Syntheses of knerachlin A and knerachlin B

Article abstract of DOI:10.1021/np960248v

The first total syntheses of knerachlin A and knerachlin B are described, starting from 2,4,6-trihydroxyacetophenone and 2,6- dihydroxyacetophenone, respectively. The key step in the synthesis is the condensation of ketone 5 with cinnamaldehyde.

Full text of DOI:10.1021/np960248v

J . Nat. Prod. 1997, 60, 277-278
277
Syn th eses of Kn er a ch lin A a n d Kn er a ch lin B
Chusheng Huang, Shijun Da, Ying Li,* and Yulin Li
State Key Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry Lanzhou University,
Lanzhou 730000, People’s Republic of China
Received February 19, 1996X
The first total syntheses of knerachlin A and knerachlin B are described, starting from 2,4,6-
trihydroxyacetophenone and 2,6-dihydroxyacetophenone, respectively. The key step in the
synthesis is the condensation of ketone 5 with cinnamaldehyde.
Sch em e 1a
Diarylpentanoids, a group of compounds having the
general structure Ar-C5-Ar, have been isolated from
some traditional medicines.1,2 Experiments have shown
that some of these compounds have interesting physi-
ological actions, they can be antiinflammatory, anti-
fungicidal, and antioxidative agents,3 as well as inhibi-
tors useful as antirheumatic and antiatherosclerotic
agents.4 Knerachlin A and knerachlin B, two new
natural products having strong antibacterial activity,
were isolated from Knema furfuracea, used in tradi-
tional medicine in tropical Africa, Asia, and Australa-
sia.5 Their structures were elucidated on the basis of
spectral data as 5-phenyl-1-(2,6-dihydroxy-4-methoxyl)-
phenyl-1-pentanone (1) and 5-phenyl-1-(2,6-dihydroxy)-
phenyl-1-pentanone (2), respectively. Their syntheses
have not been reported so far. In this paper, we wish
to describe the total syntheses of 1 and 2.
a
Key: (a) Me2SO4, K2CO3, acetone, reflux; (b) MOMCl, K2CO3,
acetone, reflux; (c) cinnamaldehyde, NaOH, EtOH-H2O, room
temperature; (d) H2-Pd, EtOH, room temperature; (e) 3N HCl-
MeOH, reflux.
2,6-Dih yd r oxy-4-m eth oxya cetop h en on e (4a ). A
solution of 2,4,6-trihydroxyacetophenone 3 (2.0 g, 11.9
mmol), Me2SO4 (1.1 g, 7.9 mmol) and anhydrous K2CO3
(0.96 g, 7.1 mmol) in Me2CO (40 mL) was stirred under
reflux for 2 h. The reaction solution was filtered and
evaporated under reduced pressure to give a solid
residue that was purified by flash column chromatog-
raphy on Si gel (petroleum ether-EtOAc, 10:1) to yield
recovered 3 (0.81 g) and 4a (0.716 g) in 56% yield (based
on unrecovered starting material) as a colorless solid:
mp 132.5-134 °C (MeOH, lit6 mp 136-137 °C); 1H
NMR(DMSO-d6) δ 2.56 (3H, s, COCH3), 3.72 (3H, s,
OCH3), 5.93 (2H, s, H-3′ and H-5′).
The 2,4,6-trihydroxyacetophenone 3 was treated with
Me2SO4 and anhydrous K2CO3 in Me2CO under reflux
for 2 h to generate 4a in 56%. Compound 4a was
protected with MOMCl in anhydrous K2CO3 and Me2CO
under reflux to give 5a . The condensation of compound
5a and cinnamaldehyde in a solution of NaOH in
aqueous EtOH at room temperature afforded 6a . Com-
pound 1 was obtained by selective hydrogenation of 6a
using Pd/C as a catalyst, followed by refluxing in HCl-
H2O-MeOH. The synthesis of 2 was carried out in the
same way as that of 1, starting from 4b. The synthetic
route is outlined in Scheme 1.
The structures of the synthetic compounds were
determinated by their IR, MS, and 1H-NMR spectral
data. The spectral data of 1 and 2 were consistent with
those of the natural products.5
2-Hyd r oxy-4-m et h oxy-6-(m et h oxym et h oxy)a ce-
top h en on e (5a ). A mixture of 4a (200 mg, 1.09 mmol),
MOMCl (266 mg, 3.3 mmol), and anhydrous K2CO3 (414
mg, 3.0 mmol) in Me2CO (20 mL) was stirred under
reflux for 2 h. Evaporation of the solution, which was
filtered after reaction, afforded 5a (195 mg, 86%) as a
white powder: mp 59-61.5 °C (EtOAc-H2O); IR ν max
Exp er im en ta l Section
Gen er al Exper im en tal P r ocedu r es. Melting points
were measured on a Kofler hot stage and are uncor-
rected. IR spectra were obtained on a FT-170-SX
spectrometer. 1H-NMR spectra were recorded on a
Varian FT-80A instrument in CDCl3 solution, and
chemical shifts were recorded in ppm units using Me4Si
as internal standard. MS were measured on a ZAB-
HS spectrometer by direct inlet at 70 eV and by FAB.
1
3010, 2941, 1615, 1572 cm-1; H NMR δ 2.62 (3H, s,
COCH3), 3.49 (3H, s, OCH2OCH3), 3.78 (3H, s, OCH3),
5.22 (2H, s, OCH2OCH3), 6.08 and 6.11 (each 1H, br s,
W1/2 ) 2.5 Hz, H-3′ and H-5′); EIMS m/ z [M]+ 226 (83),
211 (6), 195 (12), 181 (28), 152 (100), 95 (22).
2-H yd r oxy-6-(m et h oxym et h oxy)a cet op h en on e
(5b). A mixture of 4b (200 mg, 1.32 mmol), MOMCl
(421 mg, 5.28 mmol), anhydrous K2CO3 (729 mg, 5.28
X Abstract published in Advance ACS Abstracts, February 1, 1997.
S0163-3864(96)00248-0 CCC: $14.00
© 1997 American Chemical Society and American Society of Pharmacognogy

278 J ournal of Natural Products, 1997, Vol. 60, No. 3
Notes
mmol), and Me2CO (20 mL) was stirred under reflux
for 2 h. The reaction mixture was treated as described
for 5a to give 5b (219 mg, 85%): a light yellowish liquid;
IR ν max 3020, 2930, 1620, 1580 cm-1; 1H NMR δ 2.76
(3H, s, COCH3), 3.53 (3H, s, OCH2OCH3), 5.29 (2H, s,
OCH2OCH3), 6.6 (2H, d, J ) 8.2 Hz, H-3′ and H-5′), 7.32
(1H, t, J ) 8.2 Hz, H-4′); EIMS m/ z [M]+ 196 (27), 165
(6), 153 (1), 122 (27), 108 (6), 77 (8), 45 (100).
5-P h en yl-1-[2-h yd r oxy-4-m et h oxy-6-(m et h oxy-
m eth oxy)p h en yl]-2,4-p en ta d ien -1-on e (6a ). To a
solution of NaOH (110 mg, 2.69 mmol) in EtOH (3 mL)
and H2O (1 mL) was added 5a (390 mg, 1.73 mmol) and
cinnamaldehyde (225 mg, 1.73 mmol) at room temper-
ature. After being stirred for 2 h, the reaction mixture
was treated with 10 mL of H2O, extracted with EtOAc
(3 ×10 mL), and the EtOAc extract dried over anhy-
drous MgSO4 and evaporated under reduced pressure.
The residue was purified by Si gel column chromatog-
raphy, eluted with petroleum ether-EtOAc (v/v 10:1)
to give the yellowish solid 6a (375 mg, 64%): IR ν max
3410, 2943, 1621, 1581, 1152, 1057 cm-1; 1H NMR δ 3.58
(3H, s, OCH2OCH3), 3.64 (3H, s, OCH3), 5.29 (2H, s,
OCH2OCH3), 6.12 (2H, s, H-3 and H-5), 7.0-7.9 (9H,
m); EIMS m/ z [M]+ 340 (28), 295 (10), 167 (100), 129
(90).
5-P h e n yl-1-[2-h yd r oxy-6-(m e t h oxym e t h oxy)-
p h en yl]-1-p en ta n on e (7b). The reaction and workup
sequences of 6b (167 mg, 0.54 mmol) were the same as
for 6a to afford 7b (155 mg, 93%) as a yellowish oil: IR
ν max 3060, 2931, 1625, 1599, 1452, 1233, 1046 cm-1
;
1H NMR δ 1.70-1.9 (4H, m), 2.71 (2H, m, CH2C6H5),
3.14 (2H, m, CH2CO), 3.52 (3H, s, OCH2OCH3), 5.26(2H,
s, OCH2OCH3), 6.58 (1H, br s, W1/2 ) 2.5 Hz), 6.68 (1H,
br s, W1/2 ) 2.5 Hz), 7.25 (5H, br s, C6H5); EIMS m/ z
[M]+ 314 (5), 282 (6), 181 (9), 151 (9), 137 (37), 91 (32),
45 (100).
5-P h en yl-1-(2,6-d ih yd r oxy-4-m eth oxyp h en yl)-1-
p en ta n on e (1). Compound 7a (125 mg, 0.363 mmol)
was dissolved in 3 N HCl (2 mL) and MeOH (1 mL).
After stirring 30 min at 100 °C, the mixture was
extracted with CH2Cl2 (3 × 10 mL) and the extract dried
over anhydrous MgSO4 and evaporated. The residue
was purified by Si gel column chromatography eluted
with petroleum ether-EtOAc (v/v 10:1) to give 1 (85 mg,
78%), as colorless needles: mp 100-102 °C (EtOAc-
H2O, lit5 mp 101-102 °C); IR ν max 3236, 3060, 3023,
1
2931, 1628, 1587, 1206, 1161, 1080 cm-1; H NMR δ
1.65-1.83 (4H, m, 2 CH2), 2.66 (2H, t, J ) 7.0 Hz,
CH2C6H5), 3.11 (2H, t, J ) 7.0 Hz, CH2CO), 3.79 (3H, s,
OCH3), 5.95 (2H, s, H-3′ and H-5′), 7.23 (5H, br s, C6H5);
FABMS m/ z [M+ + H] 301; anal. C 71.96%, H 6.71%,
Calcd for C18H20O4, C 72.24%, H 6.98%.
5-P h e n yl-1-[2-h yd r oxy-6-(m e t h oxym e t h oxy)-
p h en yl]-2,4-p en ta d ien -1-on e (6b). To a solution of
NaOH (99 mg, 2.47 mmol) in EtOH (2.6 mL) and H2O
(1.0 mL) was added 5b (200 mg, 1.02 mmol) and
cinnamaldehyde (135 mg, 1.02 mmol) at room temper-
ature, and the mixture was stirred for 4 h. Workup and
purification of the reaction mixture were the same as
for 6a to afford 6b, a yellowish gum (215 mg, 68%); IR
ν max 3060, 2953, 1677, 1648, 1626, 1577, 1453, 1232
cm-1; 1H NMR δ 3.54 (3H, s, OCH3), 5.31 (2H, s, OCH2-
OCH3), 6.6-7.8 (12H, m); EIMS m/ z [M]+ 310 (17), 265
(14), 187 (3), 157 (7), 115 (39), 91 (10), 45 (100).
5-P h en yl-1-[2-h yd r oxy-4-m et h oxy-6-(m et h oxy-
m eth oxy)p h en yl]-1-p en ta n on e (7a ). Compound 6a
(170 mg, 0.5mmol) and Pd/C (50 mg) in EtOH (10 mL)
were stirred under a hydrogen atmosphere at room
temperature for 4 h. The reaction mixture was filtered
off, then evaporated under reduced pressure to give an
oily residue. The residue was purified by flash column
chromatography on Si gel with petroleum ether-EtOAc
(v/v 10:1) to yield 7a (160 mg, 93%) as a light yellowish
oil: IR ν max 3061, 2938, 2859, 1621, 1595, 1429, 1209,
5-P h en yl-1-(2,6-d ih yd r oxyp h en yl)-1-p en t a n on e
(2). The reaction and workup of 7b was the same as
for 7a . Compound 7b (100 mg, 0.318 mmol) afforded 2
(71 mg, 83%), colorless needles: mp 107-109 °C (EtOAc-
H2O, lit.5 mp 107-108 °C); IR ν max 3326, 3026, 2930,
1
2857, 1630, 1596, 1452, 1232, 1040 cm-1; H NMR δ
1.72-1.81 (4H, m, 2 CH2), 2.69 (2H, t, J ) 7.1 Hz,
CH2C6H5), 3.18 (2H, t, J ) 6.8 Hz, CH2CO), 6.40 (2H,
d, J ) 8.2 Hz, H-3′ and H-5′), 7.14-7.34 (6H, m, H-4′
and C6H5). FABMS m/ z [M+ + H] 271 anal. C 75.53%,
H 6.71%, calcd for C17H18O3, C 75.70%, H 6.95%.
Ack n ow led gm en t. This project was financially sup-
ported by the Natural Science foundation of Gansu
Province.
Refer en ces a n d Notes
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1
1158, 1058 cm-1; H NMR δ 1.66-1.84 (4H, m), 2.67
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(2H, t, J ) 6.8 Hz, CH2C6H5), 3.07 (2H, t, J ) 6.8 Hz,
CH2CO), 3.49 (3H, s, OCH2OCH3), 3.62 (3H, s, OCH3),
5.21 (2H, s, OCH2OCH3), 6.13-6.18 (each 1H, d, J )
2.5 Hz, H-3′ and H-5′), 7.24 (5H, br s, C6H5); EIMS m/ z
[M]+ 344 (15), 289 (18), 211 (13), 152 (61), 117 (26), 91
(35), 45 (100).
(6) Shinoda, J . J . Pharm. Soc. J pn. 1928, 48, 1178-1179.
NP960248V