TY - JOUR
T1 - Isothiourea-catalysed enantioselective pyrrolizine synthesis
T2 - Synthetic and computational studies
AU - Stark, Daniel G.
AU - Williamson, Patrick
AU - Gayner, Emma
AU - Musolino, Stefania F.
AU - Kerr, Ryan W. F.
AU - Taylor, James E.
AU - Slawin, Alexandra M. Z.
AU - O'Riordan, Timothy J. C.
AU - Macgregor, Stuart Alan
AU - Smith, Andrew D.
PY - 2016/10/14
Y1 - 2016/10/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84989257470&partnerID=8YFLogxK
U2 - 10.1039/c6ob01557c
DO - 10.1039/c6ob01557c
M3 - Article
C2 - 27489030
AN - SCOPUS:84989257470
SN - 1477-0520
VL - 14
SP - 8957
EP - 8965
JO - Organic and Biomolecular Chemistry
JF - Organic and Biomolecular Chemistry
IS - 38
ER -