Subscribe to RSS
DOI: 10.1055/s-2003-40987
Peptide Syntheses via Ugi Reactionswith Ammonia
Publication History
Publication Date:
05 August 2003 (online)
![](https://www.thieme-connect.de/media/synlett/200311/lookinside/thumbnails/10.1055-s-2003-40987-1.jpg)
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
-
1a
Wagner I.Musso H. Angew.Chem., Int. Ed. Engl. 1983, 22: 816 ; Angew. Chem. 1983 , 95, 827 -
1b
Annual reports, In Amino Acids, Peptides and Proteins, Specialist PeriodicalReports, Chem. Soc.: London
-
1c
Faulkner DJ. Nat. Prod. Rep. 2002, 19: 1 - 2
Gräfe U. Biochemieder Antibiotika Spektrum; Heidelberg: 1992. -
3a
Barluenga J.Campos PJ.Gonzáles CM.Suárez JC. J. Org. Chem. 1991, 56: 2234 -
3b
Marshall RG. Tetrahedron 1993, 49: 3547 -
4a
Seebach D.Beck AK.Studer A. In Modern Synthetic Methods Vol.7:Ernst B.Leumann C. VCH; Weinheim: 1995. p.1 -
4b
Kazmaier U.Maier S. J. Org. Chem. 1999, 64: 4574 -
5a
Ugi I. Isonitrile Chemistry AcademicPress; New York: 1971. -
5b
Ugi I. Chem.-Ztg. 1997, 74: 9 -
5c
Dömling A.Ugi I. Angew. Chem.Int. Ed. 2000, 39: 3168 ; Angew. Chem. 2000, 112, 3300 and references cited therein -
6a
Ugi I.Steinbrückner C. Chem.Ber. 1961, 94: 2797 -
6b
Keating TA.Armstrong RW. J.Org. Chem. 1998, 63: 867 - 7
Ugi I.Offermann K. Chem. Ber. 1964, 97: 2996 - 8
Ugi I.Offermann K.Herlinger H.Marqharding D. Liebigs Ann. Chem. 1967, 709: 1 -
9a
Urban R.Ugi I. Angew.Chem. 1975, 87: 67 -
9b
Siegmüller F.Ugi I. Tetrahedron 1986, 42: 5931 -
10a
Kunz H.Pfrengle W. J.Am. Chem. Soc. 1988, 110: 651 -
10b
Kunz H.Pfrengle W.Sager W. TetrahedronLett. 1989, 30: 4109 -
10c
Lehnhoff S.Goebel M.Karl RM.Klösel R.Ugi I. Angew.Chem., Int. Ed. Engl. 1995, 34: 1104 ; Angew. Chem. 1995, 107, 1208 -
10d
Ziegler T.Kaiser H.Schlömer R.Koch C. Tetrahedron 1999, 55: 8397 -
10e
Oertel K.Zech G.Kunz H. Angew.Chem. Int. Ed. 2000, 39: 1431 ; Angew. Chem. 2000, 112, 1489 - 11
Tempest PA.Brown SD.Armstrong RW. Angew. Chem., Int. Ed. Engl. 1996, 35: 460 ; Angew. Chem. 1996, 108, 689 - 12
Hebach C.Kazmaier U. Chem. Commun. 2003, 596 -
13a
Miller SJ.Grubbs RH. J. Am. Chem. Soc. 1995, 117: 5855 -
13b
Clark TD.Ghadiri MR. J.Am. Chem. Soc. 1995, 117: 12364 -
13c
Miller SJ.Blackwell HE.Grubbs RH. J. Am. Chem. Soc. 1996, 118: 9606 -
13d
Williams RM.Liu J. J. Org. Chem. 1998, 63: 2130 -
13e
Gao Y.Lane-Bell P.Vederas JC. J.Org. Chem. 1998, 63: 2133 -
13f
Cabrejas LMM.Rohrbach S.Wagner D.Kallen J.Zenke G.Wagner J. Angew. Chem. Int. Ed. 1999, 38: 2443 ; Angew. Chem. 1999, 111, 2595 - 17
Floyd CD.Harnett LA.Miller A.Patel S.Saroglou L.Whittaker M. Synlett 1998, 637
References
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).
15Preparation 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).
16Preparation 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 (sbr,3 H), 0.99 (d, J = 6.6 Hz, 3 H), 1.00(d, J = 6.5Hz, 3 H), 1.32 (sbr, 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 (sbr, 1 H), 6.63 (d, 1 H, J = 7.5Hz), 7.39-7.53 (m, 5 H), 7.79-7.82 (m, 2 H).
18General 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.
191H 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 (dbržJ = 9.0Hz, 1 H), 7.33 (sbr, 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 (dbr, J = 9.0Hz, 1 H), 7.33 (sbr, 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 (dbr, J = 8.5Hz, 1 H), 7.35 (sbr, 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 (dbr, J = 9.0Hz, 1 H), 7.04 (dbr, J = 8.5Hz, 1 H), 7.36 (sbr, 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 (dbr, J = 9Hz, 1 H), 6.95 (dbr, J = 9Hz, 1 H), 7.18 (tbr, 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 (dbr, J = 9.0Hz, 1 H), 7.07 (dbr, J = 9.0Hz, 1 H), 7.31 (tbr, 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 (sbr, 6 H), 7.49 (dbr, 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 (sbr, 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 (sbr, acidic H’s), 7.48-7.65(m, 3 H), 7.82-7.99 (m, 2 H).