Isothiourea-catalyzed acylative kinetic resolution of tertiary α-hydroxy esters

Shen Qu; Samuel Smith; Victor Laina-Martin; Rifahath Neyyappadath; Mark David Greenhalgh; Andrew David Smith

doi:10.1002/anie.202004354

Isothiourea-catalyzed acylative kinetic resolution of tertiary α-hydroxy esters

Shen Qu, Samuel Smith, Victor Laina-Martin, Rifahath Neyyappadath, Mark David Greenhalgh, Andrew David Smith

School of Chemistry

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

Abstract

A highly enantioselective isothiourea-catalyzed acylative kinetic resolution (KR) of acyclic tertiary alcohols has been developed. Selectivity factors of up to 200 were achieved for the KR of tertiary alcohols bearing an adjacent ester substituent, with both reaction conversion and enantioselectivity found to be sensitive to the steric and electronic environment at the stereogenic tertiary carbinol centre. For more sterically-congested alcohols, the use of a recently-developed isoselenourea catalyst was optimal, with equivalent enantioselectivity but higher conversion achieved in comparison to the isothiourea HyperBTM. Diastereomeric acylation transition state models are proposed to rationalize the origins of enantiodiscrimination in this process. This KR procedure has also been translated to a continuous flow process using a polymer-supported variant of the catalyst.

Original language	English
Pages (from-to)	16572-16578
Number of pages	8
Journal	Angewandte Chemie International Edition
Volume	59
Issue number	38
Early online date	16 Jul 2020
DOIs	https://doi.org/10.1002/anie.202004354
Publication status	Published - 14 Sept 2020

Keywords

Kinetic resolution
Enantioselectivity
Acyl transfer
Organocatalysis
Tertiary alcohol

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Qu-2020-Isothiourea-catalyzed-AngChem-CC
Copyright © 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Final published version, 2.25 MBLicence: CC BY

Cite this

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title = "Isothiourea-catalyzed acylative kinetic resolution of tertiary α-hydroxy esters",

abstract = "A highly enantioselective isothiourea-catalyzed acylative kinetic resolution (KR) of acyclic tertiary alcohols has been developed. Selectivity factors of up to 200 were achieved for the KR of tertiary alcohols bearing an adjacent ester substituent, with both reaction conversion and enantioselectivity found to be sensitive to the steric and electronic environment at the stereogenic tertiary carbinol centre. For more sterically-congested alcohols, the use of a recently-developed isoselenourea catalyst was optimal, with equivalent enantioselectivity but higher conversion achieved in comparison to the isothiourea HyperBTM. Diastereomeric acylation transition state models are proposed to rationalize the origins of enantiodiscrimination in this process. This KR procedure has also been translated to a continuous flow process using a polymer-supported variant of the catalyst. ",

keywords = "Kinetic resolution, Enantioselectivity, Acyl transfer, Organocatalysis, Tertiary alcohol",

author = "Shen Qu and Samuel Smith and Victor Laina-Martin and Rifahath Neyyappadath and Greenhalgh, {Mark David} and Smith, {Andrew David}",

note = "Funding: ERC under the European Union's Seventh Framework Programme (FP7/2007–2013)/E.R.C. grant agreement no. 279850. The Chinese Scholarship Scheme and University of St Andrews are thanked for a CSC Scholarship (S.Q.). Universidad Aut{\'o}noma de Madrid is thanked for a predoctoral fellowship (V.L.-M.). We thank the EPSRC Centre for Doctoral Training in Critical Resource Catalysis (CRITICAT, grant code EP/L016419/1) for funding (R.M.N.). A.D.S. thanks the Royal Society for a Wolfson Research Merit Award. ",

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doi = "10.1002/anie.202004354",

language = "English",

volume = "59",

pages = "16572--16578",

journal = "Angewandte Chemie International Edition",

issn = "1433-7851",

publisher = "John Wiley & Sons, Ltd",

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AU - Qu, Shen

AU - Smith, Samuel

AU - Laina-Martin, Victor

AU - Neyyappadath, Rifahath

AU - Greenhalgh, Mark David

AU - Smith, Andrew David

N1 - Funding: ERC under the European Union's Seventh Framework Programme (FP7/2007–2013)/E.R.C. grant agreement no. 279850. The Chinese Scholarship Scheme and University of St Andrews are thanked for a CSC Scholarship (S.Q.). Universidad Autónoma de Madrid is thanked for a predoctoral fellowship (V.L.-M.). We thank the EPSRC Centre for Doctoral Training in Critical Resource Catalysis (CRITICAT, grant code EP/L016419/1) for funding (R.M.N.). A.D.S. thanks the Royal Society for a Wolfson Research Merit Award.

PY - 2020/9/14

Y1 - 2020/9/14

N2 - A highly enantioselective isothiourea-catalyzed acylative kinetic resolution (KR) of acyclic tertiary alcohols has been developed. Selectivity factors of up to 200 were achieved for the KR of tertiary alcohols bearing an adjacent ester substituent, with both reaction conversion and enantioselectivity found to be sensitive to the steric and electronic environment at the stereogenic tertiary carbinol centre. For more sterically-congested alcohols, the use of a recently-developed isoselenourea catalyst was optimal, with equivalent enantioselectivity but higher conversion achieved in comparison to the isothiourea HyperBTM. Diastereomeric acylation transition state models are proposed to rationalize the origins of enantiodiscrimination in this process. This KR procedure has also been translated to a continuous flow process using a polymer-supported variant of the catalyst.

AB - A highly enantioselective isothiourea-catalyzed acylative kinetic resolution (KR) of acyclic tertiary alcohols has been developed. Selectivity factors of up to 200 were achieved for the KR of tertiary alcohols bearing an adjacent ester substituent, with both reaction conversion and enantioselectivity found to be sensitive to the steric and electronic environment at the stereogenic tertiary carbinol centre. For more sterically-congested alcohols, the use of a recently-developed isoselenourea catalyst was optimal, with equivalent enantioselectivity but higher conversion achieved in comparison to the isothiourea HyperBTM. Diastereomeric acylation transition state models are proposed to rationalize the origins of enantiodiscrimination in this process. This KR procedure has also been translated to a continuous flow process using a polymer-supported variant of the catalyst.

KW - Kinetic resolution

KW - Enantioselectivity

KW - Acyl transfer

KW - Organocatalysis

KW - Tertiary alcohol

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DO - 10.1002/anie.202004354

M3 - Article

SN - 1433-7851

VL - 59

SP - 16572

EP - 16578

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

IS - 38

ER -

Isothiourea-catalyzed acylative kinetic resolution of tertiary α-hydroxy esters

Abstract

Keywords

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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

Isothiourea-Catalyzed Acylative Kinetic Resolution of Acyclic Tertiary Alcohols (dataset)

Cite this

Isothiourea-catalyzed acylative kinetic resolution of tertiary α-hydroxy esters

Abstract

Keywords

Access to Document

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

Isothiourea-Catalyzed Acylative Kinetic Resolution of Acyclic Tertiary Alcohols (dataset)

Cite this