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Bergman Cyclization
Bergman Cycloaromatization

The Bergman Cyclization allows the construction of substituted arenes through the thermal or photochemical cycloaromatization of enediynes in the presence of a H• donor such as 1,4-cyclohexadiene.

Mechanism of the Bergman Cyclization

The cyclization is induced thermally or photochemically. Most cyclizations have a high activation energy barrier and therefore temperatures around 200 C are needed for the cycloaromatization. The Bergman Cyclization forms a 1,4-benzenediyl diradical - a highly reactive species, that reacts with a H• donor to give the corresponding arenes.

The interest in the Bergman Cyclization was somewhat low, due to its limited substrate scope and the availability of alternative methods for the construction of substituted arenes. However, natural products that contain the enediyne moiety have been discovered recently, and these compounds have cytotoxic activity.

An example is calicheamicin, which is able to form the reactive diradical species even under physiological conditions. Here, the Bergman Cyclization is activated by a triggering reaction. A distinguishing property of this diradical species is that it can effect a dual-strand cleavage of DNA:

With the discovery of calicheamicin and similar natural products, interest in the Bergman Cyclization has increased. Many enediynes can now be viewed as potential anticancer drugs. Thus, the development of Bergman Cyclization precursors that can undergo cyclization at room temperature has attracted much attention. Now, most publications on this topic deal with the parameters that control the kinetics of the Bergman Cyclization.

For example, as shown by calicheamicin, cyclic enediynes have a lower activation barrier than acyclic enediynes. As suggested by Nicolaou in 1988, the distance between the acetylenic carbons that form the covalent bond influences the rate of cyclization. Another theory developed by Magnus and Snyder is based on the molecular strain between ground state and transition state; this seems to be more general, especially for strained cyclic systems. Often, as both the distance and the strain are not known, the development of suitable precursors remains difficult, as exemplified by the following enediyne, in which a slight change leads to a cycloaromatization:

In contrast to the Bergman Cyclization, the Myers-Saito Cyclization of allenyl enynes exhibits a much lower activation temperature while following a similar pathway:

Cyclic enyne allenes are also reactive. Neocarzinostatin is a bacterial antibiotic that also shows antitumor activity. Here, the occurrence of a Myers-Saito Cyclization sets the stage for the cleavage of DNA:

For synthetic purposes, organometallic reagents can be used to generate a precursor to the Bergman Cyclization in which the metal center forms a part of the cumulated unsaturated system; these cyclizations occur at relatively low temperatures, as shown in the example reported by Finn (J. Am. Chem. Soc. 1995, 117, 8045). Here the cyclization can be viewed as a Myers-Saito Cyclization that gives rise to a metal-centered radical:

For a review of natural products, chelation control of the cyclization and recent developments in catalyzed Bergman Cyclizations, please refer to the review by Basak and references cited therein (Chem. Rev. 2003, 103, 4077. DOI).

Recent Literature

Photochemical and Thermal Bergman Cyclization of a Pyrimidine Enediynol and Enediynone
N. Choy, B. Blanco, J. Wen, A. Krishan, K. C. Russel, Org. Lett., 2000, 2, 3761-3764.