Mechanistic insights into a BINOL-derived phosphoric acid-catalyzed asymmetric Pictet-Spengler reaction
Overvoorde, Lois M
The Journal of Organic Chemistry
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Overvoorde, L. M., Grayson, M., Luo, Y., & Goodman, J. M. (2015). Mechanistic insights into a BINOL-derived phosphoric acid-catalyzed asymmetric Pictet-Spengler reaction. The Journal of Organic Chemistry, 80 2634-2640. https://doi.org/10.1021/jo5028134
The reaction of tryptamine and (2-oxocyclohexyl)acetic acid can be catalyzed by 3,3′-bis(triphenylsilyl)-1,1′-bi-2-naphthol phosphoric acid to give an asymmetric β-carboline. This reaction was first studied by Holloway et al. (Org. Lett. 2010, 12, 4720−4723), but their mechanistic work did not explain the high stereoselectivity achieved. This study uses density functional theory and hybrid quantum mechanics/molecular mechanics calculations to investigate this reaction and provide a model to explain its outcome. The step leading to diastereo- and enantioselectivity is an asymmetric Pictet–Spengler reaction involving an N-acyliminium ion bound to the catalyst in a bidentate fashion. This interaction occurs via hydrogen bonds between the two terminal oxygen atoms of the catalyst phosphate group and the hydrogen atoms at N and C2 of the substrate indole group. These bonds hold the transition structure rigidly and thus allow the catalyst triphenylsilyl groups to influence the enantioselectivity.
We thank Girton College, Cambridge (research fellowship to M.N.G.), the EPSRC (studentship to M.N.G.), and Unilever for support.
External DOI: https://doi.org/10.1021/jo5028134
This record's URL: http://www.repository.cam.ac.uk/handle/1810/247550
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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