Elevating 1-tert-Butyl-3-ethylcarbodiimide (TBEC) as a Reagent for Sustainable Peptide Synthesis: Quality Assessment and Minimizing Racemization, Precipitation, and Radical-Induced Side Reactions by TBEC/Oxyma Couplings in an Environmentally Sensible Solvent,Organic Process Research & Development

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Elevating 1-tert-Butyl-3-ethylcarbodiimide (TBEC) as a Reagent for Sustainable Peptide Synthesis: Quality Assessment and Minimizing Racemization, Precipitation, and Radical-Induced Side Reactions by TBEC/Oxyma Couplings in an Environmentally Sensible Solvent
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2023-06-23 , DOI: 10.1021/acs.oprd.3c00120
Jan Pawlas ₁ , Ji-Hyung Choi _{1,

2} , Christoph von Bargen ₁ , Sheila Maibom-Thomsen ₁ , Jon H. Rasmussen ₁ , Olivier Ludemann-Hombourger ₂

Affiliation

The finding that the widely used peptide coupling reagents DIC and Oxyma form the toxic H-CN (McFarland, A. D. Org. Process Res. Dev. 2019, 23, 2099) has prompted studies aimed at H-CN minimization, attained, for example, by solvent engineering (Erny, M. Org. Process Res. Dev. 2020, 24, 1341) and by substituting DIC with TBEC (Manne, S. R. Org. Process Res. Dev. 2022, 26, 2894). Here, an integrated study of TBEC/Oxyma as peptide couplers is reported, focusing not only on the performance of TBEC in the couplings but also on its cost, hazards associated with its use, sustainability of the route of synthesis, the end of life strategies, as well as the potential impact of impurities in the reagent on the synthesis. TBEC/Oxyma-mediated peptide couplings in NBP/EtOAc (1:4) proceeded with minimal racemization, free of precipitation, and radical side reactions irrespective of TBEC quality. These results hold great promise for broad adoption of TBEC/Oxyma in suitable green media as a coupling strategy for sustainable peptide synthesis from an R&D lab to a manufacturing plant.

中文翻译：

将 1-叔丁基-3-乙基碳二亚胺 (TBEC) 作为可持续肽合成的试剂：在环境敏感的溶剂中通过 TBEC/Oxyma 偶联进行质量评估并最大限度地减少外消旋化、沉淀和自由基引起的副反应

研究发现广泛使用的肽偶联试剂 DIC 和 Oxyma 形成有毒的 H-CN（麦克法兰，AD 组织。过程研究。开发。 2019 , 23 , 2099) 促进了旨在 H-CN 最小化的研究，例如通过溶剂工程实现 (厄尼，M. 组织。过程研究。开发。 2020 , 24 , 1341) 并用 TBEC 代替 DIC (曼尼，SR 组织。过程研究。开发。 2022 , 26 , 2894）。本文报道了 TBEC/Oxyma 作为肽偶联剂的综合研究，不仅关注 TBEC 在偶联中的性能，还关注其成本、与其使用相关的危害、合成途径的可持续性、寿命终止策略以及试剂中杂质对合成的潜在影响。TBEC/Oxyma 介导的肽偶联在 NBP/EtOAc (1:4) 中进行，无论 TBEC 质量如何，外消旋化程度最低，无沉淀和自由基副反应。这些结果为在合适的绿色培养基中广泛采用 TBEC/Oxyma 作为从研发实验室到制造工厂的可持续肽合成的偶联策略带来了巨大的希望。

更新日期：2023-06-23

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