Enediynes are organic compounds which can undergo Bergman cyclization and generate a diradical intermediate. These diradicals can abstract hydrogen atoms from the sugar backbone in DNA, disrupting the double helix and leading to cell death. Owing to this potential, enediynes can be used as effective antitumor drugs. A wider range of cyclization reactivity becomes possible by modifying the enediyne core by insertion of a carbonyl group, producing an enyne-ynone, which can be further modified by changing one of the two alkynes into an alkene to give a enyne-enone. These novel compounds can undergo cyclization along four different pathways, generating new diradical intermediates with simultaneous formation of a 5-, 6-, or 7-membered ring. Previous computational research studying reactivity of unsubstituted enyne-enones suggested that experimental study would yield a mixture of cyclization products, difficult to isolate from one another. By adding substituents to provide steric bulk at the alkene and alkyne termini, it is intended to disfavor cyclization pathways involving those positions to give more readily analyzable product mixtures.  In this research, density functional theory (DFT) calculations are used to determine the energetics of the four reaction pathways of phenyl and naphthyl monosubstituted and disubstituted enyne-enones to determine the reaction pathways that are preferred in each case.  Empirical dispersion corrections are included within DFT to account for dispersion interactions between substituents which occur upon cyclization. <br/>

Steric effects in the computational modeling of cyclization reactions of enyne-enones

253rd National Meeting (2017)

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