Enediynes are a class of organic compounds, which, under the right conditions, can cyclize to form diradicals. These diradicals can cleave DNA, by extracting hydrogen atoms from the sugar backbone, which ultimately destroys the encompassing cell. It is this characteristic which makes enediynes valuable in the search for possible anti-tumor drugs. Previous research showed that angular benzannelation of an unsubstituted enediyne led to improved cyclization reactivity versus the linearly benzannelated analog. This was attributed to the formation of a new aromatic ring in the angularly benzannelated case. In this research, we first examine the effect of the supporting group on the cyclization of the angular enediynes; naphthyl and quinoxaline supporting groups are considered. These two particular supporting groups are selected to test if the nitrogen heteroatom (and its lone pair of electrons) within quinoxaline affects the reaction energies as compared to the naphthyl case (which contains neither the nitrogen nor the lone pair of electrons). Second, we examine the effect of including phenyl and methoxy-phenyl substituents to determine if steric and/or electronic effects can change the favorability of C1-C6 Bergman cyclization (giving a 6-membered ring) versus C1-C5 cyclization (giving a 5-membered ring). Using density functional theory (DFT), activation and reaction energies for the angularly benzannelated enediynes are calculated for both cyclization pathways; this is conducted with both naphthyl and quinoxaline supporting groups in the cases with and without the phenyl and methoxy-phenyl substituents. Partial atomic charges are examined to reveal any interactions between the diradical and nitrogen lone pair, while nucleus-independent chemical shift (NICS) calculations are used to verify the aromaticity gained upon Bergman cyclization.

Using electronics and sterics to affect the cyclization of angularly benzannelated enediynes

253rd National Meeting (2017)

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