Myers cyclization

The reactive structural element for the Myers cyclization is an enyne allene, the heptatrienyne 6, which reacts to form a diradical species 7 ... 

In later studies by various groups, the enyneallene motif was incorporated into more complex hydrocarbon structures, allowing not only a better understanding of the Myers cyclization but also the generation of polycyclic hydrocarbons, some of them resembling the steroid core unit. Conceptually, these latter cyclizations are reminiscent of Johnson s biomimetic cyclization reactions with the main difference that here radical intermediates are involved rather than carbocations. Typical starting materials in these studies are the allenes 221 [87], 222 [88] and 223 [89], their cyclization behavior being discussed in Chapter 20. 

Thermolysis of benzoenyneallene (113) in cyclohexadiene at 75 °C produced the cycloaromatized adduct (116) in 22% yield. A biradical is believed to form through a cascade sequence involving an initial Myers cyclization. Trapping of the aryl radical centre in (114) with the tetrarylallenic moiety intramolecularly affords (115), having two triaryl radical centres. Hydrogen abstraction from cyclohexa-1,4-diene by (115)... 

Recently, Myers cyclizations were used to synthesize naphthalenic and benz[e]indene systems. Grissom and co-workers have constructed them from ene-diyne vinyl ether precursor 128 [46], The major pathway involves a Claisen rearrangement of 128 to provide the enyne-allene intermediate 129, which quickly undergoes Myers cycliza-tion to provide aldehyde 131 (Scheme 23). Bergman cyclization of the ene-diyne system to yield the tricyclic ether, 134, constitutes the minor pathway. 

Moore Myers Cyclization Moore Cyclization Myers Cyclization... 

The Myers cyclization of enyne-allenes under mild thermal conditions provides an easy access to the a,3-didehydrotoluene biradicals 10-18). Thermolysis of 22b in refluxing benzene generated the biradical 23 (Scheme 5). The phenyl radical center in 23 was then captured by the double bond intramolecularly, giving rise to the biradical 24. A subsequent 1,5-hydrogen shift produced the o-quinodimethane 25, which in turn underwent a [1,5] sigmatropic hydrogen shift to afford the indan 26. 

The cascade rearrangement of enediyne-connected amino esters has been reported to occur through 1,5- or 1,6-hydrogen atom transfer and subsequent to 1,3-proton shift and Saito-Myers cyclization (Scheme 63)7 ... 

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. 

Scheme 18. Silicon-directed radical cyclization in Myers s synthesis of (+)-tunicamycin V (97).

Full -polarization in diradicals can give rise to zwitterionic products. First examples were studied in detail by Carpenter and coworker who investigated solvent effects on rates and product distribution in Myers-Saito cyclizations.64 Polar solvents and substitution patterns that stabilize either positive or negative charges (or both) favor the zwitterionic products. For example, the presence of a dimethylamino group leads to stabilization of cations and isolation of pyrrolo-quinolines, rather than pyrido-indoles from eneyne-carbodiimides, as reported by Wang and coworkers (Scheme 14).65... 

Zwitterionic Myers-Saito-type cyclization from reference65. 

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. 

Product stabilization is much more pronounced when the enediyne or ene-yne-allene starting materials are not already part of an aromatic system, since forming an aromatic system constitutes a much higher degree of stabilization than expanding an aromatic system (Fig. 24). Conjugation of the radical center provides additional stabilization to the 71-radical formed by the Myers-Saito and Schmittel cyclizations. 

Reaction with a first aldehyde transforms 176 into the vinylphosphonium chloride 177, which for practical reasons is subjected to an anion-exchange process, leading to the phosphonium salt 178. From this, phenyllithium treatment liberates the allenic phosphorane 179, an intermediate that has previously been used to prepare allenes from aldehydes [69], in the present case providing the products 180. The same protocol has also been applied to o-alkynylbenzaldehydes to yield allenes of interest as model compounds for the study of Schmittel and Myers-type cyclization reactions [70]. 

The acetylene 27 became of interest since it undergoes a novel type of thermal cyclization reaction, later to be called the Myers or Myers-Saito cyclization (see Chapter 20 for a discussion of its relevance). The Z-diastereomer of 1,2,4-heptatrien-6-yne (27) was prepared by the sequence summarized in Scheme 5.33 [85]. 

Many of the allenic parent systems mentioned in Schemes 5.1-5.3 have been of interest in mechanistic studies. Thus, the Z-isomer of 27 can either cyclize by the Myers-Saito route to the aromatic diradical 339 or under the so-called Schmittel cyclization conditions to yield the fulvene diradical 338 (Scheme 5.51) [141], both processes being discussed thoroughly in Chapters 13 and 20. 

Since the double bond between C5 and C6 of the enynecumulene 169 is not required for the Myers-Saito cyclization, a large number of enyneallenes have been synthesized as model compounds for the neocarzinostatin chromophore and tested for DNA-cleaving activity in recent years, with the results having already been summarized extensively (cf. Chapter 20) [162]. 

The ability of (Z)-l,2,4-heptatrien-6-ynes (enyne-allenes) and the benzannulated derivatives to undergo cyclization reactions under mild thermal conditions to produce biradicals has been the main focus of their chemical reactivities [1-5]. With the development of many synthetic methods for these highly conjugated allenes, a variety of biradicals are readily accessible for subsequent chemical transformations. Cyclization of the enyne-allene 1 could occur either via the C2-C7 pathway (Myers-Saito cyclization) leading to the a,3-didehydrotoluene/naphthalene biradical 2 [6-10] or via the C2-C6 pathway (Schmittel cyclization) producing the fulvene/benzofulvene biradical 3 [11] (Scheme 20.1). 

Scheme 20.3 The Myers-Saito cyclization reaction of (Z)-l, 2,4-heptatrien-6-yne.

Thermolysis of 44 produced products derived from the Myers-Saito cyclization reaction. However, when 43 having a trimethylsilyl substituent at the acetylenic terminus was subjected to heating in the presence of 1,4-CHD at 70 °C for 3 h, the 1H-cyclobut[a]indene 46 was produced. A reaction mechanism involving an initial Schmittel cyclization to generate the benzofulvene biradical 45 followed by an intramolecular radical-radical coupling was proposed to account for the formation of the formal [2 + 2]-cycloaddition product 46. 

The benzannulated enyne-allenes 48 were likewise synthesized in situ from coupling between 41b and the bromoallene 47 (Scheme 20.11) [39]. Under the reaction conditions, 48 presumably underwent a spontaneous cation-mediated Myers-Saito cyclization reaction with a concomitant 1,2-shift of the trimethylsilyl group to give the naphthalene derivatives 49. 

Scheme 20.11 Cation-mediated Myers-Saito cyclization reaction.

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