J. Am. Chem. Soc. 1996, 118, 3049-3050
A New Powerful and Practical BLA Catalyst for
3049
Highly Enantioselective Diels-Alder Reaction: An
Extreme Acceleration of Reaction Rate by Brønsted
Acid
Kazuaki Ishihara, Hideki Kurihara, and Hisashi Yamamoto*
School of Engineering, Nagoya UniVersity
Chikusa, Nagoya 464-01, Japan
ReceiVed December 4, 1995
Spectacular advances have been achieved in recent years in
enantioselective Diels-Alder reactions catalyzed by chiral Lewis
acids.1,2 One of our recent contributions was the introduction
of a new class of chiral catalyst 1 which was presumed to be a
Brønsted acid-assisted chiral Lewis acid (BLA).2d,3 This is one
of the best catalysts for the enantioselective and exo-selective
cycloaddition of R-substituted R,â-enals with highly reactive
dienes such as cyclopentadiene.2d With BLA 1 as well as most
chiral Lewis acids, however, the corresponding reactions of
R-unsubstituted R,â-enals like acrolein and crotonaldehyde
exhibit low enantioselectivity and/or reactivity. Lack of an
R-substituent on the dienophile decreases the enantioselectivity,
and the existence of a â-substituent strikingly decreases the
selectivity and reactivity. The scope of dienophiles which are
applicable for less reactive dienes is quite limited. Our previous
contribution was the development of helical titanium catalysts
which were effective for enantioselective cycloaddition of both
R-substituted and R-unsubstituted dienophiles.2c Unfortunately,
their catalytic activities are moderate even for methacrolein
because of too much streic hindrance from bulky ligand
substituents. Thus, we initiated a study aimed at the design
and synthesis of a more practical BLA which has greater
catalytic acitivity. We report here a new type of BLA, 2a, which
was prepared from chiral triol 3a and 3,5-bis(trifluoromethyl)-
benzeneboronic acid (4). 2a was extremely effective in enan-
tioselective cycloaddition of both R-substituted and R-unsub-
stituted R,â-enals with various dienes.
Boronic acid 4 was chosen as the Lewis acidic metal
component of the new BLA. We have found that this air-stable
boronic acid has enough Lewis acidity to promote some
reactions.4 Chiral ligands for 4 require inclusion of a biphenol
moiety to form a bidentate complex with the boron atom and a
phenol moiety which functions as a Brønsted acid. Thus, several
chiral triol ligands 3a-d were designed based on the terphenol
structure and synthesized from (R)-binaphthol using the Pd(0)-
catalyzed-coupling reaction as a key step.2d,5
BLA 2a-d were prepared in situ as follows. Method A: A
mixture of chiral triol 3a (1.2 equiv) and a solution of
monomeric boronic acid 4 (1 equiv) in dichloromethane-THF6
was stirred at ambient temperature for 2 h. The resulting
colorless solution was transferred into a Schlenk tube containing
dichloromethane and powdered MS 4A (250 mg/0.05 mmol of
4, activated7), and the mixture was stirred at ambient temperature
for another 12 h. Then the solvents were evaporated, and the
resulting solid was heated to 100 °C (oil bath) for 2 h under
vacuum to dry the catalyst. After cooling to ambient temper-
ature, the Schlenk tube was charged with dichloromethane to
afford an active catalyst solution including MS 4A. Method B
(a simplification of method A): A mixture of chiral triols 3a-d
(1.2 equiv), commercial boronic acid 4 (1 equiv),6 THF (150
µL/0.05 mmol of 4, without drying),8 powdered MS 4A (250
mg/0.05 mmol of 4, nonactivated), and dichloromethane was
stirred at ambient temperature for 12 h. The active catalyst
solution was then prepared by treatment similar to method A.
For studies of the catalytic, enantioselective cycloaddition
using 2a-d, methacrolein and cyclopentadiene were selected
as the representative substrates. The results are summarized in
Table 1. In the presence of 5 mol % of 2a-d prepared by
method A or B, the reaction proceeded smoothly and was
sterically controlled to form (S)-exo-adduct enantioselectively.
On the contrary, the reactions using chiral Lewis acids prepared
from (R)-diols which do not contain a Brønsted acid component
were relatively slow under the same conditions, and low
conversion and a reduced level of absolute induction were
observed (entries 7 and 8). It should be noted that the Brønsted
acid in the BLA catalysts clearly accelerates the cycloaddition.
The substituents R1 and R2 of triol ligands 3 appear significant
in determining which is the preferable hydroxy group in 3
serving as Brønsted acid. The best enantioselectivity and highest
reactivity were obtained in the reaction using 2a (entries 1 and
2), while a dramatic decrease of rate and selectivity was
observed with 2b-d (entries 4-6). Although the formation of
two bidentate complexes between 3 and 4 is possible, R2
sterically prevents a coordination between the hydroxy group
adjacent to R2 and the boron atom.
(1) For a recent review, see: Ishihara, K.; Yamamoto, H. In AdVances
in Catalytic Processes; Doyle, M. P., Ed.; JAI Press: London, 1995; Vol.
1, p 29.
(2) For some leading articles on enantioselective Lewis acid catalyzed
Diels-Alder reaction of R,â-unsaturated aldehydes with dienes, see: (a)
Furuta, K.; Shimizu, S.; Miwa, Y.; Yamamoto, H. J. Org. Chem. 1989, 54,
1481. (b) Bao, J.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 1993,
115, 3814. (c) Maruoka, K.; Murase, N.; Yamamoto, H. J. Org. Chem.
1993, 58, 2938. (d) Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 1994,
116, 1561. (e) Ku¨ndig, E. P.; Bourdin, B.; Bernardinelli, G. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 1856. (f) Evans, D. A.; Murry, J. A.; von Matt, P.;
Norcross, R. D.; Miller, S. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 798.
(3) (a) Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.; Yamamoto, H. J.
Am. Chem. Soc. 1994, 116, 10520. (b) Aggarwal, V. K.; Anderson, E.;
Giles, R.; Zaparucha, A. Tetrahedron: Asymmetry 1995, 6, 1301.
(4) For references on chiral Lewis acid using 4, see: (a) Ishihara, K.;
Maruyama, T.; Mouri, M.; Gao, Q.; Furuta, K.; Yamamoto, H. Bull. Chem.
Soc. Jpn. 1993, 66, 3483. (b) Ishihara, K.; Mouri, M.; Gao, Q.; Maruyama,
T.; Furuta, K.; Yamamoto, H. J. Am. Chem. Soc. 1993, 115, 11490.
(5) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207.
The most striking feature in the present process is the role of
water, THF, and molecular sieves in preparation of the catalyst.
The enantioselectivity was diminished to less than 80% ee in
the reaction using 2a prepared in situ in the presence of activated
(6) Boronic acid 4, which is commercially available from Lancaster
Synthesis, Ltd., contains varying amounts of cyclic trimeric anhydrides
(boroxines). A 0.043 M solution of monomeric 4 was prepared by addition
of water (54 µL, 3 mmol), dry THF (3 mL), and dichloromethane (20 mL)
to a commerical 4 (1 mmol, >90% trimer).
(7) MS 4A was activated by heating at 200 °C under vacuum for 12 h.
(8) THF (no stabilizer) was purchased from Wako Pure Chemical
Industries, Ltd.
0002-7863/96/1518-3049$12.00/0 © 1996 American Chemical Society
Ishihara, Kazuaki
