Syntheses based on norfluorocurarine. 7. Reduction of norfluorocurarine and fluorocurarine by metallic sodium and sodium borohydride

Article abstract of DOI:10.1007/s10600-012-0398-7

Reduction of norfluorocurarine by sodium in EtOH formed deoxytetrahydronorfluorocurarine and tetrahydronorfluorocurarine. The latter was identical to the Wieland-Humlich 18-deoxyglycol. Reduction of norfluorocurarine by sodium borohydride in alkaline solu

Full text of DOI:10.1007/s10600-012-0398-7

Chemistry of Natural Compounds, Vol. 48, No. 5, November, 2012 [Russian original No. 5, September–October, 2012]
SYNTHESES BASED ON NORFLUOROCURARINE.
7
. REDUCTION OF NORFLUOROCURARINE AND
FLUOROCURARINE BY METALLIC SODIUM AND
SODIUM BOROHYDRIDE
M. M. Mirzaeva, B. Tashkhodzhaev,*
A. G. Eshimbetov, and P. Kh. Yuldashev
UDC 547.945+547.79+548.737
Reduction of norfluorocurarine by sodium in EtOH formed deoxytetrahydronorfluorocurarine and
tetrahydronorfluorocurarine. The latter was identical to the Wieland–Humlich 18-deoxyglycol. Reduction
of norfluorocurarine by sodium borohydride in alkaline solution occurred with opening of rings C and E
and formation of the new indole base 16-decarbmethoxyepistemmadenine. Reduction of fluorocurarine
chloride or iodide by sodium borohydride formed the corresponding de-acetylretuline salts. The structures
of the products were established by x-ray crystal structure analyses. Norfluorocurarine and representatives
of the ꢀ-methylenindolenine series formed indoline derivatives upon reduction in acidic and neutral solutions;
indole derivatives, in alkaline solution.
Keywords: indole alkaloids, norfluorocurarine, deoxytetrahydronorfluorocurarine, tetrahydronorfluorocurarine, XSA.
We continued synthetic transformations of the available alkaloid norfluorocurarine (1) isolated from Vinca erecta in
order to discover new physiologically active compounds based on it [1]. Norfluorocurarine was reduced in acidic and neutral
solutions. Norfluorocurarine contains a reactive aldehyde conjugated to a double bond. IR spectroscopic data [2] and the
x-ray molecular structure [3] revealed a strong intramolecular H-bond between the aldehyde and NH groups. This suggested
that 1 could convert from the ketone (1a) to the enol (1b) depending on the reaction medium.
UV spectra of 1 in EtOH were characterized by a strong absorption band at 365 nm and weaker bands at 244 and
*
3
00 nm (Fig. 1, a). According to the semi-empirical CNDO/S method, the last of these was due to nꢁꢂ electronic transitions
of the carbonyl O atom and N4. Adding base to 1 in EtOH solution produced bathochromic shifts of the absorption bands at
44 and 365 nm and caused the absorption band at 300 nm to disappear (Fig. 1). These changes in the UV bands indicated that
2
the enol tautomer formed in alkaline solution (Fig. 1, b). The enol form was energetically less favorable. The difference in the
heats of formation (ꢃH ) of the ketone and enol tautomers according to quantum-chemical calculations (semi-empirical PM6
f
approximation method) was ꢃH = 8.9 kcal/mol. The transition barrier from the ketone to enol tautomer was 13.1 kcal/mol;
f
the reverse transition barrier, 4.2 kcal/mol. The energetic similarity of the tautomers and the low barrier between them indicated
that transitions were possible at room temperature, which was confirmed by the aforementioned assumption based on
UV spectral data.
3.5
379.11
3
.0
b
365.06
2
49.77
2
2
1
.5
.0
.5
N
N
2
44.52
320.17
300.13
N
H
N
a
1.0
0.5
CH
CH
HO
O
1
a
1b
0
.0
2
20
260
300
340
380
420 450 nm
Fig. 1. UV spectra of norfluorocurarine in EtOH (a) and alkaline solution (b).
S. Yu. Yunusov Institute of the Chemistry of Plant Substances,Academy of Sciences, Republic of Uzbekistan, Tashkent,
fax: (99871) 120 64 75, e-mail: tashkhodjaev@rambler.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 5, September–
October, 2012, pp. 749–753. Original article submitted February 27, 2012.
842
0009-3130/12/4805-0842 ©2012 Springer Science+Business Media New York

Further studies of the structures of the reaction products showed that the medium determining the tautomeric state of
the alkaloid in the reductions played an important role.
The absolute configurations of the asymmetric centers in 1 are considered established [1]. Centers 3S, 7R, and 15S
were not affected in all reductions. Atoms C2 and C16 became asymmetric centers and could adopt various configurations
after reduction of the C2=C16 double bond. Stereochemical issues in the present work were solved by x-ray crystal structure
analyses (XSA) of the reduction products.
Reduction of 1 by metallic sodium in anhydrous EtOH formed two products, deoxytetrahydronorfluorocurarine (2)
and tetrahydronorfluorocurarine (3) [4]. Our structural studies showed that the latter was identical to the Wieland–Humlich
1
8-deoxyglycol that was synthesized earlier from the natural alkaloid strychnine [5].
6
7
5
9
E
3
C
N
N
4N
21
Na
OH
H
H
A
B
D
+
1
1
C
2
H
5
N
H
N
H
1
3
N
H
1
-
2
0
H
H
3
H
H
1
7
CH
CH
CH
2
1
9
18
HO
O
1
2
3
NaBH OH
4
CH X
3
3
N
CH
3
7
N
N
CH
3
NaBH
4
H
H
1
5
N
N
H
HO
N
H
X
X
H
H H
H
CH
CH
2
CH
2
HO
O
4
5
6, 7a,b
6: X = Cl; 7a: X = C
X = I, Cl
6
H
2
N
3
O
7
; 7b: X = I
E
3
3
6
N
NaBH
3
C
N
N
4
NaBH
OH
4
7
7
7
-
+
H
N
H
N
N
H
1
16
16
R
R
R
1
2, 13
8, 9
, 10, 12:R = H; 9, 11, 13:R = OH
10, 11
8
Reduction of 1 by NaBH in alkaline medium formed the indole base 16-decarbmethoxyepistemmadenine (4) with
4
opening of rings C and E (cleavage of the C3–C7 bond) but with retention of the C16 hydroxymethyl group. A similar reaction
with cleavage of the C3–C7 bond was observed after reduction of indolenine bases (without the C16 hydroxymethyl)
decarbmethoxyakuammicine (8) [6] and decarbmethoxyvinervine (9) [7], which converted into indole derivatives 10 and 11 in
alkaline solution. However, they formed indoline derivatives 12 and 13 upon reduction in acidic solution [7, 8], retaining the
norfluorocurarine cyclic framework.
Reduction of fluorocurarine (N-ꢄ-methylnorfluorocurarine) chloride (5) was described earlier. It produced
tetrahydrofluorocurarine chloride (6) [9]. We repeated this experiment. The resulting structural study showed that the reduced
alkaloid was a stereoisomer at C16 of the quaternary salt of 3 (Wieland–Humlich 18-deoxyglycol). The alkaloid deacetylretuline
is known in the literature [10]. Its quaternary salt was identical to 6 that was synthesized by us.
In summarizing the aforementioned reactions, it can be noted that indoline derivatives were formed by reduction of 1
and ꢀ-methylenindolenines in acidic and neutral solutions; indole derivatives, in alkaline solution.
The structures of the reduction products of 1, i.e., deoxytetrahydronorfluorocurarine (2), tetrahydronorfluorocurarine
(
3), and 16-decarbmethoxyepistemmadenine (4), were established by XSA. The reduction products of fluorocurarine were
studied by XSA as the picrate (7a) and iodide (7b).
Structure of 2. Figure 2 shows the XSA molecular structure of 2. The absolute configuration of the asymmetric
centers in 2 that arose as a result of reducing the C2=C16 bond corresponded with those shown in Fig. 2 (2S,16S).
The five-membered heterocycle B in the indole core adopted the 2ꢀ-envelope conformation; ring E, close to the
7
ꢀ-envelope conformation. Ring C was a distorted chair; ring D, a boat with C14 and C21 deviating from the plane of the
other four atoms. A weak intermolecular H-bond between tertiary N4 of the starting molecule and an NH group translated
along the a axis was noted in the crystal. Table 1 presents the parameters of this H-bond.
843

TABLE 1. Intermolecular H-bonds in Crystal Structures of 2, 3, 4, 7a, 7b
Compound
A…H-D
D (D-Í), A°
D (Í…A), A°
D (D…A), A°
< (DHA), deg
Symmetry
2
3
N4…H-N1
Î1…H-N1
O1…H-Ow
N4…H-O1
N4…H-O1
O1…H-Oe
N1…H-Oe
N1…H-O1
I…H-N1
0.86
0.86
0.85
0.88
1.03
0.82
0.86
1.25
0.86
2.50
2.27
1.91
1.83
1.72
1.96
2.06
2.05
3.16
3.120
3.012
2.697
2.712
2.704
2.740
2.842
3.045
3.734
130
145
153
178
158
157
157
132
126
–1 + x, y, z
x, y, z
–2 – x + y, –2 – x, 1/3 + z
–1 – y, –1 + x – y, –1/3 + z
x, –1 + y, z
4
x, y, z
–1 – x, y, –z
–x, –1/2 + y, 2 – z
x, y, z
7a
7b
N4
N4
C21
C3
C14
C3 C5
C19
C21
C20
C14
C5
C18
C20
C8
C6
C15
C6
C19
C9
C8
C7
C9
C10
C11
C12
C10
C11
C7
C17
C15
C16
C16
C18
C2
C17
C2
N1
C12
C13
C13
N1
O1
2
3
C6
C2
N4
C21
C19
C5
C20
C15
C3
C18
C8
C9
C7
C14
C10
C16
C17 O1
C11
C12
C13
N1
4
Fig. 2. Molecular structures of 2, 3, and 4.
Structure of 3. Figure 2 shows the molecular structure of 3 from an XSA. The absolute configuration of the
asymmetric centers (2S,16R) arising as a result of reducing the C2=C16 bond corresponded to those shown in Fig. 2. Whereas
H2 and H16 in 2 were syn-positioned and had the ꢀ-orientation, they were trans-positioned in 3 and H16 changed configuration
to the ꢄ-orientation.
Five-membered heterocycle B in the indole core also adopted the 2ꢀ-envelope conformation. Ring E was close to a
6
ꢄ-envelope conformation. Rings C and D in 3, in contrast with 2, had identical slightly distorted chair conformations.
The crystal cell of 3 contained a water of crystallization that formed a H-bond between N1H of the starting molecule
and a hydroxyl translated by 3 symmetry along the a axis. Table 1 shows other H-bonds formed in the crystal.
1
Structure of 4 (indole base with C3–C7 bond cleavage). Figure 2 shows the XSAmolecular structure. The asymmetric
center arising as a result of the reaction at C16 adopted the S-configuration. The C15 center retained the S-configuration.
An analysis of the bond lengths confirmed that the arbitrary double bond (initial C2=C16) shifted to C2=C7. Atoms
2
°
°
°
C2 and C7 became sp -hybridized. The N1–C2 [1.387(3) A], C2=C7 [1.363(4) A], and C7–C8 [1.423(4) A] bonds became
°
closer to those observed in the aromatic pyrrole ring [11]. The indole core was planar within ±0.011 A. Ring D had a slightly
distorted boat conformation with C14 and C21 deviating from the plane of the other four atoms.
Base 4 crystallized as a solvate with an EtOH molecule in a 1:1 ratio. The H atom of the EtOH hydroxyl approached
the hydroxyl O atom of 4 in the crystal. An unshared pair of the EtOH oxygen atom was bonded to an NH proton of a
translated molecule of 4. Table 1 presents the parameters of the intermolecular H-bonds.
844

TABLE 2. Principal Crystallographic Parameters and Characteristics of X-ray Experiments for 2, 3, 4, 7a, 7b
Parameters
2
3
4
7a
7b
Molecular Formula
MW, g/mol
System
Ñ Í N
280.40
Ñ Í N O·H Î
Ñ Í N O·Ñ Í ÎH Ñ Í N Î·Ñ Í N Î
Ñ Í N ηI
1
9
24
2
19 26
2
2
19 24
2
2
5
20 27
2
6
2
3
7
20 27
2
314.42
Trigonal
P32
342.47
Monoclinic
C2
388.92
Monoclinic
P21
438.34
Orthorhombic
P2 2 2
Orthorhombic
P2 2 2
Space group
Z
1
1
1
1 1 1
4
6
4
2
4
°
a, A
7.081 (1)
13.947 (1)
15.589 (3)
90
9.587 (1)
9.587 (1)
15.825 (2)
90
22.116 (4)
8.200 (2)
10.891 (2)
90
11.7270 (3)
7.1498 (2)
15.5200 (4)
90
9.8503 (3)
10.7390 (2)
18.2014 (3)
90
°
b, A
°
c, A
ꢀ
, deg
ꢄ, deg
ꢅ, deg
90
90
90
120
100.92 (3)
90
1939.3 (7)
1.173
101.022 (2)
90
1277.29 (5)
1.403
90
90
°
3
V, A
1539.5 (3)
1.210
0.2 ꢋ 0.3 ꢋ 0.5
4.25 ꢌ ꢇ ꢌ 68.37
0.538
1820.2 (5)
1.243
0.4 ꢋ 0.8 ꢋ 0.5
5.33 ꢌ ꢇ ꢌ 67.16
0.638
1925.39 (7)
1.512
0.5 ꢋ 0.7 ꢋ 0.9
4.78 ꢌ ꢇ ꢌ 75.96
13.123
3
ꢆ, g/cm
Crystal size, mm
0.3 ꢋ 0.4 ꢋ 0.7
4.07 ꢌ ꢇ ꢌ 60.03
0.590
0.6 ꢋ 0.4 ꢋ 0.4
Scan range ꢇꢈ
3.84 ꢌ ꢇ ꢌ 75.72
–
1
ꢉexp, cm
0.885
Number of reflections
Number of reflections
with I > 2 ꢊ (I)
1786
1497
1825
1569
1550
1502
3553
3273
3742
3324
R
1
[I > 2 ꢊ (I) and total]
2
GOOF
0.0608 (0.0708)
0.18347 (0.1961)
1.127
0.0388 (0.0477)
0.1110 (0.1182)
0.926
0.0453 (0.0465)
0.1274 (0.1297)
0.996
0.0534 (0.0563)
0.1566 (0.1606)
1.042
0.0663 (0.0723)
0.1771 (0.1802)
1.299
WR
Electron-density difference
0.25 and –0.20
0.18 and –0.13
0.24 and –0.19
0.31 and –0.43
2.03 and –2.01
°
–3
peaks,, e A
CCDC
867365
867366
867367
867368
867369
C22
C22
C5
C5
C6
C21
N4
C21
C20
N4
C6
C19
C18
C3
C14
C16
C3
C7
C19
C18
C20
C15
C8
C7
C9
C9
C8
C15
C10
C10
C11
C14
C2
C2
N1
C11
C16
C13
C13
C12
N1
C17
C17
O1
C12
O1
7
a
7b
Fig. 3. Molecular structures of cations 7a and 7b.
Structure of 16-Decarbmethoxyepistemmadenine. This was studied as the picrate (7a) and iodide (7b) salts, the
cations of which are shown in Fig. 3 in approximately the same projection. The absolute configurations of the asymmetric
centers of the cations coincided with those observed in 2, i.e., formed centers with 2S,16S-configurations.
It could be seen visually that both cations had the same framework conformation. However, the positions of the
fluxional hydroxyl were different. The crystal of 7a had a weak intramolecular H-bond between an unshared pair of the
°
°
hydroxyl O atom and the NH group with distance O1…N1 2.967 A, O1…H 2.69 A, and angle O1…N1–H 101°. The observed
difference in the position of the fluxional OH group relative to the NH group in 7a and 7b was apparently related to the
aforementioned H-bond. However, the NH group of the starting molecule was simultaneously involved in an intermolecular
H-bond with an OH group of a translated molecule (Table 1). An intermolecular H-bond between the iodide anion and the NH
proton was observed in the crystal of 7b, in contrast with 7a.
845

Heterocycle B in the indole core adopted the 2ꢀ-envelope conformation. Ring E was close to a 4ꢄ-envelope
conformation. Ring C had a boat conformation with C2 and C14 deviating from the plane of the other four atoms. Ring D was
a distorted chair.
The picrate in 7a was planar. However, the NO group of the anion was slightly twisted (up to 17°) relative to the
2
°
aromatic plane (±0.012 A). The picrate did not participate in intermolecular H-bonds. However, the ꢂ-electron systems of two
aromatic rings of picrate and the alkaloid did approach each other (3.30 A).
°
EXPERIMENTAL
UV spectra were measured on a Lambda-16 spectrophotometer (Perkin—Elmer). UV spectra were calculated using
the CNDO/S method in the Winmostar program package [12]. The geometries of the compounds were optimized by the PM6
semi-empirical method [13] in the MOPAC2009 program set [14] using XSA data for (–)-norfluorocurarine [15].
Deoxytetrahydronorfluorocurarine (2) was prepared by the literature method [1, 4], mp 185–186°C (acetone),
2
0
[
ꢀ] –61.1° (c 2.43, MeOH). C H N . UV spectrum (ꢍmax, nm, log ꢎ): 250(3.84), 300 (3.50).
D 19 24 2
Tetrahydronorfluorocurarine (3) (Wieland–Gumlich 18-deoxyglycol) was prepared by the literature method [1,
2
0
4
], mp 174–175°C (acetone, [ꢀ] –28.5° (c 1.51, MeOH). C H ON . UV spectrum (ꢍmax, nm, log ꢎ): 245 (3.80), 298
D 19 26 2
(
3.40).
1
6-Decarbmethoxyepistemmadenine (4). Norfluorocurarine (6 g) was dissolved in MeOH (100 mL), treated with
NaOH solution (10 mL, 5%), stirred vigorously, and treated in portions with NaBH (6 g) over 2 h. Fine crystals started to
4
precipitate during the reduction. The reaction mixture was left in a refrigerator for 1 d. White crystals formed. Yield 3.54 g,
1
7
mp 109–110°C (dec., aq. MeOH), [ꢀ] –41.13° (c 1.00, MeOH). C H ON . UV spectrum (ꢍmax, nm): 234, 283.
D
19 24
2
1
6-Decarbmethoxyepistemmadenine chloride (6) was prepared as before [9], mp 238–240°C (MeOH, dec.),
1
7
[
[
ꢀ] +40° (c 1.00, MeOH). C H ON Cl. UV spectrum (ꢍmax, nm): 244, 300.
D
20 27
2
1
6-Decarbmethoxyepistemmadenine picrate (7a) was prepared from fluorocurarine chloride by the literature method
9], orange crystals, mp 153°C (aq. acetone). C H ON ·C H O N .
2
0
27
2
6 2 7 3
1
6-Decarbmethoxyepistemmadenine iodide (7b). Fluorocurarine iodide (5, 6 g) was dissolved with heating in a
mixture of NaOH (100 mL, 0.2 N) and MeOH (50 mL), treated in portions with NaBH (6 g) over 2 h, and cooled in a
4
refrigerator. The resulting finely crystalline precipitate was separated (yield 4.01 g), mp 242–243°C (aq. EtOH, dec.),
1
7
[
ꢀ] +46.5° (c 1.00, MeOH). C H ON I. UV spectrum (ꢍmax, nm): 242, 300.
D 20 27 2
X-ray Structure Analysis. Single crystals of 2, 3, 4, 7a, and 7b were obtained by slow evaporation from mixtures of
MeOH and acetone at room temperature. Unit-cell constants of crystals of 2, 3, 7a, and 7b were determined and refined on an
Xcalibur Ruby CCD diffractometer (Oxford Diffraction) using Cu Kꢀ-radiation (300 K, graphite monochromator) [16].
A three-dimensional dataset of reflections was obtained on the same diffractometer. The XSA of 4 was performed on a STOE
Stadi-4 four-circle diffractometer using Cu Kꢀ-radiation (300 K, graphite monochromator, ꢇ/2ꢇ-scanning). Absorption
corrections in all instances were applied semi-empirically using the SADABS program [17]. Table 2 presents the principal
parameters of the XSA and refinement calculations for the structures of 2, 3, 4, 7a, and 7b.
The structures were solved by direct methods using the SHELXS-97 programs. Refinement calculations were carried
out using the SHELXL-97 program [18]. All nonhydrogen atoms were refined by anisotropic full-matrix least-squares method
2
(
over F ). Positions of H atoms were found geometrically and refined with fixed isotropic thermal factors Uiso = nU , where
eq
n = 1.5 for methyls and 1.2 for others and Ueq is the equivalent isotropic thermal factor of the corresponding C atoms. Atomic
coordinates of H atoms of water and hydroxyls of EtOH and alkaloids were determined experimentally from difference electron-
density syntheses and refined isotropically.
CIF files containing complete information for the studied structures were deposited in the CCDC under the numbers
given in Table 2 (http://www.ccdc.cam.ac.uk/deposit).
ACKNOWLEDGMENT
The work was supported financially by the AS, RUz, Basic Research Program (Grant FA-A7-T185).
846

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