Towards Photoswitchable Enediyne Antibiotics: Single and Two-Photon Triggering of Bergman Cyclization

Abstract

The concept of photoswitchable enediynes, which are stable in the dark but undergo efficient cycloaro-matization reaction to produce p-benzyne diradical after irradiation with light of an appropriate wavelength, is discussed. Two novel methods for the generation of reactive enediyne compounds from thermally stable precursors have been developed. In the first approach, one of the triple bonds of cyclodeca-3-ene-1,5-diynes is replaced with cyclopropenone group. Cyclopropenone-containing enediyne precursors are unable to undergo cycloaromatization because the enediyne fragment is incomplete. Photolysis of cyclopropenones results in the efficient decarbonylation and the regeneration of a triple bond thus completing the enediyne pi-system. The second method employs photo-Wolff reaction to achieve ring contraction of stable eleven-membered ring precursor enediynes. Benzannulated cyclic enediynes produced by the photodecomposition of enediyne precursor containing 2-diazo-1,3-diketones possess enolized beta-ketoester fragment and undergo remarkably facile tau(36)o = 5 min - 3 h) Bergman cyclization. The generation of reactive enediyne was also achieved with NIR light by non resonant two-photon excitation.