Catalytic and Biological Applications of Benzoxaborolones

Abstract

Though first isolated 150 years ago, boronic acids have historically been neglected species. The more recent advent of transition metal-catalyzed reactions has led to an explosion in their use as building blocks, which in turn has led to their application in many other contexts as synthetic methods improved. The presence of a largely vacant p orbital on boron lends boronic acids unique properties and makes them of particular interest for organocatalysis and in chemical manipulation of biological systems.

In Chapter 2, I describe the development of an organocatalytic process for the conversion of biomass-derived sugars to 5-hydroxymethylfurfural. Building on previously reported metal-promoted processes, I found that 2-carboxyphenylboronic acid (2-CPBA) is an optimal catalyst for this process which can promote the desired reaction without the addition of metals and is unique among boronic acids in its ability to promote the reaction.

The unique properties of 2-CPBA as a catalyst led us to further investigate its structure and reactivity. 2-CPBA was found to exist as a cyclized benzoxaborolone adduct, rather than the free carboxylic acid. In Chapter 3, I describe the consequences of this cyclization on the oxidative stability of the boronic acid. The stereoelectronic effects present in the oxaborolone ring destabilize the oxidation transition state by reducing electron donation from the cyclic oxygen to the developing p orbital on boron, leading to an improvement in the oxidative stability of these species by over four orders of magnitude while maintaining the normal reactivity of boronic acids toward nucleophiles and diols.

In Chapter 4, I describe the application of the benzoxaborolone scaffold to improve the oxidative stability of a boronic acid-based inhibitor of HIV protease. Replacement of a phenylboronic acid with a benzoxaborolone led to a ~100-fold improvement in oxidative stability, and the new inhibitor largely maintained potency toward the protease. Analysis of an X-ray crystal structure of the inhibitor-protease complex revealed that the benzoxaborolone forms a strong network of hydrogen bonds due to its oxygen-rich and anionic nature.

Appendices describe further investigations into the mechanism for conversion of glucose into HMF catalyzed by 2-CPBA, the reactivity of lignin and conversion of various biomass sources into carbohydrates in ionic liquids, and computational investigations into the stability of modifications on the benzoxaborolone scaffold toward oxidation and protodeboronation.