Synthesis of new eburnamine-type alkaloid via direct hydroalkoxylation

Article abstract of DOI:10.2478/s11696-013-0512-8

This study concerns the preparation of a new eburnamine-type alkaloid, methyl (3α,14β,15β,16α)-17,18-didehydro-14,15- dihydroeburnamine-15-methoxy-14-carboxylate (VIII). This alkaloid was prepared from (+)-17,18-dehydroapovincamine (V) using Lewis acid and/or ion exchange resin as catalyst. The hydroalkoxylation reaction of V with methanol was investigated in terms of catalyst, solvent, temperature, and time of reaction. A one-pot method for synthetising this alkaloid was established. The optimal conditions for the reaction are discussed.

Full text of DOI:10.2478/s11696-013-0512-8

Chemical Papers 68 (6) 816–822 (2014)
DOI: 10.2478/s11696-013-0512-8
ORIGINAL PAPER
Synthesis of new eburnamine-type alkaloid
via direct hydroalkoxylation
Xiong Liu, Dong-Liang Yang, Jia-Jia Liu*, Jing Zhou, Nana Zhao
Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University,
Changsha 410083, China
Received 3 August 2013; Revised 27 September 2013; Accepted 28 September 2013
This study concerns the preparation of a new eburnamine-type alkaloid, methyl (3α,14β,15β,16α)-
17,18-didehydro-14,15-dihydroeburnamine-15-methoxy-14-carboxylate (VIII ). This alkaloid was
prepared from (+)-17,18-dehydroapovincamine (V ) using Lewis acid and/or ion exchange resin
as catalyst. The hydroalkoxylation reaction of V with methanol was investigated in terms of cat-
alyst, solvent, temperature, and time of reaction. A one-pot method for synthetising this alkaloid
was established. The optimal conditions for the reaction are discussed.
c
ꢀ 2013 Institute of Chemistry, Slovak Academy of Sciences
Keywords: eburnamine-type alkaloid, catalyst, hydroalkoxylation
Introduction
preparing I by allowing apovincamine (II; Fig. 1) to
react with an alkali metal methoxide; the reaction pro-
cess includes the hydrolysis of ester. In addition, El-
lies and Rosenberg (2010) described vinpocetine and
eburnamine derivatives (III; Fig. 1) as having the abil-
ity to promote bone growth. However, no details have
been published on the synthesis of these compounds to
date, although these experiments may mean that the
structural modification of the α,β-unsaturated ester
in the structure of eburnamine-type alkaloids is likely
to afford some new derivatives with effective pharma-
cological activities. Taking this into account, and also
considering that few reports are available on its syn-
thesis, the present investigation concerned the catal-
ysed hydroalkoxylation of II and its derivatives with
methanol leading to a direct addition of methoxyl to
the 14,15 unsaturated carbon—carbon bond for the
synthesis of functionalised eburnamine-type alkaloids,
with the process avoiding the hydrolysis of ester.
With the current increase in human longevity and
the problems associated with an ageing population,
degenerative disorders which affect the brain and its
functions are attracting increased attention. Resolv-
ing these disorders would result in the ageing gen-
eration enjoying a healthier, more active and more
productive lifestyle. Eburnamine-type alkaloids, such
as vincamine and its derivatives, exert varied phar-
macological activities on cell multiplication, the car-
diovascular system, and functions of the brain. They
are in clinical use as agents for lowering blood pres-
sure and assisting cerebral vasodilation (Dehn, 1972).
Many eburnamine derivatives have been synthesised
with the aim of finding pharmacologically active com-
pounds easier to characterise and safer to administer
than the natural plant alkaloids themselves (Vas &
Gulyás, 2005). Dehn (1972) published a patent relat-
ing to a new eburnamine-type alkaloid, 14-carboxy-
15-methoxy-eburnane (I; Fig. 1). They found that the
eburnamine-type alkaloid having the formula I and
its salts possess valuable pharmacological properties.
It appears to be approximately three times less toxic
than vincamine and it effectively increases the cere-
bral flow. This patent also described a method of
Experimental
General
The reagents and chemicals (analytical grade un-
less otherwise stated) were purchased from Sinopharm
*Corresponding author, e-mail: liujj0903@163.net

X. Liu et al./Chemical Papers 68 (6) 816–822 (2014)
817
Fig. 1. Eburnamine derivatives have been synthesized by structural modification of the α,β-unsaturated ester in the structure of
eburnamine-type alkaloids.
Chemical Reagent (China) and Tianjin Damao Chem-
ical Reagent (China) NKC-9 ion exchange resin was
obtained from the Chemical Plant of NanKai Uni-
adjusted to 9.0 by adding of NH4OH. Then methanol
was removed under reduced pressure, the mixture was
extracted with CH2Cl2 (10 mL) and the organic layer
was concentrated under vacuum. The residue was pu-
rified by column chromatography on silica gel (Qing-
dao Haiyang Chemical, China) with a mixture of
petroleum ether/ethyl acetate (EtOAc; ϕr = 4 : 1)
to afford 360 mg of methyl (3α,14β,15β,16α)-17,18-
didehydro-14,15-dihydroeburnamine-15-methoxy-14-
carboxylate (VIII ) as colourless crystals. The struc-
ture of VIII was verified by IR, MS, and NMR tech-
niques.
ꢀ
versity (China). Resin complexes (P—BF3 ·Et2O and
ꢀ
P—AlCl3) were synthesized in our laboratory. Taber-
sonine was purchased from Enjoye C & G (Xiamen)
Bioengineering (China). Melting points were deter-
mined using a Hotstage microscope Boetius (China)
apparatus and are uncorrected. Elemental (C,H,N)
analysis was carried out using an Element Vario
ELIII (Germany) analyser. The infrared spectra were
recorded on a Perkin–Elmer (USA) using KBr pellets.
EI-MS was carried out using a Perkin–Elmer Auto
System XL analyser. NMR spectra were recorded
using a Bruker Avance III (Germany) spectrometer
in CDCl3. 1H NMR at 400 MHz and 13C NMR at
100 MHz. TMS was used as internal standard. Chem-
ical shift δ is given relative to TMS.
A typical one-pot synthesis of VIII from 17,18-
dehydrovincamine (VI ) was carried out as follows: VI
(2.0 g, 5.68 mmol) was added to 10 mL of anhydrous
ꢀ
methanol and resin complexes (P—BF3 · Et2O, 0.1 g)
were added at 64.5◦C. After stirring for 6.5 h, the resin
complexes were removed by filtration and the organic
layer was concentrated under vacuum. The residue
was then purified by column chromatography on silica
gel with a mixture of petroleum ether/EtOAc (ϕr =
4 : 1) to afford 1.45 g (84 %) of product (VIII ) as
colourless crystals with melting point of 183–184◦C.
Elemental analyses of (C22H26N2O3) Mw = 366.46
(calculated) C: 72.22 %; H: 7.61 %; N: 7.61 %; found C:
72.11 %; H: 7.15 %; N: 7.64. IR, ν˜/cm−1: 601, 746, 929,
956, 1076, 1099, 1215, 1274, 1338, 1360, 1454, 1743,
2801, 2850, 2932, 2957. 1H NMR (CDCl3), δ: 1.01 (3H,
t, J = 7.6 Hz, CH3(Et)), 1.64 (1H, dq, J = 7.6 Hz, J
= 14.4 Hz, CH2(Et)), 1.92 (1H, dq, J = 7.6 Hz, J =
14.4 Hz, CH2(Et)), 2.28 (1H, d, J = 4 Hz; H-14), 2.56
(1H, d, J = 4 Hz, H-15), 2.58 (1H, ddd, J = 2.8 Hz,
J = 10.4 Hz, Jgem = 14.0 Hz, H-6), 3.03 (2H, 2d, J =
3.6 Hz, J = 2.8 Hz, H-19), 3.14 (1H, ddd, J = 2.0 Hz,
J = 2.8 Hz, J = 13.6 Hz, J = 13.6 Hz, H-5), 3.32 (3H,
s, -OCH3), 3.33 (1H, ddd, J = 6.8 Hz, J = 10.4 Hz,
Jgem = 13.6 Hz, H-5), 3.42 (1H, ddd, J = 2.0 Hz, J =
6.8 Hz, Jgem = 14.0 Hz, H-6), 3.54 (3H, s, -COOCH3),
4.02 (1H, s, H-3), 5.32 (1H, d, J = 10.0 Hz, H-17), 5.52
(1H, ddd, J = 10.0 Hz, J = 3.6 Hz, J = 2.8 Hz, H-18),
7.11–7.13 (2H, dd, H-9, H-12), 7.45–7.47 (2H, m, H-10,
H-11). 13C NMR (CDCl3), δ: 8.5 (C-21), 16.7 (C-6),
35.3 (C-20), 37.6 (C-16), 38.2 (-OCH3), 43.8 (C-19),
49.7 (C-5), 49.9 (-COOCH3), 57.4 (C-3), 57.4 (C-14),
Synthesis of functionalised eburnamine-type
alkaloids
The hydroalkoxylation II and its derivatives with
methanol leading to the direct addition the di-
rect addition of methoxyl to the 14,15 unsaturated
carbon—carbon bond for the synthesis of function-
alised eburnamine-type alkaloids was performed as fol-
lows: compound II and its derivatives were allowed to
react with a solution of anhydrous methanol at 65◦C.
H2SO4, AlCl3, ZnCl2, FeCl3, BF3· Et2O, and ion ex-
change resin were used as catalysts, respectively. The
hydroalkoxylation reaction was investigated in terms
of catalyst, solvent, temperature, and time of reac-
tion. The intermediate materials (II and its deriva-
tives) in the reactions were synthesised with reference
to other reports. The structures of the products were
elucidated using a combination of UV, MS, and NMR
spectroscopic analyses.
A typical hydroalkylation procedure with metha-
nol was carried out as follows: (+)-17,18-dehydro-
apovincamine (V; 0.5 g, 1.5 mmol) was added to 5 mL
of anhydrous methanol, H2SO4 (98 %, 0.1 mL) was
added at 64.5◦C. After stirring for 8 h, 5 mL of H2O
was added and the pH of the reaction mixture was

818
X. Liu et al./Chemical Papers 68 (6) 816–822 (2014)
Fig. 2. Pathway of reaction of II with methanol.
Fig. 3. Reagents and conditions: i) permaleic acid (maleic anhydride, DMF, H2O2, 30◦C), MeOH, 5◦C; ii) Na2S2O3, 40◦C; iii)
H2SO4, EtOAc, 65◦C.
89.0 (C-15), 107.0 (C-7), 113.2 (C-12), 117.9 (C-9),
120.2 (C-10), 121.8 (C-11), 126.1 (C-18), 126.6 (C-17),
and/or the functional groups at this site have been re-
ported to exert a significant influence on their chem-
ical properties (Éles et al., 2002; Nárai et al., 1998;
Nemes et al., 2007), an attempt was made to take
advantage of V to achieve the synthesis of IV. The
preparation of V occurs through the dehydration re-
action of VI (Zajer et al., 1982), which is obtainable
from tabersonine (VII) by ring transformation using
a previously described method (Fig. 3) (Éles et al.,
2002; Nemes et al., 2007; Palmisano et al., 1988). In
the present experiment, the dehydration reaction of VI
was performed in a solution of anhydrous methanol
with H2SO4 as catalyst (Calvo Mondelo & Manresa
Ferrero, 1991). Once the reaction started, dehydra-
tion product V was detected. As the reaction mixture
continued to reflux, it was notable that VIII was also
obtained. When the dehydration reaction was carried
out in EtOAc as the solvent, dehydration compound
V, as the main product, was obtained with a yield of
95 %. These experiments indicated that the C-17–C-
18 double bond in the structure of VI plays a vital
—
128.6 (C-8), 133.1 (C-13), 137.0 (C-2), 169.3 (C O).
—
MS, m/z (Ir/%): 366 (100), 365 (28), 351 (22), 337
(92), 307 (72), 298 (12), 278 (24), 249 (82), 238 (21),
218 (21), 167 (19), 144 (25), 121 (32).
Results and discussion
The initial target was the hydroalkoxylation of II
with methanol (Fig. 2). II was allowed to react with
a solution of anhydrous methanol at 65◦C. H2SO4,
AlCl3, ZnCl2, FeCl3, BF3 ·Et2O, and ion exchange
resin were used as catalysts, respectively. During the
reactions, the formation of methoxy-eburnane (IV)
was not observed in all the above experiments. Only
the hydrolysis product of the ester was detected.
These results accord with the experiments by Kuge
et al. (1994). Considering that the C-17–C-18 dou-
ble bond in the structure of II is another impor-
tant eburnamine-type alkaloid V and the double bond

X. Liu et al./Chemical Papers 68 (6) 816–822 (2014)
819
Fig. 4. Pathway of reaction of V with methanol.
Table 1. Results of hydroalkoxylation reaction of
BF3 ·Et2O and AlCl3. The catalytic activities of the
modified resins were also calculated and the results
are shown in Table 1. The modified resins exhibited
a good catalytic activity. The screening data showed
that the ideal reaction condition was to use a strong
Lewis acid as catalyst. BF3 ·Et2O and AlCl3 share the
excellent activity in catalysing the hydroalkoxylation
reaction with yields of 87 % and 82 %, respectively.
The complexes of the NKC-9 ion exchange resin link-
ing the Lewis acids (BF3 · Et2O and AlCl3) also exhib-
ited good catalytic activity (85 % and 81 %, respec-
tively). The use of these complexes as catalyst affords
many advantages, such as substrate stabilisation, re-
action selectivity, increased yield, effective separation
of products, loss of volatility, lower hygroscopicity, and
recyclability (Whang et al., 1984). Thus, the follow-
ing procedures were carried out using the complexes
of NKC-9 ion exchange resin linking Lewis acids as
catalyst.
V
with
methanol in the presence of different catalysts
Entry
Catalyst
Yield/%
1
2
3
4
5
6
7
8
9
H2SO4
71
87
82
N/A
N/A
N/A
62
BF3 · Et2O
AlCl3
ZnCl2
FeCl3
NiCl2
NKC-9 Ion exchange resin
ꢀ
P —AlCl3
81
85
ꢀ
P —BF3 · Et2O
N/A – No reaction.
role in the hydroalkoxylation reaction. This prompted
a closer investigation of this reaction.
The investigation of the hydroalkoxylation reac-
tion of V with anhydrous methanol commenced with
a screening of different Lewis acids and ion exchange
resin. The initial screening was performed with rela-
tively high amounts of catalyst (10 mass %) and a con-
siderable excess of methanol (the solid mass to solvent
volume was 1 : 10). The reaction pathway is shown
in Fig. 4. All the primary screening experiments were
carried out in a 10 mL reactor at 65◦C for 8 h. Table 1
presents the data of these screening experiments, indi-
cating that H2SO4, BF3 · Et2O, AlCl3, and NKC-9 ion
exchange resin were able to catalyse the hydroalkoxy-
lation reaction. By contrast, the Lewis acid ZnCl2,
FeCl3, and NiCl2 were not able to catalyse the ad-
dition of methanol to V. The modified resins which
were applied as non-corrosive and readily separated
reagents and catalyst were synthesised in the search
for better catalysts (Magnotta & Gates, 1977; Neck-
ers et al., 1972; Sket & Zupan, 1983; Whang et al.,
1984). The modified resins in the present experiments
are combinations of NKC-9 ion exchange resin and
Lewis acids, prepared by the methods described by
Sket and Zupan (1983) and Whang et al. (1984). Ac-
cording to the results from the screening of different
Lewis acids, in these complexes, the Lewis acids were
Use of this solvent can significantly influence the
equilibrium state of the Lewis acid through solution
effects (Behr et al., 2012). The catalytic activities and
yields of VIII with four different polarity organic sol-
vents were investigated to discover the influence of the
type of organic solvent. In the experiments, the mixed
reaction solvents were the combination of the inves-
tigated solvent and methanol (ϕr = 1 : 1). Table 2
shows that the dielectric constant of the solvent al-
most has a negative correlation to the yield. This may
be due to the Lewis acids in the resin complexes be-
ing more conducive to combining with the solvent of
the high dielectric constant; as a result, the catalytic
activity of the catalyst decreased. However, the re-
sults of tetrahydrofuran (THF) and EtOAc did not
accord with this. Considering that these catalysts are
complexes of the Lewis acid, the ion exchange resin
and the solvents can swell the volume of the resin. A
possible reason for the low yield resulting from using
EtOAc as solvent is that the resin was not allowed to
swell effectively. As a result, it was difficult for the
reagents to diffuse into it and the catalytically active
site was not sufficiently utilised. The swell constants
of the NKC-9 ion exchange resin in these solvents are

820
X. Liu et al./Chemical Papers 68 (6) 816–822 (2014)
Table 2. Influence of solvents on activity of resin complexes as catalyst
Yield/%
Entry
Solvent
ε
Swelling ratio/%
ꢀ
P —AlCl3
ꢀ
P —BF3 · Et2O
1
2
3
4
5
–
32.7
36.7
20.7
7.58
6.02
100
90
75
85
55
81
72
78
83
57
85
71
80
88
55
DMF
Acetone
THF
EtOAc
DMF – N,N-Dimethylformamide; ε – dielectric constant.
occurs in the yield as the temperature increases from
50◦C to 60◦C. However, once the temperature is above
60◦C, the yield tends to be stable. In view of the
cost and equipment requirements, the boiling point
of methanol (64.5◦C) represents an economic temper-
ature for this reaction.
Table 3. Effect of temperature on hydroalkoxylation reaction
of V
Yield/%
Entry
Temperature/◦C
ꢀ
P —AlCl3
ꢀ
P —BF3 · Et2O
1
2
3
4
5
6
30
40
50
60
70
80
N/A
< 10
≈ 33
≈ 85
≈ 88
≈ 89
N/A
< 10
≈ 40
≈ 88
≈ 91
≈ 92
The influence of catalyst concentration was inves-
tigated by varying the concentration from 0.5 mass %
to 10 mass %, at 8 h, and 64.5◦C. Investigations of the
amount of catalyst revealed that the resin complexes
were able to catalyse the direct addition of methanol
sufficiently to the unsaturated bond even with a lower
amount of 3.0 mass %. Increasing the concentration
of the catalyst above 3.0 mass % would not enhance
the yield. This negative influence on the yield is prob-
ably due to the products being absorbed by the ion
exchange resin. It should also be noted that the sub-
strate ratio is also an important influencing factor. A
high excess of methanol favours sufficient shifting of
the equilibrium (Behr et al., 2012). However, the high
excess of methanol will lead to reductions in the con-
centrations of reaction substrate and catalyst. In or-
der to calculate these impacts, a series of experiments
were performed, with the results shown in Table 4.
The data revealed that, when the substrate ratio was
lower than 1 : 8 (solid mass/solvent volume), a high
excess of methanol had a positive effect on the yield
and “shifting of the equilibrium” was the main influ-
encing factor; if the substrate ratio was below 1 : 14,
then the yield showed an obvious decline. In this case,
the concentrations of reagents and catalyst became
the main controlling factors. The yield achieved the
maximum value and remained stable when the ratio
was within the range of 1 : 8 to 1 : 12; this stability
was the result of the interaction of the various factors
detailed above. Accordingly, 1 : 8 was selected as a
reasonable substrate ratio for the present study.
Experiments were also performed with different re-
action times to optimise the experimental conditions.
Table 5 reveals that the yields increased with the re-
action times prolonged to 5 h. Subsequently, with the
reaction time further prolonged, the yields began to
decrease. Hence, 5 h was chosen as the reaction time
for the following works. This result indicates the prod-
uct could be decomposed in the reaction condition for
a longer time, such as the hydrolysis of ester. In ad-
N/A – No reaction was detected.
given in Table 2. The data support the hypothesis pro-
posed above. Hence it is clear that THF possesses the
highest swelling ratio and a lower dielectric constant,
and that the highest hydroalkoxylation yield was ob-
tained. In addition, although EtOAc has the lowest
dielectric constant, the yield is lower than the others.
This anomaly is probably due to the swelling ratio of
the resin complex in EtOAc being so small that the
reagents could not make a good contact with the cat-
alytically active site, resulting in a low reaction rate.
Accordingly, these resin complex catalysts could be
influenced by the solvents in multiple aspects. The
swelling ratio in the solvent plays an important role
in the reaction. In the control experiment (Table 2,
Entry 1), although methanol has the higher dielectric
constant, the yields were quite satisfactory. This re-
sult is due to the highest swelling ratio and the high
excess of methanol. In the present screening experi-
ments, THF is an ideal organic solvent.
Temperature is known to be a significant issue in
a reaction system. In the present experiments, the in-
fluences of temperature on the reactions were inves-
tigated within the range of 30◦C to 80◦C. The ex-
perimental data are shown in Table 3. It was noted
that the hydroalkoxylation reaction could not pro-
ceed at 30◦C and, therefore, VIII was not detected.
As the temperature was gradually increased to 80◦C,
the results indicated that the hydroalkoxylation yield
increased with the increase in temperature. This phe-
nomenon revealed that the reaction was more likely
to proceed under a high temperature. A major change

X. Liu et al./Chemical Papers 68 (6) 816–822 (2014)
821
Table 4. Influence of catalyst concentration and effect of substrate ratio on yields
Yield/%
Entry
Catalyst concentration/mass%
Substrate ratio
ꢀ
P —AlCl3
ꢀ
P —BF3 · Et2O
1
2
3
4
5
6
7
8
9
0.5
1.0
2.0
3.0
5.0
10.0
3.0
3.0
3.0
3.0
3.0
3.0
1 : 10
1 : 10
1 : 10
1 : 10
1 : 10
1 : 10
1 : 4
1 : 6
1 : 8
1 : 10
1 : 12
1 : 14
N/A
10
45
90
88
87
32
78
90
90
90
88
N/A
13
50
93
90
90
35
81
93
93
93
90
10
11
12
N/A – No reaction was detected.
resin has a strong adsorption ability to the alkaloids
(Qin et al., 2007; Zhang et al., 2008), the deactiva-
tion of the catalyst is probably due to blocking of the
resin and active sites by entities (Mergen et al., 2008).
Hence, the reagents were difficult to diffuse into the
resin complexes and the number of available active
sites declined. Subsequent experiments were carried
out to remove the organic entities through the resin
complexes refluxing with the methanol; the regener-
ated catalyst was employed to determine the recover-
ies in activity, and the result was reflected in the yield.
The data indicated that the regenerated resin pos-
sessed a high catalytic activity (Table 6, Entry 5). The
result also revealed that the catalytic activity of the
regenerated resin could not be fully recovered. This
may mean that the wastage of Lewis acid in the resin
complexes also has a bearing on the deactivation of the
catalyst (Table 6, Entry 6). In other words, the cata-
lyst can be regenerated and recycled through refluxing
with methanol and Lewis acid and it is recyclable.
In order to simplify the reaction procedure, a one-
pot synthesis of VIII from VI was also established on
the basis of the results of the experiments detailed
above. The optimisation process was carried out us-
ing the method employed in the above experiments.
The results indicated that the optimal conditions for
the reaction were achieved using 3.5 mass % resin com-
plexes at a temperature of 64.5◦C for 6.5 h with a solid
mass-to-methanol volume ratio of 1 : 6. The complexes
of NKC-9 ion exchange resin linking Lewis acids (BF3·
Et2O and AlCl3) also exhibited good catalytic activity
(84 % and 80 %, respectively) to catalyse this one-pot
reaction.
Table 5. Influence of reaction time on yields
Yield/%
Entry
Time/h
ꢀ
P —AlCl3
ꢀ
P —BF3·Et2O
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
33
64
85
≈ 88
≈ 90
≈ 90
≈ 87
≈ 85
36
65
88
≈ 91
≈ 93
≈ 92
≈ 90
≈ 90
Table 6. Estimation of catalyst recyclability
Yield/%
Cycle
ꢀ
P —AlCl3
ꢀ
P —BF3 · Et2O
1
2
90
85
93
89
3
66
69
4
5a
6b
≈ 50
≈ 50
88
91
90
93
a) Catalyst was regenerated by refluxing with methanol; b) cat-
alyst was regenerated by refluxing with methanol and Lewis
acid.
dition, the recyclability of the catalyst was evaluated.
The recycling test was carried out under the optimised
reaction conditions detailed above. After each test,
the catalyst was separated from the product by filtra-
tion and was immediately reused. The results of the
tests are shown in Table 6. This reveals that the hy-
droalkoxylation reaction yield declined to 85 % in the
second test. After reusing the catalyst four times, the
yields were reduced to 50 %. Since the ion exchange
Structure elucidation
The stereostructure of VIII was verified by NOESY
measurements. The stereostucture that emerged from
the NMR data is shown in Fig. 5. Some of the most
significant H—H NOE interactions are depicted by ar-

822
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Éles, J., Kalaus, G., Szabó, L., Lévai, A., Greiner, I., Kajtár-
Peredy, M., Szabó, P., & Szántay, C. (2002). Synthesis
of vinca alkaloids and related compounds 98. Oxidation
with dimethyldioxirane of compounds containing the aspi-
dospermane and quebrachamine ring system. A simple syn-
thesis of (7S,20S)-(+)-rhazidigenine and (2R,7S,20S)-(+)-
rhazidine. Journal of Heterocyclic Chemistry, 39, 767–771.
DOI: 10.1002/jhet.5570390423.
Ellies, D., & Rosenberg, W. (2010). U.S. Patent No. US2010000
3324 (A1). Washington, D.C., USA: U.S. Patent and Trade-
mark Office.
Kuge, Y., Nakazawa, H., Kometani, T., Sugaya, T., Mochida,
K., & Tomioka, S. (1994). A Facile one-pot synthesis of
vinpocetine. Synthetic Communications, 24, 759–766. DOI:
10.1080/00397919408011297.
Magnotta, V. L., & Gates, B. C. (1977). Superacid polymers:
Synthesis and analysis of AlCl3 – sulfonic acid resin com-
plexes. Journal of Polymer Science, Part A: Polymer Chem-
istry, 15, 1341–1347. DOI: 10.1002/pol.1977.170150605.
Mergen, M. R. D., Jefferson, B., Parsons, S. A., & Jarvis, P.
(2008). Magnetic ion-exchange resin treatment: Impact of
water type and resin use. Water Research, 42, 1977–1988.
DOI: 10.1016/j.watres.2007.11.032.
Nárai, G., Sohár, P., Csámpai, A., & Zsadon, B. (1998). Syn-
thesis of a new δ-lactone bridget apovincamine derivative.
Heterocycles, 48, 151–154. DOI: 10.3987/com-97-7983.
Neckers, D. C., Kooistra, D. A., & Green, G. W. (1972).
Polymer-protected reagents. polystyrene-aluminum chloride.
Journal of the American Chemical Society, 94, 9284–9285.
DOI: 10.1021/ja00781a080.
Fig. 5. Most significant H—H NOE interactions of VIII.
rows. The absolute configuration of the C-15 was con-
firmed by the H-15—H-14, H-15—H-17, H-15—H-21
NOE interactions observed. The absolute configura-
tion of the C-14 was confirmed by the H-14—H-3, H-
14—H-15, H-14—H-20 NOE interactions observed.
Conclusions
In this study, a new eburnamine-type alkaloid VIII,
was obtained by the direct addition of methanol to the
α,β-unsaturated ester in the structure of eburnamine-
type alkaloids. The results revealed that the C-17–
C-18 unsaturated carbon bond in the structure of
eburnamine-type alkaloids played a central role in the
hydroalkoxylation reaction. Further investigation is
proceeding to clarify the impact of the C-17–C-18 un-
saturated carbon bonds on their chemical properties.
In addition, the reaction conditions were optimised in
terms of catalysts, solvents, substrate ratio, tempera-
ture, and time of the reaction. The highest yield was
obtained under the conditions of 3 mass % resin com-
plexes at a temperature of 64.5◦C for 5 h with the solid
mass-to-methanol volume ratio of 1 : 6. The recycla-
bility of the resin complexes was also assessed and the
complexes exhibited considerable recyclability. A one-
pot synthetic method was also established.
Nemes, A., Szántay, C., Jr., Czibula, L.,
& Greiner, I.
(2007). Synthesis of 18-hydroxyvincamines and epoxy-1,14-
secovincamines; a new proof for the aspidospermane-ebur-
nane rearrangement. Heterocycles, 71, 2347–2362. DOI:
10.3987/com-07-11114.
Palmisano, G., Danieli, B., Lesma, G., Trupiano, F., & Pilati,
T. (1988). Oxidation of .beta.-anilinoacrylate alkaloids vin-
cadifformine and tabersonine by Fremy’s salt. A mechanis-
tic insight into the rearrangement of aspidosperma to hunte-
ria alkaloids. Journal of Organic Chemistry, 53, 1056–1064.
DOI: 10.1021/jo00240a023.
Qin, X. G., Yuan, Y. J., Wu, J. C., & Yang, J. (2007). Separa-
tion of alkaloids from Sophora alopecuroides L. by adsorption
using macroporous resins. Journal of Chemical Engineering
of Japan, 40, 93–97. DOI: 10.1252/jcej.40.93.
Sket, B., & Zupan, M. (1983). Polymer-supported boron triflu-
oride. Journal of Macromolecular Science: Part A - Chem-
istry, 19, 643–652. DOI: 10.1080/00222338308069445.
Vas, A., & Gulyás, B. (2005). Eburnamine derivatives and
the brain. Medicinal Research Reviews, 25, 737–757. DOI:
10.1002/med.20043.
Whang, K. J., Lee, K. I., & Lee, Y. K. (1984). The synthesis
of polymeric catalyst using ion exchange resin and its appli-
cation for esterification. Bulletin of the Chemical Society of
Japan, 57, 2341–2342. DOI: 10.1246/bcsj.57.2341.
References
Zajer, B., Karpati, E., Kiraly, S., Keve, T., Zsadon, B., Fekete,
G., Loerincz, C., Szporny, L., Rosdy, B., Forgach, L., &
Galambos, J. (1982). Germany Patent No. DE3204630 (A1).
Munich, Germany. German Patent and Trade Mark Office.
Zhang, X., Zhan, Y., Li, Y., Song, W., & Xu, X. (2008). China
Patent No. CN101250188A. Beijing. State Intellectural Prop-
erty Office of The P.R.C.
Behr, A., Johnen, L., & Neubert, P. (2012). A sustainable route
from the renewable myrcene to methyl ethers via direct hy-
droalkoxylation. Catalysis Science & Technology, 2, 88–92.
DOI: 10.1039/c1cy00359c.
Calvo Mondelo, F., & Manresa Ferrero, M. T. (1991). Span-
ish Patent No. ES2018954A6. Madrid, Spain. Spanish Patent
and Trade Mark Office.
Dehn, F. B. (1972). UK Patent No. GB1382609A. Newport, UK.
Intellectual Property Office.