Total synthesis of (±)-joubertinamine from 3-(3,4-dimethoxyphenyl)- 5-bromo-2-pyrone

Article abstract of DOI:10.1021/ol071381p

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).

Full text of DOI:10.1021/ol071381p

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
ccho@hanyang.ac.kr
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

Scheme 1. Retrosynthesis
Scheme 2. Synthesis
3-(3,4-dimethoxyphenyl)-5-bromo-2-pyrone 7 with an eth-
ylene equivalent (Scheme 1). The methanolysis of the
resultant cycloadduct 6 and removal of phenylthio group
would furnish the key cyclohexene intermediate 4. Further
elaboration including one-carbon homologation would permit
rapid access to joubertinamine as well as mesembrine.
Scheme 2 summarizes our synthesis, beginning with the
C3-selective Stille coupling reaction5 of 3,5-dibromo-2-
pyrone with aryltin 9,6 which produced 3-(3,4-dimethoxy-
phenyl)-5-bromo-2-pyrone 7 in 72% yield. The Diels-Alder
cycloaddition reaction with phenyl vinyl sulfide provided
bicyclolactone 6 as a mixture of endo/exo isomers (2:1, 82%
combined yield). Although not necessary, the endo- and exo-
adduct were separated and carried individually through the
reaction sequence to facilitate the characterizations. Lactone
opening and protection of the resultant hydroxyl group as a
TBS ether afforded 11. The reduction of the ester group of
11 using LiAlH4 was accompanied by the concomitant
removal of the vinyl bromide to give 12 in 75% yield.
Subsequent removal of phenylthio group with Raney nickel
furnished 137 in 74% yield. The PCC oxidation to aldehyde
4 (Scheme 1) followed by the Wittig reaction provided enol
ether 14 in 62% overall yield. Treatment of 14 with TsOH
hydrolyzed both enol ether and TBS ether to afford aldehyde
15 (for structure, see the Supporting Information) in 92%
yield. Reductive amination with methylamine hydrochloride
furnished 1 in 60% yield after purification on neutral
alumina.8 Its structural integrity was further corroborated by
the conversion to mesembrine 2 according to the known
process.1r,9
In summary, we have devised a new efficient synthetic
route to (()-joubertinamine by utilizing the Diels-Alder
cycloaddition reaction of 3-(3,4-dimethoxyphenyl)-5-bromo-
2-pyrone (10 steps, 9.6% total yield).
(4) For a recent review and selected articles, see: (a) Kim, H. Y.; Cho,
C. G. Prog. Heterocycl. Chem. 2007, 18, 1. (b) Shin, I.-J.; Choi, E.-S.;
Cho, C.-G. Angew. Chem., Int. Ed. 2007, 46, 2303. (c) Shin, J.-T.; Hong,
S.-C.; Shin, S.; Cho, C.-G. Org. Lett. 2006, 8, 3339. (d) Ryu, K.; Cho,
Y.-S.; Cho, C.-G. Org. Lett. 2006, 8, 3343. (e) Chung, S.-I.; Seo, J.; Cho,
C.-G. J. Org. Chem. 2006, 71, 6701. (f) Shin, J.-T.; Shin, S.; Cho, C. G.
Tetrahedron Lett. 2004, 45, 5857. (g) Pang, S.-J.; Min, S.-H.; Lee, H.; Cho,
C.-G. J. Org. Chem. 2003, 68, 10191.
Acknowledgment. Financial support was provided by a
grant from Korean Science and Technology Foundation
Foundation (R01-2006-000-11283-0). N.T.T. thanks the BK
21 and Seoul Fellowships for support.
(5) Kim, W.-S.; Kim, H.-J.; Cho, C.-G. J. Am. Chem. Soc. 2003, 125,
14288.
(6) Suginomo, H.; Orito, K.; Yorita, K.; Ishikawa, M.; Shimoyama, N.;
Sasaki, T. J. Org. Chem. 1995, 60, 3052.
(7) The isolated exo-adduct was subjected to the same reaction sequence
to provide 13 in a similar overall yield.
Supporting Information Available: Details of experi-
mental procedures and compound characterizations. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(8) Protonated joubertinamine as an ammonium salt was obtained with
silica gel column chromatography (different 1H NMR pattern but identical
HRMS data, when compared to 1).
1
(9) The H NMR spectrum of 2 matched the literature values.
OL071381P
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Org. Lett., Vol. 9, No. 17, 2007