tert-Butylethylcarbodiimide as an Efficient Substitute for Diisopropylcarbodiimide in Solid-Phase Peptide Synthesis: Understanding the Side Reaction of Carbodiimides with OxymaPure,Organic Process Research & Development

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tert-Butylethylcarbodiimide as an Efficient Substitute for Diisopropylcarbodiimide in Solid-Phase Peptide Synthesis: Understanding the Side Reaction of Carbodiimides with OxymaPure
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2022-09-09 , DOI: 10.1021/acs.oprd.2c00220
Srinivasa Rao Manne ₁ , Damilola Caleb Akintayo ₁ , Omar Luna _{2,

3} , Ayman El-Faham ₄ , Beatriz G. de la Torre _{1,

5} , Fernando Albericio _{1,

2,

3}

Affiliation

The undesired reaction between carbodiimides (peptide coupling reagent) and OxymaPure (peptide coupling additive), which takes place in very low extension during peptide bond formation, is dependent on the steric hindrance around the carbodiimide backbone. Carbodiimides containing tertiary substituents on N such as di-tert-butylcarbodiimide do not activate the carboxylic group properly; the presence of secondary substituents such as in the case of diisopropylcarbodiimide (DIC) leads to the formation of oxadiazole and HCN; finally, primary substituents render an adduct of oxadiazine and no formation of HCN. tert-Butylethylcarbodiimide (TBEC), which is a hybrid of primary and tertiary substituents, leads to the formation of oxadiazine with no concomitant formation of HCN. Furthermore, TBEC outperforms DIC in terms of yield and minimization of racemization as it is demonstrated herein.

中文翻译：

叔丁基乙基碳二亚胺作为固相肽合成中二异丙基碳二亚胺的有效替代物：了解碳二亚胺与 OxymaPure 的副反应

碳二亚胺（肽偶联剂）和 OxymaPure（肽偶联添加剂）之间的不良反应在肽键形成过程中以非常低的延伸发生，这取决于碳二亚胺骨架周围的空间位阻。N 上含有叔取代基的碳化二亚胺，例如二叔丁基碳化二亚胺，不能适当地活化羧基；二级取代基的存在，例如在二异丙基碳二亚胺 (DIC) 的情况下会导致恶二唑和 HCN 的形成；最后，初级取代基形成恶二嗪的加合物并且不形成HCN。叔-丁基乙基碳二亚胺 (TBEC) 是伯和叔取代基的杂化物，可导致恶二嗪的形成，而不会同时形成 HCN。此外，TBEC 在产率和外消旋化最小化方面优于 DIC，如本文所示。

更新日期：2022-09-09

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