4864
identical anticholinesterase activity (with IC50, concentration required to inhibit 50% enzyme
action, values for BChE and AChE being 1.0 and 110 nM, respectively).
References
1. Guillozet, A.; Smiley, J. F.; Mash, D. C.; Mesulam, M. M. Ann. Neurol. 1997, 42, 909±918.
2. Barber, K. L.; Mesular, M. M.; Kraft, G. A.; Klein, W. L. Proc. Soc. Neurosci. 1996, 22, 1172.
3. Lehman, D. J.; Johnston, C.; Smith, A. D. Hum. Mol. Genet. 1997, 6, 1933±1936.
4. Yu, Q. S.; Holloway, H. W.; Utsuki, T.; Brossi, A.; Greig, N. H. J. Med. Chem. 1999, 42, 1855±1861.
5. Pei, X. F.; Yu, Q. S.; Lu, B. Y.; Greig, N. H.; Brossi, A. Heterocycles 1996, 42, 229±236.
6. Yu, Q. S.; Greig, N. H.; Holloway, H. W.; Brossi, A. J. Med. Chem. 1998, 41, 2371±2379.
7. Yu, Q. S.; Pei, X. F.; Holloway, H. W.; Greig, N. H.; Brossi, A. J. Med. Chem. 1997, 40, 2895±2901.
8. Yu, Q. S.; Schonenberger, B.; Brossi, A. Heterocycles 1987, 26, 1271±1275.
9. Pei, X. F.; Greig, N. H.; Flippen-Anderson, J. L.; Bi, S.; Brossi, A. Helv. Chim. Acta 1994, 77, 1412±1422.
10. He, X. S.; Greig, N. H.; Rapoport, S.; Brossi, A. Med. Chem. Res. 1992, 2, 229±237.
11. Pei, X. F.; Greig, N. H.; Bi, S.; Brossi, A.; Toome, V. Med. Chem. Res. 1995, 5, 455±461.
12. Takano, S.; Moriya, M.; Iwabuchi, Y.; Ogasawara, K. Chem. Lett. 1990, 109±112.
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13. Compound 5 (pale brown crystal): mp 88±92ꢀC; ꢀD =^42.2 (c=0.102, CH2Cl2); H NMR (300 MHz, CDCl3):
1.35 (s, 1/3 3H, C3a-CH3), 1.41 (s, 2/3 3H, C3a-CH3), 1.91±2.04 (m, 2H, H-3), 2.40±2.75 (m, 2H, H-2), 3.74 (s, 3H,
O-CH3), 3.85±4.15 (m, 2H, CH2Ph), 4.86 (s, 2/3H, H-8a), 5.22 (s, 1/3 H, H-8a), 6.61±6.71 (m, 2H), 8.12 (s, 2/3H,
N-CHO), 8.82 (s, 1/3H, N-CHO); HRMS: calcd: 322.1681 (M+), found: 322.1679.
1
14. Corey, E. J.; Balanson, R. D. J. Am. Chem. Soc. 1974, 96, 6516±6517.
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1
15. Compound 6 (pale yellow syrup): ꢀD =^201.4 (c=0.209, CH2Cl2); H NMR (300 MHz, CDCl3): 1.32 (s, 3H,
C3a-CH3), 1.63±1.71 (m, 1H, H-3a), 1.85±1.96 (m, 1H, H-3b), 2.20±2.31 (m, 1H, H-2a), 2.15±2.24 (m, 1H, H-2b),
3.80 (d, J=13.4 Hz, 1H, N-CH2Ph), 4.21 (d, J=13.4 Hz, 1H, N-CH2Ph), 5.02 (s, 1H, H-8a), 6.12 (d, J=1.7 Hz,
1H, H-4), 6.54 (dd, J=1.7, 20 Hz, 1H, H-6); 13C NMR (75 MHz, CDCl3): 23.30, 39.79, 49.70, 50.90, 54.42, 101.47,
121.65, 126.91, 128.19 (2C), 128.51 (2C), 133.37, 135.59, 138.85, 160.84, 165.63, 167.87; UV (CH2Cl2): lmax=268
nm, lmax=330 nm; HRMS: calcd: 278.1419 (M+), found: 278.1421.
22
1
16. Compound 7 (foam): ꢀD =^224.1 (c=0.054, CH2Cl2); H NMR (300 MHz, CDCl3): 1.39 (s, C3a-CH3), 1.86±
1.94 (m, 2H, H-3), 2.58±2.73 (m, 2H, H-2), 3.71±3.84 (m, 2H, CH2Ph), 4.46 (s, 1H, H-8a), 6.40±6.53 (m, 3H, H-4,
H-6 and H-7); HRMS: calcd: 280.1576 (aM+), found: 280.1578.
1
17. Compound 8 (syrup): H NMR (300 MHz, CDCl3): 1.40 (s, 1/3 3H, C3a-CH3), 1.45 (s, 2/3 3H, C3a-CH3), 1.91±
2.04 (m, 2H, H-3), 2.40±2.75 (m, 2H, H-2), 3.85±4.21 (m, 2H, CH2Ph), 4.92 (s, 2/3H, H-8a), 5.34 (s, 1/3H, H-8a),
6.61±6.71 (m, 2H), 8.20 (s, 2/3H, N-CHO), 8.89 (s, 1/3H, N-CHO).
22
1
18. Compound 9 (foam): ꢀD =^157.3 (c=0.066, CH2Cl2); H NMR (300 MHz, CDCl3): 1.25 (d, J=6.8 Hz, 6H,
(CH3)2CH), 1.46 (s, 3H, C3a-CH3), 1.98±2.11 (m, 2H, H-3), 2.70±2.98 (m, 3H, H-2 and CHMe2), 3.80±3.90 (m,
2H, CH2Ph), 4.54 (s, 1H, H-8a), 6.50±6.90 (m, 2H); HRMS: calcd: 441.2416 (M+), found: 441.2418. Fumarate of
compound 9: white crystal, mp 137±139ꢀC.