Enantio selective synthesis of new phenylpropanoid: Isolated from Walsura trifoliata

Article abstract of DOI:10.14233/ajchem.2019.22064

A new phenylpropanoid containing flavon-3-ol has been isolated from the leaves of traditional medicinal plant, Walsura trifoliata. The structure of the compound was established on the basis of spectroscopic evidence [2D NMR, HREIMS] and by its alternative

Full text of DOI:10.14233/ajchem.2019.22064

Asian Journal of Chemistry; Vol. 31, No. 9 (2019), 2042-2046
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.22064
Enantio Selective Synthesis of New Phenylpropanoid: Isolated from Walsura trifoliata
1
1
1
L.V. RAMANA , M. SURI APPA RAO , K.M. CH. APPARAO2,* and B. NAGESWARA RAO
1Divi’s Laboratories Limited, Unit-II, Chippada, Visakhapatnam-531162, India
2Department of Chemistry, GITAM Institute of Science, GITAM University, Rushikonda, Visakhapatnam-530045, India
*Corresponding author: Fax: +91 892 2248931; Tel: +91 892 2248930; E-mail: bnrao@divislabs.com
Received: 11 March 2019;
Accepted: 24 April 2019;
Published online: 31 July 2019;
AJC-19495
A new phenylpropanoid containing flavon-3-ol has been isolated from the leaves of traditional medicinal plant, Walsura trifoliata. The
structure of the compound was established on the basis of spectroscopic evidence [2D NMR, HREIMS] and by its alternative synthesis.
The synthesis of this natural product was achieved from inexpensive and readily available starting materials of phloroglucinol dihydrate.
Key reaction sequence includes Grubbs-II RCM reaction, Wittig reaction and sharpless dihydroxylation using AD-mix α.
Keywords: Flavan 3-ol, Phenylpropanoid, Walsura trifoliata, Alternate synthesis.
of research programme [11], we have isolated a new phenyl-
propanoid-substituted flavan-3-ols, along with other com-
pounds, structures were showed in fig-1 from stem bark of
Walsura trifoliata as minor constituent. The structures of the
compound were elucidated by interpretation of 2D-NMR and
HRESIMS spectral data. Further, we also confirmed by its
structure by its alternate synthesis from the readily available in
expensive starting materials. Herein, we report the enataio-
selective synthesis of new phenylpropanoid containing flavan-
3-ol in nine steps.
INTRODUCTION
In recent years, natural product based lead compounds
has attracted for the development of novel pharmaceuticals
due to increased of incidence of deadly illnesses such asAIDS,
cancers, hepatitis, etc. In this regard, secondary metabolites
with catechin moiety have attracted organic chemists due to
their wide range of biological activities such as antioxidant,
anti-inflammatory, antithrombotic and blood pressure lowering
activities [1-3]. The green tea was the major source for catechin
metabolites and bio-methylation of these catechins may also
play a significant role in affecting the biological effects of tea.
Recently, it has been reported that among women, who regularly
consumes green tea showed reduced risk of breast cancer com-
pared with non-tea drinkers. In contrast, risk of breast cancer
did not differ between tea drinkers and non-tea drinkers among
those who were homozygous for the high activity COMT
(catechol-O-methyltransferase)allele [4]. Phenylpropanoid-
substituted flavan-3-ols are a kind of tannins that occurs in plants
of a woody habit as minor constituents. Generally, poly phenolic
constituents such as epigallo catechin gallate (EGCg) [5], epica-
techin (EC), epicatechin gallate (ECg) and epicatechin (EC)
were the main constituents in green tea [6,7]. Phenyl propanoid
constituents containing flavon 3-ols are also phenolic compounds
which possess antioxidant [8], antiestrogenic and estrogenic
pharmaceutics [9], diahrea and duodenal tumors [10]. As part
EXPERIMENTAL
All commercial available starting materials, reagents and
catalyst were purchased from sigma Aldrich, Pfizer and Avra
laboratories. These are used without purification. IR spectra
were recorded on a Nicolet-740 spectrometer with KBr pellets.
The NMR spectra were recorded on a Bruker FT-400 MHz
spectrometer at 400 MHz for 1H NMR and 150 MHz for 13C
NMR respectively, using TMS as internal standard. The
chemical shifts are expressed as δ values in parts per million
(ppm) and the coupling constants (J) are given in hertz (Hz).
HRESIMS spectra were performed on a LC-MS/MS (Agilent
Technologies 6510) Q-TOF Mass spectrometer. Column
chromatography was performed with silica gel (100–200 mesh,
Qing-dao Marine Chemical, Inc., Qingdao, China).Analytical
TLC was performed on precoated Merck plates (60 F254, 0.2
This is an open access journal, and articles are distributed under the terms of the Attribution 4.0 International (CC BY 4.0) License. This
license lets others distribute, remix, tweak, and build upon your work, even commercially, as long as they credit the author for the original
creation. You must give appropriate credit, provide a link to the license, and indicate if changes were made.

Vol. 31, No. 9 (2019)
Enantio Selective Synthesis of New Phenylpropanoid: Isolated from Walsura trifoliata 2043
OH
OH
OH
OH
O
O
OH
O
OH
O
OH
OH
OH
O
O
O
O
OH
OH
R=
OH
Me
R
OH
OH
OH
O
OH
3
1
2
Fig. 1. Few isolated compounds from bark of Walsura trifoliata
mm) and compounds were viewed under a UV lamp (254 and
365 nm) and sprayed with 10% H2SO4, followed by heating.
1-((3-(Allyloxy)-5-(benzyloxy)phenoxy)methyl)benzene
(5): To a stirred solution of K2CO3 (2.6 g, 33 mmol) in acetone
(100 mL) at 0 °C was added 3,5-bis(benzyloxy)phenol (11 g,
33 mmol), in acetone (30 mL) after 5 min. Resulting mixture
was refluxed at 55 °C up to 12 h. After completion of reaction
(monitored by TLC), mixture was allowed to cool to room
temperature and washed with brine solution (5.0 mL) then
extracted with Et2O (100 mL). The organic layer was dried
(MgSO4), filtered and concentrated in vacuo to yield 5 as a
brown oil. IR (KBr, νmax, cm–1): 3401, 2983, 2872, 1632, 1600,
1509, 1436, 1105, 1071, 937, 815, 709. 1H NMR (400 MHz,
CDCl3): δ 7.28-7.42 (m, 10H), 6.24 (t, J = 2 Hz, 2H), 6.19 (d,
J = 2 Hz, 2H), 5.97-6.13 (m, 1H), 5.38 (dq, J = 17 and 1.4
Hz, 1H), 5.26 (dq, J = 10 and 1.4 Hz,1H), 5.00 (s, 4H), 4.46
2H, OCH2Ph), 5.02 (s, 2H, OCH2Ph), 5.16 (s, 2H, OCH2OCH3),
6.31 (d, 1H, J = 2.1 Hz, ArH), 6.45 (d, 1H, J = 2.1 Hz, ArH),
5.91-6.0 (m, 1H, J = 10.0, 17.0 Hz, AllH), 4.90-4.99 (m, 2H,J
13
= 2.1,17.0 Hz, AllH),), 3.42 (d, J = 6.2 Hz, 2H). C NMR
(100 MHz, CDCl3): δ 27.3, 56.0, 70.3, 94.2, 94.5, 94.6, 110.5,
113.9, 127.0, 127.6, 127.8, 128.4, 128.5, 128.2, 136.5, 137.2,
136.9, 156.2, 156.7, 157.7, 158.4. HRESI-MS: found 413.1743
[M+Na]+, C25H26O4Na (calculated: 413.1729).
5-Vinyl-1,3-phenylene)bis(oxy)bis(methylene)dibenzene
(8): To a stirred solution of C1 Wittig salt (2.6 g, 33 mmol) in
THF (100 mL) at -5 °C and then n-BuLi (48 mmol) was allowed
to 0 °C and added the 3,5-bis(benzyloxy)phenol (11 g, 33
mmol), in THF (30 mL) after 5 min, Rm allow to room temp
and stirred until the change the variation in TLC. The mixture
was washed with brine solution (5.0 mL) and partitioned,
obtained crude was purified by column chromatography by
using hexane, ethyl acetate (9:1 ratio) to get 8 in pure form.
1H NMR (400 MHz, CDCl3): δ 7.320-7.44 (m, 10H), 6.67(1H,
s), 6.66 (1H, s), 6.60-6.66 (1H, m, J = 10.7, 17.8 Hz), 6.54 (t,
J = 2.1, 4.4, Hz, 1H), 5.70 (1H, d, J = 17.3 Hz), 5.24 (1H, d,
13
(dt, J = 5 and 1.4 Hz, 2H). C NMR (100 MHz, CDCl3): δ
68.8, 70.0, 94.7, 117.6, 127.4, 127.8, 128.4, 132.9, 136.6, 160.2
and 160.4. HRESI-MS: found C23H23O3 347.1629 [M+H]+,
(calculated: 347.1647).
13
2-Allyl-3,5-bis (benzyloxy)phenol (6): In a 100 mL,
sealed tube equipped with a magnetic stirring bar is placed
20.1 g (0.098 mol) of 1-((3-(allyloxy)-5-(benzyloxy)phenoxy)-
methyl)benzene. The tube was dipped in an oil-bath and heated
at 0.1 mm pressure. The temperature was maintained at 190-
210 °C while the mixture stirred, until the change in variation
in TLC plate. IR (KBr, νmax, cm–1): 3107, 2919, 2860, 1589,
1457, 1212, 1150, 1059, 921, 825. 1H NMR (400 MHz, CDCl3):
δ 7.23-7.36 (m, 10H), 5.98-6.26 (m, 3H), 4.93 (s, 2H), 4.88
(s, 2H), 4.82-5.09 (m, 2H), 4.02 (brs, 1H), 3.42 (d, J = 6 Hz,
2H). 13C NMR (100 MHz, CDCl3): δ 27.2, 69.8, 70.0, 93.3, 94.9,
114.6, 126.8, 127.2, 127.4, 127.6, 128.1, 128.2, 136.5, 136.6,
136.9, 155.4, 157.5, 158.2. ESI-MS.347.4 [M++H]. HRESI-
MS: found 347.1631 [M+H]+, C23H23O3 (calculated: 347.1647).
(4-Allyl-5-(methoxy)-1,3-phenylene)bis(oxy)bis(methy-
lene)dibenzene (7): To a stirred solution of NaH (2.6 g, 66
mmol) in THF (100 mL) at 0 °C was added the 2-allyl-3,5-
bis(benzyloxy)phenol (11 g, 33 mmol), in THF (30 mL). After
5 min, methoxy-methyl chloride (MOMCl) (5.0 mL, 33 mmol)
was added and the mixture allowed to warm to room tempe-
rature. Brine (5.0 mL) was then added and the reaction parti-
tioned between Et2O (100 mL) and H2O (100 mL), the organic
layer was dried (MgSO4), filtered and concentrated in vacuum
to yield 7 as a brown oil. IR (KBr, νmax, cm–1): 2928, 2854,
1604, 1525, 1431, 1127, 874. 1H NMR (400 MHz, CDCl3): δ
7.31-7.43 (m, 10H, ArH),3.46 (s, 3H, OCH2OCH3), 5.00 (s,
J = 10.7, Hz) 5.04 (s, 4H). C NMR (100 MHz, CDCl3): δ
70.1, 101.6, 105.58, 114.34, 127.5, 128.0, 128.5, 136.7, 136.8,
139.6, 160.0. HRESI-MS: found 317.1533 C22H21O2 [M+H]+
calculated: 317.1541.
(E)-(5-(3-(2,4-bis(Benzyloxy)-6-(methoxymethoxy)-
phenyl)prop-1-enyl)-1,3-phenylene)bis(oxy)bis(methylene)-
dibenzene (9): To a 0.15 M solution of 8 in DMF was added
2 eq of styrene 7 and Cl2(PCy3)RuCHPh (0.03 eq) at room
temperature under N2. The solution was refluxed at 75 °C for
2 h together with addition of two identical amounts of catalyst
at regular periods of time.After completion of reaction, concen-
tration in vacuo, purification by flash chromatography on silica
gel afforded. Resulting styrene 9 (1.3 g, 49 %) as a white solid;
m.p.: 103-104 °C. IR (KBr, νmax, cm–1): 3093, 2936, 1681,
1600, 1550, 1458. 1H NMR (400 MHz, CDCl3): δ 3.53 (s, 3H,
OCH2OCH3), 3.65-3.66 (m, 2H, CH2-CH=CH), 5.08 (s, 4H,
2xOCH2Ph), 5.11 (s, 2H, OCH2Ph), 5.15 (s, 2H, OCH2Ph),
5.25 (s, 2H, OCH2OCH3), 6.37–6.40 (m, 2H,ArCH2CH=CH),
6.41 (d, 1H, J = 2.2 Hz, ArH), 6.66 (t, 1H, J = 2.2 Hz, ArH),
6.57 (d, 1H, J = 2.2 Hz, ArH), 6.77 (s, 1H, ArH), 6.78 (s, 1H,
ArH), 7.36– 7.53 (m, 20H,ArH). 13C NMR (100 MHz, CDCl3):
δ 26.4, 56.0, 70.0, 70.1, 70.2, 70.3, 94.2, 94.4, 94.7, 100.6,
105.2, 108.3, 110.3, 127.2, 127.4, 127.6, 127.7, 127.98, 127.8,
128.4, 128.5, 128.6, 129.1, 129.4, 129.9, 136.8, 136.9, 136.6,
140.2, 156.3, 157.8, 158.6, 159.9. HRESI-MS: found 679.3046
[M+H]+, C45H43O6 (calculated: 679.3059).

2044 Ramana et al.
Asian J. Chem.
(1S,2S)-3-(2,4-bis(benzyloxy)-6-(methoxymethoxy)-
phenyl)-1-(3,5-bis(benzyloxy)phenyl)propane-1,2-diol (10):
To a solution of AD-mix-α (5.0 g) in t-BuOH (30 mL) and
H2O (30 mL) at 0 °C was added methane sulfonamide (270
mg, 2.9 mmol) followed by styrene 9 (1.5 g, 2.6 mmol) in
THF (30 mL) and the mixture stirred at 0 °C for 5 days. Solid
sodium sulfite (5 g) was added and the product was extracted
into EtOAc (50:50 mL), the combined organic layer filtered,
dried (MgSO4) and concentrated in vacuo to yield the crude
product, which was purified by flash chromatography (Silica,
80 % Et2O/hexanes) to yield the desired product 10 as a white
solid (1.0 g, 65 %, 75 % ee by HPLC that was then recrys-
tallized (80 % Et2O/EtOAc) to give enantiomerically pure 10
(740 mg, 48 %). IR (KBr, νmax, cm–1): 3517, 2925, 2917, 1590,
1456, 1137. 1H NMR (400 MHz, CDCl3): δ 3.0-3.09 (m, 2H,
ArCH2CH(OH)CH(OH), 3.55 (s, 3H, OCH2OCH3), 3.41 (s,
3H, OCH2OCH3), 4.02-4.09 (m, 1H,ArCH2CH(OH)CH(OH)),
4.59 (d, 1H, J = 4.3 Hz, ArCH2CH(OH)CH(OH), 5.11 (s, 4H,
2xOCH2Ph), 5.13 (s, 2H, OCH2Ph), 5.14 (s, 2H, OCH2Ph),
5.25 (dd, 2H, J = 9.0,6.21 Hz, OCH2OCH3), 6.47 (d, 1H, J =
2.07 Hz, ArH), 6.60 (d, 1H, J = 2.07 Hz, ArH), 6.52 (t, 1H, J
= 2.07,4.15 Hz, ArH), 6.64 (s, 1H, J = 2.07 Hz, ArH), 7.27–
7.43 (m, 20H, ArH); 13C NMR (100 MHz, CDCl3): δ 27.6,
56.4, 70.1, 70.3, 70.6, 75.7, 76.2, 94.5, 94.7, 94.9, 101.2, 105.9,
108.3, 127.3, 127.8, 128.1, 128.2, 128.7, 128.9, 136.6, 136.8,
137.0, 143.9, 156.9, 158.1, 159.0, 160.0. HRESI-MS: found
713.3099 [M+H]+, C45H45O8 (calculated: 713.3114).
(1S,2S)-3-(2,4-bis(Benzyloxy)-6-hydroxyphenyl)-1-
(3,5-bis(benzyloxy)phenyl)propane-1,2-diol (11): To a solu-
tion of diol 10 (740 mg, 1.2 mmol) in MeOH (10 mL) and Et2O
(10 mL) was added conc. HCl (5 drops) and the mixture refluxed
for 5 h. The mixture was then concentrated in vacuo, diluted
with EtOAc and washed with H2O, the organic layer was dried
(MgSO4), filtered and concentrated in vacuo to yield the product
11 as a white solid (730 mg, 85 %). IR (KBr, νmax, cm–1): 3392,
3040, 2919, 1550, 1147. 1H NMR (400 MHz, CDCl3): δ 2.84
(dd, 1H, J = 6.7, 15.1 Hz, ArCH2CH(OH)CH(OH)), 3.96 (dd,
1H, J = 2.5, 15.2 Hz, ArCH2CH(OH)CH(OH), 3.98–4.05 (td,
1H, J = 2.44,8.8 Hz, ArCH2CH(OH)CH(OH), 4.55 (d, 1H, J
= 5.8 Hz), 4.94–5.06 (m, 8H, 4xOCH2Ph), 6.26 (d, 1H, J =
2.07 Hz, ArH), 6.33 (δ, 1H, J = 2.07 Hz, ArH), 6.56 (t, 1H, J
= 2.1 Hz, ArH), 6.62 (s, 1H, ArH), 6.63 (s, 1H, ArH), 7.15–
7.48 (m, 20H, ArH). 13C NMR (100 MHz, CDCl3): δ 28.0,
70.3, 70.4, 77.1, 93.8, 96.2, 102.2, 106.4, 106.2, 127.0, 127.9,
128.0, 128.3, 128.4, 128.8, 122.9, 129.1, 137.0, 137.3, 143.2,
157.6, 158.2, 159.5, 160.4. HRESI-MS: found 669.2836
[M+H]+, C43H41O7 (calculated: 669.2852).
concentrated in vacuum to yield the crude product, which was
puried by flash chromatography (silica, 80 % Et2O/hexanes) to
yield the desired product as a white solid (1.0 g, 65 %, 75 % ee
by HPLC) that was then recrystallized (80 % Et2O/EtOAc) to
give enantiomerically pure 12 (740 mg, 48 %). IR (KBr, νmax
,
cm–1): 3569, 3070, 3038, 2930, 1597, 1592, 1149. 1H NMR (400
MHz, CDCl3): δ2.95 (dd, 1H, J = 15.1, 6.7, Hz,ArCH2CHCHO),
3.21 (dd, 1H, J = 15.1, 2.5 Hz, ArCH2CHCHO), 4.12 (d, 1H,
J = 2.4, 8.5, Hz, OCH2Ph), 4.64 (d, 1H, J = 8.5 Hz, OCH2Ph),
4.93– 5.00 (m, 8H, 4xOCH2Ph), 6.23 (d, 1H, J = 2.2 Hz, ArH),
6.30 (d, 1H, J = 2.4 Hz, ArH), 6.56 (t, 1H, J = 2.1, Hz, ArH),
6.67 (s, 1H,ArH), 6.68 (s, 1H,ArH), 7.18–7.43 (m, 20H,ArH);
13C NMR (100 MHz, CDCl3): δ 27.03, 70.01, 70.02, 81.56,
84.06, 93.5, 96.2, 101.7, 105.5, 105.9, 109.1, 127.5, 127.6,
127.8, 127.9, 128.4, 128.5, 136.6, 136.7, 137.0, 139.6, 157.6,
157.7, 159.3, 160.0. HRESI-MS: found 651.2737 [M+H]+,
C43H39O6 (calculated: 651.2746).
(R)-5,7-bis(Benzyloxy)-2-(3,5-bis(benzyloxy)phenyl)-
chroman-3-one (13): Dess-Martin periodinane (6.3 mL, 15 %
g/mL in CH2Cl2, 2.2 mmol) was added in one batch to a stirred
solution of 9 (200 mg, 1.0 mmol) in CH2Cl2 (30 mL) under an
N2 atmosphere. The mixture was stirred at room temperature
for about 2 h till TLC showed the absence of starting material.
Subsequently, saturated NaHCO3 solution (15 mL) and 10 %
Na2S2O3 aqueous solution (15 mL) were added to quench the
reaction. The organic layer was separated and the aqueous
layer was extracted with CH2Cl2. The combined organic phases
were dried (MgSO4) and evaporated. The residue was purified
by flash chromatography with toluene on silica gel and then
recrystallized in CHCl3 and ether to afford the desired compound
(110 mg, 76.0 %). IR (KBr, νmax, cm–1): 2978, 2945, 1644,
1
1584, 1137, 783. H NMR (400 MHz, CDCl3): δ 7.42–7.25
(m, 20H), 6.95 (d, J = 1.4 Hz, 1H), 6.89 (d, J = 8.2 Hz, 2H),
6.35 (d, J = 1.9 Hz, 2H), 5.23 (s, 1H), 5.13 (s, 2H), 5.10 (d, J
= 2.9 Hz, 2H), 5.01 (s, 2H), 5.00 (s, 2H), 3.64 (AB, J = 21.5
Hz, 2H).13C NMR (100 MHz, CDCl3): δ 205.0, 159.4, 157.0,
154.4, 149.1, 148.9, 137.0, 136.9, 136.4, 128.6, 128.5, 128.4,
128.1, 128.0, 127.8, 127.7, 127.5, 127.3, 127.2, 127.1, 119.9,
114.6, 113.2, 101.9, 95.7, 95.0, 83.0, 71.1, 71.0, 70.2, 70.0,
33.6. HRESI-MS: found 649.2576[M+H]+, C43H37O6
(calculated: 649.2590).
(2R,3R)-5,7-bis(Benzyloxy)-2-(3,5-bis(benzyloxy)-
phenyl)chroman-3-ol (14): Under N2 atmosphere, the ketone
13 (1.8 g, 2.6 mmol) was dissolved in dry THF (30 mL) and
the solution was cooled to -78 °C. Then L-selectride (4.0 mL,
1 M solution in THF, 4.0 mmol) was added drop-wise. The
resulting solution was stirred at -78 °C overnight. When TLC
showed the reaction was completed, saturated aqueous NaHCO3
solution (30 mL) was added to quench the reaction. The organic
layer was separated and the aqueous layer was extracted with
EtOAc. The combined organic phases were dried (MgSO4)
and evaporated. The residue was purified by flash chromato-
graphy on silica gel (EtOAc/hexane) and then recrystallized
with EtOAc and n-hexane to afford the desired product (1.6 g,
75 %) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.42-
7.29 (m, 20H), 6.49 (t, J = 1.4 Hz, 1H), 6.67 (d, J = 1.9 Hz,
2H), 6.58 (t, J = 1.9 Hz, 1H), 5.23 (s, 1H), 5.13 (s, 2H), 5.02
(d, J = 2.9 Hz, 2H), 5.01 (s, 2H), 5.00 (s, 4H), 3.52 (d, J = 21.5
(2R,3S)-5,7-bis(benzyloxy)-2-(3,5-bis(bezyloxy)phenyl
chroman-3-ol (12): To a solution of triol to a suspension of
11 (2.4 g, 3.1 mmol) in 1, 2-dichloroethane (50 mL) was
added triethyl orthoformate (1 mL), followed by PPTS (450
mg, 1.8 mmol). The mixture was stirred at room temperature
for 20 min until the solid dissolved. The mixture was then
heated to 55 °C for 5 h until TLC showed the reaction had
been completed. After evaporation of the solvent, the residue
was dissolved in DME (30 mL) and MeOH (30 mL), K2CO3
(450 mg) was added. The mixture was stirred at room tempe-
rature overnight. The combined organics dried (MgSO4) and

Vol. 31, No. 9 (2019)
Enantio Selective Synthesis of New Phenylpropanoid: Isolated from Walsura trifoliata 2045
Hz, 1H), 3.59 (d, J = 21.5 Hz, 1H).13C NMR (100 MHz, CDCl3):
δ 205.3, 160.5, 160.0, 157.7, 154.6, 149.1, 137.7, 137.2, 128.9,
128.5, 128.4, 128.1, 128.0,127.8, 127.7, 127.5, 128.8, 128.2,
127.7, 106.1, 101.9, 95.7, 95.4, 83.2, 70.4, 70.4, 70.3, 33.9.
HRESI-MS: found 651.2733[M+H]+, C43H39O6 (calculated:
651.2746).
the mixture was extracted with ethyl acetate. The combined
organic layer was dried over MgSO4, filtered, concentrated
and purified by preparative TLC (acetone, chloroform 3:7) to
afford 2 (5 mg, 90 %) (Scheme-I). IR (KBr, νmax, cm–1): 3451,
2987, 1640, 1578, 1237, 808. 1H NMR (400 MHz, CDCl3): δ
7.02 (1H, s, H-4'), 6.82 (2H, d, J = 1.9 Hz, d, H-2', H-6'), 6.69
(1H, d, J = 7.9 Hz, H-8"),6.60 (1H, d,J = 1.8 Hz,H-5"), 6.45
(1H, dd, J = 7.9, 1.9 Hz, H-9"),4.89 (1H, brs, H-2), 4.43-4.47
(2H, m, H-3, H-3"), 3.09 (2H, dd, J = 17.1,4.9 Hz, H-2"),
2.95 (2H, dd, J = 16.9, 5.1 Hz, H-4).13C NMR (100 MHz,
CDCl3): δ 170.7(C-1"), 157.2 (C-8),151.7 (C-6), 153.0 (C-
10), 145.9 (C-6"), 145.5 (C-3'), 145.4 (C-5'), 144.8 (C-7"),
135.1 (C-4"), 131.4 (C-1'), 119.1 (C-9"), 118.9 (C-2'), 116.2
(C-8"), 115.7 (C-6'), 114.9 (C-5"),114.7 (C-4'), 105.8 (C-5),
105.0 (C-9), 96.2 (C-7), 79.3 (C-2), 66.3 (C-3), 38.3 (C-2"),
34.9 (C-3"), 29.7 (C-4). HRESI-MS: found 453.1165 [M+H]+,
C24H21O9 (calculated: 453.1186).
Compound 2: A solution of globally protected (2R,3R)-
5,7-bis(benzyloxy)-2-(3,5-bis(benzyloxy)phenyl)chromantriol
(14). (30 mg, 0.18 mmol) and 10 % Pd(OH)2 (5 mg) in EtOH
(2 mL) was stirred under an atmosphere of H2 balloon for 1 h.
The mixture was then filtered through celite, concentrated in
vacuo and purified by flash chromatography (silica, Et2O) to
yield the product (2R,3R)-2-(3,5-dihydroxyphenyl)chroman-
3,5,7-triol (5 mg, 94 %) as an off yellow oil. The resulting
compound was taken with caffeic acid (7 mg, 1.008 mmol)
and 1 equiv of NaOAc (56.4 mg, 0.688 mmol) was dissolved in
THF (8 mL) under an N2 atmosphere. To the solution, 6 equiv
of TFA (50 mL, 3.90 mmol) was added and the mixture was
refluxed with stirring. The progress of reaction was continu-
ously monitored by checking the disappearance of the flavan-
3-ol spot on TLC every hour. The reaction was then quenched
by adding saturated sodium bicarbonate solution (10 mL) and
RESULTS AND DISCUSSION
Selective protection of hydroxyl group with methoxy-
methyl (MOM) chloride and remaining hydroxyl was protected
as its benzyl ethers. p-Hydroxyl containing cinnamic acid
BnO
OH
HO
OH
IV
BnO
O
I, II
III
OBn
5
OBn
OH
4
6
OBn
V
VI
BnO
OMOM
BnO
OMOM
BnO
OBn
OBn
7
OBn
8
9
OBn
VII
OBn
OBn
OBn
VIII
OBn
BnO
OH
OH
BnO
O
BnO
OMOM
OH
OBn
OH
OBn
OBn
OBn
OBn
OH
OBn
OH
12
11
10
OH
OBn
OH
OH
BnO
O
BnO
O
O
OBn
OBn
X,XI
IX
O
O
O
OH
OH
OBn
13
OBn
14
OH
OH
2
Scheme-I: Reagents and conditions: (i) NaH, benzyl bromide, DMF, room temperature, 12h, 40 % (ii) K2CO3, allyl bromde, acetone, 60
°C, 15 h, 77 %; (iii) 230 °C, 1 h, 80 %; (iv) NaH, methoxy-methyl chloride (MOMCl), THF 0 °C to room temperature, 88 %; (v)
dry DMF, Hoyida-Grubs, 75 °C, 2 h, 50 %; (vi) AD-mix-α, t-BuOH, H2O, MeSO2NH2, O °C, 5 days; (vii) HCl, MeOH, Et2O,
reux, 5 h, 90 % crude; (viii) HC (OMe)3, PPTS cat. CH2Cl2, room temperature; (a): K2CO3/MeOH/DME, room temperature; 45
%; (ix) L-Selectride/THF, -78 °C, 60 % ; (x) H2, 10 % Pd(OH)2/C, EtOAc, room temperature, 12 h. 80 % ; (xi)1eq NaOAc, 6eq
TFA, in Dry THF, 85 % yield, 90 %

2046 Ramana et al.
Asian J. Chem.
moiety is mandatory for the coupling with flavon 3-ol,due to
the formation of dienone-phenol tautomerism [12] of cinnamic
acid which was mentioned in reaction mechanism. The highest
charge density [13] at C-8 position when compared to C-6
position, indicating higher nucleophilicity of the C-8 position.
Thus, condensation of acid with flavan 3-ol at C-8 position
via dienone-phenol rearrangement to got the final product.
The synthesis was started with phloroglucinol dihydrate
(4), which was converted to the (5-(allyloxy)-1,3-phenylene)bis-
(oxy)bis(methylene)dibenzene (5) via dibenzyalation reaction
followed by allyl bromide in the presence of K2CO3 in acetone
(5) in 77 % yield. Allyl phenol 6 was obtained by Claisen
rearrangement of allylic ether (5). The hydroxyl group in 6
was further protected as its methoxy-methyl (MOM) ether by
following standard reaction conditions to yield 7 in good yields
[14]. Desired high stereo selective isomer of alkene 9 was
achieved by ring-closing metathesis of dienes 7 and 8 using
Grubbs-II catalyst [15]. The resultant alkene 9 was subjected
to sharpless dihydroxylation using AD-mix α to give the
optically active diol 10 which was purified and recrystallization
to give 10 gave a 48 % ee of pure compound (65 %) yield.
Subsequent deprotection with 3 M HCl gave triol 11 and cycli-
zation of 11 with orthoformate under acetic conditions follo-
wed by base facilitated cyclization to form 12 [16]. The trans
stereochemistry of 12 was evident from its 1H NMR spectrum.
Subsequent global debenzylation of compound 14 by hydro-
genolysis with Pd(OH)2 catalysis (48 %) to give the enantiome-
rically pure compound 14. Finally, compound 14 was subjected
TFA and sodium acetate induced coupling with 3,4-dihydroxy
cinnamic acid [13] to get the target compound (2) in good
yields.
REFERENCES
1. H. Fujiki, M. Suganuma, K. Imai and K. Nakachi, Cancer Lett., 188, 9
(2002);
https://doi.org/10.1016/S0304-3835(02)00379-8.
2. M. Monagas, M. Urpi-Sarda, F. Sánchez-Patán, R. Llorach, I. Garrido,
C. Gómez-Cordovés, C.Andres-Lacueva and B. Bartolomé, Food Funct.,
1, 233 (2010);
https://doi.org/10.1039/c0fo00132e.
3. A. Takagaki, S. Otani and F. Nanjo, Biosci. Biotechnol. Biochem., 75,
582 (2011);
https://doi.org/10.1271/bbb.100683.
4. A. Takagaki and F. Nanjo, J. Agric. Food Chem., 63, 8262 (2015);
https://doi.org/10.1021/acs.jafc.5b03676.
5. L.M.V. Tillekeratne, A. Sherette, P. Grossman, L. Hupe, D. Hupe and
R.A. Hudson, Bioorg. Med. Chem. Lett., 11, 2763 (2001);
https://doi.org/10.1016/S0960-894X(01)00577-7.
6. N. Salah, N.J. Miller, G. Paganga, L. Tijburg, G.P. Bolwell and C. Rice-
Evans, Arch. Biochem. Biophys., 322, 339 (1995);
https://doi.org/10.1006/abbi.1995.1473.
7. A.H. Wu, C.C. Tseng, D. Van Den Berg and M.C. Yu, Cancer Res., 63,
7526 (2003).
8. W. Tang, H. Hioki, K. Harada, M. Kubo andY. Fukuyama, J. Nat. Prod.,
70, 2010 (2007);
https://doi.org/10.1021/np0703895.
9. B. Wungsintaweekul, K. Umehara, T. Miyase and H. Noguchi, Phyto-
chemistry, 72, 495 (2011);
https://doi.org/10.1016/j.phytochem.2010.12.018.
10. R. Saijo, G. Nonaka and I. Nishioka, Chem. Pharm. Bull. (Tokyo), 37,
2063 (1989);
https://doi.org/10.1248/cpb.37.2063.
11. K.M. Ch Appa Rao, B.N. Rao, L.V. Ramana, and M.S. Appa Rao, J.
Pharmacog. Phytochem., 6, 1314 (2017).
12. V.P. Vitullo and N.J. Grossman, J. Am. Chem. Soc., 94, 3844 (1972);
https://doi.org/10.1021/ja00766a030.
13. S. Awale,Y. Tezuka, S. Wang and S. Kadota, Org. Lett., 4, 1707 (2002);
https://doi.org/10.1021/ol020042n.
14. J.C.Anderson, C. Headley, P.D. Stapleton and P.W. Taylor, Tetrahedron,
61, 7703 (2005);
https://doi.org/10.1016/j.tet.2005.05.086.
15. D. Forget-Champagne, M. Mondon, N. Fonteneau and J.-P. Gesson,
Tetrahedron Lett., 42, 7229 (2001);
https://doi.org/10.1016/S0040-4039(01)01376-4.
16. S.B. Wan, D. Chen, Q.P. Dou and T.H. Chan, Bioorg. Med. Chem., 12,
3521 (2004);
ACKNOWLEDGEMENTS
The authors like to thank for the support of Divis labora-
tories for the support given for completion of the work.
https://doi.org/10.1016/j.bmc.2004.04.033.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.