Highly Acid-Labile Resins for the Fmoc-/tBu-Synthesis of Protected Peptide Acids

Chemfiles Volume 3 Article 4

2-Chlorotrityl Resin


The mild cleavage conditions for the highly acid-labile 2-chlorotrityl resin provides fully protected peptide fragments for convergent synthesis and selective side-chain derivitizations.(1-5) The large steric hinderance of the trityl functionality effectively suppresses diketopiperazine (DKP) formation in the synthesis of prolyl peptides.(6,7) C-terminal Cys- and His-residues are introduced in to trityl resins, avoiding any racemization, to provide enantiomerically pure products.(3,4,8) Attachment of the first amino acid residue is effected by stirring the resin, the protected amino acid, and excess diisopropylethylamine (DIEA) in dichloromethane displacing the chloride by diisopropylethylammonium carboxylate.(3,9)

Cleavage of the final protected peptide fragment is achieved under very mild conditions using either acetic acid/trifluoroethanol (TFE)/dichloromethane (1:1:8; v/v/v), hexafluoroisopropanol (HFIP)/dichloromethane (1:4; v/v)(5) or 0.5% trifluoroacetic acid/dichloromethane (v/v).(1-5) Note that trityl chloride is moisture-sensitive, and, therefore, should be stored and handled appropriately. If the resin becomes deactivated, treatment with acetyl chloride or SOCl2 in toluene before use is recommended to restore its activity.(10)

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Materials

     

References

  1. Barlos, K. et al. Tetrahedron Lett. 1989, 30, 3943.
  2. Barlos, K. et al. ibid. 1989, 30, 3947.
  3. Barlos, K. et al. Int. J. Pept. Protein Res. 1991, 37, 513.
  4. Barlos, K. et al. Angew. Chem. 1989, 30, 3943.
  5. Bollhagen, R. et al. J. Chem. Soc., Chem. Commun. 1994, 2559.
  6. Gairi, M. et al. Int. J. Pept. Protein Res. 1995, 46, 119.
  7. Rovero, P. et al. Lett. Pept. Sci. 1995, 2, 319.
  8. Fujiwara, Y. et al. Chem. Pharm. Bull. 1994, 42, 724.
  9. Chiva, C. et al. J. Pept.Sci. 1999, 5, 131.
  10. Van Vliet, A. Innovation and Perspectives in solid-phase Synthesis, 2nd International Symposium, R. Epton, ed., Mayflower Worldwide Limited, Birmingham 1992, 425.

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