1.4 Cycloaromatization
The enediynes remain among the most potent antitumor agents to have been discovered in the past decade.1 Activation of the enediynes to undergo cycloaromatization reactions results in the formation of highly reactive diradical intermediates. The diradical species engage in atom transfer chemistry to produce neutral arene products, in the process inducing damage to key macromolecules. Several of the naturally occurring members of the enediyne family of antibiotics have entered clinical trials, and this has prompted the design of synthetic enediynes, where the enediyne “warhead” is conjugated to a targeted delivery vehicle. This section of the review will describe recent efforts using chemical synthesis to identify and improve the target specificity of designed enediynes and to establish efficient methods to achieve activation. Finally, new horizons will be examined, including the use of post-cycloaromatized enediyne templates as recognition elements for unique DNA and RNA microenvironments. The Bergman cyclization14 has received much of attention in the literature since almost all of the natural anticancer agents that have been discovered function through this mechanism. However, there are other cycloaromatization pathways that have been elucidated; those are the Myers-Saito cyclization,16 the Schmittel cyclization17,18 and the Tandem cyclization.1,19




1.4.1 Bergman Cyclization
Jones and Bergman reported a reaction which has since been known as the Bergman cyclization14 in 1972. They reported that enediynes undergo thermal cyclization on heating. Bergman then proposed a mechanism for this cyclization. His proposed mechanism involves a biradical intermediate which could abstract hydrogens from a hydrogen donor source which leads to the final aromatic product (Scheme 2).



Although there is no direct evidence of the existence of biradical, there is indirect evidence such as radical trapping experiments using TEMPO.20 There are a number of factors which influence the reactivity of enediynes. Nicolaou et al. studied a class of enediynes21 and reported that the reactivity towards Bergman cyclization could be determined by distance calculated and observed between acetylenic carbons (cd). It was concluded in their report that distances (cd) lower than 3.20Å cyclized spontaneously at all temperatures via the intermediate (Scheme 2). Enediynes with (cd) distance 3.20 to 3.31Å cyclize at 25◦C, while distances greater than 3.31Å are stable at 25◦C.

Grissom has found that the addition of one alkyl unit on a terminal carbon increases the activation energy from 25.1 kcal/mol to 28.1 kcal/mol.22 When a second alkyl unit was added the cyclization barrier was raised to 34.0 kcal/mol. It was concluded that the thermal stability of enediyne was a direct result of cd alone. The limitations of Nicolaou’s conclusions have been discussed greatly. James P. Snyder has examined a series of reactions and concluded that although cd and reactivity of enediynes are related in monocyclic systems, they do not apply consistently to more complex ring systems.23 In related calculations, the transition state for cyclization was shown to possess 35% biradical character, lending support to Bergman’s proposed mechanism. As a result, Snyder proposed that fusion of additional rings introduces competitive strain; these compounds do not benefit from the diminished kinetic barriers enjoyed by shorter cd in monocyclic systems.23


References
(18) Schmittel, M.; Maywald, M. J. Chem. Soc. , Chem. Commun. 2001, 155.
(19) Grissom, J. W.; Calkins, T. L. Tetrahedron Lett. 1992, 33, 2315.
(20) Grissom, J. W.; Calkins, T. L.; Egan, M. J. Am. Chem. Soc. 1993, 115, 11744.
(21) Nicolaou, K. C.; Zuccarello, G.; Ogawa, Y.; Schweiger, E. J.; Kumazawa, T. J. Am. Chem. Soc. 1988, 110, 4866.
(22) Jones, G. B.; Plourde, G. W. Org. Lett. 2000, 2, 1757.
(23) Snyder, J. P. J. Am. Chem. Soc. 1989, 111, 7630.