title: Cyclobutane Synthesis and Fragmentation. A Cascade Route to the Lycopodium Alkaloid (-)-Huperzine A.
abstract: An asymmetric total synthesis of the nootropic alkaloid (-)-huperzine A was completed using a cascade sequence initiated by an intramolecular aza-Prins reaction and terminated by a stereoelectronically guided fragmentation of a cyclobutylcarbinyl cation as the key step in assembling the bicyclo[3.3.1]nonene core of the natural product. Intramolecular [2 + 2]-photocycloaddition of the crotyl ether of (S)-4-hydroxycyclohex-2-enone afforded a bicyclo[4.2.0]octanone containing an embedded tetrahydrofuran in which the cyclohexanone moiety was converted to a triisopropylsilyl enol ether and functionalized as an allylic azide. The derived primary amine was acylated with α-phenylselenylacrylic acid, and the resulting amide was reacted with trimethylaluminum to give a [2 + 2]-cycloadduct, which underwent retroaldol fission to produce a fused α-phenylselenyl δ-lactam. Periodate oxidation of this lactam led directly to an α-pyridone, which was converted to a fused 2-methoxypyridine. Reductive cleavage of the activated "pyridylic" C-O bond in this tetracycle and elaboration of the resultant hydroxy ketone to a diketone was followed by chemoselective conversion of the methyl ketone in this structure to an endo isopropenyl group. Condensation of the remaining ketone with methyl carbamate in the presence of acid initiated the programmed cascade sequence and furnished a known synthetic precursor to huperzine A. Subsequent demethylation of the carbamate and the methoxypyridine, accompanied by in situ decarboxylation of the intermediate carbamic acid, gave (-)-huperzine A.
authors.affiliation: Department of Chemistry, Oregon State University , Corvallis, Oregon 97331, United States.
authors.forename: James D
authors.initials: JD
authors.lastname: White
authors.affiliation: Department of Chemistry, Oregon State University , Corvallis, Oregon 97331, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Chemistry, Oregon State University , Corvallis, Oregon 97331, United States.
authors.forename: Jungchul
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Oregon State University , Corvallis, Oregon 97331, United States.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Terinek
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry*; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry*; D003500:Cyclization; D003503:Cyclobutanes / Q000737:chemistry; D003512:Cyclohexanones / Q000737:chemistry; D032502:Lycopodium / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: C000606504:4-hydroxycyclohex-2-enone; D000470:Alkaloids; D001643:Bridged Bicyclo Compounds; D003503:Cyclobutanes; D003512:Cyclohexanones; D011725:Pyridines; D012717:Sesquiterpenes; C050426:huperzine A; C051376:4-methoxypyridine