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

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.

Keywords: cantharimides; cycloadditions; dienes; furans; phthalimide.

Figure 1

Natural product cantharidin and cantharimide.

Scheme 1

Synthetic approaches to cantharimides.

Scheme 2

Gold-catalysed synthesis of 3-alkoxyfurans 2 from propargylic alcohols 1.[27]

Figure 2

Crystal structures of cantharimides 3 f. Ellipsoids are shown at the 50 % probability level. Only hydrogen atoms belonging to the cyclic core are shown for clarity.[29]

Scheme 3

Synthesis of a 7-substituted endo-cantharimide: i) (H₂C—NMe₂)I (2 equiv), MeCN, 16 h, RT; ii) N-methylmaleimide (1.2 equiv), DMC, 24 h, RT.

Scheme 4

One-pot cantharimide synthesis from propargylic alcohol 1 a. i) N-methylmaleimide, 2 mol % PPh₃AuNTf₂, EtOH; ii) 2 mol % PPh₃AuNTf₂, EtOH then 2.5 mol % PPh₃ then N-methylmaleimide.

Scheme 5

Functional-group interconversion of enol ether endo-3 f: i) H₂, 10 % Pd/C; ii) 9-BBN then H₂O₂/NaOH; iii) SCX-2 cartridge; iv) NaBH₄, MeOH. 9-BBN=9-borabicyclo[3.3.1]nonane.

Scheme 6

Synthesis of substituted phthalimide 11 by acid-catalysed aromatisation of cantharimide intermediates.

Figure 3

Physicochemical properties of endo-cantharimides.[39]

Figure 5

M06-2X/6-31G(d)-optimized endo and exo transition states for the reaction of furan 14 d and N-methylmaleimide 15.[46] Distances in Å.

Figure 4

Calculated ΔG and ΔG^≠ values for the reactions of 2-phenylfurans 14 d and 14 i and N-methylmaleimide 15 in kJ mol⁻¹.

Scheme 7

Thermodynamic cycle involving the hydrogenation of dienes 17 and 20.