Highly anti-selective asymmetric aldol reactions using chiral zirconium catalysts. Improvement of activities, structure of the novel zirconium complexes, and effect of a small amount of water for the preparation of the catalysts

Article abstract of DOI:10.1021/ja016293t

Catalytic asymmetric aldol reactions of silyl enol ethers with aldehydes (Mukaiyama aldol reactions) have been performed using novel chiral zirconium catalysts. The reactions proceeded in high yields under mild conditions, and anti-adducts were obtained i

Full text of DOI:10.1021/ja016293t

Published on Web 03/08/2002
Highly anti-Selective Asymmetric Aldol Reactions Using
Chiral Zirconium Catalysts. Improvement of Activities,
Structure of the Novel Zirconium Complexes, and Effect of a
Small Amount of Water for the Preparation of the Catalysts
Yasuhiro Yamashita, Haruro Ishitani, Haruka Shimizu, and Shuj Kobayashi*
Contribution from the Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
CREST, Japan Science and Technology Corporation (JST), Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
Received May 28, 2001. Revised Manuscript Received December 20, 2001
Abstract: Catalytic asymmetric aldol reactions of silyl enol ethers with aldehydes (Mukaiyama aldol
reactions) have been performed using novel chiral zirconium catalysts. The reactions proceeded in high
yields under mild conditions, and anti-adducts were obtained in high diastereo- and enantioselectivities.
The catalysts were first prepared from zirconium(IV) tert-butoxide (Zr(OtBu)4), (R)-3,3′-diiodo-1,1′-
binaphthalene-2,2′-diol ((R)-3,3′-I2BINOL), a primary alcohol, and a small amount of water. It was revealed
that the primary alcohol played an important role in completing the catalytic cycle and that a small amount
of water was essential for obtaining high selectivities. Moreover, activities of the chiral zirconium catalysts
were enhanced by using new ligands, (R)-3,3′-I2-6,6′-X2BINOL (X ) Br, I, C2F5), and it has been shown
that even aldol reactions of less reactive substrates proceeded smoothly using the novel zirconium catalysts.
Finally, NMR studies of these catalysts were performed, which suggested that the catalyst would form a
dimeric structure and that the water affected the catalyst formation.
Introduction
Recently, we have shown that chiral zirconium complexes
prepared from zirconium alkoxide and chiral 1,1′-binaphthalene-
2,2′-diol (BINOL) derivatives activate azomethine compounds
Asymmetric aldol reactions provide one of the most powerful
tools for constructing chiral â-hydroxy carbonyl compounds.
In the past 2 decades, several diastereoselective aldol reactions
were developed to obtain these chiral compounds, and some of
them were successfully applied to the synthesis of biologically
important compounds.1 Furthermore, catalytic enantioselective
versions of these reactions, especially catalytic asymmetric aldol
reactions of silyl enol ethers with aldehydes (the Mukaiyama
aldol reaction) mediated by chiral Lewis acids, were elaborated
into the most powerful and efficient asymmetric aldol methodol-
ogy. Recently, several chiral Lewis acids for this reaction based
on Sn, B, Cu, Ti, etc. were developed to achieve high reactivities
and selectivities.2-4 In most systems, however, the reactions
were performed under strictly anhydrous conditions, and lower
temperatures were needed to obtain higher selectivities. Fur-
thermore, in the reactions of the silyl enol ethers derived from
propionate derivatives, most chiral Lewis acids showed syn-
diastereoselectivity, and few catalyst systems to give anti-aldol
adducts with high selectivity are known.5 Therefore, develop-
ment of anti-selective catalytic asymmetric aldol reactions is
an important target in organic chemistry.
(3) Recent examples of catalytic asymmetric Mukaiyama aldol reactions: (a)
Kobayashi, S.; Mukaiyama, T. Chem. Lett. 1989, 297. (b) Kobayashi, S.;
Uchiro, H.; Fujishita, Y.; Shiina, I.; Mukaiyama, T. J. Am. Chem. Soc.
1991, 113, 4247. (c) Mukaiyama, T.; Kobayashi, S.; Uchiro, H.; Shiina, I.
Chem. Lett. 1990, 129. (d) Kobayashi, S.; Fujishita, Y.; Mukaiyama, T.
Chem. Lett. 1990, 1455. (e) Kobayashi, S.; Uchiro, H.; Shiina, I.;
Mukaiyama, T. Tetrahedron 1993, 49, 1761. (f) Kobayashi, S.; Kawasuji,
T.; Mori, N. Chem. Lett. 1994, 217. (g) Furuta, K.; Maruyama, T.;
Yamamoto, H. J. Am. Chem. Soc. 1991, 113, 1041. (h) Ishihara, K.;
Maruyama, T.; Mouri, M.; Gao, Q.; Furuta, K.; Yamamoto, H. Bull. Chem.
Soc. Jpn. 1993, 66, 3483. (i) Parmee, R. M.; Tempkin, O.; Masamune, S.
J. Am. Chem. Soc. 1991, 113, 9365. (j) Corey, E. J.; Cywin, C. L.; Roper,
T. D. Tetrahedron Lett. 1992, 33, 6907. (k) Kiyooka, S.; Kaneko, Y.; Kume,
K. Tetrahedron Lett. 1992, 33, 4927. (l) Evans, D. A.; Kozlowski, M. C.;
Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connel, B. T.; Staples, R. J.
J. Am. Chem. Soc. 1999, 121, 669. (m) Evans, D. A.; Burgey, C. S.;
Kozlowski, M. C.; Tregay, S. W. J. Am. Chem. Soc. 1999, 121, 686. (n)
Mikami, K.; Matsukawa, S. J. Am. Chem. Soc. 1993, 115, 7039. (o) Keck,
G. E.; Krishnamurthy, D. J. Am. Chem. Soc. 1995, 117, 2363. (p) Carreira,
E. M.; Singer, R. A.; Lee, W. J. Am. Chem. Soc. 1994, 116, 8837. (q)
Sodeoka, M.; Ohrai, K.; Shibasaki, M. J. Org. Chem. 1995, 60, 2648. (r)
Denmark, S. E.; Stavenger, R. A.; Wong, K.-T.; Su, X. J. Am. Chem. Soc.
1999, 121, 4982. (s) Kru¨ger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998,
120, 837.
(4) Direct asymmetric aldol reactions were reported: (a) Yamada, Y. M. A.;
Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1997,
36, 1871. (b) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.;
Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168. (c) Yamada, Y. M. A.;
Shibasaki, M. Tetrahedron Lett. 1998, 39, 5561. (d) List, B.; Lerner, R.
A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395. (e) Notz, W.;
List, B. J. Am. Chem. Soc. 2001, 123, 7386. (f) List, B.; Pojarliev, P.;
Castello, C. Org. Lett. 2001, 3, 573. (g) Trost, B. M.; Ito, H. J. Am. Chem.
Soc. 2000, 122, 12003. (h) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem.
Soc. 2001, 123, 3367. (i) Yoshikawa, N.; Kumagai, N.; Matsunaga, S.;
Moll, G.; Ohshima, T.; Suzuki, T.; Shibasaki, M. J. Am. Chem. Soc. 2001,
123, 2466. (j) Yoshikawa, N.; Shibasaki, M. Tetrahedron, 2001, 57, 2569.
(k) Kumagai, N.; Matsunaga, S.; Yoshikawa, N.; Ohshima, T.; Shibasaki,
M. Org. Lett. 2001, 3, 1539.
(1) Review: ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon
Press: Oxford, 1991; Vol. 2, Chapter 1.
(2) Reviews of catalytic asymmetric aldol reactions: (a) Carreira, E. M. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yama-
moto, Y., Eds.; Springer: Heidelberg, 1999; Vol. 3, p 998. (b) Mahrwald,
R. Chem. ReV. 1999, 99, 1095. (c) Groger, H.; Vogel, E. M.; Shibasaki,
M. Chem. Eur. J. 1998, 4, 1137. (d) Nelson, S. G. Tetrahedron: Asymmetry
1998, 9, 357. (e) Bach, T. Angew. Chem., Int. Ed. Engl. 1994, 33, 417.
9
3292
J. AM. CHEM. SOC. 2002, 124, 3292-3302
10.1021/ja016293t CCC: $22.00 © 2002 American Chemical Society

Highly anti-Selective Asymmetric Aldol Reactions
A R T I C L E S
Table 1. Effect of Water
effectively to perform catalytic asymmetric Mannich-type
reactions,6 aza Diels-Alder reactions,7 and Strecker reactions8
in high yields with high selectivities.9 It was shown in our
studies that these chiral zirconium catalysts formed an excellent
asymmetric environment close to the zirconium catalysts.
Similarly, these catalysts were expected to activate aldehydes
effectively. We then undertook a project to develop a new
catalyst system in the Mukaiyama aldol reaction by using a
novel chiral zirconium complex. After several trials, we found
an effective catalyst system that mediated the aldol reactions
efficiently under mild conditions.10 In this article, we describe
full details of this study.
Results and Discussion
In our initial investigations, a zirconium complex prepared
from zirconium tetra-tert-butoxide (Zr(OtBu)4), (R)-3,3′-diiodo-
1,1′-binaphthalene-2,2′-diol ((R)-3,3′-I2BINOL), and a primary
alcohol was shown to be an excellent Lewis acid catalyst for
aldol reactions of silyl enol ethers with aldehydes. In most cases,
the desired anti-aldol adducts were obtained in high yields with
high diastereo- and enantioselectivities under mild conditions.
However, in the course of our studies on reactions with aliphatic
aldehydes, it was found that yields were lower than those of
reactions with other aldehydes. In addition, it was revealed that
some reactions were not reproducible. We carefully reexamined
the reaction conditions and finally found that a small amount
of water was essential for this catalyst system.11 In the reaction
of 3-phenylpropionealdehyde with the ketene silyl acetal derived
from phenyl propionate (2d), the addition of a small amount of
water improved yields and selectivities (Table 1, Chart 1). While
the addition of 5-20 mol % of water gave the best results, the
reaction did not proceed when 40 mol % of water was added.
Chart 1
Since it was suggested that a small amount of water played
an important role in the catalyst system, we decided to
reinvestigate the effect of alcohols in the model aldol reaction
of benzaldehyde with the silyl enol ether derived from S-ethyl
ethanethioate (2a) (Table 2). It was revealed that the effect of
water was significant in these substrates and that only 42% yield
and 3% ee were obtained without water (Table 2, entry 1). In
the presence of water, the reactions using normal primary
alcohols such as ethanol, propanol, and butanol gave high yields
and high enantioselectivities (entries 2-4). Other primary
alcohols such as benzyl alcohol and 2,2,2-trifluoroethanol gave
lower yields and selectivities (entries 5 and 6).12 Secondary and
tertiary alcohols such as 2-propanol and tert-butyl alcohol
decreased the yields and selectivities (entries 7 and 8). Phenol
also gave lower yield and selectivity (entry 9). When 80-120
mol % of propanol was used, the best yields and enantioselec-
tivities were obtained (entries 11-13). On the other hand, the
same levels of the yield and selectivity were obtained when
zirconium tetrapropoxide-propanol complex (Zr(OPr)4-PrOH)
was employed instead of Zr(OtBu)4 (entry 15). The use of Zr-
(OPr)4-PrOH is desirable from an economical point of view.
Other substrates were then examined, and the results are
shown in Table 3. The ketene silyl acetal derived from methyl
isobutyrate (2b) also worked well. For aldehydes, while aromatic
and R,â-unsaturated aldehydes gave excellent yields and
selectivities, aliphatic aldehydes showed high yields but some-
what lower selectivities. It should be noted that yields and
enantioselectivities were improved by using a new catalyst
system containing water.10
(5) Recent examples of anti-selective aldol reactions: (a) Mikami, K.;
Matsukawa, S. J. Am. Chem. Soc. 1994, 116, 4077. (b) Evans, D. A.;
MacMillan, W. C.; Campos, K. R. J. Am. Chem. Soc. 1997, 119, 10859.
(c) Yanagisawa, A.; Matsumoto, Y.; Nakashima, H.; Asakawa, K.;
Yamamoto, H. J. Am. Chem. Soc. 1997, 119, 9319. (d) Denmark, S. E.;
Wong, K.-T.; Stavenger, R. A. J. Am. Chem. Soc. 1997, 119, 2333. (e)
Parmee, E. R.; Hong, Y.; Tempkin, O.; Masamune, S. Tetrahedron Lett.
1992, 33, 1729.
(6) (a) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 1997, 119,
7153. (b) Kobayashi, S.; Ueno, M.; Ishitani, H. J. Am. Chem. Soc. 1998,
120, 431. (c) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2000,
122, 8180. (d) Kobayashi, S.; Hasegawa, Y.; Ishitani, H. Chem. Lett. 1998,
1131. (e) Ishitani, H.; Kitazawa, H.; Kobayashi, S. Tetrahedron Lett. 1999,
40, 2161.
(7) (a) Kobayashi, S.; Komiyama, S.; Ishitani, H. Angew. Chem., Int. Ed. 1998,
37, 979. (b) Kobayashi, S.; Kusakabe, K.; Komiyama, S.; Ishitani, H. J.
Org. Chem. 1999, 64, 4220. (c) Kobayashi, S.; Kusakabe, K.; Ishitani, H.
Org. Lett. 2000, 2, 1225.
(8) (a) Ishitani, H.; Komiyama, S.; Kobayashi, S. Angew. Chem., Int. Ed. 1998,
37, 3186. (b) Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J.
Am. Chem. Soc. 2000, 122, 762.
(9) For other examples of catalytic asymmetic reactions based on zirconium-
BINOL complexes: (a) Bedeschi, P.; Casolari, S.; Costa, A. L.; Tagliavini,
E.; Umani-Ronchi, A. Tetrahedron Lett. 1995, 36, 7897. (b) Casolari, S.;
Cozzi, P. G.; Orioli, P.; Tagliavini, E.; Umani-Ronchi, A. Chem. Commun.
1997, 2123. (c) Yu, C.-M.; Yoon, S.-K.; Choi, H.-S.; Baek, K. Chem.
Commun. 1997, 763. (d) Volk, T.; Korenaga, T.; Matsukawa, S.; Terada,
M.; Mikami, K. Chirality 1998, 10. 717. (e) Ringwald, M.; Stu¨rmer, R.;
Brintzinger, H. H. J. Am. Chem. Soc. 1999, 121, 1524. (f) Bolm, C.;
Beckmann, O. Chirality 2000, 12, 523. (g) Hanawa, H.; Kii, S.; Asao, N.;
Maruoka, K. Tetrahedron Lett. 2000, 41, 5543.
(10) For a preliminary communication, see: Ishitani, H.; Yamashita, Y.; Shimizu,
H.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 5403.
(11) In some metal-catalyzed asymmetric reactions, water affected the yields
and selectivities: Ribe, S.; Wipf, P. Chem. Commun. 2001, 299. Mikami,
K. et al. also reported that a small amount of water affected catalytic
enantioselective ene reactions using a Ti-BINOL complex; see: (a) Terada,
M.; Matsumoto, Y.; Nakamura, Y.; Mikami, K. Chem. Commun. 1997,
281. (b) Terada, M.; Matsumoto, Y.; Nakamura, Y.; Mikami, K. J. Mol.
Catal. A 1998, 132, 165. (c) Mikami, K.; Terada, M.; Matsumoto, Y.;
Tanaka, M.; Nakamura, Y. Microporous Mesoporous Mater. 1998, 21, 461.
(d) Terada, M.; Matsumoto, Y.; Nakamura, Y.; Mikami, K. Inorg. Chim.
Acta 1999, 296, 267.
We then examined diastereoselective aldol reactions using
this chiral zirconium catalyst. First, the ketene silyl acetal
(12) Katsuki and Evans reported independently that a fluorinated alcohol
accelerated catalytic asymmetric reactions; see: (a) Kitajima, H.; Katsuki,
T. Synlett 1997, 568. (b) Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1,
595.
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A R T I C L E S
Yamashita et al.
Table 2. Effect of Alcohols in the Catalytic Asymmetric Aldol
Table 4. Diastereoselective Aldol Reactionsa
Reaction Using a Chiral Zirconium Catalyst (eq 2)a
Scheme 1. Effect of Geometry of the Silyl Enolates
Table 3. Catalytic Asymmetric Aldol Reactions Using the Chiral
Zirconium Catalysta
Although the high anti-selectivities observed in these reactions
are remarkable, examination of the effect of the geometry of
the ketene silyl acetals revealed further important information
on the selectivity. Namely, when the (E)- and (Z)-ketene silyl
acetals derived from methyl propionate were employed in the
reactions with benzaldehyde, high anti-selectivities were ob-
tained in both cases, and it was confirmed that the selectivities
were independent of the geometry of the ketene silyl acetals.14
For the transition states of these reactions, acyclic pathways
are assumed (details are discussed in the following paragraphs).
Further investigations on the effect of the aldehyde structures
were performed. Reactions of other aliphatic aldehydes were
examined using a chiral zirconium catalyst consisting of Zr-
(OtBu)4, (R)-3,3′-I2BINOL, propanol, and water. In the cases
of employing normal linear aliphatic aldehydes such as hexanal
and butanal, the reactions proceeded in high selectivities.
γ-Branched aldehydes also reacted smoothly to afford the
desired anti-adducts in good yields with high diastereo- and
enantioselectivities. On the other hand, the catalyst did not work
derived from methyl propionate (2c) was employed in the
reaction with benzaldehyde. The reaction proceeded smoothly
to afford the desired anti-aldol adduct in high yield with high
diastereo- and enantioselectivities when ethanol was used as a
primary alcohol. The selectivities were further improved using
the ketene silyl acetal derived from phenyl propionate (2d). We
tested other aldehydes such as anisaldehyde, p-chlorobenzal-
dehyde, cinnamaldehyde, and 3-phenylpropionealdehyde, etc.,
and in all cases the reactions proceeded smoothly and the desired
anti-aldol adducts were obtained in high yields with high
diastereo- and enantioselectivities.13
(13) The results shown in Table 4 were obtained in 0.4-mmol-scale experiments.
The reaction of benzaldehyde with 2d was carried out in a 10-mmol-scale
experiment, and the same level of yield and selectivities was obtained (99%
yield, syn/anti ) 7/93, 99% ee (anti). See Table 4, entry 3). In addition,
the present catalytic asymmetric aldol reaction was successfully used in
an initial stage of the total synthesis of Khafrefungin; see: Kobayashi, S.;
Mori, K.; Wakabayashi, T.; Yasuda, S.; Hanada, K. J. Org. Chem. 2001,
66, 5580.
(14) Evans et al. reported chiral tin-catalyzed anti-selective aldol-type reactions
of pyruvate esters with silyl thioketene acetals.5b In these reactions, both
(E)- and (Z)-silyl thioketene acetals gave anti-adducts.
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Highly anti-Selective Asymmetric Aldol Reactions
A R T I C L E S
Scheme 3. Synthesis of (R)-3,3′-I2-6,6′-Br2BINOL and
Table 5. Effect of Structures of Aliphatic Aldehydes in Reactions
with 2da
(R)-3,3′,6,6′-I4BINOL
ethyl groups using CuC2F5 in DMF,15 to afford (R)-2,2′-bis-
(methoxymethyloxy)-6,6′-bis(pentafluoroethyl)-1,1′-binaphth-
yl. After lithiation and iodonation at the 3,3′-positions and
deprotection of the MOM groups, (R)-3,3′-I2-6,6′-(C2F5)2BINOL
was isolated as colorless needles. On the other hand, (R)-6,6′-
dibromo-3,3′-diiodo-1,1′-binaphthyl-2,2′-diol ((R)-6,6′-Br2-3,3′-
I2BINOL) and (R)-3,3′,6,6′-tetraiodo-1,1′-binaphthyl-2,2′-diol
((R)-3,3′,6,6′-I4BINOL) were synthesized according to Scheme
3. In a way similar to that shown in Scheme 2, (R)-6,6′-Br2-
BINOL was converted to its methoxymethyl (MOM) ether. The
bromo groups at the 6,6′-positions were lithiated and trimeth-
ylsilylated, and then the 3,3′-positions were lithiated and
iodonated. Finally, treatment with bromine or iodinemonochlo-
ride(ICl) afforded (R)-3,3′-I2-6,6′-Br2BINOL or (R)-3,3′,6,6′-
I4BINOL, respectively.16
Scheme 2. Synthesis of (R)-3,3′-I2-6,6′-(C2F5)2BINOL
We then evaluated the catalyst activities of the zirconium
complexes prepared from new BINOL derivatives in the aldol
reaction of benzaldehyde with the silyl enol ether derived from
S-ethyl propanethioate (2e). Compared with the catalyst prepared
from 3,3′-I2BINOL, the new catalysts prepared from 6,6′-
disubstituted-3,3′-I2BINOL showed higher activities and the
reaction proceeded much faster. In particular, the iodo and
pentafluoroethyl groups at the 6,6′-positions showed better
results to give the desired anti-adducts in high yields with high
diastereo- and enantioselectivities (Table 6). The new catalyst
system was successfully applied to the reactions of aliphatic
aldehydes. In the reactions of hexanealdehyde with the silyl enol
ether derived from phenyl propionate (2d) and S-ethyl pro-
panethioate (2e), the best results were obtained when (R)-
3,3′,6,6′-I4BINOL was employed (Table 7). The electron-
withdrawing substituents at the 3,3′- and 6,6′-positions of the
BINOL derivatives were assumed to increase Lewis acidities
of the zirconium catalysts. By changing the chiral ligands,
chemical yields were much more improved (38% to 71% in
Table 6, entries 1 and 4; 9% to 92% in Table 7, entries 4 and
6) than enantioselectivity (80% ee to 87% ee in Table 7, entries
1 and 3). We calculated charges on the oxygen atoms of the
BINOL derivatives, and the calculated charges were shown in
Table 8. It was revealed that the order of the catalyst activities
well in the reactions of R- and â-branched aliphatic aldehydes.
These effects seemed to be caused by steric interaction between
the BINOL parts (especially large diiodo atoms at the 3,3′-
positions) of the catalysts and the alkyl moieties of the
aldehydes. From these results, it was indicated that the environ-
ment around the zirconium of the catalyst was crowded and
that the catalyst recognized the structure of the aldehydes strictly.
Improvement of the Catalyst Activity. To create more
effective catalyst systems, improvement of the catalyst activity
is an important subject. In our laboratory, it was recently
revealed that introduction of stronger electron-withdrawing
groups at the 6,6′-positions of the binaphthyl rings was effective
to improve Lewis acidity of the catalyst system.6c We then
examined the effect of stronger electron-withdrawing groups
at the 6,6′-positions of (R)-3,3′-I2BINOL in this aldol system.
We chose bromo, iodo, and pentafluoroethyl groups as the
electron-withdrawing groups. These BINOL derivatives were
literature-unknown compounds, and we first started to synthesize
(R)-3,3′-diiodo-6,6′-bis(pentafluoroethyl)-1,1′-binaphthyl-2,2′-
diol ((R)-3,3′-I2-6,6′-(C2F5)2BINOL) according to Scheme 2.
(R)-6,6′-Br2BINOL was converted to its methoxymethyl
(MOM) ether, whose bromine groups at the 6,6′-positions were
first converted to iodo groups using I2 6c and then pentafluoro-
(15) Urata, H.; Fuchikami, T. Tetrahedron Lett. 1991, 32, 91.
(16) (a) Felix, G.; Dunogues, J.; Pisciotti, F.; Calas, R. Angew. Chem., Int. Ed.
Engl. 1977, 16, 488. (b) Felix, G.; Dunogues, J.; Calas, R. Angew. Chem.,
Int. Ed. Engl. 1979, 18, 402.
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A R T I C L E S
Yamashita et al.
Table 6. Improvement of Catalyst Reactivity in the Aldol Reaction
of Benzaldehyde and Silyl Enolate 2ea
NMR were measured at room temperature, and clear and simple
signals were observed (Figure 1). It was revealed that this
catalyst was stable in the presence of excess propanol at room
temperature and that almost the same spectra were obtained after
1 day. On the 13C NMR spectrum, new two kinds of signals
that corresponded to the naphthyl rings and two kinds of signals
that corresponded to the propoxide groups were observed besides
the signals that corresponded to the free BINOL. The existence
of these two kinds of sharp signals suggested that the catalyst
would form a dimeric structure. We also observed characteristic
signals of the propoxide protons that were directly connected
to the carbon atoms attached to the oxygen atoms at 3.8, 4.0,
1
4.8, and 5.2 ppm in the H NMR spectrum. The integration of
the proton signals indicated the existence of two kinds of
propoxide moieties (one pair was observed at 3.8 and 4.0 ppm;
another was at 4.8 and 5.2 ppm) in the catalyst and that the
ratio was 2:1.
The role of a small amount of water in this catalyst system
was also revealed by NMR analyses.19 In the absence of PrOH
and water, a clear 13C NMR spectrum was obtained by the
combination of Zr(OtBu)4 and 3,3′-I2BINOL (Figure 2a). When
PrOH was added to this system, rather complicated signals were
observed (Figure 2b). On the other hand, clear signals appeared
once again when water was added to the catalyst system
consisting of Zr(OtBu)4, 3,3′-I2BINOL, and PrOH (Figure 2c).
From these results, it was assumed that the role of water in this
catalyst system was to put the catalyst structure in order.
Namely, the desired structure was formed from the oligomeric
structure by adding water. This assumption was also supported
by the following experiment: we prepared the catalyst from
Zr(OtBu)4, 3,3′-I2BINOL, and PrOH in the presence of water
and performed the aldol reaction in the presence of 4Å molecular
sieves by using this catalyst.20 It was revealed that the desired
aldol adduct was obtained with high selectivity. This result also
strongly supported that the water did not influence the aldol
reaction but affected the formation of the catalyst.
Table 7. Effect of New BINOLs in the Reactions of
Hexanaldehydea
In view of the dimeric structure of the catalyst, we examined
the possibility of a nonlinear effect in the asymmetric aldol
reaction.21 The reaction of benzaldehyde with the silyl enol ether
derived from S-ethyl ethanethioate (2a) was chosen as a model,
and the chiral Zr catalysts prepared from 3,3′-I2BINOLs with
lower enantiomeric excesses were employed. It was found that
a remarkable level of positive nonlinear effect was observed as
illustrated in Figure 3. On the other hand, after the chiral Zr
catalysts were prepared from (R)-3,3′-I2BINOL and (S)-3,3′-I2-
BINOL, respectively, they were combined and correlation
between the ee of the zirconium catalyst and the ee of the
product was investigated. In this case, a linear correlation
between them was obtained (Figure 4).22 These results might
also support the dimeric structure of the catalyst, and on the
basis of these experiments, we assumed the catalyst structure
was as shown in Figure 5.23
Table 8. Calculated Charges on the Oxygen Atoms of the BINOL
Derivatives
BINOL derivatives
charge
BINOL
3,3′-I2BINOL
3,3′-I2-6,6′-Br2BINOL
3,3′,6,6′-I4BINOL
3,3′-I2-6,6′-(C2F5)2BINOL
-0.227
-0.204
-0.201
-0.202
-0.197
was almost corresponding to that of the electron density of the
BINOL derivatives.17
Structure of the Chiral Catalyst. NMR experiments were
performed to clarify the structure of the chiral zirconium catalyst.
The catalyst was prepared from 1 equiv of zirconium tetra-
propoxide-propanol complex (Zr(OPr)4-PrOH), 1 equiv of
(18) Almost similar spectra were obtained in the catalyst prepared from Zr(Ot-
Bu)4, (R)-3,3′-I2BINOL, PrOH, and H2O.
(19) Mikami et al. speculated that a small amount of water composed an active
Ti-BINOL catalyst by forming µ3-oxo complex. See ref 11a-d.
(20) The reaction of benzaldehyde with the silyl thioketene acetal derived from
S-ethyl ethanethioate (2a) was performed in the presence of 4Å MS at 0
°C for 18 h using a chiral zirconium catalyst prepared from from Zr(Ot-
Bu)4 (10 mol %), (R)-3,3′-I2BINOL (12 mol %), PrOH (50 mol %), and
H2O (20 mol %). The desired product was obtained in 83% yield with
88% ee.
3,3′-I2BINOL, and 1 equiv of H2O in toluene-d8.18 1H and 13
C
(17) All charges shown in Table 8 were evaluated by the natural population
analysis (NPA). NBO 4.0: Glendening, E. D.; Badenhoop, J. K.; Reed, A.
E.; Carpenter, J. E.; Weinhold, F.; Theoretical Chemistry Institute,
University of Wisconsin, Madison, 1996.
(21) Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. Engl. 1998, 37, 2922.
(22) Mikami, K.; Motoyama, T.; Terada, M. J. Am. Chem. Soc. 1994, 116, 2812.
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Highly anti-Selective Asymmetric Aldol Reactions
A R T I C L E S
Figure 1. 1H and 13C NMR spectra of the zirconium complex.a
Figure 2. Effect of water.
9
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A R T I C L E S
Yamashita et al.
Figure 6. Assumed transition states for the anti-selectivity.
Scheme 4. Assumed Catalytic Cycle of the Aldol Reaction
Figure 3. Correlation between the ee of the product and the ee of (R)-
3,3′-I2BINOL in the aldol reaction using the catalyst prepared from (R)-
3,3′-I2BINOLs with low ee’s.
Figure 4. Correlation between the ee of the product and the ee of the
catalyst in the aldol reaction using the catalyst prepared by mixing (R)-
and (S)-catalyst.
aldol adducts were obtained from both (E)- and (Z)-enolates,
showing that acyclic transition states were most likely. We
speculated that the origin of the anti-selectivity was ascribed
to steric interaction between the alkyl groups of aldehydes and
not the R-methyl groups of enolates but chiral Lewis acids
coordinated to carbonyl oxygens (Figure 6).24 The asymmetric
environment around the zirconium center seemed to be very
crowded because of the existence of the bulky iodo groups at
the 3,3′-positions of BINOL derivatives. Moreover, the experi-
ments wherein this zirconium complex strictly recognized the
structures of aliphatic aldehydes also seemed to indicate the
highly steric hindrance around the active site of the catalyst.
Figure 5. Assumed catalyst structure.
Catalytic Cycle. An assumed catalytic cycle of this aldol
reaction is shown in Scheme 4. First, the zirconium catalyst A
is produced by mixing Zr(OtBu)4, (R)-3,3′-I2BINOL, a primary
alcohol, and H2O. At this stage, the remaining tert-butoxide
groups are exchanged for the primary alcohols or H2O. An
aldehyde coordinated to this catalyst, and a silyl enol ether
attacks the carbonyl carbon of the aldehyde to generate
The zirconium catalyst showed anti-selectivity independent
of enolate geometry. This remarkable feature was in contrast
to most syn-selective aldol reactions mediated by chiral Lewis
acids.3 In the usual cases affording syn-aldol adducts, the
selectivity was explained by steric repulsion between the alkyl
groups of aldehydes and the R-methyl groups of enolates in
acyclic transition state models.2a,b In the present reactions, anti-
(24) (a) Mukaiyama, T.; Kobayashi, S.; Murakami, M. Chem. Lett. 1985, 447.
(b) Gennari, C.; Beretta, M., G.; Bernardi, A.; Moro, G.; Scolastico, C.;
Todeschini, R. Tetrahedron 1986, 42, 893.
(23) One of reviewers pointed out that the structure might be symmetrical
oligomers.
9
3298 J. AM. CHEM. SOC. VOL. 124, NO. 13, 2002

Highly anti-Selective Asymmetric Aldol Reactions
A R T I C L E S
was determined after acetylation or benzoylation of the hydroxy group.
intermediate B. Then, the silyl group on the carbonyl oxygen
moves to the most anionic atom in the same complex, the
oxygen of the binaphthol, to form intermediate C. Finally, the
primary alcohol reacts with this intermediate C, and the Si-O
bond or the Zr-O bond is cleaved. In the case of the cleavage
of the Si-O bond, the produced anionic oxygen attacks Zr and
the aldol product is obtained along with regeneration of the
original complex. On the other hand, when the Zr-O bond is
cleaved, another alcohol cleaves the Si-O bond. This mecha-
nism is supported by the fact that aldol adducts are obtained
with free hydroxyl groups and that trimethyl silyl ethers of
alcohols are observed by GC-MS analysis.25
Phenyl 3-Hydroxy-2-methyl-3-(4-methoxyphenyl)propanoate. IR
[cm-1] (neat) 3491, 1756, 1611, 1592, 1514, 1493, 1457, 1375, 1304,
1
1250. H NMR (CDCl3) anti isomer δ 1.14 (d, 3H, J ) 7.0 Hz), 2.74
(br, 1H), 3.03 (dq, 1H, J ) 8.8, 7.3 Hz), 3.81 (s, 3H), 4.82 (d, 1H, J
) 8.6 Hz), 6.91 (d, 2H, J ) 8.8 Hz), 7.08 (m, 2H), 7.21-7.40 (m,
5H); detectable peaks of syn isomer δ 1.34 (d, 3H, J ) 7.1 Hz), 5.07
(d, 1H, J ) 5.6 Hz). 13C NMR (CDCl3) anti isomer δ 14.3, 47.5, 55.2,
76.0, 113.8, 121.5, 125.8, 127.9, 129.3, 133.5, 150.5, 159.4, 174.4;
detectable peaks of syn isomer δ 11.9, 47.1, 55.2, 74.0, 113.7, 121.3,
127.4, 129.3, 129.4, 133.6, 150.3, 159.1, 173.8. HRMS (m/z) calcd for
C17H18O4 (M+) 286.1205, found 286.1202. HPLC (after acetylation),
Daicel Chiralcel OD, hexane/iPrOH ) 30/1, flow rate ) 0.5 mL/min:
syn isomer tR ) 17.8 min (major), tR ) 22.5 min (minor); anti isomer
tR ) 19.7 min (major), tR ) 24.3 min (minor).
Conclusion
Phenyl 3-Hydroxy-2-methyl-3-(4-chlorophenyl)propanoate. IR
[cm-1] (neat) 3480, 1754, 1594, 1491, 1457, 1412, 1376, 1309, 1227.
1H NMR (CDCl3) anti isomer δ 1.17 (d, 3H, J ) 7.1 Hz), 2.91 (br,
1H), 3.01 (dq, 1H, J ) 8.2, 7.1 Hz), 4.83 (d, 1H, J ) 8.2 Hz), 7.02-
7.05 (m, 2H), 7.20-7.40 (m, 7H); detectable peaks of syn isomer δ
1.29 (d, 3H, J ) 7.1 Hz), 5.15 (d, 1H, J ) 4.8 Hz), 6.94 (d, 2H, J )
7.5 Hz). 13C NMR (CDCl3) anti isomer δ 14.2, 47.3, 75.5, 121.4, 125.9,
128.0, 128.6, 129.4, 133.8, 139.8, 150.4, 174.1; detectable peaks of
syn isomer δ 11.2, 47.0, 73.2, 121.3, 127.5, 128.4, 133.3, 139.9, 150.2,
173.7. HRMS (m/z) calcd for C16H15O3Cl (M+) 290.0710, found
290.0706. HPLC (after acetylation), Daicel Chiralcel OD, hexane/iPrOH
) 60/1, flow rate ) 0.5 mL/min: syn isomer tR ) 21.5 min (major),
tR ) 31.1 min (minor); anti isomer tR ) 23.6 min (major), tR ) 33.6
min (minor).
We have developed anti-selective asymmetric aldol reactions
that proceeded at 0 °C under mild protic conditions to afford
the desired adducts in high yields with high diastereo- and
enantioselectivities, using a novel chiral zirconium catalyst
prepared from Zr(OtBu)4, (R)-3,3′-I2BINOL, an alcohol, and
water. The alcohol played an important role in the catalyst
turnover, and water affected the formation of the catalyst.
Furthermore, catalysts with high activities were prepared by
using the BINOLs substituted by stronger electron-withdrawing
groups. By NMR studies, it was assumed that the catalyst
formed a dimeric structure tightly in toluene. Use of the protic
additives is a unique feature of this reaction compared to other
traditional catalytic asymmetric aldol reactions, and it is expected
that this catalyst system is effective for other asymmetric
reactions of aldehydes.
Phenyl (E)-3-Hydroxy-2-methyl-4-hexenoate. IR [cm-1] (neat)
1
3442, 1757, 1673, 1593, 1493, 1457, 1377, 1233. H NMR (CDCl3)
anti isomer δ 1.28 (d, 3H, J ) 7.1 Hz), 1.74 (dd, J ) 6.4, 1.5 Hz),
2.79 (dq, 1H, J ) 7.6, 7.3 Hz), 4.28 (dd, 1H, J ) 7.6, 7.6 Hz), 5.53
(ddq, 1H, J ) 15.4, 7.6, 1.7 Hz), 5.79 (dq, 1H, J ) 15.4, 6.3 Hz), 7.08
(m, 2H), 7.22 (m, 1H), 7.37 (m, 2H); detectable peaks of syn isomer
δ 1.33 (d, 3H, J ) 7.1 Hz), 2.85 (dq, 1H, J ) 7.3, 2.2 Hz), 4.42 (dd,
1H, J ) 5.9, 5.9 Hz), 5.60 (ddq, 1H, J ) 15, 6.8, 1.5 Hz). 13C NMR
(CDCl3); anti isomer δ 13.9, 17.7, 45.8, 74.9, 121.5, 125.9, 129.4, 129.5,
130.8, 150.5, 174.2; detectable peaks of syn isomer δ 11.9, 45.4, 73.5,
121.4, 125.9, 128.9, 130.2, 173.7. HRMS (m/z) calcd for C13H16O3 (M+)
220.1099, found 220.1073. HPLC (after acetylation), Daicel Chiralcel
OJ, hexane/iPrOH ) 9/1, flow rate ) 0.5 mL/min: syn isomer tR ) 48
min (minor), tR ) 64 min (major); anti isomer tR ) 21.1 min (minor),
tR ) 22.5 min (major).
Experimental Section
Typical Experimental Procedure for Asymmetric Aldol Reactions
Using Chiral Zirconium Catalyst. A typical experimental procedure
is described for the reaction of benzaldehyde with silyl enol ether 2a.
To a suspension of (R)-3,3′-diiodo-1,1′-binaphthalene-2,2′-diol (0.048
mmol) in toluene (1.0 mL) was added Zr(OtBu)4 (0.040 mmol) in
toluene (1.0 mL) at room temperature, and the solution was stirred for
30 min. Then propanol (0.32 mmol) and H2O (0.080 mmol) in toluene
(0.5 mL) were added, and the whole was stirred for 3 h at room
temperature.26 After cooling at 0 °C, benzaldehyde (0.40 mmol) in
toluene (0.75 mL) and silyl enol ether 2a (0.48 mmol) in toluene (0.75
mL) were successively added. The mixture was stirred for 18 h, and
saturated aqueous NaHCO3 (10 mL) was added to quench the reaction.
After added dichloromethane (10 mL), the organic layer was separated
and the aqueous layer was extracted twice with dichloromethane (10
mL × 2). The organic layers were combined and dried over anhydrous
Na2SO4. After filtration and concentration under reduced pressure, the
residue was treated with THF-1 N HCl (20:1) for 1 h at 0 °C. Then
the solution was basicified with saturated aqueous NaHCO3 and
extracted with dichloromethane. The organic layers were combined and
dried over anhydrous Na2SO4. After filtration and concentration under
reduced pressure, the crude product was purified by preparative thin-
layer chromatography (benzene-ethyl acetate 20:1) to afford the desired
aldol adduct. The optical purity was determined by HPLC analysis using
a chiral column (see below). In some compounds, the optical purity
Phenyl (E)-3-Hydroxy-2-methyl-5-phenyl-4-pentenoate. IR [cm-1
]
(neat) 3446, 1756, 1653, 1593, 1493, 1455, 1376, 1241. 1H NMR
(CDCl3) anti isomer δ 1.36 (d, 3H, J ) 7.1 Hz), 2.59 (br, 1H), 2.92
(dq, 1H, J ) 7.3 Hz, 7.1 Hz), 4.51 (dd, 1H, J ) 7.3 Hz, 7.0 Hz), 6.25
(dd, 1H, J ) 16 Hz, 7.0 Hz), 6.69 (d, 1H, J ) 16 Hz), 7.07 (d, 2H, J
) 7.7 Hz), 7.17-7.41 (m, 8H); detectable peaks of syn isomer δ 1.38
(d, 3H, J ) 7.3 Hz), 2.92-3.02 (m, 1H), 4.69 (ddd, 1H, J ) 7.7, 4.6,
1.3 Hz), 6.29 (dd, 1H, J ) 16, 6.2 Hz), 6.71 (d, 1H, J ) 16 Hz). 13C
NMR (CDCl3) anti isomer δ 14.0, 45.9, 74.8, 121.5, 125.9, 126.6, 128.0,
128.6, 128.9, 129.4, 132.6, 136.2, 150.5, 173.9; detectable peaks of
syn isomer δ 11.7, 45.4, 73.3, 121.4, 126.6, 127.9, 128.4, 129.5, 132.0,
136.3, 150.4, 173.7. HRMS (m/z) calcd for C18H18O3 (M+) 282.1256,
found 282.1260. HPLC, Daicel Chiralcel OJ, hexane/iPrOH ) 4/1, flow
rate ) 0.8 mL/min: syn isomer tR ) 25.3 min (major), tR ) 35.1 min
(minor); anti isomer tR ) 41.1 min (minor), tR ) 68.8 min (major).
(25) The trimethylsilyl ether of the alcohol was detected by direct analysis of
the reaction mixture using GC-MS.
Phenyl 3-Hydroxy-2-methyloctanoate. IR [cm-1] (neat) 3465,
(26) In the reactions using (R)-3,3′-I2-6,6′-X2BINOL (X ) Br, I, C2F5), the
catalyst preparation was performed according to the following procedure:
To a suspension of (R)-3,3′-I2-6,6′-X2BINOL (0.060 mmol) in toluene (1.0
mL) was added Zr(OtBu)4 (0.040 mmol) in toluene (1.0 mL) at room
temperature, and the solution was stirred for 3 h. Propanol (0.32 mmol)
and H2O (0.080 mmol) in toluene (0.5 mL) were then added, and the whole
was stirred for 30 min at room temperature.
1
1754, 1593, 1493, 1458, 1378. H NMR (CDCl3) anti isomer δ 0.91
(t, 3H, J ) 6.6), 1.36 (d, 3H, J ) 7.1 Hz) 1.3-1.7 (m, 8H), 2.44 (br,
1H), 2.78 (dq, 1H, J ) 7.1 Hz, 7.0 Hz), 3.80 (br, 1H), 7.08 (m, 2H),
7.24 (m, 1H), 7.39 (m, 2H); detectable peaks of syn isomer δ 1.34 (d,
3H, J ) 7.1 Hz), 4.05 (br, 1H). 13C NMR (CDCl3) anti isomer δ 14.0,
9
J. AM. CHEM. SOC. VOL. 124, NO. 13, 2002 3299

A R T I C L E S
Yamashita et al.
14.3, 22.6, 25.2, 31.8, 34.7, 45.5, 73.4, 121.5, 125.9, 129.4, 150.4, 174.5;
detectable peaks of syn isomer δ 10.7, 25.7, 34.0, 44.5, 71.8, 121.4,
174.7. HRMS (m/z) calcd for C15H22O3 (M+) 250.1569, found 250.1581.
HPLC, Daicel Chiralpak AD, hexane/iPrOH ) 100/1, flow rate ) 1.0
mL/min: syn isomer tR ) 26.3 min (major), tR ) 29.3 min (minor);
anti isomer tR ) 32.0 min (minor), tR ) 42.1 min (major).
23.2, 25.6, 34.0, 52.9, 71.9, 204.3. HRMS (m/z) calcd for C11H22O2S
(M+) 218.1341, found 218.1343. HPLC, Daicel Chiralpak AS, hexane/
iPrOH ) 1000/1, flow rate ) 1.0 mL/min: syn isomer tR ) 16.5 min
(major), tR ) 19.2 min (minor); anti isomer tR ) 22.3 min (minor), tR
) 25.4 min (major).
NMR Experiments of the Chiral Zirconium Catalyst. To a
suspension of (R)-3,3′-diiodo-1,1′-binaphthalene-2,2′-diol (0.10 mmol)
in toluene-d8 (0.2 mL) was added Zr(OtBu)4 (0.10 mmol) in toluene-
d8 (0.4 mL) at room temperature, and the solution was stirred for 30
min. After a mixture of propanol (0.50 mmol) and H2O (0.10 mmol)
in toluene (0.2 mL) was added, the whole was stirred for additional 3
h at room temperature. 1H and 13C NMR experiments were then
performed.
Phenyl 3-Hydroxy-2,6-dimethylheptanoate. IR [cm-1] (neat) 3467,
1756, 1594, 1494, 1459, 1384, 1366. 1H NMR (CDCl3) anti isomer δ
0.91 (d, 3H, J ) 6.6 Hz), 0.92 (d, 3H, J ) 6.6 Hz), 1.36 (d, 3H, J )
7.1 Hz), 1.2-1.8 (m, 5H), 2.51 (br, 1H), 2.79 (dq, 1H, J ) 7.1, 7.1
Hz), 3.77 (br, 1H), 7.08 (m, 2H), 7.23 (m, 1H), 7.38 (m, 2H); detectable
peaks of syn isomer δ 4.02 (br, 1H). 13C NMR (CDCl3) anti isomer δ
14.2, 22.4, 22.7, 28.0, 32.5, 34.6, 45.5, 73.2, 121.5, 125.9, 129.4, 150.5,
174.5; detectable peaks of syn isomer δ 10.7, 22.5, 22.6, 31.8, 35.1,
44.5, 72.1, 121.4, 174.6. HRMS (m/z) calcd for C15H22O3 (M+)
250.1569, found 250.1567. HPLC, Daicel Chiralcel OJ, hexane/iPrOH
) 40/1, flow rate ) 0.8 mL/min: syn isomer tR ) 26.8 min (major),
tR ) 42.4 min (minor); anti isomer tR ) 38.4 min (minor), tR ) 60.4
min (major).
Experiments of Nonlinear Effects. Experiments Using BINOL
with Low ee. To a suspension of 3,3′-diiodo-1,1′-binaphthalene-2,2′-
diol (0.040 mmol, low ee, already prepared) in toluene (1.0 mL) was
added Zr(OtBu)4 (0.040 mmol) in toluene (1.0 mL) at room temperature,
and the solution was stirred for an additional 30 min. Then propanol
(0.32 mmol) and H2O (0.080 mmol) in toluene (0.5 mL) were added,
and the whole was stirred for 3 h at room temperature. After cooling
at 0 °C, benzaldehyde (0.40 mmol) in toluene (0.75 mL) and silyl enol
ether 2a (0.48 mmol) in toluene (0.75 mL) were successively added.
The mixture was stirred for 18 h, and saturated aqueous NaHCO3 was
added to quench the reaction. The desired product was obtained by
following the usual workup procedure.
Phenyl 5-Cyclohexyl-3-hydroxy-2-methylpentanoate. IR [cm-1
]
(neat) 3435, 1757, 1593, 1493, 1448, 1381, 1338, 1301, 1274. 1H NMR
(CDCl3) anti isomer δ 0.8-2.0 (m, 2H), 1.1-1.8 (m, 13H), 1.36 (d,
3H, J ) 7.1 Hz), 2.43 (br, 1H), 2.78 (dq, 1H, J ) 7.1, 7.1 Hz), 3.76
(br, 1H), 7.07 (m, 2H), 7.23 (m, 1H), 7.38 (m, 2H); detectable peaks
of syn isomer δ 4.01 (br, 1H). 13C NMR (CDCl3) anti isomer δ 14.2,
26.3, 26.3, 26.6, 32.0, 33.1, 33.2, 33.5, 37.6, 45.5, 73.8, 121.5, 125.9,
129.4, 150.5, 174.4; detectable peaks of syn isomer δ 10.7, 31.4, 33.3,
33.4, 33.6, 44.5, 72.1, 121.4, 174.6. HRMS (m/z) calcd for C18H26O3
(M+) 290.1882, found 290.1882. HPLC, Daicel Chiralpak AD (double),
hexane/iPrOH ) 19/1, flow rate ) 0.5 mL/min: syn isomer tR ) 37.3
min (major), tR ) 40.1 min (minor); anti isomer tR ) 42.8 min (minor),
tR ) 46.8 min (major).
Experiments Using the Catalyst Prepared by Mixing the (R)-
and (S)- Catalyst. The (R)-catalyst was prepared from Zr(OtBu)4 (0.040
mmol), (R)-3,3′-diiodo-1,1′-binaphthalene-2,2′-diol (0.10 mmol), pro-
panol (0.32 mmol), and H2O (0.080 mmol) in toluene (2.5 mL). Then
the (R)-catalyst and the (S)-catalyst, which was prepared from (S)-3,3′-
diiodo-1,1′-binaphthalene-2,2′-diol, were mixed in desired ratio, and
the mixture was used as a catalyst immediately in the reactions of
benzaldehyde and silyl enol ether 2a.
Phenyl 3-Hydroxy-2,5-dimethylhexanoate. IR [cm-1] (neat) 3432,
1
1752, 1593, 1493, 1459, 1367. H NMR (CDCl3) anti isomer δ 0.95
Synthesis of Chiral Ligands (R)-2,2′-Bis(methoxymethyloxy)-6,6′-
bis(pentafluoroethyl)-1,1′-binaphthyl. Under argon atmosphere, (R)-
6,6′-diiodo-2,2′-bis(methoxymethyloxy)-1,1′-binaphthyl (4.00 g, 6.39
mmol),6c trimethylpentafluoroethylsilane27 (TMSC2F5, 4.90 g, 25.6
mmol), copper iodide (CuI, 3.65 g, 19.2 mmol), potassium fluoride
(14.8 g, 25.5 mmol), and dimethylformamide (16 mL) were added in
a shield tube, and the whole was heated at 100 °C for 24 h.15 After
cooling to room temperature, the reaction mixture was poured into a
mixture of ethyl acetate and water. The mixture was filtered and
separated, and the aqueous layer was extracted with ethyl acetate. The
organic layers were combined and washed with water and brine and
dried over Na2SO4. After filtration and concentration under reduced
pressure, the crude product was purified by silica gel column chroma-
tography (hexane/methylenechloride) to afford (R)-2,2′-bis(methoxym-
ethyloxy)-6,6′-bis(pentafluoroethyl)-1,1′-binaphthyl (3.21 g, yield 82%)
(d, 3H, J ) 6.6 Hz), 0.97 (d, 2H, J ) 6.6 Hz), 1.37 (d, 3H, J ) 7.3
Hz), 1.4-1.6 (m, 1H), 1.6-1.7 (m, 1H), 2.38 (br, 1H), 2.75 (dq, 1H,
J ) 7.3, 6.4 Hz), 3.87 (m, 1H), 7.08 (m, 2H), 7.24 (m, 1H), 7.39 (m,
2H); detectable peaks of syn isomer δ 1.34 (d, 3H, J ) 7.3 Hz), 4.14
(m, 1H). 13C NMR (CDCl3) anti isomer δ 14.2, 21.6, 23.7, 24.5, 44.0,
46.1, 71.6, 121.5, 126.0, 129.4, 150.5, 174.5; detectable peaks of syn
isomer δ 10.8, 21.9, 23.5, 24.5, 44.0, 44.9, 121.4, 174.7. HRMS (m/z)
calcd for C14H20O3 (M+) 236.1412, found 236.1402. HPLC, Daicel
Chiralpak AD (double), hexane/iPrOH ) 40/1, flow rate ) 0.5 mL/
min: syn isomer tR ) 51.9 min (major), tR ) 53.6 min (minor); anti
isomer tR ) 59.8 min (minor), tR ) 68.9 min (major).
Phenyl 4-Cyclohexyl-3-hydroxy-2-methylbutanoate. IR [cm-1
]
1
(neat) 3469, 1757, 1593, 1493, 1449, 1348. H NMR (CDCl3) anti
isomer δ 0.8-1.1 (m, 2H), 1.1-1.8 (m, 10 H), 1.33 (d, 3H, J ) 7.1
Hz), 1.85 (br, 2H), 2.53 (br, 1H), 2.73 (dq, 1H, J ) 7.0, 7.0 Hz), 3.90
(br, 1H), 7.07 (m, 2H), 7.22 (m, 1H), 7.37 (m, 2H); detectable peaks
of syn isomer δ 1.32 (d, 3H, J ) 7.1 Hz), 4.14 (m, 1H). 13C NMR
(CDCl3); anti isomer δ 13.9, 26.0, 26.3, 26.5, 32.5, 33.8, 34.4, 42.2,
46.1, 70.9, 121.4, 125.8, 129.3, 150.4, 174.4; detectable peaks of syn
isomer δ 10.8, 26.1, 32.7, 34.0, 34.1, 41.8, 45.0, 69.2, 121.4, 174.5.
HRMS (m/z) calcd for C17H24O3 (M+) 276.1725, found 276.1727. HPLC
Daicel Chiralpak AD (double), hexane/iPrOH ) 19/1, flow rate ) 0.8
mL/min: syn isomer tR ) 23.3 min (minor), tR ) 25.5 min (major);
anti isomer tR ) 28.8 min (minor), tR ) 35.5 min (major).
as an amorphous oil. [R]24 +78.5 (c 1.02, CHCl3). IR [cm-1] (KBr)
D
1631, 1600, 1484, 1444, 1407, 1385, 1360, 1334, 1283, 1248. 1H NMR
(CDCl3) δ 3.18 (s, 6H), 5.05 (d, 2H, J ) 6.8 Hz), 5.13 (d, 2H, J ) 6.9
Hz), 7.22 (d, 2H, J ) 9.0 Hz), 7.36 (d, 2H, J ) 9.0 Hz), 7.71 (d, 2H,
J ) 9.2 Hz), 8.08 (d, 2H, J ) 9.2 Hz), 8.17 (s, 2H). 13C NMR (CDCl3)
δ 56.0, 94.8, 113.7 (tq, J ) 253, 38 Hz), 117.8, 119.2 (qt, J ) 286, 39
Hz), 120.1, 122.8 (t, J ) 5.1 Hz), 124.2 (t, J ) 24 Hz), 126.1, 127.5
(t, J ) 7.1 Hz), 128.5, 130.8, 135.3, 154.4. 19F NMR (283 MHz, CDCl3,
CF3COOH: -76.5 ppm) δ -84.8 (3F), -114.5 (2F). MS (m/z) 610
(M+). HRMS (m/z) calcd for C28H20F10O4 (M+) 610.1202, found
610.1202.
S-Ethyl 3-Hydroxy-2-methyloctanthioate. IR [cm-1] (neat) 3456,
1
1679, 1454, 1413, 1376, 1266. H NMR (CDCl3) anti isomer δ 0.88
(R)-3,3′-Diiodo-2,2′-bis(methoxymethyloxy)-6,6′-bis(pentafluoro-
ethyl)-1,1′-binaphthyl. To a solution of (R)-2,2′-bis(methoxymethyl-
oxy)-6,6′-bis(pentafluoroethyl)-1,1′-binaphthyl (3.17 g, 5.19 mmol) in
tetrahydrofuran (60 mL) was added a hexane-cyclohexane solution
(t, 3H, J ) 6.8 Hz), 1.23 (d, 3H, J ) 7.1 Hz), 1.25 (t, 3H, J ) 7.5 Hz),
1.2-1.6 (m, 8H), 2.30 (br, 1H), 2.72 (dq, 1H, J ) 7.0, 5.6 Hz), 2.88
(q, 2H, J ) 7.5 Hz), 3.68 (m, 1H); detectable peaks of syn isomer δ
2.66 (dq, 1H, J ) 7.1, 4.0 Hz), 2.87 (q, 2H, J ) 7.5 Hz), 3.89 (m, 1H).
13C NMR (CDCl3) anti isomer δ 14.0, 14.6, 15.2, 22.6, 23.2, 25.2,
31.7, 34.9, 53.5, 73.9, 204.3; detectable peaks of syn isomer δ 11.3,
(27) (a) Krishnamurti, R.; Bellew, D. R.; Prakash, G. K. S. J. Org. Chem. 1991,
56, 984. (b) Pawelke, G. J. Fluorine Chem. 1989, 42, 429.
9
3300 J. AM. CHEM. SOC. VOL. 124, NO. 13, 2002

Highly anti-Selective Asymmetric Aldol Reactions
A R T I C L E S
of s-butyllithium (1.02 M, 20.8 mL, 21.2 mmol) at -78 °C, and the
whole was stirred for 1 h at the same temperature. Iodine (7.92 g, 31.2
mmol) in tetrahydrofuran (25 mL) was then added, and the reaction
mixture was stirred for an additional 3 h. After quenching with
methanol, water and ethyl acetate were added. The organic layer was
separated, and the aqueous layer was extracted with ethyl acetate. The
organic layers were combined and treated with aqueous 10% NaHSO3
to destroy excess iodine; washed with water, saturated aqueous
NaHCO3, and brine successively; and dried over anhydrous Na2SO4.
After filtration and concentration under reduced pressure, the crude
product was purified by silica gel column chromatography (hexane/
ethyl acetate) to afford (R)-3,3′-diiodo-2,2′-bis(methoxymethyloxy)-
6,6′-bis(pentafluoroethyl)-1,1′-binaphthyl (3.19 g, yield 71%) as an
(R)-3,3′-Diiodo-2,2′-bis(methoxymethyloxy)-6,6′-bistrimethylsilyl-
1,1′-binaphthyl. To a solution of (R)-2,2′-bis(methoxymethyloxy)-6,6′-
bistrimethylsilyl-1,1′-binaphthyl (3.07 g, 5.92 mmol) in tetrahydrofuran
(30 mL) was added a solution of s-butyllithium (1.02 M, 23.2 mL,
23.7 mmol) at -78 °C. The reaction mixture was stirred for 1.5 h, and
iodine (9.01 g, 35.4 mmol) in tetrahydrofuran (15 mL) was added. The
whole was stirred for 2 h at the same temperature and quenched with
methanol. After ethyl acetate and water were added to the mixture, the
organic layer was separated and the aqueous layer was extracted with
ethyl acetate. The organic layers were combined and treated with
aqueous 10% NaHSO3 to destroy excess iodine; washed with water,
saturated aqueous NaHCO3, and brine successively; and dried over
anhydrous Na2SO4. After filtration and concentration under reduced
pressure, the crude product was purified by silica gel column chroma-
tography (hexane/ethyl acetate) to afford (R)-3,3′-diiodo-2,2′-bis-
(methoxymethyloxy)-6,6′-bistrimethylsilyl-1,1′-binaphthyl (4.30 g, yield
93%). [R]17D -33.0 (c 1.02, CHCl3). IR [cm-1] (KBr) 1422, 1391, 1249,
amorphous oil. [R]23 +3.11 (c 1.11, CHCl3). IR [cm-1] (KBr) 1629,
D
1561, 1467, 1447, 1430, 1371, 1351, 1331, 1317, 1263, 1207. 1H NMR
(CDCl3) δ 2.55 (s, 6H), 4.83 (d, 2H, J ) 5.8 Hz), 4.84 (d, 2H, J ) 6.1
Hz), 7.29 (d, 2H, J ) 9.1 Hz), 7.47 (d, 2H, J ) 8.8 Hz), 8.09 (s, 2H),
8.69 (s, 2H). 13C NMR (CDCl3) δ 56.4, 94.2, 99.8, 113.3 (tq, J ) 254,
38 Hz), 119.1 (qt, J ) 286, 39 Hz), 123.6 (t, J ) 5.3 Hz), 125.7, 126.1
(t, J ) 7.3 Hz), 126.2 (t, J ) 24 Hz), 127.4, 130.9, 135.0, 141.2, 154.7.
19F NMR (283 MHz, CDCl3, CF3COOH: -76.5 ppm) δ -84.7 (3F),
-114.8 (2F). MS (m/z) 863 (M+ + 1). Anal. Calcd for C28H18F10I2O4:
C, 39.00; H, 2.10. Found: C, 38.79; H, 2.22.
1
1200. H NMR (CDCl3) δ 0.30 (s, 18H), 2.65 (s, 6H), 4.68 (d, 2H, J
) 5.5 Hz), 4.79 (d, 2H, J ) 5.7 Hz), 7.14 (d, 2H, J ) 8.4 Hz), 7.41
(d, 2H, J ) 8.4 Hz), 7.91 (s, 2H), 8.55 (s, 2H). 13C NMR (CDCl3) δ
-1.2, 56.6, 92.2, 99.3, 125.3, 125.9, 131.1, 131.7, 132.5, 133.9, 138.1,
140.2, 152.3. MS (m/z) 770 (M+). Anal. Calcd for C30H36I2O4Si2: C,
46.76; H, 4.71; found: C, 46.67; H, 4.62.
(R)-6,6′-Dibromo-3,3′-diiodo-1,1′-binaphthalene-2,2′-diol. To a
solution of (R)-3,3′-diiodo-2,2′-bis(methoxymethyloxy)-6,6′-bistri-
methylsilyl-1,1′-binaphthyl (2.50 g, 3.24 mmol) in carbon tetrachloride
(25 mL) was added bromine (1.53 g, 9.57 mmol) at 0 °C.16 The whole
was stirred overnight at the same temperature. The reaction mixture
was quenched with aqueous 10% NaHSO3 to destroy excess bromine.
After ethyl acetate was added, the organic layer was separated; washed
with water, saturated aqueous NaHCO3, and brine successively; and
dried over anhydrous Na2SO4. After filtration and concentration under
reduced pressure, the crude product was dissolved in dichloromethane
(10 mL). To the solution was added saturated methanolic HCl (15 mL)
at 0 °C, and the mixture was stirred for 1 h. After addition of excess
water and ethyl acetate, the organic layer was separated; washed with
water, saturated aqueous NaHCO3, and brine; and dried over anhydrous
Na2SO4. After filtration and concentration under reduced pressure, the
crude product was purified by silica gel column chromatography
(hexane/ethyl aceate) to afford (R)-6,6′-dibromo-3,3′-diiodo-1,1′-bi-
naphthalene-2,2′-diol (2.08 g, yield 94%). Recrystalized product
(hexane/ethyl acetate) was used in the asymmetric reactions. Mp 277
(R)-3,3′-Diiodo-6,6′-bis(pentafluoroethyl)-1,1′-binaphthalene-2,2′-
diol. To a solution of (R)-3,3′-diiodo-2,2′-bis(methoxymethyloxy)-6,6′-
bis(pentafluoroethyl)-1,1′-binaphthyl (3.54 g, 4.11 mmol) in dichlo-
romethane (20 mL) was added saturated methanolic HCl at 0 °C, and
the mixture was stirred for 1 h. After addition of excess water, the
organic layer was separated, washed with water and brine, and dried
over anhydrous Na2SO4. After filtration and concentration under reduced
pressure, the crude product was purified by silica gel column chroma-
tography (hexane/ethyl aceate) to afford (R)-3,3′-diiodo-6,6′-bis(pen-
tafluoroethyl)-1,1′-binaphthalene-2,2′-diol (2.81 g, yield 88%). Recrys-
talized product (hexane/methylene chloride) was used in the asymmetric
reactions. Mp 204 °C. [R]23D +51.2 (c 1.01, CHCl3). IR [cm-1] (KBr)
3467, 1628, 1443, 1379, 1329, 1265, 1209, 1190. 1H NMR (CDCl3) δ
5.63 (s, 2H), 7.17 (d, J ) 9.2 Hz), 7.46 (d, 2H, J ) 8.9 Hz), 8.10 (s,
2H), 8.63 (s, 2H). 13C NMR (CDCl3) δ 88.9, 112.7, 113.4 (tq, J )
253, 38 Hz), 116.9 (qt, J ) 286, 39 Hz), 124.4 (t, J ) 5.1 Hz), 125.1
(t, J ) 24 Hz), 125.3, 126.7 (t, J ) 7.3 Hz), 129.4, 134.8, 141.2, 151.9.
19F NMR (283 MHz, CDCl3, CF3COOH: -76.5 ppm) δ -84.7 (3F),
-114.8 (2F). MS (m/z) 774 (M+). Anal. Calcd for C24H10F10I2O2: C,
37.24; H, 1.30. Found: C, 37.00; H, 1.46.
°C. [R]18 +74.3 (c 0.55, THF). IR [cm-1] (KBr) 3521, 3503, 1567,
D
1
1484, 1432, 1377, 1352, 1290, 1261, 1218. H NMR (CDCl3) δ 5.44
(R)-2,2′-Bis(methoxymethyloxy)-6,6′-bistrimethylsilyl-1,1′-binaph-
thyl. To a solution of (R)-6,6′-dibromo-2,2′-bis(methoxymethyloxy)-
1,1′-binaphthyl (5.00 g, 9.39 mmol) in tetrahydrofuran (80 mL) was
added a hexane solution of n-butyllithium (1.60 M, 14.7 mL, 23.5
mmol) at -78 °C. The reaction mixture was stirred for 1 h, then
chlorotrimethylsilane (3.06 g, 28.2 mmol) in terahydrofuran (20 mL)
was added, and the mixture was stirred for additional 3 h. After
quenching with water, diethyl ether was added. The organic layer was
separated, and the aqueous layer was extracted with diethyl ether. The
organic layers were combined, washed with water and brine, and dried
over anhydrous Na2SO4. After filtration and concentration under reduced
pressure, the crude product was purified by silica gel column chroma-
tography (hexane/ethyl acetate) to afford (R)-2,2′-bis(methoxymethyl-
oxy)-6,6′-bistrimethylsilyl-1,1′-binaphthyl (3.84 g, yield 79%). Mp 144
°C. [R]23D -7.60 (c 1.00, CHCl3). IR [cm-1] (KBr) 1615, 1580, 1472,
(s, 2H), 6.89 (d, 2H, J ) 9.0 Hz), 7.37 (dd, 2H, J ) 9.0, 2.0 Hz), 7.94
(d, 2H, J ) 2.0 Hz), 8.40 (s, 2H). 13C NMR (CDCl3) δ 88.5, 112.8,
118.6, 126.1, 129.1, 131.3, 131.5, 131.8, 139.2, 150.3. MS (m/z) 694
(M+ - 1), 695 (M+), 696 (M+ + 1), 697 (M+ + 2), 698 (M+ + 3).
Anal. Calcd for C20H10Br2I2O2: C, 34.52; H, 1.45; found: C, 34.75;
H, 1.60.
(R)-3,3′,6,6′-Tetraiodo-1,1′-binaphthalene-2,2′-diol. To a solution
of (R)-3,3′-diiodo-2,2′-bis(methoxymethyloxy)-6,6′-bistrimethylsilyl-
1,1′-binaphthyl (3.30 g, 4.28 mmol) in carbon tetrachloride (50 mL)
was added iodine chloride (2.76 g, 17.0 mmol) at -15 °C.16 The whole
was stirred for 10 min at the same temperature. The reaction mixture
was quenched with aqueous 10% NaHSO3 to destroy excess iodine
chloride. After ethyl acetate was added, the organic layer was separated;
washed with water, saturated aqueous NaHCO3, and brine successively;
and dried over anhydrous Na2SO4. After filtration and concentration
under reduced pressure, the crude product was dissolved in dichlo-
romethane (30 mL). To the solution was added saturated methanolic
HCl (20 mL) at 0 °C, and the mixture was stirred for 1 h. After addition
of excess water and ethyl acetate, the organic layer was separated;
washed with water, saturated aqueous NaHCO3, and brine; and dried
over anhydrous Na2SO4. After filtration and concentration under reduced
pressure, the crude product was purified by silica gel column chroma-
1
1440, 1403, 1368, 1329, 1266, 1247, 1200. H NMR (CDCl3) δ 0.29
(s, 18H), 3.16 (s, 6H), 4.98 (d, 2H, J ) 6.8 Hz), 5.05 (d, 2H, J ) 6.6
Hz), 7.12 (d, 2H, J ) 8.3 Hz), 7.32 (d, 2H, J ) 8.4 Hz), 7.56 (d, 2H,
J ) 9.0 Hz), 7.94 (d, 2H, J ) 9.0 Hz), 8.02 (s, 2H). 13C NMR (CDCl3)
δ -1.1, 55.8, 95.3, 117.3, 121.1, 124.5, 129.4, 129.5, 130.3, 133.8,
134.2, 135.5, 153.0. MS (m/z) 518 (M+). Anal. Calcd for C30H38O4Si2:
C, 69.45; H, 7.38. Found: C, 69.64; H, 7.45.
9
J. AM. CHEM. SOC. VOL. 124, NO. 13, 2002 3301

A R T I C L E S
Yamashita et al.
tography (benzene) to (R)-3,3′,6,6′-tetraiodo-1,1′-binaphthalene-2,2′-
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
diol (2.49 g, yield 75%). Recrystalized product (hexane/ethyl acetate)
was used in the asymmetric reactions. Mp 299 °C. [R]18 +54.9 (c
D
0.61, THF). IR [cm-1] (KBr) 3521, 3496, 1561, 1479, 1429, 1377, 1346,
1
1290, 1261, 1217. H NMR (CDCl3) δ 5.42 (s, 2H), 6.76 (d, 2H, J )
Supporting Information Available: Experimental details and
spectra (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
8.8 Hz), 7.53 (dd, 2H, J ) 9.0, 1.7 Hz), 8.16 (d, 2H, J ) 1.4 Hz), 8.37
(s, 2H). 13C NMR (CDCl3) δ 88.1, 89.8, 112.7, 126.1, 131.9, 132.1,
135.8, 136.4, 139.1, 150.4. MS (m/z) 789 (M+), 790 (M+ + 1). Anal.
Calcd for C20H10I4O2: C, 30.41; H, 1.28; found: C, 30.39; H, 1.47.
JA016293T
9
3302 J. AM. CHEM. SOC. VOL. 124, NO. 13, 2002