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Features of Auxiliaries That Enable Native Chemical Ligation beyond Glycine and Cleavage via Radical Fragmentation
Chemistry - A European Journal ( IF 3.9 ) Pub Date : 2018-02-12 , DOI: 10.1002/chem.201705927
Simon F. Loibl 1 , Andre Dallmann 1 , Kathleen Hennig 1 , Carmen Juds 1 , Oliver Seitz 1
Affiliation  

Native chemical ligation (NCL) is an invaluable tool in the total chemical synthesis of proteins. Ligation auxiliaries overcome the requirement for cysteine. However, the reported auxiliaries remained limited to glycine‐containing ligation sites and the acidic conditions applied for cleavage of the typically applied N‐benzyl‐type linkages promote side reactions. With the aim to improve upon both ligation and cleavage, we systematically investigated alternative ligation scaffolds that challenge the N‐benzyl dogma. The study revealed that auxiliary‐mediated peptide couplings are fastest when the ligation proceeds via 5‐membered rather than 6‐membered rings. Substituents in α‐position of the amine shall be avoided. We observed, perhaps surprisingly, that additional β‐substituents accelerated the ligation conferred by the β‐mercaptoethyl scaffold. We also describe a potentially general means to remove ligation auxiliaries by treatment with an aqueous solution of triscarboxyethylphosphine (TCEP) and morpholine at pH 8.5. NMR analysis of a 13C‐labeled auxiliary showed that cleavage most likely proceeds through a radical‐triggered oxidative fragmentation. High ligation rates provided by β‐substituted 2‐mercaptoethyl scaffolds, their facile introduction as well as the mildness of the cleavage reaction are attractive features for protein synthesis beyond cysteine and glycine ligation sites.

中文翻译:

辅助剂的功能,可通过甘氨酸进行天然化学连接,并通过自由基裂解进行裂解

天然化学连接(NCL)是蛋白质总化学合成中的宝贵工具。连接助剂克服了对半胱氨酸的需求。但是,已报道的助剂仍然仅限于含甘氨酸的连接位点,而用于裂解通常应用的N-苄基型键合的酸性条件会促进副反应。为了同时改善连接和切割,我们系统地研究了挑战N的其他连接支架-苄基教条。研究表明,通过5元环而不是6元环进行连接时,辅助介导的肽偶联最快。应避免在胺的α位取代。我们可能令人惊讶地观察到,其他β取代基加速了β巯基乙基支架赋予的连接。我们还描述了通过用三羧乙基膦(TCEP)和吗啉在pH 8.5的水溶液处理来去除连接助剂的潜在通用方法。13的NMR分析C标记的助剂显示裂解很可能是通过自由基触发的氧化断裂而进行的。β-取代的2-巯基乙基支架提供的高连接率,易于引入以及裂解反应的温和性是半胱氨酸和甘氨酸连接位点以外蛋白质合成的诱人特征。
更新日期:2018-02-12
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