Synthesis of triterpene acids conjugates with α-tocopherol synthetic analogs

Article abstract of DOI:10.1134/S1070428010090150

Heterodimers were synthesized of pharmacologically important α-tocopherol synthetic analogs with triterpene acids(betulonic, betulinic), potential polyfunctionsl drugs possessing antioxidant activity. The combination of the fragments of biologically active substances was performed through linkers (residues of succinic acid, hydrazine, glycine, tetramethylenediamine) binding the side chain of the antioxidant molecule with atoms C³ or C²⁸ of the terpenoid.

Full text of DOI:10.1134/S1070428010090150

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 9, pp. 1355−1363. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © A.Yu. Spivak, R.R. Mufazzalova, E.R. Shakurova, V.N. Odinokov, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46,
No. 9, pp. 1355−1362.
Synthesis of Triterpene Acids Conjugates
with α-Tocopherol Synthetic Analogs
A. Yu. Spivak, R. R. Mufazzalova, E. R. Shakurova, and V. N. Odinokov
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, Ufa, 450075 Russia
e-mail: ink@anrb.ru
Received November 23, 2009
Abstract—Heterodimers were synthesized of pharmacologically important α-tocopherol synthetic analogs
with triterpene acids(betulonic, betulinic), potential polyfunctionsl drugs possessing antioxidant activity. The
combination of the fragments of biologically active substances was performed through linkers (residues of succinic
acid, hydrazine, glycine, tetramethylenediamine) binding the side chain of the antioxidant molecule with atoms
C3 or C28 of the terpenoid.
DOI: 10.1134/S1070428010090150
We recently reported on the synthesis of a biocon-
jugate of α-tocopherol and betulonic acid with a linker
of the glycine residue [18]. In this study we obtained
the condensation products of triterpene acids with syn-
thetic analogs of α-tocopherol: hydrophilic antioxidant
6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-
2-carboxylic acid (Trolox acid) (I), chromanylmethanol
(III), and 2-(chromanyl)ethanol (V). Into the heterodimer
with betulonic acid was also involved 2,5-dimethyl-
2-(4,8,12-trimethyltridecyl)-3,4-dihydro-2H-naphtho-
[1,2-b]pyran-6-ol (naphthotocopherol) (XIII), whose
antioxidant activity in vitro exceeds that of α-tocopherol
6.9 times [19].
The active oxygen-containing free radicals [superox-
ide anion radical (O•–), hydroperoxide radical (HO2 ),
•
nitrogen oxide (NO•)] are known to initiate under the
pathophysiological conditions of oxidative stress the
cardiovascular, oncological, inflammatory, and other
diseases due to the intensification of the peroxide oxida-
tion of the cell membrane lipids [1–3]. Nowadays great
expectations are pinned on the creation of new drugs for
prevention and treatment of these diseases from hybrid
compounds where the pharmacophores of various biologi-
cally active substances are combined with fragment of
any oxidant molecules [4–6]. Numerous studies show the
promising application in these combinations of the natu-
ral lipophilic antioxidant α-tocopherol and its synthetic
analogs [7–14]. Heterodimers underlain by compounds
containing a trimethylated chroman fragment behaved as
efficient multifunctional agents possessing antitumor [7,
8], anti-inflammatory [9], cardio- [10, 11] and neuropro-
tector [12–14] properties.
To prepare the target conjugates Trolox acid (I)
was converted into hydrazide IIa by the reaction with
hydrazine monohydrate in the presence of N,N'-car-
bonyldiimidazole (CDI) [20]. Amide IIb was obtained
in the same conditions using excess (4 mol-equiv) of
1,4-diaminobutane. Hydrazide IIa and amide IIb were
used without additional purification in the synthesis of
hybride molecules XIa–XId. Chromanylmethanol (III)
was synthesized from acid I by three-stage procedure
[21, 22].
Chromanylethanol (V) was obtained from trimethyl-
hydroquinone and 4-methyl-5,6-dihydro-2H-pyran [23].
Hemisuccinate esters of alcohols IV and VI were synthe-
sized by reactions of compounds III and V with excess
succinic anhydride in the presence of catalytic quantity of
We found no publications on conjugates of tocopher-
ols with triterpenoids of lupan series (betulin, betulonic
and betulinic acids), although betulin and its available
derivatives are a class of compounds very important for
medical chemistry exhibiting a wide range of biological
activity. The special interest to the lupan terpenoids is
due to their antitumor, anti-inflammatory, and antiviral
(anti-AIDS) properties [15–17].
1355

SPIVAK et al.
1356
R1 = OH, R2 = H, R3 = OH (VII); R1 + R2 = O, R3 = Cl (VIII); R1 = OH, R2 = H, R3 = Cl (IX); R1 = OAc, R2 = H, R3 = Cl (X); R1 +
R2 = O (XIa, XId); R1 = OH, R2 = H (XIb); R1 = OAc, R2 = H (XIc); R = Bn (XIIa, XIIb), H (XIIc,XIId); n = 0 (IIa, XIa–XIc); 1
(XII a, XIIc), 2 (XIIb, XIId), 4 (IIb, XId). a, CDI, NH2NH2·H2O, THF; b , CDI, NH2(CH2)4NH2, THF; c , 1. TsOH, MeOH. 2. BnCl–
K2CO3, DMF. 3. LiAlH4, Et2O; d, C4H4O3, DMAP, Py; e , IIa, EDC, CH2Cl2; f , IIb, EDC, CH2Cl2; g , IV, DCC, DMAP, THF; h , VI,
DCC, DMAP, THF; i , 10% Pd/C, Et2O; j , CBz–Gly, DCC, DMAP, CH2Cl2; k , Boc-Gly, DCC, DMAP, CH2Cl2; l , TFA, CH2Cl2; m ,
Et3N, benzene.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

SYNTHESIS OF TRITERPENE ACIDS
1357
4-dimethylaminopyridine (DMAP) in anhydrous pyridine
at room temperature.
2R/S-mixture, adducts XIa–XIc formed as mixtures of
two diastereomers, as seen in the 1H NMR spectra by the
presence of 4 doublets of the NH groups of the hydrazide
bridge. For instance, in the spectrum of compound XIa
the doublets of CONH from the chtoman and triterpene
fragments were observed in the region 7.91 (J 4.8 Hz),
8.60 (J 5.2 Hz), and 8.00 (J 4.8 Hz), 8.72 (J 5.2 Hz) ppm.
In the 13C NMR spectra of compounds XIa–XIc a double
set was observed of the signals of the carbonyl atoms of
the amide groups in the region 171.59, 172.02 and 173.90,
174.11 ppm and of atom C2 of chroman fragment in the
region 77.96 and 78.11 ppm.
By reacting compounds IIa and IIb with chlorides of
betulonic (VIII), betulinic (IX), and O-acetylbetulinic
(X) acids [24] we synthesized conjugates XIa–XId with
a bridge from the residues of hydrazine and tetramethyl-
enediamine. The yields of “hybrids” after the purification
by column chromatography on SiO2 attained 60–65%.
The reactions proceeded at prolonged boiling (12 h) in
CH2Cl2.As the condensing agent was preferably used N-
ethyl-N’-(3-dimethylaminopropyl)carbodiimide (EDC)
(2-fold molar excess). Conjugates XIIa and XIIb with
the residue of the succinic acid as the spacer linking the
antioxidant molecule with the atom C3 of betylinic acid
(VII) were obtained by the reaction of the hemisuccinate
esters IV and VI with acid VII in THF in the presence of
dicyclohexylcarbodiimide (DCC) and DMAP. The use of
2-fold excess of the hemisuccinates and DCC resuted in
the icrease in the yield of compounds XIIa and XIIb from
~25 to 72%. The debenzylation of compounds XIIa and
XIIb cleanly proceeded by hydrogenation in the presence
of Pd/C catalyst in ethyl ether ended to the formation of
adducts XIIc and XIId in a quantitative yield, yet we
failed to perform these reactions in ethanol evidently
due to the low solubility of compounds XIIa and XIIb.
In order to prepare conjugate XVII naphthotocopherol
(XIII) synthesized directly before the reaction by pro-
cedure [25] was acylated with N-(benzyloxycarbonyl)
glycine (CBz-Gly) in the presence of DCC and catalytic
amount of DMAP. The reaction gave O-acyl derivative
of naphthotocopherol XIV in a high yield. However at
the deprotecting the amino group by the hydrogenolysis
the partial hydrogenation of the naphthalene framework
was observed leading to a mixture of substances. In
this case the use of N-(tert-butyloxycarbonyl)glycine
(Boc-Gly) proved to be more efficient. The removal of
the protecting group in compound XV occurred cleanly
at the treatment with CF3COOH in dichloromethane.
Thus prepared glycinate of naphthotocopherol (XVI)
was conjugated with betulonic acid chloride (VIII) in
the presence of Et3N. The yield of the target heterodimer
XVII after the purification by column chromatography
on SiO2 was 62%.
EXPERIMENTAL
IR spectra were recorded on a spectrophotometer Spe-
cord 75IR from pellets with KBr or solutions in CHCl3.
UV spectra were taken on a spectrophotometer Specord
M-40 from solutions in CHCl3. 1H and 13C NMR spectra
were registered on a spectrometer Bruker Avance-400
(operating frequencies 400.13 and 100.61 MHz respec-
tively), internal reference Me4Si, solvent CDCl3. The
optical rotation was measured on a polarimeter Perkin
Elmer-141. TLC was performed on Sorbfil plates (Sorb-
polymer, Krasnodar, Russia) in the system chloroform–
methanol, 20 : 1 (A), chloroform–methanol, 5 : 1 (B),
chloroform–methanol, 1 : 1 (C), development with anise
aldehyde in ethanol. The column chromatography was
performed on silica gel L (50–160 μm) of grade KSKG.
The used in the study DCC, DMAP, EDC, CDI, CBz-Gly,
Boc-Gly, 10% Pd on activated carbon, oxalyl chloride
were purchased from Fluka, Trolox acid (I), from Acros.
Hydrazide IIa was synthesized by procedure [20]. The
betulin was isolated by procedure [26], the betulonic,
betulinic, and 3-O-acetylbetulinic acids and their chlo-
rides were obtained as described in [27, 28]. Methyl-
6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylate
was synthesized by the method [21],
6-hydroxy- and
6-benzyloxy-2,5,7,8-tetramethylchroman-2-methanols
were obtained by the method [22].
N-(4-Aminobutyl)-6-hydroxy-2,5,7,8-tetramethyl-
3,4-dihydro-2H-chromen-2-carboxamide (IIb). To
a solution of 0.10 g (0.40 mmol) of compound I in 6 ml
of anhydrous THF was added 0.07 g (0.4 mmol) of CDI,
the mixture was stirred for 1 h, then to the reaction mix-
ture 0.16 ml (1.6 mmol) of 1,4-diaminobutane in 3 ml
of anhydrous THF was added. The reaction mixture
was stirred for 12 h (TLC monitoring, eluent system
C). Then the reaction mixture was evaporated, diluted
The structure of compounds XIa–XId, XIIa–XIId,
and XVII was confirmed by spectral data. In the 13C
NMR spectra of these compounds the signals of all car-
bon atoms were present corresponding to the residues
of the molecules of triterpenoid, chromanol, and the
spaicer. Inasmuch as Trolox acid was used as a racemic
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

SPIVAK et al.
1358
with 10 ml of CHCl3, the organic layer was washed with
water, dried with MgSO4, and evaporated. Yield 0.09 g
(70%), amorphous powder. IR spectrum, ν, cm–1: 3460
1.82–2.11 m (4H, H3, H6'); 2.15 s, 2.22 s, 2.27 s (3H each,
MeAr); 2.67–2.72 m (6H, H4, H2', H3'), 4.30–4.46 m
(2H, CH2O), 4.74 s (2H, CH2Ph), 7.36–7.56 m (5H, Ph).
13C NMR spectrum, δ, ppm: 11.92, 12.04, 12.92 (MeAr);
20.53 (C4), 24.14 (MeC2), 29.21 (C2', C3'), 31.81 (C3),
38.04 (C6'), 61.23 (CH2O), 73.55 (OCH2Ph), 74.79 (C2),
117.31 (C5), 123.07, 126.13, 128.20 (C4a, C7, C8), 127.80,
127.87, 128.52, 137.98 (Ph), 147.45 (C8a), 148.48 (C6),
172.51 (C4'), 176.86 (C1'). Found, %: C 70.56; H 7.77.
C26H32O6. Calculated, %: C 70.89; H 7.52.
(NH), 1680 (CONH), 1670 (CH2NH2). UV spectrum,
1
λ
max, nm (ε): 293 (3093). H NMR spectrum, δ, ppm:
1.05–1.90 m (6H, 3CH2), 1.55 s (3H, 2-Me); 2.09 s, 2.19 s
(9H, 3Me-Ar); 2.40–2.70 m (4H, H4 and CH2NH2), 3.07
m (2H, CH2NH), 3.34 m (2H, NH2), 6.40 br.s (1H, NH).
13C NMR spectrum, δ, ppm: 11.56, 11.93, 12.52 (MeAr),
20.68 (C4), 24.80 (MeC2), 26.87, 29.69 (C2', C3'), 29.70
(C3), 38.71 (C1'), 41.49 (C4'), 78.42 (C2), 118.09 (C5),
120.72, 121.56, 123.01 (C4a, C7, C8), 144.48 (C8a), 145.90
(C6), 174.41 (CONH).
Acylation of 6-hydroxy-2,5,7,8-tetramethyl-3,4-
dihydro-2H-chromen-2-carbohydrazide (IIa) with
chlorides of betulonic, betulinic, and O-acetylbetulinic
acids. To a solution of 1.1 mmol of compound IIa and
2 mmol of EDC in 15 ml of anhydrous CH2Cl2 was added
at stirring 1 mmol of freshly prepared chloride VIII–X
of the corresponding lupanic acid. The reaction mixture
was boiled for 12 h (TLC monitoring, eluent system A),
on cooling it was diluted with 25 ml of CH2Cl2, washed
with water (50 ml), dried with MgSO4, and evaporated.
The residue was subjected to column chromatography
(SiO2, eluent CHCl3) to obtain compounds XIa–XIc
respectively.
4-[(6-Benzyloxy-2,5,7,8-tetramethyl-3,4-dihydro-
2H-chromen-2-yl)methoxy]-4- oxobutanoic acid (IV).
To a solution of 0.30 g (0.9 mmol) of compound III in
10 ml of anhydrous pyridine was added at stirring 0.31 g
(3.15 mmol) of succinic anhydride, and 0.03 g (0.2 mmol)
of DMAP.After stirring for 12 h (TLC monitoring, eluent
system A) the reaction mixture was diluted with water
(2 ml), the reaction product was extracted into EtOAc
(3 × 10 ml), the organic layer was treated with 10% HCl
(3 × 20 ml), then with water solution of NaHCO3, with
water, dried with MgSO4, and evaporated. The residue
was subjected to column chromatography (9 g of SiO2,
eluent CHCl3). Yield 0.22 g (59%), colorlless amor-
phous powder. IR spectrum, ν, cm–1: 1740 (O–C=O).
UV spectrum, λmax, nm (ε): 287 (2100). 1H NMR spec-
trum, δ, ppm: 1.35 s (3H, 2-Me), 1.82–2.03 m (2H, H3);
2.14 s, 2.22 s, 2.27 s (3H each, Me-Ar); 2.69 t (2H, H4,
J 6.4 Hz), 2.78 m (4H, H2', H3'); 4.18 d, 4.24 d (2H, CH2O,
J 11.2 Hz); 4.74 s (2H, OCH2Ph), 7.36–7.56 m (5H, Ph).
13C NMR spectrum, δ, ppm: 11.85, 12.04, 12.92 (MeAr),
20.16 (C4), 22.06 (MeC2), 28.52 (C3), 28.99 (C2', C3'),
68.99 (CH2O), 73.58 (OCH2Ph), 74.81 (C2), 117.30 (C5),
123.16, 126.08, 128.33 (C4a, C7, C8), 127.81, 127.88,
128.53, 137.93 (Ph), 147.30 (C8a), 148.62 (C6), 172.02
(C4'), 177.63 (C1'). Found, %: C 70.00; H 7.08. C25H30O6.
Calculated, %: C 70.40; H 7.11.
6-Hydroxy-N'-[3-oxolup-20(29)-en-28-oyl]-2,5,7,8-
tetramethyl-3,4-dihydro-2H-chromen-2- carbohydra-
zide (XIa). Yield 65%, amorphous powder, [α]D20 +12.70°
(C 0.45, CHCl3). IR spectrum, ν, cm–1: 3390 (CONH),
1700 (C=O), 1740 (CONH). UV spectrum, λmax, nm (ε):
1
293 (2920). H NMR spectrum, δ, ppm: 0.92 s, 0.96 s,
0.98 s, 1.02 s, 1.07 s (3H each, H23', H24', H25', H26', H27');
1.17–2.50 m (29H, CH2, CH in residue of betulonic acid,
2-Me and H3 in residue of chromanol), 1.68 s (3H, H30');
2.11 s, 2.19 s, 2.23 s (3H each, MeAr); 2.64 m (3H, H4,
H13'), 3.06 m (1H, H19'); 4.61 C, 4.74 C (1H each, H29');
7.91 d, 8.60 d (0.5H each, CONH, J 4.8, J 5.6 Hz); 8.00 d,
8.72 d (0.5H each, CONH, J 4.8, J 5.2 Hz). 13C NMR
spectrum, δ, ppm: 11.34, 12.20, 12.28 (MeAr), 14.56
(C27'), 15.73 (C25'), 15.94 (C26'), 19.47 (C6'), 19.62 (C30'),
20.19 (C4), 21.01 (C11'), 21.35 (C24'), 23.70 (MeC2), 25.55
(C12'), 26.61 (C23'), 29.45 (C15'), 29.60 (C3), 30.73 (C21'),
33.11 (C16'), 33.60 (C7'), 34.13 (C2'), 36.91 (C10'), 37.76
(C22'), 38.06 (C13'), 39.62 (C1'), 40.67 (C8'), 42.44 (C14'),
46.49 (C19'), 47.33 (C4'), 49.94 (C18'), 50.22 (C9'), 54.99
(C5'), 55.29 (C17'), 77.96 and 78.11 (C2), 109.62 (C29'),
117.56 (C5), 118.87, 121.61, 122.34 (C4a, C7, C8), 143.99
(C8a), 145.81 (C6), 150.45 (C20'), 171.59 and 172.02
(C9), 173.90 and 174.11 (C28'), 218.25 (C3'). Found, %:
C 75.47; H 9.18; N 4.07. C44H64N2O5. Calculated, %:
4-[2-(6-Benzyloxy-2,5,7,8-tetramethyl-3,4-dihydro-
2H-chromen-2-yl)ethoxy]-4-oxobutanoic acid (VI)
was obtained from 0.65 g (1.9 mmol) of 2-(chromanyl)
ethanol (V), 0.67 g (6.7 mmol) of succinic anhydride, and
0.04 g (0.3 mmol) of DMAP in 10 ml of anhydrous pyri-
dine as described for compound IV. Yield 0.51 g (64%),
colorless crystals, mp 91–92°C (EtOH). IR spectrum, ν,
cm–1: 1740 (O–C=O). UV spectrum, λmax, nm (ε): 289
(2235). 1H NMR spectrum, δ, ppm: 1.35 s (3H, 2-Me),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

SYNTHESIS OF TRITERPENE ACIDS
1359
C 75.39; H 9.20; N 4.00.
(C19'), 55.31 (C5'), 55.44 (C17'), 77.93 and 78.06 (C2),
81.00 (C3'), 109.61 (C29'), 117.52 (C5), 118.97, 121.72,
122.31 (C4a, C7, C8), 143.90 (C8a), 145.85 (C6), 150.51
(C20'), 171.12 (MeCOO), 171.53 and 171.89 (C9), 173.96
and 174.11 (C28'). Found, %: C 74.67; H 9.02; N 4.09.
C46H68N2O6. Calculated, %: C 74.16; H 9.20; N 3.76.
6-Hydroxy-N'-[3β-hydroxylup-20(29)-en-28-
oyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-
carbohydrazide (XIb). Yield 65%, amorphous powder,
[α]D +5.26° (C 0.76, CHCl3). IR spectrum, ν, cm–1:
20
3390 (CONH), 1740 (CONH). UV spectrum, λmax, nm
1
6-Hydroxy-N-{4-[3-oxolup-20(29)-en-28-oylamino]
butanoyl}-2,5,7,8-tetramethyl-3,4-dihydro-2H-
chromen-2-carboxamide (XId). Yield 70%, amorphous
(ε): 294 (2462). H NMR spectrum, δ, ppm: 0.75 s,
0.85 s, 0.89 s, 0.93 s, 0.96 s (3H each, H23', H24', H25',
H26', H27'); 1.18–2.50 m (29H, CH2, CH in residue of
betulinic acid, 2-Me and H3 in residue of chromanol),
1.68 C (3H, H30'); 2.11 s, 2.18 s, 2.22 s (3H each, MeAr);
2.63 m (3H, H4, H13'), 3.06 m (1H, H19'), 3.17 d.d (1H,
H3', J 8.8, J 4.5 Hz); 4.60 s, 4.74 s (1H each, H29'); 7.94 d,
8.63 d (0.5H each, CONH, J 5.2 Hz); 8.00 d, 8.73 d (0.5H
each, CONH, J 5.6 Hz). 13C NMR spectrum, δ, ppm:
11.36, 12.20, 12.30 (MeAr), 14.65 (C27'), 15.37 (C24'),
15.92 (C25'), 16.13 (C26'), 18.28 (C6'), 19.44 (C30'), 20.19
(C4), 20.83 (C11'), 24.02 (MeC2), 25.56 (C12'), 27.37
(C2'), 27.98 (C23'), 29.48 (C3), 29.69 (C21'), 30.76 (C15'),
33.11 (C16'), 34.32 (C7'), 37.19 (C10'), 37.70 (C22'), 38.11
(C13'), 38.72 (C4'), 38.85 (C1'), 40.73 (C8'), 42.39 (C14'),
46.64 (C18'), 50.35 (C19'), 50.59 (C9'), 55.25 (C5'), 55.37
(C17'), 77.95 and 78.08 (C2), 79.99 (C3'), 109.55 (C29'),
117.54 (C5), 118.94, 121.68, 122.33 (C4a, C7, C8), 143.92
(C8a), 145.82 (C6), 150.51 (C20'), 171.54 and 171.89 (C9),
173.91 and 174.06 (C28'). Found, %: C 74.98; H 9.87;
N 4.01. C44H66N2O5. Calculated, %: C 75.17; H 9.46;
N 3.98.
20
powder, [α]D +17.20° (C 0.29, CHCl3). IR spectrum,
ν, cm–1: 3390 (CONH), 1740 (CONH), 1710 (C=O). UV
spectrum, λmax, nm (ε): 289 (1728). 1H NMR spectrum,
δ, ppm: 0.91 s, 0.95 s, 0.97 s, 1.01 s, 1.06 s (3H each,
H23', H24', H25', H26', H27'); 1.17–2.30 m (29H, CH2, CH
in residue of betulonic acid, 2-Me and H3 in residue
of chromanol), 1.68 s (3H, H30'); 1.51 s, 2.10 s, 2.18 s
(3H each, Me-Ar); 2.30–2.70 m (7H, H4, H13', CH2 in
the bridge), 3.10–3.40 m (5H, H19', CH2NH); 4.61 s,
4.74 s (1H each, H29'); 5.72 s (1H, CONH), 6.46 s (1H,
CONH). 13C NMR spectrum, δ, ppm: 11.38, 12.01, 12.33
(MeAr), 14.54 (C27'), 15.95 (C25' and C26'), 19.49 (C6'),
19.62 (C30'), 20.58 (C4), 21.00 (C11'), 21.45 (C24'), 24.30
(MeC2), 25.63 (C12'), 26.59 (C23'), 26.79 and 27.09 (CH2
in the bridge), 29.41 (C15'), 29.60 (C3), 29.68 (C21'),
33.68 (C16', C7'), 34.14 (C2'), 36.90 (C10'), 37.73 (C22'),
38.54 (C13'), 38.63 (CH2NH), 39.63 (C1'), 40.68 (C8'),
42.50 (C14'), 46.65 (C19'), 47.33 (C4'), 49.99 (C18'), 50.08
(C9'), 55.00 (C5'), 55.55 (C17'), 78.32 (C2), 109.37 (C29'),
113.95 (C5), 118.02, 119.37, 121.77 (C4a, C7, C8), 144.31
(C8a), 145.66 (C6), 150.90 (C20'), 174.44 (C9), 176.16
(C28'), 218.26 (C3'). Found, %: C 76.31; H 9.84; N 3.75.
C48H72N2O5. Calculated, %: C 76.15; H 9.59; N 3.70.
N'-[3β-Acetoxylup-20(29)-en-28-oyl]-6-hydroxy-
2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-
carbohydrazide (XIc). Yield 60%, amorphous powder,
[α]D20 +7.14° (C 1.47, CHCl3). IR spectrum, ν, cm–1: 3390
(CONH), 1740 (O–C=O), 1640 (CONH). UV spectrum,
Acylation of betulinic acid (VII) with hemisuc-
cinates of chromanols IV and VI. To a solution of
1 mmol of betulinic acid (VII) in 35 ml of anhydrous THF
was successively added at stirring 0.2 mmol of DMAP,
2.2 mmol of compound IV or VI, and 2.4 mmol of DCC.
The reaction mixture was stirred for ~24 h (TLC moni-
toring, eluent system A), the precipitate was filtered off,
the filtrate was evaporated. The residue was subjected to
column chromatography (SiO2, eluent CHCl3) to obtain
compounds XIIa and XIIb, respectively.
1
λmax, nm (ε): 293 (2284). H NMR spectrum, δ, ppm:
0.84 s, 0.87 s, 0.93 s, 0.95 s, 0.96 s (3H each, H23', H24',
H25', H26', H27'); 1.17–2.50 m (29H, CH2, CH in residue
of betulonic acid, 2-Me and H3 in residue of chromanol),
1.68 s (3H, H30'), 2.04 s (3H, OAC); 2.09 s, 2.18 s, 2.21 s
(3H each, MeAr); 2.62 m (3H, H4, H13'), 3.05 m (1H,
H19'), 4.47 t (1H, H3', J 6.8 Hz); 4.60 s, 4.73 s (1H each,
H29'); 8.08 d, 8.66 d (0.5H each, CONH, J 5.2 Hz); 8.17 d,
8.77 d (0.5H each, CONH, J 5.2 Hz). 13C NMR spectrum,
δ, ppm: 11.35, 12.18, 12.27 (MeAr), 14.61 (C27'), 15.91
(C24'), 16.19 (C25'), 16.48 (C26'), 18.16 (C6'), 19.44 (C30'),
20.19 (C4), 20.84 (C11'), 21.32 (MeCOO), 23.69 (C2'),
23.99 (MeC2), 25.52 (C12'), 27.94 (C23'), 29.46 (C3),
29.60 (C21'), 30.74 (C15'), 33.10 (C16'), 34.24 (C7'), 37.10
(C10'), 37.66 (C22'), 37.79 (C13'), 38.11 (C4'), 38.39 (C1'),
40.78 (C8'), 42.41 (C14'), 46.64 (C18'), 50.35 (C9'), 50.49
3β-O-{4-[(6-Benzyloxy-2,5,7,8-tetramethyl-3,4-
dihydro-2H-chromen-2-yl)methoxy]-4-oxobutanoyl}
betulinic acid (XIIa). Yield 72%, amorphous powder,
[α]D +9.50° (C 0.34, CHCl3). IR spectrum, ν, cm–1:
20
1730 (O–C=O). UV spectrum, λmax, nm (ε): 286 (2081).
1H NMR spectrum, δ, ppm: 0.95 s, 0.99 s, 1.00 s, 1.03 s,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

SPIVAK et al.
1360
1.08 s (3H each, H23', H24', H25', H26', H27'); 1.15–2.35 m
(29H, CH2, CH in residue of betulinic acid, 2-Me and H3
in residue of chromanol), 1.71 s (3H, H30'); 2.06 s, 2.13 s,
2.18 s (3H each, MeAr); 2.63–2.77 m (6H, H4 and CH2 in
the bridge), 3.03 m (1H, H19'), 4.12–4.21 m (2H, CH2O),
4.39–4.46 d.d (1H, H3', J 5.0, J 8.8 Hz); 4.62 s, 4.75 s (1H
each, H29'); 4.70 s (2H, OCH2Ph), 7.33–7.52 m (5H, Ph).
13C NMR spectrum, δ, ppm: 11.82, 12.00, 12.88 (MeAr),
14.68 (C27'), 16.03 (C24'), 16.17 (C25'), 16.52 (C26'), 18.15
(C6'), 19.36 (C30'), 20.14 (C11'), 20.86 (C4), 22.08 (MeC2),
23.66 (C2'), 25.45 (C12'), 27.96 (C23'), 28.49 (C15'), 29.24
(C3), 29.53 and 29.70 (CH2 in the bridge), 30.58 (C21'),
32.17 (C16'), 34.24 (C7'), 37.11 (C10', C22'), 37.86 (C13'),
38.40 (C1', C4'), 40.70 (C8'), 42.43 (C14'), 46.95 (C18'),
49.26 (C19'), 50.39 (C9'), 55.43 (C5'), 56.39 (C17'), 68.89
(CH2O), 73.52 (OCH2Ph), 74.75 (C2), 81.41 (C3'), 109.76
(C29'), 117.23 (C5), 123.12, 126.03, 128.29 (C4a, C7, C8),
127.73, 127.83, 128.48, 137.92 (Ph), 147.25 (C8a), 148.60
(C6), 150.39 (C20'), 171.94 and 172.17 (COO), 182.06
(C28'). Found, %: C 76.54; H 8.34. C55H76O8. Calculated,
%: C 76.35; H 8.25.
H 8.73. C56H78O8. Calculated, %: C 76.50; H 8.94.
Hydrogenolysis of compounds XIIa and XIIb. To
a solution of 0.1 mmol of compound XIIa or XIIb in 7 ml
of anhydrous Et2O was added 20% of Pd/C, and the reac-
tion mixture was stirred in a hydrogen atmosphere for 6
h. On completion of the reaction (TLC monitoring, eluent
systemA) the catalyst was filtered off, washed with Et2O,
the filtrate was evaporated. The residue was subjected to
column chromatography (SiO2, eluent CHCl3) to obtain
compound XIIc or XIId respectively.
3β-O-{4-[(6-Hydroxy-2,5,7,8-tetramethyl-3,4-
dihydro-2H-chromen-2-yl)methoxy]-4-oxobutanoyl}
betulinic acid (XIIc). Yield 56%, amorphous powder,
[α]D +1.20° (C 3.92, CHCl3). IR spectrum, ν, cm–1:
20
1730 (O–C=O). UV spectrum, λmax, nm (ε): 295 (2941).
1H NMR spectrum, δ, ppm: 0.90 s, 0.94 s, 0.98 s, 1.00 s,
1.08 s (3H each, H23', H24', H25', H26', H27'); 1.18–2.30 m
(29H, CH2, CH in residue of betulinic acid and 2-Me,
H3 in residue of chromanol), 1.69 s (3H, H30'); 2.09 s,
2.11 s, 2.16 s (3H each, MeAr); 2.65–2.80 m (6H, H4,
CH2 in the bridge), 3.02 m (1H, H19'), 4.12–4.19 m (2H,
CH2O), 4.50 d.d (1H, H3', J 5.0, J 9.2 Hz), 4.62 s, 4.75 s
(1H each, H29'). 13C NMR spectrum, δ, ppm: 11.29,
11.76, 12.22 (MeAr), 14.67 (C27'), 16.03 (C24'), 16.14
(C25'), 16.50 (C26'), 18.14 (C6'), 19.34 (C30'), 20.20 (C11'),
20.86 (C4), 21.89 (MeC2), 23.65 (C2'), 25.44 (C12'), 27.95
(C23'), 28.66 (C15'), 29.23 (C3), 29.53 and 29.70 (CH2 in
the bridge), 30.57 (C21'), 32.16 (C16'), 34.22 (C7'), 37.10
(C10', C22'), 37.84 (C13'), 38.40 (C1', C4'), 40.69 (C8'),
42.42 (C14'), 46.94 (C18'), 49.25 (C19'), 50.38 (C9'), 55.42
(C5'), 56.39 (C17'), 68.89 (CH2O), 73.26 (C2), 81.42 (C3'),
109.74 (C29'), 116.95 (C5), 118.57, 121.37, 122.71 (C4a,
C7, C8), 144.85 (C8a), 145.03 (C6), 150.38 (C20'), 171.95
and 172.16 (COO), 182.05 (C28'). Found, %: C 74.67; H
9.02. C48H70O8. Calculated, %: C 74.38; H 9.10.
3β-O-{4-[2-(6-Benzyloxy-2,5,7,8-tetramethyl-3,4-
dihydro-2H-chromen-2-yl)ethoxy]-4-oxo-butanoyl}
betulinic acid (XIIb). Yield 71%, colorless crystals,
mp 110–112°C (EtOH), [α]D20 +10.95° (C 0.42, CHCl3).
IR spectrum, ν, cm–1: 1760 (O–C=O). UV spectrum,
1
λ
max, nm (ε): 288 (1960). H NMR spectrum, δ, ppm:
0.84 s, 0.85 s, 0.86 s, 0.95 s, 0.99 s (3H each, H23', H24',
H25', H26', H27'); 1.18–2.40 m (31H, CH2, CH in residue
of betulinic acid, 2-Me and H3 CH2CH2O in residue
of chromanol), 1.72 s (3H, H30'); 2.11 s, 2.19 s, 2.24 s
(3H each, MeAr); 2.64–2.72 m (6H, H4 and CH2 in the
bridge), 3.04 m (1H, H19'), 4.29–4.38 m (2H, CH2O),
4.51–4.54 d.d (1H, H3', J 6.0, J 9.0 Hz); 4.63 s, 4.76 s (1H
each, H29'); 4.71 s (2H, OCH2Ph), 7.27–7.53 m (5H, Ph).
13C NMR spectrum, δ, ppm: 11.86, 12.00, 12.88 (MeAr),
14.69 (C27'), 16.03 (C24'), 16.16 (C25'), 16.50 (C26'), 18.15
(C6'), 19.36 (C30'), 20.49 (C11'), 20.87 (C4), 23.67 (MeC2),
24.16 (C2'), 25.45 (C12'), 27.93 (C23'), 29.33 (C15'), 30.59
(C3), 29.55 and 29.71 (CH2 in the bridge), 31.81 (C21'),
32.17 (C16'), 34.24 (C7'), 37.14 (C10'), 37.85 (C13', C22'),
37.99 (C4'), 38.42 (C1' and CH2CH2O), 40.70 (C8'), 42.43
(C14'), 46.96 (C18'), 49.27 (C19'), 50.39 (C9'), 55.43 (C5'),
56.42 (C17'), 61.16 (CH2O), 73.45 (OCH2Ph), 74.74 (C2),
81.38 (C3'), 109.77 (C29'), 117.20 (C5), 123.05, 126.03,
128.20 (C4a, C7, C8), 127.72, 127.81, 128.47, 137.95
(Ph), 147.37 (C8a), 148.47 (C6), 150.38 (C20'), 172.02
and 172.36 (COO), 182.42 (C28'). Found, %: C 76.65;
3β-O-{4-[2-(6-Hydroxy-2,5,7,8-tetramethyl-3,4-
dihydro-2H-chromen-2-yl)ethoxy]-4-oxobutanoyl}
betulinic acid (XIId). Yield 67%, amorphous powder,
[α]D20 +6.66° (C 0.29, CHCl3). IR spectrum, ν, cm–1:
1760 (O–C=O). UV spectrum, λmax, nm (ε): 296 (3700).
1H NMR spectrum, δ, ppm: 0.90 s, 0.94 s, 1.44 s 1.07 s
(3H each, H23', H24', H25', H26', H27'); 1.18–2.40 m (31H,
CH2, CH in residue of betulinic acid and 2-Me, H3
CH2CH2O in residue of chromanol), 1.70 s (3H, H30');
2.10 s, 2.12 s, 2.16 (3H each, MeAr); 2.62 m (6H, H4,
CH2 in the bridge), 2.99–3.04 m (1H, H19'), 4.21–4.39 m
(2H, CH2O), 4.48–4.52 d.d (1H, H3', J 5.2, J 10.0 Hz);
4.62 s, 4.75 s (1H each, H29'). 13C NMR spectrum, δ, ppm:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

SYNTHESIS OF TRITERPENE ACIDS
1361
11.28, 11.79, 12.21 (MeAr), 14.66 (C27'), 16.02 (C24'),
16.14 (C25'), 16.48 (C26'), 18.14 (C6'), 19.33 (C30'), 20.54
(C11'), 20.86 (C4), 23.65 (MeC2), 24.00 (C2'), 25.45 (C12'),
27.91 (C23'), 29.32 (C15'), 30.56 (C3), 29.54 and 29.68
(CH2 in the bridge), 31.98 (C21'), 32.52 (C16'), 34.23 (C7'),
37.10 (C10' and CH2CH2O), 37.83 (C13' and C22'), 38.34
(C4'), 38.34 (C1'), 40.69 (C8'), 42.43 (C14'), 46.93 (C18'),
49.25 (C19'), 50.39 (C9'), 55.42 (C5'), 56.34 (C17'), 61.16
(CH2O), 73.15 (C2), 81.37 (C3'), 109.73 (C29'), 116.91
(C5), 118.65, 121.33, 122.65 (C4a, C7, C8), 144.88 (C8a),
144.98 (C6), 150.40 (C20'), 172.00 and 172.36 (COO),
181.30 (C28'). Found, %: C 75.03; H 9.89. C49H72O8.
Calculated, %: C 74.78; H 9.74.
stirred for 2.5 h at room temperature, the separated pre-
cipitate was filtered off, the filtrate was evaporated. The
residue was subjected to column chromatography (18 g
of SiO2, eluent C6H14–EtOAc). Yield 0.51 g (63%),. IR
spectrum, ν, cm–1: 3380 (CONH), 1730 (O–C=O). UV
spectrum, λmax, nm (ε): 308 (4505). 1H NMR spectrum, δ,
ppm: 0.85–1.10 m (21H, Me), 1.10–1.90 m (26H, 2-Me,
CH2, CH), 2.20 s (3H, 5-Me), 2.75 t (2H, H4, J 6.8 Hz),
4.38 m (2H, CH2NH), 5.21 m (1H, NH), 7.45 m (2H, H8,
H9); 7.65 d, 8.20 d (1H each, H7, H10 J 8.0 Hz). 13C NMR
spectrum, δ, ppm: 12.70 (5-Me), 19.71, 19.73 (4'-Me, 8'-
Me), 20.68 and 21.09 (C4), 22.66, 22.75 (12’-Me), 23.76
(2-Me), 24.47, 24.83 (C2', C6', C10'), 27.99 (C12'), 28.35
(t-Bu), 31.06 (C3), 32.80 (C4'), 32.82 (C8'), 37.39, 37.40,
37.43, 37.48 (C3', C5', C7', C9'), 39.30 (C11'), 40.06 (C1'),
42.47 (CH2NH), 75.89 (C2), 80.17 (CO), 114.09 (C5),
2,5-Dimethyl-2-(4,8,12-trimethyltridecyl)-
naphtho[1,2-b]-3,4-dihydro-2H-pyran-6-yl [(ben-
zyloxycarbonyl)amino]acetate (XIV). To a solution
of 0.45 g (1 mmol) of naphthotocopherol (XIII) in
20 ml of anhydrous CH2Cl2 was added at stirring 0.02 g
(0.2 mmol) of DMAP, 0.31 g (1.5 mmol) of CBz-Gly,
and 0.31 g (1.5 mmol) of DCC. The reaction mixture
was stirred for 2 h at room temperature, the separated
precipitate was filtered off, and the filtrate was evaporated.
The residue was subjected to column chromatography
(14 g of SiO2, eluent C6H14–EtOAc, 3 : 1). Yield 0.39 g
(61%), viscous oily substance. IR spectrum, ν, cm–1: 3390
(CONH), 1720 (O–C=O). UV spectrum, λmax, nm (ε): 334
(4210). 1H NMR spectrum, δ, ppm: 1.00–1.03 m (12H,
Me), 1.24–1.98 m (26H, 2-Me, CH2, CH), 2.24 s (3H,
5-Me), 2.76 m (2H, H4), 4.41 m (2H, CH2NH), 5.25 s
(2H, CH2Ph), 5.89 (1H, NH), 7.20–7.51 (7H, H8, H9, Ph),
7.70 d, 8.30 d (2H, H7, H10, J 8.1 Hz). 13C NMR spectrum,
δ, ppm: 12.51 (5-Me), 19.65, 19.72 (4'-Me, 8'-Me), 20.97
(C4), 22.60, 22.70 (12'-Me2), 23.54 (2-Me), 24.38, 24.74
(C2', C6', C10'), 27.89 (C12'), 30.87 (C3), 32.59 (C8'), 32.68
(C4'), 37.22, 37.32, 37.38, 37.48 (C3', C5', C7', C9'), 39.30
(C11'), 40.00 (C1), 42.52 (CH2NH), 67.00 (OCH2Ph),
75.70 (C2), 113.98 (C5), 120.13, 121.85, 124.56, 124.75,
125.82, 126.20 (C6a, C7, C8, C9, C10, C10a, C4a), 127.97,
128.27, 128.37 (Ph), 136.10 (Ph), 136.39 (C10b), 146.78
(C6), 156.53 (CONH), 169.04 (COO). Found, %: C 76.73;
H 9.02; N 2.20. C41H57NO5. Calculated, %: C 76.48;
H 8.92; N 2.18.
120.22, 121.99, 124.69, 125.92 (C6a, C7, C8, C9, C10, C10a
,
C4a), 136.48 (C10b), 146.96 (C6), 156.86 (CONH), 169.33
(COO). Found, %: C 75.03; H 9.82; N 2.37. C38H59NO5.
Calculated, %: C 74.84; H 9.75; N 2.29.
2,5-Dimethyl-2-(4,8,12-trimethyltridecyl)
naphtho[1,2-b]-3,4-dihydro-2H-pyran-6-yl amino-
acetate- (XVI). To a solution of 0.37 g (0.6 mmol) of
compound XIV in 20 ml of anhydrous CH2Cl2 was added
2.4 ml of CF3COOH, the mixture was stirred at room
temperature for 5 h (TLC monitoring, eluent system
A). Then the reaction mixture was evaporated to obtain
viscous oily substance which was used in the conjuga-
tion reaction without additional purification. Yield 0.3 g
1
(97%). H NMR spectrum, δ, ppm: 0.80–1.00 m (12H,
Me), 1.00–1.80 m (26H, 2-Me, CH2, CH), 1.95 s (3H,
5-Me), 2.50 m (2H, H4), 3.49 m (2H, CH2NH), 3.99 m
(2H, NH2), 7.35 m (2H, H8, H9), 8.13 m (2H, H7, H10).
13C NMR spectrum, δ, ppm: 12.03 (5-Me), 19.66, 19.72
(4'-Me, 8'-Me), 21.02 (C4), 22.61, 22.70 (12’-Me2), 23.42
(2-Me), 24.46, 24.81 (C2', C6', C10'), 27.97 (C12'), 29.70
(C3), 32.79, 32.80 (C4', C8'), 37.29, 37.41, 37.43 (C3', C5',
C7', C9'), 39.37 (C11', C1'), 40.00 (CH2NH2), 75.95 (C2),
114.13 (C5), 119.62 (C8), 122.05 (C7), 124.74, 125.22,
126.07, 126.55 (C4a, C6a, C10a, C9, C10), 135.83 (C10b),
147.26 (C6), 166.89 (CO).
2,5-Dimethyl-2-(4,8,12-trimethyltridecyl)
naphtho[1,2-b]-3,4-dihydro-2H-pyran-6-yl N-[3-
oxolup-20(29)-en-28-oyl]-2-aminoacetate (XVII). To
a solution of 0.07 g (0.14 mmol) of compound XVI in
6 ml of anhydrous C6H6 was added at stirring 0.05 ml of
Et3N and 0.06 g (0.14 mmol) of betulonic acid chloride
(VIII). The reaction mixture was stirred for 1 h at boiling
2,5-Dimethyl-2-(4,8,12-trimethyltridecyl)
naphtho[1,2-b]-3,4-dihydro-2H-pyran-6-yl (tert-
butyloxycarbonyl)amino]acetate (XV). To a solution
of 0.60 g (1.3 mmol) of naphthotocopherol (XIII) in
20 ml of anhydrous CH2Cl2 was added at stirring 0.02 g
(0.1 mmol) of DMAP, 0.26 g (1.5 mmol) of Boc-Gly,
and 0.30 г (1.5 mmol) of DCC. The reaction mixture was
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

SPIVAK et al.
1362
and 10 h at room temperature, then it was evaporated. The
residue was subjected to column chromatography (2 g of
SiO2, eluent CHCl3). Yield 0.08 g (62%), viscous oily
substance, [α]D20 +10.98° (C 2.05, CHCl3). IR spectrum, ν,
6. Di, Stefano, A., Sozio, P., Cocco, A., Iannitelli, A., San-
tucci, E., Costa, M., Pecci, L., Nasuti, C., Cantalamessa,
F., and Pinnen, F., J. Med. Chem., 2006, vol. 49, p. 1486.
7. Nakagawa-Goto, K., Yamada, K., Nakamura, S., Chen,
T-H., Chiang, P-C., Bastow, K.F., Wang, S.-C., Spohn,
B., Hung, M.-C., Lee, F.-Yu., Lee, F.-C., and Lee, K.-H.,
Bioorg. Med. Chem. Lett., 2007, vol. 17, p. 5204.
cm–1: 3390 (CONH), 1740 (O–C=O). UV spectrum, λmax
,
1
nm (ε): 307 (5940). H NMR spectrum, δ, ppm: 0.85–
1.00 m (12H, 4"-Me, 8"-Me, 12"-Me); 1.00 s, 1.03 s, 1.08
s, 1.13 s (15H, H23', H24', H25', H26', H27'); 1.20–2.60 m
(24H, CH2, CH in residue of betulonic acid, 26H, 2-Me,
CH2, CH in residue of naphthotocopherola), 1.71 s (3H,
H30'), 2.20 (3H, 5-Me), 2.74 t (2H, H4, J 6.5 Hz), 3.04 m
(1H, H19'), 4.55 d (2H, CH2NH, J 4.4 Hz); 4.65 s, 4.76 s
(1H each, H29'); 7.31 m (1H, NH), 7.45 m (2H, H8, H9);
7.57 d, 8.21 d (1H each, H7, H10, J 7.6 Hz). 13C NMR
spectrum, δ, ppm: 12.67 (5-Me), 14.60 (C27'), 15.93 (C25',
C26'), 19.40 (C30'), 19.62, 19.65, 19.68 (4'-Me, 8'-Me,
C6'), 20.65 (C4), 21.06 (C24'), 21.38 (C11'), 22.64, 22.73
(12'-Me2), 23.70 (2-Me), 24.45, 24.81 (C2'', C6'', C10''),
25.55 (C12'), 26.58 (C23'), 27.98 (C12''), 29.71 (C15', C21'),
31.00 (C3), 32.74, 32.78 (C4'', C8'', C16'), 33.63 (C7'), 34.15
(C2'), 37.30, 37.38, 37.40, 37.42 (C3'', C5'', C7'', C9'', C10',
C13'), 38.30 (C22'), 39.38 (C11''), 39.66 (C1'), 40.12 (C1''),
40.71 (C8'), 41.22 (CH2NH2), 42.58 (C14'), 46.62 (C19'),
47.37 (C4'), 49.15 (C18'), 49.94 (C9'), 55.03 (C5'), 58.02
(C17'), 76.03 (C2), 110.01 (C29'), 114.12, 119.80, 122.14,
126.48, 125.63, 126.48 (C5, C7, C8, C9, C10, C4a, C6a,
C10a), 136.20 (C10b), 147.23 (C6), 149.87 (C20'), 166.29
(COO), 171.97 (C28'), 218.32 (C3'). Found, %: C 80.01;
H 10.38; N 1.55. C63H95NO5. Calculated, %: C 79.95;
H 10.12; N 1.48.
8. Arya, P., Alibhai, N., Qin, H., and Burton, G.W., Bioorg.
Med. Chem. Lett., 1998, vol. 8, p. 2433.
9. Goto, Y., Watanabe, N., Kogawa, N., Tsuchiya, M.,
Takahashi, O., Uchi, H., Furue, M., and Hayashi, H., Eur.
J. Pharmacol., 2002, vol. 438, p. 189.
10. Koufaki, M., Calogeropoulou, T., Rekka, E., Chryselis, M.,
Papazafiri, P., Gaitanaki, C., and Makriyannis, A., Bioorg.
Med. Chem., 2003, vol. 11, p. 5209.
11. Koufaki, M., Detsi, A., Theodorou, E., Kiziridi, Ch.,
Calogero-poulou, T., Vassilopoulos, A., Kourounakis,
A.P., Rekka, E., Kourounakis, P.N., Gaitanaki, C., and
Papazafiri, P., Bioorg. Med. Chem., 2004, vol. 12, p. 4835.
12. Jacobsen, E.J., Van, Doornik, F.J., Ayer, D.E., Belonga,
K.L., Braughler, J.M., Hall, E.D., and Houser, D.J., J. Med.
Chem., 1992, vol. 35, p. 4464.
13. Koufaki, M., Kiziridi, Ch., Alexi, X., and Alexis, M.N.,
Bioorg. Med. Chem., 2009, vol. 17, no. 17, p. 6432.
14. Muller, T., Coowar, D., Hanbali, M., Heuschling, P., and
Luu, B., Tetrahedron, 2006, vol. 62, 12025.
15. Mukherjee, R., Kumar, V., Srivastava, S.K.,Agarwal, S.K.,
and Burman, A.C., Anti-Cancer Agents in Med. Chem.,
2006, vol. 6, p. 271.
16. Tolstikov, G.A., Flekhter, O.B., Shul’ts, E.E., Baltina, L.A.,
and Tolstikov, A.G., Khimiya v interesakh ustoichivogo
razvitiya (Chemistry for Stable Development), 2005,
vol. 13, p. 1.
The study was performed under a financial support
of the Russian Foundation for Basic Research (grant no.
10-03-00105).
17. Tolstikova, T.G., Sorokina, I.V., Tolstikov, G.A., Tolsti-
kov,A.G., and Flekhter, O.B., Bioorg. Khim., 2006, vol. 32,
p. 42.
REFERENCES
18. Spivak, A.Yu., Khabibrakhmanova, O.V., Mufazza-
lova, R.R., Odinokov, V.N., and Dzhemilev, U.M., Dokl.
Akad. Nauk, 2008, vol. 423, p. 627.
1. Burlakova, E.B. and Khrapova, N.G., Usp. Khim., 1985,
vol. 54, p. 1540.
2. Khimicheskaya i biologicheskaya kinetika. Novye gori-
zonty. Biologicheskaya kinetika. Sb. obzornykh, statei.
Moscow: Khimiya, 2005, vol. 2, p. 10.
19. Mukai, K., Okabe, K., and Hosose, H., J. Org. Chem.,
1989, vol. 54, p. 557.
20. Lopez, G.V., Blanco, F., Hernandez, P., Ferreira, A.,
Piro, O.E., Batthyany, C., Gonzalez, M., Rubbo, H., and
Cerecetto, H., Bioorg. Med. Chem., 2007, vol. 15, p. 6262.
3. Nordberg, J. and Arner, E.S.J., Free Radical, Biol. Med.,
2001, vol. 31, p. 1287.
4. Odinokov, V.N., Spivak, A.Yu., and Knyshenko, O.V.,
21. Lei, H. and Atkinson, J., J. Org. Chem., 2000, vol. 65,
Bioorg. Khim., 2007, vol. 33, p. 387.
p. 2560.
5. Detsi, A., Bouloumbasi, D., Prousis, K.C., Koufaki, M.,
Athana-sellis, G., Melagraki, G., Afantitis, A., Igglessi-
Markopoulou, O., Kontogiorgis, Ch., and Hadjipavlou-
Litina, D.J., J. Med. Chem., 2007, vol. 50, p. 2450.
22. Nozawa, M., Takahashi, K., Kato, K., andAkia, H., Chem.
Pharm. Bull., 2000, vol. 48, p. 272.
23. Odinokov, V.N., Spivak, A.Yu., Emel’yanova, G.A., Ga-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

SYNTHESIS OF TRITERPENE ACIDS
1363
malevich, G.D., and Serebryakov, E.P., Izv. Akad. Nauk,
Ser. Khim., 2001, vol. 11, p. 2026.
Dzhemilev, U.M., Dokl. Akad. Nauk., 2003, vol. 39, p. 346.
26. Tolstikov, G.A., Goryaev, M.I., Kim, Kh.O., and
Khegai, R.A., Zh. Prikl. Khim., 1967, 40, 920.
24. Flekhter, O.B., Boreko, E.I., Nigmatullina, L.R.,
Tret’yakova, E.V., Pavlova, N.I., Baltina, L.A., Niko-
laeva, S.N., Savinova, O.V., Eremin, V.F., Galin, F.Z., and
Tolstikov, G.A., Bioorg. Khim., 2004, vol. 30, p. 89.
27. Shon, L.B., Kaplun, A.P., Shpilevskii, A.A., Andiya-
Prav-divyi, Yu.E., Alekseeva, S.G., Grigor’ev, V.B., and
Shvets, V.I., Bioorg. Khim., 1998, vol. 24, p. 787.
28. Hiroya, K., Takahashi, T., Miura, N., Naganuma, A., and
25. Odinokov, V.N., Spivak, A.Yu., Nazarova, O.V., Mal-
lyabaeva, M.I., Emel’yanova, G.A., Krysin, A.P., and
Sakamoto, T., Bioorg. Med. Chem., 2002, vol. 10, p. 3229.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010