Chemo-enzymatic Synthesis of Structurally Complex Sorbicillin-Derived Natural Products and Non-Natural Analogd

• Applicant: Professor Dr. Tobias A. M. Gulder
• Subject Area: Biological and Biomimetic Chemistry
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 517225070

The development of the first chemo-enzymatic syntheses of sorbicillinoid natural products using SorbC in our group over the last few years has enabled highly regio- and stereoselective access to almost all (hetero-)dimeric and simple hybrid compounds of this class and has thus made an important contribution to their synthetic availability. While these synthetic routes are significantly faster and more efficient than previous, purely chemical total syntheses, some limitations remain: the usually incomplete conversion of sorbicillin to sorbicillinol in classical batch processes, combined with the formation of undesired dimeric by-products observed in all syntheses, not only leads to the need for sometimes demanding chromatographic purifications, but importantly also to maximum yields of around 30% ( ± 5%), regardless of the specific target structure. This was acceptable for all target compounds tackled so far, which are generated directly in situ after the oxidative production of sorbicillinol. However, these limitations are problematic for required subsequent multi-stage synthetic transformations to even more complex representatives, as well es for substances that are formed via a reaction of sorbicillinol with highly functionalized reaction partners that cannot simply be used in large excess. This applies in particular to the production of larger amounts of substances for detailed biological characterization and to the derivatization of the compounds, e.g. to optimize biological activities or to install molecular probes to elucidate mechanisms of action. In this research project, we will solve these problems in a targeted manner, apply the developed methodology to establish the first stereoselective total syntheses of complex sorbicillinoids and thus lay the foundation for extensive biomedical and mechanistic follow-up investigations. Specifically, we are planning: • Immobilization of SorbC and continuous implementation of the oxidative dearomatization in flow reactors with subsequent highly selective product formation through suitable reaction control • Development of the first stereoselective synthesis of hybrid sorbicillinoids from Diels-Alder cycloaddition reactions with complex dienophiles or with multi-stage subsequent chemistry • Development of first stereoselective total syntheses of hybrid sorbicillinoids from Michael addition reactions with multi-stage subsequent chemistry • Initial work to towards elucidation of molecular modes of action, initially using the example of the antibiotic Rezishanon A

• DFG Programme: Research Grants