Continuous-flow synthesis of deuterium-labeled antidiabetic chalcones: Studies towards the selective deuteration of the alkynone core

Article abstract of DOI:10.3390/molecules21030318

Flow chemistry-based syntheses of deuterium-labeled analogs of important antidiabetic chalcones were achieved via highly controlled partial C≡C bond deuteration of the corresponding 1,3-diphenylalkynones. The benefits of a scalable continuous process in combination with on-demand electrolytic D₂ gas generation were exploited to suppress undesired over-reactions and to maximize reaction rates simultaneously. The novel deuterium-containing chalcone derivatives may have interesting biological effects and improved metabolic properties as compared with the parent compounds.

Full text of DOI:10.3390/molecules21030318

molecules
Article
Continuous-Flow Synthesis of Deuterium-Labeled
Antidiabetic Chalcones: Studies towards
the Selective Deuteration of the Alkynone Core
Sándor B. Ötvös 1,2, Chi-Ting Hsieh 1,3, Yang-Chang Wu 4,5, Jih-Heng Li 6, Fang-Rong Chang 3,7,
*
and Ferenc Fülöp 1,2,
*
1
Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary;
otvossandor@pharm.u-szeged.hu (S.B.Ö.); u98831001@gmail.com (C.-T.H.)
MTA-SZTE Stereochemistry Research Group, Hungarian Academy of Sciences, Eötvös u. 6,
H-6720 Szeged, Hungary
Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University,
Kaohsiung 807, Taiwan
School of Pharmacy, College of Pharmacy, China Medical University, Taichung 40402, Taiwan;
yachwu@mail.cmu.edu.tw
Chinese Medicine Research and Development Center, China Medical University Hospital,
Taichung 40447, Taiwan
Ph.D. Program in Toxicology and School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807,
Taiwan; jhlitox@kmu.edu.tw
Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
Correspondence: aaronfrc@kmu.edu.tw (F.-R.C.); fulop@pharm.u-szeged.hu (F.F.);
Tel: +886-7312-1101 (F.-R.C.); +36-62-545-562 (F.F.)
2
3
4
5
6
7
*
Academic Editor: Kerry Gilmore
Received: 9 February 2016 ; Accepted: 24 February 2016 ; Published: 7 March 2016
Abstract: Flow chemistry-based syntheses of deuterium-labeled analogs of important antidiabetic
chalcones were achieved via highly controlled partial C C bond deuteration of the corresponding
”
1,3-diphenylalkynones. The benefits of a scalable continuous process in combination with on-demand
electrolytic D2 gas generation were exploited to suppress undesired over-reactions and to
maximize reaction rates simultaneously. The novel deuterium-containing chalcone derivatives
may have interesting biological effects and improved metabolic properties as compared with the
parent compounds.
Keywords: chalcones; continuous-flow reactor; deuterium labeling; heterogeneous catalysis; triple
bond reduction
1. Introduction
Chalcones are 1,3-diaryl-2-propen-1-ones which belong to the flavonoid family [
occurring representatives and synthetic analogs exert a wide array of pharmacological activities, including
anticancer [ ], antiviral [ ], antibacterial [ ], anti-inflammatory [ ], antiplatelet [ ] and antitubercular [
effects (Figure 1), making the chalcone skeleton an important scaffold for drug discovery [10–14].
1–3]. Their naturally
4
5
6
7
8
9]
In recent decades, the metabolic syndrome and diabetes have become ever-increasing health
issues worldwide [15]. The associated complications of these disorders, such as stroke, cardiovascular
diseases, peripheral vascular diseases, diabetic neuropathy, renal failure, blindness and amputations,
lead to reduced life expectancy, the enhancement of disability, and enormous medical costs [16
Despite extensive biological studies on chalcones [10 14], their antidiabetic activities have scarcely
been investigated [19 21]. Our research group has previously reported that certain synthetic chalcones
) containing various halogen atoms at position 2 of ring A (Figure 2) effectively promote glucose
–18].
–
–
(1-4
Molecules 2016, 21, 318; doi:10.3390/molecules21030318
www.mdpi.com/journal/molecules

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consumption in adipocytes [22]. Structure–activity relationship analyses have established that, besides
the halogen substituents on ring A, the presence of a methoxy group on ring B contributes to the potent
antidiabetic activities observed.
Figure 1. Examples of chalcone derivatives with various biological effects: (
) antibacterial activity [ ]; ( ) antitubercular activity [ ]; ( ) anti-inflammatory effect [
activity [5]; (f) anticancer activity [4].
a
) antiplatelet activity [
8];
(
b
6
c
9
d
7
]; ( ) antiviral
e
There has recently been an upsurge of interest in isotopic labeling studies not merely in chemistry
and biochemistry [23 26], but also in environmental sciences and pharmacological research [27 28].
27],
–
,
Among the stable isotopes used for labeling studies, deuterium is of marked significance [24
–
thanks to the fact that it has the highest relative mass difference compared to its light isotope (1H),
which allows a considerably large isotope effect [29]. Deuterium not only serves as a nonradioactive,
stable isotopic tracer in the evaluation of the metabolic pathways [30] or in tracer studies to investigate
pharmacokinetics and reaction mechanisms [31,32]; as a result of the large isotope effect, H-D exchange
may also potentiate active pharmaceutical ingredients [27]. As an example, the metabolic rates of
nonlabeled derivatives and deuterated compounds are very different, and the use of deuterium-labeled
analogs may therefore help in the elimination of unwanted metabolites, which can lead in practice to
the diminution of adverse effects [33–35].
Figure 2. Antidiabetic chalcone derivatives (1–4) developed by our research group.
Inspired by the above findings, we aimed for the synthesis of deuterium-labeled derivatives of
antidiabetic chalcones
1,3-diphenylalkynone analogs (Scheme 1). We presumed that the incorporation of deuterium onto the
-unsaturated carbonyl system may not only help potentiate the pharmacological activities, but also
1-
4
by exploring the partial deuteration of the C”C bond of the corresponding
α,β
exert positive effects on the metabolic pathway of the bioactive chalcones [27]. Selective deuteration
of the alkynone core may be expected to constitute a significant synthetic challenge in view of the
easy over-reduction of the C=C bond and the carbonyl group [36]; we therefore set out to exploit the
benefits of continuous-flow processing [37–47].
Scheme 1. The proposed synthesis of deuterium-labeled chalcones.

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2. Results and Discussion
Most techniques for the synthesis of deuterium-labeled compounds rely on expensive D2 gas as a
deuterium source. Similarly to hydrogenations, the handling of D2 gas demands extreme precautions
and costly special apparatus to maintain sufficient operational safety. The conventional methods
for the production of D2 gas are fractional distillation of liquid hydrogen, pyrolysis of UD3, and
reactions of D2O with reducing agents (Na, Fe or Mg) [48]. Unfortunately, these methods involve
several drawbacks, such as the production of radioactive waste, the need for cryogenic conditions,
and the large quantity of metal sludge produced [48]. Catalytic H–D exchange reactions between H2
and D2O appear more feasible, but often do not yield sufficiently pure D2 and require long reaction
times [49–54]. Alternatively, the application of deuterated reagents and deuterated solvents as isotopic
sources eliminates the hazards of gas handling, but the costs of these special conditions severely limit
the practical applicability [55–59].
To overcome the difficulties of conventional deuterium labeling techniques, we have developed
a unique flow chemistry-based method for deuteration reactions by changing the hydrogen source
to deuterated water in an H-Cube® system (Figure 3) [36
,60,61]. This approach is safe, as D2 gas
is continuously generated in small aliquots through the electrolytic decomposition of D2O, the
consumption of which is very low, implying high deuterium efficiency. The gas generated in situ is
combined with the substrate solution via a gas–liquid mixer, and the resulting mixture is transported
to a filled catalyst bed, where the triphasic reaction takes place [62
produced can be as high as 99.9%, which ensures high deuterium incorporation ratios [36
,
63]. The purity of the D2 gas
60 61];
,
,
moreover, the precise control over the reaction conditions may enhance the efficacy of the deuteration
reactions [36,39,47,64,65].
Figure 3. Schematic outline of the continuous-flow deuteration reactor (H-Cube®).
Our synthetic strategy toward the anticipated deuterium-labeled compounds involved
continuous-flow deuteration of the corresponding ynone analogs of antiabetic chalcones
Ynones were prepared by literature procedures through the coupling of acid chlorides with terminal
acetylenes under Sonogashira conditions: PdCl2(PPh3)2/CuI as a catalyst and Et3N as a base in THF
as solvent (Scheme 2) [66 68]. The mixtures were stirred for 1 h at room temperature (RT) under a N2
atmosphere, and ynones were achieved in excellent yields after simple extractive work-up and
1–4 (Scheme 1).
5–9
–
5–9
chromatographic purification (see Experimental Section).
Scheme 2. Coupling of acid chlorides with terminal acetylenes under Sonogashira conditions to yield
the corresponding ynones as starting materials for the continuous-flow deuterations.

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We first investigated the deuteration of 1,3-diphenylprop-2-yn-1-one (5) as a nonsubstituted
model compound (Table 1). The reactions were carried out in EtOAc as aprotic solvent so as to
prevent D–H exchange and to maximize deuterium incorporation. We had previously established
that the steric hindrance generated by the halogen atom at position 2 of ring A exerts a significant
influence on the rate of deuterium incorporation, as larger substituents may block the central core
of the molecule, necessitating harsher conditions for the reaction to take place [36]. The deuteration
of
5
was therefore invest˝igated by using Lindlar catalyst (5% Pd on CaCO3, poisoned with lead) at
ambient temperature (25 C) and at pressures in the range 10-80-bar. The utilization of high pressures
in gas–liquid–solid reactions is favorable, as the elevation of pressure increases the solubility of gases,
thereby enhancing the reaction rate. Accordingly, it was found that pressurization pushed the reaction
to completion, resulting in higher total conversions, though pressures
to over-reaction of the desired dideuteroenone (5a) to give the corresponding tetradeuteroketone (5b
ě
40 bar contributed significantly
)
and pentadeuteroalcohol (5c) as side products (Table 1). At 80 bar, for example, a total conversion of 82%
was found, but the crude product mixture contained 23% of 5b, and even 5c was formed to an extent
of 4% (entry 4). If it is taken into account that 5a can be isolated from the alkynone starting material (5)
more easily than from the over-reaction products (5b and 5c), 20 bar can be selected as the pressure of
choice, with an acceptable total conversion of 57% and an excellent dideuteroenone/tetradeuteroketone
ratio of 86:14, and without detectable pentadeuteroalcohol formation (entry 2). During the reactions,
the (Z) deuterated chalcone isomer is formed, as a consequence of the mechanism of the heterogeneous
catalytic process [69]. However, the (Z) chalcone readily undergoes thermal or photochemical
isomerization to the more stable (E) form [70–72], which was detected exclusively after the purification.
It must also be noted that an O–D bond on the pentadeuterochalcone side-product (5c) was not
observed, as it is converted instantly to O–H due to exchange with moisture when it is exposed to air.
Table 1. Continuous-flow deuteration of 5 a.
Product Ratio b (%)
T (˝C)
Total Conversion b (%)
Entry
Catalyst
p (bar)
5a c
5b
5c
1
2
3
4
Lindlar catalyst
Lindlar catalyst
Lindlar catalyst
Lindlar catalyst
10
20
40
80
25
25
25
25
47
57
63
82
92
86
77
73
8
0
0
0
4
14
23
23
a: Conditions: c = 1 mg
¨
mL´1 in ethyl acetate, 1 mL min´´1 flow rate; b: Determined by GC-MS analysis of
¨
the crude material; c: During the reactions, the (Z) deuterated chalcone isomer is formed, but readily isomerizes
to the more stable (E) form.
In continuous-flow deuteration of 1-(2-fluorophenyl)-3-(4-methoxyphenyl)prop-2-yn-1-one (6)
with Lindlar catalyst, the gradual increase of the pressure from 10 to 80 bar at ambient temperature
had a pronounced influence on the rate of the reaction (Table 2). Although lower overall conversions
were achieved than in deuterations of the nonsubstituted alkynone (
5), compound 6 exhibited a lower
tendency to over-reaction, even at pressures 40 bar, which could possibly be explained by the steric
ě
hindrance generated by the fluorine atom at position 2 of ring A. Thus, 80 bar, selected as optimum
pressure, resulted in a total conversion of 63% and a dideuteroenone/tetradeuteroketone ratio of 80:20
without over-reaction to 6c (entry 4).
When the fluorine atom on phenyl ring A was replaced by chlorine (1-(2-chlorophenyl)-3-
(4-methoxyphenyl)prop-2-yn-1-one, 7), deuteration with Lindlar catalyst at 20-80 bar resulted in
conversions of only 33%-47% (Table 3, entries 1-3). 5% Pd/BaSO4 was therefore investigated next
as a more active heterogeneous catalyst (keeping in mind that activated charcoal as a catalyst

Molecules 2016, 21, 318
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support may contain protic contamination that can negatively influence deuterium incorporation) [73].
The Pd/BaSO4-mediated reactions at RT gave excellent total conversions (75% and 86% at 20 and 40 bar,
respectively), but formation of the desired dideuteroenone 7a was significantly suppressed by undesired
over-reduction to 7b, and even to 7c, affording dideuteroenone/tetradeuteroketone/pentadeuteroalcohol
ratios of 62:38:0 and 60:38:2, at 20 and 40 bar, respectively (entries 4 and 5).
Table 2. Continuous-flow deuteration of 6 a.
Product Ratio b (%)
T (˝C)
Total Conversion b (%)
Entry
Catalyst
p (bar)
6a c
6b
6c
1
2
3
4
Lindlar catalyst
Lindlar catalyst
Lindlar catalyst
Lindlar catalyst
10
20
40
80
25
25
25
25
23
40
57
63
90
86
81
80
10
14
19
20
0
0
0
0
a: Conditions: c = 1 mg
¨
mL´1 in ethyl acetate, 1 mL min´´1 flow rate; b: Determined by GC-MS analysis of
¨
the crude material; c: During the reactions, the (Z) deuterated chalcone isomer is formed, but readily isomerizes
to the more stable (E) form.
Table 3. Continuous-flow deuteration of 7 a.
Product Ratio b (%)
T (˝C)
Total Conversion b (%)
Entry
Catalyst
p (bar)
7a c
7b
7c
1
2
3
4
5
Lindlar catalyst
Lindlar catalyst
Lindlar catalyst
5% Pd/BaSO4
5% Pd/BaSO4
20
40
80
20
40
25
25
25
25
25
33
43
47
75
86
89
88
79
62
60
11
12
21
38
38
0
0
0
0
2
a: Conditions: c = 1 mg
¨
mL´1 in ethyl acetate, 1 mL min´´1 flow rate; b: Determined by GC-MS analysis of
¨
the crude material; c: During the reactions, the (Z) deuterated chalcone isomer is formed, but readily isomerizes
to the more stable (E) form.
In the case of bromine-substituted ynone 8 (1-(2-bromophenyl)-3-(4-methoxyphenyl)prop-2-yn-1-one), the
˝
efficacy of 5% Pd/BaSO4 was tested first at 40 bar employing temperatures of 50 and 70 C, to
compensate the larger steric hindrance generated by the halogen atom at position 2 of ring A (Table 4).
Despite the achievement of acceptable conversions of 50% and 53%, significant over-reduction occurred
at both temperatures, and dideuteroenone 8a was formed to extents of only 69% and 56% at 50 and
˝
70 C, respectively (entries 1 and 2). We were delighted to find that elevation of the pressure to
60 bar at ambient temperature resulted in a slight increase in conversion to 66% and a significant
improvement in chemoselectivity, with an acceptable dideuteroenone (8a)/tetradeuteroketone (8b
)
ratio of 77:23, without detectable pentadeuteroalcohol (8c) present (entry 3). An effort to further
˝
enhance the amount of 8a by raising the temperature to 50 C was unsuccessful because of the
intensified 8a-8b over-reduction (entry 4).
Finally, the continuous-flow deuteration of 1-(2-iodophenyl)-3-(4-methoxyphenyl)prop-2-yn-1-one
(9) was attempted by using 5% Pd/BaSO4 as catalyst in combination with harsher reaction conditions,
with regard to the significant steric hindrance generated by iodine (Table 5) [36]. Although the total

Molecules 2016, 21, 318
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˝
conversion at 80 bar and 50 C was only 17%, formation of the corresponding dideuteroenone (9a) was
exclusive under these conditions (entry 1). We were pleased to find that when the temperature was
elevated to 100 ˝C, the conversion rose to an acceptable level of 56%, still without the formation of
over-reaction products (entry 2). In attempts to improve the rate of the reaction, the use of 5% Pt/Al2O3
as a more active heterogeneous catalyst led to higher total conversions at RT and 20-80 bar, but it had
a pronounced negative effect on the chemoselectivity, with the unwanted tetradeuteroketone (9b
)
becoming the main product, together with significant amounts of pentadeuteroalcohol 9c (entries 3-5).
Table 4. Continuous-flow deuteration of 8 a.
Product Ratio b (%)
T (˝C)
Total Conversion b (%)
Entry
Catalyst
p (bar)
8a c
8b
8c
1
2
3
4
5% Pd/BaSO4
5% Pd/BaSO4
5% Pd/BaSO4
5% Pd/BaSO4
40
40
60
60
50
70
25
50
50
53
66
82
69
56
77
61
31
44
23
39
0
0
0
0
a: Conditions: c = 1 mg
¨
mL´1 in ethyl acetate, 1 mL min´´1 flow rate; b: Determined by GC-MS analysis of
¨
the crude material; c: During the reactions, the (Z) deuterated chalcone isomer is formed, but readily isomerizes
to the more stable (E) form.
Table 5. Continuous-flow deuteration of 9 a.
Product Ratio b (%)
T (˝C)
Total Conversion b (%)
Entry
Catalyst
p (bar)
9a c
9b
9c
1
2
3
4
5
5% Pd/BaSO4
5% Pd/BaSO4
5% Pt/Al2O3
5% Pt/Al2O3
5% Pt/Al2O3
80
80
20
40
80
50
100
25
25
25
17
56
89
95
99
100
100
28
18
7
0
0
67
68
59
0
0
5
14
34
a: Conditions: c = 1 mg
¨
mL´1 in ethyl acetate, 1 mL min´´1 flow rate; b: Determined by GC-MS analysis of
¨
the crude material; c: During the reactions, the (Z) deuterated chalcone isomer is formed, but readily isomerizes
to the more stable (E) form.
The above optimization reactions (Tables 1–5) were typically carried out on a 0.1 mmol scale.
For preparative purposes, a 10-fold scale-up was made under the selected conditions (see Table 1,
entry 2; Table 2, entry 4; Table 3, entry 4; Table 4, entry 3; and Table 5, entry 2) simply by pumping in a
larger amount of starting material. Even gram-scale deuterations can readily be performed in flow as a
function of the starting material quantity and the operation time, without any change in the reaction
conditions and without the need for re-optimization.
As a consequence of the high purity of the D2 gas employed, the deuterated target compounds
were obtained with deuterium contents (which reflect the deuterium incorporation ratio over incidental
hydrogen addition) of
ě
98%. It should also be noted that neither over-reaction products containing
reduced or partially reduced aromatic rings, nor halogen–deuterium exchange on ring A were detected,
even when Pt/Al2O3 was used as a catalyst.

Molecules 2016, 21, 318
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3. Materials and Methods
3.1. Materials
The reagents and materials were of the highest commercially available grade and were used
without further purification. Cartridges containing 5% Pt/Al2O3, 5% Pd/BaSO4 and Lindlar catalyst
were purchased from ThalesNano Inc. (Budapest, Hungary).
3.2. Synthesis of the Starting Materials
The corresponding acid chloride (1.0 mmol, 1 equiv.), terminal acetylene (1.0 equiv.), PdCl2(PPh3)2
(0.03 equiv.), CuI (0.06 equiv.) and Et3N (1.5 equiv.) were combined in THF (6 mL), and the mixture
was stirred for 1 h at ambient temperature under a N2 atmosphere. It was next diluted with water
to 12 mL, and the resulting solution was extracted with CH2Cl2 (2
ˆ
15 mL). The combined organic
layers were dried over Na2SO4 and concentrated under reduced pressure. The residue obtained was
purified by column chromatography on silica gel, with a mixture of n-hexane/EtOAc as eluent; ynones
5-9 were achieved in yields of 83%-92% [66–68].
3.3. Continuous-Flow Deuterations
Deuterations were carried out in an H-Cube® system (ThalesNano Inc.) with replacement of
the H2O hydrogen source to D2O (VWR, 99.96%) [36
,60,61]. The catalyst cartridges, with internal
dimensions of 30 4 mm, contained approximately 100 mg of 5% Pt/Al2O3, 5% Pd/BaSO4 or Lindlar
ˆ
catalyst. The selected cartrid˝ge was placed into a heating unit controlled by a built-in Peltier system
(maximum temperature: 100 C), and the system also contained a backpressure regulator that ensured
constant pressures up to a maximum of 100 bar. The continuous stream of the reaction solution was
provided by an HPLC pump (Knauer WellChrom K-120). For each reaction, a 1-mg
¨
mL´1 solution
of the corresponding ynone ( ) was prepared in ethyl acetate (HPLC grade). The mixture was
5-9
homogenized by sonication for 2 min and then pumped through the H-Cube® under the appropriate
conditions. Between two reactions, the catalyst bed was washed for 10 min with ethyl acetate at
1 mL min´1. The crude products were purified by column chromatography on silica gel with mixtures
of n-hexane/EtOAc as eluent.
3.4. Product Analysis
Ynones 5-9 and deuterium-labeled chalcones 5a-9a were characterized by NMR and GC-MS.
1H-NMR and 13C-NMR spectra were recorded in CDCl3 as an applied solvent on Bruker Avance
DRX 400 and JEOL ECS 400 instruments with TMS as the internal standard, at 400.1 and 100.6 MHz,
respectively. GC-MS analyses were carried out with a Thermofisher Scientific DSQ II Single Quadrupole
GC/MS, on a 30 m
ˆ
0.25 mm
ˆ
0.25
µ
m HP-5MS capillary colum˝n (Agilent J & W Scientific).
˝
´1
(0-25 min),
The measurement parameters: column oven temperature: from 50 to 300 C at 10 C
¨
min
˝
˝
˝
and 300 C (25-30 min); injection temperature: 250 C; ion source temperature: 200 C; EI: 70 eV;
carrier gas: He, at 1 mL L; split ratio: 1:50; and mass range: 45–800 m/z.
¨
min´1; injection volume: 5
µ
Conversions and product ratios were determined from the GC-MS spectra of the crude materials.
Deuterium contents were calculated from the relative intensities of the 1H-NMR indicator signals.
Product characterization data can be found in the Supporting Information.
4. Conclusions
Scalable continuous-flow syntheses of the deuterium-labeled derivatives of antidiabetic chalcones
were achieved in the present study. Our synthetic strategy relied on the selective C C bond deuteration
”
of the corresponding alkynone analogs in an H-Cube® system following change of the hydrogen
source to high-purity deuterated water. The methodology applied was simple and safe as it eliminated
potentially dangerous D2 gas-handling. The effects of the most important reaction conditions (catalyst,

Molecules 2016, 21, 318
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pressure and temperature) were investigated in order to determine the optimum deuteration conditions.
In spite of the possibility of facile over-reactions, the desired deuterium-labeled compounds were
attained with high selectivities.
A patent application has been filed on deuterium-labeled chalcones 6a-9a. Their biological effects
and kinetic profiles are currently under investigation in our laboratories; these results will be reported
in due course.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/
21/3/318/s1.
Acknowledgments: This study was supported by a bilateral mobility grant from the Ministry of Science and
Technology of Taiwan and the Hungarian Academy of Sciences (MOST 104-2911-1-037-051 and SNK-79/2013).
The projects of Ministry of Science and Technology of Taiwan (MOST 104-2811-B-037-018) and Kaohsiung
Medical University, Taiwan (KMU-TP104E39), awarded to F.-R.C., are greatly appreciated. We are grateful to
the Hungarian Research Foundation (OTKA K115731) for financial support. S.B.Ö. acknowledges the award of
a János Bolyai Research Scholarship and a postdoctoral fellowship (Postdoctoral Research Program) from the
Hungarian Academy of Sciences.
Author Contributions: S.B.Ö., F.F. and F.-R.C. designed the experiments, interpreted the results and wrote the
manuscript. S.B.Ö. and C.-T.H. carried out the flow and batch reactions. Y.-C.W. and J.-H.L. carried out the
analytical investigations. C.-T.H. and J.-H.L. purified the crude products. All authors discussed the results and
commented on the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of compounds 5–9 are available from the authors in mg quantities.
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