title: Competent Route to Unsymmetric Dimer Architectures: Total Syntheses of (-)-Lycodine and (-)-Complanadines A and B, and Evaluation of Their Neurite Outgrowth Activities.
abstract: Valuable synthetic routes to the Lycopodium alkaloid lycodine (1) and its unsymmetric dimers, complanadines A (4) and B (5), have been developed. Regioselective construction of the bicyclo[3.3.1]nonane core structure of lycodine was achieved by a remote functionality-controlled Diels-Alder reaction and subsequent intramolecular Mizoroki-Heck reaction. A key coupling reaction of the lycodine units, pyridine N-oxide (66) and aryl bromide (65), through C-H arylation at the C1 position of 66 provided the unsymmetric dimer structure at a late stage of the synthesis. This strategy greatly simplified the construction of the dimeric architecture and functionalization. Complanadines A (4) and B (5) were synthesized by adjusting the oxidation level of the bipyridine mono-N-oxide (67). The diverse utility of this common intermediate (67) suggests a possible biosynthetic pathway of complanadines in Nature. Both enantiomers of lycodine (1) and complanadines A (4) and B (5) were prepared in sufficient quantities for biological evaluation. The effect on neuron differentiation of PC-12 cells upon treatment with culture medium, in which human astrocytoma cells had been cultured in the presence of 1, 4, or 5 was evaluated.
authors.affiliation: Department of Chemistry, Graduate School of Science, Tohoku University, Sendai, 980-8578, Japan.
authors.forename: Le
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Chihiro
authors.identifier: http://orcid.org/0000-0002-9361-0857
authors.initials: C
authors.lastname: Tsukano
authors.affiliation: Department of Chemistry, Graduate School of Science, Tohoku University, Sendai, 980-8578, Japan.
authors.forename: Eunsang
authors.initials: E
authors.lastname: Kwon
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shirakawa
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Yoshiji
authors.initials: Y
authors.lastname: Takemoto
authors.affiliation: Department of Chemistry, Graduate School of Science, Tohoku University, Sendai, 980-8578, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hirama
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D061565:Cycloaddition Reaction; D019281:Dimerization; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008968:Molecular Conformation; D000071446:Neuronal Outgrowth / Q000187:drug effects; D010084:Oxidation-Reduction; D016716:PC12 Cells; D011725:Pyridines / Q000737:chemistry; D051381:Rats; D013237:Stereoisomerism
chemical_list: D000470:Alkaloids; D006576:Heterocyclic Compounds, 4 or More Rings; D011725:Pyridines; C550939:complanadine A; C582812:complanadine B; C585001:lycodine; C013229:pyridine N-oxide
keywords: C−H arylation; complanadine; lycodine; palladium; total synthesis