title: 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.
authors.affiliation: Department of Chemistry, Texas A&M University, College Station, Texas 77840, United States.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Kaiser
authors.forename: Jinhua
authors.initials: J
authors.lastname: Huang
authors.forename: Jiong
authors.initials: J
authors.lastname: Yang
mesh_terms: D000480:Alkynes / Q000737:chemistry; D002384:Catalysis; D003500:Cyclization; D006860:Hydrogen Bonding; D007555:Isoxazoles / Q000737:chemistry*; D009570:Nitriles / Q000737:chemistry; D053978:Pentacyclic Triterpenes; D013237:Stereoisomerism; D014315:Triterpenes / Q000138:chemical synthesis*
chemical_list: D000480:Alkynes; D007555:Isoxazoles; D009570:Nitriles; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; C050414:celastrol