Enhancement of peptide coupling reactions by 4-dimethylaminopyridine.
4-Dimethylaminopyridine (DMAP) was found to be useful in the enhancement of peptide coupling reactions mediated by dicyclohexylcarbodiimide or symmetrical anhydrides. In an automated synthesis of the model heptapeptide Boc-Ala-Cle-Ile-Val-Pro-Arg(Tos)-Gly-OCH2-Resin (Cle, cycloleucine), the efficiencies of various coupling methods such as dicyclohexylcarbodiimide, dicyclohexylcarbodiimide plus 1-hydroxybenzotriazole, and symmetrical anhydride were compared with that of dicyclohexylcarbodiimide plus 4-dimethylaminopyridine. Based on the amino acid composition of the peptide-resin samples and high pressure liquid chromatographic analyses of the protected heptapeptide amide obtained from the ammonolytic cleavage of the peptide-resin samples, it was concluded that only dicyclohexylcarbodiimide plus 4-dimethylaminopyridine gave the desired near quantitative couplings in those cycles involving the sterically hindered amino acid residues. Observations were also made that 4-dimethylaminopyridine was a useful additive in a modified symmetrical anhydride method of coupling. In the synthesis of the model tetrapeptide Leu-Ala-Gly-Val on a Pam resin, the anhydride couplings were accelerated by DMAP and the product was equivalent in homogeneity to that obtained by the best previous methods. In addition, no racemization was detectable by a sensitive chromatographic method. There also was no detectable racemization found in a DCC-DMAP coupling of Boc-Ile-OH with H-Val-OCH2-resin. However, significant racemization was observed during the coupling of Boc-Phe-OH with H-Glu(OBzl)-OCH2-resin. DMAP is recommended as an additive for coupling hindered amino acids, particularly C alpha-substituted residues, where little or no racemization is expected.
D015761:4-Aminopyridine / Q000031:analogs & derivatives*; D000596:Amino Acids / Q000032:analysis; D000631:Aminopyridines; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D010455:Peptides / Q000138:chemical synthesis
D000596:Amino Acids; D000631:Aminopyridines; D010455:Peptides; D015761:4-Aminopyridine; C003885:4-dimethylaminopyridine