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Structure Assignment, Total Synthesis, and Antiviral Evaluation of Cycloviracin B1

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Fürstner,  Alois
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Albert,  Martin
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Mlynarski,  Jacek
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Matheu,  Maribel
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Citation

Fürstner, A., Albert, M., Mlynarski, J., Matheu, M., & DeClercq, E. (2003). Structure Assignment, Total Synthesis, and Antiviral Evaluation of Cycloviracin B1. Journal of the American Chemical Society, 125(43), 13132-13142. doi:10.1021/ja036521e.


Cite as: https://hdl.handle.net/11858/00-001M-0000-000F-9805-A
Abstract
The first total synthesis of the antivirally active glycolipid cycloviracin B1 (1) is described. The approach is based on a two-directional synthesis strategy which constructs the C2-symmetrical macrodiolide core of the target by an efficient template-directed macrodilactonization reaction promoted by 2-chloro-1,3-dimethylimidazolinium chloride 14 as the activating agent. Attachment of the lateral fatty acid chains to the lactide core thus formed features not only one of the most advanced ligand-controlled addition reactions of a functionalized dialkyl zinc reagent to a polyfunctional aldehyde, but also a highly demanding Julia−Kocienski olefination of a tetrazolyl sulfone bearing electrophilic and base-labile β-hydroxy ester motifs. By virtue of the flexibility of this synthesis plan, it was possible to prepare a series of macrodiolide cores differing only in the absolute stereochemistry at the branching points as well as a host of model compounds for the fatty acid appendices of cycloviracin. Comparison of these derivatives with the natural product allowed us to establish the as yet unknown absolute stereochemistry of 6 chiral centers of 1 as (3R,19S,25R,3‘R,17‘S,23‘R). Thereby, the 13C NMR shifts of the anomeric position of the β-glycosides residing at those positions turned out to be excellent probes for the absolute configuration of the attached aglycones. The concise set of data thus obtained also makes clear that the proposed structure of the fattiviracins, a seemingly closely related family of glycoconjugates, is not matched by the published data. Finally, the biological activity of synthetic 1 and some of the key intermediates obtained en route to this natural product was investigated, showing that the entire construct is necessary for appreciable and selective antiviral activity.