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Issue 38, 2016
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Isothiourea-catalysed enantioselective pyrrolizine synthesis: synthetic and computational studies

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Abstract

The catalytic enantioselective synthesis of a range of cis-pyrrolizine carboxylate derivatives with outstanding stereocontrol (14 examples, >95 : 5 dr, >98 : 2 er) through an isothiourea-catalyzed intramolecular Michael addition-lactonisation and ring-opening approach from the corresponding enone acid is reported. An optimised and straightforward three-step synthetic route to the enone acid starting materials from readily available pyrrole-2-carboxaldehydes is delineated, with benzotetramisole (5 mol%) proving the optimal catalyst for the enantioselective process. Ring-opening of the pyrrolizine dihydropyranone products with either MeOH or a range of amines leads to the desired products in excellent yield and enantioselectivity. Computation has been used to probe the factors leading to high stereocontrol, with the formation of the observed cis-steroisomer predicted to be kinetically and thermodynamically favoured.

Graphical abstract: Isothiourea-catalysed enantioselective pyrrolizine synthesis: synthetic and computational studies

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Publication details

The article was received on 06 Jul 2016, accepted on 21 Jul 2016 and first published on 21 Jul 2016


Article type: Paper
DOI: 10.1039/C6OB01557C
Citation: Org. Biomol. Chem., 2016,14, 8957-8965
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    Isothiourea-catalysed enantioselective pyrrolizine synthesis: synthetic and computational studies

    D. G. Stark, P. Williamson, E. R. Gayner, S. F. Musolino, R. W. F. Kerr, J. E. Taylor, A. M. Z. Slawin, T. J. C. O'Riordan, S. A. Macgregor and A. D. Smith, Org. Biomol. Chem., 2016, 14, 8957
    DOI: 10.1039/C6OB01557C

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