Biocatalytic Oxidative Dearomatization and Applications in Chemoenzymatic Total Synthesis

Abstract

Natural products, compounds synthesized by all kingdoms of life, offer a wealth of structural diversity, giving rise to an array of biological activities. For centuries chemists looked to nature for the discovery of new medicines. More recently, chemists have begun to employ Nature’s tools for complex molecule synthesis in the generation of novel compounds. My thesis describes the development of new oxidative biocatalytic methods and application of these methods in the synthesis of biologically active molecules. Chapter 2 describes the substrate scope and selectivity of three wild type flavin-dependent monooxygenases enzymes. Together this enzyme suite provides complementary catalysts for asymmetric oxidative dearomatization. We have developed a positioning group strategy to overcome substrate scope limitations with one of our catalysts, described in Chapter 3. We have engineered substrates to allow for improved turnover, thus, enabling access to a wide array of o-quinol containing natural products. Pairing experimental data with computational and biophysical characterization of the substrate-protein interactions further informed our understanding of the role of the positioning group. A scalable platform for biocatalytic oxidative dearomatization has been developed allowing for gram-scale reactions, described in Chapter 4. We have applied this method in the synthesis of a number of natural products in one-pot cascades from simple arene starting materials, using oxidative dearomatization as the key synthetic step. Chapter 5 describes our work to identify stereocomplementary homologs of these monooxygenases which have allowed access to enantiomeric intermediates that can be elaborated to various azaphilone natural products. Specifically, the total syntheses of two members, trichoflectin and lunatoic acid A, are described.