Oxidative and reductive transformations of 11-keto-β-boswellic acid

Article abstract of DOI:10.1016/j.tet.2015.01.062

Extraction of frankincense - a fragrant resin obtained from plants of the genus Boswellia - followed by an oxidation furnished high yields of (3β) 3-O-acetyl-11-keto-β-boswellic acid (β-AKBA), a valuable starting material for accessing boswellic acid derivatives. Boswellic acids are fascinating triterpenoic acids that exhibit different biological activities. However, their biological potential, as well as that of their derivatives, remained unexploited due to their limited availability. In this study we were able to prepare derivatives of 11-keto-β-boswellic acid in good to excellent yields by oxidative and reductive transformations mainly in rings A and C of the triterpenoid skeleton. Among other transformations, a highly cytotoxic endoperoxide was obtained in excellent yields.

Full text of DOI:10.1016/j.tet.2015.01.062

Tetrahedron xxx (2015) 1e10
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Oxidative and reductive transformations of 11-keto-
b-boswellic acid
a
,
a
a
a
b
*
ꢀ
€
Rene Csuk , Anja Barthel-Niesen , Dieter Strohl , Ralph Kluge , Christoph Wagner ,
Ahmed Al-Harrasi c
a Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str.2, D-06120 Halle (Saale) Germany
b Martin-Luther-University Halle-Wittenberg, Inorganic Chemistry, Kurt-Mothes-Str.2, D-06120 Halle (Saale) Germany
c University of Nizwa, Chair of Oman’s Medicinal Plants and Marine Natural Products, PO Box 33, PC 616, Birkat Al-Mauz, Nizwa, Oman
a r t i c l e i n f o
a b s t r a c t
Article history:
Extraction of frankincenseda fragrant resin obtained from plants of the genus Boswelliadfollowed by an
Received 16 November 2014
Received in revised form 28 January 2015
Accepted 29 January 2015
Available online xxx
oxidation furnished high yields of (3b) 3-O-acetyl-11-keto-b-boswellic acid (b-AKBA), a valuable starting
material for accessing boswellic acid derivatives. Boswellic acids are fascinating triterpenoic acids that
exhibit different biological activities. However, their biological potential, as well as that of their de-
rivatives, remained unexploited due to their limited availability. In this study we were able to prepare
derivatives of 11-keto-b-boswellic acid in good to excellent yields by oxidative and reductive trans-
formations mainly in rings A and C of the triterpenoid skeleton. Among other transformations, a highly
cytotoxic endoperoxide was obtained in excellent yields.
Keywords:
Boswellic acid
Frankincense
Endoperoxide
Oxidation
Ó 2015 Elsevier Ltd. All rights reserved.
Reduction
1. Introduction
Frankincense is obtained from various species of plants of the
genus Boswellia. It has been used for more than 5000 years1 for
religious, medicinal, and sacrificial purposes. The resins of frank-
incense contain a broad variety2,3 of different terpenes; ursanes
and oleananetriterpenoids are among the main constituents of this
fragrant gum.
The chemical investigations4 of frankincense started as early as
in 1788 by Baer. One century later in 1898,
first isolated (together with -boswellic acids) by Tschirch and
Halbey.5,6 Boswellic acids, especially 11-keto-
-boswellic acid (KBA,
b-boswellic acid (1) was
a
b
Fig. 1. Structure and numbering of b-BA (1), b-KBA (2), and b-AKBA (3) and b-ABA (4).
2, Fig. 1) and its 3-acetate (AKBA, 3) are among the major bioactive
compounds2 of the costly gum of Bowellia spp.
While older techniques7e9 for the extraction of boswellic acids
from the gum were rather laborious and gave only low yields of 3, J.
Jauch et al. recently developed a ‘focusing approach’10,11 for the
extractive work-up of frankincense that allows a more convenient
isolation of 3 on a large preparative scale.
could be due to its limited availability. This is attributed to the fact
that there are no total syntheses of AKBA (3) to date, which in turn
resulted in high prices of this precious material. Recently, 3 and its
derivatives gained scientific interest12 due to the numerous reports
on inhibitory effect13 onto the microsomal prostaglandin E2
synthase-1, its interference14 with 5-lipoxygenase, and the ability
of 3 to inhibit15 urease. In addition, compound 3 has been sug-
gested16 for the treatment of colitis, and it was shown17 to decrease
the basal intracellular Ca2þ level. As a prerequisite for an extended
investigation of this class of compounds, we became interested in
a more systematic investigation of boswellic acids and their syn-
thetic modifications.
In contrast to other triterpenoids (e.g., ursolic acid, oleanolic
acid, glycyrrhetinic acid or maslinic acid), the number of structural
modifications on 11-keto-b-boswellic acid remained scarce, which
* Corresponding author. Tel.: þ49 345 5525660; fax: þ49 345 5527030; e-mail
address: rene.csukr@chemie.uni-halle.de (R. Csuk).
http://dx.doi.org/10.1016/j.tet.2015.01.062
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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2
R. Csuk et al. / Tetrahedron xxx (2015) 1e10
2. Results and discussion
of compound 8, which is a C-3 epimer of 5 is not unexpected due to
the only possible attack of the hydride ion on C-3.
KBA (2) and AKBA (3), together with (3
b
) 3-acetyl-
b
-boswellic
The reaction of 6 with excess methyllithium18,26,27 was more
complex. Thus, from the reaction of MeLi with the carbonyl group
at C-3 a tertiary alcohol was formed, but also a reaction occurred at
acid (4) were obtained from frankincense using a modification of
Jauch’s procedure.10,11 Deacetylation of 3 gave KBA (2) in excellent
yields. Reaction of 2(Scheme 1) with cesium carbonate in DMF18,19
furnished the methyl ester 5. Jones oxidation20 of 5 gave 65% of 6
whereas when Swern oxidation21 of 5 was employed, 91% yield of
methyl 3,11-diketo-boswelloate (6) was obtained. The structure of
6 was established by a single crystal X-ray analysis, the results of
which are depicted in Fig. 2.
the carbonyl group of the a,b-unsaturated system in ring C leading
to the formation of an exo-methylene moiety (as a consequence of
the formation of a tertiary alcohol followed by an elimination re-
action). Simultaneously, the methyl ester was transformed into
a methyl ketone. Compound 9 showed in its 1H NMR spectrum two
singlets at
d
¼5.01 and 4.92 ppm that were unambiguously assigned
to the protons of the exo-methylene group. The methyl groups
(attached to C-3 and C-24, respectively) were detected in the 1H
NMR spectrum at
spectrum of 9, the carbon of the methylene group was found at
d
¼2.24 and 1.13 ppm, respectively. In the 13C NMR
d
¼114.7 ppm whereas the newly introduced methyl groups were
detected at
d
¼30.6 and 22.2 ppm, respectively. To verify this un-
usual structure, suitable crystals of 9 were grown and submitted to
a single crystal X-ray analysis (Fig. 3). The results from this analysis
affirmed the structure deduced from its NMR spectra. The X-ray
analysis, however, revealed also the presence of an intramolecular
H-bond between H-52 and O-2 (crystallographic numbering).
Scheme 1. Synthesis of compounds 5e9: (a) EtOH, NaOH, 25 ꢀC, 12 h, 98%; (b) Cs2CO3,
THF, MeI, 25 ꢀC, 12 h, 95%; (c) (COCl)2, DMSO, THF, ꢁ78 ꢀC; NEt3, ꢁ60 ꢀC/25 ꢀC,
15 min, 91%; (d) SeO2, Ac2O, 160 ꢀC, 14 h, 78%; (e) NaBH4, THF, 25 ꢀC, 12 h, 53%; (f) THF,
MeLi (6 equiv), ꢁ70 ꢀC/25 ꢀC, 12 h, 52%.
Fig. 3. Structure of (3
a
,3b) 24-acetyl-3-hydroxy-3-methyl-11-methylene-urs-12-ene
(9) in an ORTEP representation (CCDC 1027235:
a¼8.0587(5) A, b¼15.3007(9) A, c¼22.5495(14) A P212121).
C
33H52O2; unit cell parameters:
ꢁ
ꢁ
ꢁ
Treatment of 5 (Scheme 2) with triphenylphosphane, DEAD, and
3,3-dimethylglutarimide28 gave alkene 10 whose Prileschajew re-
action with m-CPBA in THF29,30 afforded 80% of the epoxide 11. The
axially oriented methyl ester moiety in 5 shields one side of the
Fig. 2. Structure of methyl 3,11-diketo-boswelloate (6) in an ORTEP representation
ꢁ
ꢁ
(CCDC 1027236: C31H46O4; unit cell parameters: a¼10.2266(8) A, b¼11.0064(8) A,
ꢁ
c¼24.4245(17) A, P212121).
Treatment of 6 with SeO2 in acetic anhydride22e24 gave 78%
yield of compound 7. The formation of compound 7 can be
explained by an attack of the SeO2 onto the carbonyl group at po-
sition C-3 leading to an enolization. As a result of a [2,3] sigmatropic
rearrangement and a b-elimination, compound 7 was formed. The
1H NMR spectrum of 7 shows H-1 and H-2 each as a doublet cen-
tered at
d
¼7.72 and 5.87 ppm, while in its 13C NMR spectrum car-
Scheme 2. Synthesis of compounds 10e16 and 18: (a) Ph3P, 3,3-dimethylglutarimide,
DEAD, THF, 25 ꢀC, 12 h, quant.; (b) m-CPBA, THF, 25 ꢀC, 12 h, 80%; (c) H2O, TFA, reflux,
26 h, quant.; (d) NBS, 1,2-dimethoxyethane, H2O, 25 ꢀC, 12 h, 97%; (e) Na2Cr2O7, H2SO4,
H2O, 25 ꢀC, 2 h, 90%; (f) MeOH, MeONa, 25 ꢀC, 15 h, 91% (from 13); (g) AgOAc, HOAc, I2,
90 ꢀC, 12 h, 54%; (h) 1,1-thiocarbonyldiimidazole, DCM, reflux, 4 days, 79%.
bons C-1 and C-2 were detected at
d
¼159.9 and 124.5 ppm,
respectively. Interestingly, a selective reduction of 6 with NaBH4 in
THF21,25 led to an exclusive formation of (3
)-configurated 8 pos-
sessing an equatorially orientated hydroxylic moiety. The formation
b
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R. Csuk et al. / Tetrahedron xxx (2015) 1e10
3
planar molecule, and the electrophilic attack of the reagent led to
an exclusive formation of a (2 ,3 ) configurated epoxide 11. It is
noteworthy mentioning that no reaction was observed when 10
was treated with KMnO4 or OsO4. Reaction of epoxide 11 with
water in the presence of trifluoroacetic acid31 led to the formation
Another transformation of 10 in allylic position C-1 was ach-
ieved by the reaction of 10 with bromine leading to dibrominated
derivative 19. In its ESI-MS spectrum three signals for the quasi-
molecular ion were found at m/z¼625.1, 627.1, and 629.1 exhibiting
a ratio of 1:2:1 as expected for a dibrominated compound.
b
a
of trans-diol 12 via a trans-diaxial ring opening of the anellated
Compound 18 (vide supra, Scheme 2) could be accessed by
32
epoxide following FurstePlattner’s rule.
a 5 using 1,1-
BartoneMcCombie reaction44,45 starting from
€
For the synthesis of epoxide 14 being diasteromeric to 11 with
respect to positions C-2 and C-3 a different route had to be fol-
lowed. Thus, reaction of 10 with NBS in water gave the bromohy-
drin 13. This compound is characterized using its ESI-MS spectrum
by the presence of two signals for the quasimolecular ion at m/
z¼565.4 and 563.3 (isotopic pattern 1:1). In its IR spectrum the
thiocarbonyldiimidazole and tri-n-butyltin hydride, and a 54%
yield of 18 was obtained.
As far as the a,b-unsaturated carbonyl moiety of ring C is con-
cerned, reaction of 5 (Scheme 3) with the boraneeTHF complex led
to the formation of a 64:22 mixture of epimeric allyl alcohols 20
and 21.
vibration of the CeBr bond was detected at
n
¼661 cmꢁ1. The Jones
Reaction of 10 with NBS using WohleZiegler conditions46 gave
22 possessing an axially oriented bromine substituent. This selec-
tivity is a consequence of the presence of an adjacent axially ori-
ented methyl group (C-25). In addition, as shown from ab initio
calculations, an axial attack onto radicals of six-membered rings
seems to be favored47 as long as small substituents are introduced.
Thus, treatment of 10 with NCS under the same conditions afforded
mono-chlorinated 23. Reaction of 22 with sodium methoxide
proceeded under SN1 conditions to yield a mixture of epimers 24
and 25.
oxidation of 13 gave ketone 15, and the reaction of 13 with sodium
methanolate in methanol proceeded smoothly and furnished 91%
yield of the (2a,3b) configurated epoxide 14. The Woodward re-
action of 10 with iodine in the presence of silver acetate and wa-
ter33 resulted in the formation of the iodo-substituted compound
16.
Recently, we were able to show34 that a highly cytotoxic endo-
peroxide 17 (Scheme 3) could be obtained from 10 using 3.45 equiv
of Na2Cr2O7 and 12 equiv of NHS. The formation of this product can
be understood from a close inspection of a plausible mechanism of
the reaction.35e42 The reaction proved general as several similar
derivatives could be synthesized34,43 from various other triterpe-
noates as long as a double bond was present between carbons C-2
and C-3. No endoperoxide formation was observed for compound
18 (vide infra). The reaction time was significantly decreased in the
presence of sufficient oxygen, and the amount of sodium di-
chromate was reduced to 0.1 equiv. Furthermore, NHS could be
replaced by N-hydroxyphthalimide. These modifications resulted in
shorter reaction times (3 days/18 h), higher yields (45%/82%)
and an easier work-up.
3. Conclusion
To sum up, in this work we have adopted and applied many
reactions leading to modifications of
dpreferentially at positions C-1,2,3,9,11 and C-24. Of special in-
terest seems the synthesis of a 1 ,9 -1,9-peroxo derivative that was
b-boswellic acid-
a
a
conveniently obtained in 80% yield. These results provide a basic for
future and extensive exploring the chemistry of boswellic acids to
access biologically active compounds.
4. Experimental section
4.1. Generaldchemistry
Melting points are uncorrected (Leica hot stage microscope),
NMR spectra were recorded using the Varian spectrometers Gemini
2000 or Unity 500 (d given in ppm, J in Hz, internal Me4Si), MS
spectra were taken on a Finnigan MAT LCQ 7000 (electrospray,
voltage 4.1 kV, sheath gas nitrogen) instrument. The optical rota-
tion was measured on a PerkineElmer polarimeter at 20 ꢀC; TLC
was performed on silica gel (Merck 5554); elemental analyses were
performed on a Vario EL (CHNS). The solvents were dried according
to usual procedures. The purity of the compounds was determined
by HPLC and found to be >98%. Frankincense was obtained from
different commercial suppliers in bulk quantities. CCDC1027235
and CCDC1027236 contain the supplementary crystallographic
data. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.ac.uk/data_request/cif.
4.2. (3
a,4b) 3-Acetoxy-11-oxo-urs-12-en-14-oic acid
([ -AKBA, 3)
b
A suspension of finely grounded frankincense (50 g) in ether
(1 L) was stirred overnight, the solvent was decanted, and the
residue re-supended in ether (1 L), and stirring was continued for
another 12 h. The ether phases were combined, the solvent was
removed under reduced pressure, and the residue was dissolved in
ether (300 mL). Triethylamine (11.1 mL, 80.0 mmol), acetyl chloride
(5.68 mL, 80.0 mmol), and DMAP (100 mg, 0.82 mmol) were slowly
added, and stirring was continued for 12 h. Usual aqueous work-up
followed by an extraction with ether gave a residue that was
Scheme 3. Synthesis of compounds 17 and 19e25: (a) NHPI, Na2Cr2O7, acetone, O2,
40 ꢀC, 18 h, 82%; (b) Br2, CHCl3, 25 ꢀC, 2 days, 81%; (c) BH3$THF, THF, 25 ꢀC, 5 h, 64% (of
20) and 22% (of 21); (d) NBS, CCl4, AIBN (catal.), 70 ꢀC, 2 h, 83%; (e) NCS, CCl4, AIBN
(catal.), 70 ꢀC, 2 h, 79%; (f) MeONa, MeOH, reflux, 8 h, 43% (of 24) and 46% (of 25) from
22.
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4
R. Csuk et al. / Tetrahedron xxx (2015) 1e10
subjected to chromatography (silica gel, hexane/EtOAc, 9:1/8:2),
and 3 (3.38 g, 6.46%) as well as 4 (7.37 g, 14.7%, impure) were
obtained.48
A solution of fractions containing 4 (10 g), N-hydroxyph-
thalimide (16.4 g, 100 mmol) and Na2Cr2O7 dihydrate (15 g,
50 mmol) in acetone (200 mL) was stirred at 40 ꢀC overnight. The
precipitate was filtered off and washed with CHCl3 (100 mL). The
filtrate and the washings were combined, the solvents were re-
moved under reduced pressure, and the residue was subjected
22), 39.2 (C-19), 39.2 (C-20), 37.5 (C-10), 33.9 (C-1), 33.9 (C-17), 32.9
(C-7), 30.9 (C-21), 28.8 (C-28), 27.5 (C-16), 27.2 (C-15), 26.2 (C-2),
24.3 (C-23), 21.1 (C-30), 20.5 (C-27), 18.8 (C-6), 18.3 (C-26), 17.4 (C-
29), 13.2 (C-25) ppm; MS (ESI, methanol) C30H46H4: m/z¼469.6
([MꢁH]ꢁ, 100%).
4.4. (3a,4b) Methyl 3-hydroxy-11-oxo-urs-12-en-24-oate (5)
A suspension of 2 (4.73 g, 10.0 mmol) and Cs2CO3 (9.8 g,
30 mmol) in THF (50 mL) was stirred at 0 ꢀC for 30 min, then MeI
(6.23 mL, 100 mmol) was added, and stirring continued for 12 h.
The mixture was diluted with ether (500 mL), washed with water
and brine (2ꢂ50 mL each), dried (Na2SO4), and the solvents were
evaporated to yield 5 (4.63 g, 95%) as an off-white solid (sufficiently
pure for the next reactions); an analytical sample showed:
to chromatography (silica gel, CHCl3/Et2O, 9:1) to yield
3
(5.54 g, 14.8%) as a colorless solid; mp¼234e238 ꢀC (lit.:10
mp¼271e274 ꢀC); Rf¼0.66 (hexane/EtOAc/HOAc, 70:30:1); [
a]
D
¼2978s,
64.6 (c 5.22, CHCl3) (lit.:10 82 (c 1.25, CHCl3)); IR (KBr):
n
1742s, 1700m, 1661m, 1457m, 1381m, 1322m, 1246w, 1202m,
1126w, 1108w, 1081w, 1050m, 1027m, 997m cmꢁ1
; UVevis
(methanol): lmax (log
3
)¼267 nm (3.7); 1H NMR (400 MHz,
mp¼224e227 ꢀC; Rf¼0.18 (hexane/EtOAc, 8:2); [
a] 112.4 (c 3.7,
¼3441m, 2981s, 2922s, 2862m, 1723s, 1658m,
D
CDCl3):
d
¼5.53 (s, 1H, CH (12)), 5.30 (dd, 1H, CH (3), 3J¼2.9, 2.9 Hz),
CHCl3); IR (KBr):
n
2.53 (ddd, 1H, CH2 (1b), 2J¼12.9 Hz, 3J¼2.5, 2.9 Hz), 2.39 (s, 1H, CH
(9)), 2.24 (m, 1H, CH2 (2a)), 2.08 (ddd, 1H, CH2 (16a), 2J¼13.7 Hz,
3J¼4.6 13.7 Hz), 2.07 (s, 3H, CH3 (32)), 1.88 (ddd, 1H, CH2 (15a),
2J¼13.7 Hz, 3J¼4.6, 13.7 Hz), 1.72 (m, 2H, CH2 (6)), 1.64 (m, 1H, CH2
(7a)), 1.58 (m, 1H, CH2 (2b)), 1.52 (dd, 1H, CH (18), 3J¼11.2 Hz,
4J¼0.8 Hz), 1.49 (m, 1H, CH2 (22b)), 1.45 (m, 2H, CH2 (21), 1H, CH2
(7b)), 1.39 (m, 1H, CH (19)), 1.38 (dd, 1H, CH (5), 3J¼1.7, 12.0 Hz), 1.33
(s, 3H, CH3 (27)), 1.29 (m, 1H, CH2 (22a)), 1.22 (s, 3H, CH3 (23)), 1.19
(m,1H, CH2 (1a),1H, CH2 (15b)),1.17 (s, 3H, CH3 (26)),1.14 (s, 3H, CH3
(25)), 1.00 (ddd, 1H, CH2 (16b), 2J¼13.7 Hz, 3J¼2.1, 2.1 Hz), 0.93 (s,
3H, CH3 (30)), 0.92 (m, 1H, CH (20)), 0.81 (s, 3H, CH3 (28)), 0.78 (d,
1644s, 1456m, 1383m, 1320w, 1224m, 1199m, 1139w, 1122w, 1108w,
1082w, 1057m, 1036w, 1002w, 967w cmꢁ1; UVevis (methanol):
lmax (log
3
)¼267 nm (4.04); 1H NMR (400 MHz, CDCl3):
¼5.52 (s,
d
1H, CH (12)), 4.08 (dd, 1H, CH (3), 3J¼2.5, 2.9 Hz), 3.64 (s, 3H, CH3
(31)), 2.47 (ddd, 1H, CH2 (1b), 2J¼13.3 Hz, 3J¼2.9, 4.2 Hz), 2.40 (s, 1H,
CH (9)), 2.26 (m, 1H, CH2 (2a)), 2.07 (ddd, 1H, CH2 (16a), 2J¼13.7 Hz,
3J¼5.0, 13.7 Hz), 1.86 (ddd, 1H, CH2 (15a), 2J¼13.7 Hz, 3J¼5.0,
13.7 Hz), 1.80 (m, 1H, CH2 (6a)), 1.74 (m, 1H, CH2 (6b)), 1.65 (ddd, 1H,
CH2 (7a), 2J¼12.8 Hz, 3J¼3.7, 12.8 Hz), 1.53 (m, 1H, CH2 (2b)), 1.51
(dd, 1H, CH (18), 3J¼11.2 Hz, 4J¼1.2 Hz), 1.46 (m, 1H, CH2 (22b)), 1.44
(dd, 1H, CH (5), 3J¼2.9, 10.8 Hz), 1.42 (m, 1H, CH2 (7b), 2H, CH2 (21)),
1.38 (m, 1H, CH (19)), 1.33 (m, 1H, CH2 (1a), 1H, CH2 (22a)), 1.29 (s,
3H, CH3 (27)), 1.27 (s, 3H, CH3 (23)), 1.19 (m, 1H, CH2 (15b)), 1.15 (s,
3H, CH3 (26)), 1.00 (s, 3H, CH3 (25)), 0.97 (m,1H, CH2 (16b)), 0.93 (m,
1H, CH (20)), 0.92 (s, 3H, CH3 (30)), 0.80 (s, 3H, CH3 (28)), 0.77 (d,
3H, CH3 (29), 3J¼6.6 Hz) ppm; 13C NMR (125 MHz, CDCl3):
¼199.2
d
(C-11), 181.9 (C-24), 170.3 (C-31), 165.0 (C-13), 130.4 (C-12), 73.1 (C-
3), 60.3 (C-9), 58.8 (C-18), 50.4 (C-5), 46.5 (C-4), 45.0 (C-8), 43.8 (C-
14), 40.9 (C-22), 39.3 (C-19), 39.2 (C-20), 37.4 (C-10), 34.6 (C-1), 33.9
(C-17), 32.8 (C-7), 30.9 (C-21), 28.8 (C-28), 27.5 (C-16), 27.2 (C-15),
23.8 (C-23), 23.5 (C-2), 21.3 (C-30), 21.1 (C-32), 20.5 (C-27), 18.7 (C-
6), 18.4 (C-26), 17.4 (C-29), 13.2 (C-25) ppm; MS (ESI, methanol)
3H, CH3 (29), 3J¼6.2 Hz) ppm; 13C NMR (125 MHz, CDCl3):
¼199.5
d
(C-11), 177.2 (C-24), 164.9 (C-13), 130.5 (C-12), 70.7 (C-3), 60.4 (C-9),
59.0 (C-18), 51.2 (C-31), 48.7 (C-5), 47.4 (C-4), 45.0 (C-8), 43.8 (C-
14), 40.9 (C-22), 39.2 (C-19þC-20), 37.3 (C-10), 33.9 (C-1þC-17),
32.9 (C-7), 30.9 (C-21), 28.8 (C-28), 27.5 (C-16), 27.2 (C-15), 26.3 (C-
2), 24.1 (C-23), 21.1 (C-30), 20.5 (C-27), 18.9 (C-6), 18.3 (C-26), 17.4
(C-29), 13.0 (C-25) ppm; MS (ESI, methanol) C31H48O4: m/z¼485.4
([MþH]þ, 52%).
C
32H48O5: m/z¼513.5 ([MþH]þ, 100%).
4.3. (3
a,4b) 3-Hydroxy-11-oxo-urs-12-en-24-oic acid
([ -KBA, 2)
b
Compound 3 (10.0 g, 19.5 mmol) was dissolved in ethanol
(200 mL), and an aq solution of sodium hydroxide (4 M, 100 mL)
was added. After stirring at 25 ꢀC for 12 h, the pH was adjusted
(aq HCl), the product was extracted with CHCl3 (5ꢂ100 mL), and the
crude product was purified by chromatography (silica gel, hexane/
ethylacetate, 98:2) to afford pure 2 in almost quantitative yield
4.5. (4b) Methyl 3,11-dioxo-urs-12-en-24-oate (6)
Ta a solution of oxalyl chloride (263 mg, 2.06 mmol) in abs DCM
(20 mL) at ꢁ78 ꢀC, DMSO (322 mg, 4.12 mmol) in abs DCM (2 mL)
was added and stirred for 10 min, then a solution of 5 (500 mg,
1.03 mmol) in abs DCM (5 mL) was added and stirring at ꢁ60 ꢀC
(9.18 g, 98%) as
a
colorless solid; mp¼171e174 ꢀC (lit.:49
195e197 ꢀC); Rf¼0.49 (hexane/EtOAc/HOAc 70:30:1); [
a
]
118.2 (c
continued for 1 h. Triethylamine (577 mL, 4.12 mmol) was added
D
3.72, CHCl3) [lit.:10 121 (c 1.11, CHCl3)]; IR (KBr):
n
¼3466m, 2978s,
and stirring continued for 15 min. Usual aqueous work-up followed
by chromatography (silica gel, chloroform/ether, 9:1) yielded 6
(452 mg, 91%) as a colorless solid; mp¼249e253 ꢀC (lit.:20
2912s, 1695s, 1650s, 1452m, 1382m, 1349m, 1324m, 1254m, 1200m,
1117m, 1079m, 1058m, 1002m, 968m cmꢁ1; UVevis (methanol):
lmax (log
3
)¼268 nm (4.07); 1H NMR (400 MHz, CDCl3):
d
¼5.53 (s,
256e258 ꢀC); Rf¼0.10 (hexane/EtOAc, 9:1); [
a
]
121.6 (c 4.94,
D
1H, CH (12)), 4.06 (dd, 1H, CH (3), 3J¼2.5, 2.9 Hz), 2.51 (ddd, 1H, CH2
(1b), 2J¼13.3 Hz, 3J¼2.5, 2.9 Hz), 2.41 (s,1H, CH (9)), 2.30 (m,1H, CH2
(2a)), 2.07 (ddd, 1H, CH2 (16a), 2J¼13.7 Hz, 3J¼4.6, 13.7 Hz), 1.87 (m,
1H, CH2 (15a), 1H, CH2 (6a)), 1.71 (m, 1H, CH2 (6b)), 1.66 (m, 1H, CH2
(7a)), 1.55 (m, 1H, CH2 (2b)), 1.53 (dd, 1H, CH (18), 3J¼0.8, 11.2 Hz),
1.48 (m, 1H, CH2 (22b)), 1.46 (dd, 1H, CH (5), 3J¼2.5, 12.5 Hz), 1.42
(m, 2H, CH2 (21), 1H, CH2 (7b)), 1.39 (m, 1H, CH (19)), 1.33 (s, 3H, CH3
(23)), 1.32 (m, 1H, CH2 (1a)), 1.30 (s, 3H, CH3 (27)), 1.28 (m, 1H, CH2
(22a)), 1.20 (m, 1H, CH2 (15b)), 1.17 (s, 3H, CH3 (26)), 1.12 (s, 3H, CH3
(25)), 0.99 (ddd, 1H, CH2 (16b), 2J¼13.3 Hz, 3J¼2.1, 2.5 Hz), 0.93 (s,
3H, CH3 (30)), 0.92 (m, 1H, CH (20)), 0.81 (s, 3H, CH3 (28)), 0.78 (d,
CHCl3); IR (KBr):
n
¼3419m, 2971s, 2949s, 2920s, 2871m, 2848m,
1724s, 1712s, 1651s, 1616m, 1455m, 1430m, 1385m, 1364m, 1346w,
1330m, 1292w, 1271m, 1233s, 1194m, 1138m, 1123m, 1093m,
1058w, 1018w, 992m cmꢁ1; UVevis (methanol): lmax (log
3 )¼
268 nm (4.08); 1H NMR (400 MHz, CDCl3):
d¼5.55 (s, 1H, CH (12)),
3.66 (s, 3H, CH3 (31)), 3.03 (m, 1H, CH2 (1), 1H, CH2 (2)), 2.34 (s, 1H,
CH (9)), 2.33 (m, 1H, CH2 (1)), 2.07 (ddd, 1H, CH2 (16a), 2J¼13.7 Hz,
3J¼5.0, 13.7 Hz), 1.95 (m, 1H, CH2 (6b)), 1.88 (ddd, 1H, CH2 (15a),
2J¼13.7 Hz, 3J¼5.0, 13.7 Hz), 1.81 (m, 1H, CH2 (6a)), 1.61 (ddd, 1H,
CH2 (7a), 2J¼13.3 Hz, 3J¼4.2, 13.3 Hz), 1.53 (dd, 1H, CH (18),
3J¼11.2 Hz, 4J¼1.2 Hz), 1.48 (m, 1H, CH2 (7b), 1H, CH2 (22b)), 1.42 (m,
2H, CH2 (21)), 1.39 (m, 1H, CH (19)), 1.34 (s, 3H, CH3 (23)), 1.28 (s, 3H,
CH3 (25)), 1.27 (m, 1H, CH2 (2), 1H, CH2 (22a)), 1.26 (s, 3H, CH3 (27)),
1.20 (s, 3H, CH3 (26)), 1.18 (m, 1H, CH (5), 1H, CH2 (15b)), 1.00 (ddd,
3H, CH3 (29), 3J¼6.2 Hz) ppm; C NMR (125 MHz, CDCl3):
¼199.7
d
(C-11),182.5 (C-24),165.2 (C-13),130.4 (C-12), 70.4 (C-3), 60.4 (C-9),
59.0 (C-18), 48.8 (C-5), 47.2 (C-4), 45.1 (C-8), 43.8 (C-14), 40.9 (C-
Please cite this article in press as: Csuk, R.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.01.062

R. Csuk et al. / Tetrahedron xxx (2015) 1e10
5
1H, CH2 (16b), 2J¼13.3 Hz, 3J¼2.5, 2.5 Hz), 0.93 (m,1H, CH (20)), 0.92
(s, 3H, CH3 (30)), 0.81 (s, 3H, CH3 (28)), 0.77 (d, 3H, CH3 (29),
(22b)), 1.43 (m, 2H, CH2 (21)), 1.39 (s, 3H, CH3 (23)), 1.38 (m, 1H, CH
(19)), 1.30 (m, 1H, CH2 (22a)), 1.27 (s, 3H, CH3 (27)), 1.18 (m, 1H, CH2
(15b)), 1.14 (s, 3H, CH3 (26)), 1.01 (s, 3H, CH3 (25)), 1.00 (m, 1H, CH2
(1a)), 0.98 (ddd, 1H, CH2 (16b), 2J¼13.3 Hz, 3J¼2.1, 2.1 Hz), 0.92 (s,
3H, CH3 (30)), 0.90 (m, 1H, CH (20)), 0.85 (dd, 1H, CH (5), 3J¼2.9,
12.0 Hz), 0.79 (s, 3H, CH3 (28)), 0.77 (d, 3H, CH3 (29),
3J¼6.6 Hz) ppm; 13C NMR (125 MHz, CDCl3):
¼208.4 (C-3), 198.7
d
(C-11), 173.9 (C-24), 165.4 (C-13), 130.3 (C-12), 60.0 (C-9), 59.0 (C-
18), 58.4 (C-5), 57.5 (C-4), 52.1 (C-31), 44.8 (C-8), 43.8 (C-14), 41.0
(C-2), 40.8 (C-22), 39.3 (C-19), 39.2 (C-20), 37.0 (C-10), 36.6 (C-1),
33.9 (C-17), 32.6 (C-7), 30.8 (C-21), 28.8 (C-28), 27.4 (C-16), 27.3 (C-
15), 21.7 (C-23), 21.0 (C-30), 20.3 (C-27), 19.7 (C-6), 18.3 (C-26), 17.4
(C-29), 13.2 (C-25) ppm; MS (ESI, methanol) C31H46O4: m/z¼483.5
([MþH]þ, 100%), 505.4 ([MþNa]þ, 23%).
3J¼6.6 Hz) ppm; 13C NMR (125 MHz, CDCl3):
¼199.1 (C-11), 177.9
d
(C-24), 164.8 (C-13), 130.5 (C-12), 78.2 (C-3), 60.5 (C-9), 59.0 (C-18),
56.5 (C-5), 51.3 (C33), 49.1 (C-4), 44.8 (C-8), 43.7 (C-14), 40.9 (C-22),
39.8 (C-1), 39.3 (C-19), 39.3 (C-20), 37.1 (C-10), 34.0 (C-17), 32.9 (C-
7), 30.9 (C-21), 28.8 (C-28), 28.1 (C-2), 27.5 (C-16), 27.2 (C-15), 23.7
(C-23), 21.1 (C-30), 20.4 (C-27), 19.3 (C-6), 18.2 (C-26), 17.4 (C-29),
4.6. (4b) Methyl 3,11-dioxo-urs-1,12-dien-24-oate (7)
13.6 (C-25) ppm; MS (ESI, methanol)
C
31H48O4: m/z¼485.5
A solution of 6 (193 mg, 0.4 mmol) in acetic anhydride (10 mL)
containing SeO2 (111 mg, 1.0 mmol) was heated at 160 ꢀC for 14 h.
The black precipitate was filtered off, washed with chloroform
(20 mL), the solvents were removed under reduced pressure, and
the residue was subjected to chromatography (silica gel, hexane/
EtOAc 8:2) to yield 7 (150 mg, 78%) as a colorless amorphous solid;
([MþH]þ, 100%), 507.5 ([MþNa]þ, 33%); analysis calcd for C31H48O4
(484.71): C, 76.82; H, 9.98. Found: C, 76.75; H, 10.09.
4.8. (4
12-ene (9)
b) 24-Acetyl-3b-hydroxy-3a-methyl-11-methylene-urs-
Rf¼0.49 (hexane/EtOAc, 8:2); [
a
]
147.6 (c 5.38, CHCl3); IR (film):
To a solution of 6 (400 mg, 0.83 mmol) in abs THF (10 mL) at
ꢁ70 ꢀC, methyllithium (1.6 M in ether, 3.11 mL, 4.98 mmol) was
added, and the mixture was allowed to warm to 25 ꢀC. After stirring
for 12 h at 25 ꢀC, water (10 mL) was added, and the mixture
extracted with chloroform (3ꢂ50 mL). The solvents were evapo-
rated, and the residue was subjected to chromatography (silica gel,
hexane/EtOAc, 8:2) to afford 9 (200 mg, 52%) as colorless solid;
D
n
¼3449w, 2923m, 2870m, 1732s, 1679s, 1652s, 1615m, 1456m,
1385m, 1346m, 1327m, 1276m, 1234m, 1212m, 1176m, 1140m,
1121m, 1106m, 1093m, 1008w, 992m cmꢁ1; UVevis (methanol):
lmax (log
3
)¼260 nm (4.01); 1H NMR (400 MHz, CDCl3):
¼7.72 (d,
d
1H, CH (1), 3J¼10.4 Hz), 5.87 (d, 1H, CH (2), 3J¼10.4 Hz), 5.60 (s, 1H,
CH (12)), 3.61 (s, 3H, CH3 (31)), 2.57 (s, 1H, CH (9)), 2.08 (ddd, 1H,
CH2 (16a), 2J¼13.7 Hz, 3J¼4.6,13.7 Hz),1.90 (m, 2H, CH2 (6)),1.83 (m,
1H, CH2 (15a)), 1.68 (ddd, 1H, CH2 (7a), 2J¼12.9 Hz, 3J¼5.0, 12.9 Hz),
1.62 (dd, 1H, CH (5), 3J¼2.5, 11.2 Hz), 1.56 (dd, 1H, CH (18),
3J¼11.2 Hz, 4J¼1.2 Hz), 1.50 (m, 1H, CH2 (21a), 1H, CH2 (22b)), 1.47 (s,
3H, CH3 (23)), 1.44 (m, 1H, CH2 (7b)), 1.39 (m, 1H, CH (19)), 1.32 (s,
3H, CH3 (25)), 1.30 (m, 1H, CH2 (22a)), 1.28 (s, 3H, CH3 (27)), 1.27 (m,
1H, CH2 (21b)), 1.22 (m, 1H, CH2 (15b)), 1.20 (s, 3H, CH3 (26)), 1.02
(ddd, 1H, CH2 (16b), 2J¼13.7 Hz, 3J¼2.5, 2.5 Hz), 0.93 (s, 3H, CH3
(30)), 0.92 (m, 1H, CH (20)), 0.81 (s, 3H, CH3 (28)), 0.77 (d, 3H, CH3
mp¼204 ꢀC; Rf¼0.28 (hexane/EtOAc, 8:2); [
a]
145.8 (c 2.84,
D
CHCl3); IR (KBr):
n
¼3544m, 3132w, 2976m, 2954m, 2909s, 1684m,
1595w, 1455m, 1394m, 1380m, 1351m, 1276w, 1243w, 1212w,
1166m, 1151m, 1076w, 1056w, 990w cmꢁ1; UVevis (methanol):
lmax (log
3
)¼267 nm (3.96); 1H NMR (400 MHz, CDCl3):
¼7.37 (s,
d
1H, CH (12)), 5.01 (s, 1H, CH2 (33)), 4.92 (s, 1H, CH2 (33)), 2.51 (ddd,
1H, CH2 (1b), 2J¼13.6 Hz, 3J¼3.3, 3.3 Hz), 2.45 (m, 1H, CH2 (2a)), 2.29
(s, 1H, CH (9)), 2.24 (s, 3H, CH3 (32)), 2.00 (ddd, 1H, CH2 (16a),
2J¼13.7 Hz, 3J¼5.0, 13.7 Hz), 1.80 (ddd, 1H, CH2 (6a), 2J¼12.2 Hz,
3J¼3.3, 12.2 Hz), 1.78 (ddd, 1H, CH2 (15a), 2J¼13.7 Hz, 3J¼5.0,
13.7 Hz), 1.65 (ddd, 1H, CH2 (6b), 2J¼12.0 Hz, 3J¼3.1, 12.0 Hz), 1.58
(m, 2H, CH2 (7)), 1.48 (m, 1H, CH2 (1a)), 1.46 (m, 1H, CH2 (22b)), 1.40
(m, 1H, CH2 (21a)), 1.38 (m, 1H, CH (19)), 1.36 (dd, 1H, CH (18),
3J¼11.0 Hz, 4J¼1.9 Hz), 1.35 (m, 1H, CH (5)), 1.30 (m, 1H, CH2 (22a)),
1.29 (m, 1H, CH2 (2b)), 1.28 (s, 3H, CH3 (23)), 1.24 (m, 1H, CH2 (21b)),
1.18 (s, 3H, CH3 (27)),1.13 (s, 3H, CH3 (31)),1.05 (s, 3H, CH3 (25)),1.04
(m, 1H, CH2 (15b)), 0.97 (s, 3H, CH3 (26)), 0.91 (s, 3H, CH3 (30)), 0.90
(m, 1H, CH2 (16b), 1H, CH (20)), 0.79 (d, 3H, CH3 (29), 3J¼7.2 Hz),
(29), 3J¼6.6 Hz) ppm; 13C NMR (125 MHz, CDCl3):
¼198.2 (C-11),
d
196.6 (C-3), 173.7 (C-24), 166.4 (C-13), 159.9 (C-1), 129.9 (C-12),
124.5 (C-2), 59.1 (C-18), 55.1 (C-9), 54.8 (C-5), 54.4 (C-4), 52.2 (C-
31), 45.3 (C-8), 43.9 (C-14), 40.8 (C-22), 39.2 (C-19), 39.2 (C-20),
38.9 (C-10), 33.9 (C-17), 32.5 (C-7), 30.8 (C-21), 28.8 (C-28), 27.4 (C-
16), 27.2 (C-15), 21.1 (C-23), 21.1 (C-30), 20.4 (C-27), 18.9 (C-6), 18.7
(C-26), 17.4 (C-29), 16.0 (C-25) ppm; MS (ESI, methanol) C31H44O4:
m/z¼481.5 ([MþH]þ, 100%); analysis calcd for C31H44O4 (480.68): C,
77.46; H, 9.22. Found: C, 77.31; H, 9.47.
0.78 (s, 3H, CH3 (28)) ppm; 13C NMR (125 MHz, CDCl3):
d¼217.7 (C-
4.7. (3
b,4b
) Methyl 3-hydroxy-11-oxo-urs-12-en-24-oate (8)
24), 142.8 (C-11), 141.9 (C-13), 128.9 (C-12), 114.7 (C-33), 74.7 (C-3),
58.7 (C-18), 58.1 (C-5), 56.2 (C-9), 54.1 (C-4), 42.5 (C-14), 41.5 (C-10),
41.3 (C-22), 39.8 (C-19), 39.5 (C-20), 39.3 (C-8), 38.4 (C-2), 34.4 (C-
1), 33.9 (C-17), 33.7 (C-7), 31.1 (C-21), 30.6 (C32), 28.8 (C-28), 28.0
(C-16), 26.9 (C-15), 23.6 (C-27), 22.2 (C-31), 21.2 (C-30), 20.9 (C-6),
18.7 (C-23), 17.7 (C-26), 17.4 (C-29), 14.7 (C-25) ppm; MS (ESI,
To a solution of 6 (300 mg, 0.62 mmol) in abs THF (10 mL), so-
dium borohydride (118 mg, 3.12 mmol) was added, and the mixture
was stirred at 25 ꢀC for 12 h. After acidification (aq HCl, 2%), addi-
tion of brine (50 mL) and extraction with chloroform (3ꢂ30 mL),
the solvent was removed, and the residue subjected to chroma-
tography (silica gel, hexane/EtOAc, 8:2) to yield 8 (159 mg, 53%) as
methanol)
C
33H52O2: m/z¼463.5 ([MþHꢁH2O]þ, 66%), 503.5
([MþNa]þ, 35%); analysis calcd for C33H52O2 (480.77): C, 82.44; H,
a
colorless solid; mp¼262 ꢀC; Rf¼0.59 (hexane/EtOAc/HOAc,
10.90. Found: C, 82.31; H, 11.04.
70:30:1); [
a
]
D
136.2 (c 4.74, CHCl3); IR (KBr):
n
¼3543m, 2925s,
2858s, 1703s, 1663s, 1354m, 1340m, 1322m, 1294m, 1245m, 1216m,
4.9. (4b) Methyl 11-oxo-urs-2,12-dien-24-oate (10)
1197m, 1166m, 1135m, 1121m, 1094m, 1047m, 990m cmꢁ1; UVevis
(methanol): lmax (log
3
)¼268 nm (4.07); 1H NMR (400 MHz, CDCl3):
To a solution of 5 (1.55 g, 3.2 mmol), triphenylphosphane (4.2 g,
16.0 mmol) and 3.3-dimethylglutarimide (2.3 g, 16.0 mmol) in
abs THF (20 mL) at 0 ꢀC, DEAD (2.8 g, 16.0 mmol) was slowly added
and stirring at 25 ꢀC continued for 12 h. The solvent was removed
under reduced pressure, and the residue was subjected to chro-
matography (silica gel, hexane/EtOAc, 7:3) to yield 10 (1.51 g,
quant.) as a colorless solid; mp¼185e188 ꢀC; Rf¼0.76 (hexane/
d¼5.52 (s, 1H, CH (12)), 3.66 (s, 3H, CH3 (31)), 3.26 (d, 1H, CH (3),
3J¼11.6 Hz), 3.06 (ddd, 1H, CH2 (2b), 2J¼11.6 Hz, 3J¼4.2, 11.6 Hz),
2.75 (ddd, 1H, CH2 (1b), 2J¼13.3 Hz, 3J¼3.7, 4.2 Hz), 2.29 (s, 1H, CH
(9)), 2.10 (ddd, 1H, CH2 (2a), 2J¼13.3, 3J¼3.7, 13.3 Hz), 2.06 (ddd, 1H,
CH2 (16a), 2J¼13.7 Hz, 3J¼4.6, 13.7 Hz), 1.86 (ddd, 1H, CH2 (15a),
2J¼13.7 Hz, 3J¼5.0, 13.7 Hz), 1.80 (m, 1H, CH2 (6a)), 1.70 (m, 1H, CH2
(6b)), 1.60 (ddd, 1H, CH2 (7a), 2J¼12.9 Hz, 3J¼4.2, 12.9 Hz), 1.52 (dd,
1H, CH (18), 3J¼11.2 Hz, 4J¼1.2 Hz), 1.46 (m, 1H, CH2 (7b), 1H, CH2
EtOAc/HOAc, 70:30:1);
[
a]
187.4 (c 5.32, CHCl3); IR (KBr):
D
n
¼3432m, 2925s, 2869m, 1728s, 1655s, 1617m, 1456m, 1383m,
Please cite this article in press as: Csuk, R.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.01.062

6
R. Csuk et al. / Tetrahedron xxx (2015) 1e10
1356w, 1336w, 1320m, 1268m, 1201m, 1171m, 1138m, 1119m,
1052w, 1016w, 991m cmꢁ1; UVevis (methanol): lmax (log
)¼
267 nm (4.03); H NMR (400 MHz, CDCl3):
¼5.58 (m, 2H, 2CH
(3ꢂ40 mL) and chromatography (silica gel, hexane/EtOAc, 3:2)
furnished 12 (200 mg, quant.) as a colorless amorphous solid;
3
d
Rf¼0.11 (hexane/EtOAc/HOAc, 70:30:1); [
a] 107.2 (c 4.34, CHCl3);
D
(2þ3)), 5.56 (s, 1H, CH (12)), 3.61 (s, 3H, CH3 (31)), 3.06 (dd, 1H, CH2
(1b), 2J¼17.9 Hz, 3J¼3.9 Hz), 2.39 (s, 1H, CH (9)), 2.07 (ddd, 1H, CH2
(16a), 2J¼13.7 Hz, 3J¼5.0, 13.7 Hz), 1.91 (m, 1H, CH2 (6a)), 1.88 (ddd,
1H, CH2 (15a), 2J¼13.7 Hz, 3J¼5.0, 13.7 Hz), 1.72 (m, 1H, CH2 (6b)),
1.67 (m, 1H, CH2 (1a)), 1.63 (ddd, 1H, CH2 (7a), 2J¼12.9 Hz, 3J¼2.9,
12.9 Hz), 1.53 (dd, 1H, CH (18), 3J¼11.2 Hz, 4J¼1.7 Hz), 1.48 (m, 1H,
CH2 (22b)), 1.45 (m, 1H, CH2 (7b), 2H, CH2 (21)), 1.39 (m, 1H, CH
(19)), 1.31 (m, 1H, CH2 (22a)), 1.28 (s, 3H, CH3 (23)), 1.27 (s, 3H, CH3
(27)), 1.24 (dd, 1H, CH (5), 3J¼2.5, 11.6 Hz), 1.21 (m, 1H, CH2 (15b)),
1.15 (s, 3H, CH3 (26)), 1.07 (s, 3H, CH3 (25)), 0.99 (ddd, 1H, CH2 (16b),
2J¼13.3 Hz, 3J¼2.5, 2.9 Hz), 0.94 (m, 1H, CH (20)), 0.93 (s, 3H, CH3
(30)), 0.81 (s, 3H, CH3 (28)), 0.78 (d, 3H, CH3 (29), 3J¼6.6 Hz) ppm; C
IR (KBr):
n
¼3423s, 2928m, 2870m, 1724m, 1662s, 1457m, 1387m,
1245m, 1207m, 1171m, 1108w, 1050m, 994w cmꢁ1
; UVevis
(methanol): lmax (log
d
3
)¼268 nm (3.97); 1H NMR (400 MHz, CDCl3):
¼5.56 (s, 1H, CH (12)), 4.49 (d, 1H, CH (3), 3J¼8.7 Hz), 3.76 (ddd, 1H,
CH2 (2), 3J¼7.1, 7.1, 8.7 Hz), 3.70 (s, 3H, CH3 (31)), 2.44 (s, 1H, CH (9)),
2.43 (dd, 1H, CH2 (1), 2J¼14.5 Hz, 3J¼7.1 Hz), 2.07 (ddd, 1H, CH2
(16a), 2J¼13.7 Hz, 3J¼5.0, 13.7 Hz), 1.85 (ddd, 1H, CH2 (15a),
2J¼13.7 Hz, 3J¼5.0, 13.7 Hz), 1.81 (dd, 1H, CH2 (1), 2J¼14.5 Hz,
3J¼7.1 Hz), 1.75 (m, 2H, CH2 (6)), 1.62 (ddd, 1H, CH2 (7a), 2J¼12.9 Hz,
3J¼3.7,12.9 Hz),1.52 (dd,1H, CH (18), 3J¼11.2 Hz, 4J¼1.2 Hz),1.48 (m,
1H, CH2 (22b)), 1.44 (m, 2H, CH2 (21)), 1.40 (m, 1H, CH2 (7b)), 1.38
(m, 1H, CH (19)), 1.32 (m, 1H, CH2 (22a)), 1.29 (dd, 1H, CH (5), 3J¼2.5,
9.1 Hz), 1.27 (s, 3H, CH3 (27)), 1.27 (s, 3H, CH3 (23)), 1.26 (s, 3H, CH3
(25)), 1.17 (m, 1H, CH2 (15b)), 1.11 (s, 3H, CH3 (26)), 0.99 (ddd, 1H,
CH2 (16b), 2J¼13.7 Hz, 3J¼2.5, 2.5 Hz), 0.92 (s, 3H, CH3 (30)), 0.90 (m,
1H, CH (20)), 0.80 (s, 3H, CH3 (28)), 0.77 (d, 3H, CH3 (29),
NMR (125 MHz, CDCl3):
d
¼199.1 (C-11), 176.2 (C-24), 165.2 (C-13),
130.5 (C-12),130.2 (C-3),124.6 (C-2), 59.9 (C-9), 59.1 (C-18), 53.2 (C-
5), 51.6 (C-31), 44.8 (C-4), 44.4 (C-8), 43.7 (C-14), 42.3 (C-1), 40.9 (C-
22), 39.4 (C-19), 39.2 (C-20), 35.6 (C-10), 34.0 (C-17), 32.2 (C-7),
30.9 (C-21), 28.8 (C-28), 27.9 (C-23), 27.5 (C-16), 27.1 (C-15), 21.1 (C-
30), 20.3 (C-27), 19.4 (C-6), 17.7 (C-26), 17.4 (C-29), 14.9 (C-25) ppm;
MS (ESI, methanol) C31H46O3: m/z¼467.5 ([MþH]þ, 90%), 520.8
([MþNaþMeOH]þ, 26%); analysis calcd for C31H46O3 (466.70): C,
79.78; H, 9.93; found: C, 79.62; H, 10.11.
3J¼6.2 Hz) ppm; 13C NMR (125 MHz, CDCl3):
¼198.5 (C-11), 177.1
d
(C-24), 165.4 (C-13), 130.2 (C-12), 73.0 (C-3), 69.1 (C-2), 62.1 (C-9),
59.0 (C-18), 51.9 (C-31), 51.2 (C-5), 49.2 (C-4), 47.3 (C-1), 44.8 (C-8),
43.7 (C-14), 40.9 (C-22), 39.3 (C-19), 39.2 (C-20), 36.7 (C-10), 33.9
(C-17), 32.3 (C-7), 30.9 (C-21), 28.8 (C-28), 27.4 (C-16), 27.1 (C-15),
21.2 (C-23), 21.1 (C-30), 20.5 (C-27), 20.0 (C-6), 19.8 (C-26), 18.0 (C-
29), 17.4 (C-25)ppm; MS (ESI, methanol) C31H48O5: m/z¼501.5
([MþH]þ, 72%), 523.4 ([MþNa]þ, 36%); analysis calcd forC31H48O5
(500.71): C, 74.36; H, 9.66; found: C, 74.17; H, 9.81.
4.10. (2
(11)
b,3a,4b) Methyl 2,3-epoxy-11-oxo-urs-12-en-24-oate
To a solution of 10 (186 mg, 0.4 mmol) in abs THF (30 mL), m-
CPBA (346 mg, 2.0 mmol) was added, and the mixture was stirred
for 12 h. Usual aqueous work-up followed by chromatography
(silica gel, hexane/EtOAc, 8:2) gave 11 (155 mg, 80%) as a colorless
4.12. (2
24-oate (13)
a,3a,4b) Methyl-3-bromo-2hydroxy-11-oxo-urs-12-en-
solid; mp¼230 ꢀC; Rf¼0.18 (hexane/EtOAc, 8:2); [
a]D 129.4 (c 4.26,
CHCl3); IR (KBr):
n
¼3457m, 2985m, 2969m, 2948m, 2930m,
To a solution of 10 (300 mg, 0.64 mmol) in 1,2-dimethoxyethane
(30 mL), NBS (231 mg, 1.30 mmol) and water (5.2 mL) were added,
and the mixture was stirred at 25 ꢀC for 12 h. The solvents were
removed under reduced pressure, and the residue was subjected to
chromatography (silica gel, hexane/EtOAc, 8:2/1:1) to yield 13
(350 mg, 97%) as a colorless solid; mp¼225e227 ꢀC; Rf¼0.66
2868m, 1738s, 1658s, 1615m, 1457m, 1431m, 1379m, 1353w, 1333m,
1319m, 1292w, 1261m, 1239m, 1221m, 1176m, 1119m, 1058w,
1006w, 989w cmꢁ1; UVevis (methanol): lmax (log
3
)¼269 nm
(4.07); 1H NMR (400 MHz, CDCl3):
d
¼5.54 (s, 1H, CH (12)), 3.68 (s,
3H, CH3 (31)), 3.41 (d, 1H, CH (3), 3J¼3.7 Hz), 3.27 (dd, 1H, CH (2),
3J¼3.7, 5.8 Hz), 2.99 (dd, 1H, CH2 (1b), 2J¼15.8 Hz, 3J¼5.8 Hz), 2.29
(s, 1H, CH (9)), 2.05 (ddd, 1H, CH2 (16a), 2J¼13.7 Hz, 3J¼5.0, 13.7 Hz),
1.83 (ddd, 1H, CH2 (15a), 2J¼13.7.3J¼5.0, 13.7 Hz), 1.79 (m, 1H, CH2
(6a)), 1.64 (m, 1H, CH2 (6b)), 1.60 (m, 1H, CH2 (7a)), 1.57 (m, 1H, CH2
(1a)), 1.55 (dd, 1H, CH (18), 3J¼11.2 Hz, 4J¼1.2 Hz), 1.48 (m, 1H, CH2
(22b)), 1.44 (m, 1H, CH2 (7b), 1H, CH2 (21b)), 1.40 (s, 3H, CH3 (23)),
1.39 (m, 1H, CH (19)), 1.36 (m, 1H, CH2 (22a)), 1.29 (dd, 1H, CH (5),
3J¼2.5, 10.8 Hz), 1.26 (m, 1H, CH2 (21a)), 1.23 (s, 3H, CH3 (27)), 1.18
(m, 1H, CH2 (15b)), 1.07 (s, 3H, CH3 (26)), 1.03 (s, 3H, CH3 (25)), 0.98
(ddd, 1H, CH2 (16b), 2J¼13.7 Hz, 3J¼2.1, 2.5 Hz), 0.92 (s, 3H, CH3
(30)), 0.91 (m, 1H, CH (20)), 0.79 (s, 3H, CH3 (28)), 0.76 (d, 3H, CH3
(hexane/EtOAc/HOAc, 70:30:1); [a]D 129.0 (c 5.04; CHCl3); IR (KBr):
n
¼3387s, 2976s, 2923m, 2870m, 2836m, 1810w, 1776m, 1733s,
1646s, 1612m, 1462m, 1431m, 1392m, 1382m, 1370m, 1359m,
1344m, 1326m, 1297m, 1265m, 1236s, 1178m, 1149m, 1133m,
1092m, 1052m, 1018m, 998m cmꢁ1; UVevis (methanol): lmax
(log
3
)¼269 nm (4.03); 1H NMR (400 MHz, CDCl3):
¼5.55 (s,1H, CH
d
(12)), 5.15 (d, 1H, CH (3), 3J¼7.9 Hz), 4.09 (m, 1H, CH2 (2)), 3.71 (s,
3H, CH3 (31)), 2.75 (dd, 1H, CH2 (1), 2J¼14.9 Hz, 3J¼5.4 Hz), 2.40 (s,
1H, CH (9)), 2.07 (ddd, 1H, CH2 (16a), 2J¼13.7 Hz, 3J¼5.0, 13.7 Hz),
1.86 (m, 1H, CH2 (1), 1H, CH2 (15a)), 1.70 (m, 1H, CH2 (6a)), 1.63 (m,
1H, CH2 (6b), 1H, CH2 (7a)), 1.53 (d, 1H, CH (18), 3J¼11.2 Hz), 1.48 (m,
1H, CH2 (22b)), 1.46 (m, 1H, CH (5), 1H, CH2 (21a)), 1.41 (s, 3H, CH3
(23)), 1.40 (m, 1H, CH2 (7b)), 1.38 (m, 1H, CH (19)), 1.33 (s, 3H, CH3
(26)), 1.30 (m, 1H, CH2 (22a)), 1.28 (s, 3H, CH3 (27)), 1.26 (m, 1H, CH2
(21b)), 1.17 (m, 1H, CH2 (15b)), 1.13 (s, 3H, CH3 (25)), 0.99 (ddd, 1H,
CH2 (16b), 2J¼13.7 Hz, 3J¼2.5, 2.5 Hz), 0.93 (m, 1H, CH (20)), 0.92 (s,
3H, CH3 (30)), 0.79 (s, 3H, CH3 (28)), 0.77 (d, 3H, CH3 (29),
(29), 3J¼6.6 Hz) ppm; 13C NMR (125 MHz, CDCl3):
¼199.8 (C-11),
d
175.8 (C-24), 165.5 (C-13), 130.4 (C-12), 60.4 (C-9), 59.1 (C-18), 57.9
(C-3), 52.8 (C-2), 51.7 (C-31), 47.1 (C-5), 44.7 (C-8), 43.7 (C-14), 43.7
(C-4), 40.9 (C-22), 40.6 (C-1), 39.4 (C-19), 39.2 (C-20), 35.0 (C-10),
34.0 (C-17), 32.1 (C-7), 30.9 (C-21), 28.8 (C-28), 27.4 (C-16), 27.1 (C-
15), 24.1 (C-23), 21.1 (C-30), 20.3 (C-27), 18.4 (C-6), 17.4 (C-26), 17.4
(C-29), 16.5 (C-25) ppm; MS (ESI, methanol) C31H46O4: m/z¼483.4
([MþH]þ, 58%), 505.4 ([MþNa]þ, 5%); analysis calcd for C31H46O4
(482.69): C, 77.14; H, 9.60; found: C, 76.85; H, 9.84.
3J¼6.2 Hz) ppm; 13C NMR (125 MHz, CDCl3):
¼198.3 (C-11), 175.2
d
(C-24), 165.1 (C-13), 130.2 (C-12), 70.0 (C-2), 64.3 (C-3), 61.8 (C-9),
58.9 (C-18), 52.1 (C-31), 51.9 (C-5), 48.9 (C-4), 45.3 (C-1), 44.8 (C-8),
43.7 (C-14), 40.8 (C-22), 39.2 (C-19), 39.2 (C-20), 36.8 (C-10), 33.9
(C-17), 32.4 (C-7), 30.8 (C-21), 28.8 (C-28), 27.4 (C-16), 27.2 (C-23),
27.1 (C-15), 21.1 (C-30), 20.5 (C-27), 20.0 (C-6), 18.1 (C-26), 17.4 (C-
25), 14.1 (C-29) ppm; MS (ESI, methanol) C31H47BrO4: m/z¼563.3
([M(79Br)þH]þ, 20%), 565.4 ([M(81Br)þH]þ, 22%), 585.3 ([M(79Br)þ
Na]þ, 40%), 587.3 ([M(81Br)þNa]þ, 48%); analysis calcd for
4.11. (2
a,3a,4b) Methyl 2,3-dihydroxy-11-oxo-urs-12-en-24-
oate (12)
A solution of 11 (201 mg, 0.4 mmol) in water (5 mL), trifluoro-
acetic acid (0.02 mL) in abs THF (10 mL) was heated under reflux for
26 h. Usual aqueous work-up followed by extraction with CHCl3
C31H47BrO4 (563.61): C, 66.06; H, 8.41; found: C, 65.88; H, 8.63.
Please cite this article in press as: Csuk, R.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.01.062

R. Csuk et al. / Tetrahedron xxx (2015) 1e10
7
4.13. (2
(14)
a
,3
b
,4
b
) Methyl 2,3-epoxy-11-oxo-urs-12-en-24-oate
33.9 (C-17), 32.3 (C-7), 30.8 (C-21), 28.8 (C-28), 27.4 (C-16), 27.2
(C-15), 26.8 (C-23), 21.1 (C-30), 20.5 (C-27), 18.6 (C-6), 17.8 (C-26),
17.4 (C-29), 15.5 (C-25) ppm; MS (ESI, methanol) C31H45BrO4: m/
z¼561.3 ([M(79Br)þH]þ, 68%), 563.3 ([M(81Br)þH]þ, 82%), 583.3
([M(79Br)þNa]þ, 26%), 585.3 ([M(81Br)þNa]þ, 32%); analysis calcd
forC31H45BrO4 (561.59): C, 66.30; H, 8.08; found: C, 66.01; H, 8.19.
A solution of 13 (400 mg, 0.71 mmol) and sodium meth-
anolate (767 mg, 14.2 mmol) in abs MeOH (20 mL) was stirred at
25 ꢀC for 15 h. Usual aqueous work-up followed by chromatog-
raphy (silica gel, hexane/EtOAc, 8:2) furnished 14 (310 mg, 91%)
as a colorless solid; mp¼218 ꢀC; Rf¼0.57 (hexane/EtOAc/HOAc,
4.15. (2
a,3a,4b) Methyl 2-Acetoxy-3-iodo-11-oxo-urs-12-en-
70:30:1); [
a
]
176.9 (c 4.94, CHCl3); IR (KBr):
n
¼3453m, 2973s,
24-oate (16)
D
2850m, 1737s, 1654s, 1619m, 1454m, 1382m, 1341m, 1324m,
1274w, 1235m, 1212m, 1191m, 1138m, 1102m, 1059w, 1015w,
To a solution of 10 (187 mg, 0.4 mmol) and AgOAc (186 mg,
1.12 mmol) in glacial acetic acid (10 mL), iodine (178 mg, 0.7 mmol)
987w cmꢁ1; UVevis (methanol): lmax (log
3
)¼225 nm (4.24); H
NMR (400 MHz, CDCl3):
d
¼5.54 (s, 1H, CH (12)), 3.68 (s, 3H, CH3
and water (150 mL) were added, and the mixture was stirred
(31)), 3.29 (dd, 1H, CH2 (1b), 2J¼15.8 Hz, 3J¼1.7 Hz), 3.21 (m, 1H,
CH (2)), 3.08 (d, 1H, CH (3), 3J¼3.7 Hz), 2.24 (s, 1H, CH (9)), 2.18
(ddd, 1H, CH2 (6a), 2J¼12.9 Hz, 3J¼3.3, 12.9 Hz), 2.05 (ddd, 1H, CH2
(16a), 2J¼13.7 Hz, 3J¼5.0, 13.7 Hz), 1.86 (ddd, 1H, CH2 (15a),
2J¼13.7, 3J¼5.0, 13.7 Hz), 1.66 (m, 1H, CH2 (6b)), 1.57 (m, 1H, CH2
(7a)), 1.52 (dd, 1H, CH (18), 3J¼11.2 Hz, 4J¼1.2 Hz), 1.48 (m, 1H, CH2
(22b)), 1.44 (s, 3H, CH3 (23)), 1.41 (m, 1H, CH2 (7b), 1H, CH2 (21b)),
1.38 (m, 1H, CH (19)), 1.30 (m, 1H, CH2 (21a), 1H, CH2 (22a)), 1.26
(m, 1H, CH2 (1a)), 1.24 (s, 6H, 2CH3 (25þ27)), 1.17 (s, 3H, CH3 (26)),
1.16 (m, 1H, CH2 (15b)), 0.98 (ddd, 1H, CH2 (16b), 2J¼13.7 Hz,
3J¼2.5, 2.5 Hz), 0.92 (m, 1H, CH (20)), 0.91 (s, 3H, CH3 (30)), 0.86
(dd, 1H, CH (5), 3J¼2.1, 12.0 Hz), 0.79 (s, 3H, CH3 (28)), 0.76 (d, 3H,
overnight at 90 ꢀC. The solid was filtered off, washed with CHCl3
(40 mL), and the combined solvents were distilled off under re-
duced pressure. The residue was subjected to chromatography
(silica gel, hexane/EtOAc, 8:2), and 16 (140 mg, 54%) was obtained
as an off-white, amorphous solid. Rf¼0.34 (hexane/EtOAc, 8:2); [
a]
D
102.2 (c 3.72, CHCl3); IR (KBr):
n
¼3446m, 2980m, 2925m, 2868m,
1742s, 1662s, 1616w, 1458m, 1382m, 1242s, 1175m, 1097m, 1020m,
989m cmꢁ1; UVevis (methanol): lmax (log
NMR (400 MHz, CDCl3):
3
)¼270 nm (4.09); 1H
d
¼5.54 (s, 1H, CH (12)), 5.39 (d, 1H, CH (3),
3J¼6.2 Hz), 5.16 (ddd, 1H, CH (2), 3J¼4.2, 6.2, 11.2 Hz), 3.67 (s, 1H,
CH3 (33)), 2.78 (dd, 1H, CH2 (1b), 2J¼15.4 Hz, 3J¼4.2 Hz), 2.42 (s, 1H,
CH (9)), 2.08 (ddd, 1H, CH2 (16a), 2J¼13.7 Hz, 3J¼5.0, 13.7 Hz), 2.02
(s, 3H, CH3 (32)), 2.01 (dd, 1H, CH2 (1a), 2J¼15.4 Hz, 3J¼6.2 Hz), 1.86
(ddd, 1H, CH2 (15a), 2J¼13.7 Hz, 3J¼5.0, 13.7 Hz), 1.70 (m, 2H, CH2
(6)), 1.65 (m, 1H, CH2 (7a)), 1.52 (dd, 1H, CH (18), 3J¼11.2 Hz,
4J¼1.2 Hz), 1.47 (dd, 1H, CH (5), 3J¼2.1, 12.5 Hz), 1.45 (m, 1H, CH2
(22b)), 1.43 (m, 1H, CH2 (21a)), 1.42 (s, 3H, CH3 (23)), 1.40 (m, 1H,
CH2 (7b)), 1.38 (m, 1H, CH (19)), 1.32 (s, 3H, CH3 (26)), 1.29 (s, 3H,
CH3 (27)), 1.28 (m, 1H, CH2 (22a)), 1.26 (m, 1H, CH2 (21b)), 1.17 (m,
1H, CH2 (15b)), 1.15 (s, 3H, CH3 (25)), 0.99 (ddd, 1H, CH2 (16b),
2J¼12.9 Hz, 3J¼2.1, 2.9 Hz), 0.92 (s, 3H, CH3 (30)), 0.91 (m, 1H, CH
(20)), 0.80 (s, 3H, CH3 (28)), 0.77 (d, 3H, CH3 (29), 3J¼6.6 Hz) ppm;
CH3 (29), 3J¼6.2 Hz) ppm; C NMR (125 MHz, CDCl3):
¼198.8 (C-
d
11), 174.9 (C-24), 165.1 (C-13), 130.8 (C-12), 61.6 (C-9), 58.9 (C-18),
57.3 (C-3), 54.1 (C-2), 53.1 (C-5), 51.6 (C-31), 45.1 (C-8), 44.3 (C-
14), 43.7 (C-4), 40.9 (C-22), 39.3 (C-19), 39.2 (C-20), 39.2 (C-1),
36.6 (C-10), 33.9 (C-17), 32.6 (C-7), 30.9 (C-21), 28.8 (C-28), 27.5
(C-16), 27.1 (C-15), 26.9 (C-23), 21.1 (C-30), 20.4 (C-27), 20.0 (C-
6), 17.9 (C-26), 17.4 (C-29), 17.2 (C-25) ppm; MS (ESI, methanol)
C
31H46O4: m/z¼483.5 ([MþH]þ, 35%), 505.5 ([MþNa]þ, 12%);
analysis calcd for C31H46O4 (482.69): C, 77.14; H, 9.60; found: C,
76.80; H, 9.71.
13C NMR (125 MHz, CDCl3):
d¼198.5 (C-11), 170.0 (C-24), 170.0 (C-
4.14. (3
(15)
a
,4b
) Methyl 3-bromo-2,11-dioxo-urs-12-en-24-oate
31),165.5 (C-13),130.2 (C-12), 73.1 (C-2), 61.6 (C-9), 59.0 (C-18), 51.9
(C33), 51.0 (C-5), 47.5 (C-4), 44.9 (C-8), 43.9 (C-14), 41.3 (C-3), 40.9
(C-22), 39.3 (C-19), 39.2 (C-20), 37.2 (C-10), 33.9 (C-1), 32.6 (C-7),
31.5 (C-17), 30.8 (C-21), 28.8 (C-28), 27.4 (C-16), 27.2 (C-15), 26.9 (C-
23), 21.2 (C-30), 21.1 (C32, CH3COO), 20.5 (C-27), 19.5 (C-6), 18.3
(C25þ26, 2CH3), 17.4 (C-29) ppm; MS (ESI, methanol) C33H49IO5: m/
z¼675.2 ([MþNa]þ, 100%); analysis calcd for C33H49IO5 (652.64): C,
60.73; H, 7.57; found: C, 60.42; H, 7.67.
To a solution of 13 (200 mg, 0.36 mmol) in ether (30 mL), a so-
lution of sodium dichromate dihydrate (108 mg, 0.36 mmol) in
water (2.2 mL) and concd sulfuric acid (1.2 mL) was added, and the
mixture was stirred for 2 h at 25 ꢀC. The phases were separated, and
the organic phase was concentrated under reduced pressure. The
residue was subjected to chromatography (silica gel, CHCl3/Et2O,
95:5) to yield 15(180 mg, 90%) as a colorless, amorphous solid;
4.16. (1a,4b,9a) Methyl 2,3-dihydro-1,9-peroxo-11-oxo-urs-
Rf¼0.40 (CHCl3/Et2O, 95:5); [
a
]
180.3 (c 4.78, CHCl3); IR (KBr):
12-en-24-oate (17)
D
n
¼3451w, 2982m, 2948m, 2912m, 2852m, 1737s, 1711m, 1660s,
1618m, 1457m, 1433m, 1388m, 1374m, 1356w, 1322m, 1302m,
1268m, 1230s,1210m,1197m,1158m, 1109m, 1058w,1046w,1009w,
To a solution of 10 (930 mg mg, 2.0 mmol) in acetone (100 mL),
N-hydroxyphthalimide (4.08 g, 25 mmol) and Na2Cr2O7$2H2O
(60 mg, 0.2 mmol) were added. Oxygen was slowly bubbled
through this reaction mixture at 40 ꢀC for 18 h. Usual aqueous
work-up followed by chromatography (silica gel, hexane/EtOAc,
4:1) gave 17 (820 mg, 82%) as a colorless amorphous solid. Rf¼0.10
992w cmꢁ1; UVevis (methanol): lmax (log
3
)¼270 nm (4.10); 1H
NMR (400 MHz, CDCl3):
d
¼5.55 (s, 1H, CH (12)), 4.75 (d, 1H, CH (3),
4J¼1.7 Hz), 3.65 (s, 3H, CH3 (31)), 3.49 (dd, 1H, CH2 (1b), 2J¼14.9 Hz,
4J¼1.7 Hz), 3.49 (d, 1H, CH2 (1a), 2J¼14.9 Hz), 2.55 (s, 1H, CH (9)),
2.08 (ddd, 1H, CH2 (16a), 2J¼13.7 Hz, 3J¼5.0, 13.7 Hz), 1.93 (dd, 1H,
CH (5), 3J¼3.3,10.4 Hz),1.88 (m,1H, CH2 (15a)),1.82 (m, 2H, CH2 (6)),
1.72 (m, 1H, CH2 (7a)), 1.53 (dd, 1H, CH (18), 3J¼11.2 Hz, 4J¼1.2 Hz),
1.50 (m, 1H, CH2 (7b)), 1.48 (s, 3H, CH3 (23)), 1.46 (m, 1H, CH2 (22b)),
1.42 (m, 2H, CH2 (21)), 1.38 (m, 1H, CH (19)), 1.33 (s, 3H, CH3 (27)),
1.30 (m,1H, CH2 (22a)),1.22 (m,1H, CH2 (15b)),1.13 (s, 3H, CH3 (26)),
1.02 (s, 3H, CH3 (25)), 1.01 (m, 1H, CH2 (16b)), 0.95 (m, 1H, CH (20)),
0.93 (s, 3H, CH3 (30)), 0.80 (s, 3H, CH3 (28)), 0.77 (d, 3H, CH3 (29),
(hexane/EtOAc, 9:1); [
a]
65.6 (c 4.98, CHCl3); IR (KBr):
n
¼3435m,
D
2923s, 2858m, 1729s, 1675s, 1617m, 1458m, 1383m, 1262m, 1230m,
1207m, 1165m, 1128m, 1060m, 998w cmꢁ1; UVevis (methanol):
lmax (log
3
)¼270 nm (4.06); 1H NMR (400 MHz, CDCl3):
¼5.96 (d,
d
1H, CH (3), 3J¼10.0 Hz), 5.67 (s, 1H, CH (12)), 5.65 (dd, 1H, CH (2),
3J¼5.0, 10.0 Hz), 4.81 (d, 1H, CH (1), 3J¼5.0 Hz), 3.63 (s, 3H, CH3
(31)), 2.10 (ddd, 1H, CH2 (16a), 2J¼13.7 Hz, 3J¼5.0, 13.7 Hz), 2.05 (dd,
1H, CH (5), 3J¼2.1, 12.5 Hz), 1.99 (m, 2H, CH2 (6)), 1.94 (m, 1H, CH2
(7a)), 1.84 (ddd, 1H, CH2 (15a), 2J¼13.7 Hz, 3J¼5.0, 13.7 Hz), 1.56 (dd,
1H, CH (18), 3J¼10.8 Hz, 4J¼1.2 Hz), 1.47 (m, 1H, CH2 (22b)), 1.45 (m,
1H, CH (19)), 1.42 (m, 1H, CH2 (21a)), 1.40 (m, 1H, CH2 (7b)), 1.36 (s,
3H, CH3 (23)), 1.32 (s, 3H, CH3 (27)), 1.28 (m, 1H, CH2 (22a)), 1.27 (s,
3J¼6.2 Hz) ppm; 13C NMR (125 MHz, CDCl3):
¼202.1 (C-2), 197.8
d
(C-11), 173.1 (C-24), 165.6 (C-13), 130.1 (C-12), 59.7 (C-9), 59.0 (C-
18), 58.8 (C-3), 52.4 (C-31), 50.0 (C-1), 48.9 (C-5), 49.7 (C-4), 45.1 (C-
8), 43.8 (C-14), 40.8 (C-22), 40.6 (C-10), 39.3 (C-19), 39.2 (C-20),
Please cite this article in press as: Csuk, R.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.01.062

8
R. Csuk et al. / Tetrahedron xxx (2015) 1e10
3H, CH3 (25)), 1.26 (s, 3H, CH3 (26)), 1.24 (m, 1H, CH2 (21b)), 1.22 (m,
1H, CH2 (15b)), 0.96 (ddd, 1H, CH2 (16b), 2J¼13.7 Hz, 3J¼2.1, 2.7 Hz),
0.91 (s, 3H, CH3 (30)), 0.90 (m, 1H, CH (20)), 0.83 (d, 3H, CH3 (29),
3J¼6.2 Hz), 0.80 (s, 3H, CH3 (28)) ppm; 13C NMR (125 MHz, CDCl3):
1455m, 1429w, 1384m, 1372m, 1345m, 1305w, 1267m, 1232s,
1212m, 1179m, 1149m, 1129m, 1090w, 1053w, 1024w, 987w cmꢁ1
;
UVevis (methanol): lmax (log
3
)¼268 nm (4.12); 1H NMR (400 MHz,
CDCl3):
d
¼5.56 (s, 1H, CH (12)), 5.43 (d, 1H, CH (3), 3J¼9.3 Hz), 4.49
d¼193.5 (C-11), 175.6 (C-24), 166.3 (C-13), 137.0 (C-3), 127.8 (C-12),
(m, 1H, CH (2)), 3.71 (s, 3H, CH3 (31)), 3.30 (dd, 1H, CH2 (1a),
2J¼15.6 Hz, 3J¼5.9 Hz), 2.35 (s, 1H, CH (9)), 2.23 (dd, 1H, CH2 (1b),
2J¼15.6 Hz, 3J¼7.5 Hz), 2.07 (ddd, 1H, CH2 (16a), 2J¼13.7 Hz, 3J¼5.0,
13.7 Hz), 1.87 (ddd, 1H, CH2 (15a), 2J¼13.7 Hz, 3J¼5.0, 13.7 Hz), 1.65
(m, 2H, CH2 (6)), 1.60 (m, 1H, CH2 (7a)), 1.53 (d, 1H, CH (18),
3J¼11.0 Hz), 1.50 (m, 1H, CH (5)), 1.47 (m, 1H, CH2 (22a)), 1.45 (s, 3H,
CH3 (26)), 1.43 (s, 3H, CH3 (23)), 1.41 (m, 2H, CH2 (21)), 1.39 (m, 1H,
CH (19)), 1.38 (m, 1H, CH2 (7b)), 1.30 (m, 1H, CH2 (22b)), 1.27 (s, 3H,
CH3 (27)), 1.18 (m, 1H, CH2 (15b)), 1.14 (s, 3H, CH3 (25)), 0.99 (ddd,
1H, CH2 (16b), 2J¼13.7 Hz, 3J¼2.4, 2.4 Hz), 0.93 (s, 3H, CH3 (30)), 0.92
(m, 1H, CH (29)), 0.80 (s, 3H, CH3 (28)), 0.77 (d, 3H, CH3 (29),
120.4 (C-2), 90.2 (C-9), 80.1 (C-1), 60.6 (C-18), 54.3 (C-10), 51.9 (C-
31), 46.1 (C-8), 45.3 (C-5), 44.9 (C-4), 44.1 (C-14), 40.8 (C-22), 39.7
(C-19), 39.2 (C-20), 34.8 (C-17), 31.0 (C-21), 29.9 (C-7), 29.0 (C-28),
28.5 (C-15), 27.2 (C-16), 26.7 (C-23), 23.8 (C-27), 20.9 (C-30), 20.0
(C-26), 19.0 (C-6), 17.4 (C-29), 13.2 (C-25) ppm; MS (ESI, methanol)
C
31H44O5: m/z¼497.3 ([MþH]þ, 48%), 519.3 ([MþNa]þ, 78%); anal-
ysis calcd for C31H44O5 (496.68): C, 74.96; H, 8.93; found: C, 74.81;
H, 9.13.
4.17. (4b) Methyl 11-oxo-urs-12-en-24-oate (18)
3J¼6.4 Hz); 13C NMR (125 MHz, CDCl3):
¼198.0 (C-11), 173.3 (C-
d
A
solution of
5
(194 mg, 0.4 mmol) and 1,10-thio-
24), 165.6 (C-13), 130.1 (C-12), 61.9 (C-9), 61.9 (C-3), 59.0 (C-5þC-
18), 52.0 (C-31), 50.5 (C-2), 50.1 (C-1), 44.8 (C-4þC-8), 43.7 (C-14),
40.8 (C-22), 39.3 (C-19), 39.2 (C-20), 37.8 (C-10), 33.9 (C-17), 32.4
(C-7), 30.8 (C-21), 28.8 (C-28), 27.7 (C-23), 27.4 (C-16), 27.2 (C-15),
21.1 (C-30), 20.6 (C-27), 20.1 (C-6), 19.4 (C-26), 18.2 (C-25), 17.4
carbonyldiimidazole (716 mg, 4.0 mmol) in abs DCM (10 mL) was
heated under argon for 4 days under reflux. Aqueous work-up
(aq HCl, 1 N, 100 mL, CHCl3 extraction (3ꢂ50 mL)) gave a resi-
due that was dissolved in dry toluene (20 mL) and tri-n-butyltin
hydride (266 mg, 0.44 mL, 1.6 mmol) and AIBN (30 mg) were
added, and the mixture was stirred under reflux for 2 h. The
solvent was removed under reduced pressure, and the residue
was subjected to chromatography (silica gel, hexane/EtOAc, 9:1)
to afford 18 (149 mg, 79%) as a colorless solid; mp¼215 ꢀC; Rf¼0.26
(C-29) ppm; MS (ESI, methanol)
C
31H46Br2O3: m/z¼651.0
([M(2ꢂ81Br)þNa]þ, 21%), 649.1 ([M(81Br,79Br)þNa]þ, 36%), 647.2
([M(2ꢂ79Br)þNa]þ, 18%), 629.1 ([M(2ꢂ81Br)þH]þ, 7%), 627.1
([M(81Br,79Br)þH]þ, 11%), 625.2 ([M(2ꢂ79Br)þH]þ, 5%); analysis
calcd for C31H46Br2O3 (626.50): C, 59.43; H, 7.40; found: C, 59.25; H,
7.54.
(hexane/EtOAc, 9:1);
[
a
]
143.5 (c 4.24; CHCl3); IR (KBr):
D
n
¼3424m, 2976m, 2933s, 2853m, 1722s, 1667s, 1616m, 1453m,
1384m, 1334m, 1318w, 1303m, 1267m, 1236m, 1219m, 1195m,
4.19. (3
a
,4b
,11
a) Methyl 11-hydroxy-urs-12-en-24-oate (20)
1177m, 1153m, 1094m, 1058w, 1042m, 992m cmꢁ1; UVevis
and (3
a
,4b,11b
) methyl 11-hydroxy-urs-12-en-24-oate (21)
(methanol): lmax (log
CDCl3):
3
)¼269 nm (4.09); 1H NMR (400 MHz,
d
¼5.51 (s, 1H, CH (12)), 3.63 (s, 3H, CH3 (31)), 2.67 (br d,
To an ice-cold solution of 5 (400 mg, 0.83 mmol) in abs THF
(20 mL), the boraneeTHF complex (8.3 mL, 8.3 mmol, 1 M in THF)
was slowly added, and stirring at 25 ꢀC was continued for another
5 h. An aqueous solution of potassium carbonate (satd, 10 mL) and
water (10 mL) were added, and the mixture was extracted with
CHCl3 (3ꢂ50 mL). The solvent was removed under reduced pres-
sure, and the residue was subjected to chromatography (silica gel,
CHCl3/Et2O, 9:1/8:2) to yield 20 (260 mg, 64%) and 21 (90 mg,
22%).
1H, CH2 (1b), 3J¼13.3 Hz), 2.34 (s, 1H, CH (9)), 2.14 (br d, 1H, CH2
(3), 3J¼13.3 Hz), 2.06 (ddd, 1H, CH2 (16a), 2J¼13.7 Hz, 3J¼5.0,
13.7 Hz), 1.92 (m, 1H, CH2 (2)), 1.86 (ddd, 1H, CH2 (15a), 2J¼13.7 Hz,
3J¼5.0, 13.7 Hz), 1.82 (m, 1H, CH2 (6a)), 1.75 (m, 1H, CH2 (6b)), 1.61
(ddd, 1H, CH2 (7a), 2J¼12.5 Hz, 3J¼4.6, 12.5 Hz), 1.51 (d, 1H, CH (18),
3J¼11.2 Hz), 1.48 (m, 1H, CH2 (22b)), 1.45 (m, 1H, CH2 (7b), 1H, CH2
(21a)), 1.42 (m, 1H, CH2 (2)), 1.39 (m, 1H, CH (19)), 1.32 (m, 1H, CH2
(22a)), 1.28 (s, 3H, CH3 (27)), 1.26 (m, 1H, CH2 (21b)), 1.22 (m, 1H,
CH2 (15b)), 1.17 (s, 3H, CH3 (23)), 1.15 (s, 3H, CH3 (26)), 1.00 (s, 3H,
CH3 (25)), 1.02 (m, 1H, CH2 (3), 1H, CH2 (16b)), 0.95 (dd, 1H, CH (5),
3J¼2.9, 11.2 Hz), 0.92 (s, 3H, CH3 (30)), 0.91 (m, 1H, CH (20)), 0.88
(ddd, 1H, CH2 (1a), 2J¼13.2 Hz, 3J¼4.2, 13.2 Hz), 0.80 (s, 3H, CH3
(28)), 0.78 (d, 3H, CH3 (29), 3J¼6.6 Hz) ppm; 13C NMR (125 MHz,
4.19.1. Data for 20. Colorless solid; mp¼208 ꢀC; Rf¼0.12 (CHCl3/
Et2O, 9:1); [
a
]
D 128.6 (c 4.84, methanol); IR (KBr):
n
¼3606m, 3468s,
2974s, 2917s, 2862s, 1719s, 1454m, 1437m, 1409m, 1373m, 1285w,
1238m, 1202m, 1120m, 1056m, 1029m, 999m cmꢁ1; UVevis
CDCl3):
d
¼199.5 (C-11), 177.7 (C-24), 164.6 (C-13), 130.6 (C-12),
(methanol): lmax (log
3
)¼225 nm (4.36); 1H NMR (400 MHz, CDCl3):
60.5 (C-9), 59.0 (C-18), 56.9 (C-5), 51.2 (C-31), 45.1 (C-8), 43.7 (C-
14), 43.6 (C-4), 41.1 (C-1), 40.9 (C-22), 39.3 (C19. CH, C20), 37.9 (C-
3), 37.5 (C-10), 33.9 (C-17), 33.0 (C-7), 30.9 (C-21), 28.9 (C-28), 28.8
(C-23), 27.5 (C-16), 27.1 (C-15), 21.1 (C-30), 20.4 (C-27), 19.3 (C-6),
18.9 (C-2), 18.3 (C-26), 17.4 (C-29), 13.5 (C-25) ppm; MS (ESI,
methanol) C31H48O3: m/z¼469.5 ([MþH]þ, 36%), 491.4 ([MþNa]þ,
8%); analysis calcd forC31H48O3 (468.71): C, 79.44; H, 10.32; found:
C, 79.26; H, 10.31.
d
¼5.26 (d, 1H, CH (12), 3J¼4.6 Hz), 4.38 (dd, 1H, CH (11), 3J¼5.0,
5.0 Hz), 4.10 (dd, 1H, CH (3), 3J¼2.5, 3.7 Hz), 3.64 (s, 3H, CH3 (31)),
2.27 (m, 1H, CH2 (2a)), 1.99 (ddd, 1H, CH2 (16a), 2J¼13.7 Hz, 3J¼5.0,
13.7 Hz), 1.83 (ddd, 1H, CH2 (15a), 2J¼13.7.3J¼5.0, 13.7 Hz), 1.79 (m,
2H, CH2 (6)), 1.70 (m, 1H, CH2 (1b)), 1.60 (m, 1H, CH2 (2b)), 1.47 (d,
1H, CH (9), 3J¼5.0 Hz), 1.45 (m, 1H, CH2 (22b)), 1.42 (dd, 1H, CH (5),
3J¼2.1, 12.0 Hz), 1.40 (d, 1H, CH (18), 3J¼9.5 Hz), 1.39 (m, 1H, CH
(19)), 1.38 (m, 2H, CH2 (21)), 1.36 (m, 2H, CH2 (7)), 1.35 (m, 1H, CH2
(1a)), 1.30 (m, 1H, CH2 (22a)), 1.27 (s, 3H, CH3 (27)), 1.26 (s, 3H, CH3
(26)), 1.23 (s, 3H, CH3 (25)), 1.06 (ddd, 1H, CH2 (16b), 2J¼11.2 Hz,
3J¼2.1, 2.5 Hz), 1.03 (s, 3H, CH3 (23)), 1.00 (m, 1H, CH2 (15b)), 0.92
(m,1H, CH (20)), 0.90 (s, 3H, CH3 (30)), 0.82 (s, 3H, CH3 (28)), 0.76 (d,
4.18. (2
a,3a,4b) Methyl 2,3-dibromo-11-oxo-urs-12-en-24-
oate (19)
To a solution of 10 (186 mg, 0.4 mmol) in CHCl3 (10 mL) slowly
a solution of bromine (64 mg, 0.4 mmol) in CHCl3 (2 mL) was added,
and stirring at 25 ꢀC was continued for 2 days. The solvent was
removed under reduced pressure, and the residue was subjected to
chromatography (silica gel, hexane/EtOAc, 95:5) to afford 19
(203 mg, 81%) as a colorless solid; mp¼267 ꢀC; Rf¼0.45 (hexane/
3H, CH3 (29), 3J¼6.2 Hz) ppm; 13C NMR (125 MHz, CDCl3):
¼177.6
d
(C-24), 142.4 (C-13), 128.1 (C-12), 70.8 (C-3), 66.2 (C11), 58.8 (C-18),
51.9 (C-9), 51.2 (C-31), 50.1 (C-5), 47.1 (C-4), 42.9 (C-14), 41.4 (C-22),
39.8 (C-8), 39.6 (C-19), 39.5 (C-20), 38.6 (C-10), 34.0 (C-1), 33.7 (C-
17), 33.6 (C-7), 31.2 (C-21), 28.8 (C-28), 27.9 (C-16), 27.1 (C-15), 26.0
(C-2), 24.0 (C-27), 22.3 (C-23), 21.1 (C-30), 20.1 (C-6), 19.6 (C-26),
17.3 (C-29), 15.8 (C-25) ppm; MS (ESI, methanol) C31H50O4: m/
z¼469.3 ([MþHꢁH2O]þ, 100%), 509.3 ([MþNa]þ, 10%); analysis
EtOAc, 9:1); [
a
]
D 128.6 (c 5.04, CHCl3); IR (KBr):
n
¼3434m, 2968m,
2946m, 2922m, 2868m, 2852m, 1726s, 1649s, 1616w, 1473m,
Please cite this article in press as: Csuk, R.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.01.062

R. Csuk et al. / Tetrahedron xxx (2015) 1e10
9
calcd for C31H50O4 (486.73): C, 76.50; H, 10.35; found: C, 76.46; H,
10.52.
analysis calcd for C31H45BrO3 (545.59): C, 68.24; H, 8.31; found: C,
67.97; H, 8.44.
4.19.2. Data for 21. Colorless solid; mp¼193 ꢀC; Rf¼0.10 (CHCl3/
4.21. (1
24-oate (23)
a, 4b) Methyl 1-chloro-2,3-dihydro-11-oxo-urs-12-en-
Et2O, 8:2); [
a]
D 49.4 (c 4.34, methanol); IR (KBr):
n¼3554s, 3518m,
2918s, 2872m, 1710s, 1456m, 1435w, 1376m, 1325w, 1274w, 1238m,
1116w, 1085w, 1055m, 1031w, 1009w, 982w cmꢁ1; UVevis (meth-
Following the procedure given for 22, from 10 (186 mg,
0.4 mmol) and NCS (54 mg, 0.4 mmol), 23 (158 mg, 79%) was ob-
tained as a colorless amorphous solid; Rf¼0.23 (hexane/EtOAc, 9:1);
anol): lmax (log
d
3
)¼225 nm (4.37); 1H NMR (400 MHz, DMSO-d6):
¼5.05 (d,1H, CH (12), 3J¼2.5 Hz), 4.03 (m,1H, CH (11)), 3.80 (m,1H,
CH (3)), 3.31 (s, 3H, CH3 (31)), 2.04 (ddd, 1H, CH2 (1b), 2J¼13.3 Hz,
3J¼2.5, 2.5 Hz), 1.98 (m, 1H, CH2 (2a)), 1.91 (m, 1H, CH2 (16a)), 1.70
(m, 1H, CH2 (15a)), 1.60 (m, 2H, CH2 (6)), 1.55 (d, 1H, CH (9),
3J¼8.7 Hz), 1.47 (dd, 1H, CH (18), 3J¼11.2 Hz, 4J¼2.1 Hz), 1.44 (m, 1H,
CH2 (1a)), 1.36 (m, 1H, CH2 (7a), 1H, CH2 (22b)), 1.32 (m, 1H, CH2
(15b), 1H, CH2 (21a)), 1.30 (m, 1H, CH (19)), 1.26 (dd, 1H, CH (5),
3J¼2.1, 10.8 Hz), 1.24 (m, 1H, CH2 (7b), 1H, CH2 (21a), 1H, CH2 (22a)),
1.12 (s, 3H, CH3 (27)), 1.11 (s, 3H, CH3 (23)), 1.00 (s, 3H, CH3 (26)),
0.95 (m, 1H, CH2 (16b)), 0.89 (d, 3H, CH3 (30), 3J¼5.4 Hz), 0.83 (m,
1H, CH2 (2b)), 0.85 (d, 3H, CH3 (29), 3J¼5.8 Hz), 0.83 (m, 1H, CH
(20)), 0.81 (s, 3H, CH3 (25)), 0.76 (s, 3H, CH3 (28)) ppm; 13C NMR
[a
]
D 242.0 (c 4.80, CHCl3); IR (KBr):
n
¼3433w, 3046m, 2982s, 2948s,
2853m, 1727s, 1656s, 1616m, 1458m, 1382m, 1371m, 1350m, 1316m,
1303w, 1267m, 1216s, 1174m, 1140m, 1123m, 1109m, 1060w, 1026m,
990m cmꢁ1; UVevis (methanol): lmax (log
3
)¼269 nm (4.05); 1H
NMR (400 MHz, CDCl3):
d
¼5.87 (dd, 1H, CH (2), 3J¼5.8, 10.0 Hz),
5.68 (d, 1H, CH (3), 3J¼10.0 Hz), 5.57 (s, 1H, CH (12)), 5.42 (d, 1H, CH
(1), 3J¼5.8 Hz), 3.62 (s, 3H, CH3 (31)), 3.52 (s, 1H, CH (9)), 2.09 (ddd,
1H, CH2 (16a), 2J¼13.7 Hz, 3J¼5.0,13.7 Hz),1.93 (m,1H, CH (6a)),1.88
(ddd, 1H, CH2 (15a), 2J¼13.7 Hz, 3J¼5.0,13.7 Hz), 1.68 (dd, 1H, CH (5),
3J¼2.5, 12.5 Hz), 1.67 (ddd, 1H, CH2 (7a), 2J¼12.9 Hz, 3J¼3.7, 12.9 Hz),
1.57 (m, 1H, CH2 (6b)), 1.55 (dd, 1H, CH (18), 3J¼11.2 Hz, 4J¼1.2 Hz),
1.48 (m, 1H, CH2 (22b)), 1.44 (m, 1H, CH2 (7b), 2H, CH2 (21)), 1.39 (m,
1H, CH (19)), 1.32 (s, 3H, CH3 (27)), 1.32 (s, 3H, CH3 (23)), 1.30 (m, 1H,
CH2 (22a)), 1.21 (m, 1H, CH2 (15b)), 1.19 (s, 3H, CH3 (25)), 1.17 (s, 3H,
CH3 (26)), 1.00 (ddd, 1H, CH2 (16b), 2J¼13.3 Hz, 3J¼2.5, 2.5 Hz), 0.93
(s, 3H, CH3 (30)), 0.92 (m, 1H, CH (20)), 0.81 (s, 3H, CH3 (28)), 0.79
(d, 3H, CH3 (29), 3J¼6.2 Hz) ppm; 13C NMR (125 MHz, CDCl3):
(125 MHz, DMSO-d6):
d
¼177.5 (C-24), 134.0 (C-13), 130.8 (C-12),
68.6 (C-3), 66.5 (C11), 57.7 (C-5), 52.4 (C-9), 50.8 (C-31), 48.3 (C-18),
47.3 (C-4), 42.5 (C-14), 41.7 (C-8), 40.9 (C-22), 39.2 (C19, CH, C20),
38.0 (C-10), 35.5 (C-1), 33.7 (C-7), 33.3 (C-17), 30.6 (C-21), 28.4 (C-
28), 27.5 (C-2), 26.1 (C-16), 26.0 (C-15), 24.3 (C-27), 22.5 (C-23), 21.2
(C-30), 19.3 (C-6), 17.8 (C-26), 17.8 (C-29), 13.7 (C-25) ppm; MS (ESI,
methanol)
C
31H50O4: m/z¼469.5 ([MþHꢁH2O]þ, 100%), 509.3
d
¼199.0 (C-11), 175.2 (C-24), 165.7 (C-13), 132.5 (C-3), 130.2 (C-12),
([MþNa]þ, 38%); analysis calcd for C31H50O4 (486.73): C, 76.50; H,
125.5 (C-2), 65.6 (C-1), 59.1 (C-18), 53.5 (C-9), 51.8 (C-31), 45.6 (C-
5), 45.1 (C-4), 44.4 (C-8), 44.4 (C-14), 40.9 (C-22), 40.0 (C-10), 39.4
(C-19), 39.3 (C-20), 34.0 (C-17), 31.3 (C-7), 30.9 (C-21), 28.9 (C-28),
27.5 (C-16), 27.2 (C-15), 27.2 (C-23), 21.1 (C-30), 20.6 (C-27), 19.3 (C-
6), 17.7 (C-26), 17.5 (C-29), 15.2 (C-25) ppm; MS (ESI, methanol)
10.35; found: C, 76.39; H, 10.42.
4.20. (1
a,4b) Methyl 1-bromo-2,3-dihydro-11-oxo-urs-12-en-
24-oate (22)
C
31H45ClO3: m/z¼501.2 ([M(35Cl)þH]þ, 28%), 503.3 ([M(37Cl)þH]þ,
To a solution of 10 (186 mg, 0.4 mmol) in CCl4 (10 mL), NBS
(72 mg, 0.4 mmol) was added, and the mixture was warmed to
70 ꢀC, and catalytic amounts of AIBN were added. The mixture was
stirred at 70 ꢀC for 2 h, the precipitate was filtered off, and the
filtrate was evaporated under reduced pressure. The residue was
subjected to chromatography (silica gel, hexane/EtOAc, 95:5) to
afford 22 (345 mg, 83%) as a colorless solid; mp¼190e191 ꢀC;
10%), 523.2 ([M(35Cl)þNa]þ, 100%), 525.1 ([M(37Cl)þNa]þ, 35%);
analysis calcd for C31H45ClO3 (501.14): C, 74.30; H, 9.05; found: C,
74.11; H, 9.24.
4.22. (1
en-24-oate (24) and (1
11-oxo-urs-12-en-24-oate (25)
a
,4b
) Methyl 2,3-dihydro-1-methoxy-11-oxo-urs-12-
,4 ) methyl 2,3-dihydro-1-methoxy-
b
b
Rf¼0.37 (hexane/EtOAc 9:1); [
a] 320.3 (c 4.68, CHCl3); IR (KBr):
D
¼3433m, 3048w, 2972m, 2948s, 2924m, 2852m, 1727s, 1655s,
n
To a solution of 22 (165 mg, 0.3 mmol) in dry methanol (40 mL),
sodium methanolate (162 mg, 3.0 mmol) was added, and the
mixture was heated under reflux for 8 h. The solvent was removed
under reduced pressure, and the residue was subjected to chro-
matography (CHCl3) to yield 24 (64 mg, 43%) and 25 (68 mg, 46%).
1617w, 1458m, 1382m, 1370w, 1350w, 1316w, 1302w, 1267m,
1210m, 1171m, 1139m, 1122m, 1060w, 1026w, 989w cmꢁ1; UVevis
(methanol): lmax (log
d
3
)¼267 nm (4.01); 1H NMR (400 MHz, CDCl3):
¼5.97 (dd, 1H, CH (2), 3J¼5.8, 10.0 Hz), 5.74 (d, 1H, CH (1),
3J¼5.8 Hz), 5.60 (d,1H, CH (3), 3J¼10.0 Hz), 5.57 (s, 1H, CH (12)), 3.62
(s, 3H, CH3 (31)), 3.56 (s, 1H, CH (9)), 2.09 (ddd, 1H, CH2 (16a),
2J¼13.7 Hz, 3J¼5.0, 13.7 Hz), 1.92 (m, 1H, CH2 (6a)), 1.87 (ddd, 1H,
CH2 (15a), 2J¼13.7 Hz, 3J¼5.0, 13.7 Hz), 1.71 (dd, 1H, CH (5), 3J¼2.1,
12.5 Hz), 1.68 (ddd, 1H, CH2 (7a), 2J¼12.9 Hz, 3J¼3.7, 12.9 Hz), 1.57
(m, 1H, CH2 (6b)), 1.55 (dd, 1H, CH (18), 3J¼10.8 Hz, 4J¼1.2 Hz), 1.48
(m, 1H, CH (22b)), 1.43 (m, 1H, CH2 (7b), 2H, CH2 (21)), 1.39 (m, 1H,
CH (19)), 1.34 (s, 3H, CH3 (27)), 1.32 (s, 3H, CH3 (23)), 1.29 (m, 1H, CH
(22a)), 1.24 (m, 1H, CH2 (15b)), 1.23 (s, 3H, CH3 (25)), 1.16 (s, 3H, CH3
(26)), 1.02 (ddd, 1H, CH2 (16b), 2J¼13.7 Hz, 3J¼2.5, 2.5 Hz), 0.92 (s,
3H, CH3 (30)), 0.91 (m, 1H, CH (20)), 0.81 (s, 3H, CH3 (28)), 0.79 (d,
4.22.1. Data for 24. Colorless solid; mp¼191 ꢀC; Rf¼0.48 (CHCl3/
Et2O, 98:2); [
a
]
D
185.1 (c 9.70, CHCl3); IR (KBr):
n
¼3437m, 2926s,
2869m,1729s,1690m,1655s,1618m,1458m,1383m,1267m, 1215m,
1175m, 1122m, 1089m, 1043m, 990w cmꢁ1; UVevis (methanol):
lmax (log
3
)¼267 nm (4.05); 1H NMR (400 MHz, CDCl3):
¼5.92 (dd,
d
1H, CH (2), 3J¼5.4, 10.0 Hz), 5.76 (d, 1H, CH (3), 3J¼10.0 Hz), 5.56 (s,
1H, CH (12)), 4.16 (d, 1H, CH (1), 3J¼5.4 Hz), 3.61 (s, 3H, CH3 (31)),
3.45 (s, 1H, CH (9)), 3.27 (s, 3H, CH3 (32)), 2.08 (ddd, 1H, CH2 (16a),
2J¼13.7 Hz, 3J¼5.0, 13.7 Hz), 1.90 (m, 1H, CH2 (6a)), 1.87 (ddd, 1H,
CH2 (15a), 2J¼13.7 Hz, 3J¼5.0,13.7 Hz),1.63 (m,1H, CH2 (6b),1H, CH2
(7a)), 1.55 (dd, 1H, CH (18), 3J¼11.2 Hz, 4J¼1.2 Hz), 1.52 (dd, 1H, CH
(5), 3J¼2.1, 10.8 Hz), 1.48 (m, 1H, CH (22b)), 1.44 (m, 1H, CH2 (7b), 1H,
CH2 (21a)), 1.40 (m, 1H, CH (19)), 1.32 (m, 1H, CH (22a)), 1.30 (s, 3H,
CH3 (27)), 1.29 (s, 3H, CH3 (23)), 1.28 (m, 1H, CH2 (21b)), 1.20 (m, 1H,
CH2 (15b)), 1.17 (s, 3H, CH3 (26)), 1.04 (s, 3H, CH3 (25)), 1.00 (ddd, 1H,
CH2 (16b), 2J¼13.3 Hz, 3J¼2.5, 2.9 Hz), 0.95 (m, 1H, CH (20)), 0.93 (s,
3H, CH3 (30)), 0.82 (s, 3H, CH3 (28)), 0.79 (d, 3H, CH3 (29),
3H, CH3 (29), 3J¼6.6 Hz); 13C NMR (125 MHz, CDCl3):
¼198.9 (C-
d
11), 175.4 (C-24), 165.9 (C-13), 131.7 (C-3), 130.2 (C-12), 126.6 (C2,
CH]CH), 64.0 (C-1), 59.1 (C-18), 56.3 (C-9), 51.8 (C-31), 46.2 (C-5),
45.2 (C-4), 44.5 (C-8), 44.5 (C-14), 40.9 (C-22), 39.6 (C-10), 39.4 (C-
19), 39.2 (C-20), 33.9 (C-17), 31.3 (C-7), 30.9 (C-21), 28.9 (C-28), 27.5
(C-16), 27.2 (C-15), 27.0 (C-23), 21.1 (C-30), 20.8 (C-27), 19.4 (C-6),
17.6 (C-26), 17.5 (C-29), 14.1 (C-25) ppm; MS (ESI, methanol)
C
31H45BrO3: m/z¼569.1 ([M(81Br)þNa]þ, 100%), 567.1 ([M(79Br)þ
3J¼6.2 Hz) ppm; 13C NMR (125 MHz, CDCl3):
¼200.4 (C-11), 175.8
d
Na]þ, 90%), 547.2 ([M(81Br)þH]þ, 50%), 545.2 ([M(79Br)þH]þ, 45%);
(C-24),165.3 (C-13),133.6 (C-3),130.4 (C-12),123.5 (C-2), 78.4 (C-1),
Please cite this article in press as: Csuk, R.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.01.062

10
R. Csuk et al. / Tetrahedron xxx (2015) 1e10
11. Jauch, J. WO 2002085921 A2, 2002; Chem. Abstr. 2002, 137, 338024.
12. Abdel-Tawab, M.; Werz, O.; Schubert-Zsilavecz, M. Clin. Pharmacokinet. 2011, 50,
349e369.
13. Verhoff, M.; Seitz, S.; Paul, M.; Noha, S. M.; Jauch, J.; Schuster, D.; Werz, O. J. Nat.
Prod. 2014, 77, 1445e1451.
59.1 (C-18), 57.9 (C-32), 51.7 (C-31), 50.6 (C-9), 46.8 (C-5), 45.0 (C-
4), 44.3 (C-8), 44.1 (C-14), 40.9 (C-22), 39.8 (C-10), 39.3 (C-19), 39.2
(C-20), 34.0 (C-17), 31.7 (C-7), 30.9 (C-21), 28.9 (C-28), 27.5 (C-16),
27.4 (C-23), 27.2 (C-15), 21.1 (C-30), 20.5 (C-27), 19.2 (C-6), 18.1 (C-
26), 17.4 (C-29), 15.0 (C-25) ppm; MS (ESI, methanol) C32H48O4: m/
z¼497.3 ([MþH]þ, 18%), 519.5 ([MþNa]þ, 22%); analysis calcd for
14. Siemoneit, U.; Pergola, C.; Jazzar, B.; Northoff, H.; Skarke, C.; Jauch, J.; Werz, O.
Eur. J. Pharmacol. 2009, 606, 246e254.
15. Golbabaei, S.; Bazl, R.; Golestanian, S.; Nabati, F.; Omrany, Z. B.; Yousefi, B.;
Hajiaghaee, R.; Rezazadeh, S.; Amanlou, M. Daru-J. Pharm. Sci. 2013, 21.
16. Anthoni, C.; Laukoetter, M. G.; Rijcken, E.; Vowinkel, T.; Mennigen, R.; Muller,
S.; Senninger, N.; Russell, J.; Jauch, J.; Bergmann, J.; Granger, D. N.; Krieglstein,
C. F. Am. J. Physiol. Gastroint. Liver Physiol. 2006, 290, G1131eG1137.
17. Poeckel, D.; Tausch, L.; George, S.; Jauch, J.; Werz, O. J. Pharmacol. Exp. Ther.
2006, 316, 224e232.
18. Su, X. D.; Lawrence, H.; Ganeshapillai, D.; Cruttenden, A.; Purohit, A.; Reed, M.
J.; Vicker, N.; Potter, B. V. L. Bioorg. Med. Chem. 2004, 12, 4439e4457.
19. 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, 722e726.
20. Meng, Y. Q.; Zhao, L. X.; Wang, Z.; Liu, D.; Jing, Y. K. Chin. Chem. Lett. 2005, 16,
867e870.
21. Shah, B. A.; Kumar, A.; Gupta, P.; Sharma, M.; Sethi, V. K.; Saxena, A. K.; Singh, J.;
Qazi, G. N.; Taneja, S. C. Bioorg. Med. Chem. Lett. 2007, 17, 6411e6416.
22. Xu, P. F.; Chen, Y. S.; Lin, S. I.; Lu, T. J. J. Org. Chem. 2002, 67, 2309e2314.
23. Reich, H. J. Acc. Chem. Res. 1979, 12, 22e30.
C
32H48O4 (496.72): C, 77.38; H, 9.74; found: C, 77.19; H, 9.83.
4.22.2. Data for 25. Colorless solid; mp¼164 ꢀC; Rf¼0.43 (CHCl3/
Et2O, 98:2); [
a
]
54.4 (c 3.82, CHCl3); IR (KBr):
n
¼3434m, 2926s,
D
1729s, 1664s, 1616w, 1458m, 1384m, 1313w, 1231m, 1209m, 1171m,
1138m, 1122m, 1089m, 990w cmꢁ1; UVevis (methanol): lmax
(log
3
)¼269 nm (4.07); 1H NMR (400 MHz, CDCl3):
¼6.78 (d, 1H,
d
CH (3), 3J¼10.4 Hz), 5.77 (dd, 1H, CH (2), 3J¼4.6, 10.4 Hz), 5.54 (s, 1H,
CH (12)), 3.85 (d, 1H, CH (1), 3J¼4.6 Hz), 3.61 (s, 3H, CH3 (31)), 3.39
(s, 3H, CH3 (32)), 2.53 (s, 1H, CH (9)), 2.07 (ddd, 1H, CH2 (16a),
2J¼13.7 Hz, 3J¼5.0, 13.7 Hz), 1.87 (ddd, 1H, CH2 (15a), 2J¼13.7 Hz,
3J¼5.0,13.7 Hz),1.82 (m, 1H, CH2 (6a)), 1.69 (m, 1H, CH2 (7a), 1H, CH2
(6b)), 1.52 (dd, 1H, CH (18), 3J¼11.2 Hz, 4J¼1.7 Hz), 1.48 (dd, 1H, CH
(5), 3J¼2.9,10.0 Hz),1.44 (m,1H, CH (22b)),1.42 (m,1H, CH2 (7b),1H,
CH2 (21a)), 1.36 (m, 1H, CH (19)), 1.32 (m, 1H, CH (22a)), 1.29 (m, 1H,
CH2 (21b)), 1.27 (s, 6H, 2CH3 (23þ27)), 1.18 (m, 1H, CH2 (15b)), 1.15
(s, 3H, CH3 (26)), 1.08 (s, 3H, CH3 (25)), 0.99 (ddd, 1H, CH2 (16b),
2J¼13.7 Hz, 3J¼2.5, 2.5 Hz), 0.92 (s, 3H, CH3 (30)), 0.90 (m, 1H, CH
(20)), 0.80 (s, 3H, CH3 (28)), 0.75 (d, 3H, CH3 (29), 3J¼6.2 Hz) ppm;
24. Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc. 1975, 97, 5434e5447.
25. Tidgewell, K.; Harding, W. W.; Lozama, A.; Cobb, H.; Shah, K.; Kannan, P.;
Dersch, C. M.; Parrish, D.; Deschamps, J. R.; Rothman, R. B.; Prisinzano, T. E. J.
Nat. Prod. 2006, 69, 914e918.
26. Constantino, M. G.; Beltrame, M.; daSilva, G. V. J. Synth. Commun. 1996, 26,
321e329.
27. Ngatcha, B. T.; Luu-The, V.; Labrie, F.; Poirier, D. J. Med. Chem. 2005, 48,
5257e5268.
28. Sun, I. C.; Wang, H. K.; Kashiwada, Y.; Shen, J. K.; Cosentino, L. M.; Chen, C. H.;
Yang, L. M.; Lee, K. H. J. Med. Chem. 1998, 41, 4648e4657.
29. Khripach, V. A.; Zhabinskii, V. N.; Konstantinova, O. V.; Antonchick, A. P.;
Schneider, B. Steroids 2002, 67, 587e595.
13C NMR (125 MHz, CDCl3):
d
¼199.1 (C-11), 177.0 (C-24), 165.4 (C-
13), 141.5 (C-3), 130.1 (C-12), 121.2 (C-2), 77.3 (C-1), 59.1 (C-18), 58.2
(C32), 56.8 (C-9), 51.4 (C-31), 48.2 (C-5), 47.4 (C-4), 45.1 (C-8), 43.9
(C-14), 40.9 (C-22), 39.3 (C-19), 39.2 (C-20), 38.6 (C-10), 33.9 (C-17),
32.9 (C-7), 30.9 (C-21), 28.8 (C-28), 27.5 (C-16), 27.2 (C-15), 21.8 (C-
23), 21.1 (C-30), 20.6 (C-27), 18.9 (C-26), 18.1 (C-6), 17.3 (C-29), 16.3
(C-25) ppm; MS (ESI, methanol) C32H48O4: m/z¼497.4 ([MþH]þ,
65%), 519.5 ([MþNa]þ, 15%); analysis calcd for C32H48O4 (496.72): C,
77.38; H, 9.74; found: C, 77.21; H, 9.95.
30. Poza, J.; Rega, M.; Paz, V.; Alonso, B.; Rodriguez, J.; Salvador, N.; Fernandez, A.;
Jimenez, C. Biioorg. Med. Chem. 2007, 15, 4722e4740.
31. Sanchez-Abella, L.; Fernandez, S.; Armesto, N.; Ferrero, M.; Gotor, V. J. Org.
Chem. 2006, 71, 5396e5399.
32. Fuerst, A.; Plattner, P. A. Helv. Chim. Acta 1949, 32, 275e283.
33. Brosa, C.; Nusimovich, S.; Peracaula, R. Steroids 1994, 59, 463e467.
34. Csuk, R.; Niesen-Barthel, A.; Barthel, A.; Kluge, R.; Strohl, D. Eur. J. Med. Chem.
2010, 45, 3840e3843.
35. Iwahama, T.; Yoshino, Y.; Keitoku, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2000,
65, 6502e6507.
36. Robertson, J.; Pillai, J.; Lush, R. K. Chem. Soc. Rev. 2001, 30, 94e103.
37. Maillard, B.; Ingold, K. U.; Scaiano, J. C. J. Am. Chem. Soc. 1983, 105, 5095e5099.
38. Marchaj, A.; Kelley, D. G.; Bakac, A.; Espenson, J. H. J. Phys. Chem. 1991, 95,
4440e4441.
39. Bravo, A.; Bjorsvik, H. R.; Fontana, F.; Liguori, L.; Minisci, F. J. Org. Chem. 1997, 62,
3849e3857.
40. Schweitzer-Chaput, B.; Demaerel, J.; Engler, H.; Klussmann, M. Angew. Chem.,
Int. Ed. 2014, 53, 8737e8740.
41. Terent’ev, A. O.; Borisov, D. A.; Yaremenko, I. A.; Chernyshev, V. V.; Nikishin, G. I.
J. Org. Chem. 2010, 75, 5065e5071.
Acknowledgements
Thanks are due to Mrs. Ute Lammel for measuring the IR and
UVevis spectra. Support by the Grunderwerkstatt-Bio-
wissenschaften is gratefully acknowledged. The authors would like
to thank The Oman Research Council (TRC) for the generous sup-
port through the project ORG/CBS/10/002.
€
42. Terent’ev, A. O.; Borisov, D. A.; Vil’, V. A.; Dembitsky, V. M. Beilstein J. Org. Chem.
2014, 10, 34e114.
43. Niesen, A.; Barthel, A.; Kluge, R.; Kowitzsch, A.; Strohl, D.; Schwarz, S.; Csuk, R.
References and notes
€
€
1. Leutzsch, M.; Roth, A.; Steinke, K.; Sicker, D.; Siehl, H. U.; Schmid, M.; Zeller, K.
P.; Berger, S. Chem. Unserer Zeit 2013, 47, 344e354.
2. Shen, T.; Lou, H.-X. Chem. Biodivers. 2008, 5, 540e553.
3. Paul, M.; Bruning, G.; Weihrather, J.; Jauch, J. Chromatographia 2011, 74, 29e40.
4. Baer, J. E. PhD Thesis, Experimenta chemica cum gummiresinis nonnullis instituta
Erlangen, 1788.
5. Tschirch, A.; Halbey, O. Schweiz. Wchschr. Pharm. 1898, 36, 466e476.
6. Tschirch, A.; Halbey, O. Arch. Pharm. 1898, 236, 487e503.
7. Winterstein, A.; Stein, G. Z. Physiol. Chem. 1932, 208, 9e25.
8. Shao, Y.; Ho, C. T.; Chin, C. K.; Badmaev, V.; Ma, W.; Huang, M. T. Planta Med.
1998, 64, 328e331.
Arch. Pharm. 2009, 342, 569e576.
44. Chochrek, P.; Wicha, J. J. Org. Chem. 2007, 72, 5276e5284.
45. Ribeiro, N.; Streiff, S.; Heissler, D.; Elhabiri, M.; Albrecht-Gary, A. M.; Atsumi,
M.; Gotoh, M.; Desaubry, L.; Nakatani, Y.; Ourisson, G. Tetrahedron 2007, 63,
3395e3407.
46. Zimmerman, H. E.; Suryanarayan, V. Eur. J. Org. Chem. 2007, 4091e4102.
47. Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions; VCH:
Weinheim, Germany, 1996.
48. Schweizer, S.; von Brocke, A. F. W.; Boden, S. E.; Bayer, E.; Ammon, H. P. T.;
Safayhi, H. J. Nat. Prod. 2000, 63, 1058e1061.
49. Badria, F. A.; Mikhaeil, B. R.; Maatooq, G. T.; Amer, M. M. A. Z. Naturforsch., C
2003, 58, 505e516.
9. Chevrier, M. R.; Ryan, A. E.; Lee, D. Y. W.; Ma, Z. Z.; Zhang, W. Y.; Via, C. S. Clin.
Diagn. Lab. Immunol. 2005, 12, 575e580.
10. Jauch, J.; Bergmann, J. Eur. J. Org. Chem. 2003, 4752e4756.
Please cite this article in press as: Csuk, R.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.01.062