Wu Wen-Biao, Xu Bing, Yang Xue-Chun, Wu Feng, He Heng-Xian, Zhang Xu, Feng Jian-Jun
State Key Laboratory of Chemo/Biosensing and Chemometrics, Advanced Catalytic Engineering Research Center of the Ministry of Education, College of Chemistry and Chemical Engineering, Hunan University, Changsha, P. R. China.
School of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou, P. R. China.
Nat Commun. 2024 Sep 13;15(1):8005. doi: 10.1038/s41467-024-52419-x.
The absence of catalytic asymmetric methods for synthesizing chiral (hetero)bicyclo[n.1.1]alkanes has hindered their application in new drug discovery. Here we demonstrate the achievability of an asymmetric polar cycloaddition of bicyclo[1.1.0]butane using a chiral Lewis acid catalyst and a bidentate chelating bicyclo[1.1.0]butane substrate, as exemplified by the current enantioselective formal (3 + 3) cycloaddition of bicyclo[1.1.0]butanes with nitrones. In addition to the diverse bicyclo[1.1.0]butanes incorporating an acyl imidazole group or an acyl pyrazole moiety, a wide array of nitrones are compatible with this Lewis acid catalysis, successfully assembling two congested quaternary carbon centers and a chiral aza-trisubstituted carbon center in the pharmaceutically important hetero-bicyclo[3.1.1]heptane product with up to 99% yield and >99% ee.
缺乏用于合成手性（杂）双环[n.1.1]烷烃的催化不对称方法阻碍了它们在新药研发中的应用。在此，我们证明了使用手性路易斯酸催化剂和双齿螯合双环[1.1.0]丁烷底物实现双环[1.1.0]丁烷不对称极性环加成的可行性，当前双环[1.1.0]丁烷与硝酮的对映选择性形式（3 + 3）环加成就是例证。除了包含酰基咪唑基团或酰基吡唑部分的多种双环[1.1.0]丁烷外，大量硝酮与这种路易斯酸催化兼容，成功地在药学上重要的杂双环[3.1.1]庚烷产物中组装了两个拥挤的季碳中心和一个手性氮杂三取代碳中心，产率高达99%，对映体过量值>99%。
