ORGANIC
LETTERS
2008
Vol. 10, No. 10
2039-2041
Facile Synthesis of
cis-2-Alkyl-3-trialkylsilyloxycycloalkanones
via the Non-Aldol Aldol Rearrangement
of 2,3-Epoxycycloalkanols
Michael E. Jung* and Damian A. Allen
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles,
405 Hilgard AVenue, Los Angeles, California 90095
Received March 6, 2008
ABSTRACT
Silyl triflate-promoted rearrangement of cis-2,3-epoxycycloalkanols A, prepared by epoxidation of the cyclic allylic alcohol and then silylation,
afforded good yields (∼70–75%) of the cis-2-alkyl-3-silyloxycycloalkanones B, presumably via the intermediates C and D, even with quite large
r-substituents, e.g., tert-butyl. Finally, it has been shown that the stereochemistry of the epoxy alcohol is crucial as one would expect from
the mechanism.
Functionalized carbocyclic rings are important synthons in
organic synthesis. In particular, cis-2-alkyl-3-hydroxycy-
cloalkanones are valuable intermediates that can be readily
converted into a variety of motifs found in natural products.
Unfortunately, no procedures currently exist for their syn-
thesis. In acyclic systems, such ꢀ-hydroxy carbonyl com-
pounds are usually made using the aldol condensation and
asymmetric variants thereof. But few synthetic methods have
been reported for the asymmetric intramolecular aldol to
make R-alkyl ꢀ-hydroxy cyclic systems.
An alternative method to synthesize asymmetric ꢀ-hy-
droxyl carbonyl compounds is the Lewis acid promoted
semipinacol rearrangement of optically active epoxy alcohols,
obtained using methodology developed by Sharpless.1 The
activated epoxide is opened with inversion of stereochemistry
via a concerted [1,2] migration, thereby transfering the
stereochemical information from the starting material to the
product. Much of this work has focused on phenyl, vinyl,
or alkyl migration in acyclic systems.2 More recently, a few
studies have been reported in cyclic systems in an effort to
construct quaternary carbon centers. Several years ago, we
reported a semipinacol rearrangement3a involving not phenyl,
vinyl, or alkyl migration, but rather hydride migration, and
named the process the nonaldol aldol reaction3–5 (Scheme
(2) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 389. (b) Rickborn, B. In ComprehensiVe Organic Synthesis; Carbon-
Carbon σ-Bond Formation; Pattenden, G., Ed.; Pergamon Press: Oxford,
1991; Vol. 3,Chapter 3.3. (c) Whalen, D. L. AdV. Phys. Org. Chem. 2005,
40, 247.
(3) (a) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1993, 115, 12208.
(b) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1995, 117, 7379. (c)
Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1997, 119, 12150. (d)
Jung, M. E.; Marquez, R. Tetrahedron Lett. 1999, 40, 3129. (e) Jung, M. E.;
Lee, W. S.; Sun, D. Org. Lett. 1999, 1, 307. (f) Jung, M. E.; Sun, D.
Tetrahedron Lett. 1999, 40, 8343. (g) Jung, M. E.; Marquez, R. Org. Lett.
2000, 2, 1669. (h) Jung, M. E.; Lee, C. P. Tetrahedron Lett. 2000, 41,
9719. (i) Jung, M. E.; Lee, C. P. Org. Lett. 2001, 3, 333. (j) Jung, M. E.;
van den Heuvel, A. Tetrahedron Lett. 2002, 43, 8169. (k) Jung, M. E.;
Hoffmann, B.; Rausch, B.; Contreras, J.-M. Org. Lett. 2003, 5, 3159. (l)
Jung, M. E.; van den Heuvel, A.; Leach, A. G.; Houk, K. N. Org. Lett.
2003, 5, 3375. (m) Jung, M. E.; van den Heuvel, A. Org. Lett. 2003, 5,
4705. (n) Jung, M. E.; Yoo, D. Org. Lett. 2007, 9, 3543. (o) Jung, M. E.;
Zhang, T. Org. Lett. 2008, 10, 137. (p) Jung, M. E.; Yoo, D. Tetrahedron
(1) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(b) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
Lett. 2008, 49, 816
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10.1021/ol800423m CCC: $40.75
Published on Web 04/23/2008
2008 American Chemical Society