Configurational revision and progress towards a first total synthesis of vancoresmycin Max Schönenbroicher and Maximilian Seul University Bonn, Germany Vancoresmycin is a highly potent antibacterial polyketide that was first isolated by Aventis in 2002 from actinomycete Amycolatopsis sp. ST 101170. It is extremely active against a broad range of pathogenic Gram - positive bacteria, including multi-resistant strains with potencies that exceed those of vancomycin by around 100 times. 1 Unfortunately, vancoresmycin was originally published as a planar structure and a first stereochemical proposal was found to be inconclusive, preventing any synthetic approaches towards this important bioactive agent for a long time. By extensive bioinformatic analysis of the biosynthetic gene cluster involving analyses of the ketoreductase and enoylreductase domains, in combination with modular and stereoselective syntheses of elaborate fragments and extensive NMR studies, a revised stereochemistry of large parts of the polyketide chain of vancoresmycin was recently proposed in our group. 2 This information now enables the design of a directed first total synthesis which would also allow to unequivocally determine the full stereochemistry and enhance further biological studies of this scarce antibiotic agent. The design of a convergent and modular synthetic route will be presented and progress towards successful preparation of key subunits will be shown. This includes an efficient sequence of substrate and auxiliary mediated aldol couplings to set the characteristic array of hydroxyl- and methyl-bearing centers with high selectivity and yield. Furthermore, an efficient Fries rearrangement for introduction of various pendant acetyl residues to access the characteristic tetramic acid moiety with high selectivity will be presented. Finally, attempts to effectively forge these segments will be discussed and interesting first SAR data of simplified fragments will be documented. 3
References 1. C. Hopmann, M. Kurz, M. Brönstrup, J. Wink, D. LeBeller, Tetrahedron Lett. 2002 , 43 , 435–438. 2. S. Spindler, L. Wingen, M. Schönenbroicher, M. Seul, M. Adamek, S. Essig, M. Kurz, N. Ziemert, D.Menche, Org. Lett. 2021 , 23, 4, 1175-1180. 3. L. M. Wingen, M. Rausch, T. Schneider, D. Menche, ChemMedChem 2020 , 15 , 1390-1393.
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