Communications
DOI: 10.1002/anie.201005409
Organocatalysis
Asymmetric Bromolactonization Catalyzed by a C3-Symmetric Chiral
Trisimidazoline**
Kenichi Murai, Tomoyo Matsushita, Akira Nakamura, Shunsuke Fukushima, Masato Shimura,
and Hiromichi Fujioka*
Halolactonization is one of the fundamental transformations
in synthetic organic chemistry.[1] This reaction provides
synthetically useful products, which can be employed as
synthetic intermediates for divergent transformations. A
catalytic asymmetric version of this transformation would
be very attractive. However, though a number of attempts to
Scheme 1. Our working hypothesis for the development of an asym-
metric bromolactonization.
develop catalytic asymmetric halolactonization reactions
have been made,[2] and several related enantioselective
halocyclizations have been developed,[3] these reactions are
still under development. Recently, highly enantioselective
halolactonization reactions with organocatalysts were
reported.[4] Borhan and co-workers reported an enantiose-
lective chlorolactonization of 4-substituted 4-pentenoic acids
in the presence of hydroquinidine 1,4-phthalazinediyl diether
((DHQD)2PHAL),[4a] and Tang and co-workers reported an
enantioselective bromolactonization of conjugated Z enynes
with a bifunctional cinchona-alkaloid catalyst bearing a urea
moiety.[4b] However, the former reaction was limited to
chlorolactonization; bromo- and iodolactonization were not
successful, although Br and I are generally more readily
transformed into various functional groups than Cl. The latter
reaction is limited to particular substrates, such as conjugated
Z enynes. Therefore, the development of a novel efficient
method for catalytic asymmetric halolactonization is still
important. During the preparation of this manuscript, Veitch
and Jacobsen reported a tertiary-amine-catalyzed enantiose-
lective iodolactonization.[5] Herein, we present our study on
organocatalytic asymmetric halolactonization. By using the
structurally unique C3-symmetric trisimidazoline 1a, we
and the two possible bromonium intermediates would be in
equilibrium in the presence of the brominating reagent, and
the activated carboxylic acid, which would be in a chiral
environment, should react preferentially with one of the two
bromonium ions.[6] This approach is different from recent
successful approaches, which mainly involved the creation of
chiral environments around the halo cations.[4,5] The key to
this hypothesis was the appropriate choice of a chiral amine
that would have a good interaction with carboxylic acids.[7]
We envisioned that the C3-symmetric trisimidazoline 1a
(Scheme 2), which we developed recently as a new organo-
catalyst entry,[8] could be suitable for our working hypothesis,
because an interesting interaction of the trisimidazoline
derived from ethylenediamine with carboxylic acids led to
the formation of 1:3 complexes in the field of material
sciences (Scheme 2).[9]
developed
a novel asymmetric bromolactonization of
5-substituted 5-hexenoic acids.
Our working hypothesis for the development of the
enantioselective bromolactonization is shown in Scheme 1.
We assumed that if the alkenyl carboxylic acid and an
appropriate chiral amine could form an ion pair, a chiral
environment would be created. At the same time, the
carboxylic acid should be activated. Bromolactonization
would then proceed enantioselectively, because the olefin
Scheme 2. Structure of the C3-symmetric trisimidazoline 1a and the
reported 1:3 complex of a trisimidazoline with a carboxylic acid.
[*] Dr. K. Murai, T. Matsushita, A. Nakamura, S. Fukushima,
M. Shimura, Prof. Dr. H. Fujioka
To test this idea, we examined the bromolactonization of
5-phenylhex-5-enoic acid (2a) with N-bromosuccinimide
(NBS). As expected, the reaction with catalyst 1a afforded
the lactone 3a with 69% ee, even at room temperature
(Table 1, entry 1). The reaction of 2a in the presence of other
chiral amines, such as quinidine or (DHQD)2PHAL, pro-
ceeded less selectively, although 3a was formed with moder-
ate enantioselectivity with (DHQD)2PHAL (Table 1,
entries 2 and 3). Reactions with the bisimidazoline and
Graduate School of Pharmaceutical Sciences, Osaka University
1-6, Yamada-oka, Suita, Osaka, 565-0871 (Japan)
Fax: (+81)6-6879-8229
E-mail: fujioka@phs.osaka-u.ac.jp
[**] This research was financially supported by a Grant-in-Aid for
Scientific Research (B) and for Young Scientists (B) from JSPS.
Supporting information for this article is available on the WWW
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Angew. Chem. Int. Ed. 2010, 49, 9174 –9177