Constructing Four-Membered Heterocycles by Cycloisomerization
Constructing Four-Membered Heterocycles by Cycloisomerization
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DOI：
10.1021/acscatal.2c06404
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发表时间：
2023-03
期刊：
影响因子：
12.9
通讯作者：
Ayami Osato;T. Fujihara;Hiroki Shigehisa
中科院分区：
文献类型：
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作者：
Ayami Osato;T. Fujihara;Hiroki Shigehisa
四元杂环在现代药物发现中受到高度追捧，因为它们为目标分子提供了有益的特性。尽管合成研究界付出了巨大的努力，但仍需要一种简单且新的方法将这些图案纳入设计分子中。在此，我们揭示了通过金属氢化物氢原子转移/自由基极性交叉构建氧杂环丁烷和氮杂环丁烷环的环异构化策略，这在熵和熵方面都具有挑战性。该方法适用于合成多取代四元杂环。这种温和且官能团耐受的反应具有广泛的底物范围，包括螺结构，这是药物发现研究的重要主题。通过产物衍生化可以合成各种四元杂环结构单元。我们还通过氘实验和 DFT 研究讨论了反应机理，重点是四元环的形成。
Four-membered heterocycles are highly sought after in modern drug discovery as they provide beneficial properties to the target molecules. Despite tremendous efforts by the synthetic research community, there is a need for a simple and new method to incorporate these motifs into the design molecules. Herein, we reveal a cycloisomerization strategy for the construction of oxetane and azetidine rings via metal hydride hydrogen atom transfer/radical polar crossover, which is challenging both enthalpically and entropically. This method is suitable for synthesizing polysubstituted four-membered heterocycles. This mild and functional-group tolerant reaction has a broad substrate scope, including the spiro structure, which is an important motif in drug discovery research. Various four-membered heterocyclic building blocks can be synthesized by product derivatization. We also discuss the reaction mechanism, focusing on the four-membered ring formation, by deuterium experiments and DFT studies.