Catalytic [4+n]-cycloaddition using furan-fused cyclobutanone as a privileged C4 synthon

Abstract

Cycloaddition reactions play a pivotal role in synthetic chemistry for the direct assembly of cyclic architectures. However, substantial hurdles remain for extending the C4 synthon, which is mainly limited to dienes and 1,4-dipoles so far, to construct diverse heterocycles via programmable [4 + n]-cycloaddition. Here we report an atom-economic and modular intermolecular cycloaddition using furan-fused cyclobutanones (FCBs) as a novel and versatile C4 synthon. In contrast to the well-documented intramolecular cycloaddition of benzocyclobutenones (BCBs), this is a complementary version using a heteroarene-fused reagent as a C4 building block. It involves a catalytic C-C bond activation and stepwise annulation sequence, including a Rh-catalyzed highly enantioselective [4 + 2]-cycloaddition with imines and an Au-catalyzed diastereoselective [4 + 4]-cycloaddition with anthranils. The furan-fused polycyclic lactam products and their synthetic derivatives, which are pivotal motifs that present in many natural products, bioactive molecules, and materials, are inaccessible or difficult to prepare by other methods with multi-steps. Preliminary antitumor activity study of these compounds indicates that 6e and 6f exhibit high anticancer potency against colon cancer cells (HCT-116 cells, IC50 = 0.50 ± 0.05 µM) and esophageal squamous cell carcinoma cells (KYSE-520 cells, IC50 = 0.89 ± 0.13 µM), respectively.