Total synthesis of evelynin B and taccabulin D

Article abstract of DOI:10.3184/174751915X14380132772976

Concise total syntheses of biosynthetic retro-dihydrochalones evelynin B and taccabulin D isolated from roots and rhizomes of Tacca chantrieri and T. integrifolia, have been achieved from pyrogallol trimethylether in six steps and 1,3,5-trimethoxybenzene in three steps, respectively. A condensation between aldehyde and acetophenone was applied to form chalcone as a key step.

Full text of DOI:10.3184/174751915X14380132772976

458 RESEARCH PAPER
VOL. 39 AUGUST, 458–461
JOURNAL OF CHEMICAL RESEARCH 2015
Total synthesis of evelynin B and taccabulin D
Yu Huanga , Haifeng Gana and Kai Guoa,b*
aCollege of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, P.R. China
bState Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing 210009, P.R. China
Concise total syntheses of biosynthetic retro-dihydrochalones evelynin B and taccabulin D isolated from roots and rhizomes of Tacca
chantrieri and T. integrifolia, have been achieved from pyrogallol trimethylether in six steps and 1,3,5-trimethoxybenzene in three steps,
respectively. A condensation between aldehyde and acetophenone was applied to form chalcone as a key step.
Keywords: total syntheses, tacca species, retro-dihydrochalcone, Claisen–Schmidt reaction
Biosynthetic retro-dihydrochalcone derivatives represent a
significant class of compounds with broad and remarkable
potential biological properties, such as anti-ulcer,1 anti-
histamine,2 and anti-microbial,3 and anti-malarial activities.4
Therefore, it is not surprising that many synthetic methods have
been developed for these types of compounds.5-11
Evelynin B and taccabulin D (Fig. 1) are two novel retro-
dihydrochalcone-typed compounds, isolated from fresh
roots and rhizomes of Tacca chantrieri and T. integrifolia by
Moberry and co-workers in 2013.12 Compounds 1 and 2 have
antiproliferative activities against three cancer cell lines:
HeLa, A549 and PC-3.12 The IC50 values of evelynin B (1)
against HeLa, A549, and PC-3 cells are 8.8, 8.3 and 5.0 μM,
respectively, while those of taccabulin D (2) are 28.9, 40.3 and
more than 50 μM.
syntheses of evelynin B (1) and taccabulin D (2) from the
accessible starting material trimethoxybenzene which would
provide enough compounds for further biological studies.
Results and discussion
Our initial retrosynthetic analysis of 1 is outlined in Scheme 1.
We envisaged that a Claisen–Schmidt reaction could be used
to construct the main skeleton of evelynin B and taccabulin D.
Aldehyde 6, in turn, could be obtained from a cheap starting
material 1,2,3-trimethoxybenzene.
The synthesis of evelynin B is illustrated in Scheme 2.
1,2,3-Trimethoxybenzene was oxidised with 30% HNO3 to form
1,4-benzoquinone 3 in 80% yield.13 Reduction of 3 with Na2S2O4
in EtOAc for 40 min smoothly gave diphenol 4 in 84% yield.14
Dialkylation of diphenol 4 with BnBr in refluxing acetone
affords ether 5 in 86% yield.15 Aldehyde 6 was available through
Vilsmeier reaction from ether 5 in 81% yield.14 Then, aldehyde
6 was reacted with 3,4-methylenedioxyacetophenone 7 through
We have initiated the total synthesis of the two new
compounds in order to investigate the potential bioactivity
of the derivatives. We now report the concise efficient total
O
H
3CO
OCH3
OH
MeO
OMe
O
O
OCH3
OCH3
O
O
O
Evelynin B (1)
Taccabulin (2)
Fig 1. Structures of evelynin B and taccabulin D.
OBn
O
MeO
OMe
O
Evelynin B (1)
O
O
OBn
O
8
7
+
OBn
OMe
MeO
OHC
OMe
MeO
OMe
OBn
6
Scheme 1 Retrosynthetic analysis of evelynin B (1).
* Correspondent. E-mail: guok@njtech.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2015 459
a Claisen–Schmidt reaction to give the key intermediate enone
8 in 83% yield.16 Finally, enone 8 was hydrogenated in the
presence of Pd on carbon (10%) to afford diphenol 9, which was
used for next step without further purification.17 Oxidation of 9
by PCC in DCM successfully provided natural product evelynin
B (1) with 73% yield as a yellow solid in two steps.18
The total synthesis of taccabulin D is similar to that of
evelynin B (Scheme 2). 2,4,6-Trimethoxybenzaldehyde 10
was synthesised through a Vilsmeier reaction in 92% yield.7
3-Methoxy-4-hydroxyacetophenone was alkylated to give
ketone 11 in 98% yield.19 Then, a Claisen–Schmidt reaction was
used to afford enone 12 in 84% yield, followed by hydrogenation
to give the natural product taccabulin D (2) in 75% yield as a
colourless solid. The analytical and spectral data of 1 and 2 are
consistent with those described for the natural products.
accessible trimethoxybenzene in 3–6 steps (overall yields:
20% for evelynin B; 56% for taccabulin D). The mild reaction
conditions and operational simplicity make this method
attractive for the practical synthesis of these natural products
and their derivatives, which facilitates further biological
experiments. Studies towards the structure modifications of
these natural products for further pharmacological investigation
are ongoing.
Experimental
Melting points were measured on a microscopic melting point
apparatus. The IR spectra were recorded on a Bruker Tensor 27 FTIR
spectrometer with a KBr disk or film. 1H NMR and 13C NMR spectra
were taken on a Bruker AV 300 or AV 400 MHz and 75 or 100 MHz
spectrometer in CDCl3, chemical shifts are given in ppm relative to
TMS as an internal standard. Mass spectra and high resolution mass
spectra were performed on Agilent Q TOF 6520 mass spectrometer
with electron spray ionisation (ESI) as the ion mode. Optical rotations
were recorded using a sodium lamp with a Rudolph Autopol I
Automatic Polarimeter with a 1 dm tube.
Conclusions
In summary, we have developed a concise route for the first
total syntheses of evelynin B and taccabulin D starting from
O
OH
OBn
OMe
H
3CO
MeO
MeO
OCH3
OMe
OMe
i
iii
ii
MeO
OMe
O
OH
OBn
4
5
3
iv
OBn
OBn
OBn
MeO
OMe
MeO
OHC
OMe
v
O
O
O
O
O
OBn
8
O
6
7
vi
OH
OH
O
O
MeO
OMe
MeO
OMe
O
O
vii
O
O
O
O
9
Evelynin B (1)
H
3CO
H
3CO
OCH3
OCH3
CHO
viii
OCH3
OCH3
10
H
3CO
OCH3
OBn
x
OCH3
OBn
OCH3
12
O
OH
OCH3
ix
OCH3
O
O
11
xi
H
3CO
OCH3
OH
OCH3
OCH3
O
Taccabulin (2)
Scheme 2 Reagents and conditions: (i) 30% HNO , HOAc, room terature (r.t.), 1 h, 80%; (ii) 20% aq. Na S2O , EtOAc, r.t., 40 min, 84%; (iii) BnBr, K2CO ,
acetone, reflux, 24 h, 86%; (iv) POCl3, DMF, r.t., 163h, 81%; (v) 60% aq. KOH, EtOH, r.t., 2 h, 83%; (vi) H2,210%4Pd/C (30 w/w %), EtOH, 12 h; (vii) PCC (2.32
equiv.), DCM, r.t., 2 h, 73% in two steps; (viii) POCl3, DMF, r.t., 16 h, 92%; (ix) BnBr, K2CO3, KI, CH3CN, reflux, 24 h, 98%; (x) 60% aq. KOH, EtOH, r.t., 2
h, 84%; (xi) H2, 10% Pd/C (15 w/w %), EtOH, 12 h, 75%.

460 JOURNAL OF CHEMICAL RESEARCH 2015
o
2,6-Dimethoxybenzene-1,4-diol (4): Prepared by oxidation
of 1,2,3-trimethoxybenzene with 30% HNO3 in AcOH to give
benzoquinone 3, followed by reduction with Na2S2O4 in EtOAc. Yield
BnBr in refluxing CH3CN. Yield 6.0 g (98%); white solid; m.p. 87 C
(lit.20 86–88 oC). 1H NMR (300 MHz, CDCl3) δ 7.21–7.55 (m, 7H, ArH),
6.86 (d, J = 8.2 Hz, 1H, ArH), 5.20 (s, 2H, CH2), 3.91 (s, 3H, OCH3), 2.51
(s, 3H, CH3). MS (ESI) m/z (%) 257 (M+H+).
o
6.5 g (67% in two steps); brown solid; m.p. 158 C (lit.14 157–158 oC).
1H NMR (300 MHz, CDCl3) δ 5.86 (s, 2H, ArH), 3.83 (s, 6H, OCH3).
(E)-1-(4-(Benzyloxy)-3-methoxyphenyl)-3-(2,4,6-trimethoxyphenyl)
prop-2-en-1-one (12): The operating procedure was analogous to that of
compound 8. Using compound 11 (0.65 g, 2.55 mmol) and compound 7
(0.50 g, 2.55 mmol) gave 12 (0.92 g, 84%) as a green solid; m.p. 111–113
oC; IR (KBr, cm-1): ν 3083, 2939, 1640, 1555, 1251, 1141; 1H NMR (400
MHz, CDCl3) δ 8.22 (d, J = 15.8 Hz, 1H, CH =), 7.87 (d, J = 15.8 Hz, 1H,
CH =), 7.65 (d, J = 2.0 Hz, 1H, ArH), 7.58 (dd, J = 8.4, 2.0 Hz, 1H, ArH ),
7.32–7.48 (m, 5H, ArH), 6.92 (d, J = 8.4 Hz, 1H, ArH), 6.14 (s, 2H, ArH),
5.25 (s, 2H, OCH2), 3.97 (s, 3H, OCH3), 3.90 (s, 6H, OCH3), 3.86 (s, 3H,
OCH3); 13C NMR (100 MHz, CDCl3) δ 190.4, 163.0, 161.6, 151.7, 149.5,
136.6, 135.3, 132.7, 128.7, 128.0, 127.2, 122.5, 121.7, 112.2, 111.5, 106.7,
90.6, 70.8, 56.1, 55.8, 55.4; HRMS (ESI) calcd for C26H27O6 (M+H+)m/z
435.1802; found: 435.1816.
Taccabulin D (2):17 0.06 g (15 w/w %) of Pd on carbon (10%)
was added to a solution of compound 12 (0.4 g, 0.92 mmol) in
6 mL EtOAc, and the mixture was stirred at room temperature
under hydrogen atmosphere for 12 h. The mixture was filtered
and evaporated under reduced pressure. The residue was purified
by flash chromatography on silica gel to afford natural product
taccabulin D (2, 0.24 g, 75%) as a colourless solid; m.p. 116–118 oC;
IR (KBr, cm-1): ν 3446, 3003, 2940, 1670, 1606, 1264, 1144;1H NMR
(300 MHz, CDCl3) δ 7.59 (dd, J = 8.4, 1.5 Hz, 1H, ArH), 7.55 (d, J
= 1.5 Hz, 1H, ArH), 6.92 (d, J = 8.4 Hz, 1H, ArH), 6.2 9 (br s, 1H,
OH), 6.14 (s, 2H, ArH), 3.92 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 3.78
(s, 6H, OCH3), 3.01–3.03 (m, 4H, CH2);13C NMR (75 MHz, CDCl3)
δ 199.5, 159.6, 158.8, 150.1, 146.5, 130.0, 123.5, 113.8, 110.1, 110.0,
90.5, 56.0, 55.6, 55.3, 38.3, 18.6; HRMS (ESI) calcd for C19H23O6
(M+H+)m/z347.1489; found: 347.1500.
MS (ESI) m/z (%) 171 (M+H+).
2,5-Dibenzyloxy-1,3-dimethoxybenzene (5): Prepared by alkylation
of diphenol 4 with BnBr in refluxing acetone. Yield 7.8 g (86%); brown
oil.15 1H NMR (400 MHz, CDCl3) δ 7.27–7.50 (m, 10H, ArH), 6.23 (s,
2H, ArH), 5.02 (s, 2H, CH2), 4.94 (s, 2H, CH2), 3.79 (s, 6H, OCH3). MS
(ESI) m/z (%) 351 (M+H+).
3,6-Dibenzyloxy-2,4-dimethoxybenzaldehyde (6): Prepared through
Vilsmeier reaction of 2,5-dibenzyloxy-1,3-dimethoxybenzene 5
with DMF in the presence of POCl3. Yield 5.9 g (81%); yellow oil.14
1H NMR (300 MHz, CDCl3) δ 10.40 (s, 1H, CHO), 7.30–7.48 (m,
10H, ArH), 6.31 (s, 1H, ArH), 5.08 (s, 2H, CH2), 4.95 (s, 2H, CH2),
3.95 (s, 3H, OCH3), 3.83 (s, 3H, OCH3). MS (ESI) m/z (%) 379
(M+H+).
(2E)-1-(1,3-Benzodioxol-5-yl)-3-(3,6-dibenzyloxy-2,4-
dimethoxyphenyl)prop-2-en-1-one (8):16 3,4-Methylenedioxyaceto-
phenone (7, 0.09 g, 0.529 mmol) was dissolved in EtOH (2 mL) and
cooled to 0 °C. Compound 6 (0.2 g, 0.529 mmol) was added to the
solution and stirred for 10 min, 60% KOH aqueous solution (0.5 mL) was
added in one portion, and the mixture was stirred for 30 min. The mixture
was heated to room temperature and stirred for another 2 h. It was poured
into ice cold water (20 mL) and then neutralised with 2.5N HCl (10 mL).
EtOAc (30 mL) was added, and the organic phase was separated. The
aqueous phase was further extracted with EtOAc (20 mL). The combined
EtOAc extracts were washed successively with water (30 mL), brine (20
mL), dried, filtered, and evaporated under reduced pressure. The residue
was purified by column chromatography on silica gel to give 8 (0.23 g,
83%) as a green solid; m.p. 148–150 oC; IR (KBr, cm-1): ν 3033, 2941,
1648, 1583, 1439, 1245, 1114;1H NMR (300 MHz, CDCl3) δ 8.17 (d, J =
15.8 Hz, 1H, CH =), 7.90 (d, J = 15.8 Hz, 1H, CH =), 7.28–7.50 (m, 11H,
ArH), 7.22 (dd, J = 8.2, 1.4 Hz, 1H, ArH), 6.68 (d, J = 8.2 Hz, 1H, ArH),
6.38 (s, 2H, ArH), 5.99 (s, 2H, OCH2O), 5.10 (s, 2H, OCH2), 4.96 (s, 2H,
OCH2), 3.94 (s, 3H, OCH3), 3.84 (s, 3H, OCH3); 13C NMR (75 MHz,
CDCl3) δ 189.0, 156.0, 155.6, 155.1, 151.0, 148.0, 137.5, 136.0, 135.5,
135.1, 133.6, 128.8, 128.6, 128.4, 128.3, 128.2, 128.1, 127.9, 124.3,
122.6, 111.3, 108.3, 107.6, 101.6, 93.2, 75.4, 71.2, 61.6, 56.0; HRMS
(ESI) calcd for C32H29O7 (M+H+)m/z 525.1908; found: 525.1923.
Evelynin B (1):17,18 0.3 g (30 w/w %) of Pd on carbon (10%) was
added to a solution of compound 8 (1 g, 1.9 mmol) in 15 mL of
absolute ethanol, and the mixture was stirred at room temperature
under hydrogen atmosphere for 12 h. The mixture was filtered
and the filtrate was evaporated under reduced pressure, yielding
0.75 g crude product, which was used for next step without further
purification. The residue was dissolved in 25 mL DCM and PCC
(0.93 g, 4.2 mmol) was added. The mixture was stirred at room
temperature for 2 h and evaporated under reduced pressure. The
residue was purified by column chromatography on silica gel to
afford natural product evelynin B (1, 0.48 g, 73% in two steps) as a
yellow solid; m.p. 110–112 oC; IR (KBr, cm-1): ν 3070, 2948, 1684,
1667, 1644, 1601, 1242, 1086; 1H NMR (400 MHz, CDCl3) δ 7.55 (br
d, J = 8.4 Hz, 1H, ArH), 7.43 (br, 1H, ArH), 6.83 (d, J = 8.4 Hz, 1H,
ArH), 6.03 (s, 2H, OCH2O ), 5.85 (s, 1H, ArH), 3.98 (s, 3H, OCH3),
3.81 (s, 3H, OCH3), 3.04 (t, J = 7.8 Hz, 2H, CH2), 2.84 (t, J = 7.8 Hz,
2H, CH2); 13C NMR (75 MHz, CDCl3): δ 196.7, 187.1, 177.9, 157.3,
154.6, 151.7, 148.1, 132.0, 131.4, 124.3, 107.8, 107.8, 106.9, 101.8,
61.0, 56.3, 37.1, 18.9; HRMS (ESI) calcd for C18H17O7 (M+H+) m/z
345.0969; found: 345.0982.
Electronic Supplementary Information
The 1H NMR and 13C NMR spectra of 8, 12, 1 and 2 can be found
in the ESI available through stl.publisher.ingentaconnect.com/
content/stl/jcr/supp-data.
The authors are grateful for financial support from the National
High Technology Research and Development Program of China
(863 Program, grant no. 2012AA02A701), the National High
Technology Research and Development Program of China (863
Program, grant no. 2013AA031901). This was a Project Funded
by the Priority Academic Program Development of Jiangsu
Higher Education Institution.
Received 16 June 2015; accepted 10 July 2015
Paper 1503425 doi: 10.3184/174751915X14380132772976
Published online: 7 August 2015
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