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Total Synthesis and Biological Evaluation of the Cytotoxic Resin Glycosides Ipomoeassin A–F and Analogues

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Nagano, Takashi [Max Planck Institute for coal research] Pospisil, Jiri [UCL] Chollet, Guillaume [Max Planck Institute for coal research] Schulthoff, Saskia [Max Planck Institute for coal research] Hickmann, Volker [Max Planck Institute for coal research] Furstner, Alois [Max Planck Institute for coal research]

A multitasking C-silylation strategy using the readily available compound 26 as a surrogate for cinnamic acid represents the key design element of a total synthesis of all known members of the ipomoeassin family of resin glyosides. This protecting group maneuver allows the unsaturated acids decorating the glucose subunit of the targets to be attached at an early phase of the synthesis, prevents their participation in the ruthenium-catalyzed ring-closing metathesis (RCM) used to form the macrocyclic ring, and protects them against reduction during the hydrogenation of the resulting cycloalkene over Wilkinson’s catalyst. As the C-silyl group can be concomitantly removed with the O-TBS substituent using tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) in acetonitrile, no separate protecting group manipulations were necessary in the final stages, thus contributing to a favorable overall “economy of steps”. In addition to the naturally occurring ipomoeassins, a small set of synthetic analogues has also been prepared by “diverted total synthesis”. The cytotoxicity of these compounds was assayed with two different cancer cell lines. The recorded data confirm previous findings that the acylation- and oxygenation pattern of these amphiphilic glycoconjugates is highly correlated with their biological activity profile. Ipomoeassin F turned out to be the most promising member of the series, showing IC50 values in the low nanomolar range.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2009
Language Anglais
Journal information "Chemistry: A European Journal" - Vol. 15, no. 38, p. 9697 – 9706
Peer reviewed yes
Publisher Wiley ((Germany) Weinheim)
issn 0947-6539
e-issn 1521-3765
Publication status Publié
Affiliations Max Planck Institute for coal research - Department of Chemistry
UCL - SST/IMCN/MOST - Molecules, Solids and Reactivity
Links
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  142. Attempts to form diene 45 directly by reaction of 28 with lactone 42 were low yielding.
Bibliographic reference Nagano, Takashi ; Pospisil, Jiri ; Chollet, Guillaume ; Schulthoff, Saskia ; Hickmann, Volker ; et. al. Total Synthesis and Biological Evaluation of the Cytotoxic Resin Glycosides Ipomoeassin A–F and Analogues. In: Chemistry: A European Journal, Vol. 15, no. 38, p. 9697 – 9706
Permanent URL http://hdl.handle.net/2078.1/105755