title: Symmetry-Driven Strategy for the Assembly of the Core Tetracycle of (+)-Ryanodine: Synthetic Utility of a Cobalt-Catalyzed Olefin Oxidation and α-Alkoxy Bridgehead Radical Reaction.
abstract: Ryanodine (1) is a potent modulator of intracellular calcium release channels, designated as ryanodine receptors. The exceptionally complex molecular architecture of 1 comprises a highly oxygenated pentacyclic system with eleven contiguous stereogenic centers, which makes it a formidable target for organic synthesis. We identified the embedded C2 -symmetric tricyclic substructure within 1. This specific recognition permitted us to design a concise synthetic route to enantiopure tricycle 9 by utilizing a series of pairwise functionalizations. The four tetrasubstituted carbon centers of 9 were effectively constructed by three key reactions, a dearomatizing Diels-Alder reaction, the kinetic resolution of the obtained racemic 14 through asymmetric methanolysis, and the transannular aldol reaction of the eight-membered diketone 10. A new combination of cobalt-catalyzed hydroperoxidation and NfF-promoted elimination enabled conversion of the hindered olefin of 9 into the corresponding ketone, thus realizing the desymmetrization. Finally, the tetrasubstituted carbon was stereospecifically installed by utilizing the α-alkoxy bridgehead radical to deliver the core tetracycle 7 with the six contiguous tetrasubstituted carbon centers. Consequently, the present work not only accomplishes efficient assembly of four out of the five fused rings of 1, but also develops two new powerful methodologies: two-step ketone formation and bridgehead radical reaction.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan).
authors.forename: Masanori
authors.initials: M
authors.lastname: Nagatomo
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan).
authors.forename: Koji
authors.initials: K
authors.lastname: Hagiwara
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan).
authors.forename: Kengo
authors.initials: K
authors.lastname: Masuda
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan).
authors.forename: Masaki
authors.initials: M
authors.lastname: Koshimizu
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan).
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kawamata
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan).
authors.forename: Yuki
authors.initials: Y
authors.lastname: Matsui
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan).
authors.forename: Daisuke
authors.initials: D
authors.lastname: Urabe
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan). inoue@mol.f.u-tokyo.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000737:chemistry*; D002384:Catalysis; D061565:Cycloaddition Reaction; D007659:Ketones / Q000737:chemistry*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D012433:Ryanodine / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D000475:Alkenes; D001952:Bridged-Ring Compounds; D007659:Ketones; D012433:Ryanodine
keywords: natural products; peroxides; radical reactions; terpenoids; total synthesis