Solid-Phase Synthesis of Phenylalanine Containing Peptides Using a Traceless Triazene Linker

Abstract

The use of a triazene function to anchor phenylalanine to a polymeric support through its side chain is reported. To prove the usefulness of this strategy in solid-phase peptide synthesis, several bioactive peptides have been prepared including cyclic, C-modified, and protected peptides. The triazene linkage is formed by coupling the diazonium salt of Fmoc-Phe(pNH(2))-OAllyl to a MBHA-polystyrene resin previously functionalized with isonipecotic acid (90%). Further assembly of the peptide chain, cleavage from the resin using 2-5% TFA in DCM, and reduction of the resulting diazonium salt of the peptide with FeSO(4)·7H(2)O in DMF afforded the desired products in high purities (73-94%).

Triazene as a Powerful Tool for Solid-Phase Derivatization of Phenylalanine Containing Peptides: Zygosporamide Analogues as a Proof of Concept

“…The protected amino acid Fmoc-Phe( p NH 2 )-OAllyl ( 2b ) was selected to be introduced onto the solid support via triazene linkage. This building block was prepared as described previously . A 4-methyl-benzhydrylamine (MBHA)-polystyrene resin ( 2c ) (0.63 mmol·g –1 ) was functionalized with a glycine residue (internal reference amino acid) in order to control the degree of peptide loading.…”

“…8 We recently demonstrated the feasibility of this approach as a traceless methodology for the synthesis of C-terminal derivatized peptides and cyclic peptides. 9 With the aim of expanding the scope of application of triazene linker in the peptide chemistry field, we decided to explore its use for the introduction of chemical diversity in peptides.…”

“…However, acidic cleavage of the triazene resin under mild conditions yields the amine resin and the modified aryldiazonium salt that can be further reduced to afford the target molecule in a traceless manner , or chemically transformed to introduce diverse functionalities at the aromatic ring . We recently demonstrated the feasibility of this approach as a traceless methodology for the synthesis of C -terminal derivatized peptides and cyclic peptides . With the aim of expanding the scope of application of triazene linker in the peptide chemistry field, we decided to explore its use for the introduction of chemical diversity in peptides.…”

“…CHCl 3 ,); IR (ATR) 3329, 1749, 1687, 1516, 1338, 1263, 1213 cm −1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.11 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 7.6 Hz, 2H), 7.56 (m, 2H), 7.41 (m, 2H), 7.30 (m, 2H), 7.22 (d, J = 8.3 Hz, 2H), 5.86 (m, 1H), 5.31 (m, 3H), 4.70 (m, 1H), 4.62 (d, J = 5.7 Hz, 2H), 4.51 (dd, J 1 = 10 9. Hz, J 2 = 6 9.…”

“…Hz, J 2 = 6 9. Hz, 1H), 4.40 (dd, J 1 = 10.7 Hz, J 2 = 6.4 Hz, 1H), 4.19 (t, J = 6.4 Hz, 1H), 3.27 (dd, J 1 = 13.9 Hz, J 2 = 5.8 Hz, 1H), 3.16 (dd, J 1 = 13.8 Hz, J 2 = 5.9 Hz, 1H) ppm;13 C NMR (100 MHz, CDCl 3 ) δ 170.6, 155.6, 147.3, 143.8, 143.7, 143.6, 141.5 ( × 2), 131.1, 130.4 ( × 2), 127.9 ( × 2), 127.2 ( × 2), 125.0 ( × 2), 123.8 ( × 2), 120.2 ( × 2), 119.8, 66.9, 66.6, 54.6, 47.3, 38.2 ppm; ESI-HRMS calcd for C 27 H 24 N 2 O 6 Na [M + Na] + 495.1526, found 495.1527.…”