Total synthesis and biological evaluation of neodysiherbaine A and analogues

Muneo Shoji, Nobuyuki Akiyama, Koichi Tsubone, L. Leanne Lash, James M. Sanders, Geoffrey T. Swanson, Ryuichi Sakai, Keiko Shimamoto, Masato Oikawa, Makoto Sasaki

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39 Citations (Scopus)

Abstract

Dysiherbaine (1) and its congener neodysiherbaine A (2) are naturally occurring excitatory amino acids with selective and potent agonistic activity for ionotropic glutamate receptors. We describe herein the total synthesis of 2 and its structural analogues 3-8. Advanced key intermediate 16 was employed as a branching point to assemble a series of these analogues 3-8 with respect to the C8 and C9 functionalities, which would not have been accessible through manipulations of the natural product itself. The synthesis of key intermediate 16 features (i) stereocontrolled C-glycosylation to set the C6 stereocenter, (ii) concise synthesis of the bicyclic ether skeleton through chemo- and stereoselective dihydroxylation of the exo-olefin and stereoselective epoxidation of the enufo-olefin, followed by epoxide ring opening/5-exo ring closure, and (iii) catalytic asymmetric hydrogenation of enamide ester to construct the amino acid appendage. A preliminary biological evaluation of analogues for their in vivo toxicity against mice and binding affinity for glutamate receptors showed that both the type and stereochemistry of the C8 and C9 functional groups affected the subtype selectivity of dysiherbaine analogues for members of the kainic acid receptor family.

Original languageEnglish
Pages (from-to)5208-5220
Number of pages13
JournalJournal of Organic Chemistry
Volume71
Issue number14
DOIs
Publication statusPublished - 2006 Jul 7

ASJC Scopus subject areas

  • Organic Chemistry

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    Shoji, M., Akiyama, N., Tsubone, K., Lash, L. L., Sanders, J. M., Swanson, G. T., Sakai, R., Shimamoto, K., Oikawa, M., & Sasaki, M. (2006). Total synthesis and biological evaluation of neodysiherbaine A and analogues. Journal of Organic Chemistry, 71(14), 5208-5220. https://doi.org/10.1021/jo0605593