Isothiourea-catalyzed enantioselective α-alkylation of esters via 1,6-conjugate addition to para-quinone methides

Jude N. Arokianathar; Will Hartley; Calum McLaughlin; Mark David Greenhalgh; Darren Stead; Sean Ng; Alexandra Martha Zoya Slawin; Andrew David Smith

doi:10.3390/molecules26216333

Isothiourea-catalyzed enantioselective α-alkylation of esters via 1,6-conjugate addition to para-quinone methides

Jude N. Arokianathar
, Will Hartley
, Calum McLaughlin
, Mark David Greenhalgh
, Darren Stead
, Sean Ng
, Alexandra Martha Zoya Slawin
, Andrew David Smith

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

Abstract

The isothiourea-catalyzed enantioselective 1,6-conjugate addition of para-nitrophenyl esters to 2,6-disubstituted para-quinone methides is reported. para-Nitrophenoxide, generated in situ from initial N-acylation of the isothiourea by the para-nitrophenyl ester, is proposed to facilitate catalyst turnover in this transformation. A range of para-nitrophenyl ester products can be isolated, or derivatized in situ by addition of benzylamine to give amides, in up to 99% yield. Although low diastereocontrol is observed, the diastereoisomeric ester products are separable and formed with high enantiocontrol (up to 94:6 er).

Original language	English
Article number	6333
Number of pages	13
Journal	Molecules
Volume	26
Issue number	21
DOIs	https://doi.org/10.3390/molecules26216333
Publication status	Published - 20 Oct 2021

Keywords

Isothiourea
Ammonium enolate
Ayloxide
Quinone methide
Ester functionalization
1,6-conjugate addition

Access to Document

10.3390/molecules26216333Licence: CC BY

Arokianathar-2021-Isothiourea-catalyzed-Molecules-26-06333-CCBY
Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/4.0/).
Final published version, 2.86 MBLicence: CC BY

Handle.net

Persistent link to portal record

Cite this

@article{f0fc53835d4948cfa0c131b374eb292c,

title = "Isothiourea-catalyzed enantioselective α-alkylation of esters via 1,6-conjugate addition to para-quinone methides",

abstract = "The isothiourea-catalyzed enantioselective 1,6-conjugate addition of para-nitrophenyl esters to 2,6-disubstituted para-quinone methides is reported. para-Nitrophenoxide, generated in situ from initial N-acylation of the isothiourea by the para-nitrophenyl ester, is proposed to facilitate catalyst turnover in this transformation. A range of para-nitrophenyl ester products can be isolated, or derivatized in situ by addition of benzylamine to give amides, in up to 99\% yield. Although low diastereocontrol is observed, the diastereoisomeric ester products are separable and formed with high enantiocontrol (up to 94:6 er).",

keywords = "Isothiourea, Ammonium enolate, Ayloxide, Quinone methide, Ester functionalization, 1,6-conjugate addition",

author = "Arokianathar, \{Jude N.\} and Will Hartley and Calum McLaughlin and Greenhalgh, \{Mark David\} and Darren Stead and Sean Ng and Slawin, \{Alexandra Martha Zoya\} and Smith, \{Andrew David\}",

note = "Funding: We thank the ERC under the European Union's Seventh Framework Programme (FP7/2007-2013)/E.R.C. grant agreement n° 279850, AstraZeneca and EPSRC [EP/M506631/1 (J.N.A.)], Syngenta and the EPSRC Centre for Doctoral Training in Critical Resource Catalysis [CRITICAT, EP/L016419/1 (W.C.H.)], and EPSRC [EP/M508214/1 (C.M.)] for funding. A.D.S. thanks the Royal Society for a Wolfson Research Merit Award. We thank the EPSRC UK National Mass Spectrometry Facility at Swansea University. ",

year = "2021",

month = oct,

day = "20",

doi = "10.3390/molecules26216333",

language = "English",

volume = "26",

journal = "Molecules",

issn = "1420-3049",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "21",

}

TY - JOUR

T1 - Isothiourea-catalyzed enantioselective α-alkylation of esters via 1,6-conjugate addition to para-quinone methides

AU - Arokianathar, Jude N.

AU - Hartley, Will

AU - McLaughlin, Calum

AU - Greenhalgh, Mark David

AU - Stead, Darren

AU - Ng, Sean

AU - Slawin, Alexandra Martha Zoya

AU - Smith, Andrew David

N1 - Funding: We thank the ERC under the European Union's Seventh Framework Programme (FP7/2007-2013)/E.R.C. grant agreement n° 279850, AstraZeneca and EPSRC [EP/M506631/1 (J.N.A.)], Syngenta and the EPSRC Centre for Doctoral Training in Critical Resource Catalysis [CRITICAT, EP/L016419/1 (W.C.H.)], and EPSRC [EP/M508214/1 (C.M.)] for funding. A.D.S. thanks the Royal Society for a Wolfson Research Merit Award. We thank the EPSRC UK National Mass Spectrometry Facility at Swansea University.

PY - 2021/10/20

Y1 - 2021/10/20

N2 - The isothiourea-catalyzed enantioselective 1,6-conjugate addition of para-nitrophenyl esters to 2,6-disubstituted para-quinone methides is reported. para-Nitrophenoxide, generated in situ from initial N-acylation of the isothiourea by the para-nitrophenyl ester, is proposed to facilitate catalyst turnover in this transformation. A range of para-nitrophenyl ester products can be isolated, or derivatized in situ by addition of benzylamine to give amides, in up to 99% yield. Although low diastereocontrol is observed, the diastereoisomeric ester products are separable and formed with high enantiocontrol (up to 94:6 er).

AB - The isothiourea-catalyzed enantioselective 1,6-conjugate addition of para-nitrophenyl esters to 2,6-disubstituted para-quinone methides is reported. para-Nitrophenoxide, generated in situ from initial N-acylation of the isothiourea by the para-nitrophenyl ester, is proposed to facilitate catalyst turnover in this transformation. A range of para-nitrophenyl ester products can be isolated, or derivatized in situ by addition of benzylamine to give amides, in up to 99% yield. Although low diastereocontrol is observed, the diastereoisomeric ester products are separable and formed with high enantiocontrol (up to 94:6 er).

KW - Isothiourea

KW - Ammonium enolate

KW - Ayloxide

KW - Quinone methide

KW - Ester functionalization

KW - 1,6-conjugate addition

UR - https://www.mdpi.com/1420-3049/26/21/6333

UR - https://www.mdpi.com/journal/molecules/special_issues/Alexandra_Slawin

U2 - 10.3390/molecules26216333

DO - 10.3390/molecules26216333

M3 - Article

SN - 1420-3049

VL - 26

JO - Molecules

JF - Molecules

IS - 21

M1 - 6333

ER -

Isothiourea-catalyzed enantioselective α-alkylation of esters via 1,6-conjugate addition to para-quinone methides

Abstract

Keywords

Access to Document

Handle.net

Other files and links

Fingerprint

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

ERC Starting Grant EnolCat: Emulating nature: Reaction diversity and understanding through asymmetric catalysis

data underpinning "Isothiourea-Catalyzed Enantioselective α-Alkylation of Esters via 1,6-Addition to para-Quinone Methides"

CCDC 1992504: Experimental Crystal Structure Determination

Cite this

Isothiourea-catalyzed enantioselective α-alkylation of esters via 1,6-conjugate addition to para-quinone methides

Abstract

Keywords

Access to Document

Handle.net

Other files and links

Fingerprint

Projects

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

ERC Starting Grant EnolCat: Emulating nature: Reaction diversity and understanding through asymmetric catalysis

Datasets

data underpinning "Isothiourea-Catalyzed Enantioselective α-Alkylation of Esters via 1,6-Addition to para-Quinone Methides"

CCDC 1992504: Experimental Crystal Structure Determination

Cite this