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

Abstract

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 13 C 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.