Study of alkaloids of the Siberian and Altai flora 11. Synthesis of new lappaconitine derivatives

Article abstract of DOI:10.1023/B:RUCB.0000012376.73950.84

A convenient procedure was developed for the preparation of N-deacetyllappaconitine by acid hydrolysis of lappaconitine. The crystal and molecular structures of by-products of acid hydrolysis of lappaconitine, viz., 14- and 16-demethyl-N-deacetyllappaconi

Full text of DOI:10.1023/B:RUCB.0000012376.73950.84

2500
Russian Chemical Bulletin, International Edition, Vol. 52, No. 11, pp. 2500—2506, November, 2003
Study of alkaloids of the Siberian and Altai flora
1
1.* Synthesis of new lappaconitine derivatives
N. V. Anferova, I. Yu. Bagryanskaya, Yu. V. Gatilov, S. A. Osadchii,
ꢀ
M. M. Shakirov, E. E. Shults, and G. A. Tolstikov
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
9
prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383 2) 34 4752. Eꢀmail: schultz@nioch.nsc.ru
A convenient procedure was developed for the preparation of Nꢀdeacetyllappaconitine by
acid hydrolysis of lappaconitine. The crystal and molecular structures of byꢀproducts of acid
hydrolysis of lappaconitine, viz., 14ꢀ and 16ꢀdemethylꢀNꢀdeacetyllappaconitines, were estabꢀ
lished by Xꢀray diffraction analysis. Azocoupling of diazonium chlorides that were prepared
from lappaconitine Nꢀdeacetylation products with βꢀnaphthol afforded the corresponding
1
,2ꢀnaphthoquinone 1ꢀhydrazones.
Key words: alkaloids, lappaconitine, Nꢀdeacetyllappaconitines, Xꢀray diffraction analysis,
azocoupling, βꢀnaphthol.
As part of continuing screening for antiarrhythmics in
compounds 3 and 4 are also typical of most of aconitanes.
The sixꢀmembered ring A in molecule 4 adopts a slightly
distorted boat conformation. The same conformation is
observed in lappaconine hydrobromide and tatsinine perꢀ
chlorate. According to the data from the Cambridge Strucꢀ
tural Database, the ring A in aconitanes adopts a boat
conformation in 19 of 44 structures. The ring A in comꢀ
pound 3, unlike that in compound 4, assumes a chair
conformation, which is indicative of its conformaꢀ
tional lability. The orientation of the ethyl group at the
N(20) atom in molecule 3 also differs from that in 4
(the C(17)—N(20)—C(21)—C(22) torsion angles are
–157.4(4)° and –65.6(3)°, respectively). It should be
noted that the orientation of the 2ꢀaminobenzoate group
in compound 3 is similar to that in 4 (see Fig. 1). The
amino and hydroxy groups are involved in intraꢀ and
intermolecular hydrogen bonding (Table 1).
the series of derivatives of diterpenoid alkaloid lappaꢀ
conitine (1),1 we attempted to prepare a diazo derivative
of Nꢀdeacetyllappaconitine (2) containing a fragment of
primary aromatic amine.
,2
3
Amine 2 was first prepared in 1922 under the name
picrolappaconitine in 97% yield by hydrolysis of lappaꢀ
conitine 1 with 1 M H SO . Later, compound 2 was isoꢀ
2
4
4
lated from Aconitum septentrionale Koelle (synonym
A. lycoctonum L., cf. lit. ) and from Aconitum barbatum
Pers. var. puberulum Ledeb. (under the name puberanꢀ
5
6
idine). In the present study, we synthesized compound 2
by hydrolysis of lappaconitine 1 with concentrated HCl.
As a result, we prepared the target product 2, 16ꢀdemethylꢀ
Nꢀdeacetyllappaconitine (3), and 14ꢀdemethylꢀNꢀdeꢀ
acetyllappaconitine (4) in 46, 17, and 9% yields, respecꢀ
tively (Scheme 1).
The crystal and molecular structures of compounds 3
and 4 were established by Xꢀray diffraction analysis
The structures of compounds 3 and 4 were confirmed
13
also by comparing the data from their C NMR spectra
13
(
Fig. 1). The bond lengths and bond angles in molecules 3
with the C NMR spectroscopic data for compound 2. It
and 4 are identical within 3σ and are close to the standard
should be noted that the chemical shifts of the signals for
7
13
values. Of 51 structures with the aconitane skeleton availꢀ
the C(2), C(6), C(10), C(12), and C(13) atoms in the
C
8
able in the Cambridge Structural Database, only three
NMR spectrum of Nꢀdeacetyllappaconitine 2 reported
9
6
compounds, viz., lappaconine hydrobromide, tatsinine
earlier were assigned incorrectly. Taking into account
perchlorate,10 and excelsine hydroiodide, contain a subꢀ
11
the C NMR spectroscopic data for the model comꢀ
13
stituent OR at position 9. The conformations of the rings B
pound, viz., lappaconitine 1, which were obtained using
the C— C 2DꢀINADEQUATE NMR spectroscopy,
13
13
1
(
chair), C (envelope), and F (envelope) are determined
by the character of junction and are identical in all
aconitanes. The flattened boat conformation of the ring D
and the chair conformation of the piperidine ring E in
we assigned the signals for the carbon atoms in compound
2 by interchanging the chemical shifts for the carbon atꢀ
oms with the respective multiplicities (Table 2). The asꢀ
signments of the signals of the aconitane fragment in the
13
*
For Part 10, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2363—2369, November, 2003.
066ꢀ5285/03/5211ꢀ2500 $25.00 © 2003 Plenum Publishing Corporation
C NMR spectra of compounds 3 and 4 were made by
1

Alkaloids of the Siberian and Altai flora
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003 2501
Scheme 1
1
2
2
3
4
, 5, 8: R = R = Me
1
2
, 6, 9: R = H, R = Me
1
2
, 7, 10: R = Me, R = H
Reagents and conditions: i. HCl (conc.), 90—95 °C, 1 h; ii. 1) HCl; 2) NaNO , 0—5 °C; 3) βꢀnaphthol, NaOH, NaOAc.
2
comparing these spectra with the 13C NMR spectra of
compound 2 taking into account the upfield shifts of the
signals for the carbon atoms bearing the OH groups by
δ ∼ 9.4—9.8 compared to the signals for the carbon atoms
bearing the OMe groups.
Scheme 2
Alkaline hydrolysis of compounds 3 and 4 afforded
1
6ꢀ and 14ꢀdemethyllappaconines (11 and 12, respecꢀ
tively) (Scheme 2). 1ꢀDemethyllappaconine known unꢀ
der the name lappaconidine was isolated from Aconitum
septentrionale Koelle.12
NꢀDeacetyllappaconitine 2 was subjected to diazotiꢀ
zation. To prove the formation of the diazonium salt, we
carried out azocoupling with βꢀnaphthol in an alkaline
buffer (NaOH, NaOAc), which gave rise to hydrazone
(
see Scheme 1). Apparently, the latter was derived from
intermediate azo compound 5 due to the electron density
redistribution in the conjugated polyunsaturated system.
Diazotization of a mixture of compounds 2—4, which
was prepared by hydrolysis of lappaconitine 1, followed
by azocoupling with βꢀnaphthol under analogous condiꢀ
tions afforded a mixture of the corresponding hydrazones
, 11: R1 = H, R = Me
2
3
4
1
2
, 12: R = Me, R = H
8
—10 derived apparently from intermediate azo comꢀ
pounds 5—7. Individual hydrazones 8—10 were isolated
i. NaOH, EtOH, 95 °C, 2 h.

2502
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003
Anferova et al.
a
C(24)
C(13)
C(9)
C(14)
C(23)
C(12)
O(14)
O(16)
O(1)
C(10)
C(16)
C(15)
C(1)
O(9)
C(11)
C(2)
C(17)
C(5)
N(20)
C(8)
C(7)
O(8)
b
C(3)
C(6)
C(13) C(14)
C(9)
C(4)
O(4)
C(12)
C(23)
O(14)
O(16)
C(19)
C(21)
C(10)
O(1)
C(11)
C(18)
C(1)
C(16)
C(15)
C(24)
C(22)
C(6´)
O(9)
C(2)
C(3)
O(18)
C(1´)
C(17)
C(6)
C(8)
C(7)
C(22)
C(21)
C(5´)
C(5)
N(20)
O(8)
C(2´)
C(4)
O(4)
C(18)
C(4´)
C(19)
N(2´)
C(3´)
O(18)
C(1´)
C(2´)
C(6´)
Torsion angle
ω/deg
C(5´)
3
4
N(2´)
C(3)—C(4)—O(4)—C(18)
C(4)—O(4)—C(18)—C(1´)
O(4)—C(18)—C(1´)—C(2´) –179.4(4)
77.6(5)
167.0(3) –175.0(2)
177.3(2)
62.4(3)
C(4´)
C(3´)
Fig. 1. Threeꢀdimensional structures of molecules 3 (a) and 4 (b) determined by Xꢀray diffraction analysis.
by chromatography, their bright red color allowing one to
visually follow the course of chromatography.
Scheme 3
To assign the signals for the hydrogen and carbon
1
atoms of the polyunsaturated fragments in the H and
1
3
C NMR spectra of hydrazones 8—10, we synthesized a
model compound, viz., hydrazone 13, by azocoupling of
diazonium chloride prepared from methyl anthranilate 14
with βꢀnaphthol (Scheme 3).
The conclusion about the formation of 1,2ꢀnaphthoꢀ
quinone derivatives (compounds 8—10 and 13) was made
based on the chemical shifts of the C atoms of the naphꢀ
i. 1) HCl; 2) NaNO , 0—5 °C; 3) βꢀnaphthol, NaOH, NaOAc.
2
pounds of the type 5, the expected chemical shifts of the
C(2″) atom bound to the phenolic hydroxy group should
13
thyl fragments in the C NMR spectra. For azo comꢀ

Alkaloids of the Siberian and Altai flora
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003 2503
Table 1. Distances and hydrogen bond angles in the crystals of 3 and 4
Distance
d/Å
Distance
d/Å
Angle
ω/deg
3
4
3
4
3
4
N(2´)—H(2´A)
N(2´)—H(2´B)
O(8)—H(8A)
O(9)—H(9A)
O(14)—H(14B)
O(16)—H(16B)
0.88(6)
—
0.82(6)
0.83(6)
—
0.80(3)
0.91(4)
0.77(7)
1.02(4)
0.89(7)
—
H(2´A)...O(18)
H(8A)...O(14)
H(8A)...O(16)
H(9A)...O(8)
H(2´B)...O(16)
H(14B)...O(1)
H(16B)...O(9)
2.06(6)
2.46(6)
2.35(7)
2.13(6)
—
2.08(4)
2.38(6)
—
2.03(4)
2.35(4)
2.14(7)
—
N(2´)—H(2´A)...O(18)
N(2´)—H(2´B)...O(16)
O(8)—H(8A)...O(14)
126(5)
—
118(6)
146(6)
122(5)
—
137(3)
162(4)
134(6)
—
116(3)
150(5)
—
#
1
#
2
O(8)—H(8A)...O(16)
O(9)—H(9A)...O(8)
#
#
3
4
0.98(7)
—
2.15(7)
O(14)—H(14B)...O(1)
O(16)—H(16B)...O(9)
157(5)
Note. Symmetry transformations: #1 x, y – 1, z – 1; #2 –x – 1, y – 1/2, –z + 3/2; #3 x, y + 1, z; #4 x – 1, y, z.
Table 2. 13C NMR spectra of compounds 2—4 and 8—13
Atom
δ
2
3
4
8
9
10
11
12
13
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
83.1
26.9
32.1
84.6
48.6
24.2
47.7
75.7
78.6
49.0
51.0
26.4
36.9
90.3
44.9
83.0
61.6
55.7
50.1
13.6
56.3
57.9
56.1
167.7
112.2
150.6
116.8
134.1
116.4
131.6
—
84.4
26.5
31.8
84.4
48.5
24.0
47.9
75.4
78.4
49.3
50.6
25.5
40.1
91. 0
47.3
73.2
61.5
55.6
48.8
13.4
56.4
58.9
—
167.2
111.8
150.3
116.5
133.7
116.1
131.4
—
—
—
—
—
84.7
26.4
31.9
83.0
49.7
24.0
48.6
75.1
78.9
48.6
50.7
25.3
38.0
80.9
42.5
82.5
61.9
55.8
48.9
13.5
56.3
—
56.2
167.3
112.0
150.3
116.6
133.7
116.2
131.5
—
84.2
26.8
31.8
84.1
49.8
24.0
47.7
75.6
78.5
48.7
50.9
26.2
36.4
90.1
44.7
82.9
61.1
84.3
26.6
31.7
84.2
49.4
24.0
48.0
75.4
78.4
48.5
50.8
25.6
40.2
91.0
47.3
73.3
61.2
55.4
48.8
13.5
56.3
58.8
—
165.2
117.3
144.7
131.3
133.7
123.7
116.3
133.8
179.9
127.2
142.1
128.4
122.3
129.1
126.6
128.7
131.3
—
84.5
26.4
31.7
84.2
49.8
23.9
48.5
75.0
78.7
48.6
50.8
25.4
38.1
80.6
42.4
82.5
61.5
55.4
48.8
13.5
56.3
—
56.2
165.1
117.2
144.6
131.2
133.7
123.7
116.2
133.8
179.8
127.1
142.1
128.3
122.2
129.0
126.5
128.6
131.1
—
85.0
26.5
37.1
71.0
50.5
23.5
48.0
75.4
78.4
49.2
50.7
25.7
40.0
91.1
47.2
73.2
61.6
57.8
48.8
13.4
56.3
59.0
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
85.2
26.6
37.1
70.8
50.4
23.5
48.7
74.9
78.8
49.9
50.8
25.9
38.3
80.2
42.2
82.8
61.8
57.8
48.9
13.4
56.3
—
56.3
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
C(9)
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
C(17)
C(19)
NCH2
Me
55.3
48.7
13.4
56.2
57.7
55.9
—
—
—
—
—
—
1
1
1
ꢀOMe
4ꢀOMe
6ꢀOMe
OC=O
C(1´)
C(2´)
C(3´)
C(4´)
C(5´)
C(6´)
C(1″)
C(2″)
C(3″)
C(4″)
C(4a″)
C(5″)
C(6″)
C(7″)
C(8″)
C(8a″)
OCOMe
165.2
117.4
144.7
131.3
133.7
123.8
116.3
133.9
179.8
127.2
142.1
128.4
122.3
129.0
126.6
128.7
131.2
—
166.3
115.9
144.2
131.1
133.9
123.6
116.1
133.6
179.8
128.0
142.0
128.3
122.2
128.9
126.5
128.5
131.1
52.2
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—

2504
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003
Anferova et al.
appear at δ ∼ 150±10. The observed chemical shifts of the
C(2″) atoms for compounds 8—10 and 13 are in the range
δ 179.75—179.86, i.e., are close to the expected chemical
shifts for the carbon atoms of the carbonyl groups in conꢀ
separation in the UV light. Plates (30×30 cm) with thickness of a
i
sorbent layer of 2 mm and the Pr OH—Et O solvent system
2
(
1 : 9, v/v) were used.
Analytical TLC was performed using glass plates of dimenꢀ
sions 7.5×7.5 cm with a sorbent layer (0.04 g cm–2) of neutral
Al O , 5/40 µm (Chemapol, Czech Republic) containing 1 wt.%
1
3
jugated systems (cf. lit. ).
2
3
To summarize, a convenient procedure was developed
for the synthesis of Nꢀdeacetyllappaconitine by acid hyꢀ
drolysis of lappaconitine. It was established that this reꢀ
sulted in the cleavage of both the amide and ether bonds
to form the target product and byꢀproducts, viz., deꢀ
methylated Nꢀdeacetyllappaconitines. The crystal and
molecular structures of the byꢀproducts were established
by Xꢀray diffraction analysis, which unambiguously demꢀ
onstrated that these compounds are 14ꢀ and 16ꢀdemethylꢀ
Nꢀdeacetyllappaconitines. Azocoupling of diazonium
chlorides prepared from Nꢀdeacetylation products of
lappaconitines with βꢀnaphthol afforded the correspondꢀ
ing 1,2ꢀnaphthoquinone 1ꢀhydrazones.
of luminophore Kꢀ35 (Russia) and 1% of Na CO , which were
2
3
2
prepared according to a procedure described earlier. Chroꢀ
matographic bands of alkaloids were detected by irradiation of a
dried plate with UV light and were also visualized with iodine
vapor.
Lappaconitine 1 used in the study had physicochemical and
1
spectroscopic characteristics described earlier.
The molecular weights and elemental compositions of the
new compounds were determined on a Finnigan MAT (MS 8200
model) highꢀresolution mass spectrometer (EI, 70 eV).
Xꢀray diffraction study was performed on a Syntex P21
diffractometer (CuꢀKα radiation, graphite monochromator,
2θ/θ scanning technique in the range 2θ < 140°). The empirical
absorption corrections were applied based on Psi scans. The
structures were solved by direct methods using the SHELXSꢀ97
program package. The coordinates of the hydrogen atoms were
revealed from difference electron density syntheses. The strucꢀ
Experimental
2
tures were refined based on all F by the fullꢀmatrix leastꢀsquares
The IR spectra were recorded on a Vector 22 spectrometer.
The UV spectra were measured on a Specord UVꢀVIS spectroꢀ
photometer. The H and C NMR spectra of compounds 3, 4,
method with anisotropic and isotropic thermal parameters for
nonhydrogen and hydrogen atoms, respectively, using the
SHELXLꢀ97 program package.
1
13
14
and 8—12 were recorded for 10% solutions in CDCl on a Bruker
ACꢀ200 instrument (200.13 MHz for H and 50.32 MHz for C)
The atomic coordinates and thermal parameters were deꢀ
posited with the Cambridge Structural Database (refcodes
CCDC 214892 and CCDC 214893 for compounds 3 and 4,
respectively).
3
1
13
1
13
and the H and C NMR spectra of compound 13 were meaꢀ
1
sured on a Bruker DRX 500 instrument (500.13 MHz for H and
25.76 MHz for C) at 25 °C with resonance stabilization based
on the signal for deuterium of the solvent. The 2D H— H
COSY and 2D C— H NMR spectra (125 Hz for HCꢀCOSY
and 10 Hz for COLOC) were measured on a Bruker DRX 500
instrument. The spectra were recorded using the standard Bruker
software. The chemical shifts (δ) were measured with respect to
13
1
Crystals of compound 3 are orthorhombic: at T = 296 K,
1
1
3
a = 7.830(2), b = 9.252(2), c = 35.530(7) Å, V = 2573.9(9) Å ,
13
1
space group P2 2 2 , Z = 4. C H N O . M = 528.63, d
=
1
1
1
29 40
2
7
calc
1.364 g cm–3, λ = 1.54178 Å, µ = 0.794 mm , transmisꢀ
sion 0.57—0.92, 2834 independent reflections with 2θ < 140°,
wR2 = 0.1160, S = 1.039, 504 parameters were refined
(R = 0.0470 for 2112 F > 4σ).
–1
the signals of CHCl3 as the internal standard (δ 7.24 and
H
δC 76.90). The multiplicities of signals in the 13C NMR spectra
were determined according to standard procedures using J moduꢀ
lation (JMOD) and offꢀresonance irradiation of protons. Due to
Crystals of compound 4 are monoclinic: at T = 296 K,
a = 11.344(3), b = 8.821(2), c = 12.995(2) Å, β = 98.83(2)°, V =
3
1284.9(5) Å , space group P2 , Z = 2. C H N O . M = 528.63,
1
29 40
2
7
1
–3
–1
the difficulties of assigning all signals in the H NMR spectra of
dcalc = 1.366 g cm , λ = 1.54178 Å, µ = 0.795 mm , transmisꢀ
sion 0.64—0.92, 2588 independent reflections with 2θ < 140°,
wR2 = 0.0976, S = 1.032, 509 parameters were refined
(R = 0.0368 for 2447 F > 4σ). The C(2) atom is disordered over
two positions, which are denoted as C(2) and C(2A), in a ratio
of 0.81(1) : 0.19(1), respectively. The presence of C(2A) is inꢀ
dicative of a small contribution of the chair conformation of
the ring A.
the compounds described for the first time, only the characterisꢀ
tic signals are given. The 13C NMR spectroscopic data are preꢀ
1
sented in Table 2. The assignments of the signals in the H and
1
3
C NMR spectra of compound 13 were made using the correlaꢀ
1
1
13
1
tion 2D H— H COSY and 2D C— H (125 Hz for HCꢀCOSY
and 10 Hz for COLOC) experiments.
The optical rotation was measured on a Polamat A polarimꢀ
eter (Carl Zeiss, λ = 578 nm). The specific rotation is given in
Hydrolysis of lappaconitine (1). A solution of lappaconitine 1
(4.38 g, 7.5 mmol) in concentrated HCl (d = 1.19) (7.5 mL) was
heated with stirring at 95—100 °C for 1 h and then cooled
to 20 °C. The solution was diluted with water (15 mL) and
–
1
(
deg mL) (g dm) . The concentrations of solutions are given
–
1
in g (100 mL)
.
The melting points were measured on a Kofler hotꢀstage
apparatus.
Freshly distilled solvents and reagents of "pure" grade
were used.
filtered. A 25% aqueous NH was added to the filtrate to pH 8.
3
The reaction mixture was extracted with CHCl (4×10 mL), the
3
extract was concentrated in vacuo, and the residue was dried at
50 °C (3 Torr). A mixture of compounds was obtained as an
amorphous powder in a yield of 4.00 g. The mixture was subꢀ
jected to preparative TLC. Three zones of the sorbent, which
Preparative TLC was carried out on Al O3 (50—250 µm,
2
Russia), which was activated at 250 °C for 6 h and then deactiꢀ
vated to the Brockmann activity II by adding 3% of water. This
sorbent was mixed with luminophore Kꢀ35 (1 wt.%, Russia) to
enhance the sensitivity of visual control over the process of
showed blue fluorescence under UV light, with R 0.86, 0.45,
f
and 0.05 were collected; these zones correspond to individual

Alkaloids of the Siberian and Altai flora
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003 2505
compounds 2, 3, and 4, respectively. The target compounds
were eluted with methanol and the eluates were concentrated.
The yields of crystalline compounds 2, 3, and 4 were 1.86, 0.67,
and 0.36 g (46, 17, and 9%), respectively.
2819, 2927, 2965. UV (EtOH), λmax/nm (log ε): 225 (4.54), 289
(3.92), 300 (3.89), 482(4.22).
Synthesis of hydrazones 8—10. Diazotization was carried
out using an amorphous powder of a mixture of hydrolysis prodꢀ
ucts of lappaconitine 1. A mixture of compounds 2, 3, and 4 in a
ratio of ∼ 5 : 2 : 1 (0.543 g) was subjected to diazotization folꢀ
NꢀDeacetyllappaconitine (2). Rectangular plateletꢀlike
3
4
crystals (cf. lit. ), m.p. 218—220 °C (MeOH) (cf. lit. : m.p.
2
0
2
(
09—214 °C (acetone—hexane)), [α]
cf. lit. : [α]D +23.2 (c 0.9, CHCl )). The H and C NMR
3
spectra are identical with those published in the literature.
+20.8 (c 4.9, CHCl )
lowed by azocoupling with βꢀnaphthol under the aboveꢀdescribed
conditions. The chloroform extract containing a mixture of comꢀ
pounds 8—10 was subjected to preparative TLC on Al O . Three
5
78
3
6
20
1
13
4
,6
2
3
4
ꢀOꢀ(2ꢀAminobenzoyl)ꢀ20ꢀethylꢀ1α ,14α ꢀdimethoxyacoꢀ
red zones of the sorbent with R 0.85, 0.45, and 0.05 correspondꢀ
f
nitaneꢀ4,8,9,16βꢀtetrol, 16ꢀdemethylꢀNꢀdeacetyllappaconitine
ing to individual compounds 8, 9, and 10, respectively, were
collected. The target compounds were eluted with methanol.
The methanolic solutions were concentrated and then crystals
of compounds 8—10 were separated and dried. The yield were
0.208, 0.104, and 0.056 g, respectively.
(
[
3), m.p. 256—258 °C (with decomp., from MeOH),
α]57820 +20.4 (c 1.5, CHCl ). H NMR, δ: 1.08 (t, 3 H,
1
3
NCH Me, J = 7 Hz); 3.25 and 3.49 (both s, 3 H each, 1ꢀ and
2
1
7
4ꢀOMe); 5.61 (br.s, 2 H, NH ); 6.57 (m, 2 H, H(4´), H(6´));
2
.19 (t, 1 H, H(5´), J = 8 Hz); 7.73 (d, 1 H, H(3´), J = 8 Hz).
4ꢀOꢀ{2ꢀ[2ꢀ(2ꢀOxoꢀ1,2ꢀdihydronaphthalenꢀ1ꢀylidene)hydrꢀ
azino]benzoyl}ꢀ20ꢀethylꢀ1α,14α ꢀdimethoxyaconitaneꢀ4,8,9,16βꢀ
tetrol (9), red crystals, m.p. 198—200 °C (with decomp.).
Found (%): C, 65.46; H, 6.66; N, 5.77. C H N O •1.5 H O.
–
1
IR (KBr), ν/cm : 753, 995, 1041, 1098, 1147, 1210, 1244,
298, 1321, 1363, 1381, 1454, 1488, 1560, 1586, 1617, 1684
C=O), 2822, 2864, 2917, 2935, 2970, 3383 (NH), 3499 (OH).
UV (EtOH), λmax/nm (log ε): 219 (4.45), 248 (3.90), 338 (3.74).
ꢀOꢀ(2ꢀAminobenzoyl)ꢀ20ꢀethylꢀ1α ,16βꢀdimethoxyacoꢀ
nitaneꢀ4,8,9,14α ꢀtetrol, 14ꢀdemethylꢀNꢀdeacetyllappaconitine
1
(
3
9
45
3
8
2
1
Calculated (%): C, 65.89; H, 6.82; N, 5.91. H NMR, δ: 1.09 (t,
4
3 H, NCH Me, J = 7 Hz); 3.25 and 3.48 (both s, 3 H each,
2
1ꢀ and 14ꢀOMe); 6.68 (d, 1 H, H(3″), J = 10 Hz); 7.12 (t, 1 H,
H(4´), J = 8 Hz); 7.32 (t, 1 H, H(7″), J = 8 Hz); 7.44 (m, 2 H,
H(8″), H(6″)); 7.57 (m, 2 H, H(4″), H(5´)); 7.94 (d, 1 H, H(3´),
J = 7.5 Hz); 8.27 (d, 1 H, H(6´), J = 8 Hz); 8.38 (d, 1 H, H(5″),
J = 8 Hz). IR (KBr), ν/cm– : 754, 840, 1045, 1081, 1096,
1134, 1155, 1197, 1267, 1319, 1380, 1399, 1447, 1480, 1492,
1571, 1622, 1701 (C=O), 2820, 2927, 2965. UV (EtOH),
λmax/nm (log ε): 225 (4.58 sh), 289 (3.97), 300 (3.95), 485 (4.23).
4ꢀOꢀ{2ꢀ[2ꢀ(2ꢀOxoꢀ1,2ꢀdihydronaphthalenꢀ1ꢀylidene)hydrꢀ
azino]benzoyl}ꢀ20ꢀethylꢀ1α,16βꢀdimethoxyaconitaneꢀ4,8,9,14αꢀ
tetrol (10), red crystals, m.p. 192—194 °C (with decomp.).
Found (%): C, 64.47; H, 6.38; N, 5.70. C H N O •2.5H O.
(
[
4), m.p. 236—238 °C (with decomp., from MeOH),
α]57820 +22.0 (c 1.3, CHCl ). H NMR, δ: 1.08 (t, 3 H,
1
3
NCH Me, J = 7 Hz); 3.24 and 3.30 (both s, 3 H each, 1ꢀ and
2
1
1
6ꢀOMe); 5.61 (s, 2 H, NH ); 6.57 (m, 2 H, H(4´), H(6´)); 7.19
2
(
t, 1 H, H(5´), J = 8 Hz); 7.73 (d, 1 H, H(3´), J = 8 Hz).
–
1
IR (KBr), ν/cm : 756, 1077, 1111, 1145, 1178, 1232, 1254,
1
2
300, 1322, 1377, 1455, 1490, 1585, 1614, 1679 (C=O),
874, 2902, 2924, 2957, 3361 (NH), 3471 (OH). UV (EtOH),
λmax/nm (log ε): 219 (4.41), 248 (3.86), 338 (3.70).
ꢀOꢀ{2ꢀ[2ꢀ(2ꢀOxoꢀ1,2ꢀdihydronaphthalenꢀ1ꢀylidene)hydrꢀ
azino]benzoyl}ꢀ20ꢀethylꢀ1α ,14α ,16βꢀtrimethoxyaconitaneꢀ
,8,9ꢀtriol (8). A solution of NaNO (0.103 g, 1.49 mmol) in
4
3
9
45
3
8
2
1
4
Calculated (%): C, 64.26; H, 6.93; N, 5.77. H NMR, δ: 1.09 (t,
2
water (2 mL) cooled to 5 °C was gradually added to a solution of
compound 2 (0.543 g, 1 mmol) in 16% HCl (4.73 mmol, 1 mL)
cooled to 5 °C. After 5 min, an iodideꢀstarch paper test for the
presence of HNO2 in the solution was positive. βꢀNaphthol
3 H, NCH Me, J = 7 Hz); 3.23 and 3.29 (both s, 3 H each,
2
1ꢀ and 16ꢀOMe); 6.67 (d, 1 H, H(3″), J = 10 Hz); 7.10 (t, 1 H,
H(4´), J = 8 Hz); 7.29 (t, 1 H, H(7″), J = 8 Hz), 7.42 (m, 2 H,
H(8″), H(6″)); 7.55 (m, 2 H, H(4″), H(5´)); 7.92 (d, 1 H, H(3´),
J = 7.5 Hz); 8.23 (d, 1 H, H(6´), J = 8 Hz); 8.34 (d, 1 H, H(5″),
J = 8 Hz). IR (KBr), ν/cm– : 755, 841, 987, 1045, 1081,
1095, 1135, 1155, 1196, 1267, 1318, 1382, 1399, 1447, 1480,
1491, 1571, 1621, 1700 (C=O), 2820, 2928. UV (EtOH),
λmax/nm (log ε): 225 (4.49), 289 (3.87), 300 (3.84), 482 (4.16).
20ꢀEthylꢀ1α ,14α ꢀdimethoxyaconitaneꢀ4,8,9,16βꢀtetrol,
16ꢀdemethyllappaconine (11). A solution of NaOH (0.056 g,
1.4 mmol) in water (0.2 mL) was added dropwise with stirring to
a solution of compound 3 (0.212 g, 0.4 mmol) in EtOH (2.8 mL)
and the reaction mixture was heated at 95—100 °C for 2 h. The
solvent was distilled off, the residue was extracted with chloroꢀ
form, and the extract was concentrated. The residue was exꢀ
tracted with water (4×0.6 mL) and the extract was centrifuged
(5 min, 5000 rpm). Water was removed from the supernatant to
yield 0.120 g (74%) of product 11 as an amorphous powder. Highꢀ
(
4
0.144 g, 1 mmol) was suspended in a solution of NaOH (0.194 g,
.85 mmol) in water (0.5 mL) and then mixed with a solution of
1
AcONa (0.9 g, 11 mmol) in water (3.6 mL). The resulting mixꢀ
ture was heated to 40 °C until the βꢀnaphthol dissolved and then
cooled to 5 °C. Then a diazo solution cooled to 5 °C was added
dropwise with stirring. The red reaction mixture was kept at
2
0 °C for 0.5 h. The red precipitate that formed was extracted
with CHCl (4×4 mL). The extract was concentrated in vacuo to
3
2
mL and subjected to preparative TLC on Al O . The red zone
2 3
of the sorbent with R 0.85 corresponding to compound 8 was
f
collected. The target product was eluted with methanol. The
methanolic solution was concentrated and the crystals that
formed were separated and dried. The yield was 0.672 g (95%),
m.p. 190—192 °C (with decomp.). Found (%): C, 68.10; H, 6.88;
N, 5.88. C H N O •0.5 H O. Calculated (%): C, 67.96; H,
4
0
47
3
8
2
1
6
3
.86; N, 5.95. H NMR, δ: 1.09 (t, 3 H, NCH Me, J = 7 Hz);
resolution mass spectrum. Found: m/z 409.2464. C H NO .
2
22 35 6
1
.26, 3.28, and 3.38 (all s, 3 H each, 1ꢀ, 14ꢀ, and 16ꢀOMe); 6.68
Calculated: M = 409.2464. H NMR, δ: 1.03 (t, 3 H, NCH Me,
2
(
(
2
1
d, 1 H, H(3″), J = 10 Hz); 7.11 (t, 1 H, H(4´), J = 8 Hz); 7.32
t, 1 H, H(7″), J = 8 Hz); 7.43 (m, 2 H, H(8″), H(6″)), 7.55 (m,
J = 7 Hz); 3.22 and 3.47 (both s, 3 H each, 1ꢀ and 14ꢀOMe).
IR (KBr), ν/cm– : 961, 1052, 1077, 1118, 1152, 1197, 1363,
1382, 1451, 2820, 2925, 3427 (OH).
20ꢀEthylꢀ1α ,16βꢀdimethoxyaconitaneꢀ4,8,9,16α ꢀtetrol,
14ꢀdemethyllappaconine (12). Compound 12 was prepared analoꢀ
gously by refluxing compound 4 in an aqueousꢀmethanolic soluꢀ
1
H, H(4″), H(5´)); 7.94 (d, 1 H, H(3´), J = 7.5 Hz); 8.26 (d,
H, H(6´), J = 8 Hz); 8.38 (d, 1 H, H(5″), J = 8 Hz). IR (KBr),
–
1
ν/cm : 754, 843, 1081, 1094, 1134, 1155, 1197, 1267, 1318,
383, 1399, 1447, 1480, 1492, 1572, 1601, 1623, 1702 (C=O),
1

2506
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003
Anferova et al.
tion of NaOH for 6 h. An amorphous powder, yield 75%. Highꢀ
Izv. Akad. Nauk, Ser. Khim., 2003, 2354 [Russ. Chem. Bull.,
Int. Ed., 2003, 52, 2490].
2. S. A. Osadchii, N. A. Pankrushina, M. M. Shakirov,
E. E. Shults, and G. A. Tolstikov, Izv. Akad. Nauk,
Ser. Khim., 2000, 552 [Russ. Chem. Bull., Int. Ed., 2000,
49, 557].
resolution mass spectrum. Found: m/z 409.2473. C H NO .
2
2
35
6
1
Calculated: M = 409.2464. H NMR, δ: 1.02 (t, 3 H, NCH Me,
2
J = 7 Hz); 3.21 and 3.27 (both s, 3 H each, 1ꢀ and 16ꢀOMe).
–
1
IR (KBr), ν/cm : 924, 958, 986, 1087, 1120, 1154, 1197, 1298,
1
378, 1451, 1494, 1612, 2534, 2818, 2928, 3424 (OH).
Methyl 2ꢀ[2ꢀ(2ꢀoxoꢀ1,2ꢀdihydronaphthalenꢀ1ꢀylidene)hydrꢀ
3. H. Schulze, Arch. Pharm. Ber. Deutsch. Pharm. Ges., 1922,
260, 230.
azino]benzoate (13). Methyl anthranilate 14 (0.453 g, 3 mmol)
was subjected to diazotization followed by azocoupling with
βꢀnaphthol (0.432 g, 3 mmol) under the conditions of the synꢀ
thesis of hydrazone 8. The target product was extracted from the
reaction mixture with chloroform (6×15 mL). After removal of
the solvent, the extract was filtered and compound 13 was obꢀ
tained in a yield of 0.402 g (44%) as red crystals, m.p. 176—178 °C
4. L. Marion, L. Fonzes, C. K. Wilkins, J. P. Boca, F. Sandberg,
R. Thorsen, and E. Linden, Can. J. Chem., 1967, 45, 969.
5. (a) N. N. Tsvelev, Opredelitel´ sosudistykh rastenii Severoꢀ
Zapadnoi Rossii [Identifier for Vascular Plants of Northernꢀ
West Russia], Izdꢀvo SPKhFA, SanktꢀPeterburg, 2000, 280
(in Russian); (b) A. A. Isangulova, Ph. D. (Biol.) Thesis,
Ufa, 2003 (in Russian).
(
with decomp., from CHCl ). Highꢀresolution mass spectrum.
3
Found: m/z 306.1004. C H N O . Calculated: M = 306.1004.
6. D. Yu and B. C. Das, Planta Medica, 1983, 49, 85.
7. F. H. Allen, O. Kenard, D. G. Watson, L. Bramer, A. G.
Orpen, and R. Taylor, J. Chem. Soc., Perkin Trans. 2,
1987, S1.
18
14
2
3
1
H NMR, δ: 3.99 (s, 3 H, OMe); 6.58 (d, 1 H, H(3″), J = 10 Hz,
ν1/2 1.0 Hz); 7.07 (td, 1 H, H(4´), J = 8 Hz, J = 1.5 Hz); 7.24
td, 1 H, H(7″), J = 8 Hz, J = 1.5 Hz); 7.33 (dd, 1 H, H(8″), J =
∆
(
8
7
Hz, J = 1.5 Hz); 7.38 (td, 1 H, H(6″), J = 8 Hz, J = 1.5 Hz);
.47 (d, 1 H, H(4″), J = 10 Hz, ∆ν1/2 1.5 Hz); 7.51 (tdd, 1 H,
8. F. H. Allen, Acta Crystallogr., Sect. B, 2002, 58, 380.
9. G. I. Birnbaum, Acta Crystallogr., Sect. B, 1970, 26, 755.
10. J. A. Maddry, M. G. Newton, and S. W. Pelletier, J. Nat.
Prod., 1986, 49, 674.
11. S.ꢀM. Nasirov, V. G. Andrianov, Yu. T. Struchkov,
V. A. Tel´nov, M. S. Yunusov, and S. Yu. Yunusov, Khim.
Prirod. Soedin., 1974, 812 [Chem. Nat. Compd., 1974 (Engl.
Transl.)].
H(5´) J = 8 Hz, J = 2 Hz); 7.96 (dd, 1 H, H(3´), J = 7.5 Hz, J =
2
8
1
1
Hz); 8.16 (d, 1 H, H(6´), J = 8 Hz); 8.25 (d, 1 H, H(5″), J =
Hz). IR (KBr), ν/cm–1: 505, 694, 753, 779, 840, 871, 986,
081, 1093, 1132, 1151, 1196, 1217, 1262, 1321, 1401, 1446,
481, 1492, 1572, 1600, 1624, 1706 (C=O), 2852, 2945, 3028.
UV (EtOH), λmax/nm (log ε): 225 (4.68), 253 (4.10), 288 (4.09),
3
01 (4.07), 484 (4.41).
12. S. W. Pelletier, N. V. Mody, and R. S. Sawhney, Can.
J. Chem., 1979, 57, 1652.
We thank the Russian Foundation for Basic Research
13. L. A. Fedorov, Spektroskopiya YaMR organicheskikh
analiticheskikh reagentov i ikh kompleksov s ionami metallov,
[NMR Spectroscopy of Organic Analytical Reagents and Their
Complexes with Metal Ions], Nauka, Moscow, 1987, 296 pp.
for paying for the license for the Cambridge Structural
Database (Project No. 02ꢀ07ꢀ90322). This study was fiꢀ
nancially supported by the Russian Foundation for Basic
Research (Project Nos. 01ꢀ03ꢀ32431 and 02ꢀ07ꢀ90322).
(
in Russian).
1
4. G. M. Sheldrick, SHELXLꢀ97 Program for Crystal Strucꢀ
ture Refinement, Göttingen University, Göttingen (Gerꢀ
many), 1997.
References
1
. N. A. Pankrushina, I. A. Nikitina, N. V. Anferova, S. A.
Osadchii, M. M. Shakirov, E. E. Shults, and G. A. Tolstikov,
Received April 28, 2003