从[3.1.1]propellane中合成双环[3.1.1]heptanes,甲基替代的异,从[3.1.1]propellane中合成它们
Bhaskar Paul1, Ayan Dasgupta1, Nils Frank1
1Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK.
Nature protocols
|February 17, 2025
概括
研究人员开发了一种新方法来合成双循环[3.1.1] (BCHeps),它们是药物发现中有价值的meta-arene生物异构体. 这种可扩展的合成为药用化学应用提供了关键中间体.
科学领域:
- 药用化学 医学化学
- 有机合成 有机合成
- 药物发现 药物发现 药物发现
背景情况:
- 和的小环桥接碳化合物越来越多地被用作药物发现中的芳香环的生物异构剂.
- 自行车[1.1.1]坦模仿了对替代的烯,但具有特定几何性质的元烯生物异构体仍然难以开发.
- 准确的几何模拟需要一个取代出口向量角度大约120°和一个二面角大约0°.
研究的目的:
- 开发一个可扩展的合成bicyclo[3.1.1]heptanes (BCHeps) 准确模仿元竞技场几何.
- 建立用于将BCHeps功能化为药物发现关键中间体的方法.
- 为合成BCHeps及其衍生物提供高效的协议.
主要方法:
- 从乙烯4-甲酸盐中在五个步骤中合成 [3.1.1] 的多重克尺度合成.
- 光催化原子转移激素添加反应使用蓝光将[3.1.1]功能化为BCHep化物.
- 铁催化库马达合和水解/氧化以进一步衍生BCHeps.
主要成果:
- 实现了可扩展的,五步合成的[3.1.1],总产量为26-37%.
- 通过光催化反应合成了三类BCHep化物.
- 制定了用于制备与烯合的BCHeps和BCHEp碳酸的协议,总合成时间为[3.1.1]烯约53小时,BCHEp化物6-8小时,碳酸碳酸40小时.
结论:
- 已经开发了对bicyclo[3.1.1]heptanes (BCHeps) 的直接访问,为meta-arenes提供了准确的几何模仿.
- 描述的方法使BCHeps的可扩展合成和功能化成为可能,为药物化学提供了有价值的构建块.
- 这项工作解决了对meta-arene生物异构体的需求,扩大了药物发现工具包.
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