Oxidation catalysis of Nb(salan) complexes: Asymmetric epoxidation of allylic alcohols using aqueous hydrogen peroxide as an oxidant

Article abstract of DOI:10.1021/ja100795k

Several optically active Nb(salan) complexes were synthesized, and their oxidation catalysis was examined. A dimeric μ-oxo Nb(salan) complex that was prepared from Nb(OiPr)₅ and a salan ligand was found to catalyze the asymmetric epoxidation of allylic alcohols using a urea-hydrogen peroxide adduct as an oxidant with good enantioselectivity. However, subsequent studies of the time course of this epoxidation and of the relationship between the ee of the ligand and the ee of the product indicated that the μ-oxo dimer dissociates into a monomeric species prior to epoxidation. Moreover, monomeric Nb(salan) complexes prepared in situ from Nb(OiPr)₅ and salan ligands followed by water treatment were found to catalyze the epoxidation of allylic alcohols better using aqueous hydrogen peroxide in CHCl₃/brine or toluene/brine solution with high enantioselectivity ranging from 83 to 95% ee, except for the reaction of cinnamyl alcohol that showed a moderate ee of 74%. This is the first example of the highly enantioselective epoxidation of allylic alcohols using aqueous hydrogen peroxide as an oxidant.

Full text of DOI:10.1021/ja100795k

Published on Web 04/01/2010
Oxidation Catalysis of Nb(salan) Complexes: Asymmetric
Epoxidation of Allylic Alcohols Using Aqueous Hydrogen
Peroxide as an Oxidant
Hiromichi Egami, Takuya Oguma, and Tsutomu Katsuki*
Department of Chemistry, Faculty of Science, Graduate School, Kyushu UniVersity,
Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
Received January 29, 2010; E-mail: katsuscc@chem.kyushu-univ.jp
Abstract: Several optically active Nb(salan) complexes were synthesized, and their oxidation catalysis
was examined. A dimeric µ-oxo Nb(salan) complex that was prepared from Nb(OiPr)5 and a salan ligand
was found to catalyze the asymmetric epoxidation of allylic alcohols using a urea-hydrogen peroxide adduct
as an oxidant with good enantioselectivity. However, subsequent studies of the time course of this
epoxidation and of the relationship between the ee of the ligand and the ee of the product indicated that
the µ-oxo dimer dissociates into a monomeric species prior to epoxidation. Moreover, monomeric Nb(salan)
complexes prepared in situ from Nb(OiPr)5 and salan ligands followed by water treatment were found to
catalyze the epoxidation of allylic alcohols better using aqueous hydrogen peroxide in CHCl3/brine or toluene/
brine solution with high enantioselectivity ranging from 83 to 95% ee, except for the reaction of cinnamyl
alcohol that showed a moderate ee of 74%. This is the first example of the highly enantioselective epoxidation
of allylic alcohols using aqueous hydrogen peroxide as an oxidant.
1. Introduction
the epoxidation, pioneered by Sharpless, is the method using a
vanadium/hydroxamic acid complex as the catalyst.5 Later,
Yamamoto and other groups improved the catalysis of the
vanadium catalyst by introducing a bulky hydroxamic acid
ligand that prevents the formation of a catalytically inactive
multihydroxamic acid-coordinating vanadium complex.6 In
2005, Malkov et al. reported a method for the epoxidation using
a vanadium/hydroxamic acid/t-butyl hydroperoxide system in
water, with moderate to good enantioselectivity.7 Moreover,
Yamamoto and co-workers made a breakthrough in this type
of epoxidation by introducing a unique bis-hydroxamic acid
ligand.8 The scope of the reaction using the vanadium-bis-
hydroxamic acid complex is very wide: it can be applied not
only to allylic alcohols but also to homoallylic alcohols with
high enantioselectivity.8b,9 The reactions described above satisfy
the first criterion of selectivity, but they require the use of an
A number of synthesis methods have been reported to date
and used for various organic syntheses. With resource conserva-
tion and waste reduction in mind, selectivity and atom efficiency
are two important criteria for choosing a method for efficient
synthesis from among many methods.
Chiral epoxy alcohols are versatile building blocks for organic
synthesis, and asymmetric epoxidation of readily available allylic
alcohols is the most straightforward method of synthesis.1 In
1980, Sharpless and Katsuki reported a highly enantioselective,
practical epoxidation of allylic alcohols using a titanium/tartrate/
t-butyl hydroperoxide system.2 Later, a catalytic version of this
reaction was achieved by adding molecular sieves to the system.3
Subsequently, Basset and co-workers developed an enantiose-
lective epoxidation using a heterogeneous silica-supported
tantalum/tartrate complex as the catalyst.4 Another approach to
(1) For reviews of the asymmetric epoxidation of allylic alcohols, see
the following: (a) Katsuki, T. Epoxidation of Allylic Alcohols. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 2, pp 621-648.
(b) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1–299. (c) Adam,
W.; Malisch, W.; Roschmann, K. J.; Saha-Mo¨ller, C. R.; Schenk, W. A.
J. Organomet. Chem. 2002, 661, 3–16. (d) Bolm, C. Coord. Chem.
ReV. 2003, 237, 245–256. (e) Lattanzi, A.; Scettri, A. J. Organomet.
Chem. 2006, 691, 2072–2082. (f) Johnson, R. A.; Sharpless, K. B. In
Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH:
New York, 2000; pp 231-280.
(5) (a) Michaelson, R. C.; Palermo, R. E.; Sharpless, K. B. J. Am. Chem.
Soc. 1977, 99, 1990–1992. (b) Sharpless, K. B.; Verhoeven, T. R.
Aldrichimica Acta 1979, 12, 63–74.
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1999, 64, 338–339. (b) Hoshino, Y.; Yamamoto, H. J. Am. Chem.
Soc. 2000, 122, 10452–10453. (c) Hoshino, Y.; Murase, N.; Oishi,
M.; Yamamoto, H. Bull. Chem. Soc. Jpn. 2000, 73, 1653–1658. (d)
Bolm, C.; Ku¨hn, T. Synlett 2000, 899–901. (e) Bolm, C.; Beckmann,
O.; Ku¨hn, T.; Palazzi, C.; Adam, W.; Bheema, P.; Saha-Mo¨ller, C. R.
Tetrahedron: Asymmetry 2001, 12, 2441–2446. (f) Wu, H.-L.; Uang,
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A. V.; Bourhani, Z.; Kocovsky, P. Org. Biomol. Chem. 2005, 3, 3914–
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9
5886 J. AM. CHEM. SOC. 2010, 132, 5886–5895
10.1021/ja100795k  2010 American Chemical Society

Asymmetric Epoxidation of Allylic Alcohols
A R T I C L E S
alkyl hydroperoxide as the oxidant. Still, the second criterion
of ecological sustainability is a challenging issue to address.
peroxide. These reactions have been proposed to proceed via a
peroxo Ti species that is activated by hydrogen bonding with
the adjacent amino proton. Different from simple olefins, allylic
alcohols can precoordinate with a metal ion, and an (allyla-
lkoxo)(peroxo) metal species is likely to be a possible inter-
mediate for the epoxidation using hydrogen peroxide as an
oxidant. Because salalen or the salan ligand is divalent and
quadridentate, a metal-(salalen) or metal-(salan) complex was
considered to show the asymmetric catalysis of the epoxidation
of allylic alcohols, when the valency of the metal ion is five or
greater and the corresponding salalen or salan complex can adopt
heptacoordination such as in a pentagonal bipyramidal config-
uration. The titanium ion is tetravalent, and its salalen and salan
complexes generally adopt an octahedral configuration. Indeed,
these complexes scarcely or poorly catalyze the epoxidation of
allylic alcohols with low enantioselectivity.16 In contrast to the
titanium complexes, zirconium- and hafnium-(salen) com-
plexes have been reported to adopt a pentagonal bipyramidal
configuration.17 We expected that metal ions of the second and
third transition-metal series in group V would also form a
complex with a pentagonal bipyramidal configuration. Hence,
we were intrigued by the asymmetric epoxidation catalysis of
Nb- or Ta-(salan) or Nb- or Ta-(salalen) complexes.18,19
In this article, we describe the preparation of Nb- and
Ta-(salan) complexes and their asymmetric catalysis of the
epoxidation of allylic alcohols with the urea-hydrogen peroxide
adduct (UHP)20 or with aqueous hydrogen peroxide.
The ecological sustainability of oxidation primarily depends
on the oxidant used.10,11 The use of an oxidant that has a high
active oxygen content and generates a small and innocuous
coproduct such as water after oxygen-atom transfer is essential
for green oxidation. In light of this, asymmetric epoxidation
using hydrogen peroxide, in particular, aqueous hydrogen
peroxide, that is safe and cheap and generates water as a
coproduct is a topic of current interest.10 Although several highly
enantioselective methods for epoxidation using aqueous hydro-
gen peroxide at room temperature have been reported,12 no
method for the epoxidation of allylic alcohols with it has been
achieved. We have recently revealed that Ti(salalen)13,14 and
Ti(salan)13,15 complexes are excellent catalysts for the asym-
metric epoxidation of simple olefins using aqueous hydrogen
(9) (a) Zhang, W.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 286–
287. (b) Li, Z.; Zhang, W.; Yamamoto, H. Angew. Chem., Int. Ed.
2008, 47, 7520–7522.
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Oxidation Methods; Wiley-VHC: Weinheim, Germany, 2004. (b)
Noyori, R.; Aoki, M.; Sato, K. Chem. Commun. 2003, 1977–1986.
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stro¨m, U. M., Ed. Organic Reactions in Water; Blackwell Publishing:
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2772. (e) Li, C.-J.; Chen, L. Chem. Soc. ReV. 2006, 35, 68–83.
(12) (a) Julia´, S.; Masana, J.; Vega, J. C. Angew. Chem., Int. Ed. Engl.
1980, 19, 929–931. (b) Colona, S.; Molinari, H.; Banfi, S.; Julia´, S.;
Masana, J.; Alvalez, A. Tetrahedron 1983, 39, 1635–1641. (c)
Pietika¨inen, P. Tetrahedron Lett. 1994, 35, 941–944. (d) Berkessel,
A.; Frauenkron, M.; Schwekreis, T.; Steinmetz, A.; Baum, G.; Fenske,
D. J. Mol. Catal. A: Chem. 1996, 113, 321–342. (e) Pietika¨inen, P.
Tetrahedron 1998, 54, 4319–4326. (f) Arai, S.; Tsuge, H.; Shioiri, T.
Tetrahedron Lett. 1998, 39, 7563–7566. (g) Shu, L.; Shi, Y. Tetra-
hedron 2001, 57, 5213–5218. (h) Kureshy, R. I.; Kahn, N. H.; Abdi,
S. H. R.; Singh, S.; Ahmed, I.; Shunkla, R. S.; Jasra, R. V. J. Catal.
2003, 219, 1–7. (i) Tse, M. K.; Dobler, C.; Bhor, S.; Klawonn, M.;
Magerlein, W.; Hugl, H.; Beller, M. Angew. Chem., Int. Ed. 2004,
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2. Results and Discussion
2.1. Preparation of µ-Oxo-Nb(salan) Complexes. Mixing
Nb(OiPr)5 and ligand 1 in dichloromethane immediately pro-
vided an unstable monomeric Nb(salan)(OiPr)3 complex, 2,21
that was slowly converted to a µ-oxo-Nb(O)(salan) dimer
complex, 3, under ambient conditions over a period of 7-10
days (Scheme 1). The preparation of 2 and 3 was traced by 1H
NMR and MS analysis. Monomeric complex 2 decomposed
during chromatographic analysis and could not be purified
completely. However, complex 3 was purified using silica gel
column chromatography and was used for the following
(16) Titanium(salan) complexes scarcely catalyzed the epoxidation of trans-
and cis-2-hexen-1-ols whereas a titanium(salalen) complex that is an
excellent catalyst for the epoxidation of isolated olefins (ref 14b)
catalyzed the epoxidation of allylic alcohols, albeit sluggishly and with
only modest enantioselectivity: the epoxidation of cis-2-hexene-1-ol
at room temperature for 24 h gave the corresponding epoxy alcohol
of 20% ee in 30% yield.
(17) (a) Corazza, F.; Solari, E.; Floriani, C.; Chiesi-Villa, A.; Guastini, C.
J. Chem. Soc., Dalton Trans. 1990, 1335–1344. (b) Repo, T.; Klinga,
M.; Pietika¨inen, P.; Leskela¨, M.; Lo¨fgren, B. Macromolecules 1997,
30, 171–175. (c) Matsumoto, K.; Watanabe, A.; Uchida, T.; Ogi, K.;
Katsuki, T. Tetrahedron Lett. 2004, 45, 2385–2388. (d) Watanabe,
A.; Uchida, T.; Irie, R.; Katsuki, T. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5737–5742.
(13) Matsumoto, K.; Saito, B.; Katsuki, T. Chem. Commun. 2007, 3619–
3627.
(18) For niobium-catalyzed asymmetric reactions, see the following: (a)
Kobayashi, S.; Arai, K.; Shimizu, H.; Ihori, Y.; Ishitani, H.; Yamashita,
Y. Angew. Chem., Int. Ed. 2005, 44, 761–764. (b) Arai, K.; Salter,
M. M.; Yamashita, Y.; Kobayashi, S. Angew. Chem., Int. Ed. 2007,
46, 955–957. (c) Arai, K.; Lucarini, S.; Salter, M. M.; Ohta, K.;
Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2007, 129, 8103–
8111. (d) Jurcˇ´ık, V.; Arai, K.; Salter, M. M.; Yamashita, Y.; Kobayashi,
S. AdV. Synth. Catal. 2008, 350, 647–651.
(14) (a) Matsumoto, K.; Sawada, Y.; Saito, B.; Saki, K.; Katsuki, T. Angew.
Chem., Int. Ed. 2005, 44, 4935–4939. (b) Sawada, Y.; Matsumoto,
K.; Katsuki, T. Angew. Chem., Int. Ed. 2007, 46, 4559–4561.
(15) (a) Sawada, Y.; Matsumoto, K.; Kondo, S.; Watanabe, H.; Ozawa,
T.; Suzuki, K.; Saito, B.; Katsuki, T. Angew. Chem., Int. Ed. 2006,
45, 3478–3480. (b) Matsumoto, K.; Sawada, Y.; Katsuki, T. Synlett
2006, 3545–3547. (c) Shimada, Y.; Kondo, S.; Ohara, Y.; Mataumoto,
K.; Katsuki, T. Synlett 2007, 2445–2447. (d) Kondo, S.; Saruhashi,
K.; Seki, K.; Matsubara, K.; Miyaji, K.; Kubo, T.; Matsumoto, K.;
Katsuki, T. Angew. Chem., Int. Ed. 2008, 47, 10195–10198. (e)
Matsumoto, K.; Kubo, T.; Katsuki, T. Chem.sEur. J. 2009, 15, 6573–
6575. (f) Matsumoto, K.; Oguma, T.; Katsuki, T. Angew. Chem., Int.
Ed. 2009, 48, 7432–7435.
(19) For other examples of niobium-catalyzed asymmetric oxidation, see:
Miyazaki, T.; Katsuki, T. Synlett 2003, 1046–1048.
(20) Part of the preliminary studies have been communicated: Egami, H.;
Katsuki, T. Angew. Chem., Int. Ed. 2008, 47, 5171–5174.
(21) The crude mixture was submitted to MS analysis. 2: ESI+-TOFMS.
Calcd for [(C60H48N2O2)(C3H7O)2Nb]+: m/z ) 1039.3768. Found: m/z
) 1039.3738.
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A R T I C L E S
Egami et al.
Scheme 1. Preparation of µ-Oxo-Nb(salan) and Ta(salan) Complexes
epoxidation. Other dimeric Nb- and Ta-(salan) complexes
(4-7) were synthesized during the same procedure.
Table 1. Asymmetric Epoxidation of Geraniol with Dimeric Nb-
and Ta-(salan) Complexes as the Catalysta
2.2. Asymmetric Epoxidation of Allylic Alcohols with
µ-Oxo-Nb(salan) Complexes and UHP. It is known that most
polyoxo-metal complexes show epoxidation catalysis.22 Thus,
we were intrigued with the catalysis of dimeric complexes 3-7,
and we examined the epoxidation of geraniol in the presence
of 4 equiv of UHP at 20 °C in toluene (Table 1). Although the
epoxidation using 3 was slow, it had the best results (68% ee,
24%) in terms of enantioselectivity and yield, though both were
still moderate (entry 1). The reaction with complex 4 was slower
and less selective (entry 2). Complex 5 did not show epoxidation
catalysis (entry 3). The reaction with Ta complex 6 that carries
the same ligand as 3 was slower and less selective than that
with 3 (entry 4). On the basis of these results, we optimized
the reaction temperature for the epoxidation with complex 3,
and it was found that a good enantioselectivity of 81% ee and
acceptable chemical yields were obtained at 40 °C (entry 5).
The effect of solvent was also investigated at 40 °C, and toluene
was proven to be the solvent of choice in terms of enantiose-
entry
cat.
solvent
T (°C)
yields (%)
ee (%)b
1
2
3
4
5
6
7
8
3
4
5
6
3
3
3
3
3
3
3
7
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
THF
AcOEt
MeOH
toluene
toluene
20
20
20
20
40
60
40
40
40
40
40
40
24
68
10
-42
N.R.c
13
42
81
67
68
61
32
22
<5
10
40
83
9
56
10
11d
12
rac
81 (2S, 3S)
79 (2S, 3S)
58
a The reaction was carried out on a 0.5 mmol scale with catalyst (1
mol %) and UHP (4 equiv), unless otherwise mentioned. b Determined
by HPLC analysis on a chiral phase (Daicel Chiralpak OB-H) after
benzoylation. c No reaction. d Run with 2 mol % of 3.
(22) For reviews of epoxidation with polyoxometalates, see: (a) Hill, C. L.;
Prosser-McCartha, C. M. Coord. Chem. ReV. 1995, 143, 407–455.
(b) Mizuno, N.; Yamaguchi, K.; Kamata, K. Coord. Chem. ReV. 2005,
249, 1944–1956. (c) Mizuno, N.; Yamaguchi, K. Chem. Rec. 2006,
6, 12–22. (d) Bre´geault, J.-M.; Vennat, M.; Salles, L.; Piquemal, J.-
Y.; Mahha, Y.; Briot, E.; Bakala, P. C.; Atlamsani, A.; Thouvenot,
R. J. Mol. Catal. A: Chem. 2006, 250, 177–189.
lectivity and yield (entries 5 and 7-10). The epoxide was
obtained in a good yield when 2 mol % of 3 was used (entry
11). The epoxidation using 7 as the catalyst, which bears the
ligand with the same configuration as 3 and gave a single crystal
9
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Asymmetric Epoxidation of Allylic Alcohols
A R T I C L E S
Table 2. Asymmetric Epoxidation of Various Allylic Alcohols with 3
as the Catalysta
Figure 1. Initial reaction rates of the epoxidation of trans-2-hexene-1-ol
using pretreated 2 or 3 as a catalyst in the presence of UHP.
converted into the corresponding µ-oxo dimer due to steric
hindrance, did not catalyze the epoxidation of allylic alcohols.
In a continuing study, however, we encountered two meaningful
observations. It was found that in situ-prepared 2 showed
epoxidation catalysis, even after it was treated with water for
30 min, albeit with inferior enantioselectivity and yield. The
epoxidation of geraniol with this pretreated catalyst in the
presence of UHP gave the corresponding epoxide of 60% ee in
43% yield. The MS analysis of the pretreated complex indicated
the formation of a (HO)Nb(O)(salan) complex.25 Another
finding was that the oxidation with pretreated catalyst has no
induction period whereas the reaction with 3 does have an
induction period (Figure 1). X-ray analysis of µ-oxo-Nb(salan)
complex 7 indicated that the oxygen atoms of the two NbdO
bonds form hydrogen-bond pairs with the amino protons of the
salan ligand on the other Nb ion, and this hydrogen-bond pair
stabilizes the dimeric structure of the Nb(salan) complex (vide
infra). We inferred that the induction period represents the time
necessary for the cleavage of the hydrogen bond pair and an
activated species for the epoxidation is formed via a monomeric
NbdO species. Thus, we expected that an in situ-prepared and
-pretreated complex could be a better catalyst for the epoxidation
of allylic alcohol using hydrogen peroxide under aqueous
conditions.
entry
substrate
yield (%)
ee (%)b
configc
1
2
3
4
5
6
7
8
9b
9c
66
72
83
78
81
79
86
83
80d
80d
79
2S, 3R
2S, 3S
2S, 3S
2S, 3S
2S, 3S
2S, 3R
2S, 3S
2S
11a
11b
11c
13
15a
15b
80d
79d
83d
72
68
a The reaction was carried out on a 0.5 mmol scale with 2 (2 mol %)
and UHP (4 equiv) at 40 °C. b Determined by HPLC analysis on a
chiral phase. c Determined by comparison of the chiroptical data with
the literature value. d Determined by HPLC analysis on a chiral phase
after conversion to the corresponding benzoate.
suitable for X-ray analysis, provided the epoxide with 79% ee
(entry 12). A µ-oxo-Nb complex bearing the corresponding
(aR,S,S,aR)-salalen ligand (dehydrogenated 1) was also prepared
in the same manner23 and was used as the catalyst in the
epoxidation with UHP. However, its catalytic activity was poor.
Under optimized conditions, the epoxidation of various allylic
alcohols was examined (Table 2). The epoxidation of di- and
trisubstituted olefins proceeded with a similarly good level of
enantioselectivity to that of geraniol, irrespective of their
geometry (entries 1-6). However, the presence of a geminal
substituent diminished the enantioselectivity to some extent
(entries 7 and 8). It is noteworthy that the present epoxidation
is stereospecific. The oxidation with aqueous hydrogen peroxide,
which is a cheaper and easier-to-handle oxidant, was also
examined at 40 °C, but it was found to be inferior to the reaction
with UHP in terms of enantioselectivity and yield. For example,
the epoxidation of geraniol gave the epoxide at 40% ee in 38%
yield.
2.3. Asymmetric Epoxidation of Allylic Alcohols with
Aqueous Hydrogen Peroxide. In situ-prepared 2 was also used
as the catalyst in the epoxidation of geraniol using UHP in
toluene at 40 °C for 24 h. The reaction gave the corresponding
epoxide with inferior enantioselectivity (74% ee) in 42% yield.
Although complex 2 is converted to 3, this result suggests that
a Nb(salan) complex other than dimeric 3 could catalyze this
epoxidation. However, in situ-prepared 8,24 which has a
dimethylcyclohexane unit in the salan ligand and cannot be
In the communication of our preliminary study,20 we de-
scribed that complex 3 is the catalyst for epoxidation and that
it is decomposed by water. With these new results, however,
we suspected that water dissociates only the µ-oxo Nb(salan)
dimer into a monomeric Nb(salan) complex and that hydrogen
peroxide might be mainly responsible for the decomposition of
the catalyst. Hydrogen peroxide has a high coordination ability
and nucleophilicity, and many metal complexes degrade more
rapidly in its presence. Therefore, we expected that the epoxi-
dation using aqueous hydrogen peroxide would be realized in
aqueous media with the pretreated catalyst prepared from 1 if
the accumulation of hydrogen peroxide can be avoided. To
explore this possibility, we examined the reaction of 5-phenyl-
2-pentenol using 30% aqueous hydrogen peroxide at 40 °C
(Table 3). As expected, epoxidation proceeded with better
enantioselectivity and yield when aqueous hydrogen peroxide
was added dropwise rather than all at once (cf. entries 1 and
3). Moreover, the reaction in toluene/brine was found to give a
further-improved yield and enantioselectivity, which were
comparable to those obtained with a 3/UHP system (cf., entry
2 and Table 2, entry 3).
(23) (aR,S,S,aR)-µ-oxo-Nb(salalen) dimer complex: ESI+-TOFMS. Calcd
for [(C60H46N2O2)(O)Nb-O-Nb(O)(C60H46N2O2)+Na]+: m/z )
1910.5022. Found: m/z ) 1910.5019.
(24) The crude mixture was submitted for MS analysis. 8: ESI+-TOFMS.
Calcd for [(C62H52N2O2)(C3H7O)2Nb]+: m/z ) 1067.4081. Found: m/z
) 1067.4061.
(25) (HO)Nb(O)(salan)
complex:
ESI+-TOFMS.
Calcd
For
[(C60H48N2O2)Nb(OH)(O)+Na]+: m/z ) 977.2648. Found: m/z )
977.2624.
9
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A R T I C L E S
Egami et al.
Table 3. Asymmetric Epoxidation of 5-Phenyl-2-pentenol with
ligands derived from the 1,2-diphenylethylenediamines (entries
8 and 9). It was again observed that (aR,R)-salan ligand 18 was
less efficient than (aR,S)-ligand 19. Moreover, ligand 19 showed
better asymmetric induction than 1 (entry 9). Thus, we surveyed
the reaction using 19 in several solvents and found that a better
enantioselectivity was obtained in chloroform/brine (entry 10).
Eventually, high enantioselectivity of 92% ee was obtained with
ligand 20 bearing 1-naphthyl groups at the diamine subunit
(entry 11). It is of note that a complex of ligand 21 that does
not possess a binaphthyl subunit did not catalyze the epoxidation
(entry 12). It is also noteworthy that N,N′-dimethylated ligand
22 did not catalyze the epoxidation (entry 13).
Aqueous Hydrogen Peroxidea
entry
solvent
yield (%)
ee (%)b
1c
2c
3d
4d
5d
toluene
toluene/brine
toluene
toluene/H2O
toluene/brine
53
74
43
48
21
58
80
36
58
72
a The reactions were carried out on a 0.5 mmol scale with 30%
H2O2(aq) (1.5 equiv) in the presence of the catalyst that was prepared in
situ from Nb(OiPr)5 (4 mol %) and 1 (4 mol %) and pretreated with
water. b Determined by HPLC analysis using a chiral stationary phase
column (Daicel Chiralpak OD-H). c H2O2(aq) was added dropwise every
2 h in seven batches. d H2O2(aq) was added all at once.
Table 4. Optimization of the Asymmetric Epoxidation of Allylic
Alcoholsa
entry
temp (°C)
ligand
yield (%)
ee (%)b
configc
1d
2
40
40
40
40
20
60
40
40
40
40
40
40
40
1
1
1
1
1
1
17
18
19
19
20
21
22
74
80
82
71
28
55
31
46
80
81
81
81
75
80
48
52
87
91
92
2S, 3S
2S, 3S
2S, 3S
2S, 3S
2S, 3S
2S, 3S
2R, 3R
2R, 3R
2S, 3S
2S, 3S
2S, 3S
3e
4f
5
6
7
8
9
72
10g
11g
12
13
76h
81h
N.R.i
N.R.i
On the basis of these results, we examined the epoxidation
of various allylic alcohols using ligand 1, 19, or 20 in a mixed
solvent, toluene/brine or chloroform/brine, under otherwise
optimized conditions, and the best results obtained are shown
in Table 5. High enantioselectivity greater than 91% ee and
acceptable yields were obtained in the epoxidation of E-alkyl-
substituted allylic alcohols using 20 as the ligand (Table 5,
entries 1-4). The resulting epoxy alcohols were partially
oxidized under the conditions of the corresponding epoxy
aldehydes (10-20%), and the reaction mixture was treated with
NaBH4 before isolating the products. It should be noted that
the oxidation of the aldehydes occurred in an enantiomer-
differentiating manner, albeit with low selectivity, and that the
enantiomeric excesses of whole epoxides were slightly better
than for the epoxides isolated without NaBH4 treatment. The
reaction of cinnamyl alcohol was moderately enantioselective,
and the competitive OH oxidation giving the cinnam aldehyde
was observed (entry 5). As opposed to the epoxidation of
E-allylic alcohols, that of cis-2-hexenol was best carried out in
toluene/brine with a high enantioselectivity (85% ee) by using
1 as a ligand (entry 6). The reactions of trisubstituted substrates,
geraniol and nerol, were also better carried out by the catalyst
obtained from 1 (entries 7 and 8). However, the epoxidation of
geminally substituted allylic alcohols using ligands 1, 19, or
20 did not show good enantioselectivity higher than 80% ee.
To our delight, high enantioselectivity greater than 83% ee was
obtained by using 18 as a ligand, albeit with moderate yields
due to the competitive OH oxidation (entries 9-12). The use
a The reactions were carried out in toluene/brine on a 0.5 mmol scale
with 30% H2O2(aq) (1.5 equiv) in the presence of the catalyst that was
prepared in situ from Nb(OiPr)5 (4 mol %) and the ligand (5 mol %)
and pretreated with water. H2O2(aq) (1.5 equiv) was added in
a
dropwise manner, unless otherwise mentioned. b Determined by HPLC
analysis using
a chiral stationary phase column (Daicel Chiralpak
OD-H). c Determined by comparison of the chiroptical data with
literature values. d Run with 4 mol % of the ligand. e Run with 6 mol %
of the ligand. f Nb(OEt)5 was used as the metal source. g The reaction
was carried out in chloroform/brine. h The reaction mixture was treated
with NaBH4 before isolation of the product. i No reaction occurred.
Under these conditions, we further optimized the reaction in
terms of the metal/ligand ratio, reaction temperature, and ligand
structure (Table 4). The amount of ligand loading had little effect
on the yield and enantioselectivity (entries 1-3). Nb(OiPr)5 did
not catalyze the epoxidation in the absence of the salan ligand.
The reaction with the catalyst prepared from Nb(OEt)5 showed
an equal enantioselectivity to that with the catalyst prepared
from Nb(OiPr)5, albeit in a slightly reduced yield (entry 4). This
indicates that the Nb(salan) complex does not carry the alkoxide
ligand at the transition state for the epoxidation. The yield was
diminished at both lowered and raised temperatures, though
good enantioselectivity was obtained at 60 °C (entries 5 and
6). The reaction with (aR,R)-salan ligand 17 was less selective,
and the sense of asymmetric induction by it was opposite to
that by (aR,S)-1 (entry 7). Under the same conditions, we
examined the catalysis of niobium complexes bearing the salan
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5890 J. AM. CHEM. SOC. VOL. 132, NO. 16, 2010

Asymmetric Epoxidation of Allylic Alcohols
A R T I C L E S
Table 5. Asymmetric Epoxidation of Various Allylic Alcoholsa
a The reactions were carried out on a 0.5 mmol scale in the presence of the catalyst that was prepared in situ from Nb(OiPr)5 (4 mol %) and ligand
(5 mol %) and pretreated with water. 30% aqueous H2O2 (1.5 equiv.) was added in a dropwise manner, unless otherwise mentioned. b Yield after
treatment of the reaction mixture with NaBH4, unless otherwise mentioned. c Determined by HPLC analysis using a chiral stationary phase column.
d Determined by comparison of the chiroptical data with the literature values. e Determined by HPLC analysis after conversion into the corresponding
benzoate. f Yield without NaBH4 reduction. g Run with 8 mol % of Nb(OiPr)5 and 9 mol % of the ligand.
of fluorobenzene/brine as a solvent slightly improved the yields
in some reactions (entries 9 and 11). The undesired OH
oxidation is likely to be accelerated by the presence of aryl and
geminal substituents.
It is of note that high enantioselectivity greater than 83% ee
in the epoxidation of allylic alcohols using 30% aqueous
hydrogen peroxide was achieved with an appropriate Nb(salan)
complex as a catalyst, except for the epoxidation of cinnamyl
alcohol, though the yields of some reactions were moderate
because of competitive OH oxidation.
2.4. X-ray Analysis of µ-Oxo-Nb(salan) Complex 7 and
Mechanistic Consideration of the Present Epoxidation. Complex
7 showed almost identical oxidation catalysis to that of complex
3, and it gave a single crystal from dichloromethane and ether
(2: 1) (vide supra). The X-ray analysis determined its structure
unambiguously (Figure 2):26 complex 7 was an approximately
C2-symmetric µ-oxo dimer. Both Nb(salan) units of 7 adopted
a distorted octahedral configuration, and the chirality of the
niobium-bound amine nitrogen atoms was R. It is noteworthy
Figure 2. X-ray structure of µ-oxo-Nb(salan) complex 7.
that the Nb(1)-O(4) distance is 1.744 Å, a dimension appropri-
ate for a double bond. It is also noted that the Nb(1)-O(1) bond
is slightly shorter than the Nb(1)-O(2) and Nb(1)-O(3) bonds.
Moreover, the N(3)-O(4) and N(1)-O(7) distances are as short
(26) CCDC-677278 contains the supplementary crystallographic data for
as 2.824 and 2.902 Å, respectively, indicating the presence of
this article. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
hydrogen bonding between the oxo oxygen and amino hydrogen
atoms.
9
J. AM. CHEM. SOC. VOL. 132, NO. 16, 2010 5891

A R T I C L E S
Egami et al.
Scheme 2. Plausible Mechanism for the Epoxidation Using
Pretreated Complex 2 as a Catalyst
3 serves as a catalyst for the asymmetric epoxidation of allylic
alcohols with a urea-hydrogen peroxide adduct. On the basis
of the analysis of the time course of the epoxidation, we also
discovered that in situ-prepared Nb(salan) complexes catalyze
the epoxidation of allylic alcohols using aqueous hydrogen
peroxide in aqueous media. It is of note that the latter method
does not require the troublesome purification of the catalyst and
allows easy ligand tuning. Eventually, we could achieve highly
enantioselective epoxidation of allylic alcohols using aqueous
hydrogen peroxide. To the best of our knowledge, this is the
first report on the asymmetric epoxidation of allylic alcohols
using hydrogen peroxide as an oxidant and on the asymmetric
catalysis of a niobium complex in aqueous media. This study
will open a new avenue toward a sustainable system for
asymmetric oxidation.
Figure 3. Correlation between ee’s of ligand 1 and the product in the
epoxidation of 5-phenyl-2-pentenol.
The epoxidation with a pretreated catalyst has no induction
period whereas the reaction with 3 does have an induction period
(Figure 1) and the pretreated catalyst was suggested to be a
(HO)Nb(O)(salan) complex by MS analysis. Taking into
consideration the X-ray structure, the induction period represents
the necessary time for cleaving the hydrogen bond pairing
between the NdO bond and the amino protons as described
above. Because these results suggested that a genuine catalyst
is a monomeric (hydroxo)(oxo)niobium species, we examined
the relationship between the ee of ligand 1 and the ee of the
product.27 In accord with the suggestion, a linear relationship
(R2 ) 0.9962) between them was observed in the epoxidation
of 5-phenyl-2-pentenol (Figure 3).
It is known that oxo metal species gives the corresponding
peroxo metal species upon hydrogen peroxide treatment,28 and
it seemed likely that pretreated complex 2 was converted to
the corresponding peroxo species under the present conditions.
Moreover, Nb complexes of salan ligands that have an amino
proton underwent epoxidation catalysis whereas the complex
of N,N′-dimethylated salan ligand 22 did not (Table 4, entry
13). The same phenomenon has been observed in the epoxida-
tion using the Ti(salalen) or Ti(salan) complex as a catalyst.13-15
These results suggest that the resultant Nb peroxo species could
be further activated by hydrogen bond formation between the
oxygen atom of the peroxo species and the amine proton.29
However, the fact that water-treated 2 and 3 do not catalyze
the epoxidation of a simple olefin such as 1,2-dihydronaphtha-
lene suggests that the precoordination of allylic alcohol is
essential for this epoxidation. On the basis of these results, we
propose monomeric peroxo niobium species a with hepta-
coordination as a possible intermediate for the epoxidation
using the pretreated niobium-salan complex as a catalyst
(Scheme 2).
4. Experimental Section
4.1. General. 1H and 13C NMR spectra were recorded on a JEOL
JNM-AL400 spectrometer at 400 and 100 MHz, respectively. All
chemical shifts were recorded in δ relative to tetramethylsilane
(TMS). Melting points were measured with a Bu¨chi melting-point
B-545 apparatus and were uncorrected. Infrared spectra were
obtained via a KBr disk or a thin film using a KBr plate on a
Shimadzu FTIR-8400 spectrophotometer, and only diagnostic
absorptions are listed below. Optical rotation was measured with a
Jasco P-1020 polarimeter. TOFMS(ESI+) spectra were obtained
from Bruker Daltonics micrOTOF-KS1focus spectrometer. Enan-
tiomeric excesses were determined by HPLC analysis using a
Shimadzu LC-10AT-VP equipped with a column packed with an
appropriate optically active material, as described below. TLC
analysis was performed on silica gel 60 F254-coated glass plates
(Merck). Visualization was accomplished via irradiation with 254
nm UV light or spraying a 12-molybdo(VI)phosphoric acid ethanol
solution as the developing agent. Water was deionized by using an
Advantec PWR-500.
4.2. Synthesis of Salan Ligands. According to our previous
report,30 salan ligands 1, 17-19, 20, and 22 were synthesized.
4.2.1. Ligand 18. Slightly yellow powder. IR (KBr): 3053, 3024,
2851, 1624, 1583, 1495, 1433, 1352, 1315, 1250, 1109, 1026, 862,
1
821, 748, 698 cm-1. H NMR (CDCl3): δ 10.9 (bs, 2H), 8.02 (d,
2H, J ) 8.3 Hz), 7.96 (d, 2H, J ) 8.1 Hz), 7.65 (d, 2H, J ) 8.5
Hz), 7.52 (d, 2H, J ) 7.6 Hz), 7.45-7.36 (m, 4H), 7.31-7.17 (m,
14H), 7.16-7.06 (m, 4H), 7.03-6.92 (m, 8H), 6.84-6.76 (m, 4H),
4.02-3.91 (m, 4H), 3.62 (d, 2H, J ) 13.7 Hz), 2.14 (bs, 2H). 13
C
3. Conclusions
NMR (CDCl3): δ 153.4, 141.9, 140.3, 137.3, 133.7, 132.9, 132.8,
131.6, 128.5, 128.3, 128.2, 128.1, 127.9, 127.8, 127.5, 127.2, 127.1,
126.2, 126.1, 125.8, 125.5, 124.6, 123.4, 122.7, 119.3, 65.3, 49.9.
Anal. Calcd for C68H52N2O2 + 1/2H2O: C, 87.06; H, 5.69; N, 2.99.
Found: C, 87.21; H, 5.65; N, 2.95. ESI+-TOFMS. Calcd for
[C68H52N2O2+Na]+: m/z ) 951.3921. Found: m/z ) 951.3925.
4.2.2. Ligand 19. Slightly yellow powder. IR (KBr): 3053, 3026,
2849, 1624, 1597, 1495, 1431, 1354, 1319, 1252, 1204, 1111, 1026,
We found a unique asymmetric catalysis of epoxidation of
allylic alcohols using hydrogen peroxide by niobium-salan
complexes. We first discovered that µ-oxo [Nb(salan)]2 complex
(27) (a) Puchot, C.; Samuel, O.; Dunach, E.; Zhao, S.; Agami, C.; Kagan,
H. B. J. Am. Chem. Soc. 1986, 108, 2353–2357. (b) Kagan, H. B.
AdV. Synth. Catal. 2001, 343, 227–233. (c) Kitamura, M.; Suga, S.;
Oka, H.; Noyori, R. J. Am. Chem. Soc. 1998, 120, 9800–9809.
(28) Bayot, D.; Devillers, M. Coord. Chem. ReV. 2006, 250, 2610–2626.
(29) (a) Somma, F.; Canton, P.; Strukul, G. J. Catal. 2005, 229, 490–498.
(b) Ruddy, D. A.; Tilley, T. D. J. Am. Chem. Soc. 2008, 130, 11088–
11096.
(30) (a) Egami, H.; Katsuki, T. J. Am. Chem. Soc. 2007, 129, 8940–8941.
(b) Tashiro, T.; Mori, K. Tetrahedron: Asymmetry 2005, 16, 1801–
1806.
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Asymmetric Epoxidation of Allylic Alcohols
A R T I C L E S
939, 862, 822, 748, 700 cm-1. 1H NMR (CDCl3): δ 10.31 (bs, 2H),
8.00 (d, 2H, J ) 8.3 Hz), 7.92 (d, 2H, J ) 8.1 Hz), 7.68-7.61 (m,
4H), 7.40 (t, 2H, J ) 6.9 Hz), 7.31-7.01 (m, 26H), 6.94 (t, 2H, J
) 7.3 Hz), 6.67 (d, 4H, J ) 6.6 Hz), 4.02 (d, 2H, J ) 13.5 Hz),
3.55 (d, 2H, J ) 13.5 Hz), 3.44 (s, 2H), 1.76 (bs, 2H). 13C NMR
(CDCl3): δ 153.0, 142.6, 139.5, 136.7, 134.5, 132.9, 132.8, 131.2,
128.9, 128.3, 128.0, 127.8, 127.7, 127.5, 127.4, 127.1, 126.6, 126.2,
126.1, 125.5, 125.0, 124.4, 122.7, 119.1,65.1, 49.9. Anal. Calcd
for C68H52N2O2: C, 87.90; H, 5.64; N, 3.01. Found: C, 87.62; H,
5.72; N, 2.95.
24.8, 24.1. ESI+-TOFMS. Calcd for [C72H112N4Nb2O7+H]+: m/z
) 1331.6731. Found: m/z ) 1331.6729.
4.3.4. Complex 6. Light-yellow crystals. IR (KBr): 3242, 3051,
2934, 2858, 1622, 1595, 1495, 1448, 1425, 1354, 1256, 1113, 955,
1
862, 746, 700 cm-1. H NMR (CDCl3): δ 7.80-7.73 (m, 4H),
7.66-7.48 (m, 10H), 7.43-7.05 (m, 20H), 7.03-6.68 (m, 24H),
6.60-6.49 (m, 6H), 4.96-4.91 (m, 2H), 4,81 (d, 2H, J ) 14.6
Hz), 4.13-4.05 (m, 2H), 3.91-3.81 (m, 2H), 3.64-3.56 (m, 2H),
2.53-2.41 (m, 2H), 1.86-1.09 (m, 8H), 1.04-0.89 (m, 2H),
0.55-0.28 (m, 6H), -0.10 to -0.23 (m, 2H), -0.30 to -0.44 (m,
2H). 13C NMR (CDCl3): δ 155.2, 154.0, 142.9, 141.5, 139.0, 136.9,
136.6, 134.7, 133.7, 133.1, 132.1, 132.0, 131.5, 129.3, 128.5, 128.2,
128.1, 127.7, 127.5, 127.3, 127.1, 126.9, 126.8, 126.3, 126.1, 126.0,
125.9, 125.8, 125.5, 125.2, 125.0, 123.2, 122.7, 122.1, 120.5, 59.8,
51.8, 48.9, 29.1, 27.5, 24.5, 24.1. ESI+-TOFMS. Calcd for
[C120H96N4Ta2O7+H]+: m/z ) 2068.6345. Found: m/z ) 2068.6352.
4.3.5. Complex 7. Light-yellow crystals. IR (KBr): 3248, 3051,
2932, 2858, 1620, 1595, 1489, 1448, 1421, 1352, 1254, 1111, 953,
4.2.3. Ligand 20. Yellow powder. IR (KBr): 3530, 3051, 2922,
2851, 1624, 1597, 1507, 1433, 1254, 1111, 1028, 941, 858, 764,
700 cm-1. 1H NMR (CDCl3): δ 7.99 (d, 2H, J ) 8.3 Hz), 7.90 (d,
2H, J ) 8.3 Hz), 7.68-7.60 (m, 4H), 7.51-6.77 (m, 38H), 4.48
(bs, 2H), 3.99 (d, 2H, J ) 13.8 Hz), 3.33 (d, 2H, J ) 13.8 Hz). 13
C
NMR (CDCl3): δ 153.0, 143.0, 139.4, 134.8, 134.3, 133.1, 133.0,
132.9, 131.7, 131.2, 129.2, 128.7, 128.4, 128.3, 128.0, 127.9, 127.8,
127.5, 127.3, 127.1, 126.7, 126.4, 126.2, 126.1, 125.5, 125.4, 125.3,
125.0, 124.4, 124.2, 123.0, 122.6, 118.8, 58.7, 49.7. ESI+-TOFMS.
Calcd for [C76H56N2O2+H]+: m/z ) 1029.4415. Found: m/z )
1029.4412.
1
816, 748 cm-1. H NMR (CDCl3): δ 7.77 (d, 2H, J ) 8.1 Hz),
7.71 (d, 2H, J ) 8.3 Hz), 7.66 (d, 2H, J ) 8.1 Hz), 7.60-7.52 (m,
6H), 7.47-7.00 (m, 48H), 6.98-6.92 (m, 4H), 6.91-6.84 (m, 4H),
6.80 (d, 4H, J ) 8.3 Hz), 6.72 (d, 4H, J ) 8.3 Hz), 6.58-6.50 (m,
4H), 4.93-4.78 (m, 4H), 4.16-4.06 (m, 2H), 3.85-3.73 (m, 2H),
3.57-3.50 (m, 2H), 2.44-2.31 (m, 2H), 1.74-1.64 (m, 2H),
1.42-1.30 (m, 2H), 1.20-1.06 (m, 4H), 0.69-0.24 (m, 8H), -0.30
to -0.54 (m, 4H). 13C NMR (CDCl3): δ 156.4, 154.4, 141.7, 140.4,
139.5, 139.2, 138.6, 138.3, 137.2, 136.6, 136.5, 134.8, 133.7, 133.2,
132.2, 132.1, 131.9, 131.7, 129.6, 129.1, 129.0, 128.9, 128.8, 128.7,
128.6, 128.5, 128.4, 128.3, 128.2, 127.7, 127.5, 127.3, 127.2, 127.1,
126.8, 126.7, 126.6, 126.5, 126.4, 126.2, 126.1, 125.8, 125.7, 125.6,
125.5, 124.7, 124.4, 123.2, 122.6, 121.1, 119.8, 59.7, 59.3, 52.1,
49.4, 29.0, 27.5, 24.4, 23.7. Anal. Calcd for C144H112N4Nb2O7: C,
78.75; H, 5.14; N, 2.55. Found: C, 78.64; H, 5.23; N, 2.52.
4.4. Asymmetric Epoxidation of Allylic Alcohols with Hydro-
gen Peroxide. 4.4.1. µ-Oxo-Nb(salan) 3-Catalyzed Epoxidation
of Allylic Alcohols. The µ-Oxo-Nb(salan) complex (3, 18.9 mg, 2
mol %) and allylic alcohol (0.5 mmol) were dissolved in toluene, and
the mixture was raised to 40 °C. Hydrogen peroxide in the form of a
urea adduct (194 mg, 4 equiv) was added all at once. After the mixture
was stirred for 24 h, it was diluted with brine and EtOAc. The organic
phase was separated and passed through anhydrous Na2SO4. The crude
mixture was purified with silica gel chromatography (hexane/EtOAc
) 9/1). The ee value was determined by HPLC analysis on a chiral
stationary phase column. When it was necessary to convert to the
corresponding benzoate, triethylamine (1.2 equiv) and benzoyl chloride
(1.2 equiv) were added to the CH2Cl2 solution of epoxy alcohol and
the mixture was stirred for 1 h, followed by purification with silica
gel chromatography (pentane/Et2O ) 19/1).
4.3. Synthesis of µ-Oxo-Nb(salan) Complexes. 4.3.1. Complex
3. To the CH2Cl2 solution of salan ligand 1 (450 mg, 0.54 mmol)
was added Nb(OiPr)5 (210 mg, 0.54 mmol) under a nitrogen
atmosphere, and the solution immediately changed to a light-yellow
color. After the mixture was stirred for 1 h, it was exposed to air.
The composition was monitored by 1H NMR analysis. When
monomer complex 2 was completely converted, the solvent was
removed and 3 was purified with silica gel chromatography
(CH2Cl2/MeOH ) 100/1) to give 362.2 mg or a 72% yield. Light-
yellow crystals. IR (KBr): 3250, 3051, 2932, 2860, 1622, 1595,
1495, 1448, 1423, 1354, 1256, 1113, 953, 883, 748, 698, 663 cm-1
.
1H NMR (CDCl3): δ 7.78 (d, 2H, J ) 8.5 Hz), 7.74 (d, 2H, J )
8.3 Hz), 7.61 (t, 4H, J ) 8.4 Hz), 7.58-7.48 (m, 6H), 7.45-7.05
(m, 20H), 6.99 (d, 2H, J ) 8.5 Hz), 6.94-6.83 (m, 10H), 6.82-6.71
(m, 10H), 6.67-6.61 (m, 2H), 6.58-6.50 (m, 6H), 5.00-4.93 (m,
2H), 4.76 (d, 2H, J ) 14.6 Hz), 4.09-4.01 (m, 2H), 3.83-3.72
(m, 2H), 3.56 (d, 2H, J ) 10.7 Hz), 2.52-2.40 (m, 2H), 1.73-0.93
(m, 10H), 0.45-0.25 (m, 6H), -0.12- -0.26 (m, 2H), -0.30 to
-0.46 (m, 2H). 13C NMR (CDCl3): δ 156.1, 154.2, 142.7, 141.3,
138.8, 136.8, 136.3, 134.4, 133.5, 133.0, 132.0, 131.9, 131.8, 131.4,
129.1, 128.4, 127.9, 127.5, 127.3, 127.1, 126.9, 126.5, 126.2, 125.9,
125.7, 125.4, 125.3, 124.5, 122.9, 122.4, 120.6, 119.5, 59.4, 59.3,
51.9, 48.8, 28.7, 27.4, 24.2, 23.8. Anal. Calcd for C120H96N4Nb2O7
+ H2O: C, 75.46; H, 5.17; N, 2.93. Found: C, 75.41; H, 5.24; N,
2.89%. ESI+-TOFMS. Calcd for [C120H96N4Nb2O7+H]+: m/z )
1892.5512. Found: m/z ) 1892.5524.
4.3.2. Complex 4. Light-yellow crystals. IR (KBr): 2949, 2864,
1
4.4.2. In Situ Method for the Nb(salan)-Catalyzed
Asymmetric Epoxidation of Allylic Alcohols. To a CHCl3 solution
(1 mL) of salan ligand (5 mol %) was added Nb(OiPr)5 (4 mol %) at
room temperature. After stirring for 1 h, substrate (0.5 mmol) and brine
(0.5 mL) were added to the mixture. After the reaction mixture was
stirred for 30 min at 40 °C, 30% aqueous hydrogen peroxide (1.5 equiv)
was dropped into the mixture every 2 h in seven batches. After being
stirred for 24 h at 40 °C, the mixture was diluted with ethyl acetate
and brine and the two phases were separated. The organic phase was
passed through anhydrous Na2SO4 and evaporated. The residue was
analyzed via chromatography on basic silica gel (pentane/Et2O ) 3/2)
to give the product. The ee value was determined by HPLC analysis
on a chiral stationary phase column. When it was necessary to convert
to the corresponding benzoate, triethylamine (1.2 equiv) and benzoyl
chloride (1.2 equiv) were added to the CH2Cl2 solution of epoxy
alcohol and the mixture was stirred for 1 h, followed by purification
with silica gel chromatography (pentane/Et2O ) 19/1).
1593, 1445, 1423, 1352, 1252, 1113, 881, 698 cm-1. H NMR
(CDCl3): δ 18.06-7.97 (m, 2H), 7.85-7.76 (m, 2H), 7.74-6.30
(m, 56H), 5.96-5.85 (m, 4H), 4.92-4.80 (m, 2H), 4.55-4.36 (m,
4H), 3.78-3.66 (m, 2H), 2.64-2.47 (m, 4H), 2.26-2.14 (m, 2H),
1.95-1.75 (m, 4H) 1.40-0.76 (m, 14H). 13C NMR (CDCl3): δ
155.9, 155.6, 141.8, 140.9, 140.8, 140.4, 134.7, 133.2, 133.1, 133.0,
132.9, 132.8, 131.9, 128.8, 128.5, 128.2, 128.1, 127.7, 127.5, 127.4,
127.0, 126.9, 126.7, 126.5, 125.8, 125.7, 125.6, 125.5, 125.3, 125.2,
125.1, 125.0, 124.8, 124.1, 122.9, 122.7, 122.3, 121.7, 120.6, 61.7,
60.9, 52.4, 51.5, 32.2, 28.1, 25.0, 24.8. ESI+-TOFMS. Calcd for
[C120H96N4Nb2O7 + K]+: m/z ) 1930.5071. Found: m/z )
1930.5074.
4.3.3. Complex 5. Slightly yellow crystals. IR (KBr): 2953,
2866, 1474, 1442, 1242, 1165, 1128, 881, 843, 708, 544 cm-1. 1H
NMR (CDCl3): δ 7.32-7.24 (m, 2H), 7.20-7.16 (m, 2H),
6.89-6.84 (m, 2H), 6.71-6.66 (m, 2H), 4.87 (d, 2H, J ) 14.3),
4.11 (d, 2H, J ) 14.3), 3.96-3.85 (m, 2H), 3.51 (d, 2H, J ) 12.0),
3.33-3.20 (m, 2H), 2.42-2.12 (m, 6H), 1.85-0.88 (m, 86H),
0.80-0.64 (m, 2H). 13C NMR (CDCl3): δ 156.8, 155.8, 141.6,
140.0, 136.7, 136.5, 124.4, 124.2, 123.5, 123.1, 121.2, 60.0, 59.8,
52.0, 49.0, 35.4, 35.1, 34.3, 34.2, 31.8, 31.7, 31.1, 30.7, 30.0, 28.2,
4.4.2.1. (2S,3S)-3,7-Dimethyl-2,3-epoxy-6-octenol (10a, Table
5, Entry 7). Colorless oil. 69.6 mg, 82% yield. 84% ee. [R]24D -4.8
(c 2.90, CHCl3), [lit. (2S,3S)-isomer (91% ee); [R]25D -5.3 (c 3.0,
CHCl3)].3b IR (neat): 3412, 2966, 2924, 2856, 1643, 1448, 1383,
9
J. AM. CHEM. SOC. VOL. 132, NO. 16, 2010 5893

A R T I C L E S
Egami et al.
1
1223, 1033, 864 cm-1. H NMR (CDCl3): δ 5.12-5.05 (m, 1H),
3.88-3.79 (m, 1H), 3.73-3.65 (m, 1H), 2.97 (dd, 1H, J ) 4.4, 6.8
Hz), 2.13-2.03 (m, 2H), 1.75-1.59 (m, 7H), 1.52-1.43 (m, 1H),
1.30 (s, 3H). 13C NMR (CDCl3): δ 132.0, 123.2, 62.9, 61.5, 61.2,
38.6, 25.8, 23.8, 17.8, 16.9. Anal. Calcd for C10H18O2: C, 70.55;
H, 10.66. Found: C, 70.38; H, 10.59%.
1H, J ) 2.4, 6.8), 1.90-1.60 (m, 6H), 1.33-1.03 (m, 6H). 13C
NMR (CDCl3): δ 61.9, 60.2, 57.3, 39.6, 29.7, 29.0, 26.3, 25.8, 25.6.
Anal. Calcd for C9H16O2: C, 69.19; H, 10.32. Found: C, 68.91; H,
10.28.
4.4.2.8. (2S,3S)-4,4-Dimethyl-2,3-epoxypentanol (12e, Table 5,
Entry 4). Colorless oil. 34.1 mg, 52% yield. 95% ee. [R]24D -20.4
(c 1.33, CHCl3), [lit. (2S,3S)-isomer (95% ee); [R]20D -20.1 (c 1.3,
CHCl3)].34 IR (neat): 3414, 2959, 2870, 1483, 1466, 1366, 1086,
1040, 899 cm-1. 1H NMR (CDCl3): δ 3.91 (ddd, 1H, J ) 2.4, 5.4,
12.5 Hz), 3.65-3.57 (m, 1H), 3.06-3.02 (m, 1H), 2.76 (d, 1H, J
) 2.4 Hz), 1.78-1.71 (m, 1H), 0.94 (s, 9H). 13C NMR (CDCl3): δ
63.6, 62.1, 55.4, 30.6, 25.9. ESI+-TOFMS. Calcd for [C7H14O2+Na]+:
m/z ) 153.0886. Found: m/z ) 153.0885.
4.4.2.2. (2S,3R)-3,7-Dimethyl-2,3-epoxy-6-octenol (10b, Table
5, Entry 8). Colorless oil. 64.5 mg, 76% yield. 83% ee. [R]23D -18.8
(c 1.52, CHCl3), [lit. (2R, 3S)-isomer (99% ee); [R]28 +13.3 (c
D
1.09, CHCl3)].30 IR (neat): 3414, 2966, 2924, 2862, 1641, 1448,
1
1381, 1033, 866 cm-1. H NMR (CDCl3): δ 5.14-5.06 (m, 1H),
3.88-3.78 (m, 1H), 3.72-3.62 (m, 1H), 2.97 (dd, 1H, J ) 4.4, 6.8
Hz), 2.20-2.04 (m, 2H), 1.75-1.60 (m, 7H), 1.54-1.43 (m, 1H),
1.35 (s, 3H). 13C NMR (CDCl3): δ 132.2,123.0, 64.0, 61.4, 61.1,
33.0, 25.6, 24.1, 22.1, 17.6. ESI+-TOFMS. Calcd for [C10H18O2 +
Na]+: m/z ) 193.1199. Found: m/z ) 193.1194.
4.4.2.9. (2S,3S)-2,3-Epoxy-3-phenylpropanol (12f, Table 5,
Entry 5). White solid. 45.7 mg, 61% yield. 74% ee. [R]25D -38.5
(c 1.05, CHCl3), [lit. (2S,3S)-isomer (>98% ee); [R]25 -49.6 (c
D
2.4, CHCl3)].3b mp 42.7-43.0 °C. IR (KBr): 3381, 3030, 2988,
2924, 2868, 1605, 1497, 1462, 1312, 1290, 1231, 1200, 1070, 1024,
880, 768, 698 cm-1. 1H NMR (CDCl3): δ 7.40-7.23 (m, 5H), 4.05
(ddd,1H, J ) 2.2, 5.4, 12.7 Hz), 3.92 (d, 1H, J ) 2.2 Hz), 3.80
(ddd, 1H, J ) 3.9, 7.6, 12.7 Hz), 3.23 (ddd, 1H, J ) 2.2, 2.2, 3.9
Hz), 2.14-2.07 (m, 1H). 13C NMR (CDCl3): δ 136.4, 128.4, 128.2,
125.6, 62.5, 61.2, 55.6. Anal. Calcd for C9H10O2: C, 71.98; H, 6.71.
Found: C, 72.01; H, 6.74.
4.4.2.3. (2S,3S)-2,3-Epoxy-3,7,11-trimethyl-6,10-dodecadienol (10c,
Table 2, Entry 2). Colorless oil. 85.5 mg, 72% yield. 80% ee. [R]24
D
- 5.7 (c 1.083 CHCl3), [lit. (2R, 3R)-isomer (96% ee); [R]26D +6.53
(c 4.21, CHCl3)].31 IR (neat): 3416, 2964, 2922, 2856, 1663, 1448,
1383, 1223, 1105, 1074, 1034, 864 cm-1. H NMR (CDCl3): δ
1
5.14-5.05 (m, 2H), 3.88-3.78 (m, 1H), 3.73-3.64 (m 1H), 2.98
(dd, 1H, J ) 4.3, 6.7 Hz), 2.14-2.02 (m, 4H), 2.01-1.95 (m, 2H),
1.80 (br, 1H), 1.74-1.57 (m, 10H), 1.52-1.43 (m, 1H), 1.31 (s,
3H). 13C NMR (CDCl3): δ 135.6, 131.3, 124.0, 123.0, 62.9, 61.5,
61.2, 39.7, 38.6, 26.7, 25.8, 23.7, 17.8, 16.9, 16.1. Anal. Calcd for
C15H26O2: C, 75.58; H, 10.99. Found: C, 75.40; H, 11.00.
4.4.2.10. (2S,3R)-2,3-Epoxyhexanol (14, Table 5, Entry 6).
Colorless oil. 30.0 mg, 52% yield. 85% ee. [R]26 -5.4 (c 1.23,
D
CHCl3), [lit. (2S,3R)-isomer (63% ee); [R]D -2.3 (c 1.000,
CHCl3)].7a IR (neat): 3412, 2961, 2934, 2872, 1464, 1381, 1042,
914, 858, 829, 768 cm-1. 1H NMR (CDCl3): δ 3.92-3.82 (m, 1H),
3.73-3.62 (m, 1H), 3.20-3.13 (m, 1H), 3.09-3.01 (m, 1H),
2.14-2.02 (m, 1H), 1.62-1.41 (m, 4H), 1.02-0.95 (m, 3H). 13C
NMR (CDCl3): δ 61.0, 57.2, 56.9, 30.0, 20.1, 14.0. ESI+-TOFMS.
Calcd for [C6H12O2+Na]+: m/z ) 139,0730. Found: m/z )
139.0734.
4.4.2.4. (2S,3S)-2,3-Epoxy-5-phenylpentanol (12a, Table 4,
Entry 11). Colorless oil. 72.1 mg, 81% yield. 92% ee. [R]24D -45.4
(c 1.82, CHCl3), [lit. (2R,3R)-isomer (97% ee); [R]25 +42.6 (c
D
2.41, CHCl3)].32 IR (neat): 3416, 3024, 2926, 2860, 1495, 1452,
1090,1028, 880, 750, 700 cm-1. H NMR (CDCl3): δ 7.35-7.15
1
(m, 5H), 3.84 (ddd, 1H, J ) 2.7, 5.4, 12.7 Hz), 3.61-3.53 (m,
1H), 2.99 (ddd, 1H, J ) 2.2, 5.9, 5.9 Hz), 2.89-2.69 (m, 3H),
1.98-1.82 (m, 2H). 13C NMR (CDCl3): δ 140.9, 128.3, 128.2,
126.0, 61.6, 58.6, 55.4, 33.4, 32.3. Anal. Calcd for C11H14O2: C,
74.13; H, 7.92. Found: C, 73.94; H, 7.86.
4.4.2.11. (2R,3R)-2,3-Epoxy-2-methyl-3-phenylpropanol (16a,
Table 5, Entry 9). Colorless solid. 25.8 mg, 40% yield. 83% ee.
[R]25D +14.3 (c 1.00, CHCl3), [lit. (2S,3S)-isomer (>98% ee), [R]D
-16.9 (c 2.00, CHCl3)].3b mp 50.9-51.0 °C. IR (KBr): 3420, 3061,
2995, 2970, 2930, 2864, 1497, 1450, 1383, 1234, 1094, 1069, 851,
4.4.2.5. (2S,3S)-2,3-Epoxyhexanol (12b, Table 5, Entry 1).
Colorless oil. 33.3 mg, 57% yield. 91% ee. [R]22 -47.4 (c 0.66,
D
1
741, 698 cm-1. H NMR (CDCl3): δ 7.41-7.25 (m, 5H), 4.22 (s,
CHCl3), [lit. (2S,3S)-isomer (94% ee); [R]25 -46.3 (c 3.87,
D
CHCl3)].3b IR (neat): 3416, 2961, 2932, 2872, 1464, 1410, 1101,
1H), 3.86 (dd, 1H, J ) 2.9, 12.2 Hz), 3.76 (dd, 1H, J ) 8.4, 12.2
Hz), 1.99 (br, 1H), 1.09 (s, 3H). 13C NMR (CDCl3): δ 135.4, 128.0,
127.4, 126.2, 64.9, 63.7, 60.1, 13.6. Anal. Calcd for C10H12O2: C,
73.15; H, 7.37. Found: C, 72.98; H, 7.30.
1067, 1045, 899, 854 cm-1. H NMR (CDCl3): δ 3.99-3.85 (m,
1
1H), 3.70-3.57 (m, 1H), 3.04-2.88 (m, 2H), 1.94-1.83 (m, 1H),
1.62-1.39 (m, 4H), 0.97 (t, 3H, J ) 7.3 Hz). 13C NMR (CDCl3):
δ 61.7, 58.4, 55.9, 33.7, 19.4, 14.0. ESI+-TOFMS. Calcd for
[C6H12O2 + Na]+: m/z ) 139.0730. Found: m/z ) 139.0733.
4.4.2.6. (2S,3S)-2,3-Epoxyoctanol (12c, Table 5, Entry 2).
Colorless solid. 56.4 mg, 79% yield. 93% ee. [R]22D -41.9 (c 0.94,
4.4.2.12. (2R)-2,3-Epoxy-2-phenylpropanol (16b, Table 5, Entry
10). Colorless oil. 32.2 mg, 43% yield. 85% ee. [R]24 +16.9 (c
D
1.30, EtOH), [lit. (S)-isomer (98% ee); [R]25 -15.8 (c 2.53
D
EtOH)].35 IR (neat): 3412, 3059, 2922, 1496, 1448, 1385, 1088,
1
1043, 1024, 760, 700 cm-1. H NMR (CDCl3): δ 7.42-7.29 (m,
CHCl3), [lit. (2S,3S)-isomer (99% ee); [R]20 -40.4 (c 1.08,
D
CHCl3)].33 mp 37.2-37.4 °C. IR (KBr): 3280, 3132, 2954, 2928,
2853, 1460, 1375, 1080, 1038, 1007, 989, 878, 714 cm-1. 1H NMR
(CDCl3): δ 3.96-3.88 (m, 1H), 3.68-3.59 (m, 1H), 2.99-2.90 (m,
2H), 1.79 (br, 1H), 1.71-1.24 (m, 8H), 0.95-0.84 (m, 3H). 13C
NMR (CDCl3): δ 61.7, 58.5, 56.1, 31.7, 31.6, 25.7, 22.7, 14.1. Anal.
Calcd for C8H16O2: C, 66.63; H, 11.18. Found: C, 66.70; H, 11.04.
5H), 4.11 (dd, 1H, J ) 2.9, 12.7 Hz), 4.02 (dd, 1H, J ) 8.9, 12.7
Hz), 3.28 (d, 1H, J ) 5.1 Hz), 2.83 (d, 1H, J ) 5.1 Hz) 1.86 (br,
1H). 13C NMR (CDCl3): δ 137.2, 128.4, 128.0, 125.8, 63.1, 60.4,
52. 5. ESI+-TOFMS. Calcd for [C9H10O2+Na]+: m/z ) 173.0573.
Found: m/z ) 173.0577.
4.4.2.13. (+)-2,3-Epoxy-2-methyl-5-phenylpentanol (16c, Table
5, Entry 11). Colorless oil. 61.6 mg, 64% yield. 90% ee. [R]23D +29.7
(c 1.25, CHCl3). IR (neat): 3416, 3024, 2997, 2926, 2858, 1603, 1495,
4.4.2.7. (2S,3S)-3-Cyclohexyl-2,3-epoxypropanol (12d, Table
5, Entry 3). Colorless oil. 64.4 mg, 82% yield. 93% ee. [R]24D -31.3
(c 1.20, CHCl3), [lit. (2S,3S)-isomer (92% ee); [R]25D -23.9 (c 7.2,
CHCl3)].34 IR (neat): 3414, 2926, 2853, 1448, 1069, 1047,1018,
974, 881, 864, 756 cm-1. 1H NMR (CDCl3): δ 3.96-3.87 (m, 1H),
3.66-3.56 (m, 1H), 2.98 (ddd, 1H, J ) 2.4, 2.4, 4.6 Hz), 2.76 (dd,
1
1452, 1385, 1072, 1040, 866, 750, 700 cm-1. H NMR (CDCl3): δ
7.34-7.26 (m, 2H), 7.25-7.17 (m, 3H), 3.63 (dd, 1H, J ) 3.7, 12.2
Hz), 3.51 (dd, 1H, J ) 8.3, 12.2 Hz), 3.09 (dd, 1H, J ) 6.3, 6.3 Hz),
2.91-2.81 (m, 1H), 2.77-2.67 (m, 1H), 2.02-1.92 (m, 1H), 1.89-1.76
(m, 2H), 1.12 (s, 3H). 13C NMR (CDCl3): δ 140.9, 128.3, 126.0, 65.3,
61.2, 59.6, 32.8, 30.1, 14.2. Anal. Calcd for C12H16O2: C, 74.97; H,
8.39. Found: C, 74.68; H, 8.39.
(31) Kigoshi, H.; Ojika, M.; Shizuri, Y.; Niwa, H.; Yamada, K. Tetrahedron
Lett. 1982, 23, 5413–5414.
4.4.2.14. (2R)-2,3-Epoxy-2-benzylpropanol (16d, Table 5,
Entry 12). Colorless oil. 42.6 mg, 52% yield. 90% ee. [R]23D +36.1
(c 1.03, CH2Cl2), [lit. (S)-isomer (>98% ee); [R]D -39 (c 2.5,
(32) Matsunaga, S.; Kinoshita, T.; Okada, S.; Harada, S.; Shibasaki, M.
J. Am. Chem. Soc. 2004, 126, 7559–7570.
(33) Wang, H.; Kozekov, I. D.; Harris, T. M.; Rizzo, C. J. J. Am. Chem.
Soc. 2003, 125, 5687–5700.
(34) Li, X.; Borhan, B. J. Am. Chem. Soc. 2008, 130, 16126–16127.
(35) Chen, S.-T.; Fang, J.-M. J. Org. Chem. 1997, 62, 4349–4357.
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5894 J. AM. CHEM. SOC. VOL. 132, NO. 16, 2010

Asymmetric Epoxidation of Allylic Alcohols
A R T I C L E S
CH2Cl2)].36 IR (neat): 3422, 3028, 2922, 2871, 1603, 1495, 1454,
were separated. The organic phase was passed through anhydrous
Na2SO4 and evaporated. The residue was analyzed via chromatog-
raphy on basic silica gel (pentane/Et2O ) 3/2) to give the product.
The ee value was determined by HPLC analysis on a chiral
stationary phase column (Daicel Chiralpak OD-H; hexane/i-PrOH
) 95/5).
1
1400, 1051, 972, 912, 876, 804, 758, 702, 605 cm-1. H NMR
(CDCl3): δ 7.32-7.28 (m, 2H), 7.26-7.21 (m, 3H), 3.76-3.71 (dd,
1H, J ) 4.7, 12.4 Hz), 3.61-3.56 (dd, 1H, J ) 8.0, 12.4 Hz),
3.09-3.06 (d, 1H J ) 14.4 Hz), 2.89-2.87 (d, 1H, J ) 4.4 Hz),
2.89-2.85 (d, 1H, J ) 14.4 Hz), 2.67-2.66 (d, 1H, J ) 4.4 Hz),
1.87-1.84 (dd, 1H, J ) 8.0, 4.7). 13C NMR (CDCl3): δ 136.0,
129.5, 128.5, 126.8, 62.7, 60.0, 49.6, 38.2. ESI+-TOFMS. Calcd
for [C10H12O2+Na]+: m/z ) 187.0730. Found: m/z ) 187.0732.
4.5. Study of the Correlation between the ee Value of
Ligand 1 and the ee Value of Ligand 12a. Ligands 1 and ent-1
were mixed in certain ratios, and the ee’s of the mixtures were
determined by HPLC analysis on a chiral stationary phase column
(Daicel Chiralpak AD-H; hexane/i-PrOH ) 90/10).
To the toluene solution (1 mL) of each mixed ligand (5 mol %)
was added Nb(OiPr)5 (4 mol %) at room temperature. After the
mixture was stirred for 1 h, 11a (0.5 mmol) and brine (0.5 mL)
were added. After the mixture was stirred for 30 min at 40 °C,
aqueous hydrogen peroxide (1.5 equiv) was added dropwise every
2 h in seven batches. After the mixture was stirred for 24 h at 40
°C, it was diluted with ethyl acetate and brine and the two phases
These results were plotted as shown in Figure 3.
Acknowledgment. Financial support from Specially Promoted
Research 18002011 and the Global COE Program “Science for
Future Molecular Systems” from the Ministry of Education, Science,
and Culture, Japan is gratefully acknowledged. Prof. K. Sakai and
Dr. S. Masaoka, Department of Chemistry, Kyushu University, are
acknowledged for X-ray analysis. H.E. is grateful to the Research
Fellowships of the Japan Society for the Promotion of Science for
Young Scientists.
Supporting Information Available: X-ray crystallographic
data files in CIF format for complex 7 and HPLC conditions
and NMR spectral data for benzoated epoxy alcohols. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(36) Ferraboschi, P.; Brembilla, D.; Grisenti, P.; Santaniello, E. J. Org.
Chem. 1991, 56, 5478–5480.
JA100795K
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