ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 9, pp. 1318–1323. © Pleiades Publishing, Ltd.

, 2015.
Original Russian Text © O.V. Tsepaeva, A.V. Nemtarev, L.R. Grigor’eva, A.D. Voloshina, V.F. Mironov, 2015, published in Zhurnal Organicheskoi Khimii,
2015, Vol. 51, No. 9, pp. 1343–1348.

Dedicated to Full Member of the Russian Academy of Sciences

N.S. Zefirov on his 80th anniversary

Esterification of Betulin with ω-Bromoalkanoic Acids

O. V. Tsepaevaa, A. V. Nemtareva, b, L. R. Grigor’evab, A. D. Voloshinaa, and V. F. Mironova, b
a
Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences,
ul. Arbuzova 8, Kazan, 420088 Tatarstan, Russia
e-mail: a.nemtarev@mail.ru
b
Kazan (Volga Region) Federal University, ul. Kremlevskaya 18, Kazan, 420008 Tatarstan, Russia

Received July 4, 2015

Abstract—New C3- and C28-functionalized derivatives of the lupane triterpenoid betulin have been synthesized
by esterification with ω-bromoalkanoic acids, and preliminary biological screening of the obtained compounds
has been performed.

DOI: 10.1134/S1070428015090195

Betulin [1, lup-20(29)-ene-3β,28-diol] is a penta-
cyclic lupane triterpenoid that is the main component
of extractable substances from the bark of different
birch species. Its concentration in the birch bark
amounts to 10–35%. Betulin occurs not only in birch
but also in some other plants [1–3] growing on dif-
ferent continents. Several betulin derivatives, such as
betulinic and betulonic acids, 3-O-sulfates [4],
28-O-glycosides, and esters with nicotinic and caffeic
acids [5, 6], have been isolated from plant sources.
Therapeutic properties of birch bark extracts have long
been known [7]. Numerous studies on the biological
activity of betulin and its derivatives have been
reviewed in [8–12]. Antibacterial activity of triter-
penoids against gram-positive and gram-negative bac-
teria was reported in [13]. In the past decades, a large
number of mono- and diesters derived from betulin and
betulinic acid have been described [14–27] and shown
to exhibit anti-HIV [28–30], immunomodulatory
[31, 32], hepatoprotective [33], anti-inflammatory, and
antiulcer activity. The results of recent studies showed
that 28-O-(chloroacetyl)betulin is more cytotoxic than
betulinic acid against MCF-7 tumor cells [34]. It was
found that the antitumor effect of betulin derivatives
originates from induction of tumor cell apoptosis.
In the present article we describe the synthesis of
new C3- and C28-functionalized betulin derivatives via
esterification with ω-bromoalkanoic acids, and the ob-
tained compounds were tested for biological activity.
Up to now, numerous methods for esterification of
hydroxy compounds, including betulin, betulinic acid,
and their derivatives, have been developed [28, 35,
36]. However, lability of the pentacyclic triterpene
system in acid medium and steric shielding of the
hydroxy groups in the betulin molecule necessitate
the use of most selective and simultaneously mild
esterification procedures. One of such procedures is
Steglich esterification which implies reaction of car-
boxylic acids with alcohols in the presence of 4-di-
methylaminopyridine (DMAP) and N,N′-dicyclohexyl-
carbodiimide (DCC) [37]. Our experiments revealed
high selectivity of this method in the synthesis of
monoesters 2a–2c from equimolar amounts of betulin
and ω-bromoalkanoic acids (Scheme 1). In this case,
only the primary hydroxy group on C28 was involved,
while the 3-OH group remained intact. The yield of
2a–2c depended on the length of the carbon chain in
the acid and was 80–85% in the reactions with
4-bromobutanoic and 5-bromopentanoic acids and
45% for 3-bromopropanoic acid. The products were
purified by column chromatography on silica gel. Ester
2a with 3-bromopropanoic acid forms a stable com-
plex which can be decomposed only by repeated re-
crystallization from ethanol, as clearly followed from
the 1H NMR data.
The structure of 2a–2c was proved by 1H and 13C
NMR spectroscopy. Comparison of the 1H NMR spec-
tra of 2a–2c and betulin revealed an appreciable down-
field shift of the C28H2 proton signals (AX spin system)
as a result of introduction of an acyl group (see figure).

1318
 ESTERIFICATION OF BETULIN WITH ω-BROMOALKANOIC ACIDS 1319
Scheme 1.
29
CH2 CH2
30 20
Me 19 21 Me

12 18 22 Br
13 Br(CH2)nC(O)OH
25 11 26 17 OH O ( )n
Me Me DCC, DMAP Me Me
14 16 28
1 9
2 10 8 O
3 5 7
Me 15 Me
4 6 27
HO HO
23 24
Me Me Me Me
1 2a–2c

n = 2 (a), 3 (b), 4 (c).

The position of the 3-H signal changes only slightly in gave only the 28-monoester, whereas no expected bis-
going from betulin to esters 2a–2c, which reliably con- ester 3a was formed. The structure of 3b and 3c was
firmed acylation of only the 28-OH group. confirmed by IR and 1H NMR spectra. In the 1H NMR
The 13C–{1H} and 13C NMR spectra of 2a–2c were spectra of 3b and 3c, the 3-H and 28-H signals were
analyzed on the basis of the data for betulin (1) and displaced downfield, indicating esterification of the
initial bromoalkanoic acids with account taken of corresponding hydroxy groups (see figure).
signal multiplicity. Compounds 2a–2c displayed well Esters 2a–2c were tested for antimicrobial (bac-
resolved 13C–{1H} NMR spectra which contained only teriostatic and fungistatic) activity in vitro in the
one set of signals belonging to the lupane skeleton and concentration range from 500 to 0.97 μg/mL. As test
substituent on C 28 . In the upfield region (δ C 32– cultures we used gram-positive Staphylococcus aureus
34 ppm) we observed signals from the CH2Br and ATCC 209p and Bacillus cereus ATCC 8035, gram-
C(O)CH 2 groups, and sp 2 -carbon atoms of the negative Escherichia coli CDC F-50 and Pseudomonas
OC(O) and CH2=C fragments resonated in a weak field aeruginosa ATCC 9027, and fungi Aspergillus niger
(δC 172–173 and 110 ppm, respectively). Esters 2a–2c BKMF-1119, Trichophyton mentagrophytes var.
showed in the IR spectra a strong broadened absorp- gypseum 1773, and Candida albicans 855-653. The
tion band centered at 3350–3420 cm–1 due to stretching activity of 2a–2c was evaluated by the serial dilution
vibrations of the hydroxy group, a strong absorption method in a liquid nutrient medium according to
band at ~1735 cm–1 due to stretching vibrations of the standard procedures [38, 39]. No antimicrobial activity
ester carbonyl group, and bands in the regions 1660– was found for 2a–2c at the given concentrations.
1630 (C=C) and 1230–1250 cm–1 (C–O–C).
Esterification of betulin with ω-bromoalkanoic EXPERIMENTAL
acids at a ratio of 1 : 2 afforded bis-esters 3b and 3c
only with 4-bromobutanoic and 5-bromopentanoic The 1 H, 13 C, and 13 C–{ 1 H} NMR spectra were
acids (yield 60 and 70%, respectively; Scheme 2). The recorded on a Bruker Avance 500 spectrometer at
reaction of 1 with 2 equiv of 3-bromopropanoic acid 500 MHz for 1H and 125.75 MHz for 13C using CDCl3
Scheme 2.
CH2

Me
Br
2 Br(CH2)nC(O)OH O ( )n
DCC, DMAP Me Me
1 2a–2c +
O O
Me
Br
( )n O
Me Me
3b, 3c

n = 3 (b), 4 (c).

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 9 2015

1320
28-HA
29-HB 29-HA 28-HX
29-HB 29-HA
28-HX
29-HB 29-HA 3-H 28-HX
28-HA
1
Fragments of the H NMR spectra (500 MHz, CDCl3) of (a) compound 2c, (b) betulin, and (c) compound 3c.
as solvent. The IR spectra were measured in KBr on
a Bruker Vector-22 spectrometer with Fourier trans-
form. The MALDI mass spectra were obtained on
a Bruker MALDI-TOF Ultraflex III instrument using
2,5-dihydroxybenzoic acid as matrix.
3β-Hydroxylup-20(29)-en-28-yl 3-bromopropa-
noate (2a). A mixture of 0.88 g (2.0 mmol) of betulin,
0.33 g (2.1 mmol) of 3-bromopropionic acid, 0.43 g
(2.1 mmol) of DCC, and 0.04 g of DMAP in 12 mL of
methylene chloride was stirred for 24 h at room tem-
perature. The precipitate was filtered off, the solvent
was distilled off from the filtrate, and the residue was
purified by silica gel column chromatography (CHCl3–
EtOH, 100 : 0.2) followed by recrystallization from
ethanol. Yield 0.52 g (45%), mp 73–75°C. IR spec-
trum, ν, cm–1: 3356, 3070, 2940, 2868, 1735 (C=O),
1658 (C=C), 1453, 1389, 1262, 1233 (C–O–C), 1189,
1130, 1044, 1015, 982. 1 H NMR spectrum, δ, ppm
(J, Hz): 0.78 s, 0.84 s, 0.98 s, 0.99 s, and 1.05 s (3H
each, C23H3, C24H3, C25H3, C26H3, C27H3); 1.70 s (3H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 9 2015
TSEPAEVA et al.
CH2Br (a)
OC(O)CH2
3-H
19-H
28-HA (b)
3-H
19-H
CH2Br
(c)
OC(O)CH2
OC(O)CH2
19-H
δ, ppm
C30H3), 2.45 m (1H, 19-H, 3J = 10.9, 5.8), 2.96 t [2H,
C(O)CH2, 3J = 6.8], 3.20 m (1H, 3-H, 3J = 11.0, 5.0),
3.60 t (2H, CH2Br, 3J = 7.0), 3.90 d (1H, 28-HA, 2J =
11.0), 4.35 d (1H, 28-HX, 2J = 11.0), 4.61 (1H, 29-HA),
4.71 (1H, 29-H B ). 13 C NMR spectrum, δ C , ppm
(JCH, Hz): 14.79 m (C27, 1J = 124.2), 15.36 m (C24, 1J =
124.9), 16.04 br.q (C26, overlapped by the C25 signal),
16.09 br.q (C 25 , overlapped by the C 26 signal),
18.29 br.t (C6, 1J = 129.4), 19.15 m (C30, 1J = 125.0),
20.80 br.t (C11, 1J = 120.8), 25.24 br.t (C12, 1J = 121.9),
25.46 t.t [OC(O)CH 2 , 1 J = 154.4, 2 J = 4.7–5.0],
27.06 br.t (C15, 1J = 126.2), 27.42 br.t (C2, 1J = 127.2),
28.00 br.q (C23, 1J = 127.2), 29.59 br.t (C16, 1J =
129.7), 29.79 br.t (C21, 1J = 128.5), 34.21 br.t (C22, 1J =
125.6), 34.57 br.t (C7, 1J = 128.3), 37.17 br.s (C10),
37.41 br.t (CH2Br, 1J = 131.0), 37.66 br.d (C13,
overlapped by the C10 signal), 38.74 br.t (C1, 1J =
124.7), 38.87 br.s (C4), 40.91 br.s (C8), 42.72 br.s (C14),
46.44 br.s (C17), 47.71 br.d (C18, 1J = 125.2), 48.84 br.d
(C19, 1J = 125.1), 50.40 br.d (C9, 1J = 123.8), 55.33 br.d
 ESTERIFICATION OF BETULIN WITH ω-BROMOALKANOIC ACIDS
(C5, 1J = 117.2), 63.43 br.t (C28, 1J = 144.0), 78.98 br.d
(C 3 , 1 J = 1 4 2 . 6 ) , 1 0 9 . 9 0 m ( C 2 9 , 1 J = 154.2 ),
150.04 br.s (C20), 170.86 br.s (C=O). Mass spectrum:
m/z 619.0 [M + K]+. C33H52BrO3. Calculated: M 579.98.
3β-Hydroxylup-20(29)-en-28-yl 4-bromobutano-
ate (2b). A mixture of 0.88 g (2.0 mmol) of betulin,
0.35 g (2.1 mmol) of 4-bromobutanoic acid, 0.43 g
(2.1 mmol) of DCC, and 0.04 g of DMAP in 12 mL of
methylene chloride was stirred for 24 h at room tem-
perature, the progress of the reaction being monitored
by TLC. The precipitate was filtered off, the filtrate
was evaporated, and the residue was purified by
column chromatography on silica gel (CHCl3–EtOH,
100 : 1). Yield 0.95 g (80%), mp 85–87°C. IR spec-
trum, ν, cm–1: 3419, 3071, 2942, 2869, 1733 (C=O),
1641 (C=C), 1455, 1389, 1249, 1200 (C–O–C), 1130,
1033, 983. 1H NMR spectrum, δ, ppm (J, Hz): 0.77 s,
0.83 s, 0.98 s, 0.99 s, and 1.04 s (3H each, C23H3,
C 24 H 3 , C 25 H 3 , C 26 H 3 , C 27 H 3 ); 1.69 s (3H, C 30 H 3 ),
2.20 m (2H, CH2, 3J = 6.9), 2.45 m (1H, 19-H, 3J =
10.7, 5.6), 2.54 t [2H, C(O)CH2, 3J = 7.2], 3.20 (1H,
3-H, 3J = 11.0, 5.0), 3.48 (2H, CH2Br, 3J = 6.5), 3.88 d
(1H, 28-HA, 2J = 11), 4.31 d (1H, 28-HX, 2J = 11), 4.60
(1H, 29-HA), 4.70 (1H, 29-HB). 13C NMR spectrum, δC,
ppm (JCH, Hz): 14.79 m (C27, 1J = 124.0), 15.35 m
(C24, 1J = 124.7), 16.04 br.q (C26, overlapped by the
C25 signal), 16.09 br.q (C25, overlapped by the C26
signal), 18.29 br.t (C6, 1J = 123.4), 19.15 m (C30, 1J =
125.4), 20.80 br.t (C11, partially overlapped by the C6
signal), 25.23 br.t (C12, 1J = 122.4), 27.08 br.t (C15,
1
J = 125.9), 27.42 br.t (C 2 , 1 J = 125.1), 27.83 m
(CH2CH2Br, 1J = 130.5), 27.99 br.q (C23, 1J = 124.0),
29.62 br.t (C16, 1J = 128.4), 29.83 br.t (C21, 1J = 128.5),
32.65 br.t [OC(O)CH2, 1J = 128.4], 32.70 m (CH2Br,
1
J = 127.3), 34.22 br.t (C22, 1J = 126.0), 34.58 br.t (C7,
1
J = 128.8), 37.17 br.s (C10), 37.63 br.d (C13, over-
lapped by the C10 signal), 38.74 br.t (C1, 1J = 125.4),
38.87 br.s (C4), 40.91 br.s (C8), 42.72 br.s (C14),
46.43 br.s (C17), 47.80 br.d (C18, 1J = 124.0), 48.83 br.d
(C19, 1J = 124.6), 50.40 br.d (C9, 1J = 122.5), 55.33 br.d
(C5, 1J = 119.9), 62.96 br.t (C28, 1J = 145.3), 78.97 br.d
(C 3 , 1 J = 1 4 1 . 2 ) , 1 0 9 . 8 7 m ( C 2 9 , 1 J = 154.8 ),
150.07 br.s (C 20 ), 172.91 br.s (C=O). Found, %:
C 67.6; H 8.9; Br 11.6. C34H54BrO3. Calculated, %:
C 69.1; H 9.1; Br 13.5.
3β-Hydroxylup-20(29)-en-28-yl 5-bromopenta-
noate (2c). A mixture of 0.88 g (2.0 mmol) of betulin,
0.38 g (2.1 mmol) of 5-bromopentanoic acid, 0.43 g
(2.1 mmol) of DCC, and 0.04 g of DMAP in 12 mL of
methylene chloride was stirred for 24 h at room tem-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 9 2015
1321
perature (TLC). The precipitate was filtered off, the
filtrate was evaporated, and the residue was purified by
column chromatography on silica gel (CHCl3–EtOH,
100 : 1). Yield 1.0 g (85%), mp 112–115°C. IR spec-
trum, ν, cm–1: 3438, 2940, 2869, 1733 (C=O), 1628
(C=C), 1454, 1389, 1250 (C–O–C), 1193, 1044, 983.
1
H NMR spectrum, δ, ppm (J, Hz): 0.78 s, 0.84 s,
0.98 s, 0.99 s, and 1.05 s (3H each, C23H3, C24H3,
C25H3, C26H3, C27H3); 1.70 s (3H, C30H3), 1.80 m (2H,
CH2, 3J = 7.0), 1.92 m (2H, CH2, 3J = 6.9), 2.39 [2H,
C(O)CH2, 3J = 7.3], 2.45 m (1H, 19-H, 3J = 11.0, 5.7),
3.19 (1H, 3-H, 3J = 11.1, 5.0), 3.43 (2H, CH2Br, 3J =
6.5), 3.87 d (1H, 28-HA, 2J = 11.0), 4.27 d (1H, 28-HX,
2
J = 11.0), 4.60 (1H, 29-H A ), 4.70 (1H, 29-H B ).
13
C NMR spectrum, δC, ppm (JCH, Hz): 14.78 m (C27,
1
J = 124.3), 15.35 m (C24, 1J = 124.5), 16.05 br.q (C26,
overlapped by the C25 signal), 16.09 br.q (C25, over-
lapped by the C26 signal), 18.29 br.t (C6, 1J = 124.0),
19.15 m (C30, 1J = 125.4), 20.81 br.t (C11, partially
o v e r l a p p e d b y t h e C 3 0 s i g n a l ) , 2 3 . 6 0 b r. q
[OC(O)CH2CH2, 1J = 129.1], 25.23 br.t (C12, 1J =
122.1), 27.09 br.t (C15, 1J = 122.5), 27.42 br.t (C2, 1J =
124.2), 27.99 br.q (C23, 1J = 124.3), 29.63 m (C16),
29.85 m (C 21 ), 32.06 m (CH 2 CH 2 Br), 32.92 m
[OC(O)CH2], 33.45 br.t (CH2Br, 1J = 128.0), 34.22 br.t
(C22, 1J = 126.1), 34.60 br.t (C7, 1J = 128.8), 37.17 br.s
(C10), 37.62 br.d (C13, overlapped by the C10 signal),
38.74 br.t (C1, 1J = 26.1), 38.87 br.s (C4), 40.91 br.s
(C8), 42.73 br.s (C14), 46.42 br.s (C17), 47.71 br.d (C18,
partially overlapped by the C19 signal), 48.84 br.d (C19,
partially overlapped by the C18 signal), 50.40 br.d (C9,
1
J = 122.1), 55.33 br.d (C5, 1J = 118.5), 62.80 br.t (C28,
1
J = 146.7), 78.98 br.d (C3, 1J = 142.0), 109.85 m (C29,
1
J = 154.1), 150.10 br.s (C 20 ), 173.51 br.s (C=O).
Found, %: C 68.8; H 8.9; Br 12.1. C35H56BrO3. Calcu-
lated, %: C 69.5; H 9.2; Br 13.2.
Lup-20(29)-ene-3β,28-diyl bis(4-bromobutano-
ate) (3b). A mixture of 0.88 g (2.0 mmol) of betulin,
0.70 g (4.2 mmol) of 4-bromobutanoic acid, 0.86 g
(4.2 mmol) of DCC, and 0.08 g of DMAP in 12 mL of
methylene chloride was stirred for 24 h at room tem-
perature (TLC). The precipitate was filtered off, the
filtrate was evaporated, and the residue was purified by
column chromatography on silica gel (CHCl3–EtOH,
100 : 1). Yield 0.89 g (60%), mp 58–60°C. IR spec-
trum, ν, cm–1: 2946, 2871, 1731 (C=O), 1641 (C=C),
1455, 1391, 1376, 1307, 1281, 1251 (C–O–C), 1202,
1176, 1129, 1008, 980. 1 H NMR spectrum, δ, ppm
(J, Hz): 0.86 s, 0.87 s, 0.99 s, and 1.06 s (15H, C23H3,
C 24 H 3 , C 25 H 3 , C 26 H 3 , C 27 H 3 ); 1.70 s (3H, C 30 H 3 ),
1.82 m (2H, CH 2 , 3 J = 7.2), 1.93 m (2H, CH 2 , 3 J =
1322 TSEPAEVA et al.
7.7), 2.36 m [2H, OC(O)CH2, 3J = 7.2], 2.39 m [2H,
OC(O)CH2, 3J = 7.4], 2.46 m (1H, 19-H, 3J = 11.1,
5.8), 3.43 t (2H, CH2Br, 3J = 6.5), 3.44 t (2H, CH2Br,
3
J = 6.6), 3.87 d (1H, 28-HA, 2J = 11.1), 4.31 d (1H,
28-HX, 2J = 11.1), 4.50 m (1H, 3-H, 3J = 11.0, 6.4),
4.61 br.s (1H, 29-HA), 4.71 br.s (1H, 29-HB). Found,
%: C 60.58; H 8.49; Br 18.75. C38H60Br2O4. Calculat-
ed, % C 61.6; H 8.1; Br 21.6.
Lup-20(29)-ene-3β,28-diyl bis(5-bromopentano-
ate) (3b). A mixture of 0.88 g (2.0 mmol) of betulin,
0.76 g (4.2 mmol) of 5-bromopentanoic acid, 0.86 g
(4.2 mmol) of DCC, and 0.08 g of DMAP in 12 mL of
methylene chloride was stirred for 24 h at room
temperature (TLC). The precipitate was filtered off, the
filtrate was evaporated, and the residue was purified by
column chromatography on silica gel (CHCl3–EtOH,
100 : 1). Yield 1.0 g (70%), mp 49–50°C. IR spectrum,
ν, cm–1: 3438, 2940, 2869, 1733 (C=O), 1628 (C=C),
1454, 1389, 1250 (C–O–C), 1193, 1044, 983. 1H NMR
spectrum, δ, ppm (J, Hz): 0.87 s, 0.88 s, 1.00 s, and
1.06 s (15H, C 23 H 3 , C 24 H 3 , C 25 H 3 , C 26 H 3 , C 27 H 3 );
1.71 s (3H, C30H3), 2.18 m (2H, CH2, 3J = 6.8–7.0),
2.20 m (2H, CH2, 3J = 6.8–7.0), 2.21 m (2H, CH2, 3J =
6.8–7.0), 2.23 m (2H, CH2, 3J = 6.8), 2.46 m (1H,
19-H, 3J = 11.1, 6.1), 2.52 m [2H, OC(O)CH2, 3J =
7.5], 2.55 m [2H, OC(O)CH2, 3J = 7.2], 3.48 t (2H,
CH2Br, 3J = 6.5), 3.49 t (2H, CH2Br, 3J = 6.4), 3.89 d
(1H, 28-HA, 2J = 11.4), 4.32 d (1H, 28-HX, 2J = 11.4),
4.52 m (1H, 3-H, 3J = 11.0, 6.0), 4.62 m (1H, 29-HA),
4.72 m (1H, 29-H B ). Found, %: C 61.58; H 7.9;
Br 18.9. C40H64Br2O4. Calculated, %: C 62.5; H 8.3;
Br 20.8.
This study was performed under financial support
by the Russian Science Foundation (project no. 14-50-
00 014).
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