The use of the Nbb-resin for the solid-phase synthesis of peptide alkylesters and alkylamides. Synthesis of leuprolide

Tetrahedron

Volumn 53, Issue 9, 1997, Pages 3179-3194

  Nicolás, Ernesto ^a   Clemente, Javier ^a   Ferrer, Tina ^a   Albericio, Fernando ^a   Giralt, Ernest ^a  

^a UNIVERSITY OF BARCELONA   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

LEUPRORELIN;

AMINO ACID ANALYSIS; AMINO ACID SEQUENCE; ARTICLE; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; IN VITRO STUDY; METHODOLOGY; PEPTIDE SYNTHESIS; PRIORITY JOURNAL; REACTION ANALYSIS;

EID: 0031550893     PISSN: 00404020     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4020(97)00029-X     Document Type: Article

References (54)

1. tBu, tert-butyl; CMC, carboxymethylcellulose; DCM, dichloromethane; DIEA, N,N-diisopropylethylamine, DIPCDI, N,N'-diisopropylcarbodiimide; DMAP, 4-N,N-dimethylaminopiridine; DMF, N,N'-dimethylformamide; EDT, ethanditiol; ES-MS, electrospray mass spectrometry; DTE, dithioerythritol; DTT, dithiothreitol; FAB-MS, fast atom bombardment mass spectrometry; Fmoc, 9-fluorenylmethoxycarbonyl; HOBt, 1-hydroxybenzotriazole; HPLC, high-performance liquid chromatography; MBHA, p-methylbenzhydrylamine; MPLC, medium-pressure liquid chromatography; Mtr, 4-methoxy-2,3,6-trimethyl-benzenesulfonyl; Nbb-, nitrobenzamidobenzyl; -resin, poly(styrene-co-1% divinylbenzene); NMR, nuclear magnetic resonance; PyBOP, (benzotriazolyl)-N-oxypyrrolidinephosphonium hexafluorophosphate; TBAF, tetrabutylammonium fluoride; TFA, trifluoroacetic acid; THF, tetrahydrofurane; TMS, tetramethylsilane; Trt, trityl. Amino acid symbols denote L-configuration unless indicate otherwise.
2. tBu, tert-butyl; CMC, carboxymethylcellulose; DCM, dichloromethane; DIEA, N,N-diisopropylethylamine, DIPCDI, N,N'-diisopropylcarbodiimide; DMAP, 4-N,N-dimethylaminopiridine; DMF, N,N'-dimethylformamide; EDT, ethanditiol; ES-MS, electrospray mass spectrometry; DTE, dithioerythritol; DTT, dithiothreitol; FAB-MS, fast atom bombardment mass spectrometry; Fmoc, 9-fluorenylmethoxycarbonyl; HOBt, 1-hydroxybenzotriazole; HPLC, high-performance liquid chromatography; MBHA, p-methylbenzhydrylamine; MPLC, medium-pressure liquid chromatography; Mtr, 4-methoxy-2,3,6-trimethyl-benzenesulfonyl; Nbb-, nitrobenzamidobenzyl; -resin, poly(styrene-co-1% divinylbenzene); NMR, nuclear magnetic resonance; PyBOP, (benzotriazolyl)-N-oxypyrrolidinephosphonium hexafluorophosphate; TBAF, tetrabutylammonium fluoride; TFA, trifluoroacetic acid; THF, tetrahydrofurane; TMS, tetramethylsilane; Trt, trityl. Amino acid symbols denote L-configuration unless indicate otherwise.
3. 2. Hruby, V.J.; Sharma, S.D.; Collins, N.; Matsunaga, T.O.; Russel, K.C. In Synthetic Peptides. A User's Guide; G. A. Grant, Ed.; W. H. Freeman and Company: New York, 1992; pp 259-345.
4. 3. Heimbrook, D.C.; Saari, W.S.; Balishin, N.L.; Friedman, A.; Moore, K.S.; Riemen, M.W.; Kiefer, D.M.; Rotberg, N.S.; Wallen, J.W.; Oliff, A. J. Biol. Chem. 1989, 264, 11258-11262.
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23. (d) Lloyd-Williams, P.; Albericio, F.; Giralt, E. Int. J. Peptide Protein Res. 1991, 37, 58-60.
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25. (f) Lloyd-Williams, P.; Gairí, M.; Albericio, F.; Giralt, E. Tetrahedron 1993, 49, 10069-10078.
26. 15. (a) Nicolás, E.; Clemente, J.; Perelló, M.; Albericio, F.; Pedroso, E.; Giralt, E. Tetrahedron Lett. 1992, 33, 2183-2186.
27. 4-OH. Afinidad 42, 491-496 (1985).
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31. (b) Lloyd-Williams, P.; Albericio, F.; Giralt, E. Chemical Approaches to the Synthesis of Peptides and Proteins; CRC Press, Boca Raton (FL), in press.
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37. tBu. Alsina, J.; Giralt, E.; Albericio, F.; Tet. Lett., 1996, 37, 4195-4197.
38. 22. In general, retention times of peptide alkylesters and alkylamides were higher than those found for peptide carboxylic acids. The peptide methylamide that was obtained from resin 1 was an exception since it had the same chromatographic behaviour as that of the corresponding peptide carboxylic acid; however, the amino acid analysis of the former showed an additional peak of methylamine at 51 min.
39. 23. Lloyd-Williams, P.; Albericio, F.; Giralt, E. Tetrahedron 1993, 49, 11065-11133.
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43. 26. Gendrich, R.L.; Rippel, R.H.; Seely, J.H. United States Patent, n 3.914.412, 1975.
44. 2Nbb resulted in a complex mixture of products, probably due to the competition of the amino groups of the amino acid side chains with the nucleophile.
45. 28. Precautions have to be taken when histidine or cysteine are C-terminal amino acids in order to avoid racemization of these residues. In such cases, alternative methodologies are recomended; see for example (a) Akaji, K.; Kuriyama, N.; Kimura, T.; Fujiwara, Y.; Kiso, Y., Tetrahedron Lett. 1992, 33, 3177-3180.
46. (b) Green, J.; Bradley, K., Tetrahedron 1993, 49, 4141-4146.
47. (c) Zhu, Y.-F.; Blair, R.K.; Fuller, W.D., Tetrahedron Lett 1994, 35, 4673-4676.
48. 29. The use of DBU, a poor nucleophilic base, can be a good alternative in this case.
49. 30. Barany, G.; Merrifield, R. B. In The Peptides. Analysis, Synthesis, Biology; E. Gross and J. Meienhofer, Ed.; Academic Press: New York, 1979; Vol. 2, Special Methods in Peptide Synthesis, Part A; pp 1-284.
50. 31. Confirmed by amino acid analysis and FAB-MS spectrometry (retention time of the desired peptide, 13.5 min; retention time for the desarginine peptide, 15 min (see figure 2 for Chromatographic conditions).
51. 32. Dichloromethane was also used, but better yields were achieved with chloroform.
52. α-Boc groups during the synthesis. Nevertheless, unstability of Mtr protecting group under these conditions did not supose a drawback to achieve the synthesis of leuprolide in good yields.
53. 34. The amine was extracted from 1 mL of a 70% aqueous solution of ethylamine.
54. 35. The free carboxylic acid peptide and the peptide methylamide of 1 had the same Chromatographic behaviour; however, the amino acid analysis of the latter showed a peak at 51 min corresponding to methylamine