异环组件:一个未充分利用的断开,有潜力最大限度地提高高fsp3化学空间探索
Brandon M Taoka1, Ning Qi2, Zachary G Brill1
1Department of Discovery Chemistry, Merck & Co., Inc., South San Francisco, California 94080, United States.
ACS medicinal chemistry letters
|February 19, 2025
概括
化学家现在可以使用简单的碳酸和氨基酸合成各种异环化合物. 这种新方法扩大了药物发现的化学空间,在图书馆合成中取得了高的成功率.
科学领域:
- 有机化学 有机化学
- 药用化学 医学化学
- 合成化学 合成化学
背景情况:
- 异环核在药物化学中是必不可少的,但它们的合成和功能化存在挑战.
- 目前的方法往往限制了对各种化学结构的访问,特别是那些具有高Fsp3特性的化学结构.
研究的目的:
- 提出一种新的策略,用于合成使用易于获得的构建模块的异环核.
- 为了证明这种方法对药物化学应用的图书馆友好性.
- 将这种方法的效率与现有的最先进技术进行比较.
主要方法:
- 使用碳酸和氨基酸作为无处不在的构建块,以形成异环原子核.
- 开发一个图书馆友好的格式,以实现高效的合成.
- 适应和缩小微量平行药物化学 (PMC) 的合成.
主要成果:
- 开发的战略使得人们能够进入更广泛的化学空间,包括具有更高Fsp3值的类似物.
- 使用新方法成功合成了N2-英达和C2-胺.
- 在PMC库中实现了80%的成功率,相当于已建立的苏苏基和布丘瓦尔德-哈特维格合.
结论:
- 这种新的异环合成策略为药物化学家提供了一个强大的工具.
- 这种方法可方便快速访问多样化的异环库,加速药物发现计划.
- 该方法的效率和可扩展性使其成为当前功能化技术的有价值替代品.
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