ethyl (2S)-2-amino-3-phenylpropanoate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Methyl-L-phenylalanine (500 mg, 2.79 mmol) was dissolved in 1N NaOH (6 mL). Dioxane (9 mL)) was added, followed by p-toluenesulfonyl chloride (532 mg, 2.79 mmol) and the mixture was vigorously stirred for 1 hr. The volatiles were removed in vacuo and the residue was dissolved in water (30 mL) and washed with Et2O (2×30 mL) before making acidic with 1N HCl. The mixture was extracted with CHCl3 (3×30 mL) and the extracts were evaporated in vacuo to give N-(toluene-4-sulfonyl)-N-methylphenylalanine as a solid (424 mg, 45%). N-(Toluene-4-sulfonyl)-N-methylphenylalanine was coupled to L-phenylalanine ethyl ester using the procedure described in Method 3 (400 mg, 62%). The title compound was prepared via hydrolysis of the ethyl ester using NaOH in ethanol. Proton and carbon NMR analyis indicated a mixture of diastereomers. a mixture of diastereomers

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3,5-Dichlorophenyl-sulfonyl-L-proline was coupled to L-phenylalanine ethyl ester using the procedure described in Method 3 to give the ethyl ester of the title compound (348 mg, 45%).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3,5-Dichlorophenyl-sulfonyl-L-proline was coupled to L-phenylalanine ethyl ester using the procedure described in Method 3 to give the ethyl ester of the title compound (348 mg, 45%).

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of L-phenylalanine ethyl ester (8.37 g, 46.8 mmol, 1 equiv), bromoacetaldehyde diethyl acetal (10.6 mL, 70.1 mmol, 1.5 equiv), and DIEA (16.2 mL, 93.4 mmol, 2.0 equiv) in DMF (100 mL) was heated at 80° C. for 2 d. The resulting solution was cooled to 23° C., taken up in chloroform (200 mL), washed with 10% aqueous potassium carbonate (3×50 mL), dried over potassium carbonate, and concentrated. Purification of the residue by silica gel chromatography yield 7.4 g (54%) of product. 1H NMR (CDCl3) δ 1.13-1.23 (m, 9H), 2.61 (dd, 1H, J=11.8, 5.9), 2.78 (dd, 1H, J=11.8, 5.9), 2.96-3.03 (m, 2H), 3.46-3.53 (m, 1H), 3.55-3.70 (m, 4H), 4.18 (q, 2H, J=7.1), 4.57 (t, 1H, J=5.5), 7.19-7.33 (m, 5H). washed with 10% aqueous potassium carbonate (3×50 mL) dried over potassium carbonate concentrated Purification of the residue by silica gel chromatography yield 7.4 g (54%) of product

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of L-phenylalanine ethyl ester (8.37 g, 46.8 mmol, 1 equiv), bromoacetaldehyde diethyl acetal (10.6 mL, 70.1 mmol, 1.5 equiv), and DIEA (16.2 mL, 93.4 mmol, 2.0 equiv) in DMF (100 mL) was heated at 80° C. for 2 d. The resulting solution was cooled to 23° C., taken up in chloroform (200 mL), washed with 10% aqueous potassium carbonate (3×50 mL), dried over potassium carbonate, and concentrated. Purification of the residue by silica gel chromatography yield 7.4 g (54%) of product. 1H NMR (CDCl3) δ 1.13-1.23 (m, 9H), 2.61 (dd, 1H, J=11.8, 5.9), 2.78 (dd, 1H, J=11.8, 5.9), 2.96-3.03 (m, 2H), 3.46-3.53 (m, 1H), 3.55-3.70 (m, 4H), 4.18 (q, 2H, J=7.1), 4.57 (t, 1H, J=5.5), 7.19-7.33 (m, 5H). washed with 10% aqueous potassium carbonate (3×50 mL) dried over potassium carbonate concentrated Purification of the residue by silica gel chromatography yield 7.4 g (54%) of product

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The lactic acid was esterified with iso-propyl alcohol and was used along with the phenylalanine ethyl ester. An oligomerization yield of 80% was obtained with respect to phenylalanine. The positive and negative ion spectrum is provided in FIGS. 59A and 59B respectively. The positive ion spectrum reveals the strong presence of sodiated co-oligomers ions of NLA-(Phe)3-PheC-OEt+Na+ and NLA-(Phe)4-PheC-OEt+Na+ at masses 730 and 877 respectively. These peaks are separated by 147 units, which is the repeating residue unit of phenylalanine. The absence of any oligomer peaks is due to fact that the phenylaline does not oligomerize without a N-terminal starter molecule. This points to the presence of LA at the N-terminal end of the oligomer. The presence of ethyl ester (and absence of the iso-propyl ester) at the C-terminal end also reinforces this result. The negative ion spectrum reveals two sets of peaks with each set separated by 147 units. These sets represent the deprotonated co-oligomer peaks to form NLA-Phen-PheC-OEt with n having values of 3 and 4.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The lactic acid was esterified with iso-propyl alcohol and was used along with the phenylalanine ethyl ester. An oligomerization yield of 80% was obtained with respect to phenylalanine. The positive and negative ion spectrum is provided in FIGS. 59A and 59B respectively. The positive ion spectrum reveals the strong presence of sodiated co-oligomers ions of NLA-(Phe)3-PheC-OEt+Na+ and NLA-(Phe)4-PheC-OEt+Na+ at masses 730 and 877 respectively. These peaks are separated by 147 units, which is the repeating residue unit of phenylalanine. The absence of any oligomer peaks is due to fact that the phenylaline does not oligomerize without a N-terminal starter molecule. This points to the presence of LA at the N-terminal end of the oligomer. The presence of ethyl ester (and absence of the iso-propyl ester) at the C-terminal end also reinforces this result. The negative ion spectrum reveals two sets of peaks with each set separated by 147 units. These sets represent the deprotonated co-oligomer peaks to form NLA-Phen-PheC-OEt with n having values of 3 and 4.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Methyl-L-phenylalanine (500 mg, 2.79 mmol) was dissolved in 1N NaOH (6 mL). Dioxane (9 mL)) was added, followed by p-toluenesulfonyl chloride (532 mg, 2.79 mmol) and the mixture was vigorously stirred for 1 hr. The volatiles were removed in vacuo and the residue was dissolved in water (30 mL) and washed with Et2O (2×30 mL) before making acidic with 1N HCl. The mixture was extracted with CHCl3 (3×30 mL) and the extracts were evaporated in vacuo to give N-(toluene-4-sulfonyl)-N-methylphenylalanine as a solid (424 mg, 45%). N-(Toluene-4-sulfonyl)-N-methylphenylalanine was coupled to L-phenylalanine ethyl ester using the procedure described in Method 3 (400 mg, 62%). The title compound was prepared via hydrolysis of the ethyl ester using NaOH in ethanol. Proton and carbon NMR analyis indicated a mixture of diastereomers. a mixture of diastereomers

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3,5-Dichlorophenyl-sulfonyl-L-proline was coupled to L-phenylalanine ethyl ester using the procedure described in Method 3 to give the ethyl ester of the title compound (348 mg, 45%).

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under argon, bromoacetyl bromide (0.89 g, 10.2 mmol) in chloroform (10 mL) was added dropwise to a mixture of chloroform (40 mL), L-phenylalanine ethyl ester (2.3 g, 10 mmol), and triethylamine (3 mL), which was pre-cooled to −30° C. The mixture was stirred at r.t. for a further 2 hrs, and then washed with aqueous saturated potassium carbonate solution and water, then dried over sodium sulfate. The solvents were removed under reduced pressure, giving a dark oil, which was dissolved in a mixture of DCM (100 mL) and hexane (300 mL), form which a crystalline solid deposited. The crystals were dried in air, giving colourless needles (2.7 g, 79%). 1H-NMR (CDCl3): 7.29-7.31 (3H, m, Ar), 7.11-7.16 (2H, m, Ar), 4.79-4.89 (1H, m, α-H), 4.20 (2H, q, J 7.2, OCH2CH3), 3.86 (2H, s, BrCH2), 3.16 (2H, d, J 5.8, ArCH2), 1.26 (3H, t, J 7.2, OCH2CH3). m/z (ES+): 336 [M+Na]+. washed with aqueous saturated potassium carbonate solution and water dried over sodium sulfate The solvents were removed under reduced pressure giving a dark oil, which The crystals were dried in air

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under argon, bromoacetyl bromide (0.89 g, 10.2 mmol) in chloroform (10 mL) was added dropwise to a mixture of chloroform (40 mL), L-phenylalanine ethyl ester (2.3 g, 10 mmol), and triethylamine (3 mL), which was pre-cooled to −30° C. The mixture was stirred at r.t. for a further 2 hrs, and then washed with aqueous saturated potassium carbonate solution and water, then dried over sodium sulfate. The solvents were removed under reduced pressure, giving a dark oil, which was dissolved in a mixture of DCM (100 mL) and hexane (300 mL), form which a crystalline solid deposited. The crystals were dried in air, giving colourless needles (2.7 g, 79%). 1H-NMR (CDCl3): 7.29-7.31 (3H, m, Ar), 7.11-7.16 (2H, m, Ar), 4.79-4.89 (1H, m, α-H), 4.20 (2H, q, J 7.2, OCH2CH3), 3.86 (2H, s, BrCH2), 3.16 (2H, d, J 5.8, ArCH2), 1.26 (3H, t, J 7.2, OCH2CH3). m/z (ES+): 336 [M+Na]+. washed with aqueous saturated potassium carbonate solution and water dried over sodium sulfate The solvents were removed under reduced pressure giving a dark oil, which The crystals were dried in air

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl N-[(5-nitro-1H-indol-1-yl)acetyl]-L-phenylalaninate was prepared from (5-nitro-1H-indol-1-yl)acetic acid and L-phenylalanine ethyl ester following the procedure of Example 10 Step 3: MS (ESI) m/z 396; MS (ESI) m/z 394.