Catalytic enantioselective epoxidation of unfunctionalized olefins: Utility of a Ti(Oi-Pr)4-salan-H2O2 system

Article abstract of DOI:10.1055/s-2006-956496

Salan ligands bearing an ortho-substituted phenyl group at C3 and C3′ were found to serve as an effective auxiliary of a Ti(Oi-Pr) ₄-salan-H₂O₂ system for enantioselective epoxidation. Simple olefins were converted into th

Full text of DOI:10.1055/s-2006-956496

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3545
Catalytic Enantioselective Epoxidation of Unfunctionalized Olefins:
Utility of a Ti(Oi-Pr)4–Salan–H2O2 System
C
atalytic Enantios
a
elective Ep
z
u
f
U
nfunction
h
alize
d
O
lefin
i
s
ro Matsumoto, Yuji Sawada, Tsutomu Katsuki*
Department of Chemistry, Faculty of Science, Graduate School, Kyushu University 33, Hakozaki, Higashi-ku, Fukuoka, 812-8581, Japan
Fax +81(92)6422607; E-mail: katsuscc@mbox.nc.kyushu-u.ac.jp
Received 4 September 2006
Abstract: Salan ligands bearing an ortho-substituted phenyl group
at C3 and C3¢ were found to serve as an effective auxiliary of a
Ti(Oi-Pr)4–salan–H2O2 system for enantioselective epoxidation.
Simple olefins were converted into the corresponding epoxides in
good to excellent enantioselectivity.
H
H
N
O
N
O
Ti
Key words: asymmetric catalysis, epoxidations, titanium, hydro-
gen peroxide, salan ligand
3
3'
O
Ph
Ph
2
1
Figure 1 Di-m-oxo titanium–salan complex (1)
Optically active epoxides exist in many natural products
and are of importance as versatile building blocks in or-
ganic synthesis. Asymmetric epoxidation of olefins is the
most direct and useful method for the preparation of chiral
epoxides and enormous numbers of epoxidation reactions
have been reported.1 However, the development of highly
enantioselective epoxidation of unfunctionalized olefins
using aqueous hydrogen peroxide as an oxidant is still a
challenging theme for synthetic chemists and significant
efforts have been devoted toward this area.2
resultant solution was used without isolation and purifica-
tion.5 The results are summarized in Table 1. Presence of
an ortho-substituted phenyl group at C3 and C3¢ achieved
increased effectiveness of salan ligands in both yield and
enantioselectivity. The enantioselectivity was not very af-
fected by the electronic nature of the substituent. Particu-
larly, salans 2b, 2g, 2k and 2l showed better results than
the prototype 2a, in terms of enantioselectivity and yield.
The reactions with the ligand such as 2e or 2n possessing
a sterically more hindered 3,3¢-aryl group, however, gave
very low yield (entries 5 and 14). The epoxidation of 1,2-
dihydronaphthalene with them also proceeded sluggishly
and decreased ee were obtained.6
Recently, we have found that a di-m-oxo titanium–salalen
complex is an effective catalyst for asymmetric epoxida-
tion of unfunctionalized olefins with aqueous hydrogen
peroxide.3 Although the complex induces good to excel-
lent enantioselectivity in epoxidation of various olefins,
its structure is rather complicated and it measures nearly
two thousands in molecular weight. Moreover, the
synthetic method including intramolecular Meerwein–
Ponndorf–Verley reduction as the key step was poorly
applicable to the preparation of related titanium–salalen
complexes. In order to overcome these problems, we
turned our attention to a di-m-oxo titanium–salan com-
plex, which could be prepared more easily than the corre-
sponding titanium–salalen complex. In the preliminary
study, complex 1 (Figure 1) bearing a phenyl group at C3
and C3¢ was found to show high enantioselectivity in ep-
oxidation of various olefins.4 However, high catalyst
loading was needed to achieve satisfying yields. Conse-
quently, we focused on the improvement of titanium–
salan-catalyzed epoxidation.
We chose salan 2b, with which the highest enantioselec-
tivity was observed, and salan 2g, with which good enan-
tioselectivity and the best yield were realized, as the test
ligands and investigated epoxidation of various olefins
using 5 mol% of Ti(Oi-Pr)4 and 6 mol% of a salan ligand
(Table 2).7 The epoxidation of cyclic olefins gave excel-
lent enantioselectivity (entries 3–6). Generally, the reac-
tions with salan 2g gave better yields than those with 2b.
However, when the epoxidation produced an acid-sensi-
tive epoxide such as indene oxide, 2,2-dimethyl-2H-
chromene oxide or 4-methyl-1,2-dihydronaphthalene ox-
ide, the reaction with 2g gave an inferior yield to that with
2b, due to a decomposition of the product (entries 3, 6,
and 8). Epoxidation of acyclic olefins also proceeded with
high enantioselectivity greater than 87% ee (entries 1, 2,
and 7). The reaction was stereospecific and no formation
of trans-epoxide was observed in the epoxidation of cis-
enyne (entry 7).
First, we examined catalytic activities of various titani-
um–salan complexes in epoxidation of styrene. Each com-
plex was prepared in situ from Ti(Oi-Pr)4 and a
corresponding salan ligand in dichloromethane and the
Although the detailed mechanism is unclear at the present,
we have proposed that a peroxo species, which is activat-
ed by hydrogen bonding between the amino proton and
the oxygen atom of the peroxo unit, is the active species
in the epoxidation using di-m-oxo titanium–salan complex
SYNLETT 2006, No. 20, pp 3545–3547
1
8
.1
2
.2
0
0
6
Advanced online publication: 08.12.2006
DOI: 10.1055/s-2006-956496; Art ID: Y01206ST
© Georg Thieme Verlag Stuttgart · New York

3546
K. Matsumoto et al.
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Table 1 Asymmetric Epoxidation of Styrene
Table 2 Asymmetric Epoxidation of Various Olefins
R2
30% H2O2 (1.1 equiv)
Ti(Oi-Pr)4 (5 mol%), ligand (6 mol%)
R2
O
*
O
30% H2O2 (1.1 equiv)
Ti(Oi-Pr)4 (4 mol%), 2 (5 mol%)
*
R1
R1
*
CH2Cl2, r.t., 9 h
CH2Cl2, r.t., 9 h
R3
R3
Entry
1
Ligand Olefin
Yield
ee
(%)
Configb
(R)
NH HN
(R)
(%)a
2b
2g
68
80
89c
87c
S
S
OH HO
Ar
Ar
2
2
2b
2g
82
83
90d
90d
S
S
Entry Ar
Yield (%)a ee (%)b
Configc
1
2
3
4
5
6
7
8d
9
Ph (2a)
o-MeOC6H4 (2b)
27
78
89
81
83
67
85
87
87
83
85
88
87
85
85
S
S
S
S
S
S
S
R
S
S
R
R
R
S
3e
4
2b
2g
86
77
98f
98f
1S,2R
1S,2R
62
39
28
5
2b
2g
89
93
98f
98f
1S,2R
1S,2R
m-MeOC6H4 (2c)
p-MeOC6H4 (2d)
2,6-di(MeO)C6H3 (2e)
o-MeC6H4 (2f)
5
2b
2g
66
78
97g
98g
5S,6R
5S,6R
52
71
48
49
55
56
65
36
11
6
7
2b
2g
75
44
>99f
>99f
3S,4S
3S,4S
o-CF3C6H4 (2g)
o-EtC6H4 (2h)
O
o-EtOC6H4 (2i)
o-BnOC6H4 (2j)
o-Biphenyl (2k)
1-Naphthyl (2l)
2-Naphthyl (2m)
9-Anthracenyl (2n)
2b
2g
84
92
94c
96c
2R,3S
2R,3S
10
11d
12d
13d
14
8e
2b
2g
81
71
96f
93f
1R,2S
1R,2S
a Determined by 1H NMR (400 MHz) spectroscopic analysis.
b Determined by comparison of the elution order with that of the au-
thentic sample in HPLC analysis.
a Determined by 1H NMR (400 MHz) spectroscopic analysis.
b Determined by HPLC analysis (CHIRALCEL OD-H).
c Determined by comparison of the elution order with that of the au-
thentic sample in HPLC analysis.
c Determined by HPLC analysis (CHIRALCEL OD-H).
d Determined by HPLC analysis (CHIRALCEL OJ-H).
e Reaction time was 6 h.
d (S,S)-Salan was used.
f Determined by HPLC analysis (CHIRALCEL OB-H).
g Determined by HPLC analysis (CHIRALPAK AS-H).
(1, Figure 2).4 The X-ray study of the complex 1 has re-
vealed that it has a cis-b structure,4 in which two phenyl
groups at C3 and C3¢ lie close to each other and the ligand
conformation is stabilized by a CH–p interaction between
the phenyl group and the benzene ring of the salan skele-
ton. The peroxo species is also expected to adopt a cis-b
configuration. With the ligand possessing an ortho-disub-
stituted phenyl group, the two groups should cause a steric
repulsion and the stabilization through the CH–p interac-
tion should be precluded; thus, introduction of an ortho-
disubstituted phenyl group should have a significant ef-
fect on a configuration of a peroxo species and adversely
affect the desired epoxidation. In contrast, an ortho-
monosubstituted phenyl group should not exert the
adverse effect but probably strengthen the asymmetric
atmosphere constructed by a salan ligand.
O
N
O
N
O
H
Ti
O
Figure 2 Proposed active species
more effective for asymmetric epoxidation of unfunction-
alized olefins than the Ti(Oi-Pr)4–3,3¢-phenylsalan (2a)–
H2O2 system. The salan ligands are readily available and
small in molecular size,4 and the asymmetry-inducing
ability of 2b or 2g in the epoxidation of conjugated olefins
is almost equal to that of the sophisticated salalen ligand.3
Thus, the present study demonstrates the high potentiality
of 3,3¢-(ortho-substituted phenyl)salan as the chiral auxil-
iary. Clarification of the precise role of the ortho-substit-
uents and applications of the system to other oxidation
reactions are in progress.
In conclusion, the Ti(Oi-Pr)4–3,3¢-(ortho-substituted
phenyl)salan (2b or 2g)–H2O2 system was found to be
Synlett 2006, No. 20, 3545–3547 © Thieme Stuttgart · New York

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Catalytic Enantioselective Epoxidation of Unfunctionalized Olefins
3547
(3) Matsumoto, K.; Sawada, Y.; Saito, B.; Sakai, K.; Katsuki, T.
Angew. Chem. Int. Ed. 2005, 44, 4935.
(4) Sawada, Y.; Matsumoto, K.; Kondo, S.; Watanabe, H.;
Ozawa, T.; Suzuki, K.; Saito, B.; Katsuki, T. Angew. Chem.
Int. Ed. 2006, 45, 3478.
Acknowledgment
Financial support from Specially Promoted Research 18002011 is
gratefully acknowledged. K.M. is grateful for the JSPS Research
Fellowships for Young Scientists.
(5) We have already reported that the in situ prepared titanium–
salan complex was equally efficient to the isolated di-m-oxo
titanium–salan complex (1, ref. 4).
References and Notes
(6) Compound 2e: 47%, 92% ee; compound 2n: 23%, 87% ee.
(7) General Experimental Procedure.
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added a CH2Cl2 solution of Ti(Oi-Pr)4 (5 mol%, 0.50 mL)
under nitrogen atmosphere and the resultant solution was
stirred at r.t. After 1 h, olefin (0.10 mmol)and subsequently
30% H2O2 (0.11 mmol) were added and the mixture was
stirred at r.t. for 9 h. The solvent was removed under reduced
pressure and the residue was purified by silica gel
chromatography to give an epoxide. An ee was determined
by HPLC analysis using a chiral stationary phase described
in the footnote to Table 2.
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Synlett 2006, No. 20, 3545–3547 © Thieme Stuttgart · New York