Synthesis of verbenachalcone congeners and their biological assessment against activation of the NGF-mediated neurite outgrowth of PC12D cells' activity

Article abstract of DOI:10.1016/j.bmc.2005.11.055

Synthesis of the verbenachalcone derivatives 3-5 involving littorachalcone 2 from diaryl ether 7 enabled an SAR study of enhancement activity against the NGF-mediated neurite outgrowth from PC12D cells. Littorachalcone 2 and o-deoxyverbenachalcone 5 showe

Full text of DOI:10.1016/j.bmc.2005.11.055

Bioorganic & Medicinal Chemistry 14 (2006) 2753–2762
Synthesis of verbenachalcone congeners and their biological
assessment against activation of the NGF-mediated
neurite outgrowth of PC12D cells’ activity
Takamasa Tanabe,a Takahisa Ogamino,a Yoshifumi Shimizu,b
Masaya Imotob and Shigeru Nishiyamaa,*
aDepartment of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1,
Kohoku-ku, Yokohama 223-8522, Japan
bDepartment of Biosciences and Informatics, Faculty of Science and Technology, Keio University,
Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522, Japan
Received 20 October 2005; revised 24 November 2005; accepted 29 November 2005
Available online 27 December 2005
Abstract—Synthesis of the verbenachalcone derivatives 3–5 involving littorachalcone 2 from diaryl ether 7 enabled an SAR study of
enhancement activity against the NGF-mediated neurite outgrowth from PC12D cells. Littorachalcone 2 and o-deoxyverbenachal-
cone 5 showed similar activity to that of verbenachalcone 1.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
and gene expression profiles of NGF by using a tetra-
methyl derivative of 1: increase of the NGF effect by
masking phenols in the terminal aromatic rings suggest-
ed that these protic substituents might have no influence
on the activity.6 Against such a background, our atten-
tion was focused on the synthesis and SAR study of the
verbenachalcone-class natural products. In contrast to
such coupling reactions as the Ullmann coupling of
phenol precursors with halogenated counterparts, the
outstanding point of our synthetic approach3b was the
economical construction of the diaryl ether core by
dimerization of the Br,Cl-disubstituted phenol deriva-
tive under anodic oxidation conditions, followed
by chemoselective methoxylation. Introduction of
2,4-dihydroxyphenyl moieties would be performed at
the final stage to circumvent undesired side reactions
during the oxidation. We describe herein synthesis and
biological assessment of enhancement of the NGF acti-
vation of littorachalcone 2,7 isolated from the same
plant as that of 1, as well as the other congeners 3–5
(Fig. 1).
In the preceding paper,1 we described the total synthesis
of verbenachalcone 1, isolated from the aerial part of
Verbena littoralis H. B. K. (Verbenaceae).2 The typical
dimeric structure connected with a diaryl ether linkage
provides enhancement of the NGF (nerve growth fac-
tor)-mediated neurite outgrowth of PC12D cells. Our
phenolic oxidation methodology3 enabled successful
construction of the core diaryl ether by dimerization
of the corresponding o,o-dihalogenated phenol deriva-
tives, followed by introduction of an alkoxy function.
From the synthetic viewpoint, closely related rhuschal-
cone, possessing cytotoxic activity against the HT29
and HCT-116 colon tumor cell lines,4 was synthesized
by using the Ullmann coupling for its structural elucida-
tion. Cuny et al. reported a synthesis of 1 itself by a sim-
ilar coupling reaction, along with an SAR study: the
pentaacetylated 1 exhibited a stronger NGF activation
effect than the mother 1, while removal of the two
ketones decreased the activity.5 They also examined
the activation effect, inhibition of caspase induction,
2. Results and discussion
Keywords: Verbena littoralis; Verbenachalcone; Littorachalcone;
Anodic oxidation; NGF-mediated neurite outgrowth.
As experienced in the synthesis of 1,1 diaryl ether 7
would be an important synthetic precursor of 2–5. At
the outset, 7 was synthesized from the known propyl-
*
Corresponding author. Tel./fax: +81 45 566 1717; e-mail: nisiyama@
chem.keio.ac.jp
0968-0896/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.11.055

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T. Tanabe et al. / Bioorg. Med. Chem. 14 (2006) 2753–2762
The diaryl ether 8 in hand was submitted to Zn reduc-
O
OH
OH
O
OH
R
O
tion to give 11. After protection with an MOM group
and exchange of the acetyl groups to TBS groups, a bro-
mine group was lithiated, followed by conversion into
the corresponding borate ester and oxidative treatment
to give a separable mixture of 12a and 12b in 64% and
14% yields, respectively.
MeO
O
OH
OH
HO
OH
HO
Cl
Cl
OH
OH
O
O
3
1: R= OMe: Verbenachalcone
2: R= H: Littorachalcone
2.1. Synthesis of littorachalcone (2)
O
R1
According to essentially the same procedure as that of
1,1 littorachalcone 2 was synthesized from 12b (Scheme
2). Removal of chlorine atoms of 12b under hydrogen-
transfer conditions (13)9 and TBS groups gave the
corresponding alcohol, which was submitted to stepwise
oxidation through 14 and 15, followed by reaction with
MeONHMe to afford 16. Coupling with a lithiated 1810
provided the protected form 17 of 2 in good yield. Acid
treatment of 17 successfully produced 2, spectroscopic
data of which were indistinguishable to the reported
data.7
MeO
O
4: R1= OH, R2 = H
5: R1= H, R2= OH
R2
R2
HO
R1
O
R
R
1. [O]
R
Cl
O
2. Zn, H
Cl
Br
Cl
Br
HO
HO
2.2. Synthesis of the verbenachalcone congeners (3–5)
MeO
Dichloroverbenachalcone 3 was synthesized from 12a,
which upon methylation gave 19 in quantitative yield
(Scheme 2). The two TBS ethers were simultaneously
deprotected with a fluoride ion, and primary alcohols
generated were submitted to PDC oxidation to give
the dicarboxylic acid 20. After conversion to the corre-
sponding Weinreb amide 21 as described in the case of
16, coupling with a lithiated 18 provided 22. The final
acid hydrolysis as in the case of 2 gave the desired 3.
Figure 1.
benzene derivative 6,8 through stepwise halogenation in
moderate yields (Scheme 1). Upon exposure of 7 to the
standard anodic oxidation conditions [CCE (constant
current electrolysis) at 20 mA (1 ! 1.5 V vs SCE at
10 mM concentration of the substrate 7; undivided cell;
anode: glassy carbon beaker; cathode: platinum wire;
solvent: MeOH; supporting salt: LiClO4)], the desired
diaryl ether 8 (16%), along with a mixture (23%) of die-
none 9 and benzyl ether 10, was obtained. Among sever-
al conditions examined to improve the yield of 8,
reaction in a flow-cell apparatus provided the highest
yield (62%), even using a 3 g portion of 7, without pro-
duction of undesired 9 and 10. The flow-cell system
effected decrease of the undesired side reactions leading
to 9 and 10, although polymerization of the substrates
was not completely excluded.
Hydrogen-transfer reaction of 19 effected dehalogen-
ation to give 23, two TBS ether moieties of which were
manipulated by deprotection (24) and stepwise oxida-
tion as mentioned above to give the dicarboxylic acid
26 through 25 (Scheme 3). After conversion to the Wein-
reb amide 27, lithiated 2911 and 3112 were reacted to give
the coupling products 28 and 30 in 67% and 84% yields,
respectively. Their acid hydrolysis provided the deoxy-
verbenachalcones 4 and 5.
R1
OAc
Br
MeO
MeO
OAc
MeO
Cl
OAc
OAc
Cl
OAc
Cl
HO
b
R2
Cl
Br
O
Br
O
O
OH
10
6: R1= R2= H
9
8
a
7: R1= Cl, R2= Br
OAc
Cl
OTBS
Cl
OAc
Cl
OTBS
Cl
c
d
8
O
O
Br
OH
R
OMOM
11
12a: R = OH
12b: R = H
Scheme 1. Reagents and conditions: (a) SO2Cl2 (64%), then PyrÆHBr3/CHCl3–Pyr (100%). (b) CCE at 10 mA (8, 50% and a mixture of 9 and 10, 12%)
or CCE at 20 mA (flow cell, 8, 62%). (c) Zn, AcOH (70%). (d) i—MOMCl, DIPEA (100%); ii—K2CO3/MeOH (100%); iii—TBSCl. Imd/DMF
(100%); iv—n-BuLi, B(OMe)3, then NaOH, 30% H2O2 (12a, 64% and 12b, 14%).

T. Tanabe et al. / Bioorg. Med. Chem. 14 (2006) 2753–2762
2755
O
OMOM
R
OTBS
R
e
b
X
OTBS
X
f
2
OMOM
OMOM
O
O
MOMO
O
OMOM
OMOM
12b: X = Cl
14: R = CHO
a
c
OMOM
OMOM
Br
O
17
13: X = H
15: R = COOH
d
18
16: R = CON(Me)OMe
MOMO
R
O
OMOM
R
OTBS
MeO
O
Cl
g
Cl
OTBS
Cl
h
j
k
12a
3
OMOM
OMOM
Cl
OMOM
O
O
MOMO
Cl
OMe
MeO
OMOM
20: R = CO2H
19
Cl
i
OMOM
O
21: R = CON(Me)OMe
22
Scheme 2. Reagents: (a) Pd-C, HCO2NH4/EtOH (92%). (b) i—TBAF (86%); ii—Et3N, SO3-Pyr, DMSO (84%). (c) PDC/DMF (82%). (d) Et3N,
HOBt, WSCI, (MeO)MeNHÆHCl/CH2Cl2 (60%). (e) n-BuLi, 18/THF (64%). (f) TsOH/MeOH (88%). (g) MeI, K2CO3/DMF (100%). (h) i—TBAF/
THF (97%); ii—PDC/DMF (71%). (i) Et3N, HOBt, WSCI, (MeO)MeNHÆHCl/CH2Cl2 (65%). (j) n-BuLi, 18/THF (49%). (k) TsOH/MeOH (100%).
O
R
R
OMe
OR
MeO
O
N
c
X
e
OR
Me
O
OMe
25: R = CHO
MOMO
X
O
27
Me
OMOM
OMe
OMOM
N
OMe
19: R = TBS, X = Cl
23: R = TBS, X = H
24: R = X = H
O
d
a
26: R = CO2H
b
O
R1
R2
MeO
OMOM
Br
OMOM
g
f
4, 5
R2
O
29
31
MOMO
Br
R1
O
28: R1= OMOM, R2= H
30: R1= H, R2= OMOM
Scheme 3. Reagents: (a) Pd-C, HCO2NH4/EtOH (84%). (b) TBAF/THF (100%). (c) Dess–Martin periodinane/CH2Cl2 (81%). (d) PDC/DMF (52%).
(e) Et3N, HOBt, WSCI, (MeO)MeNHÆHCl/CH2Cl2 (96%). (f) n-BuLi, 29/THF (28: 67%); n-BuLi, 31/THF (30: 84%). (g) TsOH/MeOH (4: 94%;
5: 100%).
2.3. Biological activity
was used for other samples. A possibility of the inhibi-
tion of neurite outgrowth by the solvent in these entries
was excluded, since NGF-treated PC12D cells still
showed normal neurite outgrowth in the presence of
1% DMSO. Further assessment in higher concentra-
tions of active samples revealed that 2 and 5 at
30 mM dramatically enhanced the outgrowth of neu-
rites similar to 1. These data indicated that a MeO
group adjacent to the diaryl ether linkage, as well as
phenols at ortho-positions to the carbonyl functions
in the terminal aromatic moieties, might have no posi-
tive roles to enhance the activity. Interestingly, 4, an
isomer of 5 lacking a p-phenol, exhibited an inhibitory
activity, which might possess some reasons regarding
The effect on neurite outgrowth by the synthetic sam-
ples was evaluated by counting the number of neu-
rite-bearing PC12D cells (Figs. 2–4). No sole effect by
the samples at 10 and 30 mM concentrations on the
outgrowth of neurites was observed. On the other
hand, when PC12D cells were treated with NGF, the
addition of the synthetic samples at 10 mM concentra-
tion exhibited enhancement activities on neurite out-
growth similar to 1, although 4, 22, 28, and 30
showed inhibition of neurite outgrowth. These inhibito-
ry samples were submitted to the assessment as 1%
DMSO solutions for their insolubility to MeOH, which

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T. Tanabe et al. / Bioorg. Med. Chem. 14 (2006) 2753–2762
Figure 2. Enhancement of neurite growth by verbenachalcone and its derivatives in PC12D cells (concd 10 lM). White columns are controls only
using NGF at 0, 5, and 30 ng/mL concentrations.
Figure 3. Enhancement of neurite growth by verbenachalcone and its derivatives in PC12D cells (concd 30 lM). White columns are controls only
using NGF at 0, 5, and 30 ng/mL concentrations.
hydrogen bonding of the ketones. As Cuny also report-
ed its crucial effect,5 substitution of the aromatic moi-
eties might play an important part to express the
high enhancement activity. In addition, the activity ap-
peared even in the absence of the terminal aromatics
(15, 21). Inhibitory activity of 14 and 25 carrying alde-
hydes rather than the neurite outgrowth enhancement
was observed in 30 lM concentration. Remarkable dif-
ference between the Weinreb amide (21) and carboxylic
acid (20) in the chlorine series was also observed: while
the former provided the moderate activity, the latter
disturbed it. Detailed investigation is still in progress.
4. Experimental
4.1. General
IR spectra were recorded on a JASCO Model A-202
spectrophotometer. 1H NMR and 13C NMR spectra
were obtained on JEOL JNM EX-270 and JEOL JNM
GX-400 spectrometers in CDCl3 using tetramethylsilane
as an internal standard, unless otherwise stated. High-
resolution mass spectra were obtained on a Hitachi
M-80 B GC–MS spectrometer operating at an ioniza-
tion energy of 70 eV. Melting points were measured on
a Yanaco MP-S3 and are uncorrected. Silica-gel column
chromatography was carried out using Kanto Chemical
silica 60N (spherical, neutral, 63–210 lm). Preparative
and analytical thin-layer chromatographies (TLC) were
carried out on silica-gel plates (Kieselgel 60 F254, E.
Merck AG, Germany). The reaction was monitored by
UV (254 nm) light and/or stained with 5% phosphomo-
lybdic acid in ethanol as a developing agent, followed in
the latter case by heating on an electric plate. A flow-cell
apparatus of HX-201 (Hokuto-Denko) was used. Work-
up procedure: a mixture was partitioned between EtOAc
or CHCl3 and H2O. The organic layer was washed with
brine, dried (Na2SO4), and then evaporated.
3. Conclusion
Anodic oxidation of the mixed halogenated phenol
derivative 7 provided the diaryl ether possessing a Br
and a Cl substituents, which enabled the selective intro-
duction of a methoxy group. Successful synthesis of lit-
torachalcone 2 and the verbenachalcone congeners 3–5
was accomplished from the corresponding diaryl ethers
7. Biological assessment of the synthesized samples
revealed new information on the enhancement of
NGF activation.

T. Tanabe et al. / Bioorg. Med. Chem. 14 (2006) 2753–2762
2757
(2 mL) was stirred at 0 ꢁC for 3 h. The mixture was worked
up, and the residue was purified by silica gel column chro-
matography (hexane/EtOAc = 3:1) to give 7 (88.1 mg,
100%) as colorless needles: mp 79.5–80 ꢁC (Et2O); IR
(KBr) 3367, 1714 cmꢀ1; 1H NMR d 1.91 (tt, 2H, J = 6.4,
7.7 Hz), 2.06 (s, 3H), 2.59 (t, 2H, J = 7.7 Hz), 4.07 (t, 2H,
J = 6.4 Hz), 5.76 (br, 1H), 7.12 (d, 1H, J = 1.7 Hz), 7.24
(d, 1H, J = 1.7 Hz); 13C NMR d 21.0, 30.0, 30.9, 63.4,
110.0, 120.4, 128.6, 130.9, 135.0, 146.7, 170.9; HRMScalcd
forC11H1279Br35ClO3:(M+) 305.9658, found m/z305.9616.
A
B
C
D
4.3. Anodic oxidation of 7
A mixture of 7 (31 mg, 0.1 mmol) and LiClO4 (0.1 M) in
MeOH (200 mL) was electrolyzed (CCE at 10 mA, in an
undivided cell using a glassy carbon beaker or a
platinum net as anodes, a platinum wire as a cathode,
3 F/mol), under an Ar atmosphere. After evaporation
and work-up, the residue was separated by silica gel
column chromatography using (hexane/EtOAc = 3:1)
to afford 3-[3-(4-(3-acetyloxypropyl)-2-bromo-6-chloro-
phenoxy)-5-chloro-1-methoxy-4-oxocyclohexa-2,5-die-
nyl]propyl acetate 8 (14 mg, 50%) and a 3:1 mixture of
3-(5-bromo-3-chloro-4-hydroxyphenyl)-3-methoxypropyl
acetate 9 and 3-(3-bromo-5-chloro-1-methoxy-4-oxocy-
clohexa-2,5-dienyl)propyl acetate 10 (4 mg, 12%, 1:3 =
1
9/10 determined by H NMR).
Compound 8: IR (film) 2939, 1738, 1693 cmꢀ1 1H
;
NMR d 1.59 (m, 2H), 1.79 (m, 2H), 2.00 (t, 2H,
J = 7.8 Hz), 2.03 (s, 3H), 2.08 (s, 3H), 2.70 (t, 2H,
J = 7.8 Hz), 3.22 (s, 3H), 4.00 (t, 2H, J = 6.4 Hz), 4.13
(t, 2H, J = 6.4 Hz), 5.31 (d, 1H, J = 2.9 Hz), 6.95 (d,
1H, J = 2.9 Hz), 7.28 (d, 1H, 2.0 Hz), 7.40 (d, 1H,
J = 2.0 Hz); 13C NMR d 20.86, 20.89, 23.0, 29.6, 31.3,
36.7, 53.1, 63.3, 63.7, 117.3, 121.0, 128.1, 129.8, 130.1,
132.0, 133.4, 141.7, 144.5, 147.0, 148.4, 170.7, 170.8,
172.7; HRMS calcd for C23H2579Br35Cl2O7: (MꢀCl)
1
527.0470, found m/z 527.0450. Compound 9: H NMR
d 1.68 (t, 2H, J = 6.4 Hz), 1.85 (t, 2H, J = 6.4 Hz),
2.06 (s, 3H), 3.27 (s, 3H), 4.06 (t, 2H, J = 6.4 Hz), 6.97
(d, 1H, J = 2.8 Hz), 7.23 (d, 1H, J = 2.8 Hz). Compound
10: 1H NMR d 1.90 (m, 1H), 2.03 (m, 1H), 2.05 (s, 3H),
3.20 (s, 3H), 4.11–4.22 (complex, 3H), 5.91 (s, 1H), 7.25
(d, 1H, J = 2.0 Hz), 7.36 (d, 1H, J = 2.0 Hz).
Figure 4. (A) Ordinary shape of PC12D cells in 1% MeOH solution.
(B) Neurite outgrowth of the cells by NGF (5 lM). (C) Inhibition of
the outgrowth by NGF (5 lM) and 22 (10 lM). (D) Enhancement of
neurite outgrowth of the cells by NGF (5 lM) and 2 (30 lM).
4.2. 3-(5-Bromo-3-chloro-4-hydroxyphenyl)propyl acetate (7)
4.4. Anodic oxidation under flow-cell conditions
A mixture of 62 (21 mg, 0.11 mmol) and SO2Cl2 (41 mL,
0.53 mmol) was stirred at 0 ꢁC for 5 h under an Ar
atmosphere. After the addition of satd aq NaHCO3,
the mixture was worked up. Purification by preparative
A mixture of 7 (2.94 g, 9.6 mmol), pyridine (0.78 mL,
9.6 mmol), and LiClO4 (51.9 g, 0.49 mol) in MeOH
(960 mL) was electrolyzed (CCE at 20 mA, flow rate:
0.4 mL/min, 3.0 V, 3.0 F/mol) by using a flow-cell appara-
tus.AftertheadditionofaqNaHCO3. andCHCl3, themix-
ture was evaporated to give a residue, which was worked
up. A crude was separated by a silica gel column (hexane/
EtOAc = 3:1) to afford 8 (1.67 g, 62%) as a colorless oil.
TLC (hexane/EtOAc = 3:1) afforded
(15.6 mg, 64%) as a colorless oil: IR (film) 3402, 2956,
a
chloride
1
1714 cmꢀ1; H NMR d 1.90 (tt, 2H, J = 6.4, 7.7 Hz),
2.06 (s, 3H), 2.60 (t, 2H, J = 7.7 Hz), 4.07 (t, 2H,
J = 6.4 Hz), 5.73 (s, 1H), 6.92 (d, 1H, J = 8.4 Hz), 6.96
(dd, 1H, J = 8.4, 1.5 Hz), 7.13 (d, 1H, J = 1.5 Hz); 13C
NMR d 21.0, 30.2, 31.1, 63.6, 116.1, 119.6, 128.1,
128.5, 134.2, 149.5, 171.1; HRMS calcd for
C11H1335ClO3: (M+) 228.0552, found m/z 228.0592.
4.5. 3-[5-(4-(3-Acetyloxypropyl)-2-bromo-6-chlorophenoxy)-
3-chloro-4-hydroxyphenyl]propyl acetate (11)
A mixture of 8 (1.91 g, 3.4 mmol) and Zn powder (8.9 g)
in THF (34 mL)–AcOH (11 mL) was stirred at 0 ꢁC
overnight. The mixture was filtered through a Celite
A mixture of the chloride (62 mg, 0.27 mmol) and PyrÆ
HBr3 (148 mg, 0.46 mmol) in CHCl3 (3 mL)–pyridine

2758
T. Tanabe et al. / Bioorg. Med. Chem. 14 (2006) 2753–2762
pad, and the filtrate was evaporated. Purification by a
silica gel column (hexane/EtOAc = 3:1) afforded 11
(1.26 g, 70%) and unreacted 8 (0.145 g, 8%).
worked up. The residue was purified by silica gel column
chromatography (hexane/EtOAc = 20:1) to afford a sil-
oxy ether (375 mg, 100%) as a colorless oil: IR (film)
1
2929, 2858 cmꢀ1; H NMR d 0.00 (s, 6H), 0.07 (s, 6H),
Compound 11: mp 97–98 ꢁC (colorless needles from hex-
0.85 (s, 9H), 0.92 (s, 9H), 1.67 (tt, 2H, J = 6.1, 7.8 Hz),
1.84 (tt, 2H, J = 6.1, 7.8 Hz), 2.47 (t, 2H, J = 7.8 Hz),
2.69 (t, 2H, J = 7.8 Hz), 3.53 (t, 2H, J = 6.1 Hz), 3.64 (t,
2H, J = 6.1 Hz), 3.71 (s, 3H), 5.35 (s, 2H), 6.05 (d, 1H,
J = 1.7 Hz), 6.90 (d, 1H, J = 1.3 Hz), 7.26 (d, 1H,
J = 1.3 Hz), 7.39 (d, 1H, J = 1.7 Hz); 13C NMR d ꢀ5.19
(·2), 18.38, 18.40, 25.8, 26.0, 31.2, 31.5, 33.8, 34.1, 57.9,
61.7, 61.8, 98.9, 112.2, 118.1, 123.5, 128.71, 128.74,
129.9, 132.2, 138.8, 139.6, 142.0, 145.0, 149.9; HRMS
calcd for C32H5179Br35Cl2O5Si2: (MꢀBr) 641.2649, found
m/z 641.2692.
1
ane/EtOAc): IR (KBr) 3531, 3519, 2960, 1732 cmꢀ1; H
NMR d 1.80 (tt, 2H, J = 6.5, 7.7 Hz), 2.01 (tt, 2H,
J = 6.3, 7.8 Hz), 2.01 (s, 3H), 2.08 (s, 3H), 2.48 (t, 2H,
J = 7.7 Hz), 2.70 (t, 2H, J = 7.8 Hz), 4.00 (t, 2H,
J = 6.5 Hz), 4.12 (t, 2H, J = 6.3 Hz), 6.04 (s, 1H), 6.12 (d,
1H, J = 1.4 Hz), 6.88 (d, 1H, J = 1.4 Hz), 7.28 (d, 1H,
J = 1.7 Hz), 7.41 (d, 1H, J = 1.7 Hz); 13C NMR d 21.0
(·2), 29.7, 30.0, 31.3, 31.4, 63.35, 63.42, 112.0, 118.1,
120.4, 123.4, 128.9, 129.7, 132.0, 133.1, 140.0, 141.2,
144.2, 145.7, 170.81, 170.84; HRMS calcd for
C22H2479Br35Cl2O6: (M+H)533.0132, found m/z533.0164.
To a solution of the siloxy ether (390 mg, 0.54 mmol) in
dry THF (2 mL) was added n-BuLi (0.41 mL, 1.58 M
solution in hexane, 0.65 mmol) under an Ar atmosphere
at ꢀ78 ꢁC. After 3 min, B(OMe)3 (0.6 mL, 5.4 mmol)
was added to the mixture. After being stirred for 2 h,
the reaction mixture was treated with 3 M NaOH
(1.0 mL, 13 mmol) and 30% H2O2 (1.0 mL, 35 mmol)
at 0 ꢁC, and further stirred overnight. The reaction
was quenched with NH4Cl aq and worked up. Purifica-
tion by a silica gel column (hexane/EtOAc = 8:1) affor-
ded 12a (226 mg, 64%) as a colorless oil, along with
12b (89 mg, 14%) as a colorless oil.
4.6. 3-Chloro-2-[3-chloro-2-(methoxymethoxy)-5-(3-(tert-
butyldimethylsiloxy)propyl)phenoxy]-5-[3-(tert-butyldim-
ethylsiloxy)propyl]phenol 12a and 1-chloro-3-[2-chloro-4-
(3-(tert-butyldimethylsiloxy)propyl)phenoxy]-2-(methoxy-
methoxy)-5-[3-(tert-butyldimethylsiloxy)propyl]benzene (12b)
A mixture of 11 (29.2 mg, 0.055 mmol), MOMCl
(0.01 mL, 0.11 mmol), and DIPEA (0.04 mL, 0.22 mmol)
in CH2Cl2 (0.5 mL) under an Ar atmosphere was stirred
overnight. The reaction was quenched by the addition
of NH4Cl, and the mixture was worked up. A crude was
purified by a silica gel column (hexane/EtOAc = 3:1) to
afford a MOM-ether (36.5 mg, 100%) as a colorless oil:
Compound 12a: IR (film) 3336, 2929, 2858 cmꢀ1
;
IR (film) 2956, 1738 cmꢀ1
;
1H NMR d 1.80 (tt, 2H,
1H NMR d 0.05 (s, 6H), 0.06 (s, 6H), 0.86 (s, 9H),
0.91 (s, 9H), 1.68 (tt, 2H, J = 6.1, 7.7 Hz), 1.84 (tt, 2H,
J = 6.1, 7.7 Hz), 2.49 (t, 2H, J = 7.7 Hz), 2.63 (t,
2H, J = 7.7 Hz), 3.54 (t, 2H, J = 6.1 Hz), 3.64 (t, 2H,
J = 6.1 Hz), 3.64 (s, 3H), 5.26 (s, 2H), 6.28 (d,
1H, J = 1.7 Hz), 6.77 (d, 1H, J = 2 Hz), 6.84 (d, 1H,
J = 1.7 Hz), 6.93 (d, 1H, J = 2 Hz), 7.39 (s, 1H); 13C
NMR d ꢀ5.21, ꢀ5.17, 18.36, 18.40, 26.00, 26.03, 31.5,
31.7, 33.9, 34.0, 57.5, 61.8, 62.0, 98.8, 113.3, 116.2,
121.1, 123.9, 128.0, 135.8, 139.6, 141.5, 149.7, 150.4;
HRMS calcd for C32H5235Cl2O6Si2: (M+H), 659.2755,
found m/z 659.2772.
J = 6.5, 7.7 Hz), 2.01 (tt, 2H, J = 6.4, 7.8 Hz), 2.01 (s,
3H), 2.08 (s, 3H), 2.49 (t, 2H, J = 7.7 Hz), 2.71 (t, 2H,
J = 7.8 Hz), 3.71 (s, 3H), 4.00 (t, 2H, J = 6.5 Hz), 4.12
(t, 2H, J = 6.4 Hz), 5.35 (s, 2H), 6.04 (d, 1H,
J = 1.8 Hz), 6.91 (d, 1H, J = 1.7 Hz), 7.28 (d, 1H,
J = 1.8 Hz), 7.41 (d, 1H, J = 1.7 Hz); 13C NMR d 20.97,
21.00, 29.8, 29.9, 31.3, 31.6, 57.9, 63.3, 63.4, 98.9, 112.1,
118.2, 123.4, 129.0, 129.8, 132.0, 137.8, 139.9, 141.0,
145.3, 149.9, 170.8 (·2); HRMS calcd for
C24H2779Br35Cl2O7: (M) 576.0315, found m/z 576.0296.
A mixture of the ether (308 mg, 0.53 mmol) and K2CO3
(221 mg, 1.6 mmol) in MeOH (5 mL) was stirred at room
temperature overnight; the reaction mixture was filtered,
and the filtrate was evaporated. The residue was worked
up. Purification by silica gel column chromatography
(hexane/EtOAc = 1:1) afforded a diol (270 mg, 100%) as
1
Compound 12b: IR (film) 2929, 2858 cmꢀ1; H NMR d
0.00 (s, 6H), 0.04 (s, 6H), 0.86 (s, 9H), 0.90 (s, 9H), 1.71
(tt, 2H, J = 6.6, 7.7 Hz), 1.80 (tt, 2H, J = 6.6, 7.7 Hz),
2.52 (t, 2H, J = 7.7 Hz), 2.64 (t, 2H, J = 7.7 Hz), 3.55 (t,
2H, J = 6.6 Hz), 3.59 (s, 3H), 3.61 (t, 2H, J = 6.6 Hz),
5.19 (s, 2H), 6.5 (br, 1H), 6.77 (d, 1H, J = 8.3 Hz), 6.98
(br, 1H), 7.00 (d, 1H, J = 8.3 Hz), 7.24 (br, 1H); 13C
NMR d ꢀ5.21, ꢀ5.18, 18.4 (·2), 26.00, 26.02, 31.2, 31.4,
34.0, 34.2, 57.7, 61.8, 61.9, 99.0, 117.6, 119.2, 124.3,
125.0, 128.0, 128.6, 130.4, 138.9, 139.3, 141.8, 149.8,
149.9; HRMS calcd for C32H5235Cl2O5Si2: (MꢀCl),
607.3039, found m/z 607.3083.
1
a colorless oil: IR (film) 3375, 2939 cmꢀ1; H NMR d
1.67 (tt, 2H, J = 6.2, 7.1 Hz), 1.84 (tt, 2H, J = 6.2,
7.1 Hz), 2.30 (br, 2H), 2.44 (t, 2H, J = 7.1 Hz), 2.66 (t,
2H, J = 7.1 Hz), 3.51 (t, 2H, J = 6.2 Hz), 3.61 (t, 2H,
J = 6.2 Hz), 3.67 (s, 3H), 5.30 (s, 2H), 6.03 (br, 1H), 6.87
(br, 1H), 7.25 (br, 1H), 7.36 (br, 1H); 13C NMR d 31.0,
31.4, 33.5, 33.7, 57.8, 61.3, 61.5, 98.8, 112.0, 118.0,
123.3, 128.7, 129.8, 132.0, 138.5, 139.5, 141.8, 144.9,
149.8; HRMS calcd for C20H2379Br35Cl2O5: (M)
492.0104, found m/z 492.0082.
4.7. 1-(Methoxymethoxy)-4-[3-(tert-butyldimethylsiloxy)-
propyl]-2- [4-(3-(tert-butyldimethylsiloxy)propyl)phenoxy]-
benzene (13)
A mixture of the diol (236 mg, 0.48 mmol), imidazole
(487 mg, 7.2 mmol), and TBSCl (360 mg, 1.2 mmol) in
DMF (5 mL, 0.1 M) under an Ar atmosphere was stirred
for 6 h. After the addition of H2O, the mixture was
A mixture of 12b (267 mg, 0.42 mmol), Pd-C (100 mg),
and HCO2NH4 (78.4 mg, 1.3 mmol) in EtOH (5 mL)
was stirred at 60 ꢁC for 5 h under an Ar atmosphere.

T. Tanabe et al. / Bioorg. Med. Chem. 14 (2006) 2753–2762
2759
The reaction mixture was filtered and the filtrate was
evaporated. The residue was worked up and purified
by silica gel column chromatography (hexane/
EtOAc = 10:1) to afford 13 (220 mg, 92%) as a colorless
2H), 6.79 (br, 1H), 6.86 (d, 1H, J = 8.2 Hz), 6.90 (br,
1H), 7.12 (d, 1H, J = 7.9 Hz), 10.1 (br, 2H); 13C NMR
d 29.8, 30.0, 35.7, 35.9, 56.2, 95.4, 117.5, 117.7, 120.7,
124.1, 129.3, 134.2, 135.0, 146.3, 146.9, 156.1, 178.7,
178.8; HRMS calcd for C20H22O7: (M), 374.1363, found
m/z 374.1342.
1
oil: IR (film) 2929, 2857 cmꢀ1; H NMR d 0.00 (s, 6H),
0.06 (s, 6H), 0.86 (s, 9H), 0.88 (s, 9H), 1.71–1.84 (com-
plex, 4H), 2.52–2.64 (complex, 4H), 3.38 (s, 3H), 3.55–
3.62 (complex, 4H), 5.11 (s, 2H), 6.78 (d, 1H,
J = 1.7 Hz), 6.83 (d, 1H, J = 8.6 Hz), 6.87 (dd, 1H,
J = 1.7, 8.2 Hz), 7.07 (d, 1H, J = 8.2 Hz), 7.09 (d, 1H,
J = 8.6 Hz); 13C NMR d ꢀ5.21, ꢀ5.18, 18.4 (·2), 26.0
(·2), 31.27, 31.30, 34.4, 34.6, 56.1, 62.1, 62.2, 95.5,
117.0, 117.7, 121.0, 124.2, 129.2, 136.0, 137.0, 146.1,
146.5, 155.8; HRMS calcd for C32H54O5Si2: (MꢀC4H9),
517.2803, found m/z 517.2843.
4.10. N-Methoxy-3-[4-[2-(methoxymethoxy)-5-(2-(N-meth-
oxy-N-methylcarbamoyl)ethyl)phenoxy]phenyl]-N-meth-
ylpropanamide (16)
Compound 16 (48.2 mg, 0.13 mmol) was treated at
room temperature with Et3N (0.22 mL), HOBt
(214 mg, 1.3 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-
carbodiimide (WSCI) (121 mg, 0.52 mmol), and (MeO)-
MeNHÆHCl (61.7 mg, 0.52 mmol) in CH2Cl2 (2 mL).
After the addition of 0.5M HCl, the mixture was worked
up. The residue was purified by a silica gel column
(EtOAc) to give 16 (35.7 mg, 60%) as a colorless oil:
4.8. 3-[4-(2-(Methoxymethoxy)-5-(3-oxopropyl)phenoxy)-
phenyl]propanal (14)
1
A mixture of 13 (219 mg, 0.63 mmol) and TBAF (1 M in
THF, 1.9 mL, 1.9 mmol) in THF (5 mL) was stirred at
0 ꢁC for 3 h under an Ar atmosphere. After evaporation
and work-up, a crude product was purified by a silica
gel column (CHCl3/MeOH = 15:1) to afford a diol
(113 mg, 86%) as a colorless oil: IR (film) 3348,
2935 cmꢀ1; 1H NMR d 1.53 (br, 2H), 1.76–1.92 (complex,
4H), 2.60 (t, 2H, J = 7.8 Hz), 2.67 (t, 2H, J = 7.8 Hz), 3.42
(s, 3H), 3.63 (t, 2H, J = 6.5 Hz), 3.66 (t, 2H, J = 6.5 Hz),
5.13 (s, 2H), 6.80 (d, 1H, J = 1.8 Hz), 6.86 (d, 1H,
J = 8.6 Hz), 6.90 (dd, 1H, J = 1.8, 8.4 Hz), 7.11 (d, 1H,
J = 8.4 Hz), 7.13 (d, 1H, J = 8.6 Hz); 13C NMR d 31.3
(·2), 34.2, 34.3, 56.2, 62.1, 62.2, 95.5, 117.2, 117.8,
120.9, 124.2, 129.3, 135.8, 136.7, 146.1, 146.6, 155.9;
HRMS calcd for C20H26O5: (M), 346.1777, found m/z
346.1737.
IR (film) 2937, 2825, 1662 cmꢀ1; H NMR d 2.67 (t,
2H, J = 7.6 Hz), 2.72 (t, 2H, J = 7.6 Hz), 2.86 (t, 2H,
J = 7.8 Hz), 2.92 (t, 2H, J = 7.8 Hz), 3.16 (s, 3H), 3.18
(s, 3H), 3.42 (s, 3H), 3.61 (s, 3H), 3.63 (s, 3H), 5.13 (s,
2H), 6.83 (d, 1H, J = 2.0 Hz), 6.87 (d, 1H, J = 8.8 Hz),
6.95 (dd, 1H, J = 2.0, 8.3 Hz), 7.14 (d, 1H, J = 8.3 Hz),
7.15 (d, 1H, J = 8.8 Hz); 13C NMR d 29.7, 29.9, 32.2
(·2), 33.7, 33.8, 56.1 (·2), 61.2, 95.5, 117.2, 117.8,
120.9, 124.3, 129.3, 135.3, 136.1, 146.0, 146.8, 156.0,
173.5 (·2); HRMS, calcd for C24H32N2O7: (M),
460.2207, found m/z 460.2160.
4.11. MOM-protected 2-demethoxylittorachalcone (17)
To a stirring solution of 18 (138 mg, 0.5 mmol) in dry
THF (2 mL) was added n-BuLi (1.58 M solution in hex-
ane, 0.3 mL, 0.48 mmol) under an Ar atmosphere at
ꢀ78 ꢁC. A solution of 16 (21.7 mg, 0.047 mmol) in dry
THF was added (1 mL), and the mixture was stirred for
further 30 min. After the addition of aq NH4Cl, the mix-
ture was worked up and purified by a silica gel column
(hexane/EtOAc = 5:1) to afford 17 (22.2 mg, 64%) as a
colorless oil: IR (film) 2929, 1666 cmꢀ1; 1H NMR d 2.92
(t, 2H, J = 7.4 Hz), 2.99 (t, 2H, J = 7.4 Hz), 3.22 (t, 2H,
J = 7.8 Hz), 3.27 (t, 2H, J = 7.8 Hz), 3.42 (s, 3H), 3.43
(s, 3H), 3.47 (s, 3H), 3.47 (s, 3H), 3.48 (s, 3H), 5.13 (s,
2H), 5.19 (s, 2H), 5.20 (complex, 4H), 5.24 (s, 2H), 6.70
(dd, 1H, J = 2.0, 8.8 Hz), 6.73 (dd, 1H, J = 2.0, 8.8 Hz),
6.80 (d, 1H, J = 2.0 Hz), 6.82 (d, 1H, J = 2.0 Hz), 6.84
(d, 1H, J = 2.0 Hz), 6.86 (d, 1H, J = 8.8 Hz), 6.95 (dd,
1H, J = 2.0, 7.6 Hz), 7.13 (d, 1H, J = 7.6 Hz), 7.15 (d,
1H, J = 8.8 Hz), 7.70 (d, 1H, J = 8.8 Hz), 7.74 (d, 1H,
J = 8.8 Hz); 13C NMR d 29.76, 29.85, 45.1, 45.3, 56.0,
56.2, 56.3, 56.47, 56.52, 94.1, 94.4, 94.46, 94.50, 95.53,
102.7, 102.8, 108.9, 117.2, 117.8, 120.9, 122.4, 122.5,
124.3, 129.3, 132.12, 132.14, 135.8, 136.6, 146.1, 146.7,
155.9, 157.8, 157.9, 161.47, 161.49, 199.3, 199.5; HRMS
calcd for C40H46O13: (M), 734.2938. found m/z 734.2931.
A mixture of the diol (22.1 mg, 0.064 mmol), Et3N (0.29
mL), and SO3-Pyr (162 mg, 1 mmol) in a 1:1 mixture of
DMSO and CH2Cl2 (1 mL) was stirred at room temper-
ature for 2 h. After the addition of H2O, the mixture was
worked up. The residue was separated by a silica gel col-
umn (hexane/EtOAc = 3:1) to afford 14 (18.4 mg, 84%)
1
as a colorless oil: IR (film) 2924, 1721 cmꢀ1; H NMR:
d 2.69–2.79 (complex, 4H), 2.83–2.95 (complex, 4H),
3.41 (s, 3H), 5.13 (s, 2H), 6.80 (br, 1H), 6.86 (d, 1H,
J = 8.2 Hz), 6.91 (d, 1H, J = 8.6 Hz), 7.11 (d, 1H,
J = 8.6 Hz), 7.14 (d, 1H, J = 8.2 Hz), 9.78 (s, 1H), 9.81
(s, 1H); 13C NMR d 27.4 (·2), 45.2, 45.4, 56.2, 95.4,
117.3, 117.8, 120.9, 124.3, 129.2, 134.3, 135.1, 146.0,
147.0, 156.1, 201.1, 201.4; HRMS calcd for C20H22O5:
(M), 342.1465, found m/z 342.1422.
4.9. 3-[4-(5-(2-Carboxyethyl)-2-(methoxymethoxy)phen-
oxy)phenyl]propionic acid (15)
A mixture of 14 (54.1 mg, 0.16 mmol) and PDC
(476 mg, 1.3 mmol) in DMF (2 mL, 0.1 M) was stirred
at room temperature overnight. After the addition of
H2O, the mixture was worked up. Purification by a silica
gel column (CHCl3/MeOH = 15:1) to afford 15
(48.2 mg, 82%) as a colorless oil: IR (film) 3300–3000
(br), 2925, 2854, 1711 cmꢀ1; 1H NMR d 2.60–2.65 (com-
plex, 4H), 2.82–3.00 (complex, 4H), 3.41 (s, 3H), 5.14 (s,
4.12. Littorachalcone (2)
A solution of 17 (11.1 mg, 0.0015 mmol) in MeOH
(1 mL) in the presence of TsOH (20 mg) was stirred at
room temperature overnight. After evaporation, the

2760
T. Tanabe et al. / Bioorg. Med. Chem. 14 (2006) 2753–2762
mixture was worked up and purified by preparative TLC
(hexane/EtOAc = 3:2) to afford 2 (6.8 mg, 88%) as a col-
purified by silica gel column chromatography (EtOAc)
to afford 20 (6.8 mg, 71%) as a colorless oil: IR (film)
1
1
orless oil: IR (film) 3348, 2925, 1707 cmꢀ1; H NMR d
3300–3000 (br), 2929, 1709 cmꢀ1; H NMR d 2.50 (t,
2.82 (t, 2H, J = 7.6 Hz), 2.85 (t, 2H, J = 7.6 Hz), 3.13
(t, 2H, J = 7.6 Hz), 3.18 (t, 2H, J = 7.6 Hz), 6.20
(s, 2H), 6.28 (dd, 1H, J = 2.0, 8.8 Hz), 6.30 (dd, 1H,
J = 2.0, 8.8 Hz), 6.65 (d, 1H, J = 2.0 Hz), 6.67 (d, 1H,
J = 2.0 Hz), 6.76 (d, 1H, J = 2.0 Hz), 6.79 (d,
1H, J = 8.8 Hz), 6.86 (dd, 1H, J = 2.0, 7.6 Hz), 7.11 (d,
1H, J = 7.6 Hz), 7.11 (d, 1H, J = 8.8 Hz), 7.67 (d, 1H,
J = 8.8 Hz), 7.72 (d, 1H, J = 8.8 Hz); 13C NMR d
40.03, 40.05, 60.5 (·2), 103.4, 108.57, 108.62, 113.7,
113.8, 117.3, 117.7, 121.8, 125.8, 130.2, 133.48, 133.54,
133.8, 135.8, 143.6, 148.0, 157.1, 165.2, 165.3, 166.00,
166.02, 204.6, 204.7; HRMS calcd for C30H26O8: (M),
514.1625, found m/z 514.1625.
2H, J = 6.6 Hz), 2.75 (complex, 4H), 2.97 (t, 2H,
J = 7.1 Hz), 3.70 (s, 3H), 3.71 (s, 3H), 5.35 (s, 2H),
6.11 (br, 1H), 6.74 (br, 1H), 6.85 (br, 1H), 6.93 (s,
1H); 13C NMR d 29.7, 30.6, 35.2, 35.3, 56.1, 57.9,
98.9, 111.7, 111.9, 121.7, 123.1, 128.49, 128.51, 136.9,
137.5, 138.4, 140.3, 151.2, 152.8, 178.6, 178.8; HRMS
calcd for C21H2235Cl2O8: (M), 472.0689, found m/z
472.0687.
4.15. N-Methoxy-3-[2-chloro-5-methoxy-4-[3-chloro-2-
(methoxymethoxy)-5-(2-(N-methoxy-N-methylcarbamoyl)-
ethyl)phenoxy]phenyl]-N-methylpropanamide (21)
Compound 20 (29.8 mg, 0.063 mmol) was treated with
Et3N (0.4 mL), HOBt (94 mg, 0.69 mmol), WSCI
(132 mg, 0.25 mmol), and MeONHMeÆHCl (67.6 mg,
0.25 mmol) in CH2Cl2 (3 mL), as described in the case
of 16 to afford 21 (23 mg, 65%) as a colorless oil: IR
4.13. 1-[5-Chloro-4-(3-chloro-2-(methoxymethoxy)-5-(3-(tert-
butyldimethylsiloxy)propyl)-3-methoxyphenyl)]-3-(tert-butyl-
dimethylsiloxy)propane (19)
A mixture of 12a (10.4 mg, 0.016 mmol), K2CO3
(21.8 mg, 0.16 mmol), and MeI (0.01 mL, 0.16 mmol)
in DMF (05 mL) was stirred overnight under an Ar
atmosphere. After work-up, the residue was separated
by a silica gel column (hexane/EtOAc = 40:1) to afford
19 (10.7 mg, 100%) as a colorless oil: IR (film) 2928,
(film) 2937, 1731 cmꢀ1 1H NMR d 2.61 (t, 2H,
;
J = 7.8 Hz), 2.73 (t, 2H, J = 7.8 Hz), 2.79 (t, 2H,
J = 7.6 Hz), 2.99 (t,. 2H, J = 7.6 Hz), 3.14 (s, 3H), 3.21
(s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 3.70 (s, 3H), 3.74 (s,
3H), 5.35 (s, 2H), 6.17 (d, 1H, J = 2.0 Hz), 6.79 (d,
1H, J = 1.2 Hz), 6.89 (d, 1H, J = 2.0 Hz), 6.94 (d, 1H,
J = 1.2 Hz); 13C NMR d 30.1, 30.4, 32.2 (·2), 33.3,
33.4, 56.1, 57.8, 61.2, 61.3, 98.8, 111.6, 112.3, 121.5,
122.8, 128.38, 128.44, 137.0, 137.7, 140.0, 140.1, 150.9,
153.0, 173.0 (·2); HRMS calcd for C25H3235Cl2N2O8:
(M), 558.1633, found m/z 558.1531.
1
2857 cmꢀ1; H NMR d 0.00 (s, 6H), 0.07 (s, 6H), 0.86
(s, 9H), 0.92 (s, 9H), 1.66 (tt, 2H, J = 6.2, 7.6 Hz), 1.86
(tt, 2H, J = 6.2, 7.6 Hz), 2.45 (t, 2H, J = 7.6 Hz), 2.68
(t, 2H, J = 7.6 Hz), 3.53 (t, 2H, J = 6.2 Hz), 3.66 (t,
2H, J = 6.2 Hz), 3.72 (s, 3H), 3.73 (s, 3H), 5.35 (s,
2H), 6.11 (d, 1H, J = 1.6 Hz), 6.72 (d, 1H, J = 1.5 Hz),
6.85 (d, 1H, J = 1.6 Hz), 6.90 (d, 1H, J = 1.5 Hz); 13C
NMR d ꢀ5.28, ꢀ5.24, 18.26, 18.30, 25.9, 26.0, 31.4,
31.9, 33.99, 34.04, 56.0, 57.7, 61.7, 61.8, 98.8, 111.5,
112.2, 121.6, 122.8, 128.16, 128.19, 136.8, 138.5, 139.6,
140.7, 150.8, 152.8; HRMS calcd for C33H5435Cl2O6Si2:
(MꢀOMe), 641.2648, found m/z 641.2623.
4.16. MOM-protected 2,20-dichloroverbenachalcone (22)
Compound 21 (23.9 mg, 0.043 mmol) was reacted with a
lithiated 18 (190 mg, 0.69 mmol) in dry THF (2 mL),
essentially the same procedure as in the case of 17 to af-
ford 22 (17.6 mg, 49%) as a colorless oil: IR (film) 2954,
1
1666 cmꢀ1; H NMR d 2.79 (t, 2H, J = 7.8 Hz), 3.03 (t,
4.14. 3-[4-[5-(2-Carboxyethyl)-3-chloro-2-(methoxymeth-
oxy)phenoxy]-5-chloro-3-methoxyphenyl]propanoic acid (20)
2H, J = 7.3 Hz), 3.13 (t, 2H, J = 7.8 Hz), 3.33 (t, 2H,
J = 7.3 Hz), 3.45 (s, 3H), 3.48 (s, 3H), 3.48 (s, 3H),
3.50 (s, 3H), 3.70 (s, 3H), 3.72 (s, 3H), 5.16 (s, 2H),
5.19 (s, 2H), 5.21 (s, 2H), 5.27 (s, 2H), 5.35 (s, 2H),
6.18 (br, 1H), 6.71 (dd, 1H, J = 2.0, 8.8 Hz), 6.74 (dd,
1H, J = 2.0, 8.8 Hz), 6.90 (br, 1H), 6.94 (br, 1H), 7.69
(d, 1H, J = 8.8 Hz), 7.76 (d, 1H, J = 8.8 Hz); 13C
NMR d 30.1, 30.2, 44.7, 44.9, 56.0, 56.1, 56.3, 56.5,
56.6, 57.9, 94.1, 94.3, 94.5, 94.6, 98.9, 102.7, 102.8,
108.7, 108.86, 108.94, 111.7, 112.3, 121.5, 122.1, 122.2,
122.8, 128.30, 128.33, 128.4, 129.7, 132.2, 138.2, 139.9,
140.6, 150.9, 153.0, 157.9, 161.6, 161.7, 198.8, 198.9;
HRMS calcd for C41H46O1435Cl2Na: (M+Na),
855.2162, found m/z 855.2187.
A mixture of 19 (99.2 mg, 0.15 mmol) and TBAF (1 M
in THF solution, 0.44 mL, 0.45 mmol) in THF (3 mL)
was stirred for 2 h and then evaporated. The residue
was worked up and purified by a silica gel column
(EtOAc) to afford a diol (63.6 mg, 97%) as a colorless
oil: IR (film) 3365, 2937 cmꢀ1 1H NMR d 1.71 (tt,
;
2H, J = 6.3, 7.4 Hz), 1.91 (tt, 2H, J = 6.3, 7.4 Hz), 2.07
(br, 2H), 2.47 (t, 2H, J = 7.4 Hz), 2.71 (t, 2H,
J = 7.4 Hz), 3.56 (t, 2H, J = 6.3 Hz), 3.70 (t, 2H,
J = 6.3 Hz), 3.70 (s, 3H), 3.72 (s, 3H), 5.35 (s, 2H),
6.13 (br, 1H), 6.74 (br, 1H), 6.86 (br, 1H), 6.91 (br,
1H); 13C NMR d 31.4, 31.9, 33.77, 33.81, 56.1, 57.8,
61.7 (·2), 98.8, 111.4, 112.2, 121.6, 122.7, 128.26,
128.31, 136.8, 138.2, 139.7, 140.5, 150.8, 152.9; HRMS
calcd for C21H2635Cl2O6: (M), 444.1104, found m/z
444.1101.
4.17. 2,20-Dichloroverbenachalcone (3)
A mixture of 22 (8 mg, 0.01 mmol) and TsOH (30 mg) in
MeOH (0.4 mL) was stirred at room temperature over-
night to afford 3 (6.2 mg, 100%) as a yellow oil: IR (film)
The diol (9 mg, 0.02 mmol) was treated with PDC
(76 mg, 0.2 mmol) in DMF (0.5 mL) for 3.5 h. After
the addition of H2O, the mixture was worked up and
3355, 2927, 1699 cmꢀ1 1H NMR d 2.69 (t, 2H,
;
J = 7.3 Hz), 2.77 (br, 2H), 2.93 (t, 2H, J = 7.6 Hz),
3.06 (t, 2H, J = 7.3 Hz), 3.29 (t, 2H, J = 7.6 Hz), 3.62

T. Tanabe et al. / Bioorg. Med. Chem. 14 (2006) 2753–2762
2761
(s, 3H), 6.19 (d, 1H, J = 2.4 Hz), 6.20 (d, 1H,
J = 2.0 Hz), 6.21 (d, 1H, J = 2.4 Hz), 6.28 (dd, 2H,
J = 2.4, 8.8 Hz), 6.32 (dd, 2H, J = 2.4, 8.8 Hz), 6.84 (d,
1H, J = 2.0 Hz), 6.96 (br, 1H), 6.97 (br, 1H), 7.64 (d,
1H, J = 8.8 Hz), 7.75 (d, 1H, J = 8.8 Hz), 12.57 (s,
1H), 12.62 (s, 1H); 13C NMR d 29.4, 29.6, 38.9, 39.2,
56.1, 103.27, 103.33, 108.05, 108.10, 111.5, 112.8,
113.0, 114.7, 120.0, 121.5, 123.0, 128.2, 131.89, 131.93,
132.6, 139.8, 140.5, 145.4, 152.9, 164.00, 164.05, 165.1,
202.6, 202.9; HRMS, calcd for C31H26O935Cl2: (M),
612.0954, found m/z 612.0955.
worked up. Purification by a silica gel column (hexane/
EtOAc = 1:1) afforded 25 (9.1 mg, 81%) as a colorless
1
oil: IR (film) 3423, 2927, 1722 cmꢀ1; H NMR d 2.68
(t, 2H, J = 6.9 Hz), 2.80 (t, 2H, J = 6.9 Hz), 2.82 (t,
2H, J = 6.9 Hz), 2.95 (t, 2H, J = 6.9 Hz), 3.45 (s, 3H),
3.84 (s, 3H), 5.18 (s, 2H), 6.63 (d, 1H, J = 1.8 Hz),
6.68 (dd, 1H, J = 1.5, 8.2 Hz), 6.75 (d, 1H, J = 8.2 Hz),
6.82 (d, 1H, J = 1.5 Hz), 6.98 (dd, 1H, J = 1.8, 8.2 Hz),
7.12 (d, 1H, J = 8.2 Hz), 9.76 (s, 1H), 9.83 (s, 1H); 13C
NMR d 27.5, 27.9, 45.3, 45.4, 56.0, 56.2, 95.5, 112.7,
117.7, 118.7, 118.9, 120.2, 123.2, 134.8, 136.2, 144.0,
146.0, 146.9, 150.3, 201.25, 201.28; HRMS calcd for
C21H24O6: (M+H), 373.1650, found m/z 373.1657.
4.18. 1-[4-(2-(Methoxymethoxy)-5-(3-(tert-butyldimeth-
ylsiloxy)propyl)-3-methoxyphenyl)]-3-(tert-butyldimeth-
ylsiloxy)propane (23)
4.21. 3-[4-(5-(2-Carboxyethyl)-2-(methoxymethoxy)phen-
oxy)-3-methoxyphenyl]propanoic acid (26)
A mixture of 19 (232 mg, 0.34 mmol), Pd-C (100 mg),
and HCO2NH4 (200 mg, 3.4 mmol) in EtOH (50 mL)
was heated 60 ꢁC for 3 h under an Ar atmosphere. The
reaction mixture was treated with essentially the same
procedure as in the case of 13 to afford 23 (174 mg,
A mixture of 25 (70.6 mg, 0.19 mmol) and PDC
(708 mg, 1.9 mmol) in DMF (2 mL) was stirred at room
temperature overnight. After the addition of H2O, the
mixture was worked up, and purification by a silica gel
column (CHCl3/MeOH = 15:1) afforded 26 (39.4 mg,
52%) as a colorless oil: IR (film) 3000–3400 (br), 2933,
1
84%) as a colorless oil: IR (film) 2929, 2856 cmꢀ1; H
NMR d 0.00 (s, 6H), 0.04 (s, 6H), 0.86 (s, 9H), 0.90 (s,
9H), 1.71 (tt, 2H, J = 6.3, 7.7 Hz), 1.82 (tt, 2H,
J = 6.3, 7.7 Hz), 2.52 (t, 2H, J = 7.7 Hz), 2.64 (t, 2H,
J = 7.7 Hz), 3.44 (s, 3H), 3.56 (t, 2H, J = 6.3 Hz), 3.63
(t, 2H, J = 6.3 Hz), 3.82 (s, 3H), 5.16 (s, 2H), 6.63 (d,
1H, J = 2.0 Hz), 6.66 (dd, 1H, J = 1.7, 7.9 Hz), 6.72 (d,
1H, J = 7.9 Hz), 6.79 (d, 1H, J = 1.7 Hz), 6.81 (dd, 1H,
J = 2.0, 8.3 Hz), 7.08 (d, 1H, J = 8.3 Hz); 13C NMR d
ꢀ5.15, ꢀ5.14, 18.40, 18.44, 26.0 (·2), 31.4, 31.9, 34.46,
34.50, 55.9, 56.1, 62.3 (·2), 95.7, 112.8, 117.6, 118.7,
118.9, 120.4, 123.2, 136.9, 137.9, 143.8, 145.6, 147.0,
150.1; HRMS calcd for C33H56O6Si2: (MꢀOMe),
537.3429, found m/z 573.3438.
1
1709 cmꢀ1; H NMR d 2.55 (t, 2H, J = 6.9 Hz), 2.71
(t, 2H, J = 7.3 Hz), 2.81 (t, 2H, J = 6.9 Hz), 2.95 (t,
2H, J = 7.3 Hz), 3.48 (s, 3H), 3.79 (s, 3H), 5.21 (s,
2H), 6.56 (br, 1H), 6.72 (d, 1H, J = 8.4 Hz), 6.81 (com-
plex, 3H), 7.11 (d, 1H, J = 8.2 Hz), 10.0 (br, 2H); 13C
NMR d 29.9, 30.6, 35.66, 35.75, 55.9, 56.2, 95.6, 113.0,
117.60, 117.63, 120.0, 120.6, 122.9, 134.9, 136.1, 140.3,
143.7, 145.7, 150.5, 178.91, 178.94; HRMS calcd for
C21H24O8: (MꢀOH), 373.1442, found m/z 387.1411.
4.22. N-Methoxy-3-[3-methoxy-4-[2-(methoxymethoxy)-5-
(2-(N-methoxy-N-methylcarbamoyl)ethyl)phenoxy]phenyl]-
N-methylpropanamide (27)
4.19. 3-[4-(5-(3-Hydroxypropyl)-2-(methoxymethoxy)phen-
oxy)-3-methoxyphenyl]propan-1-ol (24)
Compound 26 (16.4 mg, 0.041 mmol) was treated with
Et3N (0.25 mL), HOBt (60 mg, 0.45 mmol), WSCI
(86 mg, 0.23 mmol), and (MeO)NHMeÆHCl (43.6 mg,
0.23 mmol) in CH2Cl2 (0.8 mL), as described in the case
of 21 to afford 27 (19.0 mg, 96%) as a colorless oil: IR
Compound 23 (65.6 mg, 0.11 mmol) was treated with
TBAF (1 M in THF, 0.33 mL, 0.33 mmol) in THF
(1 mL) to afford 24 (48.4 mg, 100%) as a colorless oil:
1
IR (film) 3367, 2937 cmꢀ1; H NMR d 1.59 (br, 2H),
(film) 2937, 1662 cmꢀ1 1H NMR d 2.64, (t, 2H,
;
1.79 (tt, 2H, J = 6.4, 7.7 Hz), 1.90 (tt, 2H, J = 6.4,
7.7 Hz), 2.56 (t, 2H, J = 7.7 Hz), 2.69 (t, 2H,
J = 7.7 Hz), 3.46 (s, 3H), 3.60 (t, 2H, J = 6.4 Hz), 3.68
(t, 2H, J = 6.4 Hz), 3.83 (s, 3H), 5.18 (s, 2H), 6.64 (d,
1H, J = 2.0 Hz), 6.68 (dd, 1H, J = 1.7, 8.1 Hz), 6.75 (d,
1H, J = 8.1 Hz), 6.81 (d, 1H, J = 1.7 Hz), 6.83 (dd, 1H,
J = 2.0, 8.2 Hz), 7.11 (d, 1H, J = 8.2 Hz); 13C NMR d
31.4, 31.9, 34.2, 34.3, 56.0, 56.2, 62.1, 62.2, 95.6, 112.8,
117.7, 118.7, 118.9, 120.4, 123.2, 136.4, 137.6, 143.8,
145.7, 147.0 150.2; HRMS calcd for C21H28O6:
(MꢀOMe), 345.1711, found m/z 345.1726.
J = 7.6 Hz), 2.75 (t, 2H, J = 7.6 Hz), 2.82 (t, 2H,
J = 7.8 Hz), 2.94 (t, 2H, J = 7.8 Hz), 3.15 (s, 3H), 3.19
(s, 3H), 3.46 (s, 3H), 3.59 (s, 3H), 3.63 (s, 3H), 3.84 (s,
3H), 5.18 (s, 2H), 6.68 (d, 1H, J = 2.0 Hz), 6.72 (dd,
1H, J = 1.5, 7.8 Hz), 6.75 (d, 1H, J = 7.8 Hz), 6.86 (d,
1H, J = 1.5 Hz), 6.88 (dd, 1H, J = 2.0, 8.3 Hz), 7.12 (d,
1H, J = 8.3 Hz); 13C NMR d 30.0, 30.5, 32.2 (·2), 33.8
(·2), 56.0, 56.1, 61.2, 61.3, 95.6, 112.9, 117.8, 118.8,
118.9, 120.4, 123.3, 135.9, 137.2, 144.0, 145.9, 147.0,
150.2, 173.4 (·2); HRMS calcd for C25H34N2O8:
(M+H), 491.2390, found m/z 491.2355.
4.20. 3-[3-Methoxy-4-(2-(methoxymethoxy)-5-(3-oxopro-
pyl)phenoxy)phenyl]propanal (25)
4.23. MOM-protected p-dehydroxyverbenachalcone (28)
Compound 27 (24.9 mg, 0.051 mmol) was reacted with a
lithiated 29 (117 mg, 0.54 mmol) in dry THF (2 mL),
essentially the same procedure as in the case of 17 to af-
ford 28 (21.9 mg, 67%) as a colorless oil: IR (film) 2933,
To a solution of 24 (11.3 mg, 0.03 mmol) in CH2Cl2
(2 mL) were added pyridine (0.01 mL, 0.09 mmol) and
the Dess–Martin periodinane (76 mg, 0.09 mmol) at
room temperature under an Ar atmosphere. After being
stirred for 2 h, the reaction was quenched with H2O and
1
1674 cmꢀ1; H NMR d 2.89 (t, 2H, J = 7.6 Hz), 3.02 (t,
2H, J = 7.6 Hz), 3.21 (t, 2H, J = 7.6 Hz), 3.33 (t, 2H,

2762
T. Tanabe et al. / Bioorg. Med. Chem. 14 (2006) 2753–2762
J = 7.6 Hz), 3.43 (s, 3H), 3.45 (s, 3H), 3.47 (s, 3H), 3.82
(s, 3H), 5.18 (s, 2H), 5.19 (s, 2H), 5.25 (s, 2H), 6.70 (d,
1H, J = 8.3 Hz), 6.72 (br, 1H), 6.73 (d, 1H,
J = 7.8 Hz), 6.85 (br, 1H), 6.88 (d, 1H, J = 8.3 Hz),
7.03–7.07 (complex, 2H), 7.11 (d, 1H, J = 7.8 Hz), 7.16
(d, 1H, J = 8.3 Hz), 7.18 (d, 1H, J = 8.3 Hz), 7.39–7.44
(complex, 2H), 7.59 (d, 1H, J = 6.3 Hz), 7.63 (d, 1H,
J = 6.3 Hz); 13C NMR d 29.8, 30.2, 45.3, 45.4, 55.9,
56.2, 56.38, 56.44, 94.3, 94.5, 95.6, 112.9, 114.7, 114.8,
117.7, 118.81, 118.84, 120.3, 121.70, 121.75, 123.3,
129.0, 129.1, 129.9, 130.0, 133.1, 133.2, 136.1, 137.4,
143.9, 145.8, 147.0, 150.2, 155.8, 201.6, 201.7; HRMS
calcd for C37H41O10: (M+H), 645.2700, found m/z
645.2700.
2H, J = 7.3 Hz), 3.80 (s, 3H), 6.27 (br, 1H), 6.65 (br,
1H), 6.76 (d, 1H, J = 8.3 Hz), 6.83–6.91 (complex,
7H), 7.84 (d, 1H, J = 8.3 Hz), 7.86 (d, 2H, J = 8.3 Hz),
8.34 (br, 1H), 8.43 (br, 1H); 13C NMR d 29.9, 30.6,
39.7, 40.1, 55.9, 112.9, 115.3, 115.7, 117.6., 120.5,
120.7, 123.6, 129.0, 129.2, 130.5, 133.1, 138.3, 143.3,
144.6, 145.2, 150.4, 161.19, 161.24, 198.3, 198.5; HRMS
calcd for C31H28O7: (M+H), 513.1911, found m/z
513.1938.
4.27. Bioassay
PC12D cells were trypsinized for dissociation and seed-
ed on 48-well culture plates (2 · 104 cells/well). After
24 h, the medium was replaced with fresh medium con-
taining 12% FBS and 2% CS. NGF at final concentra-
tion of 5 ng/mL and verbenachalcone or its congeners
at 10 and 30 lM were added to the medium. After
48 h, the morphology of PC12D cells was observed by
microscope. Cells with process-length of more than
twice the diameter of a cell body were scored as neu-
rite-bearing cells.
4.24. p-Dehydroxyverbenachalcone (4)
Protecting groups of 28 (10.6 mg, 0.016 mmol) were re-
moved with TsOH (20 mg) in MeOH (1 mL) as in the
case of 2 to afford 4 (7.9 mg, 94%) as a yellow oil: IR
1
(film) 3423, 2927, 1639 cmꢀ1; H NMR d 2.92 (t, 2H,
J = 7.6 Hz), 3.06 (t, 2H, J = 7.6 Hz), 3.23 (t, 2H,
J = 7.6 Hz), 3.35 (t, 2H, J = 7.6 Hz), 3.85 (s, 3H), 6.06
(s, 1H), 6.73 (d, 1H, J = 1.5 Hz), 6.79 (dd, 1H, J = 1.5,
6.4 Hz), 6.84–7.00 (complex, 8H), 7.44–7.49 (complex,
2H), 7.70 (d, 1H, J = 6.8 Hz), 7.76 (d, 1H, J = 6.8 Hz),
12.28 (s, 1H), 12.29 (s, 1H); 13C NMR d 29.5, 29.9,
40.1, 40.2, 56.0, 112.9, 115.9, 118.0, 118.46, 118.53,
118.8, 118.9, 119.2, 120.7, 120.8, 123.9, 129.7, 129.8,
132.6, 136.3, 136.4, 137.9, 143.5, 144.7, 145.5, 150.6,
162.3, 205.0, 205.3; HRMS calcd for C31H28O7: (M),
512.1832, found m/z 512.1829.
Acknowledgments
This work was supported by a Grant-in-Aid for the 21st
Century COE program ‘Keio Life Conjugated Chemis-
try’, as well as Scientific Research C from the Ministry
of Education, Culture, Sports, Science and Technology,
Japan. The authors were indebted to Mr. Y. Shimizu of
their Faculty for his technical assistance.
4.25. MOM-protected o-dehydroxyverbenachalcone (30)
References and notes
Compound 27 (24.9 mg, 0.051 mmol) was reacted with a
lithiated 31 (123 mg, 0.57 mmol) in dry THF (2 mL),
essentially the same procedure as in the case of 17 to af-
ford 30 (27.4 mg, 84%) as a colorless oil: IR (film) 2933,
1. Tanabe, T.; Doi, F.; Ogamino, T.; Nishiyama, S. Tetra-
hedron Lett. 2004, 45, 3477–3480.
2. Li, Y.; Matsunaga, K.; Kato, R.; Ohizumi, Y. J. Nat.
Prod. 2001, 64, 806–808.
3. (a) Yamamura, S.; Nishiyama, S. Synlett 2002, 533–543;
(b) Takahashi, M.; Konishi, H.; Iida, S.; Nakamura, K.;
Yamamura, S.; Nishiyama, S. Tetrahedron 1999, 55, 5295–
5302.
4. (a) Mdee, L. K.; Yeboah, S. O.; Abegaz, B. M. J. Nat.
Prod. 2003, 66, 599–604; (b) Masesane, I. B.; Yeboah, S.
1
2827, 1678 cmꢀ1; H NMR d 2.91 (t, 2H, J = 7.8 Hz),
3.03 (t, 2H, J = 7.6 Hz), 3.15 (t, 2H J = 7.8 Hz), 3.26
(t, 2H, J = 7.6 Hz), 3.46 (s, 3H), 3.48 (s, 3H), 3.48 (s,
3H), 3.83 (s, 3H), 5.18 (s, 2H), 5.23 (s, 2H), 5.23 (s,
2H), 6.70 (d, 1H, J = 2.0 Hz), 6.74 (complex, 2H), 6.86
(br, 1H), 6.90 (dd, 1H, J = 2.0, 8.3 Hz), 7.05 (d, 1H,
J = 8.8 Hz), 7.07 (d, 1H, J = 8.8 Hz), 7.13 (d, 1H,
J = 8.3 Hz), 7.89 (d, 1H, J = 8.8 Hz), 7.95 (d, 1H,
J = 8.8 Hz); 13C NMR d 29.7, 30.1, 40.16, 40.24, 55.9,
56.2, 56.3 (·2), 94.0 (·2), 95.6, 112.8, 115.6, 115.7,
117.7, 118.8, 118.9, 120.3, 123.3, 130.08, 130.11,
130.66, 130.70, 135.9, 137.2, 143.9, 145.9, 147.0, 150.2,
160.88, 160.91, 197.69, 197.74; HRMS calcd for
C37H41O10: (M+H), 645.2700, found m/z 645.2690.
O.; Liebscher, J.; Mugge, C.; Abegaz, B. M. Phytochem-
¨
istry 2000, 53, 1005–1008.
5. Xing, X.; Padmanaban, D.; Yeh, L.-A.; Cuny, G. D.
Tetrahedron 2002, 58, 7903–7910.
6. Yeh, L.-A.; Padmanaban, D.; Ho, P.; Xing, X.; Rowley,
P.; Morse, L. J.; Jensen, R. V.; Cuny, G. D. Bioorg. Med.
Chem. Lett. 2005, 15, 1193–1196.
7. Li, Y.; Ishibashi, M.; Chen, X.; Ohizumi, Y. Chem.
Pharm. Bull. 2003, 51, 872–874.
8. Posner, G. H.; Oda, M. Tetrahedron Lett. 1981, 22, 5003–
5006.
9. This compound was also produced by exhaustive hydrog-
enolysis of 11.
4.26. o-Deoxyverbenachalcone (5)
Protecting groups of 30 (15.8 mg, 0.025 mmol) were re-
moved with TsOH (23 mg) in MeOH (1 mL) to afford
5 (13.9 mg, 100%) as a yellow oil: IR (film) 3334, 2927,
´
´
10. Novak, Z.; Timari, G.; Kotschy, A. Tetrahedron 2003, 59,
7509–7513.
11. Townsend, C. A.; Bloom, L. M. Tetrahedron Lett. 1981,
22, 3923–3924.
12. Kipping, F. B.; Wren, J. J. J. Chem. Soc. 1957, 3246–3251.
1
1660 cmꢀ1; H NMR d 2.89 (t, 2H, J = 7.8 Hz), 3.04
(t, 2H, J = 7.3 Hz), 3.14 (t, 2H, J = 7.8 Hz), 3.24 (t,