Optical purifications via self-disproportionation of enantiomers by achiral chromatography: Case study of a series of α-CF3-containing secondary alcohols

Article abstract of DOI:10.1002/chir.22180

This work demonstrates that self-disproportionation of enantiomers via achiral chromatography can be recommended as inexpensive and general method for optical purification of enantiomerically enriched compounds. In particular, the advantage of this approach over conventional recrystallization is that it can be used for both crystalline as well as liquid compounds.

Full text of DOI:10.1002/chir.22180

CHIRALITY 25:365–368 (2013)
Optical Purifications via Self-Disproportionation of Enantiomers by
Achiral Chromatography: Case Study of a Series of a-CF3-containing
Secondary Alcohols
3
4
5
1
ALEXANDER E. SOROCHINSKY,1,2 TOSHIMASA KATAGIRI, TAIZO ONO, ALICJA WZOREK, JOSÉ LUIS ACEÑA,
*
AND VADIM A. SOLOSHONOK1,2
*
1Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, San Sebastián, Spain
2IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
3Department of Applied Chemistry, Faculty of Engineering, Okayama University, 3-1-1, Tsushimanaka, Kita-ku, Okayama, Japan
4National Institute of Advanced Industrial Science and Technology (AIST), Nagoya, Aichi Prefecture, Japan
5Institute of Chemistry, The Jan Kochanowski University in Kielce, witokrzyska 15, Kielce, Poland
ABSTRACT
This work demonstrates that self-disproportionation of enantiomers via achiral
chromatography can be recommended as inexpensive and general method for optical purifica-
tion of enantiomerically enriched compounds. In particular, the advantage of this approach over
conventional recrystallization is that it can be used for both crystalline as well as liquid com-
pounds. Chirality, 25:365–368, 2013. © 2013 Wiley Periodicals, Inc.
KEY WORDS: fluorine and compounds; enantiomeric purification; chiral recognition;
chromatography
INTRODUCTION
virtually any chiral compound.5,8,26–35 Similar to the phenome-
non of nonlinear effects in asymmetric catalysis,27,28 the origin
of the SDE under the conditions of achiral chromatography is
the dynamic formation of homo- or heterochiral high-order
species which have different chromatographic behaviour as
compared with monomers or other low-order species.3–6 There-
fore, different compounds possessing different qualities of the
corresponding homo- and heterochiral interactions show differ-
ent magnitude of the SDE; or readiness for separation of race-
mate from the excess enantiomer. Obviously, compounds
possessing noticeable magnitude of SDE are of great interest
both for theoretical studies as well as for the development of
practical applications.
Current asymmetric synthesis allows preparation of chiral
compounds in high enantiomeric purity but quite rarely in
enantiomeric pure (>99% ee) form.1 Furthermore, it is gener-
ally accepted practice that the analytical data reported in the
literature for chiral compounds are measured on samples as
they are obtained by asymmetric reactions without further
purification to enantiomerically pure state. While for most
synthetic and reaction chemistry aspects it is not detrimental
to report enantiomerically impure compounds, this practice
represents one of the deficiencies of the current organic
chemistry methodology.2 Apparently, the major reason for
reporting chiral compounds of various enantiomeric purities,
is the painstaking, expensive and time-consuming efforts usu-
ally associated with the purification of enantiomerically
enriched samples to optically pure form. Thus, currently avail-
able methods for enantiomeric purification are unacceptably
limited to crystallization, diastereomeric derivatization and
preparative chromatography on chiral stationary phases. Con-
sequently, the development of new, inexpensive and simple
enantiomeric purification methods is of critical importance
and will undoubtedly find overwhelming support from all
chemistry practitioners. In this context, one of the promising
areas is the self-disproportionation of enantiomers (SDE)3–6
demonstrating that optical purification of enantiomerically
enriched compounds via separation of racemate from the excess
enantiomer†7 can be achieved under achiral conditions of any
type of phase-transition8–20 or achiral chromatography.21–25 In
particular, the latter approach might be a method of very
general application as it can be applied for crystalline as well
as liquid compounds. However, the SDE still awaits a
comprehensive study to explore its practical potential for
enantiomeric purifications.
RESULTS AND DISCUSSION
It was demonstrated that due to the multifactorial, special
properties of fluorine and its substituents, fluorine-containing
compounds might generally be expected to show significant
level of the SDE via achiral chromatography.36–42 Following this
lead, we decided to study a series of a-trifluoromethyl-
containing secondary alcohols 1a-f (Fig. 1) readily available in
racemic and enantiomerically enriched form via reactions of the
appropriate nucleophiles with the corresponding racemic or
enantiomerically enriched (S)-3,3,3-trifluoro-1,2-epoxypropane.43–46
We found that regular, gravity-driven column chromatogra-
phy of amino alcohol 1a of ~75% ee, on achiral silica gel and
using hexane/ethyl acetate (10/1) as an eluent, showed quite
noticeable magnitude of SDE producing enantiomerically
*Correspondence to: Vadim A. Soloshonok, Department of Organic Chemis-
try I, Faculty of Chemistry, University of the Basque Country, Paseo Manuel
Lardizábal 3, 20018 San Sebastián, Spain. E-mail: vadym.soloshonok@ehu.es;
Toshimasa Katagiri, Department of Applied Chemistry, Faculty of Engineering,
Okayama University, 3-1-1, Tsushimanaka, Kita-ku, Okayama 700-8530, Japan.
E-mail: tkata@cc.okayama-u.ac.jp
Received for publication 14 February 2013; Accepted 20 March 2013
DOI: 10.1002/chir.22180
Published online in Wiley Online Library
(wileyonlinelibrary.com).
The SDE via achiral chromatography is of very general
nature and, under certain conditions, can be expected for
†It is very important not to mistake an optical purification via the SDE
with a resolution (separation) of enantiomers.
© 2013 Wiley Periodicals, Inc.

366
SOROCHINSKY ET AL.
TABLE 1. SDE of compound (S)-1a via flash chromatography
on achiral silica gel using hexane/ethyl acetate (15/1) as eluent
Fractiona
Mass (mg)
(S)/(R) (mg)
ee (%)b
(starting sample)
180
24
40
36
30
21
15
6
157.5/22.5
19.4/4.6
33.6/6.4
31.1/4.9
27.3/2.7
19.5/1.5
13.9/1.1
5.5/0.5
75
63
68
73
82
85
85
84
1
2
3
4
5
6
7
Fig. 1. Secondary a-CF3 alcohols 1a-f used in this study.
aVolume of collected fractions: ~10 mL.
bEnantiomeric composition was determined by GC (CYCLOSIL-b, 30 m
length, 0.25 mm i.d.)
depleted (71% ee) first and enantiomerically enriched (83%
ee) last fractions (Dee = 12.0%).{ Straightforward optimization
of this result with application of a less polar eluent (hexane/
ethyl acetate 15/1) and flash chromatography47 allowed the
improvement of the magnitude of SDE (Dee = 22.0%). As one
can see from the Table 1, starting with compound 1a of 75%
ee (180 mg), first fraction was of 63% ee while the fractions
5 and 6 were enantioenriched up to 85% ee. As one can see,
the structure of 1a obviously suggests that H-bonding inter-
actions should be of great importance for intermolecular
interactions, which play a role in the SDE process. Conse-
quently, to further optimize the magnitude of SDE we looked
for an eluent which should not contain a solvent which could
significantly interfere with H-bonded interactions between
molecules of compound 1a. However, 1a still should be solu-
ble in the designed eluent to allow the normal chromato-
graphic process.
Considering dielectric constants and hydrogen bonding
properties of a series of solvents, we found that mixtures of
c-hexane, benzene and di-tert-butyl ether, in a ratio of 1/1/0.1
can serve as a reasonably good eluent for this preliminary
study. The data given in Table 2, show that the magnitude of
SDE under these conditions is about 50% Dee and that the frac-
tions 6–9 contain pure enantiomer. The overall amount of
enantiomerically pure (S)-1a collected in these fractions was
55mg, out of 157.5 mg of the (S)-enantiomer contained in the
initial mixture, which corresponds to a 35% yield. It should be
emphasized that transformation of (S)-1a of 75% ee to
enantiomerically pure (S)-1a using conventional recrystalliza-
tion, requires triple crystallization (Et2O/hexane) and gives
the target product with 42% yield.43 While both procedures
can be further optimized to increase the yield of the
enantiomerically pure (S)-1a, it seems quite obvious that SDE
via achiral chromatography can easily match the practicality
and experimental convenience of recrystallization as an enantio-
meric purification procedure.
TABLE 2. SDE of compound (S)-1a via flash chromatography
on achiral silica gel using c-hexane/benzene/di-tert-butyl ether
(1/1/0.1) as eluent
Fractiona
Mass (mg)
(S)/(R) (mg)
ee (%)b
(starting sample)
180
16
23
27
30
25
26
17
10
2
157.5/22.5
12.1/3.9
17.8/5.2
21.5/5.5
24.4/5.6
22.5/2.5
26/0
75
51
55
59
63
1
2
3
4
5
6
7
8
9
80
>99
>99
>99
>99
17/0
10/0
2/0
aVolume of collected fractions: ~10 mL.
bEnantiomeric composition was determined by GC (CYCLOSIL-b, 30 m
length, 0.25 mm i.d.)
TABLE 3. SDE of compounds (S)-1b-f (75% ee) via flash
chromatography on achiral silica gel using c-hexane/benzene/
di-tert-butyl ether (1/1/0.1) as eluent
Highest
ee (%)a
Lowest
ee (%)a
Yield of pure
Δee (%) enantiomer (%)
Entry
(S)-1
1
2
3
4
5
1b
1c
1d
1e
1f
99
99
99
99
99
31
33
28
30
21
68
66
71
69
78
39
41
44
40
53
aEnantiomeric composition was determined by GC (CYCLOSIL-b, 30 m
length, 0.25 mm i.d.)
With these results in hand we next studied the SDE via
achiral chromatography of compounds 1b-f (Fig. 1) using
the same initial enantiomeric purity (~75% ee) and chromato-
graphic conditions as for 1a. The data obtained are presented
in Table 3. Compound 1b bearing N,N-dimethyl moiety,
showed a chromatographic profile similar to that of 1a,
allowing isolation of enantiomerically pure 1b in the last eluted
fractions. In this case, the magnitude of SDE was slightly
greater (Dee = 68%) and the isolated yield of enantiomerically
pure (S)-1b was higher (39%, entry 1). Compound 1c,
containing the diethylamino group, showed results (entry 2)
very similar to those obtained for the N,N-dimethyl-derivative
1b, suggesting that the presence of the N-H moiety in 1a does
not play any critical role in the mechanism of the SDE in this
series. The enantiomerically pure (S)-1c was collected with
41% yield. On the other hand, derivative 1d containing an
unsubstituted amino group, gave better results showing 71%
Dee and allowing isolation of the enantiomerically pure (S)-1d
in 44% yield (entry 3). These data may suggest that the less
steric bulk on the amino function in the compounds under
study might have favourable effect on the quality of
{%Dee is the difference in % ees between maximum enantiomerical
enriched and depleted fractions
Chirality DOI 10.1002/chir

SDE OF -CF3-CONTAINING SECONDARY ALCOHOLS
367
purification of isopropyl 3,3,3-trifluoro-2-hydroxypropanoate via
achiral size-exclusion chromatography.57
CONCLUSION
In conclusion, this work demonstrates that SDE via
achiral chromatography can be recommended as a simple,
inexpensive and general method for optical purification of
enantiomerically enriched compounds. In particular, the ad-
vantage of this approach over conventional recrystallization
is that it can be used for both crystalline as well as liquid
compounds.
Fig. 2. Infinite intermolecular hydrogen N-H-O bonding network in the
crystals of N-benzyl derivative (S)-1a. Hydrogen atoms are omitted for clarity.
intermolecular interactions. Thus, in agreement with this
assumption, compound 1e bearing piperidyl moiety gave lower
values of the SDE (69% Dee, entry 4) but still, the
enantiomerically pure (S)-1e was isolated in a quite reasonable
40% yield. Finally, the ethoxy-containing derivative 1f, structur-
ally different from the rest of the compounds used in this study,
gave the most notable results. In this case the first fraction was
noticeably enantiomerically depleted (21% ee, entry 5) provid-
ing for the highest in this study Dee of 78% ee. The isolated yield
of enantiomerically pure (S)-1f was 53%. One may assume that
the quality of the intermolecular interactions in this case is
noticeably better as compared with the b-amino-containing
derivatives 1a-e.
ACKNOWLEDGMENTS
VAS, JLA and AES thank IKERBASQUE, Basque Foundation
for Science, for generous financial support
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Chirality DOI 10.1002/chir