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Preparation, Modification, and Evaluation of Cruentaren A and Analogues

MPG-Autoren
http://pubman.mpdl.mpg.de/cone/persons/resource/persons58429

Bindl,  Martin
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons58643

Jean,  Ludovic
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons58380

Fürstner,  Alois
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Zitation

Bindl, M., Jean, L., Herrmann, J., Müller, R., & Fürstner, A. (2009). Preparation, Modification, and Evaluation of Cruentaren A and Analogues. Chemistry – A European Journal, 15(45), 12310-12319. doi:10.1002/chem.200901817.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-000F-8F3D-8
Zusammenfassung
An expeditious total synthesis of the highly cytotoxic F-ATPase inhibitor cruentaren A (1) is described based on a ring-closing alkyne metathesis (RCAM) reaction for the formation of the macrocylic ring. Other key transformations comprise a C-acylation of the benzyl lithium reagent derived from orsellinic acid ester 9 with Weinreb amide 7, a CBS reduction of the resulting ketone 10, and a Soderquist propargylation of aldehyde 21 with allenylborane (S)-27 to set the C-15 chiral center of the required alcohol fragment 25. The RCAM precursor 33 was assembled by acylation of 25 with acid fluoride 32, since more conventional methods for ester bond formation were unproductive. Moreover, the choice of the protecting groups, in particular for the secondary alcohol at C-9, which is prone to engage in translactonization, turned out to be critical; a relatively stable TBDPS ether had to be chosen for this site, which was removed in the final step of the synthesis with aqueous HF since other fluoride sources met with failure. The successful synthetic route was then expanded beyond the natural product, bringing a series of analogues into reach that feature incremental but deep-seated structural modifications. Three of these fully synthetic compounds turned out to be as or even more cytotoxic than cruentaren A itself against L-929 mouse fibroblast cells, reaching IC50 values as low as 0.7 ng mL−1.