Enantioselective isothiourea catalysed Michael-Michael-lactonisation cascade; synthesis of δ-lactones and 1,2,3,4-substituted cyclopentanes

Emily R. T. Robinson; Aileen B. Frost; Pilar Elías-Rodríguez; Andrew D. Smith

doi:10.1055/s-0036-1588636

Enantioselective isothiourea catalysed Michael-Michael-lactonisation cascade; synthesis of δ-lactones and 1,2,3,4-substituted cyclopentanes

Emily R. T. Robinson, Aileen B. Frost, Pilar Elías-Rodríguez, Andrew D. Smith

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

Abstract

This manuscript describes the application of α,β-unsaturated acyl ammonium intermediates in a Michael-Michael-lactonisation cascade process to furnish δ-lactones. Generation of α,β-unsaturated acyl ammonium intermediates was achieved upon addition of isothiourea catalyst HyperBTM into α,β-unsaturated acid chlorides. Subsequent reaction with enonemalonates gave access to δ-lactones in 20-64% yield, 72.5:27.5 to 95:5 er and 81:19 to >95:5 dr. Additionally, application of a ring-opening protocol yielded1,2,3,4-substituted cyclopentanes in 28-77% yield, 76:24 to 98:2 er and 86:14 to >95:5 dr. Interestingly, highest er was observed at high reaction temperatures, with 70˚C proving optimal. This effect was investigated by conducting an Eyring analysis, which indicated that differential activation entropy rather than differential activation enthalpy is responsible for enantiodiscrimination in this process.

Original language	English
Pages (from-to)	409-423
Number of pages	15
Journal	Synthesis
Volume	49
Issue number	2
Early online date	23 Nov 2016
DOIs	https://doi.org/10.1055/s-0036-1588636
Publication status	Published - Jan 2017

Keywords

Lewis base catalysis
α,β-unsaturated acyl ammonium intermediates
Isothiourea catalysis
Cascades
Enantioselective catalysis

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10.1055/s-0036-1588636

Smith_2016_Synthesis_Enantioselective_AAM
© Georg Thieme Verlag Stuttgart - New York. This work has been made available online in accordance with the publisher’s policies. This is the author created, accepted version 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/10.1055/s-0036-1588636
Accepted author manuscript, 1.73 MB

Clean catalysis for sustainable develop: Clean catalysis for sustainable development
Smith, A. D. (PI)
EPSRC
1/11/12 → 31/10/17
Project: Standard
Clean catalysis for sustainable develop: Clean catalysis for sustainable development
Kamer, P. C. J. (PI)
EPSRC
1/11/12 → 31/10/17
Project: Standard

Data undeprinning "Enantioselective isothiourea catalysed Michael-Michael-Lactonisation cascade; synthesis of δ-lactones and 1,2,3,4-substituted cyclopentanes"
Robinson, E. (Creator), Frost, A. B. (Creator), Elías-Rodríguez, P.E.-R. (Creator) & Smith, A. D. (Creator), University of St Andrews, 14 Dec 2016
DOI: 10.17630/08eb25ec-9059-4b5e-86a0-9d9106dc34ad
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@article{1f69a36ff9064e2a80bf68e9cc86e8b1,

title = "Enantioselective isothiourea catalysed Michael-Michael-lactonisation cascade; synthesis of δ-lactones and 1,2,3,4-substituted cyclopentanes",

abstract = "This manuscript describes the application of α,β-unsaturated acyl ammonium intermediates in a Michael-Michael-lactonisation cascade process to furnish δ-lactones. Generation of α,β-unsaturated acyl ammonium intermediates was achieved upon addition of isothiourea catalyst HyperBTM into α,β-unsaturated acid chlorides. Subsequent reaction with enonemalonates gave access to δ-lactones in 20-64% yield, 72.5:27.5 to 95:5 er and 81:19 to >95:5 dr. Additionally, application of a ring-opening protocol yielded1,2,3,4-substituted cyclopentanes in 28-77% yield, 76:24 to 98:2 er and 86:14 to >95:5 dr. Interestingly, highest er was observed at high reaction temperatures, with 70˚C proving optimal. This effect was investigated by conducting an Eyring analysis, which indicated that differential activation entropy rather than differential activation enthalpy is responsible for enantiodiscrimination in this process.",

keywords = "Lewis base catalysis, α,β-unsaturated acyl ammonium intermediates, Isothiourea catalysis, Cascades, Enantioselective catalysis",

author = "Robinson, {Emily R. T.} and Frost, {Aileen B.} and Pilar El{\'i}as-Rodr{\'i}guez and Smith, {Andrew D.}",

note = "The authors thank the EPSRC (ERTR – grant code EP/J500549/1; ABF - grant code EP/J018139/1), the Spanish government for a FPU Fellowship and the University of Seville (V Plan Propio de Investigaci{\'o}n) for financial support (PER). This work was supported by the European Research Council under the European Union{\textquoteright}s Seventh Framework Programme (FP7/2007–2013) ERC grant agreement no. 279850. ADS thanks the Royal Society for a Wolfson Research Merit Award. ",

year = "2017",

month = jan,

doi = "10.1055/s-0036-1588636",

language = "English",

volume = "49",

pages = "409--423",

journal = "Synthesis",

issn = "0039-7881",

publisher = "Georg Thieme Verlag",

number = "2",

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TY - JOUR

T1 - Enantioselective isothiourea catalysed Michael-Michael-lactonisation cascade; synthesis of δ-lactones and 1,2,3,4-substituted cyclopentanes

AU - Robinson, Emily R. T.

AU - Frost, Aileen B.

AU - Elías-Rodríguez, Pilar

AU - Smith, Andrew D.

N1 - The authors thank the EPSRC (ERTR – grant code EP/J500549/1; ABF - grant code EP/J018139/1), the Spanish government for a FPU Fellowship and the University of Seville (V Plan Propio de Investigación) for financial support (PER). This work was supported by the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013) ERC grant agreement no. 279850. ADS thanks the Royal Society for a Wolfson Research Merit Award.

PY - 2017/1

Y1 - 2017/1

N2 - This manuscript describes the application of α,β-unsaturated acyl ammonium intermediates in a Michael-Michael-lactonisation cascade process to furnish δ-lactones. Generation of α,β-unsaturated acyl ammonium intermediates was achieved upon addition of isothiourea catalyst HyperBTM into α,β-unsaturated acid chlorides. Subsequent reaction with enonemalonates gave access to δ-lactones in 20-64% yield, 72.5:27.5 to 95:5 er and 81:19 to >95:5 dr. Additionally, application of a ring-opening protocol yielded1,2,3,4-substituted cyclopentanes in 28-77% yield, 76:24 to 98:2 er and 86:14 to >95:5 dr. Interestingly, highest er was observed at high reaction temperatures, with 70˚C proving optimal. This effect was investigated by conducting an Eyring analysis, which indicated that differential activation entropy rather than differential activation enthalpy is responsible for enantiodiscrimination in this process.

AB - This manuscript describes the application of α,β-unsaturated acyl ammonium intermediates in a Michael-Michael-lactonisation cascade process to furnish δ-lactones. Generation of α,β-unsaturated acyl ammonium intermediates was achieved upon addition of isothiourea catalyst HyperBTM into α,β-unsaturated acid chlorides. Subsequent reaction with enonemalonates gave access to δ-lactones in 20-64% yield, 72.5:27.5 to 95:5 er and 81:19 to >95:5 dr. Additionally, application of a ring-opening protocol yielded1,2,3,4-substituted cyclopentanes in 28-77% yield, 76:24 to 98:2 er and 86:14 to >95:5 dr. Interestingly, highest er was observed at high reaction temperatures, with 70˚C proving optimal. This effect was investigated by conducting an Eyring analysis, which indicated that differential activation entropy rather than differential activation enthalpy is responsible for enantiodiscrimination in this process.

KW - Lewis base catalysis

KW - α,β-unsaturated acyl ammonium intermediates

KW - Isothiourea catalysis

KW - Cascades

KW - Enantioselective catalysis

U2 - 10.1055/s-0036-1588636

DO - 10.1055/s-0036-1588636

M3 - Article

SN - 0039-7881

VL - 49

SP - 409

EP - 423

JO - Synthesis

JF - Synthesis

IS - 2

ER -

Enantioselective isothiourea catalysed Michael-Michael-lactonisation cascade; synthesis of δ-lactones and 1,2,3,4-substituted cyclopentanes

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Clean catalysis for sustainable develop: Clean catalysis for sustainable development

Clean catalysis for sustainable develop: Clean catalysis for sustainable development

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Data undeprinning "Enantioselective isothiourea catalysed Michael-Michael-Lactonisation cascade; synthesis of δ-lactones and 1,2,3,4-substituted cyclopentanes"

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