An efficient synthesis of the potent phytoestrogens 8-prenylnaringenin and 6-(1,1-dimethylallyl)naringenin by europium(III)-catalyzed Claisen rearrangement

Article abstract of DOI:10.1016/S0040-4020(00)01078-4

Starting from commercially available naringenin (3), the flavanoids 8-prenylnaringenin (1) and 6-(1,1-dimethylallyl)naringenin (2) have been prepared in racemic form using prenyl ether 5 as a general intermediate. While a domino Claisen-Cope rearrangement of 5 was the key step in the synthesis of 1, the cytotoxic compound 2 was additionally secured via a europium(III)-catalyzed Claisen rearrangement of 5 at low temperature. Both 1 and 2 display strong estrogenic activities.

Full text of DOI:10.1016/S0040-4020(00)01078-4

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1015±1018
An ef®cient synthesis of the potent phytoestrogens
-prenylnaringenin and 6-(1,1-dimethylallyl)naringenin by
europium(III)-catalyzed Claisen rearrangement
8
a
a,p
b
Sven Gester, Peter Metz, Oliver Zierau and G uÈ nter Vollmer
b
a
Institut f uÈ r Organische Chemie, Technische Universit aÈ t Dresden, Mommsenstrabe 13, D-01062 Dresden, Germany
b
Institut f uÈ r Zoologie, Technische Universit aÈ t Dresden, Mommsenstrabe 13, D-01062 Dresden, Germany
Dedicated to Professor G uÈ nter Domschke on the occasion of his 70th birthday
Received 24 October 2000; accepted 10 November 2000
AbstractÐStarting from commercially available naringenin (3), the ¯avanoids 8-prenylnaringenin (1) and 6-(1,1-dimethylallyl)naringenin
2) have been prepared in racemic form using prenyl ether 5 as a general intermediate. While a domino Claisen±Cope rearrangement of 5 was
the key step in the synthesis of 1, the cytotoxic compound 2 was additionally secured via a europium(III)-catalyzed Claisen rearrangement of
at low temperature. Both 1 and 2 display strong estrogenic activities. q 2001 Elsevier Science Ltd. All rights reserved.
(
5
1
is depicted in Scheme 1. Chemoselective acetylation of the
C(7) and C(4 ) phenolic hydroxyl groups of 3 set the stage
5
1
. Introduction
0
for installation of the requisite prenyl ether moiety at C(5).
1
The ¯avanoid 8-prenylnaringenin (1) (Fig. 1) isolated from
2
the plants Marshallia grandi¯ora, Sophora tomentosa
3,4
Whereas attempts to O-alkylate diacetate 4 with prenyl
bromide in the presence of potassium carbonate or under
4
and Humulus lupulus has recently been shown to be an
16
5
,6
extremely potent phytoestrogen. Moreover, 1 displays a
17
phase transfer catalysis conditions met with failure,
4
,7
18
Mitsunobu reaction of 4 with prenyl alcohol smoothly
strong antifungal activity as well. In order to further
investigate these interesting properties, an ef®cient access
to this compound was desired that would supply suf®cient
amounts of 1 for biological studies. So far, 1 has been
prepared either by unselective direct C-prenylations
of the commercially available citrus ¯avanoid naringenin
delivered the desired substrate 5 for the key sigmatropic
event in good yield.
1
9
4
,7±10
For the uncatalyzed thermal rearrangement of 5, re¯ux in
decalin turned out to effect the cleanest transformation to 6
(Table 1), whereas no conversion of 5 was noted after 2 d of
(3) or by an equally low yielding route starting from phloro-
acetophenone.
1
1
Here we report a convenient four-step sequence from
racemic 3 to 1 via a domino Claisen±Cope rearrange-
1
2,13
ment
have also used this novel route for the ®rst synthesis of
-(1,1-dimethylallyl)naringenin (2), which has recently
that delivers 1 in 42±45% overall yield. We
6
been isolated from the leaves of Monotes engleri and
found to exhibit a signi®cant cytotoxic activity against
several human tumor cell lines.
1
4
2. Results and discussion
The conversion of naringenin (3) to 1 and 2 along these lines
Keywords: physiologically active compounds; ¯avanoids and iso¯ava-
noids; rearrangements; catalysis; Mitsunobu reactions.
p Corresponding author. Fax: 149-351-463-3162;
e-mail: metz@coch01.chm.tu-dresden.de
Figure 1.
0040±4020/00/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01078-4

1
016
S. Gester et al. / Tetrahedron 57 (2001) 1015±1018
Scheme 1.
2
3,24
re¯ux in toluene, and complete consumption of 5 to give an
intractable product mixture was observed after 4 h re¯ux in
DMF. After 2 h at re¯ux in decalin, 5 was nearly completely
consumed to give a 3:1 mixture of 6 and 7. Upon extending
the reaction time to 2 d, only the Claisen±Cope product 6
was observed. With the aim of enhancing the proportion of
estrogen inducible yeast screen estrogen receptor assay.
The yeast strain used contained both a stably transfected
estrogen receptor-a construct and an expression plasmid
carrying estrogen-responsive sequences controlling the
reporter gene lac-Z encoding the enzyme b-galactosidase.
Estrogenic activity could directly be read in a colorimetric
assay from the enzymatic hydrolysis of chlorophenol red
b-d-galactopyranoside by monitoring the absorbance at
2
0,21
7
gated. To this end, prenyl ether 5 was treated with catalytic
, catalysis
of the Claisen rearrangement was investi-
2
1
amounts of Eu(fod) in chloroform at different tempera-
23
540 nm. In a concentration-dependent analysis of reporter
3
tures (Table 1). While the Eu(III)-complex did not cause any
conversion at room temperature, heating for 6 h at 408C
allowed the isolation of a 1.2:1 mixture of 6 and 7 in high
yield. Remarkably, after 12 h at 608C 6 and 7 were formed
in a 7.0:1 ratio, which points to a Eu(III)-catalysis of the
gene activity, halfmaximal induction of b-galactosidase
activity is a direct measure for the af®nity of the compound
to the estrogen receptor-a and therefore for estrogenic
activity.
2
0
Cope rearrangement step as well. Thus, with proper
temperature control, the Eu(fod) accelerated reaction is
Applying these criteria it becomes apparent that 1 and 2
exhibit a clearcut estrogenic activity, whereas the parent
compound 3 is void of this activity (Fig. 2). Further it is
apparent that the relative activity of 1 and 2 is 2±3 orders of
magnitude less potent than the natural female sex hormone
estradiol. Nevertheless, with a halfmaximal activity at a
3
preferable to the purely thermal process for the production
of both 6 or 7 in terms of overall yield. Since no preparative
separation of 6 and 7 was achieved, the mixture of these
diacetates was subjected to a potassium carbonate catalyzed
2
2
27
solvolysis, whereupon 8-prenylnaringenin (1) and 6-(1,1-
dimethylallyl)naringenin (2) could be easily isolated as pure
isomers.
concentration of 1 slightly lower than 10 M we con®rm
6
previous observations that 1 represents at least in vitro the
most potent phytoestrogen identi®ed so far.
With suf®cient amounts of 1 and 2 in our hands, in vitro
testing of their estrogenic potency was performed. For the
assessment of the estrogenicity we applied the widely used
3. Experimental
3
.1. General experimental information
For general experimental information see Ref. 25.
.1.1. 2-(4-Acetoxy-phenyl)-5-hydroxy-4-oxo-chroman-
Table 1. Rearrangement of prenyl ether 5
a
b
c
Method
T (8C)
t (h)
Ratio 6:7
Yield 617 (%)
3
A
A
B
B
188
188
40
2
48
6
3.0:1
.20:1
1.2:1
7.0:1
73
62
81
92
d
7-yl acetate (4). To a solution of 3 (1.361 g, 5.00 mmol)
in dry pyridine (5 mL) is added dropwise at room tempera-
ture acetic anhydride (0.94 mL, 10.0 mmol). After stirring
the mixture for 24 h at room temperature, it is poured into
ice-cold water (30 mL). The ocher precipitate is separated
by ®ltration, washed twice with a small amount of ice-cold
water and recrystallized from methanol (50 mL). The
60
12
a
3 3
A: Decalin, re¯ux; B: CHCl , 10 mol% Eu(fod) .
b
c
d
By preparative separation after solvolysis to 112.
Isolated yield.
Only 6 observed.

S. Gester et al. / Tetrahedron 57 (2001) 1015±1018
1017
Figure 2. Estrogenic activity of 8-prenylnaringenin (1) and 6-(1,1-dimethylallyl)naringenin (2). 1 and 2 like the corresponding positive control estradiol
E2/1) activate b-galactosidase reporter activity, whereas naringenin (3) in contrast to the corresponding positive control estradiol (E2/2) does not. Note, 1 and
have been measured in the same assay, whereas 3 has been measured separately. Therefore, two reference curves were included. For the sake of
(
2
28
comparability, data have additionally been normalized by setting absorbance units measured at 10 M estradiol in each experimental set at 100% and
calculating all other data points accordingly.
resultant material is washed with a small amount of ice-cold
methanol and dried at 608C to yield 4 (1.452 g, 82%) as a
major product (R 0.41) from a diethyl ether/pentane
f
mixture to give 5 (1.027 g, 74%) as a white solid. R 0.41
f
slightly sandy solid. R 0.69 (ethyl acetate/pentane, 1:2);
f
(ethyl acetate/pentane, 1:2); m.p. 121±1228C (diethyl ether/
pentane); IR (KBr): 1768, 1683, 1608, 1510, 1437, 1371,
m.p. 141±1428C (MeOH); IR (KBr): 1747, 1657, 1629,
1
2
1
1
587, 1373, 1217, 1183, 1128, 1085, 1021 cm ; H NMR
21 1
1198, 1137, 1103 cm ; H NMR (CDCl , 500 MHz): d
3
(
(
d6-DMSO, 300 MHz): d 2.26 (s, 3H), 2.28 (s, 3H), 2.90
dd, 1H, Jˆ17.2 Hz, Jˆ2.8 Hz), 3.46 (dd, 1H, Jˆ17.2 Hz,
1.71 (s, 3H), 1.77 (s, 3H), 2.28 (s, 3H), 2.29 (s, 3H), 2.79
(dd, 1H, Jˆ16.5 Hz, Jˆ2.8 Hz), 2.99 (dd, 1H, Jˆ16.5 Hz,
Jˆ13.2 Hz), 4.59 (d, 2H, Jˆ6.3 Hz), 5.41 (dd, 1H,
Jˆ13.2 Hz, Jˆ2.8 Hz), 5.51 (t, 1H, Jˆ6.3 Hz), 6.29 (d,
1H, Jˆ2.2 Hz), 6.40 (d, 1H, Jˆ2.2 Hz), 7.12 (d, 2H,
Jˆ13.2 Hz), 5.73 (dd, 1H, Jˆ13.2 Hz, Jˆ2.8 Hz), 6.37 (d,
1
H, Jˆ2.2 Hz), 6.38 (d, 1H, Jˆ2.2 Hz), 7.21 (d, 2H,
1
3
Jˆ8.5 Hz), 7.59 (d, 2H, Jˆ8.5 Hz), 11.93 (s, 1H); C
NMR (d -DMSO, 75 MHz): d 20.88 (q), 20.96 (q), 42.31
1
3
Jˆ8.6 Hz), 7.44 (d, 2H, Jˆ8.6 Hz); C NMR (CDCl ,
6
3
(t), 78.30 (d), 101.80 (d), 102.95 (d), 105.90 (s), 122.10 (d,
intense), 128.09 (d, intense), 135.78 (s), 150.72 (s), 158.06
125 MHz): d 18.32 (q), 21.05 (q), 21.14 (q), 25.74 (q),
45.69 (t), 66.32 (t), 78.55 (d), 99.82 (d), 103.11 (d),
109.52 (s), 118.82 (d), 121.88 (d, intense), 127.23 (d,
intense), 136.05 (s), 138.17 (s), 150.71 (s), 156.29 (s),
161.04 (s), 163.63 (s), 168.36 (s), 169.28 (s), 189.00 (s);
MS (GC/MS, 70 eV) m/z (relative intensity): 424 (44)
(
(
[
s), 162.03 (s), 162.22 (s), 168.29 (s), 169.23 (s), 197.79
s); MS (GC/MS, 70 eV) m/z (relative intensity): 356 (43)
1
1
1
M ], 314 (33) [M ZCH CO], 313 (26) [M ZCH CO],
2 3
1
73 (9), 272 (51) [M ZCH COZCH CO], 271 (65)
2
2 2
1
M ZCH COZCH CO], 43 (100) [CH CO ]. Anal.
1
1
1
1
[
calcd for C H O : C, 64.04; H, 4.53. Found C, 64.18; H,
[M ], 382 (41) [M ZCH CO], 381 (100) [M ZCH CO].
2 3
2
3
3
Anal. calcd for C H O : C, 67.91; H, 5.70. Found C,
24 24 7
1
9
16
7
4.55.
68.14; H, 5.89.
3
4
4
.1.2. 2-(4-Acetoxy-phenyl)-5-(3-methyl-but-2-enyloxy)-
-oxo-chroman-7-yl acetate (5). To a solution of diacetate
(1.160 g, 3.26 mmol), triphenylphosphine (1.041 g, 3.97
3.2. General procedure for Claisen rearrangement of
prenyl ether (5) to 2-(4-acetoxy-phenyl)-5-hydroxy-8-(3-
methyl-but-2-enyl)-4-oxo-chroman-7-yl acetate (6) and
2-(4-acetoxy-phenyl)-6-(1,1-dimethyl-allyl)-5-hydroxy-
4-oxo-chroman-7-yl acetate (7)
mmol) and 3-methyl-2-buten-1-ol (0.48 mL, 4.84 mmol) in
dry THF (40 mL) cooled to 08C is added dropwise over
45 min under argon a solution of diethyl azodicarboxylate
(
0.82 mL, 5.25 mmol) in dry THF (10 mL). The resultant
Thermal reaction: A solution of 5 (200 mg, 0.471 mmol) in
dry decalin (10 mL) is heated to re¯ux for the time indicated
in Table 1. The solvent is removed in vacuo, and the residue
is subjected to ¯ash chromatography (ethyl acetate/pentane,
1:3) to give a mixture of 6 and 7 (R 0.54 for both compo-
f
nents) in the yield listed in Table 1.
yellow solution is allowed to warm to room temperature and
stirred for 2 h. After removal of the solvent in vacuo, the
brownish residue is dissolved in a small amount of ethyl
acetate and subjected to ¯ash chromatography (ethyl
acetate/pentane, 1:2) followed by recrystallization of the

1
018
S. Gester et al. / Tetrahedron 57 (2001) 1015±1018
Europium(III)-catalyzed reaction: A solution of 5 (500 mg,
.18 mmol) in dry CHCl (0.2 mL) is treated with Eu(fod)3
Sumpter, Brunel University, UK, for kindly providing the
yeast-based estrogen receptor screening assay.
1
3
(
124 mg, 0.118 mmol). After stirring the mixture for the
time and at the temperature listed in Table 1, it is directly
subjected to ¯ash chromatography (ethyl acetate/pentane,
References
1:3) to give a mixture of 6 and 7 (R 0.54 for both compo-
nents) in the yield listed in Table 1.
f
1. Harborne, J. B.; Baxter, H. In The Handbook of Natural
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2
3
4
. Bohlmann, F.; Zdero, C.; King, R. M.; Robinson, H.
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3
6
.3. Solvolysis of 6 and 7 to 8-prenylnaringenin (1) and
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1
978, 26, 3863±3870.
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The mixture of 6 and 7 (407 mg, 0.96 mmol) obtained from
a Eu(III)-catalyzed run (6 h 408C, 81%) is treated with
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2
2
3
5
. H aÈ nsel, R.; Schulz, J. Arch. Pharm. 1988, 321, 37±40.
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6
4
3
1
999, 83, 2249±2252.
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2
2
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over Na SO , and the solvent is removed in vacuo. The
2
4
crude product is subjected to ¯ash chromatography
CH Cl /methanol, 20:1) and the separated components 1
(
2
2
995±998. (b) Jain, A. C.; Gupta, R. C.; Sarpal, P. D.
Tetrahedron 1978, 34, 3563±3567.
and 2 are recrystallized from CHCl3 to give pure 1
157 mg, 48%) and 2 (128 mg, 39%) as white solids.
(
9
. Nagar, A.; Gurjal, V. K.; Gupta, S. R. Tetrahedron Lett. 1978,
3, 2031±2034.
2
3
2
1
.3.1. 8-Prenylnaringenin (1). R 0.19 (CH Cl /MeOH,
f 2 2
1
0. Ito, C.; Mizuno, T.; Matsuoka, M.; Kimura, Y.; Sato, K.;
Kajiura, I.; Omura, M.; Ju-Ichi, M.; Furukawa, H. Chem.
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0:1); m.p. 1938C; IR (KBr): 3317, 1640, 1603, 1519,
442, 1378, 1344, 1267, 1229, 1171, 1074, 834 cm ; H
2
1 1
NMR (d -DMSO, 500 MHz): d 1.53 (s, 3H), 1.58 (s, 3H),
6
2
1
1
1. Sherif, E. A.; Islam, A.; Krishnamurti, M. Ind. J. Chem. (Sect.
B) 1982, 21, 478±479.
.71 (dd, 1H, Jˆ17.1 Hz, Jˆ3.0 Hz), 3.07 (d, 2H,
Jˆ7.2 Hz), 3.20 (dd, 1H, Jˆ17.1 Hz, Jˆ12.6 Hz), 5.08 (t,
2. Ziegler, F. E. In Comprehensive Organic Synthesis, Trost,
B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon Press:
Oxford, 1991; 5, pp 875±898.
1
H, Jˆ7.2 Hz), 5.42 (dd, 1H, Jˆ12.6 Hz, Jˆ3.0 Hz), 5.96
(
9
s, 1H), 6.79 (d, 2H, Jˆ8.5 Hz), 7.31 (d, 2H, Jˆ8.5 Hz),
1
3
.57 (s, 1H), 10.77 (s, 1H), 12.11 (s, 1H); C NMR (d -
6
1
1
1
3. (a) Burling, E. D.; Jefferson, A.; Scheinmann, F. Tetrahedron
965, 21, 2653±2669. (b) Cairns, N.; Harwood, L. M.; Astles,
DMSO, 125 MHz): d 17.62 (q), 21.30 (t), 25.58 (q), 41.95
t), 78.24 (d), 95.31 (d), 101.81 (s), 106.94 (s), 115.17 (d,
intense), 122.71 (d), 128.10 (d, intense), 129.26 (s), 130.23
s), 157.60 (s), 159.73 (s), 161.20 (s), 164.41 (s), 196.76 (s);
1
(
D. P. J. Chem. Soc., Perkin Trans. 1 1994, 3101±3107.
4. Seo, E.-K.; Silva, G. L.; Chai, H.-B.; Chagwedera, T. E.;
Farnsworth, N. R.; Cordell, G. A.; Pezzuto, J. M.; Kinghorn,
A. D. Phytochemistry 1997, 45, 509±515.
(
1
MS (GC/MS, 70 eV) m/z (relative intensity): 340 (66) [M ],
1
85 (18) [M ZC H ], 247 (16) [M ZC H OH], 165 (100).
1
2
Anal. calcd for C H O : C, 70.57; H, 5.92. Found C,
4 7 6 5
5. Baudouin, G.; Tillequin, F.; Koch, M. J. Nat. Prod. 1983, 46,
2
0
20
5
6
6. Bu, X.; Zhao, L.; Li, Y. Synthesis 1997, 1246±1248.
81±687.
7
0.23; H, 5.88.
1
1
7. McKillop, A.; Fiaud, J.-C.; Hug, R. P. Tetrahedron 1974, 30,
1
3
.3.2. 6-(1,1-Dimethylallyl)naringenin (2). Rf 0.35
379±1382.
(
CH Cl /MeOH, 20:1); m.p. 1638C; IR (KBr): 3361, 1638,
2
2
2
1
1
594, 1447, 1346, 1156, 1101, 838 cm ; H NMR (d -
18. (a) Mitsunobu, O. Synthesis 1981, 1±28. (b) Hughes, D. L.
Org. React. 1992, 42, 335±656.
1
6
DMSO, 500 MHz): d 1.49 (s, 6H), 2.66 (dd, 1H, Jˆ
1
9. (a) Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1±252.
1
1
1
7.1 Hz, Jˆ2.9 Hz), 3.25 (dd, 1H, Jˆ17.1 Hz, Jˆ
2.9 Hz), 4.75 (dd, 1H, Jˆ10.6 Hz, Jˆ1.2 Hz), 4.80 (dd,
H, Jˆ17.3 Hz, Jˆ1.2 Hz), 5.39 (dd, 1H, Jˆ12.9 Hz,
(
(
b) Moody, C. J. Adv. Heterocycl. Chem. 1987, 42, 203±244.
c) Wipf, P. In Comprehensive Organic Synthesis, Trost,
B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon Press:
Oxford, 1991; 5, pp 827±873.
Jˆ2.9 Hz), 5.92 (s, 1H), 6.22 (dd, 1H, Jˆ17.3 Hz, Jˆ
1
9
0.6 Hz), 6.79 (d, 2H, Jˆ8.5 Hz), 7.30 (d, 2H, Jˆ8.5 Hz),
.58 (s, 1H), 10.64 (s, 1H), 13.18 (s, 1H); C NMR (d -
6
1
3
20. Lutz, R. P. Chem. Rev. 1984, 84, 205±247.
2
2
2
2
1. Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 815±
16.
DMSO, 125 MHz): d 28.92 (q), 28.95 (q), 40.16 (s), 42.14
t), 78.07 (d), 95.45 (d), 101.75 (s), 107.38 (t), 112.29 (s),
15.21 (d, intense), 128.35 (d, intense), 128.98 (s), 149.99
8
(
1
2. Nicolaou, K. C.; Smith, A. L.; Wendeborn, S. V.; Hwang,
C. K. J. Am. Chem. Soc. 1991, 113, 3106±3114.
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(
d), 157.77 (s), 160.41 (s), 162.90 (s), 165.84 (s), 196.74 (s).
1
4. Gaido, K. W.; Leonard, L. S.; Lovell, S.; Gould, J. C.; Babai,
5, 241±248.
Acknowledgements
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Financial support of this work by the Fonds der Chemischen
Industrie is gratefully acknowledged. We thank Professor J.