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Enantioselective α‐Etherification of Branched Aldehydes via an Oxidative Umpolung Strategy
Author(s) -
Lamhauge Johannes N.,
Corti Vasco,
Liu Yidong,
Jørgensen Karl Anker
Publication year - 2021
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202105721
Subject(s) - umpolung , nucleophile , enantioselective synthesis , chemistry , kinetic resolution , organocatalysis , benzoquinone , amine gas treating , organic chemistry , combinatorial chemistry , phenol , catalysis
Saturated carbonyl compounds are, via their enolate analogues, inherently nucleophilic at the α‐position. In the presence of a benzoquinone oxidant, the polarity of the α‐position of racemic α‐branched aldehydes is inverted, allowing for an enantioselective etherification using readily available oxygen‐based nucleophiles and an amino acid‐derived primary amine catalyst. A survey of benzoquinone oxidants identified p ‐fluoranil and DDQ as suitable reaction partners. p ‐Fluoranil enables the preparation of α‐aryloxylated aldehydes using phenol nucleophiles in up to 91 % ee , following either a one‐step or a two‐step, one‐pot protocol. DDQ allows for a more general etherification protocol in combination with a broader range of alcohol nucleophiles with enantioselectivities up to 95 % ee . Control experiments and isolation of a key quinol intermediate supports a mechanism proceeding via an S N 2 dynamic‐kinetic resolution. These studies provide the basis for an aminocatalytic umpolung concept that allows for the asymmetric construction of tertiary ethers in the α‐position of aldehydes.