Photochemical Generation and Reversible Cycloaromatization of a 9-Membered Ring Cyclic Enediyne

Abstract

The extreme cytotoxicity of natural enediyne antibiotics is attributed to the ability of the (Z)-3-ene-1,5-diyne fragment incorporated into a 10- or 9-membered ring cyclic system to undergo Bergman cyclization and producing dDNA-damaging p-benzyne diradical. The rate of this reaction strongly depends on the ring size. Thus 11-membered ring enediynes are stable, 10-membered ring analogs undergo slow cycloaromatization under ambient conditions or mild heating. Very little is known about reactivity of 9-membered ring enediynes due to their instability. We have developed a thermally stable photo-precursor of 1 of 9-membered enediyne 2, in which one of the triple bonds is replaced by the cyclopropenone group. UV irradiation of 1 results in the efficient decarbonylation (?254 = 0.34) and the formation of reactive enediyne 2. The latter undergoes clean cycloaromatization to 2,3-dihydro-1H-cyclopenta[b]naphthalen-1-ol (4) with ca. 2 h a life-time in isopropanol at 25 �C. The rate of this reaction depends linearly on the concentration of hydrogen donor and shows primary kinetic isotope effect in 2-propanol-d8. These observations, along with high negative entropy of activation, indicate that enediyne 2 exists in a rapid equilibrium with p-benzyne diradical 3. The rate-limiting step of the cycloaromatization reaction is hydrogen abstraction by the diradical 3. Synthesis of cyclopropenone 1 and DNA-clevaging activity of the photo-generated enediyne 2 will be also discussed.