Scope, limitations and mechanistic analysis of the HyperBTM-catalyzed acylative kinetic resolution of tertiary heterocyclic alcohols

Samuel Smith; Mark D. Greenhalgh; Taisiia Feoktistova; Daniel M. Walden; James E. Taylor; David B. Cordes; Alexandra M. Z. Slawin; Paul Ha-Yeon  Cheong; Andrew D. Smith

doi:10.1002/ejoc.202101111

Scope, limitations and mechanistic analysis of the HyperBTM-catalyzed acylative kinetic resolution of tertiary heterocyclic alcohols

Samuel Smith, Mark D. Greenhalgh, Taisiia Feoktistova, Daniel M. Walden, James E. Taylor, David B. Cordes, Alexandra M. Z. Slawin, Paul Ha-Yeon Cheong^*, Andrew D. Smith^*

^*Corresponding author for this work

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

Abstract

The full scope and limitations of the catalytic acylative kinetic resolution of a range of tertiary heterocyclic alcohols (78 examples, s up to >200) is reported under operationally-simple conditions, using low loadings of a commercially available Lewis basic isothiourea catalyst, HyperBTM (generally 1 mol %). The protocol is highly effective for the kinetic resolution of 3-substituted 3-hydroxyoxindole and α-substituted α-hydroxylactam derivatives bearing up to three potential recognition motifs at the stereogenic tertiary carbinol center. The full power of this methodology has been showcased through the synthesis of highly enantioenriched biologically-active target compounds in both enantiomeric forms. To provide further insight into the reaction mechanism, a detailed kinetic analysis of this Lewis base-catalyzed acylation of tertiary alcohols is reported using the variable time normalization analysis (VTNA) method.

Original language	English
Article number	e202101111
Pages (from-to)	30-43
Number of pages	14
Journal	European Journal of Organic Chemistry
Early online date	11 Nov 2021
DOIs	https://doi.org/10.1002/ejoc.202101111
Publication status	Published - 11 Jan 2022

Keywords

Kinetic resolution
Enantioselectivity
Acyl transfer
Organocatalysis
Tertiary alcohol

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10.1002/ejoc.202101111

Smith_2021_EJoC_Scope-limitation_AAM
Copyright © 2021 Wiley-VCH GmbH. This work has been made available online in accordance with publisher policies or with permission. Permission for further reuse of this content should be sought from the publisher or the rights holder. This is the author created accepted manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://doi.org/10.1002/ejoc.202101111
Accepted author manuscript, 3.57 MB

RS Wolfson Merit Award: Developing Catalysis Research: New Reaction Discoveries and Practical Applications
Smith, A. D. (PI)
The Royal Society
1/01/15 → 31/12/19
Project: Fellowship
ERC Starting Grant EnolCat: Emulating nature: Reaction diversity and understanding through asymmetric catalysis
Smith, A. D. (PI)
European Commission
1/10/11 → 30/06/17
Project: Standard

data underpinning "Scope, limitations and mechanistic analysis of the HyperBTM-catalyzed acylative kinetic resolution of tertiary heterocyclic alcohols"
Smith, A. D. (Creator) & Greenhalgh, M. (Contributor), University of St Andrews, 12 Aug 2021
DOI: 10.17630/f069ab41-9f98-438b-83b7-197307dab28d
Dataset

File
A C=O•••isothiouronium interaction dictates enantiodiscrimination in acylative kinetic resolution of tertiary heterocyclic alcohols (dataset 2)
Greenhalgh, M. D. (Creator), Smith, S. (Creator), Walden, D. M. (Creator), Taylor, J. E. (Creator), Brice, Z. (Creator), Robinson, E. (Creator), Fallan, C. (Creator), Cordes, D. B. (Creator), Slawin, A. M. Z. (Creator), Richardson, H. C. (Creator), Grove, M. A. (Creator), Ha-Yeon Cheong, P. (Creator) & Smith, A. D. (Creator), Cambridge Crystallographic Data Centre, 2017
https://dx.doi.org/10.5517/ccdc.csd.cc1pq5k4 and one more link, https://dx.doi.org/10.5517/ccdc.csd.cc1pq5l5 (show fewer)
Dataset

Cite this

Smith, S., Greenhalgh, M. D., Feoktistova, T., Walden, D. M., Taylor, J. E., Cordes, D. B., Slawin, A. M. Z., Cheong, P. H.-Y., & Smith, A. D. (2022). Scope, limitations and mechanistic analysis of the HyperBTM-catalyzed acylative kinetic resolution of tertiary heterocyclic alcohols. European Journal of Organic Chemistry, 30-43. Article e202101111. https://doi.org/10.1002/ejoc.202101111

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title = "Scope, limitations and mechanistic analysis of the HyperBTM-catalyzed acylative kinetic resolution of tertiary heterocyclic alcohols",

abstract = "The full scope and limitations of the catalytic acylative kinetic resolution of a range of tertiary heterocyclic alcohols (78 examples, s up to >200) is reported under operationally-simple conditions, using low loadings of a commercially available Lewis basic isothiourea catalyst, HyperBTM (generally 1 mol %). The protocol is highly effective for the kinetic resolution of 3-substituted 3-hydroxyoxindole and α-substituted α-hydroxylactam derivatives bearing up to three potential recognition motifs at the stereogenic tertiary carbinol center. The full power of this methodology has been showcased through the synthesis of highly enantioenriched biologically-active target compounds in both enantiomeric forms. To provide further insight into the reaction mechanism, a detailed kinetic analysis of this Lewis base-catalyzed acylation of tertiary alcohols is reported using the variable time normalization analysis (VTNA) method.",

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

author = "Samuel Smith and Greenhalgh, {Mark D.} and Taisiia Feoktistova and Walden, {Daniel M.} and Taylor, {James E.} and Cordes, {David B.} and Slawin, {Alexandra M. Z.} and Cheong, {Paul Ha-Yeon} and Smith, {Andrew D.}",

note = "The research leading to these results has received funding from the ERC under the European Union's Seventh Framework Programme (FP7/2007-2013)/E.R.C. grant agreement n° 279850. 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. P.H.-Y.C. is the Bert and Emelyn Christensen Professor and gratefully acknowledges financial support from the Stone Family of OSU. Financial support from the National Science Foundation (NSF) (CHE-1352663) is acknowledged. D.M.W. acknowledges the Bruce Graham and Johnson Fellowships of OSU. D.M.W. and P.H.-Y.C. acknowledge computing infrastructure in part provided by the NSF Phase-2 CCI, Center for Sustainable Materials Chemistry (CHE-1102637).",

year = "2022",

month = jan,

day = "11",

doi = "10.1002/ejoc.202101111",

language = "English",

pages = "30--43",

journal = "European Journal of Organic Chemistry",

issn = "1434-193X",

publisher = "Wiley-VCH, Weinheim",

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T1 - Scope, limitations and mechanistic analysis of the HyperBTM-catalyzed acylative kinetic resolution of tertiary heterocyclic alcohols

AU - Smith, Samuel

AU - Greenhalgh, Mark D.

AU - Feoktistova, Taisiia

AU - Walden, Daniel M.

AU - Taylor, James E.

AU - Cordes, David B.

AU - Slawin, Alexandra M. Z.

AU - Cheong, Paul Ha-Yeon

AU - Smith, Andrew D.

N1 - The research leading to these results has received funding from the ERC under the European Union's Seventh Framework Programme (FP7/2007-2013)/E.R.C. grant agreement n° 279850. 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. P.H.-Y.C. is the Bert and Emelyn Christensen Professor and gratefully acknowledges financial support from the Stone Family of OSU. Financial support from the National Science Foundation (NSF) (CHE-1352663) is acknowledged. D.M.W. acknowledges the Bruce Graham and Johnson Fellowships of OSU. D.M.W. and P.H.-Y.C. acknowledge computing infrastructure in part provided by the NSF Phase-2 CCI, Center for Sustainable Materials Chemistry (CHE-1102637).

PY - 2022/1/11

Y1 - 2022/1/11

N2 - The full scope and limitations of the catalytic acylative kinetic resolution of a range of tertiary heterocyclic alcohols (78 examples, s up to >200) is reported under operationally-simple conditions, using low loadings of a commercially available Lewis basic isothiourea catalyst, HyperBTM (generally 1 mol %). The protocol is highly effective for the kinetic resolution of 3-substituted 3-hydroxyoxindole and α-substituted α-hydroxylactam derivatives bearing up to three potential recognition motifs at the stereogenic tertiary carbinol center. The full power of this methodology has been showcased through the synthesis of highly enantioenriched biologically-active target compounds in both enantiomeric forms. To provide further insight into the reaction mechanism, a detailed kinetic analysis of this Lewis base-catalyzed acylation of tertiary alcohols is reported using the variable time normalization analysis (VTNA) method.

AB - The full scope and limitations of the catalytic acylative kinetic resolution of a range of tertiary heterocyclic alcohols (78 examples, s up to >200) is reported under operationally-simple conditions, using low loadings of a commercially available Lewis basic isothiourea catalyst, HyperBTM (generally 1 mol %). The protocol is highly effective for the kinetic resolution of 3-substituted 3-hydroxyoxindole and α-substituted α-hydroxylactam derivatives bearing up to three potential recognition motifs at the stereogenic tertiary carbinol center. The full power of this methodology has been showcased through the synthesis of highly enantioenriched biologically-active target compounds in both enantiomeric forms. To provide further insight into the reaction mechanism, a detailed kinetic analysis of this Lewis base-catalyzed acylation of tertiary alcohols is reported using the variable time normalization analysis (VTNA) method.

KW - Kinetic resolution

KW - Enantioselectivity

KW - Acyl transfer

KW - Organocatalysis

KW - Tertiary alcohol

U2 - 10.1002/ejoc.202101111

DO - 10.1002/ejoc.202101111

M3 - Article

SN - 1434-193X

SP - 30

EP - 43

JO - European Journal of Organic Chemistry

JF - European Journal of Organic Chemistry

M1 - e202101111

ER -

Scope, limitations and mechanistic analysis of the HyperBTM-catalyzed acylative kinetic resolution of tertiary heterocyclic alcohols

Abstract

Keywords

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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 "Scope, limitations and mechanistic analysis of the HyperBTM-catalyzed acylative kinetic resolution of tertiary heterocyclic alcohols"

A C=O•••isothiouronium interaction dictates enantiodiscrimination in acylative kinetic resolution of tertiary heterocyclic alcohols (dataset 2)

Cite this