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Site-, enantio- and stereo-selectivities of the 1,3-dipolar cycloaddition reactions of oxanorbornadiene with C,N-disubstituted nitrones and dimethyl nitrilimines: a DFT mechanistic study

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Abstract

1,3-Dipolar cycloaddition of nitrones to oxanorbornadienes is an important method for the enantioselective synthesis of highly substituted 5-membered heterocycles such as furans and isoxazolidines, which have high utility in the chemical and pharmaceutical industries. The mechanism of the reaction and the effects of substituents on the (3 + 2) cycloaddition reactions (32CA) of C,N-dialkyl nitrones with a series of substituted oxanorbornadienes have been studied with focus on the site-selectivity (attack on the more substituted double bond of the oxanorbornadiene derivatives versus attack on the less substituted double bond), enantioselectivity and stereo-selectivity using density functional theory calculations at the M06/6-311++G(d,p) of theory. The results showed that the addition step to form the bicyclic isoxazolidines cycloadducts has generally low barriers compared to the cycloreversion step which converts the cycloadducts into furans and monocyclic isoxazolidines. Generally, electron-withdrawing substituents favour the nitrone attack on the highly substituted double bond, while electron-donating substituents favour the attack on less substituted double bond. The R enantiomers are generally favoured over the S enantiomers, and exo stereo-isomers are generally favoured over the endo stereo-isomers, irrespective of substituents.

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Acknowledgements

The authors are very grateful to the National Council for Tertiary Education, Republic of Ghana, for a research Grant under the Teaching and Learning Innovation Fund (TALIF/KNUST/3/0008/2005), and to South Africa’s Centre for High Performance Computing for access to additional computing resource on the Lengau cluster.

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  1. Theoretical and Computational Chemistry Laboratory, Department of Chemistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

    Ernest Opoku, Grace Arhin, George Baffour Pipim, Anita Houston Adams, Richard Tia & Evans Adei

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Opoku, E., Arhin, G., Pipim, G.B. et al. Site-, enantio- and stereo-selectivities of the 1,3-dipolar cycloaddition reactions of oxanorbornadiene with C,N-disubstituted nitrones and dimethyl nitrilimines: a DFT mechanistic study. Theor Chem Acc 139, 16 (2020). https://doi.org/10.1007/s00214-019-2529-8

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