Cycloaromatization dynemicin

Two derivatives, compound 94, which bears an esperamicin core with an epoxide trigger, and 95, which is a hybrid between esperamicin and dynemicin A cores,have been reported (Scheme 19.25). Both compounds, after trifluoroacetamide removal, underwent cycloaromatization and showed an interesting antitumor activity in vivo in mice. 

Magnus, P. Eisenbeis, S.A. Rose, W.C. Zein, N. Solomon, W. Studies on dynemicin. A nonradical cycloaromatization pathway for the azabicyclo [7.3.1]enediyne core structure initiated by thiolate addition. J. Am. Chem. Soc. 1993, 775, 12627-12628. 

Magnus, P, and Fairhurst. R.A.. Relative rates of cycloaromatization of dynemicin azabicy-clo[7.3.1]enediyne core sti-uctiues. An unusual change in ASlexcit.), 7. Chem. Soc., Chem. Commun., 1541, 1994. 

Scheme 7-69 Synthesis and chemistry of cobalt complexes of dynemicin A model systems. Triggering of the Bergman cycloaromatization by decomplexation (Nicolaou et al.).

The instability of the enediyne-containing dynemicin model compounds in which the epoxide had been opened prompted Nicolaou et al. to seek a means by which they could tame the reactivity of the cis-diois sufficiently to observe them (253, 254]. By comparing the resonance energies of benzene (36 kcal/mol), naphthalene (61 kcal/mol) and anthracene(84 kcal/mo ) it was reasoned that there would be less of a driving force for cycloaromatization of the diols 346 and 347 compared with 345 (Scheme 7-73). Indeed, treatment of 343 and 344 with silica... 

The final example in the table (example 5, Table 6.9) is one of a class of similar cyclizations found in several families of antibiotics. For example, it has been argued that the activity of antibiotics such as Dynemicin A (Figure 6.17) results from initial binding (intercalation) of the antibiotic into the minor groove of deoxyribonucleic acid (DNA Chapter 14) followed by cycloaromatization of the enediyne system to produce a diradical intermediate. The diradical then irreversibly finks to the DNA by hydrogen abstraction, damaging it permanently. 

The endiyne and enyne-allene have attracted the attention, as they undergo facile cycloaromatization to produce reactive biradicals [1], which could mimic the DNA-cleaving mechanism and properties of the new class of very potent antitumor antibiotics calicheamicins [2], esperamicins [3], neocarzinostatin [4], and dynemicins [5]. 

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