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A Backbone Linker for BOC-Based Peptide Synthesis and On-Resin Cyclization: Synthesis of Stylostatin 1
Bourne, GT, Meutermans, WDF, Alewood, PF, McGeary, RP, Scanlon, M, Watson, AA and Smythe, ML (1999) A Backbone Linker for BOC-Based Peptide Synthesis and On-Resin Cyclization: Synthesis of Stylostatin 1. J Organic Chemistry, 64 9: 3095-3101.
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| Author(s) |
Bourne, GT
Meutermans, WDF
Alewood, PF
McGeary, RP
Scanlon, M
Watson, AA
Smythe, ML
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| Title |
A Backbone Linker for BOC-Based Peptide Synthesis and On-Resin Cyclization: Synthesis of Stylostatin 1
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| Journal name |
J Organic Chemistry
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| Publication date |
1999
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| Volume number |
64
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| Issue number |
9
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| ISSN |
0022-3263
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| Start page |
3095
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| End page |
3101
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| Total pages |
7
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| Place of publication |
Washington DC
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| Publisher |
American Chemical Society
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| Collection year |
1999
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| Subject |
C1
780103 Chemical sciences
250301 Organic Chemical Synthesis
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| 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.
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| Keyword(s) |
Chemistry, Organic
Solid-phase Synthesis
Combinatorial Organic-synthesis
To-tail Cyclization
Cyclic-peptides
Drug Discovery
Molecular Diversity
Libraries
Generation
Somatostatin
Technologies
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