title: Domino double Michael-Claisen cyclizations: a powerful general tool for introducing quaternary stereocenters at C4 of cyclohexane-1,3-diones and total synthesis of diverse families of sterically congested alkaloids.
abstract: Reactions of substituted acetone derivatives with acrylic acid esters (>200 mol %) in the presence of t-BuOK (200 mol %) in t-BuOH-THF (1:1 by volume) turned out to proceed as a cascade process consisting of the first Michael addition, the second Michael addition, and the last Claisen reaction to afford 4,4-disubstituted cyclohexane-1,3-diones. Only more substituted enolates play the role of a Michael donor in this cascade process, and therefore the ketone took up two alkoxycarbonylethyl groups on the same carbon bearing more substituents. Such intermediates were followed by intramolecular Claisen reactions leading to cyclohexane-1,3-diones bearing quaternary stereogenic centers at C(4), which bears an alkoxycarbonylethyl group and the substituent of the starting acetone derivatives. Thus-obtained 4,4-disubstituted cyclohexane-1,3-diones were successfully employed for total syntheses of intricate alkaloids of biological interest such as (+)-aspidospermidine, (+/-)-galanthamine, (+/-)-lycoramine, and (+/-)-mesembrine, all featuring quaternary stereogenic centers. DFT calculations provided us with clear-cut explanations for the observed chemoselectivity of the cascade process involving ketone-based enolates under thermodynamically controlled conditions.
authors.affiliation: Department of Medical and Bioengineering Science, Graduate School of Natural Science and Technology, Okayama University, Tsushima, Okayama, Japan 700-8530. teruhiko@cc.okayama-u.ac.jp
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kudo
authors.forename: Ken
authors.initials: K
authors.lastname: Kuroyabu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uchida
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kudoh
authors.forename: Seiki
authors.initials: S
authors.lastname: Saito
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis*; D047151:Amaryllidaceae Alkaloids / Q000138:chemical synthesis; D003500:Cyclization; D003512:Cyclohexanones / Q000737:chemistry*; D005702:Galantamine / Q000138:chemical synthesis; D026121:Indole Alkaloids / Q000138:chemical synthesis; D011804:Quinolines / Q000138:chemical synthesis; D013237:Stereoisomerism
chemical_list: D000470:Alkaloids; D047151:Amaryllidaceae Alkaloids; D003512:Cyclohexanones; D026121:Indole Alkaloids; D011804:Quinolines; C409672:aspidospermidine; D005702:Galantamine; C011300:mesembrine; C500482:lycoramine