Computationally Guided Catalyst Design in the Type I Dynamic Kinetic Asymmetric Pauson–Khand Reaction of Allenyl Acetates

The Rh­(I)-catalyzed
allenic Pauson–Khand reaction (APKR)
is an efficient, redox-neutral method of synthesizing α-acyloxy
cyclopentenones. An enantioselective APKR could provide access to
chiral, nonracemic α-acyloxy and α-hydroxy cyclopentenones
and their corresponding redox derivatives, such as thapsigargin, a
cytotoxic natural product with potent antitumor activity. Rapid scrambling
of axial chirality of allenyl acetates in the presence of Rh­(I) catalysts
enables the conversion of racemic allene to enantiopure cyclopentenone
product in a dynamic kinetic asymmetric transformation (DyKAT). A
combined experimental and computational approach was taken to develop
an effective catalytic system to achieve the asymmetric transformation.
The optimization of the denticity, and steric and electronic properties
of the ancillary ligand (initially (S)-MonoPhos,
58:42 er), afforded a hemilabile bidentate (S)-MonoPhos-alkene-Rh­(I)
catalyst that provided α-acyloxy cyclopentenone product in up
to 14:86 er. Enantioselectivity of the Rh­(I)-(S)-MonoPhos-alkene
catalyst was rationalized using ligand-substrate steric interactions
and distortion energies in the computed transition states. This asymmetric
APKR of allenyl acetates is a rare example of a Type I DyKAT reaction
of an allene, the first example of DyKAT in a cyclocarbonylation reaction,
and the first catalyst-controlled enantioselective APKR.