Enantioselective formal (3 + 3) cycloaddition of bicyclobutanes with nitrones enabled by asymmetric Lewis acid catalysis

• Published in: Nature communications Vol. 15; no. 1; pp. 8005 - 9
• Main Authors: Wu, Wen-Biao, Xu, Bing, Yang, Xue-Chun, Wu, Feng, He, Heng-Xian, Zhang, Xu, Feng, Jian-Jun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.09.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 639/638/403/933; 639/638/549/972; 639/638/77/883; Acids; Alkanes; Antifungal agents; Asymmetry; Butane; Butanes; Carbon; Catalysis; Catalysts; Chelation; Chemical synthesis; Cycloaddition; Drug development; Drug discovery; Enantiomers; Heptanes; Humanities and Social Sciences; Imidazole; Lewis acid; multidisciplinary; Pyrazole; Pyrazoles; Science; Science (multidisciplinary); Substrates
• ISSN: 2041-1723; 2041-1723
• 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 . The absence of catalytic asymmetric methods for synthesizing chiral (hetero)bicyclo[n.1.1]alkanes has hindered their application in new drug discovery. Herein the authors report an enantioselective formal (3 + 3) cycloaddition of bicyclobutanes with nitrones using a chiral Lewis acid catalyst for the synthesis of hetero-bicyclo[3.1.1]heptane.