The term enediyne refers to organic compounds containing a carbon-carbon double bond lying between two carbon-carbon triple bonds. These compounds can undergo Bergman cyclization to form transient benzenoid diradicals that have the ability to abstract hydrogen atoms from the deoxyribose moiety on the backbone of DNA strands, causing DNA strand cleavage and inducing cell apoptosis. As a result, enediynes have been proposed as a core for anticancer drugs. To increase the range of cyclization pathways, we have modified the enediyne core by insertion of a carbonyl group, producing an enediynone. This new unsaturated system can undergo cyclization along four different pathways, generating new diradical intermediates with simultaneous formation of 5-, 6-, or 7-membered rings. Previous experimental study on the cyclization reactivity of unsubstituted enediynones yielded a complicated mixture of products. Therefore, the aim of this project is to make the product mixture more readily analyzable by adding substituents that provide steric bulk at the alkyne termini. This is intended to disfavor the two cyclization pathways involving these positions. Density functional theory (DFT) calculations are used to determine the energetics of the four reaction pathways of phenyl and naphthyl monosubstituted and disubstituted enediynones to determine the preferred reaction pathways in each case. To account for dispersion interactions between substituents which occur upon cyclization, empirical dispersion corrections are included within the DFT calculations. A correction based upon coupled-cluster calculations accounts for DFT errors in the interaction between the diradicals and any aromaticity that develops in the newly formed rings.<br/>

Steric effects in the computational modeling of enediynone cyclization reactions

253rd National Meeting (2017)

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