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 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.The addition of neocarzinostatin, the calichemicins, the esperamicins, dynemicin A, kedarcidin, C-1027 and maduropeptin to the arsenal of anticancer agents has inspired many chemists to participate in a world-wide search for chemotherapeutics that function by similar mechanisms as these natural products.1 Most of the latter compounds (the calichemicins, the esperamicins, dynemicin A, kedarcidin, C-1027) contain or form (maduropeptin) a highly strained 1,5-hexadiyn-3-ene substructure, which isomerizes at body temperature or below to a benzene-1,4-biradical by a Bergman cyclization.2 Neocarzinostatin is a highly strained dienediyne that can react to 7-octyne-1,2,3,5-tetraenes,3 which in turn cycloaromatize to styrene biradicals (" neocarzinostatin cyclization Ï). In 1989, Saito and Myers and their respective coworkers recognized that 6-heptyne-1,2,4-trienes (from now on " enyneallenes Ï, 3) can also cycloaromatize (" SaitoÈMyers cyclization Ï, Scheme 1).4 They thereby form short-lived toluene-a,meta biradicals 4, which abstract hydrogen atoms from easily oxidizable compounds (1,4-cyclohexadiene, thiols or DNA) to give toluenes 6. SaitoÈMyers cyclizations have since then been encountered in many en...

The Bis(enol triflate) Route to Dienediyne Models of the Biradical Forming and DNA-Cleaving Natural Product Neocarzinostatin Chromophore

“…41 Whether at the same time 1,4-cyclohexadiene was present or not had only a marginal effect upon the yields and product compositions. Each substrate afforded two types of products.…”

A McMurry Route to the Dienediyne Portion of Models of the Neocarzinostatin Chromophore

“…The solvent was removed in vacuo. Flash chromatography of the residue (petroleum ether/tert-butyl methyl ether, 4:1 Ǟ 1:2) afforded the title compound (3.11 g, 95% (18): At Ϫ78°C DMSO (10.3 ml, 11.3 g, 145 mmol, 2.2 equiv.) was slowly added to oxalyl chloride (6.95 ml, 9.22 g, 72.6 mmol, 1.1 equiv.)…”

“…With respect to the step requirement, however, our bistriflate strategy is superior; this is especially true in view of our findings of ref. [18] .…”

“…4 Ǟ 5; Scheme 2) [18] [19] or analogous 1,8-additions [18] [20] giving enyneallenyl ketones 5 which cycloaromatize by the Saito-Myers mode. [18] The present study aimed at synthesizing and cycloaromatizing (an)other type-4 dienediyne(s) by ring-closing McMurry reactions 8 Ǟ 11 and 9 Ǟ 12 (Scheme 3). This approach complements our strategically different McMurry route to bicyclic trienediynes [21] and follows conceptionally our synthesis of the tricyclic dienediyne 10 from ketoaldehyde 7.…”

“…[17] From these investigations, conjugated dienediyne ketones emerged as a reliable source of biradicals: They are easily engaged in 1,6-additions of a thiol (e.g. 4 Ǟ 5; Scheme 2) [18] [19] or analogous 1,8-additions [18] [20] giving enyneallenyl ketones 5 which cycloaromatize by the Saito-Myers mode. [18] The present study aimed at synthesizing and cycloaromatizing (an)other type-4 dienediyne(s) by ring-closing McMurry reactions 8 Ǟ 11 and 9 Ǟ 12 (Scheme 3).…”