Short microwave-assisted modular synthesis of naturally occurring oxygenated bibenzyls

Article abstract of DOI:10.1515/znb-2015-0047

The naturally occurring oxygenated bibenzyls lunularin and m-O-methyllunularin were prepared in a modular synthesis in four steps from two appropriate iodophenols and trimethylsilylacetylene utilizing microwaveassisted Sonogashira couplings as the crucial steps. The antimicrobial activity of the resulting natural products was evaluated in an agar diffusion assay.

Full text of DOI:10.1515/znb-2015-0047

Z. Naturforsch. 2015; aop
JSürhgeon Krrtaumss*i,cUrrsoulawKoapvp aen-daFrsansziBsratcehedr modular synthesis of
naturally occurring oxygenated bibenzyls
DOI 10.1515/znb-2015-0047
our group described a synthesis by a palladium-catalyzed
Received March 13, 2015; accepted April 30, 2015
cross-coupling of styrene derivatives and phenyl triflates [9].
These published syntheses require five or six steps and lead
to the target compounds in poor to moderate total yields.
This prompted us to work out a novel, modular syn-
Abstract: The naturally occurring oxygenated bibenzyls
lunularin and m-O-methyllunularin were prepared in a thesis of oxygenated bibenzyls utilizing iodoarenes as
modular synthesis in four steps from two appropriate building blocks for both aromatic rings and trimethylsilyla-
iodophenols and trimethylsilylacetylene utilizing micro- cetylene as the central C2 building block. Both C,C coupling
wave-assisted Sonogashira couplings as the crucial steps. reactions were to be performed by transition metal-cata-
The antimicrobial activity of the resulting natural prod- lyzed coupling reactions. The Sonogashira coupling [10] is
ucts was evaluated in an agar diffusion assay.
an important reaction in the synthesis of natural products,
with a wide area of applications [11–14]. In the last years,
Keywords: antimicrobial activity; lunularin; microwave- microwave-assisted Sonogashira couplings have been
assisted synthesis; Sonogashira reaction.
included in modern organic synthesis [15].
1 Introduction
2 Results and discussion
Lunularin (1a), its m-O-methyl ether (1b) (Fig. 1), as well
as several related bibenzyls were isolated from liverworts
(Hepaticaceae), algae, and higher plants such as Hydran-
gea or Morus macroura [1–5]. In addition, numerous dimers
of these compounds were isolated from liverworts. The
bibenzyls show a broad variety of pharmacological effects
like antibiotic, antifungal, as well as plant growth inhibi-
tory activities. Lunularin (1a) is a metabolite of lunularic
acid (Fig. 1), formed by enzymatic decarboxylation. Bio-
synthesis of lunularin is starting from phenylalanine and
three units of malonyl-CoA and leads via prelunularic acid
and lunularic acid to lunularin [6].
Until now, several total syntheses of these natural
polyketides were published. The first total syntheses of
lunularin were described by Huneck in 1976 [7] and Gorham
in 1977 [1] using a Wittig reaction as key step. A similar
approach was used by Sawada et al. in 2012 [8]. In 2000,
2.1 Chemistry
4-Iodophenol (2) was reacted in a microwave reactor
with trimethylsilylacetylene (3) under Sonogashira
conditions (CuI, tertiary amine, Pd catalyst) to give the
alkyne 4. The Sonogashira reaction could be catalyzed
by bis(triphenylphosphine)palladium(II) dichloride or
1,1′-[bis(diphenylphosphino)ferrocene]palladium(II)
dichloride, with either catalyst excellent yields were
obtained (Scheme 1).
Cleavage of the trimethylsilyl group of 4 was first
attempted with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
in acetonitrile/water (19:1) [16], but this reaction led to
a hydration of the alkyne function to give 4-hydroxy-
acetophenone (8) in 29 % yield (Scheme 2). Alkaline
cleavage of the trimethylsilyl group with methanolic K2CO3
led to the terminal alkyne 5 in about 25 % yield [17]. Best
results for the cleavage of the trimethylsilyl group were
obtained with tetra-n-butylammonium fluoride (TBAF) in
methanol, which led to a quantitative desilylation of 4 (for
related Sonogashira couplings with phenoxide-mediated
in situ-desilylation, see Ref. [18]). The first two steps of
this approach gave almost quantitative yields, so the
crude products can as well be used for further conversion
without purification by column chromatography.
*Corresponding author: Jürgen Krauss, Department of Pharmacy
– Center for Drug Research, Ludwig-Maximilians-University Munich,
Butenandtstrasse 5-13, D-81377 Munich, Germany,
Fax: +49-89-218077171, E-mail: hjkra@cup.uni-muenchen.de
Ursula Kopp and Franz Bracher: Department of Pharmacy – Center
for Drug Research, Ludwig-Maximilians-University Munich,
Butenandtstrasse 5-13, D-81377 Munich, Germany
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ꢀJ. Krauss et al.: Short microwave-assisted modular synthesis of bibenzyls
2ꢀ
coupling of 5 [19] (Scheme 2). This dimer was difficult to
separate from 7a/7b by column chromatography, but after
hydrogenation (see below), it was much easier to separate
the resulting diarylbutane derivative 10.
Subsequent hydrogenation of 7a/7b under Pt cataly-
sis gave the target compounds 1a and 1b. Lunularin (1a)
was obtained in an overall yield of 57 %, its methyl ether
1b in 34 % yield.
OR
HO
OH
HO
O
OH
:
=
1a R H:
Lunularin
=
CH3
Lunularic acid
:
1b R
Fig. 1:ꢁ Lunularin and related compounds.
Si
2.2 Antimicrobial evaluation
Si
I
3
The antimicrobial activity of target compounds 1a and
1b was evaluated in an agar diffusion assay [20] against
four bacteria (Gram-negative: Escherichia coli and
Pseudomonas marginalis; Gram-positive: Staphylococcus
equorum and Streptococcus entericus) and four fungi (the
yeasts Candida glabrata and Yarrowia lipolytica, the mold
Aspergillus niger, and the dermatophyte Hyphopichia
burtonii) (Table 1). Lunularin (1a) showed weak antibiotic
activity against Gram-positive bacteria and antifungal
activity in this assay, compared to the reference sub-
stances tetracycline (antibacterial) and clotrimazole
(antifungal). Astonishingly, m-O-methyllunularin (1b)
showed a different antimicrobial spectrum and showed
significantly higher antifungal activity than lunularin.
,
Pd(PPh3)2Cl2 CuI
HO
HO
N(CH2CH3)2CH3
100 %
4
2
I
OR
TBAF, methanol
97 %
6a−b
Pd(PPh Cl CuI
,
2
)
2
3
5
HO
N(CH2CH3)2CH3
36−61 %
R
O
H
,
2
Pt
1a
1b
96−99 %
HO
=
7a R
H
=
7b R
CH3
3 Conclusion
Scheme 1:ꢁ Synthesis of lunularin (1a) and m-O-methyllunularin (1b).
We have worked out a novel, modular four-step synthesis
In a second Sonogashira reaction under the same con- of oxygenated bibenzyls starting from readily available
ditions, arylalkyne 5 was reacted with 3-iodophenol (6a) building blocks (iodoarenes, trimethylsilylacetylene) uti-
or 3-iodoanisole (6b) to give the diarylalkynes 7a and 7b. lizing two consecutive microwave-assisted Sonogashira
As by-product of the Sonogashira reaction, a trace amount couplings. This protocol does not require protective groups
of the 1,3-diyne 9 was obtained as a product of a Glaser for phenolic residues and should be applicable to the
DBU
O
4
H2O, AcCN
HO
8
OH
OH
Pd(PPh ) Cl CuI
H Pt
,
2
,
2
3 2
5
HO
9
10
HO
Scheme 2:ꢁ Side reactions of the lunularin synthesis.
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ꢀ3
J. Krauss et al.: Short microwave-assisted modular synthesis of bibenzylsꢀ
Table 1:ꢁAgar diffusion assay (50 μg per disc; diameter of inhibition, in mm).
ꢀ
E. coliꢀ
P. marginalisꢀ
S. equorumꢀ
Str. entericusꢀ
Y. lipolyticaꢀ
C. glabrataꢀ
A. nigerꢀ
H. burtonii
1a
1b
ꢃ
ꢃ
0ꢃ
0ꢃ
32ꢃ
0ꢃ
0ꢃ
0ꢃ
28ꢃ
0ꢃ
11ꢃ
10ꢃ
28ꢃ
11ꢃ
9ꢃ
10ꢃ
34ꢃ
12ꢃ
7ꢃ
15ꢃ
0ꢃ
7ꢃ
12ꢃ
0ꢃ
0ꢃ
10ꢃ
0ꢃ
6
10
0
Tetracycline ꢃ
Clotrimazoleꢃ
22ꢃ
18ꢃ
20ꢃ
25
synthesis of numerous related natural products and related layers were dried over Na2SO4, the solvent was evapo-
compounds. In the agar diffusion assay, m-O-methyllunu- rated, and the residue purified with FCC (isohexane-ethyl
larin (1b) showed a remarkable antifungal activity.
acetate 3:1) to give 380 mg (100 %) of 4 as a brown oil.
1
– H NMR (400 MHz, CDCl3): δ ꢀ=ꢀ 0.23 (s, 9 H, 3 CH3), 6.76
(d, J ꢀ=ꢀ 8.8 Hz, 2 H, aromat. CH), 7.34 (d, J ꢀ=ꢀ 8.8 Hz, 2 H,
aromat. CH). – 13C NMR (125 MHz, CDCl3): δ ꢀ=ꢀ 0.19 (3 CH3),
92.12 (quat. C), 105.39 (quat. C), 114.98 (quat. C), 115.48
(2 aromat. CH), 133.51 (2 aromat. CH), 156.44 (quat. C).
These data are in accordance with those published in
4 Experimental section
4.1 General information
+
Ref. [12]. – GC-MS (EI): m/z (%) ꢀ=ꢀ 190 (23) [M] , 175 (100).
All solvents used were of HPLC grade or p.a. grade and/or – HRMS: m/z ꢀ=ꢀ 190.0814 (calcd. 190.0815 for C11H14O2Si,
+
−1
purified according to standard procedures. Chemical rea- [M] ). – IR (KBr): ν (cm ) ꢀ=ꢀ 3322, 2959, 2155, 1662, 1607,
gents were purchased from Sigma Aldrich (Schnelldorf, 1508, 1437, 1251, 1230, 1167, 1100, 867, 840.
Germany) and Acros (Geel, Belgium). Microwave-assisted
reactions were carried out in a microwave reactor Dis-
cover SP (CEM GmbH, Kamp-Lintfort, Germany). IR 4.3 4-Ethynylphenol (5)
spectra: Perkin-Elmer FT-IR Paragon 1000 (Perkin Elmer,
Rodgau, Germany); MS: Hewlett Packard MS-Engine, elec- 4 (380 mg, 2.0 mmol) was dissolved in 20 mL methanol,
tron ionization (EI) 70 eV, chemical ionization (CI) with and 1.0 g (2.0 mmol) of TBAF was added. The suspension
CH4 (300 eV); GC-MS: Shimadzu GC17A, carrier gas: He, was stirred for 12 h at ambient temperature, and then,
column: fused silica capillary column 30 m, detector: MS: the solvent was evaporated. The residue was dissolved in
EI (70 eV) (Shimadzu Europa GmbH, Duisburg, Germany). 20 mL of 2 M aqueous HCl and extracted with ethyl acetate
NMR: Avance III HD 400 MHz Bruker BioSpin (1H, (3 ꢀ×ꢀ 20 mL). The combined organic layers were dried over
13
400 MHz; C, 100 MHz); Avance III HD 500 MHz Bruker Na2SO4, and the solvent was evaporated. The residue was
BioSpin (1H, 500 MHz; 13C, 125 MHz) (Bruker, Billerica, purified by FCC (isohexane-ethyl acetate 2:1) to give 230 mg
1
MA, USA); melting points: Büchi Melting Point B-540 (not (97 %) of 5 as a pale brown oil. – H NMR (400 MHz, [D4]
corrected) (Büchi Labortechnik AG, Flawil, Switzerland); methanol): δ ꢀ=ꢀ 4.24 (s, 1 H, CH), 4.32 (s, 1 H, OH), 6.78 (m,
flash column chromatography (FCC): silica gel 60 (230– 2 H, aromat. CH), 7.35 (m, 2 H, aromat. CH). – 13C NMR (125
400 mesh; E. Merck, Darmstadt, Germany).
MHz, CDCl3): δ ꢀ=ꢀ 79.07 (CH), 87.87 (quat. C), 116.81 (quat. C),
119.25 (2 aromat. CH), 137.50 (2 aromat. CH), 161.77 (quat. C).
+
– GC-MS (EI): m/z (%) ꢀ=ꢀ 118 (100) [M] . – IR (KBr): ν (cm–1)
4.2 4-((Trimethylsilyl)ethynyl)phenol (4)
ꢀ=ꢀ 3264, 1657, 1603, 1582, 1512, 1361, 1280, 1170, 838. These
data are in accordance with those published in Ref. [21].
4-Iodophenol (2) (440 mg, 2.0 mmol) and trimethylsilyla-
cetylene (0.42 mL, 3.0 mmol) were dissolved in 10 mL of
diethylmethylamine and 10 mL of dimethylformamide, 4.4 4-Hydroxyacetophenone (8)
and then, 60 mg (0.30 mmol) of CuI and 70 mg (0.10 mmol)
of PdCl2(PPh3)2 were added. The solution was stirred in a 4 (380 mg, 2.0 mmol) was dissolved in acetonitrile/water
microwave reactor at 60 °C for 20 min (100 W) under N2 (19:1), and 304 mg (2.0 mmol) of DBU was added. The
atmosphere. The solvent was evaporated, and the residue solution was stirred for 1 h at 70 °C in a microwave reactor
was dispersed in 20 mL aqueous 2 M HCl and extracted (210 W). The solvent was evaporated, and the residue
with diethyl ether (3 ꢀ×ꢀ 20 mL). The combined organic was purified by FCC (isohexane-ethyl acetate 2:1) to give
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ꢀJ. Krauss et al.: Short microwave-assisted modular synthesis of bibenzyls
4ꢀ
70 mg (29 %) of 4-hydroxyacetophenone as a brown solid. the mixture was stirred under H2 atmosphere for 12 h.
– 1H NMR (400 MHz, CDCl3): δ ꢀ=ꢀ 2.57 (s, 3 H, CH3), 5.90 (s, The catalyst was filtered off and the solvent was evapo-
1 H, OH), 6.89 (d, J ꢀ=ꢀ 8.8 Hz, 2 H, aromat. CH), 7.91 (d, J ꢀ=ꢀ rated; the residue was purified by FCC (isohexane-ethyl
8.8 Hz, 2 H, aromat. CH).
acetate 2:1) to give 200 mg (96 %) of 1a as a pale brown
1
solid; m.p. 125 °C (Ref. [7], 106 °C). – H NMR (400 MHz,
CD2Cl2): δ ꢀ=ꢀ 2.73 (s, 4 H, 2 CH2), 5.35 (s, 2 H, 2 OH), 6.57
4.5 3-[(4-Hydroxyphenyl)ethynyl]phenol (7a) (s, 1 H, aromat. CH), 6.63 (m, 1 H, aromat. CH), 6.66
(d, J ꢀ=ꢀ 7.8 Hz, 2 H, 2 aromat. CH), 6.92 (m, 1 H, aromat.
5 (210 mg, 1.78 mmol), 3-iodophenol (6a) (440 mg, CH), 6.95 (d, J ꢀ=ꢀ 7.8 Hz, 2 H, aromat. CH), 7.04 (dd, J ꢀ=ꢀ
2.0 mmol), CuI (60 mg, 0.30 mmol), and PdCl2(PPh3)2 8.1 Hz, J ꢀ=ꢀ 8.1 Hz, 1 H, aromat. CH). – C NMR (100 MHz,
13
(70 mg, 0.10 mmol) were reacted according to the pro- CD2Cl2): δ ꢀ=ꢀ 35.91 (CH2), 37.12 (CH2), 111.88 (aromat. CH),
cedure described for 4 to give 228 mg (61 %) of 7a as a 114.23 (2 aromat. CH), 114.54 (aromat. CH), 119.95 (aromat.
pale-brown solid after purification by FCC (isohexane/eth- CH), 128.59 (aromat. CH), 128.70 (2 aromat. CH), 133.02
1
ylacetate 3:1); m.p. 172 °C. – H NMR (400 MHz, [D4]meth- (quat. C), 143.90 (quat. C), 153.21 (quat. C), 155.02 (quat. C).
+
anol): δ ꢀ=ꢀ 3.94 (s, 2 H, 2 OH), 6.79 (m, 3 H, aromat. CH), – GC-MS (EI): m/z (%) ꢀ=ꢀ 214 (10) [M] , 122 (2), 107 (100).
6.90–7.23 (m, 2 H, aromat. CH), 7.38 (m, 3 H, aromat. CH). All spectroscopic data were in full accordance with those
13
– C NMR (125 MHz, [D4]methanol): δ ꢀ=ꢀ 88.32 (quat. C), published in Refs. [4, 8, 9].
90.03 (quat. C), 115.36 (quat. C), 116.41 (aromat. CH), 116.53
(2 aromat. CH), 118.79 (aromat. CH), 123.71 (aromat. CH),
126.12 (quat. C), 130.53 (aromat. CH), 134.09 (2 aromat. CH),
4.8 4-((3-Methoxyphenyl)ethyl)phenol;
158.54 (quat. C), 159.20 (quat. C). – GC-MS (EI): m/z (%) ꢀ=ꢀ
(m-O-methyllunularin) (1b)
+
210 (100) [M] , 181 (12), 152 (19). – HRMS: m/z ꢀ=ꢀ 210.0706
+
(calcd. 210.0681 for C14H10O2, [M] ).
7b (148 mg, 0.63 mmol) was dissolved in 2 mL of ethyl
acetate and 25 mL of methanol, 50 mg of platinum on
carbon (5 %) was added, and the mixture was stirred
4.6 4-((3-Methoxyphenyl)ethynyl)
under H2 atmosphere for 12 h. The catalyst was filtered off,
phenol (7b)
the solvent was evaporated, and the residue was purified
by FCC (isohexane-ethyl acetate 2:1) to give 142 mg (99 %)
of 1b as a pale-brown oil. – 1H NMR (400 MHz, [D4]metha-
nol): δ ꢀ=ꢀ 2.80 (m, 4 H, 2 CH2), 3.72 (s, 3 H, CH3), 4.92 (s,
1 H, OH), 6.71 (d, J ꢀ=ꢀ 8.4 Hz, 2 H, aromat. CH), 6.67–6.75
(m, 3 H, aromat. CH), 6.97 (d, J ꢀ=ꢀ 8.4 Hz, 2 H, aromat.
CH), 7.14 (dd, J ꢀ=ꢀ 7.6 Hz, J ꢀ=ꢀ 7.6 Hz, 1 H, aromat. CH). – 13C
NMR (100 MHz, CDCl3): δ ꢀ=ꢀ 39.75 (CH2), 41.05 (CH2), 57.11
(CH3), 113.86 (aromat. CH), 116.72 (aromat. CH), 117.59 (2
aromat.CH),123.53(aromat.CH),131.75(aromat.CH),132.05
(2 aromat. CH), 135.51 (quat. C), 146.36 (quat. C), 157.97
(quat. C), 162.59 (quat. C). – GC-MS (EI): m/z (%) ꢀ=ꢀ 228 (27)
5 (235 mg, 1.9 mmol), 6b (468 mg, 2.0 mmol), CuI (60 mg,
0.30 mmol), and PdCl2(PPh3)2 (70 mg, 0.10 mmol) were
reacted according to the procedure described for 4 to give
158 mg (36 %) of 7b as a pale-brown oil after purification
by FCC (isohexane-ethyl acetate 4:1). – 1H NMR (400 MHz,
CDCl3): δ ꢀ=ꢀ 3.83 (s, 3 H, OCH3), 6.82 (d, J ꢀ=ꢀ 8.5 Hz,
2 H, aromat. CH), 6.88 (dd, J ꢀ=ꢀ 2.0 Hz, J ꢀ=ꢀ 7.8 Hz, 1 H,
aromat. CH), 7.04 (s, 1 H, aromat. CH), 7.11 (d, J ꢀ=ꢀ 7.8 Hz,
1 H, aromat. CH), 7.25 (dd, J ꢀ=ꢀ 7.8 Hz, J ꢀ=ꢀ 7.8 Hz, 1 H,
13
aromat. CH), 7.43 (d, J ꢀ=ꢀ 8.5 Hz, 2 H, aromat. CH). – C
NMR (100 MHz, CDCl3): δ ꢀ=ꢀ 55.31 (OCH3), 87.88 (quat. C),
89.19 (quat. C), 114.65 (aromat. CH), 115.23 (quat. C), 115.61
(2 aromat. CH), 116.15 (aromat. CH), 124.05 (aromat. CH),
124.58 ( quat. C), 129.39 (aromat. CH), 133.30 (2 aromat.
CH), 156.08 (quat. C), 159.31 (quat. C). – GC-MS (EI): m/z
+
[M] , 121 (14), 107 (100). – HRMS: m/z ꢀ=ꢀ 228.1141 (calcd.
+
13
228.1150 for C15H16O2, [M] ). The C NMR data were in full
accordance with those published in Ref. [2].
+
(%) ꢀ=ꢀ 224 (100) [M] , 181 (21), 152 (19). – HRMS: m/z ꢀ=ꢀ
224.0817 (calcd. 224.0837 for C15H12O2, [M] ).
+
4.9 4,4′-(Buta-1,3-diyne-1,4-diyl)
diphenol (9)
4.7 Lunularin (1a)
This compound was obtained as by-product of the synthe-
+
ses of 7a and 7b. – GC-MS (EI): m/z (%) ꢀ=ꢀ 234 (100) [M] ,
7a (204 mg, 0.97 mmol) was dissolved in 25 mL of metha- 176 (13). The spectroscopic data are in full accordance with
nol, 40 mg of platinum on carbon (5 %) was added, and those published in Ref. [22].
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ꢂꢁꢁꢁ
ꢀ5
J. Krauss et al.: Short microwave-assisted modular synthesis of bibenzylsꢀ
[3] R. P. Pryce, L. P. Linton, Phytochemistry 1974, 13, 2497.
4.10 4,4′-(Butane-1,4-diyl)diphenol (10)
[4] N. H. Soekamto, S. A. Achmad, E. L. Ghisalberti, E. H. Hakim,
Y. M. Syah, Indones. J. Chem. 2005, 5, 207.
[5] D. C. Harrowven, S. L. Kostiuk, Nat. Prod. Rep. 2012, 29, 223.
[6] S. Friedrich, M. Rüffer, Y. Asakawa, M. H. Zenk, Phytochemistry
1999, 52, 1195.
This compound was obtained as by-product of the syn-
thesis of 1a and 1b, after not extensively purified samples
of 7a/7b had been subjected to catalytic hydrogenation.
1
– H NMR (400 MHz, CD2Cl2): δ ꢀ=ꢀ 1.62 (t, J ꢀ=ꢀ 7.0 Hz, 4 H,
[7] S. Huneck, Tetrahedron 1976, 32, 109.
[8] H. Sawada, M. Okazaki, D. Morita, T. Kuroda, K. Matsuno,
Y. Hashimoto, H. Miyachi, Bioorg. Med. Chem. Lett. 2012, 22,
7444.
[9] F. Bracher, J. Krauss, A. Bornatsch, Nat. Prod. Lett. 2000, 14,
305.
[10] K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975,
4467.
[11] K. C. Nicolaou, W.-M. Dai, Angew. Chem. Int. Ed. Engl. 1991, 30,
1387.
2 CH2), 2.57 (t, J ꢀ=ꢀ 7.0 Hz, 4 H, 2 CH2), 5.05 (s, 2 H, 2 OH),
6.75 (d, J ꢀ=ꢀ 8.1 Hz, 4 H, aromat. CH), 7.02 (d, J ꢀ=ꢀ 8.1 Hz, 4 H,
aromat. CH). – 13C NMR (100 MHz, CD2Cl2): δ ꢀ=ꢀ 31.7 (2 CH2),
35.16 (2 CH2), 115.27 (4 aromat. CH), 129.75 (4 aromat. CH),
135.39 (quat. C), 154.14 (quat. C). – GC-MS (EI): m/z (%) ꢀ=ꢀ
+
242 (10) [M] , 212 (27), 165 (15), 107 (100). – HRMS: m/z ꢀ=ꢀ
+
242.1305 (calcd. 242.1307 for C16H18O2, [M] ).
[12] J. Krauss, I. Wetzel, F. Bracher, Nat. Prod. Res. 2004, 18, 397.
[13] J. Krauss, F. Bracher, Arch. Pharm. Pharm. Med. Chem. 2004,
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1972, 46, 255.
4.11 Agar diffusion assay [20]
The bacteria and fungi were cultivated on an AC agar
(Sigma). The substances were placed on the agar on 6-mm
paper discs, each impregnated with 50 μg of the tested com-
pound or 50 μg of the reference drug. The bacteria media
were incubated for 24 h at 32 °C, the fungi media for 48 h at
28 °C. The diameters of the zones of inhibition (mm) were
registered manually. Tests were performed in duplicate.
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[19] C. Glaser, Chem. Ber. 1869, 2, 422.
[20] DIN 58940-84:2002-10, Medical microbiology – susceptibility
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against antifungal agents, Beuth-Verlag, Berlin, 2009.
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Graphical synopsis
Jürgen Krauss, Ursula Kopp and Franz
Bracher
Short microwave-assisted modular
synthesis of naturally occurring
oxygenated bibenzyls
DOI 10.1515/znb-2015-0047
Z. Naturforsch. 2015; x(x)b: xxx–xxx
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