Mechanism of the Masamune-Bergman reaction. Part 3: The transition state for Calicheamicin models.
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 sp2centres instead of two sp3 centres. The purpose is to find out how these structural modifications to the classic Bergman affect the mechanism.
TS1 is shown below for this model and the computed free energy barrier for this cyclisation is 42.5 kcal/mol at the uωB97XD/Def2-TZVPP level, <S2> = 0.345. FAIR Data DOI: 10.14469/hpc/14583[cite]10.14469/hpc/14583[/cite]. This compares with 33.0 kcal/mol calculated for the -(CH2)4- version, for which <S2> = 0.266. To prepare for modelling the full Calicheamicin molecule, the basis set for this model was reduced to Def2-SVPP and at this level ΔG‡ was 43.0 kcal/mol, <S2> = 0.368, the difference being small enough that the reduction in basis set seems unlikely to affect the results. The C-C bond forming lengths are 1.957 (Deft-TZVPP) and 1.989Å (Def2-SVPP).
Now for a larger model containing the entire Calicheamicin molecule. Two possibilities were explored; one where the geometry of the system was fully optimised in isolation to yield a conformation for Calicheamicin which folded in upon itself and for which ΔG‡ (Def2-SVPP) 40.1 kcal/mol, <S2> 0.368.
The second model used the initial geometry of Calicheamicin as obtained from a crystal structure of the ligand folded into the minor grove of a DNA fragment and which has a much more linear form. The reactant in this mode was +6.1 kcal/mol higher in energy than the previous and TS1 was 4.6 kcal/mol higher, leading to ΔG‡ 38.6 kcal/mol, <S2> 0.367.
So what conclusions can we draw from these extended models of the Bergman cyclisation? The activation free energies for all three models are in the range 42.5 – 38.6 kcal/mol, which is a great deal higher than a value commensurate with a facile room temperature reaction (~22±3). The observation that Calicheamicin can in fact be characterised as a crystal structure when bound to DNA suggests that the cyclisation barrier cannot be too low, but conversely the range 42.5 – 38.6 kcal/mol appears too large for Calicheamicin to easily activate into a biradical in order to abstract hydrogen atom and end up causing strand scission. Might the simplistic model of a split UHF wavefunction resulting in values of <S2> 0.37 be the problem? Well, a similar approach was taken to modelling the Stevens rearrangement [cite]10.59350/4010f-fvr26[/cite]. Using a plain non-biradical closed shell wavefunction, a barrier of ~48 kcal/mol was obtained, but this reduced to 14 kcal/mol when the UHF method was applied (<S2> 0.421), so this model appears to work well in those circumstances. The jury must still be out on whether the Bergman cyclisation mechanism is being correctly modelled here or whether something more complex is going on.
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