Asymmetric amination of meso-epoxide with vegetable powder as a low-toxicity catalyst

Article abstract of DOI:10.3390/molecules25143197

This paper describes the scope and limitation of substrates subjected to asymmetric amination with epoxides catalyzed by a soluble soybean polysaccharide (Soyafibe S-DN), which we recently discovered from the reaction of 1,2-epoxycyclohexane with cyclopropylamine. Various meso-epoxides reacted with various amines afforded the corresponding products with good enantiomeric selectivity. Since it was found that pectin was found to have a catalytic ability after screening commercially available polysaccharides, we studied 33 different vegetable powders having pectic substances, and we found that many vegetable powders showed catalytic ability. These results should guide in using vegetable components as low-toxic catalysts for the production of pharmaceuticals.

Full text of DOI:10.3390/molecules25143197

molecules
Article
Asymmetric Amination of meso-Epoxide with
Vegetable Powder as a Low-Toxicity Catalyst
Yuki Takeuchi 1,2,*, Tatsuhiro Asano 1, Kazuya Tsuzaki 1, Koichi Wada 1 and Hiroyuki Kurata 3
1
Kyowa Pharma Chemical Co., Ltd., Chokeiji, Takaoka, Toyama 933-8511, Japan;
tatsuhiro.asano@kyowa-kirin.co.jp (T.A.); kazuya.tsuzaki@kyowa-kirin.co.jp (K.T.);
koichi.wada@kyowa-kirin.co.jp (K.W.)
Graduate School of Engineering, Fukui University of Technology, Fukui 910-8505, Japan
2
3
Organization for Fundamental Education, Fukui University of Technology, Fukui 910-8505, Japan;
kurata@fukui-ut.ac.jp
*
Correspondence: yuki.takeuchi@kyowa-kirin.co.jp
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 23 June 2020; Accepted: 10 July 2020; Published: 13 July 2020
Abstract: This paper describes the scope and limitation of substrates subjected to asymmetric
amination with epoxides catalyzed by a soluble soybean polysaccharide (Soyafibe S-DN), which we
recently discovered from the reaction of 1,2-epoxycyclohexane with cyclopropylamine. Various
meso-epoxides reacted with various amines afforded the corresponding products with good
enantiomeric selectivity. Since it was found that pectin was found to have a catalytic ability
after screening commercially available polysaccharides, we studied 33 different vegetable powders
having pectic substances, and we found that many vegetable powders showed catalytic ability.
These results should guide in using vegetable components as low-toxic catalysts for the production
of pharmaceuticals.
Keywords: polysaccharide; asymmetric amination; low-toxicity catalyst; pectin
1. Introduction
Chiral
β-aminoalcohol units are found in many bioactive compounds used for the
therapeutic treatment of various diseases [
1
–
3
]. Chiral trans- -aminocyclohexanol derivatives
β
are particularly useful substrates as key intermediates for the synthesis of 1-cyclopropyl-1-
((1R,2R)-2-hydroxycyclohexyl)-3-(3-((2-oxo-1,2-dihydroquinolin-6-yl)oxy)propyl)urea, which is a
phosphodiesterase III inhibitor with vascular hypertrophy effects, and (R)-1-((1R,2R)-2-(3,4-
dimethoxyphenethoxy)cyclohexyl)-pyrrolidin-3-ol, which is an antiarrhythmic agent (Figure 1) [
The most effective method to synthesize chiral trans- -aminocycloalkanols is the catalytic asymmetric
amination of the corresponding 1,2-epoxycycloalkanes. Although many catalytic systems have been
reported for this reaction, most of them are based on organometallic complexes, such as titanium [ ],
scandium [ ], cobalt [10], zinc [11], magnesium [12], and niobium [13]. The permissible concentrations
4–6].
β
7,8
9
of elemental impurity in pharmaceuticals are strictly prescribed by the Q3D guideline established
by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use. Therefore, a low-toxicity catalyst for pharmaceutical production is highly sought
after. In addition, green chemistry protocols must be applied for pharmaceutical production [14].
We have previously reported that soy products, especially the soybean polysaccharide Soyafibe
S-DN, are effective catalysts for the asymmetric amination of 1,2-epoxycyclohexane to synthesize
(1R,2R)-2-(cyclopropylamino)cyclohexan-1-ol (1a) (Figure 2) [15]. We have also reported that Soyafibe
S-DN is reusable without further treatment and has a low environmental impact.
Molecules 2020, 25, 3197; doi:10.3390/molecules25143197
www.mdpi.com/journal/molecules

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Figure 1. Structures of active pharmaceutical ingredients containing the trans-β-aminocyclohexanol moiety.
Figure 2. Asymmetric synthesis of (1R,2R)-2-(cyclopropyl-amino)cyclohexan-1-ol (1a) catalyzed by a
soy product.
Soyafibe S-DN is composed of soluble soy polysaccharides and is highly safe and easily
available [16]. It is made from the cake obtained after soy milk extraction and is used in large
quantities as a food additive in the food industry, e.g., as a stabilizer for dairy products [17]. Our results
showed that the catalytic activity of Soyafibe S-DN was due to the polysaccharide. In other words,
we have developed a new and highly safe catalytic system for the asymmetric amination of epoxides,
wherein soybean or the dietary fiber contained in soybean acted as the catalyst. Therefore, it is suitable
for use in pharmaceutical manufacturing processes that require the use of highly safe compounds.
In this paper, we report the scope of the reactants in asymmetric amination using Soyafibe S-DN.
We also report the results of the reaction of 1,2-epoxycyclohexane with cyclopropylamine catalyzed by
vegetables other than soy.
2. Results and Discussion
2.1. Substrate Scope for Epoxide
Initially, to obtain a suitable epoxide, cyclopropylamination was carried out for 136 h on five
types of epoxides (
2,
4
–
7). The conversion and enantiomeric excess (ee) of the five corresponding
trans- -cyclopropylaminoalkanols (1a
β
,
4a–7a) obtained are listed in Table 1. Thus, Soyafibe S-DN
catalyzed the cyclopropylamination of all the five epoxides studied. In addition, epoxides with 5-
or 6-membered ring skeletons were found to be particularly suitable. In terms of enantioselectivity,
1,2-epoxycyclopentane and 1,2-epoxycyclohexane were the desirable substrates. The absolute
configurations of the products were not identified except for 1a (1a has (R,R) configuration).
The reaction time for studying the epoxide scope was 136 h, but it is presumed that the reaction
proceeded faster for 1,2-epoxycyclopentane and 1,2-epoxycyclohexane. Indeed, in the experiment
using 1,2-epoxycyclohexane at a 35 g scale, the conversion to 1a was 95% in 26 h. This section may
be divided by subheadings. It should provide a concise and precise description of the experimental
results, their interpretation, as well as the experimental conclusions that can be drawn.
2.2. Substrate Scope for Amine
The amine substrate scope was studied using
corresponding trans- -aminocyclohexanols are listed in Table 2. The absolute configurations of the
products were not identified except for 1a 1a has (R,R) configuration). Table 2 shows that the Soyafibe
2 as the substrate. The conversion and ee of the
β
(
S-DN-catalyzed amination of epoxides proceeded with a wide range of amines, including ammonia.
Aliphatic amines are particularly suitable but are unsuitable when they bear bulky substituents such as
the tert-butyl group. The amines that afforded relatively high ee in this reaction had moderately hindered
substituents, such as cyclopropyl, isopropyl, propargyl, 3-pentyl, and 2-phenylethyl groups. Except for

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amines bearing branched-chain substituents such as propargyl and 2-phenylethyl, the aforesaid
substituents and nucleophiles bearing these substituents are suitable for this catalytic system. Similarly,
since cyclopentylamine has a branched structure similar to the cyclopentane ring, the ee of the product
was moderate.
Table 1. Epoxide scope of the reaction.
Entry
Epoxide
X
Product
Conv. (%)
% ee
Control a
2
2
2
4
5
6
7
-C2H4-
-C2H4-
-C2H4-
-CH2-
-O-
1a
1a
1a
4a
5a
6a
7a
1
-
1
2 b
3
4
5
98
95
98
83
17
55
65
64
67
21 c
35 c
4
-C3H6-
H, H
6
Conversions and enantiomeric excess (ee) were determined by GC analysis (date available in Supplementary
a
Materials). The reaction was carried out for 22 h without the soluble soybean polysaccharide Soyafibe S-DN.
b
c
Using 2 at 25 g scale for 24 h. Determined by HPLC analysis.
Table 2. Screening of amines.
Entry
Amine
Product
Conv. (%)
% ee
R
R’
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3a
3b
3c
3d
3e
Cyclopropyl
Propyl
Isopropyl
Allyl
Propargyl
tert-Butyl
3-Pentyl
Cyclopentyl
Benzyl
H
H
H
H
H
H
H
H
H
1a
1b
1c
1d
1e
1f
1g
1h
1i
98
87
97
96
98
4
37
99
90
100
74
99
57
22
65
39
58
32
53
3f
32
81
3g
3h
3i
48
30 a
59 a
29
3j
2-Phenylethyl
Methyl
H
1j
3k
3m b
3n
3o
Methyl
1k
1m
1n
1o
–(CH2)4-
Phenyl
H
29
H
H
18 a
26
a
b
Conversions and ee were determined by GC analysis. Determined by HPLC analysis. 3m is pyrrolidine.
2.3. Proposed Reaction Mechanism
Based on the obtained results, we propose the reaction scheme as shown in Figure 3. The structures
of the soluble soy polysaccharides are composed of rhamnogalacturonan, galacturonan, homoarabinan,
homogalactan, xylan, and neutral sugars [17 18]. The addition of water is indispensable for the reaction
,
in the presence of Soyafibe S-DN; the amount of water suitable for this reaction was found to be 0.2–0.5
times the weight of Soyafibe S-DN. Any deviation from this amount of water resulted in a decreased

Molecules 2020, 25, 3197
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conversion rate and ee [15]. An aqueous solution of a small amount of Soyafibe S-DN covers the grain.
Therefore, Soyafibe S-DN can act as an emulsifier that can be transferred to water from toluene.
Figure 3. Proposed reaction scheme.
The amination of aliphatic epoxides with aliphatic amines in water in the absence of any catalyst
afforded the corresponding
β-aminoalcohols in good yields [19]. We believe that the reaction is
promoted by the water-containing polysaccharide chain by fixing the epoxide and drawing the amine
in its vicinity. Epoxide amination was slow in the solution around the grain, while the epoxide entered
between the polysaccharide chains in the grain relatively fast. The active site of this catalyst is the
undissolved polysaccharide moiety in the solution, similar to a sponge soaked in water. For large
epoxides such as
6, it is difficult to reach the active site, and the ring-opening reaction with amines
proceeds slowly. On the other hand, epoxide
7
, which has a smaller backbone than the other epoxides,
is difficult to immobilize on the chain despite its capability to enter the active site. Therefore,
the conversion is moderate.
The enantioselectivity of the product is attributable to the structure of the polysaccharide catalyst.
When the reaction was conducted using a highly nucleophilic amine, the reaction progressed more
rapidly in the solution of polysaccharide; thus, a lower ee was obtained (Table 2, entries 9, 11, and 12).
When the product was obtained with a high ee, it was presumed that the reaction proceeded in the
network of the sugar chain constituting the undissolved Soyafibe S-DN. The epoxide is fixed by the
network and is attacked by the amine from a less sterically hindered side. In the vicinity of this site,
there is space where the amine can be fixed to some extent, and an amine that can fit here gives the
corresponding product in high ee (Table 2, entries 1, 3, 5, 7, and 10). By contrast, it is estimated that
amines with structures that are difficult to fit in this site yield products in lower ee.
2.4. Screening of Polysaccharides as Catalysts
Soyafibe S-DN is reportedly composed of pectin-like polysaccharides [18], which are responsible for
the activity of this catalyst in the asymmetric amination of epoxides. Therefore, we investigated whether
commercially available polysaccharides can catalyze the cyclopropylamination of 2. The reaction
was carried out for 16 h. The conversion and the ee values of the obtained product 1a for different
polysaccharide catalysts are shown in Table 3.
Pectin, consisting of galacturonan and rhamnogalacturonan, functioned as a catalyst to give 1a
On the other hand, pectic acid obtained by hydrolysis of the methyl ester of pectin afforded no products.
When 0.6 mmol of 3a was used as the substrate, catalysis by neither pectin nor pectic acid gave any
products; 3a was also not detected by GC in the reaction solution. Since the amine was retained on the
carboxyl group of pectin and pectic acid, and no reaction occurred, the amount of 3a was increased
to 1.2 mmol. Consequently, the amine was detected in both the experiments, but the product was
obtained only with pectin. The following polysaccharides did not function as catalysts: dextran
.

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composed only of glucose, chitosan composed of glucosamine and its acetate, carrageenan composed
of sulfated galactose, curdlan composed of 1,3-glucan, arabinogalactan consisting of arabinose and
galactose, gum arabic composed of arabinogalactan, and xanthan gum composed of glucose, mannose,
and glucuronic acid. The components common to pectin and Soyafibe S-DN are galacturonan and
rhamnogalacturonan [17,18]. Therefore, they could play important roles in the catalysis of asymmetric
amination of epoxides. The difference in activity between pectin and Soyafibe S-DN can be attributed
to the different shapes of the molecules. Soyafibe S-DN is highly branched star-shaped, while pectin
has few branches and is rod-shaped [18]. Since the catalyst was not dissolved in the reaction system,
the catalytic activity depended on the surface area. Hence, we assume that the catalytic activity is
higher for Soyafibe S-DN.
Table 3. Screening of polysaccharides as catalysts.
Entry
Polysaccharide
Conv. (%) a
%ee a
Pectin (from citrus) b
Dextran
1
2
3
4
5
9
1
2
4
4
42
0
0
0
−1
Chitosan
Carrageenan
Curdlan
(+)-Arabinogalactan
(from lurch wood)
Gum Arabic
6
0
-
7
8
9
1
0
0
0
-
-
Xanthan gum
Pectinic acid b
a
b
Conversions and ee were determined by GC analysis. 1.2 mmol of cyclopropylamine was used.
2.5. Screening of Vegetables
Pectic substances are found in many plant species [20]. Therefore, we next screened the edible
parts and seeds of plants other than soybean for catalysis of the reaction of
carried out for 16 h.
2 with 3a. The reaction was
The 33 kinds of plants screened herein were obtained from the market as food. The commercially
available vegetable powders (carrot, pumpkin, lotus root, turmeric, tomato, coffee, citron, tea, garlic,
nutmeg, basil, ginger, rice barn, and wheat germ) were used without further processing. Vegetables not
commercially available in powdered form (peanut, almond, kiwifruit, apple, pomelo seed, pistachio,
kidney bean, green pea, banana, chickpeas, olive, ginkgo, red bean, pepper, perilla, sunflower seed,
kelp, seaweed, and hijiki) were dried under reduced pressure and then pulverized and washed with
hexane to remove oil, and the washed and dried powders were used as catalysts. The results for
reactions with conversion >3% are listed in Table 4. Many kinds of plants can promote this reaction.
The conversion and ee values of 1a differed depending on the type of plant used to prepare the catalyst,
due to the differences in structure and polysaccharide content of the vegetables. The use of kiwifruit,
carrot, pomelo, and pumpkin powders as catalysts gave 1a with >50% ee. When tea powder was used
as the catalyst, the highest conversion (29%) among the plants used was achieved; however, the ee
achieved was as low as 28%. The use of turmeric powder as the catalyst gave the (S,S) isomer-rich
product with 14% ee.

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Table 4. Screening of vegetables.
Entry
Vegetable
Conv. (%) c
% ee c
1
2
3
4
5
6
7
8
9
10
11
12
13
Kiwifruit (peel) a
Carrot b
9
12
9
8
7
7
4
4
3
71
62
54
54
47
33
32
31
26
28
27
14
−14
Pomelo (seed) a
Pumpkin b
Pistachio (seed) a
Potato (Mashed) b
Citron (peel) a
Lotus root b
Apple (seed) a
Tea (leaf) a
29
5
4
Kidney bean (seed) a
Green pea (seed) a
Turmeric b
11
a
b
Commercially available vegetables were used after drying, pulverizing, and degreasing. Commercially available
c
dried powders were used without treatment. Conversions and ee were determined by GC analysis.
2.6. Evaluation of Catalytic Performance of Carrot Powder
Carrot powder was identified as the most effective and readily available among the screened
plants. Therefore, the amination of 2 with five different C-3 amines were carried out for 136 h using
carrot powder as the catalyst to examine the compatibility of the substrate. The results are summarized
in Table 5.
Table 5. Amination of epoxide using carrot powder.
Entry
Amine
Product
Conv. (%)
% ee
R
R’
1
2
3
4
5
3a
3b
3c
3d
3e
Cyclopropyl
Propyl
Isopropyl
Allyl
H
H
H
H
H
1a
1b
1c
1d
1e
47
21
23
19
27
59
13
51
8
Propargyl
2
Conversions and ee were determined by GC analysis.
When
2
was reacted with amines having branched substituents, 1a and 1c were obtained with
1d, and 1e were
moderate ee. On the other hand, when amines with linear substituents were used, 1b
,
obtained with low ee. The conversion and the ee of all the products obtained using carrot powder
as the catalyst were lower than those obtained using Soyafibe S-DN. The difference in these results
could be due to the different preparation methods of carrot powder and Soyafibe S-DN. Soyafibe
S-DN is produced by extracting polysaccharides from the cake obtained after soy milk extraction and
contains a large amount of pectin-like substances. On the other hand, carrot powder is prepared by
drying the root; therefore, it contains many ingredients other than the polysaccharides, and the pectin
content is lower than that in Soyafibe S-DN. Since pectin and pectin-like substances are the catalytically
active ingredients, catalysts with higher pectin contents have higher activities. Pectin and pectin-like

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substances are some of the most complex natural polysaccharides [21
,22], and the correlation between
structure and catalytic activity could not be clarified. However, if the correlation between the structure
of pectin and substrate is determined, a new catalytic system using a polysaccharide can be pioneered.
3. Conclusions
In summary, we investigated the suitability of using a soluble soybean polysaccharide
(Soyafibe S-DN) as a catalyst for the asymmetric amination of epoxides. Soyafibe S-DN
catalyzed the amination of epoxides with 5-membered or 6-membered ring backbones; particularly,
the cyclopropylamination of 1,2-epoxycyclohexane and 1,2-epoxycyclopentane gave the corresponding
trans-
with 1,2-epoxycyclohexane in the presence of this catalyst system to give the corresponding optically
active trans- -aminocyclohexanols. The ee of the product was relatively high when an amine with a
β-cyclopropylaminoalcohols with good enantioselectivities. Many of the amines that reacted
β
branched structure was used as the substrate; particularly, 3-aminopentane showed the highest ee (81%)
in this study. We have shown that the asymmetric amination of 1,2-epoxycyclohexane proceeded even
when using the powder of different types of vegetables containing pectin and pectin-like substances as
catalysts other than Soyafibe S-DN. These results suggested that the pectin or pectin-like substances
in the catalyst play important roles in catalytic function. The catalytic activity can be enhanced by
purifying the pectin contained in various vegetables. Therefore, we have pioneered a new research topic
to identify polysaccharides contained in vegetables as low-toxicity catalysts with low environmental
impact for pharmaceutical production.
4. Materials and Methods
4.1. General Procedure
Conversion and enantiomeric excess (ee) were determined by GC analysis on a SHIMADZU
GC-2010 or by HPLC analysis on an Agilent 1100 Series instrument by comparison with synthesized
racemic compounds. NMR spectra were recorded on a JEOL AL-300 (1H NMR 300.40 MHz, 13C NMR
1
75.45 MHz) spectrometer. H NMR chemical shifts were reported in parts per million (ppm) relative to
tetramethylsilane (0 ppm) in CDCl3, except for the broad peaks. 13C NMR chemical shifts for were
reported in parts per million (ppm) relative to CDCl3 (77.16 ppm) with complete proton decoupling.
High-resolution electrospray-ionization mass spectra (HRMS (ESI)) were recorded with on a Waters
Xevo G2-XS QTof mass spectrometer.
4.2. Materials
All the reagents were obtained commercially and used as received, unless otherwise noted.
The solvents, ammonia, dimethylamine, triethylamine, chlorotrimethylsilane, and pectin (from citrus)
were purchased from KANTO CHEMICAL Co., Inc. (Tokyo, Japan). Epoxides, amines other than the
ones mentioned above, dextran, chitosan, carrageenan, curdlan, (+)-arabinogalactan (from lurch wood),
and xanthan gum were purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Gum arabic
was purchased from NACALAI TESQUE, Inc. (Kyoto, Japan). Soyafibe S-DN was purchased from Fuji
Oil Co., Ltd. (Osaka, Japan). Pumpkin (powdered), carrot (powdered), tomato (powdered), and lotus
(powdered) were purchased from Kodama Foods Co., Ltd. (Hiroshima, Japan). Turmeric (powdered)
was purchased from NIPPON FUNMATSU YAKUHIN Co., Ltd. (Osaka, Japan). Kiwifruit, pomelo,
pistachio, potato (mashed), citron, apple, tea, kidney beans, and green pea were obtained from a
general store.
4.3. Procedure and Analytical Data: General Procedure for Pretreatment of Vegetable
Approximately 5 g of vegetable pieces were dried under reduced pressure in a desiccator at 60 ◦C
and were powdered using a pulverizer. The obtained powders were washed with hexane and dried
under reduced pressure.

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4.4. General Procedure for Catalytic Amination of Epoxide with Amine at the 0.5 mL Scale
A mixture of epoxide (0.49 mmol), amine (0.60 mmol), and a catalyst (100 mg) in toluene (0.42 mL)
and water (0.02 mL) was shaken at 40 ◦C for the specified time. After removing the catalyst by filtration,
the filtrate was analyzed by GC and HPLC. The conversion was calculated as follows, using the concept
of effective carbon number (ECN) [23]:
Conversion (%) = 100 × (Ap/Rp)/((Ap/Rp) + (As/RS))
Ap = peak area for aminoalcohol from filtrate
AS = peak area for epoxide from filtrate
Rp = response of aminoalcohol
RS = response of epoxide
4.5. General Procedure for Trimethylsilylation of the Product
The filtered amination solution was concentrated and redissolved in dichloromethane, and then
chlorotrimethylsilane and triethylamine were added. The reaction mixture was stirred, and the solid
precipitate was removed by filtration. The obtained solution was used for GC-analysis without
further purification.
4.6. General Procedure for Benzoation of the Product
The filtered amination solution was concentrated and redissolved in acetonitrile, and then
benzoyl chloride and triethylamine were added. The reaction mixture was stirred for 30 min, and the
precipitated solid was removed by filtration. The obtained solution was used for HPLC analysis
without further purification.
4.7. General Procedure for Synthesis of Racemic Aminoalcohol
A mixture of epoxide (15 mmol), amine (15 mmol), and LiCl (0.13 g, 3.1 mmol) in methanol (8 mL)
was stirred at 50 ◦C for 48 h. The reaction mixture was concentrated under reduced pressure to obtain
a crude oil. The crude oil was purified by bulb-to-bulb distillation.
trans-2-(Cyclopropylamino)cyclohexan-1-ol (1a): This compound was used for analysis without
purification. The ee value and the conversion were determined by GC (Supelco
30 m 0.25 mm 0.25
m; carrier gas, He (pressure 94 kPa); column temperature, 120 ◦C); Retention
time(tR) of (S,S)-1a, 26.9 min; tR of (R,R)-1a, 27.4 min; tR of 1,2-epoxycyclohexane, 4.2 min. H NMR
(300.40 MHz, CDCl3): 0.19–0.55 (4H, m), 0.94–1.07 (1H, m), 1.18–1.30 (3H, m), 1.71–1.76 (2H, m),
2.00–2.06 (1H, m), 2.19–2.36 (3H, m), 3.06–3.14 (1H, m). 13C NMR (75.45 MHz, CDCl3):
5.69 (CH2),
β-DEX 120,
×
×
µ
1
δ
δ
7.22 (CH2), 24.19 (CH2), 24.85 (CH2), 27.50 (CH), 30.71 (CH2), 33.26 (CH2), 63.54 (CH), 72.94 (CH).
HRMS (ESI): m/z calculated for C9H18NO+ [M+H]+: 156.1388, found: 156.1386.
trans-2-(Cyclopropylamino)cyclopentan-1-ol (4a): bp 105
The conversion was determined by GC (Supelco -DEX 120, 30 m
carrier gas, He (pressure 94 kPa); column temperature, 130 ◦C); tR of 4a, 20.1 and 20.3 min;
tR of 1,2-epoxycyclopentane, 3.2 min. The ee value was determined by GC (Supelco -DEX 120,
−
110 ◦C (oven temperature)/0.1 mmHg.
0.25 mm 0.25 m;
β
×
×
µ
β
30 m
×
0.25 mm
×
0.25
µ
m; carrier gas, He (pressure 94 kPa); column temperature, 90 ◦C, (5min)
→
130 ◦C, 20 ◦C/min) after trimethylsilylation; tR of both enantiomer of trimethylsilylated-4a, 15.5 min and
1
15.7 min, respectively. H NMR (300.40 MHz, CDCl3):
(3H, m), 1.88–1.99 (1H, m), 2.03–2.29 (2H, m), 2.90–2.97 (1H, m), 3.85 (1H, q, J = 6.31 Hz). 13C NMR
δ 0.31–0.52 (4H, m), 1.27–1.40 (1H, m), 1.48–1.79
(75.45 MHz, CDCl3):
δ 5.89 (CH2), 6.46 (CH2), 20.08 (CH2), 29.30 (CH), 30.13 (CH2), 32.12 (CH2), 66.95
(CH), 72.21 (CH). HRMS (ESI): m/z calculated for C8H16NO+ [M+H] +: 142.1232, found: 142.1225.
trans-4-(Cyclopropylamino)tetrahydrofuran-3-ol (5a): This compound was used for analysis without
purification. The conversion was determined by GC (Supelco
β-DEX 120, 30 m
×
0.25 mm
×
0.25 µm;

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carrier gas, He (pressure 94 kPa); column temperature, 155 ◦C); tR of 5a, 20.1 min; tR of
3,4-epoxytetrahydrofuran, 2.6 min. The ee value was determined by HPLC (Daicel CHIRALPAK
AS-RH, 150 mm
×
0.46 mm; mobile-phase A: water, mobile-phase B: acetonitrile, gradient: 15% B in
15 min, 15–80% B in 20 min; flow rate: 1.0 mL/min; temperature: 30 ◦C; detection: UV absorbance at
254 nm) after benzoate; tR of both enantiomer of benzoated-5a, 26.2 min and 28.2 min, respectively.
1H NMR (300.40 MHz, CDCl3):
δ
0.41–0.53 (4H, m), 2.12–2.19 (1H, m), 3.27–3.31 (1H, m), 3.61–3.68
(2H, m), 3.97 (1H, dd, J = 9.61, 5.41 Hz), 4.06 (1H, dd, J = 9.01, 5.41 Hz), 4.21 (1H, q, J = 2.40 Hz).
13C NMR (75.45 MHz, CDCl3):
δ 6.18 (CH2), 6.35 (CH2), 28.93 (CH), 66.57 (CH), 71.90 (CH2), 73.62
(CH2), 75.59 (CH). HRMS (ESI): m/z calculated for C7H14NO2+ [M+H]+: 144.1025, found: 144.1016.
trans-2-(Cyclopropylamino)cycloheptan-1-ol (6a): This compound was used for analysis without
purification. The conversion was determined by GC (Supelco
0.25
tR of 1,2-epoxycyloheptane, 4.8 min. The ee value was determined by HPLC (Daicel CHIRALPAK
β
-DEX 120, 30 m
×
0.25 mm
◦
×
µ
m; carrier gas, He (pressure 94 kPa); column temperature, 145 C); tR of 6a, 27.2 min;
AS-RH, 150 mm
×
0.46 mm; mobile-phase A: water, mobile-phase B: acetonitrile, gradient: 15% B in
15 min, 15–80% B in 20 min; flow rate: 1.0 mL/min; temperature: 30 ◦C; detection: UV absorbance at
254 nm) after benzoate; tR of both enantiomers of benzoated-6a, 25.3 min and 28.5 min, respectively.
1H NMR (300.40 MHz, CDCl3):
(1H, m), 2.07–2.14 (1H, m), 2.21–2.28 (1H, m), 2.33–2.41 (1H, m), 3.06–3.16 (1H, m). 13C NMR (75.45 MHz,
δ
0.22–0.56 (4H, m), 1.21–1.32 (1H, m), 1.39–1.71 (7H, m), 1.89–1.99
CDCl3):
δ 6.20 (CH2), 7.13 (CH2), 22.08 (CH2), 23.71 (CH2), 26.55 (CH2), 27.62 (CH), 29.90 (CH2), 32.75
(CH2), 65.76 (CH), 74.90 (CH). HRMS (ESI): m/z calculated for C10H20NO+ [M+H]+: 170.1545, found:
170.1536.
trans-3-(Cycloropropylamino)butan-2-ol (7a): bp 135–140 ◦C (oven temperature)/0.1 mmHg. The ee value
and the conversion were determined by GC (Supelco
β
-DEX 120, 30 m
×
0.25 mm
×
0.25 µm; carrier
gas, He (pressure 94 kPa); column temperature, 110 ◦C); tR of both enantiomers of 7a, 11.0 min and
1
11.3 min, respectively; tR of cis-2,3-epoxybutane, 2.6 min. H NMR (300.40 MHz, CDCl3):
δ 0.22–0.31
(1H, m), 0.36–0.55 (3H, m), 1.12 (3H, d, J = 6.31 Hz), 1.31 (3H, d, J = 11.7 Hz), 2.19–2.26 (1H, m),
2.40–2.50 (1H, m), 3.21–3.30 (1H, m). 13C NMR (75.45 MHz, CDCl3):
δ 6.18 (CH2), 7.08 (CH2), 16.46
(CH3), 19.25 (CH3), 27.81 (CH), 60.21 (CH), 70.21 (CH). HRMS (ESI): m/z calculated for C7H17NO+
(M+H)+: 130.1232, found: 130.1225.
trans-2-(Propylamino)cyclohexan-1-ol (1b): bp 115–120 ◦C (oven temperature)/0.2 mmHg. The ee value
and the conversion was determined by GC (Supelco
β
-DEX 120, 30 m
×
0.25 mm
×
0.25 µm; carrier gas,
He (pressure 94 kPa); column temperature, 130 ◦C); tR of both enantiomer of 1b, 20.0 min and 20.3 min,
1
respectively; tR of 1,2-epoxycyclohexane, 4.2 min. H NMR (300.40 MHz, CDCl3):
δ 0.90–0.99 (4H, m),
1.21–1.29 (3H, m), 1.42–1.55 (2H, m), 1.71–1.73 (2H, m), 2.02–2.22 (3H, m), 2.39–2.47 (1H, m), 2.70–2.79
(1H, m), 3.10–3.18 (1H, m). 13C NMR (75.45 MHz, CDCl3):
11.69 (CH3), 23.60 (CH2), 24.39 (CH2),
δ
25.03 (CH2), 30.43 (CH2), 33.52 (CH2), 45.54 (CH2), 63.47 (CH), 73.46 (CH). HRMS (ESI): m/z calculated
for C9H20NO+ [M+H]+: 158.1545, found: 158.1539.
trans-2-(Isopropylamino)cyclohexan-1-ol (1c): bp 135–140 ◦C (oven temperature)/0.1 mmHg. The ee value
and the conversion were determined by GC (Supelco
β
-DEX 120, 30 m
×
0.25 mm
×
0.25 µm; carrier
gas, He (pressure 94 kPa); column temperature, 120 ◦C); tR of both enantiomers of 1c, 12.9 min and
1
13.2 min, respectively; tR of 1,2-epoxycyclohexane, 4.2 min. H NMR (300.40 MHz, CDCl3):
δ 0.82–0.94
(1H, m), 1.00 (3H, d, J = 6.31 Hz), 1.06 (3H, d, J = 6.31 Hz), 1.20–1.31 (3H, m), 1.69–1.73 (2H, m), 2.06–2.10
(2H, m), 2.18–2.26 (1H, m), 2.69 (1H, sept, J = 6.31 Hz), 3.09 (1H, m). 13C NMR (75.45 MHz, CDCl3):
δ
22.79 (CH3), 24.28 (CH2), 24.73 (CH3), 25.36 (CH2), 31.29 (CH2), 32.98 (CH2), 45.05 (CH), 60.64 (CH),
73.87 (CH). HRMS (ESI): m/z calculated for C9H20NO+ [M+H]+: 158.1545, found: 158.1535.
trans-2-(Allylamino)cyclohexan-1-ol (1d): This compound was used for analysis without purification.
The ee value and the conversion were determined by GC (Supelco
µ
β
-DEX 120, 30 m
×
0.25 mm
×
0.25
m; carrier gas, He (pressure 94 kPa); column temperature, 120 ◦C); tR of both enantiomers of 1d
,

Molecules 2020, 25, 3197
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34.8 min and 35.2 min, respectively; tR of 1,2-epoxycyclohexane, 4.2 min. 1H NMR (300.40 MHz,
CDCl3): 0.92–1.04 (1H, m), 1.19–1.31 (3H, m), 1.70–1.72 (2H, m), 1.97–2.07 (2H, m), 2.24–2.32 (1H,
m), 3.11–3.26 (2H, m), 3.26–3.42 (1H, m), 5.06–5.22 (1H, m), 5.84–5.97 (1H, m). 13C NMR (75.45 MHz,
δ
CDCl3):
δ 24.28 (CH2), 24.71 (CH2), 30.07 (CH2), 33.62 (CH2), 49.17 (CH2), 62.65 (CH), 73.27 (CH), 115.61
(CH2), 126.85 (CH). HRMS (ESI): m/z calculated for C9H18NO+ [M+H]+: 156.1388, found: 156.1378.
trans-2-(Propargylamino)cyclohexan-1-ol (1e): This compound was used for analysis without purification.
The ee value and the conversion were determined by GC (Supelco
β
-DEX 120, 30 m
×
0.25 mm
×
0.25 µm;
carrier gas, He (pressure 94 kPa); column temperature, 125 ◦C); tR of both enantiomers of 1e, 47.1 min
and 47.6 min, respectively; tR of 1,2-epoxycyclohexane, 4.5 min. 1H NMR (300.40 MHz, CDCl3):
δ
0.92–1.05 (1H, m), 1.21–1.38 (3H, m), 1.68–1.73 (2H, m), 1.96–2.08 (2H, m), 2.24 (1H, t, J = 2.40 Hz),
2.40–2.48 (1H, m), 3.21–3.29 (1H, m), 3.47 (2H, dq, J = 16.82, 2.40 Hz). 13C NMR (75.45 MHz, CDCl3):
δ
24.31 (CH2), 24.56 (CH2), 29.79 (CH2), 33.80 (CH2), 35.35 (CH2), 62.01 (CH), 71.30 (C), 73.61 (CH),
82.22 (CH). HRMS (ESI): m/z calculated for C9H16NO+ [M+H]+: 154.1232, found: 154.1222.
trans-2-(tert-Butylamino)cyclohexan-1-ol (1f): bp 100–105 ◦C (oven temperature)/0.1 mmHg. The ee value
and the conversion were determined by GC (Supelco
β
-DEX 120, 30 m
×
0.25 mm
×
0.25 µm; carrier
gas, He (pressure 94 kPa); column temperature, 130 ◦C); tR of both enantiomers of 1f, 15.6 min and
1
16.0 min, respectively; tR of 1,2-epoxycyclohexane, 4.2 min. H NMR (300.40 MHz, CDCl3):
δ 0.90–1.19
(1H, m), 1.13 (9H, s), 1.24–1.32 (3H, m), 1.67–1.71 (2H, m), 1.98–2.07 (2H, m), 2.19–2.27 (1H, m), 2.89–2.97
(1H, m). 13C NMR (75.45 MHz, CDCl3):
δ 24.47 (CH2), 25.88 (CH2), 30.63 (CH3), 32.64 (CH2), 34.88
(CH2), 50,68 (C), 58.13 (CH), 74.31 (CH). HRMS (ESI): m/z calculated for C10H22NO+ [M+H]+: 172.1701,
found: 172.1691.
trans-2-(Pentan-3-ylamino)cyclohexan-1-ol (1g): bp 150–155 ◦C (oven temperature)/0.1 mmHg. The ee
value and the conversion were determined by GC (Supelco
β
-DEX 120, 30 m
×
0.25 mm
×
0.25 µm;
carrier gas, He (pressure 94 kPa); column temperature, 130 ◦C); tR of both enantiomers of 1g, 30.3 min,
and 31.3 min, respectively; tR of 1,2-epoxycyclohexane, 4.2 min. 1H NMR (300.40 MHz, CDCl3):
δ
0.83–0.94 (7H, m), 1.20–1.56 (7H, m), 1.69–1.73 (2H, m), 2.05–2.09 (2H, m), 2.14–2.22 (1H, m), 2.44–2.52
(1H, m), 3.02–3.10 (1H, m). 13C NMR (75.45 MHz, CDCl3):
δ
8.99 (CH3), 10.26 (CH2), 24.28 (CH3), 25.40
(CH2), 26.19 (CH2), 26.89 (CH2), 31.14 (CH2), 32.89 (CH2), 56.76 (CH), 61.14 (CH), 74.12 (CH). HRMS
(ESI): m/z calculated for C11H24NO+ [M+H]+: 186.1858, found: 186.1849.
trans-2-(Cyclopentylamino)cyclohexan-1-ol (1h): bp 170–175 ◦C (oven temperature)/0.1 mmHg. The ee
value and the conversion were determined by GC (Supelco
β
-DEX 120, 30 m
×
0.25 mm
×
0.25 µm;
carrier gas, He (pressure 94 kPa); column temperature, 155 ◦C); tR of both enantiomers of 1h, 24.7 min
and 25.1 min, respectively; tR of 1,2-epoxycyclohexane, 3.4 min. 1H NMR (300.40 MHz, CDCl3):
δ
0.83–0.95 (1H, m), 1.20–1.38 (5H, m), 1.50–1.87 (8H, m), 2.01–2.22 (3H, m), 3.01–3.09 (1H, m), 3.19–3.27
(1H, m). 13C NMR (75.45 MHz, CDCl3):
δ
23.59 (CH2), 23.79 (CH2), 24.31 (CH2), 25.27 (CH2),
30.91 (CH2), 33.08 (CH2), 32.12 (CH2), 34.59 (CH2), 56.14 (CH), 61.86 (CH), 73.75 (CH). HRMS (ESI):
m/z calculated for C11H22NO+ [M+H]+: 184.1701, found: 186.1693.
trans-2-(Benzylamino)cyclohexan-1-ol (1i): bp 175–180 ◦C (oven temperature)/0.1 mmHg. The conversion
was determined by GC (Supelco
94 kPa); column temperature, 185 C, (35min)
β
-DEX 120, 30 m
×
0.25 mm
210 C, (10 C/min)
×
◦ 0.25
µ
m; carrier gas, He (pressure
◦
◦
◦
→
→
210 C, (12 min); tR of
1i, 43.9 min; tR of 1,2-epoxycyloheptane, 3.2 min. The ee value was determined by HPLC (Daicel
CHIRALCEL OB-H, 250 mm × 0.46 mm; mobile phase, n-hexane/2-propanol/diethylamine (980:20:1);
flow rate; 0.5 mL/min, column temperature; 40 ◦C); tR of both enantiomers of 1i, 21.0 min and 28.6 min,
1
respectively. H NMR (300.40 MHz, CDCl3):
δ 0.91–1.05 (1H, m), 1.16–1.25 (3H, m), 1.71–1.74 (2H, m),
2.01–2.07 (1H, m), 2.15–2.21 (1H, m), 2.25–2.33 (1H, m), 3.16–3.24 (3H, m), 3.69 (1H, d, J = 12.92 Hz),
3.96 (1H, d, J = 12.92 Hz), 7.22–7.36 (5H, m). 13C NMR (75.45 MHz, CDCl3):
δ
24.25 (CH2), 24.85 (CH2),
30.20 (CH2), 33.40 (CH2), 50.68 (CH2), 62.89 (CH), 73.41 (CH), 126.81 (CH), 127.96 (CH), 128.25 (CH),
140.32 (C). HRMS (ESI): m/z calculated for C13H20NO+ [M+H]+: 206.1545, found: 206.1537.

Molecules 2020, 25, 3197
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trans-2-(2-Phenylethylamino)cyclohexan-1-ol (1j): This compound was used for analysis without
purification. The conversion was determined by GC (Supelco -DEX 120, 30 m 0.25 mm 0.25 m;
carrier gas, He (pressure 94 kPa); column temperature, 185 ◦C, (35min) 210 ◦C, (10 ◦C/min) 210 ◦C,
(12 min); tR of 1j, 47.4 min; tR of 1,2-epoxycyloheptane, 3.2 min. The ee value was determined by HPLC
β
×
×
µ
→
→
(Daicel CHIRALCEL OB-H, 250 mm
×
0.46 mm; mobile phase, n-hexane/2-propanol/diethylamine
(980:20:1); flow rate: 0.5 mL/min; column temperature: 40 ◦C; detection: UV absorbance at 254 nm);
tR of both enantiomers of 1j, 24.2 min and 32.2 min, respectively. 1H NMR (300.40 MHz, CDCl3):
δ
0.84–0.96 (1H, m), 1.18–1.32 (3H, m), 1.67–1.71 (2H, m), 1.99–2.07 (2H, m), 2.16–2.25 (1H, m), 2.70–2.86
(3H, m), 3.00–3.15 (2H, m), 7.18–7.32 (5H, m). 13C NMR (75.45 MHz, CDCl3):
δ
24.29 (CH2), 25.15 (CH2),
30.55 (CH2), 33.25 (CH2), 37.01 (CH2), 47.89 (CH2), 63.55 (CH), 73.62 (CH), 126.06 (CH), 128.36 (CH),
128.63 (CH), 140.06 (C). HRMS (ESI): m/z calculated for C14H22NO+ [M+H]+: 220.1701, found: 220.1694.
trans-2-(Dimethylamino)cyclohexan-1-ol (1k): bp 70–75 ◦C (oven temperature)/0.2 mmHg. The ee value
and the conversion was determined by GC (Supelco
β
-DEX 120, 30 m
×
0.25 mm
×
0.25 µm; carrier gas,
He (pressure 94 kPa); column temperature, 95 ◦C); tR of both enantiomers of 1k, 46.5 min and 47.1 min
1
respectively; tR of 1,2-epoxycyclohexane, 8.4 min. H NMR (300.40 MHz, CDCl3):
δ 1.03–1.31 (4H, m),
1.69–1.78 (3H, m), 2.07–2.33 (8H, m), 3.27–3.35 (1H, m). 13C NMR (75.45 MHz, CDCl3): δ 20.16 (CH2),
23.97 (CH2), 25.14 (CH2), 33.05 (CH2), 39.98 (CH3), 69.11 (CH), 69.36 (CH). HRMS (ESI): m/z calculated
for C8H8NO+ [M+H]+: 144.1388, found: 144.1382.
trans-(2-Hydroxycyclohexyl)pyrrolidine (1m): bp 100–105 ◦C (oven temperature)/0.1 mmHg.
The conversion was determined by GC (Supelco
He (pressure 94 kPa); column temperature, 130 ◦C); tR of 1m, 35.4 min; tR of 1,2-epoxycyclohexane,
3.4 min. The ee value was determined by GC (Supelco -DEX 120, 30 m 0.25 mm 0.25 m;
carrier gas, He (pressure 94 kPa); column temperature, 130 ◦C), (30min) 170 ◦C, 4 ◦C/min) after
trimethylsilylation; tR of both enantiomers of trimethylsilylated-1m, 23.0 min and 23.2 min, respectively.
1H NMR (300.40 MHz, CDCl3):
1.17–1.27 (4H, m), 1.69–1.78 (7H, m), 2.05–2.15 (1H, m), 2.42–2.59 (3H,
m), 2.64–2.71 (2H, m), 3.29–3.37 (1H, m). 13C NMR (75.45 MHz, CDCl3):
20.99 (CH2), 23.43 (CH2),
β-DEX 120, 30 m
×
0.25 mm
×
0.25 µm; carrier gas,
β
×
×
µ
→
δ
δ
24.03 (CH2), 25.16 (CH2), 33.13 (CH2), 47.03 (CH2), 64.78 (CH2), 70.51 (CH). HRMS (ESI): m/z calculated
for C10H20NO+ [M+H]+: 170.1545, found: 170.1537.
trans-2-(Phenylamino)cyclohexan-1-ol (1n): This compound was used for analysis without purification.
The conversion was determined by GC (Supelco
β
-DEX 120, 30 m
×
0.25 mm
×
0.25
→
µm; carrier gas,
He (pressure 94 kPa); column temperature, 185 ◦C, (35min)
→
210 ◦C, (10 ◦C/min)
210 ◦C, (12 min);
tR of 1n, 44.2 min; tR of 1,2-epoxycyloheptane, 3.2 min. The ee value was determined by HPLC (Daicel
CHIRALCEL OB-H, 250 mm × 0.46 mm; mobile phase, n-hexane/2-propanol/diethylamine (980:20:1);
flow rate: 0.5 mL/min; column temperature: 40 ◦C; detection: UV absorbance at 254 nm); tR of both
1
enantiomers of 1n, 27.1 min and 28.9 min, respectively. H NMR (300.40 MHz, CDCl3):
δ 0.98–1.11
(1H, m), 1.24–1.47 (3H, m), 1.70–1.79 (2H, m), 2.10–2.14 (2H, m), 3.10–3.18 (1H, m), 3.31–3.39 (1H, m),
6.70–6.77 (3H, m), 7.15–7.25 (2H, m). 13C NMR (75.45 MHz, CDCl3):
24.15 (CH2), 24.82 (CH2),
δ
31.42 (CH2), 33.09 (CH2), 59.89 (CH), 74.25 (CH), 114.17 (CH), 118.07 (CH), 129.18 (CH), 147.73 (C).
HRMS (ESI): m/z calculated for C12H18NO+ [M+H]+: 192.1388, found: 192.1380.
trans-2-aminocyclohexan-1-ol (1o): This compound was purchased from Sigma-Aldrich Co. Ltd. and
used without further purification. The ee value and the conversion was determined by GC (Supelco
β
-DEX 120, 30 m
×
0.25 mm
×
0.25 µ
m; carrier gas, He (pressure 94 kPa); column temperature, 120 ◦C);
tR of both enantiomers of 1o, 18.4 min and 18.8 min, respectively; tR of 1,2-epoxycyclohexane, 4.2 min.
Supplementary Materials: GC charts of compounds 1a
charts of compounds 5a, 6a, 1i, 1j and 1n.
, 4a, 7a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1k, 1m and 1o. HPLC
Author Contributions: Conceptualization, Y.T.; methodology, Y.T.; validation, K.W.; formal analysis, T.A.;
investigation, T.A. and K.T.; writing—original draft preparation, Y.T.; writing—review and editing, H.K.;
visualization, Y.T.; supervision, K.W.; project administration, K.W. All authors have read and agreed to the
published version of the manuscript.

Molecules 2020, 25, 3197
12 of 13
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
2.
3.
Paulia, K.; Henryk, M.; Elzbita, P. Synthesis, Anticonvulsant Activity and Metabolism of 4-chlor-3-
methylphenoxyethylamine Derivatives of Trans -2-aminocyclohexan-1-ol. Chirality 2015, 27, 163–169.
Klingler, F.D. Asymmetric Hydrogenation of Prochiral Amino Ketones to Amino Alcohols for Pharmaceutical
Use. Acc. Chem. Res. 2007, 40, 1367–1376. [CrossRef] [PubMed]
De Costa, B.R.; Bowen, W.D.; Hellewell, S.B.; George, C.; Rothman, R.B.; Reid, A.A.; Walker, J.M.;
Jacobson, A.E.; Rice, K.C. Alterations in the stereochemistry of the κ-selective opioid agonist U50,488
result in high-affinity σ ligands. J. Med. Chem. 1989, 32, 1996–2002. [CrossRef] [PubMed]
Koga, Y.; Kihara, Y.; Okada, M.; Nishi, T.; Inoue, Y.; Kimura, Y.; Hidaka, H.; Fukuda, N. Carbostyril Derivatives
as Antithrombotic Agents. PCT Int. Appl. WO9712869, 4 October 1997.
Koga, Y.; Kihara, Y.; Okada, M.; Inoue, Y.; Tochizawa, S.; Toga, K.; Tachibana, K.; Kimura, Y.; Nishi, T.;
Hidaka, H. 2(1H)-Quinolinone derivatives as novel anti-arteriostenotic agents showing anti-thrombotic and
anti-hyperplastic activities. Bio. Med. Chem. Lett. 1998, 8, 1471–1476. [CrossRef]
4.
5.
6.
7.
Beatch, G.N.; Ezrin, A. Uses of Ion Channel Modulating Compounds. PCT Int. Appl. WO2004098525,
3 May 2004.
Bao, H.; Zhou, J.; Wang, Z.; Guo, Y.; You, T.; Ding, K. Insight into the Mechanism of the
Asymmetric Ring-Opening Aminolysis of 4,4-Dimethyl-3,5,8-trioxabicyclo[5.1.0]octane Catalyzed by
Titanium/BINOLate/Water System: Evidence for the Ti(BINOLate)2-Bearing Active Catalyst Entities and the
Role of Water. J. Am. Chem. Soc. 2008, 130, 10116–10127. [CrossRef]
8.
9.
Kumar, M.; Kureshy, R.I.; Ghosh, D.; Khan, N.H.; Abdi, S.H.R.; Bajaj, H.C. Synthesis of Chiral Ligands
with Multiple Stereogenic Centers and Their Application in Titanium(IV)-Catalyzed Enantioselective
Desymmetrization of meso-Epoxides. Chem. Cat. Chem. 2013, 5, 2336–2342. [CrossRef]
More, G.V.; Bhanage, B.M. Asymmetric Ring Opening of meso -Epoxides with Aromatic Amines Using
(R)-(+)-BINOL-Sc(OTf)3-NMM Complex as an Efficient Catalyst. Eur. J. Org. Chem. 2013, 2013, 6900–6906.
[CrossRef]
10. Sharma, A.; Agarwal, J.; Peddinti, R.K. Direct access to the optically active VAChT inhibitor vesamicol and
its analogues via the asymmetric aminolysis of meso-epoxides with secondary aliphatic amines. Org. Biomol.
Chem. 2017, 15, 1913–1920. [CrossRef]
11. Bonollo, S.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. Zn(II)-Catalyzed Desymmetrization of meso-Epoxides by
Aromatic Amines in Water. Synlett 2008, 10, 1574–1578.
12. Bao, H.; Wu, J.; Li, H.; Wang, Z.; You, T.; Ding, K. Enantioselective Ring Opening Reaction of meso -Epoxides
with Aromatic and Aliphatic Amines Catalyzed by Magnesium Complexes of BINOL Derivatives. Eur. J.
Org. Chem. 2010, 2010, 6722–6726. [CrossRef]
13. Arai, K.; Lucarini, S.; Salter, M.M.; Ohta, K.; Yamashita, Y.; Kobayashi, S. The Development of Scalemic
Multidentate Niobium Complexes as Catalysts for the Highly Stereoselective Ring Opening of meso-Epoxides
and meso-Aziridines. J. Am. Chem. Soc. 2007, 129, 8103–8111. [CrossRef] [PubMed]
14. Cue, B.W.; Zhang, J. Green process chemistry in the pharmaceutical industry. Green Chem. Lett. Rev. 2009
2, 193–211. [CrossRef]
,
15. Takeuchi, Y.; Asano, T.; Tsuzaki, K.; Wada, K. Catalytic Asymmetric Amination of meso-Epoxide Using Soy
Polysaccharide (Soyafibe S-DN). Bull. Chem. Soc. Jpn. 2018, 91, 678–683. [CrossRef]
16. Takahashi, T.; Nakamura, A.; Kato, M.; Maeda, H.; Mandella, R.C.; Broadmeadow, A.; Ruckman, S.A. Soluble
soybean fiber: A 3-month dietary toxicity study in rats. Food Chem. Toxicol. 2003, 41, 1111–1121. [CrossRef]
17. Nakamura, A. Development of Soybean Soluble Polysaccharide Derived from “Okara”, and Application as a
Functional Food Ingredient. Nippon Shokuhin Kagaku Kougakukaishi 2011, 58, 559–566. [CrossRef]
18. Nakamura, A.; Furuta, H.; Maeda, H.; Takao, T.; Nagamatsu, Y. Structural Studies by Stepwise Enzymatic
Degradation of the Main Backbone of Soybean Soluble Polysaccharides Consisting of Galacturonan and
Rhamnogalacturonan. Biosci. Biotechnol. Biochem. 2002, 66, 1301–1313. [CrossRef]
19. Azizi, N.; Saidi, M.R. Highly Chemoselective Addition of Amines to Epoxides in Water. Org. Lett. 2005
7, 3649–3651. [CrossRef]
,

Molecules 2020, 25, 3197
13 of 13
20. Baker, R.A. Reassessment of Some Fruit and Vegetable Pectin Levels. J. Food Sci. 1997, 62, 225–229. [CrossRef]
21. Voragen, A.G.J.; Goenen, G.J.; Verhoef, R.P.; Schols, H.A. Pectin, a versatile polysaccharide present in plant
cell walls. Struct. Chem. 2009, 20, 263–275. [CrossRef]
22. Mohnen, D. Pectin Structure and Biosynthesis. Curr. Opin. Plant Biol. 2008, 11, 266–277. [CrossRef] [PubMed]
23. Scanlon, J.T.; Willis, D.E. Calculation of Flame Ionization Detector Relative Response Factors Using the
Effective Carbon Number Concept. J. Chromatogr. Sci. 1985, 23, 333–340. [CrossRef]
Sample Availability: Samples of the compounds are not available from the authors.
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