HF-Free Boc Synthesis of Peptide Thioesters for Ligation and Cyclization

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• 作者：Dr. Richard Raz ; Dr. Fabienne Burlina ; Dr. Mohamed Ismail ; Dr. Julian Downward ; Dr. Jiejin Li ; Dr. Stephen J. Smerdon ; Martin Quibell ; Dr. Peter D. White and Dr. John Offer
• 刊名：Angewandte Chemie International Edition
• 出版年：2016
• 出版时间：October 10, 2016
• 年：2016
• 卷：55
• 期：42
• 页码：13174-13179
• 全文大小：1681K
• ISSN：1521-3773

文摘

We have developed a convenient method for the direct synthesis of peptide thioesters, versatile intermediates for peptide ligation and cyclic peptide synthesis. The technology uses a modified Boc SPPS strategy that avoids the use of anhydrous HF. Boc in situ neutralization protocols are used in combination with Merrifield hydroxymethyl resin and TFA/TMSBr cleavage. Avoiding HF extends the scope of Boc SPPS to post-translational modifications that are compatible with the milder cleavage conditions, demonstrated here with the synthesis of the phosphorylated protein CHK2. Peptide thioesters give easy, direct, access to cyclic peptides, illustrated by the synthesis of cyclorasin, a KRAS inhibitor.