有效的单和双催化立体选择性化以获得-1,2,4-醇
Kurt Püntener1, Anna-Lena Glass1, Leonardo Tensi2
1Department of Process Chemistry & Catalysis, F. Hoffmann-La Roche AG, 4070 Basel, Switzerland.
Journal of the American Chemical Society
|November 10, 2025
概括
使用催化剂的新型双催化剂系统实现了高度对抗选择性的非对称化,用于合成制药中间体. 与以前的协议相比,这种方法提供了更高的效率和更低的成本.
科学领域:
- 有机合成
- 不对称的催化
- 医学化学
背景情况:
- 药物中间体的合成通常依赖于复杂的多步骤过程.
- 现有的方法,如使用缩酶的方法,可能是低效或昂贵的.
- 需要更精简和更具成本效益的不对称化技术.
研究的目的:
- 开发一种新型的一合成方法,用于特定的不对称化.
- 创建一个关键的性三醇构建块, (2R,4R) -4-) --1,2,4-三醇 ((R,R) -7a),对于GDC-6599的合成至关重要.
- 探索双催化剂系统作为单催化剂或酶方法的改进.
主要方法:
- 不对称的化4-(4-) -2-基-4-基-2-酸乙烯.
- 使用一种由Ir/{S}-SpiroPAP组成的催化剂 (LC) 和一种由Ir/{R}-Ms-DPEN组成的辅助催化剂 (AC).
- 研究了一种单一的连续反应序列,比较单个LC和双催化剂系统.
主要成果:
- 与单独的LC相比,双催化剂系统显著提高了二重选择性 (trans/cis比率18:1) 和产量 (77%).
- 在第一个化阶段,AC提高了对抗选择性 (96% ee),导致整体ee更高 (90-94% ee).
- 具有PNN连体的新型LC实现了可比质量,最高产量 (81%) 和降低成本.
结论:
- 在制药中间体的立体选择性合成中首次成功使用了一种新型的双催化系统.
- 这种方法提供了更高效,更具成本效益和高度选择性的目标三元组建块的途径.
- 开发的系统为合成复杂性分子的现有协议提供了一个有希望的替代方案.
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