Peptide Syntheses via Ugi Reactionswith Ammonia

Abstract

If ammonia is used as amine component in Ugi reactions, the desiredpeptide sometimes is obtained only as the minor product or in traces.Side reactions such as six-component couplings are responsible forthis observation. These side reactions can be suppressed by usingnon-nucleophilic alcohols, such as trifluoro­ethanol, stericallydemanding aldehydes and carboxylic acids.

Key words

ammonia - peptides - Ugi reactions - six-component coupling

References

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14

Preparation of1: Isobutyraldehyde (0.13 mL, 1.3 mmol) was added to a solutionof ammonium benzoate (139 mg, 1.0 mmol) in trifluoroethanol (2 mL)at 0 °C. After stirring for 30 min, methyl isocyanoacetate(100 mg, 1.0 mmol) was added via syringe over a period of 5 min.Trifluoroethanol was added (1.5 mL) to get a homogeneous solution.The mixture was allowed to warm to 15 °C overnight.After stirring at r.t. for further 24 h, the solution was dilutedwith CH₂Cl₂ (30 mL) and washed with 1 N KHSO₄ andsat. NaHCO₃ solution. The organic layer was dried (Na₂SO₄)and the solvent was evaporated in vacuo. The crude product was purifiedby crystallization from EtOAc and hexanes giving rise to 1 (132 mg, 0.45 mmol) as colorless crystals,mp 146-148 °C. ¹H NMR (300MHz, CDCl₃): δ = 0.96 (d, J = 6.7Hz, 3 H), 0.99 (d, J = 6.4 Hz, 3 H), 2.12(m, 1 H), 3.68 (s, 3 H), 3.79 (bs, 2 H, H₂O), 3.85 (dd, J = 17.9,3.7 Hz, 1 H), 4.05 (dd, J = 17.8, 3.8 Hz, 1 H),4.41 (m, 1 H), 7.31-7.73 (m, 5 H), 7.57-7.78 (m,2 H).

15

Preparation of2: Isobutyraldehyde (0.11 mL, 1.0 mmol) was added to a solutionof ammonium benzoate (139 mg, 1.0 mmol) in MeOH (2 mL) at 0 °C.After stirring for 40 min, the solution was warmed to 40 °Cfor 10 min, before it was cooled to 0 °C again.Methyl isocyanoacetate (100 mg, 1.0 mmol) was added via syringeover a period of 5 min. The mixture was allowed to warm to 15 °Covernight. After stirring at r.t. for further 24 h, the solutionwas diluted with CH₂Cl₂ and washed with 1N KHSO₄ and sat. NaHCO₃ solution. The organiclayer was dried (Na₂SO₄) and the solvent wasevaporated in vacuo. The crude product was purified by flash chromatographyon silica gel (hexanes/EtOAc: 7/3, 6/4,3/7, 0/1) giving rise to 2 (121mg, 0.32 mmol) as a diastereomeric mixture. ¹HNMR (300 MHz, CDCl₃): δ = 0.72 (d, J = 6.7Hz, 3 H), 0.75 (d, J = 6.7 Hz, 3 H), 1.01(d, J = 6.6Hz, 3 H), 1.03 (d, J = 6.6 Hz, 3 H), 2.08 (m,1 H), 2.98 (m, 1 H), 3.31 (s, 3 H), 3.59 (d, J = 11.2 Hz, 1 H), 3.70(s, 3 H), 3.94 (dd, J = 15.2, 2.5 Hz, 1 H),4.01-4.16 (m, 2 H), 7.32-7.40 (m, 5 H), 8.95 (bs,1 H).

16

Preparation of3: Isobutyraldehyde (0.23 mL, 2.0 mmol) was added to a solutionof ammonium benzoate (139 mg, 1.0 mmol) in MeOH (2 mL) at 0 °C.After stirring for 30 min methyl isocyanoacetate (100 mg, 1.0 mmol)was added via syringe over a period of 5 min. The mixture was allowedto warm to 15 °C over night. After stirring atr.t. for further 24 h, the solution was evaporated in vacuo. Thecrude product was crystallized from hexanes and EtOAc giving riseto 3 (226 mg, 0.68 mmol) as a colorlesssolid, mp. 171-173 °C. ¹HNMR (300 MHz, CDCl₃): δ = 0.90 (s_br,3 H), 0.99 (d, J = 6.6 Hz, 3 H), 1.00(d, J = 6.5Hz, 3 H), 1.32 (s_br, 3 H), 1.70-1.74 (m, 2 H),4.00 (d, J = 9.5Hz, 1 H), 4.73 (d, J = 7.9 Hz,1 H), 6.09 (s_br, 1 H), 6.63 (d, 1 H, J = 7.5Hz), 7.39-7.53 (m, 5 H), 7.79-7.82 (m, 2 H).

18

General Procedurefor the Ugi 4 Component Peptide Syntheses: 5 Mmol of the aldehydewere added to a 1.5 N solution of ammonia (4 mL, 6 mmol) in MeOHat 0 °C. After 10 min 5 mmol of the isonitrilewere added, followed by 5.05 mmol of the protected amino acid. Thereaction mixture was allowed to warm to r.t. overnight. To thismixture CH₂Cl₂ (50 mL) was added and the organiclayer was washed with 1 N KHSO₄ and sat. NaHCO₃ solution.Drying over Na₂SO₄ and evaporation of thesolvent gave the crude peptide, which was purified flash chromatography.The diastereomers were separated by preparative medium pressurechromatography on silica (LiChroprep Si60) using EtOAc/hexanesas eluents.

19

¹H NMR data ofall peptides 4 obtained, all of which gave satisfactoryelemental analyses. The configuration of the diastereomeric peptideswas determined by HPLC analysis (comparison with reference samplesobtained by standard peptide coupling from the (S)-aminoacids). (S,R)-4a: ¹H NMR (200 MHz,CDCl₃): δ = 0.90(d, J = 7.0Hz, 6 H), 1.02 (s, 9 H), 2.12 (m, 1 H), 3.63 (s, 3 H), 3.84 (d, J = 5.5 Hz,1 H), 4.12 (d, J = 5.5Hz, 1 H), 4.33 (m, 1 H), 4.74 (d, J = 9.0 Hz,1 H), 5.08 (s, 2 H), 6.30 (d_bržJ = 9.0Hz, 1 H), 7.33 (s_br, 6 H), 7.97 (t, J = 5.5Hz, 1 H). (S,S)-4a: ¹H NMR (200 MHz, CDCl₃): δ = 0.89(d, J = 7.0Hz, 6 H), 1.01 (s, 9 H), 2.01 (m, 1 H), 3.69 (s, 3 H), 3.85 (d, J = 5.0 Hz,1 H), 4.11 (d, J = 5.0 Hz,1 H), 4.29 (dd, J = 9Hz, J = 7.0Hz, 1 H), 4.61 (d, J = 9.0Hz, 1 H), 5.12 (s, 2 H), 6.13 (d_br, J = 9.0Hz, 1 H), 7.33 (s_br, 6 H), 7.65 (t, J = 5.5Hz, 1 H). (S,R)-4b: ¹H NMR (200 MHz,CDCl₃): δ = 0.90(d, J = 7.0Hz, 6 H), 0.99 (s, 9 H), 1.44 (s, 9 H), 2.08 (m, 1 H), 3.77 (t, J = 3.5 Hz,1 H), 4.02 (m, 1 H), 4.23 (m, 1 H), 4.63 (d, J = 9.0Hz, 1 H), 5.10 (s, 2 H), 6.31 (d_br, J = 8.5Hz, 1 H), 7.35 (s_br, 6 H), 7.42 (m, 1 H). (S,S)-4b: ¹H NMR (200 MHz,CDCl₃): δ = 0.94(d, J = 6.5 Hz,6 H), 1.01 (s, 9 H), 1.45 (s, 9 H), 2.03 (m, 1 H), 3.75 (m, 1 H),4.00 (m, 1 H), 4.23 (m, 1 H); 4.68 (d, J = 9.0Hz, 1 H), 5.12 (s, 2 H), 6.09 (d_br, J = 9.0Hz, 1 H), 7.04 (d_br, J = 8.5Hz, 1 H), 7.36 (s_br, 6 H). (S,R)-4c: ¹HNMR (200 MHz, CDCl₃): δ = 0.90(d, J = 7.0Hz, 3 H), 0.97 (d, J = 7.0Hz, 3 H), 1.04 (s, 9 H), 1.45 (s, 9 H), 1.47 (s, 9 H), 2.06-2.44(m, 1 H), 3.82-4.20 (m, 3 H), 4.52 (d, J = 8.5Hz, 1 H), 5.41 (d_br, J = 9Hz, 1 H), 6.95 (d_br, J = 9Hz, 1 H), 7.18 (t_br, J = 5.5Hz, 1 H). (S,S)-4c: ¹H NMR (200 MHz,CDCl₃): δ = 0.92(d, J = 7.0 Hz,6 H), 1.02 (s, 9 H), 1.43 (s, 9 H), 1.46 (s, 9H), 1.94-2.33 (m,1 H), 3.77-4.20 (m, 3 H), 4.53 (d, J = 9.0Hz, 1 H), 5.54 (d_br, J = 9.0Hz, 1 H), 7.07 (d_br, J = 9.0Hz, 1 H), 7.31 (t_br, J = 5.5Hz, 1 H). (S,R)-4d: ¹H NMR (200 MHz,CDCl₃): δ = 0.84(d, J = 7.5Hz, 3 H), 0.90 (d, J = 7.0Hz, 3 H), 1.05 (s, 9 H), 1.76-2.32 (m, 5 H), 3.52 (t, J = 7.0 Hz,2 H), 3.70 (s, 3 H), 3.94 (d, J = 5.0Hz, 1 H), 4.01 (d, J = 5.0Hz, 1 H), 4.25-4.56 (m, 2 H), 7.46 (m, 2 H), 7.34 (s, 5 H). (S,S)-4d: ¹H NMR (200 MHz,CDCl₃): δ = 0.84(d, J = 6.5Hz, 6 H), 1.00 (s, 9 H), 1.75-2.27 (m, 5 H), 3.57 (t, J = 6.0 Hz,2 H), 3.68 (s, 3 H), 3.93 (d, J = 5.5Hz, 1 H), 4.07 (d, J = 5.5Hz, 1 H), 4.23-4.60 (m, 2 H), 4.59 (d, J = 9.0Hz, 1 H), 5.20 (s, 2 H), 7.33 (s_br, 6 H), 7.49 (d_br, J = 9.0 Hz,1 H), 7.73 (t, J = 5.0Hz, 1 H). (S,R)-4e: ¹H NMR (200 MHz,CD₃OD): δ = 0.90-1.14 (m,12 H), 2.02 (m, 1 H), 2.31 (m, 1 H), 3.69 (s, 3 H), 4.00 (d, J = 3.5 Hz,2 H), 4.27 (d, J = 8.0Hz, 1 H), 4.53 (d, J = 8.0 Hz,1 H), 4.77 (s_br, acidic H’s), 7.48-7.63(m, 3 H), 7.84-8.00 (m, 2 H). (S,S)-4e: ¹HNMR (200 MHz, CD₃OD): δ = 0.98(d, J = 7.0Hz, 6 H), 1.02 (J = 7.0Hz, 6 H), 2.13 (m, 2 H), 3.73 (s, 3 H), 3.98 (d, J = 3.5Hz, 2 H), 4.32 (d, J = 7.5 Hz,1 H), 4.49 (d, J = 8.5Hz, 1 H), 4.79 (s_br, acidic H’s), 7.48-7.65(m, 3 H), 7.82-7.99 (m, 2 H).