Synthesis of Chiral Polyethers Containing Imidazolidinone Repeating Units and Application as Catalyst in Asymmetric Diels-Alder Reaction

Article abstract of DOI:10.1002/adsc.201500539

In this study, enantiopure imidazolidinones containing two hydroxyphenyl groups were synthesized, and the Williamson synthesis of the chiral bisphenols thus prepared with dihalides afforded polyethers containing chiral imidazolidinone repeating units. These chiral imidazolidinone polyethers exhibited excellent catalytic activity in the asymmetric Diels-Alder reaction. With the use of these polymeric catalysts, enantioselectivities up to 99% were obtained, higher than those obtained by the corresponding monomeric imidazolidinone catalyst in homogeneous solution. The polymeric catalysts were found to be insoluble in commonly used organic solvents, and they could be repeatedly used without the loss of activity.

Full text of DOI:10.1002/adsc.201500539

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DOI: 10.1002/adsc.201500539
Synthesis of Chiral Polyethers Containing Imidazolidinone
Repeating Units and Application as Catalyst in Asymmetric
Diels–Alder Reaction
Shinichi Itsuno,a,* Tatsuaki Oonami,a Nagisa Takenaka,a and Naoki Haraguchia
a
Department of Environmental & Life Sciences, Toyohashi University of Technology, Toyohashi 441-8580, Japan
Fax: (+81)-532-44-6813; e-mail: itsuno@ens.tut.ac.jp
Received: June 3, 2015; Revised: September 28, 2015; Published online: December 9, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500539.
Abstract: In this study, enantiopure imidazolidinones tained, higher than those obtained by the corre-
containing two hydroxyphenyl groups were synthe- sponding monomeric imidazolidinone catalyst in ho-
sized, and the Williamson synthesis of the chiral bis- mogeneous solution. The polymeric catalysts were
phenols thus prepared with dihalides afforded poly- found to be insoluble in commonly used organic sol-
ethers containing chiral imidazolidinone repeating vents, and they could be repeatedly used without the
units. These chiral imidazolidinone polyethers exhib- loss of activity.
ited excellent catalytic activity in the asymmetric
Diels–Alder reaction. With the use of these polymer- Keywords: asymmetric catalysis; Diels–Alder reac-
ic catalysts, enantioselectivities up to 99% were ob- tion; enantioselectivity; organocatalysis; polymers
Introduction
from that in the monomer in solution. Furthermore,
the microenvironment in the polymer may affect cata-
Chiral imidazolidinones[1,2] developed by MacMillan lytic activity and enantioselectivity. The use of chiral
have been known to be excellent organocatalysts for main-chain polymeric catalysts in asymmetric reac-
several asymmetric transformations such as Diels– tions has positively affected these reactions.[8] Appro-
Alder cycloaddition,[3] Friedel–Crafts alkylation,[4] 1,3- priately designed polymeric catalysts can provide high
dipolar cycloaddition,[5] intramolecular Michael addi- stereoselectivity in asymmetric reactions.
tion,[6] a-chlorination,[7] and a-fluorination.[7] Al-
though high enantioselectivities have been obtained
in various asymmetric reactions by the use of these
chiral imidazolidinone catalysts, in most cases, a high
catalyst loading of 20 mol% is usually required for fa-
cilitating a reaction at a reasonable rate. Furthermore,
column chromatography is necessary for separating
the catalyst before product isolation. In addition, it is
typically difficult to recover and reuse the catalyst.
The immobilization of a chiral imidazolidinone cata-
lyst may provide potential solutions to the above-
mentioned challenges.[8] Several approaches for im-
mobilizing the imidazolidinone catalyst onto solid
supports have been reported.[9,10,11,12] We have also
synthesized a polymer-immobilized chiral imidazolidi-
none 1 (Figure 1) by stable ionic bond formation be-
tween imidazolidinone and polymeric sulfonate.[13] On
the other hand, if the chiral imidazolidinone is incor-
porated into the polymer main chain as a repeating
unit, the microenvironment around the chiral imida-
zolidinone moiety in the polymer would be different ionic bonds.
Figure 1. Polymer-immobilized imidazolidinones by using
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Previously, we have developed such main-chain ment. Various imidazolidinone salts structures can be
polymers of a chiral imidazolidinone catalyst 2 prepared by using these polymers. For the synthesis
(Figure 1) by ionic bond formation between imidazo- of such chiral imidazolidinone polymers, we chose
lidinone and sulfonate.[14] Since the secondary amino a strategy that involves the synthesis of polyethers.
group of imidazolidinone easily forms the correspond- Surprisingly, the synthesis of chiral polyethers has not
ing sulfonates, the reaction between the imidazolidi- been extensively investigated. Some stereoregular
none dimer and disulfonic acid smoothly occurs to polyethers have been investigated for the polymeri-
afford chiral polymers containing chiral imidazolidi- zation of substituted epoxides.[15,16,17] However, the
none sulfonate moieties as repeating units in their synthesis of chiral polyethers by the Williamson reac-
main-chain structure. The main chain of the chiral tion has not been reported. We have synthesized bis-
polymer contains ionic bonds. This chiral ionic poly- phenol-type chiral imidazolidinones. Under William-
mer with a unique main-chain structure was success- son reaction conditions, the polycondensation of the
fully utilized as an organocatalyst in asymmetric chiral bisphenol thus prepared and dihalide afforded
Diels–Alder reaction. Some of the chiral ionic poly- chiral polyethers. In this study, we report the synthesis
meric catalysts exhibit slightly higher enantioselectivi- of chiral bisphenols containing an imidazolidinone
ty than that exhibited by the original monomeric cata- structure and their polymerization with dihalide to
lyst in the asymmetric reaction.[14] However, the cata- afford chiral imidazolidinone polyethers. The catalytic
lytic activity of the chiral imidazolidinone catalyst is activity of the chiral imidazolidinone polyethers was
affected by its salt structure. The change of the coun- examined for the Diels–Alder reaction of cinnamalde-
ter anion sometimes dramatically affects enantioselec- hyde and cyclopentadiene.
tivity. Sulfonate has always acted as the counter anion
of the previously developed polymer.[14]
In this study, we aim to synthesize chiral imidazoli- Results and Discussion
dinone polymers having structures composed of vari-
ous counter anions. Such chiral imidazolidinone poly- Synthesis of Chiral Polyethers Containing
mers can be utilized as catalysts for various asymmet- Imidazolidinone Repeating Units
ric reactions with a wide range of substrates. The in-
troduction of polymerizable functional groups on the Bisphenol-type chiral imidazolidinone 9 was synthe-
chiral imidazolidinone would make it possible to syn- sized as shown in Scheme 1. (S)-Tyrosine 3 is an a-
thesize chiral polymers containing imidazolidinone as amino acid containing a hydroxyphenyl group. Anoth-
the main-chain repeating unit. The secondary amino er hydroxyphenyl group was introduced by using 4-
groups of imidazolidinone moieties in the polymer hydroxyphenylethylamine (tyramine, 6). (S)-N-Boc-
chain are easily modified to their salts by acid treat- tyrosine (5)[18] was treated with 6 in the presence of 1-
Scheme 1. Synthesis of bisphenol-type chiral imidazolidinone monomer 9.
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Synthesis of Chiral Polyethers Containing Imidazolidinone Repeating Units
tives.[25] The repeated Williamson reaction between
the diol of the Cinchona alkaloid dimer and dihalide
afforded chiral polyethers in good yield. In this paper,
we applied the same methodology to the synthesis of
chiral imidazolidinone polymers.
As shown in Scheme 2, the disodium diphenoxide
10 of chiral imidazolidinone 9 was allowed to react
with dihalide 11 to afford the corresponding chiral
polyether 12. The treatment of 12 with acid (HX) re-
sulted in the formation of imidazolidinone salt in
each repeating unit of 13. In this polymer, the chiral
imidazolidinone (MacMillan) catalyst is fixed as the
repeating unit in the main chain of chiral polymer 13,
which was used as a chiral catalyst for enantioselec-
tive reactions including the Diels–Alder reaction. The
polymerization of 10 with 11 smoothly occurred to
afford chiral polyether 12 in high yield (Table 1). Var-
ious types of dihalides including allylic dihalide, alkyl
dihalide, and benzylic dihalides were used to prepare
chiral polyethers 12. Table 1 summarizes the molecu-
lar weight and molecular weight distribution of the
chiral imidazolidinone polyethers 12. Chiral polyether
12 containing an aromatic linker (12c, 12d, 12e) ex-
hibited relatively poor solubility in DMF. The molecu-
lar weight of the soluble part of these polymers was
determined by SEC. The treatment of chiral polyether
12 with acid (HX) yielded polymers 13 having a salt
structure.
Scheme 2. Synthesis of chiral polyethers.
hydroxybenzotriazole (HOBt) and the water-soluble
To evaluate the catalytic activity of the chiral mon-
carbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)car- omeric and polymeric imidazolidinones, the enantio-
bodiimide hydrochloride (EDC-HCl), to give 7. The selective Diels–Alder reaction between 19 and 20 was
N-Boc group from 7 was deprotected to afford a- investigated. The Diels–Alder reaction afforded cyclic
amino amide 8 having two hydroxyphenyl groups. adduct 21 in quantitative conversion with 93% ee by
The reaction of a-amino amide 8 with acetone afford- the use of the original MacMillan-HCl catalyst 14
ed the desired bisphenol-type chiral imidazolidinone (Figure 2), derived from (S)-phenylalanine (Table 2,
monomer 9. Details of the synthesis of 9 are de- entry 1).[3] Toluenesulfonate imidazolidinone catalyst
scribed in the Supporting Information.
15 (Figure 2) showed similar enantioselectivity for the
Generally, bisphenols have been known to be excel- endo adduct (92% ee) and somewhat lower enantiose-
lent monomers for the synthesis of poly- lectivity for the exo adduct (88% ee) (entry 2). Since
carbonates[19,20] and epoxy resins.[21] Various types of we used the (S)-tyrosine derivative for polymer syn-
polyethers and poly(ether ketone)s have also been thesis, imidazolidinones (16–18, Figure 2) derived
synthesized from bisphenols.[22,23,24] However, the syn- from (S)-tyrosine were applied to the same reaction.
thesis of chiral polyethers has not been extensively The asymmetric reaction smoothly proceeded with
studied. We have recently demonstrated the synthesis these catalysts at room temperature to afford chiral
of chiral polyethers from Cinchona alkaloid deriva- cyclic adducts 21 in almost quantitative conversion.
Table 1. Synthesis of chiral polymer 12 from 10 and dihalides 11.
[a]
[a]
[a]
Entry
Dihalide
Polymer
Yield [%]
Mn
Mw
Mw/Mn
1
2
3
4
5
11a
11b
11c
11d
11e
12a
92
94
95
92
87
18000
17000
12000
6800
42000
28000
37000
8700
2.4
1.6
3.1
1.3
1.1
12b
12c[b]
12d[b]
12e[b]
5100
5400
[a]
Determined by SEC using DMF as a solvent at a flow rate of 1.0 mLminÀ1 at 408C (polystyrene standard).
Partially insoluble in DMF.
[b]
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proceeded in MeOH/water=95:5 at room tempera-
ture to afford the corresponding chiral cyclic adduct
in 70% yield with 77% ee for the endo adduct and
67% ee for the exo adduct (Table 3, entry 1).
As compared with the use of monomeric catalysts
14–17, the use of polymeric chiral catalyst 13a-TsO
exhibited lower enantioselectivity. The structure of
the achiral linker R (Scheme 2) in polymer 13 affect-
ed the enantioselectivity of the reaction. The poly-
mer-containing butylene chain (13b-TsO) exhibited
high enantioselectivity (entry 2). Although chiral
polymer 13c-TsO containing a p-xylyl linker exhibited
decreased enantioselectivity (entry 3), 13d-TsO and
13e-TsO exhibited enantioselectivities higher than
80% for both endo and exo isomers of the product
Figure 2. Chiral imidazolidinones.
Imidazolidinone catalysts 17 and 18 are model com- (entries 4 and 5, respectively).
pounds for the polymeric catalyst (entries 4 and 5).
The activated iminium ion, formed by the conden-
Then, we investigated the use of chiral imidazolidi- sation of chiral imidazolidinone and cinnamaldehyde,
none salt polymers 13 in the same asymmetric Diels– underwent reaction with 20 to yield the cyclic adduct.
Alder reaction. Although chiral imidazolidinone salt The counter anion of the iminium cation should affect
polymers 13 were totally insoluble in the the enantioselectivity. To examine the effect of the
MeOH:H2O=95:5 used for the asymmetric reaction, counter anions, we tested several counter anions for
the reaction smoothly occurred in the presence of 13. this reaction. Table 4 summarizes the results obtained
For example, in the presence of 13a-TsO, the reaction using different counter anions. No major differences
Table 2. Asymmetric Diels–Alder reaction using chiral imidazolidinone catalysts.
Entry
Chiral imidazolidinone
Yield [%][a]
21
exo/endo[b]
exo ee [%][c]
endo ee [%][c]
1[d]
2[e]
3
4
5
14
15
16
17
18
94
94
94
92
94
1.3/1
55/45
55/45
65/35
51/43
93
88
92
89
92
93
92
88
93
94
[a]
Isolated yield.
Determined by 1H NMR.
[b]
[c]
[d]
[e]
Determined by GC (CHIRALDEX b-PH).
See ref.[3]
See ref.[1]
Table 3. Asymmetric Diels–Alder reaction with chiral polymeric catalyst 13-TsO.
Entry
Chiral polymeric
imidazolidinone
Catalyst loading
[mmolgÀ1]
21
Yield [%][a]
exo/endo[b]
exo ee [%][c]
endo ee [%][c]
1
2
3
4
5
13a-TsO
13b-TsO
13c-TsO
13d-TsO
13e-TsO
1.77
1.76
1.63
1.45
1.40
67
86
61
53
80
58/42
60/40
53/47
53/47
59/41
67
75
73
83
80
77
86
77
82
83
[a]
Isolated yield.
[b]
[c]
Determined by 1H NMR.
Determined by GC (CHIRALDEX b-PH).
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Synthesis of Chiral Polyethers Containing Imidazolidinone Repeating Units
Table 4. Effect of counter anion on the asymmetric Diels–Alder reaction.
Entry
Chiral polymeric
imidazolidinone
XÀ
Catalyst loading
[mmolgÀ1]
21
exo ee [%][c]
Yield [%][a]
exo/endo[b]
endo ee [%][c]
À
1
2
3
4
5
6
13c-BF4
13c-TFA
13c-MsO
13c-TsO
13c-Cl
BF4
1.89
1.80
1.86
1.63
2.09
1.84
94
94
94
61
94
94
54/46
59/41
57/43
53/47
61/39
55/45
80
93
85
73
86
76
91
97
96
77
95
92
À
CF3CO2À
CH3SO3
À
TolSO3
ClÀ
À
13c-ClO4
ClO4
[a]
Isolated yield.
[b]
[c]
Determined by 1H NMR.
Determined by GC (CHIRALDEX b-PH).
Table 5. Effect of trifluoroacetate complexes of polymeric imidazolidinones on the asymmetric Diels–Alder reaction.
Entry Chiral polymeric imidazolidinone Catalyst loading [mmolgÀ1]
21
Yield [%][a] exo/endo[b] exo ee [%][c] endo ee [%][c]
1
2
3
4
5
13a-TFA
13b-TFA
13c-TFA
13d-TFA
13e-TFA
1.97
1.97
1.80
1.58
1.52
99
68
99
94
69
57/43
59/41
59/41
61/39
59/41
86
83
93
85
90
95
91
97
91
95
[a]
[b]
[c]
Isolated yield.
Determined by 1H NMR.
Determined by GC (CHIRALDEX b-PH).
were observed in the catalytic activity and enantiose- lytic activity (Table 6, entry 2). The third cycle of
lectivity of polymeric catalysts 13c, except for the tol- reuse led to a decrease in the catalytic activity and
uenesulfonate polymer 13c-TsO, upon the the use of enantioselectivity (entry 3). The same polymeric cata-
which the reactivity and enantioselectivity decreased lyst 13c-TFA was used in the asymmetric Diels–Alder
(Table 4, entry 4). Moreover, of the polymeric cata- reactions of 2,3-dimethylbutadiene and acrolein
lysts used in this study, trifluoroacetate polymer 13c- (Scheme 3) and exhibited high catalytic activity
TFA exhibited the highest enantioselectivities for (entry 4).
both diastereomers of product 21 (entry 2).
The asymmetric reaction using 13c-TFA still pro-
Trifluoroacetates of other polymeric imidazolidi- ceeded at 08C. Almost perfect enantioselectivity was
nones were also investigated as catalysts in the asym- observed for the endo isomer of the cyclic adduct 21
metric Diels–Alder reaction. Table 5 summarizes the at 08C (entry 5). The recovered polymer 13c-TFA was
results. The combination of chiral imidazolidinone treated with TFA and used for the same reaction.
polymer 12c and TFA afforded polymeric catalyst High catalytic activity and enantioselectivity were
13c-TFA, which exhibited the highest enantioselectivi- maintained with the polymeric catalyst (entries 5 and
ties for both enantiomers of the Diels–Alder adduct 6).
21 (Table 5, entry 3).
Polymeric chiral imidazolidinone catalysts 13 were
insoluble not only in commonly used organic solvents Conclusions
such as dichloromethane, acetonitrile, ethyl acetate,
and methanol but also in water. Even though they We have successfully synthesized chiral imidazolidi-
formed a completely heterogeneous system, the asym- none polyethers 12 by the Williamson reaction of
metric reaction smoothly occurred at room tempera- chiral bisphenol-type monomer 9 with achiral diha-
ture, as shown in Table 3, Table 4 and Table 5. After lides 11. This is the first example of the synthesis of
the completion of the reaction, the polymeric catalyst chiral imidazolidinone polyethers. The treatment of
was easily separated by simple filtration or decanta- polymers 12 with acid afforded amine salt polymers
tion. Table 6 shows the recyclability of the polymeric 13. These polymers exhibited excellent catalytic activ-
catalyst as well as the effect of temperature on enan- ities in the enantioselective Diels–Alder reaction of
tioselectivity. The recovered polymer 13c-TFA was (E)-cinnamaldehyde and cyclopentadiene. High enan-
reused for the same reaction and exhibited high cata- tioselectivities were observed with the use of 13. The
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Table 6. Recycle use of polymeric imidazolidinone 13c-TFA in the asymmetric Diels–Alder reaction.
Entry
Temperature [8C]
Time [h]
Product
Yield [%][a]
exo/endo[b]
exo ee [%][c]
endo ee [%][c]
1
25
25
25
25
0
24
24
48
24
24
24
24
21
21
21
22
21
21
21
94
94
90
94
81
89
90
59/41
58/42
58/42
-
57/43
54/46
53/47
93
87
82
97
96
96
96
97
93
87
2[d]
3[e]
4[f]
5
99
99
98
6[g]
7[h]
0
0
[a]
Isolated yield.
[b]
[c]
[d]
[e]
[f]
Determined by 1H NMR.
Determined by GC (CHIRALDEX b-PH).
13c-TFA used in entry 1 was reused.
13c-TFA used in entry 2 was reused.
Diels–Alder reaction between acrolein and 2,3-dimethylbutadiene.
13c-TFA used in entry 4 was retreated with TFA and reused.
13c-TFA used in entry 6 was retreated with TFA and reused.
[g]
[h]
are uncorrected. NMR spectra were recorded on JEOL
JNM-ECS400 spectrometers in CDCl3 or DMSO-d6 at room
temperature operating at 400 MHz (1H) and 100 MHz
(13C{1H}). TMS was used as an internal standard for
1H NMR and CDCl3 for 13C NMR. Chemical shifts were re-
ported in ppm using TMS as a reference, and the J values
were recorded in Hertz. IR spectra were recorded on
a JEOL JIR-7000 FTIR spectrometer and are reported in
cmÀ1. Elemental analyses (carbon, hydrogen, nitrogen) were
performed on a Yanaco-CHN coder MT-6 analyzer. HR-MS
(ESI) spectra were recorded on a microTOF-Q II HRMS/
MS instrument (Bruker). GC analyses were performed using
a Shimadzu capillary gas chromatograph GC-2014 equipped
Scheme 3. Asymmetric Diels–Alder reaction of acrolein and
2,3-dimethylbutadiene with 13c-TFA.
structure of 11 and acid HX affected the enantioselec-
tivity. The enantioselective Diels–Alder reaction
smoothly occurred in the presence of 13c-TFA, and
higher yields and enantioselectivities (up to 99% ee)
were observed in comparison with those observed
with the use of low-molecular-weight catalysts (14, 15,
16) in solution. The polymeric catalyst was insoluble
in solvent and easily recovered by simple decantation.
The acid retreatment of the recovered polymeric cata-
lyst enabled us to repeatedly use the catalyst without
the loss of catalytic activity. Chiral imidazolidinone
salts exhibit excellent catalytic activity in several
asymmetric reactions. Currently, investigation of the
catalytic activity of chiral imidazolidinone polymers
in various asymmetric transformations other than the
Diels–Alder reaction is underway in our laboratory.
with
a capillary column (CHIRALDEX b-PH, 30 m”
0.25 mm). Size exclusion chromatography (SEC) was per-
formed using a Tosoh instrument with HLC 8020 UV
(254 nm) or refractive index detection. DMF was used as
the carrier solvent at a flow rate of 1.0 mLminÀ1 at 408C.
Two polystyrene gel columns of bead size 10 mm were used.
A calibration curve was made to determine the number-
average molecular weight (Mn) and molecular weight distri-
bution (Mw/Mn) values with polystyrene standards. Optical
rotation was recorded using a JASCO DIP-149 digital polar-
imeter using a 10 cm thermostatted microcell.
Synthesis of Chiral Polymer 12a
First, NaH (30 mg, 1.3 mmol) at 08C was added to a DMF
solution of 9 (136 mg, 0.4 mmol). Second, the reaction mix-
ture was stirred at 08C for 1 h, and trans-1,4-dibromo-2-
butene (84.8 mg, 0.4 mmol) was added. Next, the mixture
was stirred at room temperature for 20 h. Finally, diethyl
ether (20 mL) was added to the reaction mixture to precipi-
tate the chiral polymer, which was washed with water and
ether. Polymer 12a was obtained as a solid; yield: 179 mg
Experimental Section
Materials and General Considerations
All solvents and reagents were purchased from Sigma–Al-
drich, Wako Pure Chemical Industries, Ltd., or Tokyo
Chemical Industry (TCI) Co., Ltd. at the highest available
purity and were used as received, unless otherwise noted.
Reactions were monitored by thin-layer chromatography
using precoated silica gel plates (Merck 5554, 60F254).
Column chromatography was performed using a silica gel
column (Wakogel C-200, 100–200 mesh). Melting points
were recorded using a Yanaco micro melting apparatus and
1
(99%). H NMR (400 MHz, DMSO): d=1.07 (s, 3H, CH3),
1.13 (s, 3H, CH3), 2.61–2.2.76 (m, 3H, CH2CH2), 2.86–2.97
(m, 1H, CH2N), 3.03–3.18 (m, 1H, CH2Ph), 3.22–3.31 (m,
1H, CH), 3.54 (s, 1H, CH), 4.53 (s, 4H, CH2CH), 6.02 (s,
2H, CHCH2), 6.78–6.90 (m, 4H, Ar),7.09 (d, J=7.9 Hz, 2H,
Ar), 7.16 (d, J=7.9 Hz, 2H, Ar); 13C NMR: (100 MHz,
DMSO): d=27.0, 28.7, 34.7, 37.5, 42.7, 59.9, 68.1, 76.7,
4000
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Synthesis of Chiral Polyethers Containing Imidazolidinone Repeating Units
115.3, 115.4, 129.3, 130.8, 131.4, 131.6, 132.2, 157.6, 157.7,
adduct was purified by silica gel chromatography (ethyl ace-
tate/hexanes=1/19). Products exo-21 and endo-21 were ob-
tained as colorless liquids; yield: 94%. The exo/endo ratio
174.6; Mn (SEC)=1.8”104; Mw/Mn =2.4.
1
was determined to be 57/43 by H NMR by comparing the
Enantioselective Diels–Alder Reaction of (E)-
Cinnamaldehyde (19) with Cyclopentadiene (20)
using 15
proton signals of the aldehyde. The enantiomeric excess
(86% ee for exo adduct, 95% ee for endo adduct) was deter-
mined by GC analysis (Astec CHIRALDEX B-PH: injec-
tion temperature 1808C, detection temperature 1808C,
column temperature was increased from 1208C to 1508C at
58CminÀ1 and then 1808C at 18CminÀ1): retention times:
26.2 min [exo(2R)], 26.8 min [exo(2S)], 27.3 min [endo(2R)],
and 27.7 min [endo(2S)].
First, p-toluenesulfonic acid monohydrate (19.0 mg,
0.1 mmol) was added to a solution of 9 (39.0 mg, 0.1 mmol)
in methanol (1.0 mL). Next, the resulting mixture was
stirred for 2 h at room temperature. Finally, the solvent was
evaporated and the residue dried under vacuum to afford
catalyst 17. 1H NMR (400 MHz, DMSO): d=1.41 (s, 3H,
CH3), 1.49 (s, 3H, CH3), 2.65–2.76 (m, 3H, CH2CH2), 2.78–
2.88 (m, 1H, CH2N), 3.23–3.45 (m, 2H, CH2Ph), 4.43 (s, 1H,
CH), 6.69 (d, J=8.2 Hz, 2H, Ar), 6.74 (d, J=8.5 Hz, 2H,
Ar), 7.04 (d, J=8.2 Hz, 2H, Ar), 7.14 (d, J=8.2 Hz, 2H,
Ar), 9.27 (s, 1H, ArOH), 9.38 (s, 1H, ArOH); 13C NMR:
(100 MHz, DMSO): d=24.3, 25.4, 34.1, 34.5, 42.6, 49.6, 58.3,
77.9, 116.2, 116.3, 127.0, 129.5, 130.7, 131.2, 156.9, 157.5.
First, after dissolving 17 in MeOH/H2O=95/5 (v/v)
(1.0 mL), 19 (146 mg, 1.0 mmol) and 20 (206 mg, 3 mmol)
were added. Second, the reaction mixture was stirred for
24 h at room temperature and diluted with Et2O and
washed with H2O and brine. Next, the organic layer was
dried over MgSO4, filtered, and concentrated. Finally, the
product dimethyl acetal was hydrolyzed by stirring the
crude product mixture in CH2Cl2:H2O:TFA (1:0.5:0.25 mL)
for 2 h at room temperature, followed by neutralization with
a saturated NaHCO3 aqueous solution and extraction with
Et2O. The Diels–Alder adduct was purified by silica gel
chromatography (ethyl acetate/hexane=1/19). Products exo-
21 and endo-21 were obtained as colorless liquids; yield:
92%. The exo/endo ratio was determined to be 65/35 by
1H NMR by comparing the proton signals of the aldehyde.
The enantiomeric excess was determined by GC analysis
(Astec CHIRALDEX B-PH: injection temperature 1808C,
detection temperature 1808C, column temperature was in-
creased from 1208C to 1508C at 58CminÀ1 and then 1808C
at 18CminÀ1): retention times: 26.2 min [exo(2R)], 26.8 min
[exo(2S)], 27.3 min [endo(2R)], and 27.7 min [endo(2S)].
Acknowledgements
This study has been supported by JSPS KAKENHI (Grant-
in-Aid for Scientific Research)) Grant Number 15K05517
and MEXT KAKENHI (Grant-in-Aid for Scientific Re-
search on Innovative Areas) Grant Number 15H00732.
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