Relative Reactivity of Benzothiophene-Fused Enediynes in the Bergman Cyclization

To find promising
analogues of naturally occurring enediyne antibiotics
with a sufficient reactivity in the Bergman cyclization and moderately
stable under isolation and storage, a scale of relative enediynes
reactivity was created on the basis of calculated free activation
energies for the Bergman cyclization within 12 known and new benozothiophene,
benzene, and cinnoline annulated 9- and 10-membered enediynes. To
verify the predicted reactivity/stability balance, three new carbocyclic
enediynes fused to a benzothiophene core bearing 3,4,5-trimethoxybenzene,
fluoroisopropyl, and isopropenyl substituents were synthesized using
the Nicholas-type macrocyclization. It was confirmed that annulation
of a 3,4,5-trimethoxybenzene moiety to a 10-membered enediyne macrocycle
imparts high reactivity to an enediyne while also conferring instability
under ambient temperature. Fluoroisopropyl-substituted 10-membered
enediyne from the opposite end of the scale was found to be stable
while moderately reactive in the Bergman cyclization. Along with the
experimentally confirmed moderate reactivity (DSC kinetic studies),
(fluoroisopropyl)­enediyne showed a significant DNA damaging activity
in plasmid cleavage assays comparable with the known anticancer drug
Zeocin.