Enantioselective Synthesis of Chiral Oxime Ethers: Desymmetrization and Dynamic Kinetic Resolution of Substituted Cyclohexanones

Article abstract of DOI:10.1002/anie.201611602

Axially chiral cyclohexylidene oxime ethers exhibit unique chirality because of the restricted rotation of C=N. The 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 phosphoric acid catalyzed dynamic kinetic resolution of α-substituted cyclohexanones has been performed and yields versatile intermediates in high yields and enantioselectivities.

Full text of DOI:10.1002/anie.201611602

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201611602
German Edition: DOI: 10.1002/ange.201611602
Organocatalysis
Enantioselective Synthesis of Chiral Oxime Ethers: Desymmetrization
and Dynamic Kinetic Resolution of Substituted Cyclohexanones
Sri Krishna Nimmagadda, Sharath Chandra Mallojjala, Lukasz Woztas, Steven E. Wheeler, and
Jon C. Antilla*
=
Abstract: Axially chiral cyclohexylidene oxime ethers exhibit
axes which arise from the restricted rotation about the C N
=
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
À
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:
http://dx.doi.org/10.1002/anie.201611602.
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acid.[12] Inspired by these results, and our continuous interest
in chiral BINOL-derived phosphoric acid and phosphate
complexes,[13] we envisioned the asymmetric synthesis of
benzofurans could be feasible by reacting 4-substituted
cyclohexanones with phenoxyamines in a similar fashion.
To investigate our hypothesis, we started with the reaction
of O-phenylhydroxylamine (1) with 4-phenyl cyclohexanone
(2) in dichloromethane at 458C using P1. Unfortunately, we
did not observe the benzofuran product 4, but full conversion
of the starting materials into the condensed product, the
cyclohexylidene oxime ether 3 was obtained (Table 1). To our
Table 1: Optimization of reaction conditions for desymmetrization of
4-phenyl cyclohexanone.[a]
Scheme 2. Substrate scope for the synthesis of chiral cyclohexylidene
oximes.[20]
and excellent yields (3b,c). The 3,5-disubstituted and 2,4-
disubstituted phenyl substrates offered little improvement in
selectivity (3d,e). The absolute configuration for 3b was
assigned based on the X-ray crystal structure[20] and all other
compounds were assigned analogously. It is noteworthy that
the phenyl group of 1 is pivotal for enantiomeric induction, as
using aliphatic oxyamines afforded only racemic products.
Similarly, the scope for 4-substituted cyclohexanones,
substrates with both electron-releasing and electron-with-
drawing groups on the phenyl group are well tolerated
(Scheme 3). Even the aliphatic groups, 4-methyl and 4-ethyl,
afforded good enantioselectivities (3m,n). Our efforts to
further extend the utility for these novel chiral compounds in
asymmetric benzofuran synthesis failed to retain the enantio-
selectivity.[14]
Entry
Catalyst
Solvent
T [8C]
t [h]
16
16
2
ee [%][b]
1[c]
2[c]
3[c]
4
5
6
7
8
9
P1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
toluene
THF
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
45
45
RT
RT
RT
RT
RT
RT
RT
10
54
62
62
64
40
64
58
52
70
91
83
Mg(P1)2
Mg(P1)2
Ca(P1)2
Mg(P1)2
Mg(P1)2
Mg(P1)2
Mg(P1)2
Mg(P1)2
Mg(P1)2
Sr(P1)2
P1
0.5
0.5
0.5
0.5
0.5
0.5
2
10
11
12
À78
À78
À78
2
2
[a] Reaction conditions: 1 (0.15 mmol), 2 (0.22 mmol), catalyst
(5 mol%) [b] Determined by chiral-phase HPLC analysis. [c] Without
molecular sieves. M.S.=molecular sieves, THF=tetrahydrofuran.
surprise Mg(P1)2 gave 3 with 54% enantiomeric excess (ee).
Intrigued by the unique stereoselectivity of these unprece-
dented compounds, we proceeded to optimize the reaction
conditions. The condensation of 1 and 2 proceeds smoothly at
room temperature with Mg(P1)2 in presence of molecular
sieves, and showed slightly better selectivity than Ca(P1)2
(entries 4 and 5). Screening of solvents was not helpful
increasing the stereoselectivity compared to that for dichloro-
methane (entries 6–9). Lowering the reaction temperature to
À788C improved the enantioselectivity to 70% (entry 10). To
our delight, Sr(P1)2 in dichloromethane at À788C proved to
be the ideal conditions for the axially chiral 3 with good
enantioselectivity.
With the optimal reaction conditions in hand, we then
explored the substrate scope for this desymmetrization
reaction. As shown in (Scheme 2), substituents on the para
position of the phenyl ring of 1 gave good enantioselectivity
Scheme 3. Substrate scope for the synthesis of chiral cyclohexylidene
oximes.
2
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Table 2: Optimization of reaction conditions for dynamic kinetic reso-
lution of 2-phenyl cyclohexanones.[a]
To gain additional insight into the origin of stereoselec-
tivity, we examined entry 12 of Table 1 at the PCM-wB97X-
D/def2-TZVP//PCM-B97-D/def2-TZVP level of theory,[15]
thereby computing free energies within the quasi-RRHO
approximation of Grimme.[16] The stereocontrolling step is the
dehydration of the intermediate alcohol in the presence of the
chiral phosphoric acid in an E1-like process, as depicted in
Figure 1. In this transition state (TS), the substrate is bound to
Entry
Catalyst
Solvent
T [8C]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
P1
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
À78
84
76
80
60
56
74
75
58
75
86
20
38
13
97
90
60
82
94
93
88
Mg(P1)2
Sr(P1)2
Mg(P1)2
Ca(P1)2
Mg(P1)2
Mg(P1)2
Mg(P1)2
Mg(P1)2
P1
À78
À78
À78
À78
À30
À50
À65
À65 to À50
À70 to À50
10
[a] Reaction conditions: 1e (0.07 mmol), 5 (0.05 mmol), catalyst
(5 mol%) [b] Yield of isolated product. [c] Determined by chiral-phase
HPLC analysis.
groups showed that O-(2,4-dinitrophenyl)hydroxylamine
(1e) in dichloromethane at À788C showed improvement in
selectivity with moderate yield (Table 2, entry 2). Interest-
ingly, by changing the solvent to toluene both Mg(P1)2 and
Ca(P1)2 furnished products with excellent enantioselectivity
but with moderate yields (entries 4 and 5). Upon screening
various conditions, it became clear that there was strong
temperature dependence for this reaction. Lower yields could
be attributed to decomposition of the starting hydroxylamine
because of subdued kinetics in the condensation process,
under lower temperatures. However, raising the temperature
often afforded poorer stereoinduction. To our delight, by
slowly increasing the temperature from À708C to À508C in
toluene with P1 as a catalyst, good yield and enantioselectiv-
ity of 6 could be attained. Having established the optimized
reaction conditions, a variety of substrates 5 were synthesized.
Electron-releasing groups and electron-withdrawing groups
are tolerated and lead to good yields and enantioselectivities
(Scheme 4; 6a–f). Even an alkyl and chloro group in the
a-position of the cyclohexanone gave excellent enantioselec-
tive products.
Further utility of these compounds was demonstrated by
the reduction of 6a with BH3·THF followed by N-acetylation
to yield cis-7 (Scheme 5).[18] The absolute configuration for
the 2-substituted cyclohexanone oxime ethers 6 was assigned
by comparison with 7, which was reported in literature.
In conclusion, we have developed an efficient catalytic
asymmetric reaction for the desymmetrization of 4-phenyl
cyclohexanones to novel axially chiral cyclohexylidene oxime
ethers. To show the utility of this methodology, we have
demonstrated the DKR[19] process of a-branched cyclohex-
anones to yield useful products. A computational study of the
desymmetrization of a 4-substituted cyclohexanone is in
excellent agreement with the obtained experimental ee val-
ues, and provides insight into the mode of stereoinduction.
Figure 1. Computed TS structures leading to the favored (TS) and
disfavored (TS’) stereoisomeric oxime ethers, along with relative free
energies in kcalmolÀ1
.
the catalyst by an NH···O hydrogen-bonding interaction. The
phosphoric acid simultaneously protonates the hydroxy group
as it leaves as a water molecule. An extensive conformational
search (see Table S2 in the Supporting Information) yielded
the lowest-lying TS structures leading to the favored and
disfavored stereoisomers of the oxime ether shown in
Figure 1. The corresponding free-energy difference between
these two structures (1.2 kcalmolÀ1) leads to a computed ee
value of 91%, which is in reasonable agreement with the
experimental value. This computed ee value is improved to
80% upon consideration of a Boltzmann weighted sum of all
TS conformations, and is in excellent agreement with the
experimental value (83%; Table 1). Upon examining the
lowest-lying structures in Figure 1, the favored TS exhibits
greater shape complementarity between the substrate and
chiral binding pocket of the catalyst, thus leading to a more
favorable NH···O interaction (as reflected in the H···O
distances; see Figure 1), as well as stabilizing CH···p inter-
actions with one of the aryl substituents of the catalyst.
We envisioned, this methodology could also be used in the
DKR of 2-substituted cyclohexanones. The group of List[17]
reported an efficient direct reductive amination of a-
branched ketones by a DKR process catalyzed by chiral
BINOL phosphoric acid. Screening of different O-protecting
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Keywords: chirality · enantioelectivity · kinetic resolution ·
organocatalysis · oximes
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Acknowledgments
The synthetic work was supported by internal start-up
funding at the University of South Florida. The work at
TAMU was supported by the National Science Foundation
(Grant CHE-1266022) and The Welch Foundation (Grant A-
1775). Portions of this work were performed with high
performance research computing resources provided by
Texas A&M University (http://hprc.tamu.edu).
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Conflict of interest
The authors declare no conflict of interest.
4
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[20] CCDC 1491317 (3b) contains the supplementary crystallo-
graphic data for this paper. These data are provided free of
charge by The Cambridge Crystallographic Data Centre.
[13] For recent publications from our lab: a) S. K. Nimmagadda, Z.
Zhang, J. C. Antilla, Org. Lett. 2014, 16, 4098; b) G. Ingle, M. G.
Manuscript received: November 28, 2016
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Organocatalysis
An ax to grind: A enantioselective syn-
thesis of axially chiral cyclohexylidene
oximes has been developed by catalytic
desymmetrization of 4-substituted cyclo-
hexanones with O-arylhydroxylamines in
the presence of a chiral BINOL-derived
strontium phosphate. In addition, the
dynamic kinetic resolution of a-substi-
tuted cyclohexanones has been per-
formed and yields versatile intermediates
in high yields and enantioselectivities.
M.S.=molecular sieves.
S. K. Nimmagadda, S. C. Mallojjala,
L. Woztas, S. E. Wheeler,
J. C. Antilla*
&&& — &&&
Enantioselective Synthesis of Chiral
Oxime Ethers: Desymmetrization and
Dynamic Kinetic Resolution of
Substituted Cyclohexanones
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!