Abstract
The Bergman cycloaromatization (BC) in which a cis-alkene-1,2-diyne (enediyne) cyclizes to form a p-benzyne diradical, typically is a very endothermic reaction, requiring a substantial amount of energy (i.e. high temperature) for it to proceed. This reaction received very little attention until a decade after its discovery, when the natural enediynes were isolated and shown to be the most active antitumor agents every discovered. Having BC at the heart of their mode of action, these natural enediynes have been very challenging to mimic from synthetic standpoints. Of particular interest is to be able to design and synthesize an enediyne that is stable at room temperature, while also being capable of being triggered to undergo BC under ambient conditions. Although a relatively new concept, metal-induced BC reactions have generally been known to decrease the demanding energy barrier. The work presented here describes several synthetic strategies towards arenediyne crown eithers and the synthesis of several arenediyne hydrazone/Schiff base ligands with extended n-systems. These synthesized enediynes are useful ligands, capable of metal-cordination and hence potentially decreasing the BC energy barrier. BC reactions of enediyne intermediates are also reported.
Highlights
1.1 The Enediyne AntibioticsEver since the discovery of the calicheamicins, 1esperamicins[2] and dynemicins 3 in the late 1980s, chemical structures possessing enediyne units have been the subject of avid scientific research.[4]
Scheme 5 shows the initial one pot synthesis routes investigated for the synthesis of desired arenediyne crown ethers 23c and 23d
The electronic and geometric factors associated with the Bergman cyclization has been the center of extensive study, but minor structural variations within or surrounding the enediyne core commonly results in diverse thermal reactivities
Summary
Ever since the discovery of the calicheamicins, 1esperamicins[2] and dynemicins 3 in the late 1980s, chemical structures possessing enediyne units have been the subject of avid scientific research (figure 1).[4]. The general mechanism of DNA cleavage is highly dependent on this enediyne infrastructure, where nearby functionalities act as a "delivery service" to the target DNA and allow for eventual triggering of the enediyne 4'warhead."[6] The consequent change in molecular geometry results in the generation of the highly reactive 1,4-benzenoid radical, capable of quickly abstracting hydrogen atoms from the minor groove of DNA, prompting cell death (figure 2). Key to this mechanism is the generation of this highly unstable biradical via the Bergman cycloaromatization,[7] previously described by Robert Bergman (scheme 1).
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