A new route to the synthesis of pyranoflavone and pyranochalcone natural products and their derivatives

Article abstract of DOI:10.1055/s-2006-926294

The total synthesis of biologically active pyranoflavone natural products 1 and 2 was carried out starting from 2H-pyran. The synthesis of pyranochalcone natural products, lonchocarpin (9) and 4-hydroxylonchocarpin (10), and their derivatives 30-32 is des

Full text of DOI:10.1055/s-2006-926294

PAPER
603
A New Route to the Synthesis of Pyranoflavone and Pyranochalcone Natural
Products and their Derivatives
S
ynthesis of Pyran
o
oflavone and
n
Pyranochalc
g
one Natural
Produ
R
cts and their
D
er
o
ivatives k Lee,* Do Hoon Kim
School of Chemical Engineering and Technology, Yeungnam University, Gyeongsan 712-749, Korea
Fax +82(53)8104631; E-mail: yrlee@yu.ac.kr
Received 23 May 2005; revised 5 September 2005
R2
Abstract: The total synthesis of biologically active pyranoflavone
natural products 1 and 2 was carried out starting from 2H-pyran.
The synthesis of pyranochalcone natural products, lonchocarpin (9)
and 4-hydroxylonchocarpin (10), and their derivatives 30–32 is de-
scribed. This synthetic route also provides biologically interesting
materials such as b-tubaic acid (24), desmethyl isoencecalin (25),
and isoencecalin (27).
R1
R6
O
OR5
R3
O
O
R7
O
R8
R4
O
Key words: 2H-pyran, pyranoflavones, pyranochalcones, b-tubaic
acid, desmethyl isoencecalin, isoencecalin
1 R1 = R2 = R3 = R4 = H
2 R1 + R2 = OCH2O, R3 = R4 = H
3 R1 = R2 = R4 = H, R3 = OCH3 Karanjachromene
4 R1 + R2 = OCH2O, R3 = OCH3, R4 = H Pongachromene
5 R1 = R3 = H, R2 = R4 = OH Atalantoflavone
Pyranoflavones and pyranochalcones are an abundant
subclass of the flavonoids and are widely distributed in
nature.1 Among these, pyranoflavones 1–4 were isolated
from Lonchocarpus subglaucescens or latifolius, a tropi-
cal plant genus of more than 100 species found in Ameri-
ca, Africa, and the Caribbean Islands (Figure 1).2
Pyranoflavones 5–6 were isolated from Atalantia racemo-
sa.3 Pyranoflavones 7–8 were isolated from Artocarpus
chama or communis, evergreen trees distributed over trop-
ical regions of Asia.4 Pyranochalcones 9–13 have been
isolated from Lonchocarpus utilus or subglaucescens dis-
tributed in tropical America, Africa, and the Caribbean is-
lands.2a,5 Pyranochalcones 14–16 were primarily isolated
from Pongamia glabra.6 Members of the pyranoflavones
and pyranochalcones have been associated with a wide
variety of biological activities such as antimutagenic, an-
timicrobial, anti-ulcer, and antitumor activities and some
plants are used in traditional medicines in China and Eu-
rope.7 This wide range of biological properties has stimu-
lated interest in the synthesis of naturally occurring
pyranoflavones and pyranochalcones. Although there are
currently several methods available to synthesize pyra-
noflavonoids, there are only a few synthetic routes to pyr-
anoflavones and pyranochalcones.8
6 R1 = OCH3, R2 = R4 = OH, R3 = H Racemoflavone
7 R1 = R2 = R4 = OH, R3 = H Artochamins C
8 R1 = H, R2 = OCH3, R3 = CHOHCHC(CH3)2, R4 = OH Artocommunol CE
9 R5 = R6 = R7 = R8 = H Lonchocarpin
10 R5 = R6 = R8 = H, R7 = OH 4-Hydroxylonchocarpin
11 R5 = R6 = R8 = H, R7 = OCH3 4-Methoxylonchocarpin
12 R5 = R6 = H, R7 = R8 = OH 3,4-Dihydroxylonchocarpin
13 R5 = R6 = H, R7 = R8 = OCH3 3,4-Dimethoxylonchocarpin
14 R5 = R6 = H, R7 = OH, R8 = OCH3 Pongachalcone II
15 R5 = R6 = H, R7 = R8 = OCH2O Glabrachromene II
16 R5 = H, R6 = R7 = R8 = OCH3 Glabrachalcone
Figure 1
First, further investigation for the synthesis of 2H-pyrans
was done concerning the reactions between 1,3-cyclohex-
anedione (17) and 3-methyl-2-butenal in the presence of
several catalysts (Table 1). Both indium (III) chloride (50
mol%) and ytterbium (III) triflate (10 mol%) in refluxing
acetonitrile gave 18 in 59 and 72% yields, respectively.
With pyridine as reactant and solvent, 18 was obtained in
56% yield. Interestingly, with ethylenediamine diacetate
(10 mol%) as catalyst, the cycloadduct was also produced
in increased yield. The best yield was obtained in benzene
(92%), and other solvents resulted in 61% (methanol) and
88% (dichloromethane).
We recently reported a one-pot synthesis of 2H-pyrans us-
ing a tandem Knoevenagel–electrocyclic reaction in the
presence of ytterbium (III) triflate or indium (III) chlo-
ride.9 We used a 2H-pyran derivative as the key starting
material in the construction of natural pyranoflavones and
pyranochalcones. We describe herein the total synthesis
of the two natural pyranoflavones 1 and 2 and the two nat-
ural pyranochalcones 9 and 10.
In the next step, the synthesis of pyranoflavone natural
products was attempted as shown in Scheme 1. Transfor-
mation of 18 with LDA at –78 °C, followed by treatment
with ethyl cyanoformate, gave 19 in 83% yield. Oxidation
of 19 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) in refluxing dioxane afforded 20 in 90% yield.
Currently, there are a number of methods available for the
preparation of the 4-pyrone ring of flavones, including the
Allan–Robinson method,10 the Baker–Venkataraman re-
arrangement,11 synthesis from chalcones,12 and an in-
tramolecular Wittig reaction.13 Among these, we
SYNTHESIS 2006, No. 4, pp 0603–0608
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x
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x
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0
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Advanced online publication: 11.01.2006
DOI: 10.1055/s-2006-926294; Art ID: F09205SS
© Georg Thieme Verlag Stuttgart · New York

604
Y. R. Lee, D. H. Kim
PAPER
The synthesis of pyranochalcone natural products lon-
chocarpin (9) and 4-hydroxylonchocarpin (10), was
achieved starting from compound 20 (Scheme 2). Lon-
chocarpin (9) and 4-hydroxylonchocarpin (10), isolated
from Cubé resin, were shown to interrupt mitochondrial
electron transport by inhibition of NADH.5 The synthetic
route to pyranochalcones 9 and 10 has already been re-
ported by Nicolaou.8c Hydrolysis of 20 by treatment with
NaOH in methanol gave b-tubaic acid (24, 97%), which
was isolated from the roots of Derris elliptica and was
shown to exhibit strong antimicrobial activity.15 The
methods available for the preparation of b-tubaic acid suf-
fer from the disadvantage of many reaction steps or low
yields.16 Thus simpler and more convenient methods for
its synthesis are needed. The spectral data of our synthetic
material 24 are consistent with those reported in the liter-
ature.16 Treatment of 24 with an excess of MeLi afforded
desmethyl isoencecalin (25, 68%), which was isolated
from Blepharispermum subseeile.17 It was also shown to
have strong antifungal, antibacterial, and antiimplantation
activities.18 Before its isolation from a natural source, 25
had already been synthesized by other groups.19 In order
to build the chalcone skeletons, an aldol reaction was next
attempted by treatment with several bases. Reaction of 25
with benzaldehyde in methanolic KOH and NaOH gave
no products, possibly because of the presence of the acidic
phenol group. However, we were able to introduce the
chalcone skeleton by treatment with LDA. When 25 was
treated with 22 in the presence of an excess of LDA, lon-
chocarpin (9) was obtained in 98% yield. Reaction of 25
with aldehyde 26, followed by cleavage of the [2-(tri-
methylsilyl)ethoxy]methyl ether (SEM ether) with tetra-
butylammonium fluoride (TBAF), gave 4-hydroxy-
lonchocarpin (10) in 90% yield. The spectral data of our
synthetic materials 9 and 10 agreed with those reported in
the literature.8a,20
Table 1 Effect of Catalysts and Solvents in the Reaction of 17 and
3-Methyl-2-butenal
O
O
O
H
O
O
18
17
Catalyst
Conditions
Yield (%)
InCl3 (50 mol%)
MeCN, reflux, 5 h
MeCN, reflux, 5 h
MgSO4, reflux, 5 h
MeOH, r.t., 5 h
59
72
56
61
Yb(OTf)3 (10 mol%)
Pyridine (excess)
Ethylenediamine diacetate
(10 mol%)
Ethylenediamine diacetate
(10 mol%)
CH2Cl2, r.t., 7 h
88
Ethylenediamine diacetate
(10 mol%)
Benzene, reflux, 3 h 92
attempted construction of the 4-pyrone ring by using the
von Strandtmann approach.14 Treatment of 20 with dimsyl
anion in benzene afforded b-keto sulfoxide 21 (70%),
which was easily converted by treatment with 22 and 23
in the presence of piperidine, first at 40 °C and then at
110 °C, to the corresponding pyranoflavones 1 and 2 in 99
and 95% yields, respectively. The spectroscopic proper-
ties of our synthetic materials are in agreement with those
reported in the literature.2a The synthesis of pyranofla-
vones 1 and 2 has been reported before. In connection
with an on-going program for the development of new
drug candidates as potent anti-HIV agents, the total syn-
thesis of 1 was carried out by Lee and co-workers.8a An-
other group has also achieved the synthesis of 2 starting
from 2,4-dihydroxyacetophenone in low yield.8b
O
LDA, THF
–78 °C
O
O
O
OH
DDQ
EtO
EtO
dioxane
reflux
ethyl cyanoformate
O
O
O
18
19 83%
20 90%
O
O
S
O
OH
H
DMSO
22
O
NaH
piperidine
toluene
reflux
benzene
O
O
21 70%
O
piperidine
1
99%
toluene
O
H
reflux
O
O
O
O
O
23
O
O
95%
2
Scheme 1
Synthesis 2006, No. 4, 603–608 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyranoflavone and Pyranochalcone Natural Products and their Derivatives
605
O
OH
O
OH
O
OH
LDA (3 equiv)
O
MeLi (4 equiv)
NaOH
MeOH
20
HO
toluene
reflux
O
O
O
H
98%
lonchocarpin (9)
97%
68%
22
β-tubaic acid (24)
desmethyl isoencecalin (25)
i) LDA (3 equiv)
O
H
26
SEMO
ii) TBAF, THF
O
OH
HO
O
90%
4-hydroxylonchocarpin (10)
Scheme 2
Finally, the synthesis of pyranochalcone derivatives was All experiments were carried out under nitrogen atmosphere. Merck
precoated silica gel plates (Art. 5554) with fluorescent indicator
were used for analytical TLC. Flash column chromatography was
performed using silica gel 9385 (Merck). Melting points were deter-
mined in capillary tubes on a Fisher–Johns apparatus and are uncor-
attempted from desmethyl isoencecalin (25) as depicted in
Scheme 3. Methylation of 25 with methyl iodide in the
presence of potassium carbonate in acetone gave
isoencecalin (27) in 84% yield.19a,21 Treatment of 27 with
rected. IR spectra were recorded on a Jasco FTIR 5300
1
aldehydes 28 and 29 in ethanolic NaOH solution gave
pyranochalcones 30 and 31 as unnatural products in 88
and 95% yields, respectively. On the other hand, reaction
of 27 with aldehyde 26 in ethanolic NaOH solution, fol-
lowed by cleavage of the silyl ether group with TBAF,
gave 32 in 82% yield.
spectrophotometer. H NMR spectra were recorded on a Bruker
Model ARX (300 MHz) spectrometer in CDCl3 using 7.26 ppm as
the solvent chemical shift. 13C NMR spectra were recorded on a
Bruker Model ARX (75 MHz) spectrometer in CDCl3 using 77.0
ppm as the solvent chemical shift. HRMS mass spectra were carried
out on Jeol JMS-700 spectrometer by the Korea Basic Science In-
stitute (Daegu).
In conclusion, a new synthetic route to biologically active
pyranoflavones and pyranochalcones was developed
starting from 2H-pyran. The synthetic routes yield pyra-
noflavone natural products 1 and 2, and pyranochalcone
natural products and their derivatives, lonchocarpin (9), 4-
hydroxylonchocarpin (10) and 30–32. This synthetic
route also provides biologically interesting b-tubaic acid
(24), desmethyl isoencecalin (25), and isoencecalin (27).
2,2-Dimethyl-2,6,7,8-tetrahydrochromen-5-one (18)
To a solution of 1,3-cyclohexanedione (1.12 g, 10.0 mmol) and 3-
methyl-2-butenal (1.68 g, 20.0 mmol) in benzene (50 mL) was add-
ed ethylenediamine diacetate (180 mg, 1.00 mmol) at r.t. The reac-
tion mixture was refluxed for 3 h and then cooled to r.t. H2O was
added and the solution was extracted with EtOAc. Evaporation of
solvent and purification by column chromatography on silica gel
gave 18 (1.639 g, 92%) as a liquid.
O
OCH3
O
OCH3
MeI
NaOH
EtOH
25
K2CO3
R2
O
O
O
R1
84%
isoencecalin (27)
H
30 R1 = OMe, R2 = H 88%
31 R1 = H, R2 = OMe
95%
R2
i) NaOH
EtOH
R1
O
28 R1 = OMe, R2 = H
29 R1 = H, R2 = OMe
H
26
ii) TBAF, THF
SEMO
O
OCH3
HO
O
32
82%
Scheme 3
Synthesis 2006, No. 4, 603–608 © Thieme Stuttgart · New York

606
Y. R. Lee, D. H. Kim
PAPER
IR (neat): 2926, 1645, 1611, 1455, 1399, 1375, 1266, 1188, 1130,
1010, 905 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.38 (d, J = 10.0 Hz, 1 H), 5.21 (d,
J = 10.0 Hz, 1 H), 2.39–2.34 (m, 4 H), 1.99–1.90 (m, 2 H), 1.37 (s,
6 H).
1H NMR (300 MHz, CDCl3): d = 12.50 (s, 1 H), 7.49 (d, J = 8.9 Hz,
1 H), 6.66 (d, J = 10.1 Hz, 1 H), 6.37 (d, J = 8.9 Hz, 1 H), 5.58 (d,
J = 10.1 Hz, 1 H), 4.24 (q, 2 H), 2.73 (s, 3 H), 1.44 (s, 6 H).
HRMS: m/z [M+] calcd for C14H16O4S: 280.0769; found: 280.0767.
6¢¢,6¢¢-Dimethylpyrano-[2¢¢,3¢¢:7,8]-flavone (1)
13C NMR (75 MHz, CDCl3): d = 195.3, 172.1, 123.2, 116.1, 110.9,
A solution of benzaldehyde (22) (0.178 g, 1.68 mmol) in dry tolu-
ene (3 mL) was slowly added to a warm solution (40 °C) of 21 (0.40
g, 1.4 mmol) in dry toluene (20 mL) containing a catalytic amount
of piperidine (4 drops) and the resulting mixture was allowed to re-
flux for 3 h. After distillation of the solvent, the residue was purified
by flash column chromatography on silica gel to give 1 (0.429 g,
99%) as a solid.
80.1, 36.8, 29.0, 28.5, 28.5, 21.0.
HRMS: m/z [M+] calcd for C11H14O2: 178.0994; found: 178.0996.
2,2-Dimethyl-5-oxo-5,6,7,8-tetrahydro-2H-chromene-6-car-
boxylic Acid Ethyl Ester (19)
To a solution of LDA (10.0 mmol) in dry THF (50 mL) was added
a solution of 18 (1.50 g, 8.4 mmol) in THF (2 mL) at –78 °C. The
reaction mixture was stirred at –78 °C for 1 h and ethyl cyanofor-
mate (1.25 g, 12.6 mmol) in THF (2 mL) was added at –78 °C. The
resulting mixture was stirred at –78 °C for 1 h, then allowed to
warm to r.t. and stirring was continued overnight. Sat. NH4Cl soln
(30 mL) was added carefully dropwise and the aq layer was extract-
ed with EtOAc (3 × 50 mL). The combined organic layers were
washed with brine, dried over MgSO4, and evaporated under re-
duced pressure. The resulting oil was purified by flash column chro-
matography on silica gel to give 19 (1.746 g, 83%) as a liquid.
Mp 135–136 °C (lit2a 137 °C).
IR (KBr): 3055, 2984, 2920, 2851, 1647, 1591, 1576, 1441, 1397,
1381, 1366, 1215, 1190, 1130, 1113, 1080, 1030, 839 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.98 (d, J = 8.7 Hz, 1 H), 7.90–
7.87 (m, 2 H), 7.53–7.51 (m, 3 H), 6.92 (d, J = 10.0 Hz, 1 H), 6.84
(d, J = 8.7 Hz, 1 H), 6.74 (s, 1 H), 5.74 (d, J = 10.0 Hz, 1 H), 1.53
(s, 6 H).
13C NMR (75 MHz, CDCl3): d = 178.4, 162.8, 157.7, 152.6, 132.4,
131.6, 130.7, 129.4, 129.3, 126.4, 126.3, 126.2, 115.4, 115.3, 115.2,
109.6, 107.5, 77.9, 28.0, 28.0.
IR (neat): 2980, 1738, 1659, 1591, 1416, 1366, 1323, 1267, 1206,
1142, 1096, 1011, 893 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.38 (d, J = 10.0 Hz, 1 H), 5.24 (d,
J = 10.0 Hz, 1 H), 4.40–4.14 (m, 2 H), 3.34 (dd, J = 8.8, 4.9 Hz, 1
H), 2.58–2.10 (m, 4 H), 1.38 (s, 3 H), 1.37 (s, 3 H), 1.26 (t, J = 7.1
Hz, 3 H).
3¢,4¢-Methylenedioxy-6¢¢,6¢¢-dimethylpyrano-[2¢¢,3¢¢:7,8]-flavone
(2)
A solution of aldehyde 23 (0.32 g, 2.1 mmol) in dry toluene (3 mL)
was slowly added to a warm solution (40 °C) of 21 (0.50 g, 1.8
mmol) in dry toluene (20 mL) containing a catalytic amount of pip-
eridine (4 drops); the resulting mixture was allowed to reflux for 3
h. After distillation of the solvent, the residue was purified by flash
column chromatography on silica gel to give 2 (0.590 g, 95%) as a
solid.
HRMS: m/z [M+] calcd for C14H18O4: 250.1205; found: 250.1202.
5-Hydroxy-2,2-dimethyl-2H-chromene-6-carboxylicAcidEthyl
Ester (20)
A mixture of 19 (1.60 g, 6.39 mmol) and DDQ (2.18 g, 9.6 0 mmol)
in dry dioxane (40 mL) was heated under reflux for 3 h. The result-
ing mixture was cooled in an ice bath and the solids were removed
by filtration through Celite. The filtrate was evaporated under re-
duced pressure and purified by flash column chromatography on sil-
ica gel to give 20 (1.429 g, 90%) as a liquid.
Mp 230–232 °C (lit2a 231.9 °C).
IR (KBr): 2982, 2920, 1640, 1584, 1503, 1449, 1395, 1381, 1337,
1294, 1254, 1215, 1115, 1076, 1036, 930, 862 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.96 (d, J = 8.8 Hz, 1 H), 7.44 (d,
J = 8.3 Hz, 1 H), 7.31 (s, 1 H), 6.96–6.82 (m, 3 H), 6.61 (s, 1 H),
6.07 (s, 2 H), 5.74 (d, J = 10.2 Hz, 1 H), 1.53 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 177.9, 162.4, 157.5, 152.2, 150.6,
148.5, 130.5, 126.0, 125.9, 121.1, 117.7, 115.2, 115.0, 115.0, 109.5,
108.7, 106.3, 106.1, 101.8, 77.7, 28.2, 28.2.
IR (neat): 2978, 2930, 1672, 1613, 1462, 1397, 1375, 1331, 1265,
1194, 1138, 1113, 1073, 1015, 899 cm–1.
1H NMR (300 MHz, CDCl3): d = 11.24 (s, 1 H), 7.61 (d, J = 8.8 Hz,
1 H), 6.69 (d, J = 10.0 Hz, 1 H), 6.31 (d, J = 8.8 Hz, 1 H), 5.55 (d,
J = 10.0 Hz, 1 H), 4.34 (q, J = 7.1 Hz, 2 H), 1.42 (s, 6 H), 1.37 (t,
J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 170.7, 159.3, 158.7, 130.8, 128.6,
116.5, 109.6, 108.8, 105.9, 77.9, 61.4, 30.1, 28.6, 14.7.
HRMS: m/z [M+] calcd for C14H16O4: 248.1049; found: 248.1050.
b-Tubaic Acid (24)
Compound 20 (1.10 g, 4.43 mmol) was refluxed with 20% NaOH
soln (3 mL) in MeOH (20 mL) for 5 h. MeOH was evaporated under
reduced pressure, the residue was treated with ice-water and acidi-
fied with 2 N HCl soln. The combined organic layers were washed
with brine, dried over MgSO4, filtered, and evaporated under re-
duced pressure. The resulting residue was purified by flash column
chromatography on silica gel to give 24 (0.946 g, 97%) as a solid.
1-(5-Hydroxy-2,2-dimethyl-2H-chromen-6-yl)-2-methanesulfi-
nylethanone (21)
A mixture of dry DMSO (2.6 mL) and NaH (0.263 g, 10.4 mmol,
95%) in dry benzene (30 mL) was heated under N2 at 80 °C for 2 h.
The solution was cooled to 35 °C and treated dropwise with 20
(1.30 g, 5.24 mmol) in dry benzene (4 mL). The reaction mixture
was then stirred for 1 h and quenched with sat. NH4Cl soln (30 mL).
The mixture was extracted with EtOAc (3 × 30 mL). The combined
organic layers were washed with brine, dried over MgSO4, filtered,
and evaporated under reduced pressure. The resulting residue was
purified by flash column chromatography on silica gel to give 21
(1.028 g, 70%) as a liquid.
Mp 159–160 °C.
IR (KBr): 3000 (br, OH), 1657, 1462, 1426, 1383, 1335, 1263,
1211, 1165, 1111, 1071, 947, 895 cm–1.
1H NMR (300 MHz, CDCl3): d = 10.88 (s, 1 H), 7.67 (d, J = 8.8 Hz,
1 H), 6.67 (d, J = 10.0 Hz, 1 H), 6.35 (d, J = 8.8 Hz, 1 H), 5.56 (d,
J = 10.0 Hz, 1 H), 1.44 (s, 6 H).
Desmethyl isoencecalin (25)
Compound 24 (0.850 g, 3.87 mmol) was refluxed with MeLi (15.4
mmol) in toluene (30 mL) for 5 h. The resulting mixture was cooled
in an ice bath and quenched with a sat. NH4Cl soln (30 mL). The
mixture was extracted with EtOAc (3 × 30 mL). The combined or-
IR (neat): 2932, 2888, 1628, 1603, 1481, 1429, 1379, 1333, 1289,
1215, 1190, 1161, 1115, 1100, 1015, 899 cm–1.
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Synthesis of Pyranoflavone and Pyranochalcone Natural Products and their Derivatives
607
ganic layers were washed with brine, dried over MgSO4, filtered,
and evaporated under reduced pressure. The resulting residue was
purified by flash column chromatography on silica gel to give 25
(0.572 g, 68%) as a solid.
treated with H2O and acidified with 1 N HCl soln. The combined or-
ganic layers were washed with brine, dried over MgSO4, filtered,
and evaporated under reduced pressure. The resulting residue was
purified by flash column chromatography on silica gel to give 27
(1.073 g, 84%) as a solid.
Mp 101–103 °C.
Mp 102–103 °C.
IR (neat): 2976, 2930, 1630, 1618, 1487, 1426, 1366, 1329, 1273,
1211, 1165, 1125, 1071, 896 cm–1.
1H NMR (300 MHz, CDCl3): d = 12.95 (s, 1 H), 7.49 (d, J = 8.8 Hz,
1 H), 6.69 (d, J = 10.0 Hz, 1 H), 6.31 (d, J = 8.8 Hz, 1 H), 5.56 (d,
J = 10.0 Hz, 1 H), 2.51 (s, 3 H), 1.43 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 203.1, 160.1, 160.0, 132.0, 128.6,
116.2, 114.2, 109.6, 108.7, 78.1, 28.7, 26.6.
IR (KBr): 2978, 1673, 1592, 1463, 1371, 1271, 1115, 1070, 988,
891 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.53 (d, J = 8.5 Hz, 1 H), 6.56 (m,
2 H), 5.63 (d, J = 10.0 Hz, 1 H), 3.76 (s, 3 H), 2.55 (s, 3 H), 1.40 (s,
6 H).
13C NMR (75 MHz, CDCl3): d = 198.2, 158.4, 157.3, 131.5, 130.8,
124.7, 116.9, 115.1, 113.0, 77.2, 63.4, 30.6, 28.4.
Lonchocarpin (9)
To a solution of 25 (0.250 g, 1.15 mmol) in dry THF (20 mL) and
LDA (3.3 mmol) was added benzaldehyde (22) (0.146 g, 1.38
mmol) in THF (1 mL) at –78 °C. The resulting mixture was stirred
at –78 °C for 1 h, then allowed to warm to r.t., and stirring was con-
tinued overnight. Sat. NH4Cl soln (30 mL) was added dropwise
carefully and the aq layer was extracted with EtOAc (3 × 50 mL).
The combined organic layers were washed with brine, dried over
MgSO4, and evaporated under reduced pressure. The resulting oil
was purified by flash column chromatography on silica gel to give
9 (0.344 g, 98%) as a solid.
(E)-1-(5-Methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(3-meth-
oxyphenyl)propenone (30)
To a solution of 27 (0.20 g, 0.86 mmol) in EtOH (10 mL) and H2O
(2 mL) was added NaOH (0.07 g, 1.8 mmol) and m-anisaldehyde 28
(0.141 g, 1.03 mmol) at r.t. The reaction mixture was stirred for 6 h
at r.t. Evaporation of EtOH and extraction with EtOAc (3 × 50 mL),
washing with 2 N HCL soln and brine, drying over MgSO4 and re-
moval of the solvent, followed by flash column chromatography on
silica gel gave 30 (0.266 g, 88%) as a liquid.
IR (neat): 2974, 2936, 1654, 1636, 1596, 1463, 1370, 1319, 1261,
1162, 1110, 1076, 1050, 984, 888 cm–1.
Mp 92–94 °C.
IR (KBr): 3055, 2972, 2932, 1638, 1588, 1483, 1352, 1279, 1235,
1211, 1114, 1046, 898 cm–1.
1H NMR (300 MHz, CDCl3): d = 13.64 (s, 1 H), 7.86 (d, J = 15.5
Hz, 1 H), 7.70 (d, J = 8.9 Hz, 1 H), 7.64–7.60 (m, 2 H), 7.54 (d,
J = 15.5 Hz, 1 H), 7.41–7.33 (m, 3 H), 6.74 (d, J = 10.0 Hz, 1 H),
6.52 (d, J = 8.9 Hz, 1 H,), 5.58 (d, J = 10.0 Hz, 1 H), 1.44 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 192.3, 161.4, 160.3, 144.7, 135.2,
131.1, 131.0, 129.4, 128.9, 128.6, 120.7, 116.2, 114.5, 109.8, 108.8,
78.3, 28.8.
1H NMR (300 MHz, CDCl3): d = 7.66 d, J = 15.3 Hz, (1 H), 7.53 (d,
J = 8.5 Hz, 1 H), 7.48 (d, J = 15. 3 Hz, 1 H), 7.30 (dd, J = 8.1, 8.0
Hz, 1 H), 7.20 (d, J = 8.0 Hz, 1 H), 7.10 (s, 1 H), 6.90 (d, J = 8.1 Hz,
1 H), 6.62 (dd, J = 10.0, 8.5 Hz, 2 H), 5.66 (d, J = 10.0 Hz, 1 H),
3.80 (s, 3 H), 3.73 (s, 3 H), 1.43 (6 H, s).
13C NMR (75 MHz, CDCl3): d = 191.1, 160.3, 158.8, 156.9, 143.4,
136.9, 131.8, 131.0, 130.3, 126.9, 125.9, 121.4, 116.8, 116.4, 115.2,
113.8, 113.2, 77.3, 63.8, 55.7, 28.5.
HRMS: m/z [M+] calcd for C22H22O4: 350.1518; found: 350.1516.
4-Hydroxylonchocarpin (10)
(E)-1-(5-Methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(4-meth-
oxyphenyl)propenone (31)
To a solution of 25 (0.250 g, 1.15 mmol) in dry THF (20 mL) and
LDA (3.3 mmol) was added aldehyde 26 (0.347 g, 1.37 mmol) in
THF (1 mL) at –78 °C. The resulting mixture was stirred at –78 °C
for 1 h, then allowed to warm to r.t., and stirring was continued
overnight. Sat. NH4Cl soln (30 mL) was added dropwise carefully
and the aq layer was extracted with EtOAc (3 × 50 mL). The com-
bined organic layers were washed with brine, dried over MgSO4,
and evaporated under reduced pressure. The resulting oil was puri-
fied by flash column chromatography on silica gel to give 10 (0.332
g, 90%) as a solid.
To a solution of 27 (0.290 g, 1.25 mmol) in EtOH (10 mL) and H2O
(2 mL) was added NaOH (0.10 g, 2.5 mmol) and p-anisaldehyde
(29) (0.204 g, 1.49 mmol) at r.t. The reaction mixture was stirred for
6 h at r.t. Evaporation of EtOH and extraction with EtOAc (3 × 50
mL), washing with 2 N HCl soln and brine, drying over MgSO4 and
removal of the solvent, followed by flash column chromatography
on silica gel gave 31 (0.416 g, 95%) as a liquid.
IR (neat): 2970, 2934, 2839, 1647, 1592, 1512, 1369, 1253, 1173,
1076, 1042, 985, 888 cm–1.
Mp 199–201 °C.
1H NMR (300 MHz, CDCl3): d = 7.67 (d, J = 15.8 Hz, 1 H), 7.56–
7.50 (m, 3 H), 7.38 (d, J = 15.8 Hz, 1 H), 6.89 (d, J = 8.7 Hz, 2 H),
6.63 (d, J = 10.0 Hz, 1 H), 6.61 (d, J = 8.6 Hz, 1 H), 5.67 (d,
J = 10.0 Hz, 1 H), 3.82 (s, 3 H), 3.73 (s, 3 H), 1.44 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 191.1, 161.8, 157.7, 156.6, 143.5,
132.3, 131.6, 131.0, 130.5, 128.2, 126.1, 124.3, 116.9, 115.2, 114.8,
114.7, 113.0, 77.2, 63.7, 55.7, 28.4.
IR (KBr): 3379, 1634, 1606, 1580, 1512, 1289, 1248, 1235, 1167,
1116, 896 cm–1.
1H NMR (300 MHz, CDCl3): d = 13.60 (s, 1 H), 7.82 (d, J = 15.5
Hz, 1 H), 7.72 (d, J = 8.8 Hz, 1 H), 7.55 (d, J = 8.6 Hz, 2 H), 7.43
(d, J = 15.5 Hz, 1 H), 6.87 (d, J = 8.6 Hz, 2 H), 6.74 (d, J = 10.1 Hz,
1 H), 6.37 (d, J = 8.8 Hz, 1 H), 5.59 (d, J = 10.1 Hz, 1 H), 1.46 (s, 6
H).
13C NMR (75 MHz, CDCl3): d = 192.0, 163.0, 160.8, 158.4, 144.4,
130.6, 130.5, 128.1, 117.8, 116.0, 115.9, 115.8, 108.3, 108.2, 77.4,
28.4.
HRMS: m/z [M+] calcd for C22H22O4: 350.1518; found: 350.1518.
(E)-3-(4-Hydroxyphenyl)-1-(5-methoxy-2,2-dimethyl-2H-
chromen-6-yl)propenone (32)
To a solution of 27 (0.320 g, 1.38 mmol) in EtOH (10 mL) and H2O
(2 mL) was added NaOH (0.110 g, 2.75 mmol) and aldehyde 26
(0.407 g, 1.61 mmol) at r.t. The reaction mixture was stirred for 6 h
at r.t. Evaporation of EtOH and extraction with EtOAc (3 × 50 mL),
washing with 2 N HCl soln and brine, drying over MgSO4, and re-
moval of the solvent gave the residue. To a solution of the residue
Isoencecalin (27)
To a solution of 25 (1.20 g, 5.50 mmol) and K2CO3 (1.147 g, 8.30
mmol) in acetone (30 mL) was added MeI (0.937g, 6.60 mmol) in
acetone (2 mL). The reaction mixture was stirred at r.t. for 10 h. The
solvent was evaporated under reduced pressure, the residue was
Synthesis 2006, No. 4, 603–608 © Thieme Stuttgart · New York

608
Y. R. Lee, D. H. Kim
PAPER
Okada, K.; Kinoshida, T. Chem. Pharm. Bull. 1992, 40,
in THF (10 mL) was added a 1.0 M TBAF soln in THF (2.1 mL, 2.1
mmol) and the mixture was stirred at r.t. for 3 h. After distillation of
the solvent, the residue was purified by flash column chromatogra-
phy on silica gel to give 32 (0.380 g, 82%) as a solid.
392. (c) Haraguchi, H.; Tanimoto, K.; Tamura, Y.; Mizutani,
K.; Kinoshita, T. Phytochemistry 1998, 48, 125.
(d) Mitscher, L. A.; Park, Y. H.; Clark, D.; Beal, J. L. J. Nat.
Prod. 1980, 43, 259. (e) Nishino, H.; Yoshioko, K.;
Iwashima, A.; Takizawa, H.; Konishi, S.; Okamoto, H.;
Pkabe, H.; Shibata, S.; Fujiki, H.; Sugimura, T. Jpn. J.
Cancer Res. 1986, 77, 33. (f) Okada, K.; Tamura, Y.;
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Pharm. Bull. 1989, 37, 2528. (g) van Marle, J.; Arasen, P.
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Mp 147–148 °C.
IR (KBr): 2977, 2935, 1634, 1590, 1514, 1372, 1282, 1169, 1114,
1079, 985, 889 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.67 (d, J = 15.8 Hz, 1 H), 7.52–
7.47 (m, 3 H), 7.37 (d, J = 15.8 Hz, 1 H), 6.85 (d, J = 8.5 Hz, 2 H),
6.62 (d, J = 10.0 Hz, 1 H), 6.61 (d, J = 8.6 Hz, 1 H), 5.67 (d,
J = 10.0 Hz, 1 H), 3.76 (s, 3 H), 1.42 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 192.4, 159.1, 158.0, 156.7, 144.7,
134.1, 131.7, 131.1, 130.9, 127.7, 125.9, 123.8, 116.8, 116.7, 116.5,
114.9, 113.1, 77.4, 63.8, 28.5.
(8) (a) Yu, D.; Chen, C.-H.; Brossi, A.; Lee, K.-H. J. Med.
Chem. 2004, 47, 4072. (b) Tan, W.; Li, W.-D. Z.; Huang,
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C.; Pfefferkorn, J. A.; Cao, G.-Q. Angew. Chem. Int. Ed.
2000, 39, 734. (d) Nicolaou, K. C.; Pfefferkorn, J. A.;
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Am. Chem. Soc. 2000, 122, 9939. (e) Narender, T.; Gupta,
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Y.; Lee, S. H. Synthesis 2001, 1851. (b) Lee, Y. R.; Kim, D.
H.; Shim, J.-J.; Kim, S. K.; Park, J. H.; Cha, J. S.; Lee, C.-S.
Bull. Korean Chem. Soc. 2002, 23, 998.
Acknowledgment
This work was supported by the Korea Research Foundation Grant
(KRF-2003-041-C00183).
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Synthesis 2006, No. 4, 603–608 © Thieme Stuttgart · New York