Isothiourea-mediated asymmetric Michael-lactonisation of trifluoromethylenones: a synthetic and mechanistic study

Louis C. Morrill; James Douglas; Tomas Lebl; Alexandra M. Z. Slawin; David J. Fox; Andrew D. Smith

doi:10.1039/c3sc51791h

Isothiourea-mediated asymmetric Michael-lactonisation of trifluoromethylenones: a synthetic and mechanistic study

Louis C. Morrill, James Douglas, Tomas Lebl, Alexandra M. Z. Slawin, David J. Fox^*, Andrew D. Smith

^*Corresponding author for this work

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

Abstract

HBTM-2.1 promotes the catalytic asymmetric intermolecular Michael-lactonisation of arylacetic acids and trifluoromethylenones in the presence of pivaloyl chloride, giving C(6)-trifluoromethyldihydropyranones with high diastereo- and enantiocontrol (up to 95 : 5 dr and >99% ee) that are readily derivatised to diverse synthetic building blocks containing trifluoromethyl-stereogenicity. Kinetic studies indicate the reaction is first order with respect to both in situ formed mixed anhydride and catalyst concentration, with a primary kinetic isotope effect observed using a, alpha,alpha-di-deuterio 4-fluorophenylacetic acid, consistent with rate determining deprotonation of an intermediate acyl isothiouronium ion.

Original language	English
Pages (from-to)	4146-4155
Number of pages	10
Journal	Chemical Science
Volume	4
Issue number	11
DOIs	https://doi.org/10.1039/c3sc51791h
Publication status	Published - 2013

Keywords

ACYL-TRANSFER CATALYST
BICYCLIC-BETA-LACTONES
SECONDARY BENZYLIC ALCOHOLS
MILD ELECTROPHILIC TRIFLUOROMETHYLATION
C-CARBOXYL TRANSFER
ENANTIOSELECTIVE ALPHA-TRIFLUOROMETHYLATION
KINETIC RESOLUTION CATALYSTS
PROMOTED BIS-CYCLIZATIONS
AMIDINE-BASED CATALYSTS
SILYL KETENE ACETALS

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@article{c08f32c6f16b46babc300bd201c5553e,

title = "Isothiourea-mediated asymmetric Michael-lactonisation of trifluoromethylenones: a synthetic and mechanistic study",

abstract = "HBTM-2.1 promotes the catalytic asymmetric intermolecular Michael-lactonisation of arylacetic acids and trifluoromethylenones in the presence of pivaloyl chloride, giving C(6)-trifluoromethyldihydropyranones with high diastereo- and enantiocontrol (up to 95 : 5 dr and >99% ee) that are readily derivatised to diverse synthetic building blocks containing trifluoromethyl-stereogenicity. Kinetic studies indicate the reaction is first order with respect to both in situ formed mixed anhydride and catalyst concentration, with a primary kinetic isotope effect observed using a, alpha,alpha-di-deuterio 4-fluorophenylacetic acid, consistent with rate determining deprotonation of an intermediate acyl isothiouronium ion.",

keywords = "ACYL-TRANSFER CATALYST, BICYCLIC-BETA-LACTONES, SECONDARY BENZYLIC ALCOHOLS, MILD ELECTROPHILIC TRIFLUOROMETHYLATION, C-CARBOXYL TRANSFER, ENANTIOSELECTIVE ALPHA-TRIFLUOROMETHYLATION, KINETIC RESOLUTION CATALYSTS, PROMOTED BIS-CYCLIZATIONS, AMIDINE-BASED CATALYSTS, SILYL KETENE ACETALS",

author = "Morrill, {Louis C.} and James Douglas and Tomas Lebl and Slawin, {Alexandra M. Z.} and Fox, {David J.} and Smith, {Andrew D.}",

note = "We thank the Royal Society for a University Research Fellowships (A.D.S) and The Carnegie Trust for the Universities of Scotland (L.C.M) for funding. The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007–2013)/ERC grant agreement no. 279850. We also thank the EPSRC National Mass Spectrometry Service Centre (Swansea).",

year = "2013",

doi = "10.1039/c3sc51791h",

language = "English",

volume = "4",

pages = "4146--4155",

journal = "Chemical Science",

issn = "2041-6520",

publisher = "Royal Society of Chemistry",

number = "11",

}

TY - JOUR

T1 - Isothiourea-mediated asymmetric Michael-lactonisation of trifluoromethylenones: a synthetic and mechanistic study

AU - Morrill, Louis C.

AU - Douglas, James

AU - Lebl, Tomas

AU - Slawin, Alexandra M. Z.

AU - Fox, David J.

AU - Smith, Andrew D.

N1 - We thank the Royal Society for a University Research Fellowships (A.D.S) and The Carnegie Trust for the Universities of Scotland (L.C.M) for funding. The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007–2013)/ERC grant agreement no. 279850. We also thank the EPSRC National Mass Spectrometry Service Centre (Swansea).

PY - 2013

Y1 - 2013

N2 - HBTM-2.1 promotes the catalytic asymmetric intermolecular Michael-lactonisation of arylacetic acids and trifluoromethylenones in the presence of pivaloyl chloride, giving C(6)-trifluoromethyldihydropyranones with high diastereo- and enantiocontrol (up to 95 : 5 dr and >99% ee) that are readily derivatised to diverse synthetic building blocks containing trifluoromethyl-stereogenicity. Kinetic studies indicate the reaction is first order with respect to both in situ formed mixed anhydride and catalyst concentration, with a primary kinetic isotope effect observed using a, alpha,alpha-di-deuterio 4-fluorophenylacetic acid, consistent with rate determining deprotonation of an intermediate acyl isothiouronium ion.

AB - HBTM-2.1 promotes the catalytic asymmetric intermolecular Michael-lactonisation of arylacetic acids and trifluoromethylenones in the presence of pivaloyl chloride, giving C(6)-trifluoromethyldihydropyranones with high diastereo- and enantiocontrol (up to 95 : 5 dr and >99% ee) that are readily derivatised to diverse synthetic building blocks containing trifluoromethyl-stereogenicity. Kinetic studies indicate the reaction is first order with respect to both in situ formed mixed anhydride and catalyst concentration, with a primary kinetic isotope effect observed using a, alpha,alpha-di-deuterio 4-fluorophenylacetic acid, consistent with rate determining deprotonation of an intermediate acyl isothiouronium ion.

KW - ACYL-TRANSFER CATALYST

KW - BICYCLIC-BETA-LACTONES

KW - SECONDARY BENZYLIC ALCOHOLS

KW - MILD ELECTROPHILIC TRIFLUOROMETHYLATION

KW - C-CARBOXYL TRANSFER

KW - ENANTIOSELECTIVE ALPHA-TRIFLUOROMETHYLATION

KW - KINETIC RESOLUTION CATALYSTS

KW - PROMOTED BIS-CYCLIZATIONS

KW - AMIDINE-BASED CATALYSTS

KW - SILYL KETENE ACETALS

U2 - 10.1039/c3sc51791h

DO - 10.1039/c3sc51791h

M3 - Article

SN - 2041-6520

VL - 4

SP - 4146

EP - 4155

JO - Chemical Science

JF - Chemical Science

IS - 11

ER -

Isothiourea-mediated asymmetric Michael-lactonisation of trifluoromethylenones: a synthetic and mechanistic study

Abstract

Keywords

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