Synthesis of diverse salicylaldehydes for the characterization of enzymatic Dakin oxidation with 4-hydroxyacetephenone monooxygenase (HAPMO)

Abstract

In synthetic chemistry, the generation of reactive building block materials is critical to producing complex materials, like natural products and pharmaceuticals. To produce wide varieties of these building blocks, the starting materials must be reasonably amenable to divergent synthesis, wherein one compound can be converted to a diverse array of materials in few steps. One class of underexplored synthetic building blocks are catechols, which are key components of numerous valuable compounds. However, catechols remain a challenging starting material to access, as they are prone to oxidation, and difficult to modify due to the acidic 1,2-diol moiety. In contrast, salicylaldehydes can be diversified without protection procedures through cross-coupling reactions to generate a library of catechol precursors. We have identified an enzyme called HAPMO, which performs a Dakin oxidation to generate catechol from salicylaldehyde. HAPMO reactivity is underexplored and has only been shown for fluorinated derivatives. In this work, we synthesized a small library of potential salicylaldehyde substrates with unique substituents to probe the steric and electronic limitations of HAPMO. We have also begun testing substrates in reactions with purified HAPMO. The results of this study will inform future synthesis of salicylaldehyde substrates, and further studies on the native reactivity of HAPMO.