Rapid and efficient synthesis of dysiherbaine and analogues to explore structure-activity relationships.
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 S(N)2 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.
Graduate School of Life Sciences, Tohoku University, Sendai 981-8555, Japan, School of Fisheries Sciences, Kitasato University, Sanriku-cho, Iwate 022-0101, Japan. masasaki@bios.tohoku.ac.jp
Makoto
M
Sasaki
Koichi
K
Tsubone
Kunimori
K
Aoki
Nobuyuki
N
Akiyama
Muneo
M
Shoji
Masato
M
Oikawa
Ryuichi
R
Sakai
Keiko
K
Shimamoto
D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000494:pharmacology*; D003292:Convulsants / Q000138:chemical synthesis* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D007276:Injections, Intraventricular; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D018091:Receptors, AMPA / Q000187:drug effects; D018092:Kainic Acid Receptors / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000409:Alanine; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; C121741:dysiherbaine