Enantioseparation of Sulfoxides and Nitriles by Inclusion Crystallization with Chiral Organic Salts Based on l-Phenylalanine

Article abstract of DOI:10.1002/ejoc.201800003

Enantioselective inclusion of aromatic sulfoxides and nitriles was achieved in a host framework created by organic salts comprising achiral benzoic acids and a chiral primary amine (1a) derived from l-phenylalanine. Tuning of the combined achiral acid component successfully changed the chiral recognition ability of the organic salts. The guest molecules were hydrogen-bonded to form three-component inclusion crystals, and the enantiomers of nitriles and sulfoxides were separated with high selectivity up to 92 and 98 % ee. As far as we know, this is the first example of the enantioseparation of non-functionalized aromatic nitriles.

Full text of DOI:10.1002/ejoc.201800003

A Journal of
Accepted Article
Title: Enantioseparation of sulfoxides and nitriles via inclusion
crystallization with chiral organic salts based on L-phenylalanine
Authors: Koichi Kodama, Hayato Kanai, Yuki Shimomura, and Takuji
Hirose
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Enantioseparation of sulfoxides and nitriles via inclusion
crystallization with chiral organic salts based on L-phenylalanine
Koichi Kodama,* Hayato Kanai, Yuki Shimomura, and Takuji Hirose [a]
Abstract: Enantioselective inclusion of aromatic sulfoxides and
nitriles was achieved in a host framework created by organic salts
comprising achiral benzoic acids and a chiral primary amine (1a)
derived from L-phenylalanine. Tuning of the combined achiral acid
component successfully changed the chiral recognition ability of the
organic salts. The guest molecules were hydrogen-bonded to form
three-component inclusion crystals and the enantiomers of nitriles and
sulfoxides were separated with high selectivity up to 92% ee and 98%
ee. As far as we know, this is the first example of the
enantioseparation of non-functionallized aromatic nitriles.
compounds.[7] Herein, we describe enantioselective inclusion of
hydrogen-accepting guest compounds such as alkyl phenyl
sulfoxides
and
-alkylphenylacetonitriles
by
inclusion
crystallization with chiral organic salts using a natural L-amino
acid as an inexpensive chiral source.
Recently we reported enantioselective inclusion of aromatic
sulfoxides by the salt of phenylurea-modified L-phenylalanine and
an achiral primary amine.[7e] The urea moiety facilitated the
inclusion because of its hydrogen-donating ability as well as its
conformational restriction of the terminal phenyl group. Prompted
by this result, we investigated the salts with opposite
combinations, that is, a chiral amine (1a)[8] with a hydrogen-
donating phenylhydrazide moiety combined with suitable achiral
carboxylic acids (2a-2j) for the inclusion of methyl phenyl
sulfoxide (3a), because the hydrazide moiety has been
recognized as a potential hydrogen bond donor.[9] Organic salts
1a·2 were crystallized from acetonitrile in the presence of guest
sulfoxide 3a (5 equiv.). The results are summarized in Table 1.
Enantiomer separation by crystallization is an economic, easy-to-
handle, and reproducible process used to prepare optically active
compounds in both labolatory and industrial scales.[1] In particular,
enantioselective inclusion crystallization of guest compounds
through a chiral organic host framework has been well studied
because this method enables the enantioseparation of neutral
guest compounds such as alcohols.[2] In most cases, the primary
driving force for the inclusion and chiral recognition of the neutral
guests is the formation of a hydrogen bond, therefore this method
has been applied not only to hydrogen bond donors like alcohols,
but also to hydrogen bond acceptors such as ketones, ethers, and
sulfoxides.[3]
Table 1. Enantioselective inclusion of 3a with the salts of a chiral amine (1a)
and achiral carboxylic acids (2a-2j)
Nitriles are also hydrogen bond acceptors and are an important
class of compounds that are used as versatile precursors of
carboxylic acids, amides, and amines in organic synthesis. In
addition, chiral nitriles are important for the manufacture of
various pharmaceuticals.[4] Asymmetric cyanation of carbonyl
compounds or imines produces optically active nitriles with a
hydroxy, carbonyl or an amino group.[5] However, accessing
optically active nitriles without other functional groups remains a
challenge. A few examples of asymmetric synthesis and
enzymatic methods have been reported to access non-
functionalized nitriles in their optically active form, but these
methods suffer from multiple reaction steps, use of complex chiral
ligands, and low activity.[6] Despite many studies on host-guest
inclusion crystals, enantioseparation of -alkylated chiral nitriles
without any other functional groups has not been reported to date,
as far as we know. This is likely because the rigid and linear
structure of the nitrile functionality prevents efficient host/guest
molecular packing in the inclusion crystal.
Entry
Acid
Yield (%)[a]
Inclusion ratio of
Ee (%)[c]
3a (%)[b]
1
2
2a
2b
2c
2d
2e
2f
50[d]
53
50
40
2 (S)
48 (S)
3
Not crystallized
-
4
38
60
46 (R)
5
Not crystallized
Not crystallized
Not included
-
-
6
We have been studying about multi-component chiral hosts
based on ammonium-carboxylate organic salts, which allows the
construction of an asymmetric space by simply mixing two
7
2g
2h
2i
68
77[d]
57
8
130
Not included
120
56 (S)
82 (S)
9
[a]
Dr. K. Kodama, H. Kanai, Y. Shimomura, Prof. T. Hirose
Department of Applied Chemistry, Graduate School of Science and
Engineering, Saitama University
10
2j
68[d]
255 Shimo-Okubo, Sakura-ku, Saitama 338-8570 (Japan)
E-mail: kodama@mail.saitama-u.ac.jp
http://www.apc.saitama-u.ac.jp/ykogyo/
[a] Yield of 1a calculated based on the initially used 1a. [b] Determined by
1H NMR analysis based on 1a. [c] Determined by HPLC analysis. [d] Excess
amount (10–20%) of 2 was incorporated in the salts 1a·2.
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10.1002/ejoc.201800003
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COMMUNICATION
enantioselectivity for the dialkyl sulfoxide (3g), which is likely due
to the flexible benzyl group on its stereogenic center.
Guest inclusion was also achieved by suspending the salt in the
guest solution. Suspending the salt 1a·2h in a toluene solution of
3a-3g overnight and subsequent filtration afforded inclusion
crystals for three sulfoxides 3a, 3b, and 3g (Table S2).
Furthermore, the enantioselectivities of 3b and 3g were highly
improved up to 98% ee and 66% ee, respectively. The powder
XRD pattern of the 1a·2h·3b inclusion crystal prepared by the
suspension method was almost identical to that prepared by direct
crystallization from the solution (Figure S1). This indicates that the
chiral recognition mechanism should be common between the
two methods. Such an improved selectivity by the suspension
method has also been observed in other host-guest systems,
which is probably due to the pre-formation of the chiral host
framework.[11] The thermogravimetric analysis (TGA) of the
inclusion crystal 1a·2h·3b showed weight loss beginning at
150 °C, which is consistent with its melting point (146–148 °C,
Figure S2). This thermal stability of the inclusion crystal
suggested that the host-guest interaction was strong enough to
prevent desorption of 3b by heating.
The crystal structure of 1a·2h·3b revealed that the salt of 1a
and 2h formed a one-dimensional columnar hydrogen-bonding
network[12] and guest 3b was incorporated between columnar
structures mainly by a hydrogen bond with the phenolic hydroxy
group of 2h (Figure 1a).[13] The hydrazide moiety of 1a was
important for the guest inclusion because the nitrogen atom was
hydrogen-bonded with the carboxylate oxygen atom of 2h to
confine the position of the terminal phenyl group of 1a and create
an asymmetric space (Figure 1b). The high enantiopurity of (S)-
3b was attributable to two CH/ interactions that fix both the
phenyl and ethyl groups of (S)-3b.[14] It was confirmed that the
Among the investigated acids, the salts of diphenylacetic acid
(2b) and benzoic acid (2d) showed moderate enantioselectivity
for 3a, while the ratio of included 3a was low (entries 2 and 4).
After further screening of the commercially available substituted
benzoic acids (2e-2j), 2h and 2j with a phenolic hydroxy group
were found to be a suitable achiral carboxylic acid for selective
inclusion of (S)-3a up to 82% ee (entries 8 and 10). It is
noteworthy that both enantiomers of 3a are available by changing
the achiral carboxylic acid 2 by using 1a with the same chirality.
In contrast, when the N-phenylhydrazide moiety of chiral amine
1a was exchanged to the corresponding benzylamide (1b) or
benzamide (1c) moiety, salts 1·2h and 1·2j did not crystallize in
the presence of 3a.[10] Also, when L-phenylglycine was used as
the initial chiral source instead of L-phenylalanine, the
corresponding N-phenylhydrazide derivative (1d) showed no
chiral recognition for 3a by salt formation with 2h and 2j (Table
S1). These results indicate that both L-phenylalanine and N-
phenylhydrazide moieties of 1a are essential for the
enantioselective inclusion of 3a when combined with 2h and 2j.
In the next step, the scope of selective inclusion of seven
aromatic sulfoxides (3a-3g) was investigated using the salts of
1a·2h and 1a·2j (Table 2). Both salts generally showed high
inclusion ratio and moderate enantioselectivities for S-enantiomer
of alkyl aryl sulfoxides (3a-3f). The sulfoxides (S)-3d and (S)-3f
were obtained with high enantiopurity (90% ee) by salts 1a·2h and
1a·2j, respectively (entries 4 and 13), while no chiral recognition
occurred when the salt was exchanged (entries 6 and 11). It is
advantageous that the chiral recognition ability of the salts was
easily controlled by changing only the achiral acid component for
the target guest molecules. Both salts afforded much lower
Table 2. Enantioselective inclusion of sulfoxides 3a-3g with the salts of 1a and achiral carboxylic acids (2h or 2j)
Conducted with 1a·2h
Conducted with 1a·2j
Entry
Guest
Yield (%)[a]
Inclusion ratio of
Ee (%)[c]
Entry
Guest
Yield (%)[a]
Inclusion ratio of
Ee (%)[c]
3 (%)[b]
3 (%)[b]
77
67
63
70
85
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
130
120
120
120
120
56 (S)
86 (S)
50 (S)
90 (S)
46 (S)
-
8
3a
3b
3c
3d
3e
3f
120
120
110
150
170
82 (S)
80 (S)
38 (S)
2 (S)
68
73
57
62
66
63
9
10
11
12
13
14
Rac.
Not crystallized
90 (S)
2 (R)
110
110
3g
48
100
10(R)
3g
69
[a] Excess amount (10–20%) of 2 was incorporated in the salts 1a·2 and the yield of 1a calculated based on the initially used 1a. [b] Determined by 1H NMR
analysis based on 1a. [c] Determined by HPLC analysis.
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powder XRD pattern simulated from the single crystal data was
identical with those of experimentally obtained bulk solids of
inclusion crystals (Figure S1).
condition. Four chiral nitriles (4b-4e) with various alkyl groups on
the -position of phenylacetonitrile were also incorporated in salt
1a·2h, although the inclusion ratio gradually decreased with the
length of the alkyl groups, likely because of the limited space
created by the salt. Except for 4e, S-enantiomers of 4 were
preferentially included and 3-methyl-2-phenylbutyronitrile (4d)
was included in a 1:1 ratio with such a high selectivity of 92% ee
(entry 7). When nitriles 4f-4h with a methyl group on the phenyl
ring of 4b were used, only the para-substituted derivative 4h was
enantioselectively included (entry 11). Finally, the nitriles with a
benzyl group (4i) and a stereogenic center on the -position (4j)
also produced inclusion crystals, although the selectivity was
rather low because of their flexible structures (entries 12 and 13).
Contrary to the inclusion of sulfoxides 3, the inclusion of 4b with
1a·2h salt by the suspension method in toluene was unsuccessful.
The TGA of 1a·2h·4b showed partial weight loss at 90 °C before
melting, which indicated that desorption of guest 4b from the salt
is easier than that of 3b (Figure S3).
a)
Table 3. Enantioselective inclusion of aromatic nitriles 4a-4j with the salt of
1a·2h
b)
Entry
Guest
Yield (%)[a]
Inclusion ratio of
Ee (%)[c]
4 (%)[b]
1
2[d]
3[e]
4[f]
5
4a
4a
4a
4a
4b
4c
4d
4e
4f
80
79
75
80
83
91
82
65
68
63
70
78
78
100
70
82 (S)
66 (S)
66 (S)
81 (S)
72 (S)
80 (S)
92 (S)
Rac.
100
100
110
40
6
Figure 1. Structure of inclusion crystal 1a·2h·(S)-3b. a) Top view of the
columnar structures. Oxygen, nitrogen, and sulfur atoms are represented with
red, blue, and yellow, respectively. The arrows show CH/ interactions. b)
Schematic representation of the hydrogen-bonded network. The dotted lines
show hydrogen bonds.
7
100
30
8
9
Rac.
50
10
11
12
13
4g
4h
4i
Not included
80
-
The wide space around the phenolic hydroxy group of 2h used
to capture 3 by formation of a hydrogen bond prompted us to
examine the inclusion of aromatic nitriles (4) as guest compounds
(Table 3). When 1a·2h was recrystallized from a CH3CN solution
in the presence of 5 equiv. of 2-phenylbutyronitrile (4a), inclusion
crystals were obtained and an equimolar amount of 4a was
incorporated in the salt crystal. In addition, the enantiopurity of the
included 4a was as high as 82% ee (entry 1). As far as we know,
this is the first example of the enantioselective inclusion of nitriles
without any other hydrogen-bonding functional groups. When the
initial amount of 4a was decreased to 2 or 3 equiv., the inclusion
ratio/enantiopurity of 4a was lowered (entries 2-3). In contrast,
when the amount of 4a is doubled to 10 equiv., almost no
improvement occurred in the enantioselectivity (entry 4). Finally,
addition of 5 equiv. of the guest was found to be the optimal
18 (S)
16 (R)
33 (S)
90
4j
100
[a] Yield of 1a calculated based on the initially used 1a. Excess amount
(10%) of 2h was incorporated in the salt 1a·2h. [b] Determined by 1H NMR
analysis based on 1a. [c] Determined by HPLC analysis. [d] 2 equiv. of 4a
was used. [e] 3 equiv. of 4a was used. [f] 10 equiv. of 4a was used.
The enantiopurity of the included 4a was improved by
recrystallization of the inclusion crystals. An additional
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recrystallization of 1a·2h·4a (68% ee) from CH3CN resulted in the
inclusion crystal with 88% ee of (S)-4a, although the inclusion
ratio was decreased from 90% to 50%. This suggests that the
enantiopurity of liquid nitriles 4 can be improved by repeated
crystallization with organic salt 1a·2h, which is also applicable to
the enantio-enriched nitriles obtained by other methods such as
asymmetric synthesis. Although the structures of three-
component inclusion crystals 1a·2h·4 are unknown because of
their poor diffraction properties, salt 1a·2h afforded solvated
crystals when prepared from CH3CN or ethyl acetate (Figure 2).[13]
In these crystals, 1a and 2h constructed a columnar structure and
the solvent molecules were incorporated through the formation of
a hydrogen bond with the phenolic hydroxy group of 2h, which
was common to 1a·2h·(S)-3b. Such an inclusion of hydrogen-
accepting solvents as well as the consistent S-selectivity for
sulfoxides 3 and nitriles 4 implies that 4 could be incorporated in
the salt crystal in a similar manner.
practical enantioseparation of nitriles as well as other hydrogen-
accepting neutral guest compounds.
Keywords: Enantioseparation • Inclusion crystal • Hydrogen
bond • Nitrile • Hydrazide
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Figure 2. Structure of inclusion crystals a) 1a·2h·EtOAc and b) 1a·2h·CH3CN.
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In summary, organic salts composed of a chiral primary amine
derived from L-phenylalanine and achiral carboxylic acids were
developed for enantioselective inclusion of aromatic sulfoxides
and nitriles. Both the acids and amines are easily available;
therefore, this result affords a straightforward method to access
optically active nitriles without other functional groups. Further
optimization of the chiral organic salts will lead to improved and
[13] CCDC 1577954-1577956 contain the supplementary crystallographic
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Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Optical Resolution
Koichi Kodama,* Hayato Kanai, Yuki
Shimomura, Takuji Hirose
Enantiomer separation of nitriles
(~92%ee) and sulfoxides (~98%ee)
by inclusion crystallization with chiral
organic salts of 4-hydroxybenzoic
acids and a chiral primary amine
derived from L-phenylalanine is
described, which is the first example
of the direct enantioseparation of
aromatic nitriles without other
functional groups.
Page No. – Page No.
Enantioseparation of sulfoxides and
nitriles via inclusion crystallization
with chiral organic salts based on L-
phenylalanine
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