C3-Symmetric Boron Lewis Acid with a Cage-Shape for Chiral Molecular Recognition and Asymmetric Catalysis

Article abstract of DOI:10.1002/chem.201605712

Chiral Lewis acids play an important role in the precise construction of various types of chiral molecules. Here, a cage-shaped borate 2 was designed and synthesized as a chiral Lewis acid that possesses a unique C₃-symmetric structure composed of three homochiral binaphthyl moieties. The highly symmetrical structure of 2 with homochirality was clearly elucidated by X-ray crystallographic analysis. The peculiar chiral environment of 2?THF exhibited chiral recognition of some simple amines and a sulfoxide. Moreover, the application of 2?THF to hetero-Diels–Alder reactions as a chiral Lewis-acid catalyst afforded the enantioselective products, which were obtained through an entropy-controlled pathway according to the analysis of the relationship between optical yield and reaction temperature. In particular, the robust chiral reaction field of 2?THF allowed the first example of an asymmetric hetero-Diels–Alder reaction with a simple diene despite the requirement of high temperature.

Full text of DOI:10.1002/chem.201605712

A Journal of
Accepted Article
Title: C3-Symmetric Boron Lewis Acid with a Cage-Shape for Chiral
Molecular Recognition and Asymmetric Catalysis
Authors: Akihito Konishi, Koichi Nakaoka, Hikaru Maruyama, Hideto
Nakajima, Tomohiro Eguchi, Akio Baba, and Makoto Yasuda
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To be cited as: Chem. Eur. J. 10.1002/chem.201605712
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C3-Symmetric Boron Lewis Acid with a Cage-Shape for Chiral
Molecular Recognition and Asymmetric Catalysis
Akihito Konishi,[a,b] Koichi Nakaoka,[a] Hikaru Maruyama,[a] Hideto Nakajima,[a] Tomohiro Eguchi,[a] Akio
Baba,[a] and Makoto Yasuda*[a]
Abstract: Chiral Lewis acids have played an important role in the
precise construction of various types of chiral molecules. Here, we
designed and synthesized a cage-shaped borate 2 as a chiral Lewis
acid, which possesses a unique C3-symmetric structure composed of
three homochiral binaphthyl moieties. The highly symmetrical
structure of 2 with homochirality was clearly elucidated by X-ray
crystallographic analysis. The peculiar chiral environment of 2·THF
examples giving high enantioselectivity have been reported using
C3-symmetric trisimidazoline as an organocatalyst for carbon-
carbon bond formation or cyclization reactions.[14–16] In this
context, the design of a novel type of C3-symmetric Lewis acid for
chiral recognition remains a challenging problem. Here, we have
synthesized a new type of C3-symmetric chiral Lewis acid that has
a rigid structure and a cage-shaped ligand framework. These
exhibited the chiral recognition of some simple amines and a sulfoxide. have shown effective recognition of simple amines and the
Moreover, the application of 2·THF to hetero Diels-Alder reactions as
a chiral Lewis acid catalyst successfully gave the enantioselective
products, which proceeded through an entropy-controlled path
according to the analysis of the relationship between optical yield and
reaction temperature. In particular, the robust chiral reaction field of
2·THF allowed the first example of an asymmetric hetero Diels-Alder
reaction using a simple diene despite the requirement of high
temperature.
possibility of application to some organic reactions.
We recently reported a cage-shaped borate 1 with an
intramolecular triaryloxy ligand, as shown in Figure 1 (A). These
exist as a racemic mixture of helical structures of P- and M-
forms.[17–19] The enantiomers lie in a fast interconversion between
the two forms, even at room temperature, and, thus, one or two
of them seem impossible to isolate under usual conditions. We
also succeeded in synthesizing ortho-aryl substituted or
heteroaromatic ring-fused cage-shaped borates, which also exist
as a racemic mixture.[17,20,21] As shown in Figure 1 (B), if the
phenyl groups in the cage-shaped borate 1 are replaced by
binaphthyl units like 2, which have an axial chirality, the borate
gives diastereomers rather than enantiomers. The equilibrium
may lie at one side of the two diastereomers and thus a single
isomer could be isolated for chiral recognition.
Chiral Lewis acids contribute to organic synthesis in the
construction of various types of stereocontrolled molecules, and
numerous studies of them have been reported.[1,2] Most have C2-
symmetric structures probably due to the ease of preparation and
a mechanism that allows chiral recognition.[3] Surprisingly, studies
of Lewis acids with C3-symmetric structures for chiral recognition
are scarce. Therefore, few strategies for the design of C3-
symmetric Lewis acids are available for chiral recognition or
asymmetric catalysis. Some C3-symmetric Lewis acids[4–8] have
been prepared, but in most cases they exist as a racemic mixture
and are not separated as individual enantiomers because of the
relatively low energy barrier between them.[9,10] Bull and Davidson,
et al., prepared a pseudo-C3-symmetric titanium Lewis acid with
a propeller-like chirality,[11] which was applied to the asymmetric
oxidation of sulfide, although the enantioselectivity was moderate
even in the highest case.[12] The ligation of an optically active
substrate to a racemic C3-symmetric Lewis acid induces
homochirality on the complex, and its effective steric environment
leads to a high stereoselective reaction system.[13] A few
Figure 1. C3-symmetric cage-shaped borate in conformational exchange. A)
The cage-shaped borate 1 exists in an enantiomeric mixture. B) The cage-
shaped borate 2 with a binaphthyl unit that has a homo axial chirality exists in a
diastereomeric mixture.
[a]
Dr. A. Konishi, K. Nakaoka, H. Maruyama, Dr. H. Nakajima, T.
Eguchi, Prof. Dr. A. Baba, Prof. Dr. M. Yasuda
Department of Applied Chemistry
Graduate School of Engineering
Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871 (Japan)
E-mail: yasuda@chem.eng.osaka-u.ac.jp
Dr. A. Konishi
Center for Atomic and Molecular Technologies,
Graduate School of Engineering,
The binaphthyl-containing chiral cage-shaped borate 2 was
synthesized starting from readily available (R)-1,1’-bi-2-naphthol
(BINOL), as shown in Scheme 1. Preparation of methoxy-
binaphthyl 3[22] from (R)-BINOL[23,24] and its lithiation at the ortho-
position followed by condensation with ethyl chloroformate gave
tris(2-methoxybinaphthyl)methanol 4. Reduction of the carbinol 4
[b]
Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871 (Japan)
Supporting information for this article is given via a link at the end of
the document.
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by a Me2SiHCl/InCl3 system[25] and deprotection of methoxy
groups afforded the tris(2-hydroxybinaphthyl)methane 6 with axial
chirality at three binaphthyl moieties. Mixing the compound 6 with
BH3·THF at 60 °C for 8 h generated the cage-shaped borate
2·THF with a release of H2, which was ligated by THF, in a
quantitative yield.[26] A ligand exchange readily took place in the
presence of 3,5-dibromopyridine without a dissociation of the
cage-shaped ligand to give 2·PyBr2.
To estimate the peculiarities of 2 based on its C3-symmetric
homochiral cage shapes as a chiral Lewis acid, the molecular
recognition of chiral amines was first examined. High chiral
recognition of functional amines[28] and ammonium ions were
attained,[29,30] because these have extra interaction sites with the
Lewis acid center, but a molecular recognition of simple neutral
amines has been limited.[31] Although supramolecular
nanocapsules assembled from cyclodextrin derivatives effectively
resolve simple aromatic amines in specific cases,[32] the ability of
chiral recognition has been moderate for simple amines and
remains a challenging problem.
Figure 2. X-ray crystal structures of 2·PyBr2. Thermal ellipsoids are at the 50%
probability level. Some hydrogens are omitted for clarity. A) Side view. B) Top
view (3,5-dibromopyridine is omitted for clarity).
We have examined racemic 1-phenylethylamine 7 for chiral
recognition via use of the homochiral cage-shaped borate 2·THF
(Figure 3 and Table 1, see also Figure S1). The mixture of an
excess amount of racemic 1-phenylethylamine
7 to the
Scheme 1. Synthesis of homochiral cage-shaped borate 2 with C3-symmetry.
homochiral cage-shaped borate 2·THF in CD2Cl2 was observed
via 1H NMR measurement (Figure 3 (A)). After mixing 7 with
2·THF for 5 min at room temperature, the homochiral cage-
shaped borate 2 definitely formed diastereomeric complexes with
the amine as a 1:1 mixture of R- and S- amine adducts with 2.
The new two-doublet signals, which corresponded to the methyl
protons of the diastereomeric complexes of the amine with 2,
1
The H NMR spectra of the cage-shaped borates ligated
with THF or 3,5-dibromopyridine (2·THF and 2·PyBr2) clearly
showed the existence of a single isomer of two possible
diastereomers in CDCl3 solution at room temperature (see
supporting information). After complexation, an up-field shift of the
tethered C-H and a downfield shift of the 4-H of naphthyl ring were
1
discretely appeared at around -1 ppm in the H NMR spectrum,
presumably because the ring current from the rigid binaphthyl
moieties effectively separated these signals from those of free
amines. However, after the mixture was allowed to stand for 43 h
at 80 °C, the 1H NMR spectrum of the amine adducts dramatically
changed and clearly showed the convergence of the signals into
that of a diastereomeric complex; while the signal of the S amine
adduct with 2 at -0.72 ppm almost disappeared, but the intensity
of the signal of the R amine adduct with 2 at -0.99 ppm increased.
The ratio between R- and S- amine adducts with 2 reached 18:1
(Entry 1 in Table 1), showing the highly selective enantio
recognition of the simple amine.
1
observed in the H NMR spectra probably because of the rigid
structure of the complex. The signal of the ligating pyridine
appeared in the up-field shift region by anisotropic effect of the
neighboring naphthyl groups.[20] Changing the temperature from -
50 to 50 °C did not affect the spectra of the diastereomeric mixture.
The helical structure was not changed, and the equilibrium
overwhelmingly stayed on the one side.
The dibromopyridine-ligated complex gave a suitable crystal
in X-ray analysis, and its ORTEP drawings are shown in Figure
2.[27] A robust C3-symmetric structure surrounded by three
naphthyl groups was determined. All binaphthyl axes had (S)-
forms that originated from the starting (R)-BINOL, and a propeller
structure around boron had a (P)-type. The top view clearly shows
the C3-symmetric structure of this complex. The one species of a
homochiral diastereomer existed in either solution or solid-states
due to the large energy difference between the diastereomers.
When
racemic
1-(2-naphthyl)ethylamine
8
was
employed,[32] the chiral recognition of 8 with 2·THF was more
significant. After achieving equilibrium between the free amine
and the amine adduct with 2, the ratio reached a higher level of
R:S (amine adducts with 2·THF) at 23:1 (Figure 3 (B) and Entry 2
in Table 1). An effective recognition of the chirality of amines by
chiral metal complexes is known only in the case of functionalized
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amines with chelation ability to the metal center.[28] In our case,
higher recognition was successful when using a C3-symmetrical
cage-shaped chiral borate.
Next, in order to investigate the catalytic ability of the chiral
borate complex for an asymmetric synthesis as a chiral Lewis acid,
the reaction of a cycloaddition of the Danishefsky diene 10 with
aldehydes 11a and b in hetero Diels-Alder reactions was chosen
as a model transformation (Table 2 (A)). In the use of
benzaldehyde 11a, the cycloadduct 12a was obtained in 77%
yield with 31% enantiomeric excess (ee) (Entry 1). Higher
enantioselectivity and yields were successfully obtained using
cyclohexanecarboxaldehyde 11b, which gave 84% ee in 78%
yield (Entry 2). The replacement of a nucleophile from the
Danishefsky diene to allyltributylstannane 13 simultaneously
supported a good yield and high selectivity (Table 2 (B)); after
optimization of the reaction conditions, the reaction with 5.0 mol%
of 2·THF at 60 °C afforded the corresponding carbonyl adduct 14
in 71% yield with 89% ee (entry 2).
PPM
PPM
-0.6
-0.7
-0.8
-0.9
-1.0
-1.1
-0.6
-0.7
-0.8
-0.9
-1.0
-1.1
Table 2. Asymmetric reactions using chiral cage-shaped borate 2·THF.
PPM
-1.0
PPM
-0.5
-0.6
-0.7
-0.8
-0.9
-0.5
-0.6
-0.7
-0.8
-0.9
Figure 3. 1H NMR spectra of the amine adducts with 2·THF around the methyl
proton signals in CD2Cl2. A) 1-phenylethylamine and B) 1-(2-
7
naphthyl)ethylamine with 2·THF; (left) After mixing the amine with 2·THF for 5
min at room temperature, and (right) after achieving equilibrium at 80 °C.
In the use of methyl phenyl sulfoxide 3, even at the initial
stage after mixing of the sulfoxide with 2·THF, a ratio of 7:1 was
observed and remained unchanged after further stirring for
several hours (Entry 3 in Table 1, and Figure S2). As a low Lewis
basicity of the sulfoxide compared to amines, a fast ligand
exchange and fast equilibrium between the diastereomeric
adducts was accomplished due to the robust and highly
symmetric chiral environment of 2·THF.
Table 1. Recognition of chiral substrates by complexation with 2·THF.
We found an interesting relationship between the reaction
temperature and enantioselectivity, which was notably observed
in the case of the reaction of the Danishefsky diene 10 with 1-
naphthaldehyde 11c (Table 3). Elevating the temperature led to a
higher level of enantioselectivity, and a lower temperature
afforded lower selectivity and the opposite stereoisomer.[33] These
results suggest that the entropic effect in the transition state is
more important than enthalpy in this system. The aldehyde-borate
complex could be attacked by the Danishefsky diene from either
face of the carbonyl group. The difference in the activation
enthalpy, H‡, between them should have been small, but the
difference in the activation entropy S‡ was relatively large
owing to the steric demands of aryl substituents on the substrate
and the catalyst. As shown in Figure S3, we estimated the H‡
and S‡ values from the plot of ln [(100 + %ee)/(100 - %ee)] as
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Table 4. Asymmetric reactions using chiral cage-shaped borate 2·THF.
a function of the reciprocal of temperature (1/T) to afford 6.72
kJ/mol and 27.2 J/(mol·K), respectively. These values suggest
that the entropy term (TS) should be a dominant factor in
determining the reaction profile above room temperature. This
property enables reactions to accelerate at higher temperatures
with increases in enantioselectivity that are uncommon in organic
synthesis.
Table 3. Relationship between temperature and enantioselectivity in the
reaction of the Danishefsky’s diene 10 with 1-naphthaldehyde 11c catalyzed by
2·THF.
In summary, a new type of Lewis acid with C3-symmetry
showed unique properties by recognizing simple amines and an
asymmetric catalyst. A sterically hindered reaction field was
important for the recognition of chirality and an interesting
temperature dependency of enantioselectivity. This borate could
be an important template for C3-symmetric Lewis acid chemistry
as a novel type of chiral Lewis acids.
Acknowledgements
This work was supported by JSPS KAKENHI Grants Number
JP15H05848 in Middle Molecular Strategy and JP16K21137. A.K.
also thanks the Hattori Hokokai Foundation for financial support.
We thank Dr. Nobuko Kanehisa for valuable advice regarding X-
ray crystallography. Thanks are due to Mr. H. Moriguchi, Faculty
of Engineering, Osaka University, for assistance in obtaining the
MS spectra.
We suspected that this catalyst 2·THF could work even at
high temperature, although it was not desirable for a general
asymmetric synthetic procedure. An asymmetric hetero Diels-
Alder reaction using a simple diene was a very challenging
problem[34] for organic synthesis because it has low reactivity and
requires high temperature, as well as either a large amount of
catalytic loading, or an extended reaction time to complete the
reaction. Therefore, the cage-shaped chiral borate 2·THF was
applied to the reaction system of the simple diene 15 with p-
cyanobenzaldehyde 11d and gratifyingly afforded the product 16
enantioselectively. At room temperature, the yield was quite low
(17%) as expected, but 60% ee was obtained (Entry 3 in Table 4).
Higher temperature reasonably improved the yields and
surprisingly only a minimal loss of enantioselectivity with a greater
than 50% ee (Entry 1). After optimization of the reaction
conditions, neat conditions at 60 °C gave the product in 78% yield
with 58% ee (Entry 2). It should be noted that this represents the
first example of an asymmetric hetero Diels-Alder reaction using
a simple diene. The robust chiral reaction field of our Lewis acid
catalyst, which is a result of sterically congested aromatic systems,
could successfully lead to the compatibility of high reactivity and
acceptable enantioselectivity even at high temperature.
Keywords: Chiral Lewis acid • Cage-shaped borate • Hetero
Diels-Alder reaction • Chiral molecular recognition • binaphthyl
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Akihito Konishi, Koichi Nakaoka, Hikaru
Maruyama, Hideto Nakajima, Tomohiro
Eguchi, Akio Baba, and Makoto
Yasuda, *
Chiral Cage-shaped Borate: C3-
symmetric cage-shaped borate with
homochiral binaphthyl cores was
synthesized and characterized as a
single diastereomer. This borate
exhibited chiral recognition and
behaved as a chiral Lewis acid catalyst
with an unusual relationship between
stereoselectivity and temperature. The
robust and high-symmetric chiral
environment given by the binaphthyl
cores characterized the peculiar
stereoselective reactivity.
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C3-Symmetric Boron Lewis Acid with
a Cage-Shape for Chiral Molecular
Recognition and Asymmetric
Catalysis
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