Synthesis of natural homoisoflavonoids having either 5,7-dihydroxy-6-methoxy or 7-hydroxy-5,6-dimethoxy groups

Article abstract of DOI:10.3390/molecules21081058

Naturally occurring homoisoflavonoids containing either 5,7-dihydroxy-6-methoxy or 7-hydroxy-5,6-dimethoxy groups such as the antiangiogenic homoisoflavanone, cremastranone, were synthesized via three or four linear steps from the known 4-chromenone. This facile synthesis includes chemoselective 1,4-reduction of 4-chromenone and selective deprotection of 3-benzylidene-4-chromanone a containing C7-benzyloxy group.

Full text of DOI:10.3390/molecules21081058

molecules
Article
Synthesis of Natural Homoisoflavonoids Having
Either 5,7-Dihydroxy-6-methoxy or
7-Hydroxy-5,6-dimethoxy Groups
Hyungjun Lee 1, Yue Yuan 1, Inmoo Rhee 2, Timothy W. Corson 3 and Seung-Yong Seo 1,
*
1
College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University,
Incheon 21936, Korea; a13079@naver.com (H.L.); wonwol@gmail.com (Y.Y.)
2
Department of Bioscience and Biotechnology, Sejong University, Seoul 05006, Korea; nature@sejong.ac.kr
Departments of Ophthalmology, Eugene and Marilyn Glick Eye Institute,
Biochemistry and Molecular Biology, and Pharmacology and Toxicology,
Indiana University School of Medicine, Indianapolis, IN 46202, USA; tcorson@iu.edu
Correspondence: syseo@gachon.ac.kr; Tel.: +82-32-820-4949
3
*
Academic Editor: Derek J. McPhee
Received: 14 July 2016; Accepted: 9 August 2016; Published: 13 August 2016
Abstract: Naturally occurring homoisoflavonoids containing either 5,7-dihydroxy-6-methoxy or
7-hydroxy-5,6-dimethoxy groups such as the antiangiogenic homoisoflavanone, cremastranone,
were synthesized via three or four linear steps from the known 4-chromenone. This facile
synthesis includes chemoselective 1,4-reduction of 4-chromenone and selective deprotection of
3-benzylidene-4-chromanone a containing C7-benzyloxy group.
Keywords: homoisoflavanone; cremastranone; 4-chromanone; 4-chromenone 1,4-reduction
1. Introduction
Recently, the antiangiogenic homoisoflavonoid cremastranone (
armeniacum, Chionodoxa luciliae, Scilla natalensis, Merwilla plumbea, and Cremastra appendiculata was
synthesized for the first time by us [ ]. Its naturally occurring congeners ( 10), which contain
either 5,7-dihydroxy-6-methoxy or 7-hydroxy-5,6-dimethoxy groups, have been reported already as
shown in Figure 1 and most of them lack common names other than eucomnalin ( ; autumnalin)
and 3,9-dihydroeucomnalin ( ; 3,9-dihydroautumnalin). Two review articles deal with the natural
origins and structures of most homoisoflavonoids [ ], and thereafter various studies of the
homoisoflavonoids have been published [ 11]. Nevertheless, there have not been synthetic efforts
towards such homoisoflavonoids since the synthesis of and was reported in 1971 [12]. A chemical
synthesis of 5,6,7-trisubstituted homoisoflavonoids has the potential to provide a general and expedient
entry into a plethora of analogues potentially with interesting biological activities [13 15]. Herein we
1), isolated from the plants Muscari
1–
6
2–
9
4
7,8
9–
4
9
–
report the first synthesis of cremastranone’s derivatives in three or four steps from the known
4-chromenone, involving a chemoselective 1,4-reduction and manipulation of protecting groups.
Molecules 2016, 21, 1058; doi:10.3390/molecules21081058
www.mdpi.com/journal/molecules

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Figure 1. Naturally occurring homoisoflavonoids containing either 5,7-dihydroxy-6-methoxy (i.e., 1–5
and 8–10) or 7-hydroxy-5,6-dimethoxy (6 and 7).
2. Results and Discussion
In our initial approach to cremastranone (1), the acetophenone 11 as starting material was treated
with N,N-dimethylformamide dimethyl acetal, followed by catalytic hydrogenation to afford the
4-chromanone 13 in a good yield (Scheme 1) [14]. However, aldol condensation of 13 with isovanillin
gave the unstable benzylidene products (i.e., 14a) in a low yield; the free OH group on C7 is thought to
hamper the general aldol condensation as well as the stability of the desired products. To overcome
this drawback, the benzylation of the phenol group on C7 was adopted prior to aldol condensation.
The aldol condensation of 16 with isovanillin afforded the desired compound 15a in good yield.
Scheme 1. Our previous approach using 5,6,7-trisubstituted 3-benzyl-4-chromanone for the reported
synthesis of cremastranone (bold arrow) [14] and the alternative pathway (normal arrow).
To improve chemical yield and decrease reaction steps, we focused on the direct conversion of
either the acetophenone 11 or the chromenone 12 into the desired chromanone 16. However, it was
reported that the formation of a 4-chromanone from a 2-hydroxyacetophenone (i.e., 11) is
challenging [16]. The direct conversion of 12 to 16 was attempted under some reduction conditions
(Table 1) [17]. Even careful catalytic hydrogenation is not likely to control a partial reduction of only
the double bond. Among metal hydride reagents, the reduction using 1.5 equivalent of NaBH4 did not
proceed over 5 h, forming only a small amount of 4-chromanol 17 (<10%). Treatment with excess NaBH4
afforded only 4-chromanol 17 in 50% yield (80% based on the recovered 12). Diisobutylaluminum
hydride (DIBAL) reduction at
low yields. To our delight, the reduction by LiAlH4 underwent only 1,4-addition of hydride without
over-reduction quantitatively and had the advantage of being reproducible on a gram scale.
−
60 ◦C led to the nonselective generation of 16 (20%) and 17 (20%) in

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Table 1. Reduction conditions of 7-benzyloxy-5,6-dimethoxy-4-chromenone (12).
Yield (%) a
Entry
Condition
16
13
17
b
1
2
2
3
4
H2, Pd/C, MeOH, rt
NaBH4 (1.5 eq), EtOH, rt
NaBH4 (2.5~5.0 eq), EtOH, rt
99
-
-
-
-
20
99
-
-
-
-
<10
50
20
-
◦
DIBAL c (1.0 eq), THF:toluene (1:1),
−
60 C
◦
LiAlH4 (2.0 eq), THF:Et2O (1:1), −60 C
Isolated yield; b not found; c diisobutylaluminum hydride.
a
With 16 in hand, we turned to the synthesis of natural 3-benzyl-4-chromanones
containing 5,7-dihydroxy-6-methoxy and 7-hydroxy-5,6-dimethoxy groups, similar to cremastranone
(Scheme 2). To accomplish this, the 4-chromanone 16 was coupled with a 3,4-disubstituted
benzaldehyde (i.e., vanillin or 3,4-dibenzyloxybenzaldehyde) or a 4-substituted benzaldehyde
(i.e., 4-methoxybenzaldehyde or 4-benzyloxybenzaldehyde) under acidic conditions to afford
3-benzylidene-4-chromanones (18a
trimethylsilyl iodide (TMSI)-promoted C5-demethylation of 15b and 15c provided the desired
and , respectively. In a similar manner, using catalytic hydrogenation 18d and 18e were transformed
to
(1H- and 13C-NMR, mass spectrometry) of synthetic
–18e). Catalytic hydrogenation of 18b and 18c, followed by
2
3
6
and
7, which were treated with TMSI to provide
4
2
and
5
[
, respectively. The spectroscopic properties
,
3,
4
2
], ], 18], and 19] were compatible
5
[
5
6
[
7 [
with those of all the natural products (see Supplementary Materials).
Scheme 2. Synthesis of natural products, 5,6,7-trisubstituted 3-benzyl-4-chromanones.
On the other hand, for the synthesis of three 3-benzylidene-4-chromanones (
5,7-dihydroxy-6-methoxy group, the C7-benzyl group of the synthesized benzylidene intermediates
18c 18e) should be removed while keeping the C3–C9 double bond intact. With 18e in hand, we
8–10) containing a
(
–
next attempted the debenzylation on C7 as shown in Table 2. Whereas the general condition of
catalytic hydrogenation under H2 and Pd/C afforded the saturated 3-benzyl-4-chromanone such as the

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synthesis of 7, a small amount (3 mol %) of Pd/C catalyst and a short reaction time (5 min) led to the
desired product 19 in moderate yield. TMSI and HBr selectively provided 19, which was demethylated
only on the C5 position. But no product formation was observed with the treatment of TiCl and lithium
naphthalenide. Unfortunately, the two and three benzyl groups of 18c and 18d, respectively, could not
be cleaved simultaneously before the saturation of the C3–C9 double bond, using various conditions
of catalytic hydrogenation.
Table 2. C7-debenzylation conditions of 5,6,7-trisubstituted 3-benzylidene-4-chromanone (18e).
Yield (%) a
Entry
Condition
19
20
1
2
3
4
5
a
H2, Pd/C (3 mol %), MeOH, rt
TMSI b, CH2Cl2, rt
65
-
-
60
60
◦
HBr (47%), 50 C
TiCl4 (1 eq), CH2Cl2, 0 C
Li, naphthalene, THF, −25 C
-
◦
NR c
NR
◦
Isolated yield; b trimethylsilyl iodide; c no reaction.
Finally, the debenzylated compound 19 was treated with TMSI to provide the desired
yield as shown in Scheme 3. The spectroscopic properties (1H- and 13C-NMR, mass spectrometry)
of synthetic were compatible with those of the natural product 20]. Having failed to access
8 in good
8
8
[
9
and 10 via the debenzylation strategy, further studies on other protecting groups on C7 such as PMB
(4-methoxybenzyl), MOM (methoxymethyl) and Ms (methanesulfonyl) instead of benzyl ether are
under investigation.
Scheme 3. Synthesis of natural 3-benzylidene-4-chromanone 8.
3. Materials and Methods
3.1. General Information
All starting materials and reagents were obtained from commercial suppliers and were used
without further purification. Air- and moisture-sensitive reactions were performed under an argon
atmosphere. Flash column chromatography was performed using silica gel 60 (230–400 mesh,
Merck KGaA, Darmstadt, Germany) with the indicated solvents. Thin-layer chromatography was
performed using 0.25 mm silica gel plates (Merck KGaA). 1H- and 13C-NMR spectra were recorded on a
Bruker 600 MHz spectrometer as solutions in deuteriochloroform (CDCl3) or methanol-d4 (Cambridge
Isotope Laboratory, Andover, MA, USA). 1H-NMR data were reported in the order of chemical shift,
multiplicity (s, singlet; d, doublet; t, triplet; m, multiplet; and/or multiple resonances), number of

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protons, and coupling constant (J) in hertz (Hz). High-resolution mass spectra (HRMS) were recorded
on a JEOL JMS-700 (EI) (JEOL Ltd., Tokyo, Japan) and an Agilent 6530 Q-TOF LC/MS/MS system
(ESI) (Agilent Technologies, Inc., Santa Clara, CA, USA).
3.2. Synthesis
7-(Benzyloxy)-5,6-dimethoxychroman-4-one (16). To a solution of the acetophenone (11) (100 mg,
0.33 mmol) in toluene (2.0 mL) was added N,N-dimethylformamide dimethyl acetal (52 µL, 0.39 mmol).
◦
◦
After stirring for 18 h at 80 C, the mixture was cooled to 0 C and c-HCl (0.2 mL) was added.
After stirring for 1 h at 50 ◦C. The reaction mixture was diluted with ethyl acetate and the organic
phase was washed with water and brine, and dried over anhydrous MgSO4. The solvent was
removed under reduced pressure and purified by flash column chromatography on silica gel
(
ethyl acetate:n-hexane = 1:2) to afford 7-(benzyloxy)-5,6-dimethoxy-4H-chromen-4-one (12) (101 mg,
1
97%). H-NMR (CDCl3, 600 MHz)
δ 7.63 (d, 1H, J = 6.0 Hz), 7.46–7.40 (m, 4H), 7.37 (t, 1H, J = 6.6 Hz),
6.71 (s, 1H), 6.17 (d, 1H, J = 6.0 Hz), 5.20 (s, 2H), 3.97 (s, 3H), 3.92 (s, 3H); 13C-NMR (150 MHz,
CDCl3) 176.2, 156.8, 154.6, 152.9, 140.7, 135.5, 128.8, 128.4, 127.2, 114.2, 113.8, 97.6, 70.9, 62.1, 61.5,
30.9. To a stirred solution of 4-chromenone (12) (10 mg, 0.03 mmol) in dry THF and Et2O (1:1) at
60 ◦C a solution of LiAlH4 in dry THF was added under N2 atmosphere. After stirring for 5 min,
δ
−
the reaction mixture was diluted with ethyl acetate and the organic phase was washed with water
and brine, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and
purified by flash column chromatography on silica gel (ethyl acetate:n-hexane = 1:2) to afford the
1
7-(benzyloxy)-5,6-dimethoxychroman-4-one (16) (10 mg, 99%). H-NMR (CDCl3, 600 MHz)
δ 7.43–7.37
(m, 4H), 7.35–7.33 (m, 1H), 6.29 (s, 1H), 5.13 (s, 1H), 4.42 (t, 2H, J = 6.0 Hz), 3.92 (s, 3H), 3.82 (s, 3H), 2.71
(t, 2H, J = 6.0 Hz); 13C-NMR (150 MHz, CDCl3)
δ 189.1, 159.8, 158.4, 154.4, 137.7, 135.8, 128.7, 128.2,
127.2, 109.8, 97.4, 70.6, 66.8, 61.6, 61.3, 38.7.
(E)-7-(Benzyloxy)-3-(3-hydroxy-4-methoxybenzylidene)-5,6-dimethoxychroman-4-one (18a). To a solution
of the 4-chromanone (16) (80 mg, 0.26 mmol) in benzene (5 mL) was added 3-hydroxy-4-
◦
methoxybenzaldehyde (58 mg, 0.38 mmol) and p-toluenesulfonic acid (7 mg, 0.03 mmol) at 0 C.
The reaction mixture was refluxed for 12 h. After cooling to room temperature, the reaction mixture
was concentrated under reduced pressure. The residue was purified by flash column chromatography
on silica gel (ethyl acetate:n-hexane = 1:2) to afford the resulting 3-benzylidene-4-chromanone (18a
)
1
(60 mg, 53%). H-NMR (600 MHz, CDCl3)
δ 7.73 (s, 1H), 7.42–7.38 (m, 4H), 7.35–7.33 (m, 1H), 6.90
(d, 1H, J = 8.4 Hz), 6.86–6.83 (m, 2H), 6.30 (s, 1H), 5.22 (d, 2H, J = 1.8 Hz), 5.13 (s, 2H), 3.99 (s, 3H), 3.94
(s, 3H), 3.85 (s, 3H); 13C-NMR (150 MHz, CDCl3)
179.6, 159.2, 158.2, 154.9, 147.6, 145.5, 138.1, 136.3,
δ
135.8, 130.1, 128.7, 128.2, 128.0, 127.2, 123.2, 115.8, 110.8, 110.6, 97.5, 70.6, 67.6, 61.7, 61.3, 56.0; HRMS
(EI): mass calculated for C26H24O7 [M+], 448.1522; found, 448.1521.
(E)-7-(Benzyloxy)-3-(4-hydroxy-3-methoxybenzylidene)-5,6-dimethoxychroman-4-one (18b). To a solution
of the 4-chromanone (16) (80 mg, 0.26 mmol) in benzene (5 mL) was added 4-hydroxy-3-
◦
methoxybenzaldehyde (58 mg, 0.38 mmol) and p-toluenesulfonic acid (7 mg, 0.03 mmol) at 0 C.
The reaction mixture was refluxed for 12 h. After cooling to room temperature, the reaction mixture
was concentrated under reduced pressure. The residue was purified by flash column chromatography
on silica gel (ethyl acetate:n-hexane = 1:2) to afford the resulting 3-benzylidene-4-chromanone (18b
)
1
(65 mg, 57%). H-NMR (600 MHz, CDCl3)
δ 7.76 (s, 1H), 7.43–7.38 (m, 4H), 7.35–7.32 (m, 1H), 6.97
(d, 1H, J = 8.4 Hz), 6.82 (d, 1H, J = 1.8 Hz), 6.79 (dd, 1H, J = 7.8 and 1.8 Hz), 6.30 (s, 1H), 5.22 (d, 2H,
J = 1.2 Hz), 5.13 (s, 2H), 3.99 (s, 3H), 3.91 (s, 3H), 3.85 (s, 3H); 13C-NMR (150 MHz, CDCl3)
δ
179.5, 159.1,
158.2, 154.9, 146.9, 146.5, 138.1, 136.5, 135.8, 129.8, 128.7, 128.2, 127.2, 127.1, 123.7, 114.6, 112.7, 110.8, 97.5,
70.6, 67.6, 61.7, 61.3, 56.0; HRMS (EI): mass calculated for C26H24O7 [M+], 448.1522; found, 448.1521.
(E)-7-(Benzyloxy)-3-(3,4-bis(benzyloxy)benzylidene)-5,6-dimethoxychroman-4-one (18c). To a solution of the
4-chromanone (16) (80 mg, 0.25 mmol) in benzene (5 mL) was added 3,4-bis(benzyloxy)benzaldehyde
◦
(120 mg, 0.38 mmol) and p-toluenesulfonic acid (7 mg, 0.03 mmol) at 0 C. The reaction mixture

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was refluxed for 12 h. After cooling to room temperature, the reaction mixture was concentrated
under reduced pressure. The residue was purified by flash column chromatography on silica gel
(ethyl acetate:n-hexane = 1:2) to afford the resulting 3-benzylidene-4-chromanone (18c) (55 mg, 36%).
1H-NMR (600 MHz, CDCl3)
δ
7.68 (s, 1H), 7.46–7.31 (m, 15H), 6.96 (d, 2H, J = 9.0 Hz), 6.82 (dd, 2H,
J = 4.8 and 3.0 Hz), 6.29 (s, 1H), 5.22 (s, 2H), 5.19 (s, 2H), 5.13 (s, 2H), 5.04 (d, 2H, J = 1.8 Hz), 3.98 (s, 3H),
3.85 (s, 3H); 13C-NMR (150 MHz, CDCl3)
179.5, 159.1, 158.2, 154.9, 150.0, 148.4, 138.1, 136.8, 136.7,
δ
136.1, 135.8, 130.1, 128.7, 128.6, 128.6, 128.4, 128.2, 128.0, 127.9, 127.5, 127.2, 127.2, 124.1, 116.9, 114.2,
110.8, 97.5, 71.4, 71.0, 70.6, 67.5, 61.7, 61.3; HRMS (EI): mass calculated for C39H34O7 [M+], 614.2305;
found, 614.2308.
(E)-7-(Benzyloxy)-3-(4-(benzyloxy)benzylidene)-5,6-dimethoxychroman-4-one (18d). To a solution of the
4-chromanone (16) (121 mg, 0.39 mmol) in benzene (5 mL) was added 4-(benzyloxy)benzaldehyde
◦
(122 mg, 0.58 mmol) and p-toluenesulfonic acid (7 mg, 0.03 mmol) at 0 C. The reaction mixture
was refluxed for 12 h. After cooling to room temperature, the reaction mixture was concentrated
under reduced pressure. The residue was purified by flash column chromatography on silica gel
(ethyl acetate:n-hexane = 1:2) to afford the resulting 3-benzylidene-4-chromanone (18d) (104 mg, 54%).
1H-NMR (600 MHz, CDCl3)
δ
7.78 (s, 1H), 7.44–7.38 (m, 8H), 7.35–7.33 (m, 2H), 7.24 (d, 2H, J = 9.0 Hz),
7.24 (dd, 2H, J = 6.6 and 1.8 Hz), 6.30 (s, 1H), 5.21 (d, 2H, J = 1.8 Hz), 5.13 (s, 2H), 5.11 (s, 2H), 4.00
(s, 3H), 3.85 (s, 3H); 13C-NMR (150 MHz, CDCl3)
179.6, 159.6, 159.1, 158.2, 154.9, 138.1, 136.4, 136.1,
δ
135.8, 131.7, 129.8, 128.7, 128.7, 128.2, 128.1, 127.5, 127.4, 127.2, 115.0, 110.8, 97.5, 70.6, 70.1, 67.6, 61.7,
61.3; HRMS (EI): mass calculated for C32H28O6 [M+], 508.1886; found, 508.1885.
(E)-7-(Benzyloxy)-5,6-dimethoxy-3-(4-methoxybenzylidene)chroman-4-one (18e). To a solution of the
4-chromanone (16) (82 mg, 0.26 mmol) in benzene (5 mL) wa◦s added 4-methoxybenzaldehyde (50
µL,
0.39 mmol) and p-toluenesulfonic acid (7 mg, 0.03 mmol) at 0 C. The reaction mixture was refluxed for
12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica gel (ethyl acetate:n-hexane = 1:2)
1
to afford the resulting 3-benzylidene-4-chromanone (18e) (78 mg, 75%). H-NMR (600 MHz, CDCl3)
δ
7.78 (s, 1H), 7.44–7.38 (m, 8H), 7.35–7.33 (m, 2H), 7.24 (d, 2H, J = 9.0 Hz), 7.24 (dd, 2H, J = 6.6 and
1.8 Hz), 6.30 (s, 1H), 5.21 (d, 2H, J = 1.8 Hz), 5.13 (s, 2H), 5.11 (s, 2H), 4.00 (s, 3H), 3.85 (s, 3H); 13C-NMR
(150 MHz, CDCl3) 179.6, 159.6, 159.1, 158.2, 154.9, 138.1, 136.4, 136.1, 135.8, 131.7, 129.8, 128.7, 128.7,
δ
128.2, 128.1, 127.5, 127.4, 127.2, 115.0, 110.8, 97.5, 70.6, 70.1, 67.6, 61.7, 61.3; HRMS (EI): mass calculated
for C26H24O6 [M+], 432.1573; found, 432.1573.
7-Hydroxy-3-(3-hydroxy-4-methoxybenzyl)-5,6-dimethoxychroman-4-one
(15a). A solution of the
3-benzylidene-4-chromanone (18a) (35 mg, 0.07 mmol) and 10% Pd/C (10 mg) in MeOH was placed
under an atmosphere of hydrogen. After stirring for 1 h, the reaction mixture was diluted with ethyl
acetate, filtered through a Celite pad, and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (ethyl acetate:n-hexane = 1:1) to afford the
1
3-benzyl-4-chromanone (15a) (22 mg, 87%). H-NMR (600 MHz, CD3OD)
δ
6.82 (d, 1H, J = 14.4 Hz),
6.67 (d, 1H, J = 1.8 Hz), 6.63 (dd, 1H, J = 8.4 and 2.4 Hz), 6.16 (s, 1H), 4.21 (dd, 1H, J = 11.4 and 4.2 Hz),
4.04 (dd, 1H, J = 11.4 and 7.2 Hz), 3.82 (s, 3H), 3.79 (s, 3H), 3.75 (s, 3H), 3.00 (dd, 1H, J = 13.2 and
4.2 Hz), 2.66–2.60 (m, 1H), 2.58 (dd, 1H, J = 13.8 and 10.8 Hz); 13C-NMR (150 MHz, CD3OD)
δ 192.4,
160.0, 158.5, 154.4, 146.3, 146.2, 136.4, 131.2, 119.9, 115.6, 111.5, 107.3, 99.1, 68.6, 60.4, 60.1, 55.0, 48.2,
32.0; HRMS (ESI): mass calcd for C19H20O7 [M + H+], 361.1281; found 361.1270.
7-Hydroxy-3-(4-hydroxy-3-methoxybenzyl)-5,6-dimethoxychroman-4-one
(15b). A solution of the
3-benzylidene-4-chromanone (18b) (21 mg, 0.05 mmol) and 10% Pd/C (5 mg) in MeOH was placed
under an atmosphere of hydrogen. After stirring for 1 h, the reaction mixture was diluted with ethyl
acetate, filtered through a Celite pad and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (ethyl acetate:n-hexane = 1:1) to afford the
1
3-benzyl-4-chromanone (15b) (15 mg, 73%). H-NMR (600 MHz, CDCl3)
δ 6.84 (d, 1H, J = 8.4 Hz),

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6.73–6.69 (m, 2H), 6.31 (s, 1H), 4.26 (dd, 1H, J = 11.4 and 4.2 Hz), 4.10 (dd, 1H, J = 11.4 and 7.2 Hz), 3.91
(s, 3H), 3.91 (s, 3H), 3.87 (s, 3H), 3.16 (dd, 1H, J = 13.8 and 4.2 Hz), 2.73 (m, 1H), 2.65–2.61 (m, 1H);
13C-NMR (150 MHz, CDCl3)
δ 191.6, 159.8, 155.5, 153.5, 146.5, 144.2, 135.2, 130.2, 121.9, 114.3, 111.4,
108.7, 98.8, 68.8, 61.5, 61.4, 55.9, 48.6, 32.6; HRMS (EI): mass calculated for C19H20O7 [M+], 360.1209;
found, 360.1208.
3-(3,4-Dihydroxybenzyl)-7-hydroxy-5,6-dimethoxychroman-4-one (15c). A solution of the 3-benzylidene-4-
chromanone (18c) (20 mg, 33 µmol) and 10% Pd/C (3.5 mg) in MeOH was placed under an atmosphere
of hydrogen. After stirring for 1 h, the reaction mixture was diluted with ethyl acetate, filtered through
a Celite pad and concentrated under reduced pressure. The residue was purified by flash column
chromatography on silica gel (ethyl acetate:n-hexane = 1:1) to afford the 3-benzyl-4-chromanone (15c
)
(11 mg, 99%). 1H-NMR (600 MHz, CDCl3)
δ
6.79 (d, 1H, J = 8.4 Hz), 6.77 (d, 1H, J = 2.4 Hz), 6.63
(dd, 1H, J = 8.4 and 1.8 Hz), 6.30 (s, 1H), 4.26 (dd, 1H, J = 11.4 and 4.2 Hz), 4.09 (dd, 1H, J = 8.4 and
4.2 Hz), 3.90 (s, 3H), 3.89 (s, 3H), 3.08 (dd, 1H, J = 13.8 and 4.2 Hz), 2.70–2.67 (m, 1H), 2.62 (dd, 1H,
J = 13.8 and 10.8 Hz); 13C-NMR (150 MHz, CDCl3)
δ 192.2, 159.9, 155.9, 153.5, 143.8, 142.5, 135.2, 131.0,
121.6, 116.0, 115.3, 108.5, 98.9, 68.8, 61.5, 61.4, 48.5, 32.4; HRMS (EI): mass calculated for C18H18O7 [M+],
346.1053; found, 346.1056.
7-Hydroxy-3-(4-hydroxybenzyl)-5,6-dimethoxychroman-4-one (6). A solution of the 3-benzylidene-4-
chromanone (18d) (23 mg, 0.05 mmol) and 10% Pd/C (5 mg) in MeOH was placed under an atmosphere
of hydrogen. After stirring for 1 h, the reaction mixture was diluted with ethyl acetate, filtered through
a Celite pad and concentrated under reduced pressure. The residue was purified by flash column
chromatography on silica gel (ethyl acetate:n-hexane = 1:1) to afford the 3-benzyl-4-chromanone (
6
)
1
(14 mg, 94%). H-NMR (600 MHz, CDCl3)
δ
7.09 (d, 2H, J = 8.4 Hz), 6.78 (d, 2H, J = 8.4 Hz), 6.30 (s, 1H),
4.62 (dd, 1H, J = 11.4 and 4.2 Hz), 4.08 (dd, 1H, J = 11.4 and 7.2 Hz), 3.91 (s, 3H), 3.90 (s, 3H), 3.15
(dd, 1H, J = 13.8 and 4.2 Hz), 2.73–2.69 (m, 1H), 2.66 (dd, 1H, J = 13.8 and 10.2 Hz); 13C-NMR (150 MHz,
CDCl3)
δ 191.7, 159.8, 155.6, 154.3, 153.5, 135.2, 130.3, 130.3, 115.4, 108.6, 98.8, 68.8, 61.5, 61.4, 48.5, 32.0;
HRMS (EI): mass calculated for C18H18O6 [M+], 330.1103; found, 330.1102.
7-Hydroxy-5,6-dimethoxy-3-(4-methoxybenzyl)chroman-4-one ( ). A solution of the 3-benzylidene-4-
7
chromanone (18e) (23 mg, 0.05 mmol) and 10% Pd/C (5 mg) in MeOH was placed under an atmosphere
of hydrogen. After stirring for 1 h, the reaction mixture was diluted with ethyl acetate, filtered through
a Celite pad and concentrated under reduced pressure. The residue was purified by flash column
chromatography on silica gel (ethyl acetate:n-hexane = 1:2) to afford the 3-benzyl-4-chromanone (
7
)
1
(13 mg, 80%). H-NMR (600 MHz, CD3COCD3)
δ
7.07–7.05 (m, 2H), 6.76–6.73 (m, 2H), 6.09 (dd, 1H,
J = 4.8 and 3.0 Hz), 4.14 (d, 1H, J = 4.2 Hz), 3.94 (d, 1H, J = 8.4 Hz), 3.71 (s, 3H), 3.71–3.62 (m, 6H),
3.00–3.98 (m, 1H), 2.62–2.61 (m, 1H), 2.53–2.49 (m, 1H); 13C-NMR (150 MHz, CDCl3)
190.0, 159.6,
δ
158.5, 157.1, 154.7, 136.3, 160.8, 130.8, 130.1, 113.9, 108.5, 99.1, 69.1, 60.8, 60.6, 54.6, 48.3, 31.5; HRMS
(EI): mass calculated for C19H20O6 [M+], 344.1260; found, 344.1257.
7-Hydroxy-3-(3-hydroxy-4-methoxybenzyl)-5,6-dimethoxychroman-4-one (2). To a solution of the
7-hydroxy-5,6-dimethoxy-4-c◦hromanone (15b) (10 mg, 0.03 mmol) in CH2Cl2 (5 mL) was added
TMSI (5 µL, 0.09 mmol) at 0 C for 1 h. The mixture was concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (ethyl acetate:n-hexane = 1:2) to afford the
1
5,7-dihydroxy-6-methoxy-4-chromanone (
2
) (7.1 mg, 71%). H-NMR (600 MHz, CD3OD)
δ
6.81 (d, 1H,
J = 1.8 Hz), 6.73 (d, 1H, J = 7.8 Hz), 6.67 (dd, 1H, J = 8.4 and 1.8 Hz), 5.90 (s, 1H), 4.25 (dd, 1H, J = 11.4
and 4.2 Hz), 4.09 (dd, 1H, J = 11.4 and 7.2 Hz), 3.83 (s, 3H), 3.77 (s, 3H), 3.12 (dd, 1H, J = 13.8 and
4.8 Hz), 2.86–2.81 (m, 1H), 2.68 (d, 1H, J = 10.2 Hz); 13C-NMR (150 MHz, CD3OD)
δ 199.3, 160.1, 159.3,
156.0, 148.2, 145.5, 130.0, 129.6, 121.9, 115.4, 112.8, 102.1, 95.0, 69.5, 60.1, 55.5, 47.3, 32.7; HRMS (EI):
mass calculated for C18H18O7 [M+], 346.1053; found, 346.1054.
3-(3,4-Dihydroxybenzyl)-5,7-dihydroxy-6-methoxychroman-4-one
(3
). To
a
solution of the
7-hydroxy-5,6-dimethoxy-4-chromanone (15c) (20 mg, 0.03 mmol) in CH2Cl2 (5 mL) was added

Molecules 2016, 21, 1058
8 of 10
◦
TMSI (5 µL, 0.09 mmol) at 0 C for 1 h. The mixture was concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (ethyl acetate:n-hexane = 1:2) to afford the
1
5,7-dihydroxy-6-methoxy-4-chromanone (
3
) (12 mg, 99%). H-NMR (600 MHz, CD3OD)
δ
6.71 (d, 1H,
J = 8.4 Hz), 6.67 (d, 1H, J = 2.4 Hz), 6.55 (dd, 1H, J = 7.8 and 1.8 Hz), 5.91 (s, 1H), 4.24 (dd, 1H, J = 11.4
and 4.2 Hz), 4.08 (dd, 1H, J = 11.4 and 7.2 Hz), 3.77 (s, 3H), 3.05 (dd, 1H, J = 13.8 and 4.2 Hz), 2.80–2.75
(m, 1H), 2.60 (dd, 1H, J = 13.8 and 10.2 Hz); 13C-NMR (150 MHz, CD3OD)
δ 200.0, 160.5, 159.9, 156.7,
146.2, 144.9, 130.6, 130.2, 121.2, 116.9, 116.2, 102.8, 95.5, 70.0, 60.7, 47.9, 33.0; HRMS (EI): mass calculated
for C17H16O7 [M+], 332.0896; found, 332.0898.
5,7-Dihydroxy-3-(4-hydroxybenzyl)-6-methoxychroman-4-one (
4). To a solution of the 7-hydroxy-5,6-
dimethoxy-4-chr◦omanone (
6
) (10 mg, 0.03 mmol) in CH2Cl2 (5 mL) was added TMSI (5 L,
µ
0.09 mmol) at 0 C for 1 h. The mixture was concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (ethyl acetate:n-hexane = 1:2) to afford the resulting
1
5,7-dihydroxy-6-methoxy-4-chromanone (
4
) (9.8 mg, 86%). H-NMR (600 MHz, CD3OD)
δ
7.06 (d, 2H,
J = 8.4 Hz), 6.73 (d, 2H, J = 8.4 Hz), 5.90 (s, 1H), 4.23 (dd, 1H, J = 11.4 and 4.2 Hz), 4.07 (dd, 1H, J = 10.8
and 7.2 Hz), 3.77 (s, 3H), 3.10 (dd, 1H, J = 13.8 and 4.8 Hz), 2.82–2.77 (m, 1H), 2.67 (dd, 1H, J = 13.8 and
10.2 Hz); 13C-NMR (150 MHz, CD3OD)
δ
199.8, 160.4, 159.7, 156.8, 156.5, 130.7, 130.0, 129.7, 116.0, 102.5,
95.4, 69.8, 60.5, 47.8, 32.6; HRMS (EI): mass calculated for C17H16O6 [M+], 316.0947; found, 316.0945.
5,7-Dihydroxy-6-methoxy-3-(4-methoxybenzyl)chroman-4-one ( ). To a solution of the 7-hydroxy-5,6-
5
dimethoxy-4-chromanone (
0.18 mmol) at 0 C for 1 h. The mixture was concentrated in vacuo. The residue was purified
7
) (19 mg, 0.06 mmol) in CH2Cl2 (5 mL) was added TMSI (10 L,
µ
◦
by flash column chromatography on silica gel (ethyl acetate:n-hexane = 1:2) to afford the resulting
1
5,7-dihydroxy-6-methoxy-4-chromanone (
5
) (15 mg, 80%). H-NMR (600 MHz, CD3OD)
δ
7.15 (d, 2H,
J = 8.4 Hz), 6.86 (d, 2H, J = 8.4 Hz), 5.90 (s, 1H), 4.23 (dd, 1H, J = 11.4 and 4.2 Hz), 4.06 (dd, 1H, J = 11.4
and 7.8 Hz), 3.77 (s, 3H), 3.76 (s, 3H), 3.13 (dd, 1H, J = 13.8 and 4.8 Hz), 2.84–2.79 (m, 1H), 2.70 (dd, 1H,
J = 13.8 and 10.2 Hz); 13C-NMR (150 MHz, CD3OD)
δ 200.1, 160.7, 160.1, 160.0, 156.9, 131.4, 131.2, 130.4,
115.1, 103.0, 95.8, 70.3, 61.0, 55.7, 48.1, 32.9; HRMS (EI): mass calculated for C18H18O6 [M+], 330.1103;
found, 330.1102.
(E)-7-Hydroxy-5,6-dimethoxy-3-(4-methoxybenzylidene)chroman-4-one
(
19).
A
solution of the
3-(4-methoxybenzylidene)-4-chromanone (18e) (37 mg, 0.09 mmol) and 3% Pd/C (4.8 mg) in
MeOH was placed under an atmosphere of hydrogen. After stirring for 5 min, the reaction mixture
was diluted with ethyl acetate, filtered through a Celite pad and concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica gel (ethyl acetate:n-hexane = 1:3)
to afford the debenzylated 3-(4-methoxybenzylidene)-4-chromanone (19) (11 mg, 35%). 1H-NMR
(600 MHz, CDCl3)
δ
7.78 (s, 1H), 7.26 (d, 2H, J = 7.8 Hz), 6.96 (d, 2H, J = 9.0 Hz), 6.31 (s, 1H), 5.22
179.7, 160.4,
(d, 2H, J = 1.8 Hz), 3.97 (s, 3H), 3.94 (s, 3H), 3.85 (s, 3H); 13C-NMR (100 MHz, CDCl3)
δ
159.4, 155.3, 153.8, 136.2, 135.4, 131.7, 129.6, 127.1, 114.1, 110.4, 98.9, 67.4, 61.5, 61.4, 55.3; HRMS (EI):
mass calculated for C19H18O6 [M+], 342.1103; found, 342.1106.
(E)-5,7-Dihydroxy-6-methoxy-3-(4-methoxybenzylidene)chroman-4-one
3-(4-methoxybenzylidene)-4-chromanone (19) (15 mg, 0.04 mmol) in CH2Cl2 (5 mL) was added TMSI
(13
L, 0.09 mmol) at 0 ◦C for 1 h. The mixture was concentrated in vacuo. The residue was purified
by flash column chromatography on silica gel (ethyl acetate:n-hexane = 1:3) to afford the resulting
5,7-dihydroxy-6-methoxy-4-chromanone ( 7.80 (s,
) (9.1 mg, 63%). 1H-NMR (600 MHz, CDCl3)
1H), 7.27 (d, 2H, J = 7.2 Hz), 6.97 (d, 2H, J = 8.4 Hz), 6.03 (s, 1H), 5.28 (d, 2H, J = 1.8 Hz), 3.95 (s, 3H),
(8). To a solution of the
µ
8
δ
3.86 (s, 3H); 13C-NMR (100 MHz, CDCl3)
δ 185.9, 160.8, 157.8, 157.2, 155.2, 137.2, 132.0, 128.4, 127.3,
126.7, 114.2, 103.3, 94.0, 67.4, 60.9, 55.4; HRMS (EI): mass calculated for C18H16O6 [M+], 328.0947;
found, 328.0945.

Molecules 2016, 21, 1058
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4. Conclusions
In summary, we have successfully demonstrated the first total synthesis of naturally occurring
homoisoflavonoids containing either a 7-hydroxy-5,6-dimethoxy or 5,7-dihydroxy-6-methoxy group
on the A ring in four or five steps from the commercially available 11. The key features of this
synthetic route involve the following: (1) LiAlH4-mediated selective 1,4-reduction of 4-chromenone;
(2) the aldol condensation of arylaldehydes, followed by catalytic hydrogenation; (3) TMSI-mediated
C5-demethylation; (4) the selective debenzylation of 3-benzylidene-4-chromanone. These studies
provide a timely contribution to the development of a practical synthetic approach to a variety of
homoisoflavonoid analogues. Extension of this approach in the synthesis of various natural products
and analogues and establishment of structure-activity relationship (SAR) profiles for 5,6,7-trisubstituted
homoisoflavonoids compared to antiangiogenic cremastranone are currently underway.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/
21/8/1058/s1.
Acknowledgments: This work was supported by grants from the Basic Science Research Program through the
National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2013R1A1A2007151) and
the Korea Health Technology R & D Project through the Korea Health Industry Development Institute (KHIDI),
funded by the Ministry of Health & Welfare (HI14C1135) to S.-Y.S.; grants from the Bright Focus Foundation,
and NIH/NEI R01EY025641 to T.W.C., and an unrestricted grant from Research to Prevent Blindness, Inc.
Author Contributions: H.L. and Y.Y. performed the experiments and analyzed all data. I.R. and T.W.C. conceived
and suggested the research work. S.-Y.S. conceived and directed the investigations and composed the manuscript
with revisions provided by the other authors. All authors read and approved the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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©
2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC-BY) license (http://creativecommons.org/licenses/by/4.0/).