Synthesis of novel 8,14-secoursane derivatives: Key intermediates for the preparation of chiral decalin synthons from ursolic acid

Article abstract of DOI:10.1002/hlca.201100452

The novel 8,14-secoursatriene derivative 6 was synthesized starting from ursolic acid (1) via methyl esterification of the 17-carboxylic acid group and benzoylation of the 3-hydroxy group (→ 2; Scheme 1), ozone oxidation of the C(12)=C(13) bond (→ 3), dehydrogenation with Br₂/HBr (→ 4), enol acetylation of the resulting carbonyl group (→ 5; Scheme 2), and ring-C opening with the aid of UV light (→ 6). Ring-C-opened dienone derivative 7 of ursolic acid was also obtained via selective hydrolysis of 6 (Scheme 2). Both compounds 6 and 7 are key intermediates for the preparation of chiral decalin synthons from ursolic acid.

Full text of DOI:10.1002/hlca.201100452

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Synthesis of Novel 8,14-Secoursane Derivatives: Key Intermediates for the
Preparation of Chiral Decalin Synthons from Ursolic Acid
by Chongnan Zhang, Haijun Yang*, Guangying Lꢀ, Cailin Liu, Yun Tang, and Laibao Liu
State Key Laboratory Cultivation Base for Nonmetal Composite and Functional Materials, Southwest
University of Science and Technology, Sichuan, Mianyang 621010, P. R. China
(phone: þ 86-816-2419076; fax: þ 86-816-2419076; e-mail: yanghaijun@swust.edu.cn)
The novel 8,14-secoursatriene derivative 6 was synthesized starting from ursolic acid (1) via methyl
esterification of the 17-carboxylic acid group and benzoylation of the 3-hydroxy group (!2; Scheme 1),
ozone oxidation of the C(12)¼C(13) bond (! 3), dehydrogenation with Br2/HBr (!4), enol acetylation
of the resulting carbonyl group (! 5; Scheme 2), and ring-C opening with the aid of UV light (!6).
Ring-C-opened dienone derivative 7 of ursolic acid was also obtained via selective hydrolysis of 6
(Scheme 2). Both compounds 6 and 7 are key intermediates for the preparation of chiral decalin synthons
from ursolic acid.
Introduction. – Ursolic acid (¼(3b)-3-hydroxyurs-12-en-28-oic acid; 1), a penta-
cyclic triterpene, is widely distributed in nature. Large available amounts and a low
price allow its use as a suitable starting material for the semisynthesis of other
biologically or chemically significant compounds [1]. Nowadays, a large number of
ursane derivatives have been synthesized by transformations of ring A [2], ring C [3],
and the 17-carboxylic acid group [4] of ursolic acid. However, very few ursane
derivatives are used as pharmaceuticals, although their bioactivities can be improved to
some extent via structure modifications [5]. Actually, most of the modifications are
simple transformations based on the basic skeleton of ursolic acid. As far as bioactivity
screening is concerned, it is interesting to get access to ursane derivatives with novel
structures via synthesis or isolation of new natural products.
Decalin is one of the most prevalent structural units present in natural products that
possess diverse and significant biological activities [6] and olfactory and fixative
properties [7]. Generally, these compounds have complex structures with multiple
chiral centers. Total syntheses of these compounds are usually rather inefficient in view
of tedious synthetic routes, expensive chiral reagents, low yields, vigorous reaction
conditions, and the low optical purities obtained [8]. To date, most of these syntheses
are based on transformation of terpenes such as sclareolide [9], abietic acid [10],
labdanolic acid [11], sclareol [12], manool [13], larixol [14], and communic acid [15] or
well-established synthetic chiral materials such as the WielandꢀMiescher ketone
[6a][16]. Nevertheless, almost all these semisynthetic materials are comparatively rare
and expensive, bearing no functional groups at ring A (C(1) to C(4)) and, therefore,
may not be employed to synthesize compounds with functional groups at ring A.
Interestingly, ursolic acid is characterized by a chiral trans-decalin framework of the
rings AB and a chiral cis-decalin framework of the rings DE, which could be used as
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 95 (2012)
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versatile precursors for a large number of natural products with similar chiral decalin
units [17]. However, ursolic acid was rarely reported in the semisynthesis of the above
targets due to the lack of suitable transformation methods. Thus, it would be highly
advantageous to develop a simple method for the preparation of chiral decalin synthons
derived from the rings AB and DE of ursolic acid. To the best of our knowledge, there
are no reports about the preparation of chiral decalin synthons from ursolic acid. We
have previously developed a novel method, which involved oxidative cleavage of a key
8,14-secooleanatriene derivative or its hydrolytic product, a dienone derivative, with
peracid, to provide chiral decalin synthons derived from the rings AB and DE of
oleanolic acid [18]. Application of this method to ursolic acid requires access to the
8,14-secoursatriene derivative or its hydrolytic dienone product.
In this article, the novel 8,14-secoursatriene derivative 6 was synthesized from
ursolic acid (1) via a series of reactions. Ring-C-opened dienone derivative 7 of ursolic
acid was also obtained via selective hydrolysis of 6. Both of the ursane derivatives 6 and
7 have novel 8,14-seco structures, which could be used for bioactivity screening and/or
preparation of chiral decalin synthons from ursolic acid.
Results and Discussion. – Methyl (3b)-3-(benzoyloxy)urs-12-en-28-oate (2) was
prepared according to reported procedures starting from ursolic acid (1) via methyl
esterification of the 17-carboxylic acid group [19], followed by benzoylation of the 3-
hydroxy group [20] (Scheme 1). Oxidation of compound 2 with O3 gave a 12-oxo
compound 3, which is actually the rearrangement product of the intermediate 12,13-
fusedoxirane derivative in the presence of acid [21]. In the preparation of the a,b-
unsaturated keto derivative 4, a catalytic amount of HBr in AcOH (35%) was used as a
Scheme 1. Synthesis of a,b-Unsaturated Keto Derivative 4 from Ursolic Acid (1)
a) 1. CH2N2, THF, 0 – 58; 2. BzCl, Py; total yield 75%. b) O3, CHCl3; 83%. c) Br2, HBr in AcOH, AcOH,
708; 47%.

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catalyst, which could catalyze the dehydrogenation of 12-oxo compound 3 to 4 with
Br2, introducing a C(9)¼C(11) bond [22] (Scheme 1). Without HBr in AcOH as
catalyst, the dehydrogenation rate with Br2 was very slow at the beginning. However,
HBr was produced gradually while the reaction proceeded, and the reaction rate
increased correspondingly.
Siddiqui et al. [23] found that the 12-oxo group was to 100% in the enol form in the
synthesis of a (3b)-3-hydroxy-11,12-dioxoursan-28-oic acid derivative, indicating that
enol acetylation of the 12-oxo group should be possible. With Ac2O as acylation
reagent, different acids or bases such as pyridine, AcONa, H2SO4, TsOH, and H2SO4/
TsOH were tried as catalyst for the enol acetylation of 4 to 5. When a base such as
pyridine or AcONa was used as catalyst, a low conversion rate was observed even at a
high temperature during a long reaction time. However, H2SO4/TsOH was a very
effective catalyst, and the enol acetate 5 was obtained from 4 in 78% yield (Scheme 2).
Ring C of 5 is a cyclohexadiene system and has a trans-disposition between MeꢀC(8)
and MeꢀC(14). The specific structure of ring C could undergo a photochemically
allowed six-electron-system antarafacial reaction [24], which could lead to ring-C
opening between C(8) and C(14); this process would take place via a photochemical
electrocyclic conrotatory reaction similar to that evidenced in the preparation of
previtamin D [25]. Thus, irradiation of 5 in different solvents such as CH2Cl2, CHCl3,
EtOH, or AcOEt in a Pyrex flask under Ar with a 500-W high-pressure Hg lamp gave
an (acetyloxy)-substituted triene derivative 6 in 85% yield (Scheme 2). Interestingly,
when compound 5 was irradiated in a quartz flask, another product 9 was also observed
gradually after triene 6 was produced. A mixture 6/9 was hydrolyzed with KOH/
MeOH/H2O and then benzoylated with benzoyl chloride, giving dienone derivative 7 as
Scheme 2. Synthesis of Novel 8,14-Secoursatriene Derivative 6 and Dienone Derivative 7
a) Ac2O, H2SO4/TsOH; 78%. b) hn, Pyrex, AcOEt; 85%. c) KOH, MeOH, H2O; 82% (7) and 4% (8). d)
BzCl, Py; 87%.

Helvetica Chimica Acta – Vol. 95 (2012)
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the only product (Scheme 3). Moreover, the two products 6 and 9 interconverted, when
irradiated in a quartz flask. These results indicate that compound 9 is the (11Z)-isomer
of 6 [26]. The different results obtained in the Pyrex and quartz flasks must be due to
light of different wavelengths and, therefore, energy entering the reaction vessel.
Scheme 3. Hydrolysis and Benzoylation of the Mixture of 6/9
a) 1. KOH, MeOH, H2O; 2. BzCl, Py; total yield 85%.
The (acetyloxy)-substituted triene derivative 6 could be used as a key precursor for
the preparation of chiral decalin synthons by means of the oxidative cleavage method
reported previously [18]. The three ester groups present in 6 have different reactivities,
the 12-enol ester being the most reactive, allowing for its chemoselective hydrolysis.
Different amounts of KOH were tried to hydrolyze compound 6. When 0.8 equiv. of
KOH was used, 6 was not consumed completely and dienone derivative 7 was the only
product. When 1.2 equiv. of KOH was used, 7 and 3-hydroxydienone derivative 8 were
produced in 82% and 4% yields, respectively. Treatment of the mixture 7/8 with
benzoyl chloride gave as a sole product 7 in high yield (Scheme 2). Dienone derivative
7 has an oxo group at C(12), which could undergo a BaeyerꢀVilliger reaction to give the
desired chiral decalin synthons derived from ursolic acid.
Conclusions. – An (acetyloxy)-substituted triene derivative 6, which has a novel
8,14-seco structure, was prepared from ursolic acid in six reaction steps. Selective
hydrolysis of 6 gave a novel 8,14-secoursadienone derivative 7. Both compounds 6 and
7 are key intermediates for the preparation of chiral decalin synthons derived from
ursolic acid. Bearing the novel 8,14-seco structures, they could also be used for
bioactivity screening. Compounds 3 – 7 were characterized by spectral data (1H- and
13C-NMR, IR, and MS; see Exper. Part).
The authors are grateful to the National Natural Science Foundation of China (Grant 20802059)
Experimental Part
General. All materials were of commercial reagent grade and used without further purification.
Column chromatography (CC): silica gel (SiO2, 200 – 300 mesh). TLC: precoated plates (SiO2 GF254
,
38 – 48 mm) activated at 1108 for 2 h, detection by UV light, I2, and/or an 8% EtOH soln. of
phosphomolybdic acid. M.p.: X-T4 melting-point apparatus; uncorrected. IR Spectra: Nicolet-5700 FT-
IR spectrometer; ˜n in cmꢀ1. NMR Spectra: Bruker-Advance-600 spectrometer; in CDCl3; d in ppm rel. to

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Helvetica Chimica Acta – Vol. 95 (2012)
Me4Si as internal standard, J in Hz. ESI-MS: Varian 1200 LC/MS spectrometers; in m/z. HR-ESI-MS:
BioTOF-Q mass spectrometer; in m/z.
Methyl (3b,13z)-3-(Benzoyloxy)-12-oxoursan-28-oate (3). A soln. of 2 (1 g, 1.7 mmol) in CHCl3
(30 ml) was treated with ozone at r.t. until 2 disappeared (TLC monitoring). The soln. was concentrated,
and the residue purified by CC(SiO2, petroleum ether/AcOEt 20 :1): 3 (0.85g, 83%). Colorless crystals.
1
M.p. 242 – 2448. IR (KBr): 2930, 2873, 1718, 1662, 1452, 1275, 1114, 713. H-NMR (600 MHz, CDCl3):
8.04 (d, J ¼ 7.3, 2 arom. H); 7.55 (dd, J ¼ 7.4, 7.4, 1 arom. H); 7.44 (dd, J ¼ 7.7, 7.7, 2 arom. H); 4.75 (ddd, J ¼
12.1, 4.8, 4.8, HꢀC(3)); 3.72 (s, MeOOCꢀC(17)); 2.88 – 2.75 (m, HꢀC(18)); 2.61 (d, J ¼ 4.1, HꢀC(13));
1.36 (s, Me); 1.04 (s, Me); 1.01 (s, Me), 0.95 (s, 2 Me); 0.77 (d, J ¼ 6.2, Me); 0.70 (d, J ¼ 6.3, Me).
13C-NMR (150 MHz, CDCl3): 215.8; 179.0; 166.2; 132.8; 130.9; 129.5; 128.3; 81.1; 59.1; 55.4; 52.1; 50.6;
46.8; 43.5; 43.1; 40.4; 39.7; 38.2; 38.1; 37.2; 36.6; 34.0; 32.0; 31.8; 29.3; 28.1; 27.7; 25.9; 24.7; 23.6; 20.3; 20.1;
18.1; 17.6; 16.9; 16.1. ESI-MS: 613 ([M þ Na]þ). HR-ESI-MS: 613.3863([M þ Na]þ, C38H54NaOþ5 ; calc.
613.3869).
Methyl (3b,13z)-3-(Benzoyloxy)-12-oxours-9(11)-en-28-oate (4) To a soln. of 3 (500 mg, 0.85 mmol)
in AcOH (25 ml) were added a soln. of Br2 (0.06 ml, 1.17 mmol) in AcOH (2 ml) and a drop of HBr in
AcOH (35%). The mixture was maintained at 708 for 12 h, and then at 258 for 24 h. The resulting soln.
was poured into ice/H2O. The formed light yellow precipitate was washed with sat. aq. NaHSO3 soln., sat.
aq. NaHCO3 soln., and H2O, dried in vacuo, and separated by CC(SiO2, petroleum ether/AcOEt 15 :1): 4
(223mg, 47%). Colorless cubic crystals. M.p. 252 – 2548. IR (KBr): 2930, 2873, 1720, 1660, 1452, 1275,
1114, 713. 1H-NMR (600 MHz, CDCl3): 8.04 (d, J ¼ 8.2, 2 arom. H); 7.56 (dd, J ¼ 7.4, 7.4, 1 arom. H); 7.44
(dd, J ¼ 7.6, 7.6, 2 arom. H); 5.82 (s, HꢀC(11)); 4.72 (ddd, J ¼ 11.8, 4.4, 4.4, HꢀC(3)); 3.67 (s,
MeOOCꢀC(17)); 3.01 – 3.05 (m, HꢀC(18)); 2.64 (d, J ¼ 9.9, HꢀC(13)); 1.59 (s, Me); 1.43 (s, Me); 1.32 (s,
Me); 1.23 (s, Me); 1.07 (d, J ¼ 9.9, Me); 0.97 (s, Me); 0.86 (s, Me). 13C-NMR (150 MHz, CDCl3): 200.4;
179.1; 175.8; 166.1; 132.9; 130.7; 129.5; 128.4; 121.8; 80.2; 51.5; 50.4; 48.7; 45.2; 44.8; 44.3; 41.5; 40.3; 38.7;
38.0; 36.9; 32.7; 31.8; 28.0; 27.9; 26.6; 25.1; 23.9; 23.8; 21.9; 20.8; 19.7; 17.9; 17.3; 16.9; 16.4. ESI-MS: 611
([M þ Na]þ). HR-ESI-MS: 611.3707 ([M þ Na]þ, C38H52NaOþ5 ; calc. 611.3712).
Methyl (3b)-12-(Acetyloxy)-3-(benzoyloxy)ursa-9(11),12-dien-28-oate (5). To a soln. of 4 (1 g,
1.7 mmol) in Ac2O (10 ml) were added a drop of conc. H2SO4 soln. and a catalytic amount of TsOH
(20 mg). The reddish mixture was stirred at r.t. for 10 h and then poured into ice/H2O. The precipitate
was filtered, washed with sat. aq. NaHCO3 soln. and H2O, dried, and purified by CC(SiO2, petroleum
ether/AcOEt 20 :1): 5 (0.84g, 78%). Colorless needle crystals. M.p. 257 – 2608. IR (KBr): 2976, 2949,
2924, 2875, 1755, 1716, 1452, 1274, 1116, 711. 1H-NMR (CDCl3, 600 MHz): 8.04 (d, J ¼ 7.4, 2 arom. H);
7.55 (dd, J ¼ 7.4, 7.4, 1 arom. H); 7.44 (dd, J ¼ 7.7, 7.7, 2 arom. H); 5.45 (s, HꢀC(11)); 4.75 (ddd, J ¼ 10.9, 4.7,
4.7, HꢀC(3)); 3.57 (s, MeOOCꢀC(17)); 2.80 (d, J ¼ 12.5, HꢀC(18)); 2.15 (s, MeCOOꢀC(12)); 1.29 (s,
Me); 1.13 (s, Me); 1.04 (s, Me); 1.03 (s, Me); 0.97 (s, Me); 0.96 (d, J ¼ 6.5, Me); 0.93 (d, J ¼ 6.6, Me).
13C-NMR (150 MHz, CDCl3): 177.5; 169.0; 166.3; 156.0; 142.6; 132.8; 130.9; 129.5; 128.3; 125.3; 115.2;
81.1; 51.6; 51.1; 47.0; 43.6; 42.9; 40.1; 39.6; 39.0; 38.7; 38.3; 36.8; 36.3; 31.9; 30.6; 28.3; 27.1; 25.1; 24.2; 24.0;
21.1; 21.0; 20.9; 18.6; 18.1; 17.0; 16.5. ESI-MS: 653 ([M þ Na]þ). HR-ESI-MS: 653.3813 ([M þ Na]þ,
C40H54NaOþ6 ; calc. 653.3818).
Methyl (3b)-12-(Acetyloxy)-3-(benzoyloxy)-8,14-secoursa-8,11,13-trien-28-oate (6). A soln. of
5
(100 mg, 0.16 mmol) in AcOEt (20 ml) in a Pyrex flask under Ar was irradiated with a 500-W high-
pressure Hg lamp at r.t. until 5 disappeared (TLC monitoring). Then, the soln. was concentrated and the
resluting syrup purified by CC(SiO2, petroleum ether/AcOEt 25 :1): 6 (85mg, 85%). Colorless
amorphous powder. IR (KBr): 2948, 2873, 1719, 1646, 1453, 1368, 1275, 1203, 1115, 712. 1H-NMR
(CDCl3, 600 MHz): 8.05 (d, J ¼ 7.6, 2 arom. H); 7.55 (dd, J ¼ 7.3, 7.3, 1 arom. H); 7.44 (dd, J ¼ 7.7, 7.7, 2
arom. H); 5.84 (s, HꢀC(11)); 4.78 (ddd, J ¼ 11.7, 4.4, 4.4, HꢀC(3)); 3.63 (s, MeOOCꢀC(17)); 2.30 (d, J ¼
9.3, HꢀC(18)); 2.13 (s, MeCOOꢀC(12)); 1.53 (s, Me); 1.43 (s, Me); 1.17 (s, 2 Me): 1.08 (s, Me); 0.98 (d,
J ¼ 5.4, Me); 0.92 (d, J ¼ 5.1, Me). 13C-NMR (150 MHz, CDCl3): 177.5; 169.3; 166.3; 148.3; 136.9; 133.3;
132.7; 132.0; 131.1; 129.5; 128.3; 119.2; 111.9; 81.6; 51.5; 46.9; 42.4; 39.0; 38.8; 38.7; 38.2; 36.9; 36.2; 34.7;
30.8; 30.0; 28.6; 26.9; 24.3; 23.1; 21.8; 21.6; 21.5; 20.6; 18.9; 18.7; 17.1; 14.1. ESI-MS: 653 ([M þ Na]þ).
HR-ESI-MS: 653.3813 ([M þ Na]þ, C40H54NaOþ6 ; calc. 653.3818).
Methyl (3b)-3-(Benzoyloxy)-12-oxo-8,14-secoursa-8,13-dien-28-oate (7) and Methyl (3b)-3-(Hy-
droxy)-12-oxo-8,14-secoursa-8,13-dien-28-oate (8). Method A: To a soln. of 6 (500 mg, 0.79 mmol) in

Helvetica Chimica Acta – Vol. 95 (2012)
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MeOH (25 ml) were added KOH (52 mg, 0.93 mmol) and H2O (1.0 ml). The mixture was stirred at r.t.
until 6 disappeared (TLC monitoring). Then, H2O (25 ml) was added, and the mixture was extracted
three times with CH2Cl2. The combined org. phase was washed with H2O and brine, dried (MgSO4), and
concentrated and the residue purified by CC(SiO2, petroleum ether/AcOEt 10 :1): 7 (384mg, 82%) and 8
(18mg, 4%).
Method B: As described in Method A with 6 (500 mg, 0.79 mmol), MeOH (25 ml), KOH (52 mg,
0.93 mmol), and H2O (1.0 ml). The combined org. phase was washed with H2O and brine and dried
(MgSO4). To this CH2Cl2 soln. were added pyridine (5 ml) and benzoyl chloride (0.12 ml). The resulting
soln. was stirred at r.t. until 8 was consumed completely, which was then washed with H2O, 5% aq. HCl
soln., sat. aq. NaHCO3 soln., and brine, dried (MgSO4), and concentrated. The resulting residue, was
purified by CC(SiO2, petroleum ether/AcOEt 10 :1): 7 (407 mg, 87%). Colorless crystals. M.p. 202 – 2048.
1
IR (KBr): 2965, 2933, 2875, 1718, 1685, 1630, 1455, 1280, 1117, 972, 713. H-NMR (600 MHz, CDCl3):
8.05 (d, J ¼ 7.6, 2 arom. H); 7.54 (dd, J ¼ 7.4, 7.4, 1 arom. H); 7.43 (dd, J ¼ 7.7, 7.7, 2 arom. H); 4.79 (ddd, J ¼
11.5, 5.5, 5.5, HꢀC(3)); 3.66 (s, MeOOCꢀC(17)); 3.46 (d, J ¼ 18.7, 1 HꢀC(11)); 3.25 (d, J ¼ 18.6,
1 HꢀC(11)); 2.74 (d, J ¼ 10.4, HꢀC(18)); 1.69 (s, Me); 1.34 (s, Me); 1.04 (s, Me); 0.97 (s, 2 Me); 0.91 (d,
J ¼ 6.1, Me); 0.88 (d, J ¼ 6.2, Me).13C-NMR (150 MHz, CDCl3): 205.3; 177.7; 166.2; 146.2; 139.0; 138.2;
132.6; 131.1; 129.5; 128.8; 128.3; 81.4; 51.7; 50.4; 46.8; 44.5; 42.5; 39.9; 38.8; 38.1; 37.9; 35.4; 34.2; 33.3;
30.8; 30.0; 29.7; 28.1; 24.1; 23.0; 20.8; 20.2; 19.9; 18.7; 17.1; 16.8. ESI-MS: 611 ([M þ Na]þ). HR-ESI-MS:
611.3707 ([M þ Na]þ, C38H52NaOþ5 ; calc. 611. 3712).
Compound 8: Colorless cubic crystals. IR: 3448, 2945, 2864, 1728, 1692, 1631, 1455. ESI-MS:
507([M þ Na]þ).
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Received November 17, 2011