Enzymatic Synthesis of O-Heterocyclic Scaffolds by Cyclization & Ring Expansion Reactions

Abstract

The assembly of complex molecular frameworks is one of the major tasks of an organic chemist. Over the past decades, numerous tactics for the construction of such complex entities have emerged. To fulfill these tasks, classical methods often require the use of orthogonal protecting group strategies to preserve the molecular integrity, however, these tactics become more and more challenging and insufficient as the molecule gains in complexity. In this regard, enzymes offer the possibility to manipulate or implement delicate functionalities without the need for protecting groups. With the tremendous developments in the field of protein engineering in order to easily access recombinant enzymes, biocatalysis is increasingly gaining importance in organic synthesis. Heterocycles are key parts of the synthetic-organic target scope and thus, their efficient assembly represents a pivotal task in modern chemistry where particularly the stereoselective construction of these building blocks poses a crucial and recurring challenge. As the general theme of this thesis, the presented work features the application of chemoenzymatic methods for the synthesis of heterocyclic building blocks where novel biocatalytic approaches have been developed that imitate non-natural, classical chemical processes. Especially the so-called Achmatowicz rearrangement, the oxidative ring expansion of furfuryl alcohols and amines to six-membered O- and N-heterocycles, respectively, plays a central role in the thesis. Both synthetic routes to access the required substrates, as well as their application in the Achmatowicz rearrangement to prepare pyranones and piperidinones, is described. Here, a novel method to prepare furfurylamines, as well as a new lipase-mediated Achmatowicz rearrangement, is presented. Moreover, the versatility of the newly developed methods is demonstrated in a multi-catalytic natural product synthesis. Additionally, in the perspective to extend the biocatalytic toolbox, investigations on a biocatalytic decomposition of diazo compounds as a trigger for sigmatropic oxonium ylide rearrangements is presented, where lytic polysaccharide monooxygenases are reported for the first time to act as a catalyst in a protein-mediated Kirmse rearrangement.