Enediynes Bergman cyclization

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." ... 

Recently, Tour et al. [32] described attempts to prepare PPP derivatives via a Bergman cyclization, starting from substituted enediynes, e.g. poly(2-phenyl-1,4-phenylene) (18) from l-phenyl-hex-3-en-l,5-diyne or the structurally related poly(2-phenyl-1,4-naphthalene) (19) from l-phenylethynyl-2-ethynylbenzene. 

Novel pyrimidine enediynes 104 prepared by Russell and co-workers undergo Bergman cyclization to give tricyclic products 105 . Pyrimidines 104 were also shown to cleave dsDNA under appropriate conditions. 

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. 

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

This analysis confirms that the effect of cyclic constraints is not purely steric but also has an electronic component. Another aspect of this dichotomy is shown in Fig. 11 which illustrates the decrease in the energy gap between the frontier in-plane rc-MOs. The decrease in the C1-C6 distance destabilizes the occupied MO where the interaction between the end orbitals is antibonding and, at the same time, stabilizes the empty MO where the 7i -orbitals overlap constructively. As a result, the efficiency of the photochemical Bergman cyclization should increase and, indeed, the most efficient photo-Bergman cyclizations reported in the literature involve cyclic enediynes.43 Again, the analogy with interrupted [2 + 2] photocycloaddition is instructive. 

Scheme 13 Bergman cyclization of enediynes bearing ort/zo-substituents.

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.

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. 

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. 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. 

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). 

Scheme 16 Model enediynes used in photochemical Bergman cyclization.

Enediynes amino, 127, 20, 217 antiaromatic region in, 14-15 Bergman cyclization, 3, 18, 25 C1-C5 cyclization of, 5f 25 cyclic, strain and antiaromaticity in, 11-16... 

Enediynes tend to undergo Bergman cyclizations, and the C4-C9 bond can be made in this way. The C5 and C8 radicals produced thereby can each abstract H from Cl and C12, respectively. Fragmentation of the C10-C11 bond, then radical-radical combination gives the product. 

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-... 

Bergman cyclization of the enediyne alcohol 985 gave the tetrahydrobenzoquinazoline 986, both thermally and photochemically in isopropanol, while the analogous ketone only showed efficient thermal cyclization <20000L3761>. 

A Bergman-like [99,100] cyclization has been employed to synthesize substi-tuted-PPPs 23 [101]. Using this strategy enediynes are cyclized and subsequently coupled upon thermal treatment, as shown in Scheme 28. The polymers obtained in this manner are 2,3-disubstituted and display number average molecular weights on the order of 1500-2500 g/mol. 

Various cross-conjugated enediynes undergo Bergman-type cycloaromatizations upon reduction with potassium metal, generating anions of fulvenes and fulvalene derivatives (Scheme l).6 Not all cross-conjugated enediynes yield cyclized dianions upon reduction some give uncyclized, Y-shaped, cross-conjugated dianions, whereas others apparently yield radical anions that either dimerize or persist as monomers. 

The Bergman Cyclization (or Myers-Saito Cyclization) allows the construction of substituted arenes through the thermal or photochemical cycloaromatization of enediynes in the presence of a H donor such as 1,4-cyclohexadiene. 

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. 

With the discovery of calicheamicin and similar natural products, interest in the Bergman Cyclization has increased. Many enediynes can now be viewed as potential anticancer drugs. Thus, the development of Bergman Cyclization precursors that can undergo cyclization at room temperature has attracted much attention. Now, most publications on this topic deal with the parameters that control the kinetics of the Bergman Cyclization. 

E. M. Brzostowska, R. Hoffmann, C. A. Parish, Tuning the Bergman Cyclization by Introduction of Metal Fragments at Various Positions of the Enediyne. Metalla-Bergman Cyclizations. J. Am. Chem. Soc. 2007, 129, 4401-4409. 

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. 

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