title: Asymmetric Total Synthesis of (+)-Ryanodol and (+)-Ryanodine.
abstract: (+)-Ryanodine (1) is the ester derivative of 1H-pyrrole-2-carboxylic acid and the complex terpenoid (+)-ryanodol (2), which possesses eleven contiguous stereogenic centers on the ABCDE-ring system. Compound 1 is known to be a potent modulator of intracellular calcium release channels, whereas the activity of 2 is significantly weaker. To chemically construct 1, the multiple oxygen functional groups must be installed on the fused pentacycle in stereoselective fashions and the extremely hindered C3-hydroxy group must be acylated in a site-selective manner. First, the total synthesis of 2 was accomplished by introducing the five stereocenters from the previously prepared enantiopure ABDE-ring 7. Stereoselective construction of the C3-secondary, C2- and C6-tertiary alcohols was achieved by three nucleophilic reactions. The C9- and C10-trisubstituted carbon centers were regio- and stereoselectively introduced by hydroboration/oxidation of the six-membered C-ring, which was formed by the ring-closing metathesis reaction. Direct esterification of the C3-alcohol with pyrrole-2-carboxylic acid proved unsuccessful; therefore, we developed a new, two-step protocol for attachment of the pyrrole moiety. The C3-hydroxy group was first converted into the less sterically cumbersome glycine ester, which was then transformed into the pyrrole ring through condensation with 1,3-bis(dimethylamino)allylium tetrafluoroborate. This procedure resulted in the first total synthesis of 1.
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: 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). inoue@mol.f.u-tokyo.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
mesh_terms: D000438:Alcohols / Q000737:chemistry*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011758:Pyrroles / Q000737:chemistry*; D012433:Ryanodine / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: C000608461:1H-pyrrole-2-carboxylic acid; D000438:Alcohols; D011758:Pyrroles; D012433:Ryanodine
keywords: acylation; natural products; regioselectivity; terpenoids; total synthesis