Asymmetric Total Synthesis of Indole Diterpenes Paspalicine, Paspalinine, and Paspalinine-13-ene

Abstract

Paspaline-derived indole diterpenes (IDTs) are structurally complex mycotoxins with unique tremorgenic activity. Reported are asymmetric total syntheses of three paspaline-derived IDTs paspalicine, paspalinine and paspalinine-13-ene. Our synthesis features a green Achmatowicz rearrangement/bicycloketalization for the efficient construction of FG rings (75 % yield) and a cascade ring-closing metathesis of dienyne for highly regioselective formation of CD rings (72 % yield). Other highlights include four palladium-mediated reactions (Stille, aza-Wacker, Suzuki, and Heck) to forge the BE rings and the installation of two continuous all-carbon quaternary stereocenters via reductive ring-opening of cyclopropane and α-methylation of the conjugate ester. Our new synthetic strategy is expected to be applicable to the chemical synthesis of other paspaline-derived IDTs and will facilitate the bioactivity studies of these agriculturally and pharmacologically important IDTs.

Keywords: Achmatowicz rearrangement; Indole diterpenes; Natural products; Ring-closing metathesis; Total synthesis.