A Backbone Linker for BOC-Based Peptide Synthesis and On-Resin Cyclization:  Synthesis of Stylostatin 1^,

Abstract

We have developed a new 4-alkoxybenzyl-derived linker that anchors the C-terminal amino acid to the resin through the alpha-nitrogen atom. The linker allows BOC solid-phase peptide assembly and peptide cleavage using standard HF protocols. This linking strategy provides a versatile on-resin route to cyclic peptides and avoids the diketopiperazine formation that is prominent when using FMOC chemistry on backbone linkers. The linker was prepared by forming the aryl ether from 4-hydroxybenzaldehyde and bromovaleric acid. Subsequent reductive amination of the aldehyde with an allyl-protected amino acid ester and acylation of the resulting secondary amine provided the tertiary amide. After linking the amide to the resin, standard BOC SPPS, followed by allyl deprotection, cyclization, and HF cleavage gave cyclic peptides in high purity. To exemplify the strategy, the cytotoxic heptapeptide, stylostatin 1, was synthesized from two linear precursors. For comparison purposes, the yields of the on-resin and solution-phase cyclization were determined and found to be dependent upon the linear precursor. This linker technology provides new solid-phase avenues in accessing libraries of cyclic peptides.

The cyclization of peptides and depsipeptides

“…Pseudostellarin D, cyclo (Gly-Gly-Tyr-Pro-Leu-Ile-Leu) has been synthesized in the solution phase [119] via pnitrophenyl ester which took 10 days to achieve success. In contrast, for the synthesis of stylostatin, cyclo (Ile-Pro-Phe-Asn-EtGly-Leu-Ala), a resin linker attached to the α-nitrogen of a C-terminal residue (Ala in this case), was used to assemble the linear precursor, which was then cyclized on-resin [120].…”

Solid-phase synthesis of isoalloxazines using merrifield resin

“…The absorption spectra were recorded on Shimadzu UV-260 spectrophotometer and absorption maxima were expressed in nm. 1 H NMR was recorded on Bruker Avance 300 spectrometer using TMS as an internal reference (chemical shift in ppm). Fluorescence spectra were recorded at the excitation value 420 nm on a Jobin Youn JY-3CS spectrofluorimeter and emission maxima were expressed in nm.…”

“…1,2 Further, the polymer-supported synthesis has also been applied in a variety of organic reactions including the synthesis of natural products, heterocycles and in medicinal chemistry. [3][4][5][6][7][8][9][10] Synthesis of 10-substituted isoalloxazines by the acidic cyclocondensation of 2-substituted aminoanilines with alloxan monohydrate in aqueous and organic solvents has been reported by us.…”

Solid‐Supported Synthesis of Bicyclic Peptides Containing Three Parallel Peptide Chains

“…[23] Accordingly, glycine was attached to the resin by the symmetrical anhydride method, and the chain was elongated by two leucine residues using Fmoc chemistry with HATU/ DIEA [24,25] activation. The branching unit 1 was then coupled similarly to obtain tetrapeptide 4 (Scheme 2) bearing three orthogonally protected amino groups.…”