Total Synthesis of the Flavonoid Natural Product Houttuynoid A

Article abstract of DOI:10.1021/acs.jnatprod.7b00791

The first total synthesis of the antiviral flavonoid houttuynoid A (1) has been achieved from aryl ketone 6 and benzofuran aldehyde 5 in nine linear steps. The C₆-C₃-C₆ structure of the flavonoid was synthesized by an I₂-catalyzed oxa-Michael addition of a chalcone intermediate, generated by the Claisen-Schmidt condensation of 5 and 6. This work provides a method for the synthesis of houttuynoids and provides a reference for the synthesis of the remaining members of the houttuynoid family.

Full text of DOI:10.1021/acs.jnatprod.7b00791

Article
pubs.acs.org/jnp
Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX
Total Synthesis of the Flavonoid Natural Product Houttuynoid A
Jie Jian,†,⊥ Jilin Fan,†,⊥ Hui Yang,† Ping Lan,§ Manmei Li,† Peijun Liu,‡ Hao Gao,*,†
and Pinghua Sun*,†
†Department of Medicinal Chemistry and Institute of Traditional Chinese Medicine and Natural Products, College of
Pharmacy/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan
University, Guangzhou 510632, People’s Republic of China
§Department of Food Science and Engineering, College of Science and Engineering, Jinan University, Guangzhou 510632, People’s
Republic of China
‡Pharmacy School, Zunyi Medical University, Zunyi 563003, People’s Republic of China
S
* Supporting Information
ABSTRACT: The first total synthesis of the antiviral
flavonoid houttuynoid A (1) has been achieved from aryl
ketone 6 and benzofuran aldehyde 5 in nine linear steps. The
C6−C3−C6 structure of the flavonoid was synthesized by an I2-
catalyzed oxa-Michael addition of a chalcone intermediate,
generated by the Claisen−Schmidt condensation of 5 and 6.
This work provides a method for the synthesis of houttuynoids
and provides a reference for the synthesis of the remaining
members of the houttuynoid family.
blocking viral membrane fusion.7 This compound also turned
erpes simplex virus (HSV) infections are still considered
out to have broad antiviral properties against a range of α-
Ha significant and widespread health concern. So far, eight
herpesviruses, including HSV-2 and varicella zoster,7 and
distinct human herpes viruses have been identified. HSV-1 is
further investigation of houttuynoid A for its potential as an
anti-HSV drug is thus warranted. However, the paucity of this
natural product from plant sources led us to investigate the
total synthesis of houttuynoid A (1).
the main cause of oral infections and is commonly associated
with cold sores, while HSV-2 is mostly linked to genital
herpes.1 As ubiquitous and contagious viruses, their presence
may have unpredictable consequences in neonates and in
immune-suppressed patients.2 Although acyclovir (ACV) and
related nucleoside analogues are valuable drugs for the
treatment of infection and the suppression of dissemination,
the similarity in their mechanisms leads to cross-resistance
among drug-resistant strains.3 However, natural products have
historically played an important role as a source of therapeutic
agents, and extensive attention has been given to the antiviral
natural products found in both traditional herbal medicines and
plants.4 For instance, Houttuynia cordata, an herbal medicine
that has been used in conjunction with conventional herbal
medicine to treat the Severe Acute Respiratory Syndrome
(SARS) outbreak in 2003, showed promising therapeutic ability
toward HSV-1.5 Our continuing efforts on the antiviral
properties within this herbal medicine led to the isolation
and identification of several flavonoids, named houttuynoids
A−J.6 The houttuynoids belong to a new class of flavonoids
that display excellent in vitro inhibitory activities against HSV-
1.6
The distinctive molecular architectures of the houttuynoid
family made them attractive target structures for chemical
synthesis. Recently, Schmalz and co-workers reported a concise
total synthesis of houttuynoid B (2) based on a Baker−
Venkataraman rearrangement employing a glycosylated sub-
strate to establish the functionalized carbon skeleton.8 This is
the only synthesis work toward the houttuynoid family, and the
most potent member, houttuynoid A (1), has not been
synthesized yet. The structure of 1 differs from 2 only with
regard to the substitution at the C-2″ position of the
benzofuran moiety (Figure 1). Interestingly, this structural
difference leads to varying IC50 values (23.5 vs 57.7 μM),6
which indicated that the substitution at C-2″ greatly influences
the activity. Herein the concise total synthesis of houttuynoid
A, which could allow further biological studies on this potential
drug, is reported.
RESULTS AND DISCUSSION
■
The protocol used to prepare target 1 is shown in the
retrosynthetic analyses shown in Figure 2. It is anticipated that
this could be obtained using standard functional group
The antiviral mechanism of action of the houttuynoids is
under investigation in our laboratory. The latest data7 on
houttuynoid A, the most potent member of this family, verified
that it could inhibit HSV-1 multiplication and prevent lesion
formation in an HSV-1 infection mouse model. Further studies
indicated that houttuynoid A inactivated HSV-1 infectivity by
Received: October 11, 2017
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
DOI: 10.1021/acs.jnatprod.7b00791
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
Scheme 1. Reaction Sequence Leading to 5
Figure 1. Structures of houttuynoid A (1) and houttuynoid B (2).
generated dimethyldioxirane (DMDO) followed by an acid-
induced rearrangement,15 the 3-hydroxyflavone 16 was
obtained in 62% yield. Various glycosylation attempts of 16
failed, possibly due to a hydrogen bond between the 3-hydroxy
and carbonyl groups. Gratifyingly, after selective deprotection
of the 5-benzyloxy group16 via refluxing in HOAc/H2O, the
glycosylation of 17 with 1817 afforded chromenone 19 in
almost quantitative yield. The acetyl and benzyl protecting
groups of 19 were subsequently removed by standard
hydrolysis and hydrogenation processes to afford the ester 20
in 98% yield. On exposure to DIBAl-H, 20 was reduced to the
target houttuynoid A (1) in 54% yield. The observed and
reported spectroscopic data (1H NMR, 13C NMR, MS, and
HRMS) were identical6a (Table 1). However, the specific
rotation of synthesized houttuynoid A (1) was of the same sign
but larger magnitude than reported for the natural product
{[α]2D7 −24.7 (c 0.5, MeOH) vs [α]2D5 −1.1 (c 0.5, MeOH)
reported6a for houttuynoid A}. Such a discrepancy probably
results from the presence of impurities in the natural product.
Table 1 shows the comparison of the NMR data for natural
houttuynoid A and synthesized houttuynoid A.
Figure 2. Retrosynthetic analysis of houttuynoid A (1).
interconversions (FGIs) from compound 3, which itself would
be formed through an oxa-Michael addition and oxidation9 of
the chalcone 4 followed by a methylation of the C-2″
hydroxycarbonyl group. This compound is to be generated
from a Claisen−Schmidt condensation10 of 1-[2,4-bis (benzyl-
oxy)-6-hydroxyphenyl]ethanone 6 with benzofuran aldehyde 5.
It was expected that compound 5 could be prepared from
commercially available starting materials.
Scheme 1 summarizes the preparation of intermediate 5 and
started with the regioselective benzylation11 of the para-
hydroxy group of 3,4-dihydroxybenzaldehyde (7) to afford
benzaldehyde 8 as the major product (76%). Treatment of the
latter compound with iodine monochloride afforded the iodide
(9) in 90% yield. Protection of the formyl group as an acetal
(10) prior to the conjugate addition12 of the phenol (10) to
methyl dodec-2-ynoate (11)13 in the presence of K3PO4 gave
the aryl ether 12 in 84% yield. Compound 12 was subjected to
an intramolecular Heck reaction14,12a to establish the
benzofuran skeleton (13) in 79% yield. Hydrolysis of the 1,3-
dioxanyl group with HCl in moist tetrahydrofuran (THF)
afforded the key intermediate 5 (90%).
The elaboration of compound 5 to target 1 was achieved
using the chemistry shown in Scheme 2 and involved an initial
Claisen−Schmidt condensation of 1-[2,4-bis(benzyloxy)-6-
hydroxyphenyl]ethanone 6 and aldehyde 5, using NaOH as
base10 to give chalcone 4 in almost quantitative yield. The latter
compound was converted into the 4H-chromen-4-one
derivative 14 (89% yield) using a catalytic amount of I2 in
DMSO at 110 °C.9 Methylation of the hydroxycarboxyl group
at C-2″ (15) was necessary before the oxidation step at C-3
could be done. The introduction of a hydroxy group at C-3 was
a major obstacle in Schmalz’s initial work8 toward houttuynoid
B. However, when compound 15 was treated with in situ
The present work describes a useful protocol toward the
synthesis of the most potent member of the houttuynoid
family. Highlights of the approach include the efficient six-step
sequence to the polysubstituted benzofuran 5, the DMDO
hydroxylation at C-3, and the regioselective galactosylation at
C-3. This synthesis should pave the way to other houttuynoid-
type natural products.
EXPERIMENTAL SECTION
■
General Experimental Procedures. Melting points were
measured on an Optimelt (MPA 100) automated melting point
system and are uncorrected. Optical rotations were determined with a
1
JASCO P-2000 instrument. H and 13C NMR spectra were obtained
using 300 and 400 MHz Bruker Biopsy GmbH instruments. Chemical
shifts are reported in parts per million (ppm δ) referenced to the
1
residual H resonance of the solvents (CDCl3, 7.26 ppm; DMSO-d6,
2.50 ppm). 13C spectra were referenced to the residual 13C resonance
B
DOI: 10.1021/acs.jnatprod.7b00791
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
1
Scheme 2. Synthesis of Houttuynoid A (1)
Table 1. Comparison of the 13C and H NMR Data of
Synthesized Houttuynoid A (1) and the Natural Product
13C NMR (δC)
1H NMR (δH)
a
b
c
d
no. houttuynoid A compound 1
houttuynoid A
compound 1
2
158.6
134.3
178.0
161.3
98.7
158.6
134.3
178.1
161.3
98.6
3
4
5
12.61, s
12.62, s
6
6.22, d (1.8)
6.22, d (1.2)
7
164.5
93.7
164.2
93.6
8
6.16, d (1.8)
6.16, d (1.2)
9
156.7
104.5
113.7
124.6
142.3
144.8
111.0
128.9
185.1
117.4
170.9
26.6
156.7
104.5
113.7
124.5
142.2
144.5
110.9
128.9
185.1
117.4
171.0
26.6
10
1′
2′
3′
4′
5′
6′
6.86, d (8.3)
7.71, d (8.3)
9.90, s
6.86, d (8.3)
7.71, d (8.3)
9.90, s
1″
2″
3″
4″
5″
6″
7″
8″
9″
10″
11″
12″
1‴
2‴
3‴
4‴
5‴
6‴
3.15, br
1.74, m
1.31, m
1.25
3.17, t (7.4)
1.76, m
1.32, m
1.24
27.7
27.7
28.6
28.6
28.8
28.8
28.6
28.6
1.25
1.24
28.6
28.6
1.25
1.24
31.2
31.2
1.25
1.24
22.1
22.1
1.25
1.24
13.9
13.9
0.83, t (6.7)
5.23, d (7.7)
3.28
0.84, t (6.7)
5.13, d (6.7)
3.27
102.2
71.1
102.1
71.0
73.1
73.1
3.28
3.27
67.7
67.7
3.63, m
3.26
3.61, m
3.26
75.5
75.5
60.0
60.0
3.43, dd (9.5, 5.4)
3.25
3.40, m
3.26
a
b
Data obtained from ref 6a recorded in DMSO-d6 at 100 MHz. Data
c
recorded in DMSO-d6 at 100 MHz. Data obtained from ref 6a
recorded in DMSO-d6 at 400 MHz. Data recorded in DMSO-d6 at
d
400 MHz.
solvents were purchased from commercial sources and used without
further purification. Dichloromethane and dimethylformamide (DMF)
were distilled from CaH2. Where necessary, reactions were performed
under an argon atmosphere.
of the solvents (CDCl3, 77.16 ppm; DMSO-d6, 39.50 ppm). Splitting
patterns are designated as follows: s, singlet; br, broad; d, doublet; dd,
doublet of doublets; t, triplet; q, quartet; m, mulitplet. Coupling
constants (J) are reported in hertz (Hz). Electrospray ionization mass
spectra (ESIMS) were obtained on a Finnigan LCQ Advantage MAX
mass spectrometer (Applied Biosystems, 4000 Q TRAP). High-
resolution mass spectra (HRMS) were obtained on an Agilent 6210
series LC/MSD TOF mass spectrometer. Analytical HPLC was
performed on a Dionex HPLC system equipped with an Ultimate
3000 pump, an Ultimate 3000 diode array detector (DAD), an
Ultimate 3000 column compartment, and an Ultimate 3000
autosampler (Dionex, USA) using a Phenomenex Gemini C18 column
(4.6 × 250 mm, 5 μm). Semipreparative HPLC was carried out on a
Dionex HPLC system equipped with an Ultimate 3000 pump and an
Ultimate 3000 RS variable-wavelength detector (Dionex, USA) using a
Phenomenex Gemini C18 column (10.0 × 250 mm, 5 μm). Flash
chromatography was performed using Qingdao Haiyang 200−300
mesh silica gel. For thin-layer chromatography (TLC) analysis
Qingdao Haiyang GF254 silica gel plates were used. All reagents and
4-(Benzyloxy)-3-hydroxybenzaldehyde (8). According to the
protocol described by Couladouros and Soufli,18a a magnetically
stirred mixture of 3,4-dihydroxybenzaldehyde 7 (30.0 g, 217.4 mmol, 1
equiv) and KI (722 mg, 4.35 mmol, 0.02 equiv) in DMF (150 mL)
was treated with K2CO3 (30.0 g, 217.4 mmol, 1 equiv). The mixture
was stirred for 4 h at 60 °C under an Ar atmosphere before being
cooled to room temperature. BnBr (28.5 mL, 239.1 mmol, 1.1 equiv)
was added dropwise, and the reaction mixture was stirred at the same
temperature for 24 h before being quenched by 10% HCl. The mixture
was poured into water and extracted with EtOAc (3 × 250 mL). The
organic layers were combined and concentrated to give an off-white
solid, which was dissolved in 10% aqueous NaOH solution and stirred
at room temperature for another 30 min. The precipitate was removed
by filtration, and the pH of the filtrate was adjusted to 1 by 10% HCl.
The resulting precipitate was filtered and washed with water to give
compound 8 (37.7 g, 76%), which was crystallized from EtOAc to give
a crystalline solid: mp 120.9−122.9 °C, lit.18b mp 120−122 °C (dec);
C
DOI: 10.1021/acs.jnatprod.7b00791
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
1H NMR (300 MHz, CDCl3) δ 9.82 (1H, s), 7.50−7.35 (7H, m), 7.04
(1H, J = 8.3 Hz, d), 5.95 (1H, brs), 5.20 (2H, s); 13C NMR (75 MHz,
CDCl3) δ 191.2, 151.1, 146.4, 135.3, 130.9, 129.0, 128.9, 128.0, 124.5,
114.5, 111.6, 71.4; ESIMS m/z 251 [M + Na]+; HRESIMS m/z
229.0865 [M + H]+ (calcd for C14H13O3, 229.0859).
MHz, CDCl3) δ 7.46 (1H, J = 8.7 Hz, d), 7.35−7.27 (5H, m), 6.99
(1H, J = 8.7 Hz, d), 5.57 (1H, s), 5.06 (2H, s), 4.68 (1H, s), 4.32−4.18
(2H, m), 4.09−3.95 (2H, m), 3.61 (3H, s), 3.05−2.92 (2H, m), 2.22
(1H, J = 12.6, 5.1 Hz, qt), 1.73 (2H, m), 1.49−1.19 (13H, m), 0.88
(3H, J = 6.7 Hz, t); 13C NMR (75 MHz, CDCl3) δ 174.1, 167.7, 150.8,
142.1, 136.0, 134.4, 128.6, 128.2, 127.4, 125.4, 113.9, 104.6, 95.7, 93.8,
70.8, 67.6, 50.8, 32.0, 31.4, 29.7, 29.7, 29.6, 29.4, 27.4, 25.7, 22.8, 14.2;
ESIMS m/z 623 [M + H]+; HRESIMS m/z 623.1864 [M + H]+ (calcd
for C30H40IO6, 623.1864).
4-(Benzyloxy)-3-hydroxy-2-iodobenzaldehyde (9). A magneti-
cally stirred mixture of 8 (4.0 g, 17.54 mmol, 1 equiv) in pyridine (20
mL) at 0 °C was treated with a solution of iodine monochloride (3.4 g,
21.05 mmol, 1.2 equiv) in 1,4-dioxane (40 mL) via cannula, and the
flask was wrapped with alumina foil and allowed to warm to 18 °C.
After being stirred for 48 h, the solution was concentrated, water (20
mL) was added, and the resulting solution was acidified to pH = 1 by
concentrated HCl. The mixture was extracted into EtOAc (3 × 18
mL), and the extracts were combined and washed sequentially with
saturated aqueous NaHSO3 (2 × 15 mL), water (2 × 15 mL), and
then brine (15 mL). The organic layer was dried over Na2SO4, filtered,
and concentrated to give an off-white solid, which was recrystallized
from petroleum ether/EtOAc to afford compound 919 (1.49 g, 90%)
as a white, crystalline solid: mp 140 °C, lit.8 mp 138−141 °C (dec);
1H NMR (300 MHz, CDCl3) δ 10.01 (1H, s), 7.51 (1H, J = 8.5 Hz,
d), 7.41 (5H, s), 6.97 (1H, J = 8.5 Hz, d), 6.47 (1H, brs), 5.22 (2H, s);
13C NMR (75 MHz, CDCl3) δ 195.0, 149.9, 146.0, 135.0, 129.0, 129.0,
129.0, 128.0, 123.7, 111.4, 71.7; ESIMS m/z 355 [M + H]+;
HRESIMS m/z 354.9834 [M + H]+ (calcd for C14H12IO3, 354.9831).
6-(Benzyloxy)-3-(1,3-dioxan-2-yl)-2-iodophenol (10). A sol-
ution of 9 (5.5 g, 15.54 mmol, 1 equiv), propane-1,3-diol (15.6 mL,
217.50 mol, 14 equiv), and p-toluenesulfonic acid (133.6 mg, 0.78
mmol, 0.05 equiv) in toluene (75 mL) was refluxed in a Dean−Stark
apparatus. When no more water separated from the reaction system,
the mixture was cooled and diluted with EtOAc (100 mL). The
organic layer was washed with saturated NaHCO3 solution (50 mL)
and brine (50 mL), dried over Na2SO4, filtered, and concentrated. The
resulting dark brown solid was purified by flash column chromatog-
raphy on silica gel (petroleum ether/EtOAc, 11:1) to give 10 (5.3 g,
82%) as a white solid: mp 129−131 °C; 1H NMR (300 MHz, CDCl3)
δ 7.51−7.29 (5H, m), 7.19 (1H, J = 8.5 Hz, d), 6.89 (1H, J = 8.5 Hz,
d), 6.37 (1H, s), 5.60 (1H, s), 5.10 (2H, s), 4.33−4.18 (2H, m), 4.11−
3.95 (2H, m), 2.22 (1H, m), 1.56−1.35 (1H, m); 13C NMR (75 MHz,
CDCl3) δ 145.5, 145.4, 135.8, 133.7, 128.7, 128.5, 127.7, 119.0, 111.8,
104.5, 85.4, 71.3, 67.5, 25.6; ESIMS m/z 413 [M + H]+; HRESIMS m/
z 413.0242 [M + H]+ (calcd for C17H18IO4, 413.0244).
Methyl 7-(Benzyloxy)-4-(1,3-dioxan-2-yl)-2-nonylbenzofur-
an-3-carboxylate (13). To a solution of 12 (4.7 g, 7.6 mmol, 1
equiv) in anhydrous DMF (50 mL) was added Pd (OAc)2 (85 mg,
0.38 mmol, 0.05 equiv), PPh3 (0.2 g, 0.76 mmol, 0.1 equiv), and
Ag2CO3 (3.0 g, 7.6 mmol, 1 equiv). The mixture was stirred at 110 °C
for 15 h under an Ar atmosphere before being cooled to room
temperature and diluted with water (200 mL). The solution was
extracted with EtOAc (3 × 100 mL). The combined organic extracts
were washed with brine, dried over Na2SO4, filtered, and concentrated.
The crude product was purified by flash column chromatography on
silica gel (petroleum ether/EtOAc, 12:1) to give compound 13 (3.0 g,
1
79%) as a white, amorphous solid: H NMR (300 MHz, CDCl3) δ
7.52−7.28 (6H, m), 6.83 (1H, J = 8.5 Hz, d), 6.19 (1H, s), 5.28 (2H,
s), 4.18 (2H, J = 10.7, 5.2 Hz, dd), 4.05 (2H, J = 12.2, 2.4 Hz, td), 3.94
(3H, s), 3.06−2.95 (2H, m), 2.18 (1H, J = 12.2, 5.2 Hz, qt), 1.78 (2H,
m), 1.49−1.22 (13H, m), 0.90 (3H, J = 6.7 Hz, t); 13C NMR (75
MHz, CDCl3) δ 165.2, 164.7, 144.1, 143.6, 136.7, 128.6, 128.1, 127.4,
124.9, 124.5, 121.2, 110.6, 108.2, 98.6, 71.0, 66.8, 51.8, 31.9, 29.5, 29.4,
29.3, 28.3, 26.0, 22.7, 14.2; ESIMS m/z 495 [M + H]+; HRESIMS m/z
495.2745 [M + H]+ (calcd for C30H39O6, 495.2741).
Methyl 7-(Benzyloxy)-4-formyl-2-nonylbenzofuran-3-car-
boxylate (5). To a solution of 13 (6.0 g, 12.1 mmol) in THF (50
mL) at 0 °C was added concentrated HCl (4 mL) dropwise. The
mixture was stirred at 0 °C for 1.5 h and diluted with water (100 mL)
and CH2Cl2 (100 mL), and the aqueous layer was extracted with
CH2Cl2 (3 × 250 mL). The organic layers were combined, washed
with water (100 mL) and saturated NaHCO3 solution (250 mL), dried
over Na2SO4, filtered, and concentrated. The resulting white solid was
purified by flash column chromatography on silica gel (petroleum
ether/EtOAc, 7:1) to give aldehyde 5 (4.75 g, 90%) as a white,
1
amorphous solid: H NMR (300 MHz, CDCl3) δ 10.58 (1H, s), 7.83
(1H, J = 8.5 Hz, d), 7.51−7.29 (5H, m), 6.92 (1H, J = 8.5 Hz, d), 5.34
(2H, s), 3.94 (3H, s), 3.13−3.03 (2H, m), 1.92−1.69 (2H, m), 1.48−
1.15 (12H, m), 0.86 (3H, J = 6.8 Hz, t); 13C NMR (75 MHz, CDCl3)
δ 191.3, 167.6, 165.1, 148.5, 143.4, 135.8, 128.8, 128.5, 127.5, 127.5,
127.3, 123.4, 110.4, 108.0, 71.2, 52.1, 31.9, 29.5, 29.4, 29.4, 29.3, 28.5,
28.3, 22.7, 14.2; ESIMS m/z 437 [M + H]+; HRESIMS m/z 437.2320
[M + H]+ (calcd for C27H33O5, 437.2328).
Methyl Dodec-2-ynoate (11). According to the procedure
described by Trost and Livingston,13a a magnetically stirred solution
of 1-undecyne (8.0 g, 53.0 mmol, 1 equiv) in anhydrous THF (120
mL) at −78 °C was treated with n-BuLi (36.0 mL of a 1.6 M solution
in hexanes, 58.3 mmol, 1.1 equiv). After being stirred for 45 min,
methyl chloroformate (6.0 g, 63.0 mmol, 1.2 equiv) was added
dropwise, and the mixture was warmed to room temperature before
being quenched with saturated aqueous NH4Cl (25 mL) and extracted
with Et2O (3 × 30 mL). The combined organic layer was washed with
water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and
concentrated to give 11 (11.0 g, 98%) as a yellow oil, which was used
(E)-7-(Benzyloxy)-4-[3-(2,4-bis(benzyloxy)-6-hydroxyphen-
yl)-3-oxoprop-1-en-1-yl]-2-nonylbenzofuran-3-carboxylic Acid
(4). A magnetically stirred mixture of aldehyde 5 (2.1 g, 4.9 mmol, 1
equiv) and 1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)ethanone 6 (1.7 g,
4.9 mmol, 1 equiv) in absolute EtOH (10 mL) at 50 °C was treated
with 50% aqueous NaOH solution (5 mL) dropwise. After addition,
the solution was cooled to 18 °C and stirred for another 48 h before
being treated with crushed ice and then neutralized with 5% aqueous
HCl. The precipitate was filtered and recrystallized from aqueous
EtOH to give chalcone 4 (3.6 g, 98%) as yellow needles: mp 115−116
1
in the subsequent step without further purification. H NMR (300
MHz, CDCl3) δ 3.74 (3H, s), 2.31 (2H, J = 7.1 Hz, t), 1.61−1.49 (2H,
m), 1.43−1.16 (12H, m), 0.87 (3H, J = 6.7 Hz, t); 13C NMR (75
MHz, CDCl3) δ 154.4, 90.1, 72.9, 52.7, 32.0, 29.5, 29.4, 29.1, 28.9,
27.6, 22.8, 18.8, 14.2; ESIMS m/z 211 [M + H]+; HRESIMS m/z
211.1693 [M + H]+ (calcd for C13H23O2, 211.1693).
1
°C; H NMR (300 MHz, DMSO-d6) δ 14.51 (1H, s), 9.12 (1H, J =
15.5 Hz, d), 7.67 (1H, J = 15.5 Hz, d), 7.57−7.27 (15H, m), 6.75 (1H,
J = 8.6 Hz, d), 6.63 (1H, J = 8.6 Hz, d), 6.39 (1H, J = 1.9 Hz, d), 6.23
(1H, J = 1.9 Hz, d), 5.36 (2H, s), 5.20 (2H, s), 5.16 (2H, s), 3.00 (2H,
J = 7.4 Hz, t), 1.72−1.53 (2H, m), 1.34−1.11 (12H, m), 0.83 (3H, J =
6.4 Hz, t); 13C NMR (75 MHz, DMSO-d6) δ 191.9, 167.0, 165.5,
165.3, 164.8, 161.3, 144.9, 142.6, 141.5, 136.5, 136.3, 135.7, 129.0,
128.7, 128.6, 128.5, 128.2, 128.1, 128.1, 127.9, 127.8, 126.7, 125.4,
123.1, 121.0, 111.0, 108.9, 105.9, 95.0, 92.6, 71.1, 70.2, 69.8, 31.2, 28.9,
28.6, 28.6, 28.5, 27.7, 27.5, 22.1, 13.9; ESIMS m/z 753 [M + H]+;
HRESIMS m/z 753.3429 [M + H]+ (calcd for C48H49O8, 753.3422).
7-(Benzyloxy)-4-[5, 7-bis(benzyloxy)-4-oxo-4H-chromen-2-
yl]-2-nonylbenzofuran-3-carboxylic Acid (14). A magnetically
Methyl 3-[6-(Benzyloxy)-3-(1,3-dioxan-2-yl)-2-
iodophenoxy]dodec-2-enoate (12). To a magnetically stirred
solution of 10 (25.0 g, 60.68 mmol, 1 equiv) in anhydrous DMF
(200 mL) were added K3PO4 (14.2 g, 66.75 mmol, 1.1 equiv) and 11
(15.3 g, 72.8 mmol, 1.2 equiv) dropwise via syringe. The resulting
mixture was heated at 110 °C under an Ar atmosphere for 16 h. After
being cooled, the mixture was diluted with water (100 mL) and
extracted with EtOAc (3 × 300 mL). The combined organic extracts
were washed with brine (300 mL), dried over Na2SO4, filtered, and
concentrated. The resulting dark brown oil was purified by flash
column chromatography on silica gel (petroleum ether/EtOAc, 8:1) to
1
give 12 (31.7 g, 84%) as a white, amorphous solid: H NMR (300
D
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stirred mixture of chalcone 4 (2.3 g, 3.1 mmol, 1 equiv) in anhydrous
DMSO (30 mL) was treated with a catalytic amount of I2 (80 mg, 0.31
mmol, 0.1 equiv). The mixture was heated to 110 °C for 1.5 h under
an Ar atmosphere before being cooled to room temperature. The
reaction was quenched by 10% HCl (5 mL). The aqueous layer was
extracted with EtOAc (3 × 100 mL). The combined organic extracts
were washed with brine (150 mL), dried over Na2SO4, filtered, and
concentrated. The resulting residue was dissolved in a minimum
amount of warm MeOH (40 °C) and left at room temperature to
crystallize, providing the title compound 14 as a white, crystalline
solid. The mother liquor was concentrated and subjected to
purification by flash chromatography on a silica gel column
(MeOH/CH2Cl2, 1:100) to afford flavone 14 (2.1 g in total, 89%):
Methyl 7-(Benzyloxy)-4-[7-(benzyloxy)-3,5-dihydroxy-4-
oxo-4H-chromen-2-y-l]-2-nonylbenzofuran-3-carboxylate
(17). A magnetically stirred mixture of 16 (200 mg, 0.256 mmol) in
HOAc/H2O (13:3, v/v 16 mL) was stirred at 110 °C for 16 h. After
cooling to room temperature, the mixture was extracted with CH2Cl2
(3 × 30 mL). The combined organic layer was washed with brine (40
mL), dried over Na2SO4, and concentrated in vacuo. The residue was
purified by flash chromatography on a silica gel column (petroleum
ether/EtOAc, 6:1) to afford 17 (150 mg, 85%) as a yellowish,
1
amorphous solid: H NMR (400 MHz, CDCl3) δ 11.87 (1H, s), 7.64
(1H, J = 7.9 Hz, d), 7.56−7.28 (10H, m), 6.95 (1H, J = 7.9 Hz, d),
6.48−6.44 (2H, m), 5.36 (2H, s), 5.10 (2H, s), 3.48 (1H, s), 3.37 (3H,
d), 3.10 (2H, J = 7.5 Hz, t), 1.81 (2H, m), 1.44−1.20 (12H, m), 0.88
(3H, J = 6.2 Hz, t); 13C NMR (100 MHz, CDCl3) δ 175.4, 166.5,
164.7, 164.5, 161.1, 157.1, 147.9, 145.9, 143.7, 136.2, 136.0, 135.8,
128.8, 128.8, 128.5, 128.4, 127.7, 127.5, 127.0, 125.8, 115.7, 110.8,
108.3, 104.6, 98.9, 93.1, 71.2, 70.6, 51.8, 32.0, 29.6, 29.4, 29.4, 29.4,
28.3, 27.9, 22.8, 14.2; ESIMS m/z 691 [M + H]+; HRESIMS m/z
691.2922 [M + H]+ (calcd for C42H43O9, 691.2902).
1
mp 127−128 °C; H NMR (300 MHz, CDCl3) δ 7.57−7.15 (16H,
m), 6.83 (1H, J = 8.4 Hz, d), 6.49 (1H, J = 2.1 Hz, d), 6.40 (1H, s),
6.25 (1H, J = 2.1 Hz, d), 5.30 (2H, s), 4.91 (2H, s), 4.86 (2H, s),
3.11−2.92 (2H, m), 1.78 (2H, m), 1.46−1.15 (12H, m), 0.85 (3H, J =
6.7 Hz, t); 13C NMR (75 MHz, CDCl3) δ 178.4, 166.6, 166.1, 163.8,
163.1, 159.8, 159.5, 146.2, 143.6, 136.5, 136.3, 135.8, 128.9, 128.6,
128.6, 128.4, 128.3, 127.7, 127.6, 126.5, 125.6, 118.6, 110.9, 110.2,
109.4, 108.4, 98.2, 94.0, 71.2, 70.4, 70.3, 32.0, 29.6, 29.6, 29.5, 29.5,
28.4, 28.0, 22.8, 14.3; ESIMS m/z 751 [M + H]+; HRESIMS m/z
751.3270 [M + H]+ (calcd for C48H47O8, 751.3265).
2,3,4,6-Tetra-O-acetyl-α-bromo-D-galactopyranose (18). A
solution of HBr in HOAc (33% w/w, 9.1 mL, 40.98 mmol, 8 equiv)
was added dropwise over 10 min to a solution of penta-O-acetyl-β-D-
galactopyranose20a (2.0 g, 5.1 mmol, 1 equiv) in CH2Cl2 (4 mL) at 0
°C. The resulting mixture was warmed to room temperature and kept
stirring for 4 h before being diluted with CH2Cl2 (13 mL) and washed
with saturated aqueous NaHCO3 solution (2 × 30 mL) and water (20
mL). The combined organic layer was dried over Na2SO4 and
concentrated to give 18 (2.0 g, 96%) as a white, foamy solid. The
product was pure enough to proceed with the next step without
Methyl 7-(Benzyloxy)-4-[5,7-bis(benzyloxy)-4-oxo-4H-chro-
men-2-yl]-2-nonylbenzofuran-3-carboxylate (15). To a solution
of 14 (1.6 g, 2.1 mmol, 1 equiv) and K2CO3 (435 mg, 3.15 mmol, 1.5
equiv) in DMF (10 mL) was added MeI (0.2 mL, 3.15 mmol, 1.5
equiv) dropwise. After stirring at 18 °C for 1.5 h, the mixture was
poured into water (30 mL) and extracted with CH2Cl2 (3 × 30 mL).
The combined organic layer was evaporated to provide 15 (1.6 g,
further purification. Mp 84−85 °C, lit.20b mp 84−87 °C (dec); H
1
1
NMR (300 MHz, CDCl3) δ 6.68 (1H, J = 3.9 Hz, d), 5.50 (1H, J = 2.2
Hz, d), 5.39 (1H, J = 10.6, 3.3 Hz, dd), 5.03 (1H, J = 10.6, 3.9 Hz, dd),
4.47 (1H, J = 6.6 Hz, t), 4.13 (2H, J = 11.4, 6.6 Hz, qd), 2.14 (3H, s),
2.10 (3H, s), 2.05 (3H, s), 2.00 (3H, s); 13C NMR (75 MHz, CDCl3)
δ 170.4, 170.1, 170.0, 169.8, 88.2, 71.1, 68.1, 67.8, 67.1, 60.9, 20.8,
20.8, 20.7, 20.6.
99%) as a white, amorphous powder: H NMR (300 MHz, CDCl3) δ
7.70−7.27 (16H, m), 6.90 (1H, J = 8.4 Hz, d), 6.51 (1H, J = 2.1 Hz,
d), 6.49 (2H, J = 2.1 Hz, d), 5.36 (2H, s), 5.24 (2H, s), 5.07 (2H, s),
3.33 (3H, s), 3.16−2.99 (2H, m), 1.82 (2H, m), 1.50−1.17 (12H, m),
0.98−0.75 (3H, m); 13C NMR (75 MHz, CDCl3) δ 177.6, 166.4,
164.8, 163.0, 163.0, 159.9, 159.9, 146.1, 143.6, 136.5, 136.2, 135.7,
128.9, 128.8, 128.7, 128.6, 128.5, 127.9, 127.8, 127.5, 126.7, 126.4,
125.3, 118.8, 111.0, 110.6, 109.8, 108.4, 98.6, 94.1, 71.2, 70.8, 70.7,
52.0, 32.0, 29.6, 29.4, 29.4, 29.4, 28.2, 27.8, 22.8, 14.2; ESIMS m/z 765
[M + H]+; HRESIMS m/z 765.3447 [M + H]+ (calcd for C49H49O8,
765.3422).
(2R,3S,4S,5R,6S)-2-(Acetoxymethyl)-6-{[7-(benzyloxy)-2-(7-
(benzyloxy)-3-(methoxycarbonyl)-2-nonylbenzofuran-4-yl)-5-
hydroxy-4-oxo-4H-chromen-3-yl]oxy}tetrahydro-2H-pyran-
3,4,5-triyl Triacetate (19). A magnetically stirred mixture of 17 (80
mg, 0.116 mmol, 1 equiv) in anhydrous DMF (5 mL) was treated with
18 (70 mg, 0.174 mmol, 1.5 equiv) and K2CO3 (71.8 mg, 0.5 mmol,
4.3 equiv). The mixture was stirred under an Ar atmosphere for 12 h at
18 °C before being quenched with water. The resulting mixture was
extracted with EtOAc (3 × 20 mL). The organic layer was washed with
brine (20 mL), dried over Na2SO4, filtered, and concentrated to give
compound 19 (117 mg, 99%) as a yellow, amorphous powder, which
was pure enough to proceed to the next step. [α]2D7 = −20.5 (c 0.5,
MeOH); 1H NMR (300 MHz, CDCl3) δ 12.59 (1H, s), 7.59 (1H, J =
8.5 Hz, d), 7.55−7.32 (10H, m), 6.90 (1H, J = 8.5 Hz, d), 6.43 (1H, J
= 2.2 Hz, d), 6.37 (1H, J = 2.2 Hz, d), 5.37 (2H, s), 5.32 (1H, J = 7.9
Hz, d), 5.28 (1H, J = 3.4 Hz, d), 5.18 (1H, J = 10.3, 7.9 Hz, dd), 5.08
(2H, s), 4.98 (1H, J = 10.3, 3.4 Hz, dd), 3.84−3.69 (3H, m), 3.38 (3H,
s), 3.16−3.06 (2H, m), 2.06 (3H, s), 2.04 (3H, s), 1.95 (3H, s), 1.92
(3H, s), 1.80 (2H, m), 1.46−1.18 (12H, m), 0.87 (3H, J = 6.2 Hz, t);
13C NMR (75 MHz, CDCl3) δ 177.9, 170.3, 170.3, 170.2, 169.7, 166.9,
164.6, 164.2, 162.2, 159.2, 156.9, 146.0, 143.4, 136.2, 135.8, 134.6,
128.9, 128.8, 128.5, 128.5, 128.1, 127.7, 127.6, 126.3, 115.8, 110.3,
107.8, 106.3, 100.5, 99.0, 93.1, 71.3, 71.0, 70.8, 70.6, 69.0, 66.9, 60.8,
51.8, 32.0, 29.6, 29.6, 29.4, 29.4, 28.3, 28.2, 22.8, 21.0, 20.8, 20.7, 20.7,
14.3; ESIMS m/z 1021 [M + H]+; HRESIMS m/z 1021.3851 [M +
H]+ (calcd for C56H61O18, 1021.3852).
Methyl-4-{5,7-dihydroxy-4-oxo-3-[(2S,3R,4S,5R,6R)-3,4,5-tri-
hydroxy-6-hydroxymethyltetrahydro-2H-pyran-2-yl-oxy]-4H-
chromen-2-yl}-7-hydroxy-2-nonylbenzofuran-3-carboxylate
(20). Step i: A magnetically stirred mixture of 19 (50 mg, 0.049 mmol,
1 equiv) in THF/MeOH (1:1, v/v 4 mL) was treated with K2CO3 (35
mg, 0.25 mmol, 5 equiv). The mixture was stirred for 1.5 h at 18 °C
and neutralized using a cation exchange resin, filtered, and
concentrated in vacuo. Step ii: A magnetically stirred mixture of
crude product obtained by step i in THF/MeOH (1:1, v/v 4 mL) was
Methyl 7-(Benzyloxy)-4-[5,7-bis(benzyloxy)-3-hydroxy-4-
oxo-4H-chromen-2-yl]-2-nonylbenzofuran-3-carboxylate (16).
A magnetically stirred mixture of 15 (1.6 g, 2.05 mmol) in CH2Cl2/
acetone (4:3, v/v 70 mL) was treated with a carbonate buffer (90 mL,
see below), and the biphasic mixture was stirred vigorously at 18 °C.
Oxone solution (5.5 g in 60 mL of water) was added dropwise over 40
min while the pH of the solution was maintained alkaline (∼pH 9).
After stirring for 16 h, a further portion of Oxone solution was added,
and the mixture was stirred for another 16 h before the organic layer
was separated. The aqueous phase was extracted with CH2Cl2 (2 × 50
mL). The combined organic layers were washed with saturated sodium
thiosulfate (150 mL) and brine (150 mL), dried over Na2SO4, and
filtered. p-Toluenesulfonic acid (5 mg) was added to the filtrate, and
the mixture was stirred at room temperature for 1 h and filtered to
remove the solids. The filtrate was concentrated in vacuo to provide
the crude product, which was purified by flash chromatography on a
silica gel column (petroleum ether/EtOAc, 6:1) to provide the
1
hydroxyflavone 16 (993 mg, 62%) as a yellow, amorphous solid: H
NMR (300 MHz, CDCl3) δ 7.73−7.29 (16H, m), 6.95 (2H, J = 8.5
Hz, d), 6.53 (1H, s), 6.51 (1H, s), 5.37 (2H, s), 5.25 (2H, s), 5.08
(2H, s), 3.34 (3H, s), 3.09 (2H, J = 7.6 Hz, t), 1.82 (2H, m),1.44−1.18
(12H, m), 0.87 (3H, J = 6.5 Hz, t); 13C NMR (75 MHz, CDCl3) δ
171.9, 166.1, 164.8, 163.3, 159.6, 159.1, 145.5, 144.0, 143.8, 137.9,
136.4, 136.3, 135.7, 128.9, 128.8, 128.8, 128.6, 128.4, 128.0, 127.9,
127.5, 126.8, 125.6, 116.2, 111.0, 108.5, 107.3, 97.9, 93.9, 71.3, 70.9,
70.8, 51.8, 32.0, 29.6, 29.4, 29.4, 28.3, 27.9, 22.8, 14.2; ESIMS m/z 781
[M + H]+; HRESIMS m/z 781.3379 [M + H]+ (calcd for C49H49O9,
781.3371). Buffer: NaHCO3 (7.6 g) and Na2CO3 (16 g) in water (400
mL).
E
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Article
treated with Pd(OH)2 (3 mg). The mixture was stirred under a
hydrogen atmosphere for 12 h at 18 °C before being filtered through a
pad of Celite and concentrated in vacuo to give 20 (32 mg, 98%) as a
yellowish, amorphous powder: [α]2D7 = −17.3 (c 0.5, MeOH); 1H
NMR (300 MHz, DMSO-d6) δ 12.64 (1H, s), 7.90 (1H, J = 8.3 Hz,
d), 6.81 (1H, J = 8.4 Hz, d), 6.20 (1H, J = 1.9 Hz, d), 6.13 (1H, J = 1.9
Hz, d), 5.31 (1H, J = 7.1 Hz, d), 5.11 (1H, s), 4.51 (2H, s), 3.66 (1H,
s), 3.48 (3H, J = 3.6 Hz, d), 3.43−3.30 (5H, m), 3.26 (3H, s), 3.01
(2H, J = 7.4 Hz, t), 1.72 (2H,m), 1.25 (12H, J = 16.6 Hz, d), 0.83 (3H,
J = 6.6 Hz, t); 13C NMR (75 MHz, DMSO-d6) δ 177.9, 165.0, 164.6,
163.7, 161.3, 158.0, 156.4, 145.1, 142.2, 133.5, 128.9, 125.5, 112.9,
110.3, 110.0, 104.0, 101.7, 98.9, 93.3, 75.7, 73.0, 71.0, 67.8, 60.2, 51.6,
31.3, 28.9, 28.7, 28.6, 28.5, 27.5, 27.0, 22.1, 14.0; ESIMS m/z 695 [M
+ Na]+; HRESIMS m/z 673.2497 [M + H]+ (calcd for C34H41O14,
673.2491).
4-{5,7-Dihydroxy-4-oxo-3-[(2S,3R,4S,5R,6R)-3,4,5-trihy-
droxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl-oxy]-4H-
chromen-2-yl}-7-hydroxy-2-nonylbenzofuran-3-carbaldehyde
(1). A magnetically stirred mixture of 20 (15 mg, 0.022 mmol) in
CH2Cl2 (3 mL) at −78 °C was treated with DIBAL-H (33 μL, 0.033
mmol, 1.0 M in toluene, 1.5 equiv). The mixture was stirred at the
same temperature for 2 h before being quenched by a solution of
aqueous sodium potassium tartrate (5 mL, 10% w/v) and warmed to
room temperature. After being stirred vigorously for 12 h, the mixture
was diluted with CH2Cl2 (5 mL) and washed with brine (5 mL). The
organic layer was concentrated in vacuo and purified by HPLC using a
C18 column (t = 13.8 min, 75% MeCN/H2O) (8 mL/min) to give
houttuynoid A (1) as a yellowish, amorphous powder (7.6 mg),
recovering 20 (3 mg), and the yield based on recovered starting
materials = 66%. [α]D27 = −24.7 (c 0.5, MeOH); lit.:6 [α]2D5 = −1.1 (c
0.5, MeOH); 1H NMR (400 MHz, DMSO-d6) see Table 1; 13C NMR
(100 MHz, DMSO-d6) see Table 1; ESIMS 643.3 [M + H]+;
HRESIMS m/z 643.2396 [M + H]+ (calcd for C33H39O13, 643.2385).
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.7b00791.
1H and 13C NMR spectra of all new compounds (PDF)
́ ̀
(11) Romanov-Michailidis, F.; Viton, F.; Fumeaux, R.; Leveques, A.;
AUTHOR INFORMATION
Actis-Goretta, L.; Rein, M.; Williamson, G.; Barron, D. Org. Lett. 2012,
14, 3902−3905.
■
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204−213.
*Tel: + 86 20 85220747. E-mail: tghao@jnu.edu.cn (H. Gao).
*Tel: + 86 20 85221367. Fax: + 86 20 85221367. E-mail:
tsunph@jnu.edu.cn (P. Sun).
ORCID
Manmei Li: 0000-0003-2423-3119
Hao Gao: 0000-0003-1178-0121
Pinghua Sun: 0000-0001-8963-6731
Author Contributions
⊥J. Jian and J. Fan contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by grants from the
National Natural Science Foundation of China (Nos. 81373285
and 81422054), the Guangdong Province Universities and
Colleges Pearl River Scholar Funded Scheme (H.G., 2014), the
Guangdong Special Support Program (2016TX03R280), and
K. C. Wong Education Foundation (H.G., 2016).
F
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