Synthesis and antibacterial activity of littorachalcone and related diphenyl ethers

Article abstract of DOI:10.1016/j.bmcl.2008.02.082

Littorachalcone (1) and diacid 10 were synthesized by direct routes. The antibacterial activity of 1, 10 and synthetic precursors were evaluated. Dialdehyde 3a showed potent antibacterial activity.

Full text of DOI:10.1016/j.bmcl.2008.02.082

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 2329–2332
Synthesis and antibacterial activity of littorachalcone
and related diphenyl ethers
George A. Kraus,a,* Ganesh Kumar,a Gregory Phillips,b
Kris Michalsonb and Maria Manganob
aDepartment of Chemistry, Iowa State University, Ames, IA 50011, USA
bDepartment of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA 50011, USA
Received 11 January 2008; revised 25 February 2008; accepted 29 February 2008
Available online 6 March 2008
Abstract—Littorachalcone (1) and diacid 10 were synthesized by direct routes. The antibacterial activity of 1, 10 and synthetic pre-
cursors were evaluated. Dialdehyde 3a showed potent antibacterial activity.
ꢀ 2008 Published by Elsevier Ltd.
OH
X
Littorachalcone (1), a novel dihydrochalcone dimer, was
isolated from the aerial parts of V. littoralis H. B. K.
along with several flavonoids by Li and coworkers.1 A
related compound verbenachalcone (2) was discovered
by Li in 2001.2 Both littorachalcone and verbenachal-
cone elicited a significant enhancement of nerve growth
factor-mediated neurite outgrowth from PC12D cells.
Recently, both littorachalcone and analogs of verbena-
chalcone have been synthesized3 (see Fig. 1).
HO
O
OH
OH
O
O
OH
1
: X =H
2: X =OMe
Figure 1. Structures of littorachalcone (1) and verbenachalcone (2).
OR
Our plan for the synthesis of littorachalcone is shown
below. Dialdehyde 3a will react with two equivalents
of the protected 2,4-dihydroxyacetophenone 4 to gener-
ate the target compound. The dialdehyde, in turn, would
be generated from commercially available para-tolyl
ether (5) by hydroxylation, protection, and oxidation.
Our route is significantly more direct and operationally
convenient than that of Nishiyama3 because we desym-
metrize commercially available para-tolyl ether, thus
avoiding the protection and deblocking steps necessary
in the Nishiyama diaryl ether synthesis (see Fig. 2).
O
O
1
H
H
O
O
3a: R = Piv
3b: R = H
5
OMe
O
OMe
4
Figure 2. Retrosynthetic analysis for 1.
peroxide-mediated oxidation of the aryl boronic acid es-
ter provided 6 in 82% yield. Protection of the alcohol
with pivaloyl chloride and triethylamine afforded ester
7 in 90% yield. We then evaluated two methods to gen-
erate dialdehyde 3a from ester 7. Radical bromination
of 7 using NBS in carbon tetrachloride afforded a dibro-
mide that was unstable to storage. Attempts to convert
the dibromide to dialdehyde 3a using either tetraalkyl-
ammonium chromate5 or N-methylmorpholine oxide6
afforded a mixture of mono aldehyde and dialdehyde
Ether 5 was hydroxylated by taking advantage of the
selective metalation of diaryl ethers developed initially
by Gilman and coworkers.4 Treatment of 5 with n-butyl
lithium at 0 ꢁC followed by the addition of trimethyl bo-
rate afforded a boronic acid ester. Subsequent hydrogen
Keywords: Chalcones; Antibacterials; Aldol.
*
Corresponding author. Tel.: +1 515 294 7794; fax: +1 515 294
0105; e-mail: gakraus@iastate.edu
0960-894X/$ - see front matter ꢀ 2008 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2008.02.082

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G. A. Kraus et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2329–2332
OR
OR
n-BuLi
(MeO)3B
O
O
CAN
5
3a
H2O2
CO2H
HO2C
6: R =H
7: R = Piv
Piv-Cl
9: R = Me
10:
R =H
Scheme 1. Synthesis of 3.
Figure 3. Structures of 9 and 10.
along with unidentified polar byproducts. Direct oxida-
tion of 7 with ceric ammonium nitrate7 in aqueous acetic
acid at 25 ꢁC produced dialdehyde 3a in 63% yield (see
Scheme 1).
ity of 1, 10, and their synthetic precursors have been
evaluated. Dialdehyde 3a showed potent antibacterial
activity.
The transformation of 3a into littorachalcone involves
the aldol condensation of two equivalents of a 2,4-dialk-
oxyacetophenone (4) with 3a followed by the reduction
of the double bond and deprotection. Although many
simple chalcones have been prepared by the reaction
of an acetophenone with an aromatic aldehyde in protic
solvents, there are few examples of highly hydroxylated
chalcones prepared in this manner.8 Most syntheses uti-
lized di- or trimethoxy acetophenones. In our hands, the
use of 2,4-dimethoxyacetophenone in protic solvents
afforded only modest yields of aldol products. The opti-
mal conditions involved the use of the anion of 2,4-
dimethoxyacetophenone generated using lithium diiso-
propylamide (LDA) in THF at À78 ꢁC and aldehyde
3a. The bis-aldol adduct was produced in 39% yield,
with approximately 30% of the mono-aldol product
and about 20% of dialdehyde 3a. The resulting hydroxy
ketone was cleanly dehydrated to 8 using p-toluenesul-
fonic acid. The resulting enone was reduced using so-
dium borohydride and nickel chloride.9 The pivalate
group was cleaved using KOH in water and the methyl
ethers were cleaved using boron tribromide10 (see
Scheme 2).
Acknowledgment
We thank ISU for partial support of this research.
References and notes
1. Li, Yushan; Ishibashi, Masami; Chen, Xigui; Ohizumi,
Yasushi Chem. Pharmaceut. Bull. 2003, 51, 872.
2. Li, Yu-Shan; Matsunaga, Kimihiro; Kato, Ryoko; Ohiz-
umi, Yasushi J. Nat. Products 2001, 64, 806.
3. Tanabe, Takamasa; Ogamino, Takahisa; Shimizu, Yoshi-
fumi; Imoto, Masaya; Nishiyama, Shigeru Bioorg. Med.
Chem. 2006, 14, 2753; Xing, Xuechao; Padmanaban,
Deepa; Yeh, Li-An; Cuny, Gregory D. Tetrahedron 2002,
58, 7903; Tanabe, Takamasa; Doi, Fuminao; Ogamino,
Takahisa; Nishiyama, Shigeru Tetrahedron Lett. 2004, 45,
3477.
4. Gribble, G. W. Sci. Synth. 2006, 8a, 357.
5. Suhana, Harindran; Srinivasan, Panyencheri C. Synth.
Commun. 2003, 33, 3097.
6. Olsen, Jacob; Seiler, Paul; Wagner, Bjoern; Fischer,
Holger; Tschopp, Thomas; Obst-Sander, Ulrike; Banner,
David W.; Kansy, Manfred; Mueller, Klaus; Diederich,
Francois Org. Biomolec. Chem. 2004, 2, 1339.
7. Trahanovsky, W. S.; Young, L. B. J. Org. Chem. 1966, 31,
2033.
Diacid 9 was isolated from Curcuma chuanyujin by Tak-
eda and coworkers as part of a study to identify new
plant antioxidants.11 Compound 10 could be readily
synthesized from dialdehyde 3 by a Wittig reaction using
carboethoxymethylene triphenylphosphorane followed
by hydrolysis of the triester using KOH in methanol
(see Fig. 3).
8. Ahluwalia, Vinod K.; Khanduri, Chandra H.; Mehta,
Vimal D.; Sharma, Narain D. Indian J. Chem. B 1988,
27B, 67.
9. Khurana, J. M.; Sharma, P. Bull. Chem. Soc. Japan 2004,
77, 549.
10. Khatib, S.; Nerya, O.; Musa, R.; Shmuel, M.; Tamia, S.;
Voya, J. Bioorg. Med. Chem. 2005, 13, 433.
11. Huang, J.; Ogihara, Y.; Gonda, R.; Takeda, T. Chem.
Pharm. Bull. 2000, 48, 1228.
We further tested the antimicrobial properties of com-
pound A by measuring the minimum inhibitory concen-
tration (MIC) using the microdilution method described
by Andrews.12 The MIC value for compound A was
ꢀ25 mg/L, while the MIC for ampicillin was ꢀ75 mg/L.
12. Andrews, J. M. J. Antimicrob. Chemother. 2001, 48, 5.
13. Experimental and spectral data for title compounds:
5-Methyl-2-(4-methylphenoxy)-phenol (6). To the stirred
solution of p-tolyl ether (1.98 g, 10 mmol) in 20 mL of
THF and 20 mL of ether, n-BuLi (2.5 M solution in
hexane, 4.4 mL, 11 mmol) was added at rt. This solution
was boiled for 6 h. Trimethyl borate (1.14 g, 11.0 mmol)
Littorachalcone (1) and diacid 10 were synthesized by
direct and scalable pathways.13 The antibacterial activ-
OPiv
MeO
1. NaBH4,
NiCl2
1. LDA,
O
OMe
3a
4
1
2. PTSA
2. KOH
3. BBr3
OMe
O
O
OMe
8
Scheme 2. Synthesis of 1.

G. A. Kraus et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2329–2332
2331
was then added dropwise. The resulting mixture was
boiled for an additional 6 h. The reaction was cooled to
0 ꢁC and hydrogen peroxide (30% solution in water,
12 mL) followed by aqueous sodium hydroxide (3 N,
12 mL) solution was added. It was stirred at rt for 1 h and
then at 40 ꢁC for 2 h, acidified with 10% HCl and then
extracted with ethyl acetate. The organic layer was dried
over anhydrous MgSO4 and the solvent was removed. The
residue was purified by flash chromatography on silica gel
(EtOAc/hexanes, 1:10) to give compound 6 (1.75 g, 82%
yield).
purified by column chromatography (EtOAc/hexanes, 1:1)
to provide the aldol product (0.42 g, 39% yield).
To a stirred solution of aldol product (0.10 g, 0.15 mmol)
in 1,2-dichloroethane, was added catalytic p-toluenesul-
fonic acid. The solution was heated to 50 ꢁC and stirred
for 6 h. After this the reaction was diluted with CH2Cl2
and washed with water. The organic layer was dried over
anhydrous MgSO4, the solvent was removed, and the
crude product was purified by silica gel flash chromatog-
raphy (EtOAc/hexanes, 1:1) to provide compound 8
(0.040 g, 41% yield).
1H NMR (400 MHz, CDCl3) d 7.13 (d, J = 8.4 Hz, 2H),
6.89 (d, J = 8.8 Hz, 2H), 6.85 (s, 1H), 6.76 (d, J = 8.4 Hz,
1H), 6.64 (d, J = 8 Hz, 1H), 2.33 (s, 3H), 2.31 (s, 3H). 13C
NMR (100 MHz, CDCl3) d 155.08, 147.35, 141.59, 134.79,
133.08, 130.48, 130.36, 121.27, 118.85, 117.84, 116.86,
115.56, 21.25, 20.90.
1H NMR (400 MHz, CDCl3) d 7.67 (d, J = 8.8 Hz, 2H),
7.57–7.53 (m, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.37–7.32 (m,
3H), 7.28 (d, J = 2 Hz, 1H), 6.96 (d, J = 8 Hz, 1H), 6.89 (d,
J = 8.8 Hz, 2H), 6.47 (d, J = 8 Hz, 2H), 6.40 (s, 2H), 3.81–
3.77 (m, 16H), 1.13 (s, 9H).
13C NMR (100 MHz, CDCl3)
d
190.55, 190.41,
2,2-Dimethyl-propionic acid 2-(4-methylphenoxy)phenyl
ester (7). To a stirred solution of compound 6 (1.8 g,
8.4 mmol) in THF (20 mL), triethyl amine (0.976 g,
9.66 mmol) was added. The mixture cooled to 0 ꢁC and
trimethylacetyl chloride (1.08 g, 8.98 mmol) was added at
0 ꢁC. The solution warmed to rt and stirred for 2 h. After
this the reaction mixture was filtered through Celite,
diluted with CH2Cl2 and washed with water. The organic
layer was dried over anhydrous MgSO4 and the solvent
was removed. The residue was purified by flash chroma-
tography on silica gel (EtOAc/hexanes, 1:10) to furnish
compound 7 (2.25 g, 90% yield).
176.52,164.47, 164.39, 160.63, 160.59, 158.54, 148.95,
143.02, 141.37, 140.52, 133.13, 132.83, 131.01, 130.20,
128.56, 127.69, 127.24, 126.48, 123.54, 122.44, 122.32,
121.32, 118.15, 105.41, 98.89, 98.87, 56.05, 56.00, 55.81,
39.36, 27.26.
1-(2,4-dihydroxyphenyl)-3-[4-[4-[3-(2,4-dihydroxyphenyl)-
3-oxopropyl]-2-hydroxyphenoxy]phenyl]-1-propanone (1).
Compound 8 (40 mg, 0.06 mmol) was dissolved in 5 mL of
methanol and NiCl2Æ6H2O (285 mg, 1.2 mmol) followed
by 0.5 mL of water was added to this solution with
stirring. After 5 min, NaBH4 (18 mg, 0.48 mmol) was
added and the reaction was stirred vigorously at rt. After
6 h the reaction mixture was poured into water and the
aqueous layer was extracted with CH2Cl2. The organic
layer was dried over anhydrous MgSO4 and the solvent
was removed. The crude product was purified by flash
chromatography (EtOAc/hexanes, 1:1) to furnish a dike-
tone (0.03 g, 72% yield).
Diketone (0.10 g, 0.15 mmol) was dissolved in 5 mL of
ethanol and KOH (0.080 g, 1.5 mmol) in 5 mL of water
was added with stirring to this solution. The resulting
mass was boiled for two hours. The reaction mixture was
then poured into brine and acidified with 10% HCl
solution. The product was extracted with EtOAc, the
organic layer was dried over anhydrous MgSO4, the
solvent was removed, and the crude product was filtered
through silica gel column to provide the hydroxydiketone
(0.060 g, 76% yield).
1H NMR (400 MHz, CDCl3) d 7.07 (d, J = 8 Hz, 2H),
6.98–6.95 (m, 2H), 6.89 (d, J = 8 Hz, 1H), 6.83 (d,
J = 6.8 Hz, 2H), 2.34 (s, 3H), 2.29 (s, 3H), 1.21 (s, 9H).
13C NMR (100 MHz, CDCl3) d 176.78, 155.67, 145.91,
142.48, 134.37, 132.28, 130.36, 130.18, 127.43, 124.30,
120.89, 118.81, 117.44, 39.26, 27.29, 21.02, 20.86.
2,2-Dimethyl-propionic acid 5-formyl-2-(4-formyl-phen-
oxy)-phenyl ester (3). The compound
7
(1.10 g,
3.69 mmol) was dissolved in 20 mL of aqueous acetic
acid. To this solution was added ceric ammonium nitrate
(11 g, 20 mmol) solution in 20 mL of aqueous acetic acid
in 10 minutes at rt. The reaction was stirred overnight. The
reaction was diluted with water and extracted with ethyl
acetate. The organic layer was washed with saturated
sodium bicarbonate solution, dried over anhydrous
MgSO4 and the solvent was removed. The residue was
purified by silica gel chromatography (EtOAc/hexanes,
1:3) to yield compound 3 (0.76 g, 63% yield).
To a stirred solution of the hydroxy diketone (0.040 g,
0.07 mmol) was added boron tribromide (0.17 g,
0.70 mmol) at 0 ꢁC. The solution was stirred for 24 h at
rt. The reaction mixture was quenched with water and
poured into brine. The mixture was extracted with ethyl
acetate. (3 · 50 mL). The combined organic extracts were
dried over MgSO4 and the solvent was removed. The
crude product was purified by preparative TLC (EtOAc/
hexanes, 1:1) to yield 1 (0.010 g, 40% yield).
1H NMR (300 MHz, CDCl3) d 9.97 (s, 1H), 9.95 (s, 1H),
7.89 (d, J = 9 Hz, 2H), 7.78 (d, J = 8.7 Hz, 1H), 7.73 (d,
J = 2 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.11 (d,
J = 8.7 Hz, 2H), 1.21 (s, 9H). 13C NMR (100 MHz,
CDCl3) d 190.79, 190.13, 176.25, 161.33, 152.26, 143.39,
133.85, 132.58, 132.30, 132.25, 129.19, 125.21, 121.45,
119.59, 118.26, 39.38, 27.16.
1-(2,4-dimethoxyphenyl)-3-[4-[4-[3-(2,4-dimethoxyphenyl)-
3-oxoprop-2-enyl]-2-pivaloxyphenoxy]phenyl]-2-propene-
one (8). To a stirred solution of diisopropyl amine (0.55 g,
5.5 mmol) in THF (10 mL), n-BuLi (2.5 M solution in
hexane, 2 mL, 5 mmol) at 0 ꢁC was added and the solution
was cooled to À78 ꢁC. To this solution was added a
solution of 2,4-dimethoxyacetophenone (0.86 g, 4.8 mmol)
in THF (5 mL) at À78 ꢁC and stirred for 30 min. A
solution of compound 3 (0.52 g, 1.6 mmol) in THF (5 mL)
was added to the reaction at the same temperature. The
resulting mixture was warmed to 0 ꢁC and the reaction
was quenched by adding acetic acid (1 mL in 5 mL of
THF). The reaction was diluted with water and extracted
with CH2Cl2. The organic layer was dried over anhydrous
MgSO4 and the solvent was removed. The residue was
1H NMR (400 MHz, CDCl3) d 7.87–7.83 (m, 2H), 7.25 (d,
J = 8.8 Hz, 2H), 6.95 (d, J = 2 Hz, 1H), 6.85–6.79 (m, 4H),
6.44–6.41 (m, 2H), 6.33 (t, J = 2.4 Hz, 2H), 3.34–3.29 (m,
4H), 3.00–2.96 (m, 4H). MS: m/e: 514, 363, 352, 313, 286,
264, 185, 163, 149, 108. HRMS: m/e calc 514.1628, m/e
found: 514.1635.
Diacid 10. To a stirred solution of 3a (0.05 g, 0.15 mmol)
in dioxane (5 mL), carboethoxymethylene triphenylphos-
phorane (0.26 g, 0.6 mmol), potassium bicarbonate
(0.12 g, 1.2 mmol) and chloroform (5 ml) were added.
The mixture was heated to 110 ꢁC for 18 h. It was cooled
to rt, diluted with ethyl acetate and washed with water.
The organic layer was dried over MgSO4 and the solvent
was removed. The residue was further purified by column
chromatography (EtOAc/hexane, 4:6). To the stirred

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G. A. Kraus et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2329–2332
solution of the above compound (0.05 g, 0.1 mmol) in 131.92, 129.64, 130.21, 119.64, 119.35, 115.48, 115.32,
10 ml of 50% aqueous ethanol, potassium hydroxide
(0.017 g, 0.3 mmol) was added. The mixture was heated
to reflux for 3 h. After this the mixture was diluted with
ethyl acetate and washed with 10% HCl solution. The
organic layer was dried over MgSO4 and was concen-
trated. The residue was further purified by column
chromatography (EtOAc/hexane 7:3) to give compound
10 (0.015 g, 92%).
114.12.
Methods. Bacterial cultures were prepared by inoculating
5 ml of nutrient broth with single colonies of Bacillus
cereus and cultured overnight with aeration at 37 ꢁC.
The next day, 100 ll of the culture was removed and
mixed with 3 ml of nutrient top agar (nutrient broth
containing 7% agar) and the mixture plated onto the
surface of a nutrient agar plate. After the agar solidified,
a 5 mm diameter sterile filter disc was aseptically placed
in the center of the plate. 10 ll of each compound in
DMSO was pipetted onto the filter disc. After allowing
several minutes to dry at room temperature, the plates
were incubated overnight at 37 ꢁC.
1H NMR (400 MHz, acetone-d6) d 7.70–7.61 (multiplet,
4H), 7.35 (s, 1H), 7.24 (d, J = 8 Hz, 1H) 7.07 (d, J = 8 Hz,
1H) 7.69 (d, J = 8 Hz, 2H), 6.46 (d, J = 4 Hz, 1H), 6.42 (d,
J = 4 Hz, 1H). 13C NMR (100 MHz, acetone-d6) 172.66,
171.5, 158.62, 146.79, 145.33, 140.79, 138.95, 134.92,