HETEROCYCLES

Short Paper | Regular issue | Vol. 83, No. 11, 2011, pp. 2577-2588
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 Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan

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 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).

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

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 with styrene oxide in the presence of Ca(OTf)27 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 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%.
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.

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) or a 400 MHz (100 MHz for 13C) 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 (4H, sxt, J = 7.2 Hz), 1.85-1.98 (2H, m), 2.40 (1H, bs), 3.28-3.45 (10H, m); 13C-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 under H2 atmosphere for 3h at rt and filtered. The filtrate was evaporated to give 1c (32 mg, 0.10 mmol) in 79% yield: a colorless oil; 1H-NMR (CDCl3) δ 1.41-1.50 (2H, m), 1.86-1.92 (2H, m), 2.25 (1H, bs), 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); 13C-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), 3.78-3.83 (2H, m), 3.97-4.03 (2H, m); 13C-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 of methyl iodide (90% yield): brownish needles; mp 132 oC (CHCl3/AcOEt); 1H-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, m), 5.61 (2H, d, J = 10.4 Hz), 5.72 (2H, d, J = 16.8 Hz), 6.17-6.26 (2H, m); 13C-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.
(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 instead of 1-iodobutane (11% yield): pale-yellow oil; 1H-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 Hz), 7.28-7.37 (10H, m); 13C-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 material (88% yield): colorless crystals; mp 274 °C; 1H-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, 13.4 Hz), 4.31-4.38 (2H, m); 13C-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, 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]25D -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 = 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 (1H, bs), 4.65 (1H, dd, J = 3.6, 8.4 Hz), 7.23-7.39 (5H, m); 13C-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]25D -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 = 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, 10.8 Hz), 7.24-7.23 (1H, m), 7.32-7.40 (4H, m); 13C-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]25D +21.4 (c 0.51, MeOH); 1H-NMR (CDCl3) δ 1.97 (1H, m), 2.07 (1H, m), 2.24 (1H, 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]25D -5.20 (c 2.19, MeOH); 1H-NMR (CDCl3) δ 1.94 (1H, m), 2.09 (1H, m), 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), 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: 14% yield from 1a; pale-yellow oil; 1H-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), 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); 13C-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]25D -50.142 (c 2.24, CHCl3); 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]25D +4.19(c 1.96, CHCl3); 1H-NMR (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 (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]25D +12.3 (c 1.46, CHCl3); 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]25D -61.0 (c 2.67, CHCl3); 1H-NMR (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% yield: colorless oil; [α]25D +3.10 (c 0.87, CHCl3); 1H-NMR (CDCl3) δ 1.89 (1H, m), 2.07 (1H, m), 2.27 (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 (AcOEt:MeOH = 9:1 as eluent) to give 3ab (106 mg 0.24 mmol) in 54% yield: brown oil; [α]25D +6.40 (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 was calculated by 1H 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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