Efficient access to 2-isobetulinic acid, 2-isooleanolic acid, and 2-isoursolic acid

Article abstract of DOI:10.1021/jo801232s

(Chemical Equation Presented) An efficient access to 2-isobetulin, 2-isobetulinic acid, 2-isooleanolic acid, and 2-isoursolic acid has been developed. The key step is a novel one-pot conversion of 2,3-dihydroxy triterpenes to 3-deoxy-2-oxo triterpenes. This method provides a new access to 3-deoxy-2-substituted pentacyclic triterpenes as potential therapeutic agents against metabolic diseases, tumors, and HIV infection.

Full text of DOI:10.1021/jo801232s

Efficient Access to 2-Isobetulinic Acid,
2-Isooleanolic Acid, and 2-Isoursolic Acid
Jia Hao, Pu Zhang, Xiaoan Wen, and Hongbin Sun*
Center for Drug DiscoVery, College of Pharmacy, China
Pharmaceutical UniVersity, 24 Tongjiaxiang,
Nanjing 210009, China
hbsun2000@yahoo.com
ReceiVed June 8, 2008
FIGURE 1. Natural triterpenes and their A-ring regioisomers.
inhibitors of glycogen phosphorylases (GP),4 which has been
regarded as a therapeutic approach to type 2 diabetes and its
complications.5 On the other hand, structural modifications based
on natural triterpenes have been extensively explored to find
more potent pentacyclic triterpenes as preventive and therapeutic
agents.1,6,7 Studies on structure-activity relationships (SAR)
of pentacyclic triterpenes showed that A-ring functions had a
significant impact on biological activities.4,6,7 In this regard, it
should be interesting and of biological importance to see how
the 2ꢀ-hydroxy-3-deoxy function would affect biological activi-
ties in contrast to naturally occurring pentacyclic triterpenes with
3ꢀ-hydroxy function. Herein, we report an efficient access to
2-isobetulin (5), 2-isobetulinic acid (6), 2-isooleanolic acid (7),
and 2-isoursolic acid (8) (Figure 1), which are A-ring regioi-
somers of betulin, betulinic acid, oleanolic acid, and ursolic acid,
respectively. To the best of our knowledge, this is the first report
of syntheses of the title compounds.
An efficient access to 2-isobetulin, 2-isobetulinic acid,
2-isooleanolic acid, and 2-isoursolic acid has been developed.
The key step is a novel one-pot conversion of 2,3-dihydroxy
triterpenes to 3-deoxy-2-oxo triterpenes. This method pro-
vides a new access to 3-deoxy-2-substituted pentacyclic
triterpenes as potential therapeutic agents against metabolic
diseases, tumors, and HIV infection.
For the synthesis of 2-isobetulinic acid (6), 2ꢀ,3ꢀ-diol 12
was prepared as a key intermediate (Scheme 1). Treatment of
betulin (4) with tritylchloride in the presence of 4-(dimethy-
lamino)pyridine (DMAP), followed by oxidation with pyri-
dinium chlorochromate (PCC) furnished ketone 10.8 Treatment
of 10 with a large excess of potassium tert-butoxide under air
led to formation of diketone 11,9 which existed in the form of
R,ꢀ-unsaturated ketone. Reduction of 11 with sodium borohy-
dride gave diol 12 (68% from 10).
Pentacyclic triterpenes have recently attracted much attention
due to their great potential as multitarget therapeutics.1 Betulinic
acid (1), oleanolic acid (2), and ursolic acid (3) (Figure 1) are
three representative members of the pentacyclic triterpene family
that are widely distributed throughout the plant kingdom. A
variety of biological properties have been ascribed to pentacyclic
triterpenes.1 Triterpenes 2 and 3 are among the major effective
components of some well-known Traditional Chinese Medicines
(TCM) such as Rehmannia Six Formula (Liu Wei Di Huang
Wan), which is one of the most commonly used Chinese herb
formulas in the world. On the other hand, pentacyclic triterpenes
have also been clinically used in the form of single components,
for example, 2 has been used as a nonprescription antihepatitis
drug for more than 20 years in China.2 Betulinic acid (1) is
currently undergoing phase II clinical trial for treatment of
melanoma.3 Furthermore, synthetic pentacyclic triterpene de-
rivatives also find potential clinical utilization, as evidenced by
PA-457 (a synthetic derivative of 1), which is being tested in a
phase II clinical trial as a first-in-class anti-HIV agent.3 Recently,
we first reported that 1, 2, 3, betulin (4), and other naturally
occurring pentacyclic triterpenes represented a novel class of
Interestingly, reaction of 2ꢀ,3ꢀ-diol 12 with p-toluenesulfonyl
chloride in pyridine at slightly elevated temperature did not give
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Ni, P. Z. Bioorg. Med. Chem. Lett. 2005, 15, 4944–4948. (b) Wen, X. A.; Sun,
H. B.; Liu, J.; Cheng, K. G.; Zhang, P.; Zhang, L. Y.; Hao, J.; Zhang, L. Y.; Ni,
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J. M.; Oikonomakos, N. G. J. Med. Chem. 2008, 51, 3540–3554.
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Sun, H. B. Bioorg. Med. Chem. Lett. 2006, 16, 2915–2919. (b) Wen, X. A.;
Zhang, P.; Liu, J.; Zhang, L. Y.; Wu, X. M.; Ni, P. Z.; Sun, H. B. Bioorg. Med.
Chem. Lett. 2006, 16, 722–726. (c) Wen, X. A.; Xia, J.; Cheng, K. G.; Liu, J.;
Zhang, L. Y.; Ni, P. Z.; Sun, H. B. Bioorg. Med. Chem. Lett. 2007, 17, 5777–
5782. (d) Chen, J.; Liu, J.; Gong, Y. C.; Zhang, L. Y.; Hua, W. Y.; Sun, H. B.
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Biedermann, D.; Markova, L.; Urban, M.; Sarek, J. Nat. Prod. Rep. 2006, 23,
394–411.
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10.1021/jo801232s CCC: $40.75
Published on Web 08/19/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7405–7408 7405

SCHEME 1
SCHEME 2
FIGURE 2. Proposed mechanism for the formation of 13 and 10.
the anticipated tosyl esters as the major products, but instead
gave ketone 13 in 63% yield, together with ketone 10 (35%) as
a minor product (Scheme 2). The structure of 13 was confirmed
by spectroscopic means. This reaction was intriguing since it
might open a new access to the 3-deoxy-2-substituted triterpene
scaffold10 that could be valuable in the synthesis of new
biologically active pentacyclic triterpenes. Detailed investigation
of this process led to a proposed mechanism for the formation
of 13 and 10 (Figure 2).
SCHEME 3
As shown in Figure 2, 2ꢀ,3ꢀ-diol 12 might be first converted
to tosylates 12a and 12b, respectively. It was found that
tosylation reactions proceeded very slowly at temperatures
below 30 °C. Both tosylates 12a and 12b seemed to be
unstable under reaction conditions, and were subject to
elimination reactions upon raising the temperature to about
60 °C, resulting in 10 and 13, respectively. The fact that 13
was produced as the major product indicated that formation
of tosylate 12b should be more favored over that of tosylate
12a. This assumption seems to conflict with our observation11
that 2ꢀ-OH is likely less sterically hindered than 3ꢀ-OH since
when treating 2ꢀ,3ꢀ-diols such as 12 with tert-butyldimeth-
ylsilyl chloride (TBDMSCl) in the presence of imidazole in
DMF, 2-O-silylated products would be obtained as the major
products (>70%) together with 3-O-silylated products as the
minor products. A reasonable explanation for this conflict is
that although formation of tosylate 12a might be kinetically more
favored over that of tosylate 12b due to a smaller steric
hindrance at C-2 than at C-3, the overall reaction should be
thermodynamically controlled since tosylate 12a might be
extremely unstable due to very strong 1,3-interactions of the
2-tosylate group with the methyl groups at C-24 and C-25.
Thereby, once tosylate 12a is formed, it would be either quickly
subject to elimination to furnish 10 or converted to tosylate 12b
via an intramolecular transesterification. In fact, tosylate 12a
could not be isolated and identified even at low temperature
probably due to this instability. On the other hand, if the reaction
was terminated before its completion, tosylate 12b could be
isolated and its structure was determined by spectroscopic data
(see the Supporting Information).
Stereoselective reduction of 13 with sodium borohydride
produced 2ꢀ-hydroxy triterpene 14 in 89% yield, together with
2R-hydroxy isomer 14a (10%) (Scheme 3). The stereochemical
structures of 14 and 14a were determined by NOE spectroscopic
data (see the Supporting Information). Deprotection of 14 with
PPTS afforded 2-isobetulin (5) in quantitative yield.
Acetylation of 14 with acetic anhydride in the presence of
4-(dimethylamino)pyridine (DMAP) in anhydrous pyridine,
followed by deprotection with PPTS afforded alcohol 15 in 80%
yield for two steps (Scheme 4). Oxidation of 15 with pyridinium
chlorochromate (PCC) gave aldehyde 16 (92%), which was
further oxidized with sodium chlorite (NaClO2) and sodium
dihydrogenophosphate in a mixture of t-BuOH/THF/2-methyl-
2-butene12 to furnish triterpene acid 17 (86%). Hydrolysis of
17 with aqueous sodium hydroxide in methanol gave 2-iso-
betulinic acid (6) in 96% yield.
(10) Sejbal, J.; Klinot, J.; Protiva, J.; Vystrcil, A. Collect. Czech., Chem.
Commun. 1986, 51, 118–127.
(11) (a) Cheng, K. G.; Zhang, P.; Liu, J.; Xie, J.; Sun, H. B. J. Nat. Prod.
Submitted for publication. (b) Hao, J.; Zhang, X. L.; Sun, H. B. Unpublished
results.
(12) Clive, D. L. J.; Wickens, P. L.; da Silva, G. V. J. J. Org. Chem. 1995,
60, 5532–5536.
7406 J. Org. Chem. Vol. 73, No. 18, 2008

SCHEME 4
In conclusion, we have established an efficient method for
the syntheses of 2-isobetulin, 2-isobetulinic acid, 2-isooleanolic
acid, and 2-isoursolic acid. The key step is a novel one-pot
conversion of 2ꢀ,3ꢀ-dihydroxy triterpenes to 3-deoxy-2-oxo
triterpenes. This methodology provides a new access to 3-deoxy-
2-substituted pentacyclic triterpenes that may find potential
utilities as therapeutic agents against metabolic diseases, tumors,
and HIV infection. Biological evaluation of the title compounds
and further derivatization of this triterpene scaffold are currently
in progress and will be reported in due course.
Experimental Section
General Procedure for the Preparation of Diols 12, 20,
and 21. To a solution of 28-O-trityllup-20(29)-en-28-ol-3-one (10)
(1.14 g, 1.67 mmol) in tert-butyl alcohol (80 mL) was added
potassium tert-butoxide (2.07 g, 18.4 mmol). The reaction mixture
was stirred under air at 30 °C for 10 h. After the solvent was
removed in vacuo, 1 N HCl (15 mL) was added. The mixture was
extracted with ethyl acetate (3 × 35 mL). The combined extract
was washed with saturated sodium bicarbonate solution and brine,
dried over anhydrous sodium sulfate, filtered, and concentrated in
vacuo to give crude diketone 11. Crude diketone 11 was used for
the next reaction without further purification. To a solution of the
above diketone 11 in tetrahydrofuran (25 mL) and ethanol (5 mL)
was added sodium borohydride (176 mg, 4.65 mmol) at 0 °C. The
reaction mixture was then warmed to room temperature and stirred
for 1 h. The reaction was quenched with 1 N HCl (25 mL), and
then the organic solvents were evaporated. The residue was
extracted with ethyl acetate (3 × 30 mL). The combined extract
was washed with saturated sodium bicarbonate solution and brine,
dried over anhydrous sodium sulfate, filtered, and concentrated in
vacuo. The crude product was purified by column chromatography
(petroleum ether-ethyl acetate, 8:1) to give diol 12 as a white solid
(798 mg, 68% from 10). Mp 199-201 °C; IR (KBr) 3592, 3440,
3062, 2948, 2871, 1709, 1643, 1483, 1364, 1374, 1314, 1218, 1061,
SCHEME 5
SCHEME 6
1
992, 888, 638 cm-1; H NMR (CDCl3) δ 0.53 (s, 3 H), 0.88 (s, 3
H), 0.96 (s, 6 H), 1.07 (s, 3 H), 1.63 (s, 3 H), 2.04-2.23 (m, 6 H),
2.90 and 3.13 (d, J ) 8.8 Hz, each 1 H), 3.15 (d, J ) 3.4 Hz, 1 H),
4.02-4.03 (m, 1 H), 4.51 and 4.58 (d, J ) 2.0 Hz, each 1 H),
7.46-7.50 (m, 6 H), 7.26-7.32 (m, 6 H), 7.21-7.24 (m, 3 H);
13C NMR (CDCl3) δ 14.7, 15.9, 17.0, 17.1, 18.1, 19.1, 20.9, 25.2,
26.8, 29.4, 29.6, 29.7, 29.9, 30.2, 34.1, 35.2, 36.8, 37.2, 38.1, 40.7,
42.6, 44.4, 47.6, 47.7, 48.9, 50.8, 55.2, 59.6, 71.2, 85.9, 109.3,
126.8, 127.7, 128.8, 144.5, 150.8; ESI-MS m/z 723.5 [M + Na]+.
Anal. Calcd for C49H64O3: C 83.95, H 9.20. Found: C 83.50,
H 9.10.
Alternatively, 2-isobetulinic acid (6) could also be prepared
via 4-acetamido-TEMPO-catalyzed oxidation13 of 5 without
affecting its secondary 2ꢀ-hydroxyl group (Scheme 5). This
reaction, however, was quite a tricky reaction, requiring strictly
controlled conditions. After much experimentation, 6 was
obtained in 28% yield (see the Supporting Information).
For the synthesis of 2-isooleanolic acid (7) and 2-isoursolic
acid (8), the same methodology for preparation of 13 was
employed as depicted in Scheme 6. Therefore, treatment of diol
204,6c with p-toluenesulfonyl chloride in pyridine with mild
heating up to about 60 °C afforded ketone 22 (67%), together
with ketone 18 as a minor product. Reduction of 22 with sodium
borohydride gave alcohol 24 (76%), together with a small
amount of 2R-isomer 24a (5%). Hydrogenolysis of 24 over
palladium/carbon in THF furnished 2-isooleanolic acid (7) in
92% yield. In the same fashion, 2-isoursolic acid (8) was
synthesized starting from ketone 19 (Scheme 6) (see the
Supporting Information).
General Procedure for the Preparation of Ketones 13, 22,
and 23. To a solution of diol 12 (500 mg, 0.713 mmol) in pyridine
(3 mL) was added portionwise p-toluenesulfonyl chloride (190 mg,
1 mmol). The reaction mixture was stirred at 30 °C for 12 h. After
the diol 12 was consumed completely (monitored by TLC), the
reaction temperature was raised to 60 °C, and the reaction was kept
at this temperature for another 12 h. After cooling to room
temperature, 1 N HCl (25 mL) was added into the reaction mixture.
The mixture was extracted with ethyl acetate (3 × 30 mL). The
combined extract was washed with saturated sodium bicarbonate
solution and brine, dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo. The crude product was purified by
column chromatography (petroleum ether-ethyl acetate, 80:1) to
give 13 as a white solid (308 mg, 63%), together with 10 (171 mg,
35%) as a minor product. For 13: mp 228-230 °C; IR (KBr) 3397,
3062, 2950, 1707, 1644, 1600, 1484, 1452, 1379, 1268, 1215, 1157,
1
1062, 994, 890, 761, 701, 638, 552, 477 cm-1; H NMR (CDCl3)
δ 0.50 (s, 3 H), 0.76 (s, 3 H), 0.85 (s, 3 H), 0.93 (s, 3 H), 1.03 (s,
3 H), 1.63 (s, 3 H), 1.82-1.87 (m, 1 H), 2.09-2.32 (m, 6 H), 2.90
and 3.11 (d, J ) 8.8 Hz, each 1 H), 4.52 and 4.58 (d, J ) 2.0 Hz,
each 1 H), 7.46-7.49 (m, 6 H), 7.25-7.32 (m, 6 H), 7.19-7.24
(13) Csuk, R.; Schmuck, K.; Scha¨fer, R. Tetrahedron Lett. 2006, 47, 8769–
8770.
J. Org. Chem. Vol. 73, No. 18, 2008 7407

(m, 3 H); 13C NMR (CDCl3) δ 14.7, 15.5, 17.1, 19.0, 19.1, 20.9,
23.1, 25.0, 26.9, 29.6, 29.7, 29.9, 30.1, 33.3, 33.7, 35.2, 37.2, 39.0,
40.0, 42.6, 42.9, 47.6, 47.7, 48.8, 50.0, 55.6, 56.0, 56.5, 59.6, 85.9,
109.5, 126.8, 127.7, 128.8, 144.5, 150.6, 212.2; ESI-MS m/z 721.4
[M + K]+. Anal. Calcd for C49H62O2 ·0.75H2O: C 84.50, H 9.18.
Found: C 84.52, H 9.15.
crude product was purified by column chromatography (petroleum
ether-ethyl acetate, 12:1) to give 17 as a white solid (53.3 mg,
1
86%). H NMR (CDCl3) δ 0.91 (s, 3 H), 0.94 (s, 6 H), 0.98 (s, 3
H), 1.05 (s, 3 H), 1.69 (s, 3 H), 2.00 (s, 3 H), 2.13-2.29 (m, 2 H),
2.98-3.01 (m, 1 H), 4.61, 4.74 (s, each 1 H), 5.04-5.07 (m, 1 H);
13C NMR (CDCl3) δ 14.7, 16.0, 18.5, 18.8, 19.4, 21.2, 21.6, 23.9,
25.6, 29.6, 30.6, 32.2, 32.7, 32.9, 33.9, 37.1, 37.8, 38.6, 40.9, 42.6,
43.0, 44.2, 47.0, 49.3, 51.0, 53.8, 56.4, 70.7, 109.7, 150.3, 170.5,
181.6; ESI-MS m/z 497.3 [M - H]-. Anal. Calcd for C32H50-
O4 ·0.2H2O: C 76.51, H 10.11. Found: C 76.3, H 9.96.
General Procedure for the Preparation of 2ꢀ-Hydroxy
Triterpenes 14, 24, and 25. To a solution of ketone 13 (1 g, 1.46
mmol) in tetrahydrofuran (15 mL) and ethanol (3 mL) was added
sodium borohydride (0.08 g, 2.11 mmol) at 0 °C. The reaction
mixture was warmed to room temperature and stirred for 1 h. The
reaction was quenched with 1 N HCl (25 mL), and the organic
solvents were evaporated in vacuo. The residue was extracted with
ethyl acetate (3 × 30 mL). The combined extract was washed with
saturated sodium bicarbonate solution and brine, dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo. The
crude product was purified by column chromatography (petroleum
ether-ethyl acetate, 25:1) to give 2ꢀ-hydroxy isomer 14 (885 mg,
89%) and 2R-hydroxy isomer 14a (100 mg, 10%). For 14: white
solid, mp 143-146 °C; IR (KBr) 3417, 3063, 2945, 2870, 1708,
2-Isobetulinic Acid (6). Compound 17 (50 mg, 0.1 mmol) was
dissolved in 5 mL of MeOH, then 1 mL of 4 N NaOH aq solution
was added dropwise. The reaction mixture was stirred at 40 °C for
2 h. The mixture was diluted in CH2Cl2 and washed with 10% HCl
and brine. The organic layer was dried over anhydrous sodium
sulfate, filtered, and evaporated under reduced pressure. The crude
product was purified by column chromatography (petroleum
ether-ethyl acetate, 4:1) to give 2-isobetulinic acid (6) as a white
1
solid (44 mg, 96%). Mp 259-261 °C; H NMR (C5D5N) δ 0.94
(s, 3 H), 1.05 (s, 3 H), 1.06 (s, 3 H), 1.13 (s, 3 H), 1.25 (s, 3 H),
1.77 (s, 3 H), 2.00-2.22 (m, 2 H), 2.59-2.72 (m, 2 H), 3.49-3.54
(m,1 H), 4.33-4.36 (m, 1 H), 4.76 and 4.93 (s, each 1 H); 13C
NMR (C5D5N) δ 14.9, 16.4, 19.4, 19.5, 21.7, 24.9, 26.3, 30.2, 31.3,
32.9, 31.3, 33.0, 33.1, 33.3, 34.5, 37.6, 38.4, 38.8, 41.4, 43.0, 47.5,
47.8, 48.5, 49.8, 51.56, 54.1, 56.7, 66.7, 109.9, 151.4, 178.8; ESI-
MS m/z 479.3 [M + Na]+. Anal. Calcd for C30H48O3 ·0.75H2O: C
76.63, H 10.61. Found: C 76.94, H 10.24.
1
1645, 1455, 1378, 1213, 1157, 1064, 768, 703 cm-1; H NMR
(CDCl3) δ 0.52 (s, 3 H), 0.89 (s, 3 H), 0.90 (s, 3 H), 0.98 (s, 3 H),
1.01 (s, 3 H), 1.64 (s, 3 H), 1.82-1.87 (m, 1 H), 2.17-2.20 (m, 3
H), 2.90 and 3.14 (d, J ) 8.8 Hz, each 1 H), 3.99-4.02 (m, 1 H),
4.52 and 4.58 (d, J ) 2.1 Hz, each 1 H), 7.47-7.49 (m, 6 H),
7.25-7.32 (m, 6 H), 7.22-7.24 (m, 3 H); 13C NMR (CDCl3) δ
14.7, 15.7, 19.1, 19.7, 21.2, 24.8, 25.3, 26.8, 29.9, 30.1, 32.5, 32.8,
33.6, 35.2, 37.4, 38.2, 40.8, 42.5, 46.3, 47.6, 47.7, 48.2, 48.9, 50.8,
52.7, 59.6, 67.5, 85.8, 109.3, 126.8, 127.7, 128.8, 144.5, 150.8;
ESI-MS m/z 723.4 [M + K]+. Anal. Calcd for C49H64O2 ·0.5H2O:
C 84.79, H 9.44. Found: C 84.71, H 9.69.
Preparation of 2ꢀ-O-Acetyllup-20(29)-en-28-oic Acid (17). To
a solution of aldehyde 16 (60 mg, 0.124 mmol) (see the Supporting
Information) in t-BuOH (5 mL), THF (1 mL), and 2-methyl-2-
betene (1.5 mL) was slowly added 3 mL of a freshly prepared
aqueous solution of NaH2PO4/NaClO2 (0.15 g/0.15 g) at 0 °C, and
the resulting mixture was kept at this temperature for 15 min. The
mixture was then warmed to room temperature and stirred for 1 h.
The mixture was poured into a saturated solution of NH4Cl (5 mL)
and extracted with CH2Cl2. The combined extract was washed with
saturated sodium bicarbonate solution and brine, dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo. The
Acknowledgment. This program was financially supported
by the National Natural Science Foundation of China (grants
30672523 and 90713037), research grants from the Chinese
Ministry of Education (grants 706030 and 20050316008), and
the program for New Century Excellent Talents in University
(NCET-05-0495).
Supporting Information Available: Experimental proce-
dures and spectroscopic data for compounds 5-8, 12-17,
22-25, 12b, 14a, and 24a. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO801232S
7408 J. Org. Chem. Vol. 73, No. 18, 2008