Oxidative transformations of betulinol

Article abstract of DOI:10.1016/j.tet.2008.07.042

Starting from commercially available betulinol by a combination of several selective oxidation procedures betutinal, betulinic acid, betulonal as well as betulonic acid were obtained in high yields on a multi-gram scale.

Full text of DOI:10.1016/j.tet.2008.07.042

Tetrahedron 64 (2008) 9225–9229
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Oxidative transformations of betulinol
*
´
Alexander Barthel, Sebastian Stark, Rene Csuk
Bereich Organische Chemie, Martin-Luther-Universita¨t Halle-Wittenberg, Kurt-Mothes-.St. 2, D-06120 Halle (Saale), Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 June 2008
Received in revised form 11 July 2008
Accepted 13 July 2008
Available online 17 July 2008
Starting from commercially available betulinol by a combination of several selective oxidation pro-
cedures betutinal, betulinic acid, betulonal as well as betulonic acid were obtained in high yields on
a multi-gram scale.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Betulinol
Betulinic acid
Betulinal
Betulonal
Betulonic acid
Oxidation
1. Introduction
we became interested in the development of robust but selective
oxidation procedures allowing the conversion of 1 into 2 and/or
Quite recently, several derivatives of triterpene derived com-
pounds have gained significant interest in medicinal chemistry1–5
due to their pharmaceutical activities. Of special interest are de-
rivatives of betulinol (1) with a special focus on betulinic acid (2)
since several of these compounds have shown quite promising
results in the therapy of a variety of malignous cell lines in vivo;
triterpenoic aldehyde or ketone derived compounds were reported
to possess antimelanoma as well as anti-HIV activity.6–10
into 3. As far as the oxidation of 1 to 3 is concerned, the scaling up of
our 4-acetamido-TEMPO/NaOCl2/NaOCl25 procedure proceeded
smoothly and allowed the synthesis of 3 in isolated yields >80%. In
addition, 3 can be obtained from 1 by oxidation using DMSO/oxalyl
chloride in 94% yield; up-scaling of this reaction into >100 g scale
was easily performed.
As an alternative, a two-step synthesis26,27 can be performed
consisting of a trimethylsilyl-protection of 1 yielding the bis-tri-
methylsilyloxy compound28 4 in quantitative yield followed by
a Swern-oxidation using a work-up under acidic conditions to af-
ford 3 in excellent yields.
2. Results and discussion
Either 1 or betulinal 3 is ideal starting material for the synthesis
of 2; since yields for the direct conversion of 1 into 2 dropped
slightly upon scaling up our 4-acetamido-TEMPO/NaOCl2/NaOCl
procedure, a different approach starting from 3 was investigated in
more detail. Whereas the oxidation of 3 to 2 with activated MnO2
Whereas 1 is easily accessible by extraction from natural sour-
ces11 in a very economic way, the isolation of 2 from plant material
is rather laborious and yields material of lower purity needing12–14
either further tedious chromatographic purification or exhaustive
re-crystallization at low temperatures. Usual literature known
procedures accessing 2 starting from 1 use protection–oxidation–
deprotection schemes or sequences using exhaustive oxidation
followed by partial reduction.15–21 The number of direct synthe-
ses16,22 of 2 from 1 is rather limited. Recently, we23 could demon-
strate that a TEMPO/NaClO2/NaOCl24 mediated oxidation of 1 either
leads to 2 or to betulinal (3). These methods work quite well and
result in high yields on a laboratory scale but we observed in-
complete reactions during the synthesis of 2 upon scaling up. Thus,
31
afforded only 18% of 2, the oxidation29,30 of 3 with NaMnO4
proceeded very smoothly and gave 2 in 85% isolated yield. Similar
high yields were obtained for the AgNO3-mediated oxidation of 3 to
2 as well as for the MnSO4/AgNO3/ammonium peroxodisulfate
route (Scheme 1).
The oxidation of 1 to betulonic acid (5) using the well established
Jones-oxidation32,33 utilizing CrO3/H2SO4 invariably gave lower
yields as reported in several15,34,35 patents. Many affords in opti-
mizing this reaction were undertaken and finally we could success
in obtaining reasonably high yields. However, higher yields of 5
were obtained when starting from betulonal (6) using a two-step
sequence. Betulonal (6) was obtained in >90% yield from 1 either by
* Corresponding author. Tel.: þ49 345 5525660; fax: þ49 345 5527030.
E-mail address: rene.csuk@chemie.uni-halle.de (R. Csuk).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.042

9226
A. Barthel et al. / Tetrahedron 64 (2008) 9225–9229
Scheme 1. Synthesis of betulinal, betulinic acid, betulonal, and betulonic acid from betulinol.
a Swern-type oxidation or with slightly diminished yields from
a Jones-oxidation of 1 (thus yielding 6 in about 75% yield on a multi-
gram scale). Oxidation of 1 using the IBX/HYP protocol36 gave only
5% of 5 whereas the oxidation of 6 using 2-methyl-2-butene/tert-
BuOH/sodium chlorite (procedure A)37 gave reasonably high yields
of 5; similar high yields of 5 were obtained for the permanganate
oxidation (procedure B) of 6; for both procedures yields between 70
and 75% were obtained also for scaling up into the 100 g scale.
In summary, by a combination of several selective oxidation
procedures starting from betulinol, betulinic or betulonic acid as
well as betulinal or betulonal can be accessed very easily even on
a multi-gram scale.
aq NaOH (2 N). After extraction with butylacetate (7ꢁ100 ml) the
phases were separated, the organic phase was washed (water,
brine) and dried (Na2SO4), the solvents were evaporated, and crude
2 was re-crystallized from ethanol to afford pure 2 (37.1 g, 72%,
purity >98% by HPLC).
3.2.2. From betulinal (3) by NaMnO4 oxidation
To a solution of 3 (40 g, 0.09 mol) in tert-BuOH (800 ml),
dichloromethane (200 ml), and aq NaH2PO4 (1000 ml, 1.25 M) at
25 ꢀC, an aq solution of NaMnO4 (400 ml, 1 M) was added and the
reaction mixture was stirred for 3 h. Extractive work-up with ethyl
acetate (5ꢁ200 ml) followed by evaporation of the solvent fur-
nished crude material that was either purified by crystallization
from ethanol or by chromatography (silica gel, hexanes/ethyl ace-
tate 4:1) to afford pure 2 (34 g, 85%, purity >98% by HPLC).
3. Experimental
3.1. General
3.2.3. From betulinal (3) by MnSO4/AgNO3 oxidation
To a solution of MnSO4 (0.7 g, 10 mol %) and AgNO3 (0.3 g) in
water (1000 ml), ammonium peroxodisulfate (140 g, 0.6 mol) was
added; after stirring for several minutes the reaction mixture
turned to magenta and a solution of 3 (20 g, 45 mmol) in tert-BuOH
(300 ml) and dichloromethane (100 ml) was added. Stirring at
25 ꢀC was continued for another 24 h followed by extractive work-
up with ethyl acetate (5ꢁ200 ml) and chromatography (silica gel,
toluene/ethyl acetate 4:1) to yield 2 (17 g, 85%, purity >98% by
HPLC) as a white solid.
Melting points are uncorrected (Leica hot stage microscope),
optical rotations were obtained using a Perkin–Elmer 341 polar-
imeter (1 cm microcell), NMR spectra were recorded using the
Varian spectrometers Gemini 200, Gemini 2000 or Unity 500 (
d
given in ppm, J in Hz, internal Me4Si), IR spectra (film or KBr pellet)
on a Perkin–Elmer FT-IR spectrometer Spectrum 1000, and MS
spectra were taken on an Intectra GmbH AMD 402 (electron impact,
70 eV) or on a Finnigan MAT TSQ 7000 (electrospray, voltage 4.5 kV,
sheath gas nitrogen) instrument. TLC was performed on silica gel
(Merck 5554, detection by UV absorption). The solvents were dried
according to usual procedures.
3.2.4. From betulinal (3) by MnO2 oxidation
A mixture of 3 (1.0 g, 2.4 mmol) and activated MnO2 (2.0 g,
24 mmol) in xylene (200 ml) was heated under reflux for 24 h. The
filtrate was evaporated and the residue subjected to chromatog-
raphy (silica gel, toluene/ethyl acetate 4:1) to afford 2 (0.2 g, 18%,
purity >98% by HPLC) as a colorless solid.
3.2. Synthesis of betulinic acid (2)
3.2.1. From betulinol (1) by 4-acetamido-TEMPO mediated
oxidation
An analytical sample of 2 showed: mp 313–315 ꢀC (lit.: 316–
To a 50 ꢀC warm mixture of butylacetate (1000 ml) and aq
phosphate buffer (0.67 M, pH 7.6, 450 ml) containing 1 (50.0 g,
0.11 mol), 4-acetamido-TEMPO (1.0 g, 8 mmol), Bu4NBr$H2O (1.8 g,
5.5 mmol) and aq solutions of NaOCl2 (25%, 67.6 ml, 0.22 mol) and
NaOCl (12%, 0.1 ml, 2.5 mmol) were slowly added within 120 min.
Stirring at this temperature was continued and some additional
NaOCl (12%, 100 ml, 0.19 mol) was slowly added until TLC showed
the reaction to be complete. After cooling to room temperature,
water (500 ml) was added and the pH adjusted to 8 by addition of
25
318,38–40
[
a
]
D
þ9.5 (c 0.4, CHCl3)) [lit.: [
a
]
þ9 (c 0.36, CHCl3),23
D
[a
]D: þ5 (CHCl3)27].
3.3. Synthesis of betulinal (3)
3.3.1. From betulinol (1) by TEMPO mediated oxidation
To a 30 ꢀC warm stirred mixture of dichloromethane (1000 ml)
and phosphate buffer (0.67 M, pH 6.8, 450 ml) containing betulinol

A. Barthel et al. / Tetrahedron 64 (2008) 9225–9229
9227
(1) (50 g, 113 mmol), TEMPO (1.25 g, 8 mmol) and Bu4NBr$H2O
(1.8 g, 5.5 mmol), aq solutions of NaClO2 (25%, 68 ml, 226 mmol)
and NaOCl (12%, 01 ml, 2.5 mmol) were added dropwise within
180 min and then additional aq NaOCl (180 ml, 34.7 mmol) was
slowly added. After completion of the reaction (as monitored by
TLC) and cooling to room temperature, water (500 ml) was added
and the pH adjusted to 8 by the addition of aq NaOH (2 N). The
reaction mixture was poured into ice cold water (1000 ml), the aq
phase was extracted (methyl-t.butyl-ether, 5ꢁ100 ml), and the
combined organic phases were washed (water, brine), dried
(Na2SO4), evaporated in vacuo to furnish crude 3 that was re-
crystallized from methanol to afford pure 3 (43.3 g, 87%) as white
crystals; mp 182–186 ꢀC.
þ19 (CHCl3)43); Rf¼0.48 (silica gel, hexanes/ethyl acetate, 8:2); IR
(KBr):
n
¼2942 s, 2868 m, 1726 m, 1642 w, 1604 w, 1451 m, 1388 m,
1376 m, 1300 w, 1188 w, 1106 w, 1083 w, 1044 m, 1012 m; UV–vis
(methanol): lmax (log
3
)¼214 nm (4.13); 1H NMR (500 MHz, CDCl3):
d¼9.65 (d, 1H, J¼1.7 Hz, CHO (28)), 4.74 (d, 1H, J¼2.1 Hz, CHa (30)),
4.61–4.60 (m, 1H, CHb (30)), 3.16 (dd, 1H, J¼11.2, 5.0 Hz, CHOH (3)),
2.84 (ddd, 1H, J¼11.2, 11.2, 5.8 Hz, CH (19)), 2.06 (dd, 1H, J¼9.1,
2.9 Hz, CHa (16)), 2.00 (ddd, 1H, J¼12.5, 12.5, 3.7 Hz, CH (13)), 1.90–
1.82 (m, 1H, CHa (21)), 1.77–1.70 (m, 3H, CH (18)þCHa (22)þCHa
(12)), 1.68 (s, 3H, CH3 (29)), 1.67–1.54 (m, 2H, CHa (1)þCH2 (2)),
1.53–1.29 (m, 9H, CH2 (6)þCHb (21)þCHa (15)þCHb (16)þCHa
(11)þCH2 (7)þCHb (22)), 1.27–1.13 (m, 3H, CH (9)þCHb (15)þCHb
(11)), 1.06–0.98 (m, 1H, CHb (12)), 0.96 (s, 3H, CH3 (27)), 0.95 (s, 3H,
CH3 (23)), 0.90 (s, 3H, CH3 (25)), 0.97–0.89 (m, 1H, CHb (1)), 0.80 (s,
3H, CH3 (26)), 0.74 (s, 3H, CH3 (24)), 0.65 (d, 1H, J¼10.0 Hz, CH (5));
3.3.2. From betulinol (1) via 4
To a solution of 1 (45.6 g, 0.1 mol) and imidazole (34.0 g,
0.5 mol) in dry dichloromethane (300 ml) at 0 ꢀC, chloro-
trimethylsilane (45.0 g, 0.4 mol) was slowly added and after com-
pletion of the addition stirring at 25 ꢀC was continued for another
180 min. After extraction with aq ammonium hydroxide (5%,
100 ml) and water (100 ml), the organic layers were dried (Na2SO4),
the solvents evaporated, and crude 4 (58 g, quant.) was obtained as
13C NMR (125 MHz, CDCl3):
d
¼206.8 (C28, C]O), 149.6 (C20,
C]CH2), 110.1 (C30, CH2]C), 79.0 (C3, CHOH), 59.4 (C17, Cquart.),
55.5 (C5, CH), 50.6 (C9, CH), 48.3 (C18, CH), 47.6 (C19, CH), 42.7 (C14,
Cquart.), 41.0 (C8, Cquart.), 38.9 (C4, Cquart.), 39.0 (C1, CH2), 38.8 (C13,
CH), 37.4 (C10, Cquart.), 34.5 (C7, CH2), 33.4 (C22, CH2), 30.1 (C16,
CH2), 29.4 (C21, CH2), 29.0 (C15, CH2), 28.1 (C23, CH3), 27.6 (C2, CH2),
25.7 (C12, CH2), 21.0 (C11, CH2), 19.2 (C293, CH), 18.5 (C6, CH2), 16.3
(C26, CH3), 16.1 (C25, CH3), 15.5 (C24, CH3), 14.5 (C27, CH3); MS (EI,
70 eV): m/z¼440 (32), 412 (27), 207 (75), 189 (100), 175 (43), 135
(60), 121 (53).
a colorless solid (that was directly used in the following step). An
25
analytical sample of 4 showed: mp 130 ꢀC (lit.:28 127–129 ꢀC); [
a]
D
16.5 (c 4.5, CHCl3); IR (KBr):
m, 1359 w, 1252 s, 1109 m, 1088 s, 1069 s; 1H NMR (400 MHz,
CDCl3):
¼4.65 (d,1H, J¼2.1 Hz, CHa (30)), 4.55 (dd,1H, J¼2.1, 1.2 Hz,
n
¼2954 s, 2869 m,1637 w,1456 m,1390
d
3.4. Betulonic acid (5)
CHb (30)), 3.64 (d, 1H, J¼9.5 Hz, CHa (28)), 3.20 (d, 1H, J¼9.5 Hz, CHb
(28)), 3.16 (dd, 1H, J¼11.6, 4.6 Hz, CH (3)), 2.37 (ddd, 1H, J¼11.5, 11.0,
6.8 Hz, CH (19)), 1.97–1.83 (m, 3H, J¼12.2, 12.2, 3.8 Hz, CHa
(16)þCHa (21)þCHa (22)), 1.68–1.52 (m, 4H, CH (13)þCHa (15)þCHa
(12)þCHa (1)), 1.66 (s, 3H, CH3 (29)), 1.52–1.31 (m, 9H, CH (18)þCH2
(6)þCH2 (2)þCHa (11)þCH2 (7)þCHb (21)), 1.27–1.06 (m, 9H, CH
(9)þCHb (11)þCHb (16)), 1.06–0.86 (m, 3H, CHb (15)þCHb (22)þCHb
(12)), 1.00 (s, 3H, CH3 (25)), 0.95 (s, 3H, CH3 (27)), 0.85 (s, 3H, CH3
(23)), 0.81 (s, 3H, CH3 (26)), 0.84–0.79 (m, 1H, CHb (1)), 0.71 (s, 3H,
CH3 (24)), 0.65 (d, 1H, J¼9.5 Hz, CH (5)), 0.09 (s, 9H, Si(CH3)3), 0.08
3.4.1. From 1 by Jones-oxidation
To a mixture of betulinol (1) (15 g, 33 mmol) in acetone (400 ml)
at 10 ꢀC Jones reagent [freshly prepared from CrO3 (37.5 g), sulfuric
acid (98%, 25 ml), and water (120 ml)] was added dropwise within
60 min. The mixture was stirred for 1 h at 25 ꢀC, then quenched by
the addition of methanol (300 ml) keeping the temperature <30 ꢀC.
The acetone was distilled off and the aq residue extracted with
ethyl acetate (4ꢁ250 ml). The combined organic phases were
washed (water, brine), dried (Na2SO4), the solvents were removed,
and the residue was subjected to chromatography (silica gel, hex-
anes/ethyl acetate 8:1) to afford 5 (8.4 g, 52%) as a white solid. The
content of trace amounts of chromium was below 5 ppm as de-
termined by ICP-MS.
(s, 9H, Si(CH3)3); 13C NMR (125 MHz, CDCl3):
d¼150.9 (C20,
C]CH2), 109.4 (C30, CH2]C), 79.6 (C3, CH), 60.0 (C28, CH2), 55.4
(C5, CH), 50.4 (C9, CH), 48.5 (C18, CH), 48.0 (C19, CH), 47.8 (C17,
Cquart.), 42.6 (C14, Cquart.), 40.9 (C8, Cquart.), 39.2 (C4, Cquart.), 38.8 (C1,
CH2), 37.3 (C13, CH), 37.1 (C10, Cquart.), 34.3 (C7, CH2), 34.2 (C22,
CH2), 29.9 (C21, CH2), 29.4 (C16, CH2), 28.4 (C23, CH3), 27.8 (C2,
CH2), 27.1 (C15, CH2), 25.3 (C12, CH2), 20.8 (C11, CH2), 19.1 (C29, CH),
18.5 (C6, CH2), 16.1 (C25, CH3), 15.9 (C26, CH3), 15.8 (C24, CH3), 14.7
(C27, CH3), 0.5 (Si(CH3)3), ꢂ0.5 (Si(CH3)3); 29Si (99 MHz, CDCl3):
3.4.2. From 6; procedure A
To a solution of 6 (20 g, 46 mmol) in tert-BuOH (200 ml) con-
taining 2-methyl-2-butene (10 ml, 94 mmol) a mixture of sodium
chlorite (5.0 g, 60 mmol), NaH2PO4 (7.0 g, 54 mmol) in water
(200 ml) was added and stirring at room temperature was con-
tinued for 24 h. An aq solution of NaOH (1 M, 320 ml) was added,
organic solvents were removed in vacuo, and the remaining aq
reaction mixture was extracted with dichloromethane (10ꢁ50 ml).
After drying (Na2SO4) and removal of the solvents, the residue was
subjected to chromatographic work-up (silica gel, hexanes/ethyl
acetate 4:1) and 5 (16 g, 76%) was obtained as a white solid.
d
¼16.5 (SiMe3), 14.2 (SiMe3); UV–vis (methanol): lmax
(log
)¼222 nm (4.20); MS (EI, 70 eV): m/z¼586 (14), 496 (100), 483
(81), 393 (41), 279 (18), 203 (61), 189 (56), 147 (44). Anal. Calcd for
3
C
36H66O2 (587.08): C, 73.65; H, 11.33. Found: C, 73.52; H, 11.57.
To a solution of oxalyl chloride (6.0 g, 47.1 mmol) in dry
dichloromethane (100 ml) at ꢂ78 ꢀC a solution of dry DMSO
(7.8 ml) in dry dichloromethane (100 ml) was slowly added and
stirring at ꢂ78 ꢀC was continued for another 30 min. Maintaining
this temperature a solution of 4 (25.0 g, 42.6 mmol) in dry
dichloromethane (50 ml) was slowly added and stirring at this
temperature was continued for another 180 min. Then dry tri-
ethylamine (14 ml) was added, stirring at ꢂ78 ꢀC continued for
another hour and then the reaction mixture was allowed to warm
to room temperature. Diluted aq HCl (10%, 100 ml) was added un-
der vigorous stirring, the phases were separated, the organic layer
was washed with aq Na2SO4 (2ꢁ50 ml), water (2ꢁ50 ml), and brine
(2ꢁ50 ml), the solvents were removed, and the residue was sub-
jected to chromatography (silica gel, toluene/ethyl acetate 4:1) to
afford 3 (14.1 g, 75%); mp 193 ꢀC; (lit.: 189–191;23 183–187;41 192–
3.4.3. From 6; procedure B
To an ice cold solution of 6 (17 g, 39 mmol) in 1,4-dioxane
(300 ml) and water (100 ml) an aq solution of KMnO4 (0.1 M,
390 ml) was added dropwise keeping the temperature <5 ꢀC. After
stirring for 2 h, the organic solvents were removed under di-
minished pressure and the aq phase was extracted with ethyl ac-
etate (10ꢁ50 ml). The solvent was removed and the residue
subjected to chromatography (silica gel, hexane/ethyl acetate 4:1)
to afford 5 (12 g, 70%) as a white solid; mp 245–247 ꢀC (lit.: 249–
25
25
250 ꢀC,44 258 ꢀC;45
[a
]
þ45 (c 0.51, CHCl3)) [lit.: [
a
]
þ40.1 (c
D
D
0.86, CHCl3)];46 Rf¼0.58 (silica gel, hexanes/ethyl acetate 8:2); IR
19342); [
a
]
25 17.3 (c 4.9, CHCl3) (lit.: [
a]
18.4 (c 0.4, CHCl3),23
[a]
(KBr):
n
¼2948 s, 2870 m, 1689 s, 1642 w, 1459 m, 1377 m, 1319 w,
D
D
D

9228
A. Barthel et al. / Tetrahedron 64 (2008) 9225–9229
1239 m, 1141 m, 1115 w; UV–vis (methanol): lmax (log
3
)¼218
Cquart.), 39.6 (C1, CH2), 38.7 (C13, CH), 36.9 (C10, Cquart.), 34.1 (C2,
CH2), 33.6 (C7, CH2), 33.1 (C16, CH2), 29.8 (C15, CH2), 29.1 (C21, CH2),
28.8 (C22, CH2), 26.6 (23, CH3), 25.5 (C12, CH2), 21.3 (C11, CH2), 21.0
(C24, CH3), 19.6 (C6, CH2), 19.0 (C29, CH3), 15.9 (C26, CH3), 15.7 (C25,
CH3), 14.2 (C27, CH3); MS (EI, 70 eV): m/z¼438 (49), 410 (87), 232
(46), 219 (65), 205 (100), 189 (93), 175 (67), 161 (48), 147 (51), 135
(57),121 (66),107 (63), 95 (58). Anal. Calcd for C30H46O2 (438.69): C,
82.14; H, 10.57. Found: C, 81.92; H, 10.63.
(3.90); 1H NMR (500 MHz, CDCl3):
d¼4.73 (d, 1H, J¼1.8 Hz, CHa
(30)), 4.60 (br s, 1H, CHb (30)), 3.00 (ddd, 1H, J¼10.7, 10.7, 4.9 Hz, CH
(19)), 2.51–2.36 (m, 2H, CH2 (2)), 2.27 (ddd, 1H, J¼13.1, 3.4, 3.1 Hz,
CHa (16)), 2.21 (ddd, 1H, J¼12.5, 11.9, 3.4 Hz, CH (13)), 2.04–1.95 (m,
2H, CHa (22)þCHa (21)), 1.89 (ddd, 1H, J¼12.5, 7.6, 4.6 Hz, CHa (1)),
1.74–1.67 (m, 1H, CHa (12)), 1.68 (s, 3H, CH3 (29)), 1.63 (dd, 1H,
J¼11.3 Hz, CH (18)), 1.57–1.24 (m, 13H, CHa (15)þCHb (22)þCH2
(6)þCH2 (11)þCH2 (7)þCHb (16)þCHb (21)þCHb (1)þCH (9)þCH
(5)), 1.21 (ddd, 1H, J¼13.8, 3.1 Hz, CHb (15)), 1.10–1.02 (m, 1H, CHb
(12)), 1.06 (s, 3H, CH3 (23)), 1.00 (s, 3H, CH3 (24)), 0.98 (s, 3H, CH3
(27)), 0.96 (s, 3H, CH3 (25)), 0.91 (s, 3H, CH3 (26)); 13C NMR
Acknowledgements
Our thanks are due to Dr. D. Stro¨hl and Dr. R. Kluge for numerous
NMR and MS spectra, Dr. R. Scha¨fer for helpful discussion and Mrs.
B. Niehus (CPI GmbH, Bitterfeld) for the measurement of ICP-MS.
This research was supported by the VFF Universita¨t Halle-
Wittenberg.
(125 MHz, CDCl3):
d
¼218.2 (C3, CO), 182.4 (C28, COOH), 150.3 (C20,
C]CH2), 109.7 (C30, C]CH2), 56.4 (C17, Cquart.), 54.9 (C5, CH), 49.8
(C9, CH), 49.2 (C18, CH), 47.3 (C4, Cquart.), 46.9 (C19, CH), 42.5 (C14,
Cquart.), 40.6 (C8, Cquart.), 39.6 (C1, CH2), 38.5 (C13, CH), 37.0 (C22,
CH2), 36.9 (C10, Cquart.), 34.1 (C2, CH2), 33.6 (C7, CH2), 32.1 (C16,
CH2), 30.5 (C21, CH2), 29.7 (C15, CH2), 26.6 (23, CH3), 25.5 (C12,
CH2), 21.4 (C11, CH2), 21.0 (C24, CH3), 19.6 (C6, CH2), 19.3 (C29, CH3),
15.9 (C26, CH3), 15.8 (C25, CH3), 14.6 (C27, CH3); MS (ESI, MeOH):
m/z¼453.5 (100% [MꢂH]ꢂ). Anal. Calcd for C30H46O3 (454.68): C,
79.25; H, 10.20. Found: C, 79.02; H, 10.36.
References and notes
1. Persona, M.; Geca, T.; Persona, A.; Richtr, V.; Kraitr, M. Pol. J. Chem. 2008, 82, 241.
2. Nitz, T. J.; Montalbetti, C.; Mears, R.; Gai, X.; Glen, E. PCT Int. Appl.
WO2008057420, 2008; Chem. Abstr. 2008, 585712.
3. Rajendran, P.; Jaggi, M.; Singh, M. K.; Mukherjee, R.; Burman, A. C. Invest. New
Drugs 2008, 26, 25.
4. Quian, K.; Nakagawa-Gote, K.; Yu, D.; Morris-Natschke, S. L.; Nitz, T. J.; Kilgore,
N.; Allaway, G. P.; Lee, K.-H. Bioorg. Med. Chem. Lett. 2007, 17, 6553.
5. Huang, L.; Yu, D.; Ho, P.; Lee, K.-H.; Chen, C.-H. Lett. Drug Design Discov. 2007,
4, 471.
3.5. Betulonal (6)
3.5.1. From 1 by Swern-oxidation
To a solution of oxalyl chloride (4.0 ml, 47 mmol) in dry
dichloromethane (25 ml), a solution of DMSO (6.8 ml, 96 mmol) in
dichloromethane (10 ml) was simultaneously added with a solution
of 1 (2.21 g, 10 mmol) in DMSO (15 ml)/dichloromethane (25 ml) at
ꢂ15 ꢀC. Dry triethylamine (28 ml) was added, stirring continued for
another 10 min, and the reaction mixture was then allowed to
warm to room temperature. After quenching the reaction by ad-
dition of water (50 ml) and extraction with dichloromethane
(50 ml), the combined organic phases were washed with brine
(100 ml) and dried (MgSO4), the solvents removed, and the residue
was purified by chromatography (silica gel, chloroform/methanol
10:1) to afford 6 (2.07 g, 93%) as an off-white solid.
6. Mukherjee, R.; Kumar, V.; Srivastava, S. K.; Agarwal, S. K.; Burman, A. C. Anti-
cancer Agents Med. Chem. 2006, 6, 271.
7. Bi, Y.; Xu, J.; Wu, X. Zhongguo Xinyao Zazhi 2005, 14, 23.
8. Tolstikova, T. G.; Sorokina, I. V.; Tolstikov, G. A.; Tolstiko, A. G.; Flekhter, O. B.
Russ. J. Bioorg. Chem. 2006, 32, 37.
9. Aiken, C.; Chen, C. H. Trends Mol. Med. 2005, 11, 31.
10. Yogeeswari, P.; Sriram, D. Curr. Med. Chem. 2005, 12, 657.
11. Ender, C.; Sauter, M. DE 10204278 C1, 2003; Chem. Abstr. 2003, 607453.
12. Galgon, T.; Ho¨ke, D.; Dra¨ger, B. Phytochem. Anal. 1999, 10, 187.
13. Ramadoss, S.; Siddiqui, M. J. M. PCT WO 2001064709, 2001; Chem. Abstr. 2001,
661451.
14. Dra¨ger, B.; Neubert, R.; Galgon, T.; Wohlrab, W. Ger Offen DE 19713768, 1998;
Chem. Abstr. 1998, 689287.
15. Dzhemilev, U. M.; Tolstikov, G. A.; Pokrovskii, A. G.; Salakhutindov, N. F.;
Tolstikova, T. G.; Shul’ts, E. E. RU 2317996, 2008; Chem. Abstr. 2008, 269455.
16. Pichette, A.; Liu, H.; Roy, C.; Tanguay, S.; Simard, F.; Lavoie, S. Synth. Commun.
2004, 34, 3925.
17. Baltina, L. A.; Flekhter, O. B.; Nigmatullina, L. R.; Boreko; Pavlova, N. I.; Niko-
laeva, S. N.; Savinova, O. V.; Tolstikov, G. A. Bioorg. Med. Chem. Lett. 2003, 13,
3549.
18. Kim, D. S. H. L.; Chen, Z.; Van Tuyen, N.; Pezzuto, J. M.; Qui, S.; Lu, Z.-Z. Synth.
Commun. 1997, 27, 1607.
19. Levandskij, V. A.; Polezhaeva, N. I.; Kuztnetsov, B. N. RU 2269541, 2006; Chem.
Abstr. 2006, 126094.
20. Ashavina, O. Y.; Flekhter, O. B.; Galin, F. Z.; Kabal’nova, N. N.; Baltina, L. A.;
Tolstikov, G. A. Chem. Nat. Compd. 2003, 39, 207.
21. Kogai, T. I.; Kuznetsov, B. N. RU 2271364, 2006; Chem. Abstr. 2006, 218258.
22. Menard, H.; Cirtiu, C. M.; Lalancette, J. -M.; Ruest, L.; Kaljaca, Z. PCT 2063464A1,
2006; Chem. Abstr. 2006, 604456.
23. Csuk, R.; Schmuck, K.; Scha¨fer, R. Tetrahedron Lett. 2006, 47, 8769.
24. Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J.
J. Org. Chem. 1999, 64, 2564.
25. Merbough, N.; Bobbitt, J. M.; Bruckner, C. J. Carbohydr. Chem. 2002, 21, 65.
26. Rodriguez, A.; Nomen, A.; Spur, B. W.; Godfroid, J. J. Tetrahedron Lett. 1999, 40,
5161.
27. Bansal, R. V.; Dean, B.; Hakomori, S.-i.; Toyokuni, T. J. Chem. Soc., Chem. Commun.
1991, 796.
28. Jin, J.-T.; Tian, R.-F.; Liu, L.-B.; Zhao, Y.; Li, T. S. Synth. Commun. 2006, 36, 1823.
29. Um, S. J.; Park, M. S.; Park, S.-H.; Han, H.-S.; Kwon, Y.-J.; Sin, H.-S. Bioorg. Med.
Chem. 2003, 11, 5345.
30. Saphier, S.; Hu, Y.; Sinha, S. C.; Houk, K. N.; Keinan, E. J. Am. Chem. Soc. 2005, 127,
132.
3.5.2. From 1 by Jones-oxidation
To a solution of 1 (22.1 g, 50 mmol) in 1,4-dioxane (250 ml) at
5 ꢀC freshly prepared Jones-oxidant [prepared from CrO3 (50.0 g,
0.5 mol), water (300 ml), and sulfuric acid (98%, 41 ml, 0.78 mol)]
was added in several portions and stirring was continued for an-
other 2 h. After quenching the reaction by addition of brine
(200 ml), the reaction mixture was extracted with ethyl acetate
(3ꢁ200 ml), the solvents were removed, and the residue was sub-
jected to chromatography (silica gel, hexanes/ethyl acetate 4:1) to
afford 6 (16.5 g, 75%) as an off-white solid; mp 163–166 ꢀC (lit.:
165–166 ꢀC;44 162–164 ꢀC47), [ 25 47.7 (c 4.1, CHCl3) (lit.: [
a] a]D 33.8
D
(c 0.45, CHCl3),48
ethyl acetate 8:2); IR (KBr):
[
a
]
D 52.4 (CHCl3)44); Rf¼0.83 (silica gel, hexanes/
n
¼3432 m, 3072 w, 2942 s, 2864 m,
1706 s, 1644 w, 1453 m, 1377 w, 1140 w, 1082 w, 985 w; UV–vis
(methanol): lmax (log
d
3
)¼218 nm (4.06); 1H NMR (500 MHz, CDCl3):
¼9.64 (d, 1H, J¼1.3 Hz, CHO (28)), 4.73 (br d, 1H, CHa (30)), 4.60 (br
t,1H, CHb (30)), 2.84 (ddd,1H, J¼11.5,11.1, 6.1 Hz, CH (19)), 2.51–2.41
(m, 1H, CHa (2)), 2.40–2.33 (m, 1H, CHb (2)), 2.08–1.99 (m, 2H, CHa
(21)þCH (13)), 1.91–1.80 (m, 2H, CHa (1)þCHa (15)), 1.77–1.68 (m,
3H, CHa (12)þCHa (16)þCH (18)), 1.67 (s, 3H, CH3 (29)), 1.51–1.14 (m,
14H, CHb (15)þCHb (21)þCH2 (6)þCH2 (11)þCH2(7)þCHb (1)þCH
(9)þCHb (16)þCH (5)þCH2 (22)), 1.08–1.01 (m, 1H, CHb (12)), 1.04 (s,
3H, CH3 (23)), 0.99 (s, 3H, CH3 (24)), 0.96 (s, 3H, CH3 (27)), 0.93 (s,
3H, CH3 (25)), 0.90 (s, 3H, CH3 (26)); 13C NMR (125 MHz, CDCl3):
31. Menger, F. M.; Lee, C. Tetrahedron Lett. 1981, 22, 1655.
32. Bowden, K.; Heilbron, I. M.; Jones, E. R. H.; Weedon, B. C. J. Chem. Soc. 1946, 39.
33. Westheimer, F. H.; Nicolaides, N. J. Am. Chem. Soc. 1949, 71, 25.
34. Roshchin, V. I.; Shabanova, N. Yu.; Vedernikov, D. N. RU 2190622, 2002; Chem.
Abstr. 2003, 139, 69394.
35. Pezzuto, J. M.; Kim, D. S. H. L. U.S. Patent 5,804,575, 1998; Chem. Abstr. 1998, 129,
230869.
36. Mazzitschek, R.; Mu¨lbaier, M.; Giannis, A. Angew. Chem., Int. Ed. 2002, 41, 4059.
37. Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37, 2091.
38. Robertson, A.; Soliman, G.; Owen, E. C. J. Chem. Soc. 1939, 1267.
d
¼218.0 (C3, CO), 206.5 (C28, CHO), 149.6 (C20, C]CH2), 110.2 (C30,
C]CH2), 59.3 (C17, Cquart.), 54.9 (C5, CH), 49.8 (C9, CH), 48.0 (C18,
CH), 47.5 (C19, CH), 47.3 (C4, Cquart.), 42.6 (C14, Cquart.), 40.8 (C8,

A. Barthel et al. / Tetrahedron 64 (2008) 9225–9229
9229
39. Tiwar, K. P.; Choudhary, R. N. Pol. J. Chem. 1979, 53, 551.
40. Sundararamaiah, T.; Ramraj, S. K.; Rao, K. L.; Vimalabai, V. J. Indian Chem. Soc.
1976, 53, 638.
41. Ziegler, H. C.; Franzyk, H.; Sairafianpour, M.; Tabataba, M.; Tehrani, M. D.; Ba-
gherzadeh, K.; Hagerstrand, H.; Staerk, D.; Jaroszewski, J. W. Bioorg. Med. Chem.
2004, 12, 119.
42. Monaco, P.; Previtera, L. J. Nat. Prod. 1984, 47, 673.
43. Bhattacharyya, J.; Kokpol, U.; Miles, D. H. Phytochemistry 1976, 15, 431.
44. Ruzicka, L.; Rey, E. Helv. Chim. Acta 1941, 24, 529.
45. Choi, S. Z.; Yang, M. C.; Choi, U. S.; Lee, K. R. Arch. Pharm. Res. 2006, 29,
203.
46. Ito, J.; Chang, F. R.; Wang, H.-K.; Park, Y. K.; Ikegaki, M.; Kilgore, N.; Lee, K. H.
J. Nat. Prod. 2001, 64, 1278.
47. Flekhter, O. B.; Ashavina, O.; YuBoreko, E. I.; Karachurina, L. T.; Pavlova, N. I.;
Kabal’nova, N. N.; Savinova, O. V.; Galin, F. Z.; Nikolaeva, S. N.; Zarudii, F. S.;
Baltina, L. A.; Tolstikov, G. A. Pharm. Chem. J. 2002, 36, 303.
48. Sun, I. C.; Wang, K. H.; Kashiwada, Y.; Shen, J. K.; Cosentino, L. M.; Chen, C. H.;
Yang, L. M.; Lee, K. H. J. Med. Chem. 1998, 41, 4648.