Calicheamicin diradical

The cycloaromatization of enediynes, having a structure like 1, proceeds via formation of a benzenoid 1,4-diradical 2, and is commonly called the Bergman cyclization. It is a relatively recent reaction that has gained importance especially during the last decade. The unusual structural element of enediynes as 1 has been found in natural products (such as calicheamicine and esperamicine) which show a remarkable biological activity... 

The biological activity of calicheamicin 4 (simplified structure) is based on the ability to damage DNA. At the reaction site, initially the distance between the triple bonds is diminished by an addition reaction of a sulfur nucleophile to the enone carbon-carbon double bond, whereupon the Bergman cyclization takes place leading to the benzenoid diradical 5, which is capable of cleaving double-stranded DNA." ... 

An example is calicheamicin, which is able to form the reactive diradical species even under physiological conditions. Here, the Bergman Cyclization is activated by a triggering reaction. A distinguishing property of this diradical species is that it can effect a dual-strand cleavage of DNA ... 

The cascade of events that leads to DNA cleavage by calicheamicin is shown in Scheme 19.4. It is initiated by attack on the central atom of the trisulfide by a nucleophile (probably glutathione), that causes the formation of a thiolate which is in a perfect position for adding intramolecularly to the Q ,p-unsaturated ketone to form 12. Now the bridgehead carbon atom is no longer sp hybridized and therefore cycloaromatization is not any more impeded by Bredt s rule. The reactivity of 12 is even higher than that of 10 and rapid formation of the diradical 13 takes place. 

Semmelhack, M,F, Gallagher, J.J. Minami, T. Date, T, The enol-keto trigger in initiating arene diradical formation in calicheamicin/esperamicin analogs. J. Am. Chem. Soc. 1993, 115, 11618-11619. 

Because of the DNA-cleaving ability and antitumor properties of such naturally occurring diyl precursors as calicheamicin, there has been a great deal of study directed toward the mechanism of diyl formation [32]. The rate of diradical formation has been found to depend on many factors, including (1) the distance between the two alkyne subunits (2) concentration of the trapping agent (3) substituent effects and (4) the difference in strain energy between the enediyne and the cycliza-tion transition state. 

Draw mechanism arrows to show electron movements in the Bergman cycloaromatization reaction that leads to the diradical believed responsible for the DNA-cleaving action of the antitumor agent cahcheamicin (see The Chemistry of... Calicheamicin in Section lO.llC). 

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