The Bergman Cyclization

These novel, extremely potent antibiotics all possessed one very unusual chemical structural feature an enediyne fragment within a ring. The first discovered was neocarzinostatin (NSC), which was found to be composed of a protein (NSC apoprotein) and the neocarzinostatin chromophore 30 in a 1 1 complex. The biological activity is associated with the NSC chromophore. However, it took until the discovery of the calichaemicin 31 and esperamicin 32 families in 1987 to really gamer the broad attention of chemists. Other enediyne antibiotics include the dynemicin family, the kedarcidin chromophore, namenamicin, the C-1027 chromophore,and uncialamycin.  

The cyclization of 38 has a large activation barrier and it is in fact stable at 25 °C. Calichaemicin and the other enediyne drugs are also stable at 25 C, but rapidly undergo cyclization after activation. Nicolaou et al. proposed, based on molecular mechanics (MM) calculations, that the critical factor is the distance between the terminal alkynyl carbons, a distance they called cd. When the terminal alkynes are far apart (c i 3.31 A), the enediyne is stable, and when the distance is small (cfi 3.20A), the cyclization is spontaneous. Based on this model, the 

10-membered ring enediyne 44 falls in the intermediate range (cd=3.25 A). They prepared this molecule and found that its activation energy is 23.8 kcal mol with a half-life at 37 °C of 18 h. This is consistent with the predicted intermediate-type behavior. 

Computational chemists have investigated a nnmber of relevant issues. What is the nature of the mechanism Can the cd distance predict the reactivity of the 

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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... 

Of great importance for the Bergman cyclization is the distance between the triple bonds. The reaction cannot occur at moderate temperatures if the distance is too large. Optimal reactivity at physiological temperatures is obtained by fitting the enediyne element into a ten-membered ring." ... 

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. 

At present the synthetic importance of both the Bergman cyclization and the Myers reaction remains rather small. However, because of the considerable biological activity of the natural products mentioned above, there is great mechanistic interest in these reactions in connection with the mode of action of DNA cleavage. 

This is related to the Bergman cyclization that was introduced in 18-27. 

In these reactions, a er-bond is formed at the expense of two re-bonds and, thus, the process leads to a net loss of one chemical bond that is intrinsically unfavorable thermodynamically. Formation of the new er-bond leads to ring closure, whereas the net loss of a bond leads to the formation of two radical centers, which can be either inside (the endo pattern in Scheme 1) or outside of the newly formed cycle (the exo pattern). Note that er-radicals are formed through the endo path, while exo-closures may produce either a er-radical when a triple bond is involved or a conjugated re-radical when the new bond is formed at the central carbon of an allene. The parent version of this process is the transformation of enediyne 1 into p-benzyne diradical2 (the Bergman cyclization), shown in Scheme 2. 

Although data presented in the previous section illustrate the diversity of cycloaromatization reactions, most of the following discussion will concentrate on the Bergman cyclization - a reaction that has been studied intensively in recent decades due to its role in the mechanism of biological activity of natural anticancer antibiotics.8,9 We will take advantage of the large body of data produced by this... 

Fig. 2 MO correlation diagrams for the Bergman cyclization (adopted from ref.24). Out-of-plane MOs are shown in black, in-plane MOs are shown in blue.

In a seminal work, Koga and Morokuma suggested that the high activation energy of the Bergman cyclization is due to the strong electron repulsion between the... 

Fig. 7 Internal reaction coordinate (IRC) computations for the Bergman cyclization of model enediynes.

In contrast, the stabilizing re-re interactions that lead to formation of the C1-C6 cr-bond and to cleavage of the C1-C2 and C5-C6 re-bonds the changes most directly associated with the Bergman cyclization - display a more complicated pattern. Their magnitude decreases at first, vanishes at the Nicolaou s threshold and rapidly increases at distances shorter than 3 A. 

Fig. 8 The changes in the NBO re-bond order of in-plane (re , circles) and out-of-plane (rec, diamonds) acetylenic bonds along the IRC pathway for the Bergman cyclization of (Z)-hex-3-ene-1,5-diyne.

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). 

Fig. 12 Correlation between the calculated activation energy of the Bergman cyclization and the product of natural charges at the terminal acetylenic atoms of benzannelated enediynes. Only para substituents obey the correlation. Adapted from reference49.

These computational predictions have been tested experimentally. Kinetic measurements confirmed that both ortho-N02 and ortho-CHO substituents substantially decrease activation energies for the Bergman cyclization supporting earlier computational predictions.51... 

Table 1 provides examples of amino enediynes which become much more reactive toward the Bergman cyclization upon protonation on nitrogen because the presence of a positively charged ammonium moiety alleviates the re-re repulsion of the in-plane re-orbitals. 

Table 2 Calculated energetics in kcal/mol for the Bergman cyclizations of protonated and unprotonated aminoenediynes...

An illustrative example of how rehybridization can be used to control the Bergman cyclization is provided by substituent effects at the alkyne termini of enediynes. This effect in cycloaromatization chemistry was first studied by Schreiner and coworkers, who found dramatic acceleration of the Bergman cyclization upon... 

Fig. 16 (a) Comparison of potential energy profile for the formal Cope rearrangement of 3,4-difluorohexa-l,5-diyne-3-ene with that of (Z)-hexa-l,5-diyne-3-ene, (b) Rehybridization in the C(F) bond along the reaction path. EDI = 3,4-difluoro-hex- 3-ene-l,5-diyne ED2 = 1,6-di-fluoro-hex-3-ene-l,5-diyne BZY = difluoro-l,4-didehydrobenzezne TSBC = the transition state for the Bergman cyclization TSRBC = the transition state for the retro Bergman cyclization. 

Fig. 17 The Bergman cyclizations of parent and fluoro-substituted enediynes with the triple bond and the incipient bond lengths and the activation energies calculated at the BS-UB3LYP/6-31G level.

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. 

In the case of the Bergman cyclization and the C1-C5 cyclization of enediynes, both the activation barrier for cyclization as well as the thermodynamics of the reaction became more favorable upon one-electron reduction compared to the thermal counterparts. The cyclization barrier drops by up to 12kcal/mol (in the C1-C5 cyclization) and the process becomes exothermic (as opposed to the endothermic cyclizations of the neutral counterparts) as illustrated in Fig. 19 and Fig. 20. 

The most obvious effect on cycloaromatization, as the name implies, is the formation of an aromatic system. By delocalizing electrons in an aromatic ring, the product gains a high degree of stability, which is reflected in the small endothermicity of the Bergman cyclization and the exothermicity of the Myers-Saito cyclization. Since the Schmittel and Schreiner cyclizations are not true cycloaromatization reactions per se, they do not have the beneficial effect of the formation of an aromatic system and are therefore much are more endothermic than their counterparts. 

In addition to the numerous pericyclic aromatic TSs, other reactions deserve attention. These include the Cope and Claisen rearrangements, the pericyclic reactions with Mobius TSs, the Bergman cyclizations [77,116], and the TSs for 1,5-H shifts [100,117],... 

In studies of the role of electronic effects in the Bergman cyclization, Russell and Kim reported the preparation of phenazines 173 from heterodiyne 172 <99TL3835>. The authors noted the significant rate dependence on solvent in these reactions. 

Figure 16.4. The energy profiles of the Bergman cyclization of 16 and 65 as measured by Roth et al. ...

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