Optical resolution via catalytic generation of chiral auxiliary

Article abstract of DOI:10.1016/j.tetlet.2018.12.006

A new catalytic method for separating enantiomers of racemic compounds is proposed. Catalytic asymmetric addition of racemic trans-2-substituted cyclohexanols to imines provided diastereomeric mixtures of aminals, and the subsequent separation of the enantiomers by silica-gel column chromatography and the hydrolysis of the aminals produced the alcohols in an optically active form.

Full text of DOI:10.1016/j.tetlet.2018.12.006

Accepted Manuscript
Optical Resolution via Catalytic Generation of Chiral Auxiliary
Hiroki Kiyama, Tsubasa Inokuma, Yusuke Kuroda, Yousuke Yamaoka, Kiyosei
Takasu, Ken-ichi Yamada
PII:
S0040-4039(18)31438-2
https://doi.org/10.1016/j.tetlet.2018.12.006
TETL 50469
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 October 2018
28 November 2018
3 December 2018
Please cite this article as: Kiyama, H., Inokuma, T., Kuroda, Y., Yamaoka, Y., Takasu, K., Yamada, K-i., Optical
Resolution via Catalytic Generation of Chiral Auxiliary, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.12.006
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Hiroki Kiyama, Tsubasa Inokuma, Yusuke Kuroda, Yousuke Yamaoka, Kiyosei Takasu and Ken-ichi, Yamada

1
Tetrahedron Letters
Optical Resolution via Catalytic Generation of Chiral Auxiliary.
Hiroki Kiyamab, Tsubasa Inokuma,a Yusuke Kurodab, Yousuke Yamaokab, Kiyosei Takasub and Ken-ichi,
Yamadaa,*
a Graduate School of Pharmaceutical Sciences, Tokushima University, Shomachi, Tokushima 770-8505, Japan.
b Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new catalytic method for separating enantiomers of racemic compounds is proposed. Catalytic
asymmetric addition of chiral trans-2-substituted cyclohexanols to imines provided
diastereomeric mixtures of aminals, and the subsequent separation of the enantiomers by silica-
gel column chromatography and the hydrolysis of the aminals produced the alcohols in an
optically active form.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
optical resolution
chiral alcohols
chiral magnesium phosphate
asymmetric addition
imines
Optical resolution is one of the oldest and most reliable
methodologies used to obtain optically pure chiral compounds.1
For instance,
a racemic secondary alcohol is covalently
connected to an optically pure acyl group (R*CO) producing a
mixture of diastereomeric esters, which are then separated, taking
advantage of their different physical properties (Figure 1a).
Conventional optical resolution has two important drawbacks: (1)
the maximum yield of a desired enantiomer is 50%, and (2) a
stoichiometric amount of optically pure compounds, or resolving
agents is required. The first drawback, however, becomes an
advantage when divergence is oriented and when both
enantiomers are required, such as for biological tests. With
respect to the second drawback, catalytic kinetic resolution
(Figure 1b) is one method of addressing the issue, whereby
enantiomers are resolved by a catalytic asymmetric reaction in
which the enantiomers have different reaction rates; thus, only a
catalytic amount of a chiral source is required.2 Here we propose
another concept to resolve enantiomers using a catalytic
asymmetric reaction.3
Figure 1. Separating Enantiomers of Racemic Secondary Alcohols.
Our basic proposed concept is presented in Figure 1c. When a
racemic mixture of alcohol is subjected to a catalytic asymmetric
reaction with a prochiral reactant, such as aldimine RCH=NR’,
the newly created chirality makes the products diastereomeric.4
Both alcohol enantiomers can be isolated after the separation of
the diastereomers followed by the corresponding retro-reaction.
Thus, the chirality created by the catalytic asymmetric reaction is
used as a substitute for chirality provided by a resolving agent in
conventional optical resolution. For successful resolution, the
catalytic asymmetric reaction should be highly enantioselective
and catalyst-controlled, and the product must be returnable to the
substrate by a retro-reaction under certain conditions. In contrast
to catalytic kinetic resolution, which relies on recognition of the
chirality of “the substrate” by the chiral catalyst that causes an
energy difference between the transition states of the both
substrate enantiomers, the chiral catalyst discriminate the
prochirality of “the reactant”. Thus, in principle, the selectivity of
the reactions could be less dependent on the substrate structures.
Accordingly, this method was expected to provide another
effective way to obtain enantiomeric purity in addition to optical
resolution and kinetic resolution. Chiral alcohols are fundamental
and important chiral building blocks for pharmaceutical,
agrochemical, and fragrance compounds. To demonstrate the
method, the reported asymmetric addition of alcohols to imines
 Corresponding author. Tel.: +81-88-633-7281; fax: +81-88-633-9504; e-mail: yamak@tokushima-u.ac.jp

2
5
catalyzed by chiral magnesium phosphate was applied to
CH2Cl2–MeOH under argon atmosphere at rt for 1 h, volatile
racemic secondary alcohols.
materials were removed in vacuo, and the resulting solid material
was further dried at 100 °C in vacuo, instead of through
azeotropic distillation, and freshly used as a catalyst. When 3a
prepared by the modified procedure was used, 4a and 5a were
obtained with improved ee values (from 88% and 74% to 94%
and 90%, respectively; entries 1 and 6). The improvement was
also observed with 3b, producing 4a and 5a with 97% ee and
96% ee, respectively (entry 7 vs entry 2).
First, we compared two chiral magnesium phosphates 3a6 and
3b7 in the reaction with racemic secondary alcohol (±)-1a8 (Table
1, entries 1 and 2) because these were reported as good catalysts
for the asymmetric addition of ω-halo alkanols to imines.5a The
phosphate salts were prepared according to the literature.5 A 2:1
mixture of the corresponding phosphoric acids and magnesium
tert-butoxide was stirred in CH2Cl2–MeOH under an argon
atmosphere at rt for 1 h, and volatile materials were removed in
vacuo. The addition of dry CH2Cl2 and in vacuo concentration
were repeated three times to remove the residual alcohol. In the
presence of prepared 3a and MgSO4, the reaction of (±)-1a and
imine 29 was conducted in EtOAc at rt (Table 1, entry 1). After 1
h, diastereomeric adducts 4a and 5a were quantitatively produced
and separated by silica gel column chromatography. Chiral
HPLC analysis revealed the enantiomeric excesses (ee) of 4a and
5a were 88% and 74%, respectively. The absolute configurations
of 4a and 5a were assigned on the basis of the stereochemistry of
recovered 1a (vide infra) and the enantioselectivity reported for
the addition to imine.5 The use of 3b resulted in better selectivity,
producing 4a and 5a with 92% ee and 91% ee, respectively
(entry 2). Changing the solvent to toluene or CHCl3 failed to
improve the selectivity, and the obtained products had slightly
lower ee of 89% and 90%, and 79% and 87%, respectively
(entries 3 and 4). The reaction rate significantly decreased when
the reaction was conducted in THF, where 4a and 5a were
produced in 46% and 47% yield, respectively, in 9 h (entry 5);
however, almost complete conversion was observed in 1 h when
the other solvents were used (entries 1–4).
The catalytic optical resolution protocol was conducted at a
preparative scale (Table 1, entry 8). The catalytic asymmetric
addition of (±)-1a (832 mg) to 2 furnished 4a (674 mg) and 5a
(784 mg) with 95% ee and 94% ee in 39% and 44% isolated
yields, respectively. The optical purity of 4a was enriched by
recrystallization from EtOAc–hexane to give 4a with 99% ee in
96% yield (Scheme 1). The subsequent hydrolysis produced
30
optically pure (1R,2S)-1a with [α]D –41.6 (c 1.00, CHCl3) in
97% yield. The other isomer 5a was also hydrolyzed to give
30
(1S,2R)-1a with [α]D +36.0 (c 1.13, CHCl3)10 in 92% yield.
Thus, the three-step sequence (the catalytic asymmetric addition,
the enantiomer separation, and the retro-reaction) illustrates the
proposed catalytic optical resolution.
Table 1. Optimization of the Reaction Conditions.a
Scheme 1. Recovery of Enantiomerically Enriched Alcohol 1a.
The catalytic optical resolution was applied to cyclohexanols
bearing other substituents (Scheme 2). The catalytic asymmetric
addition of 2-phenylcyclohexanol 1b to imine 2 produced
diastereomeric 4b and 5b with 92% and 93% ee in 47% and 46%
yield, respectively. tert-Butyl substituted cyclohexanol 1c11 was
also determined to be a good substrate for this reaction,
producing 4c and 5c with 96% and 95% ee in 42% and 44% yield,
respectively. The both diastereomeric adducts were separable by
silica gel column chromatography; thus, these results exemplified
the present catalytic optical resolution. Notably, the pairs of the
diastereomers (i.e., 4a–5a, 4b–5b, and 4c–5c) were produced
with almost the same yield and ee. This clearly shows that the
3b-catalyzed reaction was highly catalyst-controlled. In contrast,
the reactions of 1b and 1c using achiral catalyst, magnesium
bis(diphenyl phosphate), were substrate-controlled and produced
(1RS,2SR)-isomers 4b and 4c with slight preference over
(1RS,2RS)-isomers 5b and 5c (ca. 2:1), respectively.
4a
5a
entry
catalyst
solvent
% yield
50
% ee
88
% yield
50
% ee
74
1
2
3a
3b
EtOAc
EtOAc
toluene
CHCl3
THF
45
92
45
91
3
3b
48
89
48
90
4
3b
50
79
50
87
5b
3b
46
85
47
85
6
3ac
3bc
3bc
EtOAc
EtOAc
EtOAc
49
94
49
90
7
50
97
50
96
8d
39
95
44
94
a
The reaction was conducted with 2 (0.4 mmol), 1a (0.2 mmol), 3 (2 μmol),
and MgSO4 (50 mg) in solvent (1 mL) under Ar atmosphere. The ee’s were
determined by chiral HPLC analysis. b For 9 h. c Freshly prepared and dried at
d
100 °C in vacuo prior to use. The reaction was conducted with 2 (8.75
mmol), 1a (832 mg, 4.37 mmol), 3 (0.04 mmol), and MgSO4 (550 mg) in
EtOAc (22 mL) under Ar atmosphere for 3 h.
Scheme 2. Catalytic Asymmetric Addition of Other Cyclohexanols 1 to
Imine 2.
In this reaction, modification on the catalyst preparation
procedure effectively improved the results. After mixing the
corresponding phosphoric acids and magnesium tert-butoxide in
In summary, we have proposed a new method of separating
racemic chiral compounds using a catalytic amount of a chiral
source, namely, the catalytic optical resolution. The catalytic

3
9
(a) Cowen, B. J.; Saunders, L. B.; Miller, S. J. J. Am. Chem. Soc.
asymmetric addition of trans-2-substituted cyclohexanol to imine
produced separable mixtures of diastereomeric adducts, the
hydrolysis of which provided enantiomerically enriched alcohols.
This result clearly demonstrated that the proposed concept is
functional, and it is possible that the scope of the concept could
be extended to substrates bearing functionality other than
alcohol.
2009, 131, 6105. (b) Murry, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.;
Grabowski, E. J. J.; Reider, P. J. J. Am. Chem. Soc. 2001, 123, 9696.
10 lit. [α]D20 +49.2 (c 1, CHCl3): (a) Fronza, G.; Fogliato, G.; Fuganti,
C.; Lanati, S.; Rallo, R.; Servi, S. Tetrahedron Lett. 1995, 36, 121. (b)
Fogliato, G.; Fronza, G.; Fuganti, C.; Lanati, S.; Rallo, R.; Rigoni, R.;
Servi, S. Tetrahedron 1995, 51, 10231.
11 Alexakis, A.; Jachiet, D.; Normant, J. F. Tetrahedron 1986, 42,
5607.
Acknowledgements
We thank JSPS for Grants-in-Aid for Scientific Research (C),
MEXT for Grants-in-Aids for Scientific Research on Innovative
Areas
‘Advanced
Molecular
Transformations
by
Organocatalysts’ and ‘Middle Molecular Strategy’, and AMED
Platform for Supporting Drug Discovery and Life Science
Research. Y.K. thanks JSPS for a research fellowship for young
scientists.
Supplementary Material
Experimental detail and characterization data for new
compounds are available as a Supplementary Material.
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3
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4
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5
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8
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Highlights
 The addition gave the catalytically formed chiral auxiliary with high selectivity.
 The diastereomeric adducts were chromatographically separated.
 Recrystallization enriched the enantiomeric excess of the adduct.
 Hydrolysis of the adducts gave the enantiomers of the alcohols in high yields.
 The concept could be extended to substrates bearing other functionality.