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,[cite]10.3390/ph14050442[/cite] 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: 10.14469/hpc/14632 [cite]10.14469/hpc/14632[/cite] 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.
Calicheamicin was noted in the previous post as a natural product with antitumour properties and having many weird structural features such as an unusual "enedidyne" motif. The representation is shown below. A partial structure shown below for Calicheamicin replaces the -(CH2)4- substructure with a four carbon chain that includes two…
The Masamune-Bergman reaction[cite]10.1039/C29710001516[/cite],[cite]10.1021/ja00757a071[/cite] is an example of a highly unusual class of chemical mechanism[cite]10.1021/cr4000682[/cite] involving the presumed formation of the biradical species shown as Int1 below by cyclisation of a cycloenediyne reactant. Such a species is so reactive that it will be quickly trapped, as for example by dihydrobenzene to form…
Calicheamicin is a natural product with antitumour properties discovered in the 1980s, with the structure shown below. As noted elsewhere, this structure has many weird properties, including amongst other features an unusual "enedidyne" motif and the presence of an iodo group on an aromatic ring. Its isolated 3D structure is quite…
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