Synthesis and chemistry of chromoprotein antitumor antibiotics: Nine-membered enediynes are equilibrated with p-benzyne type biradicals

The recent discovery of nine-membered cyclic enediyne chromophores (1 for the antitumor antibiotics C-1027; 2 for kedarcidin) stabilized by specific apoproteins prompted us to synthesize a highly strained carbocyclic core structure to elucidate the specific mechanism which prevents their spontaneous aromatization. We have achieved successful synthesis of enediynes 10 and 14 as models of 1 and 2, respectively, and found the remarkable solvent dependence of the rate of cycloaromatization of 14. The kinetic data and the ESR spectra strongly indicate that the hydrogen abstraction rate of p-benzyne biradical 17 is slower than that of phenyl radical by a factor of 100, and that the equilibrium is virtually reached between 14 and 17 in CH3CN and CD2Cl2 at ambient temperature, which suggests a hypothesis that the chromophores 1 and 2 may also be equilibrated with their p-benzyne forms and are stabilized kinetically by specific apoproteins. Thus, those molecules may exist indefinitely if they remain free of hydrogen donor(s) in the holoprotein complex. The kinetics and energetics of Bergman cycloaromatization as well as our endeavours toward the total syntheses of 1 and 2 are disclosed.