Synthesis of hybrid molecules containing fragments of sesquiterpene lactones and plant alkaloids

Article abstract of DOI:10.1007/s10600-011-9774-y

The Pd-catalyzed arylation of isoalantolactone by deoxyvasicinone and lappaconitine halides occurred with formation mainly of cross-coupling products with the (E)-configuration of the double bond. Another three compounds were isolated from the reaction of

Full text of DOI:10.1007/s10600-011-9774-y

Chemistry of Natural Compounds, Vol. 46, No. 6, 2011
SYNTHESIS OF HYBRID MOLECULES CONTAINING FRAGMENTS
OF SESQUITERPENE LACTONES AND PLANT ALKALOIDS
1
1*
1
1
A. V. Belovodskii, E. E. Shulꢀts, M. M. Shakirov, V. E. Romanov,
UDC 547.314+547.94
2
2
1
B. Zh. Elmuradov, Kh. M. Shakhidoyatov, and G. A. Tolstikov
The Pd-catalyzed arylation of isoalantolactone by deoxyvasicinone and lappaconitine halides occurred
with formation mainly of cross-coupling products with the (E)-configuration of the double bond. Another
three compounds were isolated from the reaction of isoalantolactone with 6-bromodeoxyvasicinone. These
were the lactone diarylation product, a compound with the (Z)-configuration of the double bond, and a
product with a shift of the C(11,13) double bond and configuration inversion at C(8). The new compounds
are interesting as potential biologically active agents.
Keywords: isoalantolactone, 5ꢀ-iodolappaconitine, 6-bromodeoxyvasicinone, Pd acetate, cross-coupling reaction.
Many compounds with a “hybrid” structure containing different fragments in their molecules were observed among
natural plant and marine metabolites [1, 2]. In this respect the synthesis of conjugates designed by using structural analysis of
natural metabolites seems logical for the discovery of pharmacologically promising agents [3]. Sesquiterpene methylenelactones
exhibit various biological activities including antitumor [4], anti-inflammatory [5], and antiviral [6]. Recently interest in these
natural compounds has risen sharply because of their ability to inhibit human tumor growth by activating the apoptosis mechanism
that is associated with activation of the caspase cascade in such cells [7]. Therefore, the synthesis of new derivatives of
ꢁ-methylene-ꢂ-lactones of natural and synthetic origin is an active research area [8].
We showed previously that Pd-catalyzed cross-coupling is an efficient reaction for modifying sesquiterpene eudesmane-
type ꢁ-methylene-ꢂ-lactones because it occurs with retention of the exo-methylene bond [9, 10]. Herein we report results
from the reaction of isoalantolactone (1) with plant alkaloid derivatives 6-bromodeoxyvasicinone (2) (Scheme 1) and
5ꢀ-iodolappaconitine (3) (Scheme 2).
14
CH
3
CH
CH
H
H
3
3
H
H
H
1
9
O
O
O
a
10
12
O
O
R
O
BrR
2
5
+
+
+
4
11
H
2
H
H
H
CH
2
15CH
CH
2
CH
R
2
4
5
1
CH
3
O
CH
3
H
H
H
5'
R =
11'
9'
4a'
3'
N
O
O
O
O
+
+
8a'
7'
N
H
2
H
1'
CH
R
R
R
7
6
a. Pd(OAc) , (o-Tol) P, Et N, DMF, 120°C, 15 h
2
3
3
Scheme 1
1) N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences,
630090, Novosibirsk, Prosp. Akad. Lavrentꢀeva, 9, fax: (383) 330 97 52, e-mail: schultz@nioch.nsc.ru; 2) S. Yu. Yunusov
Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Tashkent, fax: (99871)
120 64 75. Translated from Khimiya Prirodnykh Soedinenii, No. 6, pp. 747–751, November–December, 2010. Original
article submitted March 4, 2010.
©
880
0009-3130/11/4606-0880 2011 Springer Science+Business Media, Inc.

CH
3
H
H
1
4
O
9
12
10
I
O
11
H
13
O
15
CH
CH
H
2
3
H
H
5'
N
H
O
H C
O
3'
3
O
N
O
+
O
a
1'
H
HO
O
N
H
18''
CH
H C
3
O
3
CH
2
O
CH
2
H
22''
19''
7''
HO
CH
1
3
H C
3
3''
21''
OH
5''N
O
H
15''
CH
11''
3
9''
OH
13''
O
O
1''
17'' O
H C
3
H
CH
3
CH
3
16''
O
3
8
CH
3
a. Pd(OAc) , (o-Tol) P, Et N, DMF, 120°C, 15 h
2
3
3
Scheme 2
The cross-coupling of 1 with 2 catalyzed by Pd(OAc) -(o-Tol) P in DMF solution in the presence of Et N formed
2
3
3
products of arylation at the C(11,13) exo-methylene bond with the (E)- and (Z)-configurations (4, 5); bis-arylation at the
C(11,13) and C(4,15) bonds (6); and C(8)-epimerization of isoalantolactone and isomerization of the C(11,13) double bond
(7). It can be seen that the last compound contains fragments of the natural lactone asterolide [11] and the alkaloid vasicinone.
Compounds 4, 6, and 7 were isolated pure (yields of 65%, 5, and 3, respectively). The content of the (Z)-isomer (5) in the
reaction mixture was 5%. The structures of the products were established using spectral data. The (E)-configuration of the
13
C(11,13) double bond in substituted lactone 4 was inferred from the presence in the C NMR spectrum (single-resonance
3
3
mode) of a C–H J-cis coupling constant between the olefinic proton and the lactone carbonyl C atom [ J = 7.0 Hz; the
3
corresponding J-trans constant for the (Z)-isomer (5) was 13.4 Hz]. The resonance for H(13) in the PMR spectrum of the
(E)-isomer (4) appeared as a singlet at 7.44 ppm; for the (Z)-isomer (5), a singlet at 7.00 ppm.
A characteristic feature of the PMR spectrum of 4 was a weak-field shift of the H(7) proton (ꢃ 3.53 ppm) compared
with the position of the corresponding proton in the spectrum of 5 (ꢃ 3.01 ppm). A distinguishing feature of the PMR spectrum
of diarylation product 6 was the presence of protons of the second aromatic substituent, the appearance of a 1H singlet for the
resonance of H(15) at 6.04 ppm, and a weak-field shift of resonances for methyl and H(3) protons (ꢄꢃ 0.13 and 0.45 ppm,
respectively). The structure of isomeric lactone 7 was confirmed by PMR spectral data that showed resonances for methylene
protons on C(13) [ꢃ 3.69 and 3.74 ppm (both doublets, J = 15.2 Hz)] and a significant increase in the difference between
chemical shifts for the H(9) protons (ꢄꢃ ~ 1.2 ppm). Moreover, strong-field proton H(9a) (ꢃ 1.12 ppm) had SSCC with the
H(8) proton (J = 11.4 Hz) that corresponded to an axial–axial arrangement. The H(5ꢀ) proton of this dimeric compound
experienced a characteristic strong-field shift (ꢃ 8.03, d, J = 1.6 Hz) compared with its location in 4 (ꢄꢃ ~ 0.35 ppm) and 5
(ꢄꢃ ~ 0.34 ppm).
The ratio of isomers could be determined from the clear differences in the PMR spectra of the reaction mixtures.
Additional proof of the configuration inversion of asymmetric C(8) in 7 came from results of a NOESY experiment. The 2D
proton nuclear Overhauser effect spectrum of 7 showed that the H(8) proton gave an NOE effect with protons of the angular
methyl on C(10) and did not exhibit effects with the H(5) proton. An NOE effect was observed for the H(8) proton upon
irradiation of the C(14)H3 protons. The H(8) proton in the proton 2D-NOESY spectrum of 4 exhibited an NOE effect with the
H(5) proton and did not give effects with protons of the angular methyl. These results indicated that asymmetric C(8) in 7 had
undergone configuration inversion.
The reaction of isoalantolactone (1) with 5ꢀ-iodolappaconitine (3) under the described conditions formed cross-
coupling product 8, which was isolated in 40% yield. It can be seen that the cross-coupling of 1 led to new possibilities for
13
modifying the diterpene alkaloid lappaconitine at the acetylaminobenzoate substituent. The PMR and C NMR spectra
contained sets of resonances confirming the formation of (E)-11-[4-acetamido-3-(aconitan-4ꢅ-yloxycarbonyl)-
881

benzylidene]eudesma-4(15),11(13)-dien-8ꢁ,12-olide (8). Also, formation of the corresponding product from a shift of the
double bond and configuration inversion at C(8) could be noticed from characteristic resonances in the PMR spectra (content
about 5%). This compound could not be isolated pure.
The high stereoselectivity of the cross-coupling of 1 with halides 2 and 3 to produce mainly products 4, 6, and 8 with
the (E)-configuration of the double bond is noteworthy. We observed previously an analogous result for arylation of 1 by
various arylhalides [9, 10]. Therefore, it is interesting that arylation of ꢁ-methylene-ꢂ-butyrolactone 9 occurred with formation
of a mixture of 3-benzylfuran-2(5H)-one (10) and ꢁ-benzylidene-ꢂ-butyrolactone (11) with the (Z)-configuration of the double
bond (Scheme 3) [12]. However, exclusive (E)-stereoselectivity in the cross-coupling of sesquiterpene lactones parthenolide
and 11,13-dehydrosantonin with arylhalides was recently communicated [13].
O
O
O
Ar
Ar
ArX
CH
2
O
O
O
+
10
11
9
Scheme 3
Thus, the Heck reaction of isoalantolactone and alkaloid derivatives produced conjugates of the terpenoid–alkaloid
type. This cross-coupling reaction was characterized by (E)-stereoselectivity.
EXPERIMENTAL
1
13
NMR spectra were taken in CDCl solutions on Bruker AM-400 [operating frequencies 400.13 ( H) and 100.78 ( C)
3
1
13
MHz] and AV-600 [operating frequencies 600.30 ( H) and 150.96 ( C) MHz] spectrometers. Resonances were assigned and
multiplicities were determined in NMR spectra using various modes of proton–proton and carbon–proton shift correlation
spectroscopies (COSY, COXH, COLOC, NOESY). Mass spectra were recorded, molecular weights were determined, and
elemental compositions were found using a DFS Thermo Scientific high-resolution mass spectrometer with ionizing-electron
energy 70 eV (vaporizer temperature 270–300°C). The molecular weight of 8 was found by analyzing an acetonitrile solution
of it using HPLC–MSD on a micrOTOF-Q103 instrument. IR spectra were recorded in KBr pellets on a Vector-22 instrument.
UV absorption spectra were recorded in EtOH on an HP 8453 UV–Vis spectrometer. Specific rotation [ꢁ] was measured in
CHCl on a PolAAr3005 polarimeter.
3
Reaction products were isolated using column chromatography over silica gel (Acros, 0.035-0.070 mm, pore diameter
6 nm) (C H :EtOAc and CHCl :EtOH eluents). Preparative TLC on a layer of silica gel (thickness 1 mm) containing K-35
6
6
3
luminophore (1%) on plates (20 ꢆ 20 cm) was also used as necessary.
Freshly distilled solvents and “pure” reagents were used.
Pd(OAc) was synthesized by the literature method [14]. Lactone 1 was isolated by extraction from Inula helenium
2
roots with subsequent separation as morpholine adducts by the literature method [15]. 6-Bromodeoxyvasicinone (2) was
prepared by a modified method. Its analytical characteristics agreed with those published [16]. 5ꢀ-Iodolappaconitine (3) was
prepared as before [17].
6-Bromodeoxyvasicinone (2). A mixture of 5-bromoanthranylic acid (8.64 g, 40 mmol) and ꢂ-butyrolactam (5.44 g,
64 mmol) was treated dropwise with POCl (26 mL), heated on a water bath for 1.5 h, cooled, decomposed with ice and
3
stirring, and treated with aqueous ammonia (1:1) until the pH was 9-10. The resulting crystals were filtered off, washed
several times with water, dried, and recrystallized from alcohol to afford 2 (9.15 g, 82%), mp 159–160°C (EtOH).
PMR spectrum (400.13 MHz, CDCl , ꢃ, ppm, J/Hz): 2.29 (2H, q, J = 7.2, H-10a, H-10b), 3.15 (2H, t, J = 8.0, H-9a,
3
H-9b), 4.19 (2H, t, J = 7.3, H-11a, H-11b), 7.49 (1H, d, J = 8.6, H-8), 7.77 (1H, dd, J = 8.6, 2.2, H-7), 8.37 (1H, d, J = 2.2,
H-5).
13
C NMR spectrum (100.61 MHz, CDCl ): 19.37 (t, C-10), 32.43 (t, C-9), 46.50 (t, C-11), 119.50 (s, C-6), 121.80 (s,
3
C-4a), 128.49 (s, C-8), 128.77 (s, C-5), 137.11 (s, C-7), 147.85 (s, C-8a), 159.62 (s, C-4), 159.79 (s, C-2).
882

Heck Reaction. A two-necked glass ampul was filled with Ar. Isoalantolactone (1, 440 mg, 1.19 mmol),
6-bromodeoxyvasicinone (500 mg, 1.19 mmol), Pd(OAc) (0.113 mmol, 6 mol%), tris-(o-tolyl)phosphine (0.34 mmol,
2
18 mol%), DMF (7 mL), and Et N (267 mg, 2.64 mmol) were placed into the ampul under a stream of Ar. The ampul was
3
°
sealed (small excess of Ar pressure). The reaction mixture was heated for 15 h at 120°C in the presence of 3-Amolecular
sieves. When the reaction was finished the system was cooled. The ampul was opened. The contents were poured into a Petri
dish and chromatographed over silica gel (eluent CHCl :EtOH, 100:0ꢇ10:1). trans-(o-Tolyl)phosphine, starting lactone
3
(CHCl eluent), the product 4 (CHCl :EtOH 100:1), a mixture of products (4, 5, 7), and compound 6 (CHCl :EtOH 10:1)
3
3
3
eluted successively. The main fraction of 4 (50%) was a pure compound after chromatography. Recrystallization of the
fractions isolated another 15% of 4. The diarylation product 6 and compound 7 were isolated by preparative TLC of separate
fractions (eluents CHCl :EtOH 100:1 for 6 and petroleum ether:EtOAc:EtOH 20:5:1 for 7).
3
7-{(E)-[(3aR,4aS,8aR,9aR)-8a-Methyl-5-methylene-2-oxodecahydronaphtho[2,3-b]furan-3(2H)-
ylidene]methyl}-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (4). Yield 65%, [ꢁ] +435° (c 0.74, CHCl ), mp 237–
D
3
238°C (EtOH). UV spectrum (EtOH, ꢈ , nm): 200, 225, 247, 317, 327sh, 341sh (log ꢉ 4.21, 4.23, 4.26, 4.32, 4.31, 4.09).
max
–1
IR spectrum (KBr, ꢊ, cm ): 835, 908, 1002, 1169, 1488, 1607, 1647, 1687, 1736, 2987.
PMR spectrum (600.30 MHz, CDCl , ꢃ, ppm, J/Hz): 0.84 (3H, s, 14-CH ), 1.24 (1H, ddd, J = 12.7, 12.5, 4.7, H-1a),
3
3
1.38 (1H, ddd, J = 13.1, 12.6, 12.3, H-6a), 1.52-1.59 (4H, m, H-1, H-2a, H-2b, H-9a), 1.93-2.02 (3H, m, H-3, H-5, H-6b), 2.23
(1H, d, J = 15.5, H-9b), 2.28-2.32 (3H, m, H-3, H-10ꢀa, H-10ꢀb), 3.22 (2H, t, J = 7.9, H-9ꢀa, H-9ꢀb), 3.53 (1H, ddd, J = 11.7, 6.0,
5.6, H-7), 4.20 (2H, t, J = 7.3, H-11ꢀa, H-11ꢀb), 4.36 (1H, s, H-15), 4.51 (1H, dd, J = 4.2, 3.7, H-8), 4.71 (1H, s, H-15), 7.44
(1H, s, H-13), 7.67 (1H, d, J = 8.5, H-8ꢀ), 7.80 (1H, dd, J = 8.5, 1.6, H-7ꢀ), 8.38 (1H, s, H-5ꢀ).
13
C NMR spectrum (150.96 MHz, CDCl ): 17.54 (q, C-14), 19.26 (t, C-10ꢀ), 22.56 (t, C-2), 24.40 (t, C-6), 32.41
3
(t, C-9ꢀ), 34.29 (s, C-10), 36.70 (t, C-3), 39.31 (d, C-7), 41.17 (t, C-9), 42.04 (t, C-1), 46.12 (d, C-5), 46.65 (t, C-11ꢀ), 76.83
(d, C-8), 106.60 (t, C-15), 120.62 (s, C-4ꢀa), 127.06 (d, C-8ꢀ), 127.44 (d, C-5ꢀ), 132.34 (s, C-6ꢀ), 133.15 (d, C-13), 133.63
(s, C-11), 134.84 (d, C-7ꢀ), 148.73 (s, C-4, C-8ꢀa), 160.09 (s, C-4ꢀ), 160.83 (s, C-2ꢀ), 171.85 (s, C-12). C H N O .
26 28
2 3
7-{(Z)-[(3aR,4aS,8aR,9aR)-8a-Methyl-5-methylene-2-oxodecahydronaphtho[2,3-b]furan-3(2H)-
ylidene]methyl}-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (5) was characterized from a mixture with 4, content 50%,
characteristic resonances are given.
PMR spectrum (400.13 MHz, CDCl , ꢃ, ppm, J/Hz): 0.88 (3H, s, 14-CH ), 2.32 (2H, t, H-10ꢀa, H-10ꢀb), 3.22 (2H, t,
3
3
J = 7.9, H-9ꢀa, H-9ꢀb), 3.01 (1H, ddd, J = 11.4, 6.4, 5.6, H-7), 4.22 (2H, t, J = 7.3, H-11ꢀa, H-11ꢀb), 4.49 (1H, d, J = 1.0, H-15),
4.63 (1H, ddd, J = 4.7, 4.6, 1.1, H-8), 4.79 (1H, d, J = 1.0, H-15), 7.00 (1H, s, H-13), 7.63 (1H, d, J = 8.6, H-8ꢀ), 8.37 (1H, d,
J = 1.6, H-5ꢀ), 8.64 (1H, dd, J = 8.6, 1.6, H-7ꢀ).
7,7ꢀ-(1E,1ꢀE)-[(3aR,4aR,8aR,9aR)-8a-Methyl-2-oxooctahydronaphtho[2,3-b]furan-3,5(2H,3aH)-
diylidene]bis(methan-1-yl-1-ylidene)bis-{2,3-dihydropyrrolo[2,1-b]-quinazolin-9(1H)-one} (6). Yield 9%. UV spectrum
(EtOH, ꢈ , nm): 202, 228, 236sh, 312, 343sh (log ꢉ 4.68, 4.66, 4.40, 4.05, 3.26).
max
PMR spectrum (400.13 MHz, CDCl , ꢃ, ppm, J/Hz): 0.97 (3H, s, 14-CH ), 1.37 (1H, ddd, J = 12.9, 12.6, 4.9, H-1a),
3
3
1.55 (1H, ddd, J = 13.2, 12.6, 12.6, H-6a), 1.63–1.70 (4H, m, H-1, H-2a, H-2b, H-9a), 1.85 (1H, ddd, J = 13.6, 11.9, 4.6, H-3),
2.18 (1H, d, J = 13.8, H-9b), 2.25–2.35 (6H, m, H-5, H-6, H-10ꢀa, H-10ꢀb, H-10ꢀꢀa, H-10ꢀꢀb), 2.94 (1H, br.d, J = 13.3,
W
= 6.7, H-3), 3.15 (2H, t, J = 7.5, H-9ꢀa, H-9ꢀb), 3.20 (2H, t, J = 7.5, H-9ꢀꢀa, H-9ꢀꢀb), 3.67 (1H, ddd, J = 11.4, 5.7, 5.2,
1/2
H-7), 4.18 (2H, t, J = 7.6, H-11ꢀa, H-11ꢀb), 4.22 (2H, t, J = 7.6, H-11ꢀꢀa, H-11ꢀꢀb), 4.59 (1H, ddd, J = 4.6, 4.6, 1.2, H-8), 6.04
(1H, s, H-15), 7.89 (1H, dd, J = 8.3, 2.0, H-7ꢀꢀ), 7.54 (1H, s, H-13), 7.55 (1H, d, J = 8.3, H-8ꢀꢀ), 7.70 (1H, d, J = 8.5, H-8ꢀ), 7.87
(1H, dd, J = 8.5, 1.9, H-7ꢀ), 8.01 (1H, d, J = 2.0, H-5ꢀꢀ), 8.49 (1H, d, J = 1.9, H-5ꢀ).
13
C NMR spectrum (100.61 MHz, CDCl ): 17.90 (q, C-14), 19.33 (t, C-10ꢀ), 19.44 (t, C-10ꢀꢀ), 22.54 (t, C-2), 24.41
3
(t, C-6), 30.41 (s, C-3), 32.33 (t, C-9ꢀꢀ), 32.53 (t, C-9ꢀ), 35.33 (t, C-10), 39.39 (d, C-7), 41.48 (t, C-9), 42.30 (t, C-1), 46.35 (t,
C-11ꢀꢀ), 46.53 (t, C-11ꢀ), 47.10 (d, C-5), 76.65 (d, C-8), 120.02 (s, C-4ꢀa), 120.57 (d, C-15), 120.83 (s, C-4ꢀꢀa), 125.86 (d, C-5ꢀ),
126.28 (d, C-5ꢀꢀ), 127.34 (d, C-8ꢀ), 127.66 (d, C-8ꢀꢀ), 132.09 (s, C-6ꢀ), 133.33 (s, C-11), 133.60 (d, C-13), 135.04 (d, C-7ꢀ),
135.18 (d, C-7ꢀꢀ), 136.43 (s, C-6ꢀꢀ), 143.89 (s, C-4), 147.18 (s, C-8ꢀꢀa), 149.67 (s, C-8ꢀa), 158.82 (s, C-2ꢀ), 160.44 (s, C-4ꢀ),
160.66 (s, C-2ꢀꢀ), 160.84 (s, C-4ꢀꢀ), 171.98 (s, C-12).
+
Mass spectrum (m/z, I , %): 600 (29) [M] , 413 (10), 399 (34), 362 (28), 239 (10), 213 (10), 199 (42), 149 (32), 147
rel
+
(20), 125 (20), 111 (24), 97 (43), 85 (58), 83 (91), 57 (100), 43 (90). Found [M] 600.2728. C H N O , calcd. MW
37 36
4 4
600.2731.
883

7-{[(4aS,8aR,9aS)-8a-Methyl-5-methylene-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydronaphtho[2,3-b]furan-3-
yl]methyl}-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (7). Amorphous solid. Yield 3%. UV spectrum (EtOH,
ꢈ
, nm): 200, 227, 269, 308, 320 (log ꢉ 4.33 ,4.28, 3.74, 3.49, 3.43).
max
PMR spectrum (600.30 MHz, CDCl , ꢃ, ppm, J/Hz): 0.88 (3H, s, 14-CH ), 1.18 (1H, dd, J = 12.1, 11.4, H-9), 1.33
3
3
(1H, ddd, J = 13.6, 13.6, 5.3, H-1), 1.53–1.63 (3H, m, H-1, H-2a, H-2b), 1.87 (1H, dd, J = 13.6, 2.4, H-5), 2.25 (2H, q, J = 7.6,
H-10ꢀa, H-10ꢀb), 2.31–2.36 (3H, m, H-3, H-6, H-9), 2.75 (1H, dd, J = 13.6, 3.0, H-6), 3.15 (2H, t, J = 7.5, H-9ꢀa, H-9ꢀb), 3.69
(1H, d, J = 15.2, H-13a), 3.74 (1H, d, J = 15.2, H-13b), 4.18 (2H, t, J = 7.9, H-11ꢀa, H-11ꢀb), 4.53 (1H, s, H-15a), 4.83 (1H, s,
H-15b), 4.88 (1H, dd, J = 11.4, 6.8, H-8), 7.56 (1H, d, J = 8.3, H-8ꢀ), 7.66 (1H, dd, J = 8.3, 1.6, H-7ꢀ), 8.03 (1H, d, J = 1.6, H-
5ꢀ).
13
C NMR spectrum (150.96 MHz, CDCl ): 16.31 (q, C-14), 19.38 (t, C-10ꢀ), 22.16 (t, C-2), 25.77 (t, C-6), 28.79 (t,
3
C-13), 32.28 (t, C-9ꢀ), 36.07 (t, C-3), 36.79 (s, C-10), 40.63 (t, C-1), 46.31 (t, C-11ꢀ), 47.53 (t, C-9), 49.93 (d, C-5), 77.93 (d,
C-8), 106.92 (t, C-15), 120.29 (s, C-4ꢀa), 122.64 (s, C-11), 125.05 (d, C-5ꢀ), 127.05 (d, C-8ꢀ), 134.82 (d, C-7ꢀ), 136.49 (s, C-6ꢀ),
147.77 (s, C-8ꢀa), 147.98 (s, C-4), 158.91 (s, C-2ꢀ), 160.67 (s, C-4ꢀ), 164.34 (s, C-7), 173.65 (s, C-12). C H N O .
26 28
2 3
(3aR,4aS,8aR,9aR,E)-3-{4ꢀꢀꢅ-3-[4ꢀ-Acetamido-3ꢀ-(8ꢀꢀ,9ꢀꢀ-dihydroxy-1ꢀꢀꢁ,14ꢀꢀꢁ,16ꢀꢀꢅ-trimethoxy-20ꢀꢀ-
ethylaconitan-4ꢅ-yl)oxycarbonyl)]benzylidene}-8a-methyl-5-methylenedecahydronaphtho[2,3-b]furan-2(3H)-one (8).
A two-necked glass ampul was filled with Ar. Isoalantolactone (1, 150 mg, 0.65 mmol), 5ꢀ-iodolappaconitine (3, 375 mg,
0.54 mmol), Pd(OAc) (0.03 mmol, 6 mol%), tris-(o-tolyl)phosphine (0.13 mmol, 24 mol%), DMF (4 mL), and Et N (77 mg,
2
3
0.76 mmol) were placed successively into the ampul under a stream ofAr. The ampul was sealed (small excess ofAr pressure).
°
The reaction mixture was heated for 15 h at 120°C in the presence of 3A molecular sieves. When the reaction was finished the
system was cooled. The ampul was opened. The contents were poured into a Petri dish and chromatographed over silica gel
(eluent CHCl :EtOH 100:0ꢇ10:1). Unreacted lactone (1) and product 8 (CHCl :EtOH 50:1) eluted successively. The fraction
3
3
containing the product was also purified by preparative TLC (CHCl :EtOH 10:1). Yield of 8, 40%, [ꢁ] +235° (c 0.50,
3
D
CHCl ), mp 148–152°C (CHCl ). UV spectrum (EtOH, ꢈ , nm): 200, 226, 247, 314 (log ꢉ 4.38, 4.25, 4.23, 4.40). IR
3
3
max
–1
spectrum (KBr, ꢊ, cm ): 1088, 1169, 1230, 1247, 1293, 1513, 1588, 1689, 1705, 1754.
PMR spectrum (600.30 MHz, CDCl , ꢃ, ppm, J/Hz): 0.83 (3H, s, 14-CH ), 1.11 (3H, t, J = 7, 22ꢀꢀ-CH ), 1.29-1.36
3
3
3
(2H, m, H-1a, H-6a), 1.48-1.60 (5H, m, H-1b, H-2a, H-2b, H-6ꢀꢀa, H-9a), 1.79 (1H, dd, J = 11.9, 11.6, W = 9, H-3ꢀꢀa), 1.97–
1/2
2.10 (6H, m, H-2ꢀꢀa, H-3a, H-5, H-6b, H-10ꢀꢀ, H-15ꢀꢀa), 2.12 (1H, d, J = 7.8, H-5ꢀꢀ), 2.15–2.23 (3H, m, H-9b, H-12ꢀꢀa, H-12ꢀꢀb),
2.21 (3H, s, CH CO), 2.29-2.37 (4H, m, H-3b, H-7ꢀꢀ, H-13ꢀꢀ, H-15ꢀꢀb), 2.42 (1H, dd, J = 14.8, 4.2, H-2ꢀꢀb), 2.50-2.58 (4H, m,
3
H-3ꢀꢀb, H-19ꢀꢀa, H-21ꢀꢀa, H-21ꢀꢀb), 2.68 (1H, dd, J = 14.6, 7.5, H-6ꢀꢀb), 2.99 (1H, s, H-17ꢀꢀ), 3.13 (1H, dd, J = 9.9, 6.3, H-1ꢀꢀ),
3.27 (3H, s, CH OC-1ꢀꢀ), 3.28 (3H, s, CH OC-16ꢀꢀ), 3.28 (1H, m, H-16ꢀꢀ), 3.38 (3H, s, CH OC-14ꢀꢀ), 3.39-3.43 (2H, m, H-7,
3
3
3
H-14ꢀꢀ), 3.54 (1H, d, J = 11.5, C-19ꢀꢀb), 4.36 (1H, s, H-15), 4.51 (1H, dd, J = 4.6, 4.0, H-8), 4.73 (1H, s, H-15), 7.33 (1H,
W
= 3.3, H-13), 7.63 (1H, dd, J = 8.7, 1.5, H-4ꢀ), 8.15 (1H, d, J = 1.5, H-6ꢀ), 8.71 (1H, d, J = 8.8, H-3ꢀ), 11.13 (1H, s, NH).
1/2
13
C NMR spectrum (150.96 MHz, CDCl ): 13.27 (q, C-22ꢀꢀ), 17.49 (q, C-14), 22.57 (t, C-2), 23.99 (t, C-6,6ꢀꢀ), 25.38
3
(q, CH CONH), 26.12 (t, C-2ꢀꢀ), 26.47 (t, C-12ꢀꢀ), 31.69 (t, C-3ꢀꢀ), 34.32 (s, C-10), 36.17 (d, C-13ꢀꢀ), 36.68 (t, C-3), 39.25 (d,
3
C-7), 41.13 (t, C-9), 41.64 (t, C-1), 44.52 (t, C-15ꢀꢀ), 45.66 (d, C-5), 47.49 (d, C-5ꢀꢀ), 48.14 (d, C-7ꢀꢀ), 48.83 (t, C-21ꢀꢀ),
49.78 (d, C-10ꢀꢀ), 50.94 (s, C-11ꢀꢀ), 55.36 (t, C-19ꢀꢀ), 55.96 (q, OCH ), 56.39 (q, OCH ), 57.80 (q, CH OC-14ꢀꢀ), 61.30 (d, C-
3
3
3
17ꢀꢀ), 75.38 (s, C-8ꢀꢀ), 76.77 (d, C-8), 78.42 (s, C-9ꢀꢀ), 82.71 (d, C-16ꢀꢀ), 83.94 (d, C-1ꢀꢀ), 85.03 (s, C-4ꢀꢀ), 90.03 (d, C-14ꢀꢀ),
106.63 (t, C-15), 115.81 (s, C-1ꢀ), 120.53 (d, C-3ꢀ), 127.96 (s, C-11), 131.47 (s, C-5ꢀ), 132.45 (d, C-6ꢀ), 133.56 (d, C-13),
135.41 (d, C-4ꢀ), 142.39 (s, C-2ꢀ), 148.83 (s, C-4), 166.52 (s, COO), 169.15 (s, CONH), 172.27 (s, C-12). C H N O . Ions
47 62
2 10
+
–
with m/z 815.47 [M + H] and 849.418 [M + Cl] were detected by scanning positive ions of 8 (micrOTOF 103 instrument) in
–
the m/z range 500-2500. Found [M + Cl] 849.418 (MW 814.45). C H N O , calcd. MW 814.44.
47 62
2 10
ACKNOWLEDGMENT
The work was supported financially by the Russian Foundation for Basic Research (Project No. 08-03-00340).
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