A rapid and efficient total synthesis of dysiherbaine (
1), a potent and subtype-selective agonist for ionotropicglutamate 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 synthesisof neodysiherbaine A, as the starting point, and the cis-oriented amino alcohol functionality on thetetrahydropyran ring was installed by using an intramolecular S
N2 cyclization of
N-Boc-protected aminoalcohol
20. An alternative and even more efficient synthetic approach to
15 featured stereoselectiveintroduction of an amino group at C8 by iodoaminocyclization prior to constructing the bicyclic etherskeleton. The amino acid appendage was efficiently constructed by a catalytic asymmetric hydrogenationof 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 presenceand stereochemistry of the C9 hydroxy group in dysiherbaine is important for high-affinity and selectivebinding to glutamate subtype receptors.
