Regioselective synthesis of prenylisoflavones: Syntheses of luteone and luteone hydrate

Article abstract of DOI:10.1246/cl.2000.1362

The palladium-catalyzed coupling reaction of 6-iodoisoflavone, prepared from 3′-iodoacetophenone derivative, with 2-methyl-3-butyn-2-ol gave the 6-alkynylisoflavone derivative, which was hydrogenaied to give the 6-alkylhydroxyisoflavone (luteone hydrate)

Full text of DOI:10.1246/cl.2000.1362

1362
Chemistry Letters 2000
Regioselective Synthesis of Prenylisoflavones: Syntheses of Luteone and Luteone Hydrate
Masao Tsukayama,* Hironari Wada, Masashi Kishida, Masaki Nishiuchi, and Yasuhiko Kawamura
Department of Chemical Science and Technology, Faculty of Engineering, The University of Tokushima,
Minamijosanjima, Tokushima 770-8506
(Received September 4, 2000; CL-000824)
The palladium-catalyzed coupling reaction of 6-
ered that 2 would be a precursor of 1 and dehydration of 2
would lead to 1. We wish to report here on the first syntheses of
1 and 2 by using the palladium(0)-catalyzed coupling reaction5
of the corresponding iodoisoflavone with 2-methyl-3-butyn-2-ol.
The catalytic hydrogenation of 2',4'-bis(benzyloxy)-6'-
methoxymethoxyacetophenone6 over Pd/C, followed by iodina-
tion of the resultant 2',4'-dihydroxyacetophenone 3 with I2 and
iodoisoflavone, prepared from 3'-iodoacetophenone derivative,
with 2-methyl-3-butyn-2-ol gave the 6-alkynylisoflavone deriv-
ative, which was hydrogenated to give the 6-alkylhydroxy-
isoflavone (luteone hydrate) 2. Dehydration of 2 gave 2',4',5,7-
tetrahydroxy-6-prenylisoflavone (luteone).
7
H5IO6 gave the 3'-iodoacetophenone 48 in high yield.
Prenyl (=3-methyl-2-butenyl)isoflavones and (3-hydroxy-3-
methylbutyl)isoflavones are widely distributed in nature and
have antifungal activity.1 Luteone, being known as a phytoalex-
in, was first isolated in 1973 from immature fruits of Lupinus
luteus (Leguminosae).2 The structure was assigned as 2',4',5,7-
tetrahydroxy-6-(3-methyl-2-butenyl)isoflavone (1) by spectro-
scopic and chemical studies. More recently, the same isoflavone
1 was isolated from the roots of yellow lupin (L. luteus L., cv.
Barpine) together with luteone hydrate, the structure of which
was assigned to be 2',4',5,7-tetrahydroxy-6-(3-hydroxy-3-
methylbutyl)isoflavone (2) by spectroscopic analysis.3 The total
syntheses of both isoflavones 1 and 2 have not been achieved
yet; however, the dimethyl ether of luteone has been synthe-
sized.4 The reason seemes to be due to the difficulty in intro-
ducing regioselectively an alkyl or alkenyl group into the
isoflavone nucleus, protection and deprotection. In view of the
isolation of 1 and 2 from the same natural source, it is consid-
Compound 4 was converted into the bis(benzyloxy)acetophe-
none 5,8 the structure of which was determined by direct com-
parision with a sample of the isomer, 2',4'-bis(benzyloxy)-5'-
iodo-6'-methoxymethoxyacetophenone (mp 99–100 °C).6,9 The
mixture of 5 with the isomer showed a marked depression in the
melting point relative to that of each compound. The conden-
sation of 5 with 2,4-bis(benzyloxy)benzaldehyde gave the 6'-
methoxymethoxychalcone 6, and then the methoxymethyl
group in the chalcone was cleaved by treatment with dilute HCl
to give the 6'-hydroxychalcone 7. The oxidative rearrangement
of the 6'-benzoyloxychalcone 8, derived from 7, with
thallium(III) nitrate trihydrate (TTN)6,10 gave the acetal deriva-
tive 9, which was converted into the 6-iodoisoflavone 10.11
The coupling reaction of 10 with 2-methyl-3-butyn-2-ol gave
the 6-(3-hydroxy-3-methylbutynyl)isoflavone 11. The catalytic
hydrogenation of 11 gave 2',4',5,7-tetrahydroxy-6-(3-hydroxy-
1
3-methylbutyl)isoflavone (2).12 The H NMR spectrum of 2
Copyright © 2000 The Chemical Society of Japan

Chemistry Letters 2000
1363
was identical with that of a natural sample of luteone hydrate3
(Table 1). On the basis of these results, the structure of luteone
hydrate was unequivocally established to be 2',4',5,7-tetrahy-
droxy-6-(3-hydroxy-3-methylbutyl)isoflavone (2).
3
4
5
6
7
8
Y. Hashidoko, S. Tahara, and J. Mizutani, Agric. Biol.
Chem., 50, 1797 (1986).
A. C. Jain, A. Kumar, and R. C. Gupta, J. Chem. Soc.,
Perkin Trans.1, 1979, 279.
K. Sonogashira, Y. Tohda, and N. Hagihara, Tetrahedron
Lett., 1975, 4467.
M. Tsukayama, H. Li, K. Tsurumoto, M. Nishiuchi, and Y.
Kawamura, Bull. Chem. Soc. Jpn., 71, 2673 (1998).
V. K. Ahluwalia, C. Prakash, and R. S. Jolly, J. Chem.
Soc., Perkin Trans. 1, 1981, 1697.
The tribenzoate derivative 12 of 2 was converted into 5-
tosyloxyisoflavone 13, which was dehydrated with BF3·OEt2 to
give the 5-hydroxy-6-prenylisoflavone 14 and the dihydropyran
derivative 15. The formation of 15 supported definitely the
structure of 2 and decreased the yield of 14. The tosylate 13
was dehydrated with TsOH·H2O to give a mixture of the 6-
prenylisoflavone 16 and the regioisomeric 6-(3-methyl-3-
Compound 4: mp 160–161 °C; 1H NMR (400 MHz,
CDCl3) δ 2.69 (3H, s, CH3CO), 3.52 (3H, s, OCH3), 5.28
(2H, s OCH2), 5.98 (1H, s, 4'-OH), 6.44 (1H, s, 5'-H),
14.97 (1H, s, 2'-OH). Found: C, 35.25; H, 3.17%. Calcd
for C10H11O5I: C, 35.52; H, 3.28%. Compound 5: mp
96–97 °C; Found: C, 55.66; H, 4.48%. Calcd for
C24H23O5I: C, 55.61; H, 4.47%.
1
butenyl)isoflavone 17. The H NMR spectrum of the tosylate
mixture (16 and 17) showed the ratio of 16 to 17 to be 85:15
[peaks due to CH2CH=C(CH3)2 at δ=3.36 (2H, d) and
CH2CH2C(CH3)=CH2 at δ = 4.57 (2H, s)]. The mixture (16 and
17) reacted quantitatively with benzohydroximoyl chloride13 in
dry CH2Cl2 at room temperature to give a mixture of the
unchanged 6-prenylisoflavone 16 and the terminal alkene-
cyclic adduct, and then 16 was purified by silica-gel column
chromatography. The detosylation of 16 with BCl3, followed
by hydrolysis of the resultant compound 14 with 10% NaOH in
a mixture of methanol and dioxane at room temperature gave
2',4',5,7-tetrahydroxy-6-(3-methyl-2-butenyl)isoflavone (1)14
(1H NMR in Table 1), which was converted into the tetraacetate
9
M. Tsukayama, M. Kikuchi, and S. Yoshioka, Chem. Lett.,
1993, 1895.
10 L. Farkas, Á. Gottsegen, and M. Nógrádi, J. Chem. Soc.,
Perkin Trans. 1, 1974, 305.
11 Compound 10: mp 174–176 °C; H NMR (400 MHz,
1
CDCl3) δ 5.02, 5.03, 5.06 and 5.25 (each 2H, s, CH2), 6.63
(1H, dd, J=2.4 and 8.5 Hz, 5'-H), 6.67 (1H, d, J=2.4 Hz, 3'-
H), 6.73 (1H, s, 8-H), 7.20–7.75 (21H, m, Ar-H × 21), 7.78
(1H, s, 2-H). Found: C, 66.64; H, 4.58%. Calcd for
C43H33O6I: C, 66.85; H, 4.30%.
1
derivative 18. The H NMR, IR and UV spectral data for 1
were completely identical with those of a natural sample of
luteone.2,3 On the bases of these results, the structure of natural
luteone was first unequivocally established to be 2',4',5,7-
tetrahydroxy-6-(3-methyl-2-butenyl)isoflavone (1).
The present regioselective synthesis of iodoisoflavones and
the palladium(0)-catalyzed coupling reaction of iodoisoflavones
with 2-methyl-3-butyn-2-ol have shown to be an efficient and
useful procedure for the syntheses of prenyl- and alkylpoly-
hydroxyisoflavones and O-alkylated prenylisoflavones.
12 Compound 2: mp 229–231 °C (lit.,3 pale yellow glassy
solid); IR (KBr) ν 3350, 2975, 1645, 1620, 1460, 1310,
1065, 830 cm–1; UV λmax nm(log ε) (MeOH) 265 (4.45),
290sh (4.19), 345sh (3.58), (+AlCl3) 267 (4.46), (+NaOAc)
269 (4.44), 340 (3.93). Found: C, 64.22; H, 5.46%. Calcd
for C20H20O7: C, 64.51; H, 5.41%.
13 S. Kanemasa, M. Nishiuchi, A. Kamimura, and K. Hori, J.
Am. Chem. Soc., 116, 2324 (1994); M. Tsukayama, H. Li,
M. Nishiuchi, M. Takahashi, and Y. Kawamura, J. Chem.
Res. (M), 1998, 1181.
References and Notes
1
P. M. Dewick, in "The Flavonoids: Advances in Research
Since 1980," ed. by J. B. Harborne, Chapman and Hall,
London (1988); J. L. Ingham, S. Tahara, and J. B.
Harborne, Z. Naturforsch., 38C, 194 (1983); M. D.
Woodward, Phytochemistry, 18, 363 (1979); J. B.
Harborne, J. L. Ingham, L. King, and M. Payne,
Phytochemistry, 15, 1485 (1976).
14 Compound 1: mp 222–224 °C (lit.,2 mp 225–226 °C); IR
(KBr) ν 3425, 3300, 3100br.,1650, 1615, 1590, 1550,
1215, 1060, 815 cm–1; UV λmax nm(log ε) (MeOH) 266
(4.56), 280 (4.33), 340 (3.63), (+AlCl3) 271 (4.41),
(+NaOAc) 269 (4.55), 340 (3.83). Found: C, 67.55; H,
5.21%. Calcd for C20H18O6: C, 67.79; H, 5.12%.
2
H. Fukui, H. Egawa, K. Koshimizu, and T. Mitsui, Agric.
Biol. Chem., 37, 417 (1973).