Use of N-tritylamino acids and PyAOP1 for the suppression of diketopiperazine formation in Fmoc/tBu solid-phase peptide synthesis using alkoxybenzyl ester anchoring linkages

Tetrahedron Letters

Volumn 37, Issue 24, 1996, Pages 4195-4198

  Alsina, Jordi ^a   Giralt, Ernest ^a   Albericio, Fernando ^a  

^a UNIVERSITY OF BARCELONA   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

ALKOXYBENZENE DERIVATIVE; PIPERAZINEDIONE; TRITYL DERIVATIVE;

AMINO ACID ANALYSIS; AMINO ACID SEQUENCE; AMINO ACID SUBSTITUTION; ARTICLE; CARBOXY TERMINAL SEQUENCE; CATALYSIS; CHIRALITY; CITRIC ACID CYCLE; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; PEPTIDE SYNTHESIS;

EID: 0030012632     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/0040-4039(96)00793-9     Document Type: Article

References (29)

1. tBu, tert-butyl; TFE, 2,2,2-trifluoroethanol; Trt, triphenylmethyl (trityl).
2. a) Gisin, B. F.; Merrifield, R. B. J. Am. Chem. Soc. 1972, 94, 3102-3106.
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11. b) Albericio, F.; Barany, G. Int. J. Peptide Protein Res. 1985, 26, 92-97.
12. Flörsheimer, A.; Riniker, B. In Peptides 1990; Giralt, E.; Andreu, D. Eds.; ESCOM, 1991, pp-131-133.
13. Flörsheimer, A.; Riniker, B. In Peptides 1990; Giralt, E.; Andreu, D. Eds.; ESCOM, 1991, pp-131-133.
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18. Barlos, K.; Papaioannou, D.; Patrianakou, S.; Tsegenidis, T. Liebigs Ann. Chem. 1986, 1950-1955.
19. tBu solid-phase peptide synthesis was as follows; The resin was swollen by washing with DMF (3×1 min) and removed the Fmoc group with piperidine-DMF (2:8) (2×1 min, 1×10 min), washing with DMF (5×1 min). Fmoc-AA-OH and HOAt (3 fold excess relative to the amino function in both cases) was added as a solution in DMF followed by DIPCDI. The mixture was left 60 min and then filtered, washing with DMF (5×1 min).
20. 2O-DCM (2:1:97) (5×1 min), washing with DCM (3×1 min), followed by neutralization with DIEA-DCM (1:19) (3×1 min) and washing again with DCM (3×1 min), DMF (3×1 min). Fmoc-Phe-OH and HOAt (3 fold excess relative to the amino function in both cases) was added as a solution in DMF followed by DIPCDI. The mixture was left 60 min and then filtered, washing with DMF (5×1 min), DCM (3×1 min). In both cases, qualitative ninhydrin test was used to determine completion of coupling.
21. a) Bodanzsky, M.; Bednarek, M. A.; Bodanszky, A. Int. J. Peptide Protein Res. 1982, 20, 387-395.
22. b) Bodanszky, M.; Bodanszky, A.; Casaretto, M.; Zahn, H. Int. J. Peptide Protein Res. 1985, 26, 550-556.
23. Kaiser Sr., E.; Tam, J. P.; Kubiak, T. M.; Merrifield, R. B. Tetrahedron Lett. 1988, 29, 303-306.
24. b) Kaiser Sr., E.; Picart, F.; Kubiak, T. M.; Tam, J. P.; Merrifield, R. B. J. Org. Chem. 1993, 58, 5167-5175.
25. For AB-resins up 2% of TFA can be used to remove the Trt group.
26. Carpino, L. A.; El-Faham, A.; Minor, C. A.; Albericio, F. J. Chem. Soc., Chem. Commun. 1994, 201-203.
27. For couplings without preactivation of the protected amino acid, phosphonium salts such as PyAOP are preferred to uronium salts, because the latter can give guanidinium formation (Gausepohl, H.; Pieles, U.; Frank, R. W. In Proceedings of the 12th American Peptides Symposium, Smith, J. A.; Rivier, J. E. Eds. ESCOM; 1992, pp. 131-133).
28. Yields were calculated by amino acid analysis of the resins before and after the incorporation of the Fmoc-Lys(Boc)-OH.
29. Synthesis of the same tripeptides using standard Fmoc chemistry [deprotection with piperidine-DMF (2:8) (2×1 min, 1×10 min)] gave rise 89% (AB-resin) and 67% (HMPB-resin) of DKP formation.