10.1002/anie.202105721
Angewandte Chemie International Edition
RESEARCH ARTICLE
observed absolute configuration of the chiral ethers 4 is the result
of hydrogen-bonding interactions between the tertiary amine
moiety in the catalyst and the incoming oxygen nucleophile.[12c]
This hypothesis is further corroborated by the observation of a
linear relationship correlating electron-poor phenols to higher
enantioselectivities (Scheme 4b). Hydrogen-bond interactions
have also been invoked to explain opposite absolute configuration
when using indole as the nucleophile in related
transformations.[12a,d] Based on these observations, together with
recent reports from our group about the mechanistic nature of
quinone-mediated oxidative coupling reactions,[12d] a mechanistic
proposal is outlined in Scheme 4d. The racemic quinol
intermediate 9 exists in a catalyst promoted dynamic equilibrium
between its enantiomers, promoted by successive substitutions
with tetrafluoro-1,4-benzoquinol (TFQ-H2) on (R)-I and (S)-I via
TS-I (Scheme 4c). We propose this to be a dynamic Walden-type
cycle. In the presence of nucleophile 3a, irreversible substitution
on (S)-I occurs (via TS-II, Scheme 4c), resulting in the observed
absolute configuration of (R)-4aa. Importantly, the catalyst is able
to facilitate both the racemization of 9 and the discrimination
between (R)-I and (S)-I for substitution with 3a. Although SN2
substitutions at tetrasubstituted centers with oxygen-based
nucleophiles are rare, phenols have been reported to react at the
-position to a carbonyl functionality.[2b,c, 20]
In conclusion, we have developed an aminocatalytic, oxidative
umpolung strategy for the direct enantioselective α-etherification
of aldehydes, allowing for asymmetric construction of highly
substituted chiral ethers using simple feedstock oxygen-based
nucleophiles. The proposed reaction mechanism is based on an
aminocatalytically promoted SN2 dynamic-kinetic resolution of
racemic intermediates. The methodology has a wide functional-
group tolerance and exhibits a broad scope with respect to the
hydroxyl coupling partners onto a range of α-branched aldehydes,
providing enantioselectivities up to 95% ee. We have showed that
the enantioenriched products are amenable of further synthetic
elaboration and we have proposed a possible mechanistic
scenario accounting for the observed absolute configuration. The
present work also demonstrates, how the quinone oxidant can be
tailored to expand the scope of suitable nucleophiles.
Acknowledgements
KAJ thanks Villum Investigator grant (no. 25867), Carlsberg
Foundation “Semper Ardens” and Aarhus University for financial
support. We thank Dr. Gabriel J. Reyes‐Rodríguez, Dr. Jakob
Blom, Dr. Lars A. Leth, Casper L. Barløse, and Matilde Rusbjerg
for their contributions to initial discoveries and optimizations.
Gratitude is expressed to Dr. Nomaan M. Rezayee and Dr. Lisa-
Marie Mohr for fruitful discussions and collaboration in the
preparation of substrates and catalysts.
Scheme 4. a) Formation of 4aa from isolated intermediate 9 (left).
Formation of 4aa with the isosteric catalyst 2c (right). b)
Correlating enantiomeric ratios (er) of 4 to para-Hammett values.
c) Proposed transition states for racemization of intermediate (TS-
I) and enantioselective product formation (TS-II). d) Mechanistic
proposal for the formation of 4aa. Ar: 6-Methoxynaphth-2-yl.
Keywords: α-etherification • DKR • organocatalysis • oxidative
coupling • umpolung.
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