Asymmetric Total Synthesis of (−)-Arborisidine and (−)-19-<i>epi</i>-Arborisidine Enabled by a Catalytic Enantioselective Pictet–Spengler Reaction

A five-step total synthesis of arborisidine, a caged pentacyclic monoterpene indole alkaloid, has been accomplished in both racemic and enantioselective manners. The synthesis features the following three key steps: (a) a regioselective Pictet–Spengler reaction of tryptamine with 2,3-pentanedione; (b) a chemo- and stereoselective intramolecular oxidative cyclization; and (c) a complexity-generating aza-Cope/Mannich cascade followed by in situ oxidation and epimerization. A chiral pyrenylpyrrolidino-squaramide catalyzed enantioselective Pictet–Spengler reaction between tryptamine and 2,3-pentanedione is subsequently uncovered, allowing us to develop a five-step asymmetric synthesis of (−)-arborisidine, an enantiomer of the natural substance. Both (±)-19-<i>epi</i>-arborisidine and (−)-19-<i>epi</i>-arborisidine are also synthesized, which undergo epimerization at room temperature in the presence of aqueous 2 N KOH to (±)-arborisidine and (−)-arborisidine, respectively. The 19-<i>epi</i>-isomer is also partially epimerized to arborisidine upon preparative TLC purification (eluent: MeOH/CHCl₃ saturated with NH₃) and equilibrium studies indicate that arborisidine is thermodynamically more stable than its 19-epimer. In line with Kam’s biosynthesis proposal and their purification protocol, we suspect that 19-<i>epi</i>-arborisidine could also be a natural product.