Eur. J. Org. Chem. ISSN 1099 0690skkim.skku.edu/abstract/supporting-paper70.pdf · Compound...

75
Eur. J. Org. Chem. · ISSN 10990690 https://doi.org/10.1002/ejoc.201800321 SUPPORTING INFORMATION Title: Discrimination of the Chirality of α-Amino Acids in Zn II Complexes of DPA-Appended Binaphthyl Imine Author(s): Mukesh Eknath Shirbhate, Raju Nandhakumar,* Youngmee Kim, Sung-Jin Kim, Seong Kyu Kim,* Kwan Mook Kim*

Transcript of Eur. J. Org. Chem. ISSN 1099 0690skkim.skku.edu/abstract/supporting-paper70.pdf · Compound...

  • Eur. J. Org. Chem. · ISSN 1099–0690

    https://doi.org/10.1002/ejoc.201800321

    SUPPORTING INFORMATION

    Title: Discrimination of the Chirality of α-Amino Acids in ZnII Complexes of DPA-Appended Binaphthyl Imine Author(s): Mukesh Eknath Shirbhate, Raju Nandhakumar,* Youngmee Kim, Sung-Jin Kim, Seong Kyu Kim,* Kwan Mook Kim*

  • Experimental Section:

    General

    Compound R3 was prepared according to the literature procedure1. All other chemicals were commercially available and used without further purifications. The

    solvents for dry reactions were dried with appropriate desiccants and distilled prior to use. NMR spectra were recorded on a BrukerAM 300 MHz and 500 MHz

    spectrometer in CDCl3 & DMSO-d6 solutions containing tetramethylsilane as internal standard. Chemical shifts are reported in δ unit. Melting points were measured

    with Electrothermal IA 9000 digital melting point apparatus and are uncorrected. HRMS spectra were obtained on EI or FAB mode. For column Chromatography silica

    gel of 230-400 mesh was used.

    References

    1. L. Tang, G. Wei, R. Nandhakumar, Z. Guo, Bull. Kor. Chem. Soc. 2011, 32, 3367-3371.

    SI-1. Syntheses of (R)-1 and (R)-2

  • NO

    O

    NN

    X

    O

    OH

    NOH

    O

    CHON

    N

    X

    (R)-3(R)-4a (67%) : X = CH

    O

    O

    (R)-5a (81%)

    NOH

    O

    NN

    X

    (R)-6a (89%)

    OH

    BrO

    O X

    O

    (R)-1 (73 %)

    Conc. HClMnO2, CH2Cl2

    K2CO3, CH3CN reflux

    K2CO3, CH3CNreflux

    EtOH/THFreflux reflux

    X

    Br Br

    X = CH or N

    (R)-4b (70%): X = N

    N N

    N

    H

    (R)-5b (82%)

    (R)-6b (91%)(R)-2 (77%)

    R3

    Compound binaphtholic acid (400 mg, 1.2 mmol), and 2, 2-dimethoxypropane (0.2 g, 22.24 mmol), were dissolved in dry Acetone (20 ml) and then H2SO4

    (only 1 drop) was added in the reaction mixture. The resulting mixture was stirrer room temperature for 12 hours. The resulting mixture was combine with

    Na2CO3, and extract with methylene chloride. The organic layer was dried over (NaSO4) and the solvent was concentrated under reduced pressure. The

    resulting residue was purified by silica gel column chromatography by using Ethyl acetate / Hexane (1:9) as an eluent to give compound R3. (392 mg, 87%):

    mp = 110 oC;

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 7.94 (d, 1H, 6Hz), 7.90-7.82 (m, 2H), 7.69 (bs, 1H,), 7.40 -7.27 (m, 3H), 7.27-7.20 (m, 2H), 7.18-7.15 (m,

    1H), 7.11-7.01 (m, 1H), 5.25-5.13 (m, 2H), 4.97 (s, 1H), 1.47 (s, 3H), 1.43 (s, 3H).

    13C NMR (CDCl3, 70 MHz): δ (ppm): 151.61, 149.06, 134.03, 133.52, 129.97, 129.34, 128.96, 128.26, 128.01, 127.00, 126.44, 125.19, 125.14, 125.04,

    124.60, 123.38, 121.60, 117.73, 115.01, 114.60, 100.63, 61.47, 25.54, 24.60.

  • R-4a

    Compound R-3 (200 mg, 0.56 mmol), was dissolved in dry CH3CN (20 ml) was added in charge K2CO3 (85 mg, 0.61 mmol) at room temperature and allow

    the resulting mixture to stirred for 50 min. Then m-Xylylene dibromide (146 mg, 0.56 mmol) was added in the resulting mixture and allow to stirrer at room

    temperature for 10 h. After completion of reaction the insoluble materials were removed by filtration, and combined with water and washed with methylene

    chloride. The organic layer was dried over (NaSO4) and the solvent was concentrated under reduced pressure. The resulting residue was purified by silica

    gel column chromatography by using Ethyl acetate / Hexane (1:4) as an eluent to give compound R-4a. (202 mg, 67%): mp = 80 oC;

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 7.99 (d, 1H, 9Hz), 7.95-7.87 (m, 2H), 7.46 (d, 1H, 9Hz), 7.42-7.34 (m, 2H), 7.33-7.26 (m, 3H), 7.24-7.14

    (m, 4H), 7.03 (d, 1H, 6Hz), 6.84 (s, 1H), 5.23 (s, 2H), 5.10-5.01 (m, 2H), 4.33-4.25 (m, 2H), 1.44 (s, 3H), 1.40 (s, 3H).

    13C NMR (CDCl3, 70 MHz): δ (ppm): 154.46, 148.11, 138.49, 138.01, 134.42, 133.73, 129.86, 129.61, 128.78, 128.77, 128.38, 128.16, 127.86, 127.73,

    129.25, 126.96, 126.45, 126.18, 125.91, 125.48, 124.09, 124.01, 123.76, 121.42, 120.71, 118.87, 116.51, 100.23, 71.37, 61.72, 33.69, 25.08, 24.68.

    R-4b

    Compound R-3 (200 mg, 0.56 mmol), was dissolved in dry CH3CN (20 ml) was added in charge (85 mg, 0.61 mmol) at room temperature and allow the

    resulting mixture to stirred for 50 min. Then 2,6 Bis(bromomethyl)pyridine (146 mg, 0.56 mmol) was added in the resulting mixture and allow to stirrer at

    room temperature for 10 h. After completion of reaction the insoluble materials were removed by filtration, and combined with water and washed with

    methylene chloride. The organic layer was dried over (NaSO4) and the solvent was concentrated under reduced pressure. The resulting residue was purified

    by silica gel column chromatography by using Ethyl acetate / Hexane (1:4) as an eluent to give compound R-4b. (211 mg, 70%): mp = 73 oC;

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 7.96 (d, 1H, 9Hz), 7.90 (d, 1H, 9Hz), 7.84 (d, 1H, 9Hz), 7.65 (s, 1H), 7.42 (s, 1H), 7.40-7.30 (m, 3H),

    7.26-7.12 (m, 5H), 6.82 (d, 1H, 9Hz), 5.23 (s, 2H), 5.20-5.18 (m, 2H), 4.50 (s, 2H), 1.41 (s, 3H), 1.39 (s, 3H).

    13C NMR (CDCl3, 70 MHz): δ (ppm): 158.24, 155.94, 154.01, 147.96, 137.67, 134.35, 133.65, 129.70, 129.67, 128.69, 128.12, 127.76, 126.47, 126.12,

    125.74, 125.44, 123.99, 123.95, 123.60, 122.10, 121.33, 120.48, 119.90, 118.80, 115.42, 100.16, 71.68, 61.64, 33.94, 25.92, 24.43.

  • R-5a

    Compound R-4a (390 g, 0.72 mmol), and dipicolylamine (156 mg, 0.75 mmol), were dissolved in dry CH3CN (20 ml) and then K2CO3 (299 mg, 1.44 mmol)

    was added in the reaction mixture. The resulting mixture was stirrer at refluxed temperature for 10 h. After completion of reaction the insoluble materials

    were removed by filtration, and combined with water and washed with methylene chloride. The organic layer was dried over (NaSO4) and the solvent was

    concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography by using Chloroform / Methanol (9:1) as an

    eluent to give compound R-5a. (385mg, 81%): mp = 67 oC;

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.54 (d, 2H, 6Hz), 7.89-7.79 (m, 3H), 7.62-7.47 (m, 5H), 7.45-7.24 (m, 6H), 7.19-7.11 (m, 5H), 6.97 (d, 2H,

    9Hz), 7.22-5.10 (m, 2H), 5.10-5.01 (m, 2H), 3.74 (s, 4H), 3.53 (t, 2H, 8Hz), 1.39 (s, 3H), 1.35 (s, 3H).

    13C NMR (CDCl3, 70 MHz): δ (ppm): 159.95, 154.55, 149.14, 147.99, 139.22, 137.87, 136.62, 134.38, 133.65, 129.74, 129.39, 128.67, 128.41, 128.06,

    127.79, 127.62, 126.31, 126.06, 125.83, 125.80, 125.43, 123.93, 123.90, 123.59, 123.06, 122.15, 121.28, 120.57, 118.88, 116.73, 71.79, 61.61, 60.15, 58.68,

    25.60, 24.72.

    R-5b

    Compound R-4b (390 g, 0.72 mmol), and dipicolylamine (156 mg, 0.75 mmol), were dissolved in dry CH3CN (20 ml) and then K2CO3 (299 mg, 1.44 mmol)

    was added in the reaction mixture. The resulting mixture was then stirrer at refluxed temperature for 10 h. After completion of reaction the insoluble materials

    were removed by filtration, and combined with water and washed with methylene chloride. The organic layer was dried over (NaSO4) and the solvent was

    concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography by using Chloroform / Methanol (9:1) as an

    eluent to give compound R-5b. (389mg, 82%): mp = 65 oC;;

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.55-8.53 (m, 2H), 7.91-7.88 (m, 3H), 7.67-7.55 (m, 5H), 7.40-7.30 (m, 5H), 7.26-7.12 (m, 6H), 6.80-6.74 (m,

    1H), 5.21 (s, 2H), 5.18-5.12 (m, 2H), 3.88 (s, 4H), 3.85 (s, 2H), 1.40 (s, 3H), 1.37 (s, 3H).

  • 13C NMR (CDCl3, 70 MHz): δ (ppm): 159.62, 158.66, 157.44, 154.08, 149.32, 147.95, 137.06, 136.63, 134.35, 133.66, 129.59, 129.55, 128.67, 128.08,

    127.72, 126.39, 126.05, 125.70, 125.48, 123.90, 123.85, 123.53, 123.18, 122.22, 121.51, 121.31, 119.68, 119.42, 118.88, 115.38, 100.12, 71.80, 61.64, 60.45,

    60.38, 25.78, 24.53.

    R-6a

    Compound R-5a (0.350 g, 0.65 mmol), was dissolved in THF:Et2OH (30:60 ml) and then two drops of HCl was added. The resulting mixture was then

    stirred at refluxed for 10 h, at refluxed temperature. The reaction mixture was then combine with brine solution and extract with methylene chloride. The

    organic layer was dried over (NaSO4) and the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column

    chromatography using Chloroform / Methanol (9:1) as an eluent to give compound R-6a. (291 mg, 89%): mp = 91 oC;

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.44-8.42 (m, 2H), 7.97-7.85 (m, 4H), 7.65-7.59 (m, 2H), 7.54 – 7.45 (m, 3H), 7.40-7.29 (m, 5H), 7.23-7.08

    (m, 6H), 6.98 (d, 1H, 9Hz), 6.44 (bs, 1H), 5.15 (m, 4H), 3.65 (t, 4H, 15Hz), 3.58 (d, 1H, 12Hz), 3.06(d 1H, 12Hz).

    13C NMR (CDCl3, 70 MHz): δ (ppm): 159.95, 154.55, 149.14, 147.99, 139.22, 137.87, 136.26, 134.38, 133.65, 129.74, 129.39, 128.67, 128.41, 128.06,

    127.79, 127.62, 126.31, 126.06, 125.83, 125.80, 125.43, 123.93, 123.90, 123.59, 123.06, 122.15, 121.28, 120.57, 118.88, 116.73, 71.23, 62.83, 60.03, 59.05.

    R-6b

    Compound R-5b (0.350 g, 0.65 mmol), was dissolved in THF:Et2OH (30:60 ml) and then two drops of HCl was added. The resulting mixture was then

    stirred at refluxed for 10 h, at refluxed temperature. The reaction mixture was then combine with brine solution and extract with methylene chloride. The

    organic layer was dried over (NaSO4) and the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column

    chromatography using Chloroform / Methanol (9:1) as an eluent to give compound R-6b. (297 mg, 91%): mp = 89 oC;

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.46.843 (m, 2H), 7.85.7.81 (m, 3H), 7.76 (d, 1H, 9Hz), 7.59 – 7.53 (m, 2H), 7.46 (t, 1H, 6Hz), 7.39-7.36 (m,

    2H), 7.33-7.26 (m, 4H), 7.24-7.16 (m, 3H), 7.14-7.04 (m, 3H), 6.87 (d, 1H, 6Hz), 5.27 (t, 2H, 12Hz), 5.01 (t, 2H, 6Hz), 3.76 (s, 2H), 3.71 (s, 4H).

  • 13C NMR (CDCl3, 70 MHz): δ (ppm): 159.40, 158.65, 156.26, 154.15, 151.48, 149.11, 137.41, 136.62, 134.29, 133.92, 130.42, 129.87, 129.71, 129.02,

    128.24, 128.22, 127.69, 127.14, 126.35, 125.64, 125.22, 124.32, 123.58, 123.28, 122.43, 122.18, 119.71, 118.41, 116.50, 115.50, 70.83, 63.54, 60.17, 59.81.

    R-1

    To a solution of R-6a (300 g, 0.46 mmol) was dissolved in dry methylene chloride (20 ml) and then MnO2 (25 mmol) was added. The resulting mixture was

    then stirred for 10 h, at refluxed temperature. The reaction mixture was filter through the Celite pad and the solvent was concentrated under reduced pressure.

    The resulting residue was purified by silica gel column chromatography by using Chloroform / Methanol (9:1) as an eluent to give compound R-1. (218mg,

    73%): mp = 79 oC;

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 10.54 (bs, 1H), 10.15 (s, 1H), 8.54-8.51 (m, 2H), 8.28 (s, 1H), 7.99 – 7.95 (m, 1H), 7.94 (d, 1H, 9Hz), 7.88(d, 1H,

    9Hz), 7.60-7.54(m, 2H), 7.51-7.44(m, 3H), 7.39-7.32(m, 4H), 7.31-7.21(m, 6H), 7.17 – 7.09 (m, 3H), 7.02 (s, 1H), 6.95 (d, 1H, 9Hz), 5.13 (s, 2H), 3.73 (s,

    4H), 3.51 (s, 2H).

    13C NMR (CDCl3, 70 MHz): δ (ppm): 197.06, 159.91, 154.52, 153.80, 149.14, 139.28, 138.17, 138.10, 137.60, 136.68, 133.97, 130.56, 130.25, 130.07,

    129.79, 128.52, 128.47, 128.23, 127.79, 127.611, 126.96, 125.80, 125.66, 125.19, 124.52, 124.20, 123.06, 122.36, 122.21, 118.92, 118.76, 116.09, 71.56,

    60.20, 58.74.

    MS (ES) m/z (M+H+) HRMS (ES) calcd m/z 615.2522 (C41H34N3O3) found m/z 616.2591.

    R-2

    To a solution of R-6b (300 g, 0.46 mmol) was dissolved in dry methylene chloride (20 ml) and then MnO2 (25 mmol) was added. The reaction mixture was

    then stirred for 10 h, at refluxed temperature. The reaction mixture was filter through the Celite pad and the solvent was concentrated under reduced pressure.

    The resulting residue was purified by silica gel column chromatography by using Chloroform / Methanol (9:1) as an eluent to give compound R-2. (229mg,

    77%): mp = 72 oC;

  • 1H NMR (CDCl3, 250 MHz) : δ (ppm): 10.51 (bs, 1H), 10.21 (s, 1H), 8.55-8.52 (m, 2H), 8.32 (s, 1H), 8.00 – 8.97 (m, 1H), 7.96 (d, 1H, 9Hz), 7.88 (d, 1H,

    9Hz), 7.66-7.61 (m, 2H), 7.45-7.27 (m, 7H), 7.26.-7.19 (m, 2H), 7.16-7.11 (m, 2H), 6.81 – 6.75 (m, 1H), 5.25 (t, 2H, 12Hz), 3.87 (s, 4H), 3.84 (s, 2H).

    13C NMR (CDCl3, 70 MHz): δ (ppm): 196.93, 159.52, 158.74, 157.10, 154.09, 153.77, 149.28, 138.15, 137.94, 137.20, 136.68, 133.90, 130.56, 130.41,

    129.99, 129.66, 128.46, 127.79, 127.00, 125.68, 125.09, 124.53, 124.16, 123.20, 122.42, 122.26, 121.68, 119.31, 118.88, 118.08, 115.19, 71.75, 60.36, 60.28.

    MS (ES) m/z (M+H+) HRMS (ES) calcd m/z 617.2474 (C40H33N4O3) found m/z 617.2505.

    SI-2. General procedure for preparing Zn complexes

    In a typical experiment, compound (R)-1 (0.050 g, 0.081 mmol), Zn(ClO4)2•6H2O (0.053 g, 0.178 mmol), racemic phenylalanine (2.0 eq) and KOH (0.045

    g, 0.81 mmol) were dissolved in dry MeOH (5 mL). The reaction mixture was then stirred for 8 h, at room temperature. After 8 h stirring, the reaction mixture

    was evaporated and extracted with CH2Cl2 and washed with water. TLC for the reaction mixture with an eluent of MeOH/ CH2Cl2 in 2 % indicated the

    formation of two products, diastereomers. These two diastereomers (R)-1-Zn-D-Phe and (R)-1-Zn-L-Phe, were successfully separated using column

    chromatography on alumina using CH2Cl2:MeOH (9:1) as mobile phase.

    (R)-1-Zn-L-Phe

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.45 (d, 1H, 6Hz), 8.00 (d, 1H, 6Hz), 7.82 (s, 1H), 7.69-7.66 (m, 2H), 7.63-7.61 (m, 2H), 7.49 (s, 1H), 7.45 (d, 1H,

    9Hz), 7.42-7.25 (m, 4H), 7.25-7.14 (m, 5H), 7.11-7.04 (m, 2H), 7.02-6.97 (m, 3H), 6.92 (d, 1H, 9Hz), 6.82-6.77 (m, 1H), 6.74-6.68 (m, 3H), 6.31 (d, 1H,

    9Hz), 5.32 (d, 1H, 12Hz), 5.11 (d, 1H, 15Hz), 4.89 (d, 1H, 15Hz), 4.66 (d, 1H, 18Hz), 4.04-4.00 (m, 1H), 3.79 (d, 1H, 6Hz), 3.74 (d, 1H, 6Hz), 3.57 (d, 1H,

    12Hz), 3.51-3.45 (m, 1H), 3.04 (d, 1H, 12Hz), 2.47-2.39 (m, 1H).

    (R)-1-Zn-D-Phe

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.40 (d, 1H, 6Hz), 8.15 (d, 1H, 6Hz), 7.99 (s, 1H), 7.67-7.64 (m, 1H), 7.58-7.55 (m, 1H), 7.52-7.41 (s, 1H), 7.40-

    7.27 (m, 6H), 7.20-7.08 (m, 7H), 7.04-6.94 (m, 4H), 6.89 (d, 1H, 9Hz), 6.83-6.79 (m, 1H), 6.76-6.65 (m, 3H), 6.51 (d, 1H, 6Hz), 5.44 (d, 1H, 15Hz), 5.27

  • (d, 1H, 15Hz), 4.94 (d, 1H, 15Hz), 4.77 (d, 1H, 15Hz), 4.15-4.12 (m, 1H), 3.88 (d, 1H, 15Hz), 3.72 (d, 1H, 15Hz), 3.54-3.50 (m, 1H), 3.44 (d, 1H, 9Hz),

    3.03 (d, 1H, 12Hz), 2.32-2.28 (m, 1H).

    (R)-1-Zn-L-ala:- By adopting a general procedure mention above.

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.80 (s, 1H), 8.44 (d, 1H, 3Hz), 8.07 (d, 1H, 3Hz), 7.99 (s, 1H), 7.82-7.76 (m, 2H), 7.63-7.58 (m, 2H), 7.46 (d, 1H,

    9Hz), 7.34-7.31 (m, 1H), 7.19-7.14 (m, 4H), 7.06-6.98 (m, 4H), 6.91-6.90 (m, 1H), 6.85-6.82 (m, 1H), 6.75-6.69 (m, 3H), 6.31 (d, 1H, 6Hz), 5.27 (d, 1H,

    12Hz), 5.12 (d, 1H, 18Hz), 4.84 (d, 1H, 12Hz), 4.68 (d, 1H, 15Hz), 3.98-3.95 (m, 1H), 3.80-3.72 (m, 2H), 3.64 (d, 1H, 12Hz), 3.06 (d, 1H, 12Hz), 1.29-1.27

    (m, 3H).

    (R)-1-Zn-D-ala

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.83 (s, 1H), 8.25-8.22 (m, 2H), 7.99 (s, 2H), 7.81-7.60 (m, 1H), 7.57-7.49 (m, 2H), 7.41 (d, 1H, 9Hz), 7.31-7.22 (m,

    3H), 7.19-7.13 (m, 2H), 7.13 (d, 1H, 6Hz), 7.05-6.98 (m, 2H), 6.96-6.85 (m, 3H), 6.74-6.69 (m, 3H), 6.46 (d, 1H, 9Hz), 5.40 (d, 1H, 15Hz), 5.22 (d, 1H,

    15Hz), 4.85 (d, 1H, 15Hz), 4.74 (d, 1H, 15Hz), 4.04-3.97 (m, 1H), 3.85 (d, 1H, 15Hz), 3.71 (d, 1H, 12Hz), 3.46 (d, 1H, 9Hz), 3.04 (d, 1H, 12Hz), 1.28-1.27

    (m, 3H).

    (R)-1-Zn-L-Trp:- By adopting a general procedure mention above.

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.33-8.32 (m, 2H), 7.98 (d, 1H, 3Hz), 7.84-7.78 (m, 2H), 7.69-7.67 (m, 4H), 7.45-7.36 (m, 4H), 7.19-7.13 (m, 6H),

    7.05-6.96 (m, 4H), 6.88-6.85 (m, 2H), 6.78-6.68 (m, 4H), 6.29 (d, 1H, 6Hz), 5.29 (d, 1H, 18Hz), 5.10 (d, 1H, 18Hz), 4.82 (d, 1H, 18Hz), 4.65 (d, 1H, 18Hz),

    4.15-4.12 (m, 1H), 3.76-3.68 (m, 4H), 3.02 (d, 1H, 12Hz), 2.61-2.52 (m, 1H).

    (R)-1-Zn-D-Trp

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.31-8.30 (m, 1H), 8.16-8.13 (m, 2H), 7.98 (s, 1H), 7.90 (d, 1H, 6Hz), 7.72 (s, 1H), 7.62-7.37 (m, 6H), 7.32-7.04 (m,

    6H), 6.98-6.80 (m, 8H), 6.74-6.63 (m, 3H), 6.48 (d, 1H, 6Hz), 5.43 (d, 1H, 12Hz), 5.25 (d, 1H, 18Hz), 4.89 (d, 1H, 15Hz), 4.76 (d, 1H, 15Hz), 4.26-4.23 (m,

    1H), 3.85 (d, 1H, 15Hz), 3.71-3.60 (m, 2H), 3.45 (d, 1H, 9Hz), 3.04 (d, 1H, 12Hz), 2.43-2.38 (m, 1H).

  • (R)-1-Zn-L-Val:- By adopting a general procedure mention above.

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.72 (s, 1H), 8.44 (d, 1H, 3Hz), 8.05 (d, 1H, 3Hz), 8.01 (s, 1H), 7.83-7.80 (m, 1H), 7.63-7.56 (m, 3H), 7.46-6.43 (m,

    2H), 7.25-7.10 (m, 4H), 7.08-7.10 (m, 2H), 6.99-6.88 (m, 3H), 6.83-6.71 (m, 4H), 6.30 (d, 1H, 9Hz), 5.31 (d, 1H, 12Hz), 5.12 (d, 1H, 18Hz), 4.90 (d, 1H,

    15Hz), 4.67 (d, 1H, 12Hz), 3.74-3.67 (m, 2H), 3.62 (d, 1H, 3Hz), 3.52 (d, 1H, 12Hz), 3.00 (d, 1H, 12Hz), 1.01 (d, 3H, 6Hz), 0.90-0.83 (m, 1H), 0.72 (d, 3H,

    6Hz).

    (R)-1-Zn-D-Val

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.73 (s, 1H), 8.36-8.34 (m, 1H), 8.17 (d, 1H, 6Hz), 8.00 (s, 1H), 7.96 (m, 1H), 7.81-7.78 (m, 1H), 7.59-7.56 (m, 1H),

    7.51-7.45 (m, 1H), 7.41 (d, 1H, 9Hz), 7.25-7.21 (m, 2H), 7.17-7.13 (m, 2H), 7.09-7.01 (m, 4H), 6.95-6.90 (m, 2H), 6.85-6.76 (m, 2H), 6.73-6.70 (m, 2H),

    6.50 (d, 1H, 9Hz), 5.43 (d, 1H, 12Hz), 5.27 (d, 1H, 15Hz), 4.93 (d, 1H, 18Hz), 4.72 (d, 1H, 15Hz), 3.84 (d, 1H, 15Hz), 3.67 (d, 1H, 15Hz), 3.59 (d, 1H,

    6Hz), 3.39 (d, 1H, 9Hz), 3.03 (d, 1H, 12Hz), 0.93-0.90 (m, 3H), 0.88-0.83 (m, 1H), 0.77 (d, 3H, 6Hz).

    (R)-1-Zn-L-Ser:- By adopting a general procedure mention above.

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.89 (s, 1H), 8.41 (d, 1H, 3Hz), 8.09 (d, 1H, 3Hz), 8.01 (s, 1H), 7.80-7.75 (m, 2H), 7.60-7.55 (m, 2H), 7.45 (d, 1H,

    9Hz), 7.32-7.28 (m, 1H), 7.21-7.12 (m, 4H), 7.06-6.99 (m, 4H), 6.93-6.84 (m, 2H), 6.78-6.69 (m, 3H), 6.34 (d, 1H, 9Hz), 5.21 (d, 1H, 12Hz), 5.51 (d, 1H,

    18Hz), 4.80 (d, 1H, 15Hz), 4.68 (d, 1H, 15Hz), 4.04 (t, 1H, 6Hz), 3.82-3.56 (m, 4H), 3.52 (m, 1H), 3.05 (d, 1H, 9Hz).

    (R)-1-Zn-D-Ser

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.91 (s, 1H), 8.38 (d, 1H, 3Hz), 8.25 (d, 1H, 3Hz), 8.06 (s, 2H), 7.82 (d, 1H, 6Hz), 7.60-7.55 (m, 2H), 7.42-7.40 (m,

    1H), 7.33-7.28 (m, 1H), 7.21-7.11 (m, 4H), 7.04-7.01 (m, 2H), 6.98-6.87 (m, 4H), 6.74-6.65 (m, 3H), 6.45 (d, 1H, 6Hz), 5.31 (t, 1H, 3Hz), 5.21 (d, 1H,

    12Hz), 4.82 (d, 1H, 9Hz), 4.68 (d, 1H, 9Hz), 4.04 (t, 1H, 3Hz), 3.84 (d, 1H, 9Hz), 3.73 (d, 1H, 9Hz), 3.60-3.57 (m, 1H), 3.47-3.44 (m, 2H), 3.04 (d, 1H,

    6Hz).

    (R)-2-Zn-L-Phe:- By adopting a general procedure mention above.

  • 1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.54-8.52 (m, 2H), 8.25-8.22 (m, 2H), 7.74-7.69 (m, 2H), 7.58 (s, 2H), 7.35-7.22 (m, 4H), 7.22-7.04 (m, 26H), 7.04-

    6.99 (m, 4H), 6.97-6.90 (m, 6H), 6.87-6.84 (m, 2H), 6.68 (d, 2H, 9Hz), 6.61 (d, 2H, 9Hz), 6.22-6.17 (m, 2H), 5.68 (d, 2H, 6Hz), 5.58 (d, 2H, 9Hz), 4.70 (d,

    2H, 12Hz), 4.41-4.28 (m, 6H), 4.17 (d, 2H, 15Hz), 3.58-3.52 (m, 2H), 3.14-3.06 (m, 2H), 2.56 (d, 2H, 18Hz), 2.01 (d, 2H, 18Hz).

    (R)-2-Zn-L-Trp:- By adopting a general procedure mention above.

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.53(d, 2H, 3Hz), 8.28 (d, 2H, 6Hz), 7.89-7.82 (m, 4H), 7.68-7.61 (m, 4H), 7.46-7.41 (m, 2H), 7.28-7.11 (m, 20H),

    7.00-6.80 (m, 12H), 6.62-6.60 (m, 4H), 6.50 (d, 2H, 9Hz), 6.08 (t, 2H, 9Hz), 5.72 (d, 2H, 9Hz), 5.56 (d, 2H, 9Hz), 4.74 (d, 2H, 12Hz), 4.36-4.27 (m, 6H),

    4.12 (d, 2H, 12Hz), 3.80 (d, 2H, 12Hz), 3.52-3.48 (m, 2H), 3.27-3.24 (m, 2H), 2.48 (d, 2H, 15Hz), 2.07-2.04 (m, 2H), 1.91-1.86 (m, 2H).

    (R)-2-Zn-L-Ser:- By adopting a general procedure mention above.

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.56-8.54 (m, 2H), 8.25 (d, 2H, 9Hz), 8.19 (d, 2H, 6Hz), 7.84-7.78 (m, 4H), 7.50-7.38 (m, 6H), 7.29-7.16 (m, 16H),

    7.05-7.01 (m, 4H), 6.97-6.92 (m, 2H), 6.90 (d, 2H, 9Hz), 6.77 (d, 2H, 9Hz), 6.62 (d, 2H, 9Hz), 6.29 (t, 2H, 9Hz), 5.77 (d, 2H, 9Hz), 5.66 (d, 2H, 9Hz), 4.78

    (d, 2H, 12Hz), 4.49-4.30 (m, 6H), 4.17 (d, 2H, 15Hz), 4.02-3.99 (m, 2H), 3.91 (d, 2H, 15Hz), 3.62-3.56 (m, 2H), 2.60 (d, 2H, 15Hz), 2.09-2.04 (m, 2H).

    (R)-2-Zn-D-Ser

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.57-8.55 (m, 2H), 8.32 (s, 2H), 8.21 (d, 2H, 9Hz), 8.11-8.08 (m, 2H), 7.85-7.80 (m, 2H), 7.56-7.51 (m, 2H), 7.41 (s,

    2H), 7.40-7.33 (m, 8H), 7.22-7.18 (m, 2H), 7.17 (d, 2H, 6Hz), 7.08-6.89 (m, 12H), 6.53 (d, 2H, 9Hz), 6.25 (t, 2H, 6Hz), 5.81 (d, 2H, 6Hz), 5.64 (d, 2H, 6Hz),

    4.88 (d, 2H, 12Hz), 4.44-4.30 (m, 4H), 4.30 (d, 2H, 15Hz), 4.41-4.09 (m, 2H), 3.98 (t, 2H, 6Hz), 3.90-3.79 (m, 2H), 3.68 (d, 2H, 15Hz), 2.74 (d, 2H, 15Hz),

    2.05 (d, 2H, 15Hz).

    (R)-2-Zn-L-Ala:- By adopting a general procedure mention above.

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.56 (d, 2H, 3Hz), 8.26 (d, 2H, 9Hz), 8.19 (d, 2H, 3Hz), 7.83-7.79 (m, 4H), 7.49-7.47 (m, 2H), 7.46-7.16 (m, 22H),

    7.04 (d, 2H, 9Hz), 6.94 (t, 2H, 9Hz), 6.89 (d, 2H, 9Hz), 6.79 (d, 2H, 9Hz), 6.64 (d, 2H, 9Hz), 6.26 (t, 2H, 6Hz), 5.77 (d, 2H, 9Hz), 5.64 (d, 2H, 9Hz), 4.81

    (d, 2H, 12Hz), 4.49-4.34 (m, 2H), 4.24 (d, 2H, 15Hz), 4.02-3.92 (m, 2H), 3.92 (d, 2H, 15Hz), 2.61 (d, 2H, 15Hz), 2.12 (d, 2H, 15Hz), 1.34 (d, 6H, 9Hz).

  • (R)-2-Zn-D-Ala

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.56 (d, 2H, 3Hz), 8.18 (d, 2H, 9Hz), 8.12 (d, 2H, 3Hz), 7.94 (m, 2H), 7.81-7.75 (m, 2H), 7.59 (s, 2H), 7.51-7.46 (m,

    2H), 7.38-7.33 (m, 2H), 7.28-7.11 (m, 14H), 7.05-6.92 (m, 8H), 6.86-6.81 (m, 4H), 6.60 (d, 2H, 6Hz), 6.21 (t, 2H, 6Hz), 5.76 (d, 2H, 9Hz), 5.73 (d, 2H,

    9Hz), 4.80 (d, 2H, 12Hz), 4.45 (d, 2H, 5Hz), 4.37 (m, 2H), 4.25 (d, 2H, 15Hz), 3.80-3.75 (m, 2H), 2.67 (d, 2H, 15Hz), 1.99 (d, 2H, 15Hz), 1.45 (d, 6H, 9Hz).

    (R)-2-Zn-L-Met: By adopting a general procedure mention above.

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.55-8.54 (m, 2H), 8.28 (d, 2H, 6Hz), 8.23 (d, 2H, 3Hz), 7.86-7.81 (m, 4H), 7.46-7.37 (m, 5H), 7.33-7.16 (m, 17H),

    7.05 (d, 4H, 9Hz), 6.96-6.91 (m, 2H), 6.88 (d, 2H, 9Hz), 6.81 (d, 2H, 9Hz), 6.62 (d, 2H, 9Hz), 6.29-6.24 (m, 2H), 5.74 (d, 2H, 9Hz), 5.61 (d, 2H, 9Hz), 4.76

    (d, 2H, 15Hz), 4.50 (d, 2H, 15Hz), 4.39-4.34 (m, 2H), 4.25 (d, 2H, 15Hz), 4.07-4.00 (m, 2H), 3.90 (d, 2H, 15Hz), 2.58 (d, 2H, 15Hz), 2.26-2.21 (m, 4H),

    2.08-2.06 (m, 6H), 1.96-1.94 (m, 4H).

    (R)-2-Zn-D-Met

    1H NMR (CDCl3, 250 MHz) : δ (ppm): 8.56-8.55 (m, 2H), 8.14-8.01 (m, 4H), 7.85-7.75 (m, 2H), 7.58-7.47 (m, 2H), 7.40-7.38 (m, 2H), 7.29-7.26 (m, 4H),

    7.20-7.17 (m, 6H), 7.17-7.13 (m, 4H), 7.06-7.05 (m, 4H), 6.98-6.90 (m, 8H), 6.85-6.84 (m, 4H), 6.51 (d, 2H, 3Hz), 6.23 (t, 2H, 6Hz), 5.76-5.74 (m, 4H),

    4.89 (d, 2H, 9Hz), 4.47 (d, 2H, 9Hz), 4.42-4.39 (m, 2H), 4.28 (d, 2H, 9Hz), 3.93-3.91 (m, 2H), 3.69 (d, 2H, 9Hz), 2.73-2.71 (m, 2H), 2.40-2.35 (m, 4H),

    2.01-2.03 (m, 6H), 1.93-1.83 (m, 4H).

    SI-3. Crystallographic data

    Table S1. Crystallographic data for (R)-1-L-Ser and (R)-2-L-Phe.

    (R)-1-L-Ser (R)-2-L-Phe

    Empirical formula C46H40.5ClN4.5O6Zn C98H78N10O8Zn2

  • Formula weight 853.15 1654.44

    Temperature (K) 296(2) 296(2)

    Wavelength (Å ) 0.71073 Å 0.71073 Å

    Space group P21 P43212

    a(Å ) 12.8655(15) 14.6370(10)

    b(Å ) 8.9081(11) 14.6370(10)

    c(Å ) 21.613(3) 42.771(3)

    α(°) 90.00 90.00

    β(°) 95.7534(16) 90.00

    γ(°) 90.00 90.00

    Volume(Å 3) 2464.5(5) 9163.4(14)

    Z 2 4

    Density (calc.) (Mg/m3) 1.150 1.199

    Absorption coeff.( mm-1) 0.599 0.583

    Crystal size (mm) 0.01 x 0.08 x 0.20 0.10 x 0.330 x 0.30

    Reflections collected 57551 73241

    Independent reflections 8589 [R(int) = 0.1627] 11261 [R(int) = 0.0932]

    Data/restraints/parameters 8589 / 58 / 572 11261 / 0 / 473

    Goodness-of-fit on F2 0.987 1.038

    Final R indices [I>2σ(I)] R1 = 0.0847, wR2 = 0.2081 R1 = 0.1138, wR2 = 0.2922

  • SI-4. Energy Calculation

    Procedure for calculation.

    Starting geometries for optimizing all (R)-1-amino acids were derived from the X-ray crystallography data for (R)-1-L-Ser. The positions of the side

    group and the -hydrogen were interchanged to obtain the starting geometry of the (R)-1-D-Ser. For both the L- and D-isomers, the side group were

    replaced by H or phenyl to give the starting geometries for the Ala or Phe complexes, respectively. For the Phe or Ser complexes, multiple starting

    geometries with varying torsional angles in phenyl ring or hydroxyl moiety were prepared. The starting geometries were then optimized at the B3LYP/6-

    31G level of theory. The conformers whose energies are less than 4 kcal/mol higher than the lowest energy conformer were then further optimized at the

    B3LYP/6-311G(d) level of theory. Vibrational frequencies were also obtained to calculate the zero-point energy correction and thermodynamic energies.

    R indices (all data) R1 = 0.1346, wR2 = 0.2433 R1 = 0.1839, wR2 = 0.3315

    Absolute structure parameter - 0.27(4)

    Largest diff. peak and hole (e.Å -

    3) 1.223 and -0.337 1.213 and -0.619

    CCDC number 1549322 1556304

  • Starting geometries for optimizing dimeric (R)-2-amino acids were derived from the X-ray crystallography data for (R)-2-L-Phe-L-Phe. The positions of

    the side group and the -hydrogen were interchanged to obtain the starting geometries of (R)-2-D-Phe-L-Phe or (R)-2-D-Phe-D-Phe. Multiple starting

    geometries with varying the phenyl ring torsion were prepared. Unfortunately, we were not able to obtain optimized structures at the DFT level of theory

    since the number of atoms in the dimeric complex is too large. Instead, we report the result from the semi-empirical PM3 calculations.

    1. Energies and Geometries

    Table S1. a Energies (in kcal/mol) of (R)-1-amino acids calculated at the B3LYP/6-311G(d) level of theory

    amino acid

    (conformer) L-Ala D-Ala

    L-Ser

    (A)b

    L-Ser

    (B)b D-Ser L-Phe

    D-Phe

    (A)

    D-Phe

    (B)

    Ee 0 1.29 0 4.54 2.83 0 0.79 -0.23

    E0 0 1.27 0 4.04 2.88 0 0.69 -0.24

    H 0 1.24 0 4.35 2.92 0 0.70 -0.34

    G 0 1.01 0 3.71 2.69 0 0.40 0.48

    a Ee is the calculated electronic energy, while the zero point energy is included in E0. H and G are the enthalpy and the Gibbs free energy at 1 atm and

    298 K. implies that the values are relative to the lowest energy L-isomer. b Conformer B is optimized directly from X-ray crystallography structure.

    Conformer B is optimized from a starting geometry with the COH angle in the side group rotated to make intramolecular H-bonding with the carboxylate

    group. As the result, conformer B is more stable. (This condition in isolated state may be different from that in the crystalline state.) See Figure S2.

  • Figure S1. Optimized geometry of (R)-1-L-Ala (left) and (R)-1-D-Ala (right)

  • Figure S2. Optimized geometry of (R)-1-L-

    Ser (top left for conformer A and top right

    for conformer B) and (R)-1-D-Ser (bottom)

  • Figure S3. Optimized geometry of (R)-1-L-

    Phe (top) and (R)-1-D-Phe (bottom left for

    conformer A and bottom right for conformer

    B)

  • SI-5. Spectroscopies

  • SI-6. HPLC showing the exclusive formation of (R)-2 with L-forms of Phe and Trp

    Complex [(R)-2-Zn-L-Phe]2

    The diastereomer was determined by HPLC with an Shiseido Pak-C18 column (5 μm, 4.6 × 250 mm) (H2O/MeOH = 14/86, λ = 280 nm, 1.0

    mL/min). [(R)-2-Zn-L-Phe]2 (major diastereomer) = 18.458 min.

  • Complex [(R)-2-Zn-DL-Phe]2

    The diastereomer was determined by HPLC with an Shiseido Pak-C18 column (5 μm, 4.6 × 250 mm) (H2O/MeOH = 14/86, λ = 280 nm, 1.0

    mL/min). [(R)-2-Zn-DL-Phe]2 (major diastereomer) = 18.409 min., which match with the [(R)-2-Zn-L-Phe]2 (major diastereomer).

  • Complex [(R)-2-Zn-D-Phe]2

    The diastereomer was determined by HPLC with an Shiseido Pak-C18 column (5 μm, 4.6 × 250 mm) (H2O/MeOH = 14/86, λ = 280 nm, 1.0

    mL/min). [(R)-2-Zn-D-Phe]2 (major diastereomer ) = 1.984 min.

  • Complex [(R)-2-Zn-L-Try]2

    The diastereomer was determined by HPLC with an Shiseido Pak-C18 column (5 μm, 4.6 × 250 mm) (H2O/MeOH = 14/86, λ = 280 nm, 1.0

    mL/min). [(R)-2-Zn-L-Try]2 (major diastereomer) = 9.365 min.

  • Complex [(R)-2-Zn-DL-Try]2

    The diastereomer was determined by HPLC with an Shiseido Pak-C18 column (5 μm, 4.6 × 250 mm) (H2O/MeOH = 14/86, λ = 280 nm, 1.0

    mL/min). [(R)-2-Zn-DL-Try]2 (major diastereomer) = 9.422 min., which match with the [(R)-2-Zn-L-Try]2 (major diastereomer).

  • Complex [(R)-2-Zn-D-Try]2

    The diastereomer was determined by HPLC with an Shiseido Pak-C18 column (5 μm, 4.6 × 250 mm) (H2O/MeOH = 14/86, λ = 280 nm, 1.0

    mL/min). [(R)-2-Zn-D-Try]2 (major diastereomer) = 1.730 min.