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

• Published in: Chemistry : a European journal 2016-01, Vol.22 (1), p.222-229
• Main Authors: Nagatomo, Masanori, Hagiwara, Koji, Masuda, Kengo, Koshimizu, Masaki, Kawamata, Takahiro, Matsui, Yuki, Urabe, Daisuke, Inoue, Masayuki
• Format: Article
• Language: English
• Subjects: Alkenes - chemistry; Bridged-Ring Compounds - chemical synthesis; Bridged-Ring Compounds - chemistry; Carbon; Catalysis; Channels; Cycloaddition Reaction; Ketones; Ketones - chemistry; Modulators; Molecular Structure; natural products; Olefins; Oxidation-Reduction; peroxides; radical reactions; Radicals; Receptors; Recognition; Ryanodine - chemical synthesis; Ryanodine - chemistry; Stereoisomerism; terpenoids; total synthesis
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201503640

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. Total synthesis of ryanodine, part 1: (+)‐Ryanodine (1) is a potent modulator of intracellular calcium release channels, designated as ryanodine receptors. A simple and efficient strategy for the enantioselective construction of the core tetracycle by specific recognition of the C2‐symmetric substructure embedded within 1 was devised (see scheme; MOM=methoxymethyl). Moreover, a two‐step ketone formation and a α‐alkoxy bridgehead radical reaction were developed as the new powerful methodologies.