p-Cresol As a Reversible Acylium Ion Scavenger in Solid-Phase Peptide Synthesis
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- 作者：Les P. Miranda ; Alun Jones ; Wim D. F. Meutermans ; and Paul F. Alewood
- 刊名：Journal of the American Chemical Society
- 出版年：1998
- 出版时间：February 25, 1998
- 年：1998
- 卷：120
- 期：7
- 页码：1410 - 1420
- 全文大小：228K
- 年卷期：v.120,no.7(February 25, 1998)
- ISSN：1520-5126
文摘
In this work we have defined the nature of the p-cresoland p-thiocresol adducts generated fromacylium ions during HF cleavage, following contemporary Boc/benzylsolid-phase peptide synthesis. Contraryto the results in previous reports, we found that bothp-cresol and p-thiocresol predominantly form arylestersunder typical cleavage conditions. Initially we investigated anumber of small peptides containing either asingle glutamate residue or a C-terminal long-chain aminoacid which allowed us to unambiguously characterizethe "scavenged" side products. Whereas, thep-cresol esters are stable at 0 
C they rearrangeirreversibly athigher temperatures (5-20 C) to form aryl ketones. Bycontrast, p-thiocresol esters do not undergo aFriesrearrangement but readily undergo further additions ofp-thiocresol to form ketenebisthioacetals andtrithioortho esters, even at low temperatures. Importantly, we found byLC/MS and FT-ICR MS analysis that peptidescontaining p-cresol esters at glutamyl side chains aresusceptible to amidation and fragmentation reactions atthese sites during standard mild base workup procedures. Thesignificance of these side reactions was furtherdemonstrated in the synthesis of neutrophil immobilization factor, a26-residue peptide, containing four glutamicacid residues. The side reactions were largely avoided by mildhydrogen peroxide-catalyzed hydrolysis whichconverted the p-cresol adducts to the free carboxylic acidsin near quantitative yield. The choice ofp-cresolas a reversible acylium ion scavenger when coupled with the simpleworkup conditions described is broadlyapplicable to Boc/benzyl peptide synthesis and will significantlyenhance the quality of peptides produced.
C they rearrangeirreversibly athigher temperatures (5-20 C) to form aryl ketones. Bycontrast, p-thiocresol esters do not undergo aFriesrearrangement but readily undergo further additions ofp-thiocresol to form ketenebisthioacetals andtrithioortho esters, even at low temperatures. Importantly, we found byLC/MS and FT-ICR MS analysis that peptidescontaining p-cresol esters at glutamyl side chains aresusceptible to amidation and fragmentation reactions atthese sites during standard mild base workup procedures. Thesignificance of these side reactions was furtherdemonstrated in the synthesis of neutrophil immobilization factor, a26-residue peptide, containing four glutamicacid residues. The side reactions were largely avoided by mildhydrogen peroxide-catalyzed hydrolysis whichconverted the p-cresol adducts to the free carboxylic acidsin near quantitative yield. The choice ofp-cresolas a reversible acylium ion scavenger when coupled with the simpleworkup conditions described is broadlyapplicable to Boc/benzyl peptide synthesis and will significantlyenhance the quality of peptides produced.