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

TY - JOUR

T1 - Synthesis of dicarba-cyclooctapeptide Somatostatin analogs by conventional and MW-assisted RCM

T2 - A study about the impact of the configuration at Cα of selected amino acids

AU - Pratesi, Alessandro

AU - Stazzoni, Samuele

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

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

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.

KW - Cyclooctapeptides

KW - Dicarba-analogues of somatostatin

KW - Micro-wave assisted peptide synthesis

KW - Microwaves-driven RCM

KW - Ring closing metathesis (RCM)

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U2 - 10.1016/j.cep.2017.02.005

DO - 10.1016/j.cep.2017.02.005

M3 - Article

AN - SCOPUS:85014130948

VL - 122

SP - 365

EP - 372

JO - Chemical Engineering and Processing - Process Intensification

JF - Chemical Engineering and Processing - Process Intensification

SN - 0255-2701

ER -