Resins for the Synthesis of C-Terminal Modified Peptides

ChemFiles Volume 3 Article 4

Hydroxymethylbenzoic acid (HMBA) is a useful and versatile benzyl ester derived linker, completely resistant to acids (even to liquid HF) but easily cleavable by a variety of nucleophilic reagents to give access to peptides with diverse C-terminal functionalities.(1-3) Because the HMBA resin is TFA stable, on-resin side-chain deprotection can also be achieved. Peptide acids are obtained by saponification.(2, 3) Ammonolysis or amminolysis provides primary or secondary amides.(2-4) Peptide alcohols can be synthesized by boron hydride reduction-cleavage procedure of the C-terminal benzyl ester. Reductive cleavage is effected rapidly using LiBH4 in THF.(5) Transesterification of the peptide resin benzyl ester linkage releases peptide esters. Tertiary amines may serve as catalysts, but better results are described employing either KCN(6, 7) or LiBr/1,8-diazabicyclo(5.4.0)undec-7-ene (DBU).(8) Hydrazinolysis of peptidyl resins provides protected peptide hydrazides, precursors for subsequent fragment condensations via azide coupling.(9) Coupling of the first amino acid residue is accomplished employing either carbodiimide/dimethylaminopyridine (DMAP) in dichloromethane,(10) 2,6-dichlorobenzoyl chloride/pyridine in dimethylformamide,(11) or 1-(2-mesitylenesulfonyl)-3-nitro-1H-1,2,4-triazole (MSNT) in the presence of N-methylimidazole.(12, 13)

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  1. Sheppard, R. C.; Williams, B. J. Int. J. Pept. Protein Res. 1982, 20, 451.
  2. Stewart, J. M.; Young, J. D. Solid-Phase Peptide Synthesis (2nd ed.), Pierce Chemical Co., Rockford, IL, 1984.
  3. Atherton, E.; Sheppard, R. C., Solid-Phase Peptide Synthesis: A Practical Approach. Oxford University Press: New York City, 1989.
  4. Mergler, M.; Nyfelder, R. Innovation and Perspectives in solid-phase Synthesis, 2nd International Symposium, Epton, R. Ed., Mayflower Worldwide Ltd., Birmingham 1992; p. 429.
  5. Stewart, J. M.; Morris, D. H. U.S. Patent 4,254,023, 1981.
  6. Moore, G. J.; McMaster, D. Int. J. Pept. Protein Res. 1978,11,140.
  7. Moore, G. J.; Kwok, Y. C. Can. J. Biochem. 1980, 58, 641.
  8. Seebach, D. et al. Helv. Chim. Acta 1991, 74, 1102.
  9. Meienhofer, J. The Peptides: Analysis, Synthesis, Biology, Gross, E. Meienhofer, J. Eds, Vol. 1, Academic Press: New York, 1979; Vol. 1, P 198.
  10. Chang, C. D.; Meienhofer, J. Int. J. Peptide Protein Res. 1978, 11, 246.
  11. Sieber, P. Tetrahedron Lett. 1987, 28, 6147.
  12. Blankemeyer-Menge, B. et al. Tetrahedron Lett. 1990 31, 1701.
  13. Nielsen, J. Tetrahedron Lett. 1996 31, 1710.

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