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

J Org Chem. 2013 Jun 21;78(12):6297-302. doi: 10.1021/jo400612v. Epub 2013 Jun 10.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alkynes / chemistry
  • Catalysis
  • Cyclization
  • Hydrogen Bonding
  • Isoxazoles / chemistry*
  • Nitriles / chemistry
  • Pentacyclic Triterpenes
  • Stereoisomerism
  • Triterpenes / chemical synthesis*

Substances

  • Alkynes
  • Isoxazoles
  • Nitriles
  • Pentacyclic Triterpenes
  • Triterpenes
  • celastrol