A backbone linker for BOC-based peptide synthesis and on-resin cyclization: Synthesis of stylostatin 1

Gregory T. Bourne, Wim D.F. Meutermans, Paul F. Alewood, Ross P. McGeary, Martin Scanlon, Andrew A. Watson, Mark L. Smythe

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72 Citations (Scopus)

Abstract

We have developed a new 4-alkoxybenzyl-derived linker that anchors the C-terminal amino acid to the resin through the α-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.

Original languageEnglish
Pages (from-to)3095-3101
Number of pages7
JournalThe Journal of Organic Chemistry
Volume64
Issue number9
DOIs
Publication statusPublished - 30 Apr 1999
Externally publishedYes

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