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Philipps-Universität Marburg
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Abstract
In this thesis a stereocontrolled, convergent and modular synthetic route for the total synthesis of the structurally unique natural product Granaticin A is investigated. The natural product, a carbohydrate derived pyronaphthoquinone, has been isolated from several strains of Streptomyces and shows anticancer activity against KB cells as well as against P-388 lymphocytic leukemia in mice. Grantaicin A inhibits the protein synthesis by interacting with the Leucyl-tRNA-synthetase and with the rRNA.
The tetracyclic main core of the natural product was retrosynthetically disassembled into an A- and CD-fragment, which are according to a convergent design of comparable complexity. The A-fragment, a cyclic anhydride, is prepared starting from p-dimethoxyaldehyde in 8 linear steps in an overall yield of 17% (≥ 95% ee). In comparison to a previously reported racemic route, the CD-fragment was generated in an enantiomerically pure and more efficient synthesis (14 steps, 17%, ≥ 95% ee). Key steps for the synthesis include an investigation of an assymmetric Sharpless dihydroxylation and a subsequent substrate-controlled selective reduction.
The coupling of the two fragments was envisigned via an halogen-metal-exchange of the CD-fragment (lithium or magnesium species) followed by an intermolecular nucleophilic addition to the A-fragment. The structure of the quinone motif should be implemented on a second, intramolecular bond formation via a Friedel-Crafts acylation. The discribed coupling strategy was established on a model system, coupling the transmetalised CD-fragment to a simplified cyclic anhydride. The ring closure of such a highly functionalised system under Lewis acidic conditions can be achieved. In addition, studies on an alternative construction of the B ring were performed.
According to the conditions developed for the less complex system, the optimal conditions for coupling of the CD-fragment with the A-fragment can be transfered with a good yield and only the desired regioisomer was obtained. The transfer of the Friedel-Crafts conditions to the natural product precursor are currently under investigation.
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Dates
Created: 2011Issued: 2012-05-18Updated: 2012-06-08
Faculty
Fachbereich Chemie
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
Granaticin AFriedel-Crafts-acylationNatural product synthesisNaturstoffsyntheseGranticin A
DFG-subjects
Friedel-Crafts-Reaktion
DDC-Numbers
540
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Bachmann Janina (102080078X): Neue Konzepte zur Totalsynthese von Granaticin A. : Philipps-Universität Marburg 2012-05-18. DOI: https://doi.org/10.17192/z2012.0261.
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This item has been published with the following license: In Copyright