Synthesis, iron(II)-induced cleavage and in vivo antimalarial efficacy of 10-(2-hydroxy-1-naphthyl)-deoxoqinghaosu (-deoxoartemisinin)

Abstract

A convenient methodology for attaching an acid-stable UV chromophore onto the qinghaosu (artemisinin) framework with readily available dihydroqinghaosu acetate as the starting material is presented. The resulting derivatives of deoxoqinghaosu may be used as a sensitive probe in the mechanistic and biological/pharmacological investigations. As the first application of the present methodology, naphth-2-ol is attached to qinghaosu nucleus through a carbon–carbon single bond by a boron trifluoride-catalyzed Friedel–Crafts alkylation. A previously undetected racemization at C-9 mediated by an enol ether under the reaction conditions (BF₃·OEt₂, CH₂Cl₂) that have been widely used for preparing C-10 derivatives of dihydroqinghaosu is observed. The knowledge gained from the present work may assist the rational design of new trioxane-type antimalarial agents.

References

1. J.-M. Liu, M.-Y. Ni, J.-F. Fan, Y.-Y. Tu, Z.-H. Wu, Y.-L. Wu and W.-S. Chou, Acta Chim. Sin., 1979, 37, 129(in Chinese)(Chem. Abstr., 1980, 92, 94594w).
2. China Cooperative Research Group, J. Trad. Chin. Med., 1982, 2, 17(in Chinese).
3. Y.-L. Wu and Y. Li, Med. Chem. Res., 1995, 5, 569.
4. W.-M. Wu, Z.-J. Yao, Y.-L. Wu, K. Jiang, Y.-F. Wang, H.-B. Chen, F. Shan and Y. Li, Chem. Commun., 1996, 2213.
5. W.-M. Wu, Y.-K. Wu, Y.-L. Wu, Z.-J. Yao, C.-M. Zhou, Y. Li and F. Shan, J. Am. Chem. Soc., 1998, 120, 3316.
6. H.-M. Gu, B.-F. Lu and Z.-X. Qu, Acta Pharmacol. Sin., 1980, 1, 48(in Chinese)(Chem. Abstr., 1981, 94, 24954f).
7. Y. Li, P.-L. Yu, Y.-X. Chen, L.-Q. Li, Y.-Z. Gai, D.-S. Wang and Y.-P. Zheng, Acta Pharm. Sin., 1981, 16, 429(in Chinese)(Chem. Abstr., 1983, 97, 92245n).
8. Posner et al. recently reported a similar Friedel–Crafts alkylation using fluoride as activated alkylating agent, see: (a) S. H. Woo, M. H. Parker, P. Polypradith, J. Northrop and G. H. Posner, Tetrahedron Lett., 1998, 39, 1533Jung and Lee also reported another access to the UV chromophore-carrying QHS derivatives, where the aromatic groups are connected to the QHS nucleus through a C–C σ bond before the 1,2,4-trioxane framework is constructed: (b) M. Jung and S. Lee, Heterocycles, 1997, 45, 1055Mai et al. reported an analogue bearing a substituent at C-10 via a C–C σ bond: (c) V. T. Mai, V. T. Nguyen and V. C. Pham, Tap Chi Hoa Hoc, 1997, 35, 11 (Chem. Abstr., 1997, 127, 190855).
9. G. H. Posner and C. H. Oh, J. Am. Chem. Soc., 1992, 114, 8328.
10. See e.g. (a) C. W. Jefford, F. Favarger, M. da G. H. Vicente and Y. Jacruier, Helv. Chim. Acta, 1995, 78, 452; (b) C. W. Jefford, M. G. H. Vicente, Y. Jacquier, F. Favarger, J. Mareda, P. Millasson-Schmidt, G. Brunner and U. Burger, Helv. Chim. Acta, 1996, 79, 1475; (c) A. J. Bloodworth and A. Shah, Tetrahedron Lett., 1995, 36, 7551; (d) G. H. Posner, J. N. Cumming, P. Ploypradith and C. H. Oh, J. Am. Chem. Soc., 1995, 117, 5885; (e) G. H. Posner, D.-S. Wang, J. N. Cumming, C. H. Oh, A. N. French, A. L. Bodley and T. A. Shapiro, J. Med. Chem., 1995, 38, 2273; (f) G. H. Posner, S. B. Park, L. Gonzalez, D.-S. Wang, J. N. Cumming, D. Klinedinst, T. A. Shapiro and M. D. Balci, J. Am. Chem. Soc., 1996, 118, 3537; (g) G. H. Posner, D.-S. Wang, L. Gonzalez, X.-L. Tao, J. N. Cumming, D. Klinedinst and T. A. Shapiro, Tetrahedron Lett., 1996, 37, 815; (h) G. H. Posner, L. Gonzalez, J. N. Cumming, D. Klinedinst and T. A. Shapiro, Tetrahedron, 1997, 53, 37; (i) G. H. Posner, C. H. Oh, D. S. Wang, L. Gerena, W. K. Milhous, S. Meshnick and W. Asawamahasadka, J. Med. Chem., 1994, 37, 1256; (j) M. A. Avery, P.-C. Fan, J. M. Karle, J. D. Bonk, R. Miller and D. K. Goins, J. Med. Chem., 1996, 39, 1885; (k) M. A. Avery, S. Mehrotra, J. D. Bonk, J. A. Vroman, D. K. Goins and R. Miller, J. Med. Chem., 1996, 39, 2900; (l) M. A. Avery, S. Mehrotra, T. L. Johnson, J. D. Bonk, J. A. Vroman and R. Miller, J. Med. Chem., 1996, 39, 4149.
11. J. N. Cumming, P. Ploypradith and G. H. Posner, Adv. Pharmacol., 1997, 37, 253 and references therein. We thank Professor Posner for a generous copy of this review.
12. For example, N. Acton, J. M. Karle and R. Miller, J. Med. Chem., 1993, 36, 2552.