Umpolung Strategy for α-Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles

Jakob Blom; Gabriel Jose Reyes Rodriguez; Henriette N. Tobiesen; Johannes N. Lamhauge; Marc V. Iversen; Casper L. Barløse; Niels Hammer; Matilde Rusbjerg; Karl Anker Jørgensen

doi:10.1002/anie.201911793

Umpolung Strategy for α-Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles

Jakob Blom, Gabriel Jose Reyes Rodriguez, Henriette N. Tobiesen, Johannes N. Lamhauge, Marc V. Iversen, Casper L. Barløse, Niels Hammer, Matilde Rusbjerg, Karl Anker Jørgensen^*

^*Corresponding author for this work

Department of Chemistry

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

Nucleophile–nucleophile coupling is a challenging transformation in organic chemistry. Herein we present a novel umpolung strategy for α-functionalization of aldehydes with nucleophiles. The strategy uses organocatalytic enamine activation and quinone-promoted oxidation to access O-bound quinol-intermediates that undergo nucleophilic substitution reactions. These quinol-intermediates react with different classes of nucleophiles. The focus is on an unprecedented organocatalytic oxidative α-thiolation of aldehydes. The reaction scope is demonstrated for a broad range of thiols and extended to chemoselective bioconjugation, and applicable to a large variety of aldehydes. This strategy can also encompass organocatalytic enantioselective coupling of α-branched aldehydes with thiols forming quaternary thioethers. Studies indicate a stereoselective formation of the intermediate followed by a stereospecific nucleophilic substitution reaction at a quaternary stereocenter, with inversion of configuration.

Original language	English
Journal	Angewandte Chemie - International Edition
Volume	58
Issue	49
Pages (from-to)	17856-17862
ISSN	1433-7851
DOIs	https://doi.org/10.1002/anie.201911793
Publication status	Published - 2 Dec 2019

Keywords

bioconjugation
enantioselective α-thiolation
organocatalysis
oxidative thiolation
umpolung

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10.1002/anie.201911793

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@article{392d5730182a45178029cd1380085d7f,

title = "Umpolung Strategy for α-Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles",

abstract = "Nucleophile–nucleophile coupling is a challenging transformation in organic chemistry. Herein we present a novel umpolung strategy for α-functionalization of aldehydes with nucleophiles. The strategy uses organocatalytic enamine activation and quinone-promoted oxidation to access O-bound quinol-intermediates that undergo nucleophilic substitution reactions. These quinol-intermediates react with different classes of nucleophiles. The focus is on an unprecedented organocatalytic oxidative α-thiolation of aldehydes. The reaction scope is demonstrated for a broad range of thiols and extended to chemoselective bioconjugation, and applicable to a large variety of aldehydes. This strategy can also encompass organocatalytic enantioselective coupling of α-branched aldehydes with thiols forming quaternary thioethers. Studies indicate a stereoselective formation of the intermediate followed by a stereospecific nucleophilic substitution reaction at a quaternary stereocenter, with inversion of configuration.",

keywords = "bioconjugation, enantioselective α-thiolation, organocatalysis, oxidative thiolation, umpolung",

author = "Jakob Blom and {Reyes Rodriguez}, {Gabriel Jose} and Tobiesen, {Henriette N.} and Lamhauge, {Johannes N.} and Iversen, {Marc V.} and Barl{\o}se, {Casper L.} and Niels Hammer and Matilde Rusbjerg and J{\o}rgensen, {Karl Anker}",

year = "2019",

month = dec,

day = "2",

doi = "10.1002/anie.201911793",

language = "English",

volume = "58",

pages = "17856--17862",

journal = "Angewandte Chemie - International Edition",

issn = "1433-7851",

publisher = "Wiley - VCH Verlag GmbH & CO. KGaA",

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}

Umpolung Strategy for α-Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles. / Blom, Jakob; Reyes Rodriguez, Gabriel Jose; Tobiesen, Henriette N. et al.
In: Angewandte Chemie - International Edition, Vol. 58, No. 49, 02.12.2019, p. 17856-17862.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Umpolung Strategy for α-Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles

AU - Blom, Jakob

AU - Reyes Rodriguez, Gabriel Jose

AU - Tobiesen, Henriette N.

AU - Lamhauge, Johannes N.

AU - Iversen, Marc V.

AU - Barløse, Casper L.

AU - Hammer, Niels

AU - Rusbjerg, Matilde

AU - Jørgensen, Karl Anker

PY - 2019/12/2

Y1 - 2019/12/2

N2 - Nucleophile–nucleophile coupling is a challenging transformation in organic chemistry. Herein we present a novel umpolung strategy for α-functionalization of aldehydes with nucleophiles. The strategy uses organocatalytic enamine activation and quinone-promoted oxidation to access O-bound quinol-intermediates that undergo nucleophilic substitution reactions. These quinol-intermediates react with different classes of nucleophiles. The focus is on an unprecedented organocatalytic oxidative α-thiolation of aldehydes. The reaction scope is demonstrated for a broad range of thiols and extended to chemoselective bioconjugation, and applicable to a large variety of aldehydes. This strategy can also encompass organocatalytic enantioselective coupling of α-branched aldehydes with thiols forming quaternary thioethers. Studies indicate a stereoselective formation of the intermediate followed by a stereospecific nucleophilic substitution reaction at a quaternary stereocenter, with inversion of configuration.

AB - Nucleophile–nucleophile coupling is a challenging transformation in organic chemistry. Herein we present a novel umpolung strategy for α-functionalization of aldehydes with nucleophiles. The strategy uses organocatalytic enamine activation and quinone-promoted oxidation to access O-bound quinol-intermediates that undergo nucleophilic substitution reactions. These quinol-intermediates react with different classes of nucleophiles. The focus is on an unprecedented organocatalytic oxidative α-thiolation of aldehydes. The reaction scope is demonstrated for a broad range of thiols and extended to chemoselective bioconjugation, and applicable to a large variety of aldehydes. This strategy can also encompass organocatalytic enantioselective coupling of α-branched aldehydes with thiols forming quaternary thioethers. Studies indicate a stereoselective formation of the intermediate followed by a stereospecific nucleophilic substitution reaction at a quaternary stereocenter, with inversion of configuration.

KW - bioconjugation

KW - enantioselective α-thiolation

KW - organocatalysis

KW - oxidative thiolation

KW - umpolung

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JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

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Umpolung Strategy for α-Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles

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Keywords

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