11-[(2-methylpropan-2-yl)oxycarbonylamino]undecanoic acid

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

Procedure: N-BOC-11-aminoundecanoic acid (Bachem, 0.60 g, 2.0 mmoles) was activated with disuccinimidylcarbonate (0.56 g, 2.2 mmoles) and 4-dimethylamino-pyridine (0.02 g, 0.2 mmoles) in 10 mL of dimethylformamide/pyridine (2/1, v/v) and reacted with the resin product from Part C for 60 minutes at room temperature. The resulting resin was separated by filtration, the N-α-BOC group was removed with trifluoroacetic acid in dichloromethane, and the resulting resin was treated with 90% hydrogen fluoride/anisole (v/v) for 60 minutes at 0° C. The hydrogen fluoride was removed by evaporation, and the product was extracted into 30% acetic acid/water and then lyophilized. The crude material was purified by reverse phase HPLC on a Waters Deltapak RPC-18 column using a linear gradient of 1% to 35% acetonitrile (0.05% trifluoroacetic acid) in water (0.05% trifluoroacetic acid) over 30 minutes at 15 mL/min, which after lyophilization, gave 84.8 mg of 98% pure (by HPLC) L-leucine, N-[[(11-amino-undecanoyl)-L-seryl]-L-lysyl]-, bis-trifluoroacetate. v/v) and reacted with the resin product from Part C for 60 minutes at room temperature The resulting resin was separated by filtration the N-α-BOC group was removed with trifluoroacetic acid in dichloromethane the resulting resin was treated with 90% hydrogen fluoride/anisole (v/v) for 60 minutes at 0° C The hydrogen fluoride was removed by evaporation the product was extracted into 30% acetic acid/water The crude material was purified by reverse phase HPLC on a Waters Deltapak RPC-18 column over 30 minutes

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

Procedure: N-BOC-11-aminoundecanoic acid (Bachem, 0.60 g, 2.0 mmoles) was activated with disuccinimidylcarbonate (0.56 g, 2.2 mmoles) and 4-dimethylamino-pyridine (0.02 g, 0.2 mmoles) in 10 mL of dimethylformamide/pyridine (2/1, v/v) and reacted with the resin product from Part C for 60 minutes at room temperature. The resulting resin was separated by filtration, the N-α-BOC group was removed with trifluoroacetic acid in dichloromethane, and the resulting resin was treated with 90% hydrogen fluoride/anisole (v/v) for 60 minutes at 0° C. The hydrogen fluoride was removed by evaporation, and the product was extracted into 30% acetic acid/water and then lyophilized. The crude material was purified by reverse phase HPLC on a Waters Deltapak RPC-18 column using a linear gradient of 1% to 35% acetonitrile (0.05% trifluoroacetic acid) in water (0.05% trifluoroacetic acid) over 30 minutes at 15 mL/min, which after lyophilization, gave 84.8 mg of 98% pure (by HPLC) L-leucine, N-[[(11-amino-undecanoyl)-L-seryl]-L-lysyl]-, bis-trifluoroacetate. v/v) and reacted with the resin product from Part C for 60 minutes at room temperature The resulting resin was separated by filtration the N-α-BOC group was removed with trifluoroacetic acid in dichloromethane the resulting resin was treated with 90% hydrogen fluoride/anisole (v/v) for 60 minutes at 0° C The hydrogen fluoride was removed by evaporation the product was extracted into 30% acetic acid/water The crude material was purified by reverse phase HPLC on a Waters Deltapak RPC-18 column over 30 minutes

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

Procedure: 1,1′-Carbonyldiimidazole (118 mg, 0.73 mmol) was added to a solution of acid 3 (200 mg, 0.66 mmol) in tetrahydrofuran (5 mL) and the mixture stirred for 4 hours. A solution of N-tert-butoxycarbonylpiperazine (148 mg, 0.79 mmol) in tetrahydrofuran (2 mL) was added and the reaction stirred for an additional 14 hours at room temperature. The solvent was then removed under vacuum and the residual oil purified by column chromatography (silica gel, gradient 99:1 to 95:5 dichloromethane/methanol, v/v) to afford 7 (204 mg, 66%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.27 (m, 12H), 1.41-1.51 (m, 21H), 1.56-1.66 (m, 5H), 2.32 (t, 2H, J=7.5 Hz), 3.08-3.11 (m, 2H), 3.38-3.41 (m, 2H), 3.56-3.59 (m, 2H), 4.51 (br, 1H); m/z (ESI) 470 [C25H47N3O5+H]+. the reaction stirred for an additional 14 hours at room temperature The solvent was then removed under vacuum the residual oil purified by column chromatography (silica gel, gradient 99:1 to 95:5 dichloromethane/methanol, v/v)

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

Procedure: 1,1′-Carbonyldiimidazole (118 mg, 0.73 mmol) was added to a solution of acid 3 (200 mg, 0.66 mmol) in a mixture of tetrahydrofuran (5 mL) and dichloromethane (1 mL). The resulting solution was stirred at ambient temperature for 4 h. 3-(Dimethylamino)propylamine (0.10 mL, 0.79 mmol) was then added and stirring continued for 14 hours at room temperature. The solvent was then removed under vacuum. The resulting residue was dissolved in dichloromethane (10 mL) and washed sequentially with aqueous sodium bicarbonate (1×10 mL), and then water (1×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give compound 4 (154 mg, 61%) as a clear oil: 1H NMR (500 MHz, CDCl3) δ 1.27 (m, 12H), 1.57 (br, 14H), 1.56-1.65 (m, 2H), 1.67-1.74 (m, 2H), 2.16 (t, 2H, J=7.5 Hz), 2.32 (s, 6H), 2.51 (t, 2H, J=6.7 Hz) 3.29-3.33 (m, 2H), 4.51 (br, 1H); m/z (ESI) 386 [C21H43N3O3+H]+. stirring continued for 14 hours at room temperature The solvent was then removed under vacuum The resulting residue was dissolved in dichloromethane (10 mL) washed sequentially with aqueous sodium bicarbonate (1×10 mL) The organic layer was dried over anhydrous sodium sulfate concentrated

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

Procedure: 1,1′-Carbonyldiimidazole (118 mg, 0.73 mmol) was added to a solution of acid 3 (200 mg, 0.66 mmol) in a mixture of tetrahydrofuran (5 mL) and dichloromethane (1 mL). The resulting solution was stirred at ambient temperature for 4 h. 3-(Dimethylamino)propylamine (0.10 mL, 0.79 mmol) was then added and stirring continued for 14 hours at room temperature. The solvent was then removed under vacuum. The resulting residue was dissolved in dichloromethane (10 mL) and washed sequentially with aqueous sodium bicarbonate (1×10 mL), and then water (1×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give compound 4 (154 mg, 61%) as a clear oil: 1H NMR (500 MHz, CDCl3) δ 1.27 (m, 12H), 1.57 (br, 14H), 1.56-1.65 (m, 2H), 1.67-1.74 (m, 2H), 2.16 (t, 2H, J=7.5 Hz), 2.32 (s, 6H), 2.51 (t, 2H, J=6.7 Hz) 3.29-3.33 (m, 2H), 4.51 (br, 1H); m/z (ESI) 386 [C21H43N3O3+H]+. stirring continued for 14 hours at room temperature The solvent was then removed under vacuum The resulting residue was dissolved in dichloromethane (10 mL) washed sequentially with aqueous sodium bicarbonate (1×10 mL) The organic layer was dried over anhydrous sodium sulfate concentrated

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

Procedure: 1,1′-Carbonyldiimidazole (118 mg, 0.73 mmol) was added to a solution of acid 3 (200 mg, 0.66 mmol) in a mixture of tetrahydrofuran (5 mL) and dichloromethane (1 mL). The resulting solution was stirred at ambient temperature for 4 h. 3-(Dimethylamino)propylamine (0.10 mL, 0.79 mmol) was then added and stirring continued for 14 hours at room temperature. The solvent was then removed under vacuum. The resulting residue was dissolved in dichloromethane (10 mL) and washed sequentially with aqueous sodium bicarbonate (1×10 mL), and then water (1×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give compound 4 (154 mg, 61%) as a clear oil: 1H NMR (500 MHz, CDCl3) δ 1.27 (m, 12H), 1.57 (br, 14H), 1.56-1.65 (m, 2H), 1.67-1.74 (m, 2H), 2.16 (t, 2H, J=7.5 Hz), 2.32 (s, 6H), 2.51 (t, 2H, J=6.7 Hz) 3.29-3.33 (m, 2H), 4.51 (br, 1H); m/z (ESI) 386 [C21H43N3O3+H]+. stirring continued for 14 hours at room temperature The solvent was then removed under vacuum The resulting residue was dissolved in dichloromethane (10 mL) washed sequentially with aqueous sodium bicarbonate (1×10 mL) The organic layer was dried over anhydrous sodium sulfate concentrated

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

Procedure: N-BOC-11-aminoundecanoic acid (Bachem, 0.60 g, 2.0 mmoles) was activated with disuccinimidylcarbonate (0.56 g, 2.2 mmoles) and 4-dimethylamino-pyridine (0.02 g, 0.2 rnmoles) in 10 mL of dimethylformamide/pyridine (2/1, v/v) and reacted with the resin product from Part C for 60 minutes at room temperature. The resulting resin was separated by filtration, the N-α-BOC group was removed with trifluoroacetic acid in dichloromethane, and the resulting resin was treated with 90% hydrogen fluoride/anisole (v/v) for 60 minutes at 0° C. The hydrogen fluoride was removed by evaporation, and the product was extracted into 30% acetic acid/water and then lyophilized. The crude material was purified by reverse phase HPLC on a Waters Deltapak RPC-18 column using a linear gradient of 1% to 35% acetonitrile (0.05% trifluoroacetic acid) in water (0.05% trifluoroacetic acid) over 30 minutes at 15 mL/min, which after lyophilization, gave 84.8 mg of 98% pure (by HPLC) L-leucine, N-[[(11-amino-undecanoyl)-L-seryl]-L-lysyl]-, bis-trifluoroacetate. HRMS: (M+H) calcd 530.3918, found 530.3919. Amino acid analyses: calcd serine 1.00, lysine 1.00, leucine 1.00; found: serine 1.05, lysine 1.00, leucine 1.05. v/v) and reacted with the resin product from Part C for 60 minutes at room temperature The resulting resin was separated by filtration the N-α-BOC group was removed with trifluoroacetic acid in dichloromethane the resulting resin was treated with 90% hydrogen fluoride/anisole (v/v) for 60 minutes at 0° C The hydrogen fluoride was removed by evaporation the product was extracted into 30% acetic acid/water The crude material was purified by reverse phase HPLC on a Waters Deltapak RPC-18 column over 30 minutes

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound 1 (29.0 g, 96.2 mmol) was dissolved in anhydrous tetrahydrofuran (500 mL). The solution was cooled to 0° C. under a dry inert atmosphere. Borane-tetrahydrofuran complex (1.0 M, 144 mL, 144 mmol) was added dropwise with stirring over 1 hour. The cooling bath was removed and the reaction was allowed to warm to room temperature and stirred an additional 2 hours. The reaction was then quenched by the slow, careful addition of saturated aqueous sodium bicarbonate solution (100 mL). The mixture was diluted with water (400 mL), and the tetrahydrofuran was removed in vacuo. The resulting mixture was extracted three times with ethyl acetate (200 mL portions), and the organic extracts were combined. The ethyl acetate solution was washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. A white waxy solid was obtained (27.1 g, 98% yield), which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6): δ 1.23 (m, 14H), 1.30–1.43 (m, 13H), 2.88 (q, J=6.7 Hz, 2H), 3.36 (q, J=6.3 Hz, 2H), 4.31 (t, J=5.1 Hz, 1H), 6.74 (t, J=5.2 Hz, 1H). 13C NMR (75 MHz, DMSO-d6): δ 25.13, 26.27, 28.25, 28.74, 28.98, 29.03, 29.11, 29.48, 32.56, 60.72, 77.21, 155.55. HRMS (ESI-pos): calcd for C16H34NO3 288.2539, obsd 288.2535. Borane-tetrahydrofuran complex (1.0 M, 144 mL, 144 mmol) was added dropwise The cooling bath was removed to warm to room temperature stirred an additional 2 hours The reaction was then quenched by the slow, careful addition of saturated aqueous sodium bicarbonate solution (100 mL) The mixture was diluted with water (400 mL) the tetrahydrofuran was removed in vacuo The resulting mixture was extracted three times with ethyl acetate (200 mL portions) The ethyl acetate solution was washed with brine (100 mL) dried over anhydrous magnesium sulfate filtered evaporated in vacuo A white waxy solid was obtained (27.1 g, 98% yield), which was used in the next step without further purification

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

Procedure: N-BOC-11-aminoundecanoic acid (Bachem, 0.60 g, 2.0 mmoles) was activated with disuccinimidylcarbonate (0.56 g, 2.2 mmoles) and 4-dimethylamino-pyridine (0.02 g, 0.2 mmoles) in 10 mL of dimethylformamide/pyridine (2/1, v/v) and reacted with the resin product from Part C for 60 minutes at room temperature. The resulting resin was separated by filtration, the N-α-BOC group was removed with trifluoroacetic acid in dichloromethane, and the resulting resin was treated with 90% hydrogen fluoride/anisole (v/v) for 60 minutes at 0° C. The hydrogen fluoride was removed by evaporation, and the product was extracted into 30% acetic acid/water and then lyophilized. The crude material was purified by reverse phase HPLC on a Waters Deltapak RPC-18 column using a linear gradient of 1% to 35% acetonitrile (0.05% trifluoroacetic acid) in water (0.05% trifluoroacetic acid) over 30 minutes at 15 mL/min, which after lyophilization, gave 84.8 mg of 98% pure (by HPLC) L-leucine, N-[[(11-amino-undecanoyl)-L-seryl]-L-lysyl]-, bis-trifluoroacetate. v/v) and reacted with the resin product from Part C for 60 minutes at room temperature The resulting resin was separated by filtration the N-α-BOC group was removed with trifluoroacetic acid in dichloromethane the resulting resin was treated with 90% hydrogen fluoride/anisole (v/v) for 60 minutes at 0° C The hydrogen fluoride was removed by evaporation the product was extracted into 30% acetic acid/water The crude material was purified by reverse phase HPLC on a Waters Deltapak RPC-18 column over 30 minutes