Total syntheses of the parvistemoline alkaloids enabled by stereocontrolled Ir/Pd-catalyzed allylic alkylation

The functionalized polycycle with densely contiguous tertiary stereocenters is a formidable challenge in synthesizing the parvistemoline family of Stemona alkaloids. We herein report their catalytic, asymmetric total syntheses in 13–14 steps from commercially available 2-(methoxycarbonyl)-pyrrole, featuring the development and deployment of an Ir/Pd-synergistically-catalyzed allylation of α-non-substituted keto esters with secondary aryl-substituted alcohols, stereodivergently accessible to four stereoisomers. Using chiral Pd-enolate and Ir π-allyl complex under neutral conditions, no epimerization occurs. Additionally, the other two adjacent stereogenic centers can be installed diastereoselectively by Zn(BH4)2-promoted reduction and Krische’s Ir-catalyzed 2-(alkoxycarbonyl)allylation. Oxy-Michael addition delivered the fused tetrahydrofuran-γ-lactone scaffold. At the later stage, hydrogenation or oxidation of pyrrole moiety furnished groups of tetrahydropyrrole and pyrrolidone. Finally, vinylogous Mannich reaction of an in situ generated iminium ion or Krische’s Ir-catalyzed 2-(alkoxycarbonyl)allylation of aldehyde installed the monocyclic lactone for parvistemonine (2) and didehydroparvistemonine (3), respectively.