Total Synthesis, Relay Synthesis, and Structural Confirmation of the C18-Norditerpenoid Alkaloid Neofinaconitine

The first total synthesis of the
C18-norditerpenoid aconitine alkaloid
neofinaconitine and relay syntheses of neofinaconitine and 9-deoxylappaconitine
from condelphine are reported. A modular, convergent synthetic approach
involves initial Diels–Alder cycloaddition between two unstable
components, cyclopropene 10 and cyclopentadiene 11. A second Diels–Alder reaction features the first
use of an azepinone dienophile (8), with high diastereofacial
selectivity achieved via rational design of siloxydiene component 36 with a sterically demanding bromine substituent. Subsequent
Mannich-type N-acyl­iminium and radical cyclizations
provide complete hexacyclic skeleton 33 of the aconitine
alkaloids. Key endgame transformations include the installation of
the C8-hydroxyl group via conjugate addition of water to a putative
strained bridghead enone intermediate 45 and one-carbon
oxidative truncation of the C4 side chain to afford racemic neofinaconitine.
Complete structural confirmation was provided by a concise relay synthesis
of (+)-neofinaconitine and (+)-9-deoxylappaconitine from condelphine,
with X-ray crystallographic analysis of the former clarifying the
NMR spectral discrepancy between neofinaconitine and delphicrispuline,
which were previously assigned identical structures.