Synthesis of betulonic aldehyde derivatives

Article abstract of DOI:10.1134/S1068162012070114

Selective functionalization of betulonic aldehyde (the oxidation product of betulin) was studied with the aim of obtaining new physiologically active substances. We developed a method for the synthesis of azomethine derivatives at the C-28 aldehyde group

Full text of DOI:10.1134/S1068162012070114

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2012, Vol. 38, No. 7, pp. 740–742. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © E.S. Kurbatov, V.V. Kostrub, S.V. Kurbatov, 2011, published in Khimija Rastitel’nogo Syr’ja, 2011, No. 3, pp. 81–83.
LOWꢀMOLECULARꢀWEIGHT
COMPOUNDS
Synthesis of Betulonic Aldehyde Derivatives
E. S. Kurbatov, V. V. Kostrub, and S. V. Kurbatov1
Southern Federal University, Department of Chemistry, ul. Sorge 7, RostovꢀonꢀDon, 344090 Russia
Received, October 7, 2019; in final form, March 18, 2011
Abstract—Selective functionalization of betulonic aldehyde (the oxidation product of betulin) was studied
with the aim of obtaining new physiologically active substances. We developed a method for the synthesis of
azomethine derivatives at the Cꢀ28 aldehyde group and benzylidene derivatives at the 2ꢀmethylene group of
the A ring. The structure of the synthesized products was proved by 1H NMR.
Keywords: betulin, betulonic aldehyde, 3,4,5ꢀtrimethoxyaniline, nitrobenzaldehyde
DOI: 10.1134/S1068162012070114
1
INTRODUCTION
reasons. It is found that antitumor properties of colchꢀ
icine from Colchicum speciosum are due to its ability to
interact with tubulin because the structure of this alkaꢀ
loid contains the trimethoxyphenyl fragment, which is
complementary to one of the tubulin binding sites
[10]. The usefulness of the introduction of the triꢀ
methoxyphenyl fragment to enhance antitumor propꢀ
erties of compounds of various classes is found experiꢀ
mentally (e.g., [11] and literature cited therein). The
formation of azomethine (V) is confirmed by the
appearance in 1HNMR spectra of signals of protons of
the methoxyl groups in the range of 3.8–3.9 ppm and
aromatic protons at 6.21 ppm with the corresponding
intensities. The signal of the azomethine proton
appropriately shifts to 7.93 ppm.
It is known that betulin (I) contained in large
amounts (30–40%) in the birch bark Betula pendula
,
and easily retrieved from it with accessible solvents [1],
shows a wide range of biological activity [2]. Chemical
transformations of betulin allow one to obtain its
derivatives, which possess pronounced antitumor [3]
and antiviral [4] activities combined with low toxicity
[2]. The most developed and promising direction is the
oxidation of betulin to betulinic [5] and betulonic
acids and subsequent synthetic modification of these
acids [2].
Against this background, an unexpectedly littleꢀstudꢀ
ied object is another oxidized derivative of betulin (I),
namely betulonic aldehyde (II), the antiviral activity
of which is also known [6, 7]. Despite the molecule of
betulonic aldehyde containing several reactive fragꢀ
ments, only the Prince reaction at the C20–C29 bond [8]
and the reductive amination at the aldehyde group [9]
are described to date according to Chemical Abstracts.
One of the side processes during the synthesis of
benzylidene derivative (VI) could be the selfꢀcondenꢀ
sation of betulonic aldehyde. To avoid this, we used
obviously more active nitroꢀbenzaldehyde. Moreover,
the presence of an electronꢀacceptor substituent in the
system of conjugated C=C–C=O bonds must faciliꢀ
tate the subsequent reactions of nucleophilic addition
In this paper, we report first examples of the syntheꢀ
sis of betulonic aldehyde derivatives at the aldehyde
group and the 2ꢀmethylene group of the A ring. Betuꢀ
lonic aldehyde (II) was synthesized by oxidation of betuꢀ
line (I) with pyridinium chlorochromate (PCC) [6].
1
and/or cycloaddition at the A ring [12]. H NMR
spectrum of (VI) contains proton signals of the nitroꢀ
phenyl ring in the range of 7.5ꢀ8.2 ppm. Proton signals
of the methylene group at the second position of the A
ring of betulonic aldehyde, which are among the most
weak field signals in the spectrum (and therefore can
be easily identified), disappear.
RESULTS AND DISCUSSION
The interaction of aldehyde (II) with 3,4,5ꢀtriꢀ
methoxyaniline (III) leads to azomethine (V). The
choice of the aromatic amine is due to the following
1
Corresponding author: eꢀmail: kurbatov@sfedu.ru.
740

SYNTHESIS OF BETULONIC ALDEHYDE DERIVATIVES
741
29
29
30
12
30
12
20
18
20
18
21
22
21
19
19
22
13
13
11
11
28
H
25
26
17
16
17
16
25
26
28
PCC
14
14
15
15
1
4
1
4
9
6
9
6
O
O
10
10
2
3
2
3
8
7
8
7
H
27
27
H
5
5
O
O
I
II
23
24
23
24
O−
N+
O
H2N
O
O
O
IV
H
O
III
29
29
O−
4'
+
30
12
30
12
3'
N
20
18
5'
6'
20
18
21
22
19
O
21
22
19
13
2'
13
11
11
28
H
28
25
26
17
16
H
17
16
25
26
14
31
14
15
2'
15
1
4
9
6
1
4
9
6
10
N
3'
O
2
3
8
7
O
10
2
3
8
7
27
27
5
4'
5
6'
O
O
VI
O
5'
V
23
24
23
24
O
6.21 s (2H, H2',6'), 7.93 s (1H, CH=N). Found, %: C
77.72, H 9.40, N 2.12. C39H57NO4. Calculated, %: C
77.57, H 9.51, N 2.32.
The synthesized new derivatives of betulonic aldeꢀ
hyde demonstrate the possibility of its selective conꢀ
densation at both the aldehyde group and 2ꢀmethylene
group of the A ring that opens up new ways of funcꢀ
tionalization of betulin and preparation of derivatives
potentially useful in practice.
2ꢀ(3'ꢀnitroꢀbezylidene)ꢀ3ꢀoxolupꢀ20(29)ꢀenꢀ28ꢀal
(VI).
mꢀNitroꢀbenzaldehyde (0.152 g, 1 mmol) and
0.05 mL of 40% aqueous KOH were added to a susꢀ
pension of betulonic aldehyde (II) (0.438 g, 1 mmol)
in 5mL of methanol. The reaction mixture was stirred
for 10 min at room temperature followed by boiling for
15 min. A precipitate after cooling was filtered off and
EXPERIMENTAL
1H NMR spectra were registered on a Bruker DPXꢀ
250 spectrometer (250 MHz) in deuterochloroform
kept on molecular sieves 4 Å. The internal standard was
tetramethylsilane. Betulin, pyridinium chlorochroꢀ
recrystallized from methanol. The yield 0.42 g (73%),
1
colorless crystals, Tm 181°C. H NMR spectra,
δ
,
mate, 3,4,5ꢀtrimethoxianiline, and
mꢀnitroꢀbnzaldeꢀ
ppm: 0.78 s (3H, H3C25), 0.94 s (3H, H3C26), 0.99 s
(3H, H3C27), 1.13 s (3H, H3C24), 1.14 s (3H, H3C23),
1.05–2.27 m (21H, H2C1,6,7,11,12,15,16a,21,22 and
HC5,9,13,18), 1.70 s (3H, H3C30), 2.80–3.05 m (2H,
HC16b,19), 4.64 and 4,75 both br.s (both 1H, H2C29),
hyde were from SigmaꢀAldrich (United States).
3ꢀoxolupꢀ20(29)ꢀenꢀ28ꢀ(3',4',5'ꢀtrimethoxyphenyl)
aldimine (V). A mixture of betulonic aldehyde (II)
(0.438 g, 1 mmol), 3,4,5ꢀtrimethoxyaniline (II) (0.183 g,
1 mmol), and acetic acid (0.1 mL) was bolide in methꢀ
anol (15 mL) for 2 h. A precipitate after cooling was
filtered off and recrystallized from methanol. The
yield 0.38 g (63 %), colorless crystals, Tm 218°C.
7.46 s (1H, HC30), 7.58 dd (1H,
7.67 d (1H, = 7.6 Hz, H6'), 8.17 d (1H,
J
= 8.2, 7.6 Hz, H5'),
= 8.2 Hz,
J
J
1H NMR spectra,
(3H, H3C26), 1.01 s (3H, H3C27), 1.02 s (3H, H3C24),
1.06 (21H,
(3H, H3C23), 1.15–2.18
δ
, ppm: 0.90 s (3H, H3C25), 0.99 s
H4'), 8.22 s (1H, H2'), 9.64 s (1H, CH=O). Found, %: C
77.90; H 8.46; N 2.33. C37H49NO4. Calculated, %: C
77.72; H 8.64; N 2.45.
s
m
H2C1,6,7,11,12,15,16a,21,22 and HC5,9,13,18), 1.71 s (3H,
H3C30), 2.35–2.52 m (3H, H2C2,16b), 2.65–2.80 m
(1H, HC19), 3.82 s (3H, CH3O4'), 3.87 s (6H,
CH3O3',5'), 4.62 and 4.73 both br. s (both 1H, H2C29),
The work was supported by the CRDF Foundation
and Ministry of Education (project RNP
2.2.2.3/16011) and Research Schools Support Proꢀ
gram (project NShꢀ3233.2010.3).
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
No. 7
2012

742
KURBATOV et al.
7. Pohjala, L., Alakurtti, S., Ahola, T., YliꢀKauhaluoma, J.,
REFERENCES
and Tammela, P., J. Natur. Prod., 2009, vol. 72, no. 11,
pp. 1917–1926.
1. Kislitsyn, A.N., Khim. Drev., 1994, no. 3, pp. 3–28.
8. Rybina, A.V., Shepelevich, I.S., Talipov, R.F., Galin, F.Z.,
and Spirikhin, L.V., Khim. Prir. Soedin., 2006, no. 5,
pp. 529–531.
9. Xu, Z.Q., Koohang, A., Mar, A.A., Majewski, N.D.,
Eiznhamer, D.A., and Flavin, M.T., US Patent No. WO
2007112043 A2, Chem. Abstr., vol. 147, 406972.
10. Ravelli, R.B.G., Gigant, B., Curmi, P.A., Jourdain, I.,
Lachkar, S., Sobel, A., and Knossow, M., Nature, 2004,
vol. 428, pp. 198–202.
11. Romagnli, R., Baraldi, P., Carrion, M., CruzꢀLopez, O.,
Cara, C., Tolomeo, M., Grimaudo, S., Cristina, A.,
Pipitone, M., Balzarini, J., Kandil, S., Brancale, A.,
2. Tolstikov, G.A., Flekhter, O.B., Shul’ts, E.E., Baltina, L.A.,
and Tolstikov, A.G., Khim. Interes. Ustoich. Razvit.
,
2005, no. 13, pp. 1–30.
3. Sorokina, I.V., Tolstikova, T.G., Zhukova, N.A.,
Petrenko, N.I., Uzenkova, N.V., Shul’ts, E.E., and
Popova, N.A., Bull. Exp. Biol. Med., 2006, vol. 142,
no. 7, pp. 78–81.
4. Flekhter, O.B., Boreko, E.I., Nigmatullina, L.R.,
Tret’yakova, E.V., Pavlova, N.I., Baltina, L.A.,
Nikolaeva, S.N., Savinova, O.V., Eremin, V.F., Galin, F.Z.,
and Tolstikov, G.A., Russ. J. Bioorg. Chem., 2004,
vol. 30, no. 1, pp. 89–98.
Sarkar, T., and Hamel, E., Bioorg. Med. Chem. Letts.
2008, vol. 18, pp. 5041–5045.
,
5. Kogai, T.I. and Kuznetsov, B.N., Khim. Rastit. Syr’ya
2008, no. 2, pp. 95–98.
,
12. Desenko, S.M. and Orlov, V.D., Azageterotsikly na
osnove aromaticheskikh nepredel’nykh ketonov (Azaheteꢀ
rocycles Based on Aromatic Unsaturated Ketones),
Kharkov, 1998.
6. Wie, Y., Maa, C.ꢀM., and Hattori, M., Eur. J. Med.
Chem., 2009, vol. 41, pp. 4112–4120.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
No. 7
2012