ORGANIC
LETTERS
2007
Vol. 9, No. 17
3391-3392
Total Synthesis of (
from
±)-Joubertinamine
3-(3,4-Dimethoxyphenyl)-5-bromo-2-pyrone
Nguyen Thanh Tam and Cheon-Gyu Cho*
Department of Chemistry, Hanyang UniVersity, Seoul, Korea 133-791
Received June 12, 2007
ABSTRACT
The regioselective synthesis and Diels−Alder cycloaddition of 3-(3,4-dimethoxyphenyl)-5-bromo-2-pyrone provided a new efficient synthetic
route to joubertinamine (9.6% total yield over 10 steps).
The sceletium family of mesembrine alkaloids as well as
their seco-congeners have been the synthetic target of
considerable efforts over the past decades (Figure 1).1 Long
known to the Khoi-khoi and San peoples as a mood enhancer,
sedative, analgesic, and appetite/thirst suppressant, these
compounds have recently proven potentially useful in the
treatment of depressive states, psychological or psychiatric
disorders with an anxiety component, alcohol and drug
dependence, bulimia nervosa, and obsessive-compulsive
disorders.2
Unlike mesembrine 2, there are only a few synthetic
studies reported in the literature for joubertinamine 1,
with incomplete characterizations.1n-r,3 In connection with
(1) For the synthesis of mesembrine, see: (a) Paul, T.; Malachowski,
W. P.; Lee, J. Org. Lett. 2006, 8, 4007. (b) Taber, D. F.; He, Y. J. Org.
Chem. 2005, 70, 7711. (c) Chavan, S. P.; Khobragade, D. A.; Pathak, A.
B.; Kalkote, U. R. Tetrahedron Lett. 2004, 45, 5263. (d) Rigby, J. H.; Dong,
W. Org. Lett. 2000, 2, 1673. (e) Ogasawara, K.; Yamada, O. Tetrahedron
Lett. 1998, 39, 7747. (f) Langlois, Y.; Dalko, P. I.; Brun, V. Tetrahedron
Lett. 1998, 39, 8979. (g) Denmark, S. E.; Marcin, L. R. J. Org. Chem.
1997, 62, 1675. (h) Mori, M.; Kuroda, S.; Zhang, C.; Sato, Y. J. Org. Chem.
1997, 62, 3263. (i) Yoshimitsu, T.; Ogasawara, K. Heterocycles 1996, 42,
135. (j) Nemoto, H.; Tanabe, T.; Fukumoto, K. J. Org. Chem. 1995, 60,
6785. (k) Takano, S.; Samizu, K.; Ogasawara, K. Chem. Lett. 1990, 1239.
(l) Kosugi, H.; Miura, Y.; Kanna, H.; Uda, H. Tetrahedron: Asymmetry
1993, 4, 1409. (m) Meyers, A. I.; Hanreich, R.; Wanner, K. T. J. Am. Chem.
Soc. 1985, 107, 7776. For the synthesis of joubertinamine, see: (n) Hoshino,
O.; Ishizaki, M.; Sawaki, S.; Yuasa, M.; Umezawa, Chem. Pharm. Bull.
1988, 36, 3373. (o) Jeffs, P. W.; Redfearn, R.; Wolfram, J. J. Org. Chem.
1983, 48, 3861. (p) Sa´nchez, I. H.; Soria, J. J.; Larraza, M. I.; Flores, H. J.
Tetrahedron Lett. 1983, 24, 551. (q) Psotta, K.; Wiechers, A. Tetrahedron
Lett. 1979, 35, 255. (r) Psotta, K.; Strelow, F.; Wiechers, A. J. Chem. Soc.,
Perkin Trans. 1 1979, 1063.
Figure 1. Selected examples of sceletium alkaloids.
our recent effort exploring the synthetic utility of 3,5-
dibromo-2-pyrone,4 we envisioned that the basic carbon
skeletons, including the characteristic quarternary carbon
center of sceletium family alkaloids, could be efficiently
constructed by the Diels-Alder cycloaddition reaction of
(2) (a) Jin, Z. Nat. Prod. Rep. 2005, 22, 111. (b) Smith, M. T.; Crouch,
N.; Gericke, N.; Hirst, M. J. Ethnopharmacol. 1996, 50, 119. (c) Gericke,
N. P.; VanWyk, B.-E.; PCT Int. Appl., WO 9746234 CAN 128: 80030,
1997.
(3) No 13C NMR data were reported. One report (ref 1o) contains
1
incorrect H NMR spectral data.
10.1021/ol071381p CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/28/2007