Molecular Design, Chemical Synthesis, Kinetic Studies, Calculations, and Biological Studies of Novel Enediynes Equipped with Triggering, Detection, and Deactivating Devices. Model Dynemicin A Epoxide and cis-Diol Systems

Abstract

A series of enediyne model systems of the dynemicin A type equipped with triggering and modulating/ signaling devices were designed, synthesized, and studied. Specifically, compounds 16,18,25, and 27 were synthesized via ring closures involving intramolecular acetylide additions to carbonyl groups followed by deoxygenation. Compounds 16 and 25 underwent cycloaromatization to systems 28 and 29, respectively, upon acid treatment. These conversions were observed with significant changes in the UV and fluorescence spectra of the compounds involved. Compounds 18 and 27, upon activation with base (DBU or basic buffer solution), were converted to free amino epoxides 30 and 31 which were further transformed into cis-diols 8 and 9, respectively, by exposure to silica gel in wet benzene. Kinetic studies used to determine the free energies of activation (ΔG*) for the cycloaromatization of 8 (22.6 kcal/mol, 30 °C) and 9 (25.7 kcal/mol, 37 °C) to products 32 and 33, respectively. Ab initio calculations regarding the reactivity of these systems were in agreement with the experimental findings. The isolation of compounds 8, 9, 30, and 31 provide strong support for the postulated intermediates in the dynemicin A reaction cascade. The physical, chemical, and biological profiles of the reported compounds may provide the basis for further applications in mechanistic, biological, and medical studies. © 1993, American Chemical Society. All rights reserved.