Peptide Syntheses via Ugi Reactionswith Ammonia

Uli Kazmaier; Christina Hebach

doi:10.1055/s-2003-40987

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Synlett 2003(11): 1591-1594
DOI: 10.1055/s-2003-40987

LETTER

Peptide Syntheses via Ugi Reactionswith Ammonia

Uli Kazmaier*, Christina Hebach
Institut für Organische Chemie, Universität des Saarlandes, Postfach151150, 66041 Saarbrücken, Germany
Fax: +49(681)3022409; e-Mail: u.kazmaier@mx.uni-saarland.de;

Further Information

Publication History

Received 16 May 2003
Publication Date:
05 August 2003 (online)

Abstract
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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).

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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).