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Irreversible Endo-Selective Diels–Alder Reactions Of Substituted Alkoxyfurans: A General Synthesis Of Endo-Cantharimides

R. W. Foster, Laure Benhamou, M. J. Porter, D. Bučar, H. Hailes, Christopher J. Tame, T. Sheppard
Published 2015 · Chemistry, Medicine

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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.
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