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

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DOI

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 languageEnglish
JournalAngewandte Chemie - International Edition
Volume58
Issue49
Pages (from-to)17856-17862
ISSN1433-7851
DOIs
Publication statusPublished - 2 Dec 2019

    Research areas

  • bioconjugation, enantioselective α-thiolation, organocatalysis, oxidative thiolation, umpolung

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