Resins for the Boc-/Bzl-Synthesis of Peptide Acids

ChemFiles Volume 3 Article 4

Merrifield Resins

The classic Merrifield reaction scheme for SPPS starts with an esterification of the protected C-terminal residue onto chloromethylated polystyrene, a standard support for Boc-/Bzl-synthesis of peptide acids.(1-3) The benzyl ester linkage, however, is not sufficiently stable to repetitive acidolytic treatment (25% trifluoroacetic acid), which is normally necessary to remove the Bocgroup. Loss of 1-2% peptide after each acidolysis step limits the applicability of Merrifield resins in peptide synthesis to the preparation of smaller peptides only. Nevertheless, quantitative cleavage of the peptide acid from the resin requires strong acidic conditions employing HF together with appropriate scavengers or trifluoromethanesulfonic acid (TFMSA), trimethylsilyl trifluoromethane sulfonate (TMSOTf), HBr/trifluoroacetic acid (TFA).(1-3) Hydrogenolysis,(4)  transesterification with methoxides to provide peptide esters(5) and treatment with reducing agents like LiBH4 (6) or diisobutylaluminum hydride (DIBAH)(7) to isolate the corresponding alcohols are also described in the literature. Coupling of the first amino acid residue to the resin is achieved by using either carboxylic acid cesium salts in conjunction with a catalytic amount of KI,(8-10)  (CH3)4N salts(11)  or anhydrous KF.(12)

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  1. Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149. 
  2. Merrifield, R. B. J. Am. Chem. Soc. 1964, 86, 304.
  3. Stewart, J. M.; Young, J. D. solid-phase Peptide Synthesis (2nd Ed.), Pierce Chemical Co.: Rockford III, 1984.
  4. Schlatter J. M. et al. Tetrahedron Lett. 1977, 2851.
  5. Frenette, R. et al. Proc. Natl. Acad. Sci. USA 1994, 90, 6906.
  6. Stewart, J. M.; Morris, D. H. U.S. Patent 4,254,023, 1981.
  7. Kurth, M. J. et al. J. Org. Chem. 1994, 59, 5862.
  8. Gisin, B. F. Helv. Chim. Acta 1973, 53, 1476. 
  9. Wang, S. S. et al. J. Org. Chem. 1977, 42, 1286. 
  10. Hudson, D.; Kenner, G. W. Int. J. Biol. Macromol. 1980, 2, 63.
  11. Loffet, A. Int. J. Protein Res. 1971, 3, 297. 
  12. Horiki, K.; Inouye, K. Chem. Lett. 1978, 165.

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