Berberine and coptisine free bases

Article abstract of DOI:10.1016/j.molstruc.2003.09.018

The free bases of protoberberine alkaloids berberine and coptisine and related compounds have been examined. The ¹H and ¹³C NMR data of 8-hydroxy-7,8-dihydroberberine (2a), 8-hydroxy-7,8-dihydrocoptisine (2b), bis(7,8-dihydroberberin-8-yl) ether (3a), 8-oxoberberine (5a), and 8-oxocoptisine (5b) as well as X-ray data of compounds 2a, 5a, and 5b are reported and discussed.

Full text of DOI:10.1016/j.molstruc.2003.09.018

Journal of Molecular Structure 687 (2004) 135–142
www.elsevier.com/locate/molstruc
Berberine and coptisine free bases
a,
Ji ˇr ´ı Dost a´ l , Stanislav Man , Pavlına Seckarova , Dagmar Hulova , Marek Necas ,
b
c
c
d
*
´
Milan Pot a´ cˇ ek , Jarom ´ı r Tou sˇ ek , Roger Dommisse , Walter Van Dongen , Radek Marek
ˇ ´ˇ ´
´
ˇ
b
e
f
f
c
a
Department of Biochemistry, Faculty of Medicine, Masaryk University, Komensk e´ ho n a´ m. 2, CZ-662 43 Brno, Czech Republic
b
Department of Organic Chemistry, Faculty of Science, Masaryk University, Kotl a´ rˇ sk a´ 2, CZ-611 37 Brno, Czech Republic
c
National Center for Biomolecular Research, Faculty of Science, Masaryk University, Kotl a´ rˇ sk a´ 2, CZ-611 37 Brno, Czech Republic
d
Department of Inorganic Chemistry, Faculty of Science, Masaryk University, Kotl a´ rˇ sk a´ 2, CZ-611 37 Brno, Czech Republic
e
Department of Theoretical and Physical Chemistry, Faculty of Science, Masaryk University, Kotl a´ rˇ sk a´ 2, CZ-611 37 Brno, Czech Republic
f
Department of Chemistry, University of Antwerp, Groenenborgelaan 171, B-2020 Antwerpen, Belgium
Received 15 July 2003; revised 12 September 2003; accepted 30 September 2003
Abstract
1 13
The free bases of protoberberine alkaloids berberine and coptisine and related compounds have been examined. The H and C NMR data
of 8-hydroxy-7,8-dihydroberberine (2a), 8-hydroxy-7,8-dihydrocoptisine (2b), bis(7,8-dihydroberberin-8-yl) ether (3a), 8-oxoberberine
(5a), and 8-oxocoptisine (5b) as well as X-ray data of compounds 2a, 5a, and 5b are reported and discussed.
q 2003 Elsevier B.V. All rights reserved.
Keywords: Berberine; Coptisine; Protoberberine alkaloids; NMR spectroscopy; X-ray crystallography
1
. Introduction
2. Experimental
2.1. General procedures
Berberine (1a) and coptisine (1b) are quaternary
protoberberine alkaloids. In the form of salts 1 these
alkaloids are brightly colored and contribute to tissue
coloring of many species of the Berberidaceae, Papaver-
aceae, and other plant families [1]. Both alkaloids display a
number of biological activities and are of current medical
interest [2–4]. They are characterized by the sensitivity to
nucleophilic attack and several 8-substituted adducts have
been described, e.g. with cyanide [5], methoxide [6],
chloroform [7], liquid ammonia [8]. In alkaline environ-
ment, like other typical alkaloids [9], the salts of berberine
Melting points were determined on a Mettler FP51
apparatus and are uncorrected. IR spectra were recorded on
an ATI Mattson Genesis FTIR spectrophotometer. Mass
spectra were taken with a Micromass Q-TOF-2 spec-
trometer using electrospray (HRESIMS, Accurate Mass
Spectra) and a Fisons Trio 1000 quadrupole spectrometer
using electron ionization (70 eV, EIMS).
2D NMR spectra were recorded with Bruker Avance
DRX-400 and DRX-500 spectrometers operating at fre-
1
quencies of 400.13 ( H), 100.62 MHz ( C) and 500.13
13
(
1a) and coptisine (1b) are converted to their free bases.
1
13
H), 125.76 MHz ( C), respectively. The measurement
(
Although the structures of iminium cations 1 are well
known the structures of free bases have not been system-
atically investigated in detail. Continuing our research on
free bases of quaternary isoquinoline alkaloids [10–12] we
report here a structural study on berberine and coptisine free
bases and closely related compounds (Fig. 1).
temperature was 303 K. Solutions were prepared by
dissolving compounds (5–80 mg) in 500–700 ml of
dimethylsulfoxide-d , dichloromethane-d , and chloro-
6
2
1
form-d. TMS was used as an internal standard for H and
1
3
C spectra. For detailed experimental setup see Refs.
10,13].
Diffraction data were collected on a Kuma KM-4 four-
[
*
Corresponding author. Tel.: þ420-542-126-519; fax: þ420-542-126-
00.
E-mail address: jrdostal@med.muni.cz (J. Dost a´ l).
circle single crystal diffractometer using either v–2u scan
(5a) or v scan mode (2a, 5b), and corrected for Lorentz and
2
0022-2860/$ - see front matter q 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2003.09.018

136
J. Dost a´ l et al. / Journal of Molecular Structure 687 (2004) 135–142
Fig. 1. Structural formulas with atom numbering.
þ
polarisation effects. Structure solution and refinement was
done by using a SHELXTL program package [14]. Atomic
coordinates and geometric parameters of compounds 2a, 5a,
and 5b have been deposited at the Cambridge Crystal-
lographic Data Centre (CCDC), Cambridge, UK (CCDC
Ref. nos. are in Table 3).
m=z 353 (M , 3), 352 (17), 351 (51), 337 (16), 336
þ
(M –OH, 100), 322 (50), 307 (26), 292 (23). X-ray
analysis: Figs. 3 and 4; Tables 3 and 4.
(B) Berberine chloride (1a, X ¼ Cl, 5 mg) was dissolved
in DMSO-d (550 ml) and 10% NaOH in H O (100 ml) was
6
2
added. The mixture was shaken thoroughly and immediately
Berberine chloride (1a, X ¼ Cl), berberine hydrogensul-
fate (1a, X ¼ HSO ), and coptisine chloride (1b, X ¼ Cl),
4
all of plant origin, were kindly donated by Professor Ji rˇ ´ı
Slav ´ı k (Masaryk University, Brno, Czech Republic).
Spectral characteristics of alkaloids 1 were consistent with
their structures.
Table 1
1
H NMR chemical shifts (ppm) of the compounds 2–5 in DMSO-d
6
a,b
2a
a
3a
a
Atom
2a
2b
4a
5a
5b
1
7.33 7.25
6.84 6.76
2.90 2.87
3.45 3.30
6.09 5.96
7.01 6.76
6.91 6.58
6.17 6.07
6.06 5.99
7.15
6.62
7.05 7.13 7.45 7.46
6.47 6.60 6.89 6.91
2
2
1
.2. Preparation of compounds
4
5
2.86, 2.89 Nd
3.51, 3.72 Nd
Nd
Nd
2.88 2.87
4.12 4.09
6
.2.1. 8-Hydroxy-7,8-dihydroberberine (2a)
8
6.18
6.94
6.90
6.08
6.56 6.40
–
–
(A) Berberine hydrogensulfate (1a, X ¼ HSO ,
00 mg) was dissolved in water (20 ml) and the aqueous
11
12
Nd
Nd
Nd
Nd
7.49 7.34
7.39 7.19
4
1
2
9
9
3
6.00 6.08 7.04 7.10
6.05 6.06
solution was overlayered with diethyl ether (40 ml). A
saturated aqueous solution of NaOH was added, the
mixture was shaken gently and left at ambient tempera-
ture to evaporate. After 2 days, a few light yellow
crystals of 2a were collected. Crystals suitable for X-ray
analysis were separated under microscope. M.p. 144–
-OCH
-OCH
-OCH
2
2
3
O
O
5.93, 5.95 5.88 Nd
–
5.99, 6.02
–
–
–
–
6.19
3.87
3.86
Nd
–
3.91
3.85
Nd
4.05 4.00 3.79
3.91 3.97 3.87
–
–
–
10-OCH3
8-OH
–
Nd
–
–
–
Nd, not observed or assigned.
a
1
1
49 8C. IR spectrum (KBr): 3444 (OH), 2935, 1603,
In CD
2 2
Cl .
2
495, 1382, 1367, 1230, 1169, 1092, 1038 cm . EIMS
1
b
Data from Ref. [12].

J. Dost a´ l et al. / Journal of Molecular Structure 687 (2004) 135–142
137
Table 2
Crystallization from ethanol afforded 33 mg of light yellow
crystals of 5a. M.p. 201–203 8C. IR spectrum (KBr): 2929,
1645 (CyO), 1618, 1599, 1490, 1385, 1275, 1225, 1176,
13
C NMR chemical shifts (ppm) of the compounds 2–5 in DMSO-d
6
a,b
a
a
Atom
2a
2b
2a
3a
4a
5a
5b
2
1
1
13
1100, 1095 cm . H and C NMR data: Tables 1 and 2.
HRESIMS m=z 352.1176 (calcd. for C H NO , 352.1185).
1
2
3
4
104.88 104.88 104.96 104.91 104.89 104.62 104.69
20 18
5
147.12 147.08 147.29 Nd
147.51 147.46 147.82 Nd
Nd
Nd
146.91 146.92
147.96 147.97
Slow recrystallization of 5a from isopropanol afforded
crystals suitable for X-ray analysis (Fig. 5, Table 3).
108.70 108.67 108.16 107.93 108.20 107.83 107.86
4
5
6
8
8
9
1
1
1
1
1
1
1
2
9
9
1
a
129.97 130.08 129.73 129.50 Nd
129.85 129.84
27.69 27.61
38.77 38.63
2
.2.5. 8-Oxocoptisine (5b)
30.57 30.65 30.48 Nd
46.42 46.09 46.66 Nd
Nd
Nd
Following NMR measurements of the compound 2b the
DMSO-d solution of 2b was left at ambient temperature.
78.69 79.35 79.50 82.80 80.90 158.70 158.18
124.89 114.96 123.46 122.57 122.29 118.50 109.82
145.40 143.39 146.17 145.97 143.53 148.32 146.07
149.85 144.57 150.33 150.04 150.89 150.86 145.66
6
a
After 6 months light yellow crystals emerged on the NMR
tube walls and were identified as oxocoptisine (5b). M.p.
0
1
83–285 8C. X-ray analysis: Fig. 6, Table 3. H and
13
2
C
NMR data: Tables 1 and 2. HRESIMS m=z 336.0871 (calcd.
1
113.79 108.30 114.58 Nd
119.71 116.57 119.72 Nd
Nd
Nd
119.11 113.95
122.52 119.36
2
2a
128.07 129.02 127.68 128.44 128.74 131.80 131.60
95.24 95.09 95.34 96.19 96.98 100.81 101.57
137.23 137.44 136.72 137.22 136.94 134.96 134.83
for C H NO , 336.0872).
5
1
9
14
3
3a
3b
126.51 126.76 126.21 126.21 Nd
101.71 101.69 100.99 100.82 Nd
123.12 123.14
101.31 101.33
3. Results and discussion
-OCH
-OCH
-OCH
2
2
3
O
O
–
101.33
–
–
–
–
102.07
61.45
56.90
–
–
61.01 61.14 61.14
56.07 56.29 56.34
60.76
56.34
–
–
The formation of protoberberine free bases requires a
0-OCH
3
much higher pH value (.12) compared to other isoquino-
line alkaloids. This fact is advantageously used for the
effective separation of quaternary protoberberines from
alkaloid mixtures [15]. The pK values of methoxide adducts
formation for berberine and coptisine are 15.4 and 13.8,
respectively [16]. The free bases of 1 are primarily 8-
hydroxyadducts 2, sometimes called heterocyclic pseudo-
bases [17]. The compounds 2 are rather unstable species
sensitive both to acids (which convert them immediately to
salts 1) and to nucleophilic reagents (which may form other
types of adducts). The EI-mass spectra of both compounds 2
showed molecular ions of weak intensities and base peaks
Nd, not observed or assigned.
a
In CD
2
Cl .
2
b
Data from Ref. [12].
1 13
measured. H and C chemical shifts of 2a are in Tables 1
and 2, respectively.
2
.2.2. 8-Hydroxy-7,8-dihydrocoptisine (2b)
(
A) Coptisine chloride (1b, X ¼ Cl) was treated like 1a
in the preparation of 2a. A few light yellow crystals of 2b
were obtained. M.p. not observed (decomp. .240 8C). IR
spectrum (KBr): 3430 (OH), 2891, 1605, 1481, 1385, 1275,
þ
corresponding to iminium cations 1 (M –OH).
2
1
þ
1
230, 1170, 1040 cm . EIMS m=z 337 (M , 3), 336 (12),
þ
3
35 (47), 321 (76), 320 (M –OH, 100), 292 (10).
3.1. NMR studies
(
in DMSO-d (550 ml) and 10% NaOH in H O (100 ml) was
B) Coptisine chloride (1b, X ¼ Cl, 5 mg) was dissolved
1 13
The H and C NMR spectra of quaternary berberine salt
1a were analyzed and unambiguously assigned by Blasko
6
2
added. The mixture was shaken thoroughly and immediately
1 13
measured. H and C chemical shifts of 2b are in Tables 1
and 2, respectively.
1 13
et al. [18]. The H and C NMR chemical shifts of 8-
hydroxyadducts 2a and 2b in DMSO-d are listed in Tables
6
1 and 2, respectively. The strategy of signal assignment was
analogous to that reported previously [10–12].
2
.2.3. Bis(7,8-dihydroberberin-8-yl) ether (3a and 4a)
Berberine chloride (1a, X ¼ Cl, 80 mg) was suspended
In the NMR spectra of 2a and 2b, the signals of H-8 (C-8)
atoms at 6.09 (78.69) and 5.96 (79.35) ppm, respectively,
are of the highest information value. They are significant
indicators of hemiaminoacetal structures similarly as it was
proved in pseudobases of benzophenanthridine alkaloids
[10]. However, the intensities of both H-8 and C-8 signals
decreased during time until the peaks disappeared com-
pletely. The explanation of this phenomenon may be in
consecutive replacement of the H-8 atom with deuterium.
As a consequence the C-8 signal was split to a triplet. The
in dichloromethane-d (1 ml) and 20% NaOH in H O
2
2
(
with Na CO , and H and C NMR spectra were measured.
100 ml) was added, the organic phase was separated, dried
13
1
2
3
In addition to signals of 2a, the compounds 3a and 4a were
detected and their NMR signals were partially assigned
(
Tables 1 and 2).
2
.2.4. 8-Oxoberberine (5a)
Berberine hydrogensulfate (1a, X ¼ HSO , 200 mg) was
4
1
dissolved in water and 30% NaOH in H O (4 ml) was added.
2
signals of OH groups have not been observed in the H
spectra probably due to the fast chemical exchange in
The mixture was refluxed for 3 h. A precipitate of 5a was
collected and treated with hot 3% hydrochloric acid.
DMSO-d solution.
6

138
J. Dost a´ l et al. / Journal of Molecular Structure 687 (2004) 135–142
Table 3
Crystal data and refinement parameters of compounds 2a, 5a, and 5b
Parameter
2a
5a
5b
CCDC reference no.
Empirical formula
Formula weight
213767
213769
213768
C
20
H19NO
5
C
20
H
17NO
5
19 5
C H13NO
353.36
150(2)
0.71073
351.35
150(2)
0.71073
Triclinic
P-1
335.30
120(2)
0.71073
Triclinic
P-1
Temperature (K)
˚
Wavelength (A)
Crystal system
Space group
Monoclinic
C2=c
˚
a (A)
˚
b (A)
˚
c (A)
15.225(2)
16.950(2)
26.270(3)
90
7.265(2)
14.751(2)
15.752(3)
109.80(1)
92.57(2)
101.10(2)
1547.5(6)
4
7.282(1)
10.107(2)
10.567(2)
113.24(3)
102.07(3)
93.97(3)
688.8(2)
2
a (deg)
b (deg)
g (deg)
98.86(2)
90
3
˚
Volume (A )
6698(1)
Z
16
3
Density calculated (Mg/m )
1.402
1.508
1.617
2
1
)
Absorption coefficient (mm
Fð000Þ
0.101
0.109
0.119
2976
736
348
Crystal size (mm)
Crystal colour
0.4 £ 0.4 £ 0.1
Light-yellow
3.33–25.00
218 ! 18
220 ! 14
231 ! 31
22630/5883
5883/0/476
1.140
0.5 £ 0.3 £ 0.2
Light-yellow
2.38–25.00
28 ! 8
0.3 £ 0.3 £ 0.2
Light-yellow
3.70–25.00
28 ! 8
u Range (deg)
Index range, h
Index range, k
216 ! 16
218 ! 0
212 ! 12
212 ! 6
Index range, l
Reflections collected/unique
Data/restraints/parameters
GOF
5443/5253
5253/0/473
1.020
3889/2347
2347/0/279
1.129
2
Final R=wR ðI . 2s=IÞ
0.0891/0.2073
0.1465/0.2665
0.0337/0.0933
0.0727/0.1095
0.0331/0.0939
0.0381/0.0969
2
Final R=wR (all data)
Protoberberine pseudobases 2 are unstable in solution,
during a short time (about 12 h) they undergo disproportio-
nation and other products are formed, predominantly 8-
oxoderivatives 5. In the case of coptisine, 8-hydroxydihy-
drocoptisine (2b) and 8-oxocoptisine (5b) were present in
solution immediately after alkalization of coptisine chloride
aminoacetals in quaternary benzophenanthridine alkaloids
[11,20,23–26]. Due to anisotropic effects the signals of H-8
atoms are in more deshielded region at 6.56 (3a) and
6.40 ppm (4a) compared with the H-8 signals in 2a.
Quantum chemistry calculations for analogical derivative
(
rapidly increased on account of the compound 2b. The H
1b) in DMSO-d . The content of oxocoptisine (5b) then
6
1
1
3
and C chemical shifts of 5a and 5b are gathered in Tables
and 2. Oxoberberine (5a) was therefore prepared
1
synthetically in order to get unambiguous NMR assignment.
Oxoderivatives 5 are stable six-membered lactams, resistant
to acids. The disproportionation of heterocyclic pseudo-
bases seems to be a general feature observed also in other
systems [17,19,20]. Therefore, oxoberberine (5a) and
oxocoptisine (5b) isolated from plants [21,22] are very
probably artifacts rather than genuine alkaloids.
The investigation of berberine free base in CD Cl2
2
revealed some new facts. The organic phase contained not
only pseudobase 2a but also two minor components which
1
13
were identified by long-range H– C chemical shift
correlation experiments [23,24] as diastereomers of bimo-
lecular
0
bis(7,8-dihydroberberin-8-yl)
0
ether
3a
0
0
(
8R,8 R þ 8S,8 S, racemate) and 4a (8R,8 S ¼ 8S,8 R,
meso-form). The ratio of the three components was roughly
0:2:1 (2a:3a:4a). This is a clear analogy with bimolecular
Fig. 2. A portion of GSQMBC spectrum of compounds 2a, 3a, and 4a (top)
and a detail of 3a and 4a (bottom).
1

J. Dost a´ l et al. / Journal of Molecular Structure 687 (2004) 135–142
139
Fig. 3. A perspective view of 8-hydroxydihydroberberine (2a).
Fig. 4. Four H-bonded molecules of 8-hydroxydihydroberberine (2a).

140
J. Dost a´ l et al. / Journal of Molecular Structure 687 (2004) 135–142
Table 4
Hydrogen-bonding parameters (A, deg) in the compound 2a
the asymmetric unit. In the following, only one of those
molecules is described and discussed. The second
molecule is very similar, the only significant difference
results from the conformational flexibility of the methoxy
pendants, causing O20–C15 group (and its corresponding
counterpart in the other molecule) to be rotated in the
opposite directions. The R-values for 2a are rather high,
mainly due to a small crystal of lower quality, resulting
into a lower diffracting power and relatively high number
of unobserved reflections. Nevertheless, the residual
electron density map does not show any significant
features, thus we believe in model adequacy.
˚
D–H· · ·A
D–H
H· · ·A
D· · ·A
D–H· · ·A
0
O19–H19· · ·O19
0
0.84
0.84
1.93
1.92
2.756(4)
2.719(4)
167.1
158.2
0
00
O19 –H19 · · ·O19
D, donor atom; A, acceptor atom.
of sanguinarine [11] showed that the racemate is the
preferable isomer. Therefore we expect that the dominant
diastereomer could be 3a. However, further measurements
and/or calculations will be required to confirm this
suggestion. To the best of our knowledge this is the first
report of such a bimolecular derivative in protoberberine
All bond lengths and angles in 8-hydroxydihydroberber-
ine (2a) are within normal ranges. The C8–O19 bond
˚
distance is 1.440(5) A. The sum of the three valence angles
around nitrogen is 353.98, which indicates that the
1
13
alkaloids. The H and C chemical shifts of compounds 3a
and 4a are summarized in Tables 1 and 2. Because of their
low concentrations only some H and C atoms were assigned.
Fig. 2 shows a portion of GSQMBC spectrum [27] with C8/
H8 crosspeaks of compounds 2a, 3a, and 4a.
2
3
hybridization of N gets closer to sp rather than to sp .
The partially hydrogenated heteroring B adopts a twisted
half chair conformation while the ring C conformation
resembles a shallow half chair. The atom C8 deviates from
1
5
The N NMR chemical shifts of 8-hydroxydihydrober-
berine (2a) and 8-oxoberberine (5a) d 88.4 and 153.8 ppm,
respectively, were published in our previous studies [28,29].
˚
the plane calculated through C and D rings by 0.373(5) A.
The hemiaminoacetal hydroxyl group C8–OH is in axial
position with respect to the ring C conformation (Fig. 3).
The methoxy group attached to C9 atom is almost
perpendicular to the plane D, while the other MeO group
is nearly in-plane. Corresponding torsion angles are
2117.7(5) [C8a–C9–O20–C15], 71.3(5) [C10–C9–
O20–C15], 175.7(4) [C9–C10–O21–C16], and 23.6(6)8
[C11–C10–O21–C16]. This is a common feature in
tertiary berberine 8-adducts [5,8,12] as well as in quaternary
3
.2. X-ray diffraction analysis of compounds 2a, 5a, and 5b
Crystal data and refinement parameters including
CCDC reference numbers of compounds 2a, 5a, and 5b
are listed in Table 3. In the crystal structure of 2a
there are two crystallographically unique molecules in
Fig. 5. A perspective view of oxoberberine (5a).

J. Dost a´ l et al. / Journal of Molecular Structure 687 (2004) 135–142
141
Fig. 6. A perspective view of oxocoptisine (5b).
berberine salts [5,30,31]. The dioxolane ring C2–C3–
O18–C14–O17 is reasonably planar, with the mean
˚
deviation from a plane being 0.0511 A. The angle between
two aromatic rings A and D is 148.5(2)8.
of 5a and 5b are packed in columns along the x and z axis,
respectively. There are no H-bonds, molecules are held
together by van der Waals forces.
The crystal structure of 8-hydroxydihydroberberine (2a)
involves an interesting system of H-bonds. There are four
H-bonds between hydroxyl groups linking four molecules
of 2a and giving rise to a central eight-membered
heterocycle with alternating H and O atoms (Fig. 4).
The geometric parameters of the hydrogen bonds are listed
in Table 4. Hydroxyl groups are hidden inside four-
molecular clusters and may be relatively protected against
potential chemical attack in the solid phase, while in
solution the compound 2a rapidly reacts as it was shown
during NMR measurements. The molecule of 2a bears one
stereogenic center, the carbon atom C8. Nevertheless,
because of its synthetic origin, the compound was obtained
as a crystalline racemate. To the best of our knowledge
this is the first report on X-ray study of an isoquinoline-
alkaloid pseudobase.
4. Conclusions
The free bases of quaternary protoberberine alkaloids
berberine and coptisine are unstable 8-hydroxy adducts 2
(pseudobases). They are readily converted to salts 1 (by the
action of acids), to 8-oxoderivatives 5 (in strongly alkaline
environment) or to other adducts (in the presence of a
reactive nucleophile). The structure of 8-hydroxydihydro-
berberine (2a) was supported by X-ray analysis. It was
proven that, in non-polar solvent, bimolecular aminoacetal
derivatives of berberine 3a and 4a can be formed.
Unlike quaternary salts of berberine (1a), 8-hydroxydi-
hydroberberine (2a) is tested for its biological activities
quite rarely. Recently the compound 2a has been reported to
be evaluated in cytotoxicity assays [32] and for antiproto-
zoal effects [33]. Unfortunately, the paper [32] does not
state any characteristics of 2a. There is some doubt about
the identity of 2a in the paper [33] because of preparation
method (treatment with 10% HCl) and some differences in
Contrary to 8-hydroxydihydroberberine (2a) the planar-
ity of both 8-oxoberberine (5a, Fig. 5) and 8-oxocoptisine
(
5b, Fig. 6) is more pronounced, particularly in one of the
two crystallographically independent molecules of oxober-
berine. The planarity of all condensed ring systems is
disturbed mainly by atoms C5 and C6 in ring B. All bond
distances and angles are within normal ranges, the shortest
1
H NMR chemical shifts with our data.
˚
one being in the C8yO oxo group: 1.232(2)/1.230(2) A in
Acknowledgements
˚
a, 1.235(1) A in 5b. The sum of bond angles around
5
nitrogen N7 is 359.78/359.72 (5a) and 359.978 (5b), which
2
corresponds to sp hybridization. The two methoxy groups
in 5a are oriented in similar manner as in 2a. The molecules
This work was supported by the grant of the Ministry of
Education of the Czech Republic (LN00A016) and GACR
(203/02/0436).

1
42
J. Dost a´ l et al. / Journal of Molecular Structure 687 (2004) 135–142
[18] G. Blasko, G.A. Cordell, S. Bhamarapravati, C.W.W. Beecher,
References
Heterocycles 27 (1988) 911.
19] J. Dost a´ l, M. Pot a´ cˇ ek, M. Nechv a´ tal, Collect. Czech. Chem. Commun.
[
[
[
[
[
[
[
[
[
[
1] D.S. Bhakuni, S. Jain, in: A. Brossi (Ed.), The Alkaloids, vol. 28,
Academic Press, New York, 1986, Chapter 2.
5
8 (1993) 395.
20] J. Dost a´ l, H. Bocho ˇr a´ kov a´ , E. T a´ borsk a´ , J. Slav ´ı k, M. Pot a´ cˇ ek, M.
Bud eˇ sˇ ´ı nsk y´ , E. de Hoffmann, J. Nat. Prod. 59 (1996) 599.
21] P.M.M. Pinho, M.M.M. Pinto, A. Kijjoa, K. Pharadal, J.G. Diaz, W.
Herz, Phytochemistry 31 (1992) 1403.
2] G.A. Cordell, M.L. Quinn-Beattie, N.R. Farnsworth, Phytother. Res.
1
5 (2001) 183.
[
[
3] J.P. Hu, N. Takahashi, T. Yamada, Oral Dis. 6 (2000) 297.
4] C.W. Lau, X.Q. Yao, Z.Y. Chen, W.H. Ko, Y. Huang, Cardiovasc.
Drug Rev. 19 (2001) 234.
22] A. Rahman, S. Ahmad, M.K. Bhatti, M.I. Choudhary, Phytochemistry
4
0 (1995) 593.
23] R. Marek, V. Sklen a´ rˇ , J. Dost a´ l, J. Slav ´ı k, Tetrahedron Lett. 37 (1996)
655.
24] R. Marek, J. Tou sˇ ek, L. Kr a´ l ´ı k, J. Dost a´ l, V. Sklen a´ rˇ , Chem. Lett.
1997) 369.
ˇ
5] S. Man, M. Pot a´ cˇ ek, M. Ne cˇ as, Z. Z a´ k, J. Dost a´ l, Molecules 6 (2001)
[
433.
1
[
[
[
6] M.L. Contreras, S. Rivas, R. Rozas, Heterocycles 22 (1984) 101.
7] M. Shamma, M. Rahimizadeh, J. Nat. Prod. 49 (1986) 398.
ˇ
8] S. Man, J. Dost a´ l, M. Ne cˇ as, Z. Z a´ k, M. Pot a´ cˇ ek, Heterocycl.
(
25] J. Dost a´ l, E. T a´ borsk a´ , J. Slav ´ı k, M. Pot a´ cˇ ek, E. de Hoffmann, J. Nat.
Prod. 58 (1995) 723.
Commun. 7 (2001) 243.
9] J. Dost a´ l, J. Chem. Educ. 77 (2000) 993.
[
26] J. Dost a´ l, J. Slav ´ı k, M. Pot a´ cˇ ek, R. Marek, O. Humpa, V. Sklen a´ rˇ , J.
Tou sˇ ek, E. de Hoffmann, R. Rozenberg, Collect. Czech. Chem.
Commun. 63 (1998) 1045.
[
[
[
[
10] P. Se cˇ k a´ rˇ ov a´ , R. Marek, J. Dost a´ l, R. Dommisse, E.L. Esmans, Magn.
Reson. Chem. 40 (2002) 147.
ˇ
11] J. Tou sˇ ek, R. Dommisse, J. Dost a´ l, Z. Z a´ k, L. Pieters, R. Marek,
[
27] R. Marek, L. Kr a´ l ´ı k, V. Sklen a´ rˇ , Tetrahedron Lett. 38 (1997) 665.
´
J. Mol. Struct. 613 (2002) 103.
12] R. Marek, P. Se cˇ k a´ rˇ ov a´ , D. Hulov a´ , J. Marek, J. Dost a´ l, V. Sklen a´ rˇ ,
J. Nat. Prod. 66 (2003) 481.
28] R. Marek, J. Marek, J. Dostal, E. Taborska, J. Slavık, R. Dommisse,
´ ´ ´
[
Magn. Reson. Chem. 40 (2002) 687.
[29] R. Marek, O. Humpa, J. Dost a´ l, J. Slav ´ı k, V. Sklen a´ rˇ , Magn. Reson.
Chem. 37 (1999) 195.
13] R. Marek, J. Tou sˇ ek, J. Dost a´ l, J. Slav ´ı k, R. Dommisse, V. Sklen a´ rˇ ,
Magn. Reson. Chem. 37 (1999) 781.
[30] B.M. Kariuki, W. Jones, Acta Crystallogr. C51 (1995) 1234.
[31] J. Marek, D. Hulov a´ , J. Dost a´ l, R. Marek, Acta Crystallogr. C59
(2003) in press.
[
14] SHELXTL, Version 5.10, Bruker AXS Inc., Madison, WI, USA, 1997.
15] J. Slav ´ı k, L. Slav ´ı kov a´ , Collect. Czech. Chem. Commun. 60 (1995)
[
1
034.
ˇ
[32] L. Orfila, M. Rodriguez, T. Colman, M. Hasegawa, E. Merentes, F.
Arvelo, J. Ethnopharmacol. 71 (2000) 449.
[
16] V. Sim a´ nek, V. Preininger, J. Lasovsk y´ , Collect. Czech. Chem.
Commun. 41 (1976) 1050.
[33] B. Nyasse, E. Nkwengoua, B. Sondengam, C. Denier, M. Willson,
Pharmazie 57 (2002) 358.
[
17] J.W. Bunting, Adv. Heterocycl. Chem. 25 (1979) 1.