Partial alkyne reduction in flow: Adaptation of the lindlar protocol as part of a flow synthesis of combretastatin A-4

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Abstract

Combretastatin A-4 (1) is a natural product isolated from the South African bushwillow tree Combretum caffrum. It is endowed with a powerful inhibitory activity on microtubule formation as well as a related antiangiogenic activity.[1-2] As such, 1 has a strong potential in the anticancer therapy, prompting the development of new derivatives.[3-6] We have turned our attention to the design of a synthetic procedure for 1 performed entirely in flow, which should enable continuous and rapid production of this useful compound and its derivatives in significant quantities.
Presented in this poster is a crucial step in this synthetic strategy - a selective semi-reduction of the triple bond of an alkyne precursor to the Z-double bond in the final product. The Lindlar-type hydrogenation in flow has been described only scarcely and for products typically more stable than Z-stilbenes.[7] We therefore set out to explore this technique and decided to expand it to a wider range of structurally various alkynes.

References
[1] C. M. Lin, S. B. Singh, P. S. Chu, R. O. Dempcy, J. M. Schmidt, G. R. Pettit, E. Hamel, Mol. Pharmacol. 1988, 34, 200.
[2] D. J. Kerr, E. Hamel, M. K. Jung, B. L. Flynn, Bioorg. Med Chem. 2007, 15, 3290.
[3] M. Marrelli, F. Conforti, G. A. Statti, X. Cachet, S. Michel, F. Tillequin, F. Menichini, Curr. Med. Chem. 2011, 18, 3035.
[4] Y. S. Shan, J. Zhang, Z. Liu, M. Wang, Y. Dong, Curr. Med. Chem. 2011,18, 523.
[5] C. Spatafora, C. Tringali, Anticancer Agents Med. Chem. 2012, 12, 902.
[6] R. Mikstacka, T. Stefanski, J. Rozanski, Cell. Mol. Biol. Lett. 2013, 18, 368.
[7] S. Chandrasekhar, B.V.D. Vijaykumar, B. Mahesh Chandra, Ch. Raji Reddy, P. Naresh, Tet. Lett. 2011, 52, 3865.
Original languageEnglish
PagesP17
Number of pages1
Publication statusPublished - 5 Dec 2013
Event17th Sigma-Aldrich Organic Synthesis Meeting - Duinse Polders, Blankenberge, Belgium
Duration: 5 Dec 20136 Dec 2013

Symposium

Symposium17th Sigma-Aldrich Organic Synthesis Meeting
CountryBelgium
CityBlankenberge
Period5/12/136/12/13

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