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15. The lowest energy conformation of 11 was compared to
the crystal structure of (Overall RMS of over-
1
˚
lay = 0.61 A) utilizing Chem3D Ultra (v.10.0), available
from CambridgeSoft Inc., 100 CambridgePark Drive,
Cambridge, MA 02140 USA. The X-ray structure of
(ꢀ)-cytisine was retrieved from: Freer, A. A.; Robins, D.
J.; Sheldrake, G. N. Acta Cryst. 1987, C43, 1119.
16. Made by the method of Cossy, J.; Pete, J.-P. Bull. Soc.
Chim. Fr. 1979, 559.
17. Available from the Aldrich Chemical Company, Cat #
42,069-7.
18. Compound 7 is oxidatively unstable, converting com-
pletely to the pyrrole over several days when exposed to
air.
19. The assays were conducted according to the protocols in
the supplementary information in Ref. 11.
20. General procedure for the pyridone cyclizations: To a 35-
mL round-bottom flask was added 6-methoxypyridine
substrate (either 9 or 14). The mixture was cooled to 0 °C
and treated with N,N-diisopropylethylamine (4 equiv),
followed by the addition of methansulfonyl chloride
(1.5 equiv). The reaction mixture was stirred at 0 °C for
1 h, then allowed to warm to room temperature. The
reaction mixture was stirred at room temperature for 16 h
then was partitioned between sodium bicarbonate and
dichloromethane. The crude reaction mixture was dried
with magnesium sulfate, and the solvent was evaporated.
Flash chromatography was performed on silica gel using
with 2.5–10% methanol/ethyl acetate to yield the pyridone
(10: 64% yield; 1H NMR (CDCl3, 400 MHz) 7.3 (dd, 1H),
7.25 to 7.17 (m, 5H), 6.35 (d, J = 9.1 Hz, 1H), 6.00 (d,
J = 7.1 Hz, 1H), 4.29 (dd, J = 9.1 Hz, J = 13.3 Hz, 1 H),
3.95 (dd, 1H), 3.78 (t, J = 7.9 Hz, 1H), 3.60 (d,
J = 12.9 Hz, 1H), 3.48 (d, J = 12.9 Hz, 1H), 3.02 (m,
1H), 3.54 (d, J = 9.1 Hz, 1H), 2.66 (t, 2H), 2.50 (t, 1H)
ppm; mass spectrum (APCI) m/e 267 p + 1) (15: 82% yield;
1H NMR (CDCl3, 400 MHz) 7.51 (t, 1H), 6.35 (t, 1H),
6.39 (d, J = 8.7 Hz, 1H), 4.23(d, J = 6.6 Hz, 2H), 3.90 to
3.82 (m, 2H), 3.65 to 3.53 (m, 2H), 1.49 (d, J = 5.8 Hz,
1H), 1.45 (s, 9H), 1.32 (d, J = 5.8 Hz, 1H) ppm. Mass
spectrum (APCI) m/e 289 p + 1).
14. For aromatic analogs of the pyridone ring, see: (a) Coe, J.
W.; Vetelino, M. G.; Bashore, C. G.; Wirtz, M. C.;
Brooks, P. R.; Arnold, E. P.; Lebel, L. A.; Fox, C. B.;
Sands, S. B.; Davis, T. I.; Schulz, D. W.; Rollema, H.;
Tingley, F. D.; O’Neill, B. T. Bioorg. Med. Chem. Lett
2005, 15, 2974; A very interesting N ! C acyl migration
on (ꢀ)-cytisine has been reported: (b) Rouden, J.; Ragot,
A.; Gouault, S.; Cahard, D.; Plaquevent, J.-C.; Lasne, M.-
C. Tetrahedron: Asymmetry 2002, 13, 1299.