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Mechanistic insights into a BINOL-derived phosphoric acid-catalyzed asymmetric Pictet-Spengler reaction.


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Type

Article

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Authors

Overvoorde, Lois M 
Grayson, Matthew N 
Luo, Yi 
Goodman, Jonathan M 

Abstract

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.

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Keywords

0202 Atomic, Molecular, Nuclear, Particle and Plasma Physics

Journal Title

J Org Chem

Conference Name

Journal ISSN

0022-3263
1520-6904

Volume Title

80

Publisher

American Chemical Society (ACS)
Sponsorship
We thank Girton College, Cambridge (research fellowship to M.N.G.), the EPSRC (studentship to M.N.G.), and Unilever for support.