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Hetero-Diels–Alder reactions of quinone methides: the origin of the α-regioselectivity of 3-methylene-1,2,4-naphthotriones

Delarmelina, Maicon, Ferreira, Sabrina B., da Silva, Fernando de C., Ferreira, Vitor F. and Carneiro, José Walkimar de M. 2020. Hetero-Diels–Alder reactions of quinone methides: the origin of the α-regioselectivity of 3-methylene-1,2,4-naphthotriones. Journal of Organic Chemistry 85 (11) , pp. 7001-7013. 10.1021/acs.joc.0c00215

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The regioselective formation of α- and β-lapachone via hetero-Diels–Alder reactions was investigated by experimental and computational approaches. The experimentally observed α-selectivity was explored in detail, revealing that the lower energy barrier for the formation of α-lapachone is a result of lower Pauli repulsion throughout the reaction path, when compared to the β-isomer. By comparing equivalent points on both α- and β-lapachone potential energy surfaces (PES), according to the activation strain model (ASM) and energy decomposition analysis (EDA), we were able to demonstrate that the Pauli repulsion term increases more significantly when going from reactants to TSβ than to TSα, resulting in lower interaction energy in the early stages of the reaction path and in a later transition state for β-lapachone. Moreover, we confirmed that regio- and diastereoselectivity trends previously reported for other quinone methide intermediates are also observed for 3-methylene-1,2,4-naphthotriones, such as small endo/exo diastereoselectivity, as well as pronounced ortho/meta regioselectivity for reactions performed with dienophile containing electron-releasing groups. The results presented here provide a deeper understanding of the reactivity of quinone methide derivatives, aiding the future rational design of the reaction condition, structural modification of possible quinone methide intermediates, and the development of more selective synthetic routes for quinone derivatives.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Publisher: American Chemical Society
ISSN: 0022-3263
Last Modified: 05 Aug 2020 11:31

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