The phase transfer catalysed synthesis of isoflavone-O-glucosides

Article abstract of DOI:10.1039/a804406f

Daidzin 1, genistin 2, ononin 3 and sissotrin 4 are the major products of the phase transfer catalysed reaction between the isoflavone aglycones daidzein, genistein, formononetin and biochanin A, respectively, and 1-bromo-2,3,4,6-tetra-O-acetyl-α-glucopyranose. Complete proton and carbon NMR assignments are presented for compounds 1-4.

Full text of DOI:10.1039/a804406f

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The phase transfer catalysed synthesis of isoflavone-O-glucosides
Philip Lewis, Seppo Kaltia and Kristiina Wähälä*,†
Laboratory of Organic Chemistry, Dept. of Chemistry, PO Box 55, University of Helsinki,
FIN-00014, Helsinki, Finland
Daidzin 1, genistin 2, ononin 3 and sissotrin 4 are the major products of the phase transfer catalysed
reaction between the isoflavone aglycones daidzein, genistein, formononetin and biochanin A, respectively,
and 1-bromo-2,3,4,6-tetra-O-acetyl-á-glucopyranose. Complete proton and carbon NMR assignments are
presented for compounds 1–4.
glycosylation, yields are increased significantly and the reaction
times reduced. The method is adaptable to other polyhydroxy
isoflavones and the sugar moiety is easily varied.
Introduction
The isoflavone-O-glucosides daidzin (daidzein 7-O-β--gluco-
pyranoside)1–8 1, genistin (genistein 7-O-β--glucopyrano-
side)1–9 2, ononin (formononetin 7-O-β--glucopyrano-
side)8,10,11 3 and sissotrin (biochanin A 7-O-β--glucopyrano-
side)8,12 4 have been isolated from numerous plant and food
sources. More recently in a metabolism study of orally admin-
istered isoflavones, daidzin and partially unhydrolysed daidzin
were identified in rat faeces.13 Structurally related unhydrolysed
flavone-O-glycosides have been detected in human plasma.14
Interest has grown in isoflavone-O-glycosides, in particular
genistin and daidzin, due to the results of a number of bio-
logical studies. Notably daidzin possesses antidipsotropic
activity.15–18 Results show that it is effective in suppressing
voluntary alcohol consumption in a pharmacogenetic rat
model of alcoholism.15 Two patents also claim anti-intoxication
properties19 and for use in the treatment of alcohol dependence
or alcohol abuse.20 Daidzin is a potent selective inhibitor of
human mitrochondrial aldehyde dehydrogenase in vitro.21 Other
in vitro work shows daidzin to have antioxidant activity similar
in level to that of vitamin E.22 Daidzin and genistin are added
to commercial formulations to act as radical scavengers,
dermal angiogenesis inhibitors and antiproliferic agents against
melanomas,23,24 Both also inhibit melanin formation in vitro,23
and show high hypolipidemic activity in rats.25 Ononin is
a principal inhibitor of Epstein–Barr virus early antigen
activation in vitro.26,27
In addition to their synthesis, we have carried out a thorough
NMR analysis to allow complete and unambiguous assign-
ments of the proton and carbon spectra for the four isoflavone
7-mono-O-glucosides daidzin 1, genistin 2, ononin 3 and sis-
sotrin 4. The results are shown in Tables 1 and 2.
Results and discussion
This is the first report of the synthesis of isoflavone-O-
glucosides using phase transfer catalysis, involving the
tetrabutylammonium bromide catalysed reaction of an iso-
flavone anion with α-tetraacetylbromoglucose (Scheme 1).34
OAc
AcO
OH
AcO
HO
Br
O
CH2OH
8
OAc
HO
O
7
+
HO
O
O
O
O
2
2′
5′
3′
4′
6
R1
O
6′
OR2
OH
Previous methods for the synthesis of isoflavone-O-gluco-
sides are low yielding, e.g. daidzin (9%),28 genistin (17%),29 sis-
sotrin (13%)30 and ononin (5–22%).31,32 In our hands Zemplén’s
9% KOH solution used for the base catalysed reaction of α-
acetylbromoglucose with unprotected hydroxyisoflavones in
acetone to produce genistin29 and ononin32 causes mainly
isoflavone C-ring cleavage (Waltz showed C-ring cleavage using
5% aqueous KOH)33 and anomeric hydrolysis of the α-acetyl-
bromoglucose, but no glycosylation. There have also been other
attempts28,30,31 to prepare isoflavone glucosides but none of
them involve direct glycosylation on the isoflavone aglycone.
Usually, pre-formed deoxybenzoin glycosides, prepared by
reaction of the deoxybenzoin with α-acetylbromoglucose in
basic aqueous acetone, were cyclized to the corresponding
isoflavone glucosides.28,31 Sissotrin has been prepared by methyl-
ation of the free 4Ј-hydroxy group in genistin and thus lacks
the glycosylation step altogether.30
1 R1 = R2 = H, Daidzin
2 R1 = OH, R2 = H, Genistin
3 R1 = H, R2 = Me, Ononin
4 R1 = OH R2 = Me, Sissotrin
Scheme 1
The products from this aqueous–organic two phase reaction
are the isoflavone-O-(tetra-O-acetyl-β--glycopyranosides).
Deprotection of the sugar moiety is carried out using standard
procedures (NaOMe–MeOH) to give the isoflavone-O-β--
glucosides 1–4.
This methodology produces ononin 3 and sissotrin 4 in
reasonable yields of 48 and 52% respectively. The regioselect-
ivity in the reaction of genistein and daidzein is towards the
7-position. Thus daidzin 1 (40%) and genistin 2 (42%) are
obtained preferentially. This correlates well with CAMEO35
calculations that show the acidity to be much greater at the
7- than the 4Ј-position. No 1,2-cis glucosides were found during
routine analysis. Selectivity towards the 1,2-trans or β-gluco-
sides suggests either an SN2 mechanism or reaction of the
α-acetylbromo sugar via a cyclic acyl oxonium ion, with attack
by the phenolate thus being limited to the β-position.
We present now a simple method for the direct glycosylation
of the unprotected isoflavone aglycone. It is regioselective,
providing the more common 7-O-glucosides, and stereospecific
to yield the naturally occurring β-anomer. In this method of
† E-Mail: kristiina.wahala@helsinki.fi
J. Chem. Soc., Perkin Trans. 1, 1998
2481

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Table 1 The 1H NMR spectra of daidzin 1, genistin 2, ononin 3 and sissotrin 4 (300 MHz, [2H6]DMSO)
Daidzin
Genistin
Ononin
Sissotrin
δ/ppm multiplicity J/Hz
Proton
δ/ppm multiplicity J/Hz
δ/ppm multiplicity J/Hz
δ/ppm multiplicity J/Hz
2
5
6
8
8.48
8.15
7.24
7.33
7.51
6.92
9.64
5.21
3.41
3.41
3.30
3.58
3.58
3.83
5.54
5.24
5.18
4.71
s
d
dd
d
d
d
s
d
m
m
m
m
m
m
d
d
d
t
—
8.35
12.93
6.55
6.79
7.44
6.91
9.95
5.09
3.42
3.42
3.31
3.55
3.55
3.79
5.52
5.24
5.15
4.70
s
s
—
8.50
8.12
7.21
7.30
7.6
s
d
dd
d
dd
dd
s
d
m
m
m
m
m
m
br s
br s
br s
br s
—
9.0
8.57
13.01
6.58
6.83
7.63
7.12
3.89
5.17
3.38
3.38
3.28
3.57
3.57
3.80
5.50
5.23
5.16
4.70
s
s
d
d
dd
dd
s
—
OH
2.1
9.0
9.0, 2.1
2.1
8.4
8.4
OH
7.5
—
—
—
—
—
OH
2.2
2.2
8.7
8.7
OH
7.14
—
—
—
—
—
d
d
d
d
s
d
m
m
m
m
m
m
d
d
d
t
9.0, 2.4
2.4
8.7, 2.1
8.7, 2.1
OMe
7.5
—
—
—
—
—
—
—
—
—
—
2.1
2Ј, 6Ј
3Ј, 5Ј
4Ј
1Љ
2Љ
3Љ
4Љ
5Љ
6Љa
6Љb
2Љ-OH
3Љ-OH
4Љ-OH
6Љ-OH
8.7, 2.1
8.7, 2.1
OMe
7.5
—
—
—
—
—
—
4.8
4.2
4.2
5.4
7.06
3.85
5.17
3.31
3.31
3.25
3.54
3.54
3.77
5.51
5.25
5.18
4.67
d
m
m
m
m
m
m
d
d
d
t
—
—
4.2
4.2
5.1
5.4
4.6
4.3
4.3
5.4
Table 2 The 13C NMR spectra of daidzin 1, genistin 2, ononin 3 and
sissotrin 4 (75 MHz, [2H6]DMSO)
the glucosyl and aromatic hydroxy protons. The assignment of
these previously unreported exchangeable hydroxy protons has
proved to be an easy way to ensure the correct structural
assignment for each glucoconjugate.
δ/ppm
1
Although the aromatic part of the H NMR spectrum of
Carbon
Daidzin
Genistin
Ononin
Sissotrin
these compounds can be tentatively assigned based on α-to-
oxygen and ortho-to-oxygen shifts and integrals, the confirm-
ation of assignments comes from COSY 135 and/or TOCSY
spectroscopy. The GHSQC spectrum provides the most effect-
ive way to make HC-COSY type correlations. For instance, the
C-6Љ/H-6Љα/H-6Љβ system of daidzin and the associated chem-
ical shifts can be easily recognized in the GHSQC spectrum.
Also other glucose methine proton assignments can be
obtained from the GHSQC spectrum when the glucose carbon
atoms have been assigned (see below). Because the hydroxy pro-
tons cannot have correlations in a GHSQC spectrum the ano-
meric proton of daidzin (δ 5.21) is picked out from the 5-signal
2
3
4
5
6
7
8
153.1
123.7
174.7
126.9
115.5
161.4
103.5
118.5
157.0
122.3
130.0
115.0
157.2
100.2
73.2
155.4
121.9
182.0
162.5
100.4
163.9
95.4
107.0
158.1
123.4
131.0
115.9
158.3
100.7
73.9
153.7
124.0
174.7
127.0
115.7
161.5
103.4
118.4
157.1
123.4
130.1
113.6
159.0
100.0
73.2
154.9
122.2
180.4
161.6
99.7
163.0
94.6
106.1
157.2
122.7
130.2
113.8
159.2
99.9
4a
8a
1Ј
2Ј, 6Ј
3Ј, 5Ј
4Ј
1Љ
2Љ
3Љ
1
pattern in the region δ 5.6–4.7 in the H NMR spectrum. As
3
73.1
76.5
usual, the HC-correlation spectrum optimized for JCH- and
2JCH-couplings (GHMBC in this case) proved to be very helpful
for assigning the NMR spectra of this kind of molecules. Not
only can the otherwise difficult to assign quaternary carbons
(C-3, C-4a, C-7, C-8a, C-1Ј and C-4Ј) be unequivocally recog-
nized but also confirmation of the O-7-glucoside structure of
daidzin is provided by the clear correlation between H-1Љ (δ
5.21) and C-7 (δ 161.4). Carefully prepared samples give also
clear correlations for the hydroxy protons in the HMBC spectra
which can be used to assign signals from the glucose part of the
molecule (see below). The assignment of the glucose hydroxys
and carbons of daidzin using OH-correlations in the GHMBC
spectrum proceeded as follows: C-1Љ (δ 100.2), C-6Љ (δ 60.7),
H-1Љ (δ 5.21), H-6Љa (δ 3.58) and H-6Љb (δ 3.83) were easily
assigned based on chemical shift correlation rules and correl-
ations in the GHSQC spectrum and can be used as entry points
for further analysis. Also the OH-6Љ proton (δ 4.71) is recogniz-
able by its triplet structure. This hydroxy has two correlations in
the GHMBC spectrum, to δ 60.7 due to C-6Љ and δ 77.2 which
must then be C-5Љ. The low field OH signal (δ 5.54) has a correl-
ation to C-1Љ at δ 100.2; this hydroxy is then OH-2Љ. The
hydroxy at δ 5.18 has a correlation to δ 77.2 (C-5Љ) and must
therefore be OH-4Љ. The remaining aliphatic hydroxy at δ 5.24
must be OH-3Љ. The OH-4Љ has two additional correlations, to δ
76.5 and 69.7, which are assigned to C-3Љ and C-4Љ or vice versa.
However, the OH-2Љ proton has a correlation to δ 76.5 which
must then be assigned to C-3Љ. Thus, the signal at δ 69.7 must
be due to C-4Љ. These assignments are corroborated by other
appropriate correlations to OH-2Љ and OH-3Љ in the hydroxy
76.5
77.2
76.5
4Љ
5Љ
6Љ
OMe
69.7
77.2
60.7
—
70.4
78.1
61.5
—
69.6
77.3
60.2
55.2
69.6
77.3
60.7
55.3
Daidzein 7-β-4Ј-α-di-O--glycopyranose (12%) and genistein
7-β-4Ј-α-di-O--glucopyranose (9%) are formed as minor
products.
NMR Spectra
Previously, H NMR assignments for daidzin 1,36–40 genistin
1
2,37,39–41 ononin 342–46 and sissotrin 447 have been limited mainly
to the aglycone region of the compound and assignment of the
anomeric proton. 13C Assignments have been more complete,
however details of verification by 2D NMR spectroscopy have
not been provided. One exception involves the full proton
assignment of daidzin 1.36 Unfortunately this paper does not
report a carbon spectrum or details of how proton assignments
were carried out.
In our NMR analysis we have used a number of 2-
dimensional NMR techniques including gradient selected
heteronuclear single quantum correlation (GHSQC), gradient
selected heteronuclear multiple bond correlation (GHMBC),
COSY 90-135, TOCSY and NOESY spectra, to obtain com-
plete proton and carbon assignments. Interestingly we have
found that with careful sample preparation using rigorously
dried [2H6]DMSO, we have been able to view and assign both
2482
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
region of the GHMBC spectrum. The remaining C-13 signal at
δ 73.2 is then C-2Љ which is confirmed by its correlation to δ 5.54
(OH-2Љ) and δ 5.24 (OH-3Љ). This completes the assignment of
hydroxy groups and carbon signals of the sugar moiety in the
NMR spectra. Table 1 contains the proton assignments for
compounds 1–4. Table 2 shows the full carbon data for each of
the isoflavone 7-O-β--glucosides.
Table 1; δC(75 MHz, [2H6]DMSO) Table 2; m/z (FAB) 431
(Mϩ).
Biochanin A 7-O-â-D-glucopyranoside (sissotrin) 4. A white
solid (methanol–water), mp 212–214 ЊC [lit.,30 214–215 ЊC
(methanol–water)]; [α]D24 Ϫ32.7 (c 0.001 g mlϪ1 in DMSO) (lit.,49
[α]D20 Ϫ24.4 in methanol); δH(300 MHz, [2H6]DMSO) Table 1;
δC(75 MHz, [2H6]DMSO) Table 2; m/z (FAB) 447 (Mϩ).
Acknowledgements
Experimental
We thank Jorma Matikainen, Ph. lic. for running the mass
spectra. Financial support for Philip Lewis from the Finnish
Graduate School of Bioorganic Chemistry is gratefully
acknowledged.
General experimental procedures
NMR Spectra were recorded on a Varian Gemini 2000 spec-
trometer or Varian Inova 300 spectrometer, proton and carbon
assignments being evaluated from GHMQC, GHMBC, COSY
90–135 TOCSY and NOESY spectra where necessary. J Values
are given in Hz. Samples of the compounds for NMR spec-
troscopy were dried in vacuum (under 0.01 mbar) at room tem-
perature overnight. Pre-dried 4 Å molecular sieves were added
under Ar to [2H6]DMSO, 72 hours prior to use. To prevent
contamination by moisture, NMR samples were prepared and
the tubes sealed under Ar.
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Synthesis of isoflavone-O-â-D-glucosides
An isoflavone (1 equiv.) in 2.5% aqueous NaOH was stirred at
room temperature for 15 min. To this was added a dichloro-
methane solution of tetrabutylammonium bromide (1.2
equiv.) and 1-bromo-2,3,4,6-tetra-O-acetyl-α-glucopyranose34
(1.2 equiv.). The two phase mixture was stirred vigorously for
5 h before the reaction mixture was neutralized (1  H2SO4),
extracted with ethyl acetate, washed with brine, dried (Na2SO4)
and evaporated to yield the crude isoflavone-O-β--(tetra-O-
acetyl glycopyranosides) as a yellow oil. This was dissolved in a
solution of sodium methoxide in methanol (0.54 g 100 mlϪ1
)
and left at 4 ЊC for 12 h. Neutralization with Amberlite resin
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oil pump provided the crude isoflavone-O-glucosides. Initial
purification was carried out using reversed-phase preparative
TLC (eluent MeOH–H2O, 65:35). Further purification was
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(eluent MeOH–H2O, 50:50, injection volume 500 µl, flow rate
5 ml minϪ1).
Daidzein 7-O-â-D-glucopyranoside (daidzin) 1. A white solid
(methanol–water), mp 235–236 ЊC [lit.,48 235–237 ЊC (water)];
[α]D24 Ϫ24.1 (c 0.001 g mlϪ1 in DMSO) (lit.,46 [α]D26 Ϫ20.2 in
DMSO); δH(300 MHz, [2H6]DMSO) Table 1; δC(75 MHz,
[2H6]DMSO) Table 2; m/z (FAB) 417 (Mϩ).
Genistein 7-O-â-D-glucopyranoside (genistin) 2. A white solid
(methanol–water), mp 252–254 ЊC [lit.,29 255 ЊC (methanol–
water)]; [α]D24 Ϫ32.0 (c 0.001 g mlϪ1 in [2H6]DMSO) (lit.,37 [α]D24
Ϫ36.6 in DMSO); δH(300 MHz, [2H6]DMSO) Table 1; δC(75
MHz, [2H6]DMSO) Table 2; m/z (FAB) 433 (Mϩ).
Formononetin 7-O-â-D-glucopyranoside (ononin) 3. A white
solid (methanol–water), mp 213–215 ЊC [lit.,48 213–214 ЊC
(methanol–water)]; [α]D24 Ϫ25.6 (c 0.001 g mlϪ1 in DMSO)
(lit.,48 [α]D20 Ϫ23.1 in pyridine); δH(300 MHz, [2H6]DMSO)
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Paper 8/04406F
Received 10th June 1998
Accepted 25th June 1998
2484
J. Chem. Soc., Perkin Trans. 1, 1998