Mechanism of the Masamune-Bergman reaction.
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 the final product. This cycloenediyne is not just an obscure chemical curiosity, the motif is incorporated into the natural product Calicheamicin, which is a potent antitumor antibiotic discovered in the 1980s. This drug owes its activity to the cyclisation TS1 shown below, which for n=2 occurs at the low temperature of 310K. The resulting biradical Int1 is a potent hydrogen abstractor, the species acting this way for hydrogen atoms associated with deoxyribose of DNA, ultimately leading to strand scission. Although I have explored many a mechanism on this blog using computational methods, I have never included any biradical examples. Here I explore the computational aspects of this reaction, and also include a pathway proceeding vis TS2- Int2 – TS3 in which hydrogen abstraction precedes cyclisation, in order to see how competitive such an alternative might be as a function of the ring size (n in scheme below).
The computational procedure was ωB97XD/Def2-TZVPP and the FAIR data is collected at DOI: 10.14469/hpc/14546 [cite]10.14469/hpc/14546[/cite]. A spin unrestricted procedure is adopted using an approximation to allow for biradicaloid species, namely an initial first guess at the wavefunction using the keyword guess(mixed) which mixes what would be the HOMO and the LUMO of the molecule in a closed shell sense to allow a combination which includes an open shell singlet with one electron in the HOMO and one electron in the LUMO (a biradical). Part of the purpose of this approach is to try to find out if it gives reasonable results for such a mechanism. I will introduce the spin expectation operator <S2> to help identify biradicals. For closed shell singlets it has the value 0.0, for a pure biradical it has the value 1.0. Thus for species Int1, the values are typically ~0.995 and for the preceding TS1 ~ 0.3 to 0.57. IRC (Intrinsic reaction coordinate) calculations for TS1 show a smooth transition from values of <S2> = 0.0 (Reactant) through to 1.0 (Int1).The results are shown below for three values of n, revealing that as the ring size increases (ending with an acyclic system Et2) the free energy barrier increases significantly, as indeed is reported[cite]10.1039/C29710001516[/cite],[cite]10.1021/ja00757a071[/cite]. The alternative pathway proceeding via TS2 is always higher in free energy and varies much less with ring size. This route can therefore be firmly excluded from contention.
†<S2> =0.27. ‡Final Product (n=2) = -620.327868 (-116.1 kcal/mol)
This computational modelling largely agrees with the observations made for this reaction, with just one inconsistency. For n=2, the reaction is reported as taking place at 37°C, for which a typical free energy barrier would be in the region of ~24±2 kcal/mol,[cite]10.1021/ja00045a005[/cite] around 9 kcal/mol lower than the computed value at this level of theory. This could originate from either a deficiency in the computational model, possibly in the handling of the open shell biradicaloid character by use of a simple spin unrestricted model,[cite]10.1021/ja402445a[/cite] or incursion of some lower energy process into the mechanism (free radical involvement?). I will continue probing this issue to see if its origins can be identified.
In the next part of this blog, I will investigate the mechanism as applied to Calicheamicin to see how the more complex bicycloenediyne nature of this natural product affects it.
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