Angewandte
Communications
Chemie
Organocatalysis
Enantioselective Synthesis of Chiral Oxime Ethers: Desymmetrization
and Dynamic Kinetic Resolution of Substituted Cyclohexanones
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Abstract: Axially chiral cyclohexylidene oxime ethers exhibit
axes which arise from the restricted rotation about the C N
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unique chirality because of the restricted rotation of C N. The
bond and high activation energy barrier for nitrogen inver-
sion.[8] To date, only two reports have described the enantio-
selective resolution of chiral cyclohexylidene oximes. In 1990,
Toda first reported the successful isolation of optically active
oximes by the conventional second-order asymmetric trans-
formation starting from racemic compounds (Scheme 1a)[9]
first catalytic enantioselective synthesis of novel axially chiral
cyclohexylidene oximes has been developed by catalytic
desymmetrization of 4-substituted cyclohexanones with
O-arylhydroxylamines and is catalyzed by a chiral BINOL-
derived strontium phosphate with excellent yields and good
enantioselectivities. In addition, chiral BINOL-derived phos-
phoric acid catalyzed dynamic kinetic resolution of a-sub-
stituted cyclohexanones has been performed and yields versa-
tile intermediates in high yields and enantioselectivities.
T
he development of novel asymmetric reactions has been
one of the prime foci of modern synthetic organic chemistry.
Substantial advances have been made in asymmetric synthesis
of compounds with central chirality by using transition metals
and organocatalytic methods. In addition, compounds with
axial chirality, planar chirality, and helical chirality have
attracted recent attention because of their importance in
synthesis and asymmetric catalysis.[1] Axially chiral com-
pounds, also known as atropisomers, exhibit unique chirality
because of the non-coplanar arrangement of groups about an
imaginary axis. This arrangement is attributed to the
restricted rotation around either a single or double bond.[2]
Although the first axially chiral compound was observed in
1910,[3] their importance was not realized until recently as
a consequence of their occurrence in natural products and
their application as chiral ligands.[4] Over the last decade,
tremendous progress has been made for the synthesis of
axially chiral biaryls, allenes, spiranes, and cyclohexylidenes.[5]
However, methods for catalytic enantioselective synthesis of
cyclohexylidene oximes and its analogues are scarce.
Scheme 1. Synthesis of chiral cyclohexylidene oximes.
Later, in 1994, Hoshino et al. demonstrated the kinetic
resolution of phenylcyclohexanone oxime esters by lipase-
catalyzed transesterification[9b] to give optically active oximes
and oxime esters (Scheme 1b). Herein, we report the first
enantioselective synthesis of chiral cyclohexylidene oxime
ethers by desymmetric condensation of 4-phenylcyclohexa-
none with aryloxyamine catalyzed by a chiral BINOL
phosphate complex (Scheme 1c). We further applied this
methodology in the dynamic kinetic resolution of 2-substi-
tuted cyclohexanones.
Oximes and oxime ethers are versatile intermediates and
key structural motifs present in several biologically active
compounds which exhibit medicinal properties.[6] Recent
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progress in C H activation proved that oxime ethers are
efficient directing groups in several synthetic transforma-
tions.[7] Chiral cyclohexylidene oximes contain stereogenic
Desymmetrization and dynamic kinetic resolution (DKR)
processes are represented as powerful synthetic tools for
converting meso or prochiral substrates into enantiopure
compounds.[10] Versatile desymmetrization reactions of pro-
chiral cyclohexanones by Michael addition,[10c–e] aldol reac-
tion,[10f–h] Schmidt reaction,[10i,j] and Baeyer–Villiger oxida-
tion[10k–m] have been reported. The group of List[11] developed
elegant strategies for catalytic asymmetric Fischer indole
synthesis and chiral indoline synthesis with substituted cyclo-
hexanone-derived phenylhydrazones using chiral phosphoric
[*] S. K. Nimmagadda, Dr. L. Woztas, Prof. Dr. J. C. Antilla
Department of Chemistry, University of South Florida
4202 East Fowler Avenue, CHE 205A, Tampa, FL 33620 (USA)
E-mail: jantilla@usf.edu
S. C. Mallojjala, Prof. S. E. Wheeler
Department of Chemistry, Texas A&M University
College Station, TX 77843 (USA)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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