Activation of enediynes by photochemical ring contraction: Design, synthesis and reactivity of cyclic enediynes containing diazodicarbonyl moiety

Of all recently discovered antibiotics, the natural enediyne antibiotics possibly show the most promise as prospective drugs for the treatment of various forms of cancer. Unfortunately, low selectivity and stability and high general toxicity of natural enediynes, as well as designed compounds based on essential structural features of natural enediyne antibiotics, prevented their use in clinical practice thus far. In an attempt to address this issue we suggested employing an approach to pro-drug design that makes it possible not only to utilise stable and thus relatively non-toxic enediynes, but also to achieve a certain degree of spatial and temporal control over their action. We have suggested to explore the feasibility of photochemical or thermal ring contraction reactions as tools to activate cyclic enediynes toward Bergman cycloaromatisation.; A number of cyclic enediynes have been prepared in this work. While oxacyclic enediyne 3.29 could not be prepared in a satisfactory yield and cyclic enediyne precursors 6.14 and 6.26 were found to be thermally unstable, carbocyclic diazodicarbonyl enediynes 4.18 and 5.15 were prepared in excellent synthetic yields. We have shown that eleven-membered and bigger homologous cyclic enediynes containing a diazodicarbonyl moiety are thermally stable at room temperature, however they undergo an efficient photochemical ring contraction reaction transforming them into smaller cyclic systems, which are much more prone to Bergman cyclisation. The versatility of the concept was demonstrated on the eleven-membered diazoenediynedione 4.18. Thermal (100°C) or photochemical (UV irradiation) Wolff rearrangement of this otherwise stable compound results in formation of unstable ring contraction products, which undergo facile Bergman cyclisation into the corresponding dihydroanthracene derivatives. All transformations involved in the process were studied in greater detail on the less active larger homologue, the diazoenediynedione 5.15.; We have also found that Wolff rearrangement of a diazodicarbonyl moiety conjugated with the extended pi-system of the enediyne fragment results in formation of highly enolised oxocarboxylic acid derivatives, which exhibit rates of Bergman cyclisation much greater than those reported for simpler enediynes of the same ring size. The rate of Bergman cyclisation was found to greatly depend on the nature and position of substituents directly attached to the conjugated dienediyne fragment formed upon Wolff rearrangement of diazoenediynediones. (Abstract shortened by UMI.)...