Irreversible endo-selective diels-alder reactions of substituted alkoxyfurans: a general synthesis of endo-cantharimides.

Robert W Foster,Helen C Hailes,Michael J Porter,Dejan‐Krešimir Bučar,Laure Benhamou,Christopher J Tame,Tom D Sheppard

doi:10.1002/chem.201406286

Robert W Foster, Helen C Hailes + Show 5 more

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https://doi.org/10.1002/chem.201406286

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Abstract

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.

Highlights

To access new areas of chemical space, medicinal chemistry programs are increasingly focusing on fragments and scaffolds with rigid 3D structures that contain a significant proportion of sp3 carbon atoms.[1]
The cantharimide was formed with a clear preference for the endo diastereomer and the two isomers could be readily separated by flash column chromathe high stereoselectivity for the exo diastereomer observed, believed to be the result of a highly reversible cy- Table 1. [4+2] cycloaddition of 3-alkoxyfurans 2 with N-methylmaleimide
It is possible to access the corresponding endo-cantharimide by a Diels–Alder reaction of furan with maleimide;[23] experimental and computational studies have shown that this reaction is under thermodynamic control with the exo-cantharimide being the thermodynamic product.[24]

Summary

Introduction

To access new areas of chemical space, medicinal chemistry programs are increasingly focusing on fragments and scaffolds with rigid 3D structures that contain a significant proportion of sp3 carbon atoms.[1]. The cyclization underwent rapid and endo-selective reactions with N-methyl- was effective when 3-methoxyfuran 2 b was used as maleimide to generate kinetically stable cantharimide prod- a diene, giving the corresponding adduct in excellent yield as ucts.

Results

Conclusion