Irreversible endo-Selective Diels-Alder Reactions of Substituted Alkoxyfurans: A General Synthesis of endo-Cantharimides

The [4+2] cycloaddition of 3‐alkoxyfurans with N‐substituted maleimides provides the first general route for preparing endo‐cantharimides. Unlike the corresponding reaction with 3H furans, the reaction can tolerate a broad range of 2‐substitued furans including alkyl, aromatic, and heteroaromatic groups. The cycloaddition products were converted into a range of cantharimide products with promising lead‐like properties for medicinal chemistry programs. Furthermore, the electron‐rich furans are shown to react with a variety of alternative dienophiles to generate 7‐oxabicyclo[2.2.1]heptane derivatives under mild conditions. DFT calculations have been performed to rationalize the activation effect of the 3‐alkoxy group on a furan Diels–Alder reaction. No going back! 3‐Alkoxyfurans have been shown to readily undergo irreversible [4+2] cycloaddition reactions with maleimides to form kinetically stable endo‐cantharimides, which have promising medicinal properties. This reactivity has been explored using DFT calculations and the reaction scope expanded to include a wide variety of dienophiles (see scheme).