Synthetic studies directed towards the potent cytotoxic natural product ottelione A: stereoselective construction of the complete framework

Abstract

A stereoselective strategy for the rapid acquisition of the complete framework (dideoxyottelione A) of the promising cytotoxic agent ottelione A, with four contiguous stereogenic centres on a hydrindane skeleton and a sensitive 4-methylenecyclohex-2-enone functionality, from the readily available Diels–Alder adduct of 1,2,3,4-tetrachloro-5,5-dimethoxycyclopentadiene and norbornadiene, is delineated.

References

1. S.-E. N. Ayyad, A. S. Judd, W. T. Shier and T. R. Hoye, J. Org. Chem., 1998, 63, 8102.
2. J. Leboul and J. Prevost, French Patent WO96/00205, 1996(Chem. Abstr., 1996, 124, 242296).
3. H. Li, H. Li, X. Qu, C. Zhao, Y. Shi, L. Guo and Z. Yuan, Zhongguo Zhongyao Zazhi (Chin. J. Chin. Mat. Med.), 1995, 20, 115, 128.
4. D. F. Murray, M. W. Baum and M. Jones, Jr, J. Org. Chem., 1986, 51, 1; M. E. Jung and H. L. Rayle, Synth. Commun., 1994, 24, 197; H. Wild, J. Org. Chem., 1994, 59, 2748.
5. K. Mackenzie, J. Chem. Soc., 1960, 473; R. K. McCulloch, A. R. Rye and D. Wege, Aust. J. Chem., 1974, 27, 1929.
6. All compounds were fully characterized on the basis of their spectral and analytical data. Selected data for 8: δ_H(300 MHz, CDCl₃): 7.31–7.13 (m, 5H), 6.42 (dd, 1H, J 6.9, 3.6), 6.28 (dd, 1H, J 6.9, 3.6), 5.80 (ddd, 1H, J 17.7, 10.2, 7.2), 5.02–4.92 (m, 2H), 2.96 (m, 1H), 2.81 (dd, 1H, J 13.2, 6.0), 2.58 (dd, 1H, J 13.2, 8.4), 2.47–2.27 (m, 3H), 2.04–1.95 (m, 1H), 1.80–1.63 (m, 2H), 1.27–1.16 (m, 1H); δ_C(75 MHz, CDCl₃) 203.2, 141.1, 141.0, 132.9, 132.4, 128.6 (2C), 128.4 (2C), 126.0, 113.8, 51.2, 50.4, 47.1, 47.0. 46.3, 44.7, 41.1, 40.1; m/z(70 eV, EI) 264 (M⁺). For 12: δ_H(500 MHz, CDCl₃) 7.36–7.18 (m, 5H, arom), 6.97 (d, 1H, J 10, H₆), 5.93 (d, 1H, J 10, H₅), 5.67 (ddd, 1H, J 17.2, 10.2, 8.2, H₈), 5.39 (s, 1H, H₁₁), 5.25 (s, 1H, H₁₁), 5.02 (d, 1H, J 10.2, H₉), 4.90 (d, 1H, J 17.1, H₉), 3.02 (d of quintet, 1H, J 8, 3.4, H₃), 2.94 (dd, 1H, J 15, 7.2, H₁₀), 2.78 (dd, 1H, J 10.8, 8.5, H_7a), 2.70 (dd, 1H, J 13.6, 8.7, H₁₀), 2.62 (dd, 1H, J 8.2, 3.5, H_3a), 2.30–2.23 (m, 1H, H₁), 2.03–1.97 (m, 1H, H₂), 1.25 (ddd, 1H, J 13.1, 10.5, 7.5, H₂); δ_C(75 MHz, CDCl₃) 199.7 (C quat.), 145.6 (CH), 140.5 (2C, C quat.), 140.4 (CH), 129.0 (2C, CH), 128.3 (2C, CH), 126.4 (CH), 126.0 (CH), 121.6 (CH₂), 115.9 (CH₂), 53.7 (CH), 50.1 (CH), 48.7 (CH), 42.5 (CH₂), 41.2 (CH), 37.5 (CH₂); m/z(70 eV, EI) 264 (M⁺). For 14: δ_H(500 MHz, CDCl₃) 7.26–7.10 (m, 5H, arom), 7.01 (d, 1H, J 10, H₆), 5.92 (d, 1H, J 10, H₅), 5.87 (ddd, 1H, J 17.2, 10, 7, H₈), 5.44 (s, 1H, H₁₁), 5.35 (s, 1H, H₁₁), 5.04 (d, 1H, J 17.2, H₉), 4.97 (d, 1H, J 10, H₉), 3.18–3.10 (m, 1H, H₃), 2.98 (dd, 1H, J 13.4, 4.1, H₁₀), 2.78 (t, 1H, J 8.3, H_7a), 2.70 (dd, 1H, J 7.9, 4, H_3a), 2.34 (dd, 1H, J 13.3, 10.3, H₁₀), 2.05–1.90 (m, 2H, H₁, H₂), 1.22 (ddd, 1H, J 13.1, 9.5, 7.5, H₂); δ_C(75 MHz, CDCl₃) 199.5 (C quat.), 145.6 (CH), 142.2 (CH), 141.8 (C quat.), 140.6 (C quat.), 128.7 (2C, CH), 128.3 (2C, CH), 126.5 (CH), 126.0 (CH), 121.4 (CH₂), 113.3 (CH₂), 55.1 (CH), 49.3 (CH), 46.3 (CH), 43.7 (CH), 40.5 (CH₂), 37.1 (CH₂); m/z(70 eV, EI) 264 (M⁺).