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Scope and limitations of pseudoprolines as individual amino acids in peptide synthesis

Abstract

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.

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Scheme 1
Fig. 1
Fig. 2

Abbreviations

BOP:

(Benzotriazol–1–yloxy)tris(dimethylamino)phosphonium hexafluorophosphate

DCM:

Dichloromethane

DIC:

N,N′-Diisopropylcarbodiimide

DIPEA:

N,N-Diisopropylethylamine

DMP:

2,2-Dimethoxypropane

DMF:

N,N-Dimethylformamide

EA:

Ethyl acetate

Fmoc:

Fluorenylmethoxycarbonyl

HATU:

1–[Bis(dimethylamino)methylene]–1H–1,2,3–triazolo[4,5–b]pyridinium 3–oxide hexafluorophosphate

HOAt:

1–Hydroxy–7–azabenzotriazole

HOBt:

1-Hydroxybenzotriazole

MTBE:

Methyl tert-butyl ether

NMP:

N-Methylpyrrolidone

PE:

Petroleum ether

PIP:

4-Methylpiperidine

PPTS:

P-toluenesulfonic acid

PTSA:

Pyridinium p-toluenesulfonate

SA:

Symmetrical anhydride

SPPS:

Solid phase peptide synthesis

TFA:

Trifluoroacetic acid

TFFH:

Fluoro–N,N,N′,N′–tetramethylformamidinium hexafluorophosphate

THF:

Tetrahydrofurane

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Correspondence to Dmitry A. Senko.

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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

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Keywords

  • Peptides
  • Solid-phase synthesis
  • Aggregation
  • Difficult sequences
  • Pseudoprolines