effected epimerization to the desired configuration at the
spiroketal center. In the Inoue/Hirama work, the desired
spiroketal was formed selectively with an unprotected tertiary
hydroxyl group at C15. The authors hypothesize that the
observed selectivity is due to a long-range hydogen-bond
stabilization (Figure 1),15 which is likely to be highly specific
In subsequent experiments, after the protecting group
removal (CSA, MeOH, rt, 10 h), methanol was replaced by
solvents of decreasing polarity listed in Table 1. As the
solvent polarity decreased, we observed an increased ratio
of the desired diastereomer to its C19 epimer. Equilibration
in dichloromethane delivered a 2.7:1 ratio of 16 and 17, the
ratio in toluene was 4.8:1, and the optimal selectivity (9.8:
1) was achieved when cyclohexene was used as the solvent.
We attribute this increased selectivity to a more pronounced
anomeric effect in nonpolar solvent17 rather than to a
hydrogen-bond stabilization related to that proposed by
Hirama and co-workers,15 especially because an alternative
hydrogen bonding is possible in the C19 epimer 17 (Figure
1).14
In an optimized protocol, we achieved an 88% yield of
desired spiroketal 16 after only one recycling of 17 and other
byproducts (Scheme 5). Protecting group installation was
Figure 1. Analysis of hydrogen bond stabilization in 16, 17, and
Inoue/Hirama’s intermediate.
Scheme 5
to the structure of the product and therefore not general.16
On the other hand, we noted that one of the significant
differences between the Kishi and Inoue/Hirama spiroket-
alizations was the solvent. Because the effect of the solvent
on the extent and sometimes even the position of anomeric
equilibria is well-established,17 we undertook a brief study
to determine the inluence of the solvent on the selectivity of
bis-spiroketalization of diketone 15 (Table 1).
accomplished using successive treatment with TIPSCl and
TESCl, and the tert-butyl ester was efficiently reduced to
aldehyde 18 directly with DIBAL at -78 °C.
Table 1. Solvent Effect on the Spiroketalization
isolated yield (%)
In summary, we developed a convergent enantioselective
synthesis of the B,C,D-dispiroketal fragment of pinnatoxins
using an efficient enzymatic resolution to establish the
stereocenters at C12 and C23. The tricyclic ring system was
assembled by an optimized acid-catalyzed spiroketalization
in a nonpolar solvent to enhance the anomeric stabilization
of the desired diastereomer.
entry
solvent
methanol
dichloromethane
toluene
16
17
1
2
3
4
49
62
63
78
22
23
13
8
cyclohexane
When the spiroketalization was performed in methanol, a
2.2:1 ratio of diastereomeric spiroketals was obtained favor-
ing the desired diastereomer (16), along with other isomers
and partially ketalized byproducts. This result is almost
identical to that observed recently by Kishi and co-workers
in the course of the total synthesis of pteriatoxins (2.1:1 ratio
of the isomers in methanol).18
Acknowledgment. This work was supported by the
Department of Chemistry and Biochemistry, Florida State
University, and in part by the ACS Petroleum Research Fund
(43838-G1). C.-D.L. thanks the MDS Research Foundation
for a postdoctoral fellowship. We thank Dr. Umesh Goli of
the Department of Chemistry for the assitance with HRMS
experiments.
(13) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
Supporting Information Available: Experimental pro-
1
(14) McCauley, J. A.; Nagasawa, K.; Lander, P. A.; Mischke, S. G.;
Semones, M. A.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 7647.
(15) Sakamoto, S.; Sakazaki, H.; Hagiwara, K.; Kamada, K.; Ishii, K.;
Noda, T.; Inoue, M.; Hirama, M. Angew. Chem., Int. Ed. 2004, 43, 6505.
(16) Perron, F.; Albizati, K. F. Chem. ReV. 1989, 89, 1617.
(17) (a) Tvaroska, I.; Carver, J. P. J. Phys. Chem. 1994, 98, 9477. (b)
Tvaroska, I.; Carver, J. P. Carbohydr. Res. 1998, 309, 1. (c) deHoog, A. J.;
Buys, H. R.; Altona, C.; Havinga, E. Tetrahedron 1969, 25, 3365. (d)
Lemieux, R. U.; Pavia, A. A,; Martin, J. C.; Watanabe, K. A. Can. J. Chem.
1969, 47, 4427. (e) Praly, J.-P.; Lemieux, R. U. Can. J. Chem. 1987, 65,
213.
cedures, characterization data, and copies of H NMR and
13C NMR spectra for new compounds described in this paper.
This material is available free of charge via the Internet at
OL071266E
(18) Matsuura, F.; Peters, R.; Anada, M.; Harried, S. S.; Hao, J.; Kishi,
Y. J. Am. Chem. Soc. 2006, 128, 7463.
Org. Lett., Vol. 9, No. 16, 2007
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