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Noncovalent interactions as a solution for the metal-free one-pot asymmetric synthesis of (S)-2-aryl-2,3-dihydro-4(1H)-quinolones

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Abstract

4-Quinolones compose a remarkable class of compounds that show various pharmacological applications. In particular, the activities of both (S) and (R) enantiomers of 2-aryl-2,3-dihydro-4(1H)-quinolones have made them an object of befitting interest for asymmetric synthesis. Although readily yielded as a racemic mixture from an one-pot reaction between 2-aminoacetophenone and benzaldehyde, a pathway for the metal-free enantioselective one-pot synthesis of the (S) isomer is not completely clear. In the present work, guided by the burgeoning role of organocatalysis in asymmetric synthesis and recent experimental insight into the most likely reaction mechanism, we report the in silico screening for a roster of MacMillan chiral imidazolidinones through quantum mechanics calculations. Two stereopredictive models yielding similarly high expected ee (up to 97%) were proposed. The role of aromatic interactions for the control of enantioselectivity was systemically studied, as well as the Pro-S si-enantiofacial attack activation energies, which were found to correlate well (R2 = 0.75) with the reported Bürgi-Dunitz angle for the expected intramolecular Mannich reaction mechanism.

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Acknowledgements

The authors are thankful to the datacenter OSCAR of Universidade Federal Fluminense (UFF), where the theoretical calculations were performed. The authors are grateful to CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), and FAPERJ (Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, E-26/211.517/2021) for funding this research project. We are grateful to former and current coworkers, friends, and acquaintances for their intellectual contributions to the research in our laboratory.

Funding

FAPERJ (Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro), E-26/211.517/2021.

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Author notes

  1. Sérgio Pinheiro and Rodolfo Goetze Fiorot contributed equally to this work.

Authors and Affiliations

  1. Department of Organic Chemistry, Universidade Federal Fluminense, Outeiro de São João Batista, NiteróiRio de Janeiro, 24020-121, Brazil

    Patrick de Lima Lopes Rocha, Fernando Martins dos Santos Jr., Sérgio Pinheiro & Rodolfo Goetze Fiorot

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  1. Patrick de Lima Lopes Rocha
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PLLR drafted the manuscript, carried out the calculations and data analysis. FMS participated in the research coordination and review of the manuscript. SP conceived of the study and took part in the drafting and review of the manuscript, as well as in the preparation of artwork. RGF coordinated this research, took part in the drafting and review of the manuscript, as well as in the preparation of artwork. The authors read and approved the final manuscript.

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Correspondence to Patrick de Lima Lopes Rocha, Sérgio Pinheiro or Rodolfo Goetze Fiorot.

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de Lima Lopes Rocha, P., dos Santos, F. ., Pinheiro, S. et al. Noncovalent interactions as a solution for the metal-free one-pot asymmetric synthesis of (S)-2-aryl-2,3-dihydro-4(1H)-quinolones. J Mol Model 28, 369 (2022). https://doi.org/10.1007/s00894-022-05361-y

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