reaction. Such a strategy was first used by Oppolzer et al.
to transform chiral dienes to trisubstituted pyrrolidines for
the synthesis of kainic and allokainic acids.8 However, the
possibility of developing metal-promoted, enantioselective
variants of the intramolecular ene reaction using achiral diene
precursors led us to pursue this new approach.
required prolonged heating at 190 °C, forming 7a and 8a
(3.3:1 ratio) in good yields. The desired cis-isomer 7a was
obtained as a pure racemate by crystallization from ethyl
acetate:hexanes, mp 104-107 °C. Isomer 6a failed to cyclize
at 190 °C (entry 2) but at higher temperatures (entry 3)
afforded predominantly the trans-isomer 8a. Control experi-
ments at 210 °C indicated that diene 5a slowly isomerized
to 6a and that pure 7a epimerized only slowly (<10% after
4 d). Thus, the stereochemistry of the cyclized product was
strongly influenced by the stereochemistry of the enophile
in the diene precursor.
Dienes 5a,b and 6a,b were prepared as shown in Scheme
2 from N-prenylamine 4.9 Reaction of 4 with maleic
Scheme 2
Attempted cyclization of 5a with various metal salts
[ZnCl2, Zn(OTf)2, Cu(OTf)2] led instead to the formation of
N-prenylmaleimide. However, in the presence of ZnCl2 or
Mg(ClO4)2, diene 6a generated predominantly the desired
cis-isomer 7a (entries 4 and 5).
The N-benzoylated dienes 5b and 6b underwent faster and
higher-yielding uncatalyzed cyclizations (entries 6 and 7)
than did the parent dienes 5a and 6a, with 6b strongly
favoring the desired cis-product 7b. Stoichiometric amounts
of Mg(ClO4)2 further accelerated cyclizations of 5b and 6b
(entries 8 and 9), but with less favorable stereoselectivities.
Asymmetric intramolecular ene cyclizations have been
developed using covalently linked chiral auxiliaries.11 How-
ever, metal-promoted asymmetric versions of such reactions
using chiral ligands are rare. Intramolecular ene/conjugated
alkene cyclizations have been achieved using chiral titanium
alkoxides12 or bis-oxazoline-magnesium perchlorate.13 In
each case, stoichiometric quantities of both metal and ligand
were required, and moderate to good enantioselectivity was
observed. The cyclization of 6b was conducted with a variety
of metal-ligand combinations, and the best results were
achieved using the bis-oxazoline-magnesium system re-
ported by Desimoni et al. (entries 10-12).13 Three different
commercially available bis-oxazolines 9a-c were screened.
Optimal results were obtained using 2 equiv of both metal
and ligand, indicating that sequestration of the metal-ligand
complex by the product was significant. Ligands 9a-c were
readily recoverable by chromatography of the product
mixture and could be reused.
anhydride followed by esterification afforded 5a. Similarly,
condensation of 4 with ethyl fumaryl chloride10 afforded 6a.
Both 5a and 6a were converted to the corresponding
N-benzoyl derivatives 5b and 6b in good yields.
The thermal and metal-catalyzed intramolecular ene reac-
tions of dienes 5a,b and 6a,b can form either cis-substituted
or trans-substituted pyrrolidones 7a,b and 8a,b, respectively
(Scheme 3).
Scheme 3
All three bis-oxazolines promoted Mg(II)-catalysis, and
in each case, cyclization strongly favored the desired cis-
diastereomer. The rate enhancement was most pronounced
with diphenyl-bis-oxazoline 9c and weakest with 9a,14 as
was the enantioselectivity (presented as the ratio of dextro-
and levorotatory enantiomers in the final column in Table
(9) Semenow, D.; Shih, C.-H.; Young, W. G. J. Am. Chem. Soc. 1958,
80, 5472-5475.
(10) (a) Eisner, V.; Elvidge, J. A.; Linstead, R. P. J. Chem. Soc. 1951,
1501-1512. (b) Schoenecker, J. W.; Takemori, A. E.; Portoghese P. S. J.
Med. Chem. 1986, 29, 1868-1871.
(11) For reviews, see: (a) Mikami, K.; Shimizu, M. Chem. ReV. 1992,
92, 1021-1050. (b) Jones, G. B.; Chapman, B. J. Synthesis 1995, 475-
497.
Cyclizations were studied under a variety of conditions
(Table 1). In the absence of catalyst, cyclization of 5a
(12) Narasaka, K.; Hayashi, Y.; Shimada, S. Chem. Lett. 1988, 1609-
(7) (a) Schedler, D. J. A.; Godfrey, A. G.; Ganem, B. Tetrahedron Lett.
1993, 34, 5035-5038. (b) Schedler, D. J. A.; Li, J.; Ganem B. J. Org.
Chem. 1996, 61, 4115-4119.
(8) (a) Oppolzer, W.; Andres, H. HelV. Chim. Acta 1979, 62, 2282-
2284. (b) Oppolzer, W. Pure Appl. Chem. 1981, 53, 1181-1201. (c)
Oppolzer, W.; Thirring, K. J. Am. Chem. Soc. 1982, 104, 4978-4979.
1612.
(13) Desimoni, G.; Faita, G.; Righetti, P.; Sardone, N. Tetrahedron 1996,
52, 12019-12030.
(14) The weaker catalytic activity of complexes of 9a with Mg(II) has
been noted: Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P. J. Am.
Chem. Soc. 1999, 121, 7559-7573.
486
Org. Lett., Vol. 3, No. 3, 2001