Extended Solution-phase Peptide Synthesis Strategy Using Isostearyl-Mixed Anhydride Coupling and a New C-Terminal Silyl Ester-Protecting Group for N-Methylated Cyclic Peptide Production,Organic Process Research & Development

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Extended Solution-phase Peptide Synthesis Strategy Using Isostearyl-Mixed Anhydride Coupling and a New C-Terminal Silyl Ester-Protecting Group for N-Methylated Cyclic Peptide Production
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2021-08-23 , DOI: 10.1021/acs.oprd.1c00078
Akihiro Nagaya ₁ , Shota Murase ₁ , Yuji Mimori ₁ , Kazuya Wakui ₁ , Madoka Yoshino ₁ , Ayumu Matsuda ₂ , Yutaka Kobayashi ₂ , Haruaki Kurasaki ₂ , Douglas R. Cary ₂ , Keiichi Masuya ₂ , Michiharu Handa ₁ , Naoki Nishizawa ₁

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Herein, we present a new and efficient convergent solution-phase synthetic strategy for producing peptides containing N-methyl amino acids. Specifically, we have synthesized a model cyclic octapeptide with two N-methyl amino acids, utilizing an isostearyl-mixed anhydride coupling methodology and a novel silyl ester-protecting group, cyclohexyl di-tert-butyl silyl (cHBS). This newly developed method uses an isostearic acid chloride (ISTA-Cl) and silylation reagent that allows coupling between N- and C-terminally unprotected amino acids with sterically hindered N-methyl amino acids. High yields of four dipeptide fragments are efficiently synthesized by omitting the traditional C-terminal deprotection step. The silyl ester-protecting group at the C-terminus is stable during general peptide synthesis, and is selectively cleaved by fluoride ions. This group further suppresses diketopiperazine formation during the deprotection of the N^α-amino-protecting group. The linear octapeptide precursor is convergently synthesized utilizing protection and selective deprotection of the silyl ester-protecting group, and the cyclic octapeptide can be obtained with high purity using this novel methodology, via a route shorter than conventional solution-phase peptide synthesis strategies.

中文翻译：

使用异硬脂基混合酸酐偶联和用于 N-甲基化环肽生产的新型 C 端甲硅烷基酯保护基团的扩展液相肽合成策略

在此，我们提出了一种新的高效收敛液相合成策略，用于生产含有N-甲基氨基酸的肽。具体而言，我们利用异硬脂基混合酸酐偶联方法和新型甲硅烷基酯保护基团环己基二叔丁基甲硅烷基 (cHBS)合成了具有两个N-甲基氨基酸的模型环状八肽。这种新开发的方法使用异硬脂酰氯 (ISTA-Cl) 和甲硅烷基化试剂，使 N 和 C 末端未保护的氨基酸与空间位阻N偶联-甲基氨基酸。通过省略传统的 C 端去保护步骤，可以高效合成高产率的四个二肽片段。C-末端的甲硅烷基酯保护基团在一般肽合成过程中是稳定的，并被氟离子选择性裂解。该基团在N ^α -氨基保护基团的脱保护过程中进一步抑制二酮哌嗪的形成。利用甲硅烷基酯保护基团的保护和选择性脱保护聚合合成线性八肽前体，使用这种新方法可以通过比常规液相肽合成策略更短的路线获得高纯度的环状八肽。

更新日期：2021-09-17

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