Cyclization Bergman

The cyclization of Z-hex-3-en-l,5-diyne (equation 81) forming the diradical intermediate 52 was discovered in 1972 and was initially of largely mechan-Then it was discovered that this reaction occurs in the 

Calicheamicin y (reproduced from reference 306 with the permission of the American Chemical Society). 

Pyridine-2-thione-A-oxycarbonyl (PTOC) derivatives of carboxylic esters 53 were developed by Barton et al. and serve as a convenient source of acyloxyl radicals, which upon decarboxylation provide specific routes to free radicals (equation 82). This process can also proceed by a radical addition (equation 83). Acyl selenides (54) are a convenient source of acyl radicals, which can undergo decarbonylation also giving specific free radicals (equation 84). °  

As noted previously, free radical substitution of hydrogen by chlorine received early study, and the basic mechanisms of this process were delin- 

Free radical clocks are reactions with known rate constants such as the cyclization of 5-hexenyl radicals (equation 76) or the ring opening of cyclo-propylmethyl radicals 46 (equation 74). Competition reactions of these processes compared to other reactions permit the assignment of rate constants to 

4-Benzenediyl diradical formation from enediyne via electrocyclization. 

Example 3, Wolff rearrangement followed by the Bergman cyclization  

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 19, Spriiiger-Verlag Berlin Heidelberg 2009 

Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660-661. Robert G. Bergman (1942—) is a professor at the University of California, Berkeley. His discovery of the Bergman cyclization was completed far in advance of the discovery of ene-diyne s anti-cancer properties. 

Highly selective cross-coupling benzoin condensations have been achieved via the use of enzymatic methods.  

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 

Upon heating the enediyne la rearranges reversibly to the 1,4-benzenediyl diradical 2a, which in its turn can rearrange to the enediyne lb or—in the presence of a hydrogen donor (e.g. cyclohexa-1,4-diene)—react to the aromatic compound 3a. 

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.  

Formation of a substituted benzene through 1,4-benzenediyl diradical formation from enediyne via electrocychzation. 

Example 3, WoUf rearrangement followed by Bergman cyclizatiom 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 23, Springer International Publishing Switzerland 2014 

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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. 

The Ratnberg-Backlund reaction has been used for the preparation of strained unsaturated ring compounds that are difficult to obtain by other methods. A recent example is the synthesis of ene-diyne 5" that has been used as starting material for a Bergman cyclization ... 

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

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. 

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.

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. 

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 particular, the N02, CF3, syn-CHO, and syn-OMe groups were predicted to decrease the activation energy for Bergman cyclization by destabilizing reactants through steric repulsion between the orr/zu-substituent and the in-plane acetylenic... 

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.

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... 

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