DFT-Informed Stereo-Differentiating Asymmetric Rh(I)-Catalyzed Pauson−Khand Reaction: An 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 using vibrational circular dichroism (VCD) and 13C NMR. DFT computational results corroborate experimentally observed stereoselectivity, and the corresponding transition state structures 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 analogs within reach.