Asymmetric synthesis of a novel antinociceptive substance, incarvillateine

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The first total synthesis of a novel potent antinociceptive monoterpene alkaloid incarvillateine and its congenetic alkaloids incarvine C and incarvilline has been achieved based on the strategy using 6-epi-incarvilline as a common precursor. The strategy we have developed for assembling 6-epi-incarvilline involves the construction of an appropriately trisubstituted cyclopentanone via a three-component coupling reaction of (S)-4-siloxycyclopentenone using the organozinc reagent, generated in situ from (E)-stannylalkene, and iodomethane, affording the 2,3,4-trisubstituted cyclopentane as a single stereoisomer. Subsequent ring closure to the octahydrocyclopenta[c]pyridine was performed by means of a reductive Heck reaction using palladium(II) catalyst in the presence of formic acid. 6-Epi-incarvilline thus obtained was converted to (-)-incarvilline via C6 epimerization and (+)-incarvine C by Mitsunobu condensation with ferulic acid. The total synthesis of (-)-incarvillateine was successfully achieved by Mitsunobu condensation of 6-epi-incarvilline with the α-truxillic acid, prepared by head-to-tail photodimerization of the O-tosyl derivative of ferulic acid.