Leveraging Lewis Acid Catalysis for Cascade Construction of Multisubstituted Furans from Active Methylenes and 3-Oxetanone

The efficient synthesis of multisubstituted furans, particularly those incorporating further functionalizable groups remains a significant challenge in organic synthesis. These difficulties largely arise from reliance on prefunctionalized substrates, multistep reaction sequences, harsh conditions, and costly catalytic systems. In this work, we report a rapid, efficient, and operationally simple cascade [3 + 2]-annulation strategy that addresses these limitations while delivering excellent step and atom economy. The method exploits readily available and inexpensive active methylene compounds (including β -ketoesters, β -diketones, and related derivatives) as C–C–O 1,3-bis-nucleophiles, in combination with 3-oxetanone as a C–C 1,2-bis-electrophile, under catalysis by sustainable and low-cost Fe-salts. This robust protocol enables the construction of a diverse array of furan architectures, encompassing disubstituted, trisubstituted, and fused systems bearing alkyl, cycloalkyl, alkynyl, aryl, and heteroaryl substituents, as well as functional groups derived from nitriles, sulfones, phosphonates, and amides. The synthetic utility of the approach is further demonstrated by its gram-scale applicability and by the total synthesis of biologically relevant methylenomycin furans (MMFs), methylfuroic acid, along with formal syntheses of evodone, tubipofuran, menthofuran, maturone, isomaturone, and rabdoketones. Moreover, the method proves highly effective for late-stage diversification, as illustrated by the functionalization of bioactive natural products, including β -ionone, tonalide, progesterone, and pregnenolone. Collectively, this strategy provides a practical, versatile, and sustainable platform for the streamlined synthesis and diversification of multisubstituted furans.