Isothiourea-catalysed enantioselective pyrrolizine synthesis : synthetic and computational studies
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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.
Stark , D G , Williamson , P , Gayner , E R , 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 & Biomolecular Chemistry , vol 14 , no. 38 , pp. 8957-8965 . DOI: 10.1039/C6OB01557C
Organic & Biomolecular Chemistry
Copyright 2016 the Authors. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
DescriptionWe 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.
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