3.9.2.5. Category 5: Activation of the Prodrug via Photolysis of Cyclopropenone/Diazoketone

In this design strategy, a reactive enediyne system is protected with a group that arrests the spontaneous BC to occur at ambient conditions of a monocyclic enediyne. Although cobalt carbonyl complexation of the acetylenic moiety is a commonly used protecting group, the difficulty in the removal of such a group under photochemical conditions prohibited its use. Popik et al. have used cyclopropenone as a photocleavable protecting group to lock a benzene-fused enediyne system A. Irradiation led to cheletropic removal of carbon monoxide with consequent generation of enediyne B, which then underwent BC. It may be noted that the acetylene-protected enediyne A is thermally stable, showing no sign of decomposition even after heating at 84°C for 7 days. They have also demonstrated that the p -quinonoid cyclopropenone-containing enediyne prodrug A can be activated by photolysis via a single- or two-photon transfer to the enediyne. The latter undergoes BC at 40°C with a half-life of 88 h (Scheme 96).

Scheme 96. Photochemical in situ generation of enediyne.

Similar to the MSC, eneyne−ketones can also undergo similar cyclization chemistry to form a phenoxy diradical. The latter reaction also takes place under ambient conditions similar to the MSC. On the basis of this Saito et al. synthesized the diazoketone B via Sonogashira coupling followed by the reaction with diazomethane or methyldiazomethane with the acid chloride A. The resulting diazoketone, upon photo-irradiation (high-pressure Hg-lamp), rearranges into the ketene D. The ketene is conjugated to the eneyne system. Therefore it undergoes cycloaromatization to produce the phenoxy diradical E which was shown to induce cleavage of ds plasmid DNA (pBR322) (Scheme 97).

Scheme 97. Photo-activation through conversion of eneyne−ketene.