FROST4 October 16-18, 2013
PARTIAL ALKYNE REDUCTION IN FLOW: ADAPTATION OF
THE LINDLAR PROTOCOL PROMPTED BY A FLOW SYNTHESIS
OF COMBRETASTATIN A-4
Laurent De Backer, Eduard Dolušić, Stéphane Collin and Steve Lanners
Namur Medicine & Drug Innovation Center (NAMEDIC), Namur Research Institute for Life Sciences (NARILIS), Laboratory of Synthetic Organic Chemistry, University of Namur, B-5000 Namur, Belgium
Keywords: Lindlar reduction, combretastatin A-4
Combretastatin A-4 (1) is a natural product isolated from the South African bushwillow tree Combretum caffrum and endowed with a powerful inhibitory activity on microtubule formation as well as a related antiangiogenic activity.1-3 As such, 1 has a strong potential in the anticancer therapy. A lot of effort has been done on the development of new derivatives of this compound, in order to improve the properties such as solubility and stability and to understand the structure-activity relationships around this series.4-7 Our group has recently turned its attention to developing a synthetic procedure for combretastatin A-4 performed entirely in flow, which should enable continuous production of this useful compound and its derivatives in significant quantities. The full results of this work will be presented in due course.
A crucial step in this synthetic strategy is a selective semi-reduction of the triple bond of an alkyne precursor to the Z-double bond present in the final product. The Lindlar-type hydrogenation in flow has been described only scarcely and for products more stable than
Z-stilbenes.8 We therefore set out to explore the applicability of this technique within our synthetic procedure and also decided to expand it to a wider range of structurally various alkynes. The experimental conditions have been varied according to the general scheme below and the - rather promising - results are shown in the poster.
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References
1. Lin, C. M., et al. Mol Pharmacol 1988, 34, 200. 2. Holt, H., et al. Top. Heterocycl. Chem. 2006, 11, 465. 3. Kerr, D. J., et al. Bioorg. Med. Chem. 2007, 15, 3290. 4. Marrelli, M., et al. Curr Med Chem 2011, 18, 3035. 5. Shan, Y., et al. Curr. Med. Chem. 2011, 18, 523.
6. Spatafora, C., et al. Anticancer Agents Med Chem 2012, 12, 902.
7. Mikstacka, R., et al. Cell Mol Biol Lett 2013, doi: 10.2478/s11658-013-0094-z 8. Chandrasekhar, S., et al. Tet Lett 2011, 52, 3865.
