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

doi:10.1055/s-0029-1216736

LETTER

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;

Abstract

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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

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References

References and Notes

<A NAME="RW20008ST-1A">1a</A> O’Donnell MJ. Acc. Chem. Res. 2004, 37: 506

<A NAME="RW20008ST-1B">1b</A> Lygo B. Andrews BI. Acc. Chem. Res. 2004, 37: 518

<A NAME="RW20008ST-1C">1c</A> Vachon J. Lacour J. Chimia 2006, 60: 266

<A NAME="RW20008ST-1D">1d</A> Hashimoto T. Maruoka K. Chem. Rev. 2007, 107: 5656

<A NAME="RW20008ST-1E">1e</A> Maruoka K. Org. Process Res. Dev. 2008, 12: 679

<A NAME="RW20008ST-2A">2a</A> Thierry B. Plaquevent JC. Cahard D. Tetrahedron: Asymmetry 2001, 12: 983

<A NAME="RW20008ST-2B">2b</A> Lygo B. Crosby J. Lowdon TR. Wainwright PG. Tetrahedron 2001, 57: 2391

<A NAME="RW20008ST-2C">2c</A> Park H. Jeong B. Yoo M. Park M. Huh H. Jew S. Tetrahedron Lett. 2001, 42: 4645

<A NAME="RW20008ST-2D">2d</A> Lygo B. Andrews BI. Crosby J. Peterson JA. Tetrahedron Lett. 2002, 43: 8015

<A NAME="RW20008ST-3A">3a</A> Ooi T. Kameda M. Maruok K. J. Am. Chem. Soc. 2003, 125: 5139

<A NAME="RW20008ST-3B">3b</A> Kitamura M. Shirakawa S. Maruoka K. Angew. Chem. Int. Ed. 2005, 44: 1549

<A NAME="RW20008ST-3C">3c</A> Hashimoto T. Tanaka Y. Maruoka K. Tetrahedron: Asymmetry 2003, 14: 1599

<A NAME="RW20008ST-3D">3d</A> Han Z. Yamaguchi Y. Kitamura M. Maruoka K. Tetrahedron Lett. 2005, 46: 8555

<A NAME="RW20008ST-4">4</A> O’Donnell MJ. Bennett WD. Wu S. J. Am.Chem. Soc. 1989, 111: 2353

<A NAME="RW20008ST-5">5</A> O’Donnell MJ. Wu S. Huffman JC. Tetrahedron 1994, 50: 4507

<A NAME="RW20008ST-6">6</A> Lygo B. Wainwright PG. Tetrahedron Lett. 1997, 38: 8595

<A NAME="RW20008ST-7">7</A> Corey EJ. Xu F. Noe MC. J. Am. Chem. Soc. 1997, 119: 12414

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.

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.

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.

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).

Supplementary Material

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