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Unveiling the impact of the light source and steric factors on [2 + 2] heterocycloaddition reactions

Abstract

Information gained from in-depth mechanistic investigations can be used to control the selectivity of reactions, leading to expansion of the generality of synthetic processes and discovery of new reactivity. Here, we investigate the mechanism of light-driven [2 + 2] heterocycloadditions (Paternò–Büchi reactions) between indoles and ketones to develop insight into these processes. Using ground-state ultraviolet–visible absorption and transient absorption spectroscopy, together with density functional theory calculations, we found that the reactions can proceed via an exciplex or electron–donor–acceptor complex, which are key intermediates in determining the stereoselectivity of the reactions. We used this discovery to control the diastereoselectivity of the reactions, gaining access to previously inaccessible diastereoisomeric variants. When moving from 370 to 456 nm irradiation, the electron–donor–acceptor complex is increasingly favoured, and the diastereomeric ratio (d.r.) of the product moves from >99:<1 to 47:53. In contrast, switching from methyl to ipropyl substitution favours the exciplex intermediate, reversing the d.r. from 89:11 to 16:84. Our study shows how light and steric parameters can be rationally used to control the diastereoselectivity of photoreactions, creating mechanistic pathways to previously inaccessible stereochemical variants.

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Fig. 1: The [2 + 2] heterocycloaddition process.
Fig. 2: Spectroscopic studies of the PB reaction and identification of three different possible pathways.
Fig. 3: Computational insights into the exciplex and EDA complex manifolds.
Fig. 4: Diastereodivergent pathways with benzil.
Fig. 5: Diastereodivergent pathways with α-ketoesters.
Fig. 6: Using steric parameters to gain control over diastereoselection.
Fig. 7: Generality of the developed light-driven process and in-flow implementation.

Data availability

All relevant data supporting the findings of this study, including experimental procedures and compound characterization, NMR spectra and other spectroscopic analysis are available within the article and its Supplementary Information.

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Acknowledgements

We acknowledge P. Franceschi, P. Andreetta and G. Simionato (Department of Chemical Sciences, University of Padova) for preliminary experiments, and S. Bonacchi (Department of Chemical Sciences, University of Padova) for insightful discussions. This project was supported by Ministero dell’Università (MUR) (grant No. PRIN 2020927WY3_002 to L.D.), the European Union, European Research Concilium (ERC) (starting grant No. SYNPHOCAT 101040025 to L.D.), Cariparo, project Synergy within the call Ricerca Scientifica d’Eccellenza 2018 (to L.D.), University of Padova (to P.C.), Seal of Excellence@UNIPD (to P.C.) and QuantaCOF (to P.C.).

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J.M. and L.D. wrote the manuscript with contributions from all the authors. J.M. and L.D. conceived the project and devised the experiments. J.M. and A.V.-P. carried out the reactions and isolated and characterized the products. J.M., L.D., M.B. and A.S. rationalized the experimental results. F.R., M.N., E.C. and E.F. performed the spectroscopic investigations using TAS. P.C. and A.S. performed the DFT calculations.

Corresponding author

Correspondence to Luca Dell’Amico.

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Nature Synthesis thanks Axel Griesbeck, Norbert Hoffmann and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Peter Seavill, in collaboration with the Nature Synthesis team.

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Experimental details and DFT calculations, Supplementary sections A–M, and Supplementary Figs. S.A.1–S.K.17.

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Mateos, J., Rigodanza, F., Costa, P. et al. Unveiling the impact of the light source and steric factors on [2 + 2] heterocycloaddition reactions. Nat. Synth 2, 26–36 (2023). https://doi.org/10.1038/s44160-022-00191-5

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