LETTER
Synthesis of 5-epi-(–)-Hyacinthacine A3 and (–)-Hyacinthacine A3
985
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moderate yields. Various Lewis acids were then screened
to effect the reaction. All the Ag salts screened generally
catalyzed the reaction, but AgBF4 gave the best result.26
Other inexpensive Lewis acids were also investigated,
ZnI2 and TMSOTf27 system gave less encouraging results,
while CuI and BF3·OEt228 system furnished no product.
After catalytic hydrogenolysis of 7, (–)-2 was readily ob-
tained in 95% yield (Scheme 5). The 600 MHz NOESY
spectrum (D2O) supported the assigned stereochemistry
based on the strong NOE effects observed between the
C(9)–H and C(3)–H as well as between the C(9)–H and
(2) (a) Wrodnigg, T. M.; Steiner, A. J.; Ueberbacher, B. J.
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1
C(1)–H. The 400 MHz H and 13C NMR of compound
(–)-2 in D2O were identical to those reported for the natu-
ral (+)-hyacinthacine while the optical rotation of (–)-2
{[a]D20 –16 (c 0.50, D2O)}was opposite to that of the nat-
ural product {[a]D20 19.2 (c 0.43, D2O)}. Therefore, com-
pound (–)-2 was undisputably determined as the desired
product, (–)-hyacinthacine A3.
(4) (a) Butters, T. D.; Dwek, R. A.; Platt, F. M. Chem. Rev.
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95. (b) Asano, N.; Kuroi, H.; Ikeda, K.; Kizu, H.; Kameda,
Y.; Kato, A.; Adachi, I.; Watson, A. A.; Nash, R. J.; Fleet, G.
W. J. Tetrahedron: Asymmetry 2000, 11, 1. (c) Yamashita,
T.; Yasuda, K.; Kizu, H.; Kameda, Y.; Watson, A. A.; Nash,
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Kizu, H. J. Nat. Prod. 2004, 67, 846. (e) Kato, A.; Kato, N.;
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OBn
OH
H
N
H
7
1
10% Pd/C, H2
95%
OBn
OBn
OH
OH
5
3
N
9
Me
Me
7
(–)-2
Scheme 5 Completion of the synthesis of (–)-hyacinthacine A3
In summary, the synthesis of (–)-hyacinthacine A3 has
been achieved in five steps with an overall yield of 69%
from nitrone 11. The approach featured stepwise Grignard
addition to two sugar-derived activated imine intermedi-
ates: nitrone 11 and a-amino nitrile 19. 5-epi-(–)-Hya-
cinthacine A3 has also been synthesized starting from the
same nitrone 11 via an alternative route with intramolec-
ular reductive amination cyclization as the key step. We
have shown that, starting from the same nitrone via the
two complementary routes, both (–)-hyacinthacine A3 and
its epimer could be made. This synthetic strategy is poten-
tially general and flexible, suitable for the diversity-
oriented synthesis of 5-alkyl-hyacinthacines and their an-
alogues, which is crucial for in-depth structure–activity
study on this special class of alkaloids.
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Supporting Information for this article is available online at
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Acknowledgment
(8) (a) Asano, N.; Ikeda, K.; Yu, L.; Kato, A.; Takebayashi, K.;
Adachi, I.; Kato, I.; Ouchi, H.; Takahata, H.; Fleet, G.
Tetrahedron: Asymmetry 2005, 16, 223. (b) Yu, C.-Y.;
Asano, N.; Ikeda, K.; Wang, M.-X.; Butters, T. D.;
Wormald, M. R.; Dwek, R. A.; Winters, A. L.; Nash, R. J.;
Fleet, G. W. J. Chem. Commun. 2004, 1936. (c) Yu, C. Y.;
Huang, M. H. Org. Lett. 2006, 8, 3021. (d) Davis, B. B.;
Nash, R. J.; Watson, A. A.; Griffiths, R. C.; Jones, M. G.;
Smith, C.; Fleet, G. W. J. Tetrahedron Lett. 1996, 37, 8565.
This work is supported by The National Natural Science Foundation
of China (No. 20672117), The National Basic Research Program of
China (No. 2009CB526511), The Ministry of Science and Techno-
logy and the Ministry of Health of the P. R. of China (No.
2009ZX09501-006), and The Chinese Academy of Sciences.
References and Notes
(1) (a) Compain, P.; Martin, O. Iminosugars: From Synthesis to
Therapeutic Applications; J. Wiley and Sons: Chichester,
Synlett 2010, No. 6, 982–986 © Thieme Stuttgart · New York