Asymmetric Total Synthesis of (−)-Arborisidine and (−)-19-epi-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-epi-arborisidine and
(−)-19-epi-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-epi-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-epi-arborisidine could also be a natural product.

成功实现了五步法合成阿罗西定，一种被笼蔽的五环单萜吲哚生物碱，此过程既包括外消旋法，也包括对映选择性合成。该合成过程包含以下三个关键步骤：(a) 吲哚胺与2,3-戊二酮的区位选择性Pictet-Spengler反应；(b) 化学和立体选择性分子内氧化环化；(c) 生成复杂结构的aza-Cope/Mannich级联反应，随后进行原位氧化和构型异构化。随后揭示了一种手性芘基吡咯啶-噁唑酰胺催化的吲哚胺与2,3-戊二酮之间的对映选择性Pictet-Spengler反应，这使我们得以开发出一种五步法非对映选择性合成(-)-阿罗西定，即天然物质的异构体。同时，(±)-19-表阿罗西定和(-)-19-表阿罗西定也被合成出来，它们在室温下与水合2 N KOH存在下分别经历异构化反应生成(±)-阿罗西定和(-)-阿罗西定。在制备性薄层色谱纯化过程中（溶剂：饱和NH3的甲醇/氯仿），19-表异构体也部分异构化为阿罗西定，平衡研究显示阿罗西定在热力学上比其19-表异构体更稳定。与Kam的生物合成假设及其纯化方案相一致，我们推测19-表阿罗西定也可能是天然产物。