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Umpolung Strategy for α‐Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles
Author(s) -
Blom Jakob,
ReyesRodríguez Gabriel J.,
Tobiesen Henriette N.,
Lamhauge Johannes N.,
Iversen Marc V.,
Barløse Casper L.,
Hammer Niels,
Rusbjerg Matilde,
Jørgensen Karl Anker
Publication year - 2019
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201911793
Subject(s) - nucleophile , chemistry , umpolung , stereocenter , enantioselective synthesis , organocatalysis , combinatorial chemistry , enamine , bioconjugation , organic chemistry , catalysis
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.