Catalytic 4-exo-dig carbocyclization for the construction of furan-fused cyclobutanones and synthetic applications

Cyclobutanone is a strained motif with broad applications, while direct assembly of the aromatic ring fused cyclobutanones beyond benzocyclobutenone (BCB) skeletons remains challenging. Herein, we report a Rh-catalyzed formal [3+2] annulation of diazo group tethered alkynes involving a 4-exo-dig carbocyclization process, providing a straightforward access to furan-fused cyclobutanones. DFT calculations disclose that, by comparison to the competitive 5-endo-dig process, 4-exo-dig carbocyclization is mainly due to lower angle strain of the key sp-hybridized vinyl cationic transition state in the cyclization step. Using less reactive catalysts Rh2(carboxylate)4 is critical for high selectivity, which is explained as catalyst-substrate hydrogen bonding interaction. This method is proved successful to direct access previously inaccessible and unknown furan-fused cyclobutanone scaffolds, which can participate in a variety of post-functionalization reactions as versatile synthetic blocks. In addition, preliminary antitumor activity study of these products indicates that some molecules exhibite significant anticancer potency against different human cancer cell lines.

Automated summary

This study reports a Rh-catalyzed reaction for the direct synthesis of furan-fused cyclobutanone compounds. DFT calculations reveal the reaction mechanism and the importance of using less reactive catalysts for high selectivity. This method allows the synthesis of previously inaccessible and unknown versatile synthetic blocks, while exhibiting anticancer activity.