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.