Protected 4-carboxyoxazolidines and thiazolidines (pseudoprolines) are derivatives of serine, threonine or cysteine amino acids. Such compounds are used in peptide synthesis among the other protected amino acids. They are usually practiced when a peptide sequence is readily aggregating during synthesis due to their ability to disrupt secondary structure formation. Such compounds are usually applied as dipeptides. In present work Fmoc-protected pseudoprolines were synthesized and applied in peptide synthesis not as dipeptides but as individual amino acids. Different acylation protocols and amino acids were tested to acylate pseudoprolines. Several “difficult” peptides were synthesized to confirm the efficacy of such constructions. It was shown that pseudoprolines could be easily synthesized and used in automated or manual synthesis not as dipeptides but as ordinary amino acids.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
1–[Bis(dimethylamino)methylene]–1H–1,2,3–triazolo[4,5–b]pyridinium 3–oxide hexafluorophosphate
Methyl tert-butyl ether
Solid phase peptide synthesis
Abedini A, Raleigh DP (2005) Incorporation of pseudoproline derivatives allows the facile synthesis of human IAPP, a highly amyloidogenic and aggregation-prone polypeptide. Org Lett 7:693–696. https://doi.org/10.1021/ol047480+
Carbajo D, El-Faham A, Royo M, Albericio F (2019) Optimized stepwise synthesis of the API Liraglutide using BAL resin and pseudoprolines. ACS Omega 4:8674–8680. https://doi.org/10.1021/acsomega.9b00974
Garcia-Martin F et al (2006) The synergy of ChemMatrix resin and pseudoproline building blocks renders RANTES, a complex aggregated chemokine. Biopolymers 84:566–575. https://doi.org/10.1002/bip.20564
Guichou JF, Patiny L, Mutter M (2002) Pseudo-prolines (ΨPro): direct insertion of ΨPro systems into cysteine containing peptides. Tetrahedron Lett 43:4389–4390. https://doi.org/10.1016/S0040-4039(02)00755-4
Haack T, Mutter M (1992) Serine derived oxazolidines as secondary structure disrupting, solubilizing building blocks in peptide synthesis. Tetrahedron Lett 33:1589–1592. https://doi.org/10.1016/S0040-4039(00)91681-2
Keller M, Miller AD (2001) Access to the inaccessible sequence of Cpn 60.1 (195–217) by temporary oxazolidine protection of selected amide bonds. Bioorg Med Chem Lett 11:857–859. https://doi.org/10.1016/S0960-894X(01)00085-3
Marek P, Woys AM, Sutton K, Zanni MT, Raleigh DP (2010) Efficient microwave-assisted synthesis of human islet amyloid polypeptide designed to facilitate the specific incorporation of labeled amino acids. Org Lett 12:4848–4851. https://doi.org/10.1021/ol101981b
Mcnamara JF et al (2000) An efficient solid-phase strategy for the construction of chemokines. J Pept Sci 6:512–518. https://doi.org/10.1002/1099-1387(200010)6:10%3c512::AID-PSC269%3e3.0.CO;2-A
Page K et al (2007) Fast Fmoc synthesis of hAmylin1–37 with pseudoproline assisted on-resin disulfide formation. J Pept Sci 13:833–838. https://doi.org/10.1002/psc.909
Sampson WR, Patsiouras H, Ede NJ (1999) The synthesis of ‘difficult’ peptides using 2-hydroxy-4-methoxybenzyl or pseudoproline amino acid building blocks: a comparative study. J Pept Sci 5:403–409. https://doi.org/10.1002/(SICI)1099-1387(199909)5:9%3c403::AID-PSC213%3e3.0.CO;2-S
Spengler J, Blanco-Canosa JB, Forni L, Albericio F (2018) One-pot peptide ligation-oxidative cyclization protocol for the preparation of short-/medium-size disulfide cyclopeptides. Org Lett 20:4306–4309. https://doi.org/10.1021/acs.orglett.8b01741
Wahl F et al (1996) Pseudo-prolines as a solubilizing, structure-disrupting protection technique in peptide synthesis. J Am Chem Soc 118:9218–9227. https://doi.org/10.1021/ja961509q
White P, Keyte JW, Bailey K, Bloomberg G (2004) Expediting the Fmoc solid phase synthesis of long peptides through the application of dimethyloxazolidine dipeptides. J Pept Sci 10:18–26. https://doi.org/10.1002/psc.484
Wöhr T, Mutter M (1995) Pseudo-prolines in peptide synthesis: direct insertion of serine and threonine derived oxazolidines in dipeptides. Tetrahedron Lett 36:3847–3848. https://doi.org/10.1016/0040-4039(95)00667-2
Wong MSY, Jolliffe KA (2018) A comparison of pseudoproline substitution effects on cyclisation yield in the total syntheses of segetalins B and G. Pept Sci 110:2–10. https://doi.org/10.1002/pep2.24042
Conflict of interest
The authors declare no conflict of interest.
The study did not involve research with humans, animals or biological samples. Informed consent was not required.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Handling Editor: F. Albericio .
Below is the link to the electronic supplementary material.
About this article
Cite this article
Senko, D.A., Timofeev, N.D., Kasheverov, I.E. et al. Scope and limitations of pseudoprolines as individual amino acids in peptide synthesis. Amino Acids 53, 665–671 (2021). https://doi.org/10.1007/s00726-021-02973-1
- Solid-phase synthesis
- Difficult sequences