Synthetic glycosides containing two isosteviol fragments functionalized with D-glucopyranose

Article abstract of DOI:10.1134/S107042801404006X

The synthesis of isosteviol (16-oxo-ent-beyeran-19-oic acid) glycosides in which two isosteviol fragments functionalized with tetra-O-acetyl-D- glucopyranose are linked through a diester spacer is described for the first time.

Full text of DOI:10.1134/S107042801404006X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 4, pp. 484–488. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © B.F. Garifullin, R.R. Sharipova, I.Yu. Strobykina, V.M. Babaev, V.E. Kataev, 2014, published in Zhurnal Organicheskoi Khimii,
2014, Vol. 50, No. 4, pp. 498–502.
Synthetic Glycosides Containing Two Isosteviol Fragments
Functionalized with D-Glucopyranose
B. F. Garifullin, R. R. Sharipova, I. Yu. Strobykina, V. M. Babaev, and V. E. Kataev
Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences,
ul. Arbuzova 8, Kazan, 420088 Tatarstan, Russia
e-mail: kataev@iopc.ru
Received January 23, 2914
Abstract—The synthesis of isosteviol (16-oxo-ent-beyeran-19-oic acid) glycosides in which two isosteviol
fragments functionalized with tetra-O-acetyl-D-glucopyranose are linked through a diester spacer is described
for the first time.
DOI: 10.1134/S107042801404006X
Diterpene glycosides occur in natural sources in
different amounts. The most abundant (about 70) are
ent-kaurane glycosides [1–3], next follow (more than
20) glycosides of the pimarane and isopimarane series
[4–6], the third place (>10) is occupied by labdane
derivatives [7, 8], and the fourth, by several cembrane
[9, 10] and abietane glycosides [11, 12]. Among di-
terpene glycosides, the most common are ent-kaurane
glycosides isolated from Stevia rebaudiana (they are
more often referred to as rebaudiosides), in which the
aglycone is diterpenoid steviol (13-hydroxy-ent-kaur-
16-en-19-oic acid) [13]. The reason is that rebaudi-
osides are 250–300 times sweeter than sucrose;
therefore, they are used in China, Japan, and Southeast
Asian countries for large-scale manufacture of low-
calorie sweeteners. It should be noted that one step in
the development of the production of these sweeteners
involves chemical and enzymatic modification of
rebaudiosides with a view to enhance their taste char-
acteristics. Therefore, it is not surprising that a large
number of various glycosides have been synthesized
where the aglycone is an ent-kaurane diterpenoid,
steviol [14]. On the other hand, only one natural
glycoside is known for its isomer, ent-beyerane
diterpenoid isosteviol (I, 16-oxo-ent-beyeran-19-oic
acid) [15], which is readily obtained by acid hydrolysis
of rebaudiosides via skeletal rearrangement of steviol;
this glycoside was also isolated from Stevia rebau-
diana [16]. Although glycosylation of natural biologi-
cally active non-glycoside compounds has long been
proposed as a tool for tuning their activity [17], among
more than 150 known isosteviol derivatives [18, 19]
only three ones are synthetic glycosides [20–22].
In the present article we describe the synthesis of
new isosteviol glycosides. In the first step of our study
we compared the efficiencies of two procedures for the
synthesis of isosteviol glycoside IV. The first proce-
dure is based on the Koenigs–Knorr reaction [21], i.e.,
the reaction of isosteviol (I) with 2,3,4,6-tetra-O-
acetyl-α-D-glucopyranosyl bromide (III) prepared
from 1,2,3,4,6-pentaacetyl-β-D-glucose (II). The sec-
ond procedure involved reaction of acid chloride V
with 2,3,4,6-tetra-O-acetyl-D-glucopyranose (VI)
(Scheme 1). The yield of IV was 66% in the first
case and 4% in the second.
In the second step, 2,3,4,6-tetra-O-acetyl-α-D-
glucopyranosyl bromide (III) was brought into reac-
tion with dihydroisosteviol VII prepared by chemo-
selective reduction of isosteviol (I) with sodium tetra-
hydridoborate in methanol according to the procedure
described in [23]. Phase-transfer catalysis with tetra-
butylammonium bromide ensured glycosylation to
occur exclusively at the carboxy group of VII, while
the 16-hydroxy group remained intact (Scheme 2). The
addition of the D-glucopyranose fragment to the
carboxy group of VII followed from the disappearance
of the IR absorption band at 1690 cm–1 (COOH) and
conservation of the band at 3470 cm–1, corresponding
to stretching vibrations of the 16-OH group.
In the third step, we synthesized dinuclear iso-
steviol derivatives XI and XII by reaction of dihydro-
484

SYNTHETIC GLYCOSIDES CONTAINING TWO ISOSTEVIOL FRAGMENTS
485
Scheme 1.
OAc
Me
Me
O
Br
i
ii
+
O
O
AcO
OAc
Me
20
Me
17
Me
OH
OAc
2
4
12
1
11
OAc
3
13
O
O
9
7
10
6
III
I
14
5
16
O
OAc
8
19
O
18
Me
OAc
15
iii
AcO
OAc
1'
2'
3'
O
OAc
5'
4'
OAc
II
6'
OAc
Me
OAc
Me
OAc
O
OH
iv
v
IV
+
O
O
AcO
OAc
Me
Cl
OAc
VI
V
i: 33% HBr/AcOH, 0°C; ii: Bu4N+ Br–, K2CO3, CH2Cl2–H2O, reflux; iii: SOCl2, 50°C; iv: FeCl3 ·6H2O, MeCN, 70°C; v: CCl4, reflux.
Scheme 2.
Me
Me
O
Me
Me
OH
Me
OAc
i
III, ii
O
I
O
OH
O
Me
OH
OAc
VII
OAc
OAc
O
VIII
Cl
(IX, X)
( )n
Cl
iii
O
Me
Me
Me
Me
OAc
AcO
O
O
O
O
O
O
O
Me
Me
OH
O
III, ii
OAc
OAc
OAc
O
( )n
( )n
O
O
O
AcO
O
OAc
OAc
OH
Me
Me
O
O
O
Me
Me
Me
Me
XI, XII
XIII, XV
i: NaBH4, MeOH; ii: Bu4N+ Br–, K2CO3, CH2Cl2–H2O, reflux; iii: CH2Cl2, DMAP, pyridine.
IX, XI, XIII, n = 1; X, XII, XIV, n = 3.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 4 2014

GARIFULLIN et al.
486
isosteviol VII with octane- and decanedioyl di-
chlorides. Reactions of XI and XII with bromide III
gave dinuclear isosteviol glycosides XIII and XIV in
29 and 58% yield, respectively (Scheme 2).
(III) [29] were synthesized according to known
methods. 2,3,4,6-Tetra-O-acetyl-β-D-glucopiranosyl
acetate and tetrabutylammonium bromide were com-
mercial products (from Acros Organics). Isosteviol
glycoside IV was synthesized by reaction of isosteviol
(I) with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl
bromide (III) by analogy with the procedure described
in [21], as well as by reaction of acid chloride V with
2,3,4,6-tetraacetyl-β-D-glucopyranose (VI).
The anomeric protons in glycosides IV, VIII, XIII,
and XIV resonated in the 1H NMR spectra as doublets
3
at δ 5.68 (broadened, J1,2 = 7.9 Hz), 5.69 (broadened,
3J1,2 = 8.2 Hz), 5.68 (3J1,2 = 7.6 Hz), and 5.68 ppm
(3J1,2 = 7.4 Hz), respectively. These values consider-
ably differ from the corresponding data for 1,2,3,4,6-
penta-O-acetyl-α-D-glucopyranose (δ 6.33 ppm, d,
3J1,2 = 3.5 Hz) but approach those typical of its
2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl
16-oxo-ent-beyeran-19-oate (IV). A mixture of 0.78 g
(2.4 mmol) of isosteviol (I) and 1 mL of thionyl
chloride was heated for 2 h at 50°C. Excess thionyl
chloride was removed under reduced pressure (water-
jet pump). The residue was treated with carbon tetra-
chloride, and the solvent was removed under reduced
pressure; this procedure was repeated several times
until the thionyl chloride odor disappeared. The
product, chloride V, was dissolved in 15 mL of carbon
tetrachloride, a solution of 0.85 g (2.4 mmol) of
2,3,4,6-tetra-O-acetyl-D-glucopyranose in 10 mL of
carbon tetrachloride was added, and the mixture was
heated for 48 h under reflux. The solvent was removed
under reduced pressure, and the residue was subjected
to chromatography on silica gel using petroleum ether–
ethyl acetate (4:1) as eluent. Yield 4%, amorphous
3
β-anomer (δ 5.71 ppm, d, J1,2 = 8.3 Hz) [24]. There-
fore, compounds IV, VIII, XIII, and XIV were unam-
biguously assigned the β-glycoside structure.
All known diterpene glycosides [1–12], including
isosteviol glycosides [16, 20–22], contain only one
aglycone (monoglycosides). The described synthesis of
dinuclear glycosides with two natural diterpenoid frag-
ments as aglycones pioneers a new line in synthetic
organic chemistry.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
Avance-400 spectrometer at 400 MHz. The mass
spectra (MALDI) were obtained on a Bruker UltraFlex
III TOF/TOF mass spectrometer (a.m.u. range 200–
3000). The data were processed using FlexAnalysis 3.0
program. Given below are m/z values for monoisotopic
ions. Samples were dissolved in methylene chloride to
a concentration of 10–3 mg/mL. p-Nitroaniline used as
matrix was dissolved in methanol to a concentration of
5 mg/mL. Samples were applied by the dried drop
method. A 0.3-μL portion of the matrix solution was
applied onto a Bruker Anchor Chip target; after
evaporation of the solvent, 0.5 μL of a 1:1 mixture of
an analyte and calibration mixture was applied there-
onto. The IR spectra were recorded from films on
a Bruker Vector 22 spectrometer with Fourier trans-
form. The progress of reactions and the purity of
products were monitored by TLC on Sorbfil plates;
spots were detected by treatment with 5% H2SO4,
followed by heating to 120°C. The products were
isolated by flash chromatography using dry columns
charged with KSKG silica gel with a grain size of less
than 0.063 mm.
powder, [α]D20 = –44° (c = 0.4, CH2Cl2). H NMR
1
spectrum (CDCl3), δ, ppm: 0.60–1.90 m (19H, ent-
beyerane), 0.69 s (3H, C20H3), 0.96 s (3H, C17H3),
1.19 s (3H, C18H3), 2.00 s (3H, CH3CO), 2.02 s (3H,
CH3CO), 2.03 s (3H, CH3CO), 2.06 s (3H, CH3CO),
2.50 d.d (1H, 15α-H, J = 18.4, 3.6 Hz), 3.73–3.80 m
(1H, 5′-H), 4.02 d.d (1H, 6′-H, J = 12.4, 1.9 Hz),
4.31 d.d (1H, 6′-H, J = 12.4, 4.7 Hz), 5.06–5.13 m
(1H), 5.15–5.23 m (2H), 5.68 br.d (1H, 1′-H, J =
7.9 Hz). Mass spectrum, m/z: 671.34 [M + Na]+,
687.26 [M + K]+. C34H48O12. Calculated: [M + Na]+
671.30, [M + K]+ 687.27.
Isosteviol glycosides VIII, XIII and XIV (general
procedure). A solution of 2.4 mmol of potassium
carbonate in 5 mL of water was added to a solution of
1 mmol of compound VII or 0.5 mmol of bis-acid XI
or XII, 1 mmol of 2,3,4,6-tetra-O-acetyl-α-D-gluco-
pyranosyl bromide (III), and 0.015 g of tetrabutylam-
monium bromide in methylene chloride, and the
mixture was heated for 30 h under reflux. The organic
phase was separated and washed with water and brine,
the aqueous phase was extracted with methylene
chloride, and the extract was combined with the
organic phase and dried over anhydrous Na2SO4. The
Isosteviol (I) [25], bis-acids XI and XII [26, 27],
2,3,4,6-tetra-O-acetyl-D-glucopyranose (VI) [28], and
2,3,4,6-tetra-O-acetyl-α-D-glucopiranosyl bromide
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 4 2014

SYNTHETIC GLYCOSIDES CONTAINING TWO ISOSTEVIOL FRAGMENTS
487
products were isolated by chromatography on a dry
column charged with silica gel using first petroleum
ether–ethyl acetate (4 :1) and then ethyl acetate as
eluents.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 13-03-00054), by the Council for Grants at the
President of the Russian Federation (project no. MK-
1052.2014.3), and by the Presidium of the Russian
Academy of Sciences (program no. 8).
2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl
16-hydroxy-ent-beyeran-19-oate (VIII). Yield 47%,
amorphous powder, [α]D20 = –32° (c = 0.33, CH2Cl2).
IR spectrum, ν, cm–1: 3470 (OH), 1755 (C=O), 1226
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