Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry. This journal is The Royal Society of Chemistry 2015 Room Temperature -Arylation of Amino Acids and Peptides Using Copper(I) and β-diketone Krishna K. Sharma, Swagat Sharma, Anurag Kudwal, and Rahul Jain* Department of Medicinal Chemistry, ational Institute ofpharmaceutical Education and Research, Sector 67, S. A. S. agar, Punjab, 160 062, India Supporting Information Contents General information and materials...1 I. General procedure:...2 II. General method for synthesis of Peptides and its -arylation:...2 III. Characterization data of synthesized compounds:...3 IV. 1 H and 13 C MR spectra:...8 V. HPLC chromatograms of representative compounds:...44 General information and materials Reagents were available from commercial suppliers and used without any purification unless otherwise noted. Amino acids and esters, aryl halides, base, solvent, copper catalyst and ligands were purchased from commercial sources such as Sigma-Aldrich, Alfa-aesar, Merck, Avra,and Chem-impex. uclear magnetic resonance spectra (MR) were recorded on a BrukerAvance-III 400 spectrometer ( 1 H MR (400 MHz), 13 C MR (100 MHz)).Chemical shifts for 1 H MR were reported as δ values and coupling constants were in hertz (Hz). The following abbreviations were used for spin multiplicity: s = singlet, d = doublet, t = triplet, dd = double doublet, m = multiplet, q = quadruplet, td = triplet of doublet, dt = doublet of triplet. If Splitting patterns could not be interpreted easily are reported as multiplet (m). Chemical shifts for 13 C MR reported in ppm relative to the solvent peak. If required 5-10% v/v of CD 3 D was added in CDCl 3 while recording the spectra to enhance the solubility and prevent precipitation of arylated amino acids in CDCl 3 on long standings before recording of spectra. Thin layer chromatography was performed on Merck precoated silica gel plates(0.25 mm, 60 Å pore size) impregnated with a fluorescent indicator (254 nm).visualization on TLC was observed under UV light (254 nm), or staining with iodine. Synthesized compounds were isolated by flash chromatography on silica gel (200 400 mesh). High resolutionmass spectra (HRMS) were recorded on Bruker Maxis.Chiral HPLC measurements were performed on Shimadzu Prominence using an CHIRALPAK -WH 1
column (250mm L x 4.6mm i.d.)and the mobile phase used in this study was 0.25 mmcopper(ii) sulfate in water and 2-propanol (95 : 5), gradient run for 180 min at flow rate of 1 ml/min. HPLC analysis was performed on the same instrument using Supelcosil TM LC- 18 column (25 cm 4.6 mm, 5 μm) run for 70 min with a flow of 1 ml/min, by using a gradient of 90-0%; with buffer A was containing 0.1% trifluoroacetic acid (TFA) in water and buffer B was containing 0.1% TFA in acetonitrileand detection at 254 nm. I. General procedure for the -arylation Method A (using aryl iodide): All the solid materials were weighed in air, transferred to a 10 ml pre dried round bottom flask lined with a septum and equipped with magnetic stirring bar. All the solid material were dried by applying vacuum and then back filling with argon; this procedure was repeated for 3 times after which all the liquids including solvent were charged under positive pressure of argon. In a pre dried round bottom flask (10 ml) was added aryl iodide (2 mmol, 1.0 equiv.), amino acid (1.2 equiv.), copper iodide (5 mol%), 2- isobutyrylcyclohexanone (20 mol%),cs 2 C 3 (2.0 equiv.) and DMF (3 ml). After that the round bottom flask was sealed and allowed to stir at room temperature. For amino acids, after the completion of reaction, the crude was worked up using cold water and ethyl acetate for 2 times, the combined organic phase was then washed with aqueous 1 ah. The combined aqueous phase were acidified to ph 3-4 by using aqueous HCl and then extracted with ethyl acetate. The organic phase was dried over Mg 2 S 4, concentrated under reduced pressure and purified using flash chromatography to afford the -arylated amino acids. In the cases involving amino acid esters and peptides, a direct work up using cold water and extraction with ethyl acetate was carried out. The organic layer was dried over Mg 2 S 4 and concentrated under reduced pressure. The crude product was purified using flash chromatography to afford products. Method B (using aryl bromide). The procedure as described in method A is applied except that aryl bromides were used instead of aryl iodides and the reaction was heated at 80 C on a preheated vial block. II. General method for the synthesis of peptides and their - arylation R 1 Me H 2 (1 equiv.) (i) Boc-AA-H (1.2 equiv), DIC (1.2 equiv), HB (1.2 equiv) 50 C MW, 30 min (ii) 7-HCl, 30 min H 2 R 2 R 1 H 5a-d Me (iii) PhI (1 equiv.), CsC 3 (2 equiv), CuI (5 mol%), L4 (20 mol%), DMF (3 ml), 8 h. H R 2 R 1 H 6a-d Me In a 10 ml microwave vial equipped with a magnetic stir bar, amino acid methyl ester (1 equiv.) was dissolved in DMF (2 ml). Boc-AA-H (1.2 equiv.) was added followed by DIC (1.2 equiv.) and HB (1.2 equiv.). Reaction mixture was subjected to microwave irradiation (CEM Discover ) for 30 min at temperature 50 C. Reaction mixture was dry under vacuum and purified on automated flash column chromatography system (Biotage) to give desired peptides. Synthesized peptide were treated with 7 HCl in methanol for 30 min 2
for Bocdeprotection and neutralized with methanolic ammonia solution. These peptides were -arylated by using method A. III. Characterization data of the synthesized compounds H H (2a) -Phenyl-L-alanine (2a):Yield = 87% (2aa), 81% (2ab); dark brown oil; 1 H MR (400 MHz, CDCl 3 ): δ 7.15 (t, J = 8.5 Hz, 2H), 6.72 (t, J = 8.08 Hz, 1H), 6.61 (d, J = 6.96 Hz, 2H), 4.07 (q, J = 7.28 Hz, 1H), 1.45 (d, J = 6.08 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): 177.1, 146.4, 129.1, 118.3, 113.4, 51.8, 18.5; HRMS (ESI-TF) m/z [M+H + ] calculated for C 9 H 12 2 166.0869, found 166.0868. H H (2b) -(2-Methoxyphenyl)-L-alanine (2b):Yield = 85% (2ba), 78% (2bb); brown solid, m.p. 116-118 C; 1 H MR (400 MHz, CDCl 3 ): δ6.85 (t, J = 7.54 Hz, 1H), 6.80 (d, J = 7.4 Hz, 1H), 6.73 (t, J = 7.54 Hz, 1H), 6.56 (d, 7.68 Hz, 1H), 4.09 (q, 6.92 Hz, 1H), 3.85 (s, 3H), 1.54 (d, 6.92 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): 176.8, 146.2, 136..2, 121.1, 117.8, 115.3, 109.7, 55.4, 52.0, 18.8 ; HRMS (ESI-TF) m/z [M+H + ] calculated for C 10 H 14 3 196.0974 found 196.0945. H 2 H (2c) -(4-itrophenyl)-L-alanine (2c): Yield = 89% (2ca), 82% (2cb); brown oil; 1 H MR (400 MHz, CDCl 3 ): δ 8.06 (d, J = 9.76 Hz, 2H), 6.55 (d, J = 9.36 Hz, 2H), 4.21 (q, J = 8 Hz, 1H), 1.55 (d, 7.32 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): 175.8, 151.8, 138.4, 126.4, 111.5, 51.0, 18.3; HRMS (ESI-TF) m/z [M+H + ] calculated for C 9 H 11 2 4 211.0719 found 211.0719. H CH H (2d) -(4-Formylphenyl)-L-alanine (2d): Yield = 88% (2da), 80% (2db); light yellow oil; 1 H MR (400 MHz, CDCl 3 ): δ 9.62 (s, 1H), 7.64 (d, J = 8.72 Hz, 2H), 6.69 (d, J = 8.72 Hz, 2H), 4.14 (q, J = 7.26 Hz, 1H), 1.49 (d, J = 6.96 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ):190.8, 175.8, 163.0, 152.0, 132.4, 126.6, 112.2, 50.9, 18.4; HRMS (ESI-TF) m/z [M+H + ] calculated for C 10 H 12 3 194.0817 found 194.0820. H H (2e) -(4-Biphenyl)-L-alanine (2e): Yield = 87% (2ea), 79% (2eb); dark brown oil; 1 H MR (400 MHz, CDCl 3 ): δ7.5 (d, J = 7.68 Hz, 2H), 7.42 (d, J = 8.36 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.23 (t, J = 7.16 Hz, 1H), 6.68 (d, J = 7.32 Hz, 2H), 4.12 (d, J = 6.64 Hz, 1H), 1.50 (d, J = 6.24 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): 170.9, 146.4, 141.1, 128.6, 127.9, 126.2, 113.6, 51.8, 18.4; HRMS (ESI-TF) m/z [M+H + ] calculated for C 15 H 16 2 242.1181 found 242.1180. 3
H H (2f) -(4-tert-Butylphenyl)-L-alanine (2f): Yield = 87% (2fa), 78% (2fb); light brown oil; 1 H MR (400 MHz, CDCl 3 ): δ 7.22 (d, J = 8 Hz, 2H), 6.61 (d, J = 7.6 Hz, 2H), 4.07 (d, J = 6.28 Hz, 1H), 1.50 (d, J = 6.4 Hz, 3H), 1.27 (s, 9H); 13 C MR (100 MHz, CDCl 3 ): 173.3, 142.0, 139.5, 127.5, 126.2, 114.6, 112.9, 42.2, 33.8, 31.5, 21.8; HRMS (ESI-TF) m/z [M+H + ] calculated for C 13 H 20 2 222.1494 found 222.1494. H CF 3 H (2g) -(4-Trifluoromethylphenyl)-L-alanine (2g): Yield = 91% (2ga), 84% (2gb); brown solid, m.p. 195-197 C; 1 H MR (400 MHz, CDCl 3 ): δ7.39 (d, J = 8.72 Hz, 2H), 6.60 (d, J = 8.36 Hz, 2H), 4.15 (q, J = 6.73, 1H), 1.51 (d, J = 6.64 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): 178.1, 149.0, 126.8, 123.6, 119.5, 112.7, 51.3, 18.6; HRMS (ESI-TF) m/z [M+H + ] calculated for C 10 H 11 F 3 2 234.0742 found 234.0738. H C H (2h) -(4-Cyanophenyl)-L-alanine (2h):Yield = 83% (2ha), 78% (2hb); white solid, m.p. 102-104 C; 1 H MR (400 MHz, CDCl 3 ): δ 7.42 (d, J = 9.04 Hz, 2H), 6.58 (d, 8.36 Hz, 2H), 4.19 (q, J = 6.96 Hz, 1H), 1.55 (d, J = 6.96 Hz, 1H); 13 C MR (100 MHz, CDCl 3 ): 178.1, 150.01, 134.1, 119.9, 112.8, 99.9, 53.4, 18.4; HRMS (ESI-TF) m/z [M+H + ] calculated for C 10 H 11 2 2 191.0821 found 191.0796. H H (2i) -(4-Methylphenyl)-L-alanine (2i): Yield = 88% (2ia), 81% (2ib); light brown solid, m.p. 125-127 C; 1 H MR (400 MHz, CDCl 3 ): δ 6.98 (d, J = 8.68 Hz, 2H), 6.58 (d, J = 8.68 Hz, 2H), 4.09 (q, J = 6.84 Hz, 1H), 2.22 (s, 3H), 1.47 (d, J = 6.96 Hz, 1H); 13 C MR (100 MHz, CDCl 3 ): 177.0, 143.9, 129.7, 128.0, 114.0, 52.5, 20.2, 18.6; HRMS (ESI-TF) m/z [M+H + ] calculated for C 10 H 14 2 180.1025 found 180.1025. H H (2j) -(3-Methylphenyl)-L-alanine (2j): Yield = 87%; light brown solid, m.p. 105-107 C; 1 H MR (400 MHz, CDCl 3 ): δ 7.06 (t, J = 7.98 Hz, 1H), 6.57 (d, J = 8.52 Hz, 1H), 6.44 (d, J = 10.12 Hz, 2H), 4.06 (d, J = 7.28 Hz, 1H), 2.26 (s, 3H), 1.48 (d, J = 8.0 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): 175.8, 163.0, 152.0, 132.5, 126.6, 112.2, 50.9, 18.4, 14.0; HRMS (ESI-TF) m/z [M+H + ] calculated for C 10 H 14 2 180.1025 found 180.1023. H H (2k) solid, m.p. 112-114 C; 1 H MR (400 MHz, CDCl 3 ): δ 7.05-7.11 (m, 2H), 6.68 (t, J = 7.46 Hz, 1H), 6.55 (d, J = 7.96 Hz, -(2-Methylphenyl)-L-alanine (2k): Yield = 84%; dark brown 1H), 4.14 (q, J = 6.94 Hz, 1H), 2.19 (s, 3H), 1.53 (d, J = 6.92 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): 177.3, 144.6, 130.3, 127.0, 117.9, 110.3, 51.8, 19.0, 17.4; HRMS (ESI-TF) m/z [M+H + ] calculated for C 10 H 14 2 180.1025 found 180.1023. 4
H Br H (2l) -(4-Bromophenyl)-L-alanine (2l):Yield = 90%; yellowish oil; 1 H MR (400 MHz, CDCl 3 ): δ 7.24 (d, J = 8.32 Hz, 2H), 6.49 (d, J = 8.36 Hz, 2H), 4.05 (q, J = 7.18 Hz, 1H), 1.48 (d, J = 7.28 Hz, 2H); 13 C MR (100 MHz, CDCl 3 ): 180.8, 149.6,135.8, 133.4, 124.2,118.9, 113.7, 55.81, 22.3; HRMS (ESI-TF) m/z [M+H + ] calculated for C 9 H 11 Br 2 243.9973 found 243.9965. H Cl H (2m) -(4-Chlorophenyl)-L-alanine (2m):Yield = 82% (2ma), 75% (2mb); yellow oil; 1 H MR (400 MHz, CDCl 3 ): δ 7.11 (d, J = 9.40 Hz, 2H), 6.54 (d, J = 9.04 Hz, 2H), 4.05 (q, J = 7.06, 1H), 1.49 (d, J = 7.28 Hz, 2H); 13 C MR (100 MHz, CDCl 3 ): 176.8, 145.2, 129.1, 114.5, 51.8, 18.7; HRMS (ESI-TF) m/z [M+H + ] calculated for C 9 H 11 Cl 2 200.0478 found 200.0473. F H H (2n) -(3-Florouphenyl)-L-alanine (2n):Yield = 85%; colorless solid, m.p. 76-78 C; 1 H MR (400 MHz, CDCl 3 ): δ 7.07-7.12 (m, 1H), 6.43 (td, J = 2.6, 8.68 Hz, 1H), 6.36 (dd, J = 2.08, 8.20 Hz, 1H), 6.29 (dt, J = 2.28, 12.11 Hz, 1H), 4.10 (q, J = 6.96 Hz, 1H), 1.50 (d, J = 6.96 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): 180.1, 165.3, 162.7, 148.0, 130.6, 109.3, 105.0, 100.1, 51.5, 18.8;HRMS (ESI-TF) m/z [M+H + ] calculated for C 9 H 11 F 2 184.0782 found 184.0780. H 4a H -Phenyl-glycine (4a):Yield = 82%; colorless solid, m.p. 120-122 C; 1 H MR (400 MHz, CD 3 D): δ 7.15 (t, J = 7.98 Hz, 2H), 6.69 (t, J = 7.64 Hz, 1H), 6.61 (d, J = 6.96 Hz, 2H), 3.36 (s, 2H); 13 C MR (100 MHz, CD 3 D): 173.5, 147.3, 129.0, 117.9, 112.9, 45.4; HRMS (ESI-TF) m/z [M+H + ] calculated for C 8 H 10 2 152.0713 found 152.0712. H 4b H -Phenyl-L-valine (4b):Yield = 89%; brown solid, m.p. 104-106 C; 1 H MR (400 MHz, CDCl 3 ): δ 7.17 (t, J = 7.82 Hz, 2H), 6.73 (t, J = 7.38 Hz, 1H), 6.65 (d, J = 8 Hz, 2H), 3.85 (d, J = 5.36 Hz, 1H), 2.13-2.14 (m, 1H), 1.06 (q, J = 3.6 Hz, 6H); 13 C MR (100 MHz, CDCl 3 ): 176.3, 147.3, 129.3, 118.2, 113.6, 62.3, 19.2, 18.3; HRMS (ESI-TF) m/z [M+H + ] calculated for C 11 H 16 2 194.1182 found 194.1171. H 4c H -Phenyl-L-phenylalanine(4c):Yield = 85%; brown solid, m.p. 114-116 C; 1 H MR (400 MHz, CDCl 3 ): δ 7.24-7.30 (m, 2H), 7.20-7.23 (m, 3H), 7.16 (t, J = 6.96 Hz, 2H), 6.73 (t, J = 7.3 Hz, 1H), 6.60 (d, J = 8.36 Hz, 2H), 4.33 (t, J = 6.26 Hz, 1H), 3.23 (dd, J = 4.84, 13.88, 1H), 3.09 (dd, J = 5.60, 13.24, 1H); 13 C MR (100 MHz, CDCl 3 ): ; HRMS (ESI-TF) m/z [M+H + ] calculated for C 15 H 16 2 242.1182 found 242.1168. 5
H 4d S H -Phenyl-L-methionine (4d):Yield = 81%; 1 H MR (400 MHz, CDCl 3 ): brown oil; δ 7.17 (t, J = 7.9 Hz, 2H), 6.74 (t, J = 7.3 Hz, 1H), 6.66 (d, J = 7.84 Hz, 2H), 4.22 (t, J = 6.34 Hz, 1H), 2.65 (t, J = 7.32 Hz, 2H), 2.13-2.20 (m, 1H), 2.11 (s, 3H), 1.97-2.07 (m, 1H); 13 C MR (100 MHz, CDCl 3 ):176.3, 146.8, 129.4, 118.6, 113.6, 55.5, 32.2, 30.2, 15.3; HRMS (ESI-TF) m/z [M+H + ] calculated for C 11 H 16 2 S226.0903 found 226.0899. H 4e H -Phenyl-L-isoleucine (4e):Yield = 91%; brown solid, m.p. 165-167 C; 1 H MR (400 MHz, CDCl 3 ): δ 7.21 (t, J = 7.98 Hz, 2H), 6.78 (t, J = 7.4 Hz, 1H), 6.67 (d, J = 8 Hz, 2H), 3.98 (d, J = 5.36 Hz, 1H), 1.90-2.01 (m, 1H), 1.63-1.73 (m, 1H), 1.30-1.42 (m, 1H), 1.05 (d, J = 6.96 Hz, 3H), 1.00 (t, J = 7.48 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): 178.5, 146.9, 129.4, 113.3, 61.2, 37.9, 25.4, 15.5, 11.5; HRMS (ESI-TF) m/z [M+H + ] calculated for C 12 H 18 2 208.1339 found 208.1334. H 4f H -Phenyl-L-leucine (4f): Yield = 92%; light brown solid, m.p. 116-118 C; 1 H MR (400 MHz, CDCl 3 ): δ 7.18 (t, J = 7.36 Hz, 2H), 6.75 (t, J = 6.58 Hz, 1H), 6.64 (d, J = 7.28 Hz, 2H), 4.05 (br.s., 1H),1.81-1.89 (m, 1H), 1.61-1.71 (m, 2H), 1.00 (d, J = 6.52 Hz, 3H), 0.95 (d, J = 6.48 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): 177.7, 146.9, 129.3, 118.4, 113.4, 55.1, 42.2, 24.9, 22.7, 22.0; HRMS (ESI-TF) m/z [M+H + ] calculated for C 12 H 18 2 208.1339 found 208.1336. H 4g H 2-Methyl-2-(phenylamino)propanoic acid (4g): Yield = 85%; white solid, m.p. 173-175 C; 1 H MR (400 MHz, CDCl 3 ): δ 7.17 (t, J = 8 Hz, 2H), 6.83 (t, J = 6.94 Hz, 1H), 6.70 (d, J = 8.3 Hz, 2H), 1.52 (s, 6H); 13 C MR (100 MHz, CDCl 3 ): 178.2, 143.7, 129.0, 120.1, 117.7, 58.4, 25.5; HRMS (ESI-TF) m/z [M+H + ] calculated for C 10 H 14 2 180.1026 found 180.1019. H 4h H 4-(Phenylamino)butanoic acid (4h): Yield = 81%; yellow oil; 1 H MR (400 MHz, CDCl 3 ): δ 7.19 (t, J = 7.42, 2H), 6.71 (t, J = 7.94, 1H), 6.62 (d, J = 8.81, 2H), 3.17 (t, J = 6.86 Hz, 2H), 2.44 (t, J = 7.2 Hz, 2H), 1.95 (p, J = 7.09 Hz, 2H); 13 C MR (100 MHz, CDCl 3 ): 173.9, 148.1, 129.2, 117.3, 112.2, 43.2, 31.6, 24.6; HRMS (ESI-TF) m/z [M+H + ] calculated for C 10 H 14 2 180.1026 found 180.1026. H 4i H -Phenyl-β-alanine (4i):Yield = 78%; yellow oil; 1 H MR (400 MHz, CDCl 3 ): δ 7.18 (t, J = 8.18, 2H), 6.75 (t, J = 7.48 Hz, 1H), 6.66 (d, J = 8 Hz, 2H), 3.43 (t, J = 6.08 Hz, 2H), 2.63 (t, J = 6.34 Hz, 2H); 13 C MR (100 MHz, CDCl 3 ): 176.8, 147.0, 129.4, 118.5, 113.7, 40.0, 33.7; HRMS (ESI-TF) m/z [M+H + ] calculated for C 9 H 12 2 166.0869 found 166.0869. 6
H 4j H -Phenyl-D-phenylalanine (4j):Yield = 86%; white solid, m.p. 128-130 C; 1 H MR (400 MHz, CDCl 3 ): δ 7.29 (d, J = 8.04 Hz, 2H), 7.23 (t, J =7.04 Hz, 3H), 7.17 (t, J = 7.08 Hz, 2H), 6.74 (t, J = 6.04 Hz, 1H), 6.62 (d, J = 9.02 Hz, 2H), 4.33 (t, J = 5.54 Hz, 1H), 3.23 (dd, J = 5.52, 13.08 Hz, 1H), 3.10 (dd, J = 6.56, 14.12 Hz, 1H); 13 C MR (100 MHz, CDCl 3 ): 175.3, 146.4, 136.5, 129.2, 128.3, 126.8, 118.2, 113.5, 57.4, 38.1; HRMS (ESI-TF) m/z [M+H + ] calculated for C 15 H 16 2 242.1182 found 242.1180. H 4k H H -Phenyl-L-tryptophan (4k): Yield = 91%; white solid, m.p. 163-165 C; 1 H MR (400 MHz, CDCl 3 ): δ 7.60 (s, 1H), 7.35 (d, J = 8.44 Hz, 1H), 7.07-7.19 (m, 5H), 6.72 (t, J = 7.44 Hz, 1H), 6.59 (d, J = 9.64 Hz, 2H), 4.37 (t, J = 6.34 Hz, 1H), 3.41 (dd, J = 6.84, 16.08 Hz, 1H), 3.31 (dd,j = 7.64, 15.68 Hz, 1H) ); 13 C MR (100 MHz, CDCl 3 ): 173, 146.23, 129.3,129.2, 123.1, 121.99, 119.4, 118.5, 113.6, 111.1, 110.1, 57.1, 28.1; HRMS (ESI-TF) m/z [M+H + ] calculated forc 17 H 17 2 2 281.1289 found 281.1289. H 4l H H -Phenyl-L-serine (4l): Yield = 81%; yellow oil; 1 H MR (400 MHz, CD 3 D): δ 7.22 (t, J = 7.66 Hz, 2H), 6.89 (t, J = 7.44 Hz, 1H), 6.77 (d, J = 8.2 Hz, 2H), 4.14 (t, 5.84 Hz, 1H), 4.07 (dd, J = 4.24, 13.22 Hz, 1H), 3.95 (dd, J = 7.80, 11.81 Hz, 1H); 13 C MR (100 MHz, CDCl 3 ): 174.1, 146.3, 128.7, 118.3, 113.8, 113.7, 61.8, 58.9; HRMS (ESI-TF) m/z [M+H + ] calculated for C 9 H 12 3 182.0816 found 182.0812. H 4m -Phenyl-L-phenylalanine methyl ester (4m):Yield = 81%; pale yellow oil; 1 H MR (400 MHz, CD 3 D): δ 7.27-7.31 (m, 2H), 7.20-7.24 (m, 3H), 7.08-7.13 (m, 2H), 6.61-6.68 (m, 3H), 4.32 (t, J = 6.86 Hz, 1H), 3.60 (s, 3H), 3.10 (d, J = 6.96 Hz, 2H); 13 C MR (100 MHz, CD 3 D): 173.6, 146.4, 136.5,129.45, 129.25, 128.4, 127.02, 118.4, 113.5, 57.6, 51.9, 38.5; HRMS (ESI-TF) m/z [M+H + ] calculated for C 16 H 18 2 256.1339 found 256.1338. H 4n -Phenyl-L-isoleucine methyl ester (4n):Yield = 78%; pale yellow oil; 1 H MR (400 MHz, CDCl 3 ): δ 7.22 (t, J = 7.74Hz, 2H), 6.78 (t, J = 7.40 Hz, 1H), 6.68 (d, J = 8.52 Hz, 2H),4.22 (d, J = 8.36 Hz, 1H), 4.01 (q, J = 5.09 Hz, 1H), 3.75 (s, 3H), 1.89-1.96 (m, 1H), 1.65-1.75 (m, 1H), 1.34-1.42 (m, 1H), 1.03 (d, J = 7.40Hz); 13 C MR (100 MHz, CDCl 3 ): 174.1, 147.2, 129.3, 118.1, 113.4, 61.2, 51.7, 38.1, 25.7, 15.5, 11.5; HRMS (ESI- TF) m/z [M+H + ] calculated for C 13 H 20 2 222.1495 found 222.1494. 7
H 4o -Phenyl-L-valine methyl ester (4o):Yield = 82%; light brown oil; 1 H MR (400 MHz, CDCl 3 ): δ 7.20 (t, J = 8.18 Hz, 2H), 6.76 (t, J = 7.2 Hz, 1H), 6.66 (d, J = 8.16 Hz, 2H),3.89 (d, J = 6.28 Hz, 1H), 3.75 (s, 3H), 2.10-2.19 (m, 1H), 1.05 (q, J = 6.67 Hz, 6H); 13 C MR (100 MHz, CDCl 3 ):174.2, 147.3, 129.3, 118.2, 113.5, 62.4, 51.8, 31.6, 19.1,18.7; HRMS (ESI- TF) m/z [M+H + ] calculated for C 12 H 18 2 208.1339 found 208.1333. 4p -Phenyl-L-proline methyl ester (4p):Yield = 82%; light brown oil; 1 H MR (400 MHz, CDCl 3 ): δ 7.24 (t, J = 8.08 Hz, 2H), 6.73 (t, J = 7.40 Hz, 1H), 6.56 (d, J = 7.84 Hz, 2H), 4.26-4.29 (m, 1H), 3.73 (s, 3H), 3.58-3.63 (m, 1H), 3.38 (q, J = 8.20 Hz, 1H), 2.27-2.35 (m, 1H), 2.12-2.22 (m, 2H), 2.04-2.10 (m, 1H); ); 13 C MR (100 MHz, CDCl 3 ): 175.0, 146.6, 129.2, 116.6, 111.9, 60.7, 52.1, 48.2, 30.9, 23.8; HRMS (ESI-TF) m/z [M+H + ] calculated for C 12 H 16 2 206.1181 found 206.1178. H 4q -Phenyl-glycine methyl ester (4q):Yield = 79%; colorless oil; 1 H MR (400 MHz, CDCl 3 ): δ 7.23 (t, J = 7.88Hz, 2H), 6.78 (t, J = 7.54Hz, 1H), 6.64 (d, J = 7.52Hz, 2H), 3.95 (s, 2H), 3.81 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): 169.3, 144.6, 126.9, 115.8, 110.5, 49.4, 43.2; HRMS (ESI-TF) m/z [M+H + ] calculated for C 9 H 12 2 166.0869 found 166.0820. H 4r -Phenyl-β-alanine methyl ester (4r):Yield = 78%; colorless oil; 1 H MR (400 MHz, CDCl 3 ): δ 7.17 (t, J = 7.98 Hz, 2H), 6.71 (t, J = 7.78 Hz, 1H), 6.61 (d, J = 8.36 Hz, 2H), 3.68 (s, 3H), 3.44 (t, J = 6.44 Hz, 2H), 2.61 (t, J = 6.44 Hz, 2H); 13 C MR (100 MHz, CDCl 3 ): 172.8, 147.5, 129.3, 117.8, 113.0, 51.7, 39.5, 33.7; HRMS (ESI-TF) m/z [M+H + ] calculated for C 10 H 14 2 180.1026 found 180.1024. H H 6a Me -Phenyl-L-Leu-L-Phe-Me (6a): Yield = 63%; white solid, m.p. 93-95 C; 1 H MR (400 MHz, CDCl 3 ): 7.24-7.29 (m, 3H), 7.19-7.21 (m, 2H), 7.08 (d, J = 6.72 Hz, 2H), 6.80 (t, J = 7.42 Hz, 1H), 6.61 (d, J = 8.08 Hz, 2H), 4.87 (q, J = 6.89 Hz, 1H), 3.78 (s, 1H), 3.67-3.76 (m, 1H), 3.64 (s, 3H), 3.22 (dd, J = 5.4, 13.4 Hz, 1H), 3.03 (dd, J = 7.64, 13.90 Hz, 1H), 1.66-1.73 (m, 2H), 1.43 (q, J = 6.14 Hz, 1H), 0.98 (d, J = 4.48 Hz, 3H), 0.89 (d, 5.84 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): 174, 171.6, 146.7, 136.0, 129.4, 129.3, 129.2, 128.5, 127.0, 119.1, 113.8, 58.3, 52.8, 52.2, 42.6, 37.7,25.1, 23.1, 21.6; HRMS (ESI-TF) m/z [M+H + ] calculated for C 22 H 29 2 3 369.2177 found 369.2170. 8
H H 6b Me -Phenyl-L-Leu-β-Ala-Me (6b):Yield = 68%; white solid, m.p. 56-58 C; 1 H MR (400 MHz, CDCl 3 ): 7.18 (t, J = 8.14 Hz, 2H), 6.78 (t, J = 7.68 Hz, 1H), 6.57 (d, J = 9.18 Hz, 2H), 3.92 (s, 1H), 3.69 (d, J = 10 Hz,1H), 3.42-3.57 (m, 5H), 2.48 (t, J =5.62 Hz, 2H), 1.75-1.84 (m, 2H), 1.51-1.61 (m, 1H), 0.98 (d, J = 5.84 Hz, 3H), 0.91 (d, J = 6.24 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): 174.3, 172.5, 146.7, 129.3, 118.8, 113.3, 58.0, 51.6, 42.5, 34.6, 33.7, 25.2, 23.2, 21.6; HRMS (ESI-TF) m/z [M+H + ] calculated for C 16 H 25 2 3 293.1865 found 293.1861. H H 6c Me -Phenyl-L-Ala-L-Leu-Me (6c):Yield = 65%; white solid, m.p. 63-65 C; 1 H MR (400 MHz, CDCl 3 ): 7.21 (t, J = 7.66 Hz, 2H), 6.82 (t, J = 7.64 Hz, 1H), 6.64 (d, J = 9.04, 2H), 4.53 (q, J = 4.64 Hz, 1H), 3.84 (t, J = 6.96 Hz, 1H), 3.75 (q, J = 3.2 Hz, 1H), 3.61 (s, 3H), 2.15-2.20 (m, 1H), 1.54 (d, J = 9.4 Hz, 3H), 0.92 (d, J = 7.68 Hz, 3H), 0.98 (d, J = 7.28 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): 174.3, 171.7, 146.5, 129.1, 114.3, 56.9, 55.8, 52.1, 31.0, 29.7, 19.8, 18.8, 17.7; HRMS (ESI-TF) m/z [M+H + ] calculated forc 16 H 25 2 3 293.1865 found 293.1860. H H 6d Me -Phenyl-L-Leu-L-Ala-Me (6d):Yield = 61%; white solid, m.p. 68-70 C; 1 H MR (400 MHz, CDCl 3 ): 7.21 (t, J = 7.46 Hz, 2H), 6.81 (t, J = 7.61 Hz, 1H), 6.66 (d, J = 7.88 Hz, 2H), 4.58 (q, J = 10.1 Hz, 1H), 3.87 (s, 1H), 3.73 (q, J = 5.72 Hz, 1H), 3.6 (s, 3H), 1.78-1.88 (m, 2H), 1.61 (q, J = 7.7 Hz, 1H), 1.37 (d, J = 6.6 Hz, 3H), 1.01 (d, J = 6.16 Hz, 3H), 0.92 (d, J = 5.72 Hz, 3H); 13 C MR (100 MHz, CDCl 3 ): 174.1, 172.9, 146.9, 129.3, 119.1, 113.8, 58.3, 52.3, 47.8, 42.6, 29.7, 25.2, 23.2, 21.6, 18.1; HRMS (ESI-TF) m/z [M+H + ] calculated for C 16 H 25 2 3 293.1865 found 293.1865 9
IV. 1 H and 13 C MR spectra: -Phenyl-L-alanine (2a) 10
-(2-Methoxyphenyl)-L-alanine (2b) 11
-(4-itrophenyl)-L-alanine (2c) 12
-(4-Formylphenyl)-L-alanine (2d) 13
-(4-Biphenyl)-L-alanine (2e) 14
-(4-tert-Butylphenyl)-L-alanine (2f) 15
-(4-Trifluoromethylphenyl)-L-alanine (2g) 16
-(4-Cyanophenyl)-L-alanine (2h) 17
-(4-Methylphenyl)-L-alanine (2i) 18
-(3-Methylphenyl)-L-alanine (2j) 19
-(2-Methylphenyl)-L-alanine (2k) 20
-(4-Bromophenyl)-L-alanine (2l) 21
-(4-Chlorophenyl)-L-alanine (2m) 22
-(4-Fluorophenyl)-L-alanine (2n) 23
-Phenyl-glycine (4a) 24
-Phenyl-L-valine (4b) 25
-Phenyl-L-phenylalanine (4c) 26
-Phenyl-L-methionine (4d) 27
-Phenyl-L-isoleucine (4e) -Phenyl-L-leucine (4e) 28
-Phenyl-L-leucine (4f) 29
2-Methyl-2-(phenylamino)propanoic acid (4g) 30
4-(Phenylamino)butanoic acid (4h) -Phenyl-β-alanine (4i) 31
-Phenyl-β-alanine (4i) 32
-Phenyl-D-phenylalanine (4j) 33
-Phenyl-L-tryptophan (4k) 34
-phenyl-l-serine (4l) 35
-Phenyl-L-phenylalanine methyl ester (4m) 36
-Phenyl-L-isoleucine methyl ester (4n) 37
-Phenyl-L-valine methyl ester (4o) 38
-Phenyl-L-proline methyl ester (4p) 39
-Phenyl-L-glycine methyl ester (4q) 40
-Phenyl-β-alanine methyl ester (4r) 41
-Phenyl-L-Leu- L -Phe-Me(6a) 42
-Phenyl-L-Leu-β-Ala-Me (6b) 43
-Phenyl-L-Ala-L-Leu Me (6c) 44
-Phenyl-L-Leu-L-Ala-Me (6d) 45
V. HPLC chromatograms of representative compounds: Figure 1 Chiral HPLC Chromatograms of -phenyl-l-phenylalanine (4c) Figure 2 Chiral HPLC Chromatograms of -phenyl-d-phenylalanine (4j) Figure 3 Chiral HPLC Chromatograms of -phenyl-dl-phenylalanine 46
Figure 4 HPLC Chromatograms of -phenyl-l-leu-β-ala-me (6b) 47