A practical synthesis of betulinic acid

Article abstract of DOI:10.1016/j.tetlet.2006.10.004

A new synthetic route for the synthesis of betulinic acid from betulin has been developed. The main step of this procedure is the selective oxidation of the primary alcohol function of betulin without affecting the secondary hydroxyl group. Applying shorter reaction times and lower temperatures results in the exclusive formation of the corresponding aldehyde, betulinal.

Full text of DOI:10.1016/j.tetlet.2006.10.004

Tetrahedron Letters 47 (2006) 8769–8770
A practical synthesis of betulinic acid
*
´
Rene Csuk, Kianga Schmuck and Renate Schafer
¨
Institut f. Organ. Chemie, Martin-Luther-Universita¨t Halle-Wittenberg, Kurt-Mothes-Str. 2, D-06120 Halle, Germany
Received 20 July 2006; revised 29 September 2006; accepted 2 October 2006
Available online 20 October 2006
Abstract—A new synthetic route for the synthesis of betulinic acid from betulin has been developed. The main step of this procedure
is the selective oxidation of the primary alcohol function of betulin without affecting the secondary hydroxyl group. Applying
shorter reaction times and lower temperatures results in the exclusive formation of the corresponding aldehyde, betulinal.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
of the white birch tree, Betula alba, containing 2 up to
25% of its weight. Thus, 2 has been converted into 1
using two different synthetic routes: The first approach
utilized an oxidation of 2 to betulonic acid followed
by a reduction to afford 1. Although these two reactions
gave good to moderate yields, the reduction step re-
sulted in the formation of a mixture of epimers11–13 that
were difficult to separate. Thus, in a second synthetic
route, the use of protecting groups has been suggested;
this led to pure material albeit the whole sequence
now involving five chemical reactions14–16 thus lowering
the overall yields significantly. Quite recently, a two-step
route17 utilizing solid-supported chromium oxide and
potassium permanganate has been suggested and even
more recently, a TEMPO-mediated electrochemical ap-
proach18 has been devised. Both of these approaches,
however, are small-scale preparations and the obtained
yields only moderate. To circumvent all of these prob-
lems, we have developed a short one-step route to 1
from easily available, cheap compound 2.
Betulinic acid (1), a pentacyclic triterpene, possesses sev-
eral biological properties1–5 such as antiviral, anticancer,
anti-inflammatory, antiseptic, antimicrobial, antimalar-
ial, antileishmanial, antihelmintic, antifeedent as well
as spermicidal activities. In addition, it was shown that
1 possesses a high toxicity towards cancer cells and a
weak toxicity to healthy cells thus allowing a selective
destruction of melanoma cells6 by apoptosis. Betulinic
acid has been found in certain plants7 but only in small
amounts; it can be obtained by fractional extraction8
and subsequent recrystallization at low8,9 temperatures.
In addition, this process requires the use of very large
volumes of solvents making it less suitable for large scale
industrial applications.
Betulin (2), a naturally occurring triterpene seems to be
an ideal starting material for the synthesis of 1. It can be
isolated,10 for example, from the outer layer of the bark
Scheme 1. The synthesis of betulinic acid and betulinal.
*
Corresponding author. Tel.: +49 345 5525660; fax: +49 345 5527030; e-mail: rene.csuk@chemie.uni-halle.de
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doi:10.1016/j.tetlet.2006.10.004

8770
R. Csuk et al. / Tetrahedron Letters 47 (2006) 8769–8770
Whereas the oxidation of 2 with TEMPO19 (2,2,6,6-
tetramethyl-piperidin-1-oxyl)/NaClO2/NaOCl at 35 °C
furnished 92% of the aldehyde betulinal (3),20 the reac-
tion of 2 with 4-acetamido-TEMPO/NaClO2/NaOCl at
50 °C gave betulinic acid (1) in an 86% isolated yield.21
16. Kim, D. S. H. L.; Chen, Z.; Van Tuyen, N.; Pezzuto, J.
M.; Qiu, S.; Lu, Z.-Z. Synth. Commun. 1997, 27, 1607–
1612.
17. Pichette, A.; Liu, H.; Roy, C.; Tanguay, S.; Simard, F.;
Lavoie, S. Synth. Commun. 2004, 34, 3925–3937.
18. Menard, H.; Cirtiu, C. M.; Lalancette, J.-M.; Ruest, L.;
Kaljaca Z. PCT 2006 1063464A1; Chem. Abs. 2006,
604456.
19. Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.;
Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 1999, 64,
2564–2566.
20. Bhattacharyya, J.; Kokpol, U.; Miles, D. H. Phytochem-
istry 1976, 15, 431–433.
Preliminary work done in our laboratories indicates that
this procedure for the synthesis of 1 can be scaled up to
obtain larger amounts of 1 in a very convenient way.
The main advantages of this approach include the use
of inexpensive starting material and reagents as well as
the simplicity of the route (Scheme 1).
21. Synthesis of betulinal (3): To a 35 °C warm stirred mixture
of dichloromethane (80 ml) and phosphate buffer (0.67 M,
pH 6.8, 43 ml) containing betulin 2 (5.0 g, 11.3 mmol),
TEMPO (125 mg, 0.8 mmol) and Bu4NBrÆH2O (180 mg,
0.55 mmol) aq solutions of NaClO2 (25%, 6.8 ml,
22.6 mmol) and NaOCl (12%, 115 ll, 0.25 mmol) were
slowly added within 120 min. Additional aq NaOCl
(17.8 ml, 34.6 mmol) and Bu4NBrÆH2O (180 mg,
0.55 mmol) was then slowly added. After completion of
the reaction (as monitored by tlc) and cooling to room
temperature, water (85 ml) was added and the pH value
adjusted to 8 by the addition of aq NaOH (2 N, 10.5 ml).
The reaction mixture was poured in ice-cold water (60 ml),
the aq phase was extracted (methyl-tert-butyl-ether, 60 ml)
and the combined organic phases were washed (water,
brine), dried (Na2SO4), and the solvents were evaporated
in vacuo to afford the crude aldehyde that was subjected to
recrystallization from methanol to afford pure 3 (4.58 g,
92%) as white crystals. Mp 189–191 °C, [a]D +18.4 (c, 0.4,
CHCl3)20 (Lit.: mp 183–187;22 192–193;23 [a]D +18 (c, 0.4,
CHCl3), [a]D +19 (CHCl3)23); 1H and 13C NMR data24 as
reported. Synthesis of betulinic acid (1): To a 50 °C warm
mixture of butyl acetate (80 ml) and aq phosphate buffer
(0.67 M, pH 7.6, 43 ml) containing 2 (5.0 g, 11.3 mmol), 4-
acetamido-TEMPO25 (171 mg, 0.8 mmol), Bu4NBrÆH2O
(180 mg, 0.55 mmol) aq solutions of NaClO2 (25%,
6.76 ml, 22.6 mmol) and NaOCl (12%, 115 ll, 0.25 mmol)
were slowly added within 120 min. Stirring at this
temperature was continued and some additional NaOCl
(12%, 10 ml, 19.44 mmol) was slowly added until tlc
showed the reaction to be complete. After cooling to room
temperature, water (85 ml) was added and the pH adjusted
to 8 by the addition of aq NaOH (2 N, 0.5 ml). After
extraction with butylacetate (300 ml), the phases were
separated, the organic phase was washed (water, brine)
and dried (Na2SO4). After evaporation of the solvents,
crude 1 was recrystallized from methanol to afford pure 1
(4.43 g, 86%, >98% by HPLC). Mp 310–313 °C, [a]D +9
(c, 0.36 CHCl3 (Lit.: mp 316–31826 [a]D +5 (CHCl3)27);
ESI-MS: m/z = 456 [MÀH]À.
Acknowledgements
This research was supported by the VFF Universita¨t
Halle-Wittenberg. We are grateful to Dr. D. Stro¨hl for
NMR measurements and to Dr. R. Kluge for numerous
ESI-MS spectra.
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