halides as additives with suppression of epimerization. The
efficiency and practicality of this method is demonstrated
by the highly convergent enantioselective synthesis of (-)-
centrolobine. We envisage that a catalytic amount of Lewis
acid such as an indium3 complex will catalyze the formation
of the oxonium ion for the Prins cyclization. The carbocation
can then be trapped with halide using trimethylsilyl halide1j
as additive. Therefore, 1-phenylhex-5-en-3-ol, 1, was sub-
jected to various aldehydes in the presence of a catalytic
amount of In(OTf)3 (Scheme 1). The results are summarized
Table 1. Catalytic Prins Cyclizations with Trimethylsilyl
Halidesa
Scheme 1. Prins Cyclizations with Trimethylsilyl Halides
in Table 1.
In all cases, the Prins cyclization with various aldehydes
proceeded to form crossed 4-halo-2,6-trisubstituted THP
products with moderate to excellent yields. Especially
noteworthy is the excellent stereoselectivity observed where
only the all-cis configuration products were obtained.
Furthermore, the reaction also worked well for R,â-unsatur-
ated aldehydes and was insensitive to the steric and electronic
influences of the substrates. Note that the trimethylsilyl halide
additives serve as sources of halides and have been shown
to work well to afford the corresponding halide containing
THP compounds.
a Note: 5% yield of the meso-product 8 was obtained in each of the
entries 1-6. Meso-products containing fragments of R1 were not observed.
We proposed two key steps to obtain the chiral THP
backbone. The first step was the asymmetric allylation of
3-(4-benzyloxy)phenyl)propanal, 15, using (R)-BINOL in-
dium complex and allyltributyltin as allylating agent,6
recently reported by our group. The second key step of the
reaction would be the formation of 4-bromo-THP ring via
catalytic Prins cyclization, the main focus in this paper.
Next, we applied this methodology to the enantioselective
synthesis of (-)-centrolobine,4 17, isolated from the heart-
wood of Centrolobium robustum.5 The retrosynthetic analysis
is outlined in Scheme 2.
(2) (a) Al-Mutairi, E. H.; Crosby, S. R.; Darzi, J.; Hughes, R. A.;
Simpson, T. J.; Smith, R. W.; Willis, C. L.; Harding, J. R.; King, C. D.
Chem. Commun. 2001, 835-836. (b) Crosby, S. R.; Harding, J. R.; King,
C. D.; Parker, G. D.; Willis, C. L. Org. Lett. 2002, 4, 577-580. (c) Crosby,
S. R.; Harding, J. R.; King, C. D.; Parker, G. D.; Willis, C. L. Org. Lett.
2002, 4, 3407-3410. (d) Nokami, J.; Yoshizane, K.; Matsuura, H.; Sumida,
S.-I. J. Am. Chem. Soc. 1998, 120, 6609-6610. (e) Nokami, J.; Anthony,
L.; Sumida, S.-I. Chem. Eur. J. 2000, 6, 2909-2913. (f) Nokami, J.; Ohga,
M.; Nakamoto, H.; Matsubara, T.; Hussain, I.; Kataoka, K. J. Am. Chem.
Soc. 2001, 123, 9168-9169. (g) Loh, T.-P.; Hu, Q.-Y.; Ma, L.-T. J. Am.
Chem. Soc. 2001, 123, 2450-2451. (h) Loh, T.-P.; Tan, K.-T.; Hu, Q.-Y.
Angew. Chem., Int. Ed. 2001, 40, 2921-2922. (i) Loh, T.-P.; Lee, C.-L.
K.; Tan, K.-T. Org. Lett. 2002, 4, 2985-2987. (j) Hussain, I.; Komasaka,
T.; Ohga, M.; Nokami, J. Synlett 2002, 4, 640-642.
Scheme 2. Retrosynthetic Analysis of (-)-Centrolobine
(3) (a) Loh, T.-P. In Science of Synthesis; Yamamoto, H., Ed.; Georg
Thieme Verlag Stuttgart: New York, 2004; p 413. (b) Loh, T.-P.; Chua,
G.-L. Activation of Reactions by Lewis acid derived from Ga, In, Sb and
Bi. In AdVances in Organic Synthesis - Online; Atta-ur-Rahman, Ed. 2005,
1, in press.
(4) For other synthees of (-)-centrolobine: (a) Marumoto, S.; Jaber, J.
J.; Vitale, J. P.; Rychnovsky, S. D. Org. Lett. 2002, 4, 3919-3922. (b)
Evans, P. A.; Cui, J.; Gharpure, S. J. Org. Lett. 2003, 5, 3883-3885. (c)
Colober, F.; Mazery, R. D.; Solladie, G.; Carreno, M. Otg. Lett. 2002, 4,
1723-1725. (d) Jennings, Michael P.; Clemens, Ryan T. Tetrahedron Lett.
2005, 46, 2021-2024. (e) Lee, E.; Kim, H. J.; Jang, W. S. Bull. Korean
Chem. Soc. 2004, 25, 1609-1610. (f) Boulard, L.; BouzBouz, S.; Cossy,
J.; Franck, X.; Figadere, B. Tetrahedron Lett. 2004, 45, 6603-6605. (g)
Clarke, Paul A.; Martin, William H. C. Tetrahedron Lett. 2004, 45, 9061-
9063.
The asymmetric allylation of 15 proceeded well to give
10 in moderate yield and 84% ee. We subsequently encoun-
tered the problem of epimerization in the catalytic Prins
cyclization reaction. The use of 20 mol % of In(OTf)3 in
(5) (a) De Albuquerque, I. L.; Galeffi, C.; Casinovi, C. G.; Marini-Bettolo,
G. B. Gazz. Chim. Ital. 1964, 287. (b) Galeffi, C.; Giulio Casinovi, C.;
Marini-Bettolo, G. B. Gazz. Chim. Ital. 1965, 95, 95-100.
(6) Teo, Y. C.; Tan, K. T.; Loh, T. P. Chem. Commun. 2005, 10, 1318-
1320.
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