Regiochemistry Discoveries in the Use of Isoxazole as a Handle for the Rapid Construction of an All-Carbon Macrocyclic Precursor in the Synthetic Studies of Celastrol

Abstract

We have developed a convergent synthetic route to an all-carbon, 14-membered Z,E-macrocyclic bis-enone during our synthetic study of celastrol. The 1,3-dipolar cycloaddition of nitrile oxide and alkyne was employed for fragment coupling and introducing the 1,3-diketone moiety masked in the form of an isoxazole. We discovered that cycloaddition of the nitrile oxide and the enyne gave the rare 3,4-disubstituted isoxazole adduct under kinetic reaction conditions. The cycloaddition was found to be reversible, and the thermodynamic 3,5-disubstituted isoxazole could be obtained by isomerization of its 3,4-disubstituted isomer under elevated temperature. Our mechanistic studies support the role of hydrogen bonding in accelerating the isomerization. Consistent with our previous studies, the Z,E-macrocyclic bis-enone was found to be inactive toward the transannular bis-Michael reaction under the conditions evaluated.