Abstract
This protocol describes a method for the laboratory synthesis of enantiomerically enriched, chiral tetrahydroisoquinolines through the application of a chiral sulfinamido urea catalyst for the Povarov reaction. Tetrahydroisoquinolines are bicyclic organic frameworks present in a wide assortment of natural and synthetic biologically important compounds including martinelline, scoulerine and tubocurarine. The methodology involves the [4+2] cycloaddition of a N-arylimines with electron-rich olefins such as vinyl lactams and dihydropyrroles in the presence of a two-catalyst system consisting of an achiral strong Brønsted acid (o-nitrobenzenesulfonic acid), together with the chiral sulfinamido urea derivative 1. The anion-binding properties of the urea lead to the association of the ion pair that results from protonation of the imine substrate. Cycloaddition is followed by spontaneous proton loss with re-aromatization to provide the tetrahydroisoquinoline products in highly enantio-enriched form.
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Acknowledgements
This work was carried out with support from the US National Institutes of Health (grants no. GM-43214 and P50 GM-69721), and by fellowship support from the Dreyfus Foundation (to H.X.).
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H.X. designed and performed the experiments, and co-wrote the paper. H.Z. performed the synthesis of catalyst 1. E.N.J. designed and supervised the experiments, analyzed data and co-wrote the paper.
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Xu, H., Zhang, H. & Jacobsen, E. Chiral sulfinamidourea and strong Brønsted acid–cocatalyzed enantioselective Povarov reaction to access tetrahydroquinolines. Nat Protoc 9, 1860–1866 (2014). https://doi.org/10.1038/nprot.2014.125
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DOI: https://doi.org/10.1038/nprot.2014.125
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