Solid-Phase Synthesis of C-Terminus Cysteine Peptide Acids,Organic Process Research & Development

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Solid-Phase Synthesis of C-Terminus Cysteine Peptide Acids
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2022-11-15 , DOI: 10.1021/acs.oprd.2c00321
Sinenhlanhla N. Mthembu _{1,

2} , Amit Chakraborty ₁ , Ralph Schönleber ₃ , Fernando Albericio _{1,

4,

5} , Beatriz G. de la Torre _{1,

2}

Affiliation

Cysteine (Cys) is a key amino acid in many therapeutic peptides. For research and industrial purposes, solid-phase peptide synthesis is the method of choice for the preparation of most peptides. The solid-phase synthesis of C-terminal Cys peptide acids is problematic because it is accompanied by a side reaction, namely, the abstraction of α-H from the Cys residue, which leads to the formation of three side products: the epimer and two N-piperidinyl-Ala epimer peptides. Here, we used a chlorotrityl chloride resin to conduct a rational and in-depth study of this side reaction. The following variables were examined: removal of the fluorenylmethoxycarbonyl (Fmoc) group by different bases, the presence or absence of an acid rectifier for buffering the base, and thiol side-chain protection. In conclusion, the use of Fmoc-Cys protected with tetrahydropyran (Thp) and 4-methoxytrityl (Mmt) along with 30% 4-methylpiperidine in 0.5 M OxymaPure-DMF for Fmoc removal assures minimization of the side reaction, as demonstrated in a model peptide and confirmed for the elongation of somatostatin.

中文翻译：

C-末端半胱氨酸肽酸的固相合成

半胱氨酸 (Cys) 是许多治疗性肽中的关键氨基酸。对于研究和工业目的，固相肽合成是制备大多数肽的首选方法。C 端 Cys 肽酸的固相合成是有问题的，因为它伴随着副反应，即从 Cys 残基中提取 α-H，这导致三种副产物的形成：差向异构体和两个N-哌啶基丙氨酸差向异构肽。在这里，我们使用氯三苯甲基氯树脂对该副反应进行了合理深入的研究。检查了以下变量：通过不同碱基去除芴基甲氧基羰基 (Fmoc)、是否存在用于缓冲碱基的酸整流剂以及硫醇侧链保护。总之，使用四氢吡喃 (Thp) 和 4-甲氧基三苯甲基 (Mmt) 保护的 Fmoc-Cys 以及 30% 4-甲基哌啶在 0.5 M OxymaPure-DMF 中去除 Fmoc 可确保将副反应降至最低，如模型所示肽并证实了生长抑素的延长。

更新日期：2022-11-15

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