L.-J. Gao et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1909–1912
1911
Table 1. pK
i
values at cloned CHO cells expressing hM
muscarine receptorsa
4
1
, hM
2
, hM
3
Gibson, V. A.; McKinney, M. J. Pharmacol. Exp. Ther. 1992,
263, 663.
or hM
4
2
. (a) Coyle, J. T.; Price, D. L.; DeLong, M. R. Science 1983,
19, 1184. (b) Mash, D. C.; Flynn, D. D.; Potter, L. T. Science
hM
1
hM
2
hM
3
hM
4
1b
1985, 228, 1115. (c) Corey, G. J.; Billard, W.; Binch, H.;
Cohen-Williams, M.; Crosby, G.; Grzelak, M.; Guzik, H.;
Kozlowski, J. A.; Lowe, D. B.; Pond, A. J.; Tedesco, R. P.;
Watkins, R. W.; Coffin, V. L. Eur. J. Pharmacol. 2001, 431,
189.
6.97
5.76
6.37
6.80
5.59
5.63
6.24
5.27
5.49
5.49
8.00
6.77
7.02
8.33
6.07
6.17
5.77
5.94
5.93
6.51
7.03
5.68
5.79
6.98
6.10
6.17
5.62
5.30
4.96
5.48
7.96
6.21
6.76
8.06
6.10
6.00
5.82
5.76
5.71
6.05
3
3
3
4
4
4
5
5
5
a
b
c
a
b
c
a
b
c
5. (a) Peralta, E. G.; Ashkenazi, A.; Winslow, J. W.; Smith,
D. H.; Ramachandran, J.; Capon, D. J. EMBO J. 1987, 6,
3
923. (b) Bonner, T. I.; Buckley, N. J.; Young, A. C.; Brann,
M. R. Science 1987, 237, 527.
. Dorje, F.; Wess, J.; Lambrecht, G.; Tacke, R.; Mutschler,
E.; Brann, M. R. J. Pharmacol. Exp. Ther. 1991, 256, 727.
. (a) Kozikowski, A. P.; Fauq, A. H.; Muller, J. H.;
6
apK
values since the distribution of the K
i
values, Àlog (K
i
, concentration units), are preferred over K
values is log-normal; the calcu-
i
7
i
lated SEM values vary between Æ0.01 and Æ0.35.
McKinney, M. Bioorg. Med. Chem. Lett. 1992, 2, 797.
(b) Malaska, M. J.; Fauq, A. H.; Kozikowski, A. P.; Aagaard,
P. J.; McKinney, M. Bioorg. Med. Chem. Lett. 1993, 3,
b
Results obtained at human cloned muscarinic receptors but with
slightly different incubation conditions compared to this work (25 mM
ꢀ
sodium phosphate, 5 mM MgCl
2
, 23 C); see ref 6.
1
247. (c) Malaska, M. J.; Fauq, A. H.; Kozikowski, A. P.;
Aagaard, P. J.; McKinney, M. Bioorg. Med. Chem. Lett. 1995,
, 61.
5
Acknowledgements
8. Doller, D.; Chackalamannil, S.; Czarniecki, M.; McQuade,
R.; Ruperto, V. Bioorg. Med. Chem. Lett. 1999, 9, 901.
9
. For a lead structure with high potency and selectivity, see:
The ‘F.W.O.’ (3G005198) and the ‘Fonds de la
Recherche Scientifique Medicale’ (3.4504.99) are
´
thanked for financial assistance. M.W. thanks Dr. N. J.
Buckley (University of Leeds, UK) for the generous gift
of the stably transferred CHO cells lines. Hilde Van
Dingenen is thanked for some synthetic assistance.
Wang, J.; Chackalamannil, L. S.; Chang, W.; Greenlee, W.;
Ruperto, V.; Duffy, R. A.; McQuade, R.; Lachowicz, J. E.
Bioorg. Med. Chem. Lett. 2001, 11, 891.
1
0. For a previous account on the synthesis of N-Boc pro-
tected intermediates 8a, 8b, 8c and 9a, 9b, 9c, see ref 2d.
1. In the case of 8c, however, the semi-hydrogenation led to
1
a mixture of 10c (70%) and a derivative in which the double
bond had migrated to the trisubstituted C-4, C-11 position
with unknown configuration (30%).
References and Notes
1
2. Crystallographic data for 10a have been deposited with
1. Ritchie, E.; Taylor, W. C. The Galbulimima Alkaloids;
Manske, R. H. F., Ed.; In The Alkaloids; Academic: New
York, 1967; Vol. 9, p 529.
the Cambridge Crystallographic Data Centre as supplemen-
tary publication no. CCDC-180278.
ꢀ
13. Analytical and spectroscopic data, for 3a: mp 114 C
(recrystallization from MeOH). a =+36.5 (c 0.965, CHCl ).
2
. (a) For the total synthesis of himbacine, see: Hart, D. J.;
Wu, W.-L.; Kozikowski, A. P. J. Am. Chem. Soc. 1995, 117,
369. Also see: Hart, D. J.; Li, J.; Wu, W. L.; Kozikowski,
D
À1
3
1
IR (KBr): 2931, 1764, 1146 cm
.
H NMR (500 MHz,
9
CDCl ): d 1.02 (d, J=6.4 Hz, 3H), 1.27 (d, J=6.5 Hz, 3H),
3
A. P. J. Org. Chem. 1997, 62, 5023. (b) Chackalamannil, S.;
Davies, R. J.; Asberom, T.; Doller, D.; Leone, D. J. Am.
Chem. Soc. 1996, 118, 9812. Also see: Chackalamannil, S.;
Davies, R. J.; Wang, Y.; Asberom, T.; Doller, D.; Wong, J.;
Leone, D.; McPhail, A. T. J. Org. Chem. 1999, 64, 1932. (c)
Takadoi, M.; Katoh, T.; Ishiwata, A.; Terashima, S. Tetra-
hedron Lett. 1999, 40, 3399. (d) Hofman, S.; Gao, L.-J.; Van
Dingenen, H.; Hosten, N. G. C.; Van Haver, D.; De Clercq,
P. J.; Milanesio, M.; Viterbo, D. Eur. J. Org. Chem. 2001,
1.19–1.90 (m, 18H), 2.08 (d, J=14.4 Hz, 1H), 2.17 (q,
J=9.9 Hz, 1H), 2.23 (s, 3H), 2.92 (m, 2H), 3.13 (m, 1H), 4.47
(q, J=6.5 Hz, 1H), 5.16 (dd, J=15.3, 9.9 Hz, 1H), 5.67 (dd,
1
3
J=15.3, 8.9 Hz, 1H) ppm.
C NMR/DEPT (50 MHz,
CDCl ): d 15.7 (CH ), 19.2 (CH ), 19.4 (CH ), 19.6 (CH ),
3
3
2
3
2
26.4 (CH
2
), 27.2 (CH
2
), 28.0 (CH
2
), 28.8 (CH
2
), 32.9 (CH
2
),
2
33.6 (CH ), 34.8 (CH), 35.3 (CH), 37.4 (CH), 39.5 (CH), 40.7
(CH ), 45.8 (CH), 53.2 (CH), 61.7 (CH), 78.7 (CH), 133.1
3
+
(CH), 133.8 (CH), 179.0 (C) ppm. MS m/z (%): 345 (12) [M ],
330 (100), 302 (2), 274 (1), 248 (2), 232 (2), 182 (2), 161 (2), 138
(35), 112 (95), 91 (40), 68 (60), 55 (70), 41 (60). For 3b: mp
2
851. (e) For early studies directed toward the total synthesis
of himbacine, see: De Baecke, G.; De Clercq, P. J. Tetrahedron
Lett. 1995, 36, 7515. Also see: Hofman, S.; De Baecke, G.;
Kenda, B.; De Clercq, P. J. Synthesis 1998, 479. (f) Baldwin,
J. E.; Chesworth, R.; Parker, J. S.; Russell, T. Tetrahedron
Lett. 1995, 36, 9551. For a total synthesis of himandravine,
see: Chackalamannil, S.; Davies, R.; McPhail, A. T. Org. Lett.
ꢀ
145 C (recrystallization from MeOH). a
=À17.1 (c 0.631,
H NMR (500 MHz,
3
): d 1.01 (d, J=6.5 Hz, 3H), 1.39 (d, J=6.8 Hz, 3H),
D
À1
1
CHCl ). IR (KBr): 2926, 1771 cm
CDCl
.
3
1.05–1.90 (m, 17H), 2.09 (m, 1H), 2.19 (m, 1H), 2.23 (s, 3H),
2.48 (dt, J=9.4, 11.0 Hz, 1H), 2.68 (td, J=7.5, 1.6 Hz, 1H),
2.84 (m, 1H), 3.08 (m, 1H), 4.51 (qd, J=6.8, 4.8 Hz, 1H), 5.18
(dd, J=15.5, 9.0 Hz, 1H), 5.60 (dd, J=15.5, 8.9 Hz, 1H)
2
3
001, 3, 1427.
. (a) Gilani, S. A. H.; Cobbin, L. B. Naunyn-Schmiedeberg’s
1
3
Arch. Pharmacol. 1986, 332, 16. (b) Choo, L. K.; Mitchelson,
F. J. Pharm. Pharmacol. 1988, 40, 288. (c) Wang, J.-X.;
Roeske, W. R.; Wang, W.; Yamamura, H. Y. Brain Res. 1988,
3 3
ppm. C NMR/DEPT (50 MHz, CDCl ): d 14.2 (CH ), 18.0
(CH ), 18.9 (CH ), 19.7 (CH ), 26.7 (CH ), 27.1 (CH ), 28.3
(CH
3
2
2
2
2
2
), 28.5 (CH
2
), 32.6 (CH
), 33.2 (CH ), 33.7 (CH), 35.1
2 2
4
Dubuque, L. K.; Whiting, R. L. Br. J. Pharmacol. 1988, 95,
46, 155. (d) Eglen, R. M.; Montgomery, W. W.; Dainty, I. A.;
3
(CH), 38.2 (CH), 40.1 (CH), 41.2 (CH ), 44.6 (CH), 53.5 (CH),
61.5 (CH), 79.1 (CH), 133.8 (CH), 135.0 (CH), 179.1 (C) ppm.
+
1
9
031. (e) Lazareno, S.; Roberts, F. F. Br. J. Pharmacol. 1989,
8, 309. (f) Darroch, S. A.; Taylor, W. C.; Choo, L. K.;
MS m/z (%): 345 (6) [M ], 330 (70), 302 (3), 274 (1), 246 (1),
227 (2), 192 (2), 161 (2), 138 (40), 112 (100), 91 (48), 77 (60), 68
ꢀ
Mitchelson, F. Eur. J. Pharmacol. 1990, 182, 131. (g) Wael-
broeck, M.; Tastenoy, M.; Camus, J.; Christophe, J. Mol.
Pharmacol. 1990, 38, 267. (h) Miller, J. H.; Aagaard, P. J.;
(60), 55 (50), 41 (70). For 3c: mp 131 C (recrystallization from
MeOH). a =+51.4 (c 1.47, CHCl ). IR (KBr): 2933, 1785,
D
3
À1
1
1190 cm . H NMR (500 MHz, CDCl ): d 0.74 (m, 1H), 1.00
3