Abstract
The pyrrole-derived alkaloids with marine origin, especially their permethyl derivatives, have unique structures and promising biological activities. Marine natural product neolamellarins are a collection of lamellarin-like phenolic pyrrole compounds, which can inhibit hypoxia-induced HIF-1 activation. Many pyrrole-derived lamellarin-like alkaloids show potent MDR reversing activity. In this study, five permethylated derivatives of neolamellarin A were synthesized with their MDR reversing activity studied in order to identify new MDR reversal agents. A convergent strategy was adopted to synthesize the permethylated derivatives of neolamellarin A. Pyrrole was first converted into a corresponding N-trisisopropylsilyl (TIPS)-substituted derivative, then through iodination afforded 3,4-diiodinated pyrrole compound. The key intermediate, 3,4-disubstituent-1H-pyrrole, was obtained through desilylation of 3,4-disubstituent-1-TIPS pyrrole, which was prepared from 3,4-diiodinated pyrrole derivative and aryl boronic acid ester through Suzuki cross-coupling reaction between them. Then, the intermediate, 3,4-disubstituent-1H-pyrrole, reacted with fresh phenylacetyl chloride under n-BuLi/THF condition afforded the target compounds. Finally, we obtained five novel pyrrolic compounds, permethylated derivatives of neolamellarin A 16a–e, in 30%–37% yield through five step reactions. The bioactivity testing of these compounds are in process.
Similar content being viewed by others
References
Arafeh, K. M., and Ullah, N., 2009. Synthesis of neolamellarin A, an inhibitor of hypoxia-inducible factor-1. Natural Product Communication, 4(7): 925–926.
Axford, L. C., Holden, K. E., Hasse, K., Banwell, M. G., Steglich, W., Wagler, J., and Willis, A. C., 2008. Attempts to mimic key bond-forming events associated with the proposed biogenesis of the pentacyclic lamellarins. Australian Journal of Chemistry, 61(2): 80–93.
Banwell, M. G., Bray, A. M., Edwards, A. J., and Wong, D. J., 2002. Rapid and convergent assembly of the polycyclic framework assigned to the cytotoxic marine alkaloid halitulin. Journal of the Chemical Society, Perkin Transactions 1, 1(11): 1340–1343.
Banwell, M. G., Flynn, B. L., Hamel, E., and Hockless, D. C. R., 1997. Convergent syntheses of the pyrrolic marine natural products lamellarin-O,lamellarin-Q, lukianol-A and some more highly oxygenated congeners. Chemical Communications, 1(2): 207–208.
Boger, D. L., Boyce, C. W., Labroli, M. A., Sehon, C. A., and Jin, Q., 1999. Total syntheses of ningalin A, lamellarin O, lukianol A, and permethyl storniamide A utilizing heterocyclic azadiene Diels-Alder reactions. Journal of the American Chemical Society, 121(1): 54–62.
Boger, D. L., Soenen, D. R., Boyce, C. W., Hedrick, M. P., and Jin, Q., 2000. Total synthesis of ningalin B utilizing a heterocyclic azadiene Diels-Alder reaction and discovery of a new class of potent multidrug resistant (MDR) reversal agents. Journal of Organic Chemistry, 65(8): 2479–2483.
Bray, B. L., Mathies, P. H., Naef, R., Solas, D. R., Tidwell, T. T., and Artis, D. R., 1990. N-(Triisopropylsily1) pyrrole. A progenitor ‘par excellence’ of 3-substituted pyrroles. Journal of Organic Chemistry, 55(28): 6317–6328.
Fan, H., Peng, J., Hamann, M. T., and Hu, J. F., 2008. Lamellarins and related pyrrole-derived alkaloids from marine organisms. Chemical. Reviews, 108(1): 264–287.
Furstner, A., Krause, H., and Thiel, O. R., 2002. Efficient relay syntheses and assessment of the DNA-cleaving properties of pyrrole alkaloid derivatives permethyl sterniamide A, lycogalic acid A dimethyl ester, and the halitulin core. Tetrahedron, 58(32): 6373–6380.
He, Z., and Yudin, A. K., 2011. Amphoteric α-boryl aldehydes. Journal of the American Chemical Society, 133(35): 13770–13773.
Kang, H., and Fenical, W., 1997. Ningalins A-D: Novel aromatic alkaloids from a Western Australian ascidian of the genus Didemnum. Journal of Organic Chemistry, 62(10): 3254–3262.
Li, Q., Jiang, J., Fan, A., Cui, Y., and Jia, Y., 2011. Total synthesis of lamellarins D, H, and R and ningalin B. Organic Letter, 13(2): 312–315.
Liu, R., Liu, Y., Zhou, Y. D., and Nagle, D. G., 2007. Molecular-targeted antitumor agents. 15. Neolamellarins from the marine sponge Dendrilla nigra inhibit hypoxia-inducible factor-1 activation and secreted vascular endothelial growth factor production in breast tumor cells. Journal of Natural Products, 70(11): 1741–1745.
Menna, M., 2014. Important classes of bioactive alkaloids from marine ascidians: Structures, isolation and bioactivity. Current Topics in Medicinal Chemistry, 14(2): 207–223.
Milgram, B. C., Eskildsen, K., Richter, S. M., Scheidt, W. R., and Scheidt, K. A., 2007. Microwave-assisted piloty-robinson synthesis of 3,4-disubstituted pyrroles. Journal of Organic Chemistry, 72(10): 3941–3944.
Urban, S., Butler, M. S., and Capon, R. J., 1994. Lamellarins O and P: New aromatic metabolites from the Australian marine sponge Dendrilla cactos. Australian Journal of Chemistry, 47(10): 1919–1924.
Yin, R. J., Jiang, L., Wan, S. B., and Jiang, T., 2014. Recent progress in the research on lamellarin o and related pyrrole-derived alkaloids from marine organisms. Zhongguo Haiyang Yaowu, 33(1): 75–82.
Yuan, X., Xu, X., Zhou, X., Yuan, J., Mai, L., and Li, Y., 2007. Copper-catalyzed double N-alkenylation of amides: An efficient synthesis of di- or trisubstituted N-acylpyrroles. Journal of Organic Chemistry, 72(4): 1510–1513.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yin, R., Jiang, L., Wan, S. et al. Efficient syntheses of permethylated derivatives of neolamellarin A, a pyrrolic marine natural product. J. Ocean Univ. China 14, 329–334 (2015). https://doi.org/10.1007/s11802-015-2372-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11802-015-2372-z