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KIRSCHNING GROUP

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Latest publications

J. Hartwig, A. Kirschning:

Flow Synthesis in Hot Water: Synthesis of the Atypical Antipsychotic Iloperidone

Chem. Eur. J.  2016, 22, 3044-3052.

janantipsychotic350.jpgInductively heated steel reactors continuously perform organic transformations in water under high temperature conditions, utilizing the unique physiochemical properties of water at subcritical conditions. We demonstrated the power of this set-up in the continuous synthesis of the atypical antipsychotic drug iloperidone, in which we performed four out of five steps under aqueous conditions.

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T. J. Pfeffer, F. Sasse, C. F. Schmidt, S. Lakämper, A. Kirschning, T. Scholz:

The natural diterpene tonantzitlolone A and its synthetic enantiomer inhibit cell proliferation and kinesin-5 function

Eur. J. Med. Chem. 2016, 113, 164-170.

tonantzitlolone-homepage-teaser-352.jpgTonantzitlolone A, a diterpene isolated from the Mexican plant Stillingia sanguinolenta, shows cytostatic activity. Both the natural product tonantzitlolone A and its synthetic enantiomer induce monoastral spindle formation in cell experiments which indicates inhibitory activity on kinesin-5 mitotic motor molecules. These inhibitory effects on kinesin-5 could be verified in in vitro single-molecule motility assays, where both tonantzitlolones interfered with kinesin-5 binding to its cellular interaction partner microtubules in a concentration-dependent manner, yet with a larger effect of the synthetic enantiomer. In contrast to kinesin-5 inhibition, both tonantzitlolone A enantiomers did not affect conventional kinesin-1 function; hence tonantzitlolones are not unspecific kinesin inhibitors. The observed stronger inhibitory effect of the synthetic enantiomer demonstrates the possibility to enhance the overall moderate anti-proliferative effect of the lead compound tonantzitlolon A by chemical modification.

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I. Bulyszko, G. Dräger, A. Klenge, A. Kirschning:

Evaluation of the Synthetic Potential of an AHBA Knockout Mutant of the Rifamycin Producer Amycolatopsis mediterranei

Chem. Eur. J. 2015, 21, 19231-19242.

ilona.jpgSupplementing an AHBA(−) mutant strain of Amycolatopsis mediterranei, the rifamycin producer, with a series of benzoic acid derivatives yielded new tetraketides containing different phenyl groups. These mutasynthetic studies revealed unique reductive properties of A. mediterranei towards nitro- and azidoarenes, leading to the corresponding anilines. In selected cases, the yields of mutaproducts (fermentation products isolated after feeding bacteria with chemically prepared analogs of natural building blocks) obtained are in a range (up to 118 mg L−1) that renders them useful as chiral building blocks for further synthetic endeavors. The configuration of the stereogenic centers at C6 and C7 was determined to be 6R,7S for one representative tetraketide. Importantly, processing beyond the tetraketide stage is not always blocked when the formation of the bicyclic naphthalene precursor cannot occur. This was proven by formation of a bromo undecaketide, an observation that has implications regarding the evolutionary development of rifamycin biosynthesis.

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A. Kirschning, F. Gille, M. Wolling:

Brook Rearrangement as the Key Step in Domino Reactions

Applications of Domino Transformations in Organic Synthesis Vol. 1 (Science of Synthesis), Georg Thieme Verlag Stuttgart•New-York, 2015, 355-448.

brook-umlagerung-350.jpgThe Brook rearrangement has lost its Cinderella status over the past twenty years since being embedded into cascade reaction sequences. The powerful formation of carbanions through silyl migration has been exploited for the development of many new methodol- ogies and has been used as a key transformation in complex natural product syntheses. Now, the Brook rearrangement belongs to the common repertoire of synthetic organic chemists. 

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