Divergent and concise total syntheses of dihydrochalcones and 5-deoxyflavones recently isolated from Tacca species and Mimosa diplotricha

Article abstract of DOI:10.1016/j.tet.2015.02.017

Dihydrochalcones and 5-deoxyflavones are types of compounds possessing various biologically interesting properties. Herein, we report the concise and divergent total syntheses of several naturally occurring dihydrochalcones and 5-deoxyflavones from readily available starting materials. The divergent strategy is based around manipulation of a common chalcone scaffold and features application of Algar-Flynn-Oyamada oxidation and benzoquinone C-H activation methodologies. These are the first reported total syntheses of these biologically interesting compounds and the concise and flexible route should be readily amenable to future analogue generation. Furthermore, this work provides an illustration of the utility of divergent synthesis for the expedient and step-economical preparation of natural product libraries.

Full text of DOI:10.1016/j.tet.2015.02.017

Tetrahedron xxx (2015) 1e8
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Divergent and concise total syntheses of dihydrochalcones and
5-deoxyflavones recently isolated from Tacca species and Mimosa
diplotricha
Tze Han Sum a, Tze Jing Sum a, Jamie E. Stokes a, Warren R.J.D. Gallowaya,
,b,
David R. Spring a
*
a Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK
b Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Dihydrochalcones and 5-deoxyflavones are types of compounds possessing various biologically in-
teresting properties. Herein, we report the concise and divergent total syntheses of several naturally
occurring dihydrochalcones and 5-deoxyflavones from readily available starting materials. The divergent
strategy is based around manipulation of a common chalcone scaffold and features application of Al-
gareFlynneOyamada oxidation and benzoquinone CeH activation methodologies. These are the first
reported total syntheses of these biologically interesting compounds and the concise and flexible route
should be readily amenable to future analogue generation. Furthermore, this work provides an illus-
tration of the utility of divergent synthesis for the expedient and step-economical preparation of natural
product libraries.
Received 19 January 2015
Accepted 4 February 2015
Available online xxx
Keywords:
Natural product synthesis
Flavonoids
Dihydrochalcones
Deoxyflavones
Divergent synthesis
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
Flavonoids are a family of polyphenolic compounds. They are
ubiquitous in plants,1 and represent dietary constituents of po-
tential importance to health.2 Flavanoids are also emerging as
a potentially important new class of pharmaceutical lead sub-
strates.1 Amongst the several classes of flavonoids, dihy-
drochalcones and 5-deoxyflavones have been reported to
demonstrate a range of biologically interesting properties, in-
cluding antiinflammatory,3 antioxidant,4,5 antidiabetic,6 anti-
leishmanial,7 molluscidal8 and anticancer9 activities as well as
chemopreventive effects.10 Consequently, these compounds classes
have attracted interest from both the synthetic and medicinal
chemistry communities.11 Recently, Peng et al. reported the iso-
lation and characterization of five new dihydrochalcones, named
taccabulins BeE (1e4) and evelynin B (5) from extracts of the plant
species Tacca chantrieri and Tacca integrifolia (Fig. 1).12 Some of
these compounds were found to have interesting antiproliferative
activities against various cancer cell lines, in addition to microtu-
bule depolymerizing activities. In 2011, Lin et al. reported the
* Corresponding author. Tel.: þ44 (0)1223 336498; fax: þ44 (0)1223 336362;
Fig. 1. Naturally occurring dihydrochalcones and 5-deoxyflavones isolated from Tacca
species and Mimosa diplotricha.
e-mail address: spring@ch.cam.ac.uk (D.R. Spring).
http://dx.doi.org/10.1016/j.tet.2015.02.017
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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2
T.H. Sum et al. / Tetrahedron xxx (2015) 1e8
isolation of four previously unreported 5-deoxyflavanoes from
Mimosa diplotricha, three of which were named diplotrins AeC
(6e8).13 The cytotoxic effects of these compounds were evaluated
against several human cancer cell lines, with diplotrin B (7) found
to have the most potent antiproliferative activity.
Given the wide variety of biological activities typically associ-
ated with dihydrochalcones and 5-deoxyflavones, we were in-
terested in a more extensive biological evaluation of compounds
1e8. Furthermore, we have an on-going interest in exploring novel
chemical space, including that around such biologically privileged
structures.14 Thus, we sought to develop a concise strategy that
would provide efficient access to all of these natural compounds
and which could potentially be adapted for later library production.
Herein, we report the development of a divergent synthetic strat-
egy for the expedient synthesis of dihydrochalcones 1e5 and 5-
deoxyflavones 6e8.15 These are the first reported total syntheses
of these biologically interesting compounds.
The total synthesis of taccabulin E (4) was accomplished in
a similarly efficient manner (Scheme 3). FriedeleCrafts acylation
and methylenation of catechol (29) allowed access to intermediate
31 in good yield.21,22 ClaiseneSchmidt aldol coupling with the
previously prepared benzaldehyde 19 (Scheme 2) allowed access to
chalcone 32 is satisfactory yield. Hydrogenation and sodium bo-
rohydride mediated ketone reduction lead smoothly to taccabulin E
(4) in 83% yield over two steps.
The synthesis of evelynin B (5) relied upon Ilangovan’s recently
published quinone CeH activation methodology.23 This radical-
based strategy was utilized in place of the late-stage Clai-
seneSchmidt aldol coupling procedure (Scheme 4). The synthesis
began with 3,4-dihydroxybenzoic acid (34) and which was swiftly
converted into 36 following esterification and methylenation with
diiodomethane.24 The cyclopropanol precursor 37 was obtained in
satisfactory yield upon treatment of 36 with EtMgBr and
MeTi(OiPr)3.25 Radical coupling of 37 and benzoquinone 39, derived
from the oxidation of 38 with [bis(trifluoroacetoxy)iodo]benzene,26
proceeded to give evelynin B (5) in 27% yield.23
2. Results and discussion
With the five newly synthesized dihydrochalcones (1e5) in
hand, attention was turned towards the preparation of the 5-
deoxyflavones (6e8). A similar divergent synthetic strategy was
to be employed with the key difference being the late-stage
AlgareFlynneOyamada oxidation, which would afford the core
flavone framework (Scheme 5).
Inspired by previous work by Zhang et al. on the synthesis of
chalcones and 5-deoxyflavones, a divergent synthetic strategy to-
wards compounds 1e8 based on the use of a chalcone scaffold (of
the general form 9) as the pivotal branching point was proposed
(Scheme 1).9 It was envisaged that hydrogenation of compounds 9
would yield dihydrochalcones 10, whereas AlgareFlynneOyamada
oxidation would furnish the 5-deoxyflavone framework 11.9 It was
presumed that chalcones 9 could be easily accessed via a Clai-
seneSchmidt aldol condensation between benzaldehydes 12 and
acetophenones 13.9
The presence of hydroxyl functionality in the target diplotrins
necessitated the use of a protecting group strategy. Benzyl ethers
were chosen to protect the hydroxyl groups because their removal
is straightforward typically yielding analytically pure products
without the need for column chromatography. The synthesis
commenced with the acylation and selective methylation of pyro-
gallin (40) and resorcinol (41) to yield 44 and 45, respectively
(Scheme 5).27e30 Alongside, two of the three required aldehyde
building blocks for the ClaiseneSchmidt aldol condensation
needed synthesis. Benzaldehyde 48 was obtained from the for-
mylation of 46 with trimethyl orthoformate and AlCl3.29 Benzal-
dehyde 47 underwent selective demethylation with BBr3 in good
yield to afford 50.31 With the necessary aldehydes in hand, the free
hydroxyl functionality in 48, isovanillin (49) and 50 were protected
as benzyl ethers by reaction with benzyl bromide in the presence of
K2CO3.32e34 Union of fragments 51 and 52 with 44 and 53 with 45
by aldol coupling afforded the AlgareFlynneOyamada cyclization
precursors 54, 55 and 56 in generally acceptable yields.
Diplotrins A (6) and B (7) were rapidly obtained from 54 and 55,
respectively, by AlgareFlynneOyamada oxidation,9 methylation
and benzyl deprotection9 (Scheme 6). Simultaneously, 56 was
cyclized into the flavone scaffold by treatment with iodine in DMSO
and deprotected to afford diplotrin C (B).35
Scheme 1. Retrosynthetic analysis of the dihydrochalcones 10 and 5-deoxyflavones 11.
3. Conclusions
The total synthesis of taccabulins BeD (1e3) was achieved by
the application of this divergent synthetic strategy (Scheme 2).
The benzaldehyde precursors 18 and 19 were prepared expe-
diently from commercially available starting materials by methyl-
ation and VilsmeireHaack formylation.16,17 Benzaldehyde 21 was
obtained from 19 through use of a demethylation and MOM pro-
tection sequence.18 In parallel, the common acetophenone building
block 23 was prepared in good yield from the Eaton’s reagent in-
duced Fries rearrangement of 2-methoxyphenylacetate (22).19
Benzaldehydes 18, 21 and 19 were conveniently paired with 23
via a ClaiseneSchmidt aldol condensation to yield 24e26, re-
spectively, in up to 71% yield.9 Following methylation of 24 with
dimethyl sulfate to give 27, the key chalcone intermediates 25e27
were reduced with hydrogen and platinum(IV) oxide20 to yield
taccabulin B (1), taccabulin D (3) and 28, which was subsequently
converted to taccabulin C (2) by a HCl mediated MOM deprotection.
In summary, the first total synthesis of taccabulins BeE (1e4),
evelynin B (5) and diplotrins AeC (6e8) was accomplished from
commercially available starting materials. A concise divergent
strategy was employed whereby a common chalcone scaffold was
prepared by a ClaiseneSchmidt aldol condensation and trans-
formed into either the dihydrochalcones or the 5-deoxyflavones by
hydrogenation or AlgareFlynneOyamada oxidation, respectively.
Evelynin B (5) was also synthesized in an expedient manner from
commercially available starting materials. The Evelynin B (5)
framework was constructed through use of Ilangovan’s benzoqui-
none CeH activation methodology.23 All the final natural products
were generated on milligram (typically multimilligram) scale,
which should provide sufficient material for screening in a large
number of biological assays. The results from these studies should
yield further valuable information on the biological capabilities of
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T.H. Sum et al. / Tetrahedron xxx (2015) 1e8
3
Scheme 2. Synthesis of taccabulin B (1), C (2) and D (3).
Scheme 3. Synthesis of taccabulin E (4).
Scheme 4. Synthesis of evelynin B (5).
these natural products. The work reported herein provides an il-
lustration of the utility of divergent synthesis for the expedient and
step-economical preparation of natural product libraries. The
concise and flexible nature of our divergent route should make it
readily amenable to analogue preparation. The synthesis of struc-
turally related unnatural chalcones and 5-deoxyflavones is cur-
rently underway. The results from these investigations, along with
the outcomes of biological screening efforts, will be reported in due
course.
4. Experimental section
4.1. General information
All reagents and solvents were purchased from commercial
sources and used without further purification unless otherwise
stated. All the experiments were carried out under a nitrogen
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T.H. Sum et al. / Tetrahedron xxx (2015) 1e8
Scheme 5. Synthesis of the 5-deoxyflavone cyclization precursors.
mesh). 1H NMR and 13C NMR were recorded on a Bruker Avance
500 MHz instrument in CDCl3, (CD3)2CO and DMSO-d6. HRMS was
recorded on a Micromass Q-TOF mass spectrometer or a Waters LCT
Premier Time of Flight mass spectrometer.
4.2. General procedures
4.2.1. General procedure A: synthesis of chalcones (GP-A). To a stir-
red solution of KOH (12.0 equiv) in absolute EtOH (50 mL) cooled to
0
ꢀC in an ice-bath was added dropwise a solution of the corre-
sponding acetophenone (1.0 equiv) and aldehyde (1.0 equiv) in
EtOH (20 mL). The reaction mixture was stirred at 0 ꢀC for 1 h and
then at room temperature for 72 h under nitrogen. The resulting
mixture was then poured into ice-water (100 mL) and acidified to
pH 3e4 with 3 M HCl. The aqueous solution was extracted with
CHCl3 (3ꢁ100 mL) and the combined organic layer was washed
with satd NaHCO3 (2ꢁ100 mL), brine (2ꢁ100 mL), dried over an-
hydrous MgSO4, filtered and the solvent removed under reduced
pressure. The crude residue was purified by flash column chro-
matography over silica and recrystallized from absolute EtOH to
afford the corresponding chalcones.
4.2.2. General procedure B: synthesis of dihydrochalcones (GP-B). To
a stirred solution of the corresponding chalcone in MeOH (10 mL)
was added platinum(IV) oxide (2 mol %) and the reaction mixture
was stirred vigorously at room temperature under a hydrogen at-
mosphere until TLC analysis indicated complete consumption of
starting material. The resulting mixture was filtered through a pad
of Celite and washed with additional MeOH (2ꢁ10 mL). The com-
bined organic filtrate was concentrated in vacuo and the crude
residue was purified by flash column chromatography over silica to
afford the corresponding dihydrochalcones.
Scheme 6. Synthesis of diplotrin A (6), B (7) and C (8).
atmosphere unless otherwise stated. Melting points were mea-
€
sured using a Buchi B545 melting point apparatus and are un-
4.2.3. General procedure C: synthesis of flavonols (GP-C). To a stirred
solution of the corresponding chalcone (0.3 mmol) in MeOH (5 mL)
were added 16% NaOH (aq) (0.6 mL) and 15% H2O2 (0.3 mL). The
reaction mixture was stirred at room temperature for 24 h under
a nitrogen atmosphere. The resulting mixture was then poured into
corrected. Thin layer chromatography (TLC) was performed on
precoated Merck silica gel GF254 plates. IR spectra were recorded on
a PerkineElmer Spectrum One (FT-IR) spectrophotometer. Flash
column chromatography was performed on silica gel (230e400
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T.H. Sum et al. / Tetrahedron xxx (2015) 1e8
5
ice-water (50 mL) and acidified to pH 3e4 with 3 M HCl. The
aqueous solution was extracted with CHCl3 (3ꢁ50 mL) and the
combined organic layer was washed with satd NaHCO3 (2ꢁ50 mL),
brine (2ꢁ50 mL), dried over anhydrous MgSO4, filtered and the
solvent removed under reduced pressure. The crude residue was
purified by flash column chromatography over silica to afford the
corresponding flavonols.
151.5, 156.2, 158.7, 158.8, 198.4. HRMS (ESIꢂ) m/z¼331.1196 [MꢂH]þ
þ
found, C18H19O6 required 331.1187.
4.3.3. Synthesis of 1-(4-hydroxy-3-methoxyphenyl)-3-(2,4,6-
trimethoxyphenyl)propan-1-onedtaccabulin D (3). A mixture of
chalcone 26 (300 mg, 0.871 mmol) and platinum(IV) oxide
(11.5 mg, 0.0506 mmol) in MeOH (10 mL) was reacted according to
GP-B. The crude solid was purified by flash column chromatogra-
phy (SiO2, PE/EtOAc; 1:1) to afford 3 (241 mg, 80%) as a white
powdery solid. Mp 126e128 ꢀC. TLC Rf¼0.41 (PE/EtOAc; 1:1). IR nmax
(neat)/cmꢂ1: 3470m(br) (OeH str), 2942m (CeH str), 2841w (CeH
str), 1740 m (C]O str), 1669s, 1593s (C]C str), 1515s (C]C str),
1500m (C]C str), 1459s, 1420s, 1375w, 1295s, 1269s, 1241m, 1218s,
1200s, 1189s, 1145s, 1130m, 1109s, 1055m, 1038m, 1027m. 1H NMR
4.2.4. General procedure D: synthesis of hydroxyflavones (GP-D). To
a stirred solution of the corresponding flavone (1.0 equiv) in MeOH
(10 mL) was added 10% palladium/carbon (Pd/C) and the reaction
mixture was stirred vigorously at room temperature under a hy-
drogen atmosphere until TLC analysis indicated complete con-
sumption of starting material. The resulting mixture was filtered
through a pad of Celite and washed with additional MeOH
(2ꢁ10 mL). The combined organic filtrate was concentrated in
vacuo and the crude residue was purified by flash column chro-
matography over silica to afford the corresponding
hydroxyflavones.
(500 MHz, DMSO-d6):
d 2.76 (2H, t, J 9.0 Hz, eCH2CH2COe), 2.91
(2H, t, J 7.0 Hz, eCH2CH2COe), 3.74 (6H, s, eOCH3), 3.76 (3H, s,
eOCH3), 3.81 (3H, s, eOCH3), 6.21 (2H, s, ArH), 6.85 (1H, d, J 8.5 Hz,
ArH), 7.42 (1H, d, J 2.0 Hz, ArH), 7.49 (1H, dd, J 8.5, 2.0 Hz, ArH), 9.93
(1H, br s, OH). 13C NMR (500 MHz, DMSO-d6):
d 18.4, 37.8, 55.2, 55.5,
55.6, 90.8, 108.6, 111.1, 114.9, 122.8, 128.4, 147.5, 151.5, 158.3, 159.3,
198.1. HRMS (ESIþ) m/z¼369.1305 [MþNa]þ found, C19H22O6Naþ
required 369.1309.
4.3. Experimental details and characterization data
4.3.1. Synthesis of 1-(3,4-dimethoxyphenyl)-3-(2,3,4,6-
tetramethoxyphenyl)propan-1-onedtaccabulin B (1). A mixture of
chalcone 27 (115 mg, 0.296 mmol) and platinum(IV) oxide
(2.60 mg, 0.0114 mmol) in MeOH (5 mL) was reacted according to
GP-B. The crude residue was purified by flash column chromatog-
raphy (SiO2, PE/EtOAc; 1:1) to afford 1 (50.7 mg, 44%) as a white
powdery solid. Mp 88e90 ꢀC. TLC Rf¼0.39 (PE/EtOAc; 1:1). IR nmax
(neat)/cmꢂ1: 2953m (CeH str), 2838w (CeH str), 1738m (C]O str),
1657m, 1596s (C]C str), 1583s (C]C str), 1514s (C]C str), 1496m,
1452s, 1437m, 1407s, 1329m, 1300m, 1278m, 1261s, 1227s, 1214s,
1142m, 1128m, 1102s, 1065w, 1043m, 1021s. 1H NMR (500 MHz,
4.3.4. Synthesis of 1-(4,5-dimethylenedioxyphenyl)-3-(2,4,6-
trimethoxyphenyl)propan-1-oldtaccabulin E (4). To a stirred solu-
tion of chalcone 33 (200 mg, 0.581 mmol) in dry MeOH (10 mL)
while cooling to 0 ꢀC in an ice-bath was added NaBH4 (58.0 mg,
1.54 mmol) portionwise over 15 min under nitrogen. The reaction
mixture was first stirred at 0 ꢀC for 1 h and then at room temper-
ature for 8 h. Water (20 mL) was added to the resulting suspension
and the mixture was partitioned between CHCl3 (50 mL) and H2O
(50 mL). The layers were separated and the aqueous layer was
extracted with CHCl3 (3ꢁ20 mL). The combined organic extracts
were washed with H2O (2ꢁ50 mL), brine (2ꢁ50 mL), dried over
anhydrous MgSO4, filtered and evaporated to dryness under re-
duced pressure. The crude residue was purified by flash column
chromatography (SiO2, PE/EtOAc; 1:1) to afford 4 (190 mg, 94%) as
a white powdery solid. Mp 108e110 ꢀC. TLC Rf¼0.32 (PE/EtOAc;
2:1). IR nmax (neat)/cmꢂ1: 3439w(br) (OeH str), 2971w (CeH str),
2841w (CeH str), 1739m (C]O str), 1596s (C]C str), 1499s (C]C
str), 1488s, 1457s, 1438s, 1415m, 1375w, 1321w, 1230s, 1208s, 1148s,
1128s, 1111s, 1055w, 1034s, 1011m. 1H NMR (500 MHz, CDCl3):
CDCl3):
d 2.99 (2H, t, J 9.5 Hz, eCH2CH2COe), 3.11 (2H, t, J 6.0 Hz,
eCH2CH2COe), 3.79 (3H, s, eOCH3), 3.83 (3H, s, eOCH3), 3.88 (3H, s,
eOCH3), 3.89 (3H, s, eOCH3), 3.94 (3H, s, eOCH3), 3.95 (3H, s,
eOCH3), 6.30 (1H, s, ArH), 6.88 (1H, d, J 8.5 Hz, ArH), 7.57 (1H, d, J
2.0 Hz, ArH), 7.64 (1H, dd, J 8.5, 2.0 Hz, ArH). 13C NMR (500 MHz,
CDCl3):
d 19.2, 38.7, 55.8, 56.0, 56.0, 56.2, 60.9, 61.2, 92.5, 109.9,
110.3, 115.3, 122.8, 130.2, 136.4, 148.9, 151.9, 152.5, 153.0, 153.8,
þ
199.1. HRMS (ESIþ) m/z¼391.1735 [MþH]þ found, C21H27O7 re-
quired 391.1751.
d
1.85e1.90 (2H, m, eCH2CH2CHe), 2.75 (2H, t, J 7.0 Hz,
4.3.2. Synthesis of 1-(4-hydroxy-3-methoxyphenyl)-3-(2-hydroxy-
4,6-dimethoxyphenyl)propan-1-onedtaccabulin C (2). To a stirred
solution of chalcone 28 (69.0 mg, 0.183 mmol) in MeOH (5 mL) was
added 3 M HCl (1 mL) dropwise over 10 min and the resulting
mixture was heated at reflux for 3 h. The reaction mixture was
allowed to cool to room temperature and the solvent removed
under reduced pressure. The crude residue was resuspended in
EtOAc (30 mL), washed with H2O (3ꢁ20 mL), brine (2ꢁ20 mL),
dried over anhydrous Na2SO4, filtered and evaporated to dryness.
The crude product was purified by flash column chromatography
(SiO2, PE/EtOAc; 1:1) to afford 2 (46.5 mg, 76%) as a pale white
powdery solid. Mp 160e162 ꢀC. TLC Rf¼0.39 (PE/EtOAc; 1:1). IR nmax
(neat)/cmꢂ1: 3108w(br) (OeH str), 2999w (CeH str), 2935w (CeH
str), 2839w (CeH str),1737m (C]O str),1651m,1618m,1580s (C]C
str), 1522m (C]C str), 1501w (C]C str), 1453m, 1374m, 1297m,
1281s, 1218s, 1198s, 1188s, 1166s, 1144s, 1116w, 1096s, 1057m,
eCH2CH2CHe), 3.06 (1H, br s, OH), 3.83 (9H, s, eOCH3), 4.40e4.43
(1H, m, eCH2CH2CHe), 5.93 (2H, s, eOCH2Oe), 6.17 (2H, s, ArH),
6.74e6.79 (2H, d, J 8.0 Hz, ArH), 6.78 (1H, dd, J 8.0, 1.5 Hz, ArH), 6.83
(1H, d, J 1.5 Hz, ArH). 13C NMR (500 MHz, CDCl3):
d 18.7, 38.7, 55.3,
55.7, 72.6, 90.6, 100.8, 106.5, 107.8, 109.8, 119.1, 138.8, 146.4, 147.5,
þ
158.7, 159.4. HRMS (ESIꢂ) m/z¼345.1320 [MꢂH]þ found, C19H21O6
required 345.1333.
4.3.5. Synthesis of 1-(4,5-dimethylenedioxyphenyl)-2(-3,5-
dimethoxycyclohexa-2,5-diene-1,4-dione) propan-1-onedevelynin B
(5). To
a mixture of methylene cyclopropanol 37 (172 mg,
0.964 mmol), 2,6-dimethoxy-p-benzoquinone 39 (149 mg,
0.886 mmol) and silver nitrate (30.6 mg, 0.180 mmol) in CH2Cl2/
H2O (10 mL; 1:1 mixture) was added potassium persulfate (K2S2O8)
(715 mg, 2.65 mmol) at room temperature with stirring under ni-
trogen. The resulting biphasic reaction mixture was stirred for
a further 3 h at room temperature until TLC analysis indicated
completion of the reaction. The organic layer was separated,
washed with H2O (2ꢁ50 mL), brine (2ꢁ50 mL), dried over anhy-
drous Na2SO4, filtered and evaporated to dryness under reduced
pressure. The crude residue was purified by flash column chro-
matography (SiO2, PE/EtOAc; 1:1) to afford 5 (82.6 mg, 27%) as
a bright yellow powdery solid. Mp 78e80 ꢀC. TLC Rf¼0.44 (PE/
1026m. 1H NMR (500 MHz, DMSO-d6):
d 2.74 (2H, t, J 9.2 Hz,
eCH2CH2COe), 2.92 (2H, t, J 6.8 Hz, eCH2CH2COe), 3.68 (3H, s,
eOCH3), 3.70 (3H, s, eOCH3), 3.82 (3H, s, eOCH3), 6.04 (1H, d, J
2.4 Hz, ArH), 6.06 (1H, d, J 2.4 Hz, ArH), 6.85 (1H, d, J 8.4 Hz, ArH),
7.46 (1H, d, J 2.0 Hz, ArH), 7.51 (1H, dd, J 8.4, 2.0 Hz, ArH), 9.37 (1H, s,
OH), 9.94 (1H, s, OH). 13C NMR (500 MHz, DMSO-d6):
d
18.6, 37.9,
54.9, 55.4, 55.5, 89.7, 93.6, 107.4, 111.2, 114.9, 122.8, 128.4, 147.4,
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6
T.H. Sum et al. / Tetrahedron xxx (2015) 1e8
EtOAc; 1:1). IR nmax (neat)/cmꢂ1: 3077w (CeH str), 2942w (CeH
str), 1674s (C]O str), 1643s (C]O str), 1627m, 1598s (C]C str),
1502m (C]C str), 1489m, 1443s, 1362m, 1295w, 1272w, 1240s,
1181m, 1111m, 1086s, 1036s, 1017m. 1H NMR (500 MHz, DMSO-d6):
d 56.0, 56.5, 60.4, 61.5, 71.8, 99.9, 109.7, 112.0, 117.1, 119.5, 120.9,
127.2, 127.4, 127.9, 127.9, 128.5, 128.5,136.7, 136.8, 137.0, 141.2, 142.0,
150.0, 152.0, 152.4, 155.8, 156.0, 174.6. HRMS (ESIþ) m/z¼555.1995
þ
[MþH]þ found, C33H31O8 required 555.2013.
d
2.63 (2H, t, J 8.4 Hz, eCH2CH2COe), 3.00 (2H, t, J 7.2 Hz,
eCH2CH2COe), 3.77 (3H, s, eOCH3), 3.87 (3H, s, eOCH3), 6.04 (1H, s,
ArH), 6.13 (2H, s, eOCH2Oe), 7.03 (1H, d, J 8.4 Hz, ArH), 7.41 (1H, d, J
1.6 Hz, ArH), 7.58 (1H, dd, J 8.4, 2.0 Hz, ArH). 13C NMR (500 MHz,
4.3.8. Synthesis
flavoneddiplotrin
of
A (6). A mixture of flavone 57 (140 mg,
20,50-dihydroxy-3,7,8,40-tetramethoxy-
0.252 mmol) and 10% Pd/C (34.7 mg) in MeOH (10 mL) was reacted
according to GP-D. The crude product was purified by flash column
chromatography (SiO2, 1% MeOH/CH2Cl2) to afford 6 (83.5 mg, 88%)
as a pale yellow powdery solid. Mp 110e112 ꢀC (lit. mp17 113 ꢀC).
TLC Rf¼0.18 (1% MeOH/CH2Cl2). IR nmax (neat)/cmꢂ1: 3507w(br)
(OeH str), 3138w(br) (OeH str), 2944w (CeH str), 2846w (CeH str),
1739w, 1607s (C]O str), 1594s (C]C str), 1562m (C]C str), 1511s
(C]C str), 1449s, 1428m, 1375m, 1345m, 1286s, 1271w, 1248m,
1198s, 1164s, 1125s, 1085s, 1066m, 1030m, 1001s. 1H NMR
DMSO-d6):
d 18.4, 36.9, 56.6, 60.7, 102.0, 106.8, 107.3, 108.1, 124.4,
130.9, 147.8, 151.5, 154.5, 157.6, 177.4, 187.0, 196.7. HRMS (ESIþ) m/
z¼345.0957 [MþH]þ found, C18H17O7 required 345.0969.
þ
4.3.6. Synthesis of 1-(2-hydroxy-3,4-dimethoxyphenyl)-3-(2,5-
dibenzyloxy-4-methoxyphenyl)propenone (54). A mixture of 2-
hydroxy-3,4-dimethoxyacetophenone 44 (1.35 g, 6.88 mmol), 2,5-
dibenzyloxy-4-methoxybenzaldehyde 51 (2.35 g, 6.75 mmol) and
KOH (5.03 g, 89.6 mmol) in absolute EtOH (50 mL) was reacted
according to GP-A. The crude product was purified by flash column
chromatography (SiO2, PE/EtOAc; 5:1) and recrystallized from ab-
solute EtOH to afford 54 (968 mg, 27%) as a bright yellow-orange
powdery solid. Mp 178e180 ꢀC. TLC Rf¼0.22 (PE/EtOAc; 2:1). IR
nmax (neat)/cmꢂ1: 3004w(br) (OeH str), 2937w (CeH str), 2843w
(CeH str), 1745w, 1628m (C]O str), 1606w (C]C str), 1552s (C]C
str), 1501m (C]C str), 1444s, 1343m, 1265s, 1224s, 1199w, 1129s,
(500 MHz, DMSO-d6):
d 3.70 (3H, s, eOCH3), 3.79 (3H, s, eOCH3),
3.83 (3H, s, eOCH3), 3.94 (3H, s, eOCH3), 6.56 (1H, s, ArH), 6.82 (1H,
s, ArH), 7.26 (1H, d, J 9.2 Hz, ArH), 7.81 (1H, d, J 8.8 Hz, ArH), 8.61
(1H, s, OH), 9.25 (1H, s, OH). 13C NMR (500 MHz, DMSO-d6):
d 55.5,
56.5, 59.7, 61.0, 101.0, 108.8, 110.6, 116.1, 118.7, 120.2, 136.2, 138.8,
140.2, 149.0, 149.4, 150.5, 155.9, 15þ6.1, 173.3. HRMS (ESIþ) m/
z¼375.1062 [MþH]þ found, C19H19O8 required 375.1074.
1078s, 1005s. 1H NMR (500 MHz, CDCl3):
d
3.91 (3H, s, eOCH3), 3.92
4.3.9. Synthesis of 1-(2-hydroxy-3,4-dimethoxyphenyl)-3-(3-
benzyloxy-4-methoxyphenyl)propenone (55). A mixture of 2-
hydroxy-3,4-dimethoxyacetophenone 44 (1.00 g, 5.10 mmol), 3-
(benzyloxy)-4-methoxybenzaldehyde 52 (1.25 g, 5.16 mmol) and
KOH (3.68 g, 65.6 mmol) in absolute EtOH (50 mL) was reacted
according to GP-A. The crude product was purified by flash column
chromatography (SiO2, PE/EtOAc; 5:1) and recrystallized from ab-
solute EtOH to afford 55 (1.10 g, 51%) as a bright yellow fluffy solid.
(3H, s, eOCH3), 3.95 (3H, s, eOCH3), 5.14 (2H, s, eOCH2Ph), 5.16 (2H,
s, eOCH2Ph), 6.35 (1H, d, J 9.2 Hz, ArH), 6.61 (1H, s, ArH), 7.11 (1H, s,
ArH), 7.23 (1H, d, J 9.2 Hz, ArH), 7.32e7.36 (1H, m, ArH), 7.38e7.48
(7H, m, ArH), 7.52 (2H, d, J 7.2 Hz, ArH), 7.58 (1H, d, J 15.2 Hz, eCH]
CHCOe), 7.99 (1H, d, J 15.6 Hz, eCH]CHCOe). 13C NMR (500 MHz,
CDCl3):
d 56.0, 56.1, 60.6, 71.5, 72.2, 98.4, 102.5, 115.8, 117.5, 119.2,
125.9, 127.5, 128.0, 128.3, 128.6, 128.8, 136.3, 136.6, 137.0, 140.6,
142.3, 153.2, 154.6, 158.1, 158.2, 193.0. HRMS (ESIþ) m/z¼527.2055
Mp 148e150 ꢀC. TLC Rf¼0.45 (PE/EtOAc; 1:1). IR nmax (neat)/cmꢂ1
:
þ
[MþH]þ found, C32H31O7 required 527.2064.
3006w(br) (OeH str), 2948w (CeH str), 2841w (CeH str), 1737w,
1635m (C]O str), 1596w (C]C str), 1561m (C]C str), 1504s (C]C
str), 1455w, 1438w, 1427m, 1370m, 1352w, 1306m, 1293w, 1257s,
1220m, 1163w, 1129s, 1076s, 1021w, 1005s. 1H NMR (500 MHz,
4.3.7. Synthesis of 20,50-dibenzyloxy-3,7,8,40-tetramethoxyflavone
(57). A mixture of chalcone 54 (300 mg, 0.570 mmol), 16% NaOH
(aq) (1.14 mL) and 15% H2O2 (0.570 mL) in MeOH (10 mL) was
reacted according to GP-C. The crude product was purified by flash
column chromatography (SiO2, 1% MeOH/CH2Cl2) to afford 2-(2,5-
bis(benzyloxy)-4-methoxyphenyl)-3-hydroxy-7,8-dimethoxy-4H-
chromen-4-one (149 mg, 48%) as a pale yellow powdery solid. To
a solution of 2-(2,5-bis(benzyloxy)-4-methoxyphenyl)-3-hydroxy-
7,8-dimethoxy-4H-chromen-4-one (220 mg, 0.407 mmol) in dry
acetone (10 mL) were added anhydrous K2CO3 (169 mg, 1.22 mmol)
and dimethyl sulfate (0.116 mL, 1.22 mmol). The reaction mixture
was heated at reflux with stirring for 3 h under a nitrogen atmo-
sphere. The resulting mixture was allowed to cool to room tem-
perature and the solvent removed under reduced pressure. The
crude residue was taken up in EtOAc (30 mL) and the organic layer
washed with H2O (2ꢁ20 mL), brine (20 mL), dried over anhydrous
MgSO4, filtered and evaporated. The crude product was purified by
flash column chromatography (SiO2, 1% MeOH/CH2Cl2) to afford 57
(198 mg, 88%) as a yellow oil, which solidified on standing to give
a bright yellow crystalline solid. Mp 58e60 ꢀC. TLC Rf¼0.48 (1%
MeOH/CH2Cl2). IR nmax (neat)/cmꢂ1: 2937w (CeH str), 2840w (CeH
str), 1600s (C]O str), 1508s (C]C str), 1442s, 1416w, 1377m, 1285s,
1269s, 1220s, 1196s, 1168s, 1122m, 1084s, 1062w, 1009s. 1H NMR
CDCl3):
d 3.93 (3H, s, eOCH3), 3.96 (3H, s, eOCH3), 3.97 (3H, s,
eOCH3), 5.23 (2H, s, eOCH2Ph), 6.55 (1H, d, J 8.8 Hz, ArH), 6.94 (1H,
d, J 8.4 Hz, ArH), 7.20 (1H, d, J 2.0 Hz, ArH), 7.26e7.28 (1H, m, ArH),
7.33e7.37 (2H, m, ArH), 7.42 (2H, t, J 7.6 Hz, ArH), 7.50 (2H, d, J
6.8 Hz, ArH), 7.65 (1H, d, J 8.8 Hz, eCH]CHCOe), 7.81 (1H, d, J
15.2 Hz, eCH]CHCOe). 13C NMR (500 MHz, CDCl3):
d 56.1, 56.1,
60.7, 71.3, 102.7, 111.6, 113.4, 115.6, 117.9, 123.7, 125.8, 127.4, 127.6,
128.1, 128.7, 136.7, 144.8, 148.4, 152.3, 158.3, þ158.4, 192.3. HRMS
(ESIþ) m/z¼421.1652 [MþH]þ found, C25H25O6 required 421.1646.
4.3.10. Synthesis
of
30-benzyloxy-3,7,8,40-tetramethoxyflavone
(58). A mixture of chalcone 55 (812 mg, 1.93 mmol), 16% NaOH (aq)
(3.86 mL) and 15% H2O2 (1.93 mL) in MeOH (10 mL) was reacted
according to GP-C. The crude product was purified by flash column
chromatography (SiO2, 1% MeOH/CH2Cl2) to afford 2-(3-(benzy-
loxy)-4-methoxyphenyl)-3-hydroxy-7,8-dimethoxy-4H-chromen-
4-one (448 mg, 53%) as a pale yellow-green powdery solid. To a so-
lution of 2-(3-(benzyloxy)-4-methoxyphenyl)-3-hydroxy-7,8-
dimethoxy-4H-chromen-4-one (302 mg, 0.694 mmol) in dry ace-
tone (10 mL) were added anhydrous K2CO3 (288 mg, 2.08 mmol) and
dimethyl sulfate (0.198 mL, 2.08 mmol). The reaction mixture was
heated at reflux with stirring for 3 h under a nitrogen atmosphere.
The resulting mixture was allowed to cool to room temperature,
filtered under suction, washed with additional acetone (3ꢁ10 mL)
and the solvent removed under reduced pressure. The crude prod-
uct was purified by flash column chromatography (SiO2, 1% MeOH/
(500 MHz, CDCl3):
d 3.66 (3H, s, eOCH3), 3.81 (3H, s, eOCH3), 3.88
(3H, s, eOCH3), 3.98 (3H, s, eOCH3), 5.13 (2H, s, eOCH2Ph), 5.13 (2H,
s, eOCH2Ph), 6.65 (1H, s, ArH), 7.03 (1H, d, J 9.0 Hz, ArH), 7.07 (1H, s,
ArH), 7.23e7.31 (4H, m, ArH), 7.34e7.37 (4H, m, ArH), 7.43 (2H, d, J
7.5 Hz, ArH), 8.00 (1H, d, J 9.0 Hz, ArH). 13C NMR (500 MHz, CDCl3):
Please cite this article in press as: Sum, T. H.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.02.017

T.H. Sum et al. / Tetrahedron xxx (2015) 1e8
7
CH2Cl2) to afford 58 (308 mg, 99%) as a pale yellow powdery solid.
Mp 168e170 ꢀC. TLC Rf¼0.30 (1% MeOH/CH2Cl2). IR nmax (neat)/
cmꢂ1: 2982w (CeH str), 2939w (CeH str), 2842w (CeH str), 1741w,
1637s (C]O str),1596s (C]C str),1566m (C]C str),1506s (C]C str),
1457s, 1435s, 1425m, 1381s, 1334m, 1287s, 1270m, 1259s, 1234w,
1206s, 1187w, 1167m, 1144s, 1083s, 1062s, 1041w, 1014s. 1H NMR
and the solvent removed under reduced pressure. The crude
product was purified by flash column chromatography (SiO2, PE/
EtOAc; 2:1) to afford 59 (197 mg, 41%) as a pale yellow powdery
solid. Mp 167e169 ꢀC. TLC Rf¼0.24 (PE/EtOAc; 1:1). IR nmax (neat)/
cmꢂ1: 2920w (CeH str), 2836w (CeH str), 1739w, 1635m (C]O str),
1613s (C]C str), 1578m (C]C str), 1563m (C]C str), 1522s (C]C
str), 1434s, 1399w, 1387m, 1358s, 1264s, 1249s, 1219s, 1207s, 1197s,
(500 MHz, CDCl3):
d 3.73 (3H, s, eOCH3), 3.97 (3H, s, eOCH3), 3.99
(3H, s, eOCH3), 4.00 (3H, s, eOCH3), 5.27 (2H, s, eOCH2Ph), 7.03 (1H,
d, J 9.5 Hz, ArH), 7.05 (1H, d, J 9.0 Hz, ArH), 7.31 (1H, t, J 7.5 Hz, ArH),
7.39 (2H, t, J 8.0 Hz, ArH), 7.49 (2H, t, J 8.0 Hz, ArH), 7.84 (1H, dd, J 8.5,
1164s, 1150s, 1088m, 1035m. 1H NMR (500 MHz, CDCl3):
d 3.87 (3H,
s, eOCH3), 3.92 (3H, s, eOCH3), 3.94 (3H, s, eOCH3), 5.22 (2H, s,
eOCH2Ph), 6.62 (1H, s, ArH), 6.89 (1H, d, J 2.5 Hz, ArH), 6.98 (1H, dd,
J 9.0, 2.0 Hz, ArH), 7.10 (1H, s, CH), 7.30e7.33 (1H, m, ArH), 7.35e7.38
2.5 Hz, ArH), 7.87 (1H, d, J 2.0 Hz, ArH), 7.96 (1H, d, J 8.5 Hz, ArH). 13
C
NMR (500 MHz, CDCl3):
d
56.0, 56.4, 59.8, 61.5, 70.8, 109.7, 111.3,
(3H, m, ArH), 7.42 (2H, d, J 7.0 Hz, ArH), 8.14 (1H, d, J 9.0 Hz, ArH). 13
C
113.8, 119.0, 121.0, 122.4, 123.5,127.1, 127.9, 128.6, 136.6, 136.7, 140.4,
NMR (500 MHz, CDCl3): d 55.8, 56.0, 56.7, 71.9, 99.7, 100.2, 111.5,
147.7, 149.4, 151.7, 154.8, 156.2, 174.6. HRMS (ESIþ) m/z¼449.1584
111.9, 113.1, 114.2, 117.6, 127.0, 127.2, 128.2, 128.7, 136.3, 143.5, 152.2,
þ
[MþH]þ found, C26H25O7 required 449.1595.
152.4, 158.1, 161.0, 164.0, 178.1. HRMS (ESIþ) m/z¼419.1477 [MþH]þ
þ
found, C25H23O6 required 419.1489.
4.3.11. Synthesis
flavoneddiplotrin
of
(7). A mixture of flavone 58 (28.3 mg,
30-hydroxy-3,7,8,40-tetramethoxy-
B
4.3.14. Synthesis of 20-hydroxy-7,40,50-trimethoxyflavoneddiplotrin
C (8). A mixture of flavone 59 (101 mg, 0.242 mmol) and 10% Pd/C
(20.7 mg) in MeOH (10 mL) was reacted according to GP-D. The
crude product was purified by flash column chromatography (SiO2,
PE/EtOAc; 1:1) and recrystallized from MeOH to afford 8 (59.4 mg,
75%) as a pale yellow powdery solid. Mp 168e170 ꢀC (lit. mp17
0.0631 mmol) and 10% Pd/C (20.0 mg) in MeOH (10 mL) was reacted
according to GP-D. The crude product was purified by flash column
chromatography (SiO2, 1% MeOH/CH2Cl2) to afford 7 (11.8 mg, 52%)
as a pale yellow powdery solid. Mp 160e162 ꢀC (lit. mp17 159 ꢀC). TLC
Rf¼0.16 (1% MeOH/CH2Cl2). IR nmax (neat)/cmꢂ1: 3366w(br) (OeH
str), 2920w (CeH str), 2850w (CeH str), 1593s (C]O str), 1554m
(C]C str), 1512s (C]C str), 1456w, 1434s, 1388m, 1288s, 1208m,
1179w, 1132m, 1088s, 1064m, 1023s. 1H NMR (500 MHz, CDCl3):
170 ꢀC). TLC Rf¼0.23 (PE/EtOAc; 1:3). IR nmax (neat)/cmꢂ1
:
3136w(br) (OeH str), 2961w (CeH str), 2920w (CeH str), 2851w
(CeH str), 1737w, 1611s (C]O str), 1587m (C]C str), 1551s (C]C
str), 1519m (C]C str), 1505m (C]C str), 1442m, 1401s, 1379s,
1251m, 1213m, 1198s, 1158s, 1103m, 1031s. 1H NMR (500 MHz,
d
3.90 (3H, s, eOCH3), 4.00 (3H, s, eOCH3), 4.01 (3H, s, eOCH3), 4.03
(3H, s, eOCH3), 5.73 (1H, br s, OH), 7.00e7.06 (2H, m, ArH), 7.79e7.82
(2H, m, ArH), 7.99 (1H, d, J 9.2 Hz, ArH). 13C NMR (500 MHz, CDCl3):
DMSO-d6):
d 3.80 (3H, s, eOCH3), 3.81 (3H, s, eOCH3), 3.92 (3H, s,
d
56.0, 56.5, 60.0, 61.6, 110.1, 110.4, 114.6, 118.7, 121.1, 121.7, 124.1,
eOCH3), 6.65 (1H, s, ArH), 7.03 (1H, dd, J 8.8, 2.4 Hz, ArH), 7.08 (1H,
s, ArH), 7.32 (1H, d, J 2.4 Hz, ArH), 7.47 (1H, s, ArH), 7.91 (1H, d, J
8.8 Hz, ArH), 10.48 (1H, br s, OH). 13C NMR (500 MHz, DMSO-d6):
136.7, 140.5, 145.5, 148.7, 149.6, 155.6,þ156.5, 175.2. HRMS (ESIþ) m/
z¼359.1117 [MþH]þ found, C19H19O7 required 359.1125.
d
55.5, 56.1, 56.6, 100.9, 101.1, 108.2, 109.5, 111.3, 114.3, 116.9, 126.0,
4.3.12. Synthesis of 1-(2-hydroxy-4-methoxyphenyl)-3-(2-
benzyloxy-4,5-dimethoxyphenyl)propenone (56). A mixture of 2-
hydroxy-4-methoxyacetophenone 45 (2.07 g, 12.5 mmol), 2-
benzyloxy-4,5-dimethoxybenzaldehyde 53 (3.30 g, 12.1 mmol)
and KOH (8.83 g, 157 mmol) in absolute EtOH (50 mL) was reacted
according to GP-A. The crude product was purified by flash column
chromatography (SiO2, PE/EtOAc; 5:1) and recrystallized from ab-
solute EtOH to afford 56 (786 mg, 15%) as a bright yellow-orange
fluffy solid. Mp 208e210 ꢀC. TLC Rf¼0.26 (PE/EtOAc; 2:1). IR nmax
(neat)/cmꢂ1: 3001w(br) (OeH str), 2943w (CeH str), 2905w (CeH
str), 2827w (CeH str), 1611m (C]O str), 1578w (C]C str), 1553m
(C]C str), 1526w (C]C str), 1505m (C]C str), 1465m, 1437m,
1402w, 1392w, 1350s, 1258m, 1232m, 1215m, 1201s, 1147s, 1121s,
142.1, 152.4, 152.5, 157.5, 160.2, 163.6, 176.5. HRMS (ESIþ) m/
þ
z¼329.1006 [MþH]þ found, C18H17O6 required 329.1020.
Acknowledgements
We thank the Cambridge Commonwealth Trust for the awards
of scholarships to T.H.S. and T.J.S. D.R.S. thanks financial supports
from Chinese Academy of Sciences visiting professorship for senior
international scientists (2013T2G0010).
Supplementary data
Copies of the 1H NMR and 13C NMR spectra of the synthesized
natural products. Supplementary data associated with this article
can be found in the online version, at http://dx.doi.org/10.1016/
j.tet.2015.02.017.
1051w, 1021s. 1H NMR (500 MHz, CDCl3):
d 3.85 (3H, s, eOCH3), 3.91
(3H, s, eOCH3), 3.93 (3H, s, eOCH3), 5.16 (2H, s, eOCH2Ph), 6.30 (1H,
dd, J 9.0, 3.0 Hz, ArH), 6.44 (1H, d, J 2.5 Hz, ArH), 6.62 (1H, s, ArH),
7.07 (1H, s, ArH), 7.37 (1H, d, J 9.0 Hz, ArH), 7.41e7.48 (3H, m, ArH),
7.52 (1H, d, J 1.5 Hz, ArH), 7.54 (1H, d, J 1.5 Hz, ArH), 7.69 (1H, d, J
15.5 Hz, eCH]CHCOe), 8.02 (1H, d, J 15.5 Hz, eCH]CHCOe). 13
C
References and notes
NMR (500 MHz, CDCl3):
d 55.5, 56.1, 56.5, 71.6, 98.2, 100.7, 107.5,
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(10 mL) was added a catalytic amount of iodine (12.6 mg,
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ꢀ
~
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Please cite this article in press as: Sum, T. H.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.02.017

8
T.H. Sum et al. / Tetrahedron xxx (2015) 1e8
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Please cite this article in press as: Sum, T. H.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.02.017