol condensations. Additionally, an air-stable micelle-forming surfactant with a functional handle is proposed. The next chapter details our contributions toward a four-step bio- and organo-catalytic cascade for single-flask production of dinitroalkanes. In this system, alcohol oxidase from Komagataella pastoris (K. pastoris) oxidizes alcohol substrates to aldehydes which subsequently undergo a three-step Henry/Michael reaction to furnish 1,3-dinitroalkanes. We expanded the Henry/Michael reaction to five total aldehyde substrates and that both toxicity and enzyme inhibition contribute towards reduced yields in concurrent reactions. The final chapter chronicles our most recent system, where whole-cell bio-catalyzed alcohol oxidation has been interfaced with same-flask KPi-catalyzed Pictet-Spengler annulation. This methodology accommodates two different biocatalysts, C2-C5 linear and branched alcohols, and both m-tyramines and tryptamines to to deliver near-quantitative conversion to tetrahydroisoquioline and tryptoline products. Taken together, these studies add to the growing toolbox for upgrading alcohols under biocompatible conditions.
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Colorado School of Mines. Arthur Lakes Library