Synthetic Transformations of Sesquiterpene Lactones. 11.* Conjugates Based on Caffeine and Eudesmanolides with N-Containing Linkers

Article abstract of DOI:10.1007/s10600-020-03169-x

8-(Aminoalkylamino)caffeine or 8-(piperazinyl)caffeine were formed in high yields by reacting 8-bromo- or 8-chlorocaffeine with linear and cyclic diamines using microwave-assisted organic synthesis. These amines were highly reactive in Michael reactions with sesquiterpene lactones containing active methylene groups. Conjugates with caffeine and eudesmanolide moieties bonded by a N-containing linker were synthesized.

Full text of DOI:10.1007/s10600-020-03169-x

DOI 10.1007/s10600-020-03169-x
Chemistry of Natural Compounds, Vol. 56, No. 5, September, 2020
SYNTHETIC TRANSFORMATIONS OF SESQUITERPENE LACTONES.
*
11. CONJUGATES BASED ON CAFFEINE AND EUDESMANOLIDES
WITH N-CONTAINING LINKERS
1
1,2
1*
D. V. Reshetnikov, S. S. Patrushev, and E. E. Shults
8-(Aminoalkylamino)caffeine or 8-(piperazinyl)caffeine were formed in high yields by reacting 8-bromo- or
8-chlorocaffeine with linear and cyclic diamines using microwave-assisted organic synthesis. These amines
were highly reactive in Michael reactions with sesquiterpene lactones containing active methylene groups.
Conjugates with caffeine and eudesmanolide moieties bonded by a N-containing linker were synthesized.
Keywords: caffeine, eudesmanolides, methylenelactones, Michael reaction.
The alkaloid caffeine (1) is an available natural methylxanthine and an interesting lead compound for designing new
derivatives with valuable biological activity and lower toxicity. It was used as a platform to synthesize agents to treat cancer
of the lungs, liver, and breast and compounds enhancing stomach secretions and reducing the risk of developing gallstone
disease [2]. Research on caffeine derivatives showed that compounds with various substituents in the C-8 position were
antagonists of adenosine receptors [3, 4] and acetylcholine esterase [5, 6] and monoamine oxidase inhibitors [7]. 8-(2-Phenethyl)-
1,3,7-trimethylxanthine and 8-(phenoxymethyl)-1,3,7-trimethylxanthine were found to exhibit affinity forA andA adenosine
1
2
receptors [8], confirming the hypothesis that modification of the caffeine C-8 substituent structure could lead to agents with
increased affinity and selectivity for A , A , A , or A adenosine receptors. 8-Aminocaffeine and 8-alkylmercaptocaffeine
1
2A 2B
3
derivatives belong to this pharmacologically promising subclass [9].
The present article reports the regioselective synthesis of a series of eudesmane-xanthine conjugates using Michael
reactions of diamino-substituted caffeine derivatives with eudesmane-type lactones, e.g., isoalantolactone (2),
4,15-epoxyisoalantolactone (3), and 3-hydroxyisoalantolactone (4). The presence of an activated methylene in lactones 2–4
enabled them to undergo Michael reactions. The nucleophiles were the N-nucleophiles 8-(aminoalkylamino)caffeine and
8-(piperazinyl)caffeine.
The 8-aminocaffeine derivatives were prepared by heating 8-chlorocaffeine (5) with an excess (5 eq.) of an amine at
175–180°C [7] followed by workup with AcOH. Syntheses of caffeine diamino derivatives 6 and 7 by refluxing with an
excess of ethylenediamine (8) or hexamethylenediamine (9) (5 mmol) and 2-bromocaffeine (10) in EtOH were previously
reported [10]. In our hands, 6 and 7 were formed by reacting 8-chlorocaffeine (5) with diamines 8 and 9 (2 eq.) in
2-methoxyethanol using microwave-assisted organic synthesis (MAOS) (120°C, 3 h). Compounds 6 and 7 were isolated in
80–93% yields after column chromatography (Scheme 1). Their analytical characteristics were analogous to those in the
literature [10]. This reaction also occurred readily with cyclic amines. The reaction of 8-halocaffeine 5 or 10 with piperazine
(11) or morpholine (12) under the noted conditions gave 8-(piperazin-1-yl)caffeine 13 or 8-morpholinocaffeine 14 in 86–90%
yields. Disubstituted 8,8′-(ethane-1,2-diamino)bis[1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione] (4% yield) was isolated
from the reaction of 8-chlorocaffeine with ethylenediamine (8). An analysis of the reactions of morpholine (12) with
8-chlorocaffeine (5) or 8-bromocaffeine (10) found no difference in the course of the reaction depending on the 8-halocaffeine.
The conversion of the starting halogens and yields of 14 differed insignificantly.
______
*For No. 10, see the literature [1].
1) N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences,
9 Prosp. Akad. Lavrent′eva, Novosibirsk, 630090, e-mail: schultz@nioch.nsc.ru; 2) Novosibirsk State University, 1 Pirogova
St., Novosibirsk, 630090. Translated from Khimiya Prirodnykh Soedinenii, No. 5, September–October, 2020, pp. 733–737.
Original article submitted February 13, 2020.
©
0009-3130/20/5605-0855 2020 Springer Science+Business Media, LLC
855

O
O
N
O
N
1
N
N
N
N
N
6
b
i
N
a
N
7
8
NH(CH ) NH
Cl
2
n
2
4
N
N
O
N
O
O
9
6, 7
1
5
c
NH
X
O
O
11, 12
i
N
N
N
N
N
5 or 10
N
H
X
Br
N
O
N
O
N
13, 14
10
14
H
9
H
1
O
O
O
7
ii
12
6
10
O
O
O
7
5
ii
4
11
13
9'
2'
6
H
N
O
N
O
O
H
H
H
H
N
H
N
N
NH
H
H
N
3'
15
N
HN
(CH )
2 4
8'
N
N
N7'
1'
15
2
16
O
H
H
O
O
O
O
N
13
ii
O
N
N
N
N
H
H
H
H
O
N
O
3
19
O
N
H
H
O
O
13
ii
O
N
O
O
N
N
R
R
H
H
H
H
N
N
17, 18
2, 4
O
n = 2 (6, 8); n = 6 (7, 9); X = NH (11, 13); X = O (12, 14)
2, 17: R = H; 4, 18: R = OH
a. NCS, H O–CH Cl , 24 h; b. NH (CH ) NH (8 or 9); c. NBS
2
2
2
2
2 n
2
i. 2-methoxyethanol, MAOS, 120°C, 3 h; ii. Et N, EtOH, 55°C, 3 h
3
Scheme 1
Conjugates 15 and 16 with fragments of the natural compounds isoalantolactone (2) and caffeine (1) linked by
ethylenediamine or hexamethylenediamine were obtained by an aza-Michael reaction of 2 with 8-(2-aminoethylamino)caffeine
(6) or 8-(6-aminohexylamino)caffeine (7) in the presence of Et N in EtOH at 55°C for 3 h.
3
The degree of conversion of 2 was monitored by TLC. Conjugates 15 and 16 were isolated by column chromatography
over silica gel in 65 and 44% yields, respectively (Scheme 1). The reaction of 2 with aliphatic primary and secondary amines
(e.g., with morpholine [11]) is known to occur in alcohols at reduced temperature without a catalyst. The temperature had to
be increased and an excess of Et N had to be used for complete conversion of 2 with amines 6 and 7.
3
The reaction of methylenelactones 2–4 with 8-(piperazinyl)caffeine (13) in the presence of Et N formed conjugates
3
17–19, which were isolated in 44–60% yields. It can be seen that the yields of aza-Michael reaction products of eudesmane
methylenelactones 2–4 were practically independent of the methylenelactone structure.
The structures of the synthesized compounds were elucidated using physicochemical methods, i.e., IR, UV, PMR,
and C NMR spectroscopy [including two-dimensional (2D) NOESY, COSY, and COXH experiments] and high-resolution
13
mass spectrometry (see Experimental). PMR spectra of 15–19 showed resonances of protons in the products on C-11
(in the range 2.9–3.2 ppm as a doublet of triplets for 15 and 16 or a doublet of doublets of doublets for 17–19) and C-13
(CH N groups as a doublet of doublets at δ 2.75–3.09 ppm with geminal SSCC J = 11.7–13.2 Hz and vicinal SSCC
2
J = 4.1–7.7 Hz and a doublet of doublets in the range 2.57–3.04 with the given geminal constant and vicinal constant
J = 5.8–10.5 Hz). The stereochemistry of the new asymmetric center (11R) in 15–19 was established using the NOE-effect
(cross-peaks) between H(5)-H(7)-H(8)-H(11), which indicated they were cis-positioned (Fig. 1).
856

14
H
H
O
O
N
O
5
11
H
N
N
H
N
O
N
N
H
15
H
O
19
Fig. 1. Structurally significant NOE correlations for 19.
Cross-peaks between H(14)-H(15) confirmed the structure of the oxirane fragment and the R-configuration of C(4).
The resonances and multiplicities of the other protons of the starting lactone and the caffeine derivatives remained the same
and corresponded to the proposed structures.
High-resolution mass spectra contained strong peaks for the molecular ion, caffeine diamine, and the corresponding
sesquiterpene lactone and confirmed the empirical formula of the amination products.
EXPERIMENTAL
–1
IR spectra (ν, cm ) were taken from KBr pellets on a Vector-22 Fourier spectrometer. UV absorption spectra [λ
,
max
13
nm (log ε)] were obtained on an HP 8453 UV-Vis spectrometer in EtOH solution. PMR and C NMR spectra were recorded
in CDCl (CDCl + CD OD for 6 and 7) with TMS internal standard on Bruker AV-400 [400.13 ( H) and 100.78 MHz ( C)]
and AV-600 [600.30 ( H) and 150.96 MHz ( C)] (16 and 19) spectrometers. The structures of the synthesized compounds
were elucidated by analyzing PMR and C NMR spectra and using 2D H– H and C– H correlation spectroscopy (COSY,
1
13
3
3
3
1
13
13
1
1
13
1
13
COXH, NOESY, mixing time 1 s, delay between pulses 2 s). PMR and C NMR spectra were described using atomic
numbering of the backbone and substituents given for the structures of 1 and 15.
Mass spectra were recorded and molecular masses and elemental compositions were determined using
a DFS high-resolution mass spectrometer (Thermo Scientific) (vaporizer temperature 190–270°C, electrospray ionization
source).
Melting points were measured on a Mettler Toledo FP900 apparatus. Specific rotation [α] was measured on
D
a PolAAr3005 polarimeter and were expressed in deg⋅mL/g⋅dm. Concentrations were given in g per 100 mL of solution.
The spectral analytical studies were performed at the Khimiya Common Use Center of the SB, RAS.
The reactions of 5 with 8 or 9 were performed in an Anton Paar Monowave 300 microwave reactor.
The course of reactions and purity of products were monitored using TLC on Silufol UV-254 plates, CHCl –EtOH
3
(9:1) or C H –EtOAc (3:1) eluent, and detection by I vapor or UV radiation. Reaction products were isolated by column
6
6
2
chromatography over silica gel (Acros, 0.035–0.240 mm) with elution by CHCl –EtOH (100:0→75:25).
3
Solvents (2-methoxyethanol, EtOH, CH Cl , CHCl ) were purified by standard methods and distilled under Ar
2
2
3
immediately before use in reactions. The reagents caffeine, N-bromosuccinimide, N-chlorosuccinimide, morpholine, piperazine,
ethylenediamine, and hexamethylenediamine were purchased (Alfa Aesar).
Isoalantolactone (2) [mp 104–106°C (petroleum ether), [α] +173° (c 5.1, CHCl )] that was obtained via extraction
D
3
from Inula helenium L. followed by purification of the morpholine adduct using the literature method [11] was used in
the work. 4,15-Epoxyisoalantolactone (3) was prepared via epoxidation of 2 by the literature method [12];
3-hydroxyisoalantolactone (4), via oxidation of 2 by selenium dioxide by the literature method [13]; 8-chlorocaffeine (5) and
8-bromocaffeine (10), by reacting 1 with N-chlorosuccinimide or N-bromosuccinimide by a modified literature method [14].
The characteristics of 5 [15] and 10 [14] agreed with those in the literature.
Synthesis of 8-Amino-substituted Caffeine Derivatives. General Method. 8-Chlorocaffeine (5, 0.44 mmol,
100 mg) and the appropriate amine [ethylenediamine (8), hexamethylenediamine (9), piperazine (11), or morpholine (12)]
(1.76 mmol) were dissolved in methoxyethanol (3.5 mL). The mixture was stirred for 3 h in a microwave reactor at 120°C and
cooled. The resulting precipitate of disubstitution product (0.5–4% yield) was filtered off and rinsed with EtOH (3 × 5 mL).
The mother liquor was evaporated. The residue was worked up with H O and extracted with CHCl (3 × 20 mL). The organic
2
3
fractions were combined, dried over MgSO , and evaporated. Compounds 6, 7, 13, and 14 were purified by column
4
chromatography over silica gel (CHCl –EtOH eluent, 100:0→70:30).
3
857

8-(2-Aminoethyleneamino)caffeine [8-(2-Aminoethylamino)-1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione] (6).
–1
Yield 93%, white powder, mp 167–170°Ñ. IR spectrum (KBr, ν, cm ): 3309 (N-H), 2947, 1697 (C=O), 1649 (C=O), 1608,
1
1574, 1549, 1489, 1446, 1387, 1217, 1028, 754. UV spectrum (EtOH, λ , nm) (log ε): 213 (4.57), 293 (4.44). Í NMR
max
spectrum (400 MHz, CD OD, δ, ppm, J/Hz): 3.76 (2Í, dd, J = 5.5, 7.1, CH ), 3.70 (3H, s, NCH ), 3.51 (3H, s, NCH ), 3.35
3
2
3
3
13
(3H, s, NCH ), 3.27 (2H, dd, J = 5.5, 7.1, CH ), 2.75 (2H, br.s, NH ). C NMR spectrum (100 MHz, δ, ppm): 153.8 (C-6),
3
2
2
153.8 (C-8), 151.5 (C-2), 148.4 (C-4), 103.0 (C-5), 42.1 (CH ), 40.0 (CH ), 29.4 (NMe), 29.3 (NMe), 27.3 (NMe). Mass
2
2
spectrum (m/z, I , %): 252 (47), 223 (17), 222 (100), 209 (18), 195 (9), 165 (10), 82 (13), 67 (18), 42 (12), 36 (14); found
îòí.
+
+
m/z 252.1331 [M] ; calcd for C H N O , 252.1329 [M] .
10 16
6 2
The reaction of 5 with ethylenediamine (8) also afforded the disubstitution product 8,8′-(ethane-1,2-diamino)bis[1,3,7-
trimethyl-1H-purine-2,6(3H,7H)-dione] (4% yield), mp 370°C (dec.). Found, %: C 49.30; H 6.05; N 30.60. C H N O .
18 24 10
4
Calcd, %: C 48.64; H 5.44; N 31.51.
8-(6-Aminohexamethyleneamino)caffeine [8-(6-Aminohexylamino)-1,3,7-trimethyl-1H-purine-2,6(3H,7H)-
–1
dione] (7). Yield 80%, white powder, mp 153–156°Ñ. IR spectrum (KBr, ν, cm ): 3369 (N-H), 2935, 1703 (C=O), 1661
(C=O), 1614, 1580, 1545, 1479, 1460, 1431, 1221, 1036, 750. UV spectrum (EtOH, λ , nm) (log ε): 217 (4.56), 297 (4.49).
max
1
Í NMR spectrum (400 MHz, CDCl + CD OD, δ, ppm, J/Hz): 3.81 (2H, dd, J = 7.1, 7.8, CH NH), 3.54 (3H, s, NÑÍ ), 3.43
3
3
2
3
(3H, s, NÑÍ ), 3.34 (2H, dd, J = 7.1, 7.8, CH ), 3.27 (3H, s, NÑÍ ), 2.65 (2H, dd, J = 7.1, 8.6, CH ), 1.56 (2H, m, CH ), 1.45
3
2
3
2
2
13
(2H, m, CH ), 1.30–1.32 (2H, m, CH ), 1.17 (2H, t, J = 7.1, 8.3, CH ). C NMR spectrum (100 MHz, δ, ppm): 154.1 (C-6),
2
2
2
153.8 (C-8), 151.6 (C-2), 148.9 (C-4), 102.8 (C-5), 42.6 (CH ), 40.6 (CH ), 30.9 (CH ), 29.4 (CH ), 29.2 (2 × NÑÍ ), 27.3
2
2
2
2
3
(NÑÍ ), 26.0 (CH ), 25.9 (CH ). Mass spectrum (m/z, I , %): 308 (100), 278 (16), 236 (21), 223 (11), 222 (65), 209 (40), 165
3
2
2
rel
+
+
(7), 82 (13), 67 (9), 42 (7); found m/z 308.1958 [M] ; calcd for C H N O , 308.1955 [M] .
14 24
6 2
1,3,7-Trimethyl-8-(piperazin-1-yl)-1H-purine-2,6(3H,7H)-dione (13). Yield 90%, white powder, mp 173.7°C.
–1
IR spectrum (ν, cm ): 3317 (NH), 1695 (C=O), 1657 (C=O), 1610, 1516, 910, 746 (C=C, C=N). UV spectrum (λ
, nm)
max.
1
(log ε): 206 (4.20), 223 (4.26), 293 (4.19). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 5.10 (m, NH), 3.72 (3H, s,
NCH ), 3.50 (3H, s, NCH ), 3.36 (3H, s, NCH ), 3.20–3.22 (4H, m, 2 × CH ), 2.99–3.01 (4H, m, 2 × CH ). C NMR
3
13
3
3
3
2
2
spectrum (100 MHz, CDCl , δ, ppm): 156.5 (C-6), 154.9 (C-8), 151.7 (C-2), 147.4 (C-4), 105.2 (C-5), 50.8 (2 × CH ), 45.5
3
2
(2 × CH ), 32.4 (NÑH ), 29.5 (NÑH ), 27.6 (NÑH ). Mass spectrum (m/z, I , %): 278 (100), 236 (28), 223 (26), 222
2
3
3
3
rel
+
+
(100), 209 (48), 207 (12), 67 (20), 57 (20), 56 (20), 42 (13); found m/z 278.1485 [M] ; calcd for C H N O , 278.1486 [M] .
12 18
6 2
1,3,7-Trimethyl-8-morpholino-1H-purine-2,6(3H,7H)-dione (14). Yield 86%, white powder, mp 152.0–154.9°C.
–1
IR spectrum (ν, cm ): 1701 (C=O), 1653 (C=O), 1612, 1514, 1445, 912, 748 (C=C, C=N). UV spectrum (λ , nm) (log ε):
max
1
206 (4.18), 222 (4.29), 291 (4.19). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 3.82 (4H, dd, J = 4.6, 6.2, 2 × CH ),
3.73 (3H, s, NCH ), 3.50 (3H, s, NCH ), 3.36 (3H, s, NCH ), 3.23 (4H, dd, J = 4.6, 6.2, 2 × CH ). C NMR spectrum (100 MHz,
3
2
13
3
3
3
2
CDCl , δ, ppm): 155.7 (C-6), 154.8 (C-8), 151.5 (C-2), 147.1 (C-4), 105.3 (C-5), 66.1 (2 × CH ), 49.8 (2 × CH ), 32.2 (NÑH ),
3
2
2
3
29.4 (NÑH ), 27.5 (NÑH ). Mass spectrum (m/z, I , %): 279 (100), 264 (11), 234 (6), 222 (19), 221 (8), 220 (8), 194 (6), 193 (4),
3
3
rel
+
67 (7), 42 (6), ; found m/z 279.1320 [M] ; calcd for C H N O , 279.1326.
12 17
5 3
Synthesis of Conjugates 15–19. General Method. Caffeine derivative 6, 7, or 13 (1 mmol), the appropriate lactone
2, 3, or 4 (0.9 mmol), and Et N (2.0 mmol) were dissolved in EtOH (10 mL). The reaction mixture was stirred at 55°C for
3
3 h and at room temperature for 12 h. When the reaction was finished, the mixture was evaporated in a rotary evaporator.
The residue was chromatographed over silica gel (CHCl –EtOH eluent, 100:0→75:25).
3
1,3,7-Trimethyl-8-(2-{[(3R,3aR,4aS,8aR,9aR)-8a-methyl-5-methylene-2-oxododecahydronaphtho[2,3-b]furan-
23
3-yl]methylamino}ethylamino)-1H-purine-2,6(3H,7H)-dione (15). Yield 65%, white powder, mp 194°C; [α]
+44°
589
–1
(c 0.37, CHCl ). IR spectrum (ν, cm ): 3431 (NH), 2931, 1763 (C=O), 1697 (C=O), 1653 (C=O), 1622, 1578, 1549, 1489,
1456, 1221, 1165, 910, 720. UV spectrum (λ , nm) (log ε): 216 (4.54), 296 (4.45). Í NMR spectrum (400 MHz, CDCl , δ,
3
1
max
3
ppm, J/Hz): 4.67 (1H, d, J = 1.5, H-15), 4.52 (1H, ddd, J = 1.7, 4.2, 5.1, H-8), 4.32 (1H, d, J = 1.5, H-15), 3.65 (2H, t, J = 4.6,
CH ), 3.60 (3H, s, NCH ), 3.40 (3H, s, NCH ), 3.30–3.44 (2H, m, NH), 3.26 (3H, s, NCH ), 3.20 (1H, dt, J = 6.4, 7.0, H-11),
2
3
3
3
3.07–3.12 (3H, m, H-13, CH ), 3.04 (1H, dd, J = 5.8, 12.1, H-13), 2.57 (1H, dtd, J = 4.0, 6.0, 6.1, 12.5, H-7), 2.24 (1H, d,
2
J = 13.6, H-3), 2.08 (1H, dd, J = 1.8, 15.5, H-9), 1.89 (1H, ddd, J = 5.1, 12.6, 14.5, H-3), 1.72 (1H, d, J = 12.0, H-5), 1.43–1.50
(4H, m, H-1, 2, 2, 6), 1.41 (1H, dd, J = 4.0, 15.5, H-9), 1.15 (1H, ddd, J = 4.3, 13.2, 14.3, H-1), 1.06 (1H, dd, J = 12.6, 12.8,
13
H-6), 0.68 (3H, s, ÑH ). C NMR spectrum (100 MHz, CDCl , δ, ppm): 177.5 (C-12), 153.6 (C-6′), 152.8 (C-8′), 151.3 (C-2′),
3
3
148.5 (C-4), 148.0 (C-4′), 106.0 (C-15), 103.0 (C-5′), 78.6 (C-8), 48.3 (C-13), 45.7 (C-11), 44.6 (C-5), 44.1 (CH ), 41.6 (C-1), 40.6
2
(C-9), 39.7 (CH ), 38.6 (C-7), 36.1 (C-3), 34.2 (C-10), 29.4 (NCH ), 29.2 (NCH ), 27.2 (NCH ), 22.1 (C-2), 20.7 (C-6), 17.2
2
3
3
3
858

(ÑH ). Mass spectrum (m/z, I , %): 484 (6), 252 (57), 232 (46), 223 (32), 222 (100), 209 (40), 190 (60), 93 (34), 91 (32), 79 (32);
3
rel
+
found m/z 484.2790 [M] ; calcd for C H N O , 484.2793.
25 36
6 4
1,3,7-Trimethyl-8-(6-{[(3R,3aR,4aS,8aR,9aR)-8a-methyl-5-methylene-2-oxododecahydronaphtho[2,3-b]furan-
23
3-yl]methylamino}hexylamino)-1H-purine-2,6(3H,7H)-dione (16). Yield 44%, oily compound, [α] +23° (c 1.50 CHCl ).
589
3
–1
IR spectrum (ν, cm ): 3348 (NH), 1751 (C=O), 1709 (C=O), 1661 (C=O), 1614, 1581, 1547, 1481, 1454, 1373, 1221, 1161,
1032, 968, 744. UV spectrum (λ , nm) (log ε): 217 (4.60), 297 (4.54). Í NMR spectrum (600 MHz, CDCl , δ, ppm, J/Hz):
1
max
3
4.71 (1H, d, J = 1.3, H-15) 4.61 (1H, s, NH), 4.44 (1H, ddd, J = 1.5, 3.9, 4.7, H-8), 4.39 (1H, d, J = 1.3, H-15), 3.59 (3H, s,
NÑH ), 3.45 (3H, s, NÑH ), 3.39 (2H, dt, J = 6.2, 7.0, CH ), 3.30 (3H, s, NÑH ), 2.95 (1H, dd, J = 7.7, 11.7, H-13), 2.86 (1H,
3
3
2
3
dt, J = 6.7, 7.0, H-11), 2.71 (1H, dd, J = 7.0, 11.7, H-13), 2.56–2.63 (2H, m, CH ), 2.44 (1H, dtd, J = 4.4, 6.0, 6.3, 12.2, H-7),
2
2.26 (1H, d, J = 13.6, H-3), 2.14–2.10 (1H, m, NH), 2.09 (1H, dd, J = 1.8, 15.4, H-9), 1.92 (1H, ddd, J = 5.4, 12.5, 14.0, H-3),
1.72 (1H, d, J = 12.0, H-5), 1.57–1.62 (2H, m, CH ), 1.46–1.53 (6H, m, H-1, 2, 2, 6, CH ), 1.41 (1H, dd, J = 4.1, 15.5, H-9),
2
2
13
1.33–1.35 (4H, m, 2 × CH ), 1.16–1.18 (1H, m, H-1), 1.16 (1H, dd, J = 12.8, 13.1, H-6), 0.73 (3H, s, ÑH ). C NMR spectrum
2
3
(150 MHz, CDCl , δ, ppm): 178.3 (C-12), 153.9 (C-6′), 153.5 (C-8′), 151.6 (C-2′), 149.1 (C-4), 148.6 (C-4′), 106.2 (C-15), 102.8
3
(C-5′), 78.2 (C-8), 49.7 (C-13), 47.2 (C-11), 46.3 (C-5), 45.2 (CH ), 43.0 (CH ), 42.0 (C-1), 41.2 (C-9), 39.0 (C-7), 36.5 (C-3), 34.6
2
2
(C-10), 29.6 (CH ), 29.5 (CH ), 29.4 (NÑH ), 29.3 (NÑH ), 27.4 (NÑH ), 26.6 (CH ), 26.3 (CH ), 22.4 (C-2), 21.0 (C-6), 17.6
2
2
3
3
3
2
2
(ÑH ). Mass spectrum (m/z, I , %): 541 (13), 540 (86), 309 (14), 308 (100), 278 (15), 236 (19), 232 (13), 222 (57), 209 (32), 190
3
rel
+
(18), 41 (12); found m/z 540.3416 [M] ; calcd for C H N O , 540.3419.
29 44
6 4
1,3,7-Trimethyl-8-(4-{[(3R,3aR,4aS,8aR,9aR)-8a-methyl-5-methylene-2-oxododecahydronaphtho[2,3-b]furan-
23
3-yl]methyl}piperazin-1-yl)-1H-purine-2,6(3H,7H)-dione (17). Yield 58%, white powder, mp 144.9°C, [α]
+53°
589
–1
(c 0.24, CHCl ). IR spectrum (ν, cm ): 1757 (C=O), 1707 (C=O), 1662 (C=O), 1610, 1520, 1448, 1375, 1311, 1281, 1219,
1175, 1157, 1142, 986, 964, 750. UV spectrum (λ , nm) (log ε): 202 (4.25), 222 (4.25), 293 (4.15). Í NMR spectrum
3
1
max
(400 MHz, CDCl , δ, ppm, J/Hz): 4.75 (1H, d, J = 1.1, H-15), 4.47 (1H, ddd, J = 1.7, 4.0, 4.9, H-8), 4.43 (1H, d, J = 1.1,
3
H-15), 3.71 (3H, s, NÑH ), 3.48 (3H, s, NÑH ), 3.34 (3H, s, NÑH ), 3.20–3.28 (4H, m, 2 × CH ), 2.95 (1H, ddd, J = 4.4, 6.1,
3
3
3
2
10.4, H-11), 2.80 (1H, dd, J = 4.4, 13.0, H-13), 2.71–2.73 (2H, m, CH ), 2.69 (1H, dd, J = 10.4, 13.0, H-13), 2.52–2.57 (2H,
2
m, CH ), 2.51 (1H, dtd, J = 4.2, 6.0, 6.1, 12.2, H-7), 2.32 (1H, d, J = 12.8, H-3), 2.15 (1H, dd, J = 1.7, 15.5, H-9), 1.97 (1H,
2
ddd, J = 7.0, 12.4, 14.1, H-3), 1.78 (1H, d, J = 12.0, H-5), 1.68 (1H, ddd, J = 2.0, 5.7, 13.2, H-6), 1.50–1.58 (3H, m, H-1, 2, 2),
1.45 (1H, dd, J = 4.2, 15.5, H-9), 1.21 (1H, ddd, J = 6.0, 12.7, 13.4, H-1), 1.14 (1H, dd, J = 12.6, 13.0, H-6), 0.77 (3H, s, ÑH ).
3
13
C NMR spectrum (100 MHz, CDCl , δ, ppm): 177.4 (C-12), 156.0 (C-6′), 154.8 (C-8′), 151.6 (C-2′), 149.3 (C-4), 147.2
3
(C-4′), 106.3 (C-15), 105.3 (C-5′), 78.2 (C-8), 53.0 (C-13), 52.5 (2 × CH ), 49.5 (2 × CH ), 46.4 (C-11), 45.2 (C-5), 42.1
2
2
(C-1), 41.4 (C-9), 39.2 (C-7), 36.6 (C-3), 34.7 (C-10), 32.4 (NÑH ), 29.5 (NÑH ), 27.6 (NÑH ), 22.5 (C-2), 20.8 (C-6), 17.7
3
3
3
(ÑH ). Mass spectrum (m/z, I , %): 510 (58), 302 (27), 288 (25), 278 (67), 232 (18), 223 (22), 222 (100), 209 (90), 190 (25),
3
rel
+
91 (21), 84 (28); found m/z 510.2944 [M] ; calcd for C H N O , 510.2949.
27 38
6 4
8-(4-{[(3R,3aR,4aR,6R,8aR,9aR)-6-Hydroxy-8a-methyl-5-methylene-2-oxododecahydronaphtho[2,3-b]furan-3-
yl]methyl}piperazin-1-yl)-1,3,7-trimethyl-1H-purine-2,6(3H,7H)) (18). Yield 44%, white powder, mp 100.5–103.2°C,
23
–1
[α]
+40° (c 1.36, CHCl ). IR spectrum (ν, cm ): 3446 (OH), 1765 (C=O), 1699 (C=O), 1657 (C=O), 1612, 1520, 1448,
589
3
1391, 1375, 1313, 1283, 1221, 1167, 1051, 1038, 987, 966, 910, 750. UV spectrum (λ , nm) (log ε): 202 (4.18), 222 (4.25),
max
1
292 (4.16). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 4.98 (1H, s, H-15), 4.57 (1H, s, H-15), 4.48 (1H, ddd, J = 1.6,
3
4.0, 4.9, H-8), 4.31 (1H, t, J = 2.4, H-3), 3.71 (3H, s, NÑH ), 3.48 (3H, s, NÑH ), 3.34 (3H, s, NÑH ), 3.19–3.28 (4H, m,
3
3
3
2 × CH ), 2.95 (1H, ddd, J = 4.6, 6.1, 10.3, H-11), 2.80 (1H, dd, J = 4.3, 13.2, H-13), 2.70–2.72 (2H, m, CH ), 2.68 (1H, dd,
2
2
J = 10.5, 13.2, H-13), 2.51–2.56 (3H, m, H-7, 2H - CH ), 2.36 (1H, d, J = 12.1, H-5), 2.16 (1H, dd, J = 1.4, 15.4, H-9),
2
1.64–1.82 (4H, m, H-1, 2, 2, 6), 1.52 (1H, dd, J = 4.2, 15.5, H-9), 1.30 (1H, dt, J = 3.2, 12.7, H-1), 1.12 (1H, dd, J = 12.6, 12.8,
13
H-6), 0.76 (3H, s, ÑH ). C NMR spectrum (100 MHz, CDCl , δ, ppm): 177.4 (C-12), 156.0 (C-6′), 154.8 (C-8′), 151.6 (C-2′),
3
3
150.4 (C-4), 147.2 (C-4′), 109.5 (C-15), 105.2 (C-5′), 78.1 (C-8), 73.0 (C-3), 53.0 (C-13), 52.5 (2 × CH ), 49.4 (2 × CH ), 45.2
2
2
(C-11), 41.0 (C-9), 40.3 (C-5), 39.2 (C-7), 35.6 (C-1), 34.6 (C-10), 32.4 (NÑH ), 29.6 (NÑH ), 29.0 (C-2), 27.6 (NÑH ), 20.4 (C-6),
3
3
3
16.9 (ÑH ). Mass spectrum (m/z, I , %): 526 (11), 362 (17), 278 (100), 248 (26), 236 (14), 223 (19), 222 (98), 209 (72), 138 (15),
3
rel
+
123 (14); found m/z 526.2903 [M] ; calcd for C H N O , 526.2898.
27 38
6 5
1,3,7-Trimethyl-8-[4-({(2′R,3R,3aR,4aR,8aR,9aR)-8a-methyl-2-oxodecahydro-2H-spiro[naphtho[2,3-b]furan-
5,2′-oxiran]-3-yl}methyl)piperazin-1-yl]-1H-purine-2,6(3H,7H)-dione (19). Yield 60%, white powder, mp 108.5°C,
23
–1
[α] +9° (c 0.11, CHCl ). IR spectrum (ν, cm ): 1759 (C=O), 1707 (C=O), 1662 (C=O), 1510, 1448, 1437, 1377, 1313, 1284,
589
3
1
1217, 1194, 1146, 1009, 987, 970, 752. UV spectrum (λ , nm) (log ε): 204 (4.13), 222 (4.22), 293 (4.12). Í NMR spectrum
max
(600 MHz, CDCl , δ, ppm, J/Hz): 4.45 (1H, ddd, J = 1.9, 4.2, 4.6, H-8), 3.70 (3H, s, NÑH ), 3.48 (3H, s, NÑH ), 3.34 (3H, s,
3
3
3
859

NÑH ), 3.19–3.28 (4H, m, 2 × CH ), 2.93 (1H, ddd, J = 4.3, 6.1, 9.6, H-11), 2.75 (1H, dd, J = 4.1, 13.2, H-13), 2.66–2.70 (2H,
3
2
m, CH ), 2.64 (1H, dd, J = 1.6, 4.5, H-15), 2.57 (1H, dd, J = 9.9, 13.1, H-13), 2.54–2.56 (2H, m, CH ), 2.53 (1H, d, J = 4.5,
2
2
H-15), 2.43 (1H, dtd, J = 4.1, 5.7, 6.0, 12.4, H-7), 2.14 (1H, dd, J = 1.6, 15.5, H-9), 1.85 (1H, dd, J = 10.0, 10.6, H-3),
1.53–1.69 (5H, m, H-1, 2, 2, 5, 6), 1.44 (1H, dd, J = 4.3, 15.5, H-9), 1.32 (1H, d, J = 12.6, H-3), 1.16 (1H, ddd, J = 8.0, 9.3,
13
13.2, H-1), 0.92 (3H, s, ÑH ), 0.65 (1H, dd, J = 12.4, 12.7, H-6). C NMR spectrum (150 MHz, CDCl , δ, ppm): 177.3
3
3
(C-12), 156.0 (C-6′), 154.8 (C-8′), 151.6 (C-2′), 147.2 (C-4′), 105.2 (C-5′), 77.8 (C-8), 58.5 (C-4), 52.8 (C-13), 52.4
(2 × CH ), 50.6 (C-15), 49.3 (2 × CH ), 45.4 (C-11), 44.3 (C-5), 41.8 (C-1), 41.2 (C-9), 39.3 (C-7), 35.1 (C-3), 34.7 (C-10),
2
2
32.4 (NÑH ), 29.5 (NÑH ), 27.6 (NÑH ), 20.2 (C-2), 18.5 (ÑH ), 16.4 (C-6). Mass spectrum (m/z, I , %): 526 (88), 422 (19),
3
3
3
3
rel
318 (30), 304 (21), 290 (29), 278 (83), 248 (8), 233 (34), 223 (18), 222 (76), 209 (100), 91 (6), 84 (4); found m/z 526.2899
+
[M] ; calcd for C H N O , 526.2898.
27 38
6 5
ACKNOWLEDGMENT
The work was financially supported by RFBR grants (Project No. 18-03-01012) and the RFBR and Novosibirsk
Region Government (Project No. 19-43-543042). We thank the Khimiya Common Use Center, NIOCh, SB, RAS, for spectral
and analytical studies.
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860