Catalytic asymmetric aldol reactions in aqueous media using chiral bis-pyridino-18-crown-6 - Rare earth metal triflate complexes

Article abstract of DOI:10.1021/ja028698z

Catalytic asymmetric aldol reactions in aqueous media have been developed using Pr(OTf)₃ and chiral bis-pyrdino-18-crown-6 1. In the asymmetric aldol reaction using rare earth metal triflates (RE(OTf)₃) and 1, slight changes in the i

Full text of DOI:10.1021/ja028698z

Published on Web 02/14/2003
Catalytic Asymmetric Aldol Reactions in Aqueous Media
Using Chiral Bis-pyridino-18-crown-6-Rare Earth Metal
Triflate Complexes
Tomoaki Hamada,† Kei Manabe,† Shunpei Ishikawa,† Satoshi Nagayama,†
Motoo Shiro,‡ and Shuj Kobayashi*,†
Contribution from the Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, and Rigaku Corporation,
X-ray Research Laboratory, Matsubaracho 3-9-12, Akishima, Tokyo 196-8666, Japan
Received September 25, 2002 ; E-mail: skobayas@mol.f.u-tokyo.ac.jp
Abstract: Catalytic asymmetric aldol reactions in aqueous media have been developed using Pr(OTf)3
and chiral bis-pyridino-18-crown-6 1. In the asymmetric aldol reaction using rare earth metal triflates
(RE(OTf)3) and 1, slight changes in the ionic diameters of the metal cations greatly affected the diastereo-
and enantioselectivities of the products. The substituents (MeO, Br) at the 4-position of the pyridine rings
of the crown ether did not significantly affect the selectivities in the asymmetric aldol reaction, although
they affected the binding ability of the crown ether with RE cations and the catalytic activity of Pr(OTf)3-
crown ether complexes. From X-ray structures of RE(NO3)3-crown ether complexes, it was found that
they had similar structures regardless of the RE cations and the crown ethers used. Accordingly, the binding
ability of the crown ether with the RE cation and the catalytic activity of the complex are important for
attaining high selectivity in the asymmetric aldol reaction. Various aromatic and R,â-unsaturated aldehydes
and silyl enol ethers derived from ketones and a thioester can be employed in the catalytic asymmetric
aldol reactions using Pr(OTf)3 and 1, to provide the aldol adducts in good to high yields and stereoselec-
tivities. In the case using the silyl enol ether derived from the thioester, 2,6-di-tert-butylpyridine significantly
improved the yields of the aldol adducts.
Introduction
such drying is unnecessary for reactions in aqueous media.
Moreover, water is no doubt cheap, safe, and clean as compared
to organic solvents, and unique reactivity and selectivity which
are not attained under dry conditions are often observed in
aqueous reactions. Because water is a “solvent” in living
organisms, studies on organic reactions in aqueous media may
lead to a real understanding of life and nature; particularly, chiral
catalysts which work well in aqueous media may become
models of enzymes.
In the course of our investigations to develop new synthetic
reactions in aqueous media, we have reported lanthanide triflates
(Ln(OTf)3)-catalyzed aldol reactions of aldehydes with silyl enol
ethers in aqueous THF.4 Since then, not only Ln(OTf)3 but also
Sc(OTf)3 and Y(OTf)3 were shown to be useful for the reactions.
The most characteristic feature of these rare earth metal triflates
(RE(OTf)3) is that they act as water-compatible Lewis acids in
aqueous solvents, and they have been regarded as new types of
Lewis acids.5 RE(OTf)3 are strong Lewis acids because of the
hard character of their metal cations and the strong electron-
withdrawing effect of the trifluoromethanesulfonyl group, and
Asymmetric aldol reactions provide one of the most powerful
tools for constructing optically active â-hydroxy carbonyl
compounds.1 In the past two decades, various enantioselective
aldol reactions have been developed to pursue efficiency in
obtaining these chiral compounds. Among them, catalytic
asymmetric aldol reactions of aldehydes with silyl enol ethers
(the Mukaiyama aldol reaction2) mediated by chiral Lewis acids
have been elaborated into the most powerful and efficient
asymmetric aldol methodology.
In recent years, organic reactions in aqueous media have
attracted a great deal of attention.3 These reactions have several
advantages as compared to reactions under dry conditions, which
are required in many conventional synthetic procedures. For
example, while it is necessary to dry solvents and substrates
vigorously before use for many reactions in dry organic solvents,
† The University of Tokyo.
‡ Rigaku Corp.
(1) For reviews on asymmetric aldol reactions, see: (a) Machajewski, T. D.;
Wong, C.-H. Angew. Chem., Int. Ed. 2000, 39, 1352. (b) Carreira, E. M.
In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Heidelberg, 1999; Vol. 3, p 998. (c)
Mahrwald, R. Chem. ReV. 1999, 99, 1095. (d) Gro¨ger, H.; Vogl, E. M.;
Shibasaki, M. Chem.-Eur. J. 1998, 4, 1137. (e) Nelson, S. G. Tetra-
hedron: Asymmery 1998, 9, 357.
(4) (a) Kobayashi, S. Chem. Lett. 1991, 2187. (b) Kobayashi, S.; Hachiya, I.
J. Org. Chem. 1994, 59, 3590.
(5) (a) Kobayashi, S. Synlett 1994, 689. (b) Kobayashi, S. In Lanthanides:
Chemistry and Use in Organic Synthesis: Kobayashi, S., Ed.; Springer:
Berlin, 1999; p 63. (c) Kobayashi, S. Eur. J. Org. Chem. 1950, 15, 5. (d)
Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. ReV.
2002, 102, 2227.
(2) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1012.
(3) (a) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie Academic and
Professional: London, 1998. (b) Li, C.-J.; Chan, T.-H. Organic Reactions
in Aqueous Media; John Wiley & Sons: New York, 1997.
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J. AM. CHEM. SOC. 2003, 125, 2989-2996
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A R T I C L E S
Hamada et al.
Table 1. Effect of Solvents
many useful reactions are catalyzed by RE(OTf)3 in aqueous
media as well as in dry organic solvents.5 Only catalytic amounts
of the triflates are enough to complete the reactions in most
cases. Furthermore, RE(OTf)3 can be easily recovered after the
reactions and reused without loss of activity.
Despite these synthetic utilities of RE(OTf)3, there had been
no successful example of asymmetric reactions using chiral
RE(OTf)3 as chiral Lewis acid catalysts (catalytic asymmetric
reactions) in aqueous media. Catalytic asymmetric reactions,
especially carbon-carbon bond-forming reactions, in aqueous
media have been a subject of current importance, while only
limited examples have been reported so far.6 Therefore, we
undertook the development of catalytic asymmetric reactions
using RE(OTf)3 in aqueous media,7 and we have recently
developed the first example of RE(OTf)3-catalyzed asymmetric
aldol reactions using a chiral crown ether (1) in aqueous media.8
Herein we describe the detailed studies and further improve-
ments of the asymmetric aldol reactions in aqueous media. This
work sheds light on important factors which govern the
effectiveness of the catalytic system and will provide useful
ideas for designing new catalysts which work efficiently in
aqueous media.
entry
solvent
yield (%)
syn/anti
ee (syn) (%)
1
2
3
H2O/EtOH ) 1/3
H2O/EtOH ) 1/9
H2O/EtOH ) 1/27
H2O/THF ) 1/9
H2O/CH3CN ) 1/9
EtOH
55
85
89
73
92
51
4
88/12
91/9
93/7
73/27
87/13
85/15
57/43
76
78
80
47
61
23
28
4a
5b
6c
7d
CH2Cl2
a 31 h. b 112 h. c 16 h. d 35 h.
ethers would be a key to develop Lewis acid-catalyzed asym-
metric reactions in aqueous media. Therefore, we decided to
screen various chiral crown ethers for RE(OTf)3.13,14
After many trials, it turned out that crown ether 115-17 was
effective for catalytic asymmetric aldol reactions in aqueous
EtOH. For example, when 1 (24 mol %) and Pr(OTf) 3 (20 mol
%), one of RE(OTf)3, were used, the reaction of benzaldehyde
with silyl enol ether 2 in H2O/EtOH (1/9 (v/v)) at 0 °C for 18
h gave the desired aldol adduct in high yield with good
diastereo- and enantioselectivities (eq 1).18
Results and Discussion
Catalytic asymmetric aldol reactions using RE(OTf)3 and a
chiral ligand are difficult to achieve in aqueous media, because
competitive ligand exchange between a chiral ligand and water
easily occurs, and this leads to a decrease in the enantioselec-
tivity of the products by competition between the chiral Lewis
acid- and achiral, free Lewis acid-catalyzed pathways. While
many ligands such as aminocarboxylate type ones can coordinate
to RE cations strongly in aqueous solvents,9 these ligands also
reduce the Lewis acidity of the RE cations significantly. As a
result, the complexes are not sufficiently Lewis acidic to catalyze
the desired reactions. To overcome this problem, a chiral ligand
which coordinates to the metal cations strongly, but does not
significantly reduce the Lewis acidity of RE(OTf)3, is needed.10-12
Recently, we have reported catalytic asymmetric aldol reactions
in aqueous media using a combination of a chiral crown ether
and Pb(OTf)2.7d In these reactions, the chiral crown ether was
found not to reduce the catalytic activity of Pb(OTf)2. We
assumed that use of chiral multidentate ligands such as crown
(6) (a) Sinou, D. AdV. Synth. Catal. 2002, 344, 221. (b) Lindstro¨m, U. M.
Chem. ReV. 2002, 102, 2751. (c) Manabe, K.; Kobayashi, S. Chem.-Eur.
J. 2002, 8, 4094.
(7) We have recently reported Cu(II)- and Pb(II)-catalyzed asymmetric aldol
reactions in aqueous media: (a) Kobayashi, S.; Nagayama, S.; Busujima,
T. Chem. Lett. 1999, 71. (b) Kobayashi, S.; Nagayama, S.; Busujima, T.
Tetrahedron 1999, 55, 8739. (c) Kobayashi, S.; Mori, Y.; Nagayama, S.;
Manabe, K. Green Chem. 1999, 1, 175. (d) Nagayama, S.; Kobayashi, S.
J. Am. Chem. Soc. 2000, 122, 11531.
(8) Kobayashi, S.; Hamada, T.; Nagayama, S.; Manabe, K. Org. Lett. 2001, 3,
165.
(9) Hart, F. A. In ComprehensiVe Coordination Chemistry; Wilkinson, G.,
Gillard, R. D., McCleverty, J. A., Eds.; Pergamon Press: Oxford, 1987;
Vol. 3, Chapter 39.
(10) Engberts et al. reported a slight ligand acceleration in an asymmetric Diels-
Alder reaction in aqueous media. (a) Otto, S.; Engberts, J. B. F. N. J. Am.
Chem. Soc. 1999, 121, 6798. See also: (b) Berrisford, D. J.; Bolm, C.;
Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1995, 34, 1059. (c) Denmark,
S. E.; Wynn, T. J. Am. Chem. Soc. 2001, 123, 6199.
(11) Although the mechanism has not been fully elucidated, Yamamoto et al.
have reported that addition of a catalytic amount of triphenylphosphine
accelerates an AgOTf-catalyzed allylation of benzaldehyde with allyltri-
butyltin in aqueous THF. Yanagisawa, A.; Nakashima, H.; Ishiba, A.;
Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 4723.
We next examined the effect of solvents in this reaction
(Table 1). Use of aqueous EtOH gave good selectivities
regardless of the ratios between 1/3 and 1/27 (entries 1-3),
although the increased amount of water resulted in lower yield
because of the comparatively rapid hydrolysis of 2 (entry 1).
Lower selectivities were obtained when the reaction was carried
out in aqueous THF (entry 4) or aqueous CH3CN (entry 5).
(13) For complexation of rare earth metals with macrocyclic ligands, see: (a)
Fenton, D. E.; Vigato, P. A. Chem. Soc. ReV. 1988, 17, 69. (b) Alexander,
V. Chem. ReV. 1995, 95, 273.
(14) For chiral rare earth metal complexes, see: Aspinall, H. C. Chem. ReV.
2002, 102, 1807.
(15) Bradshaw, J. S.; Huszthy, P.; McDaniel, C. W.; Zhu, C. Y.; Dalley, N. K.;
Izatt, R. M.; Lifson, S. J. Org. Chem. 1990, 55, 3129.
(16) Bis-pyridino-18-crown-6 was first synthesized by Cram and co-workers.
Newcomb, M.; Gokel, G. W.; Cram, D. J. J. Am. Chem. Soc. 1974, 96,
6810.
(17) For preparation of crown ethers 1, 3-7, see the Supporting Information.
(18) The diastereo- and enantioselectivities of the aldol adduct were determined
according to the literature method. See: Denmark, S. E.; Wong, K.-T.;
Stavenger, R. A. J. Am. Chem. Soc. 1997, 119, 2333.
(12) We have also reported ligand-accelerated, Cd(ClO4)2-catalyzed allylation
in aqueous media. Kobayashi, S.; Aoyama, N.; Manabe, K. Synlett 2002,
483.
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Catalytic Asymmetric Aldol Reactions
A R T I C L E S
Figure 1. Enantio- and diastereoselectivities in the aldol reaction using
rare earth metal triflates and 1, and ionic diameters (8-coordination for Sc,
9-coordination for other metals) of the metal cations (RE3+). Yields: 49-
95%.
When the reaction was carried out in pure EtOH or CH2Cl2,
much lower yield and selectivities were observed (entries 6,
7).19 The results indicate that a certain amount of, but not too
much, water is essential to attain good yield and selectivities.
We discuss this effect of water later.
Effect of Metals in RE(OTf)3. In the asymmetric aldol
reaction using 1, we carried out a systematic evaluation of
RE(OTf)3. The diastereo- and enantioselectivities in the reactions
using RE(OTf)3 having metal cations of various ionic diam-
eters20 are shown in Figure 1. It was found that the selectivities
varied significantly with the ionic diameters.21 While the larger
cations such as La, Ce, Pr, and Nd gave the aldol adduct with
high diastereo- and enantioselectivities, the smaller cations such
as Dy, Y, Ho, Yb, and Sc gave lower selectivities. These results
suggest that size-fitting between crown ether 1 and the metal
cations is an important factor to attain high selectivities.
To study the effect of the electron-donating ability of the
pyridine nitrogens, we prepared novel crown ethers 317 and 417
and also carried out a screening of the metal triflates in the
aldol reactions. Crown ether 3, which has electron-donating
MeO groups at the 4-position of the pyridine rings of 1, gave
high selectivities for the larger cations and gave low selectivities
for the smaller cations, as 1 did (Figure 2). On the other hand,
the selectivity in the reactions using 4, which has electron-
withdrawing Br groups at the 4-position of the pyridine rings
of 1, was affected more significantly by the ionic diameters,
although 4 showed a trend almost similar to that of 1 and 3
(Figure 3). As a consequence, it was found that the substituents
at the 4-position of the pyridine rings of 1 did not significantly
affect the variations of the selectivities in the aldol reaction,
and, for larger cations such as La, Ce, and Pr, these crown ethers
Figure 2. Enantio- and diastereoselectivities in the aldol reaction using
rare earth metal triflates and 3. Yield: 30-89%.
Figure 3. Enantio- and diastereoselectivities in the aldol reaction using
rare earth metal triflates and 4. Yield: 22-89%.
gave the aldol adduct with the same level of diastereo- and
enantioselectivities.
(19) For effects of water in RE(OTf)3-catalyzed aldol reactions, see: ref 4b.
(20) Shannon, R. D. Acta Crystallogr. 1976, A32, 751.
Binding Ability of Chiral Crown Ethers with RE3+. The
observed variations of the selectivities shown in Figures 1-3
suggest that, in the case of the larger cations, they mostly exist
as complexes with the crown ethers in aqueous EtOH, and that,
in the case of the smaller cations, significant amounts of free
(21) Size effects of rare earth metals on enantioselectivity have been observed
in asymmetric reactions. For example: (a) Sasai, H.; Suzuki, T.; Itoh, N.;
Arai, S.; Shibasaki, M. Tetrahedron Lett. 1993, 34, 2657. (b) Evans, D.
A.; Nelson, S. G.; Gagne´, M. R.; Muci, A. R. J. Am. Chem. Soc. 1993,
115, 9800. (c) Kobayashi, S.; Ishitani, H.; Hachiya, I.; Araki, M.
Tetrahedron 1994, 50, 11623. (d) Schaus, S. E.; Jacobsen, E. N. Org. Lett.
2000, 2, 1001.
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A R T I C L E S
Hamada et al.
Table 2. Binding Constants of Crown Ethers (1, 3, or 4) with La3+
or Y3+
3+
crown ether
with La3+ (M-1
)
ee (%)b
with Y (M-1
)
ee (%)b
1
3
4
6.7 × 103
4.3 × 105
3.1 × 102
79
80
76
2.5 × 102
7.2 × 102
2.6 × 10
7
6
-1
a Determined by 1H NMR in D2O/C2D5OD (1/9) at 0 °C. b Enantio-
selectivity in the aldol reaction using the combination of each crown ether
and metal triflate under the conditions shown in eq 1.
cations exist. To elucidate the binding ability of the crown ethers,
therefore, we measured the binding constants of the crown ethers
(1, 3, 4) with La3+, which gave higher selectivities in the aldol
reaction, and with Y3+, which gave lower selectivities.
First, to determine the binding constant of 1 with La3+, we
1
carried out a H NMR study. For a 1:1.2 mixture of 1 (0.95
mM) and La(OTf)3 in D2O/CD3CD2OD (1/9) at 0 °C, two sets
of signals which correspond to the crown ether were observed
in a ratio of 26:74, the minor component being free 1. The result
indicated that the equilibrium between free 1 and 1 complexed
with the La cation was slow on the NMR time scale, and the
binding constant was calculated to be 6.7 × 103 M-1. In a
similar way, the binding constants of other complexes were also
determined. These results were summarized in Table 2 with each
selectivity in the aldol reaction using the combination of each
crown ether and the metal triflate under the conditions shown
in eq 1.
Table 2 shows that all of the crown ethers bind La3+ much
more strongly than Y3+. This result cleanly explains the better
selectivities of La(OTf)3 than those of Y(OTf)3 in the aldol
reactions. However, it is notable that 3 and 4 gave selectivities
almost similar to that of 1, although 3 binds La3+ about 60 times
more strongly than does 1, and 4 binds La3+ about 20 times
more weakly than does 1. Furthermore, the binding constant of
4 with La3+ is smaller than that of 3 with Y3+, while the
enantioselectivity using 4 and La(OTf)3 is much higher than
that using 3 and Y(OTf)3. On the basis of these results, it is
considered that not only binding ability but also other factors
such as catalytic activity of the RE(OTf)3-crown ether complex
play a vital role in attaining good selectivity. Therefore, we next
studied the catalytic activity of the complexes.
Figure 4. Initial reaction rates of the asymmetric reactions (O, Pr(OTf)3;
b, Pr(OTf)3 + 1; 0, Pr(OTf)3 + 3; 9, Pr(OTf)3 + 4).
nitrogens to the metal cation governs the Lewis acidity of the
metal and, as a consequence, the catalytic activity of the
complexes.
On the basis of these studies, the same level of enantio-
selectivity using crown ethers 1, 3, and 4 with the larger rare
earth metals such as La, Ce, and Pr can be explained as follows.
In the case of 1 and 3, which have high binding ability to the
metal cations, only very small amounts of free metal cations
exist in the solution. Therefore, the reactions proceed mainly
through a pathway catalyzed by the chiral complexes. As a
consequence, 1 and 3 afforded good selectivities, while they
decreased the reaction rate of the aldol reaction. On the other
hand, in the case of 4, which has relatively low binding ability,
small amounts of free metal cations exist. In this case, however,
the catalytic activity of the chiral complexes is close to that of
the free cations. Therefore, although a certain amount of the
racemic aldol adduct is produced through the pathway catalyzed
by the free metal cations, the reaction still proceeds mainly
through the chiral complexes-catalyzed pathway. As a conse-
quence, a significant decrease of enantioselectivity as compared
to the case of 1 or 3 was not observed.
X-ray Crystal Structures of the Complexes of RE Cation
and Crown Ethers. We tried to prepare several PrX3-1
complexes with the intent of obtaining crystal structures that
might elucidate the transition state model of the asymmetric
aldol reactions using Pr(OTf)3 and 1. Although the complexes
of RE(OTf)3 with 1 could not be isolated as crystals, the
complex suitable for single-crystal X-ray diffraction was
obtained from Pr(NO3)3 and 1.23 The complex was found to
exist as [Pr(NO3)2‚1]3[Pr(NO3)6], and a single structure for the
complex of Pr with 1 was observed. The cationic moiety was
shown in Figure 5. This complex has pseudo D2 symmetry, and
the Pr cation complexed with 1 is located almost in the center
of the crown ring. Interestingly, the methyl groups of 1 are all
in axial positions with respect to the crown ring.24 We assume
Initial Reaction Rates of the Aldol Reaction. To compare
the catalytic activity of RE(OTf)3-crown ether (1, 3, 4)
complexes, the initial reaction rates of the aldol reaction of
benzaldehyde with silyl enol ether 2 using Pr(OTf)3 and the
crown ethers (1, 3, 4) were measured. The results are shown in
Figure 4. It was found that all of the crown ethers decelerated
the reaction to various extents. In the absence of the crown
ethers, Pr(OTf)3 catalyzed the reaction at the initial rate of 1.5
× 10-4 M s-1, while 1 retarded the reaction to 1.7 × 10-5
M
s-1. The presence of MeO groups in 3 significantly reduced
the catalytic activity (2.2 × 10-6 M s-1). On the other hand, in
the case of 4, the initial rate (1.0 × 10-4 M s-1) was close to
that in the absence of the crown ethers. In the case of 3, MeO
groups increase the electron-donating ability of the pyridine
nitrogens, while Br groups decrease this ability in the case of
4.22 It appears that this electron donation from the pyridine
(23) The reaction of benzaldehyde with 2 in the presence of Pr(NO3)3 (20 mol
%) and 1 (24 mol %) in H2O/EtOH (1/9) at 0 °C for 18 h afforded the
aldol adduct in 59% yield with good selectivities (syn/anti ) 88/12 and
69% ee (syn)).
(22) The pKa values of pyridine, 4-methoxypyridine, and 4-bromopyridine in
water at 25 °C are 5.17, 6.47, and 3.71, respectively. Lange’s Handbook
of Chemistry; Dean, J. A., Lange, N. A., Eds.; McGraw-Hill Book
Company: New York, 1972; Section 5.
(24) The complex of 2,3,11,12-tetramethyl-18-crown-6 and Ca(NO3)2 or KSCN
adopts similar comformation. (a) Dyer, R. B.; Metcalf, D. H.; Ghirardelli,
R. G.; Palmer, R. A.; Holt, E. M. J. Am. Chem. Soc. 1986, 108, 3621. (b)
Aoki, S.; Sasaki, S.; Koga, K. Tetrahedron Lett. 1989, 30, 7229.
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Catalytic Asymmetric Aldol Reactions
A R T I C L E S
Figure 7. X-ray structures of complexes of Pr(NO3)3: (a) [Pr(NO3)2‚3]+
moiety in the X-ray structure of [Pr(NO3)2‚3]3[Pr(NO3)6]; (b) [Pr(NO3)2‚
4]+ moiety in the X-ray structure of [Pr(NO3)2‚4]3[Pr(NO3)6](EtOH).
Figure 5. [Pr(NO3)2‚1]+ moiety in the X-ray structure of [Pr(NO3)2‚
1]3[Pr(NO3)6]. Hydrogen atoms are omitted for clarity. (a) Top view. (b)
Side view.
Figure 8. Assumed transition state model in the asymmetric aldol reaction
using Pr3+-1.
in the complexes of 1, 3, and 4 are 2.541, 2.572, and 2.531 Å,
respectively. It is noteworthy to mention that the order of the
lengths (3 > 1 > 4) should reflect the Lewis acidity of the Pr
cation, the complex of 4 being the most Lewis acidic because
of electron-withdrawing Br groups.
From the X-ray analysis mentioned above, it was found that
the structures of complexes were not affected significantly by
the center metal cations and the crown ethers. Accordingly, the
influences of the metal cations and the crown ethers upon the
selectivities in the asymmetric aldol reactions cannot be
explained by the difference in the complex structure. As
mentioned earlier, therefore, the main factors which affect the
selectivities should be the differences in the binding ability and
the catalytic activity of the complexes.
On the basis of these X-ray structures, we propose a transition
state model which can explain the absolute configuration of the
favored enantiomer in the asymmetric aldol reaction, as shown
in Figure 8. When an aldehyde coordinates to the Pr cation
complexed with 1 in the fashion shown in Figure 8, the si face
of the coordinated aldehyde carbonyl is shielded by the methyl
substituent of 1, allowing nucleophilic attack of 2 predominantly
from the re face. The axial methyl substituent may also control
the diastereoselectivity by making the orientation of the silyl
enol ether less sterically congested. The (2R,3R)-adduct is
considered to be formed selectively in this manner.
Figure 6. X-ray structures of complexes of 1. (a) [Ce(NO3)2‚1]+ moiety
in the X-ray structure of [Ce(NO3)2‚1]3[Ce(NO3)6]. (b) [Gd(NO3)2‚1]+
moiety in the X-ray structure of [Gd(NO3)2‚1](NO3). (c) [Y(NO3)2‚1]+
moiety in the X-ray structure of [Y(NO3)2‚1](NO3)(EtOH).
that this conformation of the crown ring is crucial to create an
effective chiral environment around the Pr cation. It is also likely
that one or two of the nitrate anions are dissociated in aqueous
media and that aldehydes to be activated coordinate in place of
the nitrate anion.
We also obtained the X-ray crystal structures of the complexes
of Ce, Gd, and Y cations with 1 as shown in Figure 6. It is
noted that the structures of these complexes are very similar to
each other, and that, in all of the complexes, the methyl groups
are in axial positions. While all of the complexes adopt almost
identical conformation, the rms (root-mean-square) deviation
from the least squares plane fitted to four oxygen atoms and
two nitrogen atoms of the crown ether ring becomes larger (for
Ce, 0.323 Å; for Pr, 0.339 Å; for Gd, 0.403 Å; for Y, 0.436 Å)
as the ionic diameter of the center metal cation becomes smaller.
This deviation from the planar structure for the smaller cations
may cause a slight strain to the crown ring and may be
responsible for the lower binding constant of 1 with Y3+
.
X-ray crystal structures of the complexes of crown ethers 3
and 4 with Pr(NO3)3 were also obtained (Figure 7). In the
structures of these complexes, no particular difference from
Pr(NO3)3-1 was observed. Again, all of the methyl groups adopt
axial orientation. The average lengths of Pr-O (nitrate) bonds
Effect of Substituents of Crown Ethers. To attain higher
selectivity in the Pr(OTf)3-catalyzed aldol reaction, we synthe-
sized novel crown ethers 517 and 6,17 which have ethyl and
phenyl groups, respectively. Unfortunately, when the aldol
reactions of benzaldehyde with 2 were examined using 5 and 6
9
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A R T I C L E S
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Scheme 1. Reversal of the Sense of Enantioselection
Figure 9. Initial reaction rate of the aldol reactions (O, Pr(OTf)3 in EtOH;
b, 1-Pr(OTf)3 in EtOH; 0, Pr(OTf)3 in H2O/EtOH (1/9); 9, 1-Pr(OTf)3
in H2O/EtOH (1/9)).
In pure EtOH, the comparatively rapid ethanolysis of 2 caused
low yield (checked by TLC). In the case of CH2Cl2, the reaction
was very slow, probably because triflate anions coordinate to
Pr3+ in CH2Cl2, reducing the Lewis acidity of Pr(OTf)3 as
compared to that in aqueous EtOH.
On the other hand, we assumed the reasons for low enantio-
selectivities in EtOH and CH2Cl2 as follows. It is probable that
water in aqueous EtOH plays one or more of the following three
roles: (1) increasing the binding ability of 1 with RE3+, (2)
suppressing significant loss of the Lewis acidity of RE(OTf)3
by the coordination of 1, or (3) creating an effective chiral
environment of the RE3+-1 complex.
To elucidate which role(s) water plays, we first carried out
the measurement of the binding constant of 1 with La3+ in both
EtOH and CH2Cl2. For a 1:1.2 mixture of 1 (9.5 × 10-2 mM)
and La(OTf)3 in C2D5OD at 0 °C, the signal of free 1 was not
observed.28 Similarly, for a 1:1.2 mixture of 1 (1.1 mM) and
La(OTf)3 in CD2Cl2 at 0 °C, free 1 was not observed, either.28
These results indicate that the binding constants of 1 with La3+
in C2D5OD and CD2Cl2 are much larger than that in aqueous
EtOH. That is, water does not increase the binding ability of 1.
We next carried out the measurement of the initial reaction
rates of the aldol reactions using Pr(OTf)3-1 in EtOH and
CH2Cl2. Figures 9 and 10 indicate that the initial reaction rates
of these reactions are decreased by 1 more largely than that of
the reaction in aqueous EtOH. It was first assumed that
significant loss of the Lewis acidity by 1 decreased the
enantioselectivities in the reactions in EtOH and CH2Cl2 because
of the overwhelming, achiral Lewis acid-catalyzed pathway.
However, it is likely that a very slight amount of the product is
formed through the achiral Lewis acid-catalyzed pathway in
these reactions, because the binding of 1 with Pr3+ is considered
to be quantitative. Accordingly, it seems that water aids in
creating an effective chiral environment of the Pr3+-1 complex,
although the precise role of water is still unclear.
(Scheme 1), improvement of the selectivities was not attained.
However, it was found that crown ether 6 afforded the
enantiomer opposite to the favored one which 1 afforded. While
1 and 5 afforded the (2R,3R)-adducts selectively, 6 afforded
the (2S,3S)-adduct selectively. This unexpected reversal of the
sense of enantioselection is considered to be caused by
conformational difference of the crown rings. In the case of 6,
the phenyl groups would be in equatorial positions,25,26 and as
a consequence the geminal hydrogen atoms would be in axial
positions. It is likely that these hydrogen atoms now shield the
re face of the aldehyde carbonyl from the nucloephilic attack
of 2. In fact, crown ether 7,17 which has cyclohexane rings and
hydrogen atoms which are locked in axial positions, also
afforded the (2S,3S)-adduct, although the selectivities were
lower.
Effect of Water. The reactions in pure EtOH and CH2Cl2
gave lower yields and selectivities than those in aqueous EtOH,
as shown in Table 1. It is apparent that water plays an essential
role for attaining good yield and selectivities in this reaction.27
(25) In the 2:1 complex of NH3BH3 with meso-2,3,11,12-tetraphenyl-18-crown-
6, the phenyl groups are in equatorial positions. In the 1:1 complex of
NH3BH3 with (2R,3R,11R,12R)-2,3,11,12-tetraphenyl-18-crown-6, one pair
of vicinal phenyl groups is axial, while the other pair is equatorial. Allwood,
B. L.; Shahriari-Zavareh, H.; Stoddart, J. F.; Williams, D. J. J. Chem. Soc.,
Chem. Commun. 1984, 1461.
Catalytic Asymmetric Aldol Reactions in Aqueous Media
Using Pr(OTf)3 and 1. In the catalytic asymmetric aldol
reaction in aqueous media using Pr(OTf)3 and 1, other aldehydes
(26) In the complex of Ca(NO3)2 with (2S,3S,11S,12S)-2,3,11,12-tetraphenyl-
18-crown-6, all four phenyl groups are pseudoequatorial. Crosby, J.; Fakley,
M. E.; Gemmell, C.; Martin, K.; Quick, A.; Slawin, A. M. Z.; Shahriari-
Zavareh, H.; Stoddart, J. F.; Williams, D. J. Tetrahedron Lett. 1989, 30,
3849.
(27) For H2O-accelerated organic transformations, see: Ribe, S.; Wipf, P. Chem.
Commun. 2001, 299.
(28) In both C2D5OD and CD2Cl2, the equilibrium between free 1 and 1
complexed with the La cation was slow on the NMR time scale.
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Catalytic Asymmetric Aldol Reactions
A R T I C L E S
Table 4. Asymmetric Aldol Reactions Using Pr(OTf)3 and 1
Figure 10. Profiles of the aldol reactions (O, Pr(OTf)3 in CH2Cl2; b,
1-Pr(OTf)3 in CH2Cl2; 0, Pr(OTf)3 in H2O/EtOH (1/9); 9, 1-Pr(OTf)3 in
H2O/EtOH (1/9)).
Table 3. Asymmetric Aldol Reactions Using Pr(OTf)3 and 1
a E/Z ) 99/1. b 2,6-Di-tert-butylpyridine was not used.
Optically active â-hydroxy thioesters, which can be obtained
in the asymmetric aldol reactions using silyl enol ethers derived
from thioesters, are useful compounds because they can be
precursors of various optically active alcohols with other
functional groups. However, these silyl enol ethers are mostly
unstable in water, and successful examples of asymmetric aldol
reactions in aqueous media using these silyl enol ethers have
not been reported. Indeed, when 8 was used under the same
conditions as Table 3, moderate yield was obtained because of
rapid hydrolysis of 8 (Table 4, entry 1). However, it was found
that the addition of 2,6-di-tert-butylpyridine suppressed hy-
drolysis of 8, affording the aldol adduct in good yield.29 When
30 mol % of 2,6-di-tert-butylpyridine was used, the desired aldol
adduct was obtained in 86% yield with high diastereo- and
enantioselectivities (syn/anti ) 95/5, and 83% ee30 (syn)) (entry
2). The use of other aldehydes also gave good yields and
selectivities (entries 3-5). These results are the first examples
of catalytic asymmetric aldol reactions of silyl enol ethers
derived from thioesters in aqueous media. It seems likely that
the use of 2,6-di-tert-butylpyridine could be a versatile method
for water-sensitive substrates in Lewis acid-catalyzed asym-
metric reactions in aqueous media.
Summary
We have developed RE(OTf)3-crown ether 1 as efficient
chiral catalysts for asymmetric aldol reactions in aqueous media.
To the best of our knowledge, this is the first example of
catalytic asymmetric reactions using RE(OTf)3 in aqueous
media. Our strategy is based on the size-fitting effects of
a 20 mol % of Pr(OTf)3 and 24 mol % of 1 were used. b -20 °C. c -10
°C. d E/Z ) 9/91. e 29 h at -10 °C and then 147 h at 0 °C.
and silyl enol ethers were tested, and the results are summarized
in Table 3. Not only aromatic aldehydes (entries 1-6) but also
R,â-unsaturated aldehydes (entries 7, 8) gave good to high yields
and diastereo- and enantioselectivities. Aliphatic aldehydes such
as 3-phenylpropanal were not very good substrates in the present
catalytic system (entry 10).
(29) 2,6-Di-tert-butylpyridine was used as an additive for Lewis acid-catalyzed
aldol reactions. For example: Murata, S.; Suzuki, M.; Noyori, R.
Tetrahedron 1988, 44, 4275.
(30) The absolute configuration was determined to be 2R,3R after converting
to the methyl ester. (a) Gennari, C.; Colombo, L.; Bertolini, G.; Schimperna,
G. J. Org. Chem. 1987, 52, 2754. (b) Yamashita, Y.; Ishitani, H.; Shimizu,
H.; Kobayashi, S. J. Am. Chem. Soc. 2002, 124, 3292.
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A R T I C L E S
Hamada et al.
or -10 °C was added a solution of 1 (12-24 mol %) in H2O/EtOH
(1/9, 0.4 mL). A solution of an aldehyde (0.2 mmol) in H2O/EtOH
(1/9, 0.3 mL) and a solution of 2 (0.3 mmol) in H2O/EtOH (1/9, 0.3
mL) were then added. The whole was stirred for 18 h at the same
temperature. The reaction was quenched by addition of aqueous
NaHCO3. The mixture was extracted with CH2Cl2 three times, dried
over Na2SO4, and concentrated. The desired product was purified by
silica gel chromatography (AcOEt/hexane 1/6).
macrocyclic ligands. In fact, slight changes in ionic diameters
of the metal cations greatly affected the diastereo- and enantio-
selectivities of the aldol adducts. Although the substituents at
the 4-position of the pyridine rings of the crown ethers did not
significantly affect the selectivities in the asymmetric aldol
reaction, they affected the binding ability of the crown ethers
with RE cations and the reaction rates of the asymmetric aldol
reaction using Pr(OTf)3 and the crown ethers. Furthermore, the
structures of the chiral complexes were found not to be affected
significantly by the center metal cations and the crown ethers.
Therefore, to attain high selectivity in the asymmetric aldol
reaction, the design of a chiral crown ether, which complexes
strongly with RE(OTf)3 and does not decrease the Lewis acidity
of RE(OTf)3, is essential. In addition, the catalytic asymmetric
aldol reactions using Pr(OTf)3 and 1 also proceeded with good
to high yields and stereoselectivities, when several aldehydes
and silyl enol ethers were used. Especially in the aldol reactions
using the silyl enol ether derived from a thioester, the addition
of 2,6-di-tert-butylpyridine effectively enhanced the yields of
aldol adducts. Although the stereoselectivity and the catalytic
activity remain to be improved further, the present work will
provide a useful concept for the designing of chiral catalysts
which function effectively in aqueous media.
The diastereoselectivity and the enantioselectivity of the aldol adduct
1
formed from benzaldehyde with 2 were determined by H NMR and
HPLC analysis (Daicel Chiralpak AD, hexane/i-PrOH ) 30/1, flow
rate ) 1.0 mL/min), respectively.18
Acknowledgment. This work was partially supported by
CREST and SORST, Japan Corporation of Science and Tech-
nology, and by a Grant-in-Aid for Scientific Research from the
Japan Society of the Promotion of Science (JSPS). T.H. and
S.N. thank the JSPS fellowship for Japanese Junior Scientists.
Supporting Information Available: Experimental details for
the synthesis of crown ethers 1, 3, 4, 5, 6, and 7, and the kinetic
and binding studies, characterization data of the aldol adducts,
and crystallographic data for the complexes (PDF and CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental Section
General Procedure of the Asymmetric Aldol Reaction. To a
solution of RE(OTf)3 (10-20 mol %) in H2O/EtOH (1/9, 0.1 mL) at 0
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2996 J. AM. CHEM. SOC. VOL. 125, NO. 10, 2003