A solid-phase approach to DDB derivatives

Article abstract of DOI:10.1016/j.ejmech.2005.03.024

Since the discovery of 2,2′-dimethoxycarbonyl-4,4-dimethoxy-5,6, 5′,6′-biomethylenedioxy-biphenyl (DDB) as a potent anti-HBV agent, we have studied the structure-activity relationships of 4,4′-dimethoxy-5, 6,5′,6′-dimethenedioxy-2-alkyloxycarbonyl-2′-(4-substituted benzyl piperazin-1-yl)carbonyl-biphenyl as anti-HBV agents. Therefore, it is rational to extend this study to the 3,3′-disustituted-4,4′- dimethoxy-5,6,5′,6′-dimethenedioxy-2-alkyloxycarbonyl-2′- Serine derivatives. Thus, in an attempt to develop an efficient method for the preparation of a large number of DDB derivatives, the reaction between a DDB acid chloride and serine derivatives on solid support was studied. The structure of resulted compounds was confirmed by LC-MS and ¹H NMR analysis. Compounds 2a, 2d, 2f, 2j showed in vitro anti-HBV activity without significant toxicity up to 100 μM.

Full text of DOI:10.1016/j.ejmech.2005.03.024

European Journal of Medicinal Chemistry 40 (2005) 805–810
www.elsevier.com/locate/ejmech
Original article
A solid-phase approach to DDB derivatives
Xiuxiang Qi a, Xiaolai Wang a, Limin Wang c, Qiang Wang c, Senxiang Cheng c,
Jishuan Suo a,b,*, Junbiao Chang c,*
a Lanzhou Institute of Chemical Physics, The Chinese Academy of Sciences, Lanzhou 730000, China
b Chengdu Organic Chemicals Co., Ltd, Chinese Academy of Sciences, Chengdu 610041, China
c Key Laboratory of Fine Chemicals, Henan Academy of Sciences, No. 56, Hongzhuan Road, Zhengzhou 450002, China
Received 7 March 2005; received in revised form 17 March 2005; accepted 18 March 2005
Available online 14 July 2005
Abstract
Since the discovery of 2,2′-dimethoxycarbonyl-4,4-dimethoxy-5,6,5′,6′-biomethylenedioxy-biphenyl (DDB) as a potent anti-HBV agent,
we have studied the structure–activity relationships of 4,4′-dimethoxy-5,6,5′,6′-dimethenedioxy-2-alkyloxycarbonyl-2′-(4-substituted benzyl
piperazin-1-yl)carbonyl-biphenyl as anti-HBV agents. Therefore, it is rational to extend this study to the 3,3′-disustituted-4,4′-dimethoxy-
5,6,5′,6′-dimethenedioxy-2-alkyloxycarbonyl-2′-Serine derivatives. Thus, in an attempt to develop an efficient method for the preparation of
a large number of DDB derivatives, the reaction between a DDB acid chloride and serine derivatives on solid support was studied. The
1
structure of resulted compounds was confirmed by LC–MS and H NMR analysis. Compounds 2a, 2d, 2f, 2j showed in vitro anti-HBV
activity without significant toxicity up to 100 µM.
© 2005 Elsevier SAS. All rights reserved.
Keywords: Solid-phase; Synthesis; Scaffold; DDB; Combinatorial chemistry; Anti-HBV activity
1. Introduction
cyclooctadiene analogue. Recently, we have also reported the
structure–activity relationships of 4,4′-dimethoxy-5,6,5′,6′-
dimethenedioxy-2-alkyloxycarbonyl-2′-(4-substituted ben-
zyl piperazin, 1-yl)carbonyl-biphenyl as anti-HBV agents
[12]. These encouraging results promoted us to determine the
optimal pattern of biphenyl amide substitution, a small library,
which contained newly-built biphenyl derivatives such as
alkyl-3,3′-disubstituted-4,4′-dimethoxy-5,6,5′,6′-dimethy-
lenedioxy biphenyl-2-sustituted-2′-carboxylate 2 (Scheme 1),
was synthesized by using solid-phase chemistry (Fig. 1).
Dibenzocyclooctadiene lignans are isolated from the fruit
of schizandra Chinese, a creeping vine native to northern
China [1]. The extracts from this lignan-rich plant have been
used in Chinese and Japanese traditional medicine as protec-
tion against hepatic damage [2–5] and anti-AIDS agents [6].
This structure is interesting to organic chemists, pharmacolo-
gists, and phytochemists not only for chemical reason such
as challenging synthetic targets but also for their remarkable
biological activities. The active natural lignans all contain a
cyclooctane ring liking a biphenyl ring system, which is sub-
stituted with methoxyl and/or methylenedioxyl groups. Since
the biphenyl substitution pattern [7–9], structure–activity cor-
relations with related synthetic biphenyl compounds that also
contain bismethylenedioxyl and methoxyl group were per-
formed. Xie et al [10,11] reported the first synthesis and liver-
protective property of dimethyl-4,4′ -dimethoxy-5,6,5′,6′-
dimethylenedioxy biphenyl-2,2′-dicarboxylate (DDB), a non-
2. Results and discussion
To obtain DDB derivatives library with structure 2, the
polymer-support chemistry was aimed at the synthesis of the
nitro-activated phenyl esters 8 (Scheme 1). This ester 8, which
was prepared by displacing the hydroxyl group of phenol 6
by compound 7, reacted with different Serine derivatives, such
as 1-hydroxy-2-amino-3-sunstituted hydroxylamines 9 to give
the expected compound 2.
The macro-porous polystyrene XE-305 from Rohm and
Haas was used for making 4-hydroxy-3-nitro-benzoyl resin
* Corresponding author. Fax: +86 371 6571 9822.
E-mail address: jbchang@public2.zz.ha.cn (J. Chang).
0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2005.03.024

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X. Qi et al. / European Journal of Medicinal Chemistry 40 (2005) 805–810
Scheme 1. Solid-phase synthesis of DDB derivatives.
6. The commercial resin 5 was reacted with 4-chloro-3-
nitrobenzoyl chloride in the presence of aluminum trichlo-
ride in dry nitrobenzene at 60 °C for 5 h to give chloride 5.
The hydrolysis of 5 was carried out by using benzyltrimen-
thyl ammonium hydroxide in water and dioxane for 8 h at
90 °C to give resin 6 (Anal. Cl < 0.1; N 2.38; 1.7 mmol/g).
The amount of available hydroxyl groups of 6 was deter-
mined by the method of esterification and amide formation.
Resin 6 was esterified with an excess amount of benzoyl chlo-
ride, washed with chloroform, and reacted with benzy-
lamine. The polymer was washed with chloroform, and the
unreacted benzylamine was extracted with hydrochloric acid.
The organic phase afforded pure N-benzylbenzamide and,
from its weight, the loading on the polymer was determined
to be 1.7–1.8 mmol/g.
DDB acid chlorides 7a~d were obtained as shown in
Scheme 2. DDB was prepared according to a literature pro-
cedure [11]. The synthesis of 3,3′-Dibromo-DDB and their
anhydride 10a–b was reported [13]. Treatment of 8 with
methanol and ethanol yielded the corresponding monoester
11a and 11b, respectively. Compounds 7a–d were obtained
by treatment of 11 with thionyl chloride (SOCl2) under reflux.
The serine derivatives, 1-hydroxy-2-amino-3-sunstituted
hydroxylamines 9, were synthesized by the reaction of alde-
hyde 15 and hydroxylamine 18 (Scheme 3). Preparation of
aldehyde 15 was carried out from compound 12 via several
Fig. 1. Structure of DDB derivatives 1 and 2.

X. Qi et al. / European Journal of Medicinal Chemistry 40 (2005) 805–810
807
Scheme 2
.
simple reactions: Boc-amimo protection, and hydroxyl pro-
tection and DIBAL reaction [14,15]. O-alkylated hydroxy-
lamines 18 were also routinely prepared from the Mitsunobu
reaction of 16 with alcohol and subsequent hydrazine treat-
ment [16]. The coupling step of 15 and 18 was carried out in
methanol to give 19, which was hydrolyzed to 9 by acid depro-
tection of both amine and alcohol groups.
The DDB-attached polymeric active ester resin 8 was
obtained by the DMAP (4-dimethylamino pyridine)-catalyzed
reaction of resin 6 with four DDB–acid chlorides 7a~d,
methyl 2′-chlorocarbonyl-4,4′-dimethoxy-5,6,5′,6′-dimethy-
lenedioxy biphenyl-2-carboxylate, ethyl 2′-chlorocarbonyl-
4,4′-dimethoxy-5,6,5′,6′-dimethylenedioxy biphenyl-2-
carboxylate, methyl 2′-chlorocarbonyl-3,3′-dibromo-4,4′-
dimethoxy-5,6,5′,6′-dimethylenedioxy biphenyl-2-carbo-
xylate, ethyl 2′-chlorocarbonyl-3,3′-dibromo-4,4′-dimethoxy-
5,6,5′,6′-dimethylenedioxy biphenyl-2-carboxylate, respec-
tively. The above-mentioned benzylamine method was used
for the determination of the DDB loading and weighing the
resulting amide showed that 70–80% of the available OH
groups underwent ester. Polymeric active esters 8 reacted with
different serine derivatives, 1-hydroxy-2-amino-3-sunstituted
hydroxylamines 9 in the presence of diisopropyl ethylamine
(DIEA) at room temperature for 48 h to give alkyl-3,3′-
disubstituted-4,4′-dimethoxy-5,6,5′,6′-dimethylenedioxy
biphenyl-2-sustituted-2′-carboxylate 2 in 71~91% yield.
Analysis with IR spectrum and LC–MS/MS showed that the
biphenyls coupled with 9 selectively by the NH2 group of 9,
not OH group. Table 1 summarizes yield and purity data from
a set of representing compounds that were selected from a
synthesized library.
In conclusion, we have shown that polymer-bound
4-hydroxy-3-nitrobenzophenone can be utilized as a versa-
tile precursor for the construction of the DDB derivatives.
Those derivatives, are substituted with alkylamino amides at
the 2-position, which are normally the methyl carboxylate
group. All the synthesized DDB derivatives were evaluated
for anti-HBV. The compounds 2a, 2d, 2f, 2j showed in vitro
moderate activity against HBV(EC50 = 5.8, 2.3, 1.9, and
3.8 µM, respectively) using the HepG2 2.2.15 cells. The
Scheme 3
.

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X. Qi et al. / European Journal of Medicinal Chemistry 40 (2005) 805–810
Table 1
Synthesis of DDB amide
and then processed for Southern blot analysis. The blots were
hybridized to an HBV-specific probe, and amounts of viral
DNA were assessed in comparison with levels of DNA from
cultures not treated with the compounds. Further confirma-
tion of the viral DNA levels was obtained by processing the
cells treated with the compounds. The genomic DNA was
digested with HindIII and subjected to Southern analysis. Lev-
els of the episomal DNA were determined in relation to those
of the integrated HBV DNA. Densitometric scans were per-
formed on autoradiographs. The compounds concentrations
that caused 50% inhibition of the DNA compared with the
controls were calculated.
Number
R
R1 R2
H
Yielda Purityb
(%)
91
(%)
95
2a
Me
3. Experimental part
2b
Me
H
82
90
3.1. The preparation of the polymer-bound precursor 6
was briefly discussed in Ref. [17]. The detailed
experimental procedures are illustrated as follows
2c
Me
Et
H
H
75
90
87
96
2d
3.1.1. Preparation of the polymer
To a mixture of 50 g of macroreticular polystyrene (XE-
305, Rohm and Haas) and 100 g of 4-chloro-3-nitrobenzoyl
chloride was added a solution of 25 g of aluminum trichlo-
ride in 300 ml of dry nitrobenzene. The mixture was stirred
mechanically at 60 °C for 5 h and poured into a mixture of
150 ml of DMF, 100 ml of concentrated HCl, and 150 g of
ice.
2e
2f
Et
Et
H
H
83
71
90
85
The beads slowly turned white. They were washed with
300 ml portions of DMF/water (3:1) until the washings were
colorless, then with warm (60 °C) DMF, and finally with six
portions of 300 ml of DCM/MeOH (2:1). The dried polymer
weighed 82 g (1.88 mmol/g). Hydrolysis was carried out with
a mixture of 130 ml of 40% benzyltrimenthylammonium
hydroxide in water, 130 ml of water, and 260 ml of dioxane
for 8 h at 90 °C. The polymer was filtered, and the process
was repeated. The beads were then washed with four por-
tions of warm (60 °C) dioxane.Acetic acid (30 ml) was added
with stirring for 15 min. The polymer was washed with diox-
ane until the washings were neutral, followed by six portions
of 300 ml of DCM/MeOH (2:1). Anal. calcd: Cl, < 0.1; N,
2.38 (1.7 mmol/g). The amount of available hydroxide groups
was determined by esterifying with a three fold excess of ben-
zoyl chloride and pyridine in dry chloroform at 0–10 °C for
30 min, washing with chloroform, and reacting with excess
benzylamine. The polymer was washed with chloroform, and
excess benzylamine was extracted with hydrochloric acid. The
organic phase afforded pure N-benzylbenzamide, and from
its weight the loading on the polymer was determined to be
1.7–1.8 mmol/g, assuming quantitative reactions.
2g
Me
Br
93
95
2h
3i
Me
Me
Br
Br
82
84
91
90
2j
Et
Br
89
92
2k
Et
Et
Br
Br
81
91
89
90
2m
a Determined by weight of the crude products (TFA Salt) based on the
loading of the resins.
b Determined by LC–MS using both UV detectors and further confirmed
by 1H NMR analysis.
2.2.15 cells were grown to confluence in minimal essential
medium with 10% fetal bovine serum.At confluence the treat-
ment with the drugs was initiated, and it was then continued
for 6 days with medium changes at 3-day intervals. After the
6-day treatment, the medium was harvested, and the viral par-
ticles were precipitated with polyethylene glycol, digested,
3.1.2. Polymeric active esters
Esters of simple acids were prepared from the acid chlo-
ride and pyridine as described.Active esters of Boc-protected
amino acids were prepared by the symmetric anhydride
method as follows: 4 mmol of the Boc-protected amino acid

X. Qi et al. / European Journal of Medicinal Chemistry 40 (2005) 805–810
809
was dissolved in 6 ml of DCM (THF was added in case of
poor solubility). The solution was cooled to –10 to 0 °C and
2 mmol of DDC was added. After 30 min at 0 °C, the mixture
was filtered directly into a vessel containing 1 g of the
polymer-bonund-4-hydroxy-3-nitrobenzophenone. Pyridine
(0.5 ml) was added, and the mixture was shaken for 1 h at
room temperature. The polymer was washed with six to eight
10-ml portions of chloroform. Active esters of Boc-glycine,
Boc-phenylalanine, and Boc-o-benzyl-tyrosine were thus pre-
pared. Determination of the loading by reacting the polymers
with an excess of benzylamine and weighing the resulting
amide showed that 70–80% of the available OH groups under-
went esterfication.
pressure). The rate of addition was adjusted so as to keep the
internal temperature below –70 °C.After of addition, the reac-
tion mixture was stirred for an additional 2.5 h at –78 °C
(under an N2 atmosphere) when the TLC showed the clean
formation of product 15. The reaction was quenched by slowly
adding 70 ml of cold (–78 °C) CH3OH(H2↑ evolution) to
keep the internal temperature below –65 °C. The resulting
white emulsion was slowly poured into 1000 ml of ice-cold
1 N HCl with swirling over 15 min, and the aqueous mixture
was then extracted with EtOAc (3 × 1000 ml), dried with
MgSO4, filtered and concentrated in vacuo to give crude prod-
uct 15 as a colorless oil, which was vacuum distilled to give
1
15 32.2 g (91.0%) as a colorless liquid. H NMR(CDCl3)
dppm: 1.42(s, 9H), 1.50–1.64 (br, m, 6H), 4.06–4.09 (m, 2H),
4.20–4.35 (m, 1H), 9.53 (br, s, H).
3.2. General procedure
3.2.1. Synthesis of [N-[(1,1-dimethylethoxy)
carbonyl]-serine, methyl ester] (13)
3.2.4. General procedure representative prexperimental
procedure for mitsunobu reaction bibenzyl phthalimidooxy
(18)
H-Ser-OMe-HCl (15 g, 96.5 mmol) was dissolved in
dichloromethane (200 ml) and 2.2 equiv of triethylamine
added, then tert-butylpyrocarbonate (23.2 g, 0.106 mol) were
slowly added with vigorous stirring and cooling in an ice bath.
After stirring at 0 °C for 30 min in the solution was stirred at
room temperature for 3 h. The reaction mixture was then
evaporated and partitioned between 200 ml of ethyl acetate
and 100 ml of KHSO4 (1 M) and washed with 1 M KHSO4
(100 ml, 1 M), NaHCO3 (100 ml) and brine (3 × 50 ml).After
drying over MgSO4, the extract was taken to dryness at
reduced pressure to give 13 20.1 g as oil (yield 95%).
1H NMR (acetic-d6) d ppm: 1.43 (s, 9H, CH3, Boc), 2.50
(br, s, H, exchanged with D2O), 3.76(s, 3H, CH3, OMe), 3.85–
4.98 (m, 2H, CH2, Ser), 4.39 (m, 1H, CH, ser), 5.49 (br, 1H,
NH, exchanged with D2O).
To a stirred solution of 17a (6.6 g, 36 mmol) PPh3
(12.3 g, 47.0 mmol, 1.3 equiv) and PhthNOH (7.0 g,
43.2 mmol,1.2 equiv) in THF (100 ml) was added DIAD
(9.5 g, 47.0 mmol, 1.3 equiv) dropwise over 30 min. The mix-
ture was stirred at r.t. for 6 h. TLC showed without of starting
material. The reaction mixture was concentrated and then the
residue was dissolved in ethanol (30 ml) to get 18a as a solid.
The solid was washed with ethanol to afford a pure 18a in
93% yield as a solid. 1H NMR(CDCl3) d ppm: 5.07 (s, 2H),
7.41–7.83 (m, 13H).
3.2.5. Preparation of compound 19a
To a stirred solution of 18a (7.2 g, 22 mmol) in CH2Cl2
(150 ml) was added dropwise NH2NH2 (1.4 ml, 44 mmol).
The reaction mixture was stirred at r.t. for 4 h. Lots of solid
appeared, the mixture was filtered through celite. The filtrate
was washed by 2 N NaOH, concentrated. The residue was
purified by flash column chromatography (1:1 hexane/EtOAc)
3.2.2. 3-(1,1-Dimethylethyl)4-methyl-2,2-dimethyl-3,4-
oxazolidinedicarboxylate (14)
To a stirred solution of Boc-Ser-OMe (13, 35.8 g,
163 mmol) in CH2Cl2 (200 ml) were added DMP (100 ml,
820 mmol) and p-toluenesulfonic acid monohydrate (p-
TsOH·H2O, 3.2 g, 16.4 mmol) at 0 °C. After stirring at r.t. for
12 h, the mixture was poured into statured aq. NaHCO3
(200 ml) and then the resulting solution was extracted with
Et2O (3 × 150 ml). The organic layer was washed with stat-
ured aq. NaHCO3 (3 × 100 ml), brine (3 × 100 ml), and then
dried (Na2SO4). Concentration in vacuo gave a crude oil,
which was distilled in vacuo to give 14 as a colorless oil 39.1 g
(90%), b.p. 110–112 °C per 4 Torr. 1H NMR (CDCl3) d ppm:
1.39(s, 9H), 1.48(br, s, 3H), 1.65(br, s, 3H), 3.74(s, 3H),
4.11(dd, J = 8.5 and 8.1 Hz, 1H), 4.35(dd, J = 8.5 and 3.5 Hz,
H), 4.47(m, H).
1
to give 19a 2.8 g (63.9%) as oil. H NMR (CDCl3) dppm:
4.74 (s, 2H), 5.43 (br, s, 2H), 7.33–7.61 (m, 9H).
To a solution of 19a (2.0 g, 10 mmol) in MeOH(50 ml)
was added 15 (2.3 g, 10 mmol). The resulting mixture was
heated at 50 °C for 12 h. TLC showed without of starting
materials. After concentration under reduced pressure, the
residue was dissolved in TFA (15 ml) and H2O (50 ml) and
the mixture was stirred at r.t. for 1 h. The solvent was evapo-
rated in vacuo and statured aq NaHCO3 was added. The mix-
ture was extracted with EtOAc, dried with Na2SO4 and con-
centrated in vacuo to give 9a 1.0 g (36.2% in two steps) as
yellow oil. 1H NMR(CDCl3) d ppm: 3.28 (br, s, 2H), 3.56–
3.76 (m, 3H), 5.08 (s, 2H), 7.34–7.57 (m, 10H).
3.2.6. Preparation of compound 2
3.2.3. 1,1-Dimethylethyl-4-formyl-2,2-dimethyl-3-oxazo-
lidinecarboxylate (15)
To a stirred –78 °C solution of 14 (40.2 g, 0.155 mol) in
dry toluene (300 ml) was add ed a –78 °C solution of 1.5 M
DIBAL-H in toluene (175 ml) via cannula (using positive N2
In a single 96-well microtiter plate to produce one product
per well. For the reaction, 0.014 mmol of 8 per well in DCM,
and compound 9 (1.1 equiv). The plate was capped for 48 h
at r.t. The products were removed from the resin, washed into

810
X. Qi et al. / European Journal of Medicinal Chemistry 40 (2005) 805–810
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Acknowledgements
The authors are grateful for financial support from National
Natural Science Foundation of China (#29972009,
#20342005); the outstanding scholar Innovation Foundation
of Henan Province (0321000900).
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