Stereo-Differentiating\nAsymmetric Rh(I)-Catalyzed\nPauson–Khand Reaction: A DFT-Informed Approach to Thapsigargin\nStereoisomers

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