Bioactive Phytochemicals: Efficient Synthesis of Optically Active Substituted Flav-3-enes and Flav-3-en-3-o-R Derivatives

Article abstract of DOI:10.1155/2017/3971253

The structural core of flavene (2-phenyl-2H-chromene) is commonly found in plant flavonoids, which exhibit a wide range of biological activities and diverse pharmacological profiles (e.g., antioxidant and anticancer activities). Flavonoids have attracted significant interest in medicinal and synthetic chemistry. Substituted flav-3-ene 13 was exclusively synthesized by the stereoselective elimination of the O-mesyl moiety on C-3 of 5,7,3′,4′-tetramethoxyflavan-3-mesylate 12 with 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction of 5,7,3′,4′-tetramethoxyflavan-3-one 15 with ytterbium trifluoromethanesulfonate in methanol afforded a novel 3-O-substituted flav-3-ene derivative (3,5,7,3′,4′-pentamethoxyflav-3-ene) 17. The reduction of 4-(1,3,5-trihydroxybenzene)-5,7,3′,4′-tetra-O-benzylflavan-3-one 19b with hydrogen afforded a new compound: 3-hydroxy-4-(1,3,5-trihydroxybenzene)-5,7,3′,4′-tetrahydroxyflavan-3-en-3-ol 21 in good yield (95%), while the acetylation of 19a and 21 afforded the expected novel flav-3-en-3-acetoxy derivatives 20 (92%) and 22 (90%), respectively.

Full text of DOI:10.1155/2017/3971253

Hindawi
Journal of Chemistry
Volume 2017, Article ID 3971253, 11 pages
https://doi.org/10.1155/2017/3971253
Research Article
Bioactive Phytochemicals: Efficient Synthesis of Optically Active
Substituted Flav-3-enes and Flav-3-en-3-o-R Derivatives
Matthew Chilaka Achilonu,1 Moosa Mahmood Sedibe,2 and Karabo Shale1
1Faculty of Natural Sciences, Mangosuthu University of Technology, Umlazi, Durban, KwaZulu-Natal, South Africa
2Department of Agriculture, Faculty of Health and Environmental Sciences, Central University of Technology,
Free State, 1 Park Road, Bloemfontein 9301, South Africa
Correspondence should be addressed to Matthew Chilaka Achilonu; achilonu.matthew@mut.ac.za
Received 21 December 2016; Accepted 7 March 2017; Published 18 May 2017
Academic Editor: Bin Yu
Copyright © 2017 Matthew Chilaka Achilonu et al. is is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
e structural core of flavene (2-phenyl-2H-chromene) is commonly found in plant flavonoids, which exhibit a wide range of
biological activities and diverse pharmacological profiles (e.g., antioxidant and anticancer activities). Flavonoids have attracted
significant interest in medicinal and synthetic chemistry. Substituted flav-3-ene 13 was exclusively synthesized by the stereoselective
elimination of the O-mesyl moiety on C-3 of 5,7,3ꢀ,4ꢀ-tetramethoxyflavan-3-mesylate 12 with 1,8-diazabicyclo[5.4.0]undec-7-ene.
e reaction of 5,7,3ꢀ,4ꢀ-tetramethoxyflavan-3-one 15 with ytterbium trifluoromethanesulfonate in methanol afforded a novel 3-O-
substituted flav-3-ene derivative (3,5,7,3ꢀ,4ꢀ-pentamethoxyflav-3-ene) 17. e reduction of 4-(1,3,5-trihydroxybenzene)-5,7,3ꢀ,4ꢀ-
tetra-O-benzylflavan-3-one 19b with hydrogen afforded a new compound: 3-hydroxy-4-(1,3,5-trihydroxybenzene)-5,7,3ꢀ,4ꢀ-
tetrahydroxyflavan-3-en-3-ol 21 in good yield (95%), while the acetylation of 19a and 21 afforded the expected novel flav-3-en-
3-acetoxy derivatives 20 (92%) and 22 (90%), respectively.
1. Introduction
with cis-chalcone 6 (Scheme 1). Jurd [13] has reported that
the decolourisation of flavylium salts is caused by electron
deficiency; hence, flavylium salts are readily attacked by
exposure to water and other nucleophiles.
e structural core of flavene (e.g., flav-3-ene (1)) is composed
of 2-phenyl-2H-chromene, which is commonly categorized
as a subfamily of natural flavonoids; flavonoids exhibit a wide
range of biological activities [1–9]. Flavenes (e.g., 1 and flav-
2-ene 2) are colourless compounds, which produce different-
coloured anthocyanidins (flavylium salts) under different
pH. Anthocyanidins are red in an acidic solution, violet in
a neutral solution, and blue in an alkaline solution [10].
Flavylium salts bearing free phenolic hydroxyl groups are
extremely unstable and short-lived compounds [10, 11], while
the substituted salts are stable that served as one of the few
early sources of flavenes [10]. Some flavylium salts bearing
an OR group at position 3 afford 1, while flavylium salts with
no substituent at position 3 afforded 2 [12]. ese salts also
exhibit resonating carbonium-ion structures of types 3 and 4,
and by hydrolysis, these salts afford colourless pseudobases
of hydroxyflavene-type 5 and 7. e unstable chromenol
moiety of 5 is expected to stabilize itself by equilibration
Because of the medicinal importance of the core struc-
tural unit of flavenes, there has been significant interest in
the development of methods for scaffold construction [3–9].
However, previous studies have revealed that the synthesis
of a functionalized flavene skeleton is a challenging task [5];
hence, few methods have reported the efficient stereoselective
synthesis of flavenes [14–21]. Clark-Lewis and Jemison [14]
have reported the first synthesis of racemic 1 based on
chalcone starting materials. Zaveri [15], Pelter and Stainton
[16], Nay et al. [17], and Deodhar et al. [18] have inde-
pendently utilized similar cyclization routes to synthesize
1. e reactions involve the reduction of the C-4 carbonyl
group to a 4-hydroxyl group, followed by the elimination
of water to yield racemic 1. Casiraghi and Casnati [19]
have used cinnamaldehyde and alkyl phenoxymagnesium
bromides as the starting material to obtain racemic 1. When

2
Journal of Chemistry
H
O
C
O
OH
O
2
1
6
OH
O
O
O
O
+
+
Hydrolysis
Hydrolysis
OH
7
3
4
5
Scheme 1: Resonating flavylium salt and flavene structural core.
1 is heated under reflux in benzene in the presence of the
corresponding phenoxymagnesium bromide, it isomerizes to
2. Cardillo et al. [20] have reported a biogenetic-like synthesis
of racemic 1 from o-cinnamylphenols via the dehydrogena-
tion of DDQ, while Subramanian and Balasubramanian [21]
have synthesized racemic 1 from 1-arylprop-2-ynyl aryl ether
in good yield by a facile Claisen rearrangement. Studies
available on flavene synthesis have revealed that known
reaction protocols afford racemic flavene products. Syntheses
occurred via a cyclizable moiety, for example, chalcones and
o-cinnamylphenol, or via the reduction of the C-4 carbonyl
group and subsequent elimination of water, or the reduction
of flavylium salts. To the best of our knowledge, no study
has reported the elimination of the C-3 moiety flavan-3-ol
to form 1. With this background, the substitution of the C-
3-OH of (2R,3S) 5,7,3ꢀ,4ꢀ-tetramethoxyflavan-3-ol (catechin)
8 and (2R,3R) 5,7,3ꢀ,4ꢀ-tetramethoxyflavan-3-ol (epicatechin)
9 with a good leaving group, such as a tosyl or mesyl group,
has been hypothesized to synthesize a range of flavonoids and
optically active substituted flav-3-enes. In addition, the use
of substituted flavan-3-one for synthesizing substituted flav-
3-en-3-o-R substituted derivatives was considered. In this
study, 5,7,3ꢀ,4ꢀ-tetramethoxyflav-3-ene 13 was synthesized
in a facile, efficient manner by E2 elimination using a
nonnucleophilic strong Lewis base, as well as 3-substituted
flav-3-ene derivatives using a strong Lewis acid.
moisture-sensitive reactions were performed under inert gas.
Flash column chromatography and preparative liquid chro-
matography (PLC) were performed using Merck Kieselgel
60 (0.063–0.20 mm) silica gel with the indicated solvent or
solvent mixture. Reaction progress was monitored with a
Merck Kieselgel 60 PF thin layer chromatography (TLC)
254
sheet (aluminium back). A 2% v/v solution of formaldehyde
(40%) in concentrated H SO was used as the spray reagent.
2
4
2.2. Methods
2.2.1. Characterization Techniques. Fourier transform infrared
(FTIR) spectra were recorded on a Perkin-Elmer Spectrum
One FTIR spectrometer by utilizing the KBr pellet technique.
NMR spectra were recorded on a Bruker Avance spectrom-
eter (600 MHz) in CDCl (ꢀ 7. 24; ꢀ 77.2), methanol-ꢁ4 (ꢀ
3
4.87 and 3.31; ꢀ 49.2), or DMSO-ꢁ6 (ꢀ 2.50; ꢀ 39.5). Chemical
shifs were reported as parts per million (ppm) relative to
trimethylsilane (TMS) as the internal standard. Coupling
constants (ꢂ) were measured in hertz. High-resolution elec-
tron ionization mass spectrometry (HREIMS) measurements
were performed on a Micromass Q-TOF-2 spectrometer. Cir-
cular dichroism (CD) spectra were recorded on a Chirascan
CD spectrometer.
2.2.2. Standard Reaction Methods
Purification of Catechin (Flavan-3-ol). Crude catechin was
recrystallized by dissolving in boiling water, followed by the
filtration of the hot solution. e filtrate was allowed to
stand overnight for crystallization, and the solid was filtered
and dried in a fume hood. e characterization data of the
2. Experimental
2.1. Materials. Reagents and solvents, except THF, dichloro-
methane, and acetone, obtained from Merck, Fluka, and
Sigma-Aldrich (Bloemfontein, South Africa), were used with-
out further purification. THF was refluxed and distilled over
sodium under inert gas with benzophenone as the indicator.
Acetone was obtained by predrying commercial acetone with
anhydrous K CO for 24 h at room temperature. K CO was
catechin agreed with catechin hydrate ([ꢃꢄ]/ + 26
2)
purchased from Sigma-Aldrich.
Acetylation of Samples. Acetylation was carried out by dis-
solving the dried phenolic material in a minimum volume of
pyridine and acetic anhydride (twice the volume of pyridine
used). Afer approximately 8–24 h at ambient temperature,
the reaction was terminated by adding ice chips. Excess
pyridine was removed from the precipitate by repetitive
washing with cold water.
2
3
2
3
˚
filtered, and the solvent was distilled over 3 A molecular sieves
and stored under N . Dichloromethane was refluxed over
2
CaH under nitrogen for 12 h, followed by fresh distillation
2
under nitrogen before use. Solid starting materials were dried
in a vacuum oven at 60∘C over P O for 2–12 h. Air- and
2
5

Journal of Chemistry
3
OMe
OMe
5
2
OMe
OMe
O
4
MeO
6
3
(i), (ii), and (iii)
MeO
O
OTs
3
OMe
6
=
=
OH
5
OMe
=
11
=
= 8
(i
v)
=
= 9
OMe
OMe
MeO
O
OMs
12
OMe
Scheme 2: Mesylation and tosylation of flavan-3-ol. Reagents and conditions: (i) imidazole, THF, 1-toluenesulfonyl chloride, ice bath, (ii) step
(i), methyl triflate, ice bath; (iii) 8 or 9, THF, N-methylimidazole, step (ii), rt, 24 h, 82%; (iv) 8, MsCl, DMAP, THF, Et3N, rt to −5∘C, 99%.
Workup. Unless specified and appropriate for reaction
workup, water was added to the reaction mixture, and the
aqueous phase was extracted with diethyl ether or ethyl
acetate. e organic extract was washed with water and dried
with Na SO or MgSO , followed by the removal of solvent
of a THF (8 mL) solution of p-toluenesulfonyl chloride
(5 g, 26.2 mmol) over 10 min. Afer 1 h, the mixture was
filtered and washed with THF, and the solvent was concen-
trated under reduced pressure to afford 1-(p-toluenesulfonyl)
imidazole as white needle-like crystals. e crystals were
washed with hexane and used in the next reaction step
without further purification or characterization. e second
step involves the preparation of the sulfonating agent. First,
methyl triflate (180 mg, 1.10 mmol) was added dropwise to
a 10 mL THF solution of 1-(p-toluenesulfonyl) imidazole
(266 mg, 1.20 mmol), which was cooled to −5∘C under nitro-
gen. Second, the reaction mixture was stirred at −5∘C for
another hour to obtain the “sulfonating agent” for the third
step of tosylation. For tosylation, methylated catechin 8 or
methylated epicatechin 9 (346 mg, 1.0 mmol) was dissolved
in dry THF (10 mL) under nitrogen, and N-methylimidazole
(82 mg, 0.8 mL, 1.00 mmol) was added. e mixture was
added to the off-white sulfonating reagent. Afer another
10 min, the cooling system was removed, and the reaction
continued at room temperature for 24 h. e mixture was
chromatographed on silica gel with 1 : 1 toluene–ethyl acetate
as the solvent mixture for development, affording 10 or 11 as
a white amorphous solid in 82% yield (Scheme 2). Physical
data were in agreement with those reported previously [24].
2
4
4
under reduced pressure at approximately 40∘C. Products
were purified by TLC or flash column chromatography. Com-
pounds 8, 9, and 5,7,3ꢀ,4ꢀ-tetra-methoxyflavan-3-one 15 were
prepared according to previously reported procedures [22].
2.3. Synthesis of Flav-3-enes and Derivatives
Synthesis of 5,7,3ꢀ,4ꢀ-Tetramethoxyflavan-3-ols (8, 9). First,
K CO (38 g, 276 mmol, dried at 240∘C overnight) was added
2
3
3 2
to an anhydrous acetone solution of predried commer-
cial catechin or epicatechin (10 g, 35 mmol) under nitrogen
and stirred vigorously. Second, afer 1 h, dimethyl sulfate
((CH ) SO , 87 mg, 276 mmol) was slowly added over 30 min
4
and refluxed for 2 h. ird, at ambient temperature, K CO
2
3
was filtered, and acetone was removed under reduced pres-
sure, followed by the neutralization of the excess (CH ) SO
3 2
4
with cold ammonia (80 mL, 25% NH /H O, v/v). Next,
3
2
the crude product was extracted with ethyl acetate (2 ×
100 mL), washed with water (2 × 70 mL) and brine (70 mL),
and dried over MgSO , followed by solvent removal under
4
Synthesis of 5,7,3ꢀ,4ꢀ-Tetramethoxyflavan-3-mesylate (12).
First, a mixture of oven-dried 8 (346 mg, 1.0 mmol) and
4-dimethylaminopyridine (DMAP) (12.2 mg, 0.1 mmol) was
dissolved in dry THF (5 mL) under nitrogen. Triethylamine
(0.28 mL, 2.0 mmol) was added to a stirred solution and
cooled to approximately −5∘C in a salt-ice bath for 10 min
before methanesulfonyl chloride (172 mg, 0.28 mL, 1.5 mmol)
diluted with dry THF (0.5 mL) was added dropwise. Afer
30 min, the reaction mixture was diluted with 10 mL ethyl
acetate, washed with water (2 × 5 mL) and 5 mL brine, and
reduced pressure. Finally, 8 or 9 was obtained as an off-
white, amorphous solid (99%). e characterization of the
compound was in agreement with reported data [22, 23].
Synthesis of 5,7,3ꢀ,4ꢀ-Tetramethoxyflavan-3-tosylates (10, 11).
e target product C-3-tosylated catechin 10 or C-3 tosylated
epicatechin 11 is prepared in three steps. e first step involves
the synthesis of 1-(p-toluenesulfonyl) imidazole: An anhy-
drous THF solution (10 mL) of imidazole (3.6 g, 52.9 mmol)
was stirred under nitrogen, followed by the dropwise addition

4
Journal of Chemistry
dried over anhydrous sodium sulfate. Ethyl acetate was
removed under reduced pressure, and the crude product
was purified with silica gel PLC (toluene–acetone = 9 : 1,
(d, ꢂ = 2.3 Hz, 1H, H-8), 6.15 (d, ꢂ = 2.3 Hz, 1H, H-6), 5.40
(d, ꢂ = 3.9 Hz, 1H, H-3), 3.95–3.79 (4s, 12H, 4 × OCH ), 3.3
3
(d, ꢂ = 3.9 Hz, 2H, H-4). 13C NMR (150 MHz, CDCl ) ꢀ/ppm:
3
v/v), affording the title compound 12 (99% yield) as white
159.5 (C-5), 158.1 (C-7), 152.8 (C-10), 149.1 (C-2), 148.6 (C-3ꢀ),
148.1 (C-4ꢀ), 127.6 (C-1ꢀ), 117.2 (C-6ꢀ), 110.7 (C-5ꢀ), 107.7 (C-
2ꢀ), 101.2 (C-9), 95.7 (C-3), 93.3 (C-6), 93.0 (C-8), 55.5–55.9
1
needle-like crystals. H NMR (600 MHz, CDCl ) ꢀ/ppm:
3
6.91 (dd, ꢂ = 1.7, 8.2 Hz, 1H, H-6ꢀ), 6.90 (d, ꢂ = 1.7 Hz, 1H,
H-2ꢀ), 6.80 (dd, ꢂ = 1.7, 8.2 Hz, 1H, H-5ꢀ), 6.08 (d, ꢂ = 2.0 Hz,
1H, H-8), 6.04 (d, ꢂ = 2.0 Hz, 1H, H-6), 4.94 (m, 1H, H-3),
(4C, 4 × OCH ), 19.5 (C-4); HREIMS: ꢇ]/ 328 (M+, 100), 165
3
(65). Anal. calcd. for C H O : % C, 69.50; H, 6.14; O, 24.36;
19 20
5
found: % C, 69.52; H, 6.11.
4.90 (d, ꢂ = 7.7 Hz, 1H, H-2), 3.09 (ddd, ꢂ = 1.7, 5.3, 16.5 Hz,
1H, H-4ꢃ), 2.85 (dd, ꢂ = 7.4, 16.5 Hz, 1H, H-4ꢅ), 2.43 (s,
3H, OSO CH ). 13C NMR (150 MHz, CDCl ) ꢀ/ppm: 160.2
Synthesis of 5,7,3ꢀ,4ꢀ-Tetramethoxyflavan-3-one (15). First, the
Dess–Martin periodinane (DMP) (7.5 mL, 0.3 M solution of
DMP in CH Cl ) was added to a CH Cl (5 mL) solution of
2
3
3
(C-5), 158.6 (C-7), 154.7 (C-10), 149.6 (C-4ꢀ), 149.4 (C-3ꢀ),
129.8 (C-9), 119.8 (C-6ꢀ), 111.3 (C-2ꢀ), 110.0 (C-5ꢀ), 100.1 (C-1),
93.2 (C-8), 92.2 (C-6), 78.3 (C-2), 77.5 (C-3), 55.4–56.1 (4C, 4
× OCH ), 38.1 (C, OSO CH ), 26.5 (C-4); CD ꢆ nm: 212.00
2
2
2
2
8 (560 mg, 1.6 mmol) under nitrogen. Second, afer stirring
for 5 min, CH Cl (20 mL) moistened with 0.2 mL water
2
2
3
2
3
(2.200 × 104), 227.00 (−9.810 × 104), and 234.00 (1.190 ×
103). HREIMS: ꢇ]/ 424 (M+, 30), 328 (100). Anal. calcd. for
C H O S: % C, 56.59; H, 5.70; O, 30.15; S, 7.55; found: % C,
was added dropwise over 45 min, resulting in a cloudy
reaction mixture. e mixture was extracted with ether (2 ×
30 mL) and washed with a mixture of 10% sodium thiosulfate
(Na S O ) and saturated NaHCO (2 × 30 mL, 1 : 1, v/v),
20 24
8
2
2
3
3
56.60; H, 5.67.
which separated the layers. e water phase was extracted
with ether (20 mL), and the combined organic phases were
washed with water and brine and dried over anhydrous
sodium thiophosphate, followed by solvent removal under
Synthesis of 5,7,3ꢀ,4ꢀ-Tetramethoxyflavan-3-ene (13). First,
DBU (0.2 mL, 0.22 mmol) was added dropwise to an anhy-
drous acetonitrile solution (1.5 mL) of 12 (30 mg, 0.07 mmol)
vacuum. e crude product was filtered over SiO (4 ×
under N , and the mixture was refluxed for 24 h. Second,
2
2
4 cm glass column) with n-hexane–EtOAc = 6 : 4 and crys-
tallized from the eluent, affording white needles in 95% yield
(Scheme 4). Spectral data were in agreement with those
reported previously [20]. HREIMS: ꢇ]/ 344 (M+, 100). Anal.
calcd. for C H O : % C, 66.27; H, 5.85; O, 27.88; found: %
afer cooling to ambient temperature, the reaction solvent was
removed using a rotary evaporator. Next, the crude product
was collected using ether (10 mL), followed by washing with
water (2 × 5 mL) and brine (5 mL). Finally, the organic
phase was dried over Na SO , and the solvent was removed
19 20
6
2
4
C, 66.32; H 5.65.
under reduced pressure to obtain 13 in 99% yield as a pink
amorphous solid afer alumina PLC (toluene–EtOAc = 8 : 2).
Synthesis of 3,5,7,3ꢀ,4ꢀ-Pentamethoxyflav-3-ene (17). First,
1H NMR (600 MHz, CDCl ) ꢀ/ppm: 7.03 (d, ꢂ = 2.0 Hz, 1H,
3
H-2ꢀ), 7.01 (dd, ꢂ = 2.0, 8.1 Hz, 1H, H-6ꢀ), 6.86 (d, ꢂ = 8.1 Hz,
1H, H-5ꢀ), 6.83 (dd, ꢂ = 2.0, 10.0 Hz, 1H, H-3), 6.06 (d,
ꢂ = 2.2 Hz, 1H, H-8), 6.04 (d, ꢂ = 2.2 Hz, 1H, H-6), 5.79
(dd, ꢂ = 2.0, 3.0 Hz, 1H, H-2), 5.61 (dd, ꢂ = 3.0, 10.0 Hz, 1H,
the selected Lewis acid Yb(OTf) (200 mg, 0.32 mmol) in
3
methanol (10 mL) was added dropwise into a stirred THF
(5 mL) solution of tetramethoxy-3-oxocatechin 15 (100 mg,
0.29 mmol) at 25∘C under nitrogen. Second, the mixture was
warmed at 40∘C for approximately 6 h. Afer workup and
purification by alumina PLC (toluene–acetone = 9.9 : 0.1), two
products 17 and 18 were obtained as off-white amorphous
solids in yields of 17% and 32%, respectively. 1H NMR
H-4), 3.89–3.75 (4s, 12H, 4 × OCH ); 13C NMR (150 MHz,
3
CDCl ) ꢀ/ppm: 161.3 (C-7), 156.3 (C-5), 154.9 (C-10), 149.2
3
(C-3ꢀ), 149.1 (C-4ꢀ), 133.4 (C-1ꢀ), 119.9 (C-4), 119.8 (C-6ꢀ), 119.0
(C-3), 111.0 (C-5ꢀ), 110.6 (C-2ꢀ), 104.5 (C-9), 93.8 (C-8), 91.9
(600 MHz, CDCl ) ꢀ/ppm: 6.95 (d, ꢂ = 2.0 Hz, 1H, H-2ꢀ),
3
(C-6), 77.2 (C-2), 55.94–55.35 (4C, 4 × OCH ), CD ꢆ nm (ꢈ):
3
6.92 (dd, ꢂ = 2.0, 8.2 Hz, 1H, H-6ꢀ), 6.78 (d, ꢂ = 8.2 Hz, 1H,
H-5ꢀ), 6.07 (d, ꢂ = 2.2 Hz, 1H, H-8), 6.06 (d, ꢂ = 2.2 Hz, 1H,
H-6), 5.93 (s, 1H, H-4), 5.59 (s, 1H, H-2), 3.71–3.83 (5s, 15H,
5 × OCH ); 13C NMR (150 MHz, CDCl ) ꢀ/ppm: 159.0 (C-7),
228.50 (−2.356 × 103). HREIMS: ꢇ]/ 328 (M+, 100), 329 ((M
+ H)+, 20), 165 (65). Anal. calcd. for C H O : % C, 69.50;
19 20
5
H, 6.14; O, 24.36; found: % C, 69.52; H, 6.11.
3
3
154.9 (C-5), 151.1 (C-10), 150.9 (C-3), 149.2 (C-3ꢀ), 149.0 (C-4ꢀ),
131.4 (C-1ꢀ), 119.6 (C-6ꢀ), 111.0 (C-5ꢀ), 110.7 (C-2ꢀ), 104.7 (C-9),
Synthesis of 5,7,3ꢀ,4ꢀ-Tetramethoxyflavan Mixture (13, 14).
First, LDA (0.5 mL) was added to anhydrous THF (5 mL) at
−5∘C under inert gas. Afer 10 min, 11 (120 mg, 0.2400 mmol)
was added, the cooling system was removed, and the reaction
was gradually warmed up to ambient temperature within an
hour. Next, the reaction solvent was removed under reduced
pressure, and the crude product was purified by silica gel PLC
(CH Cl –n-hexane–EtOAc = 2 : 8 : 1, ×2) to obtain a mixture
94.1 (C-8), 92.3 (C-6), 88.1 (C-4), 77.2 (C-2), 56.1–55.3 (5C, 5 ×
OCH ); CD ꢆ nm: 216.00 (−2.566 × 104). HREIMS: ꢇ]/ 358
3
(M+, 100), 359 [M + H]+, 343 (10), 327 (12); Anal. calcd. for
C H O : % C, 67.03; H, 6.19; O, 26.79; found: % C, 67.03; H
20 22
6
6.20.
2
2
3,3,5,7,3ꢀ,4ꢀ-Hexamethoxyflavane (18). H NMR (600 MHz,
1
of flavenes 13 and 14 as an orange paste in yields of 20% and
CDCl ) ꢀ/ppm: 7.02 (d, ꢂ = 2.0 Hz, 1H, H-2ꢀ), 6.97 (dd,
24%, respectively.
3
ꢂ = 2.0 Hz, 8.4 Hz, 1H, H-6ꢀ), 6.77 (d, ꢂ = 8.4 Hz, 1H, H-5ꢀ),
5,7,3ꢀ,4ꢀ-Tetramethoxyflav-2-ene (14). H NMR (600 MHz,
1
6.21 (d, ꢂ = 2.3 Hz, 1H, H-8), 6.09 (d, ꢂ = 2.3 Hz, 1H, H-6),
CDCl ) ꢀ/ppm: 7.24 (dd, ꢂ = 2.0, 8.4 Hz, 1H, H-6ꢀ), 7.23 (d,
5.19 (d, ꢂ = 2.0 Hz, 1H, H-2), 3.85–3.32 (6s, 18H, 6 × OCH ),
3
3
ꢂ = 2.0 Hz, 1H, H-2ꢀ), 6.87 (d, ꢂ = 8.4 Hz, 1H, H-5ꢀ), 6.21
2.95 (dd, ꢂ = 2.0, 16.3 Hz, 1H, H-4ꢅ), 2.50 (d, ꢂ = 16.3 Hz, 1H,

Journal of Chemistry
5
H-4ꢃ); 13C NMR (150 MHz, CDCl ) ꢀ/ppm: 159.9 (C-5), 158.3
71.5–70.1 (4C, 4 × benzylic-CH O-), 39.3 (C-4). CD ꢆ nm
3
2
(C-7), 154.6 (C-9), 148.5 (C-4ꢀ), 148.3 (C-3ꢀ), 130.7 (C-1ꢀ), 119.7
(ꢈ): 220.00 (17.695), 243.34 (8.465). HREIMS: ꢇ]/ 772 (M+,
(C-6ꢀ), 111.2 (C-2ꢀ), 110.7 (C-5ꢀ), 101.2 (C-3), 98.2 (C-10), 93.1
25). Anal. calcd. for C H O : % C, 76.15; H, 5.22; O, 18.63;
49 40
9
(C-8), 91.6 (C-6), 76.8 (C-2), 48.6–55.8 (6C, 6 × OCH ), 25.9
found: % C, 76.11; H 5.21.
3
(C-4); CD: ꢆ nm: 216.50 (−3.312 × 102). HREIMS: ꢇ]/ 390
(M+, 100), 391 [M + H]+, 345 (8), 327 (25), 360 (22); Anal.
calcd. for C H O : % C, 64.60; H, 6.71; O 28.69; found: %
Synthesis of 4-(1,3,5-Triacetoxybenzene)-5,7,3ꢀ,4ꢀ-tetramethox-
yflav-3-en-3-acetate (20). A light orange amorphous solid
21 26
9
1
was obtained in 92% yield. H NMR (600 MHz, CDCl )
C, 64.55; H, 6.68.
3
ꢀ/ppm: 7.07 (t, ꢂ = 2.01, 2.12, 8.10 Hz, 2H, H-2ꢀ/6ꢀ), 6.92
(d, ꢂ = 2.25 Hz, 1H, H-3ꢀꢀ), 6.89 (d, ꢂ = 2.25 Hz, 1H, H-
6ꢀꢀ), 6.84 (d, ꢂ = 8.10 Hz, 1H, H-5ꢀ), 6.18 (d, ꢂ = 2.32 Hz,
1H, H-8), 6.01 (d, ꢂ = 2.32 Hz, 1H, H-6), 5.87 (s, 1H, H-2),
3.90–3.38 (4s, 12H, OCH ), 2.30–1.70 (4s, 12H, OCOCH );
Synthesis of 4-(1,3,5-Trihydroxybenzene)-5,7,3ꢀ,4ꢀ-tetrame-
thoxyflavan-3-one (19a). First, a stirred anhydrous THF
mixture of 15 (50 mg, 0.145 mmol), phloroglucinol (151 mg,
1.2 mmol), and AgBF (215 mg, 1.1 mmol) was refluxed for
4
3
3
13C NMR (150 MHz, CDCl ) ꢀ/ppm: 168.8, 168.1–167.1 (4C,
approximately 24 h under inert gas. Second, at ambient
temperature, the reaction mixture was filtered through a
wet silica gel pack using a n-hexane–ethyl acetate solvent
mixture of 5 : 5 v/v, affording the crude product. e excess
phloroglucinol was precipitated out using dichloromethane
to obtain the required product 19a in good yield (44.6 mg,
66%) as a light brown amorphous solid. IR (KBr, V/cm−1):
1724 (C=O) and 1593 (aromatic C=C stretch). 1H NMR
3
aromatic methoxy–C), 160.0–153.1 (3C, aromatic quaternary-
C), 148.5–147.5 (4C, aromatic acetoxy-C), 138.8, 127.7, 120.7,
118.9, 112.5, 112.4, 112.1, 110.9, 109.5, 103.6, 93.0, 92.2, 76.7,
54.9–54.3 (4C, OCH ) 20.1–19.1 (4C, OCOCH ); HREIMS:
3
3
ꢇ]/ 636 (M+, 100). Anal. calcd. for C H O : % C, 62.26;
33 32 13
H, 5.07; O, 32.67; found: % C, 62.25; H 5.12.
Synthesis of 4-(1,3,5-Trihydroxybenzene)-5,7,3ꢀ,4ꢀ-tetrahydrox-
yflav-3-en-3-ol (21). First, methanol (4 mL) was added to
a stirred ethyl acetate (4 mL) solution of 19b (66.9 mg,
(600 MHz, CDCl ) ꢀ/ppm: 7.11 (dd, ꢂ = 8.1, 10.0 Hz, 1H,
3
H-6ꢀ), 7.04 (d, ꢂ ꢀ= 2.0 Hz, 1H, H-2ꢀ), 6.94 (dd, ꢂ = 8.2,
10.0 Hz, 1H, H-5 ), 6.20–6.10 (m, 2H, H-3ꢀꢀ/5ꢀꢀ), 6.01 (d,
ꢂ = 2.2 Hz, 1H, H-8), 5.96 (d, ꢂ = 2.2 Hz, 1H, H-6), 5.10 (s,
0.064 mmol), followed by Pd(OH) /C (33.5 mg), and purged
2
with hydrogen for 2 min. Second, afer stirring under hydro-
gen at ambient temperature for another 1 h, the mixture was
filtered over cotton wool, and the solvent was removed under
pressure, affording title compound 21 (25 mg, 95%) as a dark
brown solid: IR (KBr, V/cm−1): 3261 (phenol OH, broad), 1603
1H, H-2), 4.58 (s, 1H, H-4), 4.02–3.3.79 (s, 12H, 4 × OCH );
3
13C NMR (150 MHz, CDCl ) ꢀ/ppm: 160.1 (C-7), 160.0
3
(C-4ꢀꢀ), 158.7 (C-2ꢀꢀ), 158.4 (C-6ꢀꢀ), 154.1 (C-10), 149.0 (C-4ꢀ),
148.8 (C-3ꢀ), 128.1 (C-1ꢀ), 118.3 (C-1ꢀꢀ), 111.3 (C-6ꢀ), 111.1
(C-5ꢀ), 109.4 (C-2ꢀ), 106.1 (C-9), 94.1 (C-8), 92.8 (C-6), 91.0
1
(2C-3ꢀꢀ/5ꢀꢀ), 82.8 (C-2), 55.2–55.9 (4 × OCH ), 38.0 (C-4);
(aromatic C=C bending). H NMR (600 MHz, MeOD-ꢁ4)
3
ꢀ/ppm: 6.82 (d, 1H, ꢂ = 2.0 Hz, H-2ꢀ), 6.73 (d, 1H, ꢂ = 8.2 Hz,
H-5ꢀ), 6.68 (dd, 1H, ꢂ = 2.0, 8.2 Hz, H-6ꢀ), 6.00 (d, 1H, ꢂ =
2.2 Hz, H-8), 5.78 (d, 1H, ꢂ = 2.2 Hz, H-6), 5.80 (s, broad,
2H, H-3ꢀꢀ/5ꢀꢀ), 4.31 (s, 1H, H-2); 13C NMR (150 MHz, MeOD-
ꢁ4) ꢀ/ppm: 157.5–155.8 (8C, aromatic–C–O), 137.8–137.2 (3C,
aromatic quaternary –C), 118.4 (C-6ꢀ), 114.7 (C-5ꢀ), 113.2 (C-
2ꢀ), 104.8 (C-3), 101.6–95.3 (2C-3ꢀꢀ/5ꢀꢀ), 95.0 (C-6), 94.2 (C-8),
78.6 (C-2), 39.3 (C-4); HREIMS: ꢇ]/ 412 (M+, 100), found
[M+ + H] 413. Anal. calcd. for C H O : % C, 61.17; H, 3.91;
CD ꢆ nm: 200.40 (−8 × 103), 237.20 (3.221 × 104). HREIMS:
ꢇ]/ 343 (100), M+ 468.4523, (M + H)+ 469 (47). Anal. calcd.
for C H O : % C, 64.10; H, 5.16; O, 30.74; found: % C,
25 24
9
64.13; H, 5.14.
Synthesis of 4-(1,3,5-Trihydroxybenzene)-5,7,3ꢀ,4ꢀ-tetra-O-ben-
zylflavan-3-one (19b). First, a mixture of 1,3,5-hydroxyben-
zene (1600 mg, 4.04 mmol), 5,7,3ꢀ,4ꢀ-tetra-O-benzylflavan-
3-one 15b (600 mg, 0.93 mmol), and AgBF (780 mg,
4
21 16
9
4.02 mmol) dried in a vacuum oven at 60∘C for approximately
2 h was dissolved in anhydrous THF (50 mL) and refluxed
under argon for 4 h. Second, the reaction mixture was
O, 34.92; found % C, 61.19; H, 3.81.
Synthesis of 4-(1,3,5-Triacetoxybenzene)-5,7,3ꢀ,4ꢀ-tetraacetox-
yflavan-3-en-3-acetate (22). A white amorphous solid was
filtered over silica gel (n-hexane–EtOAc–CHCl , 8 : 1 : 1)
3
obtained in 90% yield. 1H NMR (600 MHz, CDCl ) ꢀ/ppm:
to remove the excess phloroglucinol and silver metal. e
obtained crude product was purified by silica gel PLC
chromatography (toluene–EtOAc, 10 : 0.1) to afford 19b as a
brown amorphous solid (586 mg, 61%). IR (KBr, V/cm−1):
3032 (aromatic C–H stretch), 1591 (aromatic C=C bending),
1027 (C–O–C stretch). 1H NMR (600 MHz, DMSO-ꢁ6)
3
7. 33 (dd, ꢂ = 2.0, 8.4 Hz, 1H, H-6ꢀ), 7.21 (d, ꢂ = 2.0 Hz, 1H, H-
2ꢀ), 7.13 (d, ꢂ = 8.4 Hz, 1H, H-5ꢀ), 6.89 (d, ꢂ = 2.2 Hz, 1H, H-8),
6.87 (d, ꢂ = 2.2 Hz, 1H, H-6), 6.57 (d, ꢂ = 2.2 Hz, 2H, H-3ꢀꢀ/5ꢀꢀ),
5.91 (s, 1H, H-2), 2.22–1.61 (8s, 24H, OCOCH ); 13C NMR
3
(150 MHz, CDCl ) ꢀ/ppm: 168.9–167.9 (8C, aromatic–C–O)
3
153.3, 150.5 (C-1ꢀꢀ), 150.2 (C-10), 149.2, 149.1, 147.1 (C-1ꢀ), 143.0,
142.8, 141.9, 134.3, 127.3 (C-6ꢀ), 124.5 (C-2ꢀ), 123.4 (C-5ꢀ), 114.0
(C-6), 113.7 (C-8), 112.5 (C-3), 110.8 (C-3ꢀꢀ), 107.9 (C-5ꢀꢀ), 76.9
ꢀ/ppm: 7.40–7.09 (m, 20H, benzene-H), 6.96 (d, ꢂ = 8.3 Hz,
1H, H-5ꢀ), 6.93 (d, ꢂ = 2.0 Hz, 1H, H-2ꢀ), 6.71 (dd, ꢂ = 2.0,
8.3 Hz, 1H, H-6ꢀ), 6.27 (s, 2H, H-3ꢀꢀ/5ꢀꢀ), 6.26 (d, ꢂ = 2.3 Hz,
1H, H-8), 6.23 (d, ꢂ = 2.3 Hz, 1H, H-6), 5.33 (s, 1H, H-2),
(C-2), 31.0, 29.2, 21.1–20.0 (8C, 8 × OCOCH ); HREIMS: ꢇ]/
3
748 (M+, 100). Anal. calcd. for C H O : % C, 59.36; H, 4.31;
5.24 (s, 1H, H-4), 5.07–4.70 (m, 8H, 4 × benzylic-CH O).
2
37 32 17
13C NMR (150 MHz, DMSO-ꢁ6) ꢀ/ppm: 159.4–149.2 (8C,
aromatic–C–O), 137.8–137.2 (7C, aromatic quaternary-C),
128.8–127.6 (20C, benzene–C), 119.8 (C-6ꢀ), 115.8 (C-5ꢀ), 114.2
(C-2ꢀ), 96.7 (C-6), 95.7 (C-8), 94.4 (2C-3ꢀꢀ/5ꢀꢀ), 82.5 (C-2),
O, 36.33; found: % C, 60.5; H, 5.02.
Synthesis of 4-(1,3,5-Trihydroxybenzene)-5,7,3ꢀ,4ꢀ-tetra-O-ben-
zylflavan-3-ol (23). First, an aqueous NaOH solution

6
Journal of Chemistry
(0.15 mL, 2.0 M) was added to ethanol (3 mL), followed
possibly occurred via the pathway of an antibonding orbital,
which is “hidden” inside the heterocyclic C-ring (most
likely in a chair conformation) rather than the SN2 reaction
pathway; thus, it is not accessible to the approaching electron-
rich nucleophile [5] or by the nonnucleophilic strong base to
abstract the OH proton by E2-type elimination.
by NaBH (115.8 mg, 3.06 mmol), and carefully dissolved.
4
Second, to a stirring THF (3 mL) solution of 19b (110 mg,
0.11 mmol), methanol (5 mL) was added, followed by the
slow addition of the previously prepared NaBH solution
4
(3 mL). Afer approximately 30 min, the reaction solvent
was removed using a rotary evaporator and excess NaBH
was neutralized with water (1 mL) and 10% HCl (2 mL).
By a simple method, a mixture of 8 and a mole equivalent
of DMAP in THF under inert gas with methanesulfonyl
chloride and excess triethylamine at subzero temperatures
afforded 12 in excellent yield. Afer workup, the compound
required no further purification before use in the elimination
step. On the other hand, C-3-tosylated catechin 10 and C-3
tosylated epicatechin 11 were synthesized in three steps: (i)
synthesis of 1-(p-toluenesulfonyl)imidazole, (ii) preparation
of a sulfonating agent, and (iii) tosylation (Scheme 2).
4
e organic phase was extracted, washed with H O (×3)
2
and brine, and dried over anhydrous Na SO , followed by
2
4
solvent removal under pressure to obtain (2R,4S)-4-(1,3,5-
trihydroxybenzene)-5,7,3ꢀ,4ꢀ,-tetra-O-benzylflavan-3-ol 23
(109 mg, 99%) as a light yellow paste. IR (KBr, V/cm−1):
3031 (aromatic C–H stretch), 1603 (aromatic C=C bending),
1591 (aromatic C=C stretch), 1027 (C–O–C stretch, diaryl).
1H NMR (600 MHz, DMSO-ꢁ6) ꢀ/ppm: 7.45–7.15 (20H, m,
benzene-H), 7.06 (d, 1H, ꢂ = 1.9 Hz, H-2ꢀ), 7.01 (s br., 2H,
H-3ꢀꢀ/5ꢀꢀ), 6.98 (d, 1H, ꢂ = 8.3 Hz, H-5ꢀ), 6.87 (dd, 1H, ꢂ =
1.9, 8.3 Hz, H-6ꢀ), 6.24 (d, 1H, ꢂ = 2.3 Hz, H-8), 5.97 (d, 1H, ꢂ
e stereoselective elimination of the tosyl or the mesyl
group at the C-3 of methylated catechin in anhydrous THF
with a strong base at low temperature exclusively afforded
flav-3-ene in low yields of 5% and 15%, respectively. By reflux-
ing an anhydrous acetonitrile solution of catechin tosylate 10
or catechin mesylate 12 in the presence of DBU exclusively
afforded 13 in good yields of 82% and 99%, respectively
(Scheme 3). e reaction with 11 was repeated by substituting
acetonitrile with dry THF, followed by refluxing the mixture
for 24 h to afford 13 in a very low yield of 7.5%. is low yield is
possibly caused by a radical inhibitor present in THF, which
could retard the DBU activity. By refluxing the acetonitrile
solution of 11 in the presence of DBU, a mixture of 13 and
14 (80% combined yield) in a ratio of approximately 1 : 1 was
obtained, while the addition of 11 to an anhydrous THF
solution of lithium diisopropylamide (LDA) at approximately
−5∘C also afforded 13 and 14 (44% combined yield) as an
orange paste (Scheme 3). e product mixture of flavenes
from the elimination of 11 can be explained by the base-
catalysed trans elimination to a flav-2-ene of a hydrogen at
C-2 trans to the tosyl group at C-3. is was in contrast
to (2R,3S) tetra-O-methyl-3-O-tosyl-catechin 10, where the
hydrogen at position 2 was cis to the tosyl group at C-3,
and the only available trans hydrogen was at C-4, resulting
in the exclusive formation of flav-3-ene and the retention of
configuration at C-2. Typically, it was difficult to synthesize 2
and 1 because of their facile oxidation anthocyanidins.
= 2.3 Hz, H-6), 5.11–4.75 (8H, m, 4 × benzylic-CH O), 4.85
2
(d, ꢂ = 10.0 Hz, 1H, H-2), 4.81 (d, ꢂ = 6.5 Hz, 1H, H-4), 4.12
(dd, 1H, ꢂ = 6.2, 8.8 Hz, H-3), 3.48 (s very br., 1H, OH-3).
13C NMR (150 MHz, DMSO-ꢁ6) ꢀ/ppm: 159.0–149.1 (8C,
aromatic–C–O), 138.1–137.7 (7C, aromatic quaternary-C),
128.8–127.5 (20C, benzene–C), 121.6 (C-6ꢀ), 116.3 (C-2ꢀ), 116.0
(C-5ꢀ), 96.1 (C-6), 95.9 (2C-3ꢀꢀ/5ꢀꢀ), 94.1 (C-8), 78.6 (C-2),
71.9–70.2 (4C, 4 × benzylic–CH O), 70.7 (C-3), 32.8 (C-4);
2
CD ꢆ nm: 216.70 (22.695) and 245.01 (8.465). HREIMS: ꢇ]/
774 (M+, 100). Anal. calcd. for C H O : % C, 75.95; H, 5.46;
49 42
9
O, 18.58; found: % C, 75.99; H 5.41.
Synthesis of 4-(1,3,5-Trihydroxybenzene)-5,7,3ꢀ,4ꢀ-tetrahydrox-
yflavan-3-ol (24). First, methanol (4 mL) was added to a
stirred THF (4 mL) solution of 23 (100 mg, 0.129 mmol),
followed by Pd(OH) /C (33.5 mg), and purged with hydrogen
2
for 2 min. Second, afer 1 h under hydrogen at ambient
temperature and pressure, the mixture was filtered over
cotton wool, and the solvent was removed under pressure to
obtain 24 (50 mg, 94%) as a brown solid: IR (KBr, V/cm−1)
3261 (phenol OH, broad), 1603 (aromatic C=C bending). 1H
NMR (600 MHz, MeOD-ꢁ4) ꢀ/ppm: 6.82 (d, ꢂ = 2.0 Hz, 1H,
H-2ꢀ), 6.73 (d, ꢂ = 8.2 Hz, 1H, H-5ꢀ), 6.68 (dd, ꢂ = 2.0, 8.2 Hz,
1H, H-6ꢀ), 5.93 (d, ꢂ = 2.4 Hz, 1H, H-6), and 5.84 (d, ꢂ = 2.4 Hz,
1H, H-8), 5.88 (s, 2H, H-3ꢀꢀ/5ꢀꢀ), 5.04 (d, ꢂ = 7.2 Hz, 1H, H-
2), 4.70 (d, ꢂ = 5.2 Hz, 1H, H-4), 4.18 (dd, ꢂ = 5.2, 7.2 Hz,
1H, H-3). 13C NMR (150 MHz, MeOD-ꢁ4) ꢀ/ppm: 157.5–155.8
(8C, aromatic–C–O), 132.7–131.1 (3C, aromatic quaternary-
C), 118.4 (C-6ꢀ), 114.7 (C-5ꢀ), 113.2 (C-2ꢀ), 101.6 (C-3ꢀꢀ), 95.3
(C-5ꢀꢀ), 95.0 (C-6), 94.2 (C-8), 78.6 (C-2), 72.1 (C-3), 31.1 (C-
4). HREIMS: ꢇ]/ 414 (M+, 100). Anal. calcd. for C H O :
e 1H NMR spectra of the 3-O-derivatives 9, 10, and 11
clearly indicated the presence of an aromatic ABX system (dd,
ꢂ = 2.0, 8.0 Hz; d, ꢂ = 2.0 Hz) and an AB resonance system
(ꢂ = 2.0 Hz), representing the catechol and phloroglucinol
character of the B and A rings, respectively. From the CD
spectra of 9 and 11, the optical activities at C-2 and C-
3 were maintained. As expected, 13 exhibited three one-
proton resonances for the C-ring, a complex ABX system. e
olefinic protons on C-3 and C-4 (H-3 and H-4) were coupled
by cis-coupling (ꢂ3,4 = 10 Hz), and the proton on C-2 (H-2)
was coupled to both H-3 and H-4 (ꢂ2,3 = 3 Hz, and ꢂ2,4 = 2 Hz).
e benzylic proton H-2 was adjacent to an ether oxygen,
which was observed at ꢀ 5.76 as a doublet of doublets (ꢂ =
2.0, 3.0 Hz). Flav-3-enes contained a chiral carbon on C-2.
e HMBC correlation between C-2/C-5 and H-4 in HMBC
permitted distinction between H-4 and H-3. e 13C APT
21 18
9
% C, 60.87; H, 4.38; O, 34.75; found % C, 60.87; H 4.38.
3. Results and Discussion
Efforts to eliminate or replace the secondary hydroxyl group
at the C-3 of flavan-3-ol with a carbon–carbon bond were
seemingly elusive, and attempts resulted in the decomposi-
tion of substrates afer several hours of reaction. e non-
substitution or effective elimination of the carbon-3 moiety

Journal of Chemistry
7
OMe
OMe
O
MeO
OMe
OMe
OTs
=
MeO
O
OMe
10,
11
OMs
(iii)
12
OMe
v)
(i
(i)
OMe
OMe
MeO
O
13
OMe
OMe
OMe
O
MeO
13
+
14
OMe
Scheme 3: Synthesis of flavenes. Reagents and conditions: (i) 12, LDA, THF, ice bath, 15%; (ii) 12, DBU, MeCN, reflux, 99%; (iii) 10, LDA,
THF, ice bath, 5%; (iv) 10, DBU, MeCN, reflux, 82%; (v) 11, LDA, THF, ice bath, 44%; (vi) 11, DBU, MeCN, reflux, 80%.
OR1
R1O
O
OR1
OR1
OR1
OH
8 R1 = Me
OR1
R1O
O
(i)
OMe
17
OR1
OR1
OR1
OR1
OR1
R1O
R1O
O
O
+
(ii)
OMe
OH
OR1
OR1
O
OR1
OR1
R1O
O
15
OMe
OMe
16
OR1
18
Scheme 4: Synthesis of flav-3-en-3-o-R substituents. Reagents and conditions: (i) DMP, CH Cl , H O, 95%; (ii) Yb(OTf) , MeOH, reflux,
2
2
2
3
49%.
and HSQC spectra suggested that the signal of C-2 overlaps
with that of chloroform at ꢀ 77.2 ppm in 13C NMR spectrum.
e HSQC correlation between H-4 and C-4 permitted
distinction between C-3 and C-4. Strong correlations were
observed between protons H-2, H-3, and H-4 in the COSY
experiment, confirming the presence of the vinyl group in
the C-ring. In addition, flav-3-ene clearly exhibited a negative
Cotton effect at ꢆ = 228 nm. e observed retention of

8
Journal of Chemistry
H
configuration at C-2 indicated that optically active flav-3-ene
is successfully synthesized. Two proton signals corresponding
to the C-ring were observed in 14: a two-proton doublet (ꢂ4 =
OMe
OMe
H
5ꢀ
2ꢀ
H
3.8 Hz) on C-4 (CH group) and a one-proton triplet bonded
2
2
3
MeO
O
to C-3 (H-3), observed at ꢀ 5.40. Both allylic and benzylic
H
CH (H-4ꢁꢂ/ and C-4) groups were observed at ꢀ 3.34 and
2
CH
O
3
4
H
1
19.49 ppm in the H NMR and 13C NMR, respectively. C-2
17
OMe
was observed at ꢀ 101.25. Strong correlations were observed
between H-3 and H-4 in the COSY spectrum. Flav-2-enes did
not contain chiral carbons; therefore, optical activity is not
observed.
Scheme 5: Observed NOESY interactions between H-2 and H-2ꢀ
and H-6ꢀ for 17.
e efficient production of protected 3-oxocatechin ana-
logue 15 (Scheme 4) with the retention of configuration
at C-2 by Dess–Martin periodinane oxidation provided a
novel approach towards nucleophilic attack at C-3. In con-
trast to tetrahedral sp3-functionalized C-3 of flavan-3-ol,
the sp2-functionalized 3-oxo-group of 15 was planar, which
decreased steric effects and permitted nucleophilic attack on
the carbonyl carbon from either the ꢃ- or the ꢅ-face. Under
this premise, the C-C coupling of a nucleophile to the C-
3 of 15 with various Lewis acids (e.g., AgBF , TiCl , InCl ,
between H-4ꢅ and H-2, as well as with H-2ꢀ and H-6ꢀ, were
observed. e two methoxy groups on C-3 crowded the C-
1
ring, and line broadening was observed in the H NMR
spectrum. is result possibly indicated that conformational
correlations exist between Hꢃ-4 and H-2ꢀ/H-6ꢀ and that a
significant population of the A conformer [25] (B ring in
the axial position) is present. A positive Cotton effect was
observed at ꢆ = 239 nm.
4
4
3
and Yb(OTf) ) and solvents (CH Cl , THF, DMSO, ethanol,
3
2
2
and methanol) was attempted, which failed to yield the
expected C-3 coupling products. However, by the treatment
e condensation of methylated catechin 15a or benzy-
lated catechin 15b with phloroglucinol in the presence of
of 15 with Yb(OTf) in methanol and reflux of the reaction
3
excess AgBF in dry THF afforded C-4 coupled product
4
mixture for 6 h, 17 (17% yield) and 18 (32% yield) were
obtained, probably via a hemiacetal intermediate (3-hydroxy-
3,5,7,3ꢀ,4ꢀ-pentamethoxyflavane) 16 (Scheme 4). Both 17 and
18 exhibited a Cotton effect at wavelengths ranging from 260
to 284 nm, indicating no change in the configuration at C-
2. is observation is in contrast with the racemic products
synthesized by Clark-Lewis and Jemison [14].
19a,b (Scheme 6). e carbonyl signals for 19a,b were
absent at the expected ꢀ 204–206 ppm, probably because
of a formation of hydrogen bonding between the D-ring
neighbouring hydroxyl proton and the carbonyl oxygen. e
debenzylation of 19b by hydrogenation afforded 21 with a free
phenolic group in good yield. Flav-3-en-3-ols are versatile
precursors for flavonoids [26], which play vital roles in the
biogenesis pathway of tannins [27]. e acetylation of 19a
and 21 afforded 20 and 22, respectively, in good yield. Com-
pound 20 was characterized by the absence of the carbonyl
resonance at ꢀ 206.3 ppm in the 13C NMR spectrum of the
precursor 19a and the presence of four acetoxy resonances
Enol ether 17 was characterized by the disappearance of
the carbonyl resonance in the 13C NMR spectrum of 15 at
ꢀ 206.1 ppm and the appearance of an additional methoxy
1
resonance at ꢀ 3.73 ppm in the H NMR spectrum. e
two enol carbons C-2 and C-3 were observed at 77.2 and
150.7, respectively. e two benzylic protons at C-4 of 15
disappeared and were replaced by an olefinic resonance at
ꢀ 5.60 ppm. Structural elucidation is further supported by
mass spectrometry (M+ ion at ꢇ]/ 358), corresponding to
the addition of a methyl group and the loss of a hydrogen.
A negative Cotton effect in the ꢆ = 216 nm range was
observed in the CD spectrum suggesting that optical activity
at C-2 (2R-configuration) of the commercial catechin was
maintained. is observation was supported by proton NMR
coupling constants and the NOESY correction of the H-2 with
H-2ꢀ and H-6ꢀ. e H-4 demonstrated NOESY correlations
with the methoxy group on C-3 (Scheme 5).
1
at ꢀ 1.70, 1.95, 2.06, and 2.30 ppm, respectively, in the H
NMR spectrum of 20. e C-4 proton of 19a at 5.10 ppm
disappeared, and the olefinic group at C-3, stabilized 20,
was observed. e structure of 20 conformed to the M+
ion at ꢇ]/ 636. Octa-acetoxy 22 was characterized by eight
acetate groups with proton resonances at ꢀ 1.61, 1.66, 1.82,
1.99, 2.18, 2.20, 2.21, and 2.22 ppm, respectively, and the 13
C
NMR resonances were observed at ꢀ 20.0–21.1 ppm, with
the expected M+ ion at ꢇ]/ 748. NOESY correction of H-2
with H-2ꢀ and H-6ꢀ was observed. e H-3 and H-4 protons
signals were not observed on the NMR spectra for 20, 21,
and 22 compounds. e 2R-configuration of the compounds
was assessed via coupling constants from their respective
spectral data and NMR NOESY proton correlations (Supp.
Figure 1 in Supplementary Material available online at https://
doi.org/10.1155/2017/3971253).
Ketal 18 was characterized by the disappearance of the
carbonyl resonance of 15 at approximately ꢀ 206.1 ppm and
the appearance of two additional methoxy resonances at ꢀ
3.34 and 3.31, respectively. Ketal carbon (C-3) was observed
at ꢀ 101.2 ppm. is result was further supported by the M+
ion at ꢇ]/ 391, corresponding to the addition of two methoxy
groups (and the loss of an OH group). NOESY demonstrated
correlations between the two benzylic C-4 protons (4ꢃ and
4ꢅ) and the A ring and C-2-proton. NOESY correlations
Scheme 7 shows the proposed mechanism of the reaction
pathway to the oxidative formation of 19a,b.
e exclusive formation of 19a,b was primarily attributed
to absolute configuration on C-2 (2R), which predominantly
directed the approaching nucleophile to the anti-face (4S).

Journal of Chemistry
9
OR1
OR1
R1O
O
OR3
OR3
OR1
R3O
20 R1 = Me, R3 = Ac
OR3
(ii)
OR1
OR1
5ꢀ
4ꢀ OR1
6ꢀ
R1O
OR1
OR1
3ꢀ
O
8
R1O
O
4
2
7
OR1
2ꢀ
R1O
3
O
6
OR2
OR2
O
5
(iii)
OR1
R2O
OR1
R2O
(i)
O
OR1
ꢀꢀ OR2
6ꢀꢀ
2
1
15a
R
= Me
5ꢀꢀ
3ꢀꢀ
19a R1 = Me, R2 = H
19b R1 = Bn, R2 = H
15b R2 = Bn
21
R1 = R2 = H
OR2
OR2
(iv)
(v)
OR3
OR3
OR1
OR1
OR1
OR1
R3O
O
R1O
R1O
O
O
OR3
OR3
OR2
OR2
OR2
OR2
(vi)
OR3
R3O
OR1
R2O
OR1
R2O
OR3
OR2
OR2
3
22
R
= Ac
23 R1 = Bn, R2 = H
24 R1
= R2 = H
Scheme 6: Synthesis of 4-substituted flav-3-en-3-o-R substituent. Reagents and conditions: (i) Phlorog., AgBF , THF, reflux, 61% (19a), 59%
4
(19b); (ii) 19a, Py, (CH CO) O, 40∘C, 92%; (iii) 19b, Pd(OH) , H , EtOAc/MeOH, rt, 95%; (iv) Py, (CH CO) O, 40∘C, 90%; (v) 19b, THF,
3
2
2
2
3
2
NaOHaq/EtOH, NaBH , rt, 99%; (vi) Pd(OH) /C, H , EtOAc/MeOH, rt, 94%.
4
2
2
Notably, self-condensation products were not observed prob-
ably because of the deactivation of the nucleophilic properties
of the A ring via the enolic C-ring tautomer (Scheme 7) [22].
Substituted flav-3-enes were exclusively synthesized
efficiently by the stereoselective elimination of the 3-O-
substituent on protected catechin using DBU. 3-Substituted
flav-3-ene derivatives were prepared by treating flavan-3-
one with a strong Lewis acid in the presence of a suitable
nucleophile. Solvent choice was critical to the success of
reactions and yields of corresponding products. Optical
activities of the compounds were confirmed by CD data and
NMR spectroscopy analysis.
4. Conclusion
Few synthetic methods have been published to efficiently
synthesize flavenes, although none are stereoselective.

10
Journal of Chemistry
OR
OR
OR
OR
RO
O
RO
O
O
RO
OR
OR
+
∙
O
O
O
Ag+/-e 1
+
-H+
26
OR
OR
OR
25
15
Ag+/-e 1
OR
OR
OR
OR
OR
RO
−
+
RO
BF4
O
RO
O
O
OR
+
O
27
O
30
O
OR
RO
OR
OR
+
−
OR
29
∙ ∙
BF4
28
OR
OR
OR
OR
B
RO
O
RO
O
C
OR
A
O
O
-H+
OR
RO
OR
RO
H
OR
OR
+
D
31
19
OR
OR
Scheme 7: Proposed mechanism for the formation of 19.
Conflicts of Interest
[2] C.-W. Lee, H.-J. Choi, H.-S. Kim et al., “Biflavonoids isolated
from Selaginella tamariscina regulate the expression of matrix
metalloproteinase in human skin fibroblasts,” Bioorganic &
Medicinal Chemistry, vol. 16, pp. 732–738, 2008.
e authors declare that they have no conflicts of interest.
[3] X. Zheng, W.-D. Meng, and F.-L. Qing, “Synthesis of gem-
difluoromethylenated biflavonoid via the Suzuki coupling reac-
tion,” Tetrahedron Letters, vol. 45, no. 43, pp. 8083–8085, 2004.
Acknowledgments
Matthew Chilaka Achilonu acknowledges the financial sup-
port from the Research Innovation Fund (3513/DHET) of the
Central University of Technology Free State, as well as the
support of the Chemistry Department of the University of the
Free State during his doctoral studies.
[4] B. Gil, M. J. Sanz, M. C. Terencio, R. Gunasegaran, M. Paya,
and M. J. Alcaraz, “Morelloflavone, a novel biflavonoid inhibitor
of human secretory phospholipase A, with anti-inflammatory
activity,” Biochemical Pharmacology, vol. 53, pp. 733–740, 1997.
[5] M. K. Lee, S. W. Lim, H. Yang et al., “Osteoblast differentiation
stimulating activity of biflavonoids from Cephalotaxus koreana,”
Bioorganic & Medicinal Chemistry Letters, vol. 16, no. 11, pp.
2850–2854, 2006.
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