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Total Synthesis of Blennolide C and related C4a-functionalized Tetrahydroxanthenones

Beiträge zur organischen Synthese, Bd. 11

Emilie Gérard

ISBN 978-3-8325-2170-7
180 pages, year of publication: 2009
price: 36.00 €
Mycotoxins play an important role in the design and discovery of new biologically active compounds. Among them, the secalonic acids represent privileged structures because of their sparking antibiotic activities. These secondary metabolites, belonging to a still growing family of natural products, are either symmetrical or unsymmetrical dimers, made up of highly functionalized tetrahydroxanthenone moieties. A similar structural motif can be found in the recently isolated blennolide C, which is carrying a characteristic methyl ester group at the 4aposition of the tetrahydroxanthenone core.

A total synthesis of this natural product would offer a synthetic access to the basic molecular framework of this substance class. Thus, the aim of the present work was to develop new synthetic procedures for the total synthesis of blennolide C and related structures. In order to achieve this goal, the reaction pathway leading to the desired substitution pattern at the 4a-position was first investigated on a tetrahydroxanthenone model system. Latter was efficiently substituted with olefin moieties using a cuprate-mediated conjugate addition reaction. Further derivatization of the alkene feature, including the Lemieux-Johnson oxidation, afforded a series of highly functionalized xanthones.

Based on these results, the total synthesis of racemic blennolide C was successfully accomplished. The structure of this natural product, originally wrongly attributed to i-diversonolic ester by Simpson et al., was confirmed by X-Ray crystallography. Towards the end of this work, the true structures of diversonolic esters were elucidated by NICOLAOU and LI.[i] Our modular synthetic pathway developed for the total synthesis of blennolide C was then applied to the preparation of related compounds. This allowed significant progresses towards the total synthesis of xanthonol and secalonic acids. In conclusion, the total synthesis of blennolide C was successfully accomplished using a modular strategy featuring a conjugate addition of a carbonyl equivalent. The developed chemistry allows the construction of the basic molecular framework of this class of compounds and thus opens an expedient access to more complex natural products of the same family.

Keywords:
  • Total Synthese
  • Mykotoxine
  • Naturstoff
  • Xanthone
  • Blennolide C

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