The group of Prof. Dr. Andreas Kirschning is focused on natural product chemistry employing means and techniques of both chemistry and biology, while another main field of research represents the development of enabling methods in organic synthesis with emphasis on microreactor technology. |
 → Latest publications S. Eichner, T. Knobloch, H. G. Floss, J. Fohrer, K. Harmrolfs, J. Hermane, A. Schulz, F. Sasse, P. Spiteller, F. Taft, A. Kirschning: T. Schmidt, Prof. Dr. A. Kirschning: S. Eichner, T. Eichner, H.G. Floss, J. Fohrer, E. Hofer, F. Sasse, C. Zeilinger, A. Kirschning: J. Wegner, S.V. Ley, A. Kirschning, A.-L. Hansen, J.M. Garcia, I.R. Baxendale: J. Wegner, S. Ceylan, A. Kirschning: J. Barbier, R. Jansen, H. Irschik, S. Benson, K. Gerth, B. Böhlendorf, G. Höfle, H. Reichenbach, J. Wegner, C. Zeilinger, A. Kirschning, R. Müller: Dr. F. Taft, Dr. K. Harmrolfs, Dr. I. Nickeleit, A. Heutling, M. Kiene, Prof. Dr. N. Malek, Dr. F. Sasse, Prof. Dr. A. Kirschning: → Cooperations
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The synthetic power of three mutant strains that produce ansamitocin and geldanamycin is combined with chemical synthesis, thus leading to 27 new ansamitocin derivatives. Structure–activity studies show that the N of the carbinolamide moiety is not important for cytotoxic activity but the α-orientation of the OH group at C9 is.
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Metals are the key players in the synthesis of caralacton, a strong inhibitor of bacterial biofilms. The total synthesis is based on several metal-mediated key transformations such as the Ley and the Duthaler–Hafner aldol reactions, the Marshall reaction and Breit's substitution, as well as the Nozaki–Hiyama–Kishi and Negishi–Fu C-C coupling reactions.
The amide synthase of the geldanamycin producer, Streptomyces hygroscopicus, shows a broader chemoselectivity than the corresponding amide synthase present in Actinosynnema pretiosum, the producer of the highly cytotoxic ansamycin antibiotics, the ansamitocins. This was demonstrated when blocked mutants of both strains incapable of biosynthesizing 3-amino-5-hydroxybenzoic acid (AHBA), the polyketide synthase starter unit of both natural products, were supplemented with 3-amino-5-hydroxymethylbenzoic acid instead. Unlike the ansamitocin producer A. pretiosum, S. hygroscopicus processed this modified starter unit not only to the expected 19-membered macrolactams but also to ring enlarged 20-membered macrolactones. The former mutaproducts revealed the sequence of transformations catalyzed by the post-PKS tailoring enzymes in geldanamycin biosynthesis. The unprecedented formation of the macrolactones together with molecular modeling studies shed light on the mode of action of the amide synthase responsible for macrocyclization. Obviously, the 3-hydroxymethyl substituent shows similar reactivity and accessibility toward C-1 of the seco-acid as the arylamino group, while phenolic hydroxyl groups lack this propensity to act as nucleophiles in the macrocyclization. The promiscuity of the amide synthase of S. hygroscopicus was further demonstrated by successful feeding of four other m-hydroxymethylbenzoic acids, leading to formation of the expected 20-membered macrocycles. Good to moderate antiproliferative activities were encountered for three of the five new geldanamycin derivatives, which matched well with a competition assay for Hsp90α.
A total synthesis of millingtonine A, a diglycosylated alkaloid, has been accomplished. Millingtonine A possesses a unique racemic tricyclic core structure not known from any other natural or synthetic source until now. The synthesis features a key bond-forming radical Ueno–Stork cyclization to form the heterocyclic core.
Laboratory scaled flow-through processes have seen an explosive development over the past decade and have become an enabling technology for improving synthetic efficiency through automation and process optimization. Practically, flow devices are a crucial link between bench chemists and process engineers. The present review focuses on two unique aspects of modern flow chemistry where substantial advantages over the corresponding batch processes have become evident. Flow chemistry being one out of several enabling technologies can ideally be combined with other enabling technologies such as energy input. This may be achieved in form of heat to create supercritical conditions. Here, indirect methods such as microwave irradiation and inductive heating have seen widespread applications. Also radiation can efficiently be used to carry out photochemical reactions in a highly practical and scalable manner. A second unique aspect of flow chemistry compared to batch chemistry is associated with the option to carry out multistep synthesis by designing a flow set-up composed of several flow reactors. Besides their role as chemical reactors these can act as elements for purification or solvent switch.
The antifungal icumazole A, the potassium-ion-channel inhibitor noricumazole A, and their glycosylated derivatives are new, structurally related secondary metabolites isolated from Sorangium cellulosum. Their structures have been fully assigned by a joint strategy that relied on spectroscopy, derivatization, fragmentation, and finally the first total synthesis of noricumazole A.
