Synthesis of dicarba-cyclooctapeptide Somatostatin analogs by conventional and MW-assisted RCM: A study about the impact of the configuration at Cα of selected amino acids

Alessandro Pratesi, Samuele Stazzoni, Marco Lumini, Giuseppina Sabatino, Alfonso Carotenuto, Diego Brancaccio, Ettore Novellino, Marco Chinol, Paolo Rovero, Mauro Ginanneschi, Anna Maria Papini

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

This work describes the synthesis of thirteen cyclooctapeptides dicarba-analogues of Somatostatin, containing L- or D-allylglycine (Agl) residues at the termini of the peptide chain, through on resin Ring Closing Metathesis (RCM) of the linear octapeptides. We investigated the influence of the stereochemistry of some strategic amino acids on the propensity to give the cyclic compounds in mild conditions (refluxing DCM). Systematic individual replacement of Phe6,7,11 residues with the corresponding enantiomers, strongly favoured the ring closure by conventional heating. The yield of the cyclic products was strictly correlated to the position of this amino acid on the peptide chain. In particular substitution of Phe6 by Tyr in peptides which did not give the cyclic compounds, allowed the ring formation. The effect of the phenolic −OH function of Tyr side chain on the proximity of the terminal Agl residue was studied by NMR techniques. All the linear precursors gave cyclic somatostatin dicarba-analogues, in good to high yields and in short reaction times, by microwave-assisted RCM, performed with the 2nd generation Grubbs catalyst. The unsaturated dicarba-tether resulted in a mixture of E and Z stereoisomers in a variable ratio, depending on the sequence and the cyclization method. The E isomer was largely the most abundant in all but one the described product.

Original languageEnglish
Pages (from-to)365-372
Number of pages8
JournalChemical Engineering and Processing: Process Intensification
Volume122
DOIs
Publication statusPublished - Dec 1 2017

Fingerprint

Allylglycine
Somatostatin
Peptides
Amino acids
Amino Acids
Stereochemistry
Stereoisomerism
Enantiomers
Cyclization
Isomers
Substitution reactions
Resins
Microwaves
Nuclear magnetic resonance
Heating
Catalysts

Keywords

  • Cyclooctapeptides
  • Dicarba-analogues of somatostatin
  • Micro-wave assisted peptide synthesis
  • Microwaves-driven RCM
  • Ring closing metathesis (RCM)

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Energy Engineering and Power Technology
  • Process Chemistry and Technology
  • Industrial and Manufacturing Engineering

Cite this

Synthesis of dicarba-cyclooctapeptide Somatostatin analogs by conventional and MW-assisted RCM : A study about the impact of the configuration at Cα of selected amino acids. / Pratesi, Alessandro; Stazzoni, Samuele; Lumini, Marco; Sabatino, Giuseppina; Carotenuto, Alfonso; Brancaccio, Diego; Novellino, Ettore; Chinol, Marco; Rovero, Paolo; Ginanneschi, Mauro; Papini, Anna Maria.

In: Chemical Engineering and Processing: Process Intensification, Vol. 122, 01.12.2017, p. 365-372.

Research output: Contribution to journalArticle

Pratesi, Alessandro ; Stazzoni, Samuele ; Lumini, Marco ; Sabatino, Giuseppina ; Carotenuto, Alfonso ; Brancaccio, Diego ; Novellino, Ettore ; Chinol, Marco ; Rovero, Paolo ; Ginanneschi, Mauro ; Papini, Anna Maria. / Synthesis of dicarba-cyclooctapeptide Somatostatin analogs by conventional and MW-assisted RCM : A study about the impact of the configuration at Cα of selected amino acids. In: Chemical Engineering and Processing: Process Intensification. 2017 ; Vol. 122. pp. 365-372.
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AU - Lumini, Marco

AU - Sabatino, Giuseppina

AU - Carotenuto, Alfonso

AU - Brancaccio, Diego

AU - Novellino, Ettore

AU - Chinol, Marco

AU - Rovero, Paolo

AU - Ginanneschi, Mauro

AU - Papini, Anna Maria

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AB - This work describes the synthesis of thirteen cyclooctapeptides dicarba-analogues of Somatostatin, containing L- or D-allylglycine (Agl) residues at the termini of the peptide chain, through on resin Ring Closing Metathesis (RCM) of the linear octapeptides. We investigated the influence of the stereochemistry of some strategic amino acids on the propensity to give the cyclic compounds in mild conditions (refluxing DCM). Systematic individual replacement of Phe6,7,11 residues with the corresponding enantiomers, strongly favoured the ring closure by conventional heating. The yield of the cyclic products was strictly correlated to the position of this amino acid on the peptide chain. In particular substitution of Phe6 by Tyr in peptides which did not give the cyclic compounds, allowed the ring formation. The effect of the phenolic −OH function of Tyr side chain on the proximity of the terminal Agl residue was studied by NMR techniques. All the linear precursors gave cyclic somatostatin dicarba-analogues, in good to high yields and in short reaction times, by microwave-assisted RCM, performed with the 2nd generation Grubbs catalyst. The unsaturated dicarba-tether resulted in a mixture of E and Z stereoisomers in a variable ratio, depending on the sequence and the cyclization method. The E isomer was largely the most abundant in all but one the described product.

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