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S. Ma et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3909–3911
O
OH
O
OH
OTBS
O
O
a
b
O
H
n
n
n
n
3a n = 4
3b n = 6
3c n = 8
5a n=4, 35%
5b n=6, 45%
5c n=8, 46%
7a n = 4
7b n = 6
7c n = 8
HO
(+)-(S)-[n]-Gingerols (1)
route 1
route 2
O
OH
TMSO
OTBS
c
d
O
n
n
O
O
OH
O
CHO
+
O
HO
8a n = 4
8b n = 6
8c n = 8
9a n = 4, 44% from 5a
9b n = 6, 48% from 5b
9c n = 8, 43% from 5c
n
HO
HO
5
4
+
2
O
O
O
O
OH
+
O
H
n
H
n
e
n
3
3
HO
Scheme 1. Synthetic plan of (+)-(S)-[n]-gingerols (1).
1a n = 4, 90% yield, 74% ee
1b n = 6, 86% yield, 72% ee
1c n = 8, 89% yield, 70% ee
media, the reaction gave aldehyde self-aldolization product (6) in-
stead of the desired cross aldols (Scheme 2).
Scheme 3. Synthesis of (+)-(S)-[n]-gingerols using
reaction as key step. Reagents and conditions: (a) acetone, L-proline, 30 °C, 3 d; (b)
L
-proline catalyzed cross-aldol
We thus turned our attention to the route 2. The key intermedi-
ates b-hydroxy ketones 5a–c were synthesized based on known
procedures using acetone as reagent and reaction medium in mod-
erate yields (35–46%).16 Protection of hydroxyl group of 5a–c with
TBSCl and imidazole furnished compounds 7a–c, which was trans-
formed into silyl enol ethers 8a–c by treating with TMSOTf and i-
Pr2NEt in CH2Cl2.17 The Mukaiyama reaction between compounds
8a–c and vanillin, with simultaneous removal of the TBS, was car-
ried out to afford olefins 9a–c in good yields (44%, 48%, and 43%,
respectively) for three-step transformation.18 Finally, the target
(+)-(S)-[n]-gingerols 1a–c were obtained in 70–73% yield by hydro-
genation of compounds 9a–c with H2/Pd/C. To our delight, when
the reaction was carried out in the presence of a small amount of
Et3N (5% v/v), the yield could be improved up to 86–90% (Scheme
3). The ee values of final compounds 1a–c were determined by
HPLC analysis (chiral AS column: 74% ee, 72% ee, and 70% ee,
respectively).19
TBSCl, imidazole, CH2Cl2, rt, overnight; (c) TMSOTf, i-Pr2NEt, CH2Cl2, 0 °C, 3 h; (d)
vanillin, BF3ÁOEt2, CH2Cl2, 0 °C, 3 h; (e) H2 (1 atm), 10% Pd/C, Et3N/EtOAc (v/v) = 1/
20, rt, 4 h.
nese National Programs for High Technology Research and Devel-
opment (Nos. 2006AA020602 and 2007AA02Z147).
Supplementary data
Supplementary data associated with this article can be found, in
References and notes
1. List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395.
2. Recent reviews of chiral secondary amine catalyzed enamine chemistry, see:
(a) List, B. Acc. Chem. Res. 2004, 37, 548; (b) Notz, W.; Tanaka, F.; Barbas, C. F., III
Acc. Chem. Res. 2004, 37, 580; (c) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List,
B. Chem. Rev. 2007, 107, 5471.
In conclusion, we have developed a concise, enantioselective
approach to (+)-(S)-[n]-gingerol 1a–c in five steps in respected
overall yields (14–19%). The key step in the synthesis employs L-
3. Selected examples of proline analogues catalyzed aldol reactions, see: (a)
Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem. Soc. 2001, 123,
5260; (b) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett 2001, 1245; (c) Tang,
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Shaw, D. M.; Ley, S. V. Synlett 2004, 558; (g) Torii, H.; Nakadai, M.; Ishihara,
K.; Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983; (h) Lacoste,
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proline-promoted Hajos–Parrish–Eder–Sauer–Weichert–List–Bar-
bas aldol reaction to conveniently establish the requisite chiral
center under mild reaction conditions.
Acknowledgments
We are grateful for the financial support from School of Phar-
macy, East China University of Science and the National Science
Foundation of China (Nos. 03772648 and 30721005), and the Chi-
O
O
O
L-proline
+
H
4
HO
2
3a
O
OH
O
+
3
4
H
HO
O
2
6
Scheme 2. L-Proline catalyzed cross-aldol reaction between 2 and 3a.