Design of bronsted acid-assisted chiral Lewis acid (BLA) catalysts for highly enantioselective Diels-Alder reactions

Article abstract of DOI:10.1021/ja9810282

Bronsted acid-assisted chiral Lewis acid (BLA) was highly effective as a chiral catalyst for the enantioselective Diels-Alder reaction of both α- substituted and α-unsubstituted α,β-enals with various dienes. Hydroxy groups in optically active binaphthol derivatives and boron reagents with electron-withdrawing substituents were used as Bronsted acids and Lewis acids, respectively. Intramolecular Bronsted acids in a chiral BLA catalyst played an important role in accelerating the rate of Diels-Alder reactions and in producing a high level of enantioselectivity. In particular, excellent enantioselectivity was achieved due to intramolecular hydrogen bonding interaction and attractive π-π donor-acceptor interaction in the transition-state assembly by hydroxy aromatic groups in a chiral BLA catalyst.

Full text of DOI:10.1021/ja9810282

6920
J. Am. Chem. Soc. 1998, 120, 6920-6930
Design of Brønsted Acid-Assisted Chiral Lewis Acid (BLA) Catalysts
for Highly Enantioselective Diels-Alder Reactions
Kazuaki Ishihara,† Hideki Kurihara,‡ Masayuki Matsumoto,‡ and Hisashi Yamamoto*,‡
Contribution from the Research Center for AdVanced Waste and Emission Management (ResCWE),
Nagoya UniVersity, Furo-cho, Chikusa, Nagoya 464-8603, Japan, and Graduate School of Engineering,
Nagoya UniVersity, CREST, JST, Furo-cho, Chikusa, Nagoya 464-8603, Japan
ReceiVed March 26, 1998
Abstract: Brønsted acid-assisted chiral Lewis acid (BLA) was highly effective as a chiral catalyst for the
enantioselective Diels-Alder reaction of both R-substituted and R-unsubstituted R,â-enals with various dienes.
Hydroxy groups in optically active binaphthol derivatives and boron reagents with electron-withdrawing
substituents were used as Brønsted acids and Lewis acids, respectively. Intramolecular Brønsted acids in a
chiral BLA catalyst played an important role in accelerating the rate of Diels-Alder reactions and in producing
a high level of enantioselectivity. In particular, excellent enantioselectivity was achieved due to intramolecular
hydrogen bonding interaction and attractive π-π donor-acceptor interaction in the transition-state assembly
by hydroxy aromatic groups in a chiral BLA catalyst.
Introduction
dienophile and a chiral ligand is highly effective for inducing
asymmetry. This finding encouraged us to seek new members
of this class to achieve high enantioselectivity through the
combination of intramolecular hydrogen bonding and attractiVe
π-π donor-acceptor interaction in the transition-state assembly
by hydroxy aromatic groups in chiral Lewis acids. Thus, we
developed Brønsted acid-assisted chiral Lewis acid (BLA)
catalysts, 1-4, which are highly effective for enantioselective
Diels-Alder reactions.4,5 This paper describes a successful and
practical methodology based on this new concept, which we
believe has wide implications in catalyst design and which deals
specifically with catalysis of the Diels-Alder reaction.4
Spectacular advances have recently been achieved in enan-
tioselective Diels-Alder reactions catalyzed by chiral Lewis
acids.1 In particular, the design of chiral metal aryloxides
prepared from metal reagents and optically active binaphthol
derivatives has been one of the most intensively studied areas
in the development of new asymmetric Diels-Alder catalysts.2
Nevertheless, there are still few practical procedures available
which can be widely applied to various dienes and dienophiles.
In most cases, asymmetric induction with chiral metal aryloxides
is controlled by steric interaction between a dienophile and a
chiral ligand, but this kind of interaction is insufficient to provide
a high level of enantioselectivity.2 On the other hand, Hawkins
et al.,3a Corey et al.,3b and we3c have independently reported
that the attractive π-π donor-acceptor interaction between a
Results and Discussion
Design of BLA Using B(OMe)3. (R)-3,3′-Di(2-hydroxy-
phenyl)-2,2′-dihydroxy-1,1′-binaphthyl (5a) was synthesized
from (R)-binaphthol using the Pd(0)-catalyzed-coupling reaction
as a key step.2f,6 Reaction of (R)-tetraol 5a with B(OMe)3 in
dichloromethane at reflux with the removal of methanol (4 Å
molecular sieves (MS 4A) in a Soxhlet thimble) gave (R)-1a
as a white precipitate after 2∼3 h. To the suspension of (R)-
1a in dichloromethane was added THF (1 mL per 1 mmol of
1a) at 25 °C, and after 2 h the mixture turned to a colorless
* Corresponding author.
† ResCWE.
‡ Graduate School of Engineering.
(1) For recent reviews, see: (a) Ishihara, K.; Yamamoto, H. In AdVances
in Catalytic Processes; Doyle, M. P., Ed.; JAI Press: London, 1995; Vol.
1, p 29. (b) Ishihara, K.; Yamamoto, H. CatTech 1997, 51. (c) Dias, L. C.
J. Braz. Chem. Soc. 1997, 8, 289.
(2) For the enantioselective Diels-Alder reaction catalyzed by chiral
metal aryloxide, see B(OAr)3: (a) Kelly, T. R.; Whiting, A.; Chandrakumar,
N. S. J. Am. Chem. Soc. 1986, 108, 3510. (b) Kaufmann, D.; Boese, R.
Angew. Chem., Int. Ed. Engl. 1990, 29, 545. MeAl(OAr)2: (c) Maruoka,
K.; Conception, A. B.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1992, 65, 3501.
ClAl(OAr)2: (d) Bao, J.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem.
Soc. 1993, 115, 3814. (e) Heller, D. P.; Goldberg, D. R.; Wulff, W. D. J.
Am. Chem. Soc. 1997, 119, 10551. Ti(OAr)4: (f) Maruoka, K.; Murase,
N.; Yamamoto, H. J. Org. Chem. 1993, 58, 2938. Cl2Ti(OAr)2: (g) Reetz,
M. T.; Kyung, S. H.; Bolm, C.; Zierke, T. Chem. Ind. (London) 1986, 2409.
(h) Mikami, K.; Motoyama, Y.; Nakai, T. Tetrahedron: Asymmetry 1991,
2, 643. (i) Mikami, K.; Motoyama, Y.; Terada, M. J. Am. Chem. Soc. 1994,
116, 2812. (j) Motoyama, Y.; Terada, M.; Mikami, K. Synlett 1995, 967.
(k) Harada, T.; Takeuchi, M.; Hatsuda, M.; Ueda, S.; Oku, A. Tetrahedron:
Asymmetry 1996, 7, 2479. (l) Matsukawa, S.; Mikami, K. Tetrahedron:
Asymmetry 1997, 8, 815.
1
solution. The H NMR spectrum of 1a after the addition of
D2O showed no methanol peak. The 11B NMR spectrum of a
solution of 1a in CD2Cl2 showed a single broad peak at 10 ppm
(downfield from external BF3-Et2O). The 11B NMR data are
(4) Part of this work has been published as preliminary communica-
tions: (a) Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 1561.
(b) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118,
3049.
(5) For examples of BLA catalysts, see: (a) Ishihara, K.; Miyata, M.;
Hattori, K.; Tada, T.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 10520.
(b) Koboyashi, S.; Araki, M.; Hachiya, I. J. Org. Chem. 1994, 59, 3758.
(c) Aggarwal, V. K.; Anderson, E.; Giles, R.; Zaparucha, A. Tetrahedron:
Asymmetry 1995, 6, 1301. (d) Ishihara, K.; Kondo, S.; Kurihara, H.;
Yamamoto, H. J. Org. Chem. 1997, 62, 3026.
(3) (a) Hawkins, J. M.; Loren, S. J. Am. Chem. Soc. 1991, 113, 7794.
Hawkins, J. M.; Loren, S.; Nambu, M. J. Am. Chem. Soc. 1994, 116, 1657.
(b) Corey, E. J.; Loh, T.-P. J. Am. Chem. Soc. 1991, 113, 8966. Corey, E.
J.; Loh, T.-P.; Roper, T. D.; Azimioara, M. D.; Noe, M. C. J. Am. Chem.
Soc. 1992, 114, 8290. (c) Ishihara, K.; Gao, Q.; Yamamoto, H. J. Am. Chem.
Soc. 1993, 115, 10412.
(6) For synthesis of sterically hindered biaryls via the palladium-catalyzed
cross-coupling reaction, see: Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett
1992, 207.
S0002-7863(98)01028-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/29/1998

Catalysts for Diels-Alder Reactions
J. Am. Chem. Soc., Vol. 120, No. 28, 1998 6921
Table 1. Enantioselective Diels-Alder Reaction Catalyzed by
(R)-BLA 1a
consistent with structure 1a as the major species. Conversion
of the trigonal (B(OR)3, 11B NMR 18 ( 2 ppm) to the tetrahedral
molecule (B(OR)4-) by nucleophilic addition of a fourth ligand
increases the shielding of boron by 16 ppm.7a With B(OPh)3,
B(OPh)3 including excess PhOH, and LiB(OPh)4, the 11B NMR
peaks appear at 16.5 ppm,7b 14.5 ppm,7c and 3.0 ppm,7c
respectively. The fact that boron shielding increases in the order
[B(OPh)3 + PhOH] < 1a < LiB(OPh)4 suggests that 1a is a
tetrahedral structure close to an ionic ate complex.
a Unless otherwise noted, the reaction was carried out in freshly
distilled dichloromethane using 10 mol % of catalyst (R)-1a and 4 equiv
of the diene per aldehyde at -78 °C. b The figure given for product
shows the major diastereomer. c Isolated yield by column chromatog-
raphy for the exo/endo mixture. d Diastereoselectivity was determined
by 1H NMR analysis or GC analysis of Diels-Alder adducts. e The ee
of major isomer and the absolute configuration of its carbonyl R-carbon
are indicated. The absolute configuration indicated in entry 4 was
assigned by analogy with cyclopentadiene,3b and the others were
assigned by comparison with data in the literatures. For determination
methods, see Experimental Section. f 5 mol % of catalyst (R)-1a was
used. g (R)-6 was not formed in a detectable amount. h The reaction
temperature was -40 °C. i (R)-1b was used in place of (R)-1a. For
preparation of 1b, see Experimental Section.
group3b,8 has demonstrated that R-bromoacrolein is an outstand-
ing dienophile in a catalytic Diels-Alder process because of
the exceptional synthetic versatility of the resulting adducts. For
instance, an important intermediate for prostaglandin synthesis,
7, was synthesized with remarkable ease.3b
With BLA 1 as well as most chiral Lewis acids,1 however,
the corresponding reactions of R-unsubstituted R,â-enals such
as acrolein and crotonaldehyde exhibit low enantioselectivity
and/or reactivity. Lack of an R-substituent on the dienophile
decreases the enantioselectivity, and an existence of R, â-sub-
stituent strikingly decreases the selectivity and reactivity. To
raise the enantioselectivity for R-unsubstituted R,â-enals, the
substituent effect of chiral tetraol 1 was examined in the Diels-
Alder reaction of cyclopentadiene and acrolein.2f The enanti-
oselectivity was raised to 92% ee by using (R)-1b in place of
(R)-1a (see Table 1).
In the presence of 5 mol % of (R)-1a, R-bromoacrolein (1
equiv) and cyclopentadiene (ca. 4 equiv) underwent smooth
Diels-Alder addition (-78 °C, 4 h) to give the (1S,2S,4S)-2-
bromobicyclo[2.2.1]hept-5-ene-2-carboxaldehyde (6) in >99%
yield, >99% ee (S only), and >99% de (exo only); chiral ligand
5a was efficiently recovered.
Extremely high enantioselectivity and exo selectivity were
obtained for Diels-Alder additions of R-substituted R,â-enals
with dienes in the presence of the catalyst (R)-1a. These results
are summarized in Table 1. Enantioselectivities were in the
range >99 to 92% ee, and the major enantiomer in several cases
was found to have the predicted absolute configuration. Corey’s
To determine the activated face of the carbonyl group in the
coordination complex of methacrolein and (R)-1a, the aldol
reaction of methacrolein with trimethylsilyl enol ether derived
from acetophenone was carried out in the presence of 10 mol
(7) (a) Kidd, R. G. In NMR of Newly Accessible Nuclei; Laszlo, P., Ed.;
Academic Press: New York, 1983; Vol. 2, pp 49-77. (b) Olah, G. A.;
Wu, A. Synthesis 1991, 204 and references therein. (c) Our experimental
results.
(8) (a) Corey, E. J.; Loh, T.-P. Tetrahedron Lett. 1993, 34, 3979. (b)
Corey, E. J.; Cywin, C. L. J. Org. Chem. 1992, 57, 7372.

6922 J. Am. Chem. Soc., Vol. 120, No. 28, 1998
Ishihara et al.
Scheme 1. The Absolute Stereopreference on Mukaiyama
Aldol Reaction Promoted by (R)-1
intramolecular hydrogen bonding via the Brønsted acid, while
the latter has a helical structure.2f,11
% of (R)-1a at -78 °C for 15.5 h to form (R)-aldol adduct as
a major isomer (13%) with 78:22 enantioselectivity (Scheme
1). The reaction was stoichiometric since the boron-oxygen
bonds of (R)-1a were easily cleaved by trimethylsilyl enol ethers.
The observed stereoselectivity in this catalytic Diels-Alder
process is probably a consequence of the shielded si-face of a
carbonyl group and a high s-trans preference of R,â-enal9 if
the aldol result is relevant to the Diels-Alder transition state.3c,5d
Design of BLA Using 3,5-Bis(trifluoromethyl)phenylbo-
ronic Acid. BLA 1a is one of the best catalysts for the enantio-
and exo-selective cycloaddition of R-substituted R,â-enals with
highly reactive dienes such as cyclopentadiene.4a However, the
corresponding reactions of R-unsubstituted R,â-enals such as
acrolein and crotonaldehyde exhibit low enantioselectivity and/
or reactivity. The scope of dienophiles which are applicable
for less reactive dienes is quite limited. We previously reported
the development of helical titanium catalysts which were
effective for the enantioselective cycloaddition of both R-sub-
stituted and R-unsubstituted dienophiles.2f Unfortunately, their
catalytic activities are moderate even for methacrolein because
of an excess of steric hindrance due to the bulky substituents
of the ligands. Thus, we subsequently studied the design and
synthesis of a more practical BLA which has greater catalytic
activity in the enantioselective cycloaddition of both R-substi-
tuted and R-unsubstituted R,â-enals with various dienes.
3,5-Bis(trifluoromethyl)phenylboronic acid (17) 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 by itself.12 Chiral ligands
for 17 require the 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 18a-d were designed based on the terphenol structure
and synthesized from (R)-binaphthol using the Pd(0)-catalyzed-
coupling reaction as a key step.2f,6
The absolute stereopreference in the Diels-Alder reaction
can be easily understood in terms of the most favorable
transition-state assembly A which is proposed on the basis of
the above assumption. An attractive donor-acceptor interaction
favors coordination of the dienophile at the face of boron which
is cis to the 2-hydroxyphenyl substituent in A. We believe that
the coordination of a proton of the 2-hydroxyphenyl group with
an oxygen of the adjacent B-O bond in complex A plays an
important role in asymmetric induction; this hydrogen bonding
via the Brønsted acid would cause the Lewis acidity of boron
and π-basicity of phenoxyl moiety to increase, and the transition-
state assembly A would be stabilized. Subsequently, the π-basic
phenoxyl moiety and the π-acidic dienophile can assume a
parallel orientation at the ideal separation (3 Å) for donor-
acceptor interaction. In this conformation, the hydroxyphenyl
group blocks the re-face of olefin in the dienophile (R ) Br),
leaving the si-face open to approach by diene. This assumption
has been confirmed by experiment. Of great mechanistic
significance is the fact that the Diels-Alder reaction of
cyclopentadiene and methacrolein at -78 °C for 14 h under
catalysis by 10 mol % of the boron complex 15 prepared from
(R)-3-(2-benzyloxyphenyl)-2,2′-dihydroxy-3′-(2-hydroxyphenyl)-
1,1′-binaphthyl (16) and BH3-THF10 gave the (2S)-enantiomer
of 9 as a major product with 65% ee (exo:endo ) 97:3). With
the boron catalysts prepared from BH3-THF10 and monoiso-
propyl ether and mono-tert-butyldimethylsilyl ether of 5a, the
reactions with methacrolein exhibited low enantioselectivities
(17% ee and 29% ee, respectively), but the opposite face
selectivity ((2S)-9 as a major enantiomer) predominated. The
dramatically opposite results using the tetraol 5a and the triols
provide strong evidence for transition-state assemblies A and
B, respectively; the former has a fixed nonhelical structure via
BLA 2a-d were prepared in situ as follows. Method A.
A mixture of chiral triol 18a (1.2 equiv) and a solution of
monomeric boronic acid 17 (1 equiv) in dichloromethane-
THF13 was stirred at ambient temperature for 2 h. The resulting
colorless solution was transferred to a Schlenk tube containing
dichloromethane and powdered MS 4A (250 mg per 0.05 mmol
of 17, activated14), and the mixture was stirred at ambient
temperature for another 12 h. The solvents were then evapo-
rated and the resulting solid was heated to 100 °C (oil bath) for
2 h under vacuum to dry the catalyst. After cooling to ambient
(11) If it is assumed that the Diels-Alder reaction occurs only through
that conformation that has the dienophile and the phenyl group the closest
together in space (via the attractive interaction), the absolute stereocourse
can be understood in terms of the two possible transition-state assemblies
A and B.
(9) Interestingly, the (S)-tryptophan-derived chiral Lewis acid catalyst
system developed by Corey et al.3b appears to function via an s-cis-R-
substituted-R,â-enal complex, in contrast to our results that R,â-enal prefers
the s-trans conformation in the tartaric acid-derived chiral acyloxyborane
catalyst system3c as well as in the present system.
(10) Monoethers of 5a coexistent with B(OMe)3 in dichloromethane were
partially decomposed under a reflux condition. The reaction of methacrolein
with cyclopentadiene under catalysis by 10 mol % of the boron complex
1a prepared from BH3-THF and 5a gave (2R)-7 as major product with
86% ee (exo: endo ) 99: 1).
(12) For references on chiral Lewis acid using 17, 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.
(13) Boronic acid 17, which is commercially available from Lancaster
Synthesis, Ltd., contains varying amounts of cyclic trimeric anhydrides
(boroxines). A 0.043 M solution of monomeric 17 was prepared by addition
of water (54 mL, 3 mmol), dry THF (3 mL), and dichloromethane (20 mL)
to a commercial 17 (1 mmol, >90% trimer).
(14) MS 4A was activated by heating at 200 °C under vacuum for 12 h.

Catalysts for Diels-Alder Reactions
J. Am. Chem. Soc., Vol. 120, No. 28, 1998 6923
Table 2. Modification and Preparation of Diels-Alder Catalystsa
entry
chiral ligand
methodb yieldc (%) ee (%)d [config]
1
2
3
4
5
6
7
8
(R)-18a
A
B
Ae
B
B
B
B
B
96
94
95
89
97
63
9
99 [S]
98 [S]
48 [S]
50 [S]
77 [S]
60 [S]
45 [S]
46 [S]
(R)-18b
(R)-18c
(R)-18d
(R)-18a (MeO)f
(R)-Binaphthol
22
a The reactions were conducted in dichloromethane using aldehyde
(1 equiv, 0.25 M) and diene (4 equiv) in the presence of 5 mol % of
2 at -78 °C for 1.5 h. b See text. c Isolated yield. d The ee of major
isomer and the absolute configuration of its carbonyl R-carbon are
indicated. The absolute configuration was assigned by comparison with
data in the literature. For the determination method, see Experimental
Section. e No THF was added. f (R)-3-(2-Methoxyphenyl)-2,2′-dihy-
droxy-1,1′-binaphthyl was used.
temperature, the Schlenk tube was charged with dichloromethane
to give an active catalyst solution including MS 4A. Method
B (a simplification of method A). A mixture of chiral triols
18a-d (1.2 equiv), commercial boronic acid 17 (1 equiv),13
THF (150 mL per 0.05 mmol of 17, without drying),15 powdered
MS 4A (250 mg per 0.05 mmol of 17, nonactivated), and
dichloromethane was stirred at ambient temperature for 12 h.
The active catalyst solution was then prepared as in method A.
For studies of catalytic, enantioselective cycloaddition using
2a-d, methacrolein and cyclopentadiene were selected as
representative substrates. The results are summarized in Table
2. In the presence of 5 mol % of 2a-d prepared by method A
or B, the reaction proceeded smoothly and was controlled
sterically to form (S)-exo-adduct enantioselectively. In contrast,
the reactions using chiral Lewis acids prepared from (R)-diols
which did 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). The presence of a Brønsted acid in BLA catalysts clearly
accelerates the cycloaddition.
Figure 1. Plot of the distribution ratio of boron atom in a solution of
17 versus additional water.
The substituents R1 and R2 of triol ligands 18 appear to be
significant in determining which hydroxy group in 18 best serves
as a Brønsted acid. The best enantioselectivity and highest
reactivity were obtained in the reaction using 2a (entries 1 and
2), while a dramatic decrease in rate and selectivity was observed
with 2b-d (entries 4-6). Although the formation of two
bidentate complexes between 18 and 17 is possible, R2 sterically
prevents the formation of a complex between the hydroxy group
adjacent to R2 and the boron atom.
The most striking feature in the present process is the role of
water, THF, and MS 4A in the preparation of the catalyst. The
enantioselectivity was reduced to less than 80% ee in the
reaction using 2a prepared in situ in the presence of activated
MS 4A under anhydrous conditions. Preparation of a sufficient
amount of 2a is assumed to be difficult under these conditions
since the trimer of 17 is easily generated by dehydration and is
not readily dissociated by the addition of 18a. In fact, 17 usually
exists as a mixture of monomer, trimer, and oligomer.13 To
prevent trimerization of 17 in preparing the catalyst, 18a and
17 were mixed under aqueous conditions and then dried
(methods A and B) since the presence of water or THF
deactivates 2a; in this manner, 99% ee was obtained (entry 1).
Significantly, use of the solution obtained by filtering the MS
4A off of 2a after preparation by method B provided the same
high level of enantioselectivity. Although molecular sieves are
essential for dehydration, they may facilitate the aryloxy-ligand
exchange reaction in the in situ preparation of 2a. However,
using 2a prepared without the addition of THF gave a low
enantiomeric excess (48%, entry 3); this may be due to the
stability of monomeric 17 by coordination of THF. Actually,
more than 98% of 17 existed as a monomer in dichlo-
romethane-THF (20:3) with the addition of 2 equiv of water,
while ca. 20% of 17 is a mixture of trimer and oligomer in
dichloromethane alone (Figure 1).
The present results indicate that BLA 2a was the optimum
catalyst, and representative results in the cycloadditions between
various R,â-enals and dienes are given in Table 3. In each case
the adducts were formed in high yield with excellent enanti-
oselectivity. As expected, the additions of the less-reactive
â-substituted R,â-enals with cyclopentadiene gave very good
results. In addition, 2a was an excellent catalyst for not only
less-reactive dienophiles but also less-reactive dienes such as
acyclic dienes and cyclohexadiene. However, moderate enan-
tioselectivity was observed in the reaction of phenyl acrylate
and cyclopentadiene. Chiral ligand 18a could be recovered
readily, and could be reused efficiently. The reaction mixture
(15) THF (none stabilizer) was purchased from Wako Pure Chemical
Industries, Ltd.

6924 J. Am. Chem. Soc., Vol. 120, No. 28, 1998
Ishihara et al.
Table 3. Enantioselective Diels-Alder Reaction Catalyzed by (R)-BLA 2aa
2a (mol%)
yield (%)d
ee (%)e
entry
dienophile
dieneb
[method]c
[exo:endo]e
[config]e
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
CH2dCBrCHO
CP
CP
5 [B]f
>99 [90:10]
97 [88:12]
>99 [89:11]
65 [10:90]
95
>99 [R]
97 [R]
>99 [R]
95
91
>99 [R]
95
>99
>99
96
95 [S]
96 [S]
>99
99
95 [S]
98
75
1 [B]f
BMCP
CH
DMB
IP
CH
DMB
IP
CP
CP
CH
DMB
IP
CP
CP
CP
CP
CP
CP
CP
10 [A]
10 [B]g
10 [B]h
10 [B]
20 [B]
10 [B]
10 [B]
20 [A]i
5 [A]
95
CH2dCMeCHO
87 [11:89]
81
73
90 [98:2]
84 [3:97]
>99 [0:100]
97
(E)-MeCHdCMeCHO
CH2dCHCHO
10 [B]
10 [B]
10 [A]
20 [A]
20 [A]j
20 [B]k
20 [A]l
5 [A]
95
(E)-MeCHdCHCHO
(E)-EtCHdCHCHO
94 [10:90]
73 [9:91]
57 [18:82]
94 [26:74]
91 [2:98]
57 [25:75]
90 [28:72]
(E)-PhCHdCHCHO
(E)-EtO2CCHdCHCHO
CH2dCHCO2Ph
80
95 [R]
56 [S]
67 [S]
20 [B]m
20 [B]n
CH2dCHCO2C6H4-p-F
a Unless otherwise noted, reactions were conducted in dichloromethane using aldehyde (1 equiv, 0.25 M) and diene (4 equiv) in the presence of
2a at -78 °C for 1-24 h. b CP, cyclopentadiene; BMCP-, 1-benzyloxymethylcyclopentadiene; CH, 1,3-cyclohexadiene; DMB, 2,3-dimethylbutadiene;
IP, isoprene. c See text. d Isolated yield for the exo/endo mixture. e The ee of major isomer and the absolute configuration of its carbonyl R-carbon
are indicated. The absolute configuration indicated in entry 6 was assigned by analogy with cyclopentadiene,3b and the others were assigned by
comparison with data in the literatures. For determination methods, see Experimental Section. f Aldehyde (0.5 M) in dichloromethane. g 50 mg of
MS 4A per 0.05 mmol of 17 was used. h MS 4A was removed after preparation of 2a. i -78 °C, 50 h. j -78 °C, 72 h. k -40 °C, 38 h. l -40 °C,
60 h. m -20 °C, 4 days. n -20 °C, 39 h.
Scheme 2. Both Enantiomers Available from the Same
Chiral Tetraol 5a
was treated with aqueous 2 N NaOH, and the products were
extracted with pentane. Acidification of the aqueous layer and
extraction with dichloromethane afforded 18a (>90%). On the
whole, method A was superior to method B with regard to both
catalytic activity and enantioselectivity for the cycloaddition
(e.g., (E)-2-pentenal in Table 3).
only the endo adduct in 95% yield with 80% ee (R). This result
was much better than that (74% yield, 46% ee, exo:endo )
1:99) previously given by a CAB-catalyzed reaction.16
Design of BLA Using Bis[3,5-bis(trifluoromethyl)phenyl]-
borinic Acid. The use of arylboronic acid with electron-
withdrawing substituents such as 17 in the preparation of BLA
greatly enhanced its catalytic activity and asymmetry-inducing
ability.4b Next, we examined bis[3,5-bis(trifluoromethyl)phenyl]-
borinic acid (19) as a component of BLA to obtain an even
better asymmetric Diels-Alder catalyst. A diarylborinic acid
is a stronger Lewis acid than the corresponding boronic acid,17
and we recently reported its unique characteristics as a Lewis
acid catalyst.18 A new BLA 4 was prepared by stirring 19 and
a chiral ligand in dichloromethane in the presence of MS 4A
The high enantioselectivity and stereochemical results attained
in these reactions can be understood in terms of transition-state
model C. This model is consistent with the observed absolute
stereochemical selectivity and is analogous to that proposed for
BLA 1a.4a,5
The absolute stereopreference in the Diels-Alder reaction
catalyzed by (R)-2a is opposite that catalyzed by (R)-1a. This
means that the presence of the 3,5-bis(trifluoromethyl)phenyl
group greatly affects the asymmetric induction of BLAs prepared
from chiral ligands 5a and 18a with the same absolute
configuration. In fact, the use of BLAs 1a and 3 prepared from
the common chiral tetraol 5a in the Diels-Alder reaction,
respectively, gave an opposite enantiomer with high selectivity,
as shown in Scheme 2.
(16) Furuta, K.; Kanematsu, A.; Yamamoto, H. Tetrahedron Lett. 1989,
30, 7231.
(17) Stereodirected Synthesis with Organoboranes; Matteson, D. S., Ed.;
Springer: Berlin, Heidelberg, New York, 1995; see also references therein
cited.
(18) (a) Ishihara, K.; Kurihara, H.; Yamamoto, H. Synlett 1997, 597.
(b) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1997, 62, 5664.
We extended this approach to the intramolecular cycloaddition
of an R-unsubstituted trienal. The reaction of (E,E)-2,7,9-
decatrienal in the presence of 2a (30 mol %, method A) provided

Catalysts for Diels-Alder Reactions
J. Am. Chem. Soc., Vol. 120, No. 28, 1998 6925
Table 4. Modification and Preparation of Diels-Alder Catalystsa
entry
chiral ligand
exo:endob
ee (%)c [config]
1
2
3
4
5d
6
7
(R)-20a
(R)-18a
(R)-20b
(R)-20c
(R)-20c
(R)-binaphthol
(R)-20d
94:6
95:5
95:5
92:8
91:9
89:11
90:10
86 [R]
80 [R]
55 [R]
49 [R]
28 [R]
15 [R]
1 [R]
a The reactions were conducted in dichloromethane using methac-
rolein (1 equiv, 0.25 M) and cyclopentadiene (4 equiv) in the presence
of 5 mol % of 4 at -78 °C for 12 h. b Diastereoselectivity was
determined by 1H NMR analysis or GC analysis of Diels-Alder
reaction. c The ee of major isomer and the absolute configuration of
its carbonyl R-carbon are indicated. The absolute configuration was
assigned by comparison with data in the literature. For the determination
method, see Experimental Section. d (C6F5)2BOH was used in place of
19.
(activated powder)14 at room temperature. MS 4A was indis-
pensable in preparing 4 as well as 2, while THF and water were
not essential. It has been ascertained by 1H NMR analysis that
19 exists as a single species of monomer.18
Table 4 summarizes the results of the cycloaddition of
methacrolein and cyclopentadiene catalyzed by BLA prepared
from 19 and various (R)-binaphthol derivatives. A bulky
substituent at the 3-position of (R)-binaphthol enhanced enan-
tioselectivity (entries 1-5), while the use of chiral C2 sym-
metrical diols was less effective (entries 6 and 7). In particular,
good enantioselectivity was attained with 18a, the chiral ligand
of BLA 2a (entry 2). Finally, enantioselectivity was raised to
86% ee using the more bulky triol 20a (entry 1). Although
bis(pentafluorophenyl)borinic acid,18 which is a stronger Lewis
acid than 19, was also examined, lower enantioselectivity was
observed (entry 4 versus 5). It seems that the steric bulkiness
of the aryl groups in diarylborinic acid is important for a high
level of asymmetric induction because BLA formed from
diarylborinic acids and chiral ligands has a conformationally
flexible structure.
Table 5. Enantioselective Diels-Alder Reaction Catalyzed by
(R)-BLA 4aa
ee (%)e [config]e
yield (%)c
dienophile
dieneb [exo:endo]d
exo
endo
CH2dCHCHO
(E)-MeCHdCHCHO
CP
CP
87 [23:77]
83 [58:42]
87
83
73 [R]
47 [R]
a The reactions were conducted in dichloromethane using aldehyde
(1 equiv, 0.25 M) and cyclopentadiene (4 equiv) in the presence of 4a
at -78 °C for 14 h. b CP, cyclopentadiene. c Isolated yield for the exo/
endo mixture. d Diastereoselectivity was determined by 1H NMR
analysis or GC analysis of Diels-Alder reaction. e The absolute
configuration of the carbonyl R-carbon in Diels-Alder adducts is
indicated. The absolute configurations were assigned by comparison
with data in the literatures. For determination methods, see Experimental
Section.
Based on the above experimental results, BLA 4a was
examined in the reaction of cyclopentadiene and other repre-
sentative dienophiles, i.e., acrolein and crotonaldehyde (Table
5). The reactions proceeded smoothly, and in both cases good
enantioselectivity was observed for the exo adduct. The exo
adduct was obtained as a major diastereomer in the reaction of
crotonaldehyde and cyclopentadiene, compared with the high
endo-selectivity that is generally observed in Lewis acid-
promoted reactions.
200 (200 MHz), 300 (300 MHz), and VXR 500 (500 MHz) spectrom-
eters. High-performance liquid chromatography (HPLC) was done with
Shimazu Model 6A or 9A instruments using 4.6 mm × 25 cm Daicel
CHIRALCEL OD, OD-H, OJ, AD, and AS. Gas-liquid-phase
chromatography (GC) was done with Shimadzu Model 8A instrument
with a flame-ionization detector and a capillary column of PEG-HT
Bonded (25 m × 0.25 mm) using nitrogen as carrier gas. Optical
rotations were measured on a JASCO DIP-140 digital polarimeter.
Melting points were determined using a Yanaco MP-J3. All experi-
ments were carried out under an atmosphere of dry argon. For thin-
layer chromatography (TLC) analysis throughout this work, Merck
precoated TLC plates (silica gel 60 GF254, 0.25 mm) were used. The
products were purified by preparative column chromatography on silica
gel (E. Merck 9385). Microanalyses were accomplished at the School
of Agriculture, Nagoya University. The high-resolution mass spectra
(HRMS) were conducted at Daikin Industries, Ltd., Japan.
In experiments requiring dry solvents, ether and tetrahydrofuran
(THF) were purchased from Aldrich Chemical Co. as “anhydrous” and
stored over 4 Å molecular sieves (MS 4A). Benzene, hexane, and
toluene were dried over sodium metal. Methylene chloride was freshly
distilled from calcium hydride. R,â-Enals were freshly distilled from
MS 4A. Trimethyl borate was distilled from sodium metal under argon.
Other simple chemicals were purchased and used as such.
Conclusions
The combined use of a Brønsted acid is a new concept in
the design of chiral Lewis acid catalysts. This paper describes
a rational basis for the design of BLA complexes which possess
sufficient Lewis acidity to catalyze a wide range of synthetically
useful enantioselective Diels-Alder reactions. Intramolecular
Brønsted acids in BLA play an important role in the rate
acceleration and the high level of enantioselectivity which were
observed in the enantioselective Diels-Alder reaction. Various
boron compounds such as trialkylborate, arylboronic acid, and
diarylborinic acid can be used in the design of BLA. An
arylboronic acid with electron-withdrawing substituents has the
advantage of having strong Lewis acidity and constructing a
bidentate complex with a chiral ligand. In contrast, although
diarylborinic acid is a stronger Lewis acid, it is difficult to use
to construct a rigid monodentate complex.
Preparation of Chiral Ligands. (R)-3,3′-Di(2-hydroxyphenyl)-
2,2′-dihydroxy-1,1′-binaphthyl (5a). To a mixture of (R)-3,3′-
dibromo-2,2′-di(methoxymethoxy)-1,1′-binaphthyl (1.06 g, 2 mmol),
2-methoxyphenylboronic acid (966 mg, 6 mmol), and barium hydroxide
octahydrate (1.89 g, 6 mmol) in DME-H2O (6:1, 21 mL) under argon
was added Pd(PPh3)4 (231 mg, 0.2 mmol), and then the mixture was
degassed three times, and charged with argon.6 The mixture was
warmed to 80 °C and stirred for 12 h. The resulting mixture was cooled
Experimental Section
General. Infrared (IR) spectra were recorded on a Shimazu FT-IR
8100 spectrometer. 1H NMR spectra were measured on Varian Gemini-

6926 J. Am. Chem. Soc., Vol. 120, No. 28, 1998
Ishihara et al.
to ambient temperature, and filtered through a Celite pad; the filtrate
was diluted with saturated NH4Cl (aq) and extracted twice with ether.
The combined extracts were dried over MgSO4, filtered, and concen-
trated. The crude product was purified by column chromatography on
silica gel using hexanes-ethyl acetate (10:1 to 5:1) as eluent to give
1.16 g (99%) of (R)-3,3′-di(2-methoxyphenyl)-2,2′-di(methoxymethoxy)-
1,1′-binaphthyl as a white solid: 1H NMR (200 MHz, CDCl3) δ 2.39
(s, 6H), 3.80 (s, 6H), 4.41 (d, J ) 5.6 Hz, 2H), 4.46 (d, J ) 5.6 Hz,
2H), 6.99 (dd, J ) 0.8, 8.6 Hz, 2H), 7.07 (dd, J ) 1.0, 7.4 Hz, 2H),
7.28-7.44 (m, 8H), 7.47 (dd, J ) 1.8, 7.4 Hz, 2H), 7.82-7.88 (m,
2H), 7.88 (s, 2H).
To a solution of (R)-3,3′-di(2-methoxyphenyl)-2,2′-di(methoxy-
methoxy)-1,1′-binaphthyl (1.16 g, 1.98 mmol) in THF (20 mL) was
added 3 N HCl (20 mL) at room temperature. After being stirred for
13 h at 50 °C, the mixture was cooled to room temperature, extracted
with ether twice, and the combined extracts were dried over MgSO4,
filtered, and concentrated. The crude product was purified by column
chromatography on silica gel using hexanes-ethyl acetate (4:1 to 2:1)
as eluent to give 987 mg (>99%) of (R)-3,3′-di(2-methoxyphenyl)-
2,2′-dihydroxy-1,1′-binaphthyl as a white solid: 1H NMR (200 MHz,
CDCl3) δ 3.82 (s, 6H), 5.76 (s, 2H), 7.03 (d, J ) 8.4 Hz, 2H), 7.12 (dt,
J ) 1.0, 7.4 Hz, 2H), 7.24-7.46 (m, 8H), 7.52 (dd, J ) 1.8, 7.6 Hz,
2H), 7.85-7.92 (m, 2H), 7.93 (s, 2H).
126.13, 126.97, 127.26, 127.34, 127.41, 127.54, 128.28, 128.57, 128.81,
129.17, 129.61, 129.74, 129.82, 130.14, 131.85, 132.35, 132.41, 132.70,
133.43, 133.67, 136.18, 148.84, 151.14, 154.20, 155.95; HRMS (EI)
m/z calcd for [C39H28O4] 560.6478, found 560.6486.
(R)-3-(2-Hydroxy-3-phenylphenyl)-2,2′-dihydroxy-1,1′-binaph-
thyl (18a). To a mixture of (R)-3-bromo-2,2′-di(methoxymethoxy)-
1,1-binaphthyl (2.90 g, 6.4 mmol), 2-methoxy-3-phenylphenylboronic
acid (2.92 g, 12.8 mmol), and barium hydroxide octahydrate (4.04 g,
12.8 mmol) in DME-H2O (6:1, 56 mL) under argon was added
Pd(PPh3)4 (148 mg, 0.13 mmol), and then the mixture was degassed
three times and charged with argon.6 The mixture was warmed to 80
°C and stirred for 12 h. The resulting mixture was cooled to ambient
temperature, filtered through a Celite pad, and the filtrate was diluted
with saturated NH4Cl (aq), extracted with ether twice, and the combined
extracts were dried over MgSO4, filtered, and concentrated. The crude
product was purified by column chromatography on silica gel using
hexanes-ethyl acetate-dichloromethane (10:1:1) as eluent to give 3.49
g (98%) of (R)-3-(2-methoxy-3-phenylphenyl)-2,2′-di(methoxymethoxy)-
1,1-binaphthyl as a white solid: [R]25 ) +115.5 (c ) 1.0, CHCl3);
D
TLC (hexanes-EtOAc, 4:1), Rf ) 0.37; IR (CHCl3) 3011, 1593, 1472,
1
1460, 1240, 1200, 1150, 1073, 1036, 972, 924, 700 cm-1; H NMR
(300 MHz, CDCl3) δ 2.41 (s, 3H), 3.22 (s, 3H), 3.31 (s, 3H), 4.38 (d,
J ) 5.9 Hz, 1H), 4.49 (d, J ) 5.9 Hz, 1H), 5.06 (d, J ) 6.9 Hz, 1H),
5.18 (d, J ) 6.9 Hz, 1H), 7.22-7.65 (m, 15H,), 7.86 (d, J ) 8.3 Hz,
1H), 7.91 (d, J ) 8.2 Hz, 1H), 7.95 (d, J ) 9.3 Hz, 1H), 8.01 (s, 1H).
Anal. Calcd for C37H32O5: C, 79.84; H, 5.79. Found: C, 79.80; H,
5.88.
To a solution of (R)-3,3′-di(2-methoxyphenyl)-2,2′-dihydroxy-1,1′-
binaphthyl (987 mg, 1.98 mmol) in dichloromethane (10 mL) was added
dropwise boron tribromide (759 µL, 8 mmol) at -78 °C. The reaction
mixture was allowed to warm to 0 °C. After being stirred for 30 min,
the solution was quenched with ice-water, extracted with ether twice,
and the combined extracts were dried over MgSO4, filtered, and
concentrated. The crude product was purified by column chromatog-
raphy on silica gel using hexanes-ethyl acetate (3:1 to 2:1) as eluent
A solution of (R)-3-(2-methoxy-3-phenylphenyl)-2,2′-di(methoxy-
methoxy)-1,1-binaphthyl (3.28 g, 5.9 mmol) in 4 M HCl-THF (1:1,
40 mL) was refluxed for 5 h, and cooled to ambient temperature. After
being diluted with H2O, the mixture was extracted with ether twice.
The combined extracts were washed with saturated NaHCO3, dried over
MgSO4, filtered, and concentrated. The crude product was purified
by flash column chromatography on silica gel using hexanes-ethyl
acetate-dichloromethane (10:1:1∼7:1:1) as eluent to give 2.63 g (95%)
of (R)-3-(2-methoxy-3-phenylphenyl)-2,2′-dihydroxy-1,1-binaphthyl as
to give 922 mg (99%) of (R)-5a as a white solid: mp 145 °C; [R]23
D
) -104.4 (c 1.00, CHCl3); HPLC analysis (Daicel OD, hexane-i-
PrOH ) 1:1, flow rate ) 0.3 mL/min) for tetraacetate of (R)-5a, tR )
1
26.6 min [tR ) 23.3 min for tetraacetate of (S)-5a]; H NMR (200
MHz, CDCl3) δ 6.05 (br, 2H), 6.09 (br, 2H), 6.82 (t, J ) 7.6 Hz, 2H),
6.92 (dt, J ) 1.2, 7.2 Hz, 2H), 7.14-7.60 (m, 10H), 7.64-7.69 (m,
2H), 7.78 (s, 2H); 13C NMR (50 MHz, CDCl3) δ 114.34, 116.98, 121.37,
124.52, 124.70, 125.39, 127.42, 127.90, 128.60, 129.81, 129.88, 131.76,
132.52, 133.69, 150.07, 153.21; HRMS (FAB) m/z calcd for [C32H22O4]
470.5234, found 470.5248.
a white solid: [R]25 ) +132.4 (c ) 0.82, CHCl3); TLC (hexanes-
D
EtOAc, 4:1) Rf ) 0.25; IR (CHCl3) 3260, 1622, 1597, 1460, 1412,
1177, 1146, 1132, 1003 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.31 (s,
3H), 7.18-7.60 (m, 15H), 7.89 (d, J ) 8.8 Hz, 1H), 7.95 (d, J ) 8.5
Hz, 1H), 7.96 (d, J ) 9.1 Hz, 1H), 8.09 (s, 1H). Anal. Calcd for
C13H14O3: C, 84.59; H, 5.16. Found: C, 84.62; H, 5.34.
AlternatiVe Method. Coupling reaction of (R)-3,3′-dibromo-2,2′-
dimethoxy-1,1′-binaphthyl (1 equiv) and 2-methoxyphenylboronic acid
(2.5 equiv) in 6:1 DME-H2O solution in the presence of palladium(II)
acetate (5 mol %), tris-o-tolylphosphine (10 mol %), and barium
hydroxide (2.5 equiv) at 80 °C for 2 h resulted in formation of (R)-
3,3′-di(2-methoxyphenyl)-2,2′-dimethoxy-1,1′-binaphthyl (97%), which
was treated with 4 equiv of boron tribromide in dichloromethane at
-78 °C for 0.5 h and purified by column chromatography on silica
gel to give (R)-5a (98%).
To a solution of (R)-3-(2-methoxy-3-phenylphenyl)-2,2′-dihydroxy-
1,1-binaphthyl (2.57 g, 5.5 mmol) in CH2Cl2 (20 mL) at 0 °C under
argon was added BBr3 (1.56 mL, 16.5 mmol) slowly; the mixture was
stirred at same temperature for 1 h. After ice-cold H2O was added to
the reaction mixture to quench an excess of BBr3, the mixture was
extracted with CH2Cl2 twice. The combined extracts were washed with
saturated NaHCO3 (aq), dried over MgSO4, filtered, and concentrated.
The crude product was purified by flash column chromatography on
silica gel using hexanes-ethyl acetate-dichloromethane (7:1:1) as
(R)-3,3′-Di(2-hydroxy-3-phenylphenyl)-2,2′-dihydroxy-1,1′-bi-
naphthyl (5b). Tetraol 5b was synthesized from (R)-3,3′-dibromo-
2,2′-di(methoxymethoxy)-1,1′-binaphthyl and 2-methoxy-3-phenyl-
phenylboronic acid in 94% over yield by essentially the same procedure
eluent to give 2.30 g (93%) of (R)-18a as a white solid: [R]23.5
)
D
+121.6 (c ) 1.25, CHCl3); mp 96-97 °C; TLC (hexanes-EtOAc,
4:1), Rf ) 0.29; IR (CHCl3) 3400, 1622, 1599, 1501, 1431, 1383, 1202,
1181, 1144 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.15-7.24 (m, 3H),
7.27-7.57 (m, 12 H), 7.89 (d, J ) 7.5 Hz, 1H), 7.93-7.96 (m, 1H),
7.98 (d, J ) 8.8 Hz, 1H), 8.09 (s, 1H); HRMS (EI) m/z calcd for
[C32H22O3] 454.1569, found 454.1561.
as above: [R]30.0 ) +4.4 (c ) 0.8, CHCl3); mp 113-115 °C; TLC
D
(hexanes-EtOAc, 4:1), Rf ) 0.26; IR (KBr) 3445, 1622, 1601, 1498,
1
1427, 1321, 1225, 1134, 760, 748, 700 cm-1; H NMR (200 MHz,
CDCl3) δ 5.70-6.30 (br, 4H), 7.12-7.55 (m, 22H), 7.92 (d, J ) 7.8
Hz, 2H), 8.06 (s, 2H); 13C NMR (75 Mz, CDCl3) δ 113.80, 121.30,
124.42, 124.46, 125.46, 127.40, 127.60, 128.42, 128.73, 129.34, 129.73,
130.72, 131.24, 132.43, 133.26, 137.42, 149.67, 150.01; HRMS (EI)
m/z calcd for [C44H30O4] 622.7186, found 622.7181.
The other ligands synthesized by essentially the same procedure were
the following.
(R)-3-(2-Hydroxy-3-methylphenyl)-2,2′-dihydroxy-1,1′-binaph-
thyl (18b). [R]28.0D ) +110 (c ) 0.6, CHCl3); mp 110-112 °C; TLC
(hexanes-EtOAc, 4:1), Rf ) 0.30; IR (KBr) 3410, 1620, 1597, 1446,
1431, 1265, 1201, 1142, 960, 746 cm-1; 1H NMR (300 MHz, CDCl3)
δ 2.34 (s, 3H), 5.12 (br, 1H), 5.57 (br, 1H), 6.00 (br, 1H), 7.01 (t, J )
7.4 Hz, 1H), 7.18-7.27 (m, 3H), 7.30-7.47 (m, 7H), 7.92 (t, J ) 8.0
Hz, 2H), 8.00 (d, J ) 9.1 Hz, 1H), 8.05 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 16.40, 110.91, 112.54, 117.84, 120.97, 124.05, 124.30,
124.75, 126.45, 127.08, 127.58, 127.68, 128.47, 129.11, 129.39, 129.62,
131.20, 131.50, 132.92, 133.26, 149.39, 151.74, 152.64; HRMS (EI)
m/z calcd for [C27H20O3] 392.1413, found 392.1415.
(R)-3-(2-Benzyloxyphenyl)-3′-(2-hydroxyphenyl)-2,2′-dihydroxy-
1,1′-binaphthyl (16): [R]27.7 ) +37.6 (c ) 0.5, CHCl3); mp 115-
D
117 °C; TLC (hexanes-EtOAc, 2:1), Rf ) 0.33; IR (KBr) 3517, 3431,
1622, 1489, 1452, 1423, 1383, 1360, 1261, 1149, 1130, 897, 852, 748,
1
696 cm-1; H NMR (200 MHz, CDCl3) δ 5.07 (d, J ) 11.6 Hz, 1H),
5.08 (d, J ) 11.6 Hz, 1H), 5.60 (s, 1H), 6.03 (s, 1H), 6.29 (s, 1H),
7.06-7.54 (m, 18H), 7.55 (dd, J ) 1.6, 7.4 Hz, 1H), 7.92 (d, J ) 8.2
Hz, 2H), 8.01 (s, 2H); 13C NMR (50 MHz, CDCl3) δ 71.25, 112.95,
113.34, 115.23, 117.82, 121.36, 122.38, 124.43, 124.51, 124.66, 124.95,

Catalysts for Diels-Alder Reactions
J. Am. Chem. Soc., Vol. 120, No. 28, 1998 6927
(R)-3-(2-Hydroxyphenyl)-2,2′-dihydroxy-1,1′-binaphthyl (18c).
After a colorless solution of the catalyst (R)-1a was cooled to -78 °C,
R-bromoacrolein (80.8 µL, 1.0 mmol) and cyclopentadiene (332 µL,
4.0 mmol) were added dropwise. After 4 h, 50 µL of H2O was added
and the mixture was warmed to 25 °C, dried over MgSO4, filtrated,
and purified by eluting with hexane/ethyl acetate (10:1) to afford 201
mg of Diels-Alder adduct (1S,2S,4S)-bromoaldehyde 6 as a white solid
(1.0 mmol, >99% yield, exo:endo ) >99:1, >99% ee), and quantitative
recovery of pure (R)-5a.
[R]30.0 ) +92.0 (c ) 0.6, CHCl3); mp 97-100 °C; TLC (hexanes-
D
EtOAc, 2:1), Rf ) 0.21; IR (KBr) 3389, 1620, 1597, 1500, 1431, 1383,
1350, 1265, 1209, 1142, 848, 817, 749, 688 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.15-7.24 (m, 3H), 7.27-7.57 (m, 12 H), 7.89 (d, J ) 7.5
Hz, 1H), 7.93-7.96 (m, 1H), 7.98 (d, J ) 8.8 Hz, 1H), 8.09 (s, 1H);
13C NMR (75 MHz, CDCl3) δ 111.06, 112.75, 117.52, 117.99, 121.43,
124.03, 124.09, 124.31, 124.69, 125.35, 127.03, 127.51, 127.61, 128.40,
128.47, 129.38, 129.64, 129.80, 131.44, 131.56, 132.82, 133.04, 133.32,
149.32, 152.64, 153.38; HRMS (EI) m/z calcd for [C26H18O3] 378.1256,
found 378.1259.
Preparation of (R)-BLA 1b. A dry 25-mL round-bottom flask fitted
with a stirbar and a 10-mL pressure-equalized addition funnel (contain-
ing a cotton plug and ca. 4 g of 4 Å molecular sieves (pellets) and
functioning as a Soxhlet extractor) surmounted by a reflux condenser
was charged with (R)-5b (62.3 mg, 0.1 mmol), trimethyl borate (1.0
mL, 0.1 M solution in dichloromethane, 0.10 mmol), THF (70 µL),
and benzene (3 mL). An argon atmosphere was secured and the
solution was stirred at 45 °C for 1 h and then brought to reflux (bath
temperature 100 °C). After 3 h the reaction mixture was cooled to 25
°C and the addition funnel and condenser were quickly removed and
replaced with a septum. The solvents were pumped off, and then
dichloromethane (5 mL) was added to dissolve (R)-1b. A colorless
solution of (R)-1b was immediately used for the Diels-Alder reaction.
Preparation of (R)-BLA 2a and the Representative Procedure
of Diels-Alder Reaction. Method A. A mixture of the chiral ligand
18a (27.3 mg, 0.06 mmol) and a solution of monomeric 3,5-bis-
(trifluoromethyl)benzeneboronic acid 17 (1.16 mL, 0.05 mmol, 0.043
M) in CH2Cl2-THF-H2O (20:3:0.054) was stirred at ambient tem-
perature for 2 h. The resulting colorless solution was transferred into
a Schlenk tube containing anhydrous dichloromethane and powdered
MS 4A [250 mg, activated by heating at 200 °C under vacuum (ca. 3
Torr) for 12 h], 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 (ca. 3
Torr) to dry catalyst. After cooling to ambient temperature, the flask
was purged with argon and then charged with dichloromethane (2 mL,
distilled from CaH2). The mixture was cooled to -78 °C, dienophile
(1 mmol) was added dropwise, and 1 min later freshly distilled diene
(4 mmol) was slowly added along the wall of the flask. After the
reaction mixture was stirred under the conditions indicated in Table 2,
the reaction was quenched with pyridine (20 mL, 0.25 mmol), warmed
to ambient temperature, and filtered to remove molecular sieves. The
filtrate was washed with ether, dried (MgSO4), and concentrated to
afford the crude products. Purification by silica gel chromatography
eluting with pentane-ether provided the pure Diels-Alder adduct.
Method B (a simplification of method A). A mixture of chiral triols
18a-d (1.2 equiv), commercial boronic acid 17 (1 equiv),13 THF (150
mL per 0.05 mmol of 17, without drying),15 powdered MS 4A (250
mg per 0.05 mmol of 17, nonactivated), and dichloromethane was stirred
at ambient temperature for 12 h. The active catalyst solution was then
prepared by treatment similar to method A.
(R)-3-(2-Hydroxyphenyl)-3′-phenyl-2,2′-dihydroxy-1,1′-binaph-
thyl (18d). [R]30.2D ) +62.7 (c ) 0.6, CHCl3); mp 125-128 °C; TLC
(hexanes-EtOAc, 4:1), Rf ) 0.18; IR (KBr) 3410, 1628, 1602, 1508,
1
1489, 1425, 1360, 1239, 1200, 1128, 897, 748, 700 cm-1; H NMR
(300 MHz, CDCl3) δ 7.15-7.24 (m, 3H), 7.27-7.57 (m, 12 H), 7.89
(d, J ) 7.5 Hz, 1H), 7.93-7.96 (m, 1H), 7.98 (d, J ) 8.8 Hz, 1H),
8.09 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 112.22, 113.49, 117.26,
121.27, 124.13, 124.29, 124.39, 124.49, 125.20, 127.02, 127.33, 127.40,
127.82, 128.39, 128.56, 129. 31, 129.52, 129.68, 130.72, 131.35,
131.49, 132.56, 132.94, 133.10, 137.20, 149.29, 150.06, 153.25; HRMS
(EI) m/z calcd for [C32H22O3] 454.1570, found 474.1567.
(R)-3-(2-Hydroxy-3,5-diphenylphenyl)-2,2′-dihydroxy-1,1′-bi-
naphthyl (20a). [R]30.0 ) +93.6 (c ) 0.6, CHCl3); mp 153-155
D
°C; TLC (hexanes-EtOAc, 4:1), Rf ) 0.18; IR (KBr) 3410, 1697, 1618,
1597, 1499, 1464, 1435, 1381, 1146, 889, 818, 750, 698 cm-1; 1H NMR
(300 MHz, CDCl3) δ 5.14 (s, 1H), 5.69 (s, 1H), 6.02 (s, 1H), 7.19-
7.52 (m, 13H), 7.58-7.69 (m, 5H), 7.75 (d, J ) 2.4 Hz, 1H), 7.88-
8.01 (m, 3H), 8.16 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 111.43,
112.74, 117.79, 123.94, 124.18, 124.37, 124.67, 125.98, 126.88, 126.99,
127.38, 127.45, 127.65, 127.75, 128.39, 128.48, 128.80, 129.42, 129.55,
129.90, 130.24, 131.29, 132.81, 133.21, 133.35, 134.44, 137.50, 140.37,
149.71, 149.89, 152.53; HRMS (EI) m/z calcd for [C38H30O3] 534.2196,
found 534.2194.
(R)-3-Mesityl-2,2′-dihydroxy-1,1′-binaphthyl (20b). [R]30.0
)
D
+109.0 (c ) 0.5, CHCl3); mp 110 °C; TLC (hexanes-EtOAc, 4:1), Rf
) 0.30; IR (KBr) 3496, 1620, 1597, 1518, 1487, 1383, 1259, 1181,
821, 750, 684 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.14 (s, 3H), 2.15
(s, 3H), 2.37 (s, 3H), 5.00 (s, 1H), 5.08 (s, 1H), 7.80 (s, 2H), 7.19-
7.45 (m, 7H), 7.80 (s, 1H), 7.90 (d, J ) 8.0 Hz, 2H), 7.98 (d, J ) 8.9
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 20.48, 20.59, 21.14, 111.39,
112.44, 117.60, 123.72, 124.11, 124.22, 124.34, 127.11, 127.16, 128.26,
128.37, 128.53, 129.36, 129.46, 129.55, 130.86, 131.24, 132.53, 133.22,
133.39, 136.97, 137.14, 137.88, 150.51, 152.10; HRMS (EI) m/z calcd
for [C29H24O2] 404.1777, found 404.1782.
(R)-3-Phenyl-2,2′-dihydroxy-1,1′-binaphthyl (20c). [R]30.5
)
D
+132.0 (c ) 1.18, CHCl3); mp 152-155 °C; TLC (hexanes-EtOAc,
4:1), Rf ) 0.22; IR (KBr) 3474, 1620, 1597, 1504, 1429, 1339, 1271,
1242, 1184, 1130, 964, 814, 752, 706 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 5.11 (s, 1H), 5.28 (s, 1H), 7.15 (d, J ) 8.4 Hz, 1 H), 7.23 (d,
J ) 8.5 Hz, 1H), 7.28-7.58 (m, 8H, ArH), 7.70-7.76 (m, 2H), 7.91
Preparation of (R)-BLA 4a and the Representative Procedure
of Diels-Alder Reaction. A solution of the chiral ligand 20a (15.9
mg, 0.03 mmol) and bis[(3,5-bis(trifluoromethyl)phenyl)]borinic acid
19 (11.4 mg, 0.025 mmol) in CH2Cl2 (2 mL) was transferred into a
Schlenk tube containing anhydrous dichloromethane and powdered MS
4A [250 mg, activated by heating at 200 °C under vacuum (ca. 3 Torr)
for 12 h], and the mixture was stirred at ambient temperature for another
3 h. The mixture was cooled to -78 °C, dienophile (0.5 mmol) was
added dropwise, and 1 min later freshly distilled diene (2 mmol) was
slowly added along the wall of the flask. After the reaction mixture
was stirred under the conditions indicated in Tables 4 and 5, the reaction
was quenched with methanol, warmed to ambient temperature, and
filtered to remove molecular sieves. The filtrate was washed with ether,
dried (MgSO4), and concentrated to afford the crude products.
Purification by silica gel chromatography eluting with pentane-ether
provided the pure Diels-Alder adduct.
(t, J ) 7.5 Hz, 2 H), 7.99 (d, J ) 8.8 Hz, 1H), 8.03 (s, 1H, ArH); 13
C
NMR (75 MHz, CDCl3) δ 114.41, 111.71, 117.72, 123.97, 124.16,
124.27, 124.37, 127.40, 127.78, 128.39, 128.47, 129.43, 129.58, 130.66,
131.33, 131.47, 132.91, 133.38, 137.37, 150.23, 152.62; HRMS (EI)
m/z calcd for [C26H18O2] 362.1307, found 362.1311.
(R)-3,3′-Diphenyl-2,2′-dihydroxy-1,1′-binaphthyl (20d). Physical
properties were identical with those reported.30
Preparation of (R)-BLA 1a and the Representative Procedure
for Enantioselective Diels-Alder Reaction. A dry 25-mL round-
bottom flask fitted with a stirbar and a 10-mL pressure-equalized
addition funnel (containing a cotton plug and ca. 4 g of 4 Å molecular
sieves (pellets) and functioning as a Soxhlet extractor) surmounted by
a reflux condenser was charged with (R)-5a (23.5 mg, 0.05 mmol),
trimethyl borate (0.5 mL, 0.1 M solution in dichloromethane, 0.05
mmol), and dichloromethane (3 mL). An argon atmosphere was
secured and the solution was brought to reflux (bath temperature 50∼60
°C). After 2 h the reaction mixture was cooled to 25 °C and the addition
funnel and condenser were quickly removed and replaced with a septum.
To the white precipitate in dichloromethane was added dry THF (50
mL) at 25 °C and after 2 h the precipitate was completely dissolved.
The exo/endo ratios, % ee’s, and absolute configurations of the
Diels-Alder adducts were determined as follows.
exo-2-Bromobicyclo[2.2.1]hept-5-ene-2-carboxaldehyde (6) (En-
tries 1 and 2 in Table 1 and Entries 1 and 2 in Table 3).19 The
(19) Ishihara, K.; Gao, Q.; Yamamoto, H. J. Org. Chem. 1993, 58, 6917.

6928 J. Am. Chem. Soc., Vol. 120, No. 28, 1998
Ishihara et al.
1
exo/endo ratio was determined by H NMR and GC analyses.19 The
endo), 9.75 (s, 0.98H, exo). Anal. Calcd for C11H14O: C, 81.44; H,
8.70. Found: C, 81.48; H, 8.69. The exo/endo ratio was determined
ee was determined by reduction with NaBH4, conversion to the Mosher
ester, and H NMR and HPLC analyses (Daicel AD).19 The absolute
by H NMR analysis of Diels-Alder adducts: 1H NMR (200 MHz,
1
1
configuration was determined by conversion to the known norbornen-
CDCl3) δ 9.47 (s, 1H, CHO (endo)), 9.75 (s, 1H, CHO (exo)). The ee
was determined by GC analysis after conversion to chiral acetals by
(-)-(2R,4R)-2,4-pentanediol:20b GC (120 °C) tR ) 27.3 and 34.9 min
(endo-isomers), 42.1 min (major exo-isomer), 44.6 min (minor exo-
isomer). The absolute configuration was not established.
2-one by a literature procedure.3b
exo-7-Benzyloxymethyl-2-bromobicyclo[2.2.1]hept-5-ene-2-car-
boxaldehyde (7) (Entry 3 in Table 1 and Entry 3 in Table 3).3b 1
H
NMR (300 MHz, CDCl3) δ 1.51 (d, J ) 13.7 Hz, 1H), 2.07 (t, J ) 7.0
Hz, 1H), 2.74 (dd, J ) 3.8, 13.7 Hz, 1H), 2.91 (br, 1H), 3.22 (br, 1H),
3.36 (dd, J ) 1.8, 7.0 Hz, 2H), 4.40 (s, 2H), 6.02 (dd, J ) 2.9, 5.6 Hz,
1H), 6.32 (dd, J ) 2.9, 5.5 Hz, 1 H), 7.24-7.40 (m, 5H), 9.51 (s, 1H).
endo-Bicyclo[2.2.1]hept-5-ene-2-carboxaldehyde (13) (Entries 10
and 11 in Table 1, Entry 11 in Table 3, and Table 5).20 1H NMR
(300 MHz, CDCl3) δ 1.32 (d, J ) 8.2 Hz, 1H), 1.40-1.52 (m, 2H),
1.91 (ddd, J ) 3.6, 9.1, 12.0 Hz, 1H), 2.90 (m, 1H), 2.99 (br, 1H),
3.25 (br, 1H), 6.00 (dd, J ) 2.8, 5.9 Hz, 1H), 6.22 (dd, J ) 3.2, 5.9
Hz, 1H), 9.42 (d, J ) 3.0 Hz, 1H). The exo/endo ratio was determined
1
The exo/endo ratio was determined by H NMR analysis of Diels-
Alder adducts: 1H NMR (300 MHz, CDCl3) δ 9.28 (s, 1H, CHO (endo),
9.51 (s, 1H, CHO (exo)). The ee was determined by reduction with
NaBH4, conversion to the ester with (+)-Mosher chloride, and 1H NMR
analysis:3b 1H NMR (500 MHz, CDCl3) δ 4.61 (d, J ) 12.0 Hz, 1H,
CH ) CH (1R,2S,4R,7R)-isomer), 4.66 (d, J ) 12.0 Hz, 1H, CH )
CH (1S,2R,4S,7S)-isomer), 4.70 (d, J ) 12.0 Hz, 1H, CHdCH
(1S,2R,4S,7S)-isomer), 4.76 (d, J ) 12.0 Hz, 1H, CHdCH (1R,2S,4R,7R)-
isomer). The absolute configuration was determined by conversion to
the known norbornen-2-one by a literature procedure.3b
1
by H NMR analysis of Diels-Alder adducts and GC analysis after
conversion to chiral acetals by (2R,4R)-2,4-pentanediol:1 1H NMR (300
MHz, CDCl3) δ 9.42 (d, J ) 3.0 Hz, 1H, CHO (endo)), 9.79 (d, J )
3.0 Hz, 1H, CHO (exo)). The ee was determined by acetalization with
(-)-(2R,4R)-2,4-pentanediol and GC analysis:20 GC (90 °C) tR ) 35.4
min ((1S,2S,4S)-isomer), 41.1 min ((1R,2R,4R)-isomer), 42.6 and 44.6
min (exo-isomers). The absolute configuration was established by
comparison of optical rotation values with data in the literature.21
1-Bromo-4-methyl-3-cyclohexene-1-carboxaldehyde (8) (Entry 4
in Table 1 and Entry 6 in Table 3).19 The ee was determined by
reduction with NaBH4, conversion to benzoyl ester, and HPLC analysis
(Daicel AD). Absolute stereochemistry was assigned by analogy with
cyclopentadiene.3b
endo-3-Methylbicyclo[2.2.1]hex-5-ene-2-carboxaldehyde (14) (En-
try 12 in Table 1, Entry 15 in Table 3, and Table 5).20 1H NMR
(300 MHz, CDCl3) δ 1.18 (d, J ) 6.9 Hz, 3H), 1.44-1.51 (m, 1H),
1.55-1.60 (m, 1H), 1.77-1.87 (m, 1H), 2.34 (dd, J ) 3.2, 4.3 Hz,
1H), 2.56 (br, 1H), 3.13 (br, 1H), 6.05 (dd, J ) 2.8, 5.6 Hz, 1H), 6.29
(dd, J ) 3.0, 5.8 Hz, 1H), 9.37 (d, J ) 3.2 Hz, 1H). The exo/endo
ratio was determined by 1H NMR analysis of Diels-Alder adducts and
GC analysis after conversion to chiral acetals by (-)-(2R,4R)-2,4-
pentanediol:20 1H NMR (CDCl3) δ 9.37 (d, J ) 3.2 Hz, 1H, CHO
(endo)), 9.78 (d, J ) 3.2 Hz, 1H, CHO (exo)). The ee was determined
by acetalization with (-)-(2R,4R)-2,4-pentanediol and GC analysis:20
GC (90 °C) tR ) 22.9 min ((1S,2S,3S,4R)-isomer), 25.5 min
((1R,2R,3R,4S)-isomer), 27.1 and 28.7 min (exo-isomers). The absolute
configuration was established by comparison with authentic material
prepared independently.22
exo-2-Methylbicyclo[2.2.1]hept-5-ene-2-carboxaldehyde (9) (En-
tries 5 and 6 in Table 1, Table 2, and Table 4).20 1H NMR (300
MHz, CDCl3) δ 0.76 (d, J ) 12.0 Hz, 1H), 1.01 (s, 3H), 1.38-1.40
(m, 2H), 2.25 (dd, J ) 3.8, 12.0 Hz, 1H), 2.82 (br, 1H), 2.90 (br, 1H),
6.11 (dd, J ) 3.0, 5.7 Hz, 1H), 6.30 (dd, J ) 3.0, 5.7 Hz, 1H), 9.69 (s,
1H). The exo/endo ratio was determined by 1H NMR analysis of
Diels-Alder adducts and GC analysis after conversion to chiral acetals
by (-)-(2R,4R)-2,4-pentanediol:20 1H NMR (300 MHz, CDCl3) δ 9.40
(s, 1H, CHO (endo)), 9.69 (s, 1H, CHO (exo)). The ee was determined
by GC analysis after conversion to chiral acetals by (-)-(2R,4R)-2,4-
pentanediol:20 GC (80 °C) tR ) 37.7 and 47.6 min (endo-isomers), 51.5
min ((1S,2R,4S)-isomer), 54.7 min ((1R,2S,4R)-isomer). The absolute
configuration was established by comparison of optical rotation values
with data in the literature.21
endo-2-Bromobicyclo[2.2.2]oct-5-ene-2-carboxaldehyde (Entry 4
in Table 3).23 1H NMR (300 MHz, CDCl3) δ 1.30-1.52 (m, 2H),
1.74-1.83 (m, 1H), 1.91 (dd, J ) 2.2, 14.5 Hz, 1H), 2.30-2.40 (m,
1H), 2.59 (dt, J ) 3.0, 14.5 Hz, 1H), 2.65-2.73 (m, 1H), 2.96-3.02
(m, 1H), 6.07-6.11 (m, 1H), 6.29-6.33 (m, 1H), 8.91 (s, 1H). The
exo-2-Ethylbicyclo[2.2.1]hept-5-ene-2-carboxaldehyde (10) (Entry
7 in Table 1).26 1H NMR (200 MHz, CDCl3) δ 0.78 (t, J ) 7.4 Hz,
3H), 1.25-1.65 (m, 5H), 2.15 (dd, J ) 3.8, 12.0 Hz, 1H), 2.87 (br,
1H), 2.95 (br, 1H), 6.08 (dd, J ) 3.2, 5.6 Hz, 1H), 6.27 (dd, J ) 3.2,
5.8 Hz, 1H), 9.70 (s, 1H, CHO). The exo/endo ratio was determined
1
exo/endo ratio was determined by H NMR analysis:23 1H NMR (300
MHz, CDCl3) δ 9.14 (s, 1H, CHO (endo), 9.40 (s, 1H, CHO (exo)).
The ee was determined from 1H NMR spectrum of Diels-Alder adducts
(5 mg) in the presence of the chiral shift reagent Eu(hfc)3 (ca. 30 mg):
by H NMR analysis of Diels-Alder adducts: 1H NMR (200 MHz,
1
23
1H NMR (500 MHz, CDCl3) δ 9.71 (s, 1H, CHO (minor endo-
CDCl3) δ 9.42 (s, 1H, CHO (endo)), 9.70 (s, 1H, CHO (exo)). The ee
was determined by 1H NMR analysis after conversion to chiral acetals
by (2R,4R)-2,4-pentanediol:20b 1H NMR (500 MHz, CDCl3) δ 4.82 (s,
1H, CHO2 (minor exo-isomer), 4.85 (s, 1H, CHO2 (major exo-isomer).
The absolute configuration was not established.
isomer)), 9.73 (s, 1H, CHO (major endo-isomer)), 9.84 (s, 1H, CHO
(one exo-isomer)), 9.88 (s, 1H, CHO (another exo-isomer)). The
absolute configuration was not determined.
1-Bromo-3,4-dimethyl-3-cyclohexene-1-carboxaldehyde (Entry 5
in Table 3).19 The ee was determined by reduction with NaBH4,
conversion to the benzoyl ester, and HPLC analysis (Daicel OD-H,
hexane-i-PrOH ) 1000:1, flow rate ) 0.5 mL/min): tR ) 20.3 min
(major isomer) and 22.7 min (minor isomer). The absolute configu-
ration was not determined.
endo-2-Methylbicyclo[2.2.2]oct-5-ene-2-carboxaldehyde (Entry 7
in Table 3).31 The exo/endo ratio was determined by 1H NMR
analysis: 1H NMR (300 MHz, CDCl3) δ 9.33 (s, 1H, CHO (endo),
9.56 (s, 1H, CHO (exo)). The ee was determined by acetalization with
(-)-(2R,4R)-2,4-pentanediol and GC analysis:20b GC (80 °C) tR ) 61.6
min (major endo-isomer), 64.4 min (major exo-isomer), 70.4 min (minor
endo-isomer), 76.8 min (minor exo-isomer). The absolute configuration
was not determined.
exo-2,3-Dimethylbicyclo[2.2.1]hept-5-ene-2-carboxaldehyde (11)
(Entry 8 in Table 1 and Entry 10 in Table 3).20 1H NMR (CDCl3,
200 MHz) δ 0.76 (d, J ) 7.4 Hz, 3H), 0.87 (s, 3H), 1.20-1.50 (m,
2H), 2.55 (dq, J ) 3.6, 7.4 Hz, 1H), 2.77 (br, 1H), 2.82 (br, 1H), 6.21
(dd, J ) 3.2, 5.8 Hz, 1H), 6.31 (dd, J ) 3.0, 5.8 Hz, 1H), 9.66 (s, 1H).
The exo/endo ratio was determined by H NMR analysis: 1H NMR
1
(CDCl3, 200 MHz) δ 9.66 (s, 1H, CHO (exo)). The ee was determined
by acetalization with (-)-(2R,4R)-2,4-pentanediol and GC analysis:20b
GC (90 °C) tR ) 54.4 min (major exo-isomer), 55.9 min (minor exo-
isomer). The absolute configuration was not established.
exo-Tricyclo[5.2.1.02,6]dec-8-ene-2-carboxaldehyde (12) (Entry 9
in Table 1). 1H NMR (200 MHz, CDCl3) δ 1.00-1.40 (m, 3H), 1.40-
1.90 (m, 7H), 2.83-2.94 (m, 1H), 2.86 (s, 1H), 2.97 (s, 1H), 6.22 (dd,
J ) 3.2, 5.7 Hz, 1H), 6.32 (dd, J ) 2.6, 5.7 Hz, 1H), 9.46(s, 0.02H,
1,3,4-Trimethyl-3-cyclohexene-1-carboxaldehyde (Entry 8 in
Table 3).32 The ee was determined by acetalization with (-)-(2R,4R)-
2,4-pentanediol and 1H NMR analysis:20b 1H NMR (300 MHz, CDCl3)
(20) (a) Furuta, K.; Shimizu, S.; Miwa, Y.; Yamamoto, H. J. Org. Chem.
1989, 54, 1481. For a general procedure for the acetalization of Diels-
Alder adducts with (-)-(2R, 4R)-2,4-pentanediol, see: (b) Furuta, K.; Gao,
Q.; H. Yamamoto Org. Synth. 1995, 72, 86.
(21) Hashimoto, S.; Komeshima, N.; Koga, K. J. Chem. Soc., Chem.
Commun. 1979, 437.
(22) Sator, D.; Saffrich, J.; Helmchen, G. Synlett 1990, 197.
(23) Ku¨ndig, E. P.; Bourdin, B.; Bernardinelli, G. Angew. Chem., Int.
Ed. Engl. 1994, 33, 1856.

Catalysts for Diels-Alder Reactions
J. Am. Chem. Soc., Vol. 120, No. 28, 1998 6929
δ 4.45 (s, 1H, CHO (minor isomer)), 4.47 (s, 1H, CHO (major isomer).
The absolute configuration was not determined.
J ) 7.1 Hz, 2H), 6.09 (dd, J ) 2.5, 5.6 Hz, 1H), 6.27 (dd, J ) 3.2, 5.6
Hz, 1H), 9.55 (d, J ) 1.1 Hz, 1H, CHO). Anal. Calcd for C13H14O3:
C, 68.02; H, 7.26. Found. C, 68.08; H, 7.30. The exo/endo ratio
was determined by H NMR analysis (300 MHz): δ 9.55 (d, J ) 1.1
1,4-Dimethyl-3-cyclohexene-1-carboxaldehyde (Entry 9 in Table
3).32 The ee was determined by acetalization with (-)-(2R,4R)-2,4-
pentanediol and GC analysis:20b GC (80 °C) tR ) 33.8 min (minor
isomer), 36.7 min (major isomer). The absolute configuration was not
determined.
1
Hz, 1H, CHO (endo)), 9.85 (s, 1H, CHO (exo)). The absolute
configuration of the adduct was determined by conversion of the known
diol28 by reduction with LiAlH4. The ee was determined by analytical
GC of the chiral acetal derived from the Diels-Alder adduct and (-)-
(2R,4R)-2,4-pentanediol:20b tR ) 15.2 min (endo (3R)-isomer), 17.0 min
(endo (3S)-isomer), 18.6 min (exo isomers).
(1S,2S,4S)-Bicyclo[2.2.2]oct-5-ene-2-carboxaldehyde (Entry 12 in
Table 3).20 1H NMR (300 MHz, CDCl3) δ 1.19-1.41 (m, 2H), 1.50-
1.78 (m, 4H), 2.56 (m, 2H), 2.65 (m, 1H), 2.96 (m, 1H), 6.12 (t, J )
6.9 Hz, 1H), 6.34 (t, J ) 6.9 Hz, 1H), 9.46 (d, J ) 1.4 Hz, 1H). The
Phenyl (1S,2S,4S)-Bicyclo[2.2.1]hept-5-ene-2-carboxylate (Entry
1
20 in Table 3). [R]23.0 ) -39.8 (c ) 0.97, CHCl3); TLC (hexanes-
exo/endo ratio was determined by H NMR analysis of Diels-Alder
D
adducts:20 1H NMR (300 MHz, CDCl3) δ 9.46 (d, J ) 1.4 Hz, 1H,
CHO). The ee was determined by acetalization with (-)-(2R,4R)-2,4-
pentanediol and GC analysis:1,20b GC (80 °C) tR ) 72.9 ((1S,2S,4S)-
isomer) min, 75.5 ((1R,2R,4R)-isomer) min. The absolute configuration
was established by comparison with authentic material prepared
independently.24
EtOAc, 4:1), Rf ) 0.59; IR (film) 2976, 1759, 1593, 1495, 1335, 1198,
1
1146, 1107, 1064, 980, 922, 837, 739, 711, 691 cm-1; H NMR (300
MHz, CDCl3) δ 1.37 (d, J ) 8.2 Hz, 1H), 1.40-1.64 (m, 2H), 1.97-
2.06 (m, 1H), 2.98 (br, 1H), 3.22 (dt, J ) 8.6, 9.2 Hz, 1H), 3.39 (br,
1H), 6.08 (dd, J ) 2.9, 5.8 Hz, 1H), 6.27 (dd, J ) 3.0, 5.8 Hz, 1H),
7.01-7.41 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 29.21, 42.55, 43.49,
45.81, 121.41, 125.41, 129.18, 132.03, 138.03, 150.79, 173.04. Anal.
Calcd for C14H14O2: C, 78.48; H, 6.59. Found. C, 78.49; H, 6.52.
The exo/endo ratio and the ee were determined by reduction with
LiAlH4, conversion to the ester with (+)-Mosher chloride, and 1H NMR
analysis: 1H NMR (500 MHz, CDCl3) δ 3.89 (t, J ) 10.1 Hz, 1H,
CHHO (endo (2S)-isomer)), 3.94 (t, J ) 10.1 Hz, 1H, CHHO (endo
(2R)-isomer), 4.06 (dd, J ) 6.7, 10.7 Hz, 1H, CHHO (endo (2R)-
isomer)), 4.11 (dd, J ) 6.7, 10.7 Hz, CHHO (endo (2S)-isomer), 4.18
(dd, J ) 7.0, 11.0 Hz, 1H, CHHO (one exo isomer)), 4.23 (dd, J )
9.0, 11.0 Hz, 1H, CHHO (another exo isomer)), 4.42 (dd, J ) 6.9,
11.0 Hz, 1H, CHHO (another exo isomer)), 4.38 (dd, J ) 7.0, 11.0
Hz, 1H, CHHO (one exo isomer)), 5.87 (dd, J ) 2.9, 5.7 Hz, 1H, C(5)H
(endo (2R)-isomer)), 5.93 (dd, J ) 2.8, 5.6 Hz, 1H, C(5)H (endo (2S)-
isomer)). The absolute configuration was established by comparison
with authentic Mosher esters prepared from the corresponding aldehydes
independently.
3,4-Dimethyl-3-cyclohexene-1-carboxaldehyde (Entry 13 in Table
3).20 1H NMR (300 MHz, CDCl3) δ 1.61 (s, 3H), 1.65 (s, 3H), 1.90-
2.06 (m, 4H), 2.09-2.19 (m, 2H), 2.42-2.58 (m, 1H), 9.69 (s, 1H).
The ee was determined by acetalization with (-)-(2R,4R)-2,4-pen-
tanediol and 1H NMR analysis:1,20b 1H NMR (500 MHz, CDCl3) δ 4.59
(d, J ) 6.0 Hz, 1 H, CHO2 (major isomer)), 4.61 (d, J ) 6.0 Hz, CHO2
(minor isomer)). The absolute configuration was not determined.
4-Methyl-3-cyclohexene-1-carboxaldehyde (Entry 14 in Table
3).25 1H NMR (300 MHz, CDCl3) δ 1.65 (s, 3H), 1.67-1.78 (m, 1H),
1.93-2.05 (m, 4H), 2.17-2.24 (m, 2H), 2.40-2.50 (m, 1H), 5.40 (br,
1H), 9.70 (s, 1H). The ee was determined by acetalization with (-)-
1
(2R,4R)-2,4-pentanediol and H NMR and GC analyses:20b 1H NMR
(CDCl3, 500 MHz) δ 4.59 (d, J ) 6.0 Hz, CHO2 (minor isomer)), 4.62
(d, J ) 6.0 Hz, CHO2 (major isomer)); GC (80 °C) tR ) 91.9 min
(minor isomer), 93.9 min (major isomer). The absolute configuration
was not established.
endo-3-Ethylbicyclo[2.2.1]hex-5-ene-2-carboxaldehyde (Entries
16 and 17 in Table 3).26 1H NMR (300 MHz, CDCl3) δ 0.96 (t, J )
7.4 Hz, 3H), 1.41-1.63 (m, 5H), 2.67-2.71 (br, 1H), 3.10-3.14 (br,
1H), 6.28 (dd, J ) 3.1, 5.7 Hz, 1H), 9.38 (d, J ) 3.3 Hz, 1H). The
p-Fluorophenyl (1S,2S,4S)-Bicyclo[2.2.1]hept-5-ene-2-carboxylate
(Entry 21 in Table 3). TLC (hexanes-EtOAc, 4:1), Rf ) 0.54; IR
(film) 2979, 1758, 1500, 1337, 1271, 1190, 1144, 1107, 1015, 980,
866, 837, 746, 711 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.37 (d, J )
8.5 Hz, 1 H), 1.43-1.62 (m, 2H), 2.01 (ddd, J ) 3.6, 9.4, 11.9 Hz,
1H), 2.99 (br, 1H), 3.21 (dt, J ) 3.8, 9.4 Hz, 1H), 3.38 (br, 1H), 6.06
(dd, J ) 2.7, 5.7 Hz, 1H), 6.26 (dd, J ) 3.0, 5,7 Hz, 1H), 6.96-7.09
(m, 4H); 13C NMR (75 MHz, CDCl3) δ 29.31, 42.63, 43.51, 45.89,
49.72, 115.90 (d, JC-F ) 23.4 Hz), 122.86 (d, JC-F ) 8.7 Hz), 132.01,
138.25, 146.67, 160.05 (d, JC-F ) 246.7 Hz), 173.27. Anal. Calcd
for C14H13O2F: C, 72.40; H, 5.64. Found. C, 72.40; H, 5.65. The
exo/endo ratio and the ee were determined in the similar manner as
above.
1
exo/endo ratio was determined by H NMR analysis (500 MHz): δ
9.38 (d, J ) 3.3 Hz, 1H, CHO (endo)), 9.79 (d, J ) 2.9 Hz, 1H, CHO
(exo)). The ee was determined by acetalization with (-)-(2R,4R)-2,4-
pentanediol and GC analysis (90 °C):20b tR ) 29.0 min (major endo-
isomer), 36.0 min (minor endo-isomer), 37.8 min (minor exo-isomer),
38.5 min (major exo-isomer). The absolute configuration was not
established.
endo-3-Phenylbicyclo[2.2.1]hex-5-ene-2-carboxaldehyde (Entry
1
18 in Table 3).27 [R]23 ) -107.6 (c ) 1.2, CHCl3); H NMR (300
D
MHz, CDCl3) δ 1.59-1.65 (m, 1H), 1.79-1.84 (m, 1H), 2.98 (ddd, J
) 2.3, 3.5, 4.9 Hz, 1H), 3.09 (dd, J ) 1.6, 4.9 Hz, 1H), 3.14 (br, 1H),
6.17 (dd, J ) 2.8, 5.8 Hz, 1H), 3.34 (br, 1H), 6.17 (dd, J ) 2.8, 5.8
Hz, 1H), 6.42 (dd, J ) 3.3, 5.8 Hz, 1H), 7.13-7.34 (m, 5H), 9.60 (d,
(1R,2R,6R)-Bicyclo[4.3.0]non-4-ene-2-carboxaldehyde.16 [R]25.2
D
) -92.3 (c ) 1.05, CHCl3); TLC (hexanes-EtOAc, 4:1), Rf ) 0.46;
1
IR (film) 2957, 2870, 1725, 1455, 1435, 1111, 1067, 681 cm-1; H
1
NMR (300 MHz, CDCl3) δ 1.10-1.51 (m, 3H), 1.71-2.02 (m, 5H),
2.19-2.40 (m, 2H), 2.45-2.56 (m, 1H), 5.63 (dq, J ) 3.6, 9.9 Hz,
1H), 5.88 (m, 1H), 9.69 (d, J ) 3.0 Hz, 1H). The exo/endo ratio was
determined by 1H NMR analysis of Diels-Alder adducts and GC
analysis after conversion to chiral acetals by (-)-(2R,4R)-2,4-pen-
tanediol:16,20b 1H NMR (300 MHz, CDCl3) δ 9.67 (d, J ) 2.4 Hz, 1H,
CHO (exo)), 9.69 (d, J ) 3.0 Hz, 1H, CHO (endo)). The ee was
determined by acetalization with (-)-(2R,4R)-2,4-pentanediol and GC
analysis:16,20b GC (110 °C) tR ) 44.4 min (1R,2R,6R)-isomer), 45.4
min (one exo isomer), 46.4 min (another exo isomer), 49.9 min
((1S,2S,4S)-isomer). The absolute configuration was determined by
conversion to the known alcohol by a literature procedure.2929-32
J ) 2.3 Hz, 1H). The exo/endo ratio was determined by H NMR
analysis (500 MHz): δ 9.60 (d, J ) 2.3 Hz, 1H, CHO (endo)), 9.93
(d, J ) 2.3 Hz, 1H, CHO (exo)). The ee was determined by
acetalization with (-)-(2R,4R)-2,4-pentanediol and GC analysis (180
°C):20b tR ) 13.2 min (major endo isomer), 13.9 min (exo isomers),
14.4 min (minor endo isomer). The absolute configuration was not
established.
Ethyl (1R,2R,3R,4S)-3-Formylbicyclo[2.2.1]hept-5-ene-2-carbox-
ylate (Entry 19 in Table 3). [R]23D ) -77.6 (c ) 1.2, CHCl3); TLC
(hexanes-EtOAc, 4:1), Rf ) 0.33; IR (film) 2982, 1717, 1453, 1393,
1
1352, 1333, 1262, 1036, 729 cm-1; H NMR (300 MHz, CDCl3) δ
1.28 (t, J ) 7.1 Hz, 3H), 1.49-1.54 (m, 1H), 1.65-1.70 (m, 1H), 2.70
(dd, J ) 1.4, 3.9 Hz, 1H), 3.19 (brs, 1H), 3.33-3.39 (m, 2H), 4.17 (q,
(28) Takano, S.; Kurotaki, A.; Ogasawara, K. Tetrahedron Lett. 1987,
28, 3991.
(29) Roush, W. R.; Gillis, H. R.; Ko, A. I. J. Am. Chem. Soc. 1982,
104, 2269.
(30) Lingenfelter, D. S.; Helgeson, R. C.; Cram, D. J. J. Org. Chem.
1981, 46, 393.
(24) Cervinka, O.; Kriz, O. Collect. Czech. Chem. Commun. 1968, 33,
2342.
(25) Fray, G. I.; Robinson, R. J. Am. Chem. Soc. 1961, 83, 249.
(26) Kobayashi, S.; Murakami, M.; Harada, T.; Mukaiyama, T. Chem.
Lett. 1991, 1341.
(27) Kelly, T. R.; Maity, S. K.; Meghani, P.; Chandrakumar, N. S.
Tetrahedron Lett. 1989, 30, 1357.
(31) Geibel, K. Chem. Ber. 1970, 103, 1637.
(32) Balwin, J. E.; Lusch, M. J. J. Org. Chem. 1979, 44, 1923.

6930 J. Am. Chem. Soc., Vol. 120, No. 28, 1998
Ishihara et al.
Acknowledgment. Part of this work was financially sup-
ported by a Grant-in-Aid for Scientific Study from the Ministry
of Education, Science and Culture of the Japanese Government
and grants from the Sumitomo Fundation (92-103-325). H.K.
also acknowldeges a JSPS Fellowship for Japanese Junior
Scientists.
JA9810282