Catalytic asymmetric epoxidation of enones using La-BINOL-triphenylarsine oxide complex: Structural determination of the asymmetric catalyst

Article abstract of DOI:10.1021/ja004201e

The catalytic asymmetric epoxidation of enones using the La-BINOL-Ph₃As=O complex generated from La(O-i-Pr)₃, BINOL, and Ph₃As=O in a ratio of 1:1:1 is described herein. Using 1-5 mol % of the asymmetric catalyst, a variety of enones, including a dienone and a cis-enone, were found to be epoxidized in a reasonable reaction time, providing the corresponding epoxy ketones in up to 99% yield and with more than 99% ee. The possible structure of the actual asymmetric catalyst has been clarified by various methods, including X-ray crystal structure analysis. This is the first X-ray analysis of an alkali-metal free lanthanoid-BINOL complex. Although La(binaphthoxide)₂(Ph₃As=O)₂ (7) was observed as the major complex in the complexes' solution, generated from La(O-i-Pr)₃, BINOL, and Ph₃As=O in a ratio of 1:1:1, the possible active species turned out to be the La-BINOL-Ph₃As=O complex in a ratio of 1:1:1. A probable reaction mechanism of the catalytic asymmetric epoxidation of enones is also proposed, suggesting that preferential formation of a heterochiral complex is the reason for asymmetric amplification. Moreover, the interesting role of La(O-i-Pr)₃ for accelerating the epoxidations while maintaining high ee's is discussed.

Full text of DOI:10.1021/ja004201e

J. Am. Chem. Soc. 2001, 123, 2725-2732
2725
Catalytic Asymmetric Epoxidation of Enones Using
La-BINOL-Triphenylarsine Oxide Complex: Structural
Determination of the Asymmetric Catalyst
Tetsuhiro Nemoto,† Takashi Ohshima,† Kentaro Yamaguchi,‡ and Masakatsu Shibasaki*,†
Contribution from the Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan, and Chemical Analysis Center, Chiba UniVersity, Yayoicho, Inage-ku,
Chiba-shi 263-0022, Japan
ReceiVed December 7, 2000
Abstract: The catalytic asymmetric epoxidation of enones using the La-BINOL-Ph3AsdO complex generated
from La(O-i-Pr)3, BINOL, and Ph3AsdO in a ratio of 1:1:1 is described herein. Using 1-5 mol % of the
asymmetric catalyst, a variety of enones, including a dienone and a cis-enone, were found to be epoxidized in
a reasonable reaction time, providing the corresponding epoxy ketones in up to 99% yield and with more than
99% ee. The possible structure of the actual asymmetric catalyst has been clarified by various methods, including
X-ray crystal structure analysis. This is the first X-ray analysis of an alkali-metal free lanthanoid-BINOL
complex. Although La(binaphthoxide)2(Ph3AsdO)2 (7) was observed as the major complex in the complexes’
solution, generated from La(O-i-Pr)3, BINOL, and Ph3AsdO in a ratio of 1:1:1, the possible active species
turned out to be the La-BINOL-Ph3AsdO complex in a ratio of 1:1:1. A probable reaction mechanism of
the catalytic asymmetric epoxidation of enones is also proposed, suggesting that preferential formation of a
heterochiral complex is the reason for asymmetric amplification. Moreover, the interesting role of La(O-i-Pr)3
for accelerating the epoxidations while maintaining high ee’s is discussed.
Introduction
other methodologies such as asymmetric ligand-metal cataly-
sis,7 asymmetric phase transfer catalysis,8 and polyamino acid
catalysis.6,9 A few years ago, we reported a general catalytic
asymmetric epoxidation of enones using alkali-metal free
lanthanoid-BINOL complexes.10 These complexes were pre-
pared from Ln(O-i-Pr)3 and BINOL in a ratio of 1:1, providing
the corresponding products in up to 95% yield and up to 94%
ee. We speculated that this asymmetric induction might be
induced by the multifunctinality of the asymmetric catalysts,
where activation of both substrates (enone and peroxide) as well
as control of their position is realized at the same time.
Despite excellent yields and enantiomeric excesses (ee’s), this
catalytic process is still unsatisfactory in terms of its rather low
reactivity. Thus, we decided to overcome the drawback of our
catalytic asymmetric epoxidation by tuning the reaction condi-
tions. It is known that addition of triphenylphosphine oxide
(Ph3PdO) is effective for the enhancing the rate while maintain-
Asymmetric epoxidation of olefins is one of the most
important functional group manipulations in organic synthesis1
due to the fact that enantiomerically enriched epoxides can be
converted into various useful optically active synthetic inter-
mediates. In 1980, Sharpless et al. reported the stoichiometric
asymmetric epoxidation of allylic alcohols,2a a method which
was later improved to a catalytic version by the addition of
molecular sieves.2b Catalytic asymmetric epoxidations of un-
functionalized olefins using salen-manganese complexes have
been reported independently by Jacobsen et al.,3a Katsuki et al.,3b
and Mukaiyama et al.3c Moreover, asymmetric epoxidations of
a wide range of olefins using optically active dioxiranes4 and
hydroperoxide5 have been developed recently. Since the initial
report by Julia´ and co-workers,6 catalytic asymmetric epoxida-
tion of R,â-unsaturated ketones has been studied using several
† The University of Tokyo.
‡ Chiba University.
(6) Julia´, S.; Masana, J.; Vega, J. C. Angew. Chem., Int. Ed. Engl. 1980,
19, 929.
(1) (a) Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley:
New York, 2000. (b) ComprehensiVe Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999. (c) Noyori,
R. Asymmetric Catalysis In Organic Synthesis; John Wiley & Sons: New
York, 1994.
(2) (a) Katsuki, K.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(b) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1992.
(3) Zhang, W.; Loebach, J. L,; Wilson, S. R.; Jacobsen, E. N. J. Am.
Chem. Soc. 1990, 112, 2801. (b) Irie, R.; Noda, K.; Ito, Y.; Matsumoto,
N.; Katsuki, T. Tetrahedron Lett. 1990, 31, 7345. (c) Yamada, T.; Imagawa,
K.; Nagata, T.; Mukaiyama, T. Chem. Lett. 1992, 2231.
(7) (a) Enders, D.; Zhu, J.; Raabe, G. Angew. Chem., Int. Ed. Engl. 1996,
35, 1725. (b) Elston, C. L.; Jackson, R. F. W.; MacDonald, S. J. F.; Murray,
P. J. Angew. Chem., Int. Ed. Engl. 1997, 36, 410. (c) Yu, H.-B.; Zheng,
X.-F.; Lin, Z.-M.; Hu, Q.-S.; Huang, W.-S.; Pu, L. J. Org. Chem. 1999,
64, 8149. (d) For an impressive catalytic asymmetric epoxidation of
cinnamate esters, see: Jacobsen, E. N.; Deng, L.; Furukawa, Y.; Mart´ınez,
L. E. Tetrahedron 1994, 50, 4323.
(8) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1998, 39, 1599. (b)
Arai, S.; Tsuge, H.; Shioiri, T. Tetrahedron Lett. 1998, 39, 7563. (c) Corey,
E. J.; Zhang, F. Y. Org. Lett. 1999, 1, 1287.
(4) (a) Curci, R.; Fiorentino, M.; Serio, M. R. J. Chem. Soc., Chem.
Commun. 1984, 155. (b) Wang, Z.-C.; Shi, Y. J. Org. Chem. 1997, 62,
8622. (c) Armstrong, A.; Hayter, B. R. Chem. Commun. 1998, 621. (d)
Yang, D.; Wong, M.-K.; Yip, Y.-C.; Wang, X.-C.; Tang, M.-W.; Zheng,
Y.-C.; Cheung, K.-K. J. Am. Chem. Soc. 1998, 120, 5943. (e) Tian, H.;
She, X.; Shu, L.; Yu, H.; Shi, Y. J. Am. Chem. Soc. 2000, 122, 11551.
(5) Adam, W.; Rao, P. B.; Degen, H. G.; Saha-Mo¨ller, C. R. J. Am.
Chem. Soc. 2000, 122, 5654.
(9) For a recent review on this method, see: Porter, M. J.; Roberts, S.
M.; Skidmore, J. Bioorg. Med. Chem. 1999, 7, 2145 and references therein.
(10) (a) Bougauchi, M.; Watanabe, S.; Arai, T.; Sasai, H.; Shibasaki,
M. J. Am. Chem. Soc. 1997, 119, 2329. (b) Watanabe, S.; Kobayashi, Y.;
Arai, T.; Sasai, H.; Bougauchi, M.; Shibasaki, M. Tetrahedron Lett. 1998,
39, 7353. (c) Watanabe, S.; Arai, T.; Sasai, H.; Bougauchi, M.; Shibasaki,
M. J. Org. Chem. 1998, 63, 8090. (d) Daikai, K.; Kamaura, M.; Inanaga,
J. Tetrahedron Lett. 1998, 39, 7321.
10.1021/ja004201e CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/28/2001

2726 J. Am. Chem. Soc., Vol. 123, No. 12, 2001
Nemoto et al.
Table 1. Catalytic Asymmetric Epoxidation of Chalcone 1a to
Epoxy Ketone 2a Using the La-BINOL Complex
additives instead of Ph3PdO on the catalytic asymmetric
epoxidation, which would result in the formation of 2a more
efficiently, even in the presence of 10 mol % of an additive.
As a result, we were pleased to find that the addition of
Ph3AsdO (10 mol %) produced 2a in 95% yield and 97% ee
in only 3 min. Interestingly, different from the case of Ph3PdO,
the addition of 40 mol % of Ph3AsdO provided a less
satisfactory result, giving 2a in 92% yield and 85% ee (60 min).
This difference could be explained by the fact that the Lewis
basicity of Ph3AsdO is higher than that of Ph3PdO.12,13 From
these results, we concluded that the complex generated from
La(O-i-Pr)3, (R)-BINOL, and Ph3AsdO in a ratio of 1:1:1 was
the most effective asymmetric catalyst for the epoxidation of
chalcone (1a).
additives
(mol %)
time yield ee
(min) (%) (%)
entry
catalyst (mol %)
La(O-i-Pr)3 (10)
La-(R)-BINOL (1:1) (10)
1
2
3
4
5
6
7
8
9
480
90
30
30
30
30
60
30
30
3
90
92
98
97
94
93
92
92
96
95
64
71
97
97
95
94
85
93
95
97
La-(R)-BINOL (1:1) (10) Ph3PdO (40)
La-(R)-BINOL (1:1) (10) Ph3PdO (30)
La-(R)-BINOL (1:1) (10) Ph3PdO (20)
La-(R)-BINOL (1:1) (10) Ph3PdO (10)
La-(R)-BINOL (1:1) (10) Ph3AsdO (40)
La-(R)-BINOL (1:1) (10) Ph3AsdO (30)
La-(R)-BINOL (1:1) (10) Ph3AsdO (20)
Having developed the novel asymmetric catalyst for the
asymmetric epoxidation of chalcone (1a), next we sought to
explore the generality of this catalytic asymmetric reaction.
Table 2 summarizes the use of the asymmetric catalyst generated
from La(O-i-Pr)3, (R)-BINOL, and Ph3AsdO in a ratio of 1:1:1
for the epoxidation of various substrates. As shown, almost all
reactions proceeded to completion in reasonable reaction times
when 5 mol % of the new catalyst was used at room temperature.
Additionally, a slight improvement was achieved in almost all
cases with the exception of enones 1e and 1i in terms of yield
and ee. Aryl ketone type substrates such as 1a-c were
epoxidized smoothly and afforded the corresponding epoxy
ketones in excellent yields and enantiomeric excesses (Table
2, entries 1-4). Particularly, epoxidation of 1a proceeded quite
efficiently, and the reaction was completed in 3 h, even with
use of 1 mol % of the catalyst (Table 2, entry 2). This
asymmetric catalyst system was also quite effective for alkyl
ketone type substrates. In addition to the tert-butyl ketone
derivative 1d (Table 2, entry 5), excellent results were obtained
also in the case of the enolizable enones 1e-i14 (Table 2, entries
6-10), which are generally difficult to epoxidize.15 In particular,
the epoxidation of 1f proceeded with a big increase in terms of
enantioselectivity (>99% ee, >200:1 enantioselectivity) relative
to the previous result (94% ee, 32:1 enantioselectivity). Further-
more, we examined the epoxidation of other unique enones.
We had already reported the catalytic asymmetric epoxidation
of cis-enones using the Yb-3-hydroxymethyl-BINOL com-
plex.10c It was found that the La-BINOL-Ph3AsdO complex
also catalyzed the transformation of cis-enone 3 into cis-epoxy
ketone 4, but unfortunately the result was less satisfactory, and
4 was obtained in only 61% yield and 59% ee, together with
less than 10% of the corresponding trans-epoxy ketone (Scheme
1a). We also tried the epoxidation of dienone 5. The reaction
was completed in 3 h with the use of 5 mol % of the catalyst
and gave the product 6 in 95% yield and 96% ee with complete
regioselectivity (Scheme 1b).16 In this way, the new asymmetric
catalyst system consisting of La(O-i-Pr)3, BINOL, and Ph3Asd
O in a ratio of 1:1:1 was found to have a broad generality for
enones, affording the products in excellent yields and more than
10 La-(R)-BINOL (1:1) (10) Ph3AsdO (10)
11 La(O-i-Pr)3 (10)
Ph3AsdO (10) 480
a MS 4A was not dried (1000 mg/mmol).
ing high ee’s.10d However, addition of 3-6 equiv of Ph3PdO
to the La-BINOL complex is needed to enhance the reaction
rate, and we became interested in finding new additives which
might be more effective in terms of atom economy. Moreover,
we hoped to determine the structure of an alkali-metal free
lanthanoid-BINOL complex unequivocally by X-ray of the
complex with the new additive. The structure of the alkali-metal
free lanthanoid-BINOL complex had not been clarified, mainly
due to the specific feature of lanthanoid metals.11 In this article,
we report a catalytic asymmetric epoxidation of enones using a
novel multifunctional asymmetric catalyst, the La-BINOL-
triphenylarsine oxide (Ph3AsdO) complex. This catalyst system
exhibits much higher activity and selectivity compared to those
of Ln-BINOL complexes, affording optically active epoxy
ketones with broad generality in up to 99% yield and more than
99% ee. Furthermore, we report the first example of X-ray
analysis of an alkali-metal free lanthanoid-BINOL-Ph3Asd
O complex as well as a possible reaction mechanism of the
catalytic asymmetric epoxidation of enones.
Results and Discussion
Catalytic Asymmetric Epoxidation of Enones Using the
La-BINOL-Ph3AsdO Complex. Optimization of Reaction
Conditions and Scope and Limitations of the Reaction. In
an attempt to improve the catalytic asymmetric epoxidation of
enones developed in our group10a,b and improved in Inanaga’s
group,10d we examined the reaction in detail using chalcone (1a)
as a representative starting material. The results are summarized
in Table 1. As previously reported, the catalyst (10 mol %)
prepared from La(O-i-Pr)3 and (R)-BINOL in a ratio of 1:1 gave
the epoxide 2a in 92% yield and 71% ee (Table 1, entry 2). On
the other hand, the conditions developed by Inanaga using 40
mol % of Ph3PdO gave rise to 2a in 98% yield and 97% ee in
a much shorter reaction time (30 min). However, as shown in
entry 6 (Table 1), when the reaction was carried out in the
presence of 10 mol % of Ph3PdO, a slightly less satisfactory
result was obtained. We examined the influence of many
(12) Cruickshank, D. W. J. J. Chem. Soc. 1961, 5486.
(13) When 1i was used as a substrate, the different tendencies between
the two additives were more noticeable. For the detailed data, see the
Supporting Information.
(14) Epoxy ketone 2i can be converted into several natural coumarins
efficiently. See: Nemoto, T.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett.
2000, 41, 9569.
(15) A few successful examples using the polyleucine catalyst have been
reported. See: Adger, B. M.; Barkley, J. V.; Bergeron, S.; Cappi, M. W.;
Flowerdew, B. E.; Jackson, M. P.; McCague, R.; Nugent, T. C.; Roberts,
S. M. J. Chem. Soc., Perkin Trans. 1 1997, 3501.
(16) The Yb-BINOL complex also catalyzes this reaction (5 mol % of
the catalyst, 2 h, 87% yield, 93% ee). Watanabe, S. Ph.D. Thesis, The
University of Tokyo, 1999.
(11) Although several catalytic asymmetric reactions using alkali-metal
free lanthanoid-BINOL derivative complexes have been developed, the
catalyst structures have not been unequivocally clarified yet. However,
partial information has been obtained in some cases, see: (a) Kim, Y.-S.;
Matsunaga, S.; Das, J.; Sekine, A.; Ohshima, T.; Shibasaki, M. J. Am. Chem.
Soc. 2000, 122, 6506. (b) Furuno, H.; Hanamoto, T.; Sugimoto, Y.; Inanaga,
J. Org. Lett. 2000, 2, 49. (c) Kobayashi, S.; Ishitani, H.; Araki, M.; Hachiya,
I. Tetrahedron Lett. 1994, 35, 6325. (d) Kobayashi, S.; Araki, M.; Hachiya,
I. J. Org. Chem. 1994, 59, 3758.

Catalytic Asymmetric Epoxidation of Enones
J. Am. Chem. Soc., Vol. 123, No. 12, 2001 2727
Table 2. Catalytic Asymmetric Epoxidation of Various Enones 1a-i
a MS 4A was not dried (1000 mg/mmol). b Reference 10a. c Reference 10b. d Reference 10d. e 1 mol % of the catalyst was used. f Ar ) o-
MOMO-C6H4. g Conversion yield. h 8 mol % of the catalyst was used. i 25 mol % of the catalyst was used. j 10 mol % of the catalyst was used.
k Ar )
Scheme 1. Catalytic Asymmetric Epoxidation of cis-Enone
3 (a) and Dienone 5 (b) Using the
La-(R)-BINOL-Ph3AsdO Complex
99% ee, even at room temperature.17 It is obvious that reactions
Figure 1. Nonlinear relationship between the enantiomeric purities
which proceed at room temperature have significant practical
advantages compared to those that require low temperature for
the induction of higher selectivity. Additionally, the simple chiral
ligand, unmodified BINOL, makes this process more accessible.
Structural Determination of the La-BINOL-Ph3AsdO
Complex. In contrast to some successful examples of structural
of the product 2i and BINOL.
determination of lanthanoid asymmetric catalysts,18 little is
known about the structure of alkali-metal free Ln-BINOL
complexes.11 First we made attempts to clarify their structures
using NMR analysis. However, the 13C NMR spectrum of the
La-BINOL complex in THF was quite obscure. Additionally,
asymmetric amplification was observed in the epoxidation. Thus,
(17) Epoxidations of 1a and 1f using 5 mol % of the Yb-(R)-BINOL-
Ph3AsdO complex gave less satisfactory results, producing the correspond-
ing epoxy ketones 2a (1 h, 97%, 94% ee) and 2f (10 h, 85%, 94% ee),
respectively.
(18) Sasai, H.; Suzuki, T.; Itoh, N.; Tanaka, K.; Date, T.; Okamura, K.;
Shibasaki, M. J. Am. Chem. Soc. 1993, 115, 10372.

2728 J. Am. Chem. Soc., Vol. 123, No. 12, 2001
Nemoto et al.
Figure 2. LDI TOF MS spectra of a complexes’ solution generated from La(O-i-Pr)3 and BINOL in a ratio of 1:1: (a) positive mode and (b)
negative mode.
Figure 3. LDI TOF MS spectra of a complexes’ solution generated from La(O-i-Pr)3, BINOL, and Ph3AsdO in a ratio of 1:1:1: (a) positive mode
and (b) negative mode.
we concluded that the optically active lanthanoid complex
should exist as an oligomer.
desorption/ionization time-of-flight mass spectrometry (LDI
TOF MS) is often utilized for a structural analysis of organo-
metallic complexes, and previously we succeeded in obtaining
analyzable spectra of several lanthanoid complexes such as
LnM3tris(binaphthoxide) complex.18,22 It has also been found
that analyzable spectra can be obtained even in the case of alkali-
metal free Ln-BINOL complexes (Ln ) La or Yb).23 The
spectra of the complexes’ solution generated from La(O-i-Pr)3
and BINOL in a ratio of 1:1 are shown in Figure 2, and some
peaks a molecular weight of the order of thousands are observed
in both the positive and negative modes. Likewise, spectra of
the complexes’ solution generated from La(O-i-Pr)3, BINOL,
and Ph3AsdO in a ratio of 1:1:1 are shown in Figure 3. In
contrast to our expectation mentioned above, we could find only
some small peaks which represent oligomers, and only one
analyzable peak each was detected in the positive and negative
modes.24 The peak observed in the positive mode (MW 1067)
corresponds to the molecular weight of the cationic complex
described in Figure 4a, and the peak observed in negative mode
(MW 707) corresponds to the molecular weight of the anionic
complex described in Figure 4b. These data suggested that the
monomeric La(binaphthoxide)2(Ph3AsdO)2 complex (7) (Figure
4c) would be the major component in the solution generated
from La(O-i-Pr)3, BINOL, and Ph3AsdO in a ratio of 1:1:1,
and these results appeared to support our expectation that the
It is well known that oxygen ligands such as Ph3AsdO and
Ph3PdO have a high affinity to lanthanoid metals.19 Thus, we
expected that the newly developed asymmetric catalyst, the La-
BINOL-Ph3AsdO complex, would have a different structure,
leading to the structural determination of the complex. Our
investigation started with a comparison with the information
that had been already obtained from the La-BINOL complex.
First we measured the 13C NMR spectrum of the La-BINOL-
Ph3AsdO (1:1:1) complex in THF. The obtained spectrum,
however, was similar to that of the La-BINOL complex. Next,
we examined if asymmetric amplification might be observed
in the epoxidation using the La-BINOL-Ph3AsdO complex.
We investigated the reaction using enone 1i,20 and a positive
nonlinear effect was observed, as shown in Figure 1. Moreover,
it was of interest that a decrease in the reactivity was observed
when BINOL with low enantiomeric excess was used. In
particular, when (rac)-BINOL was used, no product could be
obtained.21 Unfortunately, at this stage, these results appeared
to suggest that the chiral lanthanoid complex would have an
oligomeric structure even in the presence of Ph3AsdO. Laser
(19) Cotton, F. A.; Wilkinson, G.; Murillo, C. A.; Bochmann, M.
AdVanced Inorganic Chemistry, 6th ed.; John Wiley & Sons: New York,
1999; p 1108.
(20) The reactions were carried out using 25 mol % of the catalyst at
room temperature and quenched after 6 h, except for the reaction using
optically pure (R)-BINOL (2 h). For detailed data, see the Supporting
Information.
(21) The results which were obtained for the reactions quenched after 6
h indicate that quenching the reactions after 2 h should lead to a negative
nonlinear relationship.
(22) Yoshikawa, N.; Yamada, M. A. Y.; Das, J.; Sasai, H.; Shibasaki,
M. J. Am. Chem. Soc. 1999, 121, 4168.
(23) Watanabe, S. Ph.D. Thesis, The University of Tokyo, 1999.
(24) In the presence of Ph3AsdO, unknown peaks were observed every
76 units of molecular weight from the base peaks (1067 and 707),
respectively.

Catalytic Asymmetric Epoxidation of Enones
J. Am. Chem. Soc., Vol. 123, No. 12, 2001 2729
Figure 6. Speculated active species in a complexes’ solution generated
from La(O-i-Pr)3, (R)-BINOL, and Ph3AsdO in a ratio of 1:1:1.
Table 3. Catalytic Asymmetric Epoxidation of 1a to Epoxy
Ketone 2a Using La-(R)-BINOL-Ph3AsdO Complexes
La(O-i-Pr)3 (x mol %)
(R)-BINOL (y mol %)
3
TBHP in decane
1a +
Ph AsdO (z mol %) 8 2a
MS 4A,a THF, rt
Figure 4. Structures corresponding to the molecular weight observed
in positive mode (a) and negative mode (b) of LDI TOF MS and (c)
the possible structure of the major complex in a complexes’ solution
generated from La(O-i-Pr)3, (R)-BINOL, and Ph3AsdO in a ratio of
1:1:1.
(1.5 equiv)
La(O-i-Pr)3 (R)-BINOL Ph3AsdO time yield ee
entry (x mol %) (y mol %) (z mol %) (min) (%) (%)
1
2
3
4
10
10
10
10
20
20
20
10
10
20
30
10
72
72
90
3
95
93
92
95
96
92
95
97
a MS 4A was not dried (1000 mg/mmol).
Furthermore, the X-ray crystal structure strongly suggests that
the lanthanum complex should exist not as an oligomeric
species, but as a monomeric species in the solution. In con-
clusion, our speculation that 7 would be the major component
in the solution generated from La(O-i-Pr)3, BINOL, and Ph3Asd
O in a ratio of 1:1:1 should be reasonable. In striking contrast
to the case of Ph3AsdO, no X-ray-grade crystals were obtained
in the presence of Ph3PdO.
Effect of Excess La(O-i-Pr)3 on the La(binaphthoxide)2-
(Ph3AsdO)2 Complex. At first, the results shown in Table 1
encouraged us to speculate that La-BINOL-Ph3AsdO com-
plex 9 (Figure 6) should exist in the complexes’ solution
generated from La(O-i-Pr)3, BINOL, and Ph3AsdO in a ratio
of 1:1:1 and might function as the most effective species.
However, the major component in the complexes’ solution
turned out to be 7. Moreover, the crystal prepared from the
complexes’ solution generated from La(O-i-Pr)3, BINOL, and
Ph3AsdO in a ratio of 1:1:3 proved to be 8 by X-ray crystal
structure analysis. These facts again made us question if the
ratio of the three components used (La-BINOL-Ph3AsdO )
1:1:1) was the best one. To solve this problem, we carried out
detailed investigations on the ratio of the three components. At
first we examined the effect of the amount of Ph3AsdO relative
to La-BINOL complex obtained in a ratio of 1:2. The results
are shown in Table 3 (entries 1-3). For all conditions, a lower
reactivity than under the best conditions (entry 4) was observed,
with the ee values remaining unchanged in all cases. Table 4
summarizes the results obtained by changing the ratio of La-
(O-i-Pr)3 and BINOL. During these investigations, the relative
amount of Ph3AsdO to that of BINOL was kept constant
because of the fact that the ratio 1:1:1 was apparently superior
to the other ratio using more than 1 equiv of Ph3AsdO to
BINOL (see Table 1). As a result, an increase in the yield was
observed proportional to a decrease in the ratio of BINOL
relative to La(O-i-Pr)3. In contrast, no change was observed with
respect to the enantiomeric excess, except for the result in entry
1. Moreover, we carried out the epoxidation of 1d using La-
BINOL-Ph3AsdO complex generated in a ratio of 1:1:0.5. As
a result, a decrease in the reactivity was observed when less
than 1 equiv of Ph3AsdO was used (Scheme 2). All these results
supported our conclusion that the La-BINOL-Ph3AsdO
complex generated in a ratio of 1:1:1 should be the best one
Figure 5. X-ray structure of La(binaphthoxide)2(Ph3AsdO)3 8 (a).
Triphenyl moieties of the triphenylarsine oxides are omitted for clarity
(b). Selected bond lengths (Å): La-O(1), 2.365(5); La-O(1*), 2.365-
(5); La-O(2), 2.684(6); La-O(2*), 2.684(6); La-O(3), 2.437(5); La-
O(3*), 2.437(5); La-O4, 2.391(8).
stable complex is formed by coordination of Ph3AsdO to the
lanthanum metal. At this stage we expected that the complex
stabilized by the coordination of Ph3AsdO could crystallize,
and after several attempts we were pleased to get X-ray-grade
crystal from the complexes’ solution generated from La(O-i-
Pr)3, BINOL, and Ph3AsdO in a ratio of 1:1:3, containing an
excess amount of Ph3AsdO relative to the best ratio for the
asymmetric epoxidation. The X-ray crystal structure analysis
is shown in Figure 5. The crystal structure turned out to be
La(binaphthoxide)2(Ph3AsdO)3 (8) (Figure 5a) with a pentago-
nal bipyramidal structure (Figure 5b). To the best of our
knowledge, this is the first X-ray crystal structure analysis of
an alkali-metal free lanthanoid-BINOL complex. Considering
the distance between the La atom and the oxygen atoms of
Ph3AsdO, it can be expected that the ligands should coordinate
strongly and contribute to the stability of the active species.

2730 J. Am. Chem. Soc., Vol. 123, No. 12, 2001
Nemoto et al.
Table 4. Catalytic Asymmetric Epoxidation of 1a to Epoxy
Ketone 2a Using La-(R)-BINOL-Ph3AsdO Complexes in a Ratio
of x:y:z
Scheme 3. Proposed Mechanism for the Generation of the
Active Catalyst
La(O-i-Pr)3 (x mol %)
(R)-BINOL (y mol %)
Ph3AsdO (z mol %)
TBHP in decane
(1.2 equiv)
1a +
8 2a
MS 4A,a THF, 25 °C, 15 min
La(O-i-Pr)3 (R)-BINOL Ph3AsdO
ratio
yield ee
entry (x mol %) (y mol %) (z mol %) (x:y:z) (%) (%)
1
2
3
4
5
6
7
8
9
5
5
5
5
5
5
5
5
5
20
10
8.3
7.1
6.3
5.6
5
20
10
8.3
7.1
6.3
5.6
5
0.5:2:2 29
80
95
96
94
95
94
96
96
96
1:2:2
57b
1.2:2:2 71b
1.4:2:2 79b
1.6:2:2 82b
1.8:2:2 88b
2:2:2
2.5:2:2 77
3:2:2 68
98b
4
3.3
4
3.3
a MS 4A was not dried (1000 mg/mmol). b Yields refer to the average
of isolated yields for three or four runs.
Scheme 2. Catalytic Asymmetric Epoxidation of 1d to
Epoxy Ketone 2d Using La-(R)-BINOL-Ph3AsdO (1:1:1)
Complexes
Figure 7. Kinetic experiments of the epoxidations using 6 mol % of
the La-(R)-BINOL-Ph3AsdO complex in a ratio of 1:2:2 with x mol
% of La(O-i-Pr)3.
and promotes the reaction most efficiently. Consequently, the
information obtained from the above investigations allowed us
to make the following deductions:
La(O-i-Pr)3 plays a key role in facilitating the transformation
of 7 to 11. To prove our assumption, we made many attempts
to detect the 1:1:1 complex under various preparative conditions
for the catalysts using several methods in the presence or
absence of TBHP. Unfortunately, however, we could not detect
any complexes directly.26 This may be due to the fact that
rapid a equilibrium might be reached between several com-
plexes in the solution. To get experimental evidence for the
beneficial effect of excess La(O-i-Pr)3, we measured initial
rates of the epoxidations of 1a using 6 mol % of the 1:2:2
complex 7 accompanied with 0-1 equiv (0-6 mol %) of excess
La(O-i-Pr)3 as the additive.27 As shown in Figure 7, an increase
in the initial rate for the reaction was observed upon the addition
of La(O-i-Pr)3 to 7. Considering the result shown in Table 4
and the fact that La(O-i-Pr)3 itself is not an effective catalyst
for the epoxidation (Table 1), this result obviously supports the
assumption discussed above.28 From these results, it is obvious
that the presence of an excess of La(O-i-Pr)3 to the 1:2:2
complex 7 should be essential for faster formation of the most
active species. In other words, these results suggested that the
transformation of 7 to 11 can be facilitated by the presence of
an excess of La(O-i-Pr)3, and the 1:1:1 complex 11 should be
(i) No change in the enantiomeric excess was observed for
all conditions (Tables 3 and 4) except for entry 1 (Table 4).
From this fact, we can speculate that the same complex should
exist under all conditions and function as the most active and
effective catalyst.
(ii) In contrast to the ee values, the reactivity was obviously
different in each case. This fact appeared to suggest that the
generation rate of the most active catalyst might be different in
each case.
(iii) Although the La-BINOL-Ph3AsdO complex generated
in a ratio of 1:1:1 was the best one for the epoxidation, the
major component existing in the solution would be the 1:2:2
complex 7.
The above-mentioned experimental information prompted
us to propose the mechanism shown in Scheme 3. In the
complexes’ solution generated from La(O-i-Pr)3, BINOL, and
Ph3AsdO in a ratio of 1:2:2, 7 exists as the major complex.25
The complex 7 reacts with TBHP to afford the La-BINOL-
Ph3AsdO complex 10, and 10 promotes the reaction. On
the other hand, in the complexes’ solution generated from
La(O-i-Pr)3, BINOL, and Ph3AsdO in the best ratio (1:1:1), 7
is formed similarly to the complexes’ solution generated from
La(O-i-Pr)3, BINOL, and Ph3AsdO in a ratio of 1:2:2. However,
1 equiv of the excess La(O-i-Pr)3 should remain in the reaction
medium. Therefore, the excess La(O-i-Pr)3 reacts with TBHP
and also 7 to afford La-BINOL-Ph3AsdO complex 11 in a
ratio of 1:1:1, and the resulting complex would function as
the most active and effective catalyst. It seems that excess
(26) In the presence of TBHP, a significant decrease in the peak
corresponding to the anionic complex (MW 707, Figure 4b) was observed
in the (-)-LDI TOF MS spectrum of the complexes’ solution generated
from La(O-i-Pr)3, BINOL, and Ph3AsdO in a ratio of 1:1:1, suggesting
that the lanthanum metal should have one BINOL unit as a ligand in the
reaction medium.
(27) The reactions were carried out according to the general conditions
for kinetic experiments. For the general conditions and the numerical data
for plots in Figure 7, see the Supporting Information.
(25) The corresponding complexes could be observed by LDI TOF
MS in the complexes’ solution generated from La(O-i-Pr)3, BINOL, and
Ph3AsdO in a ratio of 1:2:2.
(28) Moreover, epoxidation of 1a using 10 mol % of the crystal 8
afforded 2a in 71% yield and 67% ee. But addition of 1 equiv of La(O-i-Pr)3
to 8 increased both the reactivity and the selectivity (1.5 h, 95%, 78% ee).

Catalytic Asymmetric Epoxidation of Enones
J. Am. Chem. Soc., Vol. 123, No. 12, 2001 2731
Scheme 4. Proposed Mechanism for the Epoxidation of
Enones Catalyzed by the La-(R)-BINOL-Ph3AsdO
Complex
Scheme 5. Reaction Mechanism with Several La Complexes
Participating
of Ph3AsdO exists in the reaction medium, less active species
8 is formed in part, leading to a decrease in the reactivity.
Activation of the enone by coordination to the lanthanum metal
of 11 followed by Michael addition of lanthanum peroxide,
which should be on the same metal (transition state I), affords
chiral lanthanum enolate intermediate II. Subsequent formation
of the epoxy ketone followed by dissociation from the lanthanum
complex gives the lanthanum tert-butoxide complex III. Finally,
the reaction of III with TBHP regenerates the active catalyst
11. In the proposed mechanism, we showed only one lanthanum
complex, activating both enone and TBHP. However, unfortu-
nately, we cannot completely exclude a mechanism in which
several lanthanum complexes participate at the moment. Another
possible reaction mechanism is outlined in Scheme 5. The enone
is activated by one active complex, and at the same time,
lanthanum peroxide, which is the other active complex, attacks
the enone. To confirm whether a mechanism catalyzed by one
complex is more plausible or not, we carried out kinetic studies.
Unfortunately, we were not able to obtain clear results. However,
as a result of our investigations on the influence of other
solvents, it was found that the ee’s of the products did not
depend on the polarity of the reaction medium.31 These results
seem to support a mechanism catalyzed by one complex.
As mentioned above (Figure 1), we observed asymmetric
amplification in the present epoxidation. Moreover, the reac-
tion did not proceed well when (rac)-BINOL was used. We
believe that these results can be explained as follows. The
complexes’ solution generated from La(O-i-Pr)3, (rac)-BINOL
and Ph3AsdO in a ratio of 1:1:1 provided the same LDI TOF
MS spectra as those using optically pure BINOL, indicating
that a 1:2:2 complex should be formed as the major complex
in the solution. Therefore, we expected that the stability of
the La[(R)-binaphthoxide][(S)-binaphthoxide](Ph3AsdO)2 com-
plex [(R,S)-7] might be much higher than that of 7, leading to
the low reactivity and the observed asymmetric amplification.32
To obtain experimental proof which supports our speculation,
we carried out the experiments shown in Scheme 6.11b The 1:2:2
complex was prepared from BINOL with 50% ee, and the
resulting solution was allowed to stand at room temperature.
After 1 day, a white precipitate was observed. Separation
followed by hydrolysis of the white precipitate and the
supernatant with aqueous HCl gave the corresponding BINOL
with 2% and 68% ee, respectively. Moreover, the ratio of
BINOL and Ph3AsdO isolated from the white powder and the
supernatant was almost 1:1, respectively.33 From these results,
it is obvious that some heterochiral complex, which likely exists
as (R,S)-7, is formed in the solution, having lower solubility
than the corresponding homochiral complex (R,R)-7. Further-
the actual catalyst. Thus, we can now conclude that the use of
La(O-i-Pr)3, BINOL, and Ph3AsdO in a ratio of 1:1:1 gives
rise to the best catalytic system in the present asymmetric
epoxidation. In addition, it can be expected that the existence
of an excess of La(O-i-Pr)3 should cause a very fast equilibrium
to be reached between the complexes in the solution generated
from La(O-i-Pr)3, BINOL, and Ph3AsdO in a ratio of 1:1:1.
This may also be the reason for the 13C NMR result mentioned
above.
Proposed Mechanism of the Catalytic Asymmetric Ep-
oxidation of Enones Using the La-BINOL-Ph3AsdO
Complex. On the basis of the assumed most active catalyst,
we propose the reaction mechanism shown in Scheme 4. The
1:2:2 complex 7 (precatalyst),29 which is the major component
in the solution generated from La(O-i-Pr)3, BINOL, and
Ph3AsdO in a ratio of 1:1:1, reacts with an excess of
La(O-i-Pr)3 and TBHP to afford the 1:1:1 complex 11 (active
catalyst) in the reaction medium.30 However, if an excess amount
(29) The possibility that La(binaphthoxide)2(Ph3AsdO) complex might
be the efficient active precatalyst to 11 cannot be excluded because
(+)-LDI TOF MS data showed that a small amount of La(binaphthoxide)2-
(Ph3AsdO) complex existed in the reaction medium.
(30) Following is the proposed mechanism for the transformation of 7
to 11.
(31) Epoxidations of 1a using 10 mol % of the La-(R)-BINOL-
Ph3AsdO complex proceeded similarly in other solvents such as DME
(30 min, 94%, 96% ee), benzene (10 min, 93%, 96% ee), and toluene
(10 min, 95%, 95% ee).
(32) At first, we examined crystallization of the heterochiral complex
(R,S)-7 extensively. However, a crystal for X-ray analysis could not be
obtained.
(33) For the detailed experimental data for Scheme 6, see the Supporting
Information.

2732 J. Am. Chem. Soc., Vol. 123, No. 12, 2001
Nemoto et al.
Scheme 6. Correlation between Catalytic Activity and
Optical Purity of the La-(R)-BINOL-Ph3AsdO Complex
likely La[(R)-binaphthoxide][(S)-binaphthoxide](Ph3AsdO)2,
[(R,S)-7], was found to be the reason for asymmetric amplifica-
tion. Finally, we have clarified the possible reaction mechanism
of the epoxidation on the basis of various experimental results.
Further studies are currently underway.
Experimental Section
General Procedure for the Catalytic Asymmetric Epoxidations
of Enones Using the La-(R)-BINOL-Ph3AsdO Complex. To a
mixture of (R)-BINOL (7.2 mg, 0.025 mmol), triphenylarsine oxide
(8.1 mg, 0.025 mmol), and MS 4A [500 mg; MS 4A was not dried
(1000 mg/mmol of starting material)] in dry THF (2.5 mL) was added
a solution of La(O-i-Pr)3 (0.125 mL, 0.025 mmol, 0.2 M solution in
THF) at room temperature. [La(O-i-Pr)3 was purchased from Kojundo
Chemical Laboratory Co., Ltd., 5-1-28, Chiyoda, Sakado-shi, Saitama
350-0214, Japan (fax ++(81)-492-84-1351).] After the mixture was
stirred for 1 h at the same temperature, TBHP (0.12 mL, 0.6 mmol, 5
M solution in decane) was added. After the mixture was stirred for 30
min, enone 1f (73.1 mg, 0.5 mmol) was added directly, and the mixture
was stirred at room temperature. After 6 h, the reaction was quenched
by addition of 2.5% aqueous critic acid solution (5 mL) at 0 °C and
extracted with ethyl acetate (3 × 10 mL). The combined organic layers
were washed with brine (10 mL) and dried over Na2SO4. After
concentration in vacuo, the residue was purified by flash column
chromatography (SiO2, hexane/ethyl acetate 50:1) to give epoxy ketone
a Epoxidation of 1a using 6 mol% of the supernatant or using the
white precipitate treated with 6 mol% La(O-i-Pr)3. The reactions were
carried out at 0 °C, and ee’s of the product were determined after
completion of the reactions.
2f (74,9 mg, 92%, 99.2% ee) as a colorless oil. The IR, 1H NMR, 13
C
NMR, and mass spectra were identical with those of an authentic
sample.10a [R]25 +102 (c 1.0 CHCl3). The enantiomeric excess of 2f
D
more, we carried out the epoxidations of 1a using the white
precipitate and the supernatant in the presence of 1 equiv of
La(O-i-Pr)3 as the additive.34 While the reaction using the
supernatant gave the product in 92% ee with a moderate initial
rate (7.733 × 10-6 M s-1), the reaction using the white
precipitate proceeded more slowly (1.522 × 10-6 M s-1),
affording the product in 1% ee. The results clearly suggested
that the transformation of (R,S)-7 to 11 should be much slower,
even in the presence of La(O-i-Pr)3, than that of (R,R)-7 due to
the low solubility of the heterochiral complex. On the basis of
these data, it is difficult to make conclusions about the stability
of the La[(R)-binaphthoxide][(S)-binaphthoxide](Ph3AsdO)2
complex [(R,S)-7]. However, it can be emphasized that prefer-
ential formation of the heterochiral complex might be the reason
for the asymmetric amplification and the decrease in the
reactivity.
was determined by chiral stationary-phase HPLC analysis (Daicel
Chiralpak AD, i-PrOH/hexane 2/98, flow rate 1.25 mL/min, tR ) 10.7
min (3R,4S)-isomer and 11.9 min (3S,4R)-isomer, detection at 254 nm).
Preparation of the Crystal of La-bis[(R)-binaphthoxide]tris-
(triphenylarsine oxide) (8) for X-ray Analysis. To a stirred mixture
of (R)-BINOL (28.6 mg, 0.1 mmol) and triphenylarsine oxide (96.6
mg, 0.3 mmol) in THF (0.5 mL) was added a solution of La(O-i-Pr)3
(0.5 mL, 0.1 mmol, 0.2 M solution in THF). After the reaction mixture
was stirred for 1 h, the solution was concentrated to 0.125-0.15 M
and kept at room temperature under argon. After 24 h, an X-ray-grade
crystal of La-bis[(R)-binaphthoxide]tris(triphenylarsine oxide) (8) was
grown.
Data for 8: collected at -100 °C, C98H80O9As3La ) 1765.37, clear,
prism, crystal system trigonal, lattice type primitive, a ) 17.6048(6)
Å, c ) 26.653(1) Å, V ) 7153.9(5) Å3, P3221,35 Z ) 3, D ) 1.229
g/cm3, R(F) ) 0.054, Rw(F) ) 0.082, GOF ) 1.85. Hydrogen atoms
were included but not refined. THF × 1 and H2O × 1 were incorporated
in the crystal. For data collection and solution and refinement of the
structure, see the Supporting Information.
Conclusion
We have succeeded in improving catalytic asymmetric
epoxidations of enones using the novel asymmetric catalyst, the
La-BINOL-Ph3AsdO complex. This catalyst system is quite
effective for several trans-enones, including a dienone, yielding
products in up to 99% yield and more than 99% ee. Moreover,
we have carried out detailed investigations on the structural
determination of the La-BINOL-Ph3AsdO complex, including
the first X-ray crystal structure analysis of an alkali-metal free
lanthanoid-BINOL complex. The La-BINOL-Ph3AsdO com-
plex in a ratio of 1:2:2 (7) was observed as the major component
in the complexes’ solution generated from La(O-i-Pr)3, BINOL,
and Ph3AsdO in the best ratio (1:1:1). However, the La-
BINOL-Ph3AsdO complex generated in a ratio of 1:1:1 (11)
turned out to be the most active and effective catalyst.
Furthermore, preferential formation of the heterochiral complex,
Acknowledgment. We thank Mr. Shigeru Sakamoto for the
help with the X-ray structure determination of 8 and Mr. Shigeki
Matsunaga for his fruitful discussions. This work was supported
by CREST and JSPS.
Supporting Information Available: Enantiomeric excess
analysis of the epoxy ketones 2a-h, 4, and 6; experimental
procedures and spectral and analytical data for all new
compounds for the synthetic pathway to 1i; their 1H NMR and
13C NMR spectra; detailed results of catalytic asymmetric
epoxidation of 1i to 2i using La-BINOL complexes; general
conditions for the kinetic studies and experimental data of
Figures 1 and 7 and Scheme 6; and an X-ray crystallographic
file (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
JA004201E
(34) The concentration of the 1:2:2 complex in the supernatant was
calculated from the ee values of BINOL contained in the white precipitate
and the supernatant, respectively.
(35) The space group is P3221 in the case of La-bis[(S)-binaphthoxide]-
tris(triphenylarsine oxide).