Synthesis of benzyl esters of glycyrrhizic acid in the presence of phase-transfer catalysts

Article abstract of DOI:10.1023/A:1013915423088

Benzyl esters of glycyrrhizic acid were synthesized using PhCH₂Br in DMSO-CH₂Cl₂-NaOH in the presence of phase-transfer catalysts, such as tetraalkylammonium salts and 2-methyl-2-propanol.

Full text of DOI:10.1023/A:1013915423088

Russian Journal of General Chemistry, Vol. 71, No. 10, 2001, pp. 1601 1604. Translated from Zhurnal Obshchei Khimii, Vol. 71, No. 10, 2001,
pp. 1689 1692.
Original Russian Text Copyright
2001 by Kondratenko, Baltina, Mustafina, Vasil’eva, Galin, Tolstikov.
Synthesis of Benzyl Esters of Glycyrrhizic Acid in the Presence
of Phase-Transfer Catalysts
R. M. Kondratenko, L. A. Baltina, S. R. Mustafina,
E. V. Vasil’eva, F. Z. Galin, and G. A. Tolstikov
Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences, Ufa, Bashkortostan, Russia
Received May 22, 2000
Abstract Benzyl esters of glycyrrhizic acid were synthesized using PhCH2Br in DMSO CH2Cl2 NaOH
in the presence of phase-transfer catalysts, such as tetraalkylammonium salts and 2-methyl-2-propanol.
Glycyrrhizic acid (I), the most abundant saponine
in glycyrrhiza extract, is known by its high and di-
verse pharmacological activity [1]. Earlier we syn-
thesized a series of esters of glycyrrhizic acid by
treatment of the glycoside in DMSO with excess alkyl
halides (MeI, CH2=CHCH2Br, PhCH2Br) in the
presence of KOH powder [2].
convenient protected forms of the glycoside for syn-
thesis of modified analogs and oligosaccharide deri-
vatives, since benzyl groups are readily removed by
catalytic hydrogenolysis.
A
classical method of selective alkylation
(methylation, benzylation) of hydrocarbons is the
Kuhn method [3]. Tetrabutylammonium bromide has
been used to success for selective benzoylation of
hexoses [4]. Mono-O-allyl esters of monosaccharide
derivatives, which are unstable in alkaline media, have
been prepared in high yields in a CH2Cl2 50%
In the present communication we report a new
method of synthesis of tribenzyl esters of glycyrrhizic
acid (II) and its tri-O-benzyl derivative IV in a
DMSO CH2Cl2 10% aqueous NaOH mixture in the
presence of phasetransfer catalysts, such as tetraalkyl- aqueous NaOH two-phase system in the presence of
ammonium salts [tetrabutylammonium bromide (VII)
and tetraethylammonium bromide (VIII)], as well as
a tertiary alcohol (2-methyl-2-propanol) as cocatalyst.
Benzyl esters of glycyrrhizic acid present interest as
salt VII [5]. Selective benzylation of the carbohydrate
chain of glycyrrhizic acid has never been reported.
Because of the polyionic structure of the glycoside,
we failed to effect its benzylation in an organic sol-
29 30 COOR1
COOR1
20
12
O
O
18
11
28
1
10
6
27
COOR1
3
R2O
O
5
O
4
OR2
1
R2O
2
V VI
3
6
COOR1
O
5OR2
O
4
R2O
2
3
OR2
I IV
I, R1 = R2 = H; II, R1 = PhCH2, R2 = H; III, R1 = PhCH2, R2 = Ac; IV, R1 = PhCH2, R2(3 ) = R2(3 ) = R2(2 ) = PhCH2,
R2(4 ) = R2(4 ) = H; V, R1 = PhCH2, R2 = H; VI, R1 = PhCH2, R2 = Ac.
1070-3632/01/7110-1601$25.00 2001 MAIK Nauka/Interperiodica

1602
KONDRATENKO et al.
Yields of benzyl esters of glycyrrhizic acid at various reaction conditionsa
Yield of ester, % (in mixture)
Overall yield
Salt, mmol
NaOH, mmol PhCH2Br, mmol
of esters, g
II
IV
V
VII, 1.1
VII, 1.1
VII, 2.2
VII, 2.2
VIII, 2.2
6.5
6.5
6.5
13
13
5
10
10
10
10
1
1
1.2
2.2
1.7
83
86
70
52
55
14
24
22
16
24
22
a
Glycyrrhizic acid (I), 1 mmol.
vent CH2Cl2 10% aqueous NaOH mixture in the
enhances hydrolysis of the glycoside to aglucon
presence of phase-transfer catalysts. Therefore, we (glycyrrhetic acid), which increases the yield of 30-
made use of a DMSO CH2Cl2 t-BuOH 10% aqueous
NaOH mixture as solvent.
benzyl ester V. The latter was identified as 3-O-
acetate VI.
Thus, the use of phase-transfer catalysts and t-
BuOH as cocatalysts allowed us to improve the yield
of tribenzyl glycyrrhizate (II) to 83 86% and to effect
selective benzylation of the carbohydrate chain of the
glycoside.
Treatment of glycoside I with excess PhCH2Br in
DMSO CH2Cl2 10% aqueous NaOH in the presence
of salt VII at the I:PhCH2Br:NaOH:VII molar ratio
of 1:5:6.5:1 gave tribenzyl ester II (83%). The
product was isolated homogeneous by column chro-
matography on silica gel. The structure of ester II was
proved by spectral methods (1H and 13C NMR, IR,
and UV spectroscopy) and by comparison of its Rf
with that of a sample obtained earlier by esterification
of compound I with PhCH2Br in DMSO in the pre-
sence of KOH powder in an yield of 46%, as well as
by the synthesis of penta-O-acetate III [2]. By using a
double excess of PhCH2Br we improved the overall
yield of ester II to 86% (see table).
EXPERIMENTAL
The IR spectra were recorded on a Specord M-80
spectrophotometer in Vaseline oil. The electronic
absorption spectra were measured on a Specord UF-
1
400 spectrometer in methanol. The H and 13C NMR
spectra were obtained on a Bruker AM-300 spectro-
meter at 75.5 and 300 MHz with broad-band and off-
resonance proton decoupling in deuterochloroform or
deuterochloroform methanol-d4 (1:1 by volume),
internal reference TMS. The optical activity was
measured on a Perkin Elmer MC-241 polarimeter.
The melting points were determined on a Boetius hot
stage.
With a double excess of tetrabutylammonium
bromide (VII) and PhCH2Br, hydroxy groups of the
carbohydrate moiety of glycoside I undergo alkylation
and glycoside bonds are partially cleaved. From the
postreaction mixture by chromatography on silica gel
we isolated ester IV (14%) and 30-benzyl ester of the
aglucon, glycyrrhetic acid (V) (16%). The preferential
alkylation of the 2 -, 3 -, and 3 -OH groups in gly-
coside I follows from the downfield shifts of the
corresponding carbon atoms in the 13C NMR spectrum
of compound IV by 6 7 ppm compared with the spec-
trum of tribenzyl ester II [2] and the presence of
signals of 6 CH2 carbons (PhCH2Br) at 62 67 ppm.
Thin-layer chromatography was performed on
Silufol plates using the following eluents: chloro-
form methanol, 10:1 (by volume) (system A) and
chlroform methanol, 5:1 (by volume) (system B);
development was performed with 20% ethanolic
phosphoric acid with subsequent heating at 100
120 C for 2 3 min. Column chromatography was
performed on Silica gel L 100/160 m.
The purity of the glycyrrhizic acid obtained by the
procedure in [6] was ca. 95%.
The highest yield of ester IV is attained at the
I:PhCH2Br:NaOH:VII molar ratio of 1:10:13:2.
On replacement of tetrabutylammonium bromide
(VII) by tetraethylammonium bromide (VIII) (equi-
valent amount), the overall reaction yield decreased
(see table). A large excess of base (NaOH) which
bounds HBr formed in the course of the reaction
Benzylation of glycyrrhizic acid (I). To a solution
of 1 mmol of glycoside I in a mixture of 10 ml of
DMSO, 25 ml of CH2Cl2, and 5 10 ml of 10%
aqueous NaOH we added dropwise 1 2 mmol of a
trialkylammonium salt, 5 10 mmol of PhCH2Br, and
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 10 2001

SYNTHESIS OF BENZYL ESTERS OF GLYCYRRHIZIC ACID
1603
1 ml of 2-methyl-2-propanol, and the mixture was
stirred at 20 22 C for 24 h, after which it was diluted
with water (25 ml) and treated with CH2Cl2 (2
25 ml). The organic phase was washed in succession
with 5% HCl, water, 5% aqueous NaHCO3, and water,
and dried with MgSO4. The solvent was removed in a
vacuum to obtain a mixture of benzyl esters, which
was separated by column chromatography on silica
gel, eluent CHCl3 MeOH, 300:1, 200:1, 100:1, and
50:1 (step gradient, vol%). The 300:1 mixture eluted
ester V, the 200:1 mixture, ester IV, and the
spectrum (MeOH), max, nm (log ): 252 (4.1).
1H NMR spectrum (CDCl3), , ppm: 0.71 s (3H,
C28 H3), 0.82 s (3H, C24 H3), 1.02 s (3H, C23 H3),
1.16 s (3H, C25 H3), 1.18 s (3H, C29 H), 1.29 s (3H,
C27 H3), 1.36 s (3H, C26 H3), 2.32 s (1H, C9 H),
2.72 d (1H, C18 H, J 9.1 Hz), 1.9 2.1 br.s (2H,
CH2Ph), 3.20 d.d (1H, C3 H, J1 5.2 Hz, J2 4.9 Hz),
5.55 s (1H, =C12 H), 7.2 7.5 m (5H, Ph). 13C NMR
spectrum (CDCl3), C, ppm: 39.07 (C1), 78.58 (C3),
39.10 (C4), 54.88 (C5), 36.95 (C10), 200.11 (C11),
128.38 (C12), 169.04 (C13), 45.29 (C14), 31.70 (C17),
48.13 (C18), 41.02 (C19), 43.91 (C20), 37.59 (C22),
28.07 (C23), 15.58 (C24), 16.30 (C25), 18.62 (C26),
23.28 (C27), 28.20 (C28), 28.35 (C29), 176.14 (C30),
66.15 (CH2 2Ph), 126.0 136.0 (Ph). Found, %: C
78.72; H 8.96. C37H52O4. Calculated, %: C 79.24; H
9.35.
100:1
50:1 mixture, ester II.
Tribenzyl glycyrrhizate (II). Rf 0.4 (A), 0.6 (B).
[ ]2D0 +75
(c 0.04, MeOH). UV spectrum
2
(MeOH), max, nm (log ): 207 (4.56), 250 (4.14).
Published data [2]: [ ]2D0 +80 (c 0.02, EtOH). UV
spectrum (MeOH), max, nm (log ): 206 (4.54),
249 (4.18).
Benzyl 3-O-acetylglycyrrhetate (VI). From 0.2 g
of 30-benzyl ester of glycyrrhetic acid V we obtained
0.18 g (88%) of 3-O-acetate VI by a standard proce-
dure, Rf 0.7 (A), [ ]2D0 +150 2 (c 0.04, CHCl3). IR
Tribenzyl penta-O-acetylglycyrrhizate (III).
Tribenzyl ester II, 0.3 g, was acetylated with an
Ac2O PyH mixture (1:1) by a standard procedure [2],
yield 0.4 g (94%), mp 110 112 C (from aqueous
EtOH), [ ]2D0 +62 2 (c 0.04, MeOH). Published data
1
spectrum, , cm : 1750 (OAc, COOPhCH2), 1670
(C11=O), 1500 (Ph). UV spectrum (MeOH), max, nm
1
(log ): 250 (4.1). H NMR spectrum (CDCl3),
,
[2]: mp 112 C. [ ]2D0 +63 (c 0.027, EtOH). The H
ppm: 0.90, 0.96, 1.16, 1.20, 1.25, 1.36, 1.40 all s
(21H, 7Me), 1.6 1.7 d.d (2H, CH2), 2.0 s (3H, Ac),
3.7 s (1H, C3 H), 5.54 s (1H, =C12 H), 7.2 7.5 m
(5H, Ph). 13C NMR spectrum (CDCl3), C, ppm:
38.80 (C1), 80.62 (C3), 39.20 (C4), 55.23 (C5), 43.50
(C8), 60.78 (C9), 36.86 (C10), 200.00 (C11), 170.92
(C13), 45.24 (C14), 50.10 (C18), 41.00 (C19), 44.46
(C20), 38.02 (C22), 176.00 (C30), 162.50 (Ac). Found,
%: C 77.39; H 8.80. C39H54O5. Calculated, %:
C 77.70; H 9.00.
1
and 13C NMR spectra are identical to those of com-
pound III, reported in [2].
Tribenzyl tri-O-benzylglycyrrhizate (IV). Rf 0.5
(A), [ ]2D0 +60 2 (c 0.04, MeOH). IR spectrum (thin
1
film), , cm : 3600 3200 (OH), 1750 (COOPhCH2),
1670 (C11=O), 1610, 1510 (Ph). UV spectrum
(MeOH), max, nm (log ): 218 (4.75), 257 (4.33).
1H NMR spectrum (CDCl3), , ppm: 0.7 1.4 all s
(7Me3, 21H), 1.5 2.0 (2H, CH2), 4.5 s (1H, H1 ),
4.7 s (1H, H1 ), 5.1 s (1H, H3 ), 5.6 s (1H, =C12 H),
ACKNOWLEDGMENTS
7.2 7.5 m (Narom). 13C NMR spectrum (CDCl3),
,
ppm: 38.80 (C1), 87.49 (C3), 55.02 (C5), 200.08 (C11C),
127.04 (C12), 168.97 (C13), 48.24 (C18), 43.95 (C20),
28.41 (C23), 15.57 (C24), 16.33 (C25), 18.74 (C26),
23.34 (C27), 28.25 (C28), 28.41 (C29), 176.19 (C30),
The work was financially supported by the
Ministry for Science and Technology of the Russian
Federation (project no. 03.00.03.010), Khimiya i
tekhnologiya rastitel’nykh veshchestv Scientific
Council (project no. 8.1.28), and Russian Foundation
for Basic Research (Scientific School; project
no. 00-15-97363).
108.05 (C1 ), 85.17 (C2 ), 84.90 (C3 ), 71.41 (C4 ),
75.28 (C5 ), 169.96 (C6 ), 102.84 (C1 ), 84.72 (C2 ),
85.90 (C3 ), 74.21 (C4 ), 76.85 (C5 ), 169.10 (C6 );
other signals: 67.73, 67.37, 66.52, 65.35, 64.30,
61.80 (6CH2Ph), 126.9 132.9 (6Ph). Found, %: C
71.22; N 8.06. C74N98O16. Calculation, %: C 71.47;
N 7.94.
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1. Tolstikov, G.A., Baltina, L.A., Shul’ts, E.E., and Pok-
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pp. 691 709.
Benzyl glycyrrhetate (V). Rf 0.6 (A), mp 158
159 C (from aqueous EtOH), [ ]2D0 +146 2 (c 0.03,
MeOH). Published data [7]: mp 157 C, [ ]2D0 +120 .
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IR spectrum (Vaseline oil), , cm : 3600 3200 (OH),
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