Abstract
Enediynes, which can undergo Bergman cyclization and generate diradical intermediates, are potential antitumor drugs due to their ability to abstract hydrogen atoms from and cleave DNA resulting in cell death. Modification of the enediyne core by insertion of a carbonyl group produces an enediynone, which can be further modified by changing one of the two alkynes into an alkene to give a dieneynone. These compounds have a potentially richer reactivity profile than typical enediynes and can undergo cyclization along four different pathways, generating new diradical intermediates with simultaneous formation of a 5-, 6-, or 7-membered ring. Density functional theory (DFT) calculations with mPW1PW91 show that for the enediynones the C1-C7 cyclization pathway is most thermodynamically preferred. For the dieneynones, the C1-C6 pathway is most favorable thermodynamically and kinetically. Other DFT methods, BLYP and B3LYP, and BCCD(T) were applied to calculate the energetics of each pathway for the benzene-fused enediynone. The activation energies from the three DFT methods show a similar trend with BCCD(T), with those from mPW1PW91 closest to BCCD(T) (within ~2 kcal/mol). Both DFT and BCCD(T) give the same trends for ΔGrxn among the different pathways, except when aromaticity occurs in the product (as in the C1-C7 pathway for enediynones). For enediynones, cyclization pathway preference is affected by the degree of resonance stabilization in the product and the electron-withdrawing effect of the oxygen in the carbonyl group. Forming bond distances are limited in their ability to rationalize trends in activation energies. Both the benzannelation effect and NICS calculations can be used to explain differences in reaction energies, but are only applicable to the C1-C7 diradical which gains aromaticity from enediynone cyclization. The benzene-fused enediynone has been synthesized in a four-step process in 60% yield and verified by NMR, IR, and GC-MS. Enediynone reactivity was observed to be sensitive to trapping agent and reaction temperature. Cyclization occurs at 200 °C in CCl4 while alternative reactions are observed in methanol and 1,4-CHD. At 200 °C the enediynone followed the C2-C6 pathway and produced the related C2-C6 dichloro product, 2-chloro-4-(chloromethylene)naphthalen-1-one (M/Z 224) as the major product. The C1-C7 pathway was ruled out because of the mismatch between the experimental and computed 1H NMR spectra. Evidence of C1-C6 and C2-C7 cyclization products was also observed. The C1-C6 pathway cannot be precluded as both DFT and BCCD(T) calculations show that the reaction free energy of the C1-C6 product is lower than the C2-C6 product and the activation energy of the C1-C6 pathway is the lowest of all four reaction pathways.