Synthesis and stereochemistry of new N-substituted cytisine derivatives

Article abstract of DOI:10.1023/A:1013778703658

A series of new N-substituted cytisine derivatives was synthesized. The ¹H and ¹³C NMR spectra of certain compounds exhibit a doubled set of signals. This is explained by formation of diastereomeric pairs in compounds containing an asymmetric center in the substituents. The signal splitting in -COHC=CHCO₂H and HC=O (formyl) derivatives is explained by the existence of Z and E invertomers. Their stereochemical features are discussed. Amide conjugation is confirmed by temperature experiments.

Full text of DOI:10.1023/A:1013778703658

Chemistry of Natural Compounds, Vol. 37, No. 4, 2001
SYNTHESIS AND STEREOCHEMISTRY OF NEW
N-SUBSTITUTED CYTISINE DERIVATIVES
T. V. Khakimova, O. A. Pukhlyakova, G. A. Shavaleeva,
UDC 547.94;543422.25;541.620;
547.834.2;547.514.472.1
A. A. Fatykhov, E. V. Vasil
eva, and L. V. Spirikhin
A series of new N-substituted cytisine derivatives was synthesized. The 1H and 13C NMR spectra of certain
compounds exhibit a doubled set of signals. This is explained by formation of diastereomeric pairs in
compounds containing an asymmetric center in the substituents. The signal splitting in -COHC CHCO H
2
and HC O (formyl) derivatives is explained by the existence of Z and E invertomers. Their stereochemical
features are discussed. Amide conjugation is confirmed by temperature experiments.
Key words: cytisine, derivatives, amide conjugation, 1H and 13C NMR spectra.
The alkaloid cytisine is a representative of natural 3,7-diazabicyclo[3.3.1]nonanes. It is used in medicine [1] because
it possesses a wide spectrum of biological activity. Its derivatives are interesting for studying the biological activity of chiral
3,7-diazabicyclo[3.3.1]nonanes and in structural studies.
We synthesized a series of N-substituted cytisines: N-methylcytisine (1) [2], N-allylcytisine (2), N-formylcytisine (3a
and b), dimethyl-2-(N-cytisinyl)succinate [3] (4a and b), N-( -nitrilopropyl)-cytisine (5) [2], 1,4-dioxa-7-chloro-6-N-
cytisinylspiro[4.4]non-6-en-8-one (6), 1,4-dioxa-7,9-dichloro-6-N-cytisinylspiro[4.4]non-6-en-8-one (7a and b), 2-N-cytisinyl-
1,4-naphthoquinone [3] (8), and 4-oxo-4-(N-cytisinyl)butenoic acid (9a and b) [3].
8
7
O
6
5
13
4
'
1
C
11
CH CH
2
CH
2
9
R= CH
3
10
'
'
'
3
1
2
'
N-R
1
N
3
H
2
12
1
1
2
a, b
O
'
'
''
4
'
2
3
1
*CH CH CO CH
CH CH
2 2
1
C
3
N
2
2
3
'
'
'
2
CO CH
2
3
'
'
5
6
4a, b
O
O
O
O
'
'
'
3
'
5
1 C
3
Cl
'
4
*
'
'
Cl
10
CO H
2
Cl
4
'
'
'
3
'
'
4
6
3
2
'
'
4
'
2
2
C C
' O
'
' O
2
'
'
1
'
7
O 5
O 5
'
1
1
H
H
'
9
'
7
'
'
8
7
'
O
'
6
6
6
7a, b
8
9a, b
*Asymmetric center
Institute of Organic Chemistry, Ufa Scientific Center of the Russian Academy of Sciences, 450054, Ufa, Prospekt
Oktyabrya 71, fax (3472) 35 60 66, e-mail: chemorg@anrb.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 4, pp.
301-305, July-August, 2001. Original article submitted May 11, 2001.
0009-3130/01/3704-0356$25.00 ©2001 Plenum Publishing Corporation
356

TABLE 1. 13C NMR Parameters of Cytisine and Its Derivatives
C
Cytisine
1
2
3a
3b
4a
4b
5
6
7a
7b
8
9a
9b
2
3
163.37 163.44 163.48 163.20 163.05 163.34 163.34 163.25 164.01 165.4 165.31
116.38 116.38 116.37 117.65 117.34 116.63 116.50 116.47 116.01 117.43 117.43
138.53 138.47 138.44 138.59 138.96 138.66 138.66 138.46 139.92 141.39 141.34
104.70 104.54 104.35 105.75 105.00 104.62 104.62 104.39 104.10 105.11 105.30
150.89 151.32 151.46 147.93 147.93 151.07 150.75 150.61 148.93 149.91 149.91
163.49
117.70
163.1
163.2
117.05 116.81
139.42 139.43
105.17 105.29
150.56 150.87
4
138.80
5
105.49
6
153.98
7
35.32 35.16
26.03 25.13
27.50 27.69
49.48 49.77
52.72 61.93
53.69 62.24
35.35
25.77
27.88
49.83
59.73
60.11
33.68 34.40 34.40 34.29 34.98 34.93 36.26 36.03
26.12 26.17 25.62 25.62 25.31 24.97 26.14 26.06
26.92 26.54 28.25 27.59 27.57 27.91 29.26 29.03
48.73 48.48 49.77 49.54 49.55 48.52 48.76 48.76
51.99 45.88 60.40 60.23 59.65 53.98 56.36 55.63
46.94 53.24 63.17 62.97 59.11 53.14 54.74 55.43
35.10
35.16
26.07
27.91
49.58
54.20
47.85
35.16
25.96
27.91
49.39
48.83
52.82
8
28.08
9
25.97
10
11
13
1
48.88
55.38
55.87
-
-
-
-
-
45.99 134.87 160.97 161.09 53.58 52.98 52.65 63.81 63.78 63.78
183.85
166.86 167.14
137.31 137.81
125.25 125.42
166.18 166.50
2
-
-
-
-
117.03
-
-
-
-
-
-
-
-
34.40 34.29 15.32 62.07 63.58 63.58
171.12 171.12 118.19 107.51 108.91 109.11
148.76
3
-
-
-
113.38
4
51.44 51.44
170.71 170.82
-
-
160.05 160.11 159.97
107.51 109.71 109.65
182.05
5
125.53;
126.83 (C8)
132.70;
133.85 (C7)
132.01;
132.55 (C10)
6
7
-
-
-
-
-
-
-
-
-
-
51.85 51.73
-
-
191.68 187.26 187.09
45.08 66.59 66.41
-
-
In the present article, we discuss the spectral properties of these compounds. The physicochemical properties of 1 and
5, which have been previously synthesized, correspond to those published [4, 5]. Thus, reaction of cytisine with allylbromide
or formic acid gives N-allylcytisine 2 or N-formylcytisine 3a and b in yields of 87 and 95%, respectively; reaction of 1,4-dioxa-
6,7,9-trichlorospiro[4.4]non-6-en-8-one [6] or 1,4-dioxa-7,9-dichlorospiro[4.4]non-6-en-8-one [7] with cytisine gives 1,4-dioxa-
7,9-dichloro-6-N-cytisinylspiro[4.4]non-6-en-8-one (7a and b) or 1,4-dioxa-7-chloro-6-N-cytisinylspiro[4.4]non-6-en-8-one
(6) in yields of 75 and 64%, respectively.
Analysis of the 1H and 13C NMR spectra revealed that a doubled set of signals is observed for 3, 4, 7, and 9 (Table 1
lists 13C NMR spectral data of the studied compounds). According to the literature [8-10], adding substituents to the N has no
effect on the conformation of the cytisine core. This is confirmed by the fact that the chemical shifts of bridging C-8, which
are sensitive to conformational changes, are practically the same.
Compounds 4a and b and 7a and b are pairs of diastereomers that are formed when addition of a substituent creates
an asymmetric center. Signals for stereoisomeric 4a and b and 7a and b were assigned based on integrated intensities in the
1H and 13C NMR spectra [11, 12].
It is interesting that the chiral centers in 7a and b are located six bonds from each other. Nevertheless, the
diastereomeric splitting reaches 0.3 ppm. The N atom located between the chiral centers probably intensifies the transfer of
magnetic shielding by the asymmetric nuclei [13, 14]. Diastereomerism was not observed previously in cytisine derivatives with
an asymmetric center in the substituent [15, 16]. Formation of 3 and 9 also produces two stereoisomers. The maximum
difference for C-11 and C-13 in these instances is 1-2 ppm. Invertomers with hindered rotation around the N–C bond, which
are considered to be Z and E isomers, appear because of the formation of amide conjugation [17, 18]. Assignments were made
1
for 3 and 9. The chemical shifts of H-8, H-9, and H-7 in the H NMR of 3a and b are the same. All other give a pair of signals
of equal intensity. The major and minor resonances of the formyl proton occur as two singlets (3:2) at 7.88 and 7.65 ppm,
respectively, i.e., they have an unusual strong-field shift compared with that expected (~11 ppm). Crystals of the pure compound
dissolve in dry CDCl . The difference ∆δ = 7.88 - 7.65 is independent of solvent. Therefore, the difference in the chemical
3
shifts is explained only by the different stereochemistry. Double resonance, integration by parts, and 2D experiments were
357

p pm
2 .0
3 .0
4 .0
5 .0
6 .0
7 .0
8 .0
8 .0
7 .0
6 .0
5 .0
4 .0
3 .0
2.0
p pm
Fig. 1. Two-dimensional COSYHH-45 spectrum of formylcytisine
(3a, 3b).
performed to determine unambiguously all interactions in each isomer. The 2D COSY-45 (Fig. 1) and COSYLR-45 spectra
include two subspectra for each isomer. The pairs of geminal protons at 2.95-4.58 and 2.9-4.52 ppm have the greatest
difference in chemical shifts. They correspond to the C atoms at 45.88 and 46.94, respectively, as expected from the 2D
heteronuclear correlation spectra. Such a diastereotopic shift is due to the presence of a cis-carbonyl in the substituent on N
[19]. Therefore, one pair of geminal protons in the Z-isomer should belong to C-13; in the E-isomer, to C-11. The axial proton
on C-11 is broadened owing to through-space coupling with the axial proton on C-10, which in the one-dimensional spectrum
has a constant of 1.1 and 1.3 Hz in different isomers. Therefore, the minor component is the E-isomer with C-11 at 45.88 ppm
and H (2.95 ppm) and H (4.58 ppm). Other pairs of protons H (3.45 ppm) and H (3.56 ppm) on C (53.24 ppm) and H
a
e
a
e
a
(3.44 ppm) and H (3.53 ppm) on C (51.99 ppm) belong to C-13 in the E-isomer and C-11 in the Z-isomer, respectively. This
e
agrees with the literature [20, 21]. The signal in similar systems with the C atom trans to a carbonyl is located at weaker field
and to a greater extent in the E-isomer [19]. The resonance of an axial proton trans to a carbonyl in the Z-isomer is also at
weaker field relative to that in the E-isomers [19]. In COSYLR, where through-space couplings have stronger cross-peaks, the
following couplings are seen: for the Z-isomer [H-1 with H -13], for the E-isomer [H-1 with H -11].
a
a
Thus, the signal for an aldehyde proton in the Z-isomer is shifted to weaker field compared with that for the E-isomer
apparently due to deshielding of the magnetically anisotropic C-2 carbonyl because the molecular symmetry is destroyed only
by the pyridone ring. Assignments were made for 4-oxo-4-(N-cytisinyl)butenoic acid (9a and b) as follows. Amide conjugation
occurs also in this instance. However, cis and trans isomerization around the C C double bond is absent. This is confirmed
by the identical spin—spin coupling constants between protons on C-2 and C-3 (11.9 Hz). However, the E-isomer
1
predominates in this instance (3:2). Furthermore, the H NMR spectra of 9a and b show that the vicinal protons on C-2 and
C-3 of one isomer are located at weaker field. The signal of one of them is shifted to weak field up to 6.5 ppm. Such magnetic
deshielding can be explained by the Z-conformation. We can exclude H-bonding because the IR spectrum lacks the
characteristic absorption band. The presence of amide conjugation was confirmed by varying temperature. Thus, heating 9a
and b to 100oC causes the signals to coalesce in the 13C NMR because of free rotation of the substituent around the
N–COCHCHCO H bond.
2
EXPERIMENTAL
NMR spectra were recorded on a Bruker AM-300 spectrometer (1H, 300.13; 13C, 75.47 MHz). Chemical shifts are
given vs. CDCl , 77.1 ppm; (CD ) CO, 28.83; DMSO-d , 39.43 (13C) and 7.27, 2.07, and 2.50 ppm (1H). IR spectra were
3
3 2
6
recorded on a UR-20 instrument as thin layers or in mineral oil. Mass spectra were obtained in a MX-1300 spectrometer with
source temperature 100oC and ionizing-electron energy 70 and 12 eV.
N-Allylcytisine (2). A mixture of cytisine (3.39 g) and K CO (4.5 g) in acetone (75 mL) was stirred under N and
2
3
2
treated with N-allylbromide (1.56 mL, 0.2-mL portions) over 10 min. The mixture was boiled for 11 h. After the reaction was
finished K CO was filtered off and washed with acetone. The filtrate was evaporated. The solid was purified by dissolving
2
3
358

in CH Cl and passing through a layer of Al O . Solvent was evaporated to give 4.85 g (87%) of a white crystalline powder
2
2
2 3
of N-allylcytisine, mp 117-118oC.
Found (%): C 73.08, H 8.00, N 12.15. C14H18N2O. Calc. (%): C 73.01, H 7.88, N 12.16.
IR spectrum (KBr, ν/cm-1): 2900-2980 (CH ), 2870, 2810, 1660 (N–C O), 1585 (C C–C O), 1560, 960, 820, 760
2
(C C).
1
2
3
3
2
H NMR (CDCl , δ, ppm, J/Hz): 1.68 [1H, dt, H C(8), J = -12.7, J8-9 = J8-7 = 3.0], 1.8 [1H, dt, H C(8), J = -12.7,
3
3
3
J8-9 = J8-7 = 3.0], 2.18 [2H, m, HC(13)], 2.45 [1H, m, HC(9)], 2.75-2.95 [5H, m, H C(1 ), H C(11), HC(7)], 3.82 [1H, dd,
2
2
2
3
2
3
H C(10), J = -15.4, J10-9 = 6.7], 3.94 [1H, d, H C(10), J = -15.4], 4.94 [2H, m, HC(3 )], 5.45-5.60 [1H, m, HC(2 ), J2-1
=
a
e
3
3
4
3
3
6.1], 5.90 [1H, d, HC(5), J5-4 = 6.8], 6.36 [1H, dd, HC(3), J3-4 = 9.0, J3-5 = 1.1], 7.19 [1H, dd, HC(4), J3-4 = 9.0, J5-4 = 6.8].
+
Mass spectrum (EI, 70 eV), m/z [Irel (%)]: 230 [M] (50), 189 (7), 147 (15), 146 (30), 169 (30), 84 (100).
N-Formylcytisine (3a and b). A solution of cytisine (0.2 g, 1 mmole) in acetic acid (2 mL) was treated with formic
acid (90%, 6 mL, 5 mmole) and boiled for 2 h (TLC monitoring). The solvent was evaporated. The product was isolated by
column chromatographyon SiO (CHCl :CH OH, 1:1). Yield 0.22 g (95%) of 3a and b as a white crystalline powder, mp 169-
2
3
3
171 C. Found (%): C 60.72, H 6.39, N 11.61. C12H14N2O2. Calc. (%): C 66.04, H 6.47, N 12.84.
IR spectrum (KBr, ν/cm-1): 1648 (N–C O), 1632 (N–C O), 1540, 1440, 1416, 804, 744 (C C).
+
Mass spectrum (EI, 70 eV), m/z [Irel (%)]: 218 [M] (100), 190 (14), 189 (12), 147 (30), 146 (80).
1
H NMR (3a, Z-isomer) (CDCl , δ, ppm, J/Hz): 2.09 [2H, m, H C(8)], 2.50 [1H, m, HC(9)], 2.95 [1H, d, H (13),
3
2
a
2
2
4
2
J = -13.0], 3.09 [1H, m, HC(7)], 3.44 [1H, dd, H (11), J = -13.4, J = 1.1], 3.53 [1H, d, H C(11), J = -13.4], 3.88 [1H, ddd,
a
e
2
3
3
2
2
H C(10), J = -15.73, J10-9 = 6.4, J10-11 = 1.1], 4.06 [1H, d, H C(10), J = -15.73], 4.52 [1H, d, H C(13), J = -13.0], 6.00 [1H,
a
e
e
3
4
3
4
3
3
dd, HC(5), J5-4 = 6.8, J5-3 = 1.6], 6.40 [1H, dd, HC(3), J3-4 = 9.1, J3-5 = 1.6], 7.25 [1H, dd, HC(4), J4-5 = 6.8, J3-4 = 9.1],
7.88 [1H, s, COH].
1
H NMR (3b, E-isomer) (CDCl , δ, ppm, J/Hz): 2.09 [2H, m, H C(8)], 2.50 [1H, m, HC(9)], 2.90 [1H, dd, H C(11),
3
2
a
2
2
2
3
J = -13.4], 3.09 [1H, m, HC(7)], 3.45 [1H, m, H C(13), J = -13.0], 3.56 [1H, d, H C(13), J = -13.0, J10-11 = 1.3], 3.82 [1H,
ddd, H C(10), J = -13.0, J10-9 = 6.2, J10-11 = 1.3], 4.06 [1H, d, H C(10), J = -13.4], 4.58 [1H, d, H C(11), J = -13.4], 6.08
[1H, dd, HC(5), J5-4 = 6.8, J5-3 = 1.6], 6.41 [1H, dd, HC(3), J3-4 = 9.1, J3-5 = 1.6], 7.25 [1H, dd, HC(4), J4-5 = 6.8,
J3-4 = 9.1], 7.65 [1H, s, COH].
a
e
2
3
3
2
2
a
e
e
3
4
3
4
3
3
1,4-Dioxa-7,9-dichloro-6-N-cytisinylspiro[4.4]non-6-en-8-one (7a and b). A solution of 1,4-dioxa-6,7,9-
trichlorospiro[4.4]non-6-en-8-one (0.2 g, 0.82 mmole) and cytisine (0.23 g, 1.2 mmole) in benzene (5 mL) was boiled for 3 h.
The solvent was evaporated. The solid was dissolved in aqueous NaCl (10 mL). The product was extracted by CHCl
3
(3×10 mL). The combined organic extracts were dried over MgSO and evaporated. The product was purified by column
4
chromatographyover SiO (benzene:methanol, 7:1). Yield 0.25 g (75%) of 1,4-dioxa-7,9-dichloro-6-N-cytisinylspiro[4.4]non-6-
2
en-8-one.
Found (%): C 54.52, H 4.91, N 6.78, Cl 17.55. C18H18O4Cl2N2. Calc. (%): C 54.45, H 4.63, N 7.08, Cl 17.80.
IR spectrum (KBr, ν/cm -1): 1720 (C O), 1660 (N–C O), 1610, 1580 (C C–C O), 820, 760 (C C).
1
H NMR (7a) (CDCl , δ, ppm, J/Hz): 1.90 [2H, m, HC(8)], 2.49 [1H, m, HC(9)], 3.12 [1H, m, HC(7)], 3.28 [1H, d,
3
2
2
2
3
HC(11), J = -12.4], 3.44 [1H, d, HC(13), J = -13.0], 3.81 [1H, dd, HC(10), H C(10), J = -15.4, J10-9 = 5.7], 3.93-4.37 [7H,
a
2
3
m, H C(6 ), H C(7 ), HC(4 ), H C(10), H C(13)], 4.44 [1H, d, H C(11), J = -12.4], 6.01 [1H, d, HC(5), J = 6.8], 6.36 [1H,
2
2
e
e
e
3
4
3
3
dd, HC(3), J3-4 = 9.0, J3-5 = 1.1], 7.19 [1H, dd, HC(4), J3-4 = 9.0, J5-4 = 6.8].
1
2
H NMR (7b): 1.90 [2H, m, HC(8)], 2.58 [1H, m, HC(9)], 3.08 [1H, m, HC(7)], 3.31 [1H, d, HC(11), J = -12.4], 3.42
2
2
3
[1H, d, HC(13), J = -13.0], 3.73 [1H, dd, HC(10), H C(10), J = - 15.4, J10-9 = 5.7], 3.93-4.37 [7H, m, H C(6 ), H C(7 ),
a
2
2
2
3
4
HC(4 ), H C(10), H C(13)], 4.44 [1H, d, H C(11)], 6.01 [1H, d, HC(5), J = 6.8], 6.36 [1H, dd, HC(3), J3-4 = 9.0, J3-5 = 1.1],
e
e
e
3
3
7.19 [1H, dd, HC(4), J3-4 = 9.0, J5-4 = 6.8].
1,4-Dioxa-7-chloro-6-N-cytisinylspiro[4.4]non-6-en-8-one (6) was prepared analogously to 7a and b from 1,4-dioxa-
6,7-dichlorospiro[4.4]non-6-en-8-one. Yield 64%.
IR spectrum (KBr, ν/cm -1): 1720 (C O), 1660 (N–C O), 1610, 1580 (C C–C O), 820, 760 (C C).
1
H NMR (acetone-d , δ, ppm, J/Hz): 1.68-1.87 [2H, m, HC(8)], 2.30 [1H, m, HC(9)], 2.97 [1H, m, HC(7)], 3.05-3.20
6
2
3
[2H, m, HC(13)], 3.40-3.55 [2H, dd, HC(10), J = 15.4, J10-9 = 6.8], 3.85-4.30 [6H, m, 2HC(11), 4H, O–CH –CH –O], 4.42
[1H, d, HC(4 ), J = -13.0], 4.63 [1H, d, HC(4 ), J = -13.0], 6.04 [1H, d, HC(5), J4-5 = 6.6], 6.43 [1H, d, HC(3), J3-4 = 9.0],
7.15 [1H, dd, HC(4), J3-4 = 9.0, J5-4 = 6.6]. Mass spectrum (EI, 70 eV), m/z [Irel (%)]: 362 [M] , 345, 319, 216, 172, 146.
4-Oxo-4-(N-cytisinyl)butenoic Acid (9a and b). A solution of cytisine (0.190 g, 1 mmole) in toluene (5 mL) was
2
2
2
2
3
3
3
3
+
359

treated dropwise with maleic anhydride (0.196 g, 2 mmole). The mixture was stirred at room temperature for 24 h. The white
precipitate was filtered off and washed with acetone. Yield 0.216 g (75%), mp 215-217oC. Found (%): C 64.65, H 5.91, N 9.79.
C15H16N2O4. Calc. (%): C 62.49, H 5.59, N 9.72.
IR spectrum (KBr, ν/cm-1): 3480, 3435, 3110 (OH), 1715 (C C–CO H), 1660-1620 (N–C O, C C), 835, 770, 760,
2
720 (C C).
+
Mass spectrum (EI, 70 eV), m/z [Irel (%)]: 288 [M] (15), 190 (70), 189 (30), 148 (50), 147 (75), 146 (85), 98 (60),
54 (100).
1
H NMR (9a, E-isomer) (DMSO, δ, ppm, J/Hz): 1.93 [2H, br.s, H C(8)], 2.50 [1H, br.s, H C(9)], 2.88 [1H, d, H C(11),
2
a
a
2
2
J = -13.2], 3.12 [1H, br.s, HC(7)], 3.22 [1H, d, H C(13), J = -13.1], 3.27-3.50 [m, CO H], 3.60-3.80 [2H, m, H C(10),
H C(13)], 3.88 [1H, d, H C(10), J = -15.5], 4.48 [1H, d, H C(11), J = -13.2], 5.84 [1H, d, HC(3 ), J3 = 11.9], 5.90 [1H,
a
2
a
2
2
3
-2
e
e
e
3
3
3
d, HC(2 ), J2 -3 = 11.9], 6.16 [1H, d, HC(5), J5-4 = 6.7], 6.21 [1H, d, HC(3), J3-4 = 7], 7.27-7.37 [1H, m, HC(4)].
1
H NMR (9b, Z-isomer) (DMSO, δ, ppm, J/Hz): 1.93 [2H, br.s, H C(8)], 2.50 [1H, br.s, H C(9)], 2.91 [1H, d, H C(13),
2
a
a
2
J = -13.2], 3.17 [1H, br.s, HC(7)], 3.28-3.50 [2H, m, H C(11), CO H], 3.65 [3H, m, H C(10), H C(11), H C(10)], 4.31 [1H,
d, H C(13), J = 13.2], 5.92 [1H, d, HC(3 ), J3 -2 = 11.9], 6.16 [1H, d, HC(5), J5-4 6.7], 6.23 [1H, d, HC(3), J3-4 = 7], 6.49
[1H, d, HC(2 ), J2 -3 = 11.9], 7.27-7.37 [1H, m, HC(4)].
a
2
a
e
e
2
2
2
3
e
2
The work was financed by the Russian Basic Research Foundation (Grant No. 00-15-973225).
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