TY - JOUR
T1 - Enantioselective α-Etherification of Branched Aldehydes via an Oxidative Umpolung Strategy
AU - Lamhauge, Johannes N.
AU - Corti, Vasco
AU - Liu, Yidong
AU - Jørgensen, Karl Anker
PY - 2021/8
Y1 - 2021/8
N2 - 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 SN2 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.
AB - 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 SN2 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.
KW - DKR
KW - organocatalysis
KW - oxidative coupling
KW - umpolung
KW - α-etherification
UR - http://www.scopus.com/inward/record.url?scp=85111995344&partnerID=8YFLogxK
U2 - 10.1002/anie.202105721
DO - 10.1002/anie.202105721
M3 - Journal article
C2 - 34087048
AN - SCOPUS:85111995344
SN - 1433-7851
VL - 60
SP - 18728
EP - 18733
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 34
ER -