Chiral additive induced self-disproportionation of enantiomers under MPLC conditions: Preparation of enantiomerically pure samples of 1-(aryl)ethylamines from racemates

Article abstract of DOI:10.1016/j.tetasy.2016.03.004

Mixtures of enantiomerically pure (S)-N-formyl-1-phenylethyamine and various racemic N-formyl-1-arylethylamine derivatives, when submitted to achiral medium pressure liquid chromatography, afforded elution profiles in which the enantiomers of N-formyl-1-a

Full text of DOI:10.1016/j.tetasy.2016.03.004

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral additive induced self-disproportionation of enantiomers
under MPLC conditions: preparation of enantiomerically pure
samples of 1-(aryl)ethylamines from racemates
Mitsuhiro Goto a, Kaori Tateishi a, Kenki Ebine a, Vadim A. Soloshonok b,c, Christian Roussel d,
Osamu Kitagawa a,
⇑
a Department of Applied Chemistry, Shibaura Institute of Technology, 3-7-5 Toyosu, Kohto-ku, Tokyo 135-8548, Japan
b Department of Organic Chemistry I, University of the Basque Country UPV/EHU, 20018 San Sebastián, Spain
c IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
d Aix Marseille Université, Ecole Centrale Marseille, CNRS, ISM2 UMR7313, 13397 Cedex 20 Marseille, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Mixtures of enantiomerically pure (S)-N-formyl-1-phenylethyamine and various racemic N-formyl-1-
arylethylamine derivatives, when submitted to achiral medium pressure liquid chromatography, afforded
elution profiles in which the enantiomers of N-formyl-1-arylethylamines standout as separate peaks and
can be isolated. In all of the investigated N-formyl-1-arylethylamine substrates, the virtually enantiomer-
ically pure (S)-enantiomer eluted as a less polar fraction and subsequently, the (R)-enriched enantiomer
mixtures were eluted in the more polar fractions.
Received 30 January 2016
Accepted 5 March 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
In the achiral chromatography of enantiomerically enriched
compounds, it has been occasionally reported that the enan-
tiomeric excess (ee) of a compound in various fractions usually dif-
fers from the original enantiomeric excess, i.e., the enantiomeric
excess of a compound in some fractions is higher than the original
enantiomeric excess, while that in other fractions it is lower. Such a
phenomenon is known as the self-disproportionation of enan-
tiomers. The self-disproportionation of enantiomers has also
recently received much attention as a new method for enan-
tiomeric purification.1,2 Recently we discovered the efficient self-
disproportionation of enantiomers of enantiomerically enriched
N-acyl-1-phenylethylamine derivatives under the conditions of
medium pressure liquid chromatography (MPLC).3 The magnitude
of the self-disproportionation of enantiomers strongly depended
on the substituent on the amino group. Although phenethylamines
bearing sterically small N-acyl substituents, such as acetyl and for-
myl groups, showed significant self-disproportionation of enan-
tiomers (Fig. 1), in substrates bearing sterically bulky or strongly
electron-withdrawing N-tert-butoxycarbonyl, benzoyl, tosyl and
trifluoroacetyl groups, the self-disproportionation of enantiomers
magnitude was noticeably reduced.
Figure 1. Self-disproportionation of enantiomers of N-formyl-1-phenylethylamine
(69% ee) through MPLC using achiral SiO2 column.
Self-disproportionation of enantiomers via achiral chromatog-
raphy is well known to be caused by the preferential formation
of heterochiral higher order associations with a higher retention
time as compared with homochiral lower order associations
formed by excess enantiomer (Eq. 1).4–6 Hence, the self-dispropor-
tionation of enantiomers cannot be observed in the chromatogra-
phy of racemates. We theorized that if an enantiomerically pure
additive, such as compound 1, strongly associates with one or both
enantiomers of racemate 2, then either mixed homochiral or hete-
rochiral associations may be kinetically induced in the solution.
These in situ formed higher-order species are expected to have
different chromatographic behavior (Eq. 2) and may lead to the
⇑
Corresponding author. Tel.: +81 3 5859 8161; fax: +81 3 5859 8101.
E-mail address: kitagawa@shibaura-it.ac.jp (O. Kitagawa).
http://dx.doi.org/10.1016/j.tetasy.2016.03.004
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
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2
M. Goto et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
separation of the enantiomers of starting racemate 2. Such a pro-
We further envisioned that the efficiency of these results could
be improved upon by increasing the amount of chiral additive (S)-
1a and so increase the number of quality interactions between (S)-
1a and enantiomers of rac-2a. After a survey of the molar ratio
between (S)-1a and rac-2a, it was found that a ratio of 5.5:1 gave
the best result.10
cess, if realized, would constitute
a
new methodology for
resolution.7
1....
[(S)- (S)-
1
]
[(R)- ....(S)- ]
(S)-
+
(R)-
+
1
1
1
1
ð1Þ
ð2Þ
homochiral
association
heterochiral
association
This (S)-1a and rac-2a were mixed in a molar ratio of 5.5:1
(276 mg:60 mg), and subsequently subjected to MPLC on an achiral
[(S)- ....(S)-
]
(S)-1 + rac-2
[(S)-1....(R)-2]
1
2
+
column (packed 10
lm of silica gel, 20 ꢀ 250 mm) using an achiral
mixed heterochiral
association
mixed homochiral
association
eluent (hexane/AcOEt = 1). The obtained chromatographic profile
is shown in Figure 3. It should be noted that, as it was designed,
the chiral additive was completely separated, as the first eluted
fraction, from the components of compound 2a. The latter peak
due to 2a has several noticeable boundaries (shoulders). Analysis
of the enantiomeric composition of these fractions, using chiral
HPLC showed that the less polar fraction contained enantiomeri-
cally pure 2a (>99% ee, 7.9 mg, recovery yield: 26%), while the
more polar fraction was of 16% ee (48.9 mg), accounting for the
complete mass and 50:50 initial enantiomeric composition of the
racemate 2a.
Recently, we reported preliminary results on a successful self-
disproportionation of enantiomers of three racemic N-formyl-1-
arylethylamine substrates via the addition of enantiomerically
pure (S)-N-formyl-1-phenylethylamine followed by achiral MPLC
of the resultant mixture.8 In all three racemic substrates, the (S)-
enantiomers were separated with high enantiomeric purity by this
new chiral additive induced self-disproportionation of enan-
tiomers. Herein we report a full account of this study emphasising
the generality of the chiral additive induced self-disproportiona-
tion of enantiomers method as a new approach for the resolution
of various racemic substrates.
NHCHO
NHCHO
MPLC using SiO2 column
eluent: hexane / AcOEt = 1
2. Results and discussion
+
On the basis of our preliminary results, which showed a quite
impressive magnitude of the self-disproportionation of enan-
tiomers in non-racemic chiral N-acyl-1-phenylethyl amine deriva-
tives,3 we decided to use similar compounds as model substrates
for the chiral additive induced self-disproportionation of enan-
tiomers. In addition to their known self-disproportionation of
enantiomers profile, 1-phenylethylamine derivatives are struc-
turally very simple, commercially available, represent classical tar-
gets in asymmetric synthesis and are widely used in the
pharmaceutical industry.9
OMe
(S)-1a
rac-2a
276 mg
60 mg
(molar ratio = 5.5:1)
less polar fraction
(S)-2a (>99% ee, 7.9 mg)
(S)-1a
more polar fraction
(R)-2a (16% ee, 48.9 mg)
Since the substituent on the amino function has been found to
have a significant influence on the magnitude of the self-dispro-
portionation of enantiomers, we initially performed a detailed
screening of various N-acyl derivatives of chiral additive 1 and
racemate 2 by mixing them in a ratio of 1:1 and performing achiral
MPLC experiments (Fig. 2). Among the several possible combina-
tions in the (S)-1-phenylethylamine derivatives (S)-1a–d and race-
mic 1-(3-methoxyphenyl)ethylamine derivatives rac-2a,b, chiral
additive induced self-disproportionation of enantiomers was
observed only in the pairs of N-formyl derivative (S)-1a (50 mg)
and rac-2a (60 mg) and N-acetyl derivative (S)-1b (49 mg) and
rac-2b (50 mg).8 MPLC of these pairs brought about the elution of
optically active 2a (1.2 mg, 99% ee) and 2b (1.0 mg, 90% ee),
respectively.
[min]
60
40
20
retention time
Figure 3. MPLC chart of mixture in a molar ratio of (S)-1a and rac-2a = 5.5:1.
The composition in the area of 2a with several shoulders was
investigated in more detail. To this end we isolated six fractions,
as shown in Figure 4, and studied their enantiomeric composition
as well as the absolute configuration of the excess enantiomer. The
first fraction was found to be noticeably enriched (39% ee) in (S)-
2a, while the rest of the fractions (from the second to the sixth)
contained an excess of (R)-2a with gradually decreasing enan-
tiomeric purity from 23% to 10% ee.
NHCOR
(S)-1 (100% ee)
(R)-2a (23% ee)
(S)-2a (39% ee)
NHCOR
2 (racemic)
(S)-1a (R = H)
Me
(R)-2a (22% ee)
(S)-1b (R = Me)
(S)-1c (R = Et)
Ph
Me
rac-2a (R=H)
(R)-2a (20% ee)
(S)-1d (R = COOMe)
rac-2b (R=Me)
(S)-2a
(R)-2a (16% ee)
OCH3
(>99% ee)
less polar
fraction
(R)-2a (10% ee)
MPLC using SiO2 column
eluent: hexane-AcOEt
1
2
+
(S)-1 + rac-2
(S)-
+
(S)-
(R)-2
(60 mg)
[min]
50
60
retention time
1
molar ratio of (S)-
and rac-2 =1:1
column: 10µm of SiO2 (20 x 250 mm)
Figure 4. Detailed ee change of 2a in chart of Figure 3.
(S)-1a
(S)-1c
+
+
rac-2b
rac-2a
(S)-1a
+
rac-2a
1b
(S)-
+
rac-2b
Subsequently, the application of the present chiral additive
induced self-disproportionation of enantiomers to various N-for-
myl-1-arylethylamine derivatives was examined under the same
conditions (Table 1). Thus, in addition to 3-methoxyphenyl
(S)-1b + rac-2a
(S)-1d + rac-2a
Figure 2. MPLC experiment of mixture of (S)-1 and rac-2.
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M. Goto et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
derivative 2a, the procedure performed using 4-methoxy and 2-
methoxy derivatives rac-2c and rac-2d and led to the elution of
2c (99% ee) and 2d (98% ee) with high enantiomeric purity in
recovery yields of 14% and 21%, respectively (entries 2 and 3). This
method could be applied to N-formyl-1-phenyl-ethylamines rac-
2e–2i bearing various substituents such as bromo, chloro, fluoro
and methyl groups on the benzene ring (entries 4–8). For these
substrates, optically active 2e–2i were obtained with recovery
yields of 14–28% with 98–99% ee. It should be noted that the chiral
additive induced self-disproportionation of enantiomers was
observed not only in N-formyl-1-phenyl-ethylamine derivatives
rac-2a–2i but also in N-formyl-1-naphthylethylamine derivatives
rac-2j and rac-2k, and almost enantiomerically pure 2j (98% ee)
and 2k (99% ee) were obtained with recovery yields of 16% and
27%, respectively (entries 9 and 10).
enantiomerically pure 2h (99% ee) and slightly enantioenriched
2h (11–23% ee) were eluted. Similar chromatographic profiles
were also observed in the chiral additive induced self-dispropor-
tionation of enantiomers of 2c, 2f, 2g (Table 1, entries 2 and 5–6).
NHCHO
Me
NHCHO
Me
Ph
MPLC using SiO2 column
eluent: hexane / AcOEt = 1
+
F
(S)-1a
295 mg
rac-2h
60 mg
(molar ratio = 5.5:1)
(S)-2h
(S)-2h
(11% ee)
(99% ee)
(7.1 mg)
(S)-1a
(R)-2h
(23% ee)
Table 1
(R)-2h
Application of chiral additive induced self-disproportionation of enantiomers to
various racemic N-formyl-1-arylethylamines rac-2
(19% ee)
NHCHO
[min]
80
70
60
50
40
30
(S)-1a
retention time
(100 %ee)
Ph
CH3
NHCHO
NHCHO
CH3
2
+
+ (S)-1a
Figure 5. Chiral additive induced self-disproportionation of enantiomers of rac-2h
with (S)-1a.
Ar
CH3
Ar
(R)-rich
2) MPLC using achiral
SiO2 column
rac-2
2
(S)-
(> 98% ee)
NHCHO
NHCHO
Entry
Ar rac-2
rac-2 (mg)
(S)-2: recovery
weighta (mg)
and eeb (%)
Ph
Me
MPLC using SiO2 column
Me
OMe
+
eluent: hexane / AcOEt = 3/2
1
2
3
4
5
6
7
8
9
3-MeOC6H4 2a
4-MeOC6H4 2c
2-MeOC6H4 2d
3-BrC6H4 2e
4-BrC6H4 2f
4-ClC6H4 2g
60
60
57
60
60
60
60
60
60
54
7.9
99
4.3
6.1c
7.6c
5.3
6.7
7.1
8.5
5.0
7.2c
99
98
99
99
98
99
99
98
99
(S)-1a
263 mg
rac-2d
57 mg
(S)-2d + (S)-1a
(98% ee)
(6.1 mg)
(molar ratio = 5.5:1)
(S)-2d (23.5% ee)
(R)-2d (23.5% ee)
4-FC6H4 2h
4-MeC6H4 2id
Naphth-1-yl 2j
Naphth-2-yl 2k
(R)-2d (15.1% ee)
(S)-1a
10
a
b
c
Isolated recovery weight.
The ee was determined by HPLC analysis using a chiral column.
Since 2d, 2e, 2k contained chiral additive (S)-1a, their recovery weights were
evaluated by 1H NMR and HPLC.
90
80
70
60
50
40 [min]
d
Chiral additive induced self-disproportionation of enantiomers was conducted
in a molar ratio of (S)-1a and rac-2i = 3:1, while in MPLC using 5.5 equiv of (S)-1a,
the clear peak due to (S)-2i was not detected because of the complete overlap with
the peak of (S)-1a.
Figure 6. Chiral additive induced self-disproportionation of enantiomers of rac-2d
with (S)-1a.
NHCHO
In entries 2 and 5–7, the chiral additive (S)-1a was completely
separated from the components of substrates 2c, 2f–2h such as
MPLC shown in Figure 3. Meanwhile in the cases of entries 3, 4
and 10, (S)-1a could not be completely separated from the sub-
strates 2d, 2e, 2k because of a similar retention time between
the substrates and (S)-1a, and the obtained almost enantiomeri-
cally pure (S)-2d, 2e, 2k contained chiral additive (S)-1a [the recov-
ery weight of (S)-2d, 2e, 2k was evaluated by 1H NMR or HPLC
analysis]. In entries 8 and 9, although (S)-1a was not completely
separated from the components of substrates 2i and 2j, the fraction
involving the almost enantiomerically pure (S)-2i and 2j did not
contain (S)-1a (see Fig. 7).
MPLC using SiO2 column
Me
NHCHO
Me
eluent: hexane / AcOEt = 3/2
+
Ph
(S)-1a
216 mg
rac-2j
57 mg
(S)-2j
(99% ee)
(9.0 mg)
molar ratio = 5.5:1)
(
(S)-2j
(49% ee)
(R)-2j + (S)-1a
(35% ee)
Typical MPLC charts on the chiral additive induced self-dispro-
portionation of enantiomers are shown in Figures 5–7. Figure 5
shows the chiral additive induced self-disproportionation of
enantiomers of p-fluorophenyl derivative rac-2h. Similar to the
chiral additive induced self-disproportionation of enantiomers of
rac-2a (Fig. 3), chiral additive (S)-1a initially eluted and was
completely separated from substrate 2h. Subsequently almost
[min]
80
70
60
50
retention time
Figure 7. Chiral additive induced self-disproportionation of enantiomers of rac-2j
with (S)-1a.
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4
M. Goto et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Figure 6 shows the MPLC chart of the mixtures of rac-2d and
by MPLC of the mixtures to bring about the elution of almost enan-
tiomerically pure (S)-2. Direct resolution methods of racemates via
chromatography using chiral mobile12 or stationary phases13 are
known.14 However, a chiral mobile phase method requires the
use of a very large excess (>100 equiv) of a chiral selector added
to an eluent, inevitably resulting in mixtures of resolved enan-
tiomers with the chiral selector at all times. Although separation
of the enantiomers using the chiral stationary phase method is
the most popular on an analytical scale, the only disadvantage of
this approach is that the preparative chiral stationary phase col-
umns are still very expensive. Our approach based on the chiral
additive induced self-disproportionation of enantiomers provides
an inexpensive and facile research laboratory technique for the
generation of enantiomerically pure compounds starting from
racemates, although structural similarities between the racemic
substrates and a chiral additive are required to achieve the chiral
additive induced self-disproportionation of enantiomers. The
application of the present chiral additive induced self-dispropor-
tionation of enantiomers method to other compounds except for
1-arylethylamines is currently in progress.
(S)-1a. In this case, (S)-1a could not be completely separated from
2d; instead 2d was obtained with high enantiomeric purity as a
mixture with (S)-1a. Similar chromatographic profiles were also
observed in 3-bromophenyl and naphth-2-yl derivatives 2e and
2k (Table 1, entries 4 and 10).
The MPLC chart in Figure 7 shows the chiral additive induced
self-disproportionation of enantiomers of rac-2j. In this case,
almost enantiomerically pure (S)-2j was eluted first and subse-
quently a mixture of (S)-1a and slightly (R)-rich 2j was eluted.
The elution of this type was also observed in the case of 4-methyl-
phenyl derivative 2i (Table 1, entry 8).
In all of the chiral additive induced self-disproportionation of
enantiomers shown in Table 1, 2a–2k with high enantiomeric pur-
ity was always eluted as the less polar fractions and subsequently
the slightly (R)-enriched enantiomer mixture was eluted in the
end. Furthermore, the absolute stereochemistry of 2a–2k in the
less polar fractions was found to be (S).11 Thus, when (S)-1 was
used as the chiral additive, (S)-2 was obtained with high enan-
tiomeric purity as the less polar fractions without exception.
These results may be rationalized as follows (Eq. 3). We have
previously suggested3 that compounds of this class prefer to form
syndiotactic mixed heterochiral associations consisting of different
enantiomers more than isotactic mixed homo-chiral associations
consisting of the same enantiomers.5 Thus, it may be assumed that
the (S)-chiral additive reagent (S)-1a selectively forms high-order
species with the (R)-enantiomer of rac-2, which have longer reten-
tion times compared to monomeric species of the (S)-enantiomer
which elute first.
4. Experimental
4.1. General
Medium-pressure liquid chromatography (MPLC) was per-
formed on a 25 ꢀ 4 cm i.d. prepacked column (silica gel, 10
lm)
with a UV detector. High-performance liquid chromatography
(HPLC) was performed on a 25 ꢀ 0.46 cm i.d. chiral column with
a UV detector.
[(S)-1....(S)-2]
[(S)-1....(R)-2]
(S)-1
+
rac-1
+
homochiral
association
heterochiral
association
4.2. Chiral additive 1a and racemic substrates 2a–2k
ð3Þ
Chiral additive 1a and racemic substrates 2a–2k, 3, 4 are com-
mercially available.
SiO2
(S)-1
+
(S)-2
+
(R)-2
more polar
less polar
4.3. General method for the chiral additive induced self-
disproportionation of enantiomers
We also investigated the chiral additive induced self-dispropor-
tionation of enantiomers of N-formyl-1-phenylpropylamine 3 and
N-formy-2-phenylpropylamine 4 (Fig. 8). However, under the same
conditions, the efficient chiral additive induced self-disproportion-
ation of enantiomers such as N-formyl 1-arylethylamine derivatives
2 was not observed. In MPLC with 3, slightly enantioenriched
(S)-3 (13% ee) was obtained as a less polar fraction, and with 4, no
elution of enantioenriched 4 was found. Thus, 1-arylethylamine
skeleton may be required for the present chiral additive induced
self-disproportionation of enantiomers using (S)-1.
At first, rac-2a (61 mg) and (S)-1a (276 mg) were mixed in a
molar ratio of 1:5.5, and then the mixtures were separated to the
less polar fraction [(S)-2a, 7.9 mg, >99% ee] and the more polar
fraction (48.9 mg, 16% ee) by MPLC (hexane/AcOEt = 1). The ee of
2b was determined by HPLC analysis using a CHIRALCEL OD-3 col-
umn [25 cm ꢀ 0.46 cm i.d.; 10% i-PrOH in hexane; flow rate,
1.5 mL/min; (S)-2b; tR = 17.0 min, (R)-2b; tR = 11.3 min]. The abso-
lute configuration was determined based on the comparison with
authentic sample of (S)-2a, which was prepared from (S)-1-(3-
methoxyphenyl)ethylamine.
NHCHO
Me
NHCHO
Me
NHCHO
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rac-3
rac-4
rac-2
not efficient chiral
additive induced self-
disproportionation of
enantiomers
no chiral additive
induced self-
efficent chiral
additive induced self-
disproportionation of
enantiomers
disproportionation of
enantiomers
Figure 8. Application of chiral additive induced self-disproportionation of enan-
tiomers to other substrates 3 and 4 except for 2.
3. Conclusion
We have found that self-disproportionation of the enantiomers
of various racemic N-formyl-1-arylethylamines rac-2 occurs via
the addition of (S)-N-formyl-1-phenylethylamine (S)-1 followed
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Please cite this article in press as: Goto, M.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.03.004