Inversion of the Axial Information during Oxidative Aromatization in the Synthesis of Axially Chiral Biaryls with Organocatalysis as a Key Step

Article abstract of DOI:10.1002/chem.201905814

The pot-economical, highly enantioselective synthesis of axially chiral biaryls was developed by using one-pot organocatalyst-mediated domino and aromatization reactions as key steps. The axial information of the precursor, which also has central chirality, was completely inverted in the final biaryls. The inversion of the axial information occurred in the conversion of the central chirality to the axial chirality of an oxidative aromatization step.

Full text of DOI:10.1002/chem.201905814

A Journal of
Accepted Article
Title: Inversion of the axial information during oxidative aromatization
in the synthesis of axially chiral biaryls using organocatalyst as a
key step
Authors: Seitaro Koshino, Akira Takikawa, Keiichi Ishida, Tohru
Taniguchi, Kenji Monde, Eunsang Kwon, Shigenobu
Umemiya, and Yujiro Hayashi
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To be cited as: Chem. Eur. J. 10.1002/chem.201905814
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10.1002/chem.201905814
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RESEARCH ARTICLE
Inversion of the axial information during oxidative aromatization
in the synthesis of axially chiral biaryls using organocatalyst as a
key step
Seitaro Koshino,[a] Akira Takikawa,[a] Keiichi Ishida,[a] Tohru Taniguchi,[b] Kenji Monde,[b] Eunsang
Kwon,[c] Shigenobu Umemiya,[a] Yujiro Hayashi*[a]
In memory of the late Professor Dieter Enders
Abstract: The pot economical highly enantioselective synthesis of
axially chiral biaryls was developed using one-pot reactions of
organocatalyst mediated domino reaction and aromatization as key
steps. The axial information of the precursor, which possesses also
the central chirality, was completely inverted in the final biaryls. The
inversion of the axial information occurred in the conversion of the
central chirality to the axial chirality of an oxidative aromatization step.
chirality, it does not possess a defined configuration of a
stereogenic axis because of free rotation around the C2-C1' axis.
Scheme 1. Relationship of the chirality of the intermediate and the axial chirality
of the product
Previous works
Chirality conversion from central to axial (J. Rodriguez, 2017)
O
O
CF3
O
Introduction
N
H
N
H
N
O
+
O
1’
Recently there has been a great interest in axially chiral
molecules due to their use in many different scientific areas. In
enantioselective reactions, for instance, they are used as ligands
in organometallic reactions[1] and catalysts in organocatalytic
reactions.[2] A large number of natural products are found to
possess axial chirality. Axial chirality influences biological
activities,[3] and some drugs are enantiomers of axially chiral
molecules.[4] Axial chirality also affects physical properties in
material science.[5] Thus, the stereoselective construction of
axially chiral molecules is important not only in the synthetic
organic chemistry but also in other scientific fields.
Many synthetic methods for the construction of axially chiral
biaryls have been developed due to their importance.[6] One of
the most representative methods is the enantioselective coupling
of two aryl units.[7] Other methods include axial selective
desymmetrization[8] and enantioselective biaryl construction.[9]
Besides these methods, "chirality conversion from central to
axial" is another strategy, in which central chirality is converted
into axial chirality.[10] A recent example is Rodriguez’s highly
stereoselective synthesis of axially chiral biaryls from naphthol
derivatives (Eq. 1).[10f] While the intermediate possesses central
aromatization
O
(S)
NO2
2
(S)
NO2
NO2
(1)
(2)
(3)
O
2
O
OMe
1’
OMe
Cl
OMe
Central chirality
No axial information
Axial chirality
Axial information retaining via aromatization (Y. Hayashi, 2019)
R
Ph
NO2
CHO
Ph
aromatization
CHO
N
OTMS
H
2
2
1’
1’
NO2
OH
R
+
OH
R
HO
O
OH
Retained
Axial chirality
Central chirality
Axial information
This work: Axial information inverting via aromatization
R
Ph
CHO
R
Ph
OTMS
N
H
CHO
aromatization
H
1’
R
CHO
2
+
1’
OH
3
O
H
H
NO2
3
H
2
Inverted
Axial chirality
NO2
Central chirality
Axial information
In some of the reactions, however, the intermediate
possesses not only central chirality but also defined
a
configuration of a stereogenic axis.[11] The defined configuration
of the stereogenic axis of the precursor is retained in the final
axially chiral molecules, in which the axial information of the
intermediate and that of the final product are identical. There is
no reaction as far as we were aware that the axial information of
the precursor inverts completely with excellent enantioselectivity.
For instance, Thomson reported the synthesis of chiral
bisphenols via oxidative aromatization, during which a defined
configuration of a stereogenic axis has been retained.[10d] Chen
also successfully synthesized axially chiral 3-aryl pyrrole, which
retains the axial information of the precursor.[10i] Recently we
prepared axially chiral biphenyls from the domino product of o-
[a]
S. Koshino, A. Takikawa, K.Ishida, Dr. S. Umemiya, Prof. Dr. Y.
Hayashi*
Department of Chemistry, Graduate School of Science, Tohoku
University, Sendai 980-8578, Japan
E-mail: yujiro.hayashi.b7@tohoku.ac.jp
Homepage: http://www.ykbsc.chem.tohoku.ac.jp
Prof. Dr. T. Taniguchi, Prof. Dr. K Monde,
Frontier Research Center of Advanced Material and Life Science
Faculty of Advanced Life Science, Hokkaido University, Sapporo
060-0810, Japan
Prof. Dr. E. Kwon
Research and Analytical Center for Giant Molecules, Graduate
School of Science, Tohoku University, Sendai 980-8578, Japan
[b]
[c]
substituted
nitrostyrene
and
succinaldehyde
using
diphenylprolinol silyl ether (Eq. 2).[11b] The domino product exists
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RESEARCH ARTICLE
as a single conformer, possessing the central chirality with the
axial information along the C2-C1' axis, and the removal of the
central chirality afforded the axially chiral biphenyls that retain the
axial information with excellent enantioselectivity. During the
investigation to synthesize the axial chiral molecule, we found
that the axial information of the intermediates was completely
inverted during the removal of central chirality (Eq. 3), which we
will describe in this paper.
while NOE correlation between H(3)–H(6') was not detected
(Figure 1b). These results suggest that 2b exists as a single axial
conformer, in which the Me substituent at o-position of phenyl ring
exists outside of dihydronaphthalene ring, Me-outside. Thus, the
conformations in the solid state and the solution phase are similar,
and dihydronaphthalene possesses central chirality with axial
information along the C3–C1’ bond.
a)
b)
6’
NOE
H
4
H
H(Me)
Results and Discussion
1’
3
1’
Br
CHO
H
Me
CHO
H
C(1’)
C(1’)
H(3)
H
H
3
4
H(6’)
NO2
NO2
The enantio-enriched dihydronaphthalenes 2 were selected
as chiral starting materials, because they can be converted into
synthetically useful chiral biaryls in short steps. Two examples of
dihydronaphthalenes 2 with 2-substituted phenyl moiety (R = NO2
2g, OMe 2h, Eq. 3) are known to be prepared by the
enantioselective domino Michael–aldol condensation reaction
catalyzed by diphenylprolinol silyl ether reported by Enders.[12]
First, the domino reactions of 3-(2-bromophenyl)-propenal
(1a) and 3-(2-methylphenyl)propenal (1b) with 2-(nitromethyl)–
benzaldehyde were investigated in the presence of a catalytic
amount of diphenylprolinol silyl ether[13] to afford the
corresponding dihydronaphthalene derivatives 2a, 2b with
excellent enantioselectivity (Eq. 4). We determined the absolute
configuration and the conformation in the solid state of bromo
substrate 2a by X-ray crystallography (Figure 1a),[14] while Enders’
group determined the relative configuration of methoxy substrate
2h by X-ray analysis.[12] It was found that, in the both crystals of
bromo and methoxy substrates 2a and 2h, the phenyl ring stands
approximately vertically on the dihydro-naphthalene ring, in which
the dihedral angles between the H(3)(benzylic proton)–C(3)–
C(4)–H(4)(a-position of nitro group) were 80.4° and 77.8°,
respectively. It was also observed that the o-substituent of phenyl
ring overhangs, avoiding the dihydronaphthalene skeleton, which
we call as Br-outside and OMe-outside conformers in this paper
(Eq. 4).[15]
H(4)
C(4)
H(3)
Br-outside 2a
Me-outside 2b
C(4)
C(3)
H(4)
C(3)
Figure 1. Structural analysis of dihydronaphthalene 2 a) ORTEP of 2a. Thermal
ellipsoids are set at 50 % probability. b) NOE correlation of 2b
Next, density function theory (DFT) calculation was
conducted to investigate why dihydronaphthalene existed as a
single axial conformer (Figure 2). Calculations were carried out
for the substrate 2a possessing bromo substituent. The rotational
barrier of the C(3)–C(1') axis was calculated to be 49.29 kJ/mol.
This indicates that the two axial conformers such as Br-outside
and Br-inside can be easily interconverted at room temperature.
The potential energy of Br-inside conformer is higher in 15.38
kJ/mol than that of Br-outside conformer, indicating that Br-
outside conformer is favored and the ratio of abundance would
be over 500 vs 1. Therefore, the axial information of the
dihydronaphthalenes is controlled by thermodynamic stability of
the substrate.[16]
ΔG
(kJ/mol)
Br-inside 2a
49.29
Br
5 mol%
Ph
1’
H
Br-outside 2a
CHO
H
H
3
O
Ph
OTMS
NO2
N
R
CHO
H
1’
H
Br
CHO
H
CHO
15.38
R
(4)
+
H
3
NO2
NO2
H
Et2O, rt
NO2
0.00
1a: R = Br
1b: R = Me
2a: R = Br 61% yield, >99% ee
2b: R = Me 42% yield, >99% ee
Figure 2. The free energy potential profile of the interconversion between two
axial conformers of 2a
H
R
R
H
CHO
H
CHO
H
As dihydronaphthalene 2a possesses two central chiralities
and one axial information, the removal of the two central
chiralities without distorting the axial information was investigated
to provide the chiral biaryl 3a. After various investigations, it was
found that 2a can be converted into 3a via one-pot operation over
five reaction steps (1. acetalization, 2. formation of nitronate, 3.
Nef reaction, 4. keto-enol isomerization, 5. deprotection of acetal)
in 89% yield with 99% ee (Eq. 5). The synthetic sequence will be
explained vide infra. The rotation barrier of 3a is measured to be
148.5 kJ/mol, which is high enough to have an axial chirality at
room temperature. The absolute configuration of 3a was
H
H
NO2
NO2
R-outside
R-inside
In order to investigate the conformational information in the
solution phase, the NMR experiments were performed on
dihydronaphthalene having o-tolyl substituent 2b, which would
provide more NMR information than that of bromo and methoxy
substituted ones. The coupling constant between the H(3) and
H(4) is almost 0 Hz, indicating that the dihedral angle between
H(3)–C(3)–C(4)–H(4) is similar with that of the solid state of 2a
and 2h. NOE correlation between H(3)–H(Me) was observed,
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10.1002/chem.201905814
Chemistry - A European Journal
RESEARCH ARTICLE
determined by X-ray single crystal analysis,[17] and was expected
to be Sa because of the retention of the conformation of the
stereogenic axis during the transformation from 2a to 3a.
However, it was found to be Ra, which indicates that the axial
information of C3–C1’ bond of dihydronaphthalene was inverted
completely.
BuOK in d8-THF, the ROE correlations for resulted nitronate 5b
was observed not only between H(C3)–H(Me) but also between
H(C3)–H(C6'). This indicates that the nitronate 5b existed as a
mixture of two axial conformers, Me-outside and Me-inside, and
that the axial information was lost at this stage.
K
K
6’
H
H
3
Me
t-BuOK
Me
O
O
Br
CHO
HC(OMe)3
p-TsOH (cat.) t-BuOK
(6)
R
H
H
+
R
R
H
d8-THF
1’
3
Br
Me
3
H
3
H
H
(5)
O2N
O2N
NO2
CHO
ROE
ROE
(Ra)
H
THF, rt
0 ˚C
-90˚C;
aq. HCl, rt
OH
H
5b
Me-outside
2b R = CHO
4b R = CH(OMe)2
Me-outside
Me-inside
NO2
CH(OMe)3
p-TsOH
THF
89%, 99% ee
ΔG‡ = 148.5 kJ/mol
3a
Axial ” turning point ” !!
>99% ee
2a
(R = CH(OMe)2)
Five reaction steps in a one-pot sequence
As chiral biaryl 3a with opposite axial chirality is obtained, the
next questions are when and how the axial information is
redefined as completely opposite. The next intermediate after the
Nef reaction would be ketone 6 (Scheme 2), which cannot be
detected because of the facile keto-enol tautomerization to afford
naphthol 7 immediately. Thus, the DFT calculation of the ketone
6a was performed, and it indicated that the rotation barrier
between the two axial conformers is small (⊿G‡=41.54 kJ/mol),
and that each conformer can be easily interconverted (Figure 4).
It also discloses that Br-outside conformer is 1.68 kJ/mol more
stable than Br-inside conformer, indicating that the abundance
ratio of both conformers was estimated to be about 2:1. Thus, the
complete inversion of the axial information does not occur at the
ketone stage.
Figure 3. ORTEP of 3a. Thermal ellipsoids are set at 50 % probability.
In order to clarify the reason of the complete inversion of the
axial information, we investigated each step in detail. In the
following investigations, NMR experiments were carried out for
the methyl substrates, in which more NMR information can be
obtained, while DFT calculations were performed for bromo
substrates in order to reduce the calculation time. In the
transformation from 2 to 3, the following reaction steps are
involved (Scheme 2): Aldehyde 2 is protected as its acetal 4,
which is treated with t-BuOK to generate nitronate 5. Nef reaction
by the addition of dimethyldioxirane (DMDO) afforded ketone 6,
which isomerizes to naphthol 7. Deprotection of acetal afforded
biaryl 3. It should be noted that all these transformations from 2
to 3 over five reaction steps can be carried out in a single vessel
after the careful optimization of all the reaction steps based on
the pot economy.[18]
ΔG
(kJ/mol)
41.54
Br-inside 6a
Br-outside 6a
Br
H
R
H
H
R
H
O
Br
O
1.68
0.00
Figure 4. The Free energy potential profile of the interconversion between two
axial conformers of 6a (R = CHO)
Scheme 2. The synthetic scheme and intermediates from 2 to 3
MeO OMe
MeO OMe
O
H
3
R
O
HC(OMe)3
R
p-TsOH (cat.)
t-BuOK
R
H
R
H
CHO
Ar
Ar
3
R
H
THF, rt
H
0 ˚C
-90 ˚C
H
O
O
NO2
NO2
K
NO2
base
>99% ee
(R = Br)
6 inside
5
6 outside
base
2
4
Axial informatin
R-outside
Figure 5. Reaction of ketone 6 with base
MeO OMe
MeO OMe
R
CHO
aromatization
aq. HCl
＊
Ar
Ar
Based on the above findings, the complete inversion of axial
information would occur during the aromatization step from
ketone 6 to naphthol 7 as follows (Figure 5): Although the R-
inside conformer is thermodynamically unstable, the
deprotonation of a proton at C3 by base proceeds preferentially
from the R-inside conformer as it is difficult to deprotonate a
proton at C3 of R-outside conformer due to the steric hindrance
caused by base and bulky substituent. If so, the size of the base
would affect the enantioselectivity. In fact, a bulky base such as
KHMDS gave excellent enantioselectivity (96% ee), while a lower
(Ra)
OH
OH
O
99% ee (R = Br)
3
7
6
As already described, the compound 2b (R = Me) exists as a
single axial conformer (Me-outside, Eq. 6). Dimethyl acetal 4b
was also found to exist as a single axial conformer (Me-outside),
which was revealed by the NOE experiments. NOE between
H(C3)–H(Me) was observed with no NOE between H(C3)–H(C6
'). On the other hand, after treating the dimethyl acetal 4b with t-
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enantioselectivity (89% ee) was observed in the case of a smaller
base such as KOMe. Thus, the deprotonation proceeds from R-
inside conformer selectively, affording biaryl 7 with the Ra axial
chirality.[6j, 10b, 10e, 10f, 15b]
much bulkier trimethylsilyl group is also suitable to afford the
chiral biaryl 3f with excellent enantioselectivity (entry 6).
We determined the absolute configuration of 3a via X-ray
crystallographic analysis, and those of 3e and 3f based on CD
Thus, the plausible reaction mechanism of the inversion of
the axial information would be as follows (Scheme 3): The axial
information of dihydronaphthalene 2 reflects thermodynamic
stability between two axial conformers, existing as a single
conformer R-outside. Acetal 4 also exists as a single axial
conformer, R-outside. The axial information was lost at nitronate
5, in which two conformers are observed by ROE experiments.
Oxidation with DMDO afforded ketone 6, which also exists as a
mixture of two axial conformers revealed by the calculation.
Although R-inside conformer of 6 is less stable, the keto-enol
tautomerization would selectively proceed from this conformer
because of the easy access of base to a proton at C3. Thus, the
axial information is redefined with the complete inversion to afford
Ra axial enantiomer. This phenomenon essentially belongs to a
strategy of chirality conversion from central to axial, although it
seems that there is no free rotation in dihydronaphthalene 2.
Table 1: The generality of the two-pot synthesis of biaryl 3a
5 mol%
CHO
Ph
Ph
OTMS
Ar
1
HC(OMe)3
p-TsOH
N
CHO
Ar
CHO
Ar
+
H
t-BuOK DMDO
O
Et2O, rt
THF, rt
0 ˚C
-90 ˚C;
aq. HCl
H
NO2
OH
NO2
2
3
Entry
[a]
2
yield of 2 [%][b]
3
yield of 3 [%][b]
(ee of 3 [%][c]
)
(ee of 2 [%][c]
)
CHO
Br
CHO
1[d]
2[e]
3[e]
4[e]
5[f]
61
(>99)
89
Br
(99)
OH
3a
NO2
2a
CHO
CHO
Me
42
(>99)
96
Me
(98)
NO2
OH
3b
2b
Scheme 3. The reaction mechanism of the inversion of axial chiral information
from 2 to 3
CHO
CHO
Cl
67
(>99)
66
Cl
(95)
NO2
OH
3c
2c
CHO
CHO
I
acetalization;
deprotonation
60
(99)
94
R
H
I
R
(>99)
R’
H
R’
H
R’
H
NO2
OH
H
H
R
NO2
2d
3d
NO2K
5 inside
NO2K
5 outside
2, 4 outside
CHO
CHO
61
81
The axial information was lost.
DMDO
Axial information
(97)
(95)
OH
NO2
2e
3e
R
H
CHO
CHO
6[g]
75
75
TMS
TMS
R’
H
R’
H
(94)
(92)
3
H
3
R
R
O
NO2
OH
O
2f
3f
6 inside
R’
6 outside
H
H
NO2
Chirality conversion from central to axial
The axial information was redefined.
CHO
CHO
7[e]
52
76
NO2
NO2
2, 4 inside
(98)
(50)
NO2
OH
3g
R’ = CHO (2, 3)
R’ = CH(OMe)2 (4, 5, 6)
2g
R
R’
CHO
CHO
8[e]
52
70
(0)
OMe
OMe
OH
(99)
(Ra)-3
NO2
OH
3h
2h
Axial chirality
CHO
CHO
9[e]
62
79
F
F
The generality of the two-pot synthesis of axially chiral biaryls
was investigated (Table 1). The first domino Michael-aldol
condensation reactions catalyzed by diphenylprolinol silyl ether
proceeded well with all the substrates examined, affording
excellent enantioselectivities. All dihydronaphthalenes 2 exist as
a single axial conformer around the C3-C1’ axis. In the second
pot reaction, all axially chiral biaryls 3 were obtained in good yield
over five reaction steps in a one-pot operation. Excellent
enantioselectivity was observed in the substrates having a
sufficiently bulky substituent at the o-position of aromatic ring
such as Me, Cl, Br and I (entries 1-4). The substrate with naphthyl
substituent is a suitable substrate, affording bis-naphthyls with
excellent enantioselectivity (entry 5). Even the substrate with the
(99)
(0)
NO2
OH
3i
2i
[a]For first organocatalyst mediated domino reaction:
1 (1.0 mmol), 2-
(nitromethyl)benzaldehyde (1.2 mmol), catalyst (0.05 mmol), Et2O (2.0 ml).; For
oxidative aromatization: 2 (0.50 mmol), CH(OMe)3 (2.50 mmol), p-TsOH•H2O
(0.10 mmol), t-BuOK (1.00 mmol), DMDO (0.60 mmol as acetone solution).
[b]Isolated yield. [c]The ee values of the compounds were determined by HPLC
analysis on a chiral column. [d]The absolute configuration of resulted biaryl was
determined by X-ray christalography. [e]The absolute configuration was
estimated from other substrates. [f]The absolute configuration of resulted biaryl
was determined by CD spectra and DFT calculation. [g]The absolute
configuration of resulted biaryl was determined by VCD spectra and DFT
calculation
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10.1002/chem.201905814
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RESEARCH ARTICLE
and VCD[19] with the combination of DFT calculations. In all cases
of 3a - 3f, the axial information was completely inverted and Ra
enantiomers were obtained.
Experimental Section
However, the stereo-selectivity of the resulting biaryl is
moderate when it is sufficiently bulky but possesses a strong
electron withdrawing group such as a nitro group (entry 7). This
would be due to the diminishing rotational barrier along the C3–
C1' axis owing to the push-pull effect between the nitro group and
naphthol. On the other hand, when the substrate has a sterically
less bulky substituent such as fluoro or methoxy group, despite
existing as a single axial conformer in dihydronaphthalene 2, the
obtained biaryls are racemic after aromatization (entries 8 and 9).
This would be because of the rotation around the axis in the final
biaryl product owing to the small substituents.
Preparation of dihydronaphthalene 2a: To a solution of 2-nitromethyl-
benzaldehyde (1.0 mmol) and 3-(2-bromophenyl)-propenal (1.2 mmol) in
Et2O (2.0 mL) was added (S)-diphenylprolinol TMS-ether (0.05 mmol, 5
mol%). After stirring for 4 h at ambient temperature, the generated 2a as
solid was gathered by filtration and washed with Et2O (50% yield). The
filtrate was concentrated in vacuo and purified by flash column
chromatography (eluent: Ethyl acetate/Hexane = 1/3) to afford 2a (11%
yield).
Synthesis of axially chiral biaryl 3a: To a THF solution (1.0 mL) of 3,4-
dihydronaphthalenes 2a (0.50 mmol) was added trimethyl orthoformate
(2.50 mmol) and p-toluenesulfonic acid (0.10 mmol) at ambient
temperature. After stirring the reaction mixture for 2 h, t-BuOK (1.0 mmol)
was added to the reaction mixture at –90 °C, then the reaction mixture
was stirred for 30 min at 0 °C. To the reaction mixture was added
dimethyldioxirane (0.60 mmol, 0.1 M solution in acetone) at –90 °C. After
stirring the reaction mixture for 30 min, the reaction was quenched by sat.
aq. Na2S2O3, and then 1 N aqueous solution of hydrogen chloride (0.50
mL) was added to the reaction mixture at ambient temperature. After
stirring the reaction mixture for 10 min, the organic materials were
extracted with ethyl acetate (3 × 3 mL) and the organic layers were dried
with Na2SO4, filtered and concentrated in vacuo. The residue was purified
In addition, we found the all reactions from the first domino
reaction to the aromatization over seven reaction steps can be
carried out in a single vessel, and that an axially chiral biaryl 3a
was obtained in good yield without impairing the
enantioselectivity (Eq. 7). It should be noted that the yield (60%)
of the one-pot procedure is higher than the total yield of the
reaction using two reaction vessels (54% = 61% x 89%).
Br
by flash column chromatography (eluent: hexane 100%
acetate/hexane = 1/5) to afford biaryl compound 3a.
→ ethyl
5 mol%
CHO
Ph
Ph
OTMS
O
O
HC(OMe)3
p-TsOH (cat.)
Br
CHO
N
1a
+
t-BuOK
H
(7)
O
THF, rt
rt
-90˚C; aq. HCl
60% yield
rt
OH
H
Acknowledgements
98% ee
NO2
3a
Seven reaction steps in a one-pot sequence
This work was supported by JSPS KAKENHI Grant Number
JP18H04641 in Hybrid Catalysis for Enabling Molecular Syn-
thesis on Demand, and JP19H05630.
Conclusion
Conflict of interest
In summary, we developed a one-pot method of the highly
enantioselective synthesis of axially chiral biaryls 3 by converting
the central chirality to the axial chirality from dihydronaphthalenes
2 present as single axial conformers, which are generated by the
domino reaction of 3-(2-substituted-phenyl)propenals and 2-
(nitromethyl)benzaldehyde catalyzed by diphenylprolinol silyl
ether. Although the dihydronaphthalene 2 exists as a single axial
conformer, this axial information is completely inverted during the
removal of central chirality. It is a first example, as far as we are
aware, where the complete inversion of the axial information was
observed between the precursor, which possesses central
chirality and the axial information, and the final biaryl. It was
revealed that deletion and redefinition of axial information occur
in the nitronate generation and keto/enol isomerization step,
respectively. This result indicates that even if the precursor with
central chirality exists as a single axial conformer, there is no
guarantee that the axial information can be retained in the final
product. During the removal of the central chirality, the rotation
around the axis might occur. In the conversion from central to
axial chirality in the precursor with a defined configuration of a
stereogenic axis, the delicate investigation about the origin of the
axial chirality would be necessary.
The authors declare no competing financial interest.
Keywords: Axial chirality, central chirality, enantioselective
synthesis, organocatalyst
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RESEARCH ARTICLE
Entry for the Table of Contents (Please choose one layout)
Layout 2:
RESEARCH ARTICLE
Seitaro Koshino, Akira Takikawa, Keiichi
Ishida, Tohru Taniguchi, Kenji Monde,
Eunsang Kwon, Shigenobu Umemiya,
Yujiro Hayashi*
Ph
Ph
O
H
R
R
CHO
N
R
OTMS
aromatization
CHO
H
H
CHO
+
H
NO2
H
OH
NO2
Single Axial
Conformer
Deletion and Redefinition of
Axial Information
Inverted
Axial Chirality
up to >99% ee
Page No. – Page No.
up to >99% ee
Title
Unexpected inversion of axis: A new synthetic method of axially chiral biaryl was
developed. Although the key intermediate existed as a single axial conformer, the
axial information was completely inverted after aromatization. The axial inversion
phenomenon was investigated in detail and an interesting "deletion and redefinition"
mechanism was proposed. This study indicates the necessity of the careful
investigation in the conversion of the chirality from central to axial.
Inversion of the axial information
during oxidative aromatization in the
synthesis of axially chiral biaryls
using organocatalyst as a key step
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