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

Bourne, GT, Meutermans, WDF, Alewood, PF, McGeary, RP, Watson, AA and Smythe, ML (1999) A Backbone Linker for BOC-Based Peptide Synthesis and On-Resin Cyclization: Synthesis of Stylostatin 1. Journal of Organic Chemistry, 64 9: 3095-3101.


Author Bourne, GT
Meutermans, WDF
Alewood, PF
McGeary, RP
Watson, AA
Smythe, ML
Title A Backbone Linker for BOC-Based Peptide Synthesis and On-Resin Cyclization: Synthesis of Stylostatin 1
Journal name Journal of Organic Chemistry   Check publisher's open access policy
Publication date 1999
Sub-type Article
DOI 10.1021/jo9818780
Volume number 64
Issue number 9
ISSN 0022-3263
Start page 3095
End page 3101
Total pages 7
Place of publication Washington DC
Publisher American Chemical Society
Collection year 1999
Language eng
Subject C1
780103 Chemical sciences
250301 Organic Chemical Synthesis
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 fi om 4-hydroxybenzaldehyde and bromovaleric acid. Subsequent reductive amination of the aldehyde with an allyl-protected amino acid eater 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.
Keyword Chemistry, Organic
Solid-phase Synthesis
Combinatorial Organic-synthesis
To-tail Cyclization
Cyclic-peptides
Drug Discovery
Molecular Diversity
Libraries
Generation
Somatostatin
Technologies
Q-Index Code C1

Document type: Journal Article
Sub-type: Article
Collection: Institute for Molecular Bioscience - Publications
 
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