Selective Spin Transfer in Complex Polyketide Synthesis: Total Synthesis of Ajudazol A and Salimabromide

• Applicant: Professor Dr. Dirk Menche
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 400173102

Polyketides are prevalent structural features in numerous natural products with a broad range of biological activities and pharmacological properties. They are characterized by diverse assemblies of methyl and hydroxyl-bearing stereogenic centers, thus enabling very large numbers of stereochemical permutations and structures with extraordinary complexity and diversity. Prominent examples include the antibiotic salimabromide, a unique polycyclic metabolite and first natural product that was isolated from a marine myxobacterium and the highly potent respiratory chain inhibitor ajudazol A, a singular isochromanone polyketide of myxobacterial origin. The important biological properties in combination with their unique and synthetically challenging architectures render these compounds attractive targets from the perspective of synthetic and medicinal chemistry. Despite considerable progress in the chemistry of complex polyketides, there remains a high need for more convergent as well as more selective synthetic methods and in particular radical reactions are still underdeveloped in complex polyketide synthesis. This project proposes the development of two innovative spin-centered methods to access key structural features of these two complex polyketides and important natural products in general in an efficient manner. The first procedure focuses on an iodine-mediated one-pot process for stereoselective isochromanone synthesis, while the second method concentrates on the generation of quaternary centers by a titanocene-catalyzed epoxide opening followed by a radical allyltransfer reaction. These procedures will then enable highly concise first total syntheses of ajudazol A and salimabromide, which will also be important for an unambiguous structural and stereochemical assignment. Finally, designed analogs with improved biological and/or biophysical properties will be prepared to further evaluate and improve the full biological potential of these highly scarce, potent bioactive agents.

• DFG Programme: Research Grants