Selective Spin Transfer in Complex Polyketide Synthesis: Total Synthesis of Ajudazol A and Salimabromide
Final Report Abstract
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. During this project two innovative methods to access key structural features of these two complex polyketides and important natural products in general in an efficient manner. Firstly, a novel modular approach towards oxazole natural products was developed that was based on a direct oxazole functionalization strategy involving a halogen dance reaction for selective halogenation in combination with a challenging combination of sp2-sp2- and sp2-sp3-Negishi cross-coupling reactions. The second method concentrates on the generation of quaternary centers by a titanocene-catalyzed epoxide opening followed by a radical allyltransfer reaction. The first procedure has been successfully applied in a highly concise first total syntheses of ajudazol A and designed analogs with potent biological properties. Furthermore, a first enantioselective total synthesis of (+)-salimabromide was realized by an effective strategy, revealing a highly unexpected almost racemic nature of natural salimabromide.
Publications
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Enantioselective Total Synthesis of (+)-Salimabromide Reveals Almost Racemic Nature of Natural Salimabromide. Organic Letters, 21(6), 1939-1942.
Palm, André; Knopf, Christopher; Schmalzbauer, Björn & Menche, Dirk
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Total Synthesis of Ajudazol A by a Modular Oxazole Diversification Strategy. Organic Letters, 22(16), 6344-6348.
Wollnitzke, Philipp; Essig, Sebastian; Gölz, Jan Philipp; von Schwarzenberg, Karin & Menche, Dirk
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Quaternary Carbon Synthesis by Titanocene Catalyzed Radical Allyl Transfer on Epoxides. Organic Letters, 25(45), 8089-8094.
Schrempp, Michael; Wagner, Raphael; Gleich, Hermann; Gansäuer, Andreas & Menche, Dirk
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Studies on Selective Metalation and Cross-Coupling Reactions of Oxazoles. Synthesis, 55(23), 3927-3946.
Menche, Dirk; Wagner, Raphael; Wollnitzke, Philipp; Essig, Sebastian & Gölz, Jan P.
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Synthesis and biological evaluation of simplified ajudazol derivatives reveal potent 5-lipoxygenase inhibition and considerable apoptotic activity in neuroblastoma cells. Bioorganic & Medicinal Chemistry Letters, 94, 129464.
Wollnitzke, Philipp; Wagner, Raphael; Afsar, Sumaiya Yasmeen; Werner, Markus; Geschold, Robin; Müller, Christa E.; Werz, Oliver; van Echten-Deckert, Gerhild & Menche, Dirk
