An Asymmetric Approach toward the Aristotelia Alkaloid (−)-Penduncularine

TL;DR

Scientists developed a new method to synthesize a complex natural compound called (−)-penduncularine using a more efficient and scalable approach.

Contribution

A novel palladium-catalyzed ynamide cycloisomerization strategy for synthesizing the peduncularine framework is introduced.

Findings

A scalable multigram synthesis of (−)-pseudo-peduncularine was achieved.

The C7 stereocenter inversion was efficiently accomplished via a ring-opening sequence.

A catalytic asymmetric sulfonamidation enabled enantioselective synthesis.

Abstract

We report a catalytic enantioselective total synthesis
of an endocyclic
alkene regioisomer of (−)-peduncularine, termed (−)-pseudo-peduncularine,
and also a synthesis of its C7 epimer. Highlights of the syntheses
include a new strategy for the construction of the peduncularine framework
by palladium-catalyzed ynamide cycloisomerization/enamide reduction,
which could be performed on a multigram scale. By introducing the
indole side chain as a substituent on the ynamide, this approach contrasts
with previous strategies that have relied on late-stage Fischer indole
synthesis. Inversion of the C7 stereocenter installed in the cycloisomerization
process could be readily achieved by temporary azabicycle ring opening,
using an enamide hydrolysis/ketone reduction/Mitsunobu cyclization
sequence. A catalytic asymmetric sulfonamidation of a racemic allylic
benzoate enabled an enantioselective synthesis of (−)-pseudo-peduncularine.

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