pseudoproline dipeptides
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AAPPTec Pseudoproline Dipeptides


Pseudoproline Dipeptides

Pseudoproline dipeptides are useful building blocks developed by Mutter for preparing long or difficult peptides.1,2,3 In the peptide chain, the amide bond between the pseudoproline dipeptide and the preceding amino acid preferentially adopts a cis configuration.4,5 This creates a kink in the peptide backbone that prevents self-association, β-sheet formation and peptide aggregation. By disrupting aggregation and β-sheet formation, incorporation of pseudoproline dipeptides into peptides used for fragment condensation reactions can markedly improve solubility. In addition, C-terminal pseudoprolines eliminate the risk of epimerization at the C-terminal during fragment coupling.


The tendency for pseudoprolines to form a kink in the peptide backbone promotes cyclization of linear peptides.6 Park and coworkers7 found that incorporating a pseudoproline dipeptide accelerated the on resin cyclization of linear amylin (1-13). Pseudoproline dipeptides improve the synthesis of hydrophobic peptides by disrupting secondary structure and improving the solvation of the peptide.

Most commercial pseudoproline dipeptides contain oxazolidines formed from Ser or Thr. The steric hinderance and reduced nucleophilicity of the oxazolidine nitrogen atom make coupling to pseudoprolines at peptide N-terminals difficult, usually resulting in unacceptably low yields. Therefore in peptide synthesis, the pseudoproline is introduced as a preformed dipeptide unit of the type Xaa-Oxa. The oxazolidine is converted back to Ser or Thr when the peptide is cleaved from the resin with TFA.8,9 The pseudoproline unit is stable to AcOH/TFE/DCM however, so peptides for fragment condensation can be prepared on and cleaved from 2-chlorotrityl resins with the pseudoproline unit intact. As stated earlier, these peptides have improved solubility properties, making them very useful in fragment condensation reactions.

Pseudoproline dipeptides are powerful tools for enhancing the synthesis of cyclic peptides, long peptides and “difficult” peptides, often enabling the production of peptides that otherwise were impossible or impractical to synthesize.

1Mutter M., Nefzi A., Sato T., Wahl F. Wöhr T. Pept. Res. 1995, 8, 145.
2Wöhr T.,Rohwedder B., Wahl F., Nefzi A., Sato T., Sun X., Mutter M. J. Am. Chem. Soc. 1996, 118, 9218.
3White P, et al., J. Pept. Sci. 2004, 10, 18.
4Nefzi. A., Schenk K., Mutter. M . Protein Pept Lett. 1994, 1, 66.
5Dumy P, Keller M, Ryan DE, Rohwedder B, Wöhr T, Mutter M. J. Am. Chem. Soc. 1997, 119, 918.
6Skropeta D, Jolliffe KA, Turner P. J. Org. Chem. 2004, 69, 8804.
7Page K, Hood CA, Patel H, Fuentes G, Menakuru M, Park JH. J. Pept. Sci. 2007, 13, 833.
8Haack T, Mutter M. Tetrahedron Lett. 1992, 33, 1589.
9Sampson WR, Patsiouras H, Ede NJ. J. Pept. Sci. 1999, 5, 403.

AAPPTec Pseudoproline Dipeptides
  Catalog # Pseudoproline Dipeptide
  PPD001 Fmoc-Ala-Ser(ΨMe,Mepro)-OH
  PPD002 Fmoc-Ala-Thr(ΨMe,Mepro)-OH
  PPD003 Fmoc-Asn(Trt)-Ser(ΨMe,Mepro)-OH
  PPD004 Fmoc-Asn(Trt)-Thr(ΨMe,Mepro)-OH
  PPD005 Fmoc-Asp(OtBu)-Ser(ΨMe,Mepro)-OH
  PPD006 Fmoc-Asp(OtBu)-Thr(ΨMe,Mepro)-OH
  PPD007 Fmoc-Gln(Trt)-Ser(ΨMe,Mepro)-OH
  PPD008 Fmoc-Gln(Trt)-Thr(ΨMe,Mepro)-OH
  PPD009 Fmoc-Glu(OtBu)-Ser(ΨMe,Mepro)-OH
  PPD010 Fmoc-Glu(OtBu)-Thr(ΨMe,Mepro)-OH
  PPD011 Fmoc-Gly-Ser(ΨMe,Mepro)-OH
  PPD012 Fmoc-Gly-Thr(ΨMe,Mepro)-OH
  PPD013 Fmoc-Ile-Ser(ΨMe,Mepro)-OH
  PPD014 Fmoc-Ile-Thr(ΨMe,Mepro)-OH
  PPD015 Fmoc-Leu-Ser(ΨMe,Mepro)-OH
  PPD016 Fmoc-Leu-Thr(ΨMe,Mepro)-OH
  PPD017 Fmoc-Lys(Boc)-Ser(ΨMe,Mepro)-OH
  PPD018 Fmoc-Lys(Boc)-Thr(ΨMe,Mepro)-OH
  PPD019 Fmoc-Phe-Ser(ΨMe,Mepro)-OH
  PPD020 Fmoc-Phe-Thr(ΨMe,Mepro)-OH
  PPD021 Fmoc-Ser(tBu)-Ser(ΨMe,Mepro)-OH
  PPD022 Fmoc-Ser(tBu)-Thr(ΨMe,Mepro)-OH
  PPD023 Fmoc-Trp(Boc)-Ser(ΨMe,Mepro)-OH
  PPD024 Fmoc-Trp(Boc)-Thr(ΨMe,Mepro)-OH
  PPD025 Fmoc-Tyr(tBu)-Ser(ΨMe,Mepro)-OH
  PPD026 Fmoc-Tyr(tBu)-Thr(ΨMe,Mepro)-OH
  PPD027 Fmoc-Val-Ser(ΨMe,Mepro)-OH
  PPD028 Fmoc-Val-Thr(ΨMe,Mepro)-OH