A total synthesis of verbenachalcone, a bioactive diaryl ether from Verbena littoralis

Article abstract of DOI:10.1016/j.tetlet.2004.02.154

Verbenachalcone 1, isolated from the aerial part of Verbena littoralis H. B. K. (Verbenaceae), has successfully been synthesized by employing anodic oxidation of the phenol derivative 3, as the key step. The bromine and chlorine substituents of 3 effected

Full text of DOI:10.1016/j.tetlet.2004.02.154

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3477–3480
A total synthesis of verbenachalcone, a bioactive diaryl ether from
Verbena littoralis
Takamasa Tanabe, Fuminao Doi, Takahisa Ogamino and Shigeru Nishiyama*
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522,
Japan
Received 4 February 2004; revised 23 February 2004; accepted 27 February 2004
Abstract—Verbenachalcone 1, isolated from the aerial part of Verbena littoralis H. B. K. (Verbenaceae), has successfully been
synthesized by employing anodic oxidation of the phenol derivative 3, as the key step. The bromine and chlorine substituents of 3
effected regioselective introduction of a methoxy group, as well as modulating the oxidation reaction. A flow-cell type apparatus of
anodic oxidation provided the desired diaryl ether 4 in good yield.
Ó 2004 Elsevier Ltd. All rights reserved.
Verbenachalcone 1, an activator of nerve growth factor
(NGF)-mediated neurite outgrowth of PC12D cells,
possesses a dimeric structure linked through the diaryl
ether linkage.1 From the viewpoint of phenolic oxida-
tion, a biosynthesis of this molecule might involve a one-
electron oxidation process, as depicted in Scheme 1.
O
OH
OH
H3CO
O
OH
HO
OH
O
In this context, we have extensively investigated bio-
mimetic oxidation by employing electrochemical or
thallium(III) oxidation of halogenated phenols, leading
to the corresponding diaryl ethers or spiro-type prod-
ucts.2 However, construction of the diaryl ether attached
with an alkoxyl groupat the ortho-position of the phe-
nol group, would be accompanied with difficulties, not
to provide the desired diaryl ether but to produce di-
enone-type products, owing to high-oxidation potential,
which preferred the two-electron oxidation process. For
instance, anodic oxidation of eugenol was reported to
give the acetal A as a major product, which underwent
Diels–Alder reaction to yield asatone-type products
(Scheme 2).3 On the other hand, upon using basic con-
ditions, the diaryl derivative B was obtained through the
one-electron oxidation, instead of the diaryl ether C.
The anodic oxidation seemed to require an additional
factor, although regioselective coupling of aryl halides
and phenols under the Ullmann-type conditions might
Verbenachalcone (1)
Oxidation
O
OH
R
OH
R = H, OH, or OCH3
HO
Scheme 1.
assemble the desired diaryl ether.4 In contrast to such
problems in our anodic oxidation chemistry, the meth-
oxy-diaryl ether functions have been found in natural
products, such as diarylheptanolides from Juglans
mandshurica.5 As a new electrochemical access to con-
struct these functions, we utilized a mixed-halogenated
phenol (type-D), which provided the dimer (type-E)
by oxidative coupling exclusively at the Br position,
followed by Zn reduction, as depicted in Scheme 2.6
Although synthesis of verbenachalcone 1 by a con-
ventional method was recently reported,7 we describe
Keywords: Verbenachalcone; Anodic oxidation; Verbena littoralis
H. B. K.; PC12D cells; Diaryl ether.
* Corresponding author. Tel./fax: +81-45-566-1717; e-mail: nisiyama@
chem.keio.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.154

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T. Tanabe et al. / Tetrahedron Letters 45 (2004) 3477–3480
C3H5
C3H5
[O]
CH3O
CH3O
CH3O
CH3OH
CH3O
2
B
A
O
OH
OH
Eugenol
C3H5
C3H5
O
C
OH
OCH3
O
HO
OH
Diarylheptanolides (ref. 4)
OCH3
OCH3
OH
R
OH
O
O
CH3OH
R
R
Cl
R
[O]
MeOH
Cl
Br
Cl
Cl
O
Cl
Br
Br
O
R
O
Br
OH
D
R = alkyl substituents
CH3O
Cl
R
R
Zn, H
Ar
Cl
O
O
OH
Br
O
E
Scheme 2.
herein its synthesis by our own phenolic oxidation
protocol.
of 3. Compound 4 in hand was submitted to Zn
reduction to give the diaryl ether 7. After manipulation
in three steps to exchange the protecting groups (quant),
followed by introduction of a borate group, treatment
with alkaline H2O2, gave phenol 8 in 82% yield. Suc-
cessive methylation of the phenol group (quant),
removal of the chlorine atoms under hydrogen transfer
conditions (84%), and TBAF-treatment (quant), pro-
vided the corresponding alcohol 9, which on oxidation
produced dialdehyde 10 in 81% yield. Upon treatment
with a lithio derivative of 11, 10 underwent the expected
coupling to give the benzyl alcohol 12 in 27% yield,
which on oxidation gave quantitatively the protected
varbenachalcone 13. To overcome the low yield of 12,
alcohol 9 was submitted to PDC oxidation, followed by
conversion into the corresponding Weinreb amide 14.
Successful coupling with a lithio derivative of 11, pro-
duced 13 in 64% yield, which on acidic hydrolysis pro-
vided 1 in quantitative yield. Under the full range of
spectroscopic data, the synthetic sample was super-
imposable to the natural 1.
Compound 3 without the terminal tri-substituted phenyl
ring, was employed as a substrate of anodic oxidation to
prevent undesired side-reactions (Scheme 3). This com-
pound was produced by the two-step halogenation
reaction of 28 in 64% yield. Among anodic oxidation of
3 under the conditions depicted in Table 1, the expected
49 was obtained in all entries, although undesired 5 and
610 were co-produced. Addition of pyridine neutralized
the acidity of the reaction solution. The lowered oxi-
dation potential under the basic conditions, preferen-
tially produced the radical species, which underwent
dimerization to give the diaryl ether 4 (upon comparison
of entry 3 with entry 2, pyridine effected production of 4
in better yield). Although 4 was produced in ca. 50%
yield, the low substrate concentrations (entries 4 and 5)
would not be suitable to large scale experiments. When
using a diamond electrode as an anode, 5 and 6, which
were produced through cationic intermediates, were
preferentially obtained even in the presence of pyridine
(entry 6). The optimized yield was attained, when using
a flow-cell apparatus, which suppressed the undesired
two-electron oxidation leading to 5 and 6, as well as
other side reactions (entry 7). In particular, the 62%
yield in this entry was obtained, upon using a 3g portion
In conclusion, anodic oxidation of the mixed-haloge-
nated phenol 3 in a gram scale using a flow-cell appa-
ratus, provided the corresponding diaryl ether 4 in 62%
yield. The Br substituent was selectively converted into
a methoxy group, and further synthetic manipulation

T. Tanabe et al. / Tetrahedron Letters 45 (2004) 3477–3480
3479
OAc
MeO
Br
R1
MeO
MeO
Cl
OAc
OAc
Cl
OAc
Cl
OAc
Cl
b
HO
Br
O
R2
2: R1 = R2 = H
O
Br
O
OH
5
4
6
a
3: R1 = Br, R2 = Cl
R
OAc
Cl
OTBS
Cl
R
OAc
Cl
e
d
OTBS
Cl
c
4
O
O
OMe
O
Br
OH
OMOM
OH
OMOM
7
8
9: R = CH2OH
f
OMOM
Br
10: R = CHO
OH
OMOM
O
11
MeO
O
MOMO
MeO
O
h
Ar
OMOM
OMOM
g
MOMO
MOMO
Ar
13
OMOM
OMe
14
O
12
OH
O
MeO
O
N
i
j
Me
1
9
MOMO
Me
N
OMe
O
Scheme 3. Reagents and conditions: (a) (i) SO2Cl2, CHCl3, 64%; (ii) HBr3-pyr., quant. (b) See Table 1. (c) Zn–AcOH, THF, 79%. (d) (i) MOMCl,
€
Hunig base, CH2Cl2, quant; (ii) K2CO3, MeOH, quant; (iii) TBSCl, Imd, quant; (iv) B(OMe)3, n-BuLi; (v) 3M NaOH, H2O2, 82% in two steps. (e) (i)
MeI, K2CO3, DMF, quant; (ii) Pd–C, HCO2NH4, 60 °C, EtOH, 84%; (iii) TBAF, THF, quant. (f) Dess-Martin oxid., CH2Cl2, 81%. (g) 10, n-BuLi,
THF, 27%. (h) TPAP, NMO, MS4A, CH2Cl2, quant. (i) (i) PDC, DMF, 52%; (ii) Me(MeO)NH, WSCl, HOBt, Et3N, CH2Cl2, 95%. (j) (i) 10, n-BuLi,
THF (64%); (ii) TsOH, MeOH, quant.
Table 1. Anodic oxidation (CCE at 20 mA) of the phenol 3
Entries
Conditionse
Products (%)
5 + 6
Potential (V vs SCE)
Substrate conc. (mM)
Solvents
4
1a
2b
3b
4b
5b
6c
7d
1.0–1.5
1.0–1.2
0.8–0.9
1.1–1.3
1.1–1.4
2.0–2.5f
2.95–3.0
10
10
10
2
MeOH
MeOH
16
26
37
51
50
3
23
4
MeOH, pyridine
MeOH, pyridine
MeOH, pyridine
MeOH, pyridine
MeOH, pyridine
7
8
0.5
10
10
12
30
––
62
a Glassy carbon beaker (anode)–Pt wire (cathode).
b Pt net (anode)–Pt wire (cathode).
c Diamond electrode (anode)–Pt wire (cathode).
d Flow-cell carbon sheet (anode)–Pt wire (cathode); flow rate, 0.4 mL/min.
e Supporting salt LiClO4. Constant current electrolysis (CCE) at 20 mA, 3 F/mol.
f Constant current at 10 mA.
provided verbenachalcone 1. This methodology would
open up a new access to synthesis of bioactive sub-
Acknowledgements
stances carrying diaryl ether moieties with adjacent
methoxy or other functional groups.
This work was supported by Grant-in-Aid for the
21st Century COE program ‘KEIO Life Conjugate

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T. Tanabe et al. / Tetrahedron Letters 45 (2004) 3477–3480
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9. 4: IR (film) 2939, 1737, and 1693 cmꢀ1
;
1H NMR
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mixture (ca. 5 ꢁ 3:1¼5/6). Their structures and ratio
1
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