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Synlett 2009(8): 1311-1314  
DOI: 10.1055/s-0029-1216736
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Novel Chiral Phase-Transfer Catalysts and Their Application to Asymmetric Synthesis of α-Amino Acid Derivatives

Wei He, Quanjun Wang, Qiaofeng Wang, Bangle Zhang, Xiaoli Sun, Shengyong Zhang*
Department of Chemistry, School of Pharmacy, The Fourth Military Medical University, 17 West Changle Road, 710032, Xi’an Shaanxi Province, P. R. of China
Fax: +86(29)84776945; e-Mail: syzhang@fmmu.edu.cn;
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Publication History

Received 29 December 2008
Publication Date:
22 April 2009 (online)

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Abstract

To investigate the electronic and steric influences on enantioselectivities of asymmetric phase-transfer reactions, a series of chiral quaternary ammonium salts were synthesized from cinchona alkaloids and 2-chloromethylbenzimidazole or 1-chloromethyl benzotriazole. Using one of the cinchonine-derived alkaloid catalysts, enantioselective alkylations of N-(diphenylmethylene) glycine tert-butyl ester were efficiently carried out with various alkyl halides to give products in high enantiomeric excess (94-99% ee).

Key words

asymmetric catalysis - alkylation - amino acids - phase-transfer catalysis - cinchona alkaloids

8

Procedure for the Synthesis of 1a-4a
To a suspension of cinchona alkaloid (10 mmoL) in toluene (40 mL) was added 2-chloromethylbenzimidazole (10.5 mmoL), and the mixture was stirred at reflux for 3 h (TLC with CH2Cl2-MeOH = 15:1). The mixture was cooled to r.t. and filtered. The solids were collected and recrystallized in Et2O to afford the pure product.
Compound 1a: white solid (prepared from cinchonine); yield 93%; mp 182-183 ˚C; [α]D ²5 +68 (c 0.5, EtOH). IR (KBr): 3425, 2947, 1637, 1510, 1458, 1402, 746 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 8.87 (d, J = 4.6 Hz, 1 H), 7.83-7.80 (m, 2 H), 7.51-7.45 (m, 3 H), 7.27-7.16 (m, 4 H), 6.70-6.67 (m, 2 H), 6.60 (s, 1 H), 6.30 (d, J = 13.8 Hz, 1 H), 5.93 (m, 1 H), 5.30-5.23 (m, 3 H), 4.85 (m, 1 H), 4.71 (t, J = 5.2 Hz, 1 H), 4.07 (t, J = 11.2 Hz, 1 H), 3.97 (t, J = 8.5 Hz, 1 H), 3.07 (m, 1 H), 2.62 (m, 1 H), 2.35-1.78 (m, 4 H), 0.87 (m, 1 H). MS: m/z (%) 425 ([M-Cl]+, 5), 424 (10), 293 (40), 159 (20), 132 (100). Anal. Calcd for C27H29ClN4O: C, 70.34; H, 6.34; N, 12.15. Found: C, 70.32; H, 6.30; N, 12.18.
Compound 2a: white solid (prepared from cinchonidine); yield 90%; mp 175-176 ˚C. [α]D ²5 -34 (c 0.5, EtOH). IR (KBr): 3423, 3238, 2960, 1641, 1620, 1591, 1508, 1456, 746 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 8.86 (d, J = 4.4 Hz, 1 H), 7.89 (d, J = 8.3 Hz, 1 H), 7.79 (d, J = 4.6 Hz, 1 H), 7.64-7.01 (m, 7 H), 6.77 (s, 1 H), 6.57-6.46 (m, 1 H), 6.14 (d, J = 13.8 Hz, 1 H), 5.46-5.24 (m, 2 H), 5.02 (m, 2 H), 4.72 (d, J = 13.6 Hz, 1 H), 4.05 (s, 1 H), 3.63-3.50 (m, 2 H), 2.68 (d, J = 5.0 Hz, 1 H), 2.20 (s, 1 H), 2.07-1.85 (m, 4 H), 1.24 (m, 1 H), 1.11 (m, 1 H). MS: m/z (%) = 425 (5) [M - Cl]+, 424 (10), 293 (55), 159 (15), 136 (40), 132 (100). Anal. Calcd for C27H29ClN4O: C, 70.34; H, 6.34; N, 12.15. Found: C, 70.37; H, 6.31; N, 12.14.
Compound 3a: pink solid (prepared from quinidine); yield 90%; mp 210-212 ˚C (dec.); [α]D ²5 +112 (c 0.2, EtOH). IR (KBr): 3425, 2935, 1624, 1512, 1437, 1242, 1028, 743 cm-¹. ¹H NMR (400 MHz, CD3OD): δ = 8.78 (d, J = 4.6 Hz, 1 H), 8.03 (d, J = 9.4 Hz, 1 H), 7.92 (d, J = 4.8 Hz, 1 H), 7.74-7.13 (m, 6 H), 6.76 (d, J = 1.7 Hz, 1 H), 6.12-6.03 (m, 1 H), 5.35-5.27 (m, 3 H), 5.08 (d, J = 10.0 Hz, 1 H), 4.76 (t, J = 10.0 Hz, 1 H), 4.15 (t, J = 9.0 Hz, 1 H), 3.97 (s, 3 H), 3.90 (m, 2 H), 3.42 (m, 1 H), 2.79 (m, 1 H), 2.41 (t, J = 2.0 Hz, 1 H), 2.31 (s, 1 H), 1.89-1.98 (m, 4 H), 1.03 (m, 1 H). MS: m/z (%) = 455 (5) [M - Cl]+, 454 (10), 324 (35), 189 (20), 136 (100). Anal. Calcd for C28H31ClN4O2: C, 68.49; H, 6.36; N, 11.41. Found: C, 68.52; H, 6.33; N, 11.37.
Compound 4a: pink solid (preapred from quinine); yield 85%, mp 170-172 ˚C (dec.); [α]D ²5 -50 (c 0.2, CH2Cl2). IR (KBr): 3403, 1622, 1510, 1242, 1028, 748 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 8.74 (d, J = 4.4 Hz, 1 H), 7.97 (d, J = 9.1 Hz, 1 H), 7.79 (d, J = 4.4 Hz, 1 H), 7.66-7.17 (m, 6 H), 6.90 (s, 1 H), 6.59 (s, 1 H), 5.80 (d, J = 13.0 Hz, 1 H), 5. 51-5. 40 (m, 2 H), 5.17 (d, J = 7.1 Hz, 1 H), 5.00 (m, 2 H), 4.06 (d, J = 6.3 Hz, 2 H), 3.94 (t, J = 8.5 Hz, 1 H), 3.61 (s, 3 H), 3.29 (m, 1 H), 2.68 (d, J = 4.4 Hz, 1 H), 2.34 (s, 1 H), 2.26-1.83 (m, 4 H), 1.20 (m, 1 H). MS: m/z (%) = 455 (10) [M - Cl]+, 454 (15), 123 (80), 136 (40), 132 (100). Anal. Calcd for C28H31ClN4O2: C, 68.49; H, 6.36; N, 11.41. Found: C, 68.54; H, 6.40; N, 11.39.

9

Procedure for the synthesis of 1b-4b
To a suspension of the cinchona alkaloid (10 mmoL) in 40 mL toluene was added 1-chloromethylbenzotriazole(10.5 mmoL), and the mixture was stirred at reflux for 3 h (TLC with CH2Cl2-MeOH = 15:1). The solvent was evaporated under reduced pressure. The pure product was attained by chromatography using CH2Cl2-MeOH as eluent.
Compound 1b: white solid (prepared from cinchonine); yield 85%; mp 170-172 ˚C; [α]D ²5 +148 (c 0.5, EtOH). IR (KBr): 3424, 2949, 1631, 1505, 1510, 1456, 1418, 1289, 764 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 8.81-8.79 (m, 1 H), 8.73 (d, J = 7.9 Hz, 1 H), 8.65 (d, J = 8.1 Hz, 1 H), 8.04-8.01 (m, 1 H), 7.97-7.87 (m, 3 H), 7.73-7.61 (m, 1 H), 7.45-7.38 (m, 2 H), 6.86 (s, 1 H), 5.76-5.73 (m, 1 H), 5.22-5.14 (m, 2 H), 4.98-4.83 (m, 1 H), 4.86-4.75 (m, 1 H), 4.08-3.87 (m, 1 H), 3.81-3.75 (m, 1 H), 3.70-3.54 (m, 2 H), 2.95-2.89 (m, 1 H), 2.63-2.54 (m, 1 H), 2.31-1.89 (m, 5 H), 1.29-1.26 (m, 1 H). Anal. Calcd for C26H28ClN5O: C, 67.59; H, 6.11; N, 15.16. Found: C, 67.54; H, 6.16; N, 15.20. ESI-MS: 426
[M - Cl]+.
Compound 2b: white solid (prepared from cinchonidine); yield 89%; mp 230-240 ˚C (dec.); [α]D ²5 -154 (c 0.5, EtOH). IR (KBr): 3398, 3243, 2955, 1629, 1498, 1455, 760 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 8.82-8.81 (m, 1 H), 8.69 (d, J = 7.8 Hz, 1 H), 8.45-8.41 (m, 1 H), 7.95-7.77 (m, 4 H), 7.49-7.37 (m, 3 H), 7.20 (s, 1 H), 6.79 (s, 1 H), 5.42-5.31 (m, 1 H), 5.13-5.08 (m, 1 H), 4.98 (d, J = 10.2 Hz, 1 H), 4.26-4.23 (m, 1 H), 3.69-3.56 (m, 2 H), 3.22-3.19 (m, 1 H), 2.52 (s, 1 H), 1.72-1.57 (m, 1 H), 1.09-1.01 (m, 1 H), 2.11-1.93 (m, 5 H). Anal. Calcd for C26H28ClN5O: C, 67.59; H, 6.11; N, 15.16. Found: C, 66.94; H, 6.20; N, 15.19. ESI-MS: 426 [M - Cl]+.
Compound 3b: white solid (prepared from quinidine); yield 88%; mp 190-195 ˚C (dec.); [α]D ²5 +149 (c 0.5, EtOH). IR (KBr): 3428, 2946, 1623, 1508, 1460, 1239 cm-¹. ¹H NMR (300 MHz, CD3Cl): δ = 8.63 (d, J = 8.1 Hz, 1 H), 8.46 (d, J = 4.2 Hz, 1 H), 7.83-7.78 (m, 4 H), 7.40-7.37 (m, 2 H), 7.21-7.11 (m, 1 H), 6.87 (s, 1 H), 5.80-5.68 (m, 1 H), 5.15-5.10 (m, 2 H), 4.87-4.80 (m, 1 H), 4.25-4.22 (m, 2 H), 3.85 (s, 3 H), 3.66-3.57 (m, 1 H), 3.06-3.03 (m, 1 H), 2.55-2.35 (m, 3 H), 2.33-2.31 (m, 1 H), 2.17 (t, J = 12.0 Hz, 1 H), 1.87-1.71 (m, 3 H), 1.25-1.21 (m, 1 H). ESI-MS: 456.6
[M - Cl]+. Anal. Calcd for C27H30ClN5O2: C, 65.91; H, 6.15; N, 14.23. Found: C, 65.89; H, 6.19; N, 14.21.
Compound 4b: white solid (prepared from quinine); yield 90%; mp 160-162 ˚C; [α]D ²5 -122 (c 0.5, EtOH). IR (KBr): 3421, 1621, 1506, 1460, 1352, 1235 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 8.68 (s, 1 H), 8.65 (d, J = 4.5 Hz, 1 H), 7.95-7.93 (m, 1 H), 7.91 (d, J = 3.3 Hz, 1 H), 7.78 (d, J = 4.2 Hz, 1 H), 7.66-7.64 (m, 1 H), 7.56 (d, J = 13.5Hz, 1 H), 7.47 (t, J = 7.2 Hz, 1 H), 7.36 (d, J = 7.5 Hz, 1 H), 6.97 (s, 1 H), 5.46-5.34 (m, 1 H), 5.07 (br s, 1 H), 4.96-4.91 (m, 2 H), 4.14-4.11 (m, 2 H), 3.98 (s, 3 H), 3.71 (t, J = 11.4 Hz, 1 H), 3.13 (d, J = 11.4 Hz, 1 H), 2.77-2.52 (m, 4 H), 2.19-2.18 (m, 1 H), 2.08-1.99 (m, 2 H), 1.98-1.85 (m, 1 H), 1.27-1.25 (m, 1 H). ESI-MS: 456.6 [M - Cl]+. Anal. Calcd for C27H30ClN5O2: C, 65.91; H, 6.15; N, 14.23. Found: C, 65.94; H, 6.20; N, 14.29.

10

Representative Procedure for Enantioselective Catalytic Alkylation of 5 under Phase-Transfer Conditions
To a mixture of N-(diphenylmethylene) glycine tert-butyl ester (5, 295 mg, 1 mmol) and chiral catalyst 1b (46.2mg, 0.1 mmol) in CH2Cl2 (10 mL) was added BnBr (205 mg, 1.2 mmol). Then a finely powdered and dried mixture of K2CO3 (138 mg, 1 mmol) and KOH (56 mg, 1 mmol) was added to the reaction mixture. The resulting suspension was then vigorously stirred at 20 ˚C till the reaction was complete (TLC, PE-EtOAc = 20:1). The suspension was diluted with CH2Cl2 (10 mol), washed with H2O (2 × 30 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography on SiO2 (PE-EtOAc = 20:1 to 10:1) afforded the desired product 6e (258 mg, 91% yield) as a colorless oil. The ee was determined
by chiral HPLC analysis [DAICEL Chiralcel OD, hexane-
i-PrOH (98:2), flow rate = 0.4 mL/min, 23 ˚C, λ = 259 nm; t R (R, major) = 12.2 min; t R (S, minor) = 15.5 min, 99% ee]. The absolute configuration was determined by comparison of the HPLC retention time with the authentic sample synthesized by the reported procedure.

11

Acidic Hydrolysis of Alkylated Imine 6e to the Corresponding ( R )-Phenylalanine
The crude alkylated imine 6e was treated by refluxing 4 h
in HCl (4 mL, 6 mol/L), followed by neutralization of the amine hydrochloride using propylene oxide (0.8 mL) in EtOH. After being filtrated and washed with precooled Et2O and EtOH, the (R)-phenylalanine was attained in 75% yield, [α]D ²5 +32 (c 1.0, H2O), lit. [α]D ²5 +33.7 (c 2.0, H2O).