Total synthesis of (R,S)-sophoraflavanone C

Article abstract of DOI:10.1021/np980026s

Sophoratlavanone C, a C-8 geranylflavanone natural product originally isolated from Echinosophora koreensis, has been synthesized in racemic form in six steps, starting from 2,4,6-trihydroxyacetophenone and 2,4- dihydroxybenzaldehyde.

Full text of DOI:10.1021/np980026s

J . Nat. Prod. 1998, 61, 1283-1285
1283
Tota l Syn th esis of (R,S)-Sop h or a fla va n on e C
Chusheng Huang, Zhe Zhang, and Yulin Li*
National Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry, Lanzhou University,
Lanzhou 730000, People’s Republic of China
Received J anuary 29, 1998
Sophoraflavanone C, a C-8 geranylflavanone natural product originally isolated from Echinosophora
koreensis, has been synthesized in racemic form in six steps, starting from 2,4,6-trihydroxyacetophenone
and 2,4-dihydroxybenzaldehyde.
Geranylflavonoids are interesting natural products iso-
lated in recent years from some traditional medicinal
plants.1-3 Some of these flavanoids have been reported to
exhibit hypotensive,4 antibacterial,5 and antitumor6 effects.
With respect to the synthesis of geranylflavonoids, only the
8-geranylflavanone skeleton, as found in compounds 1,7 2,8
3,9 and 4,10 has not been yet prepared.
solution of sodium acetate in ethanol for 24 h to form 11
in 86% yield, followed by hydrolysis with 3N HCl in
methanol to afford (R,S)-1 in 70% yield. The spectral data
(MS, NMR) of (R,S)-1 was comparable to those reported.7
Compounds 6b and 6c are natural products isolated from
Evodia nerrillii.11 Their spectral data were consistent with
those in the literature.10 Compound 6a has been prepared
in 1% yield by the reaction of 5 with geraniol in a mixture
of ascorbic acid and 5% aqueous citric acid at 80 °C for 11
h.12 The method described in this paper (78%) is a
considerable improvement over the older procedure.
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. Melting points were
measured on Kofler hot stage and are uncorrected. IR spectra
were obtained on an FT-170-SX spectrometer. 1H NMR
spectra were obtained in CDCl3 solution on a Varian FT-80A
instrument, and chemical shifts were recorded in ppm (δ) units
using TMS as internal standard. MS were measured on ZAB-
HS and MAT44S spectrometers by direct inlet at 70ev.
2,4,6-Tr ih yd r oxy-3-ger a n yla cetop h en on e (6a ). A well-
stirred mixture of phloracetophenone (5) (1.000 g, 6 mmol),
geranyl bromide (0.876 g, 4.80 mmol), and anhydrous potas-
sium carbonate (0.415 g, 3.00 mmol) in dry Me2CO (3.5 mL)
was refluxed for 6 h. The reaction mixture was filtered and
evaporated under reduced pressure to give an oily residue that
was purified by flash column chromatography on Si gel
(petroleum ether-EtOAc, 10:1) to afford recovered 5 (228 mg)
and 6a (1.100 g), 6b (71 mg), 6c (75 mg), and 6d (25 mg) in
78%, 5%, 5%, and 1% yields (based on unrecovered starting
material), respectively. Compound 6a , a light yellow powder,
mp 105-106 °C (lit.11 mp 119-120 °C, according to lit.12 6a is
a yellow oil): 1H NMR δH 1.60 (3 H, s, Me), 1.67 (3 H, s, Me),
1.82 (3 H, s, Me), 1.80-2.20 (m, 4 H, 4′′-2H and 5-2H), 2.68
(3H, s, COMe), 3.32 (2H, d, J ) 7.0 Hz, 1′′-2H), 5.17 (1H, t, J
) 6.8 Hz, 6′′-H), 5.26 (1H, t, J ) 7.0 Hz, 2′′-H), 5.90 (1H, s,
ArH), 6.97 (1H, s, OH), 9.55 (1H, s, OH), 11.67 (1H, s, OH);
IR (KBr) νmax 1627 cm-1; EIMS m/z(%) [M]+ 304 (38), 289 (3),
261 (9), 235 (25), 219 (22), 181 (100). Compound 6b; colorless
fine crystals (EtOAc-Petroleum ether), mp 145-147 °C (lit.11
147-150 °C). Compound 6c: a white waxy substance (lit.,10
waxy substance). Compound 6d : colorless fine crystals
(EtOAc-petroleum ether), mp 71-74 °C, 1HNMR δH 1.62 (6H,
s, 2Me), 1.70 (6H, s, 2Me), 1.74 (3H, s, Me), 1.83 (3H, s, Me),
1.90-2.20 (8H, m), 2.65 (3H, s, COMe), 3.41 (2H, d, J ) 7.0
Hz), 4.56 (2H, d, J ) 6.6 Hz), 5.05-5.60 (4H, m), 5.92 (1H, s,
ArH), 6.25 (1H, s, OH), 14.41 (1H, s, OH); IR (KBr) νmax 1644
cm-1; EIMS m/z [M]+ 440 (1), 304 (30), 261 (3), 235 (6), 181
(100), 137 (2), 69 (25).
The development of a general synthetic method for this
class of compound would facilitate further studies relating
biological activity to structure. In this paper, we describe
the first total synthesis of sophoraflavanone C,7 a com-
pound isolated from Echinosophora koreensis and identified
on the basis of its spectral data as 5,7,2′,4′-tetrahydroxy-
8-geranylflavanone (1). This work provides a general
synthesis method for the 8-geranylflavanones. The syn-
thetic route is outlined in Scheme 1.
Treatment of 2,4,6-trihydroxyacetophenone (5) and gera-
nyl bromide with anhydrous potassium carbonate in dry
acetone under reflux yielded four geranyl acetophenones
6a , 6b, 6c, and 6d in 78%, 5%, 5%, and 1% yield,
respectively (6a :6b ) 15.6:1). Compound 6a was regiose-
lectively protected with chloromethyl methyl ether (MO-
MCl; DANGER carcinogenic reagent) to give compound 7
in 65% yield. A similar treatment of 8 with MOMCl gave
compound 9 in 95% yield. The condensation of 7 and 9
was achieved in a mixture of aqueous potassium hydroxide
and ethanol at 0 °C to room temperature for 36 h to give
chalcone 10 in 40% yield. Compound 10 was refluxed in a
4,6-Dim et h oxym et h oxy-2-h yd r oxy-3-(1′-ger a n yl)a ce-
top h en on e (7). A mixture of 6a (304 mg, 1 mmol), MOMCl
(200 mg, 2.5 mmol), and anhydrous K2CO3 (966 mg, 7 mmol)
in dry Me2CO (20 mL) was well stirred under reflux for 1.5 h.
Evaporation of the filtered solution afforded 7 (255 mg, 65%
* To whom correspondence should be addressed. Tel.: (+86) 931-8912595.
Fax: (+) 931-8911100. E-mail: liyl@lzu.edu.cn.
10.1021/np980026s CCC: $15.00
© 1998 American Chemical Society and American Society of Pharmacognosy
Published on Web 08/20/1998

1284 J ournal of Natural Products, 1998, Vol. 61, No. 10
Notes
Sch em e 1a
a
Key: (a ) geranyl bromide, Me2CO, K2CO3, reflux; (b) CH3OCH2Cl, K2CO3, Me2CO, reflux; (c) CH3OCH2Cl, K2CO3, acetone, reflux; (d ) KOH, H2O-EtOH
(v/v ) 1:1), 0 °C ∼ r.t; (e) NaOAc, EtOH, reflux; (f) 3NHCl, MeOH, reflux.
yield) as a deep red gum: 1H NMR (400 MHz) δ 1.58 (3H, s,
Me), 1.64 (3H, s, Me), 1.79 (3H, s, Me), 1.90-2.15 (4 H, m,
4′′-2H and 5′′-2H), 2.66 (3H, s, COMe), 3.32 (2H, d, J ) 7.0
Hz, 1′′-2H), 3.48 (3H, s, OMe), 3.58 (3H, s, OMe), 5.06 (1 H, t,
J ) 6.5 Hz, 6′′-H), 5.19 (1H, t, J ) 7.0 Hz, 2′′-H), 5.24 (2H, s,
OCH2O), 5.27 (2H, s, OCH2O), 6.40 (1H, s, ArH), 13.85 (1H, s,
OH); IR (KBr) νmax 1617 cm-1; EIMS m/z [M]+ 392 (4), 347
(10), 273 (7), 269 (3), 225 (3), 69 (10), 45 (100); HREIMS m/z
[M]+ 392.2210 (C22H32O6 requires 392.2199); a similar reaction
of 8 with MOMCl gave 9 as a white solid, mp 47-48 °C [lit.11
48 °C] in 95% yield.
rial): 1H NMR δ 1.61, 1.67, 1.69 (3H each s, 8′′-Me, 9′′-Me,
and 10′′-Me), 1.95-2.15 (4H, m, 4′′-2H and 5′′-2H), 2.86 (2 H,
d, J ) 7.6 Hz, 3-2H), 3.33 (2H, J 7.1 Hz, 1′′-2H), 3.48, 3.41,
3.58 (12H, each s, 4OMe), 5.00-5.30 (10H, m, 2′′-H, 6′′-H and
4OCH2O), 5.70 (1H, t, J ) 7.6 Hz, 2-H), 6.58 (1H, s, 6-H), 6.79
(1H, dd, J ) 8.3, 2 Hz, 5′-H), 6.85 (1H, d, J ) 2 Hz, 3′-H), 7.52
(1H, d, J ) 8.3 Hz, 6′-H); IR (KBr) νmax 1681 cm-1; EIMS m/z
[M]+ 600 (1), 555 (3), 477 (2), 383 (1), 331 (3), 221 (3), 69 (9),
45 (100); HREIMS m/z [M]+ 600.2920 (C33H44O10 requires
600.2934).
(R,S)-5,7,2′,4′-Tetr ah ydr oxy-8-(1′-ger an yl)flavan on e (1).
A solution of 11 (40 mg, 0.0667 mmol) in MeOH (5 mL) and
3N HCl (1 mL) was refluxed for 30 min, H2O (5 mL) was then
added and the mixture extracted with EtOAc. After workup,
the extract was purified by Si gel column chromatography
eluting with petroleum ether-EtOAc (8:1) to afford a yellow
oil (R,S)-1 (20 mg, 70% yield); 1H NMR (acetone-d6) δ 1.60,
1.64, 1.66 (3H, each s, 5′′-Me, 9′′-Me, and 10′′-Me), 1.90-2.30
(4H, m, 4′′-2H and 5′′-2H), 2.80 (1H, dd, J ) 17.5, 3.2 Hz, 3eq-
H), 3.10 (1H, dd, J ) 17.5, 13.3 Hz, 3ax-H), 3.30 (2H, t, J ) 7
Hz, 1′′-2H), 5.06 (1H, t, J ) 6.5 Hz, 6′′-H), 5.25 (1H, t, J ) 7
Hz, 2′′-H), 5.70 (1H, dd, J ) 13.3, 3.2 Hz, 2-H), 6.05 (1H, s,
6-H), 6.45 (1H, dd, J ) 8.3, 2 Hz, 5′-H), 6.49 (1H, d, J ) 2 Hz,
3′-H), 7.38 (1H, d, J ) 8.3 Hz, 6′-H), 12.42 (1H, s, OH); IR
(KBr) νmax 1625 cm-1; EIMS m/z [M]+ 424 (25), 406 (10), 368
(5), 219 (100), 136 (10).
2,4,4′,6′-Tetr a m eth oxym eth oxy-2′-h yd r oxy-3′-(1′-ger a -
n yl)-ch a lcon e (10). A well-stirred solution of 7 (400 mg, 1.02
mmol) and 9 (231 mg, 1.02 mmol) in EtOH (2 mL) cooled to 5
°C was added dropwise to a mixture of potassium hydroxide
(1 g) in 2 mL H2O-EtOH (2:3) cooled to 0 °C under argon.
The reaction mixture was kept in an ice bath for 3 h, then at
room temperature for 33 h. The mixture was poured into iced
water, the solution adjusted pH to 3-4 with dilute HCl, and
then extracted with Et2O. The organic extract was washed
with H2O and brine, dried over anhydrous MgSO4, and
evaporated under reduced pressure. The residue was purified
by Si gel column chromatography eluting with petroleum
ether-EtOAc (10:1) to give chalcone 10 (245 mg, 40%) as a
red liquid: 1H NMR δ 1.59, 1.66, 1.80 (3H each s, 8′′-Me, 9′′-
Me, and 10′′-Me), 1.95-2.15 (4H, m, 4′′-H and 5′′-H), 3.36 (2H,
d, J ) 7.3 Hz, 1′′-2H), 3.50 (12H, s, 4OMe), 5.00-5.50 (10H,
m, 4OCH2O, 2′′-H and 6′′-H), 6.41 (1H, s, 5′-H), 6.84 (1H, dd,
J ) 8.6 Hz, 2.2 Hz, 5-H), 6.88 (1H, d, J ) 2.2 Hz, 3-H), 7.58
(1H, d, J ) 8.6 Hz, 6-H), 7.86 (1H, d, J ) 15.8 Hz, HR), 8.19
(1H, d, J ) 15.8 Hz, Hâ), 13.69 (1H, s, OH); IR (KBr) νmax 1612
cm-1; EIMS m/z [M]+ 600 (11), 568 (2), 555 (76), 523 (10), 493
(7), 445 (27), 433 (8), 355 (12), 351 (10), 331 (43), 263 (35), 221
(69), 69 (100); HREIMS m/z [M]+ 600.2910 (C33H44O10 requires
600.2934).
Ack n ow led gm en t. This work was financially supported
by the National Nature Science Foundation of China.
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(11) (51 mg, 86% yield based on unrecovered starting mate-
(5) Schutz, B. A.; Wright, A. D.; Rali, T.; Sticher, D. Phytochemistry 1995,
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Notes
J ournal of Natural Products, 1998, Vol. 61, No. 10 1285
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NP980026S