Myers-Saito cyclization mechanism

Thermal reaction of aza-enyne-allenes 3.956a and 3.956b [18,420a,b] follow a stepwise aza-Myers-Saito cyclization mechanism via diradical... 

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. 

Scheme 9.37 The mechanism of the Myers-Saito cyclization [104a].

Earlier in this chapter different ways of cyclizing enyne-allenes were considered (Scheme 3.4). Depending on the sites of the newly formed carbon-carbon bond, they are classified as C -C (Schmittel) and C -C (Myers-Saito) cyclizations. Schmittel and coworkers [18] performed modern computational analysis of the cyclization mechanism and estimated various effects on the regioselectivity. 

The 4-aza-3-ene-l,6-diyne system 3.777 was synthesized and its DNA cleaving dependence on pH was demonstrated with respect to a cytosine target. A possible mechanism involves isomerization of the aza-enediyne to an aza-enyne-allene system. The Myers-Saito cyclization of the latter could lead to the generation of methylpyridinium diradical 3.779 (Scheme 3.94) [26, 362, 363]. The diradical cuts single-stranded cytosine DNA at 100 0.M concentration. Another possible mechanism involves alkylation by the intermediate 3.780 or the formation of carbene 3.782 via the ylide 3.781. 

Radical C -C Myers-Saito cyclization of enyne-allene, as well as the reaction of C -C cyclization do not depend on the donor properties of the solvent [427]. For enyne carbodiimides the situation is different, because the nitrogen atom is a potential donor center and is well known for the high electrophilicity of the central carbon atom of the car-bodiimide group. Indeed, the study of the thermolysis of carbodiimide 3.971a showed a strong dependence of the cyclization rate constant on the solvent properties. At 85°C, the reaction was seven times faster in dioxane k = 5.3 x 10 s ) and was nine times faster in acetonitrile K = 6.93 X 10 s ) than in benzene (k = 7.83 x 10 - s ). The rate constant of the thermal C -C cyclization of enyne-carbodiimides correlates better with the donor properties of the solvent rather than its dielectric constant, which is different from the reactions of enyne-allenes. Therefore, any discussion of the mechanism requires the consideration of alternative routes (Scheme 3.147) [424]. 

Even in 1989 the mechanism of reactions concerning enyne-allene and cumulene-enyne bond systems, known as the Myers-Saito cycloaromatization, had been thoroughly investigated [3,17,18,267,268]. Thermal cycloaromatization of the enyne-allene 3.535 (Myers-Saito C -C ) to give naphthalene 3.536 competes with the Schmittel C -C enyne-allene cyclization to give indene 3.537 [18] (Scheme 3.34). Since the discovery of these cyclizations, they have been intensively studied, in particular. 

Spontaneous cyclization of enediynes can occur as a click reaction via the formation of triazine ring. The cycloaromatization of a nonaryl enediyne occurs after its reaction with sodium azide. The azide 3.727 rearranges spontaneously to enyne-allene 3.728. The consecutive Myers-Saito cycloaromatization, involving diradical 3.729, leads to the heterocyclic product 3.730 (Scheme 3.83) [336]. Since the mechanism involves the formation of diradical 3.729 in ambient conditions, it can be used for the DNA cleavage. So, the enediyne 3.727 at 37°C for 4 hours cuts the single-stranded helix of a supercoiled DNA plasmid (pBR 322). 

---