Synthesis of 6‐/10‐Membered Ring Analogs of the Dienediyne Core of the Neocarzinostatin Chromophore by Palladium(0)‐Mediated Ring‐Closure Reactions

A strategy for the synthesis of the benzo‐annulated bicyclic dienediyne analogs 46 and 48 of the DNA‐cleaving natural product neocarzinostatin chromophore was developed. 2‐Formylcyclohexanone (9) was converted stereoselectively first into the mono(enol triflate) Z‐11 and thereafter into the bis(enol triflate) Z‐2. The isomeric triflates E‐11 and E‐2 were prepared to facilitate correct E,Z assignments. The C≡C bonds of the target dienediynes 46 and 48 were introduced with the aid of the unsymmetrical bisalkynes 17 and 16, respectively. However, the latters furnished the formers not by reactions with the monotriflate Z‐11 (Schemes 4, 7, 10) but only by reactions with the bistriflate Z‐2. The success of this approach is due to a regioselective Csp2/Csp monocoupling which unites the reaction partners and to another Pd‐catalyzed Csp2/Csp coupling which furnished the 6‐/10‐membered ring dienediyne 46 (Scheme 13) and its isomer 48 (Scheme 14). Starting from ortho‐bromobenzaldehyde and cyclohexanone these syntheses required a total of 9 and 10 steps, respectively, the longest linear sequence comprising 6 steps.