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Pseudoproline
Pseudoproline (also pseudo-proline, ψ-Pro) derivatives are artificially created dipeptides to minimize aggregation during FMOC solid-phase synthesis of peptides.
==Introduction==
The chemical synthesis of large peptides is still limited by problems of low solvation during solid phase peptide synthesis (SPPS) or limited solubility of fully protected peptide fragments: even chemoselective ligation methods are hampered by self-association of unprotected peptide blocks. The elucidation of the relationship between preferred conformation of a growing peptide chain and its physicochemical properties reveals that β-sheet (beta-sheet) formation is often paralleled by significant decrease in solvation and solubility.〔Mutter, M., Vuilleumier, S., Angew. Chem., (1989) 101, p.551; Angew. Chem. Int. Ed. Engl., (1989) 28, p.535〕〔Toniolo. C, Bonora. G. M., Multer. M., Pillai. V.N.R., Makromol. Chem. (1981) 182. p.1997〕〔Mutter. M., Pillai. V. N. R., Anzinger. H., Bayer, E., Toniolo, C, In Peptides (1980) Brunfeldt. K. Ed., Scriptor: Copenhagen. (1981) pp.660〕 Besides attempts to increase the solvation of peptides by external factors, few attempts, i.e. N-substituted Hmb amino acid derivatives〔Johnson, T., Quibell. M., Sheppard, R. C., J. Pept. Sci. (1995) 1. p.11〕 and pseudoprolines (see figure on the top right)〔Wöhr. T., Wahl. E., Nefzi. A., Rohwedder. S., Sato. T., Sun, X., Mutter. M . J. Am. Chem. Soc. (1996) 118, p.9218〕〔Dumy, P., Keller. M., Ryan, D. E., Rohwedder.B., Wöhr. T., Muller, M. J. Am. Chem. Soc, (1997) 119. p.918〕〔Keller, M., Sager. C, Dumy, P., Schutkowski. M., Fischer. G. S., Mutter. M., J. Am. Chem. Soc. (1998) 120, p.2714〕 have been reported to modify the intrinsic properties of peptides responsible for aggregation and secondary structure formation. Pseudoprolines consist of serine- (Oxa) or threonine-derived oxazolidines () and Cysteine-derived thiazolidines (THz) with Proline-like ring structure (see top right). Mutter and cooworkers〔Mutter, M., Nafzi. A., Sato. T., Sun, X., Wahl. E, Wöhr,T. Peplide Res. (1995) 8. 145.〕 have defined oxa- and thiaproline derivatives of serine, threonine, and cysteine with Ser(ψPro). Thr(ψPro), and Cys(ψPro), respectively, where the abbreviation ψPro indicates the relationship to proline (with heteroatomic ring substitution in position 4). Pseudoprolines with substitution in position 2 of the proline ring are named Ser/Thr/Cys-(ψR1,R2 Pro). Due to the preference for a cis-amide bond〔Nefzi. A., Schenk K., Mutter. M . Protein Pept Lett. (1994) 1, p.66〕 with the preceding residue of C2-substituted pseudoprolines, their incorporation results in a kink conformation of the peptide backbone, thus preventing peptide aggregation, self-association, or β-structure formation.
Hence, pseudoprolines fulfill two functions simultaneously: they serve (1) as temporary side-chain protection for Ser, Thr, and Cys and (2) as solubilizing building blocks to increase solvation and coupling rates during peptide synthesis and in subsequent chain assembly. Pseudoprolines are obtained by reacting the free amino acids with aldehydes or ketone.〔Fülop F., Mattinen J., Pihlaja K., Tetrahedron (1990) 46, p.6545〕〔Kallen RG., J. Am. Chem. Soc, (1971) 93, p.6236〕 The coupling of amino acid derivatives to a growing peptide chain containing N-terminal pseudoproline generally results in low yields because of the sterically hindered nature of the oxazolidine (thiazolidine) ring system and the decreased nucleophilicity of the nitrogen atom. Consequently, the preformation of suitably protected dipeptide derivatives of the type FMOC-Xaa1-Oxa/THz-OH is preferable for use in peptide synthesis. Two conceptually different approaches are feasible for preparing oxazolidine- and thiazolidine-ring-containing dipeptide derivatives: (1) the in situ acylation of Ser- or Thr-derived oxazolidines or Cys-derived thiazolidines using acid fluorides or N-carboxyanhydrides (NCA); and (2) the direct insertion of the oxazolidine systems into dipeptides (post-insertion) containing C-terminal Ser or Thr. The method of choice strongly depends on the nature of the pseudoproline as welI as on the substituents at C2 of the cyclic system.
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