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

Abstract

The dienediyne models 23 and 28 of the pharmacophore of the antitumor natural product neocarzinostatin were prepared. Each synthesis requires only six steps from α-formylcyclohexanone. Our approach uses two key steps. The first consists of one-pot biscoupling reactions between propargyl alcohol, 2,2-dimethyl-3-butyn-1-ol and the bis(enoltrifluoromethanesulfonate) 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 Saito–Myers cyclizatio (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 abinitio 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 Saito–Myers cyclization of enyneallenyl ketones 53 to toluene-α,meta biradicals 55 and not via neocarzinostatin-like cycloaromatizations of the tautomeric enyne[3]cumulenols 54 to styrene α,meta-biradicals 56. This is so because, on the one hand, the two cyclization modes are predicted to have similar activation barriers (Saito–Myers: 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 Saito–Myers cyclization product 55 is calculated to be considerably more stable (35.3 kcal mol^-1) than the neocarzinostatin-type cycloaromatization product 56.