Nucleophilic asymmetric epoxidation catalyzed by cyclic guanidines

Article abstract of DOI:10.3987/COM-07-S(U)49

Asymmetric nucleophilic epoxidation of chalcone and its derivatives was studied using chiral cyclic guanidine compounds. Pentacyclic guanidine 1a, which has a characteristic closed-type cavity, catalyzed the reaction to give epoxides with 39-60% ee.The newly developed tricyclic guanidine 4 drastically accelerated the reaction, and induced the asymmetric induction of chalcones with almost the same level of 1a.

Full text of DOI:10.3987/COM-07-S(U)49

HETEROCYCLES, Vol. 73, 2007
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HETEROCYCLES, Vol. 73, 2007, pp. 241 - 247. © The Japan Institute of Heterocyclic Chemistry
Received, 3rd July, 2007, Accepted, 1st October, 2007, Published online, 2nd October, 2007. COM-07-S(U)49
NUCLEOPHILIC ASYMMETRIC EPOXIDATION CATALYZED BY
CYCLIC GUANIDINES†
Tetsuya Kita,2 Bongki Shin,1 Yuichi Hashimoto,2 and Kazuo Nagasawa1*
1Department of Biotechnology and Life Science, Tokyo University of Agriculture
and Technology, Koganei, Tokyo 184-8588, Japan. knaga@cc.tuat.ac.jp
2Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi,
Bunkyo-ku, Tokyo 113-0032, Japan.
Abstract – Asymmetric nucleophilic epoxidation of chalcone and its derivatives
was studied using chiral cyclic guanidine compounds. Pentacyclic guanidine 1a,
which has a characteristic closed-type cavity, catalyzed the reaction to give
epoxides with 39-60% ee. The newly developed tricyclic guanidine 4
drastically accelerated the reaction, and induced the asymmetric induction of
chalcones with almost the same level of 1a.
Development of novel efficient catalysts for asymmetric reactions is one of the important and challenging
topics in synthetic organic chemistry. Phase-transfer catalysts (PTCs) are particularly attractive since
they have some advantages over homogeneous catalysts, and many efficient asymmetric PTCs have been
explored.1 In the course of our studies aimed at the development of PTCs, we have reported the
pentacyclic guanidine catalyst 1 (Figure 1).2 The structures of 1 were rationally designed to have a
C2-symmetrical chiral reaction cavity around the guanidine group; i.e., a substrate recognition/activation
site. One of these catalysts, 1a, which has a closed-type cavity and methyl substituents on its ether rings,
was found to induce the high enentioselectivity in the alkylation reaction of the Schiff base imine.2b In
this communication, we describe the asymmetric nucleophilic epoxidation to α,β-unsaturated ketones
catalyzed by 1 and newly synthesized tricyclic guanidine 4.
Among asymmetric epoxidation, catalytic asymmetric epoxidation of electron-deficient olefins is one of

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HETEROCYCLES, Vol. 73, 2007
the most important classes of reactions.3,4 Recently, asymmetric nucleophilic epoxidation reaction in the
presence of chiral guanidine catalysts has been reported by Taylor et al.,5 Murphy et al.,6 and Ishikawa et
al.7 We first examined our pentacyclic guanidine compounds 1a and 1b as catalyst for the epoxidation
reaction to the electron deficient alkenes.
MeO
H
OMe
H
MeO
H
OMe
H
N
N
N
N
N
N
O
O
O
O
H
H
H
H
Me
Me
1a
Me
Me
Cl
Cl
1b
Figure 1. Structures of chiral pentacyclic guanidine 1a and 1b, and their X-ray.
Nucleophilic epoxidation reaction of trans-chalcone (2a) using tert-butyl hydroperoxide (TBHP) (5
equivalents) in the presence of 1a and/or 1b (10 mol%) was examined in an aqueous 1M KOH/
dichloromethane biphasic solution conditions (Table 1). In the case of the reaction with 1a at room
temperature, 3a was obtained in 76% yield and 22% ee (entry 2). Lowering the temperature at 0 °C
improved the enantioselectivity up to 39% ee (entry 3). When toluene was used instead of
dichloromethane, no enantioselectiviy was observed (entry 4). In the case of the catalysts 1b, which has
an open-type cavity, 3a was obtained in 95%, although enantiomeric excess was only 10% (entry 5).
O
O
1 (10 mol%)
O
Ph
Ph
Ph
Ph
TBHP
CH2Cl2-KOH aq
2a
1
3a
ee%a
entry
temp (°C) time (h) yield (%)
1
2
3
4
5
---
1a
1a
1a
1b
rt
rt
0
0
0
26
26
10
76
35
55
95
---
22
39
4b
10
110
40
130
aEnantiomeric excess of 3a was determined by HPLC analysis
(DAICEL Chiralcel OD-H). Absolute configuration was determined
by comparison of the HPLC retention time and [α]D value with
reported authentic sample data.ref 8 bToluene was used instead of
dichloromethane.
Table 1. Nucleophilic epoxidation of 2a in the presence of chiral pentacyclic guanidine 1.

HETEROCYCLES, Vol. 73, 2007
243
These results are interpreted as follows based upon the alkylation reaction of Schiff base imine in the
presence of 1 (Figure 2).2b Carbonyl group in chalcone (2a) coordinates with guanidine in 1 through
hydrogen bonding, and a nucleophilic attack of the oxidant (TBHP) takes place from the less hindered
side to give (2S,3R)-3a as the major product. The structure of 1a, which has a closed-type cavity and
methyl substituents on the ether rings, effectively controlled the nucleophile approach. On the other
hand, control of the nucleophile approach was not sufficient by the structure of 1b, which has open-type
cavity, although it was effective for the acceleration of the reaction.
Me
Me
O
1a
O
Me
O
O
N
O
N
H
O
3R
N
Ph
Ph
H
2S
O
3a
Ph
ROO
Ph
2a
Me
Figure 2. Epoxidation mechanism of 2a in the presence of pentacyclic guanidine catalysts 1a.
Epoxidation reaction of the chalcone derivatives 2b-f was examined in the presence of catalyst 1a (Table
2). The 2-naphthyl and 1-naphthyl substituted derivatives 2b and 2c gave 3b and 3c in 50% and 60% ee,
respectively (entries 1 and 2).8,9 On the other hand, the enantiomeric excess was 35% in case of
anthracenyl derivative 2d (entry 3).10
1a (10 mol%)
O
O
O
TBHP
R
Ph
R
Ph
CH2Cl2-KOH aq
0 °C
3
2
time (h) yield (%)
ee%a
entry
2
R
product
2-naphthyl
140
140
140
130
160
51
77
50
60
35
38
36
1
2
3
4
5
2b
2c
2d
2e
2f
3b
3c
3d
3e
1-naphthyl
9-anthracenyl
4-nitorophenyl
>99
82
4-methoxyphenyl
22
3f
aEnantiomeric excess of 3 was determined by HPLC analysis.
Table 2. Nucleophilic epoxidation of 2 in the presence of chiral pentacyclic guanidine 1a.

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Reaction with 2e and 2f, which have similar molecular sizes as 2a, gave similar levels of asymmetric
induction as 2a.9
In all cases, the enantiomeric excesses of 3 were moderate, however, reaction times were long (130-160
h). To improve the catalytic activity of 1a, we designed the novel tricyclic guandine 4 (Figure 3). The
tricyclic guanidine 4 has an open-type cavity similar to 1b, and two benzyl groups overhang to the up
and/or down direction with respect to the tricyclic guanidine plane. The open-type cavity in 4 was
expected to improve the reactivity, and the two benzyl groups were anticipated to control the nucleophile
approach. The π-π interaction of phenyl groups between 4 and 2 was also expected to fix the reactive
complex conformation of 4 and 2.
H
OTIPS
H
TIPSO
H
H
H
N
N
N
4
H
N
H
1a
N
N
O
H
H
O
t-Bu
O
Cl
2
4
R
Figure 3. Design of novel tricyclic guanidine 4 and its prospective mechanism for epoxidation.
The chiral tricyclic guanidine 4 was synthesized based upon the 1,3-dipolar cycloaddition reaction
protocol (Scheme 1).11 Reaction of the optically active nitrone 512 with allylbenzene gave the
isoxazolidine 6 in 79% yield. The oxidation of the isoxazolidine 6 with m-CPBA effected regioselective
ring cleavage to give the nitrone 7. A second 1,3-dipolar cycloaddition reaction of 7 with allylbenzene
was conducted, and subsequent reduction of the N-O bond with NaBH4 in the presence of Mo(O)6 gave
the 2,5-disubstituted pyrrolidine 9 in 38% yield (3 steps).
After guanylation of 9 with
bis-Cbz-2-methyl-2-pseudourea in the presence of HgCl2, tricyclic guanidine was constructed under the
Mitunobu conditions followed by mesylation. Finally, Cbz group was deprotected with hydrogen over
10% Pd/C to give 4 in 30% yield (4 steps).
The epoxidation reaction of 2a-d was then examined in the presence of 4 (Table 3).13 In all cases, the
reaction was drastically accelerated to give 3a-d in quantitative yield, and the enantiomeric excesses were

HETEROCYCLES, Vol. 73, 2007
245
found to be 52, 52, 41 and 30% ee, respectively. Thus, the catalytic activity of 1a was improved by the
tricyclic guanidine 4 without losing the moderate enantioselection of 1a.
OTIPS
H
OTIPS
H
OTIPS
H
OTIPS
a
H
c
b
N
N
N
O
N
O
O
Ph
O
Ph
Ph
Ph
HO
HO
H
H
8
6
7
5
OTIPS
OTIPS
H
H
H
H
N
f-i
d
e
N
H
4
N
NH
OH
Ph
Ph
HO
Ph
Ph
OH HO
Cbz Cbz
9
10
Scheme 1. Synthesis of novel tricyclic guanidine 4. (a) Allylbenzene, toluene, 90°C, 79%; (b) m-CPBA,
CH2Cl2, 0°C; (c) Allylbenzene, toluene, 90°C, 60% (2 steps); (d) NaBH4, Mo(CO)6, CH3CN:H2O = 7:1,
64%; (e) bis-Cbz-2-methyl-2-pseudourea, HgCl2, NEt3, DMF, 69%; (f) DEAD, PPh3, toluene; (g) NaH,
MeOH, THF; (h) MsCl, NEt3, CH2Cl2; (i) Pd/C, H2, MeOH, 30% (4 steps).
4 (10 mol%)
O
O
O
TBHP
R
Ph
R
Ph
CH2Cl2-KOH aq
0 °C
3
2
time (h) yield (%)
ee%a
2
R
entry
product
phenyl
26
20
20
24
>99
>99
>99
>99
52
52
41
30
2a
2b
2c
2d
1
2
3
4
3a
3b
3c
2-naphtyl
1-naphtyl
anthracenyl
3d
aEnantiomeric excess of 3a was determined by HPLC analysis.
Table 3. Nucleophilic epoxidation of 2 in the presence of chiral tricyclic guanidine 4.
In summary, nucleophilic epoxidation reaction of chalcone and its derivatives was examined in the
presence of chiral cyclic guanidine catalysts 1 and 4. In case of the pentacyclic guanidine 1, closed-type
1a was effective for the asymmetric induction, and moderate enantiomeric excess of 3 was obtained.
The newly developed tricyclic guanidine 4 drastically accelerated the reaction, and induced the chirality
of epoxide 3 with almost the same level of 1a. Further improvements of the catalyst based upon the
structure of 4 are in progress.

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ACKNOWLEDGEMENTS
This research was supported in part by grants from Mitubishi Chemical Corporation, the Uehara
Memorial Foundation, and the Nagase Science and Technology Foundation.
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†We would like to dedicate this communication to Professor Ivar Ugi.
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13. Typical procedure for epoxidation of 2a in the presence of 4. A mixture of 2a (10 mg, 0.05 mmol)
and 4 (3 mg, 0.005 mmol) in dichloromethane (0.2 mL) and 1M KOH solution (0.25 mL) was cooled
at 0 °C. To the mixture was added TBHP (5M in decane, 0.05 mL, 0.25 mmol), and the resulting
mixture was stirred at 0 °C for 26 h. The reaction mixture was added H2O, and extracted with
dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 3a
(11 mg, 99%, 52% ee) .