Isothiourea-catalysed enantioselective pyrrolizine synthesis: Synthetic and computational studies

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

Research output: Contribution to journalArticle

11 Citations (Scopus)
42 Downloads (Pure)

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 languageEnglish
Pages (from-to)8957-8965
Number of pages9
JournalOrganic and Biomolecular Chemistry
Volume14
Issue number38
Early online date21 Jul 2016
DOIs
Publication statusPublished - 14 Oct 2016

ASJC Scopus subject areas

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Isothiourea-catalysed enantioselective pyrrolizine synthesis: Synthetic and computational studies'. Together they form a unique fingerprint.

  • Cite this

    Stark, D. G., Williamson, P., Gayner, E., Musolino, S. F., Kerr, R. W. F., Taylor, J. E., Slawin, A. M. Z., O'Riordan, T. J. C., Macgregor, S. A., & Smith, A. D. (2016). Isothiourea-catalysed enantioselective pyrrolizine synthesis: Synthetic and computational studies. Organic and Biomolecular Chemistry, 14(38), 8957-8965. https://doi.org/10.1039/c6ob01557c