Wagner-Meerwein rearrangement of steviol 16α,17- and 15α,16-epoxides

Article abstract of DOI:10.1134/S1070428010070080

16α,17- and 15α,16-Epoxy derivatives of diterpenoid steviol having ent-kaurane structure were found for the first time to undergo Wagner-Meerwein rearrangement in alkaline medium or by the action of boron trifluoride-diethyl ether complex to give products

Full text of DOI:10.1134/S1070428010070080

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 7, pp. 1006–1012. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © R.N. Khaibullin, I.Yu. Strobykina, V.E. Kataev, O.A. Lodochnikova, A.T. Gubaidullin, A.A. Balandina, Sh.K. Latypov, 2010,
published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 7, pp. 1010–1015.
Wagner–Meerwein Rearrangement of Steviol 16α,17-
and 15α,16-Epoxides
R. N. Khaibullin, I. Yu. Strobykina, V. E. Kataev, O. A. Lodochnikova, A. T. Gubaidullin,
A. A. Balandina, and Sh. K. Latypov
Arbuzov Institute of Organic and Physical Chemistry, Kazan Research Center, Russian Academy of Sciences,
ul. Arbuzova 8, Kazan, 420088 Tatarstan, Russia
e-mail: kataev@iopc.ru
Received July 9, 2009
Abstract—16α,17- and 15α,16-Epoxy derivatives of diterpenoid steviol having ent-kaurane structure were
found for the first time to undergo Wagner–Meerwein rearrangement in alkaline medium or by the action of
boron trifluoride–diethyl ether complex to give products with ent-beyerane structure. The geometric parameters
of steviol 16α,17- and 15α,16-epoxides were determined by X-ray analysis.
DOI: 10.1134/S1070428010070080
In the recent years, studies on biotransformations of
diterpenoid steviol (I, 13-hydroxy-ent-kaur-16-en-19-
oic acid) having ent-kaurane structure and its epoxy
derivative II have been reported [1–4]. Epoxide
hydrolases isolated from various microorganisms are
universal biocatalysts for asymmetric hydrolysis of
epoxides [4], and alcohols thus formed exhibit diverse
biological activity, in particular hormone [3] and anti-
hyperglycemic [2]. As concerns chemical modification
of steviol epoxides II and V, their hydrolysis in the
presence of mineral [5] and Lewis acids [6] and
reduction with lithium tetrahydridoaluminate [6] were
reported (Schemes 1, 2). In most cases, these reactions
are accompanied by the Wagner–Meerwein rearrange-
ment with formation of products having ent-beyerane
(isosteviol) skeleton, i.e., compounds IV (Scheme 1)
[5, 6], VI, and VII [6] (Scheme 2). In the present
article we describe opening of the oxirane rings in
steviol 16α,17- and 15α,16-epoxides II and V by the
action of Lewis acid (boron trifluoride–diethyl ether
complex BF3·Et2O).
Epoxide II was synthesized by oxidation of steviol
(I) with m-chloroperoxybenzoic acid by analogy to the
procedure reported in [7]. Compound II was assigned
Scheme 1.
OH
Me
OH
Me
OH
OH
12
20
Me
17
CH2
Me
11
13
COOH
Me
14
16
O
III
9
6
1
4
8
2
3
10
15
7
5
1C7 H2OH
O
18
Me
19
COOH
Me
COOH
Me
I
II
Me
COOH
IV
1006

WAGNER–MEERWEIN REARRANGEMENT OF STEVIOL 16α,17- AND 15α,16-EPOXIDES
1007
Scheme 2.
Me
OH
OH
Me
Me
Me
Me
O
O
WCl6
LiAlH4
OH
O
Me
Me
Me
COOMe
COOMe
CH2OH
VII
V
VI
the 16α (or 16S) configuration on the basis of indirect
data, namely taking into account the configuration of
C16 in III [6]. We were the first to determine the
molecular structure of II by X-ray analysis (Fig. 1).
We showed that the oxidation of steviol I under the
above conditions is completely stereoselective and that
the only product is 16α,17-epoxide II having S con-
figuration of C16.
and 1.26 ppm due to C20H3 and C18H3 groups in ent-
beyerane [9], and doublets at δ 3.51 and 3.64 ppm,
which belong to methylene protons of hydroxymethyl
group. These data indicated that the second reaction
product is 17-hydroxy-ent-16-oxobeyeran-l9-oic acid
(IV), i.e., diterpenoid having ent-beyerane (isosteviol)
structure. Compound IV was obtained previously [6]
by acid hydrolysis of 16α,17-epoxide II. According to
1
the H NMR data, compounds IV and VIII were
Alkaline hydrolysis of 16α,17-epoxide II on heat-
ing in 1.5% aqueous potassium hydroxide at the
boiling point gave a mixture of two compounds which
we failed to separate (Scheme 3). The absence of dou-
blet signals at δ 2.78 and 2.92 ppm (which are typical
of the methylene group in the oxirane ring of com-
formed in equal amounts. The above assignment of
signals from the C20H3, C18H3, and 15α-H protons is
also consistent with the data reported in [6, 10]. How-
ever, there is ambiguity in the assignment of the dou-
blet signal at δ 2.18 ppm (J = 13 Hz), which (as well as
the doublet of doublets from 15α-H at δ 2.68 ppm)
appears in a weaker field relative to most other proton
signals of isosteviol skeleton. The signal at δ 2.18 ppm
was previously assigned to 12-H [6, 10]. Later on, this
assignment was shown to be invalid both experimen-
tally and theoretically [9]. Nevertheless, erroneous as-
1
pound II) in the H NMR spectrum of the product
mixture indicated that the hydrolysis was complete.
The formation of the expected product of oxirane ring
opening, 13,16,17-trihydroxy-ent-kaur-19-oic acid,
1
followed from the presence in the H NMR spectrum
of doublets at δ 3.63 and 3.81 ppm corresponding to
methylene protons in the hydroxymethyl group on C16
and signals at δ 0.94 and 1.22 ppm due to protons in
the ent-kaurane C20H3 and C18H3 methyl groups. The
observed chemical shifts and spin–spin coupling con-
stants in the 1H NMR spectrum of the reaction mixture
are consistent with those reported for 13α,16α,17-tri-
hydroxy-ent-kaur-19-oic acid (VIII) which was syn-
thesized by enzymatic hydrolysis of suavioside isolat-
ed from sweet leaves of Rubus Suavissimus [8].
1
signment of H NMR signals still may be encountered
while analyzing the spectra of other metabolites of the
ent-kaurane and ent-beyerane series (see, e.g., [11]).
Probable reasons are considerable overlap of signals in
1
the H NMR spectra (which makes unambiguous cor-
1
relation in the 2D H–1H COSY spectrum impossible)
C3
C2
C18
C1
C10
C5
C9
C4
Scheme 3.
C11
H301
C17
O1
C15
OH
C19
O2
C6
CH2OH
Me
C7
C16
C8
OH–
OH
C20
C12
C13
O3
II
+
IV
H302
O4
H2
C14
Me
COOH
H3
VIII
1
The H NMR spectrum also contained a doublet of
doublets at δ 2.68 ppm, which is typical of the 15α-H
proton in ent-beyerane skeleton [9], singlets at δ 0.81
Fig. 1. Structure of the molecule of steviol 16α,17-epoxide
(II) according to the X-ray diffraction data; selected hydro-
gen atoms are shown.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

KHAIBULLIN et al.
1008
14-Heq
15-H
2.6
(e)
14-Hax
12-Heq
3.6
3.4
3.2
3.0
2.8
2.4
2.2
2.0
1.8
1.6
1.4
1.2
14-Hax
1.0
δ, ppm
(d)
12-Heq
12-Hax
14-Heq
3.6
3.6
3.4
3.4
3.2
3.2
3.0
3.0
2.8
2.8
2.6
2.6
2.4
2.4
2.2
2.2
2.0
2.0
1.8
1.6
1.6
1.4
1.2
3-Hax
1.0
1.0
δ, ppm
1-Hax
2-Hax
(c)
1-Heq
2-Heq
1.8
1.8
1.4
1.4
1.2
18-H
δ, ppm
(b)
3.6
3.4
3.2
3.0
2.8
2.6
2.4
2.2
2.0
1.6
1.6
1.2
1.2
1.0
1.0
δ, ppm
17-H
(a)
15-Hα
3-Heq
3.6
3.4
3.2
3.0
1
2.8
2.6
2.4
2.2
2.0
1.8
1.4
1
δ, ppm
Fig. 2. Upfield region of the H NMR spectra of compound IV (600 MHz, CDCl3, 30°C). (a) H NMR spectrum; (b, d) 1D
DPFGNOE spectra; (c, e) 1D TOCSY spectra; irradiated protons are indicated with arrows.
and similarity of the resonance frequencies of the C3
and C12 nuclei [9].
(AB spin system, δ 3.64–3.51 ppm) relative to the other
protons in the ent-beyerane skeleton, gives distinct
NOEs on signals at δ 1.86, 1.80, 1.37, and 1.31 ppm
(Fig. 2d). The latter should belong only to closely
located protons, namely to 12-H or 14-H but not to
3-H. In this case, no response was observed on the
doublet signal at δ 2.18 ppm; therefore, the corre-
sponding proton is remote from the hydroxymethyl
group, i.e., it cannot be a proton on C12. According to
the 1D TOCSY spectrum with excitation of the 15α-H
proton, doublets of doublets at δ 1.86 and 1.31 ppm
belong to C14H2 (Fig. 2e). Then the doublets of dou-
blets at δ 1.80 and 1.37 ppm (Fig. 2d) correspond to
resonance of protons on C12, the first of these belong-
ing to 12-Heq. The same also follows from the appear-
ance of the corresponding signal in the 1D TOCSY
spectrum upon excitation of 15α-H (Fig. 2e).
In this respect, compound IV isolated as individual
substance provides one more chance to demonstrate
without ambiguity that the conclusions drawn in [9]
are valid, i.e., there was confusion in the assignment of
1
the 3-H and 12-H signals. Analysis of the H NMR
spectra of compound IV allowed us to independently
correlate the position of signals from 3-H and 12-H
with clearly identifiable signals from the C18H3 and
C17H2OH protons. On the one hand, taking into ac-
count that the assignment of the C18H3 signal is beyond
doubt, this signal can be used as reference. Nuclear
Overhauser effect [12–14] observed on the C18H3
singlet upon irradiation at a frequency corresponding
to proton resonating at δ 2.18 ppm (Fig. 2b) indicates
spatial proximity of these protons. Therefore, the
signal at δ 2.18 ppm should be assigned to only 3-Heq.
The 1D TOCSY spectrum [12–14] of compound IV
with excitation of 3-Heq (Fig. 2c) made it possible to
isolate coupled spin system consisting of protons in
Thus the doublet at δ 2.18 ppm was unambiguously
assigned to 3-Heq. Correct assignment of that signal is
important, for it is characteristic not only of isosteviol
derivatives having ent-beyerane structure (e.g., IV, VI,
and VII) but also of metabolites of the ent-kaurane
series having no other substituents in the A ring than
the carboxy group on C4.
1
the A ring from overlapped signals in the H NMR
spectrum of IV. On the other hand, irradiation of the
C17H2 protons in IV, which resonate in a weaker field
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

WAGNER–MEERWEIN REARRANGEMENT OF STEVIOL 16α,17- AND 15α,16-EPOXIDES
1009
Scheme 4.
CHO
Me
Me
BF3 ·Et2O
O
Me
Me
COOMe
COOMe
IX
X
BF3 ·Et2O
BF3 ·Et2O
II
IV
OH
Me
Me
Me
Me
O
OH
O
Me
Me
COOH
COOH
XI
XII
In the IR spectrum of the product mixture we
observed strong broadened absorption bands at
1698 cm–1 and in the region 2600–2700 cm–1, which
are typical of carboxy group; in addition, a band at
3436 cm–1 was present due to stretching vibrations of
hydroxy group. The mass spectrum of the product
mixture contained molecular ion peaks with m/z 334
and 352, which belong to ent-beyerane and ent-kaur-
ane derivatives IV and VIII, respectively.
XI having a hydroxy group on C13 (unlike ent-kaur-
enoic acid methyl ester IX) gave products with ent-
beyerane structure, compounds IV and XII in quanti-
tative yield (Scheme 4). The product obtained from
16α,17-epoxide was identical to previously described
kaurenoid IV [5–7], whose formation may be ration-
alized by generation of carbocationic center on C16 as
a result of electrophilic attack by Lewis acid and sub-
sequent stabilization of the carbocation via 1,2-hydride
shift (Wagner–Meerwein rearrangement).
When alkaline hydrolysis of 16α,17-epoxide II was
carried out under more severe conditions (heating for
12 h in 10% aqueous KOH in a sealed ampule), the
fraction of product IV having ent-beyerane structure
increased approximately twofold (according to the
1H NMR data).
1
The H NMR spectrum of the product obtained
from 15α,16-epoxide XI in the presence of boron tri-
fluoride–diethyl ether complex lacked doublet at
δ 2.72 ppm, corresponding to the 15β-H proton in the
oxirane ring of XI, while a doublet at δ 3.38 ppm
appeared. In keeping with the data of [6], the latter
signal belongs to 14β-H in XII. These data indicated
Well known rearrangement of epoxides into car-
bonyl compounds by the action of Lewis acids is
widely used in organic synthesis [15–18]. When boron
trifluoride–diethyl ether complex BF3·Et2O is used as
Lewis acid, fluorohydrins [17], unsaturated alcohols,
or dienes [18] may be formed, depending on the sub-
strate structure and reaction conditions. As concerns
epoxy derivatives of the ent-kaurane series, steviol
15α,16-epoxide methyl ester (V) in the presence of
WCl6 underwent rearrangement into 14α-hydroxyiso-
steviol (VII) having ent-beyerane structure [6]
(Scheme 2), while ent-kaurane 16α,17-epoxide IX in
the presence of BF3·Et2O gave rise to aldehyde X with
ent-kaurane structure [19] (Scheme 4). We found that
the direction of the latter reaction strongly depends on
the presence (or absence) of a hydroxy group on C13.
The reactions of boron trifluoride–diethyl ether com-
plex with steviol 16α,17- and 15α,16-epoxides II and
C3
C1
C2
H15
C15
C18
C11
C16
C4
C9
C5
C10
C17
O19
C8
C19
O20
C12
C7
C6
C20
O1
C14
C13
H1
O2
H2
Fig. 3. Structure of the molecule of steviol 15α,16-epoxide
(XI) according to the X-ray diffraction data; selected hydro-
gen atoms are shown.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

KHAIBULLIN et al.
1010
that the conversion of XI was complete. The formation
of compound XII might be expected, for opening of
the 15α,16-oxirane ring in epoxide XI as a result of
electrophilic attack by Lewis acid should generate
more stable C16-centered carbocation which promotes
Wagner–Meerwein skeletal rearrangement leading to
ent-beyerane structure XII with α-oriented hydroxy
acetone–hexane. The X-ray diffraction data for com-
pound II were acquired on a SMART Apex II
diffractometer [graphite monochromator, λ(MoKα) =
0.71073 Å], and single crystals of XI were analyzed on
a Kappa Apex diffractometer [graphite monochro-
mator, λ(CuKα) = 1.54184 Å, 293 K]. The structures
were solved by the direct method. The positions and
thermal parameters of non-hydrogen atoms were re-
fined first in isotropic and then in anisotropic approxi-
mation by the full-matrix least-squares procedure.
Hydrogen atoms were placed into positions calculated
on the basis of geometry considerations and were
refined using the riding model. All calculations were
performed with the aid of SHELXL-97 software
package [20]. The absolute configuration of molecules
II and XI was set in accordance with the absolute con-
figuration of (16S)-dihydrosteviol, which was deter-
mined by us previously [21] with a high accuracy. The
complete sets of crystallographic data for structures II
and XI were deposited to the Cambridge Crystallo-
graphic Data Centre (entry nos. CCDC 726865 and
726866, respectively).
1
group on C14 (14R). In the H NMR spectrum of XII
we observed characteristic singlets at δ 0.82, 1.04, and
1.27 ppm due to protons in the C20H3, C17H3, and
C18H3 methyl groups and a doublet of doublets at
δ 2.53 ppm, which is typical of 15α-H in the ent-
beyerane skeleton [9].
We were the first to determine the molecular struc-
ture of epoxide XI by X-ray analysis (Fig. 3). Com-
pound XI was synthesized according to the procedure
described in [6] by epoxidation of a mixture of steviol
(I) and its Δ15-isomer. The (15R,16R) configuration of
the oxirane ring in XI corresponds to the 15α,16 con-
figuration of methyl ester V, which was determined by
1H NMR spectroscopy [6].
Thus we found for the first time that steviol 16α,17-
and 15α,16-epoxides having ent-kaurane structure
undergo Wagner–Meerwein rearrangement in alkaline
medium or in the presence of boron trifluoride–diethyl
ether complex to give products with ent-beyerane
skeleton.
Compound II. Monoclinic crystals; at 20°C: a =
11.5419(14), b = 7.6985(9), c = 11.761(2) Å; β =
119.100(2)°; V = 913.1(2) Å3; Z = 2; dcalc = 1.216 g×
cm–3; space group P21; μ = 0.83 cm–1. Total of 7719
reflection intensities were measured, 2107 of which
were characterized by I ≥ 2σ(I). The final divergence
factors were R = 0.035, RW = 0.094.
EXPERIMENTAL
Compound XI. Tetragonal crystals; at 20°C: a =
7.2837(2), b = 7.2837(2), c = 68.681(2) Å; V =
3643.7(2) Å3; Z = 8; dcalc = 1.219 g/cm3; space group
P43212; μ = 6.66 cm–1. Total of 7123 reflection intens-
ities were measured, 1985 of which were characterized
by I ≥ 2σ(I). The final divergence factors were R =
0.039, RW = 0.122.
1
The H NMR spectra were recorded at 30°C on
a Bruker Avance-600 spectrometer at 600 MHz using
CDCl3 as solvent and reference (CHCl3, δ 7.26 ppm).
Nuclear Overhauser effects were measured using 1D
DPFGNOE pulse sequence [14]. The IR spectra were
recorded in the range from 400 to 3600 cm–1 on
a UR-20 spectrometer and in the range from 400 to
4000 cm–1 on a Bruker Vector 22 instrument with
Fourier transform. Crystalline samples were examined
as dispersions in mineral oil or KBr pellets. The mass
spectra (electron impact, 60 eV) were obtained on
an MKh-1310 mass spectrometer at a resolution R of
10 000 with direct sample admission into the ion
source (electron collector current 30 μA, ion source
temperature 120°C, direct inlet probe temperature
120–250°C). Precise m/z values were determined using
perfluorokerosene as reference.
Physicochemical studies of the synthesized com-
pounds were performed at the Optical Spectroscopy,
Mass Spectrometry, NMR, and X-Ray Analysis De-
partments of the Federal Collective Spectral and
Analytical Center for Physicochemical Studies on the
Structure, Properties, and Composition of Substances
and Materials.
Silica gel (Chemapol) was used as sorbent for
column chromatography. The reaction mixtures were
analyzed by TLC on Silufol UV-254 plates.
Steviol 16α,17-epoxide (II, 16α,17-epoxy-13-hy-
droxy-ent-kauran-19-oic acid) was synthesized ac-
cording to the procedure described in [7]. Yield 80%,
mp 187–190°C; published data [7]: mp 207–210°C.
Single crystals of compound II for X-ray analysis
were obtained by crystallization from acetone, and
single crystals of XI, by double recrystallization from
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

WAGNER–MEERWEIN REARRANGEMENT OF STEVIOL 16α,17- AND 15α,16-EPOXIDES
1011
The spectral parameters of the product were consistent
with those reported in [7].
was added to 40 mg (0.12 mmol) of steviol 15α,16-ep-
oxide (XI) in 10 ml of benzene, and the mixture was
stirred for 2 h at 20°C. The mixture was concentrated,
treated with water, and extracted with diethyl ether.
The extracts were dried over MgSO4, and the solvent
was distilled off to obtain 14α-hydroxy-16-oxo-ent-
beyeran-19-oic acid (XII) as a colorless crystalline
substance. Yield 40 mg (100%), mp 245–247°C (from
acetone–hexane). IR spectrum, ν, cm–1: 3469 (O–H),
Alkaline hydrolysis of steviol 16α,17-epoxide
(II). Compound II, 0.09 g (0.27 mmol), was added to
a solution of 0.07 g (1.25 mmol) of potassium hydrox-
ide in 20 ml of water, the mixture was stirred for 12 h
at 100°C, diluted with water (50 ml), and carefully
acidified with acetic acid, and the white curd-like
material was filtered off and recrystallized from meth-
anol. We thus isolated 0.02 g of a white solid which
was a mixture of compounds IV and VIII.
1
1730 (C=O), 1694 (OC=O). H NMR spectrum, δ,
ppm: 0.70–2.00 m (30H, isosteviol), 0.82 s (3H,
C20H3), 1.04 s (3H, C18H3), 1.27 s (3H, C17H3),
2.53 d.d (1H, 15α-H, J = 18.6, 1.4 Hz), 3.38 d (1H,
14-H, J = 1.3 Hz).
17-Hydroxy-16-oxo-ent-beyeran-19-oic acid (IV).
IR spectrum, ν, cm–1: 3400 (O–H), 1727 (C=O), 1698
1
(COOH). H NMR spectrum, δ, ppm: 0.75–1.8 m
(28H, isosteviol), 0.81 s (3H, C20H3), 1.26 s (3H,
C18H3), 1.31 d.d (1H, 14-Hax, J = 11.3, 3.7 Hz), 1.37 d
(1H, 12-Hax, J = 12.6 Hz), 1.80 d.d (1H, 12-Heq, J =
11.4, 2.5 Hz), 1.86 d (1H, 14-Heq, J = 18.8 Hz), 2.18 d
(1H, 3-Heq, J = 12.5 Hz), 2.68 d.d (1H, 15α-H, J =
18.8, 3.7 Hz), 3.51 d and 3.64 d (1H each, 17-H, J =
11.6 Hz). Mass spectrum: m/z 334 (Irel 13%) [M]+.
This study was performed under financial support
by the Presidium of the Russian Academy of Sciences
(Fundamental Research Program nos. 18, 21) and by
the Russian Foundation for Basic Research (project
no. 10-03-22499-a).
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13α,16α,17-Trihydroxy-ent-kauran-19-oic acid
(VIII). 1H NMR spectrum, δ, ppm: 0.75–1.80 m (28H,
steviol), 0.94 s (3H, C20H3), 1.22 s (3H, C18H3), 3.81 d
and 3.63 d (1H each, 17-H, J = 11.3 Hz).
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of steviol 16α,17-epoxide (II) in 10 ml of benzene, and
the mixture was stirred for 30 min at 20°C. The
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extracted with diethyl ether. The extracts were dried
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compound IV as a colorless crystalline substance.
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Steviol 15α,16-epoxide (XI, 15α,16-epoxy-13-hy-
droxy-ent-kauran-19-oic acid) was synthesized ac-
cording to the procedure described in [6] by epoxida-
tion of a mixture of steviol (I) and its Δ15-isomer [22]
and was isolated by double recrystallization from ace-
tone–hexane. Yield 5%, mp 236–238°C. IR spectrum,
1
ν, cm–1: 3386 (O–H), 1691 (OC=O). H NMR spec-
trum, δ, ppm: 0.70–1.60 m (28H, steviol), 0.93 s (3H,
C20H3), 1.24 s (3H, C18H3), 1.38 s (3H, C17H3), 2.72 d
(1H, 15-H, J = 1.0 Hz). Found, %: C 72.00; H 9.34.
C20H30O4. Calculated, %: C 71.82; H 9.04.
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