Chemistry and Physics Faculty Articles

Title

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

Document Type

Article

Publication Date

10-9-2019

Publication Title

Angewandte Chemie International Edition

Keywords

Bioconjugation, Enantioselective α-thiolation, Organocatalysis, Oxidative thiolation, Umpolung

ISSN

1433-7851

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.

Comments

©2019 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim

Additional Comments

Villum Fonden grant #: 25867

ORCID ID

0000-0002-0566-0820

ResearcherID

V-6501-2018

DOI

10.1002/anie.201911793

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Peer Reviewed

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