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Issue 18, 2008
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Stereoselective synthesis of 2,4,5-trisubstituted piperidines by carbonyl ene and Prins cyclisations

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Abstract

An approach to 2,4,5-trisubstituted piperidines is reported, in which the key step is the Prins or carbonyl ene cyclisation of aldehydes of the type 1. Prins cyclisation catalysed by concentrated hydrochloric acid in CH2Cl2 at −78 °C afforded good yields of two of the four possible diastereomeric piperidines, with the 4,5-cis product 7 predominating in a diastereomeric ratio of up to 94 : 6. The diastereoselectivity of the cyclisation decreased as the 2-substituent increased in size, becoming unselective for very bulky 2-substituents. In contrast, cyclisation catalysed by MeAlCl2 in CH2Cl2 or CHCl3 at temperatures of between 20–60 °C, favoured the 4,5-trans diastereomer 8, in a diastereomeric ratio of up to 99 : 1. The low-temperature cyclisations catalysed by HCl proceed under kinetic control via a mechanism involving the development of significant carbocationic character, in which the 4,5-cis cation is more stable than the 4,5-trans cation as a result of overlap with the neighbouring oxygen. The cyclisations catalysed by MeAlCl2 proceed under thermodynamic control, affording the product in which both the 4- and 5-substituents are equatorial.

Graphical abstract: Stereoselective synthesis of 2,4,5-trisubstituted piperidines by carbonyl ene and Prins cyclisations

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Publication details

The article was received on 21 May 2008, accepted on 13 Jun 2008 and first published on 28 Jul 2008


Article type: Paper
DOI: 10.1039/B808644C
Org. Biomol. Chem., 2008,6, 3337-3348

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    Stereoselective synthesis of 2,4,5-trisubstituted piperidines by carbonyl ene and Prins cyclisations

    C. A. M. Cariou, B. M. Kariuki and J. S. Snaith, Org. Biomol. Chem., 2008, 6, 3337
    DOI: 10.1039/B808644C

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