C2-symmetric pyrrolidine-based chiral ammonium salts as a phase-transfer catalyst

Article abstract of DOI:10.3987/COM-11-12254

Chiral pyrrolidinium salts having substituents at the α, α' positions were synthesized to develop a chiral phase-transfer catalyst which have more simplified structure. The catalytic function of these synthesized catalysts was evaluated using asymmetric b

Full text of DOI:10.3987/COM-11-12254

HETEROCYCLES, Vol. 83, No. 11, 2011
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HETEROCYCLES, Vol. 83, No. 11, 2011, pp. 2577 - 2588. © 2011 The Japan Institute of Heterocyclic Chemistry
Received, 10th May, 2011, Accepted, 23rd August, 2011, Published online, 30th August, 2011
DOI: 10.3987/COM-11-12254
C2-SYMMETRIC PYRROLIDINE-BASED CHIRAL AMMONIUM SALTS
AS A PHASE-TRANSFER CATALYST
Tatsuya Ishikawa, Kazuhiro Nagata, Sachiko Kani, Mamoru Matsuo,
Daisuke Sano, Takuya Kanemitsu, Michiko Miyazaki, and Takashi Itoh*
School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo
142-8555, Japan; e-mail: itoh-t@pharm.showa-u.ac.jp
Abstract – Chiral pyrrolidinium salts having substituents at the α, α’ positions
were synthesized to develop a chiral phase-transfer catalyst which have more
simplified structure. The catalytic function of these synthesized catalysts was
evaluated using asymmetric benzylation of N-(diphenylmethylene)glycine
tert-butyl ester, and α,α’-disubstituded pyrrolidinium salts having an alkyl chain
with a hydroxyl group at a chiral center were found to afford moderate
enantioselectivity.
Phase-transfer catalytic asymmetric reaction has been extensively investigated in the last two decades,
because it is operationally simple, environmentally benign, and carried out under mild conditions.1
Since Dolling and co-workers reported an enantioselective alkylation of active methylene compounds
with cinchona alkaloid-derived phase-transfer catalyst (PTC) in 1984,2 numerous novel PTCs and the
asymmetric reaction using a PTC have been reported.3
Among the catalysts developed,
N-spiroquaternary ammonium salts, which are derived from 1,1’-binaphthol, and cinchona
alkaloid-derived ammonium salts are major ones. We have been investigating asymmetric reaction with
PTC and reported several new reactions.4 PTC used in the reactions, however, is expensive and required
many steps to be synthesized. Thus we next studied on the development of a PTC which has a simple
structure. In this paper we describe the synthesis of chiral pyrrolidine-based quaternary ammonium
salts5 and its evaluation for PTC.
The chiral PTC investigated were α,α’-disubstituted pyrrolidinium salts with stereogenic centers that are
adjacent to the quaternary ammonium nitrogen (Figure 1). α,α’-Disubstituted pyrrolidines 1, the
precursors of the quaternary ammonium salts, were prepared according to a literature6 method from adipic

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HETEROCYCLES, Vol. 83, No. 11, 2011
OR1
OR1
OR1
X
R1O
R1O
R1O
N
H
N
N
R5
OR4
X
R2 R2
1
R3
2
3
Figure 1
acid, and both of the enantiomers could be prepared. The chiral pyrrolidinium salts 2 were prepared by
the alkylation of 1 with some kinds of alkyl halides in the presence of K2CO3 (Table 1).
Table 1
OR1
R1O
OR1
R1O
R2I
compound 2 yield of 2
N
N
H
I
R1
R2
(%)
R2
R2
K2CO3
MeCN
39
90
16
11
87
74
88
Me
Me
Me
Me
Pr
Me
allyl
Bu
a
b
c
d
e
f
1 a-d
2 a-g
a: R1= Me
b: R1= Pr
c: R1= Bn
hexyl
Me
Me
Me
d: R1= TBS
Bn
TBS
g
Catalytic activities of the obtained quaternary ammonium salts were evaluated in the asymmetric
benzylation of glycinate Sciff base 4 (Table 2). Although the synthesized pyrrolidinium salts were
Bn
O
H
Ph
Ph
catalyst (10 mol%), BnBr (1.2 equiv)
Ph
Ph
Ot-Bu
Ot-Bu
N
N
50% aqueous KOH (13 equiv)
toluene, rt, 24 h
O
4
5
Table 2.
4
2a-g
Benzylation of glycine Schiff base using catalyst .
Entry
Catalyst
R1
R2
Yield (%)a Ee (%)b
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
Me
Me
Me
Me
Pr
Me
ally
Bu
25
31
46
51
44
43
41
24
14
21
11
0
hexyl
Me
Me
Me
Bn
2
2g
TBS
11
a
Determined by 1H NMR using mesitylene as an internal standard.
b
Determined by HPLC analysis using a chiralcel OJ-H after hydrolysis of 5.

HETEROCYCLES, Vol. 83, No. 11, 2011
2579
OMe
OH
OMe
OH
MeO
MeO
O
N
N
OMe
MeO
Ph
+
N
H
Ca(OTf)2
MeCN
reflux
6
6'
y.26%
y.26%
1a
Ph
Ph
MeI CHCl
/
MeI CHCl
/
3
3
OMe
OMe
I -
MeO
MeO
Scheme 1
+
N
+
N
I -
Me
OH
Me
OH
y. 64%
Ph
y.79%
Ph
3a
3a'
found to exhibit catalytic activity, the reaction was slow with low enantioselectivity. The results showed
that more lipophilic derivatives gave better yield, but less selectivity. Thus, it was considered that
another chiral element and functional group which can interact with the substrate were necessary to
improve the enantioselectivity. We then attempted to introduce a hydroxyl group to the alkyl chain at
β-position of ammonium nitrogen to produce the third chiral center. Pyrrolidine 1 was allowed to react
7
with styrene oxide in the presence of Ca(OTf)2 to give tertiary amine 6 as a mixture of diastereomer.
They were separated by a column chromatography, and then alkylated with methyl iodide to give
3
catalyst (10 mol%)
Bn
O
OMe
I -
H
MeO
Ph
Ph
BnBr (1.2 equiv)
Ph
Ph
+
Ot-Bu
Ot-Bu
N
N
N
Me
OH
3 a-d
50% aqueous KOH (13 equiv)
toluene, rt, 24 h
O
5
4
R
Table 3.
4
3a-d
Benzylation of glycine Schiff base using catalyst .
R
Yield (%)a
Ee (%)b
Entry
Catalyst
Temp.
3a
3a
3a'
3a'
3b
3b
3c
3c
3d
3d
1
2
3
4
5
6
7
8
9
10
phenyl
rt
42
36
44
28
61
55
49
20
40
26
22
46
4
0 oC
phenyl
rt
phenyl
phenyl
0 oC
rt
3
butyl
8
0 oC
butyl
16
16
26
24
28
p-fluorophenyl
p-fluorophenyl
2-naphthyl
2-naphthyl
rt
0 oC
rt
0 oC
a
Determined by 1H NMR using mesitylene as an internal standard.
b
5.
Determined by HPLC analysis using a chiralcel OJ-H after hydrolysis of

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HETEROCYCLES, Vol. 83, No. 11, 2011
quaternary ammonium salts 3a and 3a’ (Scheme 1). The absolute configuration of the obtained
ammonium salts at the chiral center having hydroxyl group were correlated by comparison of the NMR
data with that of ammonium salt synthesized by the reaction with (S)-styrene oxide. The other
pyrrolidinium salts 3b-d were prepared in the same way, and their activity as a chiral catalyst was
examined (Table 3). Among the newly synthesized catalysts, 3a gave moderate enantioselectivity in the
reaction of glycine imine 4 with benzyl bromide at 0 ºC (Table 3, entry 2). When the epimer of 3a at the
chiral center bearing hydroxyl group (3a’) was used as a catalyst, the enantioselectivity became low.
We next investigated the counter anion effect of catalyst 3a on the present reaction (Table 4). Catalysts
3aa and 3ab were synthesized by the reaction of 6 with Meerwein reagent and methyl
trifluoromethanesulfonate respectively. When tetrafluoroborate catalyst 3aa with a hard counter anion
was used, the reaction was accelerated to raise the yield up to 66%.
Table 4
Entry Catalyst Counter anion Yield(%)a Ee(%)b
catalyst (10 mol%)
BnBr (1.2 equiv)
Bn
Ph
Ph
Ph
Ph
Ot-Bu
Ot-Bu
N
N
1
2
3
3a
I-
36
66
30
46
41
36
50% aqueous KOH
toluene, 0 °C, 24 h
O
O
-
3aa
3ab
BF4
TfO-
4
5
a Determined by 1H NMR using mesitylene as an internal standard.
b
Determined by HPLC analysis using a chiralcel OJ-H after
5.
hydrolysis of
In Figure 2, a plausible ion pair model of matched case is shown. Our results and previously reported
ion pair model8 suggest that more stable (E)-enolate forms ion pair with PTC by both ionic and hydrogen
bonding interaction. Benzyl bromide is thought to preferentially approach from sterically less hindered
Re face of the enolate to give the product having R configuration.
In conclusion, we have synthesized quaternary ammonium salts that have
C2 symmetric pyrrolidine skeleton and as a whole simple structure
OMe
compared to the chiral PTCs reported so far. These ammonium salts
+
O
MeO
N
were shown to act as a PTC in the alkylation of glycinate imine and
afford moderate yield and enantioselectivity. The results claimed that it
might be possible to develop much simpler PTCs compared to
conventional ones in the future. These possibilities have been studied in
our laboratory.
-
H
O
BnBr
N
O
Figure 2

HETEROCYCLES, Vol. 83, No. 11, 2011
2581
EXPERIMENTAL
General. Unless otherwise specified, reagents were purchased from commercial suppliers and used
without further purification. 1H and 13C NMR spectra were recorded on a 500 MHz (125 MHz for 13C)
13
or a 400 MHz (100 MHz for C) spectrometer. All melting points are uncorrected. TLC was carried
out on a Merck Kieselgel 60 PF 254 or Fuji silysia NH-TLC. Column chromatography was performed
using Merck Kieselgel 60 (0.063–0.200 mm) or Fuji silysia NH silica gel (Chromatorex, 100-210 mesh).
Starting material
(2S,5S)-Bismethoxymethylpyrrolidine (1a) was prepared according to a reported procedure.6
Synthesis of 2, 5-bis(alkoxymethyl)pyrrolidine 1b-d.
(2S,5S)-2,5-Bis(propoxymethyl)pyrrolidine (1b).
To a solution of (2S,5S)-2,5-bis(hydroxymethyl)-1-((S)-1-phenylethyl)pyrrolidine6 (30 mg, 0.13 mmol) in
THF (1.5 mL) was added NaH in oil (60%) (26 mg, 0.65 mmol), and the solution was stirred for 30 min
at rt under Ar atmosphere. Then allyl iodide (58 µL, 0.64 mmol) was added, and the mixture was stirred
for 3 h at rt. After water (4.0 mL) was added, the mixture was extracted with CH2Cl2 (12 mL x 3). The
combined extracts were dried over anhydrous MgSO4, and concentrated by evaporation. The residue
was purified by column chromatography on silica gel (AcOEt: hexane = 1: 3 as eluent) to give
(2S,5S)-2,5-bis(allyloxymethyl)-1-((S)-1-phenylethyl)pyrrolidine (35 mg, 0.11 mmol) in 85% yield.
Thus prepared (2S,5S)-2,5-bis(allyloxymethyl)-1-((S)-1-phenylethyl)pyrrolidine (240 mg, 0.76 mmol)
was dissolved in MeOH (8.0 mL) and Pd(OH)2 (81 mg, 0.08 mmol) was added. The mixture was stirred
under H2 atmosphere for 20h at rt and filtered. The filtrate was evaporated to give 1b (162 mg, 0.75
mmol) in 99% yield: a colorless oil; 1H-NMR (CDCl3) δ 0.91 (6H, t, J = 7.2 Hz), 1.41-1.46 (2H, m), 1.58
13
(4H, sxt, J = 7.2 Hz), 1.85-1.98 (2H, m), 2.40 (1H, bs), 3.28-3.45 (10H, m); C-NMR (CDCl3) δ 10.1,
22.4, 27.4, 56.4, 72.4, 73.8; HR-FAB MS: Calcd for C12H26NO2 [M+H]+: 216.1964, Found 216.1948.
(2S,5S)-2,5-Bis(benzyloxymethyl)pyrrolidine (1c).
To a solution of (2S,5S)-N-boc-2,5-bis(hydroxymethyl)pyrrolidine9 (45 mg, 0.19 mmol) in THF (2.0 mL)
was added NaH in oil (60%) (39 mg, 0.97 mmol), and the solution was stirred for 30 min at rt. Then
benzyl bromide (120 µL, 0.97 mmol) and TBAI (7.0 mg, 0.02 mmol) were added, and the mixtue was
stirred for 16 h at rt under Ar atmosphere. After water (4.0 mL) was added, the mixture was extracted
with CH2Cl2 (12 mL x 3). The combined extracts were dried over anhydrous MgSO4, and concentrated
by evaporation. The residue was purified by column chromatography on silica gel (AcOEt: hexane =
1: 5 as eluent) to give (2S,5S)-N-benzyl-2,5-bis(benzyloxymethyl)pyrrolidine (52 mg, 0.13 mmol) in 68%
yield. Thus obtained (2S,5S)-N-benzyl-2,5-bis(benzyloxymethyl)pyrrolidine (52 mg, 0.13 mmol) was
dissolved in MeOH (1.5 mL) and Pd(OH)2 (14 mg, 0.01 mmol) was added. The mixture was stirred

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HETEROCYCLES, Vol. 83, No. 11, 2011
under H2 atmosphere for 3h at rt and filtered. The filtrate was evaporated to give 1c (32 mg, 0.10 mmol)
1
in 79% yield: a colorless oil; H-NMR (CDCl3) δ 1.41-1.50 (2H, m), 1.86-1.92 (2H, m), 2.25 (1H, bs),
13
3.33-3.45 (6H, m), 4.50 (2H, d, J = 6.0 Hz), 4.53 (2H, d, J = 6.0 Hz), 7.26-7.34 (10H, m); C-NMR
(CDCl3) δ 27.86, 56.89, 73.17, 73.81, 127.56, 127.67, 128.36, 138.41.
(2S,5S)-2,5-Bis[tert-butyl(dimethyl)silyloxymethyl]pyrrolidine (1d).
To a solution of (2S,5S)-2,5-bis(hydroxymethyl)-1-((S)-1-phenylethyl)pyrrolidine (30 mg, 0.13 mmol) in
DMF (1.5 mL) were added TBSCl (46 mg, 0.31 mmol) and imidazole (43 mg, 0.64 mmol), and the
solution was stirred for 12 h at rt under Ar atmosphere. After water (4.0 mL) was added, the mixture
was extracted with CH2Cl2 (12 mL x 3). The combined extracts were dried over anhydrous MgSO4, and
concentrated by evaporation. The residue was purified by column chromatography on silica gel
(AcOEt: hexane = 1: 10 as eluent) to give (2S,5S)-2,5-bis[tert-butyl(dimethyl)silyloxymethyl]pyrrolidine
(48 mg, 0.10 mmol) in 80% yield.
Thus prepared (2S,5S)-2,5-bis-[tert-butyl(dimethyl)-
silyloxymethyl]pyrrolidine (292 mg, 0.63 mmol) was dissolved in MeOH (7.0 mL) and Pd(OH)2 (70 mg,
0.06 mmol) was added. The mixture was stirred under H2 atmosphere for 1 h at rt and filtered. The
filtrate was evaporated to give 1d (226 mg, 0.62 mmol) in 99% yield: a colorless oil; 1H-NMR (CDCl3) δ
0.05 (12H, s), 0.88 (18H, s), 1.39-1.45 (2H, m), 1.78-1.83 (2H, m), 3.23-3.40 (2H, m), 3.46-3.53 (4H, m);
13C-NMR (CDCl3) δ -4.8, 18.8, 26.5, 27.8, 59.6, 66.6; HR-FAB MS: Calcd for C18H42NO2Si2 [M+H]+:
360.2754, Found 360.2767.
Synthesis of N,N’-dialkyl-2,5-bis(alkoxymethyl)pyrrolidinium iodide 2a-g.
(2S,5S)-N,N’-Dimethyl-2,5-bis(methoxymethyl)pyrrolidinium iodide (2a).
To a solution of 1a (107 mg, 0.67 mmol) in MeCN (4.0 mL) were added MeI (420 µL, 6.7 mmol) and
K2CO3 (370 mg, 2.68 mmol). The mixture was stirred for 3 h at rt under Ar atmosphere. After water
was added, the mixture was extracted with CH2Cl2 (15 mL x 3). The combined extracts were dried over
anhydrous MgSO4. Evaporation of the solvent gave 2a (82 mg, 0.26 mmol) in 39% yield: brown oil;
1H-NMR (CD3OD) δ 1.99-2.05 (2H, m), 2.25-2.30 (2H, m), 3.19 (6H, s), 3.41 (6H, s), 3.70-3.75 (2H, m),
13
3.78-3.83 (2H, m), 3.97-4.03 (2H, m); C-NMR (CD3OD) δ 25.5, 49.8, 59.4, 70.8, 77.9; HR-FAB MS:
Calcd for C10H22NO2 [M-I-]+: 188.1597. Found 188.1663.
(2S,5S)-N,N’-Diallyl-2,5-bis(methoxymethyl)pyrrolidinium iodide (2b).
2b was prepared in a manner similar to that described for the preparation of 2a using allyl iodide instead
o
1
of methyl iodide (90% yield): brownish needles; mp 132 C (CHCl3/AcOEt); H-NMR(CD3OD) δ
2.10-2.16 (2H, m), 2.22-2.32 (2H, m), 3.40 (6H, s), 3.76-3.83 (4H, m), 4.11-4.23 (4H, m), 4,25-4.33 (2H,
13
m), 5.61 (2H, d, J = 10.4 Hz), 5.72 (2H, d, J = 16.8 Hz), 6.17-6.26 (2H, m); C-NMR (CD3OD) δ 26.3,
60.1, 62.9, 71.6, 76.4, 127.8, 129.0; HR-FAB MS: Calcd for C14H26NO2 [M-I-]+: 240.1964, Found
240.1997. Anal. Calcd for C14H26INO2: C, 45.78; H, 7.14; N, 3.81. Found: C, 45.63; H, 7.15; N, 3.68.

HETEROCYCLES, Vol. 83, No. 11, 2011
2583
(2S,5S)-N,N’-Dibutyl-2,5-bis(methoxymethyl)pyrrolidinium iodide (2c).
2c was prepared in a manner similar to that described for the preparation of 2a using 1-iodobutane instead
of methyl iodide and the reaction mixture was refluxed for 20 h. After extraction, obtained residue was
purified by column chromatography on silica gel (AcOEt: MeOH = 10: 1 as eluent) to give 2c (16%
yield): pale-yellow oil; 1H-NMR (CDCl3) δ 1.01 (6H, t, J = 7.2 Hz), 1.40-1.44 (4H, m), 1.67-1.82 (4H, m),
2.08-2.12 (2H, m), 2.26-2.34 (2H, m), 3.23 (2H, dt, J = 4.0 Hz, 12.8 Hz), 3.32 (6H, s), 3.57 (2H, dt, J =
4.4 Hz, 12.8Hz), 3.69 (2H, d, J = 12 Hz), 3.75 (2H, dd, J = 6 Hz, 12 Hz), 4.38 (2H, d, J = 5.6 Hz);
13C-NMR (CDCl3) δ: 13.8, 20.3, 25.0, 26.3, 57.8, 59.3, 70.6, 75.5; HR-FAB MS: Calcd for C16H34NO2
[M-I-]+: 272.2590, Found 272.2620.
(2S,5S)-N,N’-Dihexyl-2,5-bis(methoxymethyl)pyrrolidinium iodide (2d).
2d was prepared in a manner similar to that described for the preparation of 2c using 1-iodohexane
1
instead of 1-iodobutane (11% yield): pale-yellow oil; H-NMR (CDCl3) δ 0.91 (6H, t, J = 6.8 Hz),
1.25-1.35 (12H, m), 1.75-1.84 (6H, m), 2.14-2.18 (2H, m), 2,32-2.36 (2H, m), 3.27 (2H, dt, J = 4.8 Hz,
12.8 Hz), 3.40 (6H, s), 3.64 (2H, dt, J = 4.8 Hz, 12.8 Hz), 3.72-3.84 (2H, m), 4.42-4.49 (2H, m);
13C-NMR(CDCl3) δ 14.3, 22.8, 24.7, 25.3, 27.0, 31.7, 58.4, 59.7, 70.9, 75.9; HR-FAB MS: Calcd for
C20H42NO2 [M-I-]+: 328.3153, Found 329.3200.
(2S,5S)-N,N’-Dimethyl-2,5-bis(propoxymethyl)pyrrolidinium iodide (2e).
2e was prepared in a manner similar to that described for the preparation of 2a using 1b as a starting
material (87% yield): brown oil; 1H-NMR (CDCl3) δ 0.93 (6H, t, J = 7.6 Hz), 1.60 (4H, sxt, J = 7.6 Hz),
2.03-2.18 (2H, m), 2.32-2.40 (2H, m), 3.42 (6H, s), 3.39-3.51 (4H, m), 3.74-3.79 (2H, m), 3.93-3.96 (2H,
m), 4.34-4.37 (2H, m); 13C-NMR (CDCl3) δ 10.7, 22.7, 24.7, 49.2, 68.6, 73.5, 76.2; HR-FAB MS: Calcd
for C14H30NO2 [M-I-]+: 244.2277, Found 244.2300.
(2S,5S)-N,N’-Dimethyl-2,5-bis(benzyloxymethyl)pyrrolidinium iodide (2f).
2f was prepared in a manner similar to that described for the preparation of 2a using 1c as a starting
material (74% yield): brown oil; 1H-NMR (CDCl3) δ 2.00-2.10 (2H, m), 2.18-2.30 (2H, m), 3.37 (6H, s),
3.75-3.81 (2H, m), 3.91-3.99 (2H, m), 4.37-4.39 (2H, m), 4.53 (2H, d, J = 12.0 Hz), 4.58 (2H, d, J = 12.0
13
Hz), 7.28-7.37 (10H, m); C-NMR (CDCl3) δ 24.6, 49.1, 67.7, 73.8, 76.0, 128.1, 128.5, 128.8, 136.4;
HR-FAB MS: Calcd for C22H30NO2 [M-I-]+: 340.2277, Found 340.2305.
(2S,5S)-N,N’-Dimethyl-2,5-bis[tert-butyl(dimethyl)silyloxymethyl]pyrrolidinium iodide (2g).
2g was prepared in a manner similar to that described for the preparation of 2a using 1d as a starting
1
material (88% yield): colorless crystals; mp 274 °C; H-NMR (CDCl3) δ 0.14 (12H, s), 0.90 (18H, s),
2.02-2.09 (2H, m), 2.27-2.42 (2H, m), 3.47 (6H, m), 3.89 (2H, dd, J = 5.8, 13.4 Hz), 4.16 (2H, dd, J = 2.2,
13
13.4 Hz), 4.31-4.38 (2H, m); C-NMR (CDCl3) δ -5.7, 17.9, 24.2, 25,6, 49.0, 61.6, 77.4; HR-FAB MS:
Calcd for C20H46NO2Si2 [M-I-]+: 388.3067, Found 388.3102. Anal. Calcd for C20H46INO2Si2: C, 46.58; H,

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HETEROCYCLES, Vol. 83, No. 11, 2011
8.99; N, 2.72. Found: C, 46.37; H, 9.07; N, 2.58.
Synthesis of 1-(2-hydroxy-2-phenylethyl)[(2S,5S)-2,5-bis(methoxymethyl)]pyrrolidine (6).
To a solution of 1a (160 mg, 1.0 mmol) in MeCN (6 mL) were added styrene oxide (57 µL, 0.5 mmol)
and Ca(OTf)2 (17 mg, 0.1 mmol). The solution was heated and refluxed for 3 d. After cooled to rt,
sat.NaHCO3 aqueous solution (10 mL) was added and extracted with CH2Cl2 (15 mL x3). The combined
extracts were dried over anhydrous MgSO4, and concentrated by evaporation. The residue was purified by
column chromatography on NH-silica gel (AcOEt: hexane = 1: 5 as eluent) to give 6 (more polar isomer)
(35 mg, 0.13 mmol) and 6’ (less polar isomer) (36 mg, 0.13 mmol).
1-[(S)-2-Hydroxy-2-phenylethyl][(2S,5S)-2,5-bis(methoxymethyl)]pyrrolidine (6): Colorless oil;
[α]25 -84.2 (c 2.39, CHCl3); 1H-NMR (CDCl3) δ 1.59-1.66 (2H, m), 1.94-1.97 (2H, m), 2.88 (1H, dd, J =
D
4.0, 13.2 Hz), 2.95 (1H, dd, J = 8.8, 13.2 Hz), 3.14-3.20 (2H, m), 3.32 (6H, s), 3.28-3.38 (4H, m), 4.27
13
(1H, bs), 4.65 (1H, dd, J = 3.6, 8.4 Hz), 7.23-7.39 (5H, m); C-NMR (CDCl3) δ 27.4, 57.7, 59.0, 62.9,
72.1, 74.5, 125.7, 127.1, 128.2, 143.3; HR-FAB MS: Calcd for C16H26NO3 [M+H]+: 280.1913, Found
280.1927. The NMR data were in agreement with those of product prepared with (S)-styrene oxide.
1-[(R)-2-Hydroxy-2-phenylethyl][(2S,5S)-2,5-bis(methoxymethyl)]pyrrolidine (6’): Colorless oil;
[α]25 -5.20 (c 2.38, CHCl3); 1H-NMR (CDCl3) δ 1.64-1.69 (2H, m), 1.95-1.99 (2H, m), 2.65 (1H, dd, J =
D
11.2, 13.2 Hz), 3.13 (1H, dd, J = 2.8, 13.2 Hz), 3.32-3.47 (6H, m), 3.36 (6H, s), 4.73 (1H, dd, J = 2.8 Hz,
13
10.8 Hz), 7.24-7.23 (1H, m), 7.32-7.40 (4H, m); C-NMR (CDCl3) δ 27.3, 56.0, 59.0, 59.7, 70.0, 74.4,
125.8, 127.2, 128.2, 142.7; HR-FAB MS: Calcd for C16H26NO3 [M+H]+: 280.1913, Found 280.1944.
General procedure for the synthesis of pyrrolidinium iodide 3.
To a solution of 6 (35 mg, 0.13 mmol) in CHCl3 (1.0 mL) was added MeI (2.0 mL), and the solution was
refluxed for 3d. The mixture was evaporated and the residue was purified by column chromatography
on NH-silica gel (AcOEt:MeOH = 9:1 as eluent) to give 3a (35 mg 0.083 mmol) in 67 % yield.
1-[(S)-2-Hydroxy-2-phenylethyl]-1-methyl-[(2S,5S)-2,5-bis(methoxymethyl)]pyrrolidinium iodide
(3a).
pale-yellow oil; [α]25 +21.4 (c 0.51, MeOH); 1H-NMR (CDCl3) δ 1.97 (1H, m), 2.07 (1H, m), 2.24 (1H,
D
m), 2.45 (1H, m), 3.34 (3H, s), 3.38 (3H, s), 3.48 (3H, s), 3.34-3.53 (2H, m), 3.70-3.95 (3H, m), 4.25-4.40
(3H, m ), 4.99 (1H, bs), 5.61 (1H, dd, J = 11.6, 2.8 Hz), 7.24-7.39 (3H, m), 7.52 (2H, d, J = 7.6 Hz);
13C-NMR (CDCl3) δ 24.2, 25.2, 46.0, 59.9, 60.0, 64.1, 67.0, 70.6, 72.5, 75.3, 126.8, 128.7, 129.3, 141.1;
HR-FAB MS: Calcd for C17H28NO3 [M-I-]+: 294.2069, Found 294.2044.
1-[(R)-2-Hydroxy-2-phenylethyl]-1-methyl-[(2S,5S)-2,5-bis(methoxymethyl)]pyrrolidinium iodide
(3a’).
79% yield; pale-yellow oil; [α]25 -5.20 (c 2.19, MeOH); 1H-NMR (CDCl3) δ 1.94 (1H, m), 2.09 (1H, m),
D
2.29 (1H, m), 2.44 (1H, m), 3.36 (3H, s), 3.39 (3H, s), 3.51 (3H, s), 3.28-3.51 (2H, m), 3.62-3.69 (2H, m),

HETEROCYCLES, Vol. 83, No. 11, 2011
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3.80-3.99 (3H, m), 4.44 (1H, m), 4.85 (1H, m), 5.77 (1H, m), 7.29-7.39 (3H, m), 7.49 (2H, d, J = 7.2 Hz);
13C-NMR (CDCl3) δ: 24.0, 24.3, 47.0, 59.42, 59.46, 64.4, 67.6, 70.1, 70.8, 73.8, 126.2, 128.3, 128.9,
141.0; HR-FAB MS: Calcd for C17H28NO3 [M+H]+: 294.2069, Found 294.2068.
1-(2-Hydroxyhexyl)-1-methyl-[(2S,5S)-2,5-bis(methoxymethyl)]pyrrolidinium iodide (3b).
Diastereomer prepared from less polar 1-(2-hydroxyhexyl)[(2S,5S)-2,5-bis(methoxymethyl)]pyrrolidine:
1
14% yield from 1a; pale-yellow oil; H-NMR (CDCl3) δ 0.91 (3H, t, J = 7.2 Hz), 1.26-1.67 (6H, m),
1.96-2.14 (2H, m), 2.29 (1H, m), 2.44 (1H, m), 3.11 (1H, d, J = 13.6 Hz), 3.40 (6H, s), 3.42 (3H, s),
13
3.58-3.75 (4H, m), 3.96 (1H, d, J = 12.4 Hz), 4.38-4.45 (2H, m), 4.59 (1H, m), 4.91 (1H, m); C-NMR
(CDCl3) δ 14.0, 22.6, 24.0, 24.3, 27.4, 36.1, 59.4, 59.5, 63.5, 65.4, 70.1, 71.0, 73.6, 76.5, 76.8; HR-FAB
MS: Calcd for C15H32NO3 [M-I-]+: 274.2382, Found 274.2405.
Diastereomer prepared from more polar 1-(2-hydroxyhexyl)[(2S,5S)-2,5-bis(methoxymethyl)]pyrrolidine:
5% yield from 1a; pale-yellow oil; 1H-NMR (CDCl3) δ 0.91 (3H, t, J = 7.2 Hz), 1.26-1.51 (6H, m), 1.90
(1H, m), 2.09 (1H, m), 2.29 (1H, m), 2.40(1H, m), 3.29-3.46 (2H, m), 3.39 (3H, s), 3.40 (6H, s), 3.55 (1H,
m), 3.71 (1H, d, J = 13.6 Hz), 3.70-3.80 (2H, m), 4.26 (1H, d, J = 12.0 Hz), 4.35 (1H, m), 4.41-4.51 (2H,
m); HR-FAB MS: Calcd for C15H32NO3 [M-I-]+: 274.2382, Found 274.2379.
1-[2-Hydroxy-2-(4-fluorophenyl)ethyl]-1-methyl-[(2S,5S)-2,5-bis(methoxymethyl)]pyrrolidinium
iodide (3c).
Diastereomer prepared from less polar 1-[2-hydroxy-2-(4-fluorophenyl)ethyl][(2S,5S)-2,5-
bis(methoxymethyl)]pyrrolidine: 29% yield from 1a; pale-yellow oil; [α]25 -50.142 (c 2.24, CHCl3);
D
1H-NMR (CDCl3) δ 2.02-2.12 (2H, m), 2.25-2.49 (2H, m), 3.30 (3H, s), 3.39 (3H, s), 3.53 (3H, s),
3.60-3.69 (2H, m), 3.75-3.84 (2H, m), 4.01 (1H, d, J = 12.8 Hz), 4.44 (1H, m), 4.70 (1H, bs), 4.88 (1H,
m), 4,93 (1H, d, J = 6.4 Hz), 5.83 (1H, m), 7.02-7.06 (2H, t, J = 8.4 Hz), 7.53-7.56 (2H, dd, J = 5.2 Hz,
8.4 Hz); 13C-NMR (CDCl3) δ 23.9, 24.2, 46.9, 59.4, 59.5, 64.2, 66.9, 69.9, 70.8, 73.7, 76.9, 115.6 (d, JC-F
= 21.4 Hz), 128.2 (d, JC-F = 8.3 Hz), 136.8, 162.5 (d, JC-F = 246.2 Hz) ; HR-FAB MS: Calcd for
C17H27FNO3 [M-I-]+: 312.1975, Found 312.1979.
Diastereomer prepared from more polar 1-[2-hydroxy-2-(4-fluorophenyl)ethyl][(2S,5S)-2,5-bis-
(methoxymethyl)]pyrrolidine: 31% yield from 1a; pale-yellow oil; [α]25 +4.19(c 1.96, CHCl3); 1H-NMR
D
(CDCl3) δ 1.90-2.04 (1H, m), 2.05-2.19 (1H, m), 2.29 (1H, m), 2.43 (1H, m), 3.35 (3H, s), 3.39 (3H, s),
3.50 (3H, s), 3.53 (1H, bs), 3.75 (1H, m), 3.85-3.95 (2H, m), 4.24-4.28 (1H, m), 4.35 (1H, d, J = 12.4 Hz),
4.41 (1H, m), 5.01 (1H, d, J = 6.4 Hz), 5.65 (1H, m), 7.02-7.07 (2H, t, J = 8.8 Hz), 7.52-7.55 (2H, dd, J =
5.6 Hz, 8.4 Hz); 13C-NMR (CDCl3) δ 23.6, 24.6, 45.5, 59.4, 59.5, 63.3, 65.7, 69.9, 72.0, 74.8, 77.2, 115.5
(d, JC-F = 21.4 Hz), 128.0 (d, JC-F = 8.3 Hz), 136.3, 161.2 (d, JC-F = 244.5 Hz); HR-FAB MS: Calcd for
C17H27FNO3 [M-I-]+: 312.1975, Found 312.1991.
1-[2-Hydroxy-2-(naphth-2-yl)ethyl]-1-methyl-[(2S,5S)-2,5-bis(methoxymethyl)]pyrrolidinium iodide

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(3d).
Diastereomer
prepared
from
less
polar
1-[2-hydroxy-2-(nathth-2-yl)ethyl][(2S,5S)-2,5-bis-
(methoxymethyl)]pyrrolidine: 36% yield from 1a; pale-yellow oil; [α]25 +12.3 (c 1.46, CHCl3);
D
1H-NMR (CDCl3) δ 1.88-2.02 (2H, m), 2.21 (1H, m), 2.35 (1H, m), 3.19 (3H, s), 3.33 (3H, s), 3.35 (1H,
m), 3.47 (3H, s), 3.51-3.58 (2H, m), 3.74-3.91 (3H, m), 4.33 (1H, m), 4.82 (1H, m), 5.00 (1H, d, J = 6.4
Hz), 5.90 (1H, m), 7.41-7.46 (2H, m), 7.57 (1H, dd, J = 1.6 Hz, 8.8 Hz), 7.75-7.77 (2H, m), 7.84 (1H, m),
8.03 (1H, s); 13C-NMR (CDCl3) δ 23.9, 24.2, 46.9, 59.28, 59.33, 64.1, 67.6, 69.8, 70.7, 73.6, 76.8, 124.0,
125.4, 126.2, 126.3, 127.5, 128.1, 128.6, 133.0, 133.1, 138.3; HR-FAB MS: Calcd for C21H30NO3 [M-I-]+:
344.2226, Found 344.2219.
Diastereomer prepared from more polar 1-[2-hydroxy-2-(nathth-2-yl)ethyl][(2S,5S)-2,5-bis-
(methoxymethyl)]pyrrolidine: 29% yield from 1a; pale-yellow oil; [α]25 -61.0 (c 2.67, CHCl3); 1H-NMR
D
(CDCl3) δ 1.75-2.01 (2H, m), 2.11-2.42 (2H, m), 3.25 (3H, s), 3.27 (3H, s), 3.39 (1H, m), 3.44 (3H, s),
3.64 (1H, m), 3.73 (1H, m), 3.92 (1H, d, J = 13.6 Hz), 4.20-4.35 (3H, m), 5.06 (1H, d, J = 5.6 Hz), 5.72
(1H, m), 5.98 (1H, bs), 7.40-7.42 (2H, m), 7.51 (1H, d, J = 8.8 Hz), 7.75-7.80 (3H, m), 7.98 (1H, s);
13C-NMR (CDCl3) δ 24.1, 25.2, 42.0, 59.9, 60.0, 67.1, 67.5, 70.7, 71.5, 72.5, 77.9, 124.5, 125.9, 126.8,
126.9, 128.2, 128.7, 129.1, 133.6, 133.8, 138.4; HR-FAB MS: Calcd for C21H30NO3 [M-I-]+: 344.2226,
Found 344.2223.
1-[(S)-2-Hydroxy-2-phenylethyl]-1-methyl-[(2S,5S)-2,5-bis(methoxymethyl)]pyrrolidinium
tetrafluoroborate (3aa).
To a solution of 6 (79 mg, 0.28 mmol) in CHCl3 (7.0 mL) was added trimethyloxonium tetrafluoroborate
(20 mg, 0.14 mmol) under Ar atmosphere, and the solution was stirred at rt for 4h. After MeOH (2.0 mL)
was added, the solution was concentrated by evaporation. The residue was purified by column
chromatography on NH-silica gel (AcOEt: MeOH = 9: 1 as eluent) to give 3aa (37 mg 0.10 mmol) in 73%
1
yield: colorless oil; [α]25 +3.10 (c 0.87, CHCl3); H-NMR (CDCl3) δ 1.89 (1H, m), 2.07 (1H, m), 2.27
D
(1H, m), 2.41 (1H, m), 3.25 (3H, s), 3.33 (3H, s), 3.34 (3H, s), 3.38 (1H, m), 3.52 (1H, d, J = 8.8 Hz),
3.63 (1H, d, J = 12.0 Hz), 3.66-3.88 (2H, m), 4.14-4.16 (2H, m), 4.25-4.28 (2H, m), 4.28 (1H, s), 5.37
(1H, dd, J = 11.8, 3.4 Hz), 7.30-7.44 (5H, m); 13C-NMR (CDCl3) δ 23.3, 24.4, 43.7, 59.1, 59.4, 63.6, 68.0,
- +
69.7, 71.8, 74.6, 77.2, 126.0, 128.4, 128.9, 140.5; HR-FAB MS: Calcd for C17H28NO3 [M-BF4 ] :
294.2069, Found 294.2082.
1-[(S)-2-Hydroxy-2-phenylethyl]-1-methyl-[(2S,5S)-2,5-bis(methoxymethyl)]pyrrolidinium
trifluoromethanesulfonate (3ab).
To a solution of 6 (124 mg, 0.44 mmol) in CHCl3 (3.0 mL) was added methyl trifluoromethanesulfonate
(145 mg, 0.88 mmol) under Ar atmosphere, and the solution was stirred at rt for 3 h. The solution was
concentrated by evaporation and the residue was purified by column chromatography on NH-silica gel

HETEROCYCLES, Vol. 83, No. 11, 2011
2587
(AcOEt: MeOH = 9: 1 as eluent) to give 3ab (106 mg 0.24 mmol) in 54% yield: brown oil; [α]25 +6.40
D
(c 0.55, CHCl3); 1H-NMR (CDCl3) δ 1.88-1.93 (1H, m), 2.05-2.10 (1H, m), 2.25-2.31 (1H, m), 2.38-2.44
(1H, m), 3.23 (3H, s), 3.32 (3H, s), 3.33 (3H, s), 3.21-3.39 (2H, m), 3.47-3.66 (2H, m), 3.71-3.95 (2H, m),
4.07-4.19 (2H, m), 4.20-4.26 (2H, m), 5.42 (1H, dd, J = 2.8 Hz, 11.2 Hz), 7.30-7.33 (1H, m), 7.36-7.40
(2H, m), 7.43-7.45 (2H, m); 13C-NMR (CDCl3) δ 23.4, 24.4, 43.9, 59.1, 59.4, 63.7, 67.8, 69.8, 71.8, 74.6,
77.2, 120.4 (q, JC-F = 317.8 Hz), 126.0, 128.4, 128.9, 140.5; HR-FAB MS: Calcd for C17H28NO3
[M-TfO-]+: 294.2069, Found 294.2082.
General procedure for the catalytic asymmetric benzylation of tert-butyl glycinate benzophenone
Schiff base.
To a solution of t-butyl N-(diphenylmethylene)glycinate (5) (50 mg, 0.17 mmol), BnBr 24 µL (0.20
mmol), and catalyst (10 mol%) in toluene (1.5 mL) was added 50% aq. KOH solution (0.41 mL). The
solution was stirred at rt or 0 oC for 24 h. After H2O was added, the mixture was extracted with CH2Cl2
(10 mL x 3). The combined organic layers were dried over MgSO4 and concentrated. The yield of 5
1
was calculated by H NMR using mesitylene as an internal standard.10 Then the obtained mixture was
dissolved in THF (1.0 mL) and 0.5 M aqueous citric acid solution (1.0 mL) was added. The mixture
was stirred at rt for 3 h. After H2O (4.0 mL) was added, the aqueous solution was washed with Et2O (10
mL x 2), then basified with sat.NaHCO3 aqueous solution. The solution was extracted with CH2Cl2 (10
mL x 4) and dried over anhydrous MgSO4. After evaporation, tert-butyl phenylalaninate was obtained
as a single product, and the enantiomeric excess was determined by HPLC analysis (Daicel Chiralcel
OJ-H, hexane: i-PrOH = 100: 1, flow rate = 0.5 mL/min, retention time; 21.2 min (R isomer) and 23.8 min
(S isomer)).
ACKNOWLEDGEMENTS
This work was supported in part by Grants-in-Aid for Scientific Research and the High-Technology
Research Center Project from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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