Rapid and efficient synthesis of dysiherbaine and analogues to explore structure-activity relationships

Makoto Sasaki, Koichi Tsubone, Kunimori Aoki, Nobuyuki Akiyama, Muneo Shoji, Masato Oikawa, Ryuichi Sakai, Keiko Shimamoto

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

(Chemical Equation Presented) A rapid and efficient total synthesis of dysiherbaine (1), a potent and subtype-selective agonist for ionotropic glutamate receptors, has been accomplished. A key intermediate 15 was synthesized by two approaches. The first synthetic route utilized compound 9, an advanced intermediate in our previous total synthesis of neodysiherbaine A, as the starting point, and the cis-oriented amino alcohol functionality on the tetrahydropyran ring was installed by using an intramolecular SN2 cyclization of N-Boc-protected amino alcohol 20. An alternative and even more efficient synthetic approach to 15 featured stereoselective introduction of an amino group at C8 by iodoaminocyclization prior to constructing the bicyclic ether skeleton. The amino acid appendage was efficiently constructed by a catalytic asymmetric hydrogenation of enamide ester 36. The synthetic route developed here provided access to several dysiherbaine analogues, including 9-epi-dysiherbaine (38), 9-deoxydysiherbaine (39), 9-methoxydysiherbaine (40), and N-ethyldysiherbaine (41). The preliminary structure-activity relationship studies revealed that the presence and stereochemistry of the C9 hydroxy group in dysiherbaine is important for high-affinity and selective binding to glutamate subtype receptors.

Original languageEnglish
Pages (from-to)264-273
Number of pages10
JournalJournal of Organic Chemistry
Volume73
Issue number1
DOIs
Publication statusPublished - 2008 Jan 4

ASJC Scopus subject areas

  • Organic Chemistry

Fingerprint Dive into the research topics of 'Rapid and efficient synthesis of dysiherbaine and analogues to explore structure-activity relationships'. Together they form a unique fingerprint.

Cite this