通过电催化交叉合,简化对向蛋白质降解剂的使用
Philipp Neigenfind1, Luca Massaro1,2, Áron Péter1
1Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, 92037, La Jolla, CA, United States.
Angewandte Chemie (International ed. in English)
|February 14, 2024
概括
一种新的Ni电催化方法简化了合成基于cereblon的降解剂 (PROTACs,CELMoDs) 的glutarimide结构. 这种高效,可扩展的反应使用廉价的起始材料,并容忍多种功能组,简化药物发现工作.
科学领域:
- 有机化学 有机化学
- 药用化学 医学化学
- 催化剂是一种催化剂.
背景情况:
- 含有谷氨胺的化合物对于开发向蛋白质降解剂,如PROTACs和CELMoDs至关重要.
- 这些结构的传统合成往往是多步骤的,繁的,并产生大量的浪费.
- 需要更高效和更容易获得的合成途径来获得这些有价值的化学实体.
研究的目的:
- 开发一种简化,单步骤的方法来合成C-C相关的谷氨胺结构.
- 为了能够制备基于cereblon的降解剂的关键中间体.
- 为合成已知和新型谷氨胺化合物提供可扩展和功能组耐受性的方法.
主要方法:
- 采用了一种新的布伦斯特德酸辅助电催化方法.
- 作为起始材料,该反应使用了廉价的,商业上可用的α-甲胺胺.
- 该方法在批量和流量条件下对可扩展性进行了评估.
主要成果:
- 开发的方法成功地在单个步骤中合成了C-C链接的谷氨胺结构.
- 反应显示了广泛的功能性群体耐受性,包括历史上有问题的群体.
- 该方法被应用到几十种已知的基于cereblon的降解中间体的简化合成.
- 批量和流量的可扩展性得到证实,通过简单的实验程序.
结论:
- 这项研究提出了一种有效和实用的方法,用于获取含有谷氨胺的化合物,这些化合物对于 PROTAC 和 CELMoD 开发至关重要.
- 电催化方法比传统的多步合成方法提供了显著的改进,减少了浪费和复杂性.
- 可扩展性和功能组耐受性使这种方法对药物化学和药物发现计划非常有价值.
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