Stereo-Differentiating Asymmetric Rh(I)-Catalyzed Pauson–Khand Reaction: A DFT-Informed Approach to Thapsigargin Stereoisomers

We report a stereo-differentiating dynamic kinetic asymmetric
Rh(I)-catalyzed
Pauson–Khand reaction, which provides access to an array of
thapsigargin stereoisomers. Using catalyst-control, a consistent stereochemical
outcome is achieved at C2for both matched and mismatched casesregardless
of the allene-yne C8 stereochemistry. The stereochemical configuration
for all stereoisomers was assigned by comparing experimental vibrational
circular dichroism (VCD) and 13C NMR to DFT-computed spectra.
DFT calculations of the transition-state structures corroborate experimentally
observed stereoselectivity and identify key stabilizing and destabilizing
interactions between the chiral ligand and allene-yne PKR substrates.
The robust nature of our catalyst-ligand system places the total synthesis
of thapsigargin and its stereoisomeric analogues within reach.