Synthesis of (R,S)-dioclein, a bioactive flavanone from the root bark of Diocleia grandiflora

Article abstract of DOI:10.1021/np960659b

Synthesis of (R,S)-dioclein, a bioactive flavanone isolated from the root bark of Dioclea grandiflora Mart. ex Benth., is described.

Full text of DOI:10.1021/np960659b

J . Nat. Prod. 1997, 60, 399-400
399
Syn th esis of (R,S)-Dioclein , a Bioa ctive F la va n on e fr om th e Root Ba r k of
Diocleia gr a n d iflor a
Paul Spearing, George Majetich,* and J nanabrata Bhattacharyya*
Department of Chemistry, University of Georgia, Athens, Georgia 30602
Received September 25, 1996X
Synthesis of (R,S)-dioclein, a bioactive flavanone isolated from the root bark of Dioclea
grandiflora Mart. ex Benth., is described.
Sch em e 1
Dioclea grandiflora Mart. ex Benth. (Leguminosae),
a vine commonly known as “macuna”, is used in the
popular medicine of northeastern Brazil.1 The root of
this plant is used in the treatment of kidney stones and
prostate gland disorders (Agra, M. F. Universidade
Federal de Paraiba, Brazil, unpublished results).
A
preliminary pharmacological screening of the EtOH
extract of the root-bark of D. grandiflora showed
significant analgesic activity in rats and mice.2 Sub-
sequently, chemical investigation of the CHCl3-soluble
part of the EtOH extract of the root-bark of D. grandi-
flora resulted in the isolation of a new flavanone,
dioclein (1), mp 160-162 °C, [R]D - 88.7°, which also
demonstrated the analgesic activity detected in the
crude extract.3,4 We required a source of dioclein for
chemical corroboration of its structure as well as for
further pharmacological studies. Here we report a
three-step synthesis of (R,S)-dioclein, which represents
the first synthesis of this natural product.
Flavanones are isomeric with the corresponding 2′-
OH chalcones, and these isomers are easily intercon-
verted using either acid or base. A common approach
to the synthesis of flavanones is, therefore, to prepare
the intermediate 2′-OH chalcone, with the other func-
tional groups protected, and isomerize to the flavanone
in acidic medium.5 However, in the case of 5′- or 6′-
hydroxychalcones, the flavanone is quite stable, and
often the chalcone cannot be isolated.6 Dioclein has a
5-OH group and was expected to be easily prepared from
the appropriate chalcone as illustrated in Scheme 1.
Surprisingly, this simple strategy proved to be trouble-
some.
In the first step, 2-hydroxy-4,5,6-trimethoxyacetophe-
none (2) was condensed with 2,5-bis(benzyloxy)benzal-
dehyde (3)7 in the presence of 50% aqueous KOH to give
2,5-bis(benzyloxy)-2′-hydroxy-4′,5′,6′-trimethoxychal-
cone (4) in 75% yield.8 We were disappointed to find
that treatment of 4 with 60% aqueous KOH in EtOH
at reflux for over 72 h gave no reaction. Similarly,
traditional acidic conditions, such as 20% or 50% aque-
ous H3PO4 or 30% HBr in HOAc,9 also failed to promote
ring closure despite heating for several days at temper-
atures between 30 and 70 °C. Decomposition of the
chalcone occurred whenever temperatures greater than
75 °C were used. Further work revealed that treatment
of 4 with KF in MeOH under reflux for 24 h yielded
flavanone 5 in 72% yield,10 while K2CO3 dissolved in
CH3CN could be used to promote cyclization at room
temperature in 68% yield, but required longer reaction
times (>48 h). Deprotection of the 2′- and 5′-benzyl
ethers, along with the selective removal of the labile C-6
methyl ether, was accomplished in 80% yield using BCl3
in CH2Cl2. The spectral (UV, IR, 1H and 13C NMR, and
MS) and chromatographic (TLC) properties of synthetic
(R,S)-dioclein were identical to those of the natural
product.3
Exp er im en ta l Section
Gen er al Exper im en tal P r ocedu r es. Melting points
were determined in a Thomas Hoover “Unimelt” ap-
paratus and are uncorrected. IR were recorded with a
Perkin-Elmer 1600 FT-IR spectrophtometer, and the
frequencies were reported in cm-1
.
1H- and 13C-NMR
spectra were recorded on a Bruker 250 MHz instrument,
and EIMS were recorded on a Finnigan 4000 spectrom-
eter.
2,5-Bis(ben zyloxy)-2′-h ydr oxy-4′, 5′,6′-tr im eth oxy-
ch a lcon e (4). To a solution of 2-hydroxy-4,5,6-tri-
methoxyacetophenone (2) (0.80 g; 3.5 mmol) and 2,5-
bis(benzyloxy)benzaldehyde (3) (1.12 g; 3.5 mmol) in
absolute EtOH (50 mL) was added 16 mL of 50%
aqueous KOH. The resulting mixture was stirred at
room temperature for 48 h. The reaction mixture was
acidified at 0 °C with 10% aqueous HCl and then
extracted with Et2O (3 × 50 mL). The combined
ethereal extracts were washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated. The
resulting solid residue was purified via column chro-
matography on Si gel (elution with hexanes-EtOAc, 9:1)
to give 1.38 g of 4 (75%), which was homogeneous by
TLC analysis [hexanes-EtOAc, 3:1; Rf (4) ) 0.36, Rf
(2) ) 0.52, Rf (3) ) 0.62]: mp 101-103 °C (recrystallized
from Me2CO) as deep orange crystals; anal. C 72.78%,
H 5.89%, calcd for C32H30O7, C 72.98%, H 5.75%; EIMS
m/ z [M]+ 526; IR 3515 (OH), 1676 (conj CdC), 1625
X Abstract published in Advance ACS Abstracts, April 1, 1997.
S0163-3864(96)00659-3 CCC: $14.00
© 1997 American Chemical Society and American Society of Pharmacognogy

400 J ournal of Natural Products, 1997, Vol. 60, No. 4
Notes
(conj CdO), 1557 (Ar), 1492 (Ar), 1454 (Ar), 1381, 1348,
1118, 821, and 737 cm-1; 1H NMR (250 MHz, CDCl3) δ
8.22 (d, 1 H, J ) 15.9 Hz), 7.93 (d, 1 H, J ) 15.9 Hz),
7.28-7.46 (m, 11 H), 6.89-7.01 (m, 2 H), 6.29 (s, 1 H),
5.14 (s, 2 H, PhCH2), 5.06 (s, 2 H, PhCH2), 3.90 (s, 3 H,
C4-OCH3), and 3.82 (s, 6 H, 2 Ar-OCH3).
mL). The resulting mixture was slowly warmed to room
temperature over a 90 min period. The reaction mixture
was quenched with saturated aqueous NaHCO3 (1.0
mL) and then extracted with Et2O (3 × 20 mL). The
combined ethereal extracts were washed with brine,
dried over anhydrous MgSO4, filtered, and concentrated.
The residue was purified by column chromatography on
Si gel (elution with hexane-EtOAc, 1:1) to yield 35 mg
(80%) of racemic dioclein, which was homogeneous by
TLC analysis (hexanes-EtOAc, 1:1; Rf 5 ) 0.87, Rf 1 )
0.46): anal. calcd for C17H16O7, C 61.43%, H 4.86%;
found C 61.23%, H 4.78%; mp 214-216 °C; HRFABMS
m/ z [M + H]+ 333.0982 (100) (calcd for C17H16O7,
333.0974); IR 1645 (ArCdO), 1558 (Ar), 1506 (Ar), 1456
2′,5′-Bis(ben zyloxy)-5,6,7-tr im eth oxyflavan on e (5)
Usin g KF . Chalcone (4) (0.61 g, 1.15 mmol) was added
to a stirred solution of KF (0.20 g) in MeOH (25 mL),
and the mixture was refluxed for 24 h. The reaction
mixture was diluted with H2O and extracted with Et2O
(5 × 30 mL). The combined ethereal extracts were
washed with brine, dried over anhydrous MgSO4, fil-
tered, and concentrated to give an oily residue. Puri-
fication via column chromatography on Si gel (elution
with hexanes-EtOAc, 9:1) afforded 0.44 g of 5 (72%),
which was homogeneous by TLC analysis (hexanes-
EtOAc, 2:1; Rf 4 ) 0.52, Rf 5 ) 0.40): mp 97-99 °C
(recrystallized from Me2CO) as cream-colored crystals;
EIMS m/ z [M]+ 526; IR 1682 (ArCdO), 1600 (Ar), 1489
(Ar), 1454 (Ar), 1262, 1103, 821, and 737 cm-1; 1H NMR
(250 MHz, CDCl3) δ 7.29-7.47 (m, 11 Ar-H), 6.90 (d, 2
H, J ) 1.4 Hz, two ArH), 6.36 (s, 1 H, C8-H), 5.07 (s, 2
H, PhCH2), 5.06 (s, 2 H, PhCH2), 5.05 (m, 1H, C2-H),
3.95 (s, 3 H, ArOCH3), 3.87 (s, 3 H, ArOCH3), 3.84 (s, 3
H, ArOCH3), 2.83-2.88 (m, 2 H, C3-H).
2′,5′-Bis(ben zyloxy)-5,6,7-tr im eth oxyflavan on e (5)
Usin g K2CO3. Chalcone (4) (38 mg, 0.07 mmol) was
added to a stirred suspension of K2CO3 (20 mg, 0.14
mmol) in CH3CN (1.0 mL), and the resulting mixture
was stirred at room temperature for 48 h. The reaction
mixture was then acidified with 10% aqueous HCl,
saturated with NaCl, and extracted with Et2O (3 × 5
mL). The combined organic extracts were washed with
brine, dried over anhydrous MgSO4, filtered, and con-
centrated. The crude residue (36 mg) was chromato-
graphed on Si gel (elution with hexanes-EtOAc, 9:1)
to give 26 mg of 5 (68%), which was identical to that
previously characterized.
1
(Ar), 1290, 1201, 1111, and 808 cm-1; H NMR (250
MHz, Me2CO-d6) δ 8.18 (s, 1 H), 7.90 (s, 1 H), 7.01 (d, 1
H, J ) 2.8 Hz, ArH), 6.66-6.79 (m, 2 H, ArH), 6.23 (s,
1 H, C8-H), 5.75 (dd, 1 H, J ) 12.8, 3.2 Hz, C2-H), 3.90
(s, 3 H, Ar-OCH3), 3.71 (s, 3 H, Ar-OCH3), 2.79-3.12
(m, 2 H, C3-H); 13C NMR (62.5 MHz, Me2CO-d6) 202.5
(s), 166.2 (s), 164.2 (s), 160.1 (s), 155.7 (s), 151.7 (s),
131.1 (s), 129.0 (s), 121.3 (d), 120.8 (d), 118.3 (d), 107.9
(s), 96.8 (d), 79.9 (d), 64.7 (q), 60.8 (q), 46.8 (t) ppm.
Refer en ces a n d Notes
(1) Andrade Lima, D. Plantas da Caatingas; Academia Brasileira
de Cieˆncias: Rio de J aneiro, Brazil, 1989; p 112.
(2) Batista, J . S.; Almeida, R. N.; Bhattacharyya, J ., Abstracts of
Papers, II. Congress de la Federacion Farmaceutica Sudameri-
cana, Montevideo, Uruguay, 1993; p 168.
(3) Bhattacharyya, J .; Batista, J . S.; Almeida, R. N. Phytochemistry
1995, 38, 277-278.
(4) Batista, J . S.; Almeida, R. N.; Bhattacharyya, J . J . Ethnophar-
macology 1995, 45, 207-210.
(5) Seshadri, T. R. The Chemistry of the Flavonoid Compounds;
Geissman, T. A., Ed.; MacMillan: New York, 1962; p 156.
(6) Narashimachari, N.; Seshadri, T. R. Proc. Ind. Acad. Sci. 1948,
27A, 223-230.
(7) Compound 3 was prepared from 2,5-dihydroxybenzaldehyde
(Aldrich Chemical Co.) using standard Williamson ether condi-
tions.
(8) Mani, R. I.; Herbert, L.; Manise, D. J . Tenn. Acad. Sci. 1991,
66, 1.
(9) J ain, A. C.; Sharma, B. N. Phytochemistry 1973, 12, 1455-1458.
(10) Harwood, L. M.; Loftus, G. C.; Oxford, A.; Thomson, C. Synth.
Commun. 1990, 20, 649-657.
Dioclein (1). To a solution of 5 (70 mg, 0.13 mmol)
in CH2Cl2 (2.0 mL) cooled to -60 °C was added dropwise
a solution of BCl3 (530 µL, 0.53 mmol) in CH2Cl2 (1.0
NP960659B