Peptide Thioester Synthesis via an Auxiliary-Mediated N–S Acyl Shift Reaction in Solution
Peptide Thioester Synthesis via an Auxiliary-Mediated N–S Acyl Shift Reaction in Solution
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DOI：
10.1007/s10989-006-9065-9
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发表时间：
2007-01
影响因子：
2.5
通讯作者：
Ken’ichiroh Nakamura;H. Mori;T. Kawakami;H. Hojo;Y. Nakahara;S. Aimoto
中科院分区：
文献类型：
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作者：
Ken’ichiroh Nakamura;H. Mori;T. Kawakami;H. Hojo;Y. Nakahara;S. Aimoto
在酸性条件下，连接到肽中主链酰胺上的4，5-二甲氧基-2-巯基苄基（Dmmb）容易通过分子内N-Sacyl移位反应转化为S-肽，并且S-肽通过分子间硫醇-硫酯交换反应产生肽硫酯。为了开发一种基于N-糖基转移反应高效制备肽硫酯的方法，对该过程中的影响因素进行了详细的分析。通过~（13）C-NMR光谱测量、反相HPLC分析、质量测量和氨基酸分析，研究了Dmmb基团在三氟乙酸（TFA）溶液中与酰胺键相连的转化和肽硫酯生成的一般特征。Dmmb基团的甲氧基对于N-糖基转移反应不是必需的，但在稳定硫酯形式中起作用。在TFA溶液中加入水可加速Dmmb基团介导的N-糖基转移反应，并抑制Dmmb基团的酸催化裂解。肽硫酯是由S-肽通过分子间硫醇-硫酯交换反应产生的，其中构成硫酯键的氨基酸残基的差向异构化最小。在合成过程中出现了硫酯键水解和S-N酰基转移等副反应，这是一个有待进一步研究的课题。
The 4,5-dimethoxy-2-mercaptobenzyl (Dmmb) group attached to a main chain amide in a peptide is easily transformed into anS-peptideviaan intramolecularN–Sacyl shift reaction under acidic conditions, and theS-peptide produces a peptide thioester through an intermolecular thiol–thioester exchange reaction. In order to develop a method for efficiently preparing peptide thioesters based on theN–Sacyl shift reaction, the factors involved in this process were analyzed in detail. The general features of the transformation at the Dmmb group attached amide bond in a trifluoroacetic acid (TFA) solution and the generation of a peptide thioester were examined by13C-NMR spectral measurements, reversed-phase (RP) HPLC analyses, mass measurements, and amino acid analyses. The methoxy group of the Dmmb group was not essential for theN–Sacyl shift reaction, but played a role in stabilizing the thioester form. The addition of water to the TFA solution accelerated theN–Sacyl shift reaction mediated by the Dmmb group and also suppressed the acid-catalyzed cleavage of the Dmmb group. A peptide thioester was produced from theS-peptideviaan intermolecular thiol–thioester exchange reaction with minimal epimerization of the amino acid residue that constituted the thioester bond. Undesirable side reactions, such as the hydrolysis of the thioester bond and anS–Nacyl shift reaction occurred during the synthetic process, which is a subject of further investigation.