Isothiourea-catalysed enantioselective pyrrolizine synthesis: synthetic and computational studies

Daniel Graham Stark; Patrick Williamson; Emma R Gayner; Stefania Francesca Musolino; Ryan William Frederick Kerr; James Edward Taylor; Alexandra Martha Zoya Slawin; Timothy J C O'Riordan; Stuart A Macgregor; Andrew David Smith

doi:10.1039/C6OB01557C

Isothiourea-catalysed enantioselective pyrrolizine synthesis: synthetic and computational studies

Daniel Graham Stark, Patrick Williamson, Emma R Gayner, Stefania Francesca Musolino, Ryan William Frederick Kerr, James Edward Taylor, Alexandra Martha Zoya Slawin, Timothy J C O'Riordan, Stuart A Macgregor, Andrew David Smith

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

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 & 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

Access to Document

10.1039/C6OB01557CLicence: CC BY

ADS-OrgBioChem-c6ob01557c_CCBY
Copyright 2016 the Authors. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
Final published version, 3.29 MBLicence: CC BY

Cite this

@article{df25d7fa38664593a3f85538ca04a20e,

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 Graham} and Patrick Williamson and Gayner, {Emma R} and Musolino, {Stefania Francesca} and Kerr, {Ryan William Frederick} and Taylor, {James Edward} and Slawin, {Alexandra Martha Zoya} and O'Riordan, {Timothy J C} and Macgregor, {Stuart A} and Smith, {Andrew David}",

note = "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{\textquoteright}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. ",

year = "2016",

month = oct,

day = "14",

doi = "10.1039/C6OB01557C",

language = "English",

volume = "14",

pages = "8957--8965",

journal = "Organic & Biomolecular Chemistry",

issn = "1477-0520",

publisher = "Royal Society of Chemistry",

number = "38",

}

TY - JOUR

T1 - Isothiourea-catalysed enantioselective pyrrolizine synthesis

T2 - synthetic and computational studies

AU - Stark, Daniel Graham

AU - Williamson, Patrick

AU - Gayner, Emma R

AU - Musolino, Stefania Francesca

AU - Kerr, Ryan William Frederick

AU - Taylor, James Edward

AU - Slawin, Alexandra Martha Zoya

AU - O'Riordan, Timothy J C

AU - Macgregor, Stuart A

AU - Smith, Andrew David

N1 - 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.

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.rsc.org/suppdata/c6/ob/c6ob01557c/c6ob01557c1.zip

UR - http://www.rsc.org/suppdata/c6/ob/c6ob01557c/c6ob01557c2.pdf

U2 - 10.1039/C6OB01557C

DO - 10.1039/C6OB01557C

M3 - Article

SN - 1477-0520

VL - 14

SP - 8957

EP - 8965

JO - Organic & Biomolecular Chemistry

JF - Organic & Biomolecular Chemistry

IS - 38

ER -

Isothiourea-catalysed enantioselective pyrrolizine synthesis: synthetic and computational studies

Abstract

Access to Document

Other files and links

Fingerprint

RS Wolfson Merit Award: Developing Catalysis Research: New Reaction Discoveries and Practical Applications

CRITICAT CDT: Critical Resource Catalysis - CRITICAT

Data underpinning - Catalytic Enantioselective Synthesis of Pyrrolizine Carboxylates using Isothiourea Catalysis: A Synthetic and Computational Study

Cite this

Isothiourea-catalysed enantioselective pyrrolizine synthesis: synthetic and computational studies

Abstract

Access to Document

Other files and links

Fingerprint

Projects

RS Wolfson Merit Award: Developing Catalysis Research: New Reaction Discoveries and Practical Applications

CRITICAT CDT: Critical Resource Catalysis - CRITICAT

Datasets

Data underpinning - Catalytic Enantioselective Synthesis of Pyrrolizine Carboxylates using Isothiourea Catalysis: A Synthetic and Computational Study

Cite this