Ca ta lytic (2 + 2)-Cycloa d d ition Rea ction s of Silyl En ol Eth er s.
A Con ven ien t a n d Ster eoselective Meth od for Cyclobu ta n e Rin g
F or m a tion
Kiyosei Takasu,* Megumi Ueno, Kazato Inanaga, and Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University,
Aobayama, Sendai 980-8578, J apan
mihara@mail.pharm.tohoku.ac.jp
Received J uly 9, 2003
An efficient catalytic (2 + 2)-cycloaddition reaction leading to the formation of cyclobutane rings
has been devised. The process transforms silyl enol ethers and R,â-unsaturated esters into
polysubstituted cyclobutanes with a high degree of trans-stereoselectivity. Both the rate and
stereoselectivity of the process can be controlled by the choice of the ester group and silyl
substituents. The results of stereochemical studies show that the cycloaddition step in this reaction
proceeds in a nonstereospecific manner and, thus, by a pathway involving sequential nucleophilic
additions via a short-lived zwitterionic intermediate.
In tr od u ction
are the usual methods used to prepare cyclobutanes, but
controlling reactivity and selectivity in these processes
often is a difficult task.
The facile and stereoselective synthesis of mono- and
polycyclic compounds from simple starting materials has
remained as one of the main goals in synthetic organic
chemistry.1 Much attention has been devoted to the
construction of cyclopropane, cyclopentane, and cyclo-
hexane rings by cycloaddition and stepwise-annulation
reactions. As a result, a number of efficient and/or
stereoselective strategies have been devised. On the other
hand, only a limited number of practical methods have
been developed to form cyclobutane ring systems from
simple substrates. This represents a deficiency in the
area of synthetic organic chemistry since cyclobutanes
abound in nature as biologically active substances2 and
are used as important synthetic intermediates in routes
targeted at medicinally useful substances.3 Photochemi-
cal (2 + 2)-cycloaddtions of alkenes and enones4 and
thermal (2 + 2)-cycloadditions of ketenes and alkenes5
We have developed a strategy for cyclobutane ring
construction involving stepwise nucleophilic addition
reactions of silyl enol ether. It is well-known that
conjugate addition reactions of enolates (or their equiva-
lents) with R,â-unsaturated carbonyl compounds afford
1,5-dicarbonyl products. In this process, the in situ
formed δ-keto-enolate is quenched by an external elec-
trophile, such as a proton (Scheme 1, path a). However,
the carbonyl group in the initially formed Michael adduct,
which originates from the enolate component, can act as
an internal electrophile in an intramolecular addition
process leading to formation of a cyclobutanol product
(Scheme 1, path b). The cyclobutanol forming reaction
can be described as a Michael-aldol-like (2 + 2)-cycload-
dition. Vinyl sulfides or selenides have been employed
in similar stepwise reactions.6 In contrast, cyclobutane
formation from silyl enol ethers, which are one of the
most easily prepared ketone-equivalents, has not been
* Corresponding author.
(1) (a) Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1990. (b) Cycloaddition Reactions in Organic
Synthesis; Kobayashi, S., J ørgensen, K. A., Eds.; Wiley-VCH: Wein-
heim, 2002.
achieved except in a limited number of cases.7,8
A
significant problem with some of the reported reactions
(2) For examples, see: (a) Kepler, J . A.; Wall, M. E.; Mason, J . E.;
Basset, C.; McPhail, A. T.; Sim, G. A. J . Am. Chem. Soc. 1967, 89,
1260-1261. (b) Wilson, B. J .; Wilson, C. H.; Hayes, A. W. Nature 1968,
220, 77-78. (c) Schenk, H.; Driessen, R. A. J .; de Gelder, R.; Goubits,
K.; Nieboer, H.; Bru¨ggemann-Rotgans, I. E. M.; Diepenhorst, P. Croat.
Chem. Acta 1999, 72, 593-606. (d) Cremin, P.; Guiry, P. J .; Wolfender,
J .-L.; Hostettmann, K.; Donnely, D. M. X. J . Chem. Soc., Perkin Trans.
1 2000, 2325-2329.
(3) For examples, see: (a) Lange, G. L.; Lee, M. Synthesis 1986,
117-120. (b) Haque, A.; Ghatak, A.; Ghosh, S.; Ghoshal, N. J . Org.
Chem. 1997, 62, 5211-5214. (c) Crimmins, M. T.; Wang, Z.; McKerlie,
L. A. J . Am. Chem. Soc. 1998, 120, 1747-1756. (d) Winkler, J . D.;
Doherty, E. M. J . Am. Chem. Soc. 1999, 121, 7425-7426. (e) Namyslo,
J . C.; Kaufmann, D. E. Chem. Rev. 2003, 103, 1485-1537.
(4) (a) Crimmins, M. T. In Comprehensive Organic Synthesis; Trost,
B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 5, pp 123-149. (b)
Bach, T.; Bergmann, H. J . Am. Chem. Soc. 2000, 122, 11525-11526.
(c) Chen, C.; Chang, V.; Cai, X.; Duesler, E.; Mariano, P. S. J . Am.
Chem. Soc. 2001, 123, 6433-6434.
(5) (a) Ulrich, H. Cycloaddition Reactions of Heterocumulenes;
Academic Press: London, 1967. (b) Ahmad, S. Tetrahedron Lett. 1991,
32, 6997-7000.
(6) (a) Yamazaki, S.; Kumagai, H.; Yamabe, S.; Yamamoto, K. J .
Org. Chem. 1998, 63, 3371-3378. (b) Narasaka, K.; Hayashi, Y.;
Shimadzu, H.; Niihata, S. J . Am. Chem. Soc. 1992, 114, 8869-8885.
(7) (a) Kuehne, M. E.; Foley, L. J . Org. Chem. 1965, 30, 4280-4284.
(b) Baar, M. R.; Ballesteros, P.; Roberts, B. W. Tetrahedron Lett. 1986,
27, 2083-2086. (c) Quendo, A.; Rousseau, G. Tetrahedron Lett. 1988,
29, 6443-6446. (d) Kniep, C. S.; Padias, A. B.; Hall, H. K., J r.
Tetrahedron 2000, 56, 4279-4288. (e) Loughlin, W. L.; McCleary, M.
A. Org. Biomol. Chem. 2003, 1, 1347-1353.
(8) To our knowledge, only two stoichiometric reactions of silyl
enolates with simple enoates have been reported. (a) Clark, R. D.;
Untch, K. G. J . Org. Chem. 1979, 44, 253-255. (b) Chan, T.-H.;
Brownbridge, P. J . Chem. Soc., Chem. Commun. 1979, 578-579. (c)
Magnus, P.; Rigollier, P.; Lacour, J .; Tobler, H. J . Am. Chem. Soc. 1992,
114, 3993-3995.
10.1021/jo034989u CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/24/2003
J . Org. Chem. 2004, 69, 517-521
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