The reaction was complete in CH2Cl2 or CH3CN within 3-5
min at room temperature. Other Lewis acids (e.g., SnCl4,
SnBr4, TiCl4, and TMSOTf) resulted in complex mixtures,
while relatively weaker Lewis acids such as InCl3 and ZnCl2,
as well as weaker protic acids (e.g., p-TsOH, CF3CO2H),
resulted in no apparent reaction or only trace conversion
(starting material was recovered).
yields, demonstrating that substitutes on olefin are not
essential to the cascade process (entries 4, 5, and 6). In
most of the aforementioned examples, the reactions pro-
ceeded with uniformly exclusive diastereoselectivity. How-
ever, a pendant phenyl group was found to have a
deleterious effect on this selectivity, providing 6f as a 3:1
diastereomeric mixture. We propose that the resulting
benzylic ion, a more stable cyclopropylcarbinyl cation
intermediate, was trapped relatively slowly by the oxygen
resulting in the low stereoselectivity. The dihydroxyl
adduct 5g underwent a 3-exo cascade cyclization to furnish
the single diastereomeric adduct 6g, which demonstrated
that the free hydroxyl group did not disturb the transfor-
mation (entry 7). Finally, it is interesting to note that in
the case of entry 8, an unexpected triol cyclopropyl
product 6h was obtained in moderate yield after quenching
with aqueous sodium bicarbonate and no tricyclic product
was observed. This indicated that the single-step trans-
formation afforded the thermodynamically favored com-
pound.
Scheme 2
.
Chirality Transfer in the Epoxide-Initiated Cascade
Cyclization
With the optically active substrates 5i and 5j, acid-induced
cyclization gave the expected products 6i and 6j in excellent
yields with high stereochemical fidelity (Scheme 2).9 More-
over, these two cases disclosed that the presence of a
carbonyl group adjacent to epoxide in the substrate did not
play an important role in this reaction.
The structures of all the products were established on the
basis of spectroscopic data (see the Supporting Information).
To assign the relative stereochemistry of the products beyond
doubt, the structures of 6g and 6h were determined unam-
biguously by X-ray crystallographysthe former has a 5,6-
membered trans-fused configuration while the latter is an
acyclic triol (Figure 2).10 It is noteworthy that compared with
other products in Table 2, 6g prensents the most similar
structural feature of mycorrhizin A, which enables the
potential investigation for further diversity-oriented synthesis8
of the angularly fused 6,3,5-tricyclic natural products.
In conclusion, we have developed an efficient method for
constructing an angularly fused 6,3,5-tricyclic system via a
cation-olefin cascade cyclization. The reaction can be
With this encouraging result in hand, we investigated
more substrates under the optimized reaction conditions
that were proven to be general and versatile, as shown in
Table 2. For example, the R,ꢀ-unsaturated substrate 5b
and lactone 5c were prepared and also successfully
converted to the corresponding products 6b and 6c in 95%
and 84% yields, respectively (entries 2 and 3). To our
delight, olefinic epoxides 5d, 5e, and 5f similarly gave
the corresponding products 6d, 6e, and 6f in excellent
(5) For reviews, see: (a) Thebtaranonth, C.; Thebtaranonth, Y. Cycliza-
tion Reactions; CRC Press: Boca Raton, 1994. (b) Taylor, S. K. Org. Prep.
Proc. Int. 1992, 24, 245. (c) Tietze, L. F.; Beifuss, U. Angew. Chem., Int.
Ed. Engl. 1993, 32, 131. (d) Johnson, W. S. Tetrahedron 1991, 47, xi-1.
(e) Bartlett, P. A. Asymm. Synth. 1984, 3, 341. (f) Aziridines and Epoxides
in Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim, 2006.
(g) Domino Reactions in Organic Synthesis; Tietze, L. F., Brasche, G.,
Gericke, K. M., Ed.; Wiley-VCH: Weinheim, 2006.
(6) (a) Conacher, H. B. S.; Gunstone, F. D. Chem. Comm. 1967, 984.
(b) Canonica, L.; Ferrari, M.; Pagnoni, U. M.; Pelizzoni, F. Tetrahedron
1969, 25, 1. (c) Shirahama, H.; Hayano, K.; Kanemoto, Y.; Misumi, S.;
Ohtsuka, T.; Hashiba, N.; Furusaki, A.; Murata, S.; Noyori, R.; Matsumoto,
T. Tetrahedron Lett. 1980, 21, 4835. (d) White, J. D.; Jensen, M. S. J. Am.
Chem. Soc. 1993, 115, 2970. (e) White, J. D.; Jensen, M. S. J. Am. Chem.
Soc. 1995, 117, 6224.
(7) Olah, G. A.; Prakash Reddy, V.; Surya Prakash, G. K. Chem. ReV.
1992, 92, 69.
(8) Schreiber, S. L. Science 2000, 287, 1964.
(9) Enantiomeric purity was determined by HPLC (see the Supporting
Information).
(10) Crystallographic data of 6g and 6h were deposited with the
Cambridge Crystallographic Data Centre (CCDC nos. 709206 and 709207).
The stereochemistries of the remaining products in Table 2 were assigned
by analogy (see the Supporting Information for further details).
Figure 2. ORTEP drawing of 6g (top CCDC no. 709206) and 6h
(bottom CCDC no. 709207).
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