Enediyne moiety

Calicheamicin y/ binds to the minor groove of DNA where its unusual enediyne moiety reacts to form a highly effective device for slicing the backbone of DNA. 

The above analysis illustrates why it is helpful to consider the enediyne moiety as two independent re-systems. As discussed above, the conjugated out-of-plane 7r-system of the reactant is smoothly transformed into the conjugate 7r-system of the product (e.g., the aromatic system of benzene) without an overall change in the number of bonds. We will refer to this group of electrons as out-of-plane MOs or simply as the re-system . In contrast, the two in-plane re-bonds are transformed in a more drastic way to the new cr-bond and a pair of radical centers. We will refer to this system of orbitals as in-plane re-bonds or as the a system . 

Fig. 11 Comparison of the energy gap between highest occupied in-plane MO and lowest unoccupied in-plane MO in acyclic (left) and cyclic (right) benzannelated enediynes. Incorporation of the enediyne moiety into a cyclic structure simultaneously increases the energy of the occupied MO and lowers the energy of the unoccupied MO.

Steric compression of enediyne moiety by ortho substituents is further illustrated in Fig. 14, which clearly shows that steric destabilization is accompanied by decrease in the distance between carbons Cl and C6. 

In this analysis, the activation barrier for both C1-C6 and C1-C5 cyclizations of enediyne radical-anions can be described as the avoided crossing between the out-of-plane and in-plane MOs (configurations). One-electron reduction populates the out-of-plane LUMO of the enediyne moiety. At the TS (the crossing), the electron is transferred between the orthogonal re-systems to the new (in-plane) LUMO. This effect leads to the accelerated cyclization of radical-anions of benzannelated enediynes, a large sensitivity of this reaction to re-conjugative effects of remote substituents and the fact that this selectivity is inverse compared to that of the Bergman cyclization. Similar electronic effects should apply to the other reductive cyclization reactions that were mentioned in the introduction. 

A very interesting experimental observation of Jones et al. illustrates a different effect of strain on the efficiency of photochemical Bergman cyclizations.43d Variations in the size of the cycle which does not incorporate the whole enediyne system, but only the vinyl part of the enediyne moiety (in contrast to the previously discussed data) affect the yield of the cycloaromatized product. Initially, an increase in the ring size leads to an increase in yield (Scheme 16). 

The interest in the Bergman Cyclization was somewhat low, due to its limited substrate scope and the availability of alternative methods for the construction of substituted arenes. However, natural products that contain the enediyne moiety have been discovered recently, and these compounds have cytotoxic activity. 

Nicolaou, K. C. ZuccaieUo, G. Rianer, C. Estevez, V. A. Dai, W. M. Design, synthesis, and study of simple monocyclic conjugated enediynes. The 10-manbered ring enediyne moiety of the enediyne anticanca antibiotics, 7. Am. Chem. Soc. 1992,114, 7360-7371. 

The presence of the enediyne moiety constitutes the most notable structural peculiarity of the antibiotics 291-295. Cleavage of DNA strands under the action of these agents was shown to occur as the result of several sequential reactions. The major event in this sequence is connected with the transformations of the enediyne system. 

As was mentioned above, the classical Bergman cyclization of conjugated enediynes proceeds at elevated temperatures (160-200 °C), while a similar transformation within the structural framework of enediyne antibiotics occurs readily at 37 Obvious considerations prompted the suggestion that the proximity of the terminal sp centers, as estimated by the critical cd distance, is the main factor governing the ease of the cyclization. This simple consideration led to the design of several monocyclic compounds containing the enediyne moiety, as shown in Scheme 4.92. ... 

Those that form the enediyne moiety first at the acyclic level and then perform a suitable cyclization. 

As an alternative preparative method of enynes, the highly strained cyclic enediyne moiety 185 was constructed by coupling the dialkynyl diiodide 183 with (Z)-l,2-distarmylethylene (184) in 80% yield in the total synthesis of dyenemicin A [82]. The presence of the epoxide in 183 is important. No coupling took place... 

When the core chromophore is changed to pyrazine (Scheme 30.23, bottom), interaction of enediyne moiety with 1,4-cyclohexadiene proceeds as a cycloaddition [40]. The latter change in reactivity is attributed to the particularly fast formation of an electrophilic triplet state that attacks the jc-bond of 1,4-CHD. In the presence of an ortho-amide functionahty, the same chromophore undergoes either a 7-endo-dig cyclization or photohydration [41]. 

Kumar et al. prepared aza-enediyne analogues by the incorporation of N-prop>argyl moiety to 2-alkynylbenzothiazolium salts (139) and the aza-enediynes (140) were proven to be the modest DNA cleavage agents. The mechanism probably involves the formation of an adduct (141) prior to cleavage of DNA. They also observed DNA cleavage with the N-methyl-2-alkynylbenzothiazolium salt, which lacks the aza-enediyne moiety (scheme-38) (Kumar et al. 2001). 

Scheme 3.54 Competing reaction cascades following addition of a radical to the enediyne moiety.

The excited states of the enediyne moiety were approximated by a weakly interacting ethylene acetylene model where the various states are expressed as linear combinations of the configurations for one ethylene and two acetylenes. The authors examined the first six excited states of 80, three triplets and three singlets. AH methods examined predicted that the spectroscopically forbidden triplet states (DBj, DBj, and DAj, respectively) He between the singlet ground state (S ) and the first singlet excited state (I Bj). 

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