Synthesis and structure-activity relationships of 2-vinylchroman-4-ones as potent antibiotic agents

Article abstract of DOI:10.1016/j.bmc.2004.12.031

A series of novel 2-vinylchroman-4-ones, analogues of the natural products Aposphaerin A and B, were identified as potent antibiotics. Derivatives exhibit a significant activity against multiresistant strains of S. aureus, such as MRSA (methicillin resist

Full text of DOI:10.1016/j.bmc.2004.12.031

Bioorganic & Medicinal Chemistry 13 (2005) 1531–1536
Synthesis and structure–activity relationships of
2-vinylchroman-4-ones as potent antibiotic agents
Uwe Albrecht,a Michael Lalk*,b and Peter Langer*,a,
aInstitut fu¨r Chemie und Biochemie, Ernst-Moritz-Arndt-Universita¨t, Soldmannstr. 16, D-17487 Greifswald, Germany
bInstitut fu¨r Pharmazie, Ernst-Moritz-Arndt-Universita¨t Greifswald, Jahnstr. 17, D-17487 Greifswald, Germany
Received 6 August 2004; revised 10 December 2004; accepted 17 December 2004
Abstract—A series of novel 2-vinylchroman-4-ones, analogues of the natural products Aposphaerin A and B, were identified as
potent antibiotics. Derivatives exhibit a significant activity against multiresistant strains of S. aureus, such as MRSA (methicillin
resistant S. aureus). The 2-vinylchroman-4-ones were efficiently prepared by Lewis acid mediated conjugate addition of vinylmag-
nesium bromide to chromones.
ꢀ 2004 Elsevier Ltd. All rights reserved.
O
1. Introduction
R1
O
O
Aposphaerin A:
The development of new antimicrobial agents represents
an important field in medicinal chemistry, due to the
increasing problem of the formation of resistant strains
of bacterial pathogenes. Natural products often repre-
sent important lead structures for the development of
new antibiotics. For example, chroman-4-ones are
widely distributed among pharmacologically relevant
natural products.1 Recently, the natural products Apos-
phaerin A and B were isolated from extracts of the endo-
phytic fungus Aposphaeria spec.2 These compounds
contain a rare 2-vinylchroman-4-one system.3,4 Herein,
we wish to report a convenient synthesis of 2-vinylchro-
man-4-ones by Lewis acid mediated conjugate addition
of vinylmagnesium bromide to chromones. The prod-
ucts exhibit a remarkable activity against several
humanpathogenic bacteria and yeast. Derivatives have
been identified which exhibit a significant activity
against multiresistant strains of S. aureus, such as
MRSA (methicillin resistant S. aureus).5 These bacteria
are often a source for severe infections in patients during
their stay in hospitals or in immunosuppressed persons.
R1 = R2 = OH, R3 = Me
Aposphaerin B:
R1 = OEt, R2 = R3 = H
R3O
R2
2. Chemistry
The direct reaction of parent chromone (1a) with vinyl-
lithium or vinyl magnesium bromide gave complex mix-
tures, due to competing 1,2- and 1,4-additions and
decomposition. The reaction of vinyl magnesisum bro-
mide (2) with benzopyrylium triflate A, generated in situ
by treatment of 1a with Me3SiOTf,6 resulted in regio-
selective conjugate addition to give the desired 2-vinyl-
chroman-4-one 3a (Scheme 1). The best yields (up to
86%) were obtained when the reaction was carried out
(a) at ꢀ78 ꢁC (reaction time: 30 min, no warming) and
(b) in the absence of base. To completely hydrolyze
the silyl enol ether moiety of intermediate B, an aqueous
solution of ammonium chloride (1 M) was used for the
work-up. The use of hydrochloric acid resulted in a sig-
nificant decrease of the yield, due to decomposition.
Keywords: Antibiotics; Chromanones; Natural product analogues;
Oxygen heterocycles; Pharmacological screening.
*
Corresponding authors. Tel.: +49 3834 864461; fax: +49 3834 864373
(P.L.); e-mail: peter.langer@uni-greifswald.de
Address: Institut fur Chemie, Universita¨t Rostock, Albert-Einstein-
¨
The Me3SiOTf mediated reaction of chromones 1a–g
with vinyl magnesium bromide (2) afforded the 2-vinyl-
chroman-4-ones 3a–g (Scheme 2, Table 1). The reaction
Str. 3a, D-18051 Rostock, Germany.
0968-0896/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.12.031

1532
U. Albrecht et al. / Bioorg. Med. Chem. 13 (2005) 1531–1536
O
O
OSiMe3
O
Me3SiOTf
_
KOtBu
OTf
+
THF, 5 min
O
O
CH2Cl2, 0°C
O
OH
4a (34%)
3a
1a
A
Scheme 3. Base mediated retro-Michael reaction of 3a.
BrMg
(2)
78 °C, 30 min
THF
_
1) Me3SiOTf
CH2Cl2
O
OSiMe3
O
NH4Cl
H2O
O
R2
R1
BrMg
THF
R1
R2
2)
O
O
OH
O
B
3a (86%)
1i,j
4b,c
Scheme 1. Synthesis of 2-vinylchroman-4-one (3a).
Scheme 4. Reaction of 1i, j with vinyl magnesium bromide, 4b
(R1 = OBn, R2 = H, 36%); 4c (R1 = H, R2 = Me, 35%).
1) Me3SiOTf
resulted in a decreasement of the yield, due to
decomposition.
CH2Cl2
O
O
O
2) R4MgBr
THF
R2
R3
R3
R4
R1
R2
R3
The reaction of chromones 1i and 1j with vinyl magne-
sium bromide resulted in the direct formation of the
open-chained products 4b and 4c, respectively (Scheme
4). The formation of 2-vinylchroman-4-ones was not
observed.
O
3a-j
1a-h
Scheme 2. Synthesis of chroman-4-ones 3a–j.
3. Pharmacological screening
Table 1. Products and yields
3
R1
R2
R3
R4
Yield (%)a
All compounds were tested against several humanpath-
ogenic bacteria to elucidate their potential as antibiotics.
The compounds 3a and b and 3d–j were subjected to an
antimicrobial screening using the paper disc diffusion
method (Table 2).7,8 Derivatives 3b, e and f showed a
remarkable antimicrobial activity. The 1-(2-hydroxy-
phenyl)-penta-2,4-dien-1-ones 4a–c proved to be non
active.
a
b
c
d
e
f
H
Cl
H
H
H
H
H
Br
H
H
H
H
H
–CH@CH2
–CH@CH2
–CH@CH2
–CH@CH2
–CH@CH2
–CH@CH2
–CH@CH2
–CH@CH2
–C„CPh
86
56
55
25
51b
50
50
60
50
58
H
CH3
OCH3
H
H
H
H
Br
Cl
H
g
h
i
CH3
OH
H
H
H
j
H
H
–CH2CH3
The activity of 2-vinylchroman-4-ones against multire-
sistant bacteria was next studied (Table 3). Derivatives
3b and 3d–g show a significant inhibitory effect on the
a Yields of isolated products.
b trans/cis = 2:1.
Table 2. Results of the antimicrobial screeninga
of 2 with 7-trimethylsilyloxychromone (1h) resulted in
formation of 7-hydroxy-2-vinylchroman-4-one (3h).
Phenylalkynyl-substituted chroman-4-one 3i was pre-
pared from 1a and lithium phenylacetylide. The reaction
of 1a with ethyl magnesium bromide afforded 2-ethyl-
chroman-4-one 3j.
3/4
Bacillus subtilis
Escherichia coli
C. maltosa
ATCC 6051
ATCC 11229
ATCC 200
3a
3b
3d
3e
3f
r
r
r
29
r
17
r
40
r
20
24
r
15
14
r
20
r
It was expected, that the pharmacological activity of 2-
vinylchroman-4-ones involves a ring-opening reaction
of the labile arylallyl-ether moiety to give 1-(2-hydroxy-
phenyl)-penta-2,4-dien-1-ones. Therefore, the synthesis
of these compounds and their pharmacological activity
were studied. Treatment of 2-vinylchroman-4-one (3a)
with KOtBu (THF, 5 min) afforded 1-(2-hydroxyphen-
yl)-penta-2,4-dien-1-one (4a) by a retro-Michael reac-
tion (Scheme 3). Extension of the reaction time
3g
3h
3i
r
r
r
r
r
r
r
3j
r
r
r
4a
4b
4c
r
r
r
r
r
r
r
r
r
a Inhibition zones are stated in diameter (cm) without the diameter of
the paper disc (6 mm), r = resistant.

U. Albrecht et al. / Bioorg. Med. Chem. 13 (2005) 1531–1536
Table 3. Results of antimicrobial screening against MRSAa
1533
3
MRSA (North-German
hospital strain)
S. aureus
S. epidermis 125
S. aureus 36881
S. aureus 38418
S. aureus 315
S. aureus 520
ATCC 6538
b
d
e
f
40
8
40
8
>40
8
38
8
38
8
38
8
38
8
20
32
10
20
32
14
18
40
20
20
30
10
20
30
10
18
30
10
18
30
12
g
a Inhibition zones are stated in diameter (cm) without the diameter of the paper disc (6 mm).
Table 4. Determination of the minimum inhibitory concentration
(MIC) using the microdilution methoda
by column chromatography (silica gel, ethyl acetate/hex-
ane = 1:50) to give the 2-vinylchroman-4-one 3.
3
B. subtilis
E. coli
Staphylococcus
ATCC 6051
ATCC 11229
aureus ATCC 6538
4.2. 2-Vinylchroman-4-one (3a)
a
b
d
e
f
17.42
4.17
60.44
4.17
34.84
7.30
Starting with 1a (0.73 g, 5.0 mmol), dissolved in 1 mL of
CH2Cl2, TMSOTf (1.44 g, 6.5 mmol), 20 mL of THF
and vinyl magnesium bromide (6.5 mL, 1 M), 3a was
obtained as a colourless oil (0.75 g, 86%). 1H NMR
(CDCl3, 300 MHz): d 2.80 (d, 3J = 7 Hz, 2H, CH2),
4.98 (dt, 3J = 7 Hz, 3J = 7 Hz, 1H, CH), 5.34 (dd,
61.27
10.12
10.12
24.49
30.63
2.53
61.27
12.65
5.62
25.31
44.53
g
33.40
a (lg/mL).
3
2
2J = 1 Hz, Jcis = 11 Hz, 1H, CH2), 5.45 (dd, J = 1 Hz,
3Jtrans = 16 Hz, 1H, CH2), 6.01 (ddt, 3J = 7 Hz,
3
3Jcis = 11 Hz, Jtrans = 16 Hz, 1H, CH), 7.01 (m, 2H,
growth of MRSA (methicillin resistant S. aureus) and of
other multiresistant strains of S. aureus.
3
3
CH), 7.47 (t, J = 7 Hz, 1H, CH), 7.88 (d, J = 7 Hz,
1H, CH). 13C NMR (CDCl3, 75 MHz): dC 42.46
(CH2), 77.79 (CH), 117.89 (CH2), 117.95 (CH), 120.88
(C), 121.28, 126.77, 135.13, 135.96 (CH), 160.99 (C),
191.50 (CO). MS (70 eV): m/z (%) = 174 (M+, 13), 154
(16), 120 (18), 92 (12), 28 (100). IR (KBr, cmꢀ1):
To evaluate the inhibitory effects of the test compounds
in solution, the minimum inhibitory concentrations
(MIC) were determined using the microdilution meth-
od.8 The results are summarized in Table 4.
~
m = 3082 (w), 1693 (s), 1651 (w), 1607 (s), 1578 (s),
1472 (s), 1464 (s), 1428 (m), 1403 (m). Anal. Calcd for
C11H10O2: C, 75.84; H, 5.79; found: C, 75.68; H, 5.59.
In conclusion, 2-vinylchroman-4-ones are strong inhibi-
tors of the growth of pathogenic and non-pathogenic
microbes. The halogenated derivatives 3b, e and f show
remarkable activities. The structure–activity relationship
experiments (SAR) revealed that the presence of a vinyl
group at carbon C-2, the arylallyl-ether subunit, is man-
datory for biological activity. The ethyl-substituted
derivative 3j and the 1-(2-hydroxyphenyl)-penta-2,4-
dien-1-ones 4a–c showed no activity against the test
strains. The presence of a chlorine or bromine atom rep-
resents an important feature for a high antimicrobial
activity.
4.3. 6-Chloro-2-vinylchroman-4-one (3b)
Starting with 1b (0.18 g, 1.0 mmol), dissolved in 0.3 mL
of CH2Cl2, TMSOTf (0.29 g, 1.3 mmol), 4 mL of THF
and vinyl magnesium bromide (1.3 mL, 1 M), 3b was
obtained as white solid (0.12 g, 56%). 1H NMR (CDCl3,
300 MHz): d 2.79 (d, 3J = 7 Hz, 2H, CH2), 4.97 (dt,
3J = 7 Hz, 3J = 7 Hz, 1H, CH), 5.38 (dd, 2J = 1 Hz,
3Jcis = 11 Hz, 1H, CH2), 5.44 (dd, 2J = 1 Hz,
3Jtrans = 16 Hz, 1H, CH2), 6.04 (ddt, 3J = 7 Hz,
3
3Jcis = 11 Hz, Jtrans = 16 Hz, 1H, CH), 6.97 (d,
3J = 8 Hz, 1H, Ar-H), 7.42 (dd, 3J = 8 Hz, 4J = 2 Hz,
4. Experimental
4
1H, Ar-H), 7.84 (d, J = 2 Hz, 1H, Ar-H). 13C NMR
4.1. General procedure for the preparation of 2-vinyl-
chroman-4-ones (3a–h)
(CDCl3, 75 MHz): dC 42.24 (CH2), 78.13 (CH), 118.47
(CH), 119.78 (C), 126.26 (CH), 126.98 (C), 134.79,
135.93 (CH), 159.55 (C), 190.56 (CO). MS (70 eV): m/z
(%) = 208 (100, M+), 181 (33), 165 (12), 154 (90), 126
To a CH2Cl2 solution of the chromone 1 was added
TMSOTf at 20 ꢁC. After stirring for 1 h at 20 ꢁC the
reaction was cooled to ꢀ78 ꢁC and THF and vinyl mag-
nesium bromide (1 M solution in THF, Aldrich) was
added. After stirring for 30 min at ꢀ78 ꢁC an aqueous
solution of NH4Cl (10 mL, 1 M) was added. The solu-
tion was warmed to room temperature. The organic
and the aqueous layer were separated and the latter
was extracted with ether (3 · 30 mL). The combined or-
ganic layers were dried (Na2SO4), filtered and the sol-
vent was removed in vacuo. The residue was purified
1
~
(47). IR (KBr, cm ): m = 1695 (s), 1604 (s), 1470 (s),
1422 (s), 1407 (w). Anal. Calcd for C11H9ClO2: C,
63.32; H, 4.35; found: C, 63.09; H 4.59.
4.4. 6-Methyl-2-vinylchroman-4-one (3c)
Starting with 1c (0.48 g, 3.0 mmol), dissolved in 0.5 mL
of CH2Cl2, TMSOTf (0.67 g, 3.9 mmol), 15 mL of THF
and vinyl magnesium bromide (3.9 mL, 1 M), 3c was

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U. Albrecht et al. / Bioorg. Med. Chem. 13 (2005) 1531–1536
obtained as a colourless oil (0.32 g, 55%). 1H NMR
(CDCl3, 300 MHz): d 2.31 (s, 3H, CH3), 2.78 (d,
3J = 7 Hz, 2H, CH2), 4.95 (dt, 3J = 7 Hz, 3J = 7 Hz,
4.7. 6-Bromo-2-vinylchroman-4-one (3f)
Starting with 1f (0.23 g, 1.0 mmol), dissolved in 0.3 mL
of CH2Cl2, TMSOTf (0.29 g, 1.3 mmol), 4 mL of THF
and vinyl magnesium bromide (1.3 mL, 1 M), 3f was ob-
tained as a colourless solid (0.13 g, 50%). 1H NMR
(CDCl3, 300 MHz): d 2.80 (d, 3J = 7 Hz, 2H, CH2),
4.97 (dt, 3J = 7 Hz, 3J = 7 Hz, 1H, CH), 5.36 (dd,
2
3
1H, CH), 5.34 (dd, J = 1 Hz, Jcis = 11 Hz, 1H, CH2),
3
5.46 (dd, 2J = 1 Hz, Jtrans = 16 Hz, 1H, CH2), 6.05
3
3
(ddt, 3J = 7 Hz, Jcis = 11 Hz, Jtrans = 16 Hz, 1H,
CH), 6.91 (d, 3J = 8 Hz, 1H, Ar-H), 7.30 (dd,
3J = 8 Hz, 4J = 2 Hz, 1H, Ar-H), 7.67 (d, 4J = 2 Hz,
1H, Ar-H). 13C NMR (CDCl3, 75 MHz): dC 20.38
(CH3), 42.64 (CH2), 77.90 (CH), 117.79 (CH2), 118.00
(CH), 120.59 (C), 126.47 (CH), 130.86 (C), 135.35,
137.18 (CH), 159.20 (C), 191.98 (CO). MS (70 eV): m/z
(%) = 188 (80, M+), 161 (16), 134 (100), 106 (20), 78
(18). The exact molecular mass for C12H12O2 m/z =
188.0837 2 ppm [M+] was determined by HRMS (EI,
3
2
2J = 1 Hz, Jcis = 11 Hz, 1H, CH2), 5.45 (dd, J = 1 Hz,
3Jtrans = 18 Hz, 1H, CH2), 6.03 (ddt, 3J = 7 Hz,
3
3Jcis = 11 Hz, Jtrans = 18 Hz, 1H, CH), 6.92 (d,
3J = 8 Hz, 1H, Ar-H), 7.55 (dd, 3J = 8 Hz, 4J = 2 Hz,
4
1H, Ar-H), 7.98 (d, J = 2 Hz, 1H, Ar-H). 13C NMR
(CDCl3, 75 MHz): dC 42.20 (CH2), 78.12 (CH), 114.14
(C), 118.51 (CH2), 120.14 (CH), 122.25 (C), 129.39,
134.77, 138.72 (CH), 159.99 (C), 190.43 (CO). MS
(70 eV): m/z (%) = 252 (100, M+), 227 (20), 225 (24),
~
70 eV). IR (KBr): m = 2923 (w), 1692 (s), 1650 (w),
1618 (s), 1578 (w), 1489 (s), 1421 (m).
200 (84), 198 (88), 170 (36). IR (KBr, cmꢀ1): m = 3434
~
(s), 1694 (s), 1599 (s), 1467 (s), 1418 (m), 1406 (w). Anal.
Calcd for C11H9BrO2: C, 52.20; H, 3.58; found: C,
52.48; H, 3.97.
4.5. 6-Methoxy-2-vinylchroman-4-one (3d)
Starting with 1d (0.53 g, 3.0 mmol), dissolved in 0.5 mL
of CH2Cl2, TMSOTf (0.67 g, 3.9 mmol), 15 mL of THF
and vinyl magnesium bromide (3.9 mL, 1 M), 3d was
obtained as a colourless oil (0.15 g, 25%). 1H NMR
(CDCl3, 300 MHz): d 2.79 (d, 3J = 7 Hz, 2H, CH2),
3.80 (s, 3H, OCH3), 4.93 (dt, 3J = 7 Hz, 3J = 7 Hz,
4.8. 6-Chloro-7-methyl-2-vinylchroman-4-one (3g)
Starting with 1g (0.20 g, 1.0 mmol), dissolved in 0.3 mL
of CH2Cl2, TMSOTf (0.29 g, 1.3 mmol), 4 mL of THF
and vinyl magnesium bromide (1.3 mL, 1 M), 3g was
2
3
1
1H, CH), 5.34 (dd, J = 1 Hz, Jcis = 11 Hz, 1H, CH2),
obtained as a colourless solid (0.11 g, 50%). H NMR
(CDCl3, 300 MHz): d 2.56 (s, 3H, CH3), 2.77 (d,
3
5.45 (dd, 2J = 1 Hz, Jtrans = 16 Hz, 1H, CH2), 6.04
3
3
3
3
3
3J = 7 Hz, 2H, CH22), 4.95 (ddd, J = 7 Hz, J = 7 Hz,
1H, CH), 5.34 (dd, J = 2 Hz, Jcis = 10 Hz, 1H, CH2),
(ddt, J = 7 Hz, Jcis = 11 Hz, Jtrans = 16 Hz, 1H, CH),
6.95 (d, 3J = 8 Hz, 1H, Ar-H), 7.10 (dd, 3J = 8 Hz,
3
4
4J = 2 Hz, 1H, Ar-H), 7.31 (d, J = 2 Hz, 1H, Ar-H).
5.44 (dd, 2J = 2 Hz, Jtrans = 17 Hz, 1H, CH2), 6.00
3
13C NMR (CDCl3, 50 MHz): dC 42.54 (CH2), 55.73
(CH3), 77.96 (CH), 107.49 (CH), 117.77 (CH2), 119.22
(CH), 120.88 (C), 125.11, 135.45 (CH), 154.14, 155.81
(C), 191.50 (CO). MS (70 eV): m/z (%) = 204 (76, M+),
177 (16), 161 (8), 150 (100), 107 (24). The exact mole-
cular mass for C12H12O3 m/z = 204.0786 2 ppm [M+]
was determined by HRMS (EI, 70 eV). IR (KBr, cmꢀ1):
3
3
(ddd, 3J = 7 Hz, Jcis = 10 Hz, Jtrans = 17 Hz, 1H,
CH), 6.91 (s, 1H, Ar-H), 7.82 (s, 1H, Ar-H). 13C
NMR (CDCl3, 75 MHz): dC 20.85 (CH3), 42.27 (CH2),
78.11 (CH), 118.31 (CH2), 120.03 (C), 120.12 (CH),
126.62 (CH), 127.70 (C), 134.99 (CH), 145.19, 159.40
(C), 190.46 (CO). MS (70 eV): m/z (%) = 222 (94, M+),
195 (28), 179 (12), 168 (100), 140 (28). IR (KBr,
cmꢀ1): m = 3436 (s), 1693 (s), 1613 (s), 1469 (m), 1452
~
m = 3435 (s), 1685 (s), 1618 (m), 1486 (s), 1461 (m),
1442 (w), 1428 (s), 1413 (w).
~
(m), 1431 (w), 1406 (s). Anal. Calcd for C12H11ClO2:
C, 64.37; H, 4.98; found: C, 64.80; H, 5.39.
4.6. 3-Bromo-2-vinylchroman-4-one (3e)
4.9. 7-Hydroxy-2-vinyl-chroman-4-one (3h)
Starting with 1e (0.22 g, 1.0 mmol), dissolved in 0.5 mL
of CH2Cl2, TMSOTf (0.29 g, 1.3 mmol), 5 mL of THF
and vinyl magnesium bromide (1.3 mL, 1 M), 3e was
obtained (130 mg, 51%) as a colourless solid (trans/
cis = 2:1). 1H NMR (CDCl3, 300 MHz): d 4.40 (d,
Starting with 7-trimethylsilyloxychromone 1h (0.47 g,
2.0 mmol), dissolved in 0.5 mL of CH2Cl2, TMSOTf
(0.58 g, 2.6 mmol), 10 mL of THF and vinyl magnesium
bromide (2.6 mL, 1 M), 3h was obtained as a colourless
solid (0.22 g, 60%). 1H NMR (CDCl3, 300 MHz): d 2.76
(d, 3J = 7 Hz, 2H, CH2), 4.96 (ddd, 3J = 7 Hz, 3J = 7 Hz,
3
3Janti = 2 Hz, 1H, CH), 4.56 (d, Jsyn = 6 Hz, 1H, CH),
3
4.80 (dd, Janti = 2 Hz, 3J = 6 Hz, 1H, CH), 5.11 (dd,
2
3
1H, CH), 5.34 (dd, J = 2 Hz, Jcis = 10 Hz, 1H, CH2),
3Jsyn = 6 Hz, 3J = 6 Hz, 1H, CH). 13C NMR (CDCl3,
75 MHz): dC 48.88, 50.02, 78.89, 81.91 (CH), 118.02
(CH), 118.17, 118.80 (C), 120.44, 121.25 (CH2),
122.16, 122.40, 127.95, 128.29, 132.06, 132.53, 136.74,
136.92 (CH), 159.18, 160.14 (C), 185.84, 184.99 (CO).
MS (70 eV): m/z (%) = 254 (24, M+), 173 (64), 145 (8),
129 (4), 120 (100). The exact molecular mass for
C11H9BrO2 m/z = 251.9786 2 ppm [M+] was deter-
mined by HRMS (EI, 70 eV). IR (KBr, cmꢀ1):
3
5.43 (dd, 2J = 2 Hz, Jtrans = 17 Hz, 1H, CH2), 6.01
3
3
(ddd, 3J = 7 Hz, Jcis = 10 Hz, Jtrans = 17 Hz, 1H,
CH), 6.51 (dd, 4J = 2 Hz, 1H, Ar-H), 6.52 (dd,
3J = 8 Hz, 1H, Ar-H), 7.83 (d, J = 8 Hz, 1H, Ar-H).
3
13C NMR (CDCl3, 75 MHz): dC 41.48 (CH2), 77.41,
102.43, 110.39 (CH), 113.56 (C), 117.33 (CH2), 128.22,
135.90 (CH), 162.48, 164.53 (C), 189.22 (CO). MS
(70 eV): m/e (%) = 190 (100, M+), 163 (32), 148 (39),
136 (98), 108 (88). The exact molecular mass for
C11H10O3 m/z = 190.0630 2 ppm [M+] was determined
~
m = 1693 (s), 1607 (s), 1579 (m), 1473 (s), 1463 (s),
1426 (w).
~
by HRMS (EI, 70 eV). IR (KBr): m = 3121 (s), 3062 (s),

U. Albrecht et al. / Bioorg. Med. Chem. 13 (2005) 1531–1536
1535
~
3040 (s), 2954 (s), 2854 (s), 2831 (s), 2771 (m), 2772 (m),
2619 (m), 1647 (s), 1600 (s), 1570 (s), 1491 (s), 1425 (m),
1401 (m).
m = 2971 (m), 2934 (w), 2880 (w), 1693 (s), 1653 (w),
1609 (s), 1578 (m), 1467 (s), 1404 (w). Anal. Calcd for
C11H12O2: C, 74.98; H, 6.86; found: C, 75.25; H, 6.76.
4.10. 7-Trimethylsilyloxychromone (1h)
4.13. (Z)-1-(2-Hydroxyphenyl)-penta-2,4-dien-1-one (4a)
Trimethylchlorosilane (1.96 g, 18 mmol) was added at
20 ꢁC to a THF solution of 7-hydroxychromone
(1.62 g, 10 mmol) and of NEt3 (1.52 g, 15 mmol). After
stirring for 36 h at 20 ꢁC the solution was concentrated
in vacuo, filtered and the solvent of the filtrate was re-
moved in vacuo to give 1h as a red solid (1.33 g, 57%).
1H NMR (CDCl3, 300 MHz): d 0.34 (s, 9H, OSiMe3),
2-Vinylchroman-4-one(0.09 g, 0.5 mmol) was added at
20 ꢁC to a THF solution (2 mL) of KOtBu (0.07 g,
0.6 mmol). After stirring for 5 min an aqueous solution
of NH4Cl (20 mL, 1 M) and ether (20 mL) were added.
The layers were separated, the aqueous layer was ex-
tracted with ether (2 · 20 mL). The combined organic
layers were dried (Na2SO4), filtered and the solvent
was removed in vacuo. The residue was purified by col-
umn chromatography (silica gel, ethyl acetate/hex-
ane = 1:50) to give 4a as a yellow liquid (0.03 g, 34%).
3
4
6.27 (d, J = 6 Hz, 1H, Ar-H), 6.83 (d, J = 2 Hz, Ar-
3
4
H), 6.89 (dd, J = 9 Hz, J = 2 Hz, 1H, Ar-H), 7.77 (d,
3J = 9 Hz, 1H, Ar-H). 13C NMR (CDCl3, 75 MHz): dC
0.09 (CH3), 107.51, 112.66, 118.88 (CH), 119.28 (C),
127.15, 154.93 (CH), 157.84, 160.20, 177.04 (C). MS
(70 eV): m/z (%) = 234 (54, M+), 219 (100). 201 (2),
3
1H NMR (CDCl3, 300 MHz): d 5.65 (d, Jcis = 10 Hz,
3
1H, CH2), 5.77 (d, Jtrans = 17 Hz, 1H, CH2), 6.61
3
3
3
(ddd, Jtrans = 17 Hz, Jcis = 10 Hz, Jcis = 8 Hz, 1H,
3
3
~
189 (6), 163 (2). IR (KBr): m = 3176 (m), 3170 (w),
CH), 6.91 (dd, Jtrans = 15 Hz, Jcis = 8 Hz, 1H, CH),
7.00 (dd, 4J = 2 Hz, 3J = 7 Hz, 1H, CH), 7.12 (d,
3Jtrans = 15 Hz, 1H, CH), 7.48 (dt, 4J = 2 Hz,
3J = 7 Hz, 2H, CH), 7.80 (dd, 4J = 2 Hz, 3J = 7 Hz,
1H, CH), 12.74 (s, 1H, OH). MS (70 eV): m/z (%) =
174 (100, M+), 147 (56), 131 (16), 121 (28), 93 (8).
The exact molecular mass for C11H10O2 m/z =
174.0681 2 ppm [M+] was determined by HRMS (EI,
1363 (m), 3099 (m), 3075 (m), 3045 (m), 2959 (m),
2823 (m), 2765 (m), 1642 (s), 1628 (s), 1594 (m), 1573
(s), 1505 (w), 1465 (w), 1454 (w), 1438 (m), 1409 (s).
Anal. Calcd for C12H14O3Si: C, 61.51; H, 6.02; found:
C, 61.48; H, 5.88.
4.11. 2-Phenylethynylchroman-4-one (3i)
70 eV). IR (KBr, cmꢀ1): m = 2962 (w), 2924 (w), 2342
~
(w), 1643 (s), 1620 (w), 1577 (s), 1487 (s), 1444 (m).
Starting with 1a (0.29 g, 2.0 mmol), dissolved in 0.5 mL
of CH2Cl2, TMSOTf (0.58 g, 2.6 mmol), 5 mL of THF
and lithium phenylacetylenide, 3i was obtained as white
solid (0.24 g, 50%). The lithio reagent was prepared by
addition of nBuLi (1.63 mL, 1.6 M) to a THF solution
of phenylacetylene (0.29 g, 2.6 mmol) at ꢀ78 ꢁC and
stirring of the solution for 1 h at 78 ꢁC. 1H NMR
(CDCl3, 300 MHz): d 3.08 (d, 3J = 7 Hz, 2H, CH2),
5.50 (t, 3J = 7 Hz, 1H), 7.06 (ddd, 3J = 7 Hz,
4J = 2 Hz, 2H, Ar-H), 7.30–7.34 (m, 3H, Ar-H), 7.40–
4.14. 1-(4-Benzyloxy-2-hydroxyphenyl)-penta-2,4-dien-1-
one (4b)
Starting with 1i (0.76 g, 3.0 mmol), dissolved in 0.5 mL
of CH2Cl2, TMSOTf (0.87 g, 3.9 mmol), 15 mL of
THF and vinyl magnesium bromide (3.9 mL, 1 M), 4b
1
was obtained as yellow solid (0.31 g, 36%). H NMR
(CDCl3, 300 MHz): d 5.10 (s, 2H, CH2), 5.60 (d,
3
4
7.44 (m, 2H, Ar-H), 7.51 (dt, J = 7 Hz, J = 2 Hz, 1H,
3Jcis = 10 Hz, 1H, CH2), 5.73 (3Jtrans = 17 Hz, 1H,
CH2), 6.51–6.66 (m, 3H, CH), 7.03 (d, Jtrans = 16 Hz,
3
4
3
Ar-H), 7.93 (dd, J = 7 Hz, J = 2 Hz, 1H, Ar-H). 13C
NMR (CDCl3, 75 MHz): dC 43.44 (CH2), 68.02 (CH),
84.47, 87.36 (C), 118.23 (CH), 121.06, 121.45 (C),
121.96 (CH), 126.94, 128.28, 129.06, 131.95, 136.20
(CH), 160.14 (C), 190.42 (CO). MS (70 eV): m/z
(%) = 248 (63, M+), 222 (100), 209 (35), 193 (34), 129
3
1H, CH), 7.31–7.51 (m, 6H, CH), 7.72 (d, Jcis = 10 Hz,
1H, CH). 13C NMR (CDCl3, 75 MHz): dC 70.20 (CH2),
102.02, 108,16 (CH), 114.12 (C), 124.51 (CH), 127.12
(CH2), 127.52, 128.29, 128.67, 131.25, 135.20, 144.36
(CH), 165.26, 166.51, 192.10 (C), 232.52 (CO). MS
(70 eV): m/e (%) = 280 (32, M+), 253 (4), 189 (4), 91
(98). IR (KBr, cmꢀ1): m = 3435 (s), 1693 (s), 1608 (s),
~
1576 (w), 1466 (s). Anal. Calcd for C17H12O2: C,
82.24; H, 4.87; found: C, 82.25; H, 5.36.
(100), 65 (6). IR (KBr, cmꢀ1): m = 3438 (s), 1637 (s),
~
1617 (s), 1576 (s), 1504 (m). Anal. Calcd for
C18H16O3: C, 77.12; H, 5.75; found: C, 77.43; H, 6.12.
4.12. 2-Ethylchroman-4-one (3j)
4.15. (Z)-1-(2-Hydroxyphenyl)-2-methylpenta-2,4-dien-1-
one (4c)
Starting with 1a (0.76 g, 3.0 mmol), dissolved in 0.5 mL
of CH2Cl2, TMSOTf (0.87 g, 3.9 mmol), 15 mL of THF
and ethyl magnesium bromide (3.9 mL, 1 M), 3j was ob-
Starting with 1j (0.16 g, 1.0 mmol), dissolved in 0.3 mL
of CH2Cl2, TMSOTf (0.29 g, 1.3 mmol), 4 mL of THF
and vinyl magnesium bromide (1.3 mL, 1 M), 4c was ob-
1
tained as a yellow oil (306 mg, 58%). H NMR (CDCl3,
300 MHz): d 1.08 (t, 3J = 7 Hz, 3H, CH3), 1.79 (dt,
3J = 7 Hz, 3J = 7 Hz, 1H, CH2), 1.88 (dt, 3J = 7 Hz,
3J = 7 Hz, 1H, CH2), 2.69 (d, 3J = 8 Hz, 2H, CH2),
4.38 (ddd, 3J = 8 Hz, 3J = 7 Hz, 3J = 7 Hz, 1H, CH),
6.99 (dt, 4J = 2 Hz, 3J = 7 Hz, 2H, CH), 7.47 (dt,
4J = 2 Hz, 3J = 7 Hz, 1H, CH), 7.87 (dd, 4J = 2 Hz,
3J = 7 Hz, 1H, CH). MS (70 eV): m/z (%) = 176 (M+,
8), 146 (4), 121 (14), 92 (6), 28 (100). IR (KBr):
1
tained as a yellow oil (0.06 g, 35%). H NMR (CDCl3,
300 MHz): d 2.10 (s, 3H, CH3), 5.51 (dd, 3Jtrans = 17 Hz,
3
3Jcis = 9 Hz, 2H, CH2), 6.54 (d, Jcis = 11 Hz, 1H, CH),
6.75 (ddd, Jtrans = 17 Hz, Jcis = 11 Hz, Jcis = 9 Hz,
3
3
3
4
3
1H, CH), 6.87 (dt, J = 1 Hz, J = 7 Hz, 1H, CH), 7.02
(dd, 4J = 1 Hz, 3J = 7 Hz, 1H, CH), 7.47 (dt,
4J = 1 Hz, 3J = 7 Hz, 1H, CH), 7.63 (dd, 4J = 1 Hz,

1536
U. Albrecht et al. / Bioorg. Med. Chem. 13 (2005) 1531–1536
3J = 7 Hz, 1H, CH), 11.74 (s, 1H, OH). MS (70 eV): m/e
the first row was pipetted out in a stepwise manner from
left to right up to the 11th row. Finally, 10 lL of the di-
luted substance was discarded from the 11th row. Each
and every well from the row 1–11 was finally filled with
100 lL diluted bacterial suspension.
(%) = 188 (M+, 97), 173 (35), 161 (100), 144 (23), 121
~
(82). IR (KBr): m = 3427 (s), 2927 (w), 1721 (m), 1620
(s), 1482 (m), 1446 (w). Anal. Calcd for C12H12O2: C,
76.57; H, 6.43; found: C, 76.43; H, 6.02.
4.16. Pharmacological screening
The wells 12A–12Dwere filled with 100 lL PBS and
100 mL bacterial suspension without test substance as
control wells. The wells 12E–12G were filled with
100 lL PBS and 100 lL bacterial suspension without
test substance as control wells. The well 12H was kept
empty for photometric blank. The plate was shaken
carefully and then incubated for 16 h at 35 ꢁC. After
incubation, the absorbance was measured at 620 nm in
a plate reader (anthos). The MIC corresponds to the
lowest concentration of the test compound that still
produces bacterial growth inhibition. It was determined
by spectrophotometry by measuring the turbidity of
inoculated liquid broth in the presence and absence of
the test compound. The highest concentration of the test
substance for the assay was 500 lg/mL and lowest
concentration was 0.0085 lg/mL unless otherwise
specified.
The bacterial cultures were obtained from the ATCC.
Isolates of MRSA (methicillin resistant S. aureus) were
obtained from the Universita¨tsklinikum Greifswald.
4.17. Assay for antimicrobial and antifungal activity
A modified disc diffusion method7,8 was used to deter-
mine the antimicrobial activity. A nutrient agar was
used for bacteria and a malt agar was used for Candida
maltosa. A sterile filter disc of 6 mm (B&Dresearch)
diameter impregnated with test compound was used
for the assay. The paper disc was placed on the agar
plate seeded with respective microorganisms. The plates
were kept in the refrigerator at 4 ꢁC for 4 h. Then the
plates were turned over to incubate overnight at 37 ꢁC
in an inverted position. In contrast, C. maltosa was incu-
bated at 28 ꢁC for 72 h. At the end of the incubation per-
iod the clear zones of inhibition around the paper disc
were measured. Negative control experiments were per-
formed by using paper discs loaded with equivalent vol-
ume of solvent and positive control experiments were
performed by use of an equivalent amount of OTC.
The concentration of the compound tested during the
experiments was 1000 nmol unless otherwise stated.
Acknowledgements
Financial support by the Deutsche Forschungsgemein-
schaft and by the state of Mecklenburg-Vorpommern
(Landesforschungsschwerpunkt ÔNeue Wirkstoffe und
ScreeningverfahrenÕ) is gratefully acknowledged.
References and notes
5. Determination of minimal inhibitory concentrations of
compounds by dilution method
1. Ro¨mpp Lexikon Naturstoffe; Fugmann, B., Lang-Fugmann,
S., Steglich, W., Eds.; Thieme: Stuttgart, 1997.
2. Krohn, K.; Michel, A.; Bahramsari, R.; Floerke, U.; Aust,
H. J.; Draeger, S.; Schulz, B.; Wray, V. Nat. Prod. Lett.
1996, 8, 43.
3. For other natural products, see: (a) Pari, K.; Rao, P. J.;
Subrahmanyam, B.; Rasthogi, J. N.; Devakumar, C.
Phytochemistry 1998, 49, 1385; for cavoxinone, see: (b)
Evidente, A. J. Nat. Prod. 1987, 50, 173.
5.1. Sample preparation
The compound (1 mg) was dissolved in 1 mL of DMSO
and serially diluted with nutrient agar medium to get the
final concentrations.
5.2. Culture of micro-organisms
4. For synthetic 2-vinylchroman-4-ones, see: (a) Karton, Y.;
Jiang, J.-l.; Ji, X.-d.; Melman, N.; Olah, M. E.; Stiles, G. L.;
Jacobson, K. A. J. Med. Chem. 1996, 39, 2293; (b) Ye, T.;
Garcia, C. F.; McKervey, M. A. J. Chem. Soc., Perkin
Trans. 1 1995, 1, 1373; (c) Gallois, E.; Defoin, A. Bull. Soc.
Chim. Belg. 1997, 106, 273; (d) De, M.; Majumdar, D. P.;
Kundu, N. G. J. Indian Chem. Soc. 1999, 76, 665. For the
antibacterial activity of 3-hydroxy-2(prop-10-enyl)chro-
mones, see: Puranik, R.; Rao, Y. J.; Krupadanam, G. L.
D. Ind. J. Chem. 2002, 41B, 868.
A column of 3 mL sterile broth was inoculated with
about the pinhead size of respective bacteria and
100 lL of the bacterial suspension was further inocu-
lated into 10 mL of sterile broth. The final inoculated
bacterial suspension was placed on an orbital shaker
(175 rpm) and incubated overnight at 25 ꢁC. For the
test, the bacterial suspension was diluted in the ratio
of 1:100.
5. German Patent application, DE 103 28 049.9, 20.06.2003.
6. For the generation of silyloxy-1-benzopyrylium triflates,
see: (a) Iwasaki, H.; Kume, T.; Yamamoto, Y.; Akiba,
K.-Y. Tetrahedron Lett. 1987, 6355; (b) Lee, Y.-G.;
Ishimaru, K.; Iwasaki, H.; Ohkata, K.; Akiba, K. J. Org.
Chem. 1991, 56, 2058; (c) Beifuss, U.; Ledderhose, S.
Synlett 1997, 313.
7. Bauer, A. W.; Kirby, W. M. M.; Sherris, J. C.; Turck, M.
Am. J. Clin. Pathol. 1966, 45, 493.
8. Wilkins, T. D.; Holdeman, J. J.; Abramson, I. J.; Moore,
W. E. C. Antimicrob. Agents Chemother. 1972, 1, 44.
5.3. Antibacterial assay
The minimal inhibitory concentration (MIC) was mea-
sured by the 10-fold serial broth dilution method. The
assay was carried out in a 96 well tray. The wells of the first
row of the tray, A1 to H1, were filled with 150 lL diluted
test substances in duplicate. From the second to 11th
row, A2 H2 to A11 H11, the wells were first filled with
100 lL of PBS. Then 10 lL of the test substance from