Total Synthesis of the Diterpenoid Alkaloid Arcutinidine Using a Strategy Inspired by Chemical Network Analysis

Arcutinidine
and other arcutinidine-type diterpenoid alkaloids
feature an intricate polycyclic, bridged framework with unusual connectivity.
A chemical network analysis approach to the arcutane skeleton enabled
the identification of highly simplifying retrosynthetic disconnections,
which indicated that the caged structure could arise from a simpler
fused ring system. On this basis, a total synthesis of arcutinidine
is reported herein, featuring an unprecedented oxopyrrolium Diels–Alder
cycloaddition which furnishes a key tetracyclic intermediate. In addition,
the synthesis utilizes a diastereoselective oxidative dearomatization/cycloaddition
sequence and a SmI2-mediated C–C coupling to forge
the bridged framework of the natural products. This synthetic plan
may also enable future investigations into the biosynthetic relationships
between the arcutanes, the related diterpenoid atropurpuran, and other
diterpenoid alkaloids.