Total Synthesis of Spiroketal Alkaloids Lycibarbarines A–C

Lycibarbarines A–C are spirocyclic alkaloids with a unique tetracyclic framework, consisting of tetrahydroquinoline and spiro-fused oxazine-sugar spiroketal subunits. The first total syntheses of lycibarbarines A–C are reported, achieved over 10 steps (longest linear sequence) each. Through this work, it was discovered that the spiroketal unit of lycibarbarines A–C exhibits unusually high resistance to acid-mediated isomerisation and epimerisation, likely due to the basic nitrogen atom. As such, the lycibarbarines present an interesting case study of preventing the interconversion of spiroketal isomers, which may prove instructive in efforts to obtain non-thermodynamic spiroketal frameworks.