Straightforward syntheses of biradical-producing bicyclic dienediynes—dienediyne ketones cycloaromatize ia the Saito–Myers and not ia the neocarzinostatin pathway

Ferri, Fabiola; Brückner, Reinhard; Herges, Rainer ORCID

The dienediyne models 23 and 28 of the pharmacophore of the antitumor natural product neocarzinostatin were prepared. Each synthesis requires only six steps from a-formylcyclohexanone. Our approach uses two key steps. The Ðrst consists of one-pot biscoupling reactions between propargyl alcohol, 2,2-dimethyl-3-butyn-1-ol and the bis(enoltriÑuoromethanesulfonate) 17. The second key step corresponds to ring-closing pinacol coupling reactions of the dialdehydes 20 and 25. The dienediyne models 23 and 28 cycloaromatized efficiently when treated with methyl thioglycolate and 1,4-cyclohexadiene at 25 ¡C via a SaitoÈMyers cyclization4 (to give the octahydroanthracenones 29, iso-29 and octahydrophenanthrenones 34, 35, respectively); in addition, we isolated compounds tentatively assigned as the octahydrobenzazulenones 30 and iso-30, which would stem from a competing Schmittel cyclization. According to density functional theory (B3LYP/6-31G*) and ab initio calculations [CASMP2(2.2)/6-31G//CAS(2.2)/6-31G], the core structures of the octahydroanthracenones and octahydrophenanthrenones obtained here and elsewhere form via the SaitoÈMyers cyclization of enyneallenyl ketones 53 to toluene-a,meta biradicals 55 and not via neocarzinostatin-like cycloaromatizations of the tautomeric enyne[3]cumulenols 54 to styrene a,meta-biradicals 56. This is so because, on the one hand, the two cyclization modes are predicted to have similar activation barriers (SaitoÈMyers: 16.0 kcal mol~1; neocarzinostatin type: 18.3 kcal mol~1) but, on the other hand, the enyneallenyl ketone 53 is a much more stable (21.1 kcal mol~1) cycloaromatization substrate than the enynecumulenol 54. In addition, the SaitoÈMyers cyclization product 55 is calculated to be considerably more stable (35.3 kcal mol~1) than the neocarzinostatin-type cycloaromatization product 56.

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Ferri, Fabiola / Brückner, Reinhard / Herges, Rainer: Straightforward syntheses of biradical-producing bicyclic dienediynes—dienediyne ketones cycloaromatize ia the Saito–Myers and not ia the neocarzinostatin pathway. 1998.

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