Improving the oxidative stability of boronic acids through stereoelectronic effects

Boronic acids represent a useful class of compounds for materials and pharmaceutical applications due to their ability to form reversible covalent linkages with biologically relevant nucleophiles, particularly with 1,2- and 1,3-diols. Unfortunately, boronic acids are metabolically unstable, undergoing rapid oxidative deboronation in the presence of reactive oxygen species and slow protodeboronation in aqueous solution. Boronic acids are often protected as boronate esters with large sterically hindered diols, which is of limited application in biological systems. Stable intramolecular esters, such as the popular benzoxaborole scaffold, offer an opportunity to modulate the reactivity of the boronic acid without the use of inefficient exogenous protecting groups. We measured the oxidative stability of phenylboronic acid and derivatives containing cyclic esters and the analogous boralactones over a range of pH. By analyzing the kinetic data in a pH-independent manner, we found that cyclic esters enhance oxidative stability modestly, whereas boralactones do so dramatically. Computational analyses reveal that the increased resistance to oxidation arises from diminished donation to the p-orbital of boron that develops during the rate-limiting step. Further investigations show the same effect also results in improved resistance to protodeboronation in boralactones. These findings provide insights into how future boronic acid pharmaceuticals can be conferred with greater metabolic stability.