Isothiourea-catalysed enantioselective pyrrolizine synthesis: Synthetic and computational studies

Daniel G. Stark; Patrick Williamson; Emma R. Gayner; Stefania F. Musolino; Ryan W.F. Kerr; James E. Taylor; Alexandra M.Z. Slawin; Timothy J.C. O'Riordan; Stuart A. Macgregor; Andrew D. Smith

doi:10.1039/c6ob01557c

Isothiourea-catalysed enantioselective pyrrolizine synthesis: Synthetic and computational studies

Daniel G. Stark, Patrick Williamson, Emma R. Gayner, Stefania F. Musolino, Ryan W.F. Kerr, James E. Taylor, Alexandra M.Z. Slawin, Timothy J.C. O'Riordan, Stuart A. Macgregor, Andrew D. Smith

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

23 Citations (SciVal)

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.

Original language	English
Pages (from-to)	8957-8965
Number of pages	9
Journal	Organic and Biomolecular Chemistry
Volume	14
Issue number	38
Early online date	21 Jul 2016
DOIs	https://doi.org/10.1039/c6ob01557c
Publication status	Published - 14 Oct 2016

Funding

We thank Syngenta and the EPSRC (grant code EP/K503162/1) (DGS), and the EPSRC Centre for Doctoral Training in Critical Resource Catalysis (CRITICAT, grant code EP/L016419/1) (ERG, SFM, RWFK) for funding. The European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) ERC Grant Agreement No. 279850 is also acknowledged (JET). ADS thanks the Royal Society for a Wolfson Research Merit Award. We also thank the EPSRC UK National Mass Spectrometry Facility at Swansea University.

ASJC Scopus subject areas

Biochemistry
Physical and Theoretical Chemistry
Organic Chemistry

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title = "Isothiourea-catalysed enantioselective pyrrolizine synthesis: Synthetic and computational studies",

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.",

author = "Stark, {Daniel G.} and Patrick Williamson and Gayner, {Emma R.} and Musolino, {Stefania F.} and Kerr, {Ryan W.F.} and Taylor, {James E.} and Slawin, {Alexandra M.Z.} and O'Riordan, {Timothy J.C.} and Macgregor, {Stuart A.} and Smith, {Andrew D.}",

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AU - Taylor, James E.

AU - Slawin, Alexandra M.Z.

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AU - Macgregor, Stuart A.

AU - Smith, Andrew D.

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Isothiourea-catalysed enantioselective pyrrolizine synthesis: Synthetic and computational studies

Abstract

Funding

ASJC Scopus subject areas

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