Neue Konzepte zur Totalsynthese von Granaticin A

Im Rahmen dieser Arbeit wurde ein stereokontrollierter, konvergenter und modularer Syntheseweg zum Aufbau des Naturstoffes Granaticin A untersucht. Granaticin A, ein aus verschiedenen Streptomyceten isoliertes Pyronaphthochinon, zeigt Antitumoraktivität an KB Zellen als auch bei P-388 lymphatischer...

Full description

Saved in:
Bibliographic Details
Main Author: Bachmann Janina
Contributors: Koert Ulrich (Prof. Dr. ) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2011
Online Access:PDF Full Text
Tags: Add Tag
No Tags, Be the first to tag this record!

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.