Asymmetric Total Syntheses of Aspidodasycarpine, Lonicerine, and the Proposed Structure of Lanciferine

Abstract

Aspidodasycarpine and lonicerine are a pair of epimeric aspidophylline-type alkaloids bearing vicinal quaternary C7 and C16. The first and enantioselective total syntheses of these molecules are described here. A Ru-catalyzed asymmetric transfer hydrogenation established the first stereocenter. An Au-promoted Toste cyclization was exploited to assemble the bridged tetracyclic core and define the geometry of the exocyclic olefin; electron deficient (p-CF3C6H4)3P was a suitable ligand for this transformation. An aldol condensation followed by an intramolecular indole C3 alkylation constructed the adjacent quaternary C7 and C16 diastereoselectively, leading to a pentacyclic lactol as an advanced common intermediate for synthesizing both alkaloids. The proposed structure of lanciferine, a highly oxidized congener of aspidodasycarpine, was synthesized from the lactol by tuning the oxidation states of various carbons.

Total Syntheses of Echitamine, Akuammiline, Rhazicine, and Pseudoakuammigine

“…Subsequently, a series of elegant syntheses of members from this family were accomplished, based on the development of powerful strategies and methods . In 2016, we reported the syntheses of aspidodasycarpine and lonicerine, both of which belong to the aspidophylline A subclass . Very recently, Garg and co‐workers disclosed for the first time the syntheses of 2 and 7 , which features their signature interrupted Fisher indole synthesis .…”

“…Face‐selective homologation was required to establish the C‐16 stereochemistry, and the C‐6−C‐7 bond could be built through intramolecular indole alkylation. Disassembly of the azabicyclo[3.3.1]nonane core of 12 revealed silyl enol ether 13 as a Toste cyclization substrate . Very recently, we exploited silver‐catalyzed Toste type cyclization of the terminal alkyne in the syntheses of Daphniphyllum alkaloids, which demonstrated the advantage of the silver version in the scale and cost aspects.…”

“…Despite few literature precedents, similar cyclization of the unfunctionalized internal alkyne should provide 12 with defined geometry of the C‐19=C‐20 bond. Compound 13 was further traced back to known precursors 14 and 15 …”

Total Synthesis of Calophyline A

“…The synthetic efforts from the research groups of Qin, Garg, Ma, Smith, MacMillan, Snyder, Zhu, and Yang have led to the inventive total syntheses of vincorine, aspidophylline A, scholarisine A, picrinine, 2‐( S )‐cathafoline, and strictamine . Most recently, the group of Li reported the elegant total syntheses of aspidodasycarpine and its congeners . These synthetic endeavors have tremendously simplified the chemical syntheses of akuammiline alkaloids and provided valuable insights for the assembly of the polycyclic architectures.…”

“…Moreover, the introduction of the neopentyl quaternary stereogenic center (C16) has been difficult in this area. The group of Li creatively addressed this problem at the relative early state of their syntheses . We, in contrast, relied on a late‐stage aldol reaction on an extremely congested bridged polycycle.…”