Rearrangements of the Betulin Core. Synthesis of Terpenoids Possessing the Bicyclo[3.3.1]nonane Fragment by Rearrangement of Lupane-Type Epoxides

Article abstract of DOI:10.1021/acs.joc.0c02560

The rearrangements of dihydrobetulin, dihydrobetulinic acid, and abeo-lupane epoxides under acidic conditions (HCl, montmorillonite K10, and BF3·Et2O) were studied. The treatment of dihydrobetulin with HCl or K10 produced abeo-lupane olefins. Their epoxid

Full text of DOI:10.1021/acs.joc.0c02560

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Article
Rearrangements of the Betulin Core. Synthesis of Terpenoids
Possessing the Bicyclo[3.3.1]nonane Fragment by Rearrangement of
Lupane-Type Epoxides
Zbigniew Pakulski,* Piotr Cmoch, Anna Korda, Roman Luboradzki, Katarzyna Gwardiak,
and Romuald Karczewski
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ABSTRACT: The rearrangements of dihydrobetulin, dihydrobetulinic
acid, and abeo-lupane epoxides under acidic conditions (HCl,
montmorillonite K10, and BF3·Et2O) were studied. The treatment of
dihydrobetulin with HCl or K10 produced abeo-lupane olefins. Their
epoxidation afforded epoxides, which, in the presence of protic or
Lewis acids, rearranged to dienes or lupanes bearing a bicyclo[3.3.1]-
nonane fragment. The structure of final products depended on the
nature of the catalyst. The HCl promoted 1,4-elimination of water,
whereas in the presence of BF3·Et2O bond migration took place
preferentially. Montmorillonite K10 favored cyclization to bicyclono-
nane.
40−60 years ago. Nowadays, it seems worthwhile to
reinvestigate some of these reactions. As expected, a variety
of possible products may be a source of promising lead
compounds for pharmaceutical applications. Also, it may be
considered as a simple pathway to chemical conversions of one
terpenoid to another, difficult to access from natural sources or
having functional groups in unusual positions.
In the presence of Lewis or mineral acids, the rearrangement
of betulin ring E takes place, leading to allobetulin (3), as
described for the first time by Schulze and Pieroh in 1922
(Scheme 1).29,30 The betulin−allobetulin rearrangement is
often observed as a side reaction which significantly decreases
the yield of betulin derivatives. For example, the rearrangement
of a lupane skeleton can occur during Schmidt glycosylation of
lupanes.30−33 Therefore, during synthesis of lupane derivatives,
careful control of reaction conditions must be taken to avoid
side reactions, especially when a hydroxy or carboxyl group is
present at the C-28 position.
INTRODUCTION
■
Birch (Betula sp.) is a common tree in the northern
hemisphere. Its wood has important historical and cultural
significance since Paleolithic times. The Iceman, whose
mummy dated to 3400−3100 BC was found in Tyrol, had
baskets made of birch bark and a copper axe fixed with birch-
tar. Birch-tar prepared by dry distillation of birch bark is found
in many archeological records across Europe.1 Nowadays,
birch wood is widely used in the paper industry. During paper
production, the waste generated in large quantities is birch
bark, the outer part of which contains up to 30% betulin (1), a
pentacyclic triterpenoid belonging to the lupane family
(Scheme 1).2,3 Betulin itself has interesting biological proper-
ties, including antiviral and antitumor activities.4−8 It has also
been used as an intermediate in the synthesis of triterpenoids
employed for biological studies.9−19 Betulinic acid (2), the
structural analogue of betulin, is also isolated from birch bark
and other plants in significant amounts and possesses
interesting biological properties.5,6,20,21
The Wagner−Meerwein rearrangement has also been
applied to the synthesis of cyclopentyl units by contraction
of the A-ring. By this path, a series of nor-oleanane derivatives
(e.g., 6) was obtained by the rearrangement of allobetulin or
Reactions of steroidal or triterpenoid olefins, alcohols, and
epoxides with either Brønsted or Lewis acids can lead to a
variety of structures, which originate from cascade Wagner−
Meerwein rearrangements.22−27 In a spectacular example,
seven such processes occurring either simultaneously or in
rapid succession were observed for triterpenoid 3β-friedela-
nol.28 Stereoelectronically favored pathways suggest that axially
oriented hydrogen atoms and alkyl groups typically migrate.
These shifts are stereospecific, and the group always migrates
on the side of the ring system on which it is originally located.
However, the majority of research in this area was carried out
Received: October 28, 2020
https://dx.doi.org/10.1021/acs.joc.0c02560
© XXXX American Chemical Society
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Scheme 1. Betulin (1) and Betulinic Acid (2) and Their Rearrangement to the Allobetulin Core (3, 4)
lupane compounds (Scheme 2).34−37 This process is especially
important from the synthetic point of view, because
In the present paper we report a simple, rapid, and high yield
conversion of the betulin scaffold by the acid-catalyzed
reaction of betulin and betulin-derived epoxides induced by a
number of catalysts including hydrogen chloride, montmor-
illonite K10, and boron trifluoride etherate. The influence of
the catalyst on rearrangement direction, position of the double
bond, and side reactions were studied. The obtained
derivatives may be considered as starting materials in the
synthesis of ceanothic acid analogues.
Scheme 2. Contraction of the A-Ring in Allobetulin
Derivatives
RESULTS AND DISCUSSION
■
Betulin, which has the same stereochemical structure of the B-,
C-, D-, and E-rings, seemed to be the perfect starting material
for the synthesis of ceanothic acid analogues. However, almost
all known direct transformations, in which the betulin A-ring
was contracted to a cyclopentyl unit, proceeded together with
betulin−allobetulin rearrangement. Therefore, we chose
dihydrobetulin 28-O-acetate (8) and methyl dihydrobetulinate
(12) as starting materials. In the absence of the double bond in
the side chain, the E-ring did not rearrange under acidic
conditions.
triterpenoids with a five-membered ring A, representing a
family of natural triterpenoids found in many plants growing
mainly in tropical and subtropical regions, have important
biological and pharmacological properties.38−41 Among them,
ceanothic acid (7, Figure 1) and its derivatives have the most
In the first attempt, treatment of betulin monoacetate 8 with
hydrogen chloride in methanol caused deacetylation to
dihydrobetulin (9) isolated in 65% yield; no product of
rearrangement was observed (Scheme 3). By comparison,
treatment of 8 with montmorillonite K10 in refluxing
chloroform afforded an unseparated mixture of 5(4→3)abeo-
lupanes 10 and 11 in high total yield (89%) with 10 being the
major product. The proportion of products varied between
1.5:1 to 3:1 depending on the batch but was not dependent on
the reaction time (24−120 h). In the presence of BF3·Et2O in
benzene at 70 °C, conversion of 8 was quite effective. Olefin
11 predominated in the reaction mixture (ca. in 2:1
proportion, isolated yield of the olefins mixture 88%).
Then we studied the rearrangement of methyl dihydrobe-
tulinate 12. As in the case of 8, treatment of 12 with hydrogen
Figure 1. Ceanothic acid (7).
remarkable biological activities.42,43 However, a low concen-
tration of those compounds in plant sources is the main
disadvantage of their use in synthesis and pharmacology.
Skeletal rearrangements of easily accessible betulin and
betulinic acid offer a promising alternative for simple chemical
conversions to ceanothic acid analogues.
a
Scheme 3. Contraction of the A-Ring in Lupane Derivatives
a
Reagents and conditions: i. HCl in MeOH, room temperature (65%), 12 h; ii. montmorillonite K10, chloroform, reflux, 72 h (10/11: 89%; 13/
14: 96%); iii. BF3·Et2O, benzene, 70 °C, 4 h (10/11: 88%; 13/14: 94%).
B
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Scheme 4. Proposed Mechanism of Lupane Core Rearrangement
a
Scheme 5. Epoxidation of Olefins 10/11 and 13/14
a
Reagents and conditions: i. m-CPBA, NaHCO3, chloroform, room temperature, 12 h (15/16: 82%; 17/18: 83%).
chloride in methanol did not give any rearrangement products,
and starting material was recovered quantitatively. In the
presence of montmorillonite K10, an unseparated mixture of
olefins 13 and 14 was isolated in 96% total yield and a varied
proportion of 13:14 (2.0−2.5:1.0). When 12 was treated with
BF3·Et2O, rearrangement proceeded highly selectively toward
olefin 14 obtained as the main product in the ratio 14:13 > 4:1
in 94% yield. Authors of a communication on a similar
transformation of allobetulin derivatives suggested that olefins
formed by rearranging the starting materials equilibrated
during the reaction, and their ratio varied with the solvent
and temperature.34
the less hindered β-face, instead of the α-face shielded by the
A-ring and angular methyl group at C-14. Proposed structures
of epoxides were confirmed by NOE and HMBC correlations,
as well as the reaction mechanism consideration, as described
below.
These epoxides were then subjected to the rearrangement
reaction.47 Treatment of 15 with hydrogen chloride in
methanol gave diene 19 in excellent yield (88%) as the sole
product (Scheme 6). Deacetylation at O-28 took place as an
independent reaction. Epoxide 17 in the presence of hydrogen
chloride decomposed and formed a complex mixture of
products.
In the presence of montmorillonite K10, rearrangement of
15 afforded a mixture of products partially isolated by column
chromatography. The main fraction was composed of two
dienes identified as 20, in which the C-25 methyl group
migrated to the C-3 position, and 21 (total yield 49%) in ca.
1.2:1.0 proportion. Olefin 22 (17%) and ketone 23 (13%)
were also isolated as minor products. Under these conditions,
epoxide 17 formed a complex mixture of products.
When BF3·Et2O was used as the catalyst, rearrangement of
15 was highly selective toward olefin 20 (74%) which was
isolated as the only product. Its deacetylation afforded free
alcohol 24 (77%). Rearrangement of 17 induced by BF3·Et2O
afforded diene 25 exclusively in high yield (72%).
As we proposed, the rearrangement of 3,5-epoxide 15 in the
presence of HCl (protic acid) occurs through cleavage of the
C−O bond to give the allyl alcohol followed by the 1,4-
elimination of water to yield 19 (Scheme 7). By comparison,
BF3·Et2O promoted migration of the methyl group from C-10
to C-5. Subsequent elimination of BF3OH and the second
migration of the methyl group from C-5 to C-3 gave diene 20.
Similar transformations have been carried out for epoxide
16. In our first attempt we used BF3·Et2O as the catalyst;
however, it caused decomposition of the starting material. In
the presence of hydrogen chloride, diene 26 (63%, contained a
As a hypothesis, in the first step contraction of ring A in 8
caused by dehydration took place, followed by isomerization of
carbocation C⊕
to C⊕
(3)
(Scheme 4). Further trans-
(3)
(4)
formation of the C⊕ depended on the catalyst properties.
In the presence of BF3·Et2O, the Westphalen-type rearrange-
ment23 involved 10β-methyl group migration to the 5β-
position and formation of the 5(4→3)abeo-5β-methyl-Δ9,10
-
25-nor derivative 11 was observed. Montmorillonite K10
catalyzed deprotonation of C⊕(3), and formation of olefin 10
was the preferred reaction pathway.
Epoxidation of the mixture of olefins 10 and 11 with m-
CPBA gave easily separable epoxides 15 and 16 in excellent
total yield (82%, Scheme 5). Oxidation of the mixture of 13
and 14 with m-CPBA gave epoxides 17 and 18 in similar total
yield (83%). Yields of individual epoxides depended on olefin
ratio in the starting mixture. When the product of the K10-
promoted rearrangement was used as a starting material, 3,5-
epoxides (15, 17) were isolated as main products, whereas the
product of BF3·Et2O-promoted rearrangement gave 9,10-
epoxides (16, 18) predominantly. We expected, that in the
presence of β-oriented angular methyl group at C-10,
epoxidation of 10 and 13 with peracid should prefer formation
of α-epoxide as observed for steroids and allobetulin
derivatives.44−46 Epoxidation of 11 and 14 should proceed at
C
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a
confirmed by X-ray crystallographic analysis (see Supporting
Information).
Scheme 6. Rearrangement of Epoxides 15 and 17
Similarly, treatment of epoxide 18 with hydrogen chloride
gave diene 30 as the main product (69%) and ketone 31 in
27% yield. Then epoxide 18 was stirred with montmorillonite
K10 to yield bridged ketone 31 in excellent isolated yield
(75%). Configuration of the diene 30 was confirmed by X-ray
crystallographic analysis (see Supporting Information).
We suggest, that the rearrangement of 9,10-epoxide 16 in
the presence of HCl proceeded via formation of allyl alcohol
and subsequent 1,4-elimination of water to give diene 26
(Scheme 9). Montmorillonite K10 promoted the Meinwald-
type rearrangement of epoxide48 in which the C1−C10 bond
migrated to the C1−C9 position and gave ketone 29 bearing
the bicyclo[3.3.1]nonane fragment. The structure of 29 proves
that the β-location of the epoxide ring in 16 was correctly
established, because the formation of 29 is possible only when
migration of the C1−C10 bond in 16 takes place from the α-
side.
The reduction of 29 with LiAlH4 in boiling tetrahydrofuran
afforded diol 32 selectively (Scheme 10). It was isolated as
monoacetate 33 in moderate yield (43% after two steps) after
acetylation of the crude reaction mixture under standard
conditions. Unreacted 29 (36%) was also recovered.
Dehydration of 33 with POCl3 in pyridine gave olefin 34 as
the main product (89%); small amounts of olefin 11 were also
identified as a contaminant in approximately 3.5:1.0 ratio.
Ketones 29 and 31 may be considered as potentially useful
starting materials for the synthesis of chiral macrocycles or
sterically hindered ligands. However, due to the hindered
position of the carbonyl group shielded by two angular methyl
groups, an isopropyl group, and cyclohexane rings, its reactivity
is significantly lowered. In fact, ketone 29 was unreactive in a
Bayer−Villiger oxidation: treatment with m-chloroperbenzoic
acid, peracetic acid, and performic acid gave no product and
starting material was recovered almost quantitatively. Further
studies toward transformation of 29 and 31 into macrocycles
are currently under investigation.
a
Reagents and conditions: i. HCl, MeOH, room temperature, 24 h
(88%); ii. montmorillonite K10, chloroform, 50 °C, 24 h (20/21:
49%, 22: 17%, and 23: 13%); iii. BF3·Et2O, benzene, room
temperature, 4 h (20: 74%; 25: 72%); iv. KOH, EtOH, reflux, 1 h
(77%).
Determination of Structures of Rearrangement
Products. The formation of rearranged products can be
rationalized mechanistically. In all studied cases, cascade
Wagner−Meerwein 1,2-migration of antiperiplanar disposed
groups, both in concerted or nonconcerted manner, is
postulated. Stereochemistry of migration determines the
structure of the final products. Expected structures were
confirmed by extended 2D NMR experiments (COSY, HSQC,
HMBC), as well as NOE and TOCSY correlations, and high
resolution mass spectra (HRMS). In the case of the above-
few percent of other olefins as contaminants) and bridged
ketone 27 (23%) were obtained in excellent total yield
(Scheme 8). Diene 26 was characterized as acetate 28 obtained
by acetylation of 26 under standard conditions (96%).
Treatment of 16 with montmorillonite K10 gave ketone 29
in 80% yield. Deacetylation of 29 gave product identical to 27
(85%). Configuration of the ketone 29 was unequivocally
Scheme 7. Proposed Mechanism of Epoxide 15 Rearrangement
D
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a
Scheme 8. Rearrangement of Epoxides 16 and 18
a
Reagents and conditions: i. HCl, MeOH, 24 h, room temperature (26: 63% and 27: 23%; 30: 69% and 31: 27%); ii. montmorillonite K10,
chloroform, 4 h, room temperature (29: 80%; 31: 75%); iii. Ac2O, pyridine (96%); iv. KOH, EtOH, 1 h, reflux (85%).
Scheme 9. Proposed Mechanism of Epoxide 16 Rearrangement
a
Scheme 10. Reduction of Ketone 29
a
Reagents and conditions: i. LiAlH4, THF, 4 h, reflux; ii. Ac2O, pyridine (43%); iii. POCl3, pyridine, 60 °C (89%).
mentioned products, in which the majority of 1H NMR signals
are in the range δ ca. 0.7−2.5 ppm, the most essential are
HMBC correlations for protons of methyl groups. They
unambiguously indicate positions of double bonds. Other
essential HMBC correlations come from the C28 methylene
protons and protons from other isolated positions (e.g.,
protons at C2, C4, and C6 carbons for 10). For complete
confirmation of the stereochemical structure, mutual spatial
interactions of protons or groups of protons were extracted
from NOE/ROE experiments. Key NOE and HMBC
correlations for studied compounds may be found in
Supporting Information. Full assignments of 1H and 13C
NMR spectroscopic data of key compounds were made and are
listed in Tables 1 and 2. Configurations of ketone 29, bearing
the bicyclo[3.3.1]nonane fragment, and diene 30 were also
confirmed by X-ray crystallographic analysis (see Supporting
Information).
literature reports on the rearrangement of hopane and
cholestane derivatives.49−53 The conversion of abeo-lupane
epoxides by protic acids leads to C−O bond cleavage and
formation of allyl alcohol, which, in the next step, releases
water in the 1,4-elimination process. In the presence of BF3·
Et2O, triterpene epoxides preferentially undergo an alkyl group
migration, rather than 1,4-elimination of water. Montmor-
illonite K10 usually prefers the elimination of water, although
in some cases bond migration products are also observed in
significant amounts. Prepared derivatives are interesting
starting materials for the synthesis of ceanothic acid analogues
by the functionalization of double bonds. The most interesting
achievement is the synthesis of triterpenes bearing
bicyclo[3.3.1]nonane fragments. They may be considered as
precursors of chiral, sterically hindered macrocycles and
ligands. Their use in synthesis is currently under investigation.
EXPERIMENTAL SECTION
■
CONCLUSIONS
The presented results clearly show that protic and aprotic acids
gave different products. These observations are in line with
■
General Procedures. Silica gel HF254 and silica gel 230−400
mesh (E. Merck) were used for TLC and column chromatography,
1
respectively. H and 13C NMR spectra were recorded at 298 K with
E
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1
Table 1. H NMR (600 MHz) Spectroscopic Data
a
a
a
a
a
b
a
a
atom no.
1
10
11
15
16
19
20
21
22
1.28
1.65
1.94
2.26
1.01
1.15
1.62
1.94
1.27
1.66
2.35
2.87 dd, J 1.9,
19.2 Hz
2.94 dd, J 2.7,
19.2 Hz
2.23
2.43
2.50
2
2.10
2.19
-
2.62 m
1.92
1.37
1.84
1.03
1.56
1.32
1.62
1.72
-
1.70
1.30
1.47
1.79
1.26
1.63
1.29
2.16
2.34
-
2.77 m
6.19 d, J 10.2
Hz
1.39
1.89
-
1.70
1.87
5.37 bs
1.75
1.79
-
1.93
1.45
3
4
6
-
2.24
1.40
2.25
1.25
1.78
1.36
2.07
1.39
1.63
1.24
1.98
1.44
1.62
1.41
1.82
1.38
7
5.64 d, J 10.2
Hz
1.38
1.48
-
1.92
-
-
1.75
1.87
-
1.33
-
-
1.61
-
-
5.35 dd, J 2.7,
5.0 Hz
2.00
-
-
1.98
-
-
9
10
11
1.74
-
1.43
1.34
1.94
1.28
1.16
1.99
1.97
1.37
1.19
1.58
1.72
1.04
1.73
1.20
1.79
1.39
1.79
1.86
1.44
1.58
0.86
1.72
2.26
1.11
1.52
1.84
1.34
1.72
1.19
1.83
1.45
1.79
1.86
1.47
1.62
0.87
1.74
1.45
1.26
1.59
1.71
1.08
1.74
1.23
1.81
1.38
1.87
1.87
1.45
1.59
0.87
1.74
1.61
1.23
1.31
1.81
1.37
1.78
1.19
1.83
1.51
1.82
1.87
1.49
1.65
0.91
1.75
2.31
1.15
1.53
1.86
1.36
1.73
1.20
1.85
1.45
1.80
1.85
1.46
1.64
0.88
1.75
2.30
1.14
1.54
1.86
1.35
1.72
1.20
1.84
1.45
1.79
1.85
1.47
1.62
0.87
1.74
12
1.24
1.60
1.73
1.25
1.82
1.24
1.94
1.32
1.73
1.86
1.47
1.60
0.84
1.82
1.71
2.03
1.95
1.24
1.94
1.23
2.02
1.42
1.63
1.86
1.44
1.66
0.92
1.92
13
15
16
18
19
20
21
22
23
24
25
26
27
28
0.97 d, J 6.9 Hz 0.89 d, J 6.6 Hz 0.95 d, J 7.1 Hz 0.90 d, J 6.6 Hz 0.99 d, J 6.9 Hz 0.75 d, J 6.8 Hz 1.09 d, J 6.9 Hz 0.96 d, J 6.8 Hz
0.90 d, J 6.9 Hz 0.93 d, J 6.6 Hz 1.06 d, J 6.8 Hz 0.92 d, J 6.6 Hz 0.96 d, J 6.8 Hz 0.91 d, J 6.8 Hz 1.02 d, J 6.8 Hz 0.92 d, J 6.8 Hz
0.85
1.12
0.92
0.80
1.18
0.86
0.85
1.13
1.02
0.88
1.10
1.05
0.87
1.19
0.87
1.03
1.18
0.91
0.94
1.18
0.91
1.23
0.86
3.84 dd,
J 1.5, 11.1 Hz
3.87 dd,
J 1.4, 11.1 Hz
3.81 dd,
J 1.5, 11.1 Hz
3.88 dd,
J 1.3, 11.2 Hz
3.33 d,
J 10.8 Hz
3.98 d,
J 11.4 Hz
3.88 dd,
J 1.5, 11.0 Hz
3.87 dd,
J 1.4, 11.1 Hz
4.25 dd,
J 1.9, 11.2 Hz
4.27 dd,
J 1.8, 11.2 Hz
4.28 dd,
J 1.9, 11.1 Hz
4.24 dd,
J 1.9, 11.2 Hz
3.80 dd,
J 1.7, 10.8 Hz
4.50 dd,
J 2.0, 11.4 Hz
4.28 d,
J 11.7 Hz
4.28 dd,
J 1.9, 11.1 Hz
29
30
0.75 d, J 6.8 Hz 0.75 d, J 6.9 Hz 0.77 d, J 6.7 Hz 0.79 d, J 6.7 Hz 0.76 d, J 6.8 Hz 0.77 d, J 6.8 Hz 0.74 d, J 6.9 Hz 0.74 d, J 6.8 Hz
0.83 d, J 6.8 Hz 0.83 d, J 6.9 Hz 0.84 d, J 6.7 Hz 0.86 d, J 6.8 Hz 0.85 d, J 6.8 Hz 0.87 d, J 6.8 Hz 0.84 d, J 6.7 Hz 0.84 d, J 6.8 Hz
CH3CO
CO2CH3
atom no.
2.05
-
2.06
-
25
2.06
-
26
2.06
-
-
29
1.73
-
2.06
-
2.06
-
-
28
a
a
a
a
b
b
a
a
a
23
30
31
1.51
33
34
1
1.58
1.83
2.16
2.19
2.37
1.34
1.84
-
1.71
1.91
1.95
1.45
1.52
-
2.34
2.40
1.41
1.85
1.09
1.61
1.22
1.91
1.40
1.95
-
2.33
2.41
1.41
1.85
1.07
1.61
1.21
1.91
1.40
1.93
-
1.27
2.30
1.00
1.59
1.60
1.82
1.50
2.33
0.97
2.57
1.53
1.95
1.48
1.89
1.26
1.91
1.14
2.12
-
1.29
1.79
1.71
2.59
1.06
1.74
1.83
1.92
1.67
1.79
1.23
2.41
-
2
1.29
1.74
1.05
1.52
1.28
1.92
1.42
1.92
-
3
4
6
-
1.24
1.49
1.42
1.93
1.46
1.68
1.14
1.37
1.18
-
7
0.95
2.11
-
1.22
1.78
-
-
9
10
11
-
-
-
-
-
-
3.43 s
0.82
1.38
5.31 m
6.08 dd, J 3.1,
10.2 Hz
6.09 dd, J 3.1,
10.2 Hz
1.24
6.26 dd, J
3.3, 10.1
Hz
1.21
5.29 m
1.52
1.92
1.82
2.05
F
https://dx.doi.org/10.1021/acs.joc.0c02560
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Table 1. continued
a
a
a
a
b
b
a
a
a
atom no.
12
23
25
1.74
26
28
29
30
31
1.29
33
34
1.15
5.51 dd, J 2.2,
10.2 Hz
5.51 dd, J 2.2,
10.3 Hz
1.11
5.83 dd, J
2.3, 10.1
Hz
1.45
1.74
1.63
1.70
1.04
1.62
1.17
1.78
1.38
1.76
1.85
1.45
1.59
0.86
1.72
2.24
2.63
1.36
1.30
1.58
0.94
1.60
1.25
1.84
1.35
1.55
1.77
1.39
1.50
0.86
1.88
1.59
2.28
1.21
1.30
1.45
2.21
1.43
2.29
1.81
1.47
1.53
1.24
1.81
1.58
1.90
0.97
1.77
1.31
1.79
1.41
1.80
2.12
1.46
2.06
1.82
1.25
1.77
1.24
1.85
1.44
1.82
1.97
1.48
1.64
0.91
1.73
13
15
2.34
1.37
1.68
1.26
1.95
1.59
1.91
1.99
1.53
1.67
0.87
1.86
2.37
1.36
1.67
1.30
1.87
1.60
1.96
2.00
1.52
1.66
0.92
1.66
3.30
1.45
1.54
1.44
2.50
1.68
2.75
2.04
1.52
1.77
1.24
1.94
16
1.36
2.22
1.43
2.33
1.93
1.49
18
19
20
21
22
1.24
1.86
0.88
1.74
23
24
0.95 d, J 6.7 Hz 0.68 d, J
0.91 d, J 6.6 Hz 0.96 d, J 6.6 Hz 0.70 d, J 6.8 Hz 0.96 d, J 6.6 0.90 d, J
Hz 6.8 Hz
0.96 d, J 6.6 Hz 0.91 d, J 6.6 Hz 0.79 d, J 6.8 Hz 0.89 d, J 6.0 0.71 d, J
0.87 d, J 6.8 Hz 0.85 d, J 6.7 Hz
6.8 Hz
0.75 d, J 6.9 Hz 0.87 d, J
0.88 d, J 6.8 Hz 0.87 d, J 6.7 Hz
6.8 Hz
Hz
0.92
1.23
0.89
-
6.8 Hz
1.05
0.76
1.15
-
25
26
27
28
1.10
1.07
0.82
3.83 d, J 11.1
Hz
0.99
0.91
0.86
-
0.93
1.06
0.74
3.37 dd, J 1.4,
10.9 Hz
0.93
1.07
0.74
3.89 dd, J 1.5,
11.1 Hz
1.12
0.81
0.97
3.83 dd, J 1.6,
11.3 Hz
1.00
1.43
1.09
0.90
1.12
0.93
3.89 d, J 11.1
Hz
3.89 dd, J 1.2,
11.1 Hz
4.21 dd,
J 1.9, 11.1 Hz
3.85 dd,
J 1.7, 10.9 Hz
4.31 dd,
J 1.8, 11.1 Hz
4.29 dd,
J 1.9, 11.3 Hz
4.21 dd,
J 1.8, 11.1 Hz
4.23 dd,
J 2.0, 11.1 Hz
29
30
0.75 d, J 6.7 Hz 0.78 d,
J 6.8 Hz
0.78 d, J 6.7 Hz 0.78 d, J 6.7 Hz 0.75 d, J 6.8 Hz 0.78 d,
J 6.8 Hz
0.90 d, J 6.9 Hz 0.90 d, J 6.8 Hz 0.81 d, J 6.9 Hz 0.93 d, J 7.0 0.88 d, J
Hz 6.9 Hz
0.77 d,
0.79 d, J 6.8 Hz 0.80 d, J 6.6 Hz
J 6.9 Hz
0.84 d, J 7.0 Hz 0.88 d, J
0.85 d, J 6.9 Hz 0.86 d, J 7.0 Hz
6.9 Hz
CH3CO
CO2CH3
2.05
-
-
-
-
2.07
-
1.68
-
-
-
2.06
-
2.06
-
3.64
3.36
3.63
a
b
In CDCl3 solution. In C6D6 solution.
Varian NMR-vnmrs600 or vnmrs500 spectrometers, using standard
experimental conditions and Varian software (ChemPack 4.1).
Configurational assignments were based on the NMR measurements,
generated using two-dimensional techniques such as COSY and
1H−13C gradient selected HSQC (g-HSQC), as well as 1H−13C
gradient selected HMBC (g-HMBC). Internal TMS was used as the
1H and 13C NMR chemical shift standard. J values are given in hertz.
High-resolution mass spectra (HRMS ESI) were acquired with
Mariner and MaldiSYNAPT G2-S HDMS (Waters) mass spectrom-
eters. Optical rotations were measured with a Jasco P-2000 automatic
polarimeter.
Single crystal X-ray diffraction measurements were carried out on
an Agilent Supernova diffractometer, at 100 K with monochromated
Cu Kα radiation (1.54184 A). The data reduction was made by using
CrysAlisPRO software.54 The structures were solved by direct
methods and refined on F2 by full-matrix least-squares by using
SHELXS97 and SHELXL97.55 All non-hydrogen atoms were refined
as anisotropic while hydrogen atoms were placed in calculated
positions and refined in riding mode. CCDC 1999008 and CCDC
2038963 contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
(hexane−ethyl acetate, 9:1) gave dihydrobetulin (9, 177 mg, 65%, a
colorless solid)56 as the only product.
Method B: To a solution of 28-O-acetyldihydrobetulin (8, 1000
mg, 2.054 mmol) in chloroform (50 mL) was added montmorillonite
K10 (1.0 g), and the mixture was refluxed for 72 h (an oil bath) under
an argon atmosphere. The whole mixture was then filtered through a
silica gel pad, and the solvents were evaporated under reduced
pressure. Column chromatography of the residue (hexane−ethyl
acetate, 20:1) gave a mixture of olefins 10 and 11 (860 mg, 89%) as a
foam.
Method C: To a solution of 28-O-acetyldihydrobetulin (8, 1000
mg, 2.054 mmol) in benzene (20 mL) was added BF3·Et2O (500 μL),
and the mixture was stirred at 70 °C (an oil bath) for 4 h under an
argon atmosphere. Then Et3N (1.0 mL) was added, and the solvents
were partially removed under reduced pressure. Column chromatog-
raphy of the residue (hexane−ethyl acetate, 20:1) gave a mixture of
olefins 10 and 11 (850 mg, 88%) as a foam.
1
Data for 10. H (600 MHz, CDCl3) and 13C{1H} NMR (150
MHz, CDCl3): see Tables 1 and 2.
1
Data for 11. H (600 MHz, CDCl3) and 13C{1H} NMR (150
MHz, CDCl3): see Tables 1 and 2.
HRMS (ESI-TOF) for a mixture of 10 and 11 m/z: [M + Na]+
calcd for C32H52O2Na 491.3865; found 491.3863.
Rearrangement of Methyl Dihydrobetulinate (12). Starting from
betulinate 12 (2.364 g, 5.000 mmol), and following method B, an
inseparable mixture of olefins 13 and 14 (2.190 g, 96%) was obtained
as a foam.
Rearrangement of 28-O-Acetyldihydrobetulin (8). Method A: To
a solution of 28-O-acetyldihydrobetulin (8, 300 mg, 0.616 mmol) in
methanol (6 mL) was slowly added acetyl chloride (100 μL), and the
mixture was stirred at room temperature for 12 h. The reaction was
quenched with Et3N (1.0 mL), and the solvents were evaporated
under reduced pressure. Column chromatography of the residue
Starting from betulinate 12 (2.840 g, 6.000 mmol), and following
method C, an inseparable mixture of olefins 13 and 14 (2.560 g, 94%)
was obtained as a foam.
G
https://dx.doi.org/10.1021/acs.joc.0c02560
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Table 2. 13C{1H} NMR (150 MHz) Spectroscopic Data
a
a
a
a
a
b
a
a
atom no.
10
11
15
16
19
20
21
22
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
CH3CO
CH3CO
CO2CH3
atom no.
41.7
27.4
136.1
26.3
139.8
19.7
32.9
41.2
49.0
49.8
23.5
26.9
37.6
42.7
27.2
29.8
46.5
48.0
44.5
29.4
21.6
34.7
21.9
21.3
19.0
14.6
14.5
62.8
14.9
22.9
21.0
171.6
26.4
27.5
59.1
29.8
42.7
37.5
29.8
40.8
131.0
141.8
26.2
27.0
38.5
43.1
27.8
29.9
46.5
47.9
44.3
29.5
21.8
34.6
23.1
22.9
18.0
25.8
17.3
62.8
14.8
22.8
21.0
171.6
-
34.6
23.2
75.8
28.5
76.3
20.1
30.2
41.1
43.1
43.4
22.8
26.6
37.4
43.1
27.1
29.8
46.4
48.0
44.5
29.4
21.6
34.7
19.1
18.4
17.9
15.4
14.6
62.8
14.8
22.9
21.0
171.7
-
28.4
27.1
58.1
29.6
40.2
35.6
27.5
40.6
67.8
78.2
24.8
27.9
38.4
42.7
29.0
29.3
46.4
47.3
44.5
29.7
21.7
34.5
22.7
22.6
16.3
21.1
20.8
62.5
14.9
22.8
21.0
171.5
-
40.2
28.1
140.5
26.5
138.7
119.2
135.2
44.9
46.8
47.9
22.1
27.7
37.1
42.7
26.7
29.3
47.9
47.9
44.3
29.3
21.7
34.1
21.6
21.3
18.8
16.9
15.9
60.7
14.8
22.9
-
30.5
30.1
53.8
34.1
142.6
19.8
29.1
40.9
139.3
133.5
118.4
29.3
34.9
39.6
28.0
30.4
47.0
48.7
45.3
29.4
22.0
34.8
18.7
17.9
25.5
20.7
16.0
62.5
15.1
23.0
20.6
170.5
-
34.0
118.0
159.6
26.3
47.1
32.5
29.3
41.1
130.2
139.8
26.5
26.8
38.5
43.4
27.8
29.9
46.5
48.0
44.3
29.5
21.8
34.6
23.9
24.0
24.7
35.3
86.0
32.7
47.9
29.4
29.2
40.7
133.7
139.1
26.3
27.0
38.5
43.1
27.9
29.8
46.5
47.8
44.3
29.4
21.8
34.5
18.8
17.4
21.9
26.0
17.4
62.8
14.8
22.8
21.0
171.6
-
25.8
17.0
62.8
14.8
22.9
21.0
171.6
-
-
-
-
a
a
a
a
b
b
a
a
a
23
25
26
28
29
30
31
33
34
1
2
3
4
5
6
7
8
31.4
34.7
222.1
28.6
58.4
18.4
27.5
40.1
40.7
46.0
23.6
27.2
37.5
42.8
26.7
29.7
46.4
47.9
44.4
29.4
21.6
34.6
20.1
19.9
19.5
15.1
29.9
29.7
53.4
33.6
26.5
27.4
59.0
29.6
43.6
38.3
28.5
39.2
131.2
147.3
125.5
125.7
39.5
41.8
26.8
29.2
48.0
46.3
43.7
30.0
22.1
33.8
23.0
23.0
18.1
25.5
26.5
27.4
59.0
29.6
43.6
38.3
28.5
39.2
131.1
147.4
125.7
125.3
39.9
41.8
26.8
29.8
46.6
46.4
43.6
29.9
22.0
34.4
23.0
23.1
18.1
25.6
36.2
21.9
55.4
28.8
48.1
41.1
27.3
47.1
53.0
218.3
30.4
22.5
38.1
43.1
28.3
29.4
47.0
47.5
44.1
29.7
21.9
35.3
24.1
18.7
21.7
19.6
26.8
27.8
59.4
29.9
43.9
38.8
29.0
39.4
131.8
147.1
125.6
126.5
42.0
42.0
29.9
32.2
57.6
47.8
43.9
30.6
23.5
37.3
23.1
23.2
18.4
25.8
35.9
21.6
55.2
28.3
48.1
40.9
26.9
46.8
53.0
220.8
29.8
22.0
39.0
42.6
30.5
31.2
57.1
47.9
43.9
29.6
22.7
37.4
24.0
18.6
20.9
19.3
38.2
22.1
50.9
29.3
38.8
36.1
29.4
43.8
41.5
81.7
33.5
21.5
38.6
43.0
27.6
29.4
46.5
47.4
44.0
29.3
23.0
34.8
24.7
18.9
24.5
19.6
28.6
23.3
53.0
30.1
46.0
35.6
29.2
42.3
143.6
50.1
116.5
28.9
34.6
40.5
26.9
29.6
46.4
48.1
45.3
29.1
21.7
34.3
23.3
22.7
22.7
24.2
142.3
19.5
28.7
40.2
139.1
132.9
118.1
28.9
35.0
38.9
30.0
31.9
56.9
48.9
44.6
29.5
22.8
37.0
18.4
17.6
25.2
20.1
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
H
https://dx.doi.org/10.1021/acs.joc.0c02560
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Table 2. continued
a
a
a
a
b
b
a
a
a
atom no.
23
25
26
28
29
30
31
33
34
27
28
29
30
CH3CO
CH3CO
CO2CH3
14.3
62.8
14.9
22.9
21.0
171.6
-
15.5
176.9
14.7
23.0
-
15.9
60.6
14.9
22.8
-
15.9
62.9
14.9
22.8
21.0
171.6
-
16.0
62.7
15.1
23.0
20.6
170.4
-
16.0
176.3
15.0
23.1
-
15.4
176.8
14.7
22.9
-
16.8
63.2
14.9
22.9
21.0
171.6
-
16.2
62.7
14.9
22.9
21.0
171.5
-
-
-
-
-
-
51.2
51.0
51.2
a
b
In CDCl3 solution. In C6D6 solution.
13 (selected data): 13C{1H} NMR (125 MHz, CDCl3) δ: 176.9
47.9, 44.1, 42.3 (C), 40.3 (C), 40.2 (C), 39.0, 37.0 (CH2), 35.6
(CH2), 31.6 (CH2), 31.2 (CH2), 29.9, 29.7, 28.4 (CH2), 28.0 (CH2),
27.6 (CH2), 27.1 (CH2), 24.8 (CH2), 22.9, 22.9 (CH2), 22.7, 22.6,
21.0, 20.5, 16.3, 14.7. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C31H50NaO3 493.3658; found 493.3651.
Rearrangement of Epoxide 15. Method D: To a solution of
epoxide 15 (150 mg, 0.309 mmol) in methanol (5 mL) and
dichloromethane (5 mL) was slowly added acetyl chloride (100 μL),
and the mixture was stirred at room temperature for 24 h. The
reaction was quenched with Et3N (1.0 mL), and the solvents were
evaporated under reduced pressure. Column chromatography of the
residue (hexane−ethyl acetate, 30:1) gave diene 19 (115 mg, 88%, a
foam) as the only product.
Method E: To a solution of epoxide 15 (200 mg, 0.413 mmol) in
chloroform (10 mL) was added montmorillonite K10 (400 mg), and
the mixture was stirred at 50 °C (an oil bath) for 24 h. The precipitate
was then removed by filtration through a short silica gel pad, and the
solvents were evaporated under reduced pressure. The residue was
purified by preparative TLC (hexane−ethyl acetate, 20:1) to yield an
inseparable mixture of olefins 20 and 21 (95 mg, 49%), olefin 22 (33
mg, 17%), and ketone 23 (25 mg, 13%), all as foams.
(CO), 139.9 (C-3 or C-5), 136.1 (C-3 or C-5), 57.1, 51.1, 49.8,
49.3, 48.9, 44.2, 42.3, 41.8, 41.0, 38.6, 37.3, 33.0, 32.0, 30.0, 29.8,
27.4, 27.0, 26.3, 23.7, 23.0, 22.8, 21.9, 21.3, 19.8, 18.9, 14.7, 14.5,
14.5.
14 (selected data): 13C{1H} NMR (125 MHz, CDCl3) δ: 176.9
(CO), 141.6 (C-3 or C-5), 131.3 (C-3 or C-5), 59.2, 57.3, 51.1,
48.6, 44.0, 42.7, 42.7, 40.5, 39.3, 37.4, 37.1, 31.8, 30.6, 29.9, 29.8,
27.5, 27.0, 26.5, 26.3, 25.6, 23.1, 22.9, 22.9, 18.0, 17.0, 14.6.
HRMS (ESI-TOF) for a mixture of 13 and 14 m/z: [M + Na]+
calcd for C31H50O2Na 477.3709; found 477.3710.
Epoxidation of Olefins 10 and 11. To a solution of olefins 10 and
11 (3.100 g, 6.613 mmol) in chloroform (100 mL) were added m-
chloroperbenzoic acid (75%, 1.96 g, 8.51 mmol) and NaHCO3 (1.43
g, 17.00 mmol), and the mixture was stirred at room temperature for
12 h and then washed with a 10% solution of Na2S2O3 (10 mL) and a
saturated solution of NaHCO3 (5 mL). The organic layer was
separated, and the aqueous layer was extracted with chloroform (20
mL) twice. Combined organic extracts were concentrated under
reduced pressure. Column chromatography of the residue (hexane−
ethyl acetate, 20:1) gave epoxide 15 (1.700 g, 53%) and epoxide 16
(930 mg, 29%), both as a foam. Yields of individual epoxides varied
and depended on the ratio of olefins in the starting mixture.
Method F: To a solution of epoxide 15 (300 mg, 0.619 mmol) in
benzene (20 mL) was added BF3·Et2O (160 μL), and the mixture was
stirred at room temperature for 4 h. The reaction was quenched with
Et3N (1.0 mL), and the solvents were partially removed under
reduced pressure. The residue was purified by column chromatog-
raphy (hexane−ethyl acetate, 20:1) to give olefin 20 (215 mg, 74%)
as the sole product.
20
Data for 15. [α]D −4.9 (c 0.25, chloroform). νmax (film): 2958,
1
2868, 1739, 1639, 1459, 1386, 1364, 1238, 1032, 755 cm−1. H (600
MHz, CDCl3) and 13C{1H} NMR (150 MHz, CDCl3): see Tables 1
and 2. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C32H52O3Na
507.3814; found 507.3816.
20
20
Data for 16. [α]D −8.1 (c 0.25, chloroform). νmax (film): 2955,
Data for 19. [α]D +24.1 (c 0.25, chloroform). νmax (film): 2955,
2869, 1739, 1458, 1386, 1365, 1235, 1032, 756 cm−1. 1H (600 MHz,
CDCl3) and 13C{1H} NMR (150 MHz, CDCl3): see Tables 1 and 2.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C32H52O3Na 507.3814;
found 507.3820.
2868, 1704, 1676, 1462, 1383, 1368, 1216, 1026, 757 cm−1. 1H (600
MHz, CDCl3) and 13C{1H} NMR (150 MHz, CDCl3): see Tables 1
and 2. HRMS (EI) m/z: [M]+ calcd for C30H48O [M]+ 424.3705;
found 424.3705.
20
Epoxidation of Olefins 13 and 14. Starting from a mixture of 13
and 14 (2.165 g, 4.760 mmol), and following the procedure above
that was used for 10 and 11, epoxides 17 (1.303 g, 58%) and 18 (550
mg, 25%) were obtained as foams. Yields of individual epoxides varied
and depended on the ratio of olefins in the starting mixture.
Data for 20. [α]D +2.7 (c 0.25, chloroform). νmax (film): 2955,
2870, 1739, 1456, 1385, 1366, 1237, 1032, 757 cm−1. 1H (600 MHz,
C6D6) and 13C{1H} NMR (150 MHz, C6D6): see Tables 1 and 2.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C32H50NaO2 489.3709;
found 489.3700.
20
1
Data for 17. [α]D −4.1 (c 0.25, chloroform). νmax (film): 2957,
Data for 21. H (600 MHz, CDCl3) and 13C{1H} NMR (150
1
2868, 1773, 1729, 1457, 1385, 1217, 1161, 1133, 988, 756 cm−1. H
MHz, CDCl3): see Tables 1 and 2.
20
NMR (500 MHz, CDCl3) δ (selected signals): 3.66 (s, 3 H, OMe),
1.06 (d, 3 H, J 6.8 Hz, CH3), 1.01 (s, 3 H, CH3), 1.00 (s, 3 H, CH3),
0.95 (d, 3 H, J 7.0 Hz, CH3), 0.85 (d, 3 H, J 6.8 Hz, CH3), 0.84 (s, 3
H, CH3), 0.75 (d, 3 H, J 6.8 Hz, CH3). 13C{1H} NMR (125 MHz,
CDCl3) δ: 176.9 (CO), 76.4 (C), 75.9 (C), 57.0 (C), 51.1, 48.9,
44.2, 43.4 (C), 43.3, 42.8 (C), 40.8 (C), 38.4, 37.3 (CH2), 34.6
(CH2), 32.1 (CH2), 29.8 (CH2), 29.7, 28.5, 26.7 (CH2), 23.2 (CH2),
23.0 (CH, CH2), 22.8 (CH2), 20.2 (CH2), 19.1, 18.4, 17.9, 15.4, 14.7,
14.6. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C31H50NaO3
493.3658; found 493.3654.
Data for 22. [α]D −29.6 (c 0.2, chloroform). νmax (film): 3465,
2956, 2869, 1698, 1459, 1385, 1368, 1029, 756 cm−1. 1H (600 MHz,
CDCl3) and 13C{1H} NMR (150 MHz, CDCl3): see Tables 1 and 2.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C32H52NaO3 507.3814;
found 507.3815.
20
Data for 23. [α]D +20.6 (c 0.2, chloroform). νmax (film): 2957,
2869, 1736, 1467, 1388, 1237, 1032, 756 cm−1. 1H (600 MHz,
CDCl3) and 13C{1H} NMR (150 MHz, CDCl3): see Tables 1 and 2.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C32H52NaO3 507.3814;
found 507.3810.
Data for 18. [α]D20 −11.4 (c 0.20, chloroform). νmax (film): 2954,
Deacetylation of 20. A mixture of acetate 20 (100 mg, 0.214
mmol) and KOH (50 mg) in ethyl alcohol (5 mL) was refluxed for 1
h (an oil bath) and then evaporated under reduced pressure. The
residue was suspended in water (5 mL) and extracted with ethyl
acetate (4 × 10 mL). The combined organic extracts were evaporated
under reduced pressure and purified by column chromatography
(hexane−ethyl acetate, 5:1) to afford 24 (70 mg, 77%) as a foam.
1
2870, 1728, 1454, 1368, 1221, 1192, 1160, 984, 896, 756 cm−1. H
NMR (500 MHz, CDCl3) δ (selected signals): 3.66 (s, 3 H, OMe),
1.02 (s, 3 H, CH3), 0.97 (s, 3 H, CH3), 0.91 (d, 3 H, J 6.4 Hz, CH3),
0.90 (d, 3 H, J 6.4 Hz, CH3), 0.87 (d, 3 H, J 7.0 Hz, CH3), 0.87 (s, 3
H, CH3), 0.77 (d, 3 H, J 6.8 Hz, CH3). 13C{1H} NMR (125 MHz,
CDCl3) δ: 176.7 (CO), 78.2 (C), 68.0 (C), 58.1, 57.0 (C), 51.2,
I
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1
1
[α]D +27.6 (c 0.3, chloroform). H NMR (600 MHz, CDCl3) δ:
5.26−5.27 (m, 1 H, H-11), 3.84 (dd, 1 H, J 1.9, 11.0 Hz, H-28), 3.35
(dd, 1 H, J 1.1, 10.9 Hz, H-28), 2.33−2.37 (m, 1 H), 2.14−2.19 (m, 2
H), 1.92−1.98 (m, 5 H), 1.44−1.85 (m, 12 H), 1.31−1.36 (m, 1 H),
0.72−1.36 (m, 3 H), 1.02 (s, 3 H, CH3), 0.99 (s, 3 H, CH3), 0.88 (s, 3
H, CH3), 0.87 (d, 3 H, J 6.8 Hz, CH3), 0.86 (d, 3 H, J 6.8 Hz, CH3),
0.80 (d, 3 H, J 6.8 Hz, CH3), 0.67 (d, 3 H, J 6.8 Hz, CH3). 13C{1H}
NMR (150 MHz, CDCl3) δ: 142.6 (CC), 139.2 (CC), 132.7
(CC), 117.8 (C-11), 60.4 (C-28), 53.4 (C), 48.2, 47.8 (C), 45.3,
40.5 (C), 39.2 (C), 34.3, 33.7 (CH2), 33.6, 29.9 (CH2), 29.7 (CH2),
29.3 (CH2), 29.2, 28.9 (CH2), 28.6 (CH2), 27.4 (CH2), 25.2, 23.0,
21.8 (CH2), 20.5, 19.5 (CH2), 18.4, 17.6, 15.7, 14.9. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C30H49O 425.3783; found 425.3780.
Rearrangement of Epoxide 17. Starting from epoxide 17 (118 mg,
0.250 mmol), and following method F, diene 25 (81 mg, 72%) was
Data for 30. Mp 142−145 °C (chloroform−methanol). H (600
MHz, C6D6) and 13C{1H} NMR (150 MHz, C6D6): see Tables 1 and
2. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C31H48NaO2
475.3552; found 475.3552.
Data for 31. [α]D20 −34.6 (c 0.20, chloroform). νmax (film): 2954,
2869, 1726, 1704, 1453, 1379, 1189, 1159, 1133, 998, 756 cm−1. H
1
(600 MHz, CDCl3) and 13C{1H} NMR (150 MHz, CDCl3): see
Tables 1 and 2. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C31H50NaO3 493.3658; found 493.3660.
Reduction of 29. A solution of 29 (207 mg, 0.427 mmol) in THF
(3 mL) was added to a suspension of LiAlH4 (160 mg, 4.2 mmol) in
THF (7 mL) and refluxed (an oil bath) under an argon atmosphere
for 4 h, cooled to room temperature, and then sat. NH4Cl (few drops)
and ethyl acetate (5 mL) were added. The whole mixture was filtered
through a short silica pad, eluted with hexane−ethyl acetate (1:1),
and evaporated to dryness. To the residue were added pyridine (3
mL) and acetic anhydride (2 mL), and the mixture was stirred at
room temperature for 2 days. Solvents were coevaporated with
toluene under reduced pressure. Preparative TLC (hexane−ethyl
acetate, 9:1) of the residue afforded recovered starting material (29,
75 mg, 36%) and 33 (96 mg, 43%, a foam).
20
obtained as a foam. [α]D +22.7 (c 0.25, chloroform). νmax (film):
2954, 2871, 1730, 1455, 1368, 1191, 1148, 758 cm−1. 1H (600 MHz,
CDCl3) and 13C{1H} NMR (150 MHz, CDCl3): see Tables 1 and 2.
HR- HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C31H48NaO2
475.3552; found 475.3539.
Rearrangement of Epoxide 16. Starting from epoxide 16 (90 mg,
0.186 mmol), and following method D, diene 26 (50 mg, 63%) and
bridged ketone 27 (19 mg, 23%) were obtained, both as foams.
Starting from epoxide 16 (291 mg, 0.600 mmol), and following
method E, bridged ketone 29 (233 mg, 80%, a colorless solid) was
obtained.
20
1
Data for 33. [α]D −10.2 (c 0.2, chloroform). H (600 MHz,
CDCl3) and 13C{1H} NMR (150 MHz, CDCl3): see Tables 1 and 2.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C32H54NaO3 509.3971;
found 509.3965.
Dehydration of 33. To a solution of 33 (115 mg, 0.236 mmol) in
pyridine (3 mL) was added POCl3 (250 μL, 2.7 mmol), and the
mixture was stirred at 60 °C (an oil bath) overnight. Aqueous workup
followed by extraction with dichloromethane, evaporation of the
solvent, and chromatography (hexane−ethyl acetate, 9:1) yielded 34
(99 mg, 89%, a foam), slightly contaminated by olefin 11.
20
Data for 26. [α]D −7.5 (c 0.3, chloroform). 1H (600 MHz,
CDCl3) and 13C{1H} NMR (150 MHz, CDCl3): see Tables 1 and 2.
HRMS (EI) m/z: [M]+ calcd for C30H48O 424.3705; found 424.3708.
20
Data for 27. [α]D −33.2 (c 0.3, chloroform). νmax (film): 3465,
2956, 2869, 1697, 1458, 1385, 1367, 1215, 1028, 755 cm−1. 1H NMR
(500 MHz, CDCl3) δ: 3.72 (d, 1 H, J 10.9 Hz, H-28), 3.33 (d, 1 H, J
10.9 Hz, H-28), 2.56−2.62 (m, 1 H), 2.40−2.46 (m, 1 H), 1.58-.194
(m, 13 H), 1.43-.152 (m, 4 H), 1.01−1.33 (m, 8 H), 1.17 (s, 3 H,
CH3), 1.06 (s, 3 H, CH3), 0.90 (d, 3 H, J 6.8 Hz, CH3), 0.86 (s, 3 H,
CH3), 0.85 (d, 3 H, J 6.8 Hz, CH3), 0.79 (d, 3 H, J 6.8 Hz, CH3), 0.71
(d, 3 H, J 6.8 Hz, CH3). 13C{1H} NMR (125 MHz, CDCl3) δ: 221.0
(CO), 60.6 (CH2), 55.2, 53.0 (C), 48.2 (C), 47.9 (C), 47.1 (C),
47.0, 44.1, 43.0 (C), 40.9 (CH2), 37.5, 35.8 (CH2), 34.1 (CH2), 29.8
(CH2), 29.4, 28.4 (CH2), 28.3, 27.8 (CH2), 26.8 (CH2), 24.0, 22.9,
22.1 (CH2), 21.7 (CH2), 21.6 (CH2), 20.9, 19.4, 18.6, 15.7, 14.9.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C30H51O2 [M + H]+
443.3889; found 443.3866.
Data for 34. H (600 MHz, CDCl3) and 13C{1H} NMR (150
1
MHz, CDCl3): see Tables 1 and 2. HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C32H52NaO2 491.3865; found 491.3865.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02560.
Crystal structure determination of compounds 29 and
30; key HMBC and NOE correlations; copies of 1H and
13C{1H} NMR spectra for compounds 10, 11, 13−20,
22−31, 33, and 34 (PDF)
20
Data for 29. [α]D −31.7 (c 0.3, chloroform). Mp 155−157 °C
(chloroform−methanol). νmax (film): 2956, 2870, 1739, 1704, 1459,
1387, 1365, 1236, 1031, 756 cm−1. 1H (600 MHz, C6D6) and
13C{1H} NMR (150 MHz, C6D6): see Tables 1 and 2. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C32H52NaO3 507.3817; found
507.3813.
Accession Codes
CCDC 1999008 and 2038963 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Acetylation of 26. A solution of 26 (24 mg, 0.057 mmol) in
pyridine (2 mL) and acetic anhydride (1 mL) was stirred at room
temperature for 24 h and then coevaporated with toluene under
reduced pressure. Preparative TLC (hexane−ethyl acetate, 20:1) of
the residue afforded 28 (25 mg, 96%) as a foam. [α]D20 −34.4 (c 0.20,
AUTHOR INFORMATION
Corresponding Author
■
1
chloroform). H (600 MHz, CDCl3) and 13C{1H} NMR (150 MHz,
CDCl3): see Tables 1 and 2. HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C32H50NaO2 489.3709; found 489.3700.
Zbigniew Pakulski − Institute of Organic Chemistry, Polish
Academy of Sciences, 01-224 Warsaw, Poland; orcid.org/
0000-0002-8085-0050; Email: zbigniew.pakulski@
icho.edu.pl
Deacetylation of 29. A mixture of acetate 29 (80 mg, 0.165 mmol)
and KOH (30 mg) in ethyl alcohol (5 mL) was refluxed for 1 h (an
oil bath) and then evaporated under reduced pressure. The residue
was suspended in water (3 mL) and extracted with ethyl acetate (4 ×
10 mL). Combined organic extracts were evaporated under reduced
pressure and purified by column chromatography (hexane−ethyl
acetate, 7:1) to afford 27 (62 mg, 85%) as a foam.
Rearrangement of Epoxide 18. Starting from epoxide 18 (74 mg,
0.157 mmol), and following method D, diene 30 (49 mg, 69%) and
bridged ketone 31 (20 mg, 27%) were obtained as foams.
Authors
Piotr Cmoch − Institute of Organic Chemistry, Polish
Academy of Sciences, 01-224 Warsaw, Poland; orcid.org/
0000-0002-8413-9290
Anna Korda − Institute of Organic Chemistry, Polish Academy
of Sciences, 01-224 Warsaw, Poland
Roman Luboradzki − Institute of Physical Chemistry, Polish
Academy of Sciences, 01-224 Warsaw, Poland
Starting from epoxide 18 (119 mg, 0.253 mmol), and following
method E, bridged ketone 31 (89 mg, 75%) was obtained as a foam.
J
https://dx.doi.org/10.1021/acs.joc.0c02560
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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Article
̌
(15) Borkova, L.; Adamek, R.; Kalina, P.; Drasar, P.; Dzubak, P.;
Gurska, S.; Rehulka, J.; Hajduch, M.; Urban, M.; Sarek, J. Synthesis
and cytotoxic activity of triterpenoid thiazoles derived from
allobetulin, methyl betulonate, methyl oleanonate, and oleanonic
acid. ChemMedChem 2017, 12, 390−398.
Katarzyna Gwardiak − Institute of Organic Chemistry, Polish
Academy of Sciences, 01-224 Warsaw, Poland
Romuald Karczewski − Institute of Organic Chemistry, Polish
Academy of Sciences, 01-224 Warsaw, Poland
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02560
(16) Kahnt, M.; Heller, L.; Grabandt, P.; Al-Harrasi, A.; Csuk, R.
Platanic acid: a new scaffold for the synthesis of cytotoxic agents. Eur.
J. Med. Chem. 2018, 143, 259−265.
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Notes
The authors declare no competing financial interest.
(18) Chrobak, E.; Kadela-Tomanek, M.; Beb̧ enek, E.; Marciniec, K.;
ACKNOWLEDGMENTS
Wietrzyk, J.; Trynda, J.; Pawełczak, B.; Kusz, J.; Kasperczyk, J.;
■
́
Chodurek, E.; Paduszynski, P.; Boryczka, S. New phosphate
derivatives of betulin as anticancer agents: Synthesis, crystal structure,
This work was financially supported by the National Science
Centre, Poland (grant no. 2016/21/B/ST5/02141).
and molecular docking study. Bioorg. Chem. 2019, 87, 613−628.
(19) Kadela-Tomanek, M.; Beb̧ enek, E.; Chrobak, E.; Marciniec, K.;
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Latocha, M.; Kusmierz, D.; Jastrzeb̧ ska, M.; Boryczka, S. Betulin-1,4-
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