Bergman diradical

When the enediyne substrate has functional groups that can trap the initially formed Bergman diradical, the rapid construction of complex fused ring systems becomes feasible. J.E. Anthony and co-workers prepared an acenaphthene derivative as well as a substituted perylene using this concept. " ... 

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." ... 

Myers has discovered a related reaction of the natural product neocarzinostatine 8 (simplified structure). As in the case of the Bergman cyclization a diradical intermediate is generated by a chemical activation step taking place at the reaction site, where it then can cleave DNA. Because of this feature, together with its discriminating affinity towards different DNA strands, neocarzinostatine is regarded as a potential antitumor agent. 

We have seen before that such diradicals can close up to give cyclopropanes (17-36). Therefore, pyrolysis of cyclopropanes can produce not only propenes but also isomerized (cis trans or optically active inactive) cyclopropanes. See, for example, Berson, J.A. Balquist, J.M. J. Am. Chem. Soc., 1968, 90, 7343 Bergman, R.G. Carter, W.L. J. Am. Chem. Soc., 1969, 91, 7411. 

Since both a acceptors and n donors at the alkyne termini are known to facilitate the Bergman cyclization, Zaleski and coworkers established a model46 in which the coordination of a Lewis acid (metal ion) would change the electronic environment in favor of diradical formation (Scheme 11). 

In the nearly 1970s, Bergman and co-workers48,49 postulated that cis-hex-2-ene, 1,5-diyne (A) upon thermolysis would undergo a thermal rearrangement to the benzene 1,4-diradical intermediate (or, 1,4-dehydrobenzene, B), which could revert to starting material or collapse to the rearrangement product (C) [Eq. (8)]. 

Other researchers have reported that the cyclization step is believed to be rate determining in the cycloaromatization (Bergman) reaction of aliphatic enediynes." It has been found that the rate-limiting step is hydrogen abstraction by benzannelation. This effect should be attributable to the faster rate of retro-Bergman cyclization from the aromatic ring-condensed 1,4-didehydrobenzene diradicals and/or the slower rate of hydrogen abstraction by them. 

Finn et al. reported the first instance of a metal-catalyzed aromatization of enediynes via vinylidene intermediates [7]. Aromatization of unstrained enediynes is knovm as Bergman cyclization and occurs at 200-250 °C via diradical intermediates [8]. Ruthenium-vinylidene complex 7 was formed when 1,2-benzodiyne 6 was treated with RuCp(PMe3)2Cl and NH4PF6 at 100 °C, ultimately giving good naphthalene product 8 ingood yields (Scheme 6.4). This process mimics Myers-Saitocyclizationof5-allene-3-... 

Figure 9.9 Bergman cycloaromatization reactions for ltex-3-ett-l,5-diyne and its perfluorinated congener, as well as a photochemical reaction scheme for generating the perfluorinated diradical from an iodinated precursor. What spectral features would be expected to be most diagnostic of the different intermediates What levels of theory would be appropriate for predicting these spectral signatures (Note that equilibrium arrows of unequal length indicate which species predominates at equilibrium.)...

Vinylcyclopropane-Cyclopentene, Bergman, Di-jr-methane, and Related Diradical Rearrangements... 

Kinetic and DFT studies have found that the rapid cycloaromatization of 2,3-diethynyl-l-methoxybenzene compared with 1,2-diethynylbenzene can be attributed to intramolecular hydrogen abstraction by the p-bcnzyne diradical intermediate from the OMe substituent. This has been shown to render the cyclization effectively irreversible by leading to a more stable diradical, and may have significant implications for the action of therapeutic enediynes.57 In general, the Bergman cycloaromatizations of 1-substituted 2,3-diethynylbenzenes have been found to be highly sensitive to the nature of the ortho-substituent, but the measurements and even the relative trends... 

The cyclization is induced thermally or photochemically. Most cyclizations have a high activation energy barrier and therefore temperatures around 200 °C are needed for the cycloaromatization. The Bergman Cyclizatic n forms a 1,4-benzenediyl diradical - a highly reactive species, that reacts with a H donor to give the corresponding arenes. 

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 ... 

A stoichiometric example of the combination of two reagents has recently been reported by O Connor in the context of the Bergman cycloaromatization. The generation of the aromatic diradical can be induced by [Cp Ru(CH3CN)3]PF6. Radical reduction occurs through HAT from CpW(CO)3H to provide a cationic Ru-arene complex as shown in Scheme 15 [35]. 

A case in point, again involving a derivative of 47, is illustrated by the cycloaromatization of 106, a starting material that has two in-built radical traps. After the diradical 107 has been generated by the Bergman process, the 1,4-diyl is intercepted by the two a,y -unsaturated ester groups and the tetracyclic product 108 is formed (Scheme 24) [60]. 

In another example, the hexaacetylene 109 - after deprotection with potassium carbonate in methanol - is subjected to typical Bergman trapping conditions, resulting in the formation of the anthracene derivative 110 [61]. As a third, more complex illustration, the aroma-tization of the triacetylene 111 may be considered. Here, the 1,4-diradical intermediate faces another triple bond as an internal trap, and, after hydrogen transfer from 1,4-cyclohexadiene, the tricyclic allylic alcohol 112 is produced [61]. 

Figure 3.3 Mechanism of action of esperamicin A i. Reduction of the trisulfide and Michael-type addition increases the freedom of movement within the enediyne allowing the formation of a diradical intermediate by means of a Bergman cyclisation. When bound to DNA, the diradical abstracts hydrogens from the DNA backbones which are subsequently trapped by oxygen and lead to strand cleavage. The star notes the location of the reactive enediyne functionality of esperamicin Ai.

Aza-enediynes are a new class of anti-neoplastic agents that produce a cytotoxic effect through an aza-Bergman cyclization (1) of an enediyne core to a 1,4-didehydrobenzene reaction intermediate. Both Bergman and benzothiazolium salt diradical cyclizations are illustrated in Eq. 1 and Eq. 2, respectively. 

A theoretical study of the biological activity of dynamicin A (52) dealt in part with the question of the cd distance. Tuttle et al. examined the Bergman cycliza-tion of 52 to 53 and compared it to cyclization of activated dynamicin A (54) to its diradical product (55). Given the size of these molecules, they optimized the structures at the relatively small B3LYP/3-21G level, but it is important to note that this level predicts the barrier for the cyclization of the 10-member ring enediyne (44) with an error of less than 1 kcal mol —clearly a situation of fortuitous cancellation of errors. Energies were then computed at B3LYP/6-31G(d). The activation enthalpy for the cyclization of 52 is 52.3 kcal mol while the barrier for cyclization of 54 is dramatically reduced to 17.9 kcal mol It is even much lower than the barrier for the cyclization of 44 (28 kcal mol ). 

Thus, dynamicin A is carefully tuned to act as a warhead toward DNA. Inactivated dynamicin A will not undergo the Bergman cyclization at body temperature because of its very high activation barrier. However, the activated form 54 has a barrier of only 17 kcal mol , sufficiently low enough for efficient reaction within the body. In order to insure that the diradical 55 has sufficient lifetime to abstract protons from DNA, the retrocyclizations back to 54 or to 56 must have a barriers greater than 12 kcal mol —the barrier for H-abstraction. These barriers are estimated as 23.5 and 25.6 kcal mol , respectively, consistent with potential high biological activity. 

Unlike the other naturally occurring enediyne molecnles, neocarzinostatin chromophore (30) is activated into an enyne-butatriene. This unusual cumulene 57 undergoes a cyclization analogous to the Bergman cyclization, proposed concurrently by Myers and Saito. This cyclization, now referred to as Myers-Saito cyclization, produces the diradical 58 that can abstract hydrogen atoms from DNA. Thus, neocarzinostatin s bioactivity is remarkably similar to calichaemicin (Figure 4.14). 

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