Concise total synthesis of 1,3-diphenylpropane derivatives griffithanes A, B and F

Article abstract of DOI:10.3184/174751915X14359076454633

Concise and efficient total syntheses of diarylpropanes griffithane A, B and F, isolated from Combretum griffithii, have been accomplished from methoxybenzaldehyde. The Claisen-Schmidt condensation between aldehyde and acetophenone was applied to form cha

Full text of DOI:10.3184/174751915X14359076454633

416 RESEARCH PAPER
VOL. 39 JULY, 416–420
JOURNAL OF CHEMICAL RESEARCH 2015
Concise total synthesis of 1,3-diphenylpropane derivatives griffithanes A, B
and F
Haifeng Gana, Weiwei Caoa, Weiyang Fenga 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 and efficient total syntheses of diarylpropanes griffithane A, B and F, isolated from Combretum griffithii, have been accomplished
from methoxybenzaldehyde. The Claisen–Schmidt condensation between aldehyde and acetophenone was applied to form chalcone as
a key step. The structures of chalcones are confirmed by crystal X-ray crystallography.
Keywords: total synthesis, diarylpropane, Combretum griffithii, chalcone
Many unique natural products isolated from plants
display different bioactivities that are very significant in
phytochemistry.1 Structures bearing the diarylpropane motif
have a diverse range of biological properties including anti-
Griffithane A, B and F (Fig. 1), are three novel diarylpropane-
typed natural products, isolated from the stems of Combretum
griffithii by Moosophon and co-workers in 2011 and 2013.14, 15
They showed compounds 1, 2 and 3 exhibited cytotoxicity towards
one or more cancer cell lines (KB, MCF-7 and NCI-H187). The
IC50 values of griffithanes A, B against KB cancer cell line are 6.7
and 17.8 μM, respectively; while those of griffithane F against KB
and MCF-7 cancer cell lines are 24.6 and 23.1 μM, respectively.
Several methods have been reported for the synthesis of new
diarylpropanes.2, 3, 9, 16 We have initiated the total synthesis of
the three new compounds in order to investigate the potential
bioactivity of the derivatives. We now report the concise efficient
total syntheses of griffithanes A, B and F from the accessible
starting material methoxybenzaldehyde.
3
inflammatory,2, antifungal,4 anti-vascular,5 anti-adipogenic,6
anti-hCNT3 (human concentrative nucleoside transporter 3),7
anti-proliferative,8 inhibiting aromatase,9 inducing TNF-α
expression,10 inhibiting DOPA decarboxylase,11 and anti-
tubercular activities.12 The diphenylpropane broussonin A
inhibited respiratory syncytial-virus (RSV) more effectively
than the standard antiviral drug ribavirin, and its anti-aromatase
activity has also been evaluated.9 Broussonin B moderately
inhibited chymotrypsin-like activity of the proteasome.13
R1
R2
OMe
Results and discussion
Intermediates including aldehydes 7, 10 and 13 and acetophenones
6 and 8 were synthesised according to literature.17-23 The key
intermediates 1,3-diphenylpropenones (chalcones) 14–16 were
synthesised by Claisen–Schmidt condensation of acetophenones
6 and 8 with aldehydes 7, 10 and 13 in 75–85% yields.10, 24-26 The
structures of 14 and 16 were confirmed by X-ray crystallography
(Fig. 2). Using literature methods,2, 16, 27 we attempted to obtain
R3
R5
H
O
R4
: R1 = OMe, R2 = H, R3 = OH, R4 = OMe, R5 = H
: R1 = OMe, R2 = OH, R3 = OMe, R4 = H, R5 = H
: R1 = OMe, R2 = H, R3 = OMe, R4 = OH, R5 = H
1
2
3
Fig. 1 Chemical structures of griffithanes A (1), B (2) and F (3).
O
MeO
BnO
OMe
OBn
=
MeO
14
OBn
OMe
MeO
OBn
OMe
=
O
16
Fig. 2 Crystal X-ray crystallography of compound 14 at 33% probability and 16 at 38% probability.
* Correspondent. E-mail: guok@ njtech.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2015 417
diphenylpropanes 1–3 by a one-step reduction of compounds
14–16, but did not succeed. Starting with compounds 14–16,
we succeeded in obtaining three natural product griffithanes
A, B and F in four steps. Firstly, 1,3-diphenylpropanones
18 and 19 were obtained by selectively reduction of double
bonds of chalcones 14 and 16 in 77–80% yields.16 Then,
reduction of compounds 18 and 19 with NaBH4 smoothly gave
1,3-diphenylpropan-1-ols 19 and 21 in 83–84% yields;10 while
compound 20 was available through atmospheric pressure
hydrogenation of chalcone 15 in ethyl acetate in 82% yield.10
After that, dehydration of compounds 19–21 with concentrated
H2SO4/dioxane or 2M HCl/THF afforded 1,3-diphenylpropenes
22–24 in 85–86% yields.10, 28
(Scheme 1). Spectral data of 1–3 are consistent with those
described for the natural products.14, 15
Conclusions
In summary, we have completed the first total syntheses
of griffithanes A,
B and F starting from accessible
methoxybenzaldehyde (overall yields: 27% for griffithane A;
42% for griffithane B and 32% for griffithane F). The mild
reaction conditions and operational simplicity make this
method attractive for a practical synthesis of these natural
products and their derivatives; this facilitates further biological
experiments. Studies towards the structure modifications
of these natural products for further pharmacological
investigation are ongoing.
Finally, the target compounds griffithanes A, B, and F
were obtained by atmospheric pressure hydrogenation of
1,3-diphenylpropenes 22–24 for 12–24h in 85–86% yields
BnO
O
H
C O
MeO
BnO
MeO
OMe
OBn
OMe
BnO
MeO
OMe
OBn
OMe
OMe
OBn
7
(b)
(a)
MeO
17
19
14
6
O
O
(c)
BnO
MeO
OMe
OBn
OMe
BnO
MeO
OMe
OBn
OMe
(d)
22
OH
(f)
H
O
H
O
OMe
MeO
OMe
1
griffithane A ( )
O
MeO
BnO
R2
R3
R1
OR6
H
C
O
H
C O
BnO
8
or
(a)
R4
OMe
MeO
OMe
MeO
OMe
13
R5
O
OBn
10
15
16
: R1 = R3 = OMe, R2 = OBn, R4 = H, R5 = H, R6 = Bn
: R1 = R3 = OMe, R2 = H, R4 = OBn, R5 = H, R6 = Bn
(b)
(c)
R2
R2
R3
R1
R
R3
R4
R1
R
O
6
O
6
(c)
R4
OMe
OMe
R5
R5
H
O
O
20
21
: R1 = R3 = OMe, R2 = OH, R4 = H,
R
5 = H, R6 = H
18
: R1 = R3 = OMe, R2 = H, R4 = OBn, R5 = H, R6 = Bn
: R1 = R3 = OMe, R2 = H,
R4 = OBn, R5 = H, R6 = Bn
(d) or (e)
R2
R2
R3
R1
R
O
6
R3
R4
R1
H
O
(f)
R4
OMe
OMe
= H
R5
R5
: R = OMe, R = OH, R = OMe, R = H,
: R1 = OMe, R2 = H, R3 = OMe, R4 = OH, R5 = H
2
3
R
23
24
: R1 = R3 = OMe, R2 = OH, R4 = H, R5 = H, R6 = H
: R1 = R3 = OMe, R2 = H, R4 = OBn, R5 = H, R6 = Bn
Scheme 1 Synthesis of griffithanes A, B and F. Reagents and conditions: (a) 60% KOH, EtOH, room temperature (rt), 12 h, 75–85%; (b) Pd(OAc)2,
NaBH4, CHCl3, MeOH, 10 h, 77–80%; (c) 10% Pd/C, EtOAc, rt, 1 atm, 24 h, 82%; (d) NaBH4, MeOH, rt, 30 min, 83–84%; (e) H2SO4, dioxane,
reflux 4–5 h, 85–86%; (f) 1M HCl, THF, reflux 2 h, 85%; (g) 10% Pd/C, EtOAc, rt, 1 atm, 12–24 h, 85–95%.

418 JOURNAL OF CHEMICAL RESEARCH 2015
Experimental
Synthesis of 1,3-diphenylpropanones (17 and 18); general procedure
A mixture of 1,3-diphenylpropenones 14 and 16 (1.02 g, 2.0 mmol)
in chloroform (4 mL), then NaBH4 (0.076 g, 2.0 mmol), Pd(OAc)2
(0.023g, 0.01 mmol) was combined in a round-bottomed flask with
magnetic stirrer capped with a rubber septum that had a deflated
balloon attached to it. Methanol (20 mL) was added into the flask
slowly through a syringe. The mixture was stirred at room temperature
for 10 h, based on TLC monitoring. The resulting mixture was filtered,
and methanol was evaporated using rotary evaporator. Brine solution
was added, and the product was extracted with CHCl3. The organic
layer was dried with anhydrous Na2SO4, filtered and evaporated under
reduced pressure. The residue was purified by column chromatography
on silica gel to give 1,3-diphenylpropanones 17 and 18 (0.79–0.82 g) in
77–80% yields as yellow solids.
Melting points were measured on a microscopic melting point
apparatus. The IR spectra were recorded on a Bruker Tensor 27
1
FTIR spectrometer with a KBr disk. H NMR and 13C NMR spectra
were taken on a Bruker AV 300 or AV 400 MHz and 75 or 100 MHz
spectrometer in DMSO-d6 or CDCl3, chemical shift 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.
Synthesis of 1,3-diarylpropenones (chalcones, 14–16) by Claisen–
Schmidt condensation of acetophenones with aldehydes; general
procedure
The appropriately substituted acetophenones 6 and 8 (0.77–0.86 g, 3
mmol) and the corresponding aldehydes 7, 10 and 13 (0.73–0.82 g, 3
mmol) were dissolved in ethanol (30 mL), followed by the addition
of a solution of 60% aq. KOH (3 mL). The reaction mixture was
stirred for 12 h at room temperature and the progress of the reaction
was monitored on TLC (petroleum ether/ethyl acetate, 3:1). After
completion of the reaction, it was diluted with water (30 mL), acidified
with 2M HCl (30 mL), and extracted with ethyl acetate. The organic
layer was dried with anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by column
chromatography on silica gel to give 1,3-diarylpropenones (chalcones)
14–16 (1.15–1.30 g) in 75–85% yields.
(E)-1-(4-(Benzyloxy)-2,5-dimethoxyphenyl)-3-(4-(benzyloxy)-3-
methoxyphenyl)prop-2-en-1-one (14): Yield 83%; yellow powder; m.p.
123–125 ºC; IR (KBr, cm-1): v 2941 (CH2), 1645 (C=O), 1511 (CH=CH),
1265 (OCH3); 1H NMR (CDCl3, 300 MHz): δ 7.63 (d, J = 15.7 Hz, 1H,
C3H), 7.25–7.46 (m, 12H, C2,C6”,Cb-d,Cb’-d’H), 7.13 (s, 1H, C6’H),
7.10 (d, J = 1.7 Hz, 1H, C2”H), 6.87 (d, J = 8.7 Hz, 1H, C5”H), 6.54 (s,
1H, C2’H), 5.22 (s, 2H, CH2), 5.18 (s, 2H, CH2), 3.91 (s, 3H), 3.88 (s, 3H),
3.77 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 189.9 (C1), 154.2 (C4’), 152.4
(C2’), 150.1 (C3”), 149.7 (C4”), 143.9 (C3), 142.1 (C5’), 136.6 (Ca),
136.3 (Ca’), 128.8 (Cc), 128.6 (Cc’), 128.5 (Cb), 128.1 (Cb’), 127.9 (Cd),
127.2 (Cd’), 127.1 (C1”), 125.3 (C6”), 122.3 (C2), 121.2 (C5”), 113.8
(C1’), 113.6 (C2”), 111.0 (C6’), 99.8 (C3’), 71.2 (C4’-PhCH2), 70.8 (C4”-
PhCH2), 56.6 (C5’OCH3), 56.4 (C3”OCH3), 56.0 (C5’OCH3); HRMS
(ESI) calcd for [C32H30O6+H]+ m/z 511.2115, found 511.2139.
1-(4-(Benzyloxy)-2,5-dimethoxyphenyl)-3-(4-(benzyloxy)-3-
methoxyphenyl)propan-1-one (17): Yield 77%; off-white powder;
m.p. 120–122 ºC; IR (KBr, cm-1): v 3060 (CH), 2958 (CH2), 1669
1
(C=O), 1518 (CH=CH), 1216 (OCH3); H NMR (CDCl3, 300 MHz):
δ 7.24–7.44 (m, 11H, C6’,BnH), 6.78–6.81 (m, 2H, C2”,C5”H), 6.69 (d,
J = 8.2 Hz, 1H, C6”H), 6.49 (s, 1H, C3’H), 5.21 (s, 2H, CH2), 5.10 (s,
2H, CH2), 3.86 (s, 6H), 3.73 (s, 3H), 3.21–3.26 (m, 2H, C2H), 2.90–2.95
(m, 2H, C3H); 13C NMR (CDCl3, 75 MHz): δ 198.9 (C1), 154.7 (C4’),
152.7 (C2’), 149.5 (C3”), 146.3 (C4”), 143.6 (C5’), 137.4 (Ca), 136.2
(Ca’), 135.3 (C1”), 128.6 (Cc), 128.4 (Cc’), 128.1 (Cd), 127.6 (Cd’),
127.2 (Cb,Cb’), 120.1(C6”), 119.4 (C2”), 114.3 (C1’), 113.3 (C5”),
112.5 (C2”), 98.9 (C3’), 71.1 (C4’,C4”-PhCH2), 56.3 (C2’OCH3),
55.9 (C5’,C3”-OCH3), 45.5 (C2), 30.2 (C3); HRMS (ESI) calcd for
[C32H32O6+H]+ m/z 513.2272, found 513.2246.
2,4-Diamino-7-chloro-5- (p-tolylthio)-5H-chromeno[2,3-b]
pyridine-3-carbonitrile (18): Yield 83%; off-white powder; m.p.
122–124 ºC; IR (KBr, cm-1): v 3061 (CH), 2961 (CH2), 1667 (C=O),
1517 (CH=CH), 1212 (OCH3); 1H NMR (CDCl3, 500 MHz): δ 7.54 (d,
J = 1.5 Hz, 1H, C2’H), 7.49 (d, J = 8.4 Hz, 1H, C6’H), 7.28–7.43 (m,
10H, BnH), 6.87 (d, J = 8.4 Hz, 1H, C5’H), 6.78 (s, 1H, C6”H), 6.51 (s,
1H, C5”H), 5.21 (s, 2H, CH2), 5.04 (s, 2H, CH2), 3.92 (s, 3H), 3.87 (s,
3H), 3.79 (s, 3H), 3.08–3.11 (m, 2H, C2H), 2.89–2.92 (m, 2H, C3H);
13C NMR (CDCl3, 75 MHz): δ 198.6 (C1), 152.3 (C2”), 149.5 (C4”),
149.1 (C4’), 142.0 (C3’), 137.6 (C3”), 136.4 (Ca,Ca’), 128.6 (C1’),
128.4 (Cc), 128.1 (Cc’), 127.7 (Cd), 127.5 (Cd’), 127.2 (Cb,Cb’), 122.5
(C1”), 121.4 (C6’), 118.3 (C6”), 112.3 (C5’), 110.8 (C2’), 98.3 (C5”),
72.5 (C3”-PhCH2), 70.8 (C4’-PhCH2), 56.6 (C2”OCH3), 56.1 (C3’,C4”-
OCH3), 38.8 (C2), 25.4 (C1); HRMS (ESI) calcd for [C32H32O6+H]+
m/z 513.2272, found 513.2294.
(E)-1-(3-(Benzyloxy)-2,4-dimethoxyphenyl)-3-(4-(benzyloxy)-
3-methoxyphenyl)prop-2-en-1-one (15): Yield 75%; yellow powder;
m.p. 128–130 ºC; IR (KBr, cm-1): v 2942 (CH2), 1647 (C=O), 1512
1
(CH=CH), 1268 (OCH3); H NMR (CDCl3, 300 MHz) δ 7.98 (d, J =
14.1 Hz, 1H, C3H), 7.61–7.65 (m, 2H, C6’,C6”H), 7.52–7.59 (m, 2H,
C2,C5H), 7.32–7.50 (m, 10H, BnH), 6.94 (d, J = 8.6 Hz, 1H, C5’H),
6.72 (d, J = 8.6 Hz, 1H, C5”H), 5.26 (s, 2H, CH2), 5.04 (s, 2H, CH2),
3.98 (s, 3H), 3.94 (s, 3H), 3.88 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ 189.0 (C1), 155.9 (C4”), 154.1 (C4’), 152.1 (C3’), 149.6 (C2”), 141.4
(C3), 139.3 (C3”), 137.4 (Ca), 136.3 (C1”), 128.6 (Cc), 128.3 (Cd),
128.0 (Cb), 127.2 (C6’), 122.6 (C6”,C1’), 121.0 (C2), 112.1 (C5’),
111.2 (C2’), 107.6 (C5”), 75.2 (C3”-PhCH2), 70.8 (C4’-PhCH2), 61.5
(C2”OCH3), 56.1 (C4”OCH3), 56.0 (C3’OCH3); HRMS (ESI) calcd for
[C32H30O6+H]+ m/z 511.2115, found 511.2160.
(E)-3-(5-(Benzyloxy)-2,4-dimethoxyphenyl)-1-(4-(benzyloxy)-
3-methoxyphenyl)prop-2-en-1-one (16): Yield 85%; yellow powder;
m.p. 126–128 ºC; IR (KBr, cm-1): v 2937 (CH2), 1649 (C=O), 1512
(CH=CH), 1263 (OCH3); 1H NMR (CDCl3, 300 MHz): δ 8.04 (d, J =
15.7 Hz, 1H, C3H), 7.64 (d, J = 1.8 Hz, 1H, C2’H), 7.57 (dd, J = 8.4,
1.8 Hz, 1H, C6’H), 7.30–7.49 (m, 11H, C2,BnH), 7.19 (s, 1H, C2”H),
6.94 (d, J = 8.4 Hz, 1H, C5’H), 6.53 (s, 1H, C5”H), 5.25 (s, 2H, CH2),
5.12 (s, 2H, CH2), 3.98 (s, 3H), 3.95 (s, 3H), 3.90 (s, 3H); 13C NMR
(CDCl3, 75 MHz): δ 189.1(C1), 155.0 (C4’), 153.3 (C3’), 152.0 (C4”),
149.6 (C3”), 142.2 (C3), 139.2 (C6”), 137.2 (Ca), 136.5 (Ca’), 132.2
(Cc), 128.7 (Cc’), 128.6 (Cd), 128.1 (Cd’), 128.0 (Cb), 127.6 (Cb’),
127.2 (C6’), 122.6 (C1’), 120.1 (C2), 115.9 (C5’), 115.6 (C2”), 112.3
(C1”), 111.4 (C2’), 97.2 (C5”), 72.4 (C3”-PhCH2), 70.9 (C4’-PhCH2),
56.3 (C6”OCH3), 56.1 (C3’,C4”-OCH3); HRMS (ESI) calcd for
[C32H30O6+H]+ m/z 511.2115, found 511.2154.
Synthesis of 1,3-diphenylpropan-1-ols (19–21); general procedure
Powdered NaBH4 (0.30 g, 7.9 mmol) was added to a stirred solution
of 1,3-diphenylpropanones 17 and 18 (0.72 g, 1.4 mmol) in MeOH
(28 mL) and the reaction mixture was stirred at room temperature
for 30 min. After completion of the reaction, MeOH was removed in
vacuo. The oily residue was washed with NaHCO3 and water, and the
mixture was extracted with ethyl acetate. The organic layer was dried
over Na2SO4 and concentrated to dryness. The residue was purified
by column chromatography on silica gel to give compounds 19 and 21
(0.60 g) as oils in 83–84% yields. A solution of 1,3-diphenylpropenone
15 (1.02 g, 2.0 mmol) in 20 mL of ethyl acetate was placed in the
reaction bottle of the atmospheric pressure hydrogenation apparatus
and to that was added 0.25 g (25 w/w %) of palladium-charcoal (10%).
The air was displaced with hydrogen and the mixture was shaken
for 24 h. The progress of the reaction was monitored by TLC. After
completion of the reaction, the palladium-charcoal was filtered and
ethyl acetate was removed under reduced pressure. The solid obtained
was purified by column chromatography on silica gel to obtain the
compound 20 (0.55 g, 82%) as an oil.
1-(4-(Benzyloxy)-2,5-dimethoxyphenyl)-3-(4-(benzyloxy)-3-
methoxyphenyl)propan-1-ol (19): Yield 77%; off-white powder; m.p.
130–132 ºC; IR (KBr, cm-1): v 3035 (CH), 2931 (CH2), 1517 (ArH),
1205 (OCH3); 1H NMR (CDCl3, 300 MHz): δ 7.24–7.42 (m, 10H,
BnH), 6.89 (s, 1H, C6’H), 6.84 (d, J = 8.2 Hz, 1H, C5”H), 6.74–6.80

JOURNAL OF CHEMICAL RESEARCH 2015 419
(m, 1H, C2”H), 6.66 (dd, J = 8.2, 1.5 Hz, 1H, C6”H), 6.50 (s, 1H,
C3’H), 5.13 (s, 2H, CH2), 5.10 (s, 2H, CH2), 4.84 (br s, 1H, C1H), 3.85
(s, 3H), 3.83 (s, 3H), 3.67 (s, 3H), 2.55–2.79 (m, 2H, C3H), 2.48 (br s,
1H, C1OH), 1.95–2.11 (m, 2H, C2H); 13C NMR (CDCl3, 75 MHz): δ
150.6 (C2’), 149.6 (C3”), 147.8 (C4’), 146.3 (C4”), 143.9 (C5’), 137.4
(Ca), 137.1 (Ca’), 135.5 (C1”), 128.5 (Cc), 128.4 (Cc’), 127.9 (Cd),
127.6 (Cd’), 127.3 (Cb), 127.2 (Cb’), 125.0 (C6”), 120.2 (C1’), 114.4
(C5”), 112.5 (C6’), 111.9 (C2”), 100.7 (C3’), 71.7 (C4’-PhCH2), 71.2
(C4”-PhCH2), 69.7 (C1), 56.9 (C2’OCH3), 55.9 (C5’,C3”-OCH3), 39.0
(C2), 31.9 (C3); HRMS (ESI) calcd for [C32H34O6+Na]+ m/z 537.2248,
found 537.2203.
3- (3-Hydroxy-3- (4-hydroxy-3-methoxyphenyl)propyl)-2,6-
dimethoxyphenol (20): Yield 82%; off-white powder; m.p. 158–160 ºC;
IR (KBr, cm-1): v 3039 (CH), 2932 (CH2), 1519 (ArH), 1206 (OCH3);
1H NMR (CDCl3, 400 MHz): δ 6.91 (d, J = 1.7 Hz, 1H, C2”H), 6.86
(d, J = 8.1 Hz, 1H, C5”H), 6.79 (dd, J = 8.1, 1.7 Hz, 1H, C6”H), 6.65
(d, J = 8.4 Hz, 1H, C6’H), 6.60 (d, J = 8.4 Hz, 1H, C3’H), 5.59 (br s,
1H, C4’OH), 5.57 (br s, 1H, C4”OH), 4.53–4.57 (m, 1H, C1H), 3.89
(s, 3H), 3.87 (s, 3H), 3.86 (s, 3H), 2.68 (t, J = 7.5 Hz, 2H, C3H), 2.38
(br s, 1H, C1OH), 1.92–2.06 (m, 2H, C2H); 13C NMR (CDCl3, 100
MHz): δ 146.5 (C2’), 146.1 (C3”), 145.2 (C4’), 144.8 (C4”), 138.5
(C5’), 136.6 (C1”), 127.6 (C6”), 119.5 (C1’), 118.9 (C5”), 114.0 (C2”),
108.4 (C6’), 106.6 (C3’), 73.3 (C1), 60.6 (C2’OCH3), 56.2 (C3”OCH3),
55.8 (C5’OCH3), 40.0 (C2), 25.9 (C3); HRMS (ESI) calcd for
[C18H22O6+Na]+ m/z 357.1309, found 357.1309.
3-(5-(Benzyloxy)-2,4-dimethoxyphenyl)-1-(4-(benzyloxy)-3-
methoxyphenyl)propan-1-ol (21): Yield 84%; off-white powder; m.p.
133–135 ºC ; IR (KBr, cm-1): v 3033 (CH), 2930 (CH2), 1518 (ArH),
1202 (OCH3); 1H NMR (CDCl3, 300 MHz): δ 7.43–7.46 (m, 4H,
Cc,Cc’H), 7.28–7.39 (m, 6H, Cb,Cb’,Cd,Cd’H), 6.93 (d, J = 1.5 Hz, 1H,
C2’H), 6.84 (d, J = 8.2 Hz, 1H, C5’H), 6.73–6.76 (m, 2H, C6’,C2”H),
6.54 (s, 1H, C5”H), 5.14 (s, 2H, C3”PhCH2), 5.07 (s, 2H, C4’PhCH2),
4.46 (dd, J = 8.5, 4.7 Hz, 1H, C1H), 3.89 (s, 6H, C3’,C6”OMe), 3.80 (s,
3H, C4”OMe), 2.61–2.67 (m, 2H, CH2, C3H), 1.85–2.00 (m, 2H, CH2,
C2H); 13C NMR (CDCl3, 75 MHz): δ 152.1 (C6”), 149.7 (C3’), 148.9
(C4”), 147.4 (C4’), 142.0 (C3”), 138.0 (C1’), 137.6 (Ca), 137.2 (Ca’),
128.4 (Cc), 128.3 (Cc’), 127.7 (Cd), 127.6 (Cd’), 127.5 (Cb,Cb’), 127.2
(C6’), 121.6 (C2”), 118.2 (C1”), 118.1 (C5’), 109.7 (C2’), 98.3 (C5”),
73.0 (C1), 72.3 (C3”-PhCH2), 71.1 (C4’-PhCH2), 56.4 (C6”OCH3), 56.2
(C4”OCH3), 55.9 (C3’OCH3), 39.4 (C2), 25.7 (C3); HRMS (ESI) calcd
for [C32H34O6+Na]+ m/z 537.2248, found 537.2248.
C3H); 13C NMR (CDCl3, 75 MHz): δ 150.9 (C4’), 149.7 (C3”), 148.1
(C4”), 146.6 (C5’), 144.1 (C2’), 137.4 (Ca), 137.1 (Ca’), 133.9 (C1”),
128.5 (C1), 128.4 (Cc), 128.0 (Cc’), 127.8 (Cd), 127.7 (Cd’), 127.3 (Cb),
127.2 (Cb’), 124.9 (C2), 120.5 (C6”), 119.2 (C1’), 114.4 (C2”), 112.6
(C5”), 110.7 (C6’), 100.9 (C3’), 71.6 (C4’-PhCH2), 71.2 (C4”-PhCH2),
56.8 (C2’OCH3), 56.4 (C5’OCH3), 56.0 (C3”OCH3), 39.4 (C3); HRMS
(ESI) calcd for [C32H32O5+H]+ m/z 497.2323, found 497.2286.
(E)-3-(3-(4-Hydroxy-3-methoxyphenyl)allyl)-2,6-dimethoxyphenol
(23): Yield 81%; off-white powder; m.p. 134–136 ºC; IR (film, cm-1):
1
v 3028 (CH), 2928 (CH2), 1519 (CH=CH), 1210 (OCH3); H NMR
(CDCl3, 400 MHz): δ 6.83–6.87 (m, 3H, C1,C6’,C2”H), 6.69 (d, J =
8.4 Hz, 1H, C6”H), 6.62 (d, J = 8.4 Hz, 1H, C5”H), 6.34 (d, J = 15.7
Hz, 1H, C2H), 6.16–6.21 (m, 1H, C3’H), 5.60 (br s, 1H, C4’OH), 5.59
(br s, 1H, C4”OH), 3.88 (s, 3H, C2’OMe), 3.87 (s, 6H, C5’,3”OMe),
3.49 (dd, J = 6.6, 1.0 Hz, C3H); 13C NMR (CDCl3, 100 MHz): δ
146.5 (C3”), 146.3 (C4’), 145.2 (C4”), 144.9 (C5’), 138.6 (C2’), 130.3
(C1”), 130.2 (C1), 127.0 (C2), 126.4 (C6”), 119.6 (C5”), 114.3 (C1’),
107.9 (C2”,C5’), 106.4 (C3’), 60.7 (C2’OCH3), 56.2 (C5’OCH3), 55.8
(C3”OCH3), 32.8 (C3); HRMS (ESI) calcd for [C18H20O5+Na]+ m/z
339.1203, found 339.1225.
(E)-1-(Benzyloxy)-5-(3-(4-(benzyloxy)-3-methoxyphenyl)allyl)-
2,4-dimethoxybenzene (24): Yield 86%; off-white syrup; IR (film,
cm-1): v 3023 (CH), 2923 (CH2), 1513 (CH=CH), 1208 (OCH3);
1H NMR (CDCl3, 300 MHz): δ 7.23–7.43 (m, 10H), 6.76–6.79 (m, 3H,
C2,C2’,C6’H), 6.54 (s, 1H, C2”H), 6.94 (d, J = 8.4 Hz, 1H), 6.53 (s, 1H,
C5”H), 6.27 (d, J = 15.7 Hz, 1H, C1H), 6.07–6.16 (m, 1H, C5’H), 5.13
(s, 2H, CH2, C4’PhCH2), 5.04 (s, 2H, CH2, C3”PhCH2), 3.87 (s, 6H,
C3’,C6”OMe), 3.80 (s, 3H, C4”OMe), 3.39 (d, J = 8.5 Hz, 2H, C3H);
13C NMR (CDCl3, 75 MHz): δ 152.1 (C6”), 149.7 (C3’), 149.1 (C4”),
147.4 (C4’), 142.1 (C3”), 137.6 (Ca’), 137.2 (Ca), 131.5 (C1’), 130.1
(C1), 128.4 (Cc’), 128.3 (Cc), 127.7 (Cd’), 127.6 (Cd), 127.5 (Cb’),
127.4 (Cb), 127.2 (C2), 120.5 (C1”), 118.9 (C6’), 118.0 (C5’), 114.2
(C2’), 109.5 (C2”), 98.5 (C5”), 72.4 (C3”-PhCH2), 71.1 (C4’-PhCH2),
56.5 (C6”OCH3), 56.4 (C4”OCH3), 56.0 (C3’OCH3), 33.9 (C3); HRMS
(ESI) calcd for [C32H32O5+H]+ m/z 497.2323, found 497.2328.
Synthesis of griffithanes A (1), B (2) and F (3); general procedure
A solution of compounds 22–24 (0.25-0.40 g, 0.8 mmol) in 8 mL of
ethyl acetate was placed in the reaction bottle of atmospheric pressure
hydrogenation apparatus and to that was added 0.063–0.1 g (25 w/w %)
of palladium-charcoal (10%). The air was displaced with hydrogen and
the mixture was shaken for 12–24 h. The progress of the reaction was
monitored by TLC. After completion of the reaction, the palladium-
charcoal was filtered and ethyl acetate was removed under reduced
pressure. The solid obtained was purified by column chromatography
on silica gel to afford natural products 1–3 (0.22–0.24 g) as yellow oils
in 85–95% yields. The structures of the synthesised compounds above
were characterised by their IR, 1H NMR, 13C NMR and HRMS spectra.
4-(3-(4-Hydroxy-3-methoxyphenyl)propyl)-2, 5-dimethoxyphenol
(griffithane A, 1): Yield 86%; Viscous oil; IR (film, cm-1): v 3417
Synthesis of 1,3-diphenylpropenes (22–24); general procedure
Two drops of concentrated H2SO4 were added to a solution of
compounds 19 and 21 (0.51 g, 1.0 mmol) in dioxane (4 mL). The
reaction mixture was refluxed for 4–5 h and the progress of reaction
was monitored by TLC. After completion of reaction, the reaction
mixture was poured over ice-cold water with vigorous stirring. The
reaction mixture was extracted with petroleum ether and the combined
organic layer was dried over Na2SO4, filtered, and evaporated under
reduced pressure. The residue was purified by column chromatography
on silica gel to give compounds 22 and 24 (0.42–0.43 g) as oils in
85–86% yields. 1M HCl (3 mL, 3 mmol) was added to a solution of
compound 20 (0.50g, 1.5 mmol) in THF (10 mL) at 0 oC. The reaction
mixture was stirred at room temperature for 10 min and refluxed
for 2 h and the progress of reaction was monitored by TLC. After
completion of the reaction, THF was removed under reduced pressure,
cooled and extracted with ethyl acetate and the combined organic
layer was dried over Na2SO4, filtered, and evaporated under reduced
pressure. The residue was purified by column chromatography on
silica gel to give compounds 23 (0.40 g, 85%) as an oil.
1
(OH), 3002 (CH), 2932 (CH2), 1511 (ArH), 1267 (OCH3); H NMR
(CDCl3, 300 MHz): δ 6.85 (br d, J = 8.4 Hz, 1H, C5”H), 6.70–6.72 (m,
2H, C2”,C6”H), 6.67 (s, 1H, C6’H), 6.56 (br s, 1H, C4”OH), 5.60 (br
s, 1H, C4’OH), 5.55 (s, 1H, C3’H), 3.88 (s, 3H, C3”OMe), 3.83 (s, 3H,
C5’OMe), 3.76 (s, 3H, C2’OMe), 2.62 (t, J = 8.0 Hz, 2H, C3H), 2.58
(t, J = 8.0 Hz, 2H, C1H), 1.87 (quint, J = 8.0 Hz, 2H, C2H); 13C NMR
(CDCl3, 75 MHz): δ 152.0 (C2’), 146.3 (C3”), 144.2 (C4’), 143.5 (C4”),
140.0 (C5’), 134.6 (C1”), 121.6 (C6”), 120.9 (C1’), 114.1 (C5”), 113.2
(C6’), 111.0 (C2”), 99.4 (C3’), 56.7 (C5’OCH3), 56.0 (C2’OCH3). 55.8
(C3”OCH3), 35.5 (C3), 32.1 (C2), 29.5 (C1); HRMS (ESI) calcd for
[C18H22O5+H]+ m/z 319.1540, found 319.1536.
(E)-1-(Benzyloxy)-4-(3-(4-(benzyloxy)-3-methoxyphenyl)prop-
1-en-1-yl)-2, 5-dimethoxybenzene (22): Yield 85%; off-white syrup;
IR (film, cm-1): v 3026 (CH), 2925 (CH2), 1516 (CH=CH), 1209
3-(3-(4-Hydroxy-3-methoxyphenyl)propyl)-2,6-dimethoxyphenol
(griffithane B, 2): Yield 95%; Viscous oil; IR (film, cm-1): v 3424
(OH), 3004 (CH), 2936 (CH2), 1512 (ArH), 1269 (OCH3); H NMR
(CDCl3, 300 MHz): δ 6.84 (d, J = 8.4 Hz, 1H, C5”H), 6.69–6.71 (m,
2H, C2”,C6”H), 6.64 (d, J = 8.4 Hz, 1H, C6’H), 6.59 (d, J = 8.4 Hz,
1H, C5’H), 5.61 (br s, 1H, OH, C4”OH), 5.54 (br s, 1H, OH, C3’OH),
3.87 (s, 6H, C4’, C3”OMe), 3.85 (s, 3H, C2’OMe), 2.58–2.64 (m, 4H,
1
1
(OCH3); H NMR (CDCl3, 300 MHz): δ 7.22–7.44 (m, 10H, 2BnH),
6.97 (s, 1H, C6’H), 6.68–6.83 (m, 4H, C1,C2”,C5”,C6”H,), 6.49 (s,
1H, C3’H), 6.16–6.21 (m, 1H, C2H), 5.13 (s, 2H, CH2), 5.12 (s, 2H,
CH2), 3.86 (s, 3H), 3.83 (s, 3H), 3.69 (s, 3H), 3.47 (d, J = 6.7 Hz, 2H,

420 JOURNAL OF CHEMICAL RESEARCH 2015
C1,C3H), 1.89 (quint, J = 8.0 Hz, 2H, C2H); 13C NMR (CDCl3, 75
MHz): δ 146.3 (C2’), 145.9 (C3’), 145.4 (C3”), 143.5 (C4”), 138.5
(C4’), 134.4 (C1”), 128.4 (C1’), 120.9 (C6’), 119.3 (C6”), 114.1 (C5”),
111.0 (C2”), 106.3 (C5’), 60.5 (C4’OCH3), 56.2 (C2’OCH3), 55.8
(C3”OCH3), 35.3 (C3), 32.5 (C2), 29.2 (C1); HRMS (ESI) calcd for
[C18H22O5+Na]+ m/z 341.1359, found 341.1376.
5-(3-(4-Hydroxy-3-methoxyphenyl)propyl)-2,4-dimethoxyphenol
(griffithane F, 3): Yield 85%; viscous oil; IR (film, cm-1): v 3382 (OH),
3003 (CH), 2934 (CH2), 1512 (ArH), 1265 (OCH3); 1H NMR (CDCl3,
300 MHz): δ 6.84 (d, J = 8.4 Hz, C5”H), 6.75 (s, C6’H), 6.70-6.71
(m, C2”,6”H), 6.50 (s, C3’H), 5.56 (br s, 1H, C5’OH), 5.29 (br s, 1H,
C4”OH), 3.88 (s, 3H, C4’OMe), 3.87 (s, 3H, C3”OMe), 3.79 (s, 3H,
C2’OMe), 2.55–2.62 (m, 4H, C1,C3H), 1.86 (quint, J = 8.0 Hz, 2H,
C2H); 13C NMR (CDCl3, 75 MHz): δ 150.9 (C2’), 146.3 (C3”), 144.6
(C4’), 143.5 (C4”), 139.2 (C5’), 134.5 (C1”), 123.4 (C1’), 120.9 (C6”),
115.8 (C6’), 114.1 (C5”), 111.0 (C2”), 97.1 (C3’), 56.5 (C2’OCH3), 56.2
(C4’OCH3), 55.8 (C3”OCH3), 35.2 (C3), 31.9 (C2), 29.0 (C1); HRMS
(ESI) calcd for [C18H22O5+H]+ m/z 319.1540, found 319.1548.
6
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Electronic Supplementary Information
Electronic Supplementary information including the data and 1H
NMR and 13C NMR spectra of 14–24, 1–3, can be found, in the
online version available from at stl.publisher.ingentaconnect.
com/content/stl/jcr/supp-data.
The authors thank the National High Technology Research
and Development Program of China (863 Program, grant no.
2012AA02A701), and the National High Technology Research
and Development Program of China (863 Program, grant no.
2013AA031901) for financial support.
21 A. Carbone, C.L. Lucas and C.J. Moody, J. Org. Chem., 2012, 77, 9179;
22 K. Kurosawa, A. Hashiba and H. Takahashi, Bull. Chem. Soc. Jpn, 1978,
51, 3612.
Received 15 May 2015; accepted 25 June 2015
Paper 1503363 doi: 10.3184/174751915X14359076454633
Published online: 9 July 2015
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