The Masamune-Bergman cyclization or Masamune-Bergman reaction or Masamune-Bergman cycloaromatization is an organic reaction and more specifically a rearrangement reaction taking place when an enediyne is heated in presence of a suitable hydrogen donor (Scheme 1).[1][2] It is the most famous and well-studied member of the general class of cycloaromatization reactions.[3] It is named for Japanese-American chemist Satoru Masamune (b. 1928) and American chemist Robert G. Bergman (b. 1942). The reaction product is a derivative of benzene.
When the enyne moiety is incorporated into a 10-membered hydrocarbon ring (e.g. cyclodeca-3-ene-1,5-diyne in scheme 2) the reaction, taking advantage of increased ring strain in the reactant, is possible at the much lower temperature of 37 °C.
Scheme 2. Bergman reaction of cyclodeca-3-ene-1,5-diyne
Naturally occurring compounds such as calicheamicin contain the same 10-membered ring and are found to be cytotoxic. These compounds generate the diradical intermediate described above which can cause single and double stranded DNA cuts.[4] There are novel drugs which attempt to make use of this property, including monoclonal antibodies such as mylotarg.[5]
A biradical mechanism is also proposed for the formation of certain biomolecules found in marine sporolides that have a chlorobenzene unit as part of their structure. In this mechanism a halide salt provides the halogen. A model reaction with the enediyene cyclodeca-1,5-diyn-3-ene, lithium bromide as halogen source and acetic acid as hydrogen source in DMSO at 37 °C supports the theory:[6][7]
Bergman cyclization with capture by lithium bromide
The reaction is found to be first-order in enediyne with the formation of p-benzyne A as the rate-limiting step. The halide ion then donates its two electrons in the formation of a new Br-C bond and radical electron involved is believed to shuttle over a transient C1-C4 bond forming the anion intermediate B. The anion is a powerful base, stripping protons even from DMSO to final product. The dibromide or dihydrogen product (tetralin) never form.
Reversible Bergman cyclization of diyne induced by an AFM tip: model (top) and false-color AFM images (bottom)
In 2015 IBM scientists demonstrated that a reversible Masamune-Bergman cyclisation of diyne can be induced by a tip of an atomic force microscope (AFM). They also recorded images of individual diyne molecules during this process.[8] When learning about this direct experimental demonstration Bergman commented, "When we first reported this reaction I had no idea that it would be biologically relevant, or that the reaction could someday be visualized at the molecular level.[9]
References
^Darby, N.; Kim, C. U.; Salaun, J. A.; Shelton, K. W.; Takada, S.; Masamune, S. (1971). "Concerning the 1,5-didehydro[10]annulene system". J. Chem. Soc. D. 1971 (23): 1516–1517. doi:10.1039/C29710001516.
^Mohamed, R. K.; Peterson, P. W.; Alabugin, I. V. (2013). "Concerted Reactions that Produce Diradicals and Zwitterions: Electronic, Steric, Conformational and Kinetic Control of Cycloaromatization Processes". Chem. Rev.113 (9): 7089–7129. doi:10.1021/cr4000682. PMID23600723.
^Lee, May D.; Ellestad, George A.; Borders, Donald B. (1991). "Calicheamicins: discovery, structure, chemistry, and interaction with DNA". Accounts of Chemical Research. 24 (8): 235–243. doi:10.1021/ar00008a003.
^Perrin, Charles L.; Rodgers, Betsy L.; O'Connor, Joseph M. (2007). "Nucleophilic Addition to a p-Benzyne Derived from an Enediyne: A New Mechanism for Halide Incorporation into Biomolecules". J. Am. Chem. Soc.129 (15): 4795–4799. doi:10.1021/ja070023e. PMID17378569.
