Stereospecific Asymmetric N-Heterocyclic Carbene (NHC)-Catalyzed Redox Synthesis of Trifluoromethyl Dihydropyranones and Mechanistic Insights

Alyn T. Davies; James E. Taylor; James Douglas; Christopher J. Collett; Louis C. Morrill; Charlene Fallan; Alexandra M. Z. Slawin; Gwydion Churchill; Andrew D. Smith

doi:10.1021/jo401433q

Stereospecific Asymmetric N-Heterocyclic Carbene (NHC)-Catalyzed Redox Synthesis of Trifluoromethyl Dihydropyranones and Mechanistic Insights

Alyn T. Davies, James E. Taylor, James Douglas, Christopher J. Collett, Louis C. Morrill, Charlene Fallan, Alexandra M. Z. Slawin, Gwydion Churchill, Andrew D. Smith^*

^*Corresponding author for this work

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

Abstract

N-Heterocyclic carbene (NHC)-catalyzed redox asymmetric hetero-Diels-Alder reactions of alpha-aroyloxyaldehydes with beta-trifluoromethyl enones generates synthetically useful dihydropyranones containing a stereogenic trifluoromethyl substituent in good yields (up to 81%) and excellent diastereoselectivity and enantioselectivity (up to >95:5 dr and >99% ee). The process is stereospecific, with use of either (E)- or (Z)-beta-trifluoromethyl enones forming syn- or anti-dihydropyranone products, respectively. Mechanistic studies through in situ kinetic analysis of the reaction reveal key differences in reactivity between chiral NHC precursor 1 and an achiral NHC precursor.

Original language	English
Pages (from-to)	9243-9257
Number of pages	15
Journal	The Journal of Organic Chemistry
Volume	78
Issue number	18
DOIs	https://doi.org/10.1021/jo401433q
Publication status	Published - 20 Sept 2013

Keywords

Diels-alder reactions
Organocatalytic michael addition
Enantioselective synthesis
Enolate equivalents
Medicinal chemistry
Catalyzed reactions
Carbonyl-compounds
4+2 Cycloaddition
Aldehydes
Enals

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10.1021/jo401433q

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Davies, A. T., Taylor, J. E., Douglas, J., Collett, C. J., Morrill, L. C., Fallan, C., Slawin, A. M. Z., Churchill, G., & Smith, A. D. (2013). Stereospecific Asymmetric N-Heterocyclic Carbene (NHC)-Catalyzed Redox Synthesis of Trifluoromethyl Dihydropyranones and Mechanistic Insights. The Journal of Organic Chemistry, 78(18), 9243-9257. https://doi.org/10.1021/jo401433q

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title = "Stereospecific Asymmetric N-Heterocyclic Carbene (NHC)-Catalyzed Redox Synthesis of Trifluoromethyl Dihydropyranones and Mechanistic Insights",

abstract = "N-Heterocyclic carbene (NHC)-catalyzed redox asymmetric hetero-Diels-Alder reactions of alpha-aroyloxyaldehydes with beta-trifluoromethyl enones generates synthetically useful dihydropyranones containing a stereogenic trifluoromethyl substituent in good yields (up to 81%) and excellent diastereoselectivity and enantioselectivity (up to >95:5 dr and >99% ee). The process is stereospecific, with use of either (E)- or (Z)-beta-trifluoromethyl enones forming syn- or anti-dihydropyranone products, respectively. Mechanistic studies through in situ kinetic analysis of the reaction reveal key differences in reactivity between chiral NHC precursor 1 and an achiral NHC precursor.",

keywords = "Diels-alder reactions, Organocatalytic michael addition, Enantioselective synthesis, Enolate equivalents, Medicinal chemistry, Catalyzed reactions, Carbonyl-compounds, 4+2 Cycloaddition, Aldehydes, Enals",

author = "Davies, {Alyn T.} and Taylor, {James E.} and James Douglas and Collett, {Christopher J.} and Morrill, {Louis C.} and Charlene Fallan and Slawin, {Alexandra M. Z.} and Gwydion Churchill and Smith, {Andrew D.}",

note = "We thank the Royal Society for a University Research Fellowship (A.D.S.), the EPSRC (C.J.C.), the EPSRC and AstraZeneca (Case award to J.D.), The Carnegie Trust for the Universities of Scotland (L.C.M.), as well as European Research Council under the European Union{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) ERC grant agreement no. 279850 (A.T.D., C.F., and J.E.T.).",

year = "2013",

month = sep,

day = "20",

doi = "10.1021/jo401433q",

language = "English",

volume = "78",

pages = "9243--9257",

journal = "The Journal of Organic Chemistry",

issn = "0022-3263",

publisher = "American Chemical Society (ACS)",

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T1 - Stereospecific Asymmetric N-Heterocyclic Carbene (NHC)-Catalyzed Redox Synthesis of Trifluoromethyl Dihydropyranones and Mechanistic Insights

AU - Davies, Alyn T.

AU - Taylor, James E.

AU - Douglas, James

AU - Collett, Christopher J.

AU - Morrill, Louis C.

AU - Fallan, Charlene

AU - Slawin, Alexandra M. Z.

AU - Churchill, Gwydion

AU - Smith, Andrew D.

N1 - We thank the Royal Society for a University Research Fellowship (A.D.S.), the EPSRC (C.J.C.), the EPSRC and AstraZeneca (Case award to J.D.), The Carnegie Trust for the Universities of Scotland (L.C.M.), as well as European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) ERC grant agreement no. 279850 (A.T.D., C.F., and J.E.T.).

PY - 2013/9/20

Y1 - 2013/9/20

N2 - N-Heterocyclic carbene (NHC)-catalyzed redox asymmetric hetero-Diels-Alder reactions of alpha-aroyloxyaldehydes with beta-trifluoromethyl enones generates synthetically useful dihydropyranones containing a stereogenic trifluoromethyl substituent in good yields (up to 81%) and excellent diastereoselectivity and enantioselectivity (up to >95:5 dr and >99% ee). The process is stereospecific, with use of either (E)- or (Z)-beta-trifluoromethyl enones forming syn- or anti-dihydropyranone products, respectively. Mechanistic studies through in situ kinetic analysis of the reaction reveal key differences in reactivity between chiral NHC precursor 1 and an achiral NHC precursor.

AB - N-Heterocyclic carbene (NHC)-catalyzed redox asymmetric hetero-Diels-Alder reactions of alpha-aroyloxyaldehydes with beta-trifluoromethyl enones generates synthetically useful dihydropyranones containing a stereogenic trifluoromethyl substituent in good yields (up to 81%) and excellent diastereoselectivity and enantioselectivity (up to >95:5 dr and >99% ee). The process is stereospecific, with use of either (E)- or (Z)-beta-trifluoromethyl enones forming syn- or anti-dihydropyranone products, respectively. Mechanistic studies through in situ kinetic analysis of the reaction reveal key differences in reactivity between chiral NHC precursor 1 and an achiral NHC precursor.

KW - Diels-alder reactions

KW - Organocatalytic michael addition

KW - Enantioselective synthesis

KW - Enolate equivalents

KW - Medicinal chemistry

KW - Catalyzed reactions

KW - Carbonyl-compounds

KW - 4+2 Cycloaddition

KW - Aldehydes

KW - Enals

U2 - 10.1021/jo401433q

DO - 10.1021/jo401433q

M3 - Article

SN - 0022-3263

VL - 78

SP - 9243

EP - 9257

JO - The Journal of Organic Chemistry

JF - The Journal of Organic Chemistry

IS - 18

ER -

Stereospecific Asymmetric N-Heterocyclic Carbene (NHC)-Catalyzed Redox Synthesis of Trifluoromethyl Dihydropyranones and Mechanistic Insights

Abstract

Keywords

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