Leveraging Lewis acid catalysis for cascade construction of multisubstituted furans from active methylenes and 3-oxetanone

The synthesis of multisubstituted furans, those incorporating further functionalizable groups, remains a significant challenge in organic synthesis. These difficulties largely arise from reliance on prefunctionalized substrates, multistep sequences, harsh conditions, and costly catalytic systems. Herein, we report a rapid, efficient, and operationally simple cascade 3 + 2-annulation that addresses these limitations while delivering step and atom economy. The method exploits readily available and inexpensive active methylene compounds (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 protocol enables the construction of diverse multisubstituted and fused furan architectures, 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 the total synthesis of biologically active methylenomycin furans (MMFs) and methylfuroic acid, and 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. The synthesis of multisubstituted furans is constrained by step-intensive, expensive, and inefficient methods. Here, the authors introduce an operationally simple Fe(III)-catalyzed 3 + 2-annulation cascade of active methylenes and 3-oxetanone, enabling the efficient construction and diversification of furan architectures, with implications for the synthesis of bioactive natural products.