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

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.