First total synthesis of (±)-glyflavanone-A

Article abstract of DOI:10.1081/SCC-120003156

First convergent synthesis (±)-glyflavanone-A (1), a novel pyranoflavanone natural product, starting from phloroacetophenone and p-anisaldehyde is described.

Full text of DOI:10.1081/SCC-120003156

SYNTHETIC COMMUNICATIONS, 32(7), 1077–1083 (2002)
FIRST TOTAL SYNTHESIS OF
(6)-GLYFLAVANONE-A
*
Wen-Fei Tan, Wei-Dong Z. Li, and Yu-Lin Li
National Laboratory of Applied Organic Chemistry and
Institute of Organic Chemistry, Lanzhou University,
Lanzhou, Gansu 730000, P.R. China.
ABSTRACT
First convergent synthesis (ꢀ)-glyflavanone-A (1), a novel
pyranoflavanone natural product, starting from phloroaceto-
phenone and p-anisaldehyde is described.
Key Words: Pyranoflavanone; Glyflavanone-A; Total syn-
thesis
In a previous paper1 of this series, we reported a facile and convergent
method for the synthesis of naturally occurring pyranoflavanones from
readily available prenylated acetophenone derivatives. In continuation of
our ongoing research program2 on the total synthesis of bioactive prenyl-
flavonoids, we herein describe the first total synthesis of (ꢀ)-glyflavanone-A
(1),3 a natural pyranoflavanoid isolated recently from the leaves of shrub
Glycosmis citrifolia (Willd.) Lindl. during a reinvestigation of the chemical
constituents of the plant which is used in folk medicine for the treatment of
certain skin disorders, i.e., itch, scabies, boils and ulcers. Along with 1,
*Corresponding author. E-mail: liyl@lzu.edu.cn
1077
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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TAN, LI, AND LI
Scheme 1. Reagents and Conditions: a) MOMCl, K2CO3, acetone, reflux, 0.5 h;
b) prenyl bromide, K2CO3, acetone, reflux, 4 h; chromatography on silica gel; c)
N,N-dimethylaniline, Ar, reflux, 4 h; d) (CH3O)2SO2, acetone, K2CO3, reflux,
0.5 h; e) MeOH, 3 N HCI, reflux, 15 min; f) DDQ, Dioxane, benzene, reflux, 4 h;
g) p-anisaldehyde, KOH, EtOH, r.t. 36 h; h) NaOAc, EtOH, reflux, 24 h.
(MOM ¼ methoxymethyl; DDQ ¼ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone).
glychalcone A (2),3 a possible biosynthetic precursor of 1, was also identi-
fied. The chemical structures of 1 or 2 were elucidated by extensive spectro-
scopic analysis. Outlined in Scheme 1 is the synthetic sequence that features
an efficient DDQ-mediated oxidative pyranocyclization of the correspond-
ing prenylated phloroacetophenone derivatives.

(6)-GLYFLAVANONE-A
1079
Selective methoxymethylation of phloroacetophone (3) (MOMCl,
K2CO3, acetone) produced 44,2j in 63% yield, which was treated with
prenyl bromide in the presence of K2CO3 in dry acetone to give the
prenyl ether 5 in 91% yield after chromatographic purification on silica
gel.5 Thermal Claisen rearrangement (N,N-dimethylaniline, reflux)6 of the
prenyl ether 5 afforded the desired para-rearranged prenyl acetophenone 6
in 80% yield. Selective O-methylation of 6 (MeO2SO2, K2CO3, acetone,
86%) followed by demethoxymethylation (3 N HCl, MeOH, 1 : 5, v/v) of
the resulting intermediate 7 gave 8 (75% from 6). DDQ-mediated oxidative
pyranocyclization (1.0 equiv., benzene, reflux)7 of prenyl acetophenone 8 led
to chromene 9 (81%, m.p. 117–120ꢁC), which was condensed with
p-anisaldehyde in an alcoholic aqueous solution of KOH to give the desired
glychalcone-A (2) in 82% yield as a colorless oil. The chalcone 2 was
cyclized in the usual manner (NaOAc, EtOH, reflux) to afford the title
compound (ꢀ)-glyflavanone-A (1) in 70% isolated yield. The synthetic
(ꢀ)-1 and 2 have shown identical spectroscopic properties as those reported
for the natural products, respectively.3,8
EXPERIMENTAL
Melting points were determined on a Kofler hot stage apparatus and
were uncorrected. IR spectra were recorded on a Nicolet 170 FT-IR spectro-
1
photometer as a KBr discs. H NMR Spectra were recorded on a Bruker
AC-80 or an AM-400 instrument in a CDCl3 solution with TMS as an
internal standard. Mass Spectra were measured on a ZAB-HS or HP-5988
mass spectrometer. Elemental analyses were performed with a MOD-1106
elemental analyzer. Purification of reagents and solvents was affected
according to standard methods. Prior to concentration under reduced press-
ure, all extracts were dried over anhydrous Na2SO4. Flash column chroma-
tography was performed on silica gel (200–300 mesh).
2-Hydroxy-4-methoxymethoxy-6-prenyloxyacetophenone (5)
To a mixture of 4 (500 mg, 1.79 mmol) and anhydrous K2CO3 (400 mg,
2.90 mmol) in dry acetone (20 ml) was added prenyl bromide (0.3 ml,
2.60 mmol). The resulting reaction mixture was refluxed for 4 h with stirring,
cooled to ambient temperature, and filtered. The filtrate was evaporated and
the residue was chromatographed on silica gel with pet. ether–ethyl acetate
(v/v, 9 : 1) to give 5 as a white solid (500 mg, 91%), m.p. 39–41ꢁC. 1H NMR
(80 MHz) d 1.74 and 1.78 (each 3H, s, C(CH3)2), 2.59 (3H, s, COCH3), 3.45

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TAN, LI, AND LI
(3H, s, OCH3), 4.53 (2H, d, J ¼ 6.6 Hz, CH2), 5.15 (2H, s, OCH2O), 5.48
(1H, t, J ¼ 6.6 Hz, CH¼), 6.03 and 6.17(each 1H, d, J ¼ 2.1 Hz, H-3,5),
13.62 (1H, s, OH, exchangeable with deuterium); MS m/z: 280 (Mþ), 235,
225, 193, 151, 69, 45.
2,6-Dihydroxy-3-prenyl-4-methoxymethoxyacetophenone (6)
A solution of 5 (600 mg, 2.14 mmol) in N,N-dimethylaniline (15 ml)
was refluxed under argon for 4.5 h. The reaction mixture was cooled to
room temperature, acidified with 3 N HCl, and extracted with ethyl acetate
(3 Â 20 ml). The combined organic phases were successively washed with 3 N
HCl, 10% aqueous NaHCO3 solution, water and brine, dried and concen-
trated. The residue was chromatographed on silica gel with pel. Ether–ethyl
acetate (4 : 1) as an eluent to afford 6 as colorless needles (550 mg, 90%),
m.p. 116–119ꢁC. IR: 3400–3100, 1613, 1591, 1517, 1429, 1367, 1279, 1225,
1
1146, 1081, 1050, 996, 966, 904, 805 cmÀ1; H NMR (80 MHz) d 1.71 and
1.80 (each 3H, s, C(CH3)2), 2.66 (3H, s, COCH3), 3.31 (2H, d, J ¼ 7.3 Hz,
CH2), 3.45 (3H, s, OCH3), 5.18 (3H, brs, OCH2O and CH¼), 6.17(1H, s,
H-5), 9.80 (1H, s, OH), 11.13 (1H, s, OH); MS m/z: 280 (Mþ), 235, 233, 225,
193, 151, 69, 45.
2-Hydroy-3-prenyl-4-methoxymethoxy-6-methoxyacetophenone (7)
A mixture of 6 (400 mg, 1.43 mmol), anhydrous K2CO3 (360 mg,
2.60 mmol) and Me2SO4 (0.20 ml, 2.12 mmol) in dry acetone (15 ml) was
refluxed for 30 min with stirring. The mixture was cooled and filtered. The
filtrate was evaporated and the residue was chromatographed on silica gel
with pet. ether–ethyl acetate (20 : 1) to give 7 as a colorless oil (360 mg,
86%). 1H NMR (80 MHz) d 1.69 and 1.80 (each 3H, s, C(CH3)2), 2.64
(3H, s, COCH3), 3.31 (2H, d, J ¼ 7.2 Hz, CH2), 3.50 and 3.89 (3H, s,
OCH3 Â 2), 5.26 (3H, brs, OCH2O and CH¼), 6.22 (1H, s, H-5), 13.99
(1H, s, OH, disappeared after deuterium exchange).
2,4-Dihydroxy-3-prenyl-6-methoxyacetophenone (8)
To a solution of 7 (160 mg, 0.54 mmol) in methanol (10 ml) was
added 2.0 ml of 3 N HCl, the resulting mixture was refluxed after 15 min,
then poured into cold water and extracted with dichloronethone (3 Â 20 ml).
The combined organic phases were washed with water and brine, dried and

(6)-GLYFLAVANONE-A
1081
concentrated. Then the residue was chromatographed on silica gel with pet.
ether–ethyl acetate (9 : 1) to give 8 as a colorless oil (120 mg, 88%).
IR: 3400–3100, 1615, 1567, 1469, 1445, 1365, 1286, 1265, 1172, 1145,
1
1107, 1081, 1024, 984, 911, 804 cmÀ1; H NMR (80 MHz) d 1.79 and 1.84
(each 3H, s, C(CH3)2), 2.63 (3H, s, COCH3), 3.39 (2H, d, J ¼ 7.1 Hz, CH2),
3.86 (3H, s, OCH3), 5.29 (1H, t, J ¼ 7.1 Hz, CH¼), 5.92 (1H, s, H-5), 6.23
(1H, s, OH), 14.38 (1H, s, OH); MS m/z: 250 (Mþ), 235, 217, 207, 195, 179,
167, 123, 91, 69, 43.
2,2-Dimethyl-5-hydroxy-7-methoxy-6-acetylchromene (9)
To a mixture of 9 (100 mg, 0.4 mmol) and DDQ (90 mg, 0.4 mmol) in
dry benzene (5 ml) was added three drops of dry dioxane and the resulting
solution was brought to reflux for 4.5 h. The reaction mixture was cooled
and filtered. The filtrate was concentrated in vacuum and the resulting
residue was chromatographed on silica gel with pet. ether–ethyl acetate
(10 : 1) to give 9 as pale yellow needles (80 mg, 81%), m.p. 117–120ꢁC IR:
3400–3100, 1640, 1623, 1597, 1500, 1447, 1424, 1391, 1358, 1320, 1268, 1204,
1
1157, 1125, 1025, 889, 830, 807 cmÀ1; H NMR (80 MHz) d 1.46 (6H, s,
CH3 Â 2), 2.62 (3H, s, COCH3), 3.87(3H, s, OC H3), 5.46 (1H, d,
J ¼ 10.0 Hz, H-3), 5.90 (1H, s, H-8), 6.67(1H, d, J ¼ 10.0 Hz, H-4), 14.29
(1H, s, OH, exchangeable with deuterium); MS m/z: 248 (Mþ), 233, 215,
200, 160, 149, 115, 77, 43.
Glychalcone-A (2)
To a mixture of the chromene 9 (50 mg, 0.20 mmol) and p-anisalde-
hyde (30 mg, 0.22 mmol) in 1.4 ml of ethanol was added a mixture of KOH
(700 mg, 12.5 mmol) in water (0.6 ml) and ethanol (0.7 ml) at 0ꢁC with stir-
ring. After stirring for 36 h under argon at 25ꢁC, the reaction mixture was
poured into ice-water, acidified to pH 2 with 3 N HCl and extracted with
dichloromethane (3 Â 10 ml); the combined organic phases were washed
with water and brine, dried and concentrated. The residue was chromoto-
graphed on silica gel with pet. ether–ethyl acetate (9 : 1) as an eluent to give 1
as a yellowish oil (60 mg, 81%). IR: 3400, 1622, 1557, 1511, 1462, 1422,
1361, 1287, 1145 cmÀ1; 1H NMR (80 MHz) d 1.47(6H, s, C(C H3)2), 3.87and
3.93 (each 3H, s, OCH3 Â 2), 5.47(1H, d, J ¼ 10.0 Hz, H-300), 5.94 (1H, s,
H-50), 6.71 (1H, d, J ¼ 10.0 Hz, H-400), 6.94 (2H, d, J ¼ 8.8 Hz, H-3,5), 7.58
(2H, d, J ¼ 8.8 Hz, H-2,6), 7.77 (1H, d, J ¼ 15.6 Hz, H-a), 7.89 (1H, d,

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TAN, LI, AND LI
J ¼ 15.6 Hz, H-b), 14.73 (1H, s, OH); M/S m/z: 366 (Mþ), 351, 232, 218, 217;
Anal. calcd for C22H22O5: C, 72.12; H, 6.05. Found: C, 71.98; H, 6.11.
(6)-Glyflavanone-A (1)
A solution of chalcone 2 (60 mg, 0.16 mmol) and sodium acetate
(400 mg, 4.88 mmol) in ethanol (5 ml) with three drops of water was refluxed
for 24 h. The reaction mixture was poured into cold water and extracted
with ethyl acetate (3 Â 20 ml). The combined organic phases were washed
with brine and dried. After evaporation of the solvent in vacuum, the
residue was chromatographed on silica gel with pet. ether–ethyl acetate
(9 : 1) as an eluent to obtain 1 as a yellowish oil (400 mg 70%). IR: 2922,
1666, 1605, 1583, 1516, 1450, 1253, 1206, 1114 cmÀ1; 1H NMR (400 MHz) d
1.44 and 1.46 (each 3H, s, C(CH3)2), 2.79 (1H, dd, J ¼ 16.4, 3.1 Hz, H-3eq),
3.01 (1H, dd, J ¼ 16.4, 13.1 Hz, H-3ax), 3.84 and 3.90 (each 3H, s,
OCH3 Â 2), 5.37(1H, dd, J ¼ 13.1, 3.1 Hz, H-2), 5.46 (1H, d, J ¼ 10.0 Hz,
H-300), 6.05 (1H, s, H-6), 6.58 (1H, d, J ¼ 10.0 Hz, H-400), 6.95 (2H, d,
J ¼ 8.4 Hz, H-30,50), 7.39 (2H, d, J ¼ 8.4 Hz, H-20,60); M/S m/z: 366 (Mþ),
351, 251, 232, 217, 203, 149, 134, 119, 91, 77. Anal. calcd for C22H22O5: C,
72.12; H, 6.05. Found: C, 72.44; H, 5.96.
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Received in the USA March 28, 2001