ORGANIC
LETTERS
2005
Vol. 7, No. 17
3641-3644
Unprecedented Alkene Stereocontrol in
the Claisen Rearrangement of Cyclic
Bis-Allylic Esters
Chris McFarland, John Hutchison, and Matthias C. McIntosh*
Department of Chemistry and Biochemistry, UniVersity of Arkansas,
FayetteVille, Arkansas 72701
Received May 18, 2005
ABSTRACT
The Ireland and ester enolate Claisen rearrangements of tertiary substituted bis-allylic esters derived from cyclohexenones afford pentenoic
acids that possess tri- and tetrasubstituted alkylidenes with unprecedented levels of stereoselectivity. In some cases the higher energy exocyclic
alkene is the major product.
The stereoselective synthesis of tri- and tetrasubstituted
alkenes is a long-standing goal of organic synthesis. Wittig-
based and transition-metal-mediated strategies offer some of
the more general strategies for stereoselective acyclic tri-
and tetrasubstituted alkene synthesis.1
The Claisen rearrangement of allyl vinyl ethers, allylic
esters, and related substrates has been employed to prepare
trisubstituted alkenes in a stereoselective fashion.2 One of
the advantages of the rearrangement lies in its ability to
concomitantly install a substituted alkene and one or two
new stereogenic carbons. We have pursued Claisen rear-
rangement approaches to the preparation of alkylidenes
derived from cycloalkenones.3,4 Difunctionalization of the
alkylidene double bond can be used for the installation of
vicinal endo- and exocyclic stereocenters that would other-
wise be difficult to access.3c,5
Because of the well-established propensity for the rear-
rangement to occur via a chairlike transition state in acyclic
substrates, secondary carbinol-derived allyl vinyl ethers and
related allyl ketene acetals almost invariably rearrange so
as to provide the R1-trans-isomer as the major product
(Scheme 1) (R1-trans and R1-cis designate the isomers in
which the R1 group is trans or cis to the CH2CH2COX
moiety, respectively).2,6 The transition state leading to the
R1-cis-isomer suffers from 1,3-diaxial interactions between
(1) For concise summary of alkene synthesis references, see: Arefolov,
A.; Langille, N. F.; Panek, J. S. Org. Lett. 2001, 3, 3281-4.
(2) For reviews, see: (a) Ziegler, F. E. Acc. Chem. Res. 1977, 10, 1423-
1452. (b) Bennett, G. B. Synthesis 1977, 10, 589-606. (c) Hill, R. K.
Asymmetric Synthesis; Morrison, J. D., Ed.; Academic: New York, 1984;
Vol. 3, pp 503-572. (d) Blechert, S. Synthesis 1989, 71-82. (e) Wipf, P.
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford,
1991; Vol 5, pp 827-873. (f) Tadano, K. Studies in Natural Products
Chemistry; Rahman, A.-U., Ed.; Elsevier: Amsterdam, 1992; pp 405-455.
(g) Pereira, S.; Srebnik, M. Aldrichimica Acta 1993, 26, 17-29. (h)
Frauenrath, H. StereoselectiVe Synthesis; Helchen, G., Hoffmann, R. W.,
Mulzer, J., Schaumann, E., Eds.; Georg Thieme: Stuttgart, 1995; Vol. E21d,
pp 3301-3756. (i) Chai, Y.; Hong, S.-p.; Lindsay, H. A.; McFarland, C.;
McIntosh, M. C. Tetrahedron 2002, 58, 2905-2928. (j) Castro, A. M. M.
Chem. ReV. 2004, 104, 2939-3002.
(3) (a) Zhang, X.; McIntosh, M. C. Tetrahedron Lett. 1998, 39, 7043-
7046. (b) McIntosh, M. C.; Hong, S.-p.; Lindsay, H. A.; Yaramasu, T.;
Zhang, X. J. Org. Chem. 2002, 67, 2042-2055. (c) Hong, S.-p.; McIntosh,
M. C. Org. Lett. 2002, 4, 19-21. Hutchison, J. M.; Hong, S.-p.; McIntosh,
M. C. J. Org. Chem. 2004, 69, 4185-4191.
(4) For Claisen approaches to alkylidenes derived from cycloalkanones,
see: (a) Cresson, P. Bull. Soc. Chim. Fr. 1964, 2618-2628; 2629. (b)
Chillous, S. E.; Hart, D. J.; Hutchinson, D. K. J. Org. Chem. 1982, 47,
5418-5420. (c) Dulcere, J. P. Rodriguez., J. Synthesis 1993, 399-405. (d)
Le Notre, J.; Brissieux, L.; Semeril, D.; Bruneau, C.; Dixneuf, P. H. Chem.
Commun. 2002, 1772-3.
(5) Hong, S.-p.; McIntosh, M. C.; Barclay, T.; Cordes, W. Tetrahedron
Lett. 2000, 41, 155-159.
10.1021/ol0511732 CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/26/2005