DOI: 10.1002/anie.201106497
Asymmetric Catalysis
Enantioselective Diels–Alder Reactions with Anomalous endo/exo
Selectivities Using Conformationally Flexible Chiral Supramolecular
Catalysts**
Manabu Hatano, Tomokazu Mizuno, Atsuto Izumiseki, Ryota Usami, Takafumi Asai,
Matsujiro Akakura, and Kazuaki Ishihara*
On the basis of Woodward–Hoffmann frontier molecular
orbital interactions and steric interactions between dienes and
dienophiles during the formation of [2+4] pericyclic transi-
tion states, endo/exo selectivity in the Diels–Alder reaction
strongly depends on the substrates.[1] Therefore, it is quite
difficult to control both enantioselectivity[2] and anomalous
endo/exo selectivity by conventional chiral catalysts, which
can discriminate only the enantiofaces of the dienophiles. For
example, in the reaction between cyclopentadiene (1) and
acrolein (2a), an endo preference is observed with regard to
second-order orbital interactions without significant steric
interactions [Eq. (1)]. In sharp contrast, in the reaction
between 1 and an a-substituted acrolein (R ¼ H), such as
methacrolein (2b), an exo preference is observed with regard
to steric interactions between the methylene moiety of 1 and
the substituent R at the a position of the dienophile [Eq. (2)].
Therefore, enantiomerically enriched endo-3a and exo-3b
have been synthesized by using many conventional chiral
catalysts.[2] Moreover, thermodynamically more stable and
enantiomerically enriched exo-3a can be generated by the
epimerization of endo-3a [Eq. (1)]. Alternatively, catalyst-
induced anomalous exo-selective Diels–Alder reactions that
contravene the endo rule have been performed by Yamamoto
and co-workers[3] in a non-asymmetric manner, and later by
Maruoka and co-workers,[4] Sibi et al.,[5] and Hayashi et al.[6]
in an asymmetric manner. In contrast, enantiomerically
enriched endo-3b with a quaternary carbon center can not
be generated by the epimerization of exo-3b or by other
known synthetic methods [Eq. (2)]. To the best of our
knowledge, no examples of catalyst-induced anomalous
endo-selective enantioselective Diels–Alder reactions with
a-substituted acroleins have been reported to date. To
address this major yet unexplored subject, catalysts must
discriminate chiral transition-state structures by precisely
recognizing the re or si face of dienophiles, and the endo or
exo approach of dienes, thus, the rational design of conforma-
tionally flexible chiral supramolecular catalysts, such as
enzymes, is necessary.[7] As such, conformationally rigid
metal–organic frameworks (MOFs) are not suitable as
artificial enzymes because they have few induced-fit proper-
ties to adapt dynamics in transition states.[8]
A chiral supramolecular catalyst (4a) was readily pre-
pared in situ from three components, which included
10 mol% of chiral (R)-3,3’-bis(5,5-dimethyl-2-oxido-1,3,2-
dioxaphosphorinan-2-yl)-BINOL (5a; BINOL = 1,1’-bi(2-
naphthol)),[9] 10 mol% of 3,5-bis(trifluoromethyl)phenylbor-
onic acid (6a), and 20 mol% of tris(pentafluorophenyl)bor-
ane (7), by taking advantage of the typical preparation of
[*] Dr. M. Hatano, T. Mizuno, Dr. A. Izumiseki, R. Usami, Dr. T. Asai,
Prof. Dr. K. Ishihara
Graduate School of Engineering, Nagoya University
Furo-cho, Chikusa, Nagoya 464-8603 (Japan)
E-mail: ishihara@cc.nagoya-u.ac.jp
boron BINOLates[10] (Scheme 1). Intermolecular acid–base
[11]
=
coordinate bonds in the two P O···B(C6F5)3 moieties are
critical for the design of conformationally flexible complex
4a; compound 7 acts as a bulky functional group to form a
chiral, narrow, and deep cavity around the Lewis acidic boron
center. Moreover, the strong electron-accepting nature of
Lewis acid 7 increases the Lewis acidity of the central boron
through conjugated bonds, thus taking advantage of Lewis
acid assisted chiral Lewis acid (LLA) catalysts.[12] The Diels–
Alder reaction between 1 and 2b was conducted in the
presence of the catalyst 4a (10 mol%) in dichloromethane at
ꢀ788C for 3 h (Scheme 2). As a result, the anomalous product
endo-(2S)-3b was obtained as the major product (99% yield,
endo/exo = 83/17) with excellent enantioselectivity (99% ee).
This result is remarkable because the use of compounds 6a
Prof. Dr. K. Ishihara
Japan Science and Technology Agency (JST), CREST
Furo-cho, Chikusa, Nagoya 464-8603 (Japan)
Dr. M. Akakura
Department of Chemistry, Aichi University of Education
Igaya-cho, Kariya, 448-8542 (Japan)
[**] Financial support for this project was partially provided by MEXT,
KAKENHI (21750094, 21200033), the Global COE Program of
MEXT, and Yazaki Memorial Foundation for Science and Technol-
ogy. We are grateful to the Tosoh Finechem Corporation and Central
Glass Co., Ltd. for providing organometallic reagents.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2011, 50, 12189 –12192
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12189