Mechanism of the Masamune-Bergman reaction. Part 4. Why was the DFT energy barrier too high for the Calicheamicin reaction?

Michael in a comment here on the mechanism of the Masamune-Bergman reaction notes that when it occurs as part of the Calicheamicin (an antibody-drug conjugate or ADC) version of this mechanism, a pre-step is first necessary. As discussed in this review article,[1] the trisulfide linkage is reduced and the resulting thiolate undergoes a facile 1,4-addition to the adjacent enone.

DFT calculations on the new form (FAIR Data DOI:[2], [2] show that the free energy barrier is reduced from 38.6 kcal/mol to 26.2 kcal/mol.

This is now a reasonable value for a thermal reaction, being a 12.4 kcal/mol reduction from the unactivated species. We can conclude that Michael’s suggestion was spot on, and suggests in turn that a DFT-biradicaloid calculation is in fact a reasonable procedure for modelling this type of system.

Author

References

  1. V. Kostova, P. Désos, J. Starck, and A. Kotschy, "The Chemistry Behind ADCs", Pharmaceuticals, vol. 14, pp. 442, 2021. https://doi.org/10.3390/ph14050442
  2. H. Rzepa, "Mechanism of the Masamune-Bergman reaction. Part 4. Why is the DFT energy barrier too high?", 2024. https://doi.org/10.14469/hpc/14632

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