Synthesis of Abyssinone II and related compounds as potential chemopreventive agents

Article abstract of DOI:10.1016/j.ejmech.2005.09.008

A facile and efficient approach to the synthesis of prenylated flavonoids as potential chemopreventive agents has been described. This features the synthesis of prenyl halide, prenylation of p-hydroxybenzaldehyde, formation of prenylated polyhydroxychalco

Full text of DOI:10.1016/j.ejmech.2005.09.008

European Journal of Medicinal Chemistry 41 (2006) 263–267
http://france.elsevier.com/direct/ejmech
Short communication
Synthesis of Abyssinone II and related
compounds as potential chemopreventive agents
Robert M. Moriarty, Simonida Grubjesic, Bhushan C. Surve, Susantha N. Chandersekera,
Om Prakash, Rajesh Naithani *
Department of Chemistry, University of Illinois at Chicago, Chicago 60607, USA
Received 2 June 2005; received in revised form 26 September 2005; accepted 29 September 2005
Available online 02 December 2005
Abstract
A facile and efficient approach to the synthesis of prenylated flavonoids as potential chemopreventive agents has been described. This features
the synthesis of prenyl halide, prenylation of p-hydroxybenzaldehyde, formation of prenylated polyhydroxychalcone and cyclization of preny-
lated polyhydroxychalcone to flavanones (15) and (16), and flavonol (17) starting from isoprene (1). The structures of all three compounds have
been characterized by NMR, IR and mass spectroscopy.
© 2005 Elsevier SAS. All rights reserved.
Keywords: Flavonoids; Abyssinone II; Prenylation; Chemoprevention; Polyhydroxychalcone; Prenylated chalcone
1. Introduction
appears that the position of prenylation rather than the number
of prenyl groups, determines the biological activity of the com-
pounds [7].
Flavonoids constitute an important class of naturally occur-
ring compounds exhibiting a wide spectrum of biological activ-
ities, which include anti-carcinogenic, anti-viral, anti-inflam-
matory and anti-fungal properties [1]. The remarkable
biological effect of hydroxy flavonoids is mainly attributed to
the presence of phenolic groups, which have high affinity for
proteins and therefore act as inhibitors of microbial enzymes
[2] as well as through their effect on uncoupling oxidative
phosphorylation [3] and inhibition of NADH dehydrogenase
of mitochondrial inner membranes [4].
Notably, there is substantial evidence that a high intake of
flavonoids lowers cancer risk [8,9]. Last decade has witnessed
an explosion of research publication on the use of flavonoids as
cancer chemopreventive agents [8,9]. A large number of flavo-
noids have been used for the chemopreventive studies in vivo,
in vitro and in human clinical trials [8,9]. Flavonoids have
shown promise to inhibit carcinogenesis by acting via a series
of mechanisms by affecting the molecular events at the initia-
tion and progression stages [8,9]. Hydroxy flavonoids with pre-
nyl group have been shown to be aromatase inhibitors. The
enzyme aromatase catalyses the final and rate-limiting step in
estrogen biosynthesis. The overall hypothesis is that these com-
pounds will be safe and effective inhibitors of estrogen-depen-
dent tumor formation.
In addition, substitution on the flavonoid ring system with
prenyl groups is thought to increase their lipophilicity and con-
sequently enhance their lipophilicity through interaction with
cellular membranes [5].
It is generally agreed that one phenolic group and certain
degree of lipophilicity are required for the activity of the flavo-
noid compounds [6]. In spite of the diversity of biological ac-
tivity exhibited by the prenylated flavonoids, there is little in-
formation as to the structure–activity relationship. However, it
2. Results and discussion
In continuation of our ongoing research in the area of cancer
chemoprevention, we have synthesized Abyssinone II, 7-hy-
droxy-2-[4-hydroxy-3-(methyl-but-2-enyl) phenyl] chroman-4-
one (15) and its derivatives. Abyssinone (II) has been isolated
from the Chinese medical plant Broussonetia papyfera. It has
* Corresponding author.
E-mail address: naithani@uic.edu (R. Naithani).
0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2005.09.008

264
R.M. Moriarty et al. / European Journal of Medicinal Chemistry 41 (2006) 263–267
been found to be one of the most active naturally occurring
aromatase inhibitors and has exhibited higher potency than
aminoglutethinide [10]. The National Cancer Institute selected
Abyssinone (II) considering its plant origin and potency for
further development through the Rapid Access to Preventive
Intervention Development (RAPID) [11]. Owing to its limited
availability from natural sources and its excellent potency,
synthesis of Abyssinone II was undertaken.
Abyssinone (II) was accomplished using the route shown
in Scheme 3. Lack of a general, efficient, regioselective meth-
od for the introduction of prenylated side chain and appropriate
protection for the phenoxy group presented a major challenge.
The first step involved synthesis of 1-bromo-3-methyl-but-2-
ene (3) using isoprene (1). The reaction of HBr in acetic acid
with isoprene at 0–4 °C resulted in formation of desired (3)
1,4-addition product along with minor amounts of undesired
(2) 1,2-addition product and the unreacted starting material
(Scheme 1) [12]. Separation of the desired compound was ac-
complished by vacuum distillation in about 45% yield.
[13]. The reaction gave a mixture of prenylated compounds
(Scheme 2).
The product contained multiple C- and O-prenylated pro-
ducts, which can be explained by the delocalization of phen-
oxide anion within the aromatic ring. Interestingly, compound
(9) was obtained where the carbonyl group of the benzalde-
hyde was replaced by a prenyl moiety. The formation of this
compound can be explained by the proposed mechanism that
goes via the elimination of the formic acid from the aromatic
ring. The desired product (8) was obtained by employing silica
gel column chromatography (hexane/acetone 12:1) followed by
crystallization as a white solid (m.p. 57–60 °C) in a low yield
of 6–8% [13].
The hydroxyl group of the para-hydroxybenzaldehyde was
protected by converting to the –OTHP derivative (10) in quan-
titative yields. Similarly, 2,4- dihydroxyacetophenone (11) was
also protected in an analogous manner to yield 1-[2-hydroxy-4-
(tetrahydropyran-2-yloxy)-phenyl] ethanone (12).
Treatment of (10) and (12) with Ba(OH)2.H2O/methanol
yielded 1-[2-hydroxy-4-(tetrahydro-pyran-2-yloxy)phenyl]-3-[3-
methyl-but-2-enyl)-4-(tetrahydro-pyran-2-yloxy)-phenyl] prope-
none (13) in about 40% yield. The deprotection of the –OTHP
group was achieved by using para-toluenesulfonic acid to yield
1-(2, 4-dihydroxyphenyl)-3-[4-hydroxy-3-(3-methyl-but-2-enyl-
phenyl] propenone (14).
The key step was the introduction of the prenyl group to 4-
hydroxybenzaldehyde, which proceeded into an unsatisfactory
yield. The different methods for the prenylation on the phenyl
group were tried without much success. The synthesis of 4-hy-
droxy-3-(3-methyl-but-2-enyl)-benzaldehyde (8) was achieved
by treatment of 1-bromo-3-methyl-but-2-ene (3) with p-hydro-
xy benzaldehyde in 10% aqueous KOH solution for 48 h at r.t.
The cyclization was carried out in NaOAc/methanol to yield
7-hydroxy-2-[4-hydroxy-3-(3-methyl-but-2-enyl)-phenyl] chro-
man-4-one (15) as a slightly yellow solid after silica gel chroma-
tography. The synthetic 15 was confirmed to be identical with
1
data reported for natural Abyssinone II by H, 13C-NMR and
mass spectra. In an attempt to convert flavanone 15 to flavone
18, we tried employing hypervalent iodine oxidation using HTIB
Scheme 1.
Scheme 2.

R.M. Moriarty et al. / European Journal of Medicinal Chemistry 41 (2006) 263–267
265
omatase (more than 90%) it was tested for dose–response and
the IC50 values were calculated where IC50 represents the con-
centration of the test compound that inhibits 50% of the en-
zyme activity. All experiments were performed in duplicate
and the mean was used for calculation of IC50. The reaction
was then quenched. The compound was tested in comparison
to aminoglutethimide, which was used as a positive control.
Name of the compound
IC50 (μM)
IC50 (μM) fluorimetric
radiometric method high through put assay
Abyssinone II
Aminoglutethimide
0.6
6.4
62
0.27
IC50 represents the concentration of the test compound that inhibits 50% of
enzyme activity.
3. Experimental
All moisture-sensitive reactions were carried out under an ar-
gon atmosphere in flame-dried glassware. Solvents and reagents
were purchased from Aldrich. Tetrahydrofuran (THF) was dis-
tilled from sodium/benzophenone. Dichloromethane (DCM) and
triethylamine were distilled from calcium hydride. Thin layer
chromatography (TLC) was carried out on Aldrich silica gel
glass plates with UV indicator. Flash column chromatography
was performed on Merck silica gel 60 (mesh 230–400). 1H- and
13C-NMR spectra were recorded on Bruker Avance (400 MHz)
or Avance (500 MHz) spectrometers. All melting points were
recorded on a Thomas–Hoover capillary melting point apparatus
and are uncorrected. Infrared spectra were recorded on ATI
Mattson Genesis series FTIR spectrometer. The Midwestern Mi-
crolab, Indianapolis, IN performed elemental analyses. Mass
spectra were obtained at the Mass Spectroscopy Service Labora-
tory, University of Illinois at Chicago.
Scheme 3.
in acetonitrile. However, instead of getting flavone, we got cy-
clization of the prenyl group at the hydroxy resulting in the for-
mation of 16 along with the starting material (15). The com-
pound showed an absence of characteristic triplet at δ 5.2 ppm
responsible for = CH(CH3)3 of the isoprenyl group of 15.
Synthesis of the flavonol 17 was carried out by treating 16
with H2O2 and sodium hydroxide. The structure of the com-
pound 16 was confirmed by NMR (absence of peaks for
methylene protons (C3–HaHb) of compound 15 and mass spec-
tra (HRMS: m/z [M + H]+ at 338).
3.1. 1-Bromo-3-methylbut-2-ene (3)
A solution of hydrogen bromide in acetic acid (45% W/V
HBr, 136 ml) was added drop-wise to isoprene (50 g,
0.734 mol) at 0 °C (ice salt bath). After stirring at 0–4 °C for
48 h, the pale yellow solution was poured into ice (400 g) and
an oily product separated, which was dissolved in dichloro-
methane and washed with water (2 × 100 ml). The organic
extracts were dried over MgSO4 and the solvent removed un-
der reduced pressure to give pale yellow oil. Distillation gave
1-bromo-3-methylbut-2-ene (3) as a colorless liquid b.p. 36–
38 °C at 15 mmHg (Ref. [12], b.p. 26–33 °C at 12 mmHg).
Yield 50 g, 45.8%. 1H-NMR (400 MHz, CDCl3) δ (ppm): 5.55
(m, 1H, = CH), 4.01 (d, 2H, CH2Br), 1.80 (s, 3H, CH3), 1.75
(s, 3H, CH3).
2.1. Activity of Abyssinone II in aromatase assay
The synthetic racemic mixture of Abyssinone II was tested
for aromatase assay using the radiometric method developed
by Thompson and Sitteri [14a] and human placental micro-
somes as source of aromatase enzyme. The briefly tested com-
3
pound was incubated with H-androstenedione, unlabeled an-
drostenedione and human placental microsomes as the source
of aromatase. The amount of released tritiated water (3H2O)
was measured to determine the amount of converted substrate.
The radiometric assay was later replaced by a highly developed
new fluorimetric high-throughput assay [14b].
Briefly, the test compound was incubated with aromatase
enzyme, NADPH regenerating system and dibenzylfluorescein
(DBF) for 30 min. The reaction was then quenched and after
standing at room temperature for 2 hours, fluorescence of
fluorscein (converted from DBF by aromatase) was measured
at 485 nm (excitation) and 530 nm (emission). Initial screening
was done at 10 μg/ml and since this significantly inhibited ar-
3.2. 4-Hydroxy-3-(3-methyl-but-2-enyl)-benzaldehyde (8)
4-Hydroxybenzaldehyde (4.01 g, 32.8 mmol) was dissolved
in 10% (w/v) aqueous KOH solution (48 ml) and 1-bromo-2-
methyl-but-2-ene (3) (10.0 g, 67.1 mmol) was added drop-wise
with stirring over 1 h at r.t. The reaction mixture was stirred at
r.t. for 48 h, and then acidified with 1 N aqueous HCl solution

266
R.M. Moriarty et al. / European Journal of Medicinal Chemistry 41 (2006) 263–267
to pH 2 and extracted with diethyl ether (3 × 100 ml). The
combined ether layers were washed with 2% aqueous
Na2CO3 solution (2 × 100 ml), water and brine, dried
(Na2SO4) and the solvent evaporated under reduced pressure
to give a dark brown oil. The resulting oil was purified by flash
chromatography over silica gel (acetone/hexane, 1:12) to afford
8 (458 mg, 2.41 mmol, yield 7.5%): white solid, m.p. = 58–
61 °C (Ref. [13] m.p. = 61 °C); Rf = 0.13 (acetone/hexane,
1:9); 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.73 (s, 3H,
CH3), 1.77 (s, 3H, CH3), 3.41 (d, J = 7.3 Hz, 2H, CH2), 5.35
(t, J = 7.5 Hz, 1H, = CH), 7.00 (dd, J = 8.2, 1.4 Hz, 1H), 7.67
(dd, J = 8.3, 1.8 Hz, 1H), 7.71 (s, 1H), 8.32 (br s, 1H, OH),
9.79 (s, 1H, CHO); 13C-NMR (500 MHz, CDCl3): 18.29,
26.23, 29.01, 116.34, 121.33, 129.22, 129.47, 131.19,
132.61, 135.41, 161.60, 192.92; FTIR (neat) υmax: 3305
(OH), 1665 (C = O), 1591 (C = C, aromatic) cm–1.
(Na2SO4) and the solvent evaporated under reduced pressure
to give a colorless oil. The resulting oil was purified by flash
chromatography over silica gel (EtOAc/hexane, 5:95) to afford
11 (4.35 g, 18.9 mmol, yield 65%): white solid, m.p. = 66–68 °
C (Ref. [15] m.p. = 67–9 °C); Rf = 0.54 (EtOAc/hexane, 3:7);
1
FTIR (neat): υmax = 1632 (C = O), 1256 (C–O–C) cm–1; H-
NMR (400 MHz, CDCl3) δ (ppm): 1.57 (m, 1H), 1.65 (m, 2H),
1.83 (m, 2H), 1.95 (m, 2H), 2.5 (s, 3H, CH3), 3.59 (m, 1H),
3.79 (m, 1H), 5.45 (t, J = 3.1 Hz, 1H), 6.52 (dd, J = 8.9,
2.4 Hz, 1H, 5-CH), 6.57 (d, J = 2.4 Hz, 1H, 3-CH), 7.60 (d,
J = 8.9 Hz, 1H, 6-CH); 13C-NMR (500 MHz, CDCl3): 18.89,
25.37, 26.63, 30.36, 62.54, 96.46, 104.35, 108.87, 114.895,
132.67, 163.94, 165.23, 203.11.
3.5. 1-[2-Hydroxy-4-(tetrahydro-pyran-2-yloxy)-phenyl]-3-[3-
(3-methyl-but-2-enyl)-4-(tetrahydro-pyran-2-yloxy)-phenyl]-
propenone (13)
The combined aqueous Na2CO3 extracts were acidified with
1 N aqueous HCl to pH 4, extracted with ether (3 × 100 ml),
dried (Na2SO4) and evaporation of solvent under reduced pres-
sure gave 1.66 g of starting 4-hydroxybenzaldehyde.
3-(3-Methyl-but-2-enyl)-4(tetrahydro-pyran-2-yloxy)-benzal-
dehyde (12) (2.61 g, 13.3 mmol) and 1-[2-hydroxy-4-(tetrahy-
dro-pyran-2-yloxy)-phenyl]-ethenone (10) (3.14 g, 13.3 mmol)
were dissolved in MeOH (55 ml) and Ba(OH)2.H2O (2.51 g,
13.3 mmol) was added. The resulting mixture was heated at
50 °C for 1 h and allowed to reach r.t. and stirred for another
24 h. The solvent was then evaporated under reduced pressure,
water (60 ml) was added and the mixture was acidified with 1 N
aqueous HCl to pH 4. The resulting mixture was then extracted
with DCM (3 × 45 ml). The combined extracts were washed
with brine, dried Na2SO4 and solvent evaporated under reduced
pressure to give orange oil. The resulting solution was purified
by flash chromatography over silica gel (EtOAc/hexane 1:9) to
afford 13 (3.69 g, 7.5 mmol, yield 56%): yellow oil.
3.3. 3-(3-Methyl-but-2-enyl)-4(tetrahydro-pyran-2-yloxy)-
benzaldehyde (10)
4-Hydroxy-3-(3-methyl-but-2-enyl)-benzaldehyde (8) (3.30 g,
17.8 mmol) and pyridinium p-toluene-sulfonate (110 mg,
0.4 mmol) were dissolved in DCM (7 ml), and 3,4-dihydro-
2H-pyran (4.60 g, 5 ml, 54 mmol) was added drop-wise under
flow of argon, at r.t. The resulting reaction mixture was stirred at
r.t. for 24 h, and then water (20 ml) was added. The organic
layer was separated and washed with water (2 × 20 ml), brine,
dried (Na2SO4) and the solvent evaporated under reduced pres-
sure to give yellow oil. The resulting oil was purified by flash
chromatography over silica gel (EtOAc/hexane, 5:95) to afford
10 as colorless oil (3.02 g, 11 mmol, yield 62%): Rf = 0.75 (30%
EtOAc/hexane); FTIR (neat): υmax = 1687 (C = O), 1594 (C = C,
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.61 (m, 3H), 1.71
(m, 3H), 1.74 (s, 3H, CH3), 1.76 (s, 3H, CH3), 1.89 (m, 4H,
CH2), 2.00 (m, 4H, CH2), 3.39 (d, J = 5.7 Hz, 2H, CH2), 3.63
(d, J = 5.7 Hz, 1H), 3.85 (t, J = 5.7 Hz, 2H, CH2), 5.28 (t,
J = 6.0 Hz, 1H, = CH), 5.52 (t, J = 3.3 Hz, 2H, O-CH), 6.60
(dd, J = 9.0, 2.4 Hz, 1H, 5′-H), 6.66 (d, J = 8.9, 2.3 Hz, 1H, 3′-
H), 7.13 (d, J = 8.4 Hz, 1H, 5-H), 7.46 (m, 3H), 7.84 (m, 2H);
13C-NMR (500 MHz, MeOH-d4): 17.90, 18.52, 18.62, 24.99,
25.17, 25.82, 28.76, 29.99, 30.28, 61.95, 62.19, 95.87, 96.08,
104.21, 108.37, 114.17, 117.73, 122.18, 127.86, 127.94;
130.18, 131.25, 132.87, 144.86, 156.99,2 163.40, 166.14,
192.10; FTIR (neat): υmax = 1632 (C = O), 1566 (C = C aro-
matic) , 1241 (C–O–C) cm–1; HRMS: m/z [M + K]+ calcd. for
C30H36O6K: 531.2149, found 531.2144.
1
aromatic), 1245 (C–O–C) cm–1; H-NMR (400 MHz, CDCl3) δ
(ppm): 1.58 (m, 2H, CH2), 1.68 (s, 3H), 1.71 (s, 3H), 1.87 (m,
2H, CH2), 1.96 (m, 2H, CH2), 3.36 (d, J = 6.8 Hz, 2H, CH2),
3.58 (m, 1H), 3.77 (m, 1H), 5.28 (t, J = 7.0 Hz, 1H, = CH),
7.16 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.64 (dd,
J = 8.5, 2.1 Hz, 1H), 9.80 (s, 1H, CHO); 13C-NMR (500 MHz,
CDCl3): 17.78, 18.50, 19.68, 25.06, 25.75, 28.61, 30.14, 30.63,
61.90, 95.84, 113.63, 121.74, 130.11, 130.49, 131.33, 159.74,
191.13; HRMS: m/z [M + H]+ calcd. for C17H23O3: 275.1647,
found 275.1650.
3.4. 1-[2-Hydroxy-4-(tetrahydro-pyran-2-yloxy)-phenyl]-
3.6. 1-(2,4-Dihydroxy-phenyl)-3-[4-hydroxy-3-(3-methyl-but-2-
ethenone (11)
enyl)-phenyl]-propenone (14)
2,4-Dihydroxyacetophenone (4.43 g, 29.1 mmol) and pyri-
dinium p-toluene-sulfonate (180 mg, 0.7 mmol) were dissolved
in DCM (70 ml), and 3,4-dihydro-2H-pyran (14.8 g, 16 ml,
176 mmol) was added drop-wise under flow of argon, at r.t.
The resulting reaction mixture was stirred at r.t. for 20 h, and
then water was added (100 ml). The organic layer was sepa-
rated and washed with water (2 × 100 ml) and brine, dried
1-[2-Hydroxy-4-(tetrahydro-pyran-2-yloxy)-phenyl]-3[3-(3-me-
thyl-but-2-enyl)-4-(tetrahydro-pyran-2-yloxy)-phenyl]-propenone
(13) (8.61 g, 17.5 mmol) and p-toluenesulfonic acid monohydrate
(122 mg, 0.6 mmol) were dissolved in methanol (90 ml) and stir-
red for 24 h at r.t. Solvent was then evaporated under reduced
pressure and water was added (150 ml). The aqueous mixture
was neutralized with saturated aqueous NaHCO3 solution to

R.M. Moriarty et al. / European Journal of Medicinal Chemistry 41 (2006) 263–267
267
pH 7 and extracted with EtOAc (3 × 50 ml). The combined or-
ganic phases were washed with water (15 ml) and brine, dried
(Na2SO4) and the solvent evaporated under reduced pressure to
give a viscous, yellow oil. The resulting oil was purified by flash
chromatography over silica gel (EtOAc/hexane, 2:8) to afford 14
(3.27 g, 10.1 mmol, yield 58%): yellow solid, m.p. = 166–168 °C;
matography over silica gel (EtOAc/hexane, 2:8) to afford 16
(60 mg, 0.18 mmol, yield 30%). 1H-NMR (400 MHz,
CDCl3) δ (ppm): 1.76 (s, 3H, CH3), 1.77 (s, 3H, CH3), 2.79
(dd, J = 17, 2.9 Hz, 1H, 3-H), 3.07 (dd, J = 13.3, 3.7 Hz, 1H,
3-H), 3.37 (d, J = 7.2 Hz, 2H, CH2), 5.31 (t, J = 7.2 Hz, 1H,
= CH), 5.36 (dd, J = 13.4, 2.8 Hz, 1H, 2-H), 5.66 (br s, 1H,
OH), 6.47 (d, J = 2.3 Hz, 1H, 8-H), 6.56 (dd, J = 8.7, 2.3 Hz,
1H, 6-H), 6.84 (d, J = 8.8 Hz, 1H, 3′-H), 7.19 (m, 2H, 2 ′,6′-
H), 7.35 (br s, 1H, OH), 7.84 (d, J = 8.7 Hz, 1H, 5-H); FTIR
(neat): υmax = 3282 (OH), 1653 (C = O), 1601 (C = C, aro-
matic) cm–1.
1
Rf = 0.13 (EtOAc/hexane, 2:8); H-NMR (400 MHz, MeOH-d4) δ
(ppm): 1.74 (s, 3H, CH3), 1.75 (s, 3H, CH3), 3.31 (dd, J = 6.8,
3.8 Hz, 2H, CH2), 5.35 (t, J = 3.8 Hz, 1H, = CH), 6.28 (d,
J = 2.4 Hz, 1H, 3′-H), 6.40 (dd, J = 8.9, 2.4 Hz, 1H, 5′-H), 6.80
(d, J = 8.3 Hz, 1H, 5–H), 7.44 (m, 2H, 2, 6-H), 7.54 (d,
J = 15.0 Hz, 1H, α-H), 7.69 (d, J = 15.0 Hz, 1H, β-H), 7.93 (d,
J = 9.0 Hz, 1H, 6′-H); 13C-NMR (500 MHz, MeOH-d4): 16.89,
24.95, 28.30, 102.81, 108.13, 113.70, 115.29, 116.92, 122.61,
126.74, 128.11, 129.17, 130.90, 132.33, 145.15, 158.46, 158.58,
160.05, 166.51, 192.54; FTIR (neat): υmax = 3375 (OH), 1628
(C = O), 1556 (C = C aromatic) cm–1; elemental analysis calcd.
for C20H20O4: C, 73.06; H, 6.21, found: C, 73.01; H, 6.14.
3.9. 3,7-Dihydroxy-2,(4-hydroxy-3-(3-methylbut-2-enyl)-4H-
chromen-4-one (17)
To a stirring solution of chalcones (13) (246 mg, 0.5 mmol)
in MeOH–THF (5 ml each) was added NaOH 16% at 0 °C. A
solution of 15% H2O2 was added. The reaction mixture was
stirred till starting material gets consumed. Reaction was acid-
ified with 2 N HCl and extracted with DCM, washed with
water, brine, dried over anhydrous Na2SO4. Purification was
done using silica gel column chromatography (EtOAc/hexane,
3:7) to afford 17 (66 mg, 0.19 mmol, 39%). 1H-NMR
(400 MHz, CDCl3) δ (ppm): 1.35 (d, J = 7.28 Hz, 6H,
2CH3), 1.78–1.86 (m, 2H, 4′-CH2), 2.76–2.83 (m, 3H, 3, 3 ′,
4′-H), 3.03–3.12 (dd, J = 13.48, 13.48 Hz, 1H, 3-H), 5.35 (d,
J = 13.38 Hz, 1H, 2-H), 5.77 (br s, OH), 6.44 (s, 1H, 8-H),
6.53 (d, J = 8.68 Hz, 1H, 6-H), 6.82 (d, J = 8.6 Hz, 1H, 7′-
H), 7.17 (m, 2H, 2 ′, 8′-H), 7.86 (d, 1H, 5-H); HRMS: m/z
[M + Na]+ calcd for C20H20O4: 346.1181, found: 347.1266.
3.7. 7-Hydroxy-2-[4-hydroxy-3-(3-methyl-but-2-enyl)-phenyl]-
chroman-4-one [Abyssinone II] (15)
1-(2,4-Dihydroxy-phenyl)-3-[4-hydroxy-3-(3-methyl-but-2-
enyl)-phenyl]-propenone (14) (1.01 g, 3.11 mmol) and sodium
acetate (4.65 g, 56.7 mmol) were mixed in ethanol and heated
under reflux for 46 h. The mixture was then allowed to reach r.
t., poured into ice water (15 ml) and extracted with methylene
chloride (3 × 20 ml). The combined organic phase was washed
with water (10 ml) and brine, dried (Na2SO4) and the solvent
evaporated under reduced pressure to give a pale yellow solid.
The resulting mixture was purified by preparative HPLC (water/
MeOH, 2:8) to afford 15 (580 mg, 1.71 mmol, yield 58%):
white solid, m.p. = 76–78 °C, Rf = 0.59 (EtOAc/hexane/MeOH,
References
1
3/7/0.08); H-NMR (400 MHz, CDCl3) δ (ppm): 1.76 (s, 3H,
[1] D. Carlo, N. Mascolo, A.A. Izzo, F. Capasso, Life Sc. 65 (1999) 337–
353.
CH3), 1.77 (s, 3H, CH3), 2.79 (dd, J = 17, 2.9 Hz, 1H, 3-H),
3.07 (dd, J = 13.3, 3.7 Hz, 1H, 3-H), 3.37 (d, J = 7.2 Hz, 2H,
CH2), 5.31 (t, J = 7.2 Hz, 1H, = CH), 5.36 (dd, J = 13.4, 2.8 Hz,
1H, 2-H), 5.66 (br s, 1H, OH), 6.47 (d, J = 2.3 Hz, 1H, 8-H),
6.56 (dd, J = 8.7, 2.3 Hz, 1H, 6-H), 6.84 (d, J = 8.8 Hz, 1H, 3′-
H), 7.19 (m, 2H, 2′,6′-H), 7.35 (br s, 1H, OH), 7.84 (d,
J = 8.7 Hz, 1H, 5-H); 13C-NMR (500 MHz, CDCl3): 18.33,
26.22, 30.14, 44.36, 80.19, 103.89, 111.27, 115.03, 116.39,
121.72, 126.14, 127.85, 128.69, 129.87, 130.99, 135.61,
155.27, 164.10, 164.42, 192.67; FTIR (neat): υmax = 3282
(OH), 1653 (C = O), 1601 (C = C, aromatic) cm–1; HRMS [M
– H]+ calcd. for C20H19O4: 323.1283, found 323.1298.
[2] D. Prusky, N.T. Keen, Plant Dis. 77 (1993) 114.
[3] P. Ravanel, M. Tissut, R. Douce, Phytochemistry 21 (1982) 2865.
[4] P. Ravanel, S. Creuzet, M. Tissut, Phytochemistry 29 (1990) 441.
[5] D. Baron, K.I. Ragai, Phytochemistry 43 (1996) 921.
[6] P.E. Laks, M.S. Pruner, Phytochemistry 27 (1989) 87.
[7] Y. Hano, Y. Yamagami, M. Kobayashi, R. Isohata, T. Nomura, Hetero-
cycles 31 (1990) 77.
[8] C.S. Yang, J.M. Landau, M.T. Huang, H.L. Newmark, Ann, Reviews
Nutrition 21 (2001) 381.
[9] W. Ren, Z. Qiao, H. Wang, L. Zhu, L. Zhang, Med. Res. Rev. 23 (2003)
519.
[10] A.D. Kinghorn, J.M. Pezzuto, D. Lee, K.P.L. Bhat, P.C.T. Int. Appl. WO
2003013554 (2003) 79.
[11] D. Lee, K.P. Bhat, H.H. Fong, N.R. Farnsworth, J.M. Pezzuto, A.D.
Kinghorn, J. Nat. Prod. 64 (2001) 1286.
[12] D.B. Anthony, S.J. Warren, Chem. Soc. Perkin Trans. 1 (1985) 2307.
[13] K. Kyogoku, K. Hatayama, S. Yokomori, T. Sek, I. Tanaka, Agric. Biol.
Chem. 1 (1975) 133.
[14] (a) E.A. Thompson, P.K. Sitteri, J. Biol. Chem. 249 (2000) 5364.(b)
D.M. Stresser, S.D. Turner, J. McNamara, P. Strocker, V.P. Miller, C.L.
Crespi, C.J. Patten, Anal. Biochem 284 (1974) 427.
[15] M. Artico, R.D. Santo, R. Costi, E. Novellino, G. Greco, S. Mars, E.
Tramontano, M.E. Marongive, A. De Montis, A.P. Lacolla, J. Med.
Chem. 41 (1990) 3948.
3.8. 2-(2,2-Dimethyl-3,4-dihydro-2-H-chromen-6-yl)-7-
hydroxy-2,3-dihydrochromen-4-one (16)
To a solution of 7-hydroxy-2-[4-hydroxy-3-(3-methyl-but-
2-enyl)-phenyl]-chroman-4-one [Abyssinone II] (15) (200 mg,
0.6 mmol) in acetonitrile (30 ml) was added HTIB (241 mg,
0.6 mmol) and the reaction mixture was refluxed for 24 h. The
reaction mixture was concentrated, washed with water and ex-
tracted with DCM. The resulting oil was purified by flash chro-