3-Phenyl-5-acyloxymethyl-2H,5H-furan-2-ones: Synthesis and biological activity of a novel group of potential antifungal drugs

Article abstract of DOI:10.1021/jm010155x

3-(Substituted phenyl)-5-acyloxymethyl-2H,5H-furan-2-ones related to the natural product (-)-incrustoporine were synthesized and their in vitro antifungal activity evaluated. The compounds with halogen substituents on the phenyl ring displayed much higher antifungal effect against Aspergillus fumigatus than selected representatives of azole antifungal drugs. In particular, the activity (1.34 μg/mL) of the most promising derivative, 3-(3,4-dichlorophenyl)-5-pivaloyloxymethyl-2H,5H-furan-2-one, was comparable to that of amphotericin B (0.5 μg/mL). Preliminary evaluation of the toxicity of the compound was carried out as well. Considering the size and properties of these molecules in comparison with those of amphotericin B, further development of this novel group of antifungals may lead to substances with better pharmacological profiles than that of the standard anti-Aspergillus drug.

Full text of DOI:10.1021/jm010155x

J . Med. Chem. 2001, 44, 2701-2706
2701
3-P h en yl-5-a cyloxym eth yl-2H,5H-fu r a n -2-on es: Syn th esis a n d Biologica l Activity
of a Novel Gr ou p of P oten tia l An tifu n ga l Dr u gs†
Milan Pour,*,‡ Marcel Sˇpula´k,‡ Vladim´ır Buchta,§ Petra Kubanova´,§ Marie Voprsˇalova´,| Vladim´ır Wso´l,
Helena Fa´kova´,‡ Petr Koudelka,‡ Hana Pourova´,‡ and Radan Schiller‡
Laboratory of Structure and Interactions of Biologically Active Molecules, Department of Inorganic and Organic
Chemistry, Faculty of Pharmacy, Charles University, Heyrovske´ho 1203, CZ-500 05 Hradec Kra´love´, Czech Republic,
Department of Biological and Medical Sciences, Faculty of Pharmacy, Charles University, Heyrovske´ho 1203,
CZ-500 05 Hradec Kra´love´, Czech Republic, Department of Pharmacology and Toxicology, Faculty of Pharmacy,
Charles University, Heyrovske´ho 1203, CZ-500 05 Hradec Kra´love´, Czech Republic, and Research Centre LN00B125,
Heyrovske´ho 1203, CZ-500 05 Hradec Kra´love´, Czech Republic
Received April 5, 2001
3-(Substituted phenyl)-5-acyloxymethyl-2H,5H-furan-2-ones related to the natural product (-)-
incrustoporine were synthesized and their in vitro antifungal activity evaluated. The compounds
with halogen substituents on the phenyl ring displayed much higher antifungal effect against
Aspergillus fumigatus than selected representatives of azole antifungal drugs. In particular,
the activity (1.34 µg/mL) of the most promising derivative, 3-(3,4-dichlorophenyl)-5-pivaloy-
loxymethyl-2H,5H-furan-2-one, was comparable to that of amphotericin B (0.5 µg/mL).
Preliminary evaluation of the toxicity of the compound was carried out as well. Considering
the size and properties of these molecules in comparison with those of amphotericin B, further
development of this novel group of antifungals may lead to substances with better pharma-
cological profiles than that of the standard anti-Aspergillus drug.
Clinically, candidiasis and aspergillosis account for
between 80% and 90% of systemic fungal infections in
immunocompromised patients. While there is a multiple
choice of drugs for the treatment of candidiasis, only
amphotericin B and itraconazole1 come into consider-
ation in the case of infections due to Aspergillus fumi-
gatus. Although the research toward a new azole
continues at an unabated pace, with examples such as
TAK-187,2 ER-30346,3 Sankyo’s amido alcohol,4 UR-
F igu r e 1.
9825,5 and most notably voriconazole6 and SCH-56592
(posaconazole)7 having been reported, the discovery and
development of new structural types of antifungal
compounds are no less desirable.
most potent 3-(3,4-dichlorophenyl)-5-methyl-2H,5H-fu-
ran-2-one exceeded that of ketoconazole against the
strain of Absidia corymbifera. Although it might seem
that this type of compounds could be a nonspecific class
of fungal inhibitors based on its Michael acceptor-like
structure, we detected virtually no in vitro activity8 in
the case of 5-methyl-3-(4-nitrophenyl)-2H,5H-furan-2-
one, which is a stronger Michael acceptor than the
3-(halophenyl) compounds. Herein we present the de-
sign, synthesis, and preliminary biological evaluation
of a novel group of potent antifungal compounds derived
from the substances described in our previous study.
We have recently published8 the synthesis and evalu-
ation of in vitro antifungal activity of a series of
5-methyl-3-phenyl-2H,5H-furan-2-ones based on a fun-
gal metabolite,9 (-)incrustoporine, as the lead structure
(Figure 1). Our results indicated that this class of
compounds is suitable for further development as
potential antimycotic agents, as some of the derivatives
displayed appreciable fungistatic effect, especially against
filamentous fungi. As regards structure-activity rela-
tionships (SARs), we found that the antifungal effect is
linked to the presence of the double bond conjugated
with the carbonyl group of the lactone ring and can be
increased by substituting the phenyl moiety at C(3) with
halogens, while it seems to be suppressed by electron-
donating substituents. In particular, the activity of the
Resu lts a n d Discu ssion
Bearing in mind that the desired biological activity
is supported by the substitution of the phenyl moiety
at C(3) with halogens, we shifted attention to the
substitution at C(5) of the furanone ring. With the
mechanism of the antifungal effect being unknown, we
assumed that while a certain degree of lipophilicity is
necessary for the compound to penetrate the fungal cell
wall, the presence of a hydrophilic moiety can play a
most vital role in binding to its biological target mol-
ecule. Thus, we designed a series of 5-hydroxymethyl
† Dedicated to Professor Karel Waisser on the occasion of his 65th
birthday.
* To whom correspondence should be addressed. Phone: +420-49-
5067277. Fax: +420-49-5210002. E-mail: pour@faf.cuni.cz.
‡ Laboratory of Structure and Interactions of Biologically Active
Molecules, Charles University.
§ Department of Biological and Medical Sciences, Charles University.
| Department of Pharmacology and Toxicology, Charles University.
Research Centre LN00B125.
10.1021/jm010155x CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/21/2001

2702 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 17
Pour et al.
Ta ble 1. Antifungal Activity of Compounds 1-4, 1a -c, 2a -c, 3a -c, and 4a -c
b
strain/MIC [µmol L-1
]
no. time,a
h
CA1c
CA2d
CPe
CK1f
CK2g
CTh
CGi
125
250
62.5
62.5
62.5
62.5
CLj
TBk
AFl
125
500
62.5
250
31.25 125
ACm
TMn
1
2
3
4
24
48
24
48
24
48
24
48
15.63
62.5
62.5
31.25
62.5
250
250
500
250
500
500
1000
250
500
62.5
125
250
250
1000
62.5
125
125
250
1000
125
250
250
500
500
31.25
125
125
250
250
1000
250
250
500
1000
500
31.25 15.63
62.5
125
125
62.5
15.63
15.63
15.63
15.63
15.63
15.63
250
500
>1000
31.25 250
62.5 250
31.25 250
62.5 250
250
>1000
>1000
>1000
1000
125
500
125
62.5
125
500
250
250
500
500
500
250
125
125
1000
500
1a
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
4c
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
1.95 31.25
62.5
>125
31.25
62.5
31.25
62.5
62.5
125
62.5
62.5
31.25
62.5
62.5
125
62.5
125
3.91
7.81
3.91
3.91
3.91
7.81
15.63
15.63
7.81
7.81
7.81
15.63
7.81
15.63
3.91
7.81
7.81
7.81
31.25
125
31.25
62.5
125
62.5
125
31.25
>125
>125
31.25
125
3.91
31.25
7.81
31.25
7.81
15.63
7.81
7.81
7.81
7.81
0.98
0.98
0.98
0.98
0.24
0.49
1.95
3.91
1.95
1.95
1.95
1.95
1.95
3.91
1.95
1.95
1.95
3.91
15.63
<0.98
15.63
0.98
15.63
0.12
1.95
0.49
3.91
0.49
1.95
1.95
3.91
0.98
3.91
e0.98
3.91
1.95
3.91
e0.98
1.95
0.49
1.95
62.5
31.25
31.25
31.25
31.25
1.95
3.91
3.91
3.91
1.95
1.95
7.81
7.81
3.91
7.81
3.91
7.81
3.91
7.81
1.95
3.91
1.95
7.81
62.5
62.5
62.5
62.5
31.25
31.25
31.25
31.25
0.98
0.98
0.98
0.98
0.49
0.98
1.95
1.95
e0.98
0.98
e0.98
e0.98
1.95
1.95
0.98
62.5
62.5
31.25
62.5
1.95
3.91
3.91
7.81
3.91
7.81
15.63
31.25
7.81
15.63
7.81
15.63
7.81
15.63
7.81
15.63
7.81
7.81
62.5
31.25
31.25
1.95
3.91
1.95
1.95
1.95
3.91
7.81
15.63
3.91
7.81
3.91
7.81
3.91
7.81
1.95
3.91
3.91
7.81
62.5
62.5
62.5
31.25
62.5
1.95
3.91
3.91
7.81
3.91
3.91
7.81
31.25
7.81
7.81
7.81
15.63
7.81
15.63
7.81
7.81
3.91
15.63
31.25 125
3.91
1.95
0.98
3.91
0.98
7.81
1.95
3.91
1.95
3.91
1.95
3.91
e0.98
3.91
0.98
3.91
0.98
3.91
0.98
3.91
15.63
7.81
3.91
7.81
7.81
31.25
7.81
15.63
3.91
7.81
7.81
7.81
7.81
15.63
3.91
7.81
3.91
7.81
7.81
1.95
7.81
1.95
7.81
7.81
15.63
3.91
15.63
3.91
15.63
3.91
15.63
3.91
7.81
7.81
7.81
31.25
15.63
15.63
7.81
15.63
3.91
15.63
3.91
7.81
7.81
15.63
7.81
15.63
7.81
15.63
7.81
1.95
1.95
1.95
15.63
a
b
72 and 120 h for Trichophyton mentagrophytes 445. Defined as 80% inhibition of the growth of control. c C. albicans ATCC44859.
C. albicans ATCC90028. e C. parapsilosis ATCC22019. f C. krusei ATCC 6258. C. krusei E28. C. tropicalis 156. C. glabrata 20/I.j C.
lusitaniae 2446/I. Trichosporon beigelii 1188. Aspergillus fumigatus 231. Absidia corymbifera 272. Trichophyton mentagrophytes
d
g
h
i
k
l
m
n
445.
Sch em e 1
corresponding methyl ester, which was enolized with
LDA. The enolate was subsequently treated with allyl
bromide and the ester group removed by hydrolysis. The
resultant 2-(substituted phenyl)pent-4-enoic acid was
subjected to epoxidation with MCPBA. Under the reac-
tion conditions (MCPBA, CHCl3, reflux for several
hours), the carboxylic function of the initially formed
epoxy acid acted as an internal nucleophile, opening the
epoxide ring with the formation of a mixture of cis and
trans 3-(substituted phenyl)-5-hydroxymethylfuran-2-
ones.
To introduce the double bond, the hydroxy group was
protected as a TBS ether, the mixture of the protected
diastereomeric furanones was enolized with LDA, and
the enolate was quenched with PhSeCl. The intermedi-
ate 3-phenylselenenyl derivative was, because of its
limited stability, oxidized without delay by MCPBA to
afford the corresponding selenoxide, which immediately
underwent a spontaneous syn elimination introducing
the double bond into the desired location. Finally, the
acidic removal of the silyl group furnished the target
compound. With a view to evaluating SARs on a
preliminary basis, we synthesized the p-methoxy de-
rivative 1 and three halogenated compounds 2, 3, and
4.
derivatives (Figure 1) because they were easily derived
from the epoxidation of 2-phenylpent-4-enoic acids,
which had served as intermediates in our synthesis of
the 5-methyl series of compounds.
The preparation of the target compounds is outlined
in general terms in Scheme 1. A commercially available
substituted phenylacetic acid was converted into the
The compounds were evaluated for their in vitro
antifungal activity against a set of human pathogenic
fungi including the representatives of both yeast and
filamentous strains using the microdilution format of
the NCCLS M27-A guidelines.10 The results are sum-

3-Phenyl-5-acyloxymethyl-2H,5H-furan-2-ones
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 17 2703
Ta ble 2. Antifungal Activity of Compounds 2c, (+)2c, and (-)2c Compared to Drug Standards
b
strain/MIC [µg mL-1
]
no.
time,a
h
CA1c
CA2d
CPe
CK1f
CK2g
CTh
CGi
CLj
TBk
AFl
1.34
ACm
TMn
(+)2c
24
48
24
48
24
48
24
48
24
48
24
48
0.67
1.34
0.67
1.34
0.17
0.67
0.06
0.06
1
1.34
2.68
1.34
2.68
0.67
0.67
e0.03
e0.03
2
2.68
5.36
2.68
5.36
1.34
1.34
0.06
0.06
2
5.36
10.73
2.68
10.73
2.67
10.73
1.04
1.04
2
5.36
10.73
2.68
5.36
1.34
2.68
2.08
2.08
2
5.36
0.67
1.34
0.67
1.34
0.17
0.34
0.13
0.26
2
1.34
2.68
1.34
2.68
0.67
1.34
0.03
0.06
2
2.68
5.36
1.34
5.36
0.67
2.68
0.06
0.06
0.25
0.25
1
10.73
10.73
5.36
21.45
2.68
5.36
16.61
16.61
2
0.34
0.67
0.34
0.34
0.08
1.17
0.52
1.04
1
10.73
2.68
5.36
1.34
2.68
8.31
8.31
2
2.68
1.34
2.68
0.67
1.34
8.31
8.31
0.25
0.5
(-)2c
2c
KETo
AMPp
FLUq
1
0.25
0.5
2
0.25
1
2
2
4
4
32
64
4
16
32
2
0.5
>128
2
4
16
2
1
1
2
1
8
16
>128
>128
>128
>128
2
a
b
72 and 120 h for Trichophyton mentagrophytes 445. Defined as 80% inhibition of the growth of control. c C. albicans ATCC44859.
C. albicans ATCC90028. e C. parapsilosis ATCC22019. f C. krusei ATCC 6258. C. krusei E28. C. tropicalis 156. C. glabrata 20/I.j C.
d
g
h
i
k
l
m
n
lusitaniae 2446/I. Trichosporon beigelii 1188. Aspergillus fumigatus 231. Absidia corymbifera 272. Trichophyton mentagrophytes
445. o Ketoconazole. Amphotericin B. Fluconazole.
p
q
marized in Table 1. In general, the antifungal effect
(expressed as the minimum inhibitory concentration
(MIC) in µmol/L) of the 5-hydroxymethyl derivatives is
moderate to low, and there appear to be no significant
differences between the activity of the p-methoxyphenyl
derivative 1 and the three halophenyl compounds 2, 3
and 4.
The next step was increasing lipophilicity of the
alcohols by conversion to esters. The compounds were
treated with several acyl chlorides under carefully
controlled conditions in CH2Cl2 with 1.5 equiv of pyri-
dine at 0 °C to yield the corresponding esters 1a -c, 2a -
c, 3a -c, and 4a -c (Scheme 2).
representative of azole antifungals, 2c possesses com-
parable activity against Candida krusei and Candida
glabrata and is superior to the drug against Candida
tropicalis. Most importantly, compound 2c (as well as
all other esters) exhibits a remarkable in vitro antifun-
gal effect against Aspergillus fumigatus (1.34 µg/mL),
which is a clear indication that this type of substances
is worthy of further development.
Because all compounds were applied in the form of
racemic mixtures, we separated alcohol 2 into (+) and
(-) enantiomers on an ID Chiralcel OD-R column with
a cellulose derivative as the chiral selector. Both isomers
were converted to the corresponding pivaloyl esters (+)-
2c and (-)2c and the compounds subjected to evalua-
tion of antifungal activity (Table 2). Surprisingly, there
are no significant differences in MICs of the optical
isomers, suggesting that there is probably no relation-
ship between chirality at C(5) and the antifungal effect.
The racemic mixture also seems to be more potent than
either enantiomer.
Sch em e 2
To obtain an idea of the toxic properties of the new
compounds, we carried out a preliminary assessment
of the toxicity of the most promising ester 2c. The value
of LD50 (mice, intraperitoneal administration) was
determined to be 54 mg/kg with the compound having
been very well absorbed through the peritoneum.
In conclusion, we have discovered a novel group of
potential antifungal compounds that are comparable to
amphotericin B as regards their in vitro efficacy against
Aspergillus fumigatus. Unlike amphotericin B, 5-acyl-
oxymethyl-3-aryl-2H,5H-furan-2-ones are relatively li-
pophilic, small, rigid molecules of low structural com-
plexity, which renders them possible targets for further
investigation and development as potential antimy-
cotics, the pharmacological profile of which may be
better than that of this standard antifungal drug. A full
account of our work, including further biological studies,
will be published in due course.
As shown in Table 1, this subtle change in structure
had a profound effect on in vitro antifungal activity.
MICs of all esters are generally much lower than those
of the parent hydroxy compounds, which seems to
indicate that one of the reasons for low activity of the
parent hydroxy compounds could be the hydrophilic
character of the primary OH group leading to a de-
creased ability of the substances to penetrate the fungal
cell wall. In the case of esters derived from 3-(halophen-
yl)-2H,5H-furan-2-ones, the decrease of MIC is quite
dramatic, which supports the previously made conclu-
sion8 that halogenation of the phenyl ring at C(3) of the
lactone moiety is important for the antifungal effect.
MIC profiles show that all esters have a broad spectrum
of activity displaying a fungistatic effect against both
yeast and filamentous strains.
Exp er im en ta l Section
Gen er a l P r oced u r es. THF was distilled from benzophe-
none ketyl and diisopropylamine from CaH2. Substituted
phenylacetic acids were obtained from Sigma-Aldrich and used
as received. All anhydrous reactions were performed in flame-
dried Schlenk tubes under Ar atmosphere. Analytical thin-
layer chromatography (TLC) was conducted on E. Merck TLC
plates (silica gel 60 F254, aluminum back). Silica gel 60 (230-
400 mesh) for column chromatography was purchased from
A comparison of one of the most promising com-
pounds, ester 2c, to selected drug standards in µg/mL
is presented in Table 2. Compared to ketoconazole, a

2704 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 17
Pour et al.
E. Merck. Melting points were determined on a Kofler block
chromatography (petroleum ether/ether 95:5) afforded the pure
product (yields in the range 80-90%).
1
and are uncorrected. H and 13C NMR spectra were recorded
for CDCl3 solutions at ambient temperature on a Varian
Mercury-Vx BB 300 spectrometer operating at 300 MHz for
1H. Chemical shifts were recorded as δ values in parts per
million (ppm) and were indirectly referenced to tetramethyl-
silane (TMS) via the solvent signal (7.26 for 1H, 77.0 for 13C
in CDCl3). All assignments were made on the basis of gCOSY,
gHSQC, and gHMBC experiments. Infrared spectra were
recorded in CDCl3 on a Nicolet Impact 400 spectrophotometer.
Low-resolution mass spectra were measured on a Magnum
Finnigan Mat apparatus.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e P r ecu r -
sor 5-Hyd r oxym eth yl-3-(su bstitu ted p h en yl)tetr a h yd r o-
fu r a n -2-on es. The methyl ester of a 2-phenylpent-4-enoic acid
(8 mmol) was dissolved in a mixture of MeOH/H2O 3:1 (40 mL),
and LiOH (10.4 mmol) was added to the solution. After 20 h
at ambient temperature, the reaction mixture was concen-
trated in vacuo, diluted with H2O, and acidified with concen-
trated HCl to pH 1. The mixture was extracted with ethyl
acetate (3×), the combined extracts dried over Na2SO4, and
the solvent evaporated to afford the corresponding acid.
A sample of 57% MCPBA (8.8 mmol) was added to a solution
of the 2-phenylpent-4-enoic acid (8 mmol) in CHCl3 (20 mL),
and the mixture was heated under reflux for 3 h. The solution
was then diluted with ethyl acetate and washed with 5% Na2-
CO3 (3×). The organic phase was dried over Na2SO4, and the
solvent was removed. Column chromatography (petroleum
ether/ethyl acetate 9:1) afforded the 3,5-disubstituted tetrahy-
drofuran-2-one as a mixture of trans and cis isomers (yields
are about 80%).
Gen er a l P r oced u r e for th e P r ep a r a tion of th e Un sa t-
u r a ted La cton es 1-4. The 3,5-disubstituted tetrahydrofuran-
2-one (6.4 mmol) was dissolved in dry DMF (10 mL), and
imidazole (7.7 mmol) and TBDMSCl (7.1 mmol) were added
to this solution. After 12 h at ambient temperature, the
reaction mixture was diluted with ethyl acetate (30 mL),
washed with 5% HCl, dried over Na2SO4, and concentrated in
vacuo. The TBS-protected tetrahydrofuran-2-one was purified
by column chromatography (petroleum ether). The yields of
the compounds were in the range 95-97%.
Butyllithium (6.6 mmol) was added to a solution of diiso-
propylamine (6.3 mmol) in dry THF (10 mL) at 0 °C under
argon. After 10 min at 0 °C, the LDA solution was cooled to
-60 °C, and a solution of the protected tetrahydrofuran-2-one
(6 mmol) in THF (2 mL) was added. The reaction temperature
was maintained at -60 °C for 30 min, and a solution of
phenylselenenyl chloride (9 mmol) in THF (5 mL) was added.
The resultant mixture was slowly allowed to warm to room
temperature (over 2 h), diluted with ethyl acetate (50 mL),
washed with saturated aqueous NH4Cl, dried over Na2SO4,
and concentrated in vacuo. The crude phenylselenenyl deriva-
tive was rapidly purified by column chromatography (petro-
leum ether/ether 98:2) and was dissolved in CHCl3 (10 mL),
and MCPBA (9 mmol) was added to the solution at 0 °C. The
reaction mixture was then stirred for 2 h at ambient temper-
ature. A further portion of CHCl3 (10 mL) was added along
with 5% aqueous Na2CO3 (20 mL). The layers were separated,
the organic phase was washed with 5% aqueous Na2CO3 (20
mL) and dried over Na2SO4, and the solvent was evaporated.
The TBS-protected product was purified by column chroma-
tography (petroleum ether/ether 9:1); TBS-protected com-
pounds 1-4 were obtained with yields in the range 50-60%.
The TBS-protected compound (3 mmol) was dissolved in a
mixture of AcOH/H2O/THF 3:1:1 (10 mL), and the solution was
maintained at 40 °C for 20 h. The reaction mixture was then
diluted with ethyl acetate (20 mL), washed with brine, dried
over Na2SO4, and concentrated in vacuo. Purification by
column chromatography (petroleum ether/ethyl acetate 8:2)
afforded the pure product (yields of compounds 1-4 were in
the range 95-97%).
In Vitr o Biologica l Stu d ies. In vitro antifungal activities
of the compounds, ketoconazole (J anssen-Cilag), fluconazole
(Pfizer), and amphotericin B (Sigma-Aldrich), were evaluated
on a panel of four ATCC (Candida albicans ATCC 44859, C.
albicans ATCC 90028, Candida parapsilosis ATCC 22019,
Candida krusei ATCC 6258) and eight clinical isolates of
yeasts (C. krusei E28, Candida tropicalis 156, Candida gla-
brata 20/I, Candida lusitaniae 2446/I, Trichosporon beigelii
1188) and filamentous fungi (Aspergillus fumigatus 231,
Absidia corymbifera 272, Trichophyton mentagrophytes 445)
from the collection of fungal strains deposited at the Depart-
ment of Biological and Medical Sciences, Faculty of Pharmacy,
Charles University, Hradec Kra´love´, Czech Republic. Three
of the above ATCC strains (C. albicans ATCC 90028, Candida
parapsilosis ATCC 22019, Candida krusei ATCC 6258) also
served as the quality control strains. All the isolates were
maintained on Sabouraud dextrose agar prior to being tested.
Minimum inhibitory concentrations (MICs) were determined
by the microdilution format of the NCCLS M27-A guidelines.10
Dimethyl sulfoxide (100%) served as a diluent for all com-
pounds; the final concentration did not exceed 2%. RPMI 1640
(Sevapharma, Prague) medium supplemented with L-glutamine
and buffered with 0.165 M morpholinepropanesulfonic acid
(Serva) to pH 7.0 by 10 N NaOH was used as the test medium.
The wells of the microdilution tray contained 100 µL of the
RPMI 1640 medium with 2-fold serial dilutions of the com-
pounds (1000-0.24 µmol/L for the new compounds) and 100
µL of inoculum suspension. Fungal inoculum in RPMI 1640
was prepared to give a final concentration of 5 × 103 ( 0.2 cfu
mL-1. The trays were incubated at 35 °C, and MICs were read
visually for filamentous fungi and photometrically for yeasts
as an optical density (OD) at 540 nm after 24 and 48 h. The
MIC values for the dermatophytic strain (T. mentagrophytes)
were determined after 72 and 120 h. The MICs were defined
as 80% inhibition of the growth of control. MICs were
determined twice and in duplicate, with the exception of 2c,
the activity of which was evaluated in five independent
measurements. The deviations from the usually obtained
values given in Tables 1 and 2 were no higher than the nearest
concentration value up and down the dilution scale.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e Meth yl
Ester s of 2-P h en ylp en t-4-en oic Acid s. A substituted phen-
ylacetic acid (10 mmol) dissolved in methanol saturated with
hydrogen chloride (100 mL) was heated under reflux for 3 h.
Methanol was removed in vacuo, and the residue was redis-
solved in ethyl acetate. The solution was washed with 5% Na2-
CO3 and dried over Na2SO4, and the solvent was evaporated
to give the corresponding methyl ester in a quantitative yield.
Butyllithium (11.0 mmol) was added to a solution of diiso-
propylamine (10.5 mmol) in dry THF (50 mL) at 0 °C under
argon. After 10 min at 0 °C, the LDA solution was cooled to
-60 °C, and a solution of the methyl phenylacetate (10 mmol)
in THF (5 mL) was added. The reaction temperature was
maintained at -60 °C for 30 min, and allyl bromide (10.5
mmol) was subsequently added dropwise. The reaction mixture
was slowly allowed to warm to room temperature (over 1 h)
in order to drive the reaction to completion. The solution was
then diluted with ethyl acetate (100 mL), washed with
saturated aqueous NH4Cl, dried over Na2SO4, and concen-
trated in vacuo to yield the crude methyl ester of the corre-
sponding 2-phenylpent-4-enoic acid. Purification by column
Gen er a l P r oced u r e for th e P r ep a r a tion of th e Ester s
1a -c, 2a -c, 3a -c, a n d 4a -c. Pyridine (1.5 mmol) and acyl
chloride (1.5 mmol) were added dropwise to a solution (0 °C)
of the alcohol (1-4) (1 mmol) in dry CH2Cl2 at 0 °C. The
reaction mixture was maintained at 0 °C for 20 h and then
diluted with ethyl acetate (20 mL), washed with brine, dried
over Na2SO4, and concentrated in vacuo. The resultant ester
was purified by column chromatography (petroleum ether/
ether 9:1). The yields of the esters were in the range 80-90%.
3-(4-Meth oxyp h en yl)-5-h yd r oxym eth yl-2H,5H-fu r a n -2-
on e (1). White crystals, mp 116-117 °C; 1H NMR (300 MHz,
CDCl3) δ 7.85-7.78 (2H, m, AA′BB′), 7.42 (1H, d, J ) 1.9 Hz,
H4), 6.95-6.89 (2H, m, AA′BB′), 5.13 (1H, ddd, J 1 ) 1.9 Hz,

3-Phenyl-5-acyloxymethyl-2H,5H-furan-2-ones
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 17 2705
J 2 ) 3.8 Hz, J 3 ) 5.5 Hz, H5), 4.05-3.96 (1H, m, -CH2O-),
3.85-3.75 (1H, m overlapped, -CH2O-), 3.83 (3H, s over-
lapped, -OCH3); 13C NMR (75 MHz, CDCl3) δ 171.94, 160.51,
142.24, 132.37, 128.45, 121.83, 114.02, 81.13, 63.10, 55.31; IR
(CDCl3) νmax 1256, 1308, 1465, 1512, 1608, 1756, 2936, 2959
cm-1; LRMS 219(M•+ - H, 1), 202(100), 187(1), 171(9), 159(3),
146(25), 132(32), 131(15), 115(9), 103(12), 89(15), 77(8), 63-
(14), 51(8); Anal. (C12H12O4) C, H.
3.9 Hz, J 3 ) 5.0 Hz, H5), 4.68 (1H, dd, J 1 ) 3.9 Hz, J 2 ) 12.0
Hz, -CH2O-), 4.61 (1H, dd, J 1 ) 5.0 Hz, J 2 ) 12.0 Hz,
-CH2O-); 13C NMR (75 MHz, CDCl3) δ 170.21, 165.24, 144.51,
140.22, 134.10, 133.15, 131.54, 131.42, 131.07, 130.77, 128.97,
128.91, 127.30, 126.23, 78.27, 63.36; IR (CDCl3) νmax 1269,
1335, 1403, 1472, 1489, 1596, 1725, 1768, 2927 cm-1; LRMS
392(M•+ - 6H, 7), 378(19), 362(2), 315(10), 285(1), 255(5), 242-
(71), 240(100), 207(38), 205(98), 184(12), 170(61), 149(60), 135-
(27), 113(9), 99(22), 87(11), 74(25), 61(13), 50(22); Anal.
(C18H11Cl3O4) C, H.
3-(3,4-Dich lor oph en yl)-5-acetyloxym eth yl-2H,5H-fu r an -
2-on e (2b). White crystals, mp 83-85 °C; 1H NMR (300 MHz,
CDCl3) δ 7.99 (1H, d, J ) 2.1 Hz, Ar), 7.71 (1H, dd, J 1 ) 2.1
Hz, J 2 ) 8.4 Hz, Ar), 7.57 (1H, d, J ) 1.9 Hz, H4), 7.49 (1H, d,
J ) 8.4 Hz, Ar), 5.26 (1H, td, J 1 ) 1.9 Hz, J 2 ) 4.6 Hz, H5),
4.42 (1H, dd, J 1 ) 4.6 Hz, J 2 ) 12.1 Hz, -CH2O-), 4.37 (1H,
dd, J 1 ) 4.6 Hz, J 2 ) 12.1 Hz, -CH2O-), 2.06 (3H, s, -CH3);
13C NMR (75 MHz, CDCl3) δ 170.53, 170.23, 144.73, 133.99,
133.11, 131.13, 130.73, 128.88, 128.79, 126.24, 78.13, 62.73,
20.58; IR (CDCl3) νmax 1336, 1367, 1384, 1472, 1553, 1747,
1765, 2928, 2958 cm-1; LRMS 299(M•+ - 2H, 1), 285(1), 267-
(1), 242(63), 240(100), 205(55), 184(7), 170(25), 149(31), 135-
3-(4-Met h oxyp h en yl)-5-(4-ch lor ob en zoyloxym et h yl)-
2H,5H-fu r a n -2-on e (1a ). White crystals, mp 150-152 °C; 1H
NMR (300 MHz, CDCl3) δ 7.96-7.90 (2H, m, AA′BB′), 7.83-
7.77 (2H, m, AA′BB′), 7.43 (1H, d, J ) 1.9 Hz, H4), 7.42-7.37
(2H, m, AA′BB′), 6.96-6.90 (2H, m, AA′BB′), 5.35 (1H, ddd,
J 1 ) 1.9 Hz, J 2 ) 3.7 Hz, J 3 ) 5.5 Hz, H5), 4.68 (1H, dd, J 1
)
3.7 Hz, J 2 ) 12.1 Hz, -CH2O-), 4.54 (1H, dd, J 1 ) 5.5 Hz, J 2
) 12.1 Hz, -CH2O-), 3.83 (3H, s, -OCH3); 13C NMR (75 MHz,
CDCl3) δ 171.26, 165.27, 160.72, 140.74, 140.01, 132.90, 131.10,
128.89, 128.53, 127.54, 121.53, 114.11, 78.04, 63.86, 55.32; IR
(CDCl3) νmax 1270, 1307, 1403, 1489, 1512, 1596, 1608, 1724,
1766, 2937, 2959 cm-1; LRMS 362(M•+ + 3H, 1), 315(3), 255-
(1), 213(1), 202(100), 187(1), 175(11), 171(18), 159(4), 146(58),
132(68), 117(19), 115(18), 103(24), 89(32), 77(13), 63(27), 51-
(13); Anal. (C19H15ClO5) C, H.
(8), 113(5), 99(12), 86(6), 74(12), 62(8), 50(10); Anal. (C13H10
Cl2O4) C, H.
-
3-(4-Meth oxyp h en yl)-5-a cetyloxym eth yl-2H,5H-fu r a n -
2-on e (1b). White crystals, mp 59-60 °C; 1H NMR (300 MHz
CDCl3) δ 7.85-7.79 (2H, m, AA′BB′), 7.37 (1H, d, J ) 1.9 Hz,
H4), 6.96-6.91 (2H, m, AA′BB′), 5.22 (1H, ddd, J 1 ) 1.9 Hz,
3-(3,4-Dich lor op h en yl)-5-p iva loyloxym eth yl-2H,5H-fu -
1
r a n -2-on e (2c). White crystals, mp 89-90 °C; H NMR (300
MHz, CDCl3) δ 7.97 (1H, d, J ) 2.1 Hz, Ar), 7.70 (1H, dd, J 1
) 2.1 Hz, J 2 ) 8.5 Hz, Ar), 7.53 (1H, d, J ) 1.9 Hz, H4), 7.49
(1H, d, J ) 8.5 Hz, Ar), 5.26 (1H, td, J 1 ) 1.9 Hz, J 2 ) 3.8 Hz,
H5), 4.51 (1H, dd, J 1 ) 3.8 Hz, J 2 ) 12.0 Hz, -CH2O-), 4.40
(1H, dd, J 1 ) 3.8 Hz, J 2 ) 12.0 Hz, -CH2O-), 1.12 (9H, s,
tBu); 13C NMR (75 MHz, CDCl3) δ 178.14, 170.31, 144.84,
133.97, 133.16, 131.03, 130.77, 128.86, 128.82, 126.21, 78.56,
61.92, 38.98 26.99; IR (CDCl3) νmax 1281, 1367, 1335, 1399,
1472, 1479, 1731, 1768, 2755, 2929, 2959, 2973 cm-1; LRMS
342(M•+ - H, 1), 327(2), 315(8), 285(1), 253(4), 242(76), 240-
(100), 205(91), 184(12), 170(54), 149(52), 135(13), 114(8), 99-
(19), 85(9), 74(23), 62(12), 50(20); Anal. (C16H16Cl2O4) C, H.
(+)3-(3,4-Dich lor op h en yl)-5-p iva loyloxym eth yl-2H,5H-
fu r a n -2-on e ((+)2c). [R]D +12.8° (c 0.7, CHCl3); all other data
are identical with those of the racemate.
J 2 ) 3.9 Hz, J 3 ) 5.5 Hz, H5), 4.40 (1H, dd, J 1 ) 3.9 Hz, J 2
)
12.0 Hz, -CH2O-), 4.32 (1H, dd, J 1 ) 5.5 Hz, J 2 ) 12.0 Hz,
-CH2O-), 3.84 (3H, s, -OCH3), 2.06 (3H, s, -CH3); 13C NMR
(75 MHz, CDCl3) δ 171.25, 170.62, 160.68, 140.92, 132.61,
128.51, 121.60, 114.09, 77.94, 63.22, 55.32, 20.62; IR (CDCl3)
νmax 1256, 1307, 1367, 1465, 1512, 1609, 1747, 1758, 2840,
2937, 2959 cm-1; LRMS 263(M•+ + H, 1), 249(1), 202(100), 185-
(1), 171(7), 159(2), 146(18), 132(16), 131(10), 117(6), 115(7),
103(9), 89(9), 77(3), 63(8), 51(4); Anal. (C14H14O5) C, H.
3-(4-Meth oxyph en yl)-5-pivaloyloxym eth yl-2H,5H-fu r an -
2-on e (1c). White crystals, mp 92-94 °C; 1H NMR (300 MHz,
CDCl3) δ 7.82-7.77 (2H, m, AA′BB′), 7.34 (1H, d, J ) 1.9 Hz,
H4), 6.95-6.90 (2H, m, AA′BB′), 5.21 (1H, ddd, J 1 ) 1.9 Hz,
J 2 ) 3.6 Hz, J 3 ) 4.4 Hz, H5), 4.47 (1H, dd, J 1 ) 4.4 Hz, J 2
)
12.0 Hz, -CH2O-), 4.38 (1H, dd, J 1 ) 3.6 Hz, J 2 ) 12.0 Hz,
-CH2O-), 3.83 (3H, s, -OCH3), 1.13 (9H, s, tBu); 13C NMR
(75 MHz, CDCl3) δ 178.14, 171.36, 160.60, 141.14, 132.52,
128.47, 121.64, 114.07, 78.34, 62.34, 55.29, 38.85, 27.00; IR
(CDCl3) νmax 1257, 1281, 1463, 1480, 1512, 1609, 1729, 1766,
2937, 2973 cm-1; LRMS 303(M•+ - H, 1), 255(1), 238(1), 213-
(1), 202(100), 187(1), 171(9), 159(2), 146(28), 132(33), 117(10),
115(8), 103(12), 89(15), 77(5), 63(12), 50(7); Anal. (C17H20O5)
C, H.
(-)3-(3,4-Dich lor op h en yl)-5-p iva loyloxym eth yl-2H,5H-
fu r a n -2-on e ((-)2c). [R]D -12.2° (c 0.3, CHCl3); all other data
are identical with those of the racemate.
3-(3-Ch lor op h en yl)-5-h yd r oxym et h yl-2H ,5H -fu r a n -2-
on e (3). White crystals, mp 75-77 °C; 1H NMR (300 MHz,
CDCl3) δ 7.85-7.83 (1H, m, Ar), 7.76-7.72 (1H, m, Ar), 7.61
(1H, d, J ) 1.9 Hz, H4), 7.36-7.33 (2H, m, Ar), 5.16 (1H, ddd,
J 1 ) 1.9 Hz, J 2 ) 3.8 Hz, J 3 ) 4.9 Hz, H5), 4.04 (1H, dd, J 1
)
3.8 Hz, J 2 ) 12.2 Hz, -CH2O-), 3.84 (1H, dd, J 1 ) 4.9 Hz, J 2
) 12.2 Hz -CH2O-); 13C NMR (75 MHz, CDCl3) δ 171.30,
146.02, 134.63, 131.83, 130.84, 129.93, 129.54, 127.09, 125.16,
81.31, 62.62; IR (CDCl3) νmax 1329, 1419, 1476, 1568, 1595,
1762, 2933, 3604 cm-1; LRMS 225(M•+, 1), 208(32), 206(100),
189(2), 171(46), 150(4), 133(13), 126(2), 115(30), 101(8), 87(4),
75(7), 63(5), 50(6); Anal. (C11H9ClO3) C, H.
3-(3,4-Dich lor op h en yl)-5-h yd r oxym eth yl-2H,5H-fu r a n -
2-on e (2). White crystals, mp 102-104 °C; 1H NMR (300 MHz,
CDCl3) δ 7.98 (1H, d, J ) 2.2 Hz, Ar), 7.71 (1H, dd, J 1 ) 2.2
Hz, J 2 ) 8.5 Hz, Ar), 7.62 (1H, d, J ) 1.9 Hz, H4), 7.47 (1H, d,
J ) 8.5 Hz, Ar), 5.17 (1H, ddd, J 1 ) 1.9 Hz, J 2 ) 3.8 Hz, J 3
)
5.0 Hz, H5), 4.10-4.00 (1H, m, -CH2O-), 3.91-3.82 (1H, m,
-CH2O-); 13C NMR (75 MHz, CDCl3) δ 171.02, 146.07, 133.75,
133.00, 130.98, 130.66, 129.01, 128.86, 126.22, 81.27, 62.56;
3-(3-Ch lor op h e n yl)-5-(4-ch lor ob e n zoyloxym e t h yl)-
2H,5H-fu r a n -2-on e (3a ). White crystals, mp 190-191 °C; 1H
NMR (300 MHz, CDCl3) δ 7.95-7.90 (2H, m, AA′BB′), 7.84-
7.81 (1H, m, Ar), 7.75-7.69 (1H, m, Ar), 7.60 (1H, d, J ) 1.9
Hz, H4), 7.43-7.38 (2H, m, AA′BB′), 7.38-7.34 (2H, m, Ar),
5.39 (1H, ddd, J 1 ) 1.9 Hz, J 2 ) 3.8 Hz, J 3 ) 5.2 Hz, H5), 4.69
(1H, dd, J 1 ) 3.8 Hz, J 2 ) 12.0 Hz, -CH2O-), 4.60 (1H, dd, J 1
) 5.2 Hz, J 2 ) 12.0 Hz, -CH2O-); 13C NMR (75 MHz, CDCl3)
δ 170.44, 165.25, 144.40, 140.16, 134.78, 132.37, 131.54,
131.09, 130.92, 130.04, 129.85, 128.94, 127.16, 125.21, 78.21,
63.47; IR (CDCl3) νmax 1270, 1335, 1370, 1403, 1489, 1595,
1726, 1773, 2927, 3073 cm-1; LRMS 331(1), 307(1), 244(1), 208-
(33), 206(100), 189(1), 171(63), 150(7), 136(29), 115(42), 101-
(15), 87(5), 75(14), 63(6), 50(11); Anal. (C18H12Cl2O4) C, H.
3-(3-Ch lor op h en yl)-5-a cetyloxym eth yl-2H,5H-fu r a n -2-
IR (CDCl3) νmax 1328, 1393, 1472, 1553, 1763, 2935, 3611 cm-1
;
LRMS 259(M•+, 1), 240(100), 205(37), 184(4), 170(14), 149(22),
134(4), 113(4), 99(7), 86(3), 74(8), 62(5), 50(8); Anal. (C11H8-
Cl2O3) C, H.
(+)3-(3,4-Dich lor op h en yl)-5-h yd r oxym eth yl-2H,5H-fu -
r a n -2-on e ((+)2). [R]D +16.3° (c 1.4, CHCl3); all other data
are identical with those of the racemate.
(-)3-(3,4-Dich lor op h en yl)-5-h yd r oxym eth yl-2H,5H-fu -
r a n -2-on e ((-)2). [R]D -16.8° (c 1.0, CHCl3); all other data
are identical with those of the racemate.
3-(3,4-Dich lor op h en yl)-5-(4-ch lor oben zoyloxym eth yl)-
2H,5H-fu r a n -2-on e (2a ). White crystals, mp 136-138 °C; 1H
NMR (300 MHz, CDCl3) δ 7.96 (1H, d, J ) 2.1 Hz, Ar), 7.95-
7.89 (2H, m, AA′BB′), 7.69 (1H, dd, J 1 ) 2.1 Hz. J 2 ) 8.4 Hz,
Ar), 7.62 (1H, d, J ) 1.9 Hz, H4), 7.48 (1H, d, J ) 8.4 Hz, Ar),
1
on e (3b). White crystals, mp 71-72 °C; H NMR (300 MHz,
CDCl3) δ 7.86-7.83 (1H, m, Ar), 7.77-7.73 (1H, m, Ar), 7.55
(1H, d, J ) 1.9 Hz, H4), 7.39-7.35 (2H, m, Ar), 5.28-5.24 (1H,
7.44-7.38 (2H, m, AA′BB′), 5.40 (1H, ddd, J 1 ) 1.9 Hz, J 2
)

2706 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 17
m, H5), 4.45-4.33 (2H, m, -CH2O-), 2.06 (3H, s, -CH3); 13
NMR (75 MHz, CDCl3) δ 170.37, 170.26, 144.48, 134.62,
131.94, 130.52, 129.90, 129.65, 127.01, 125.10, 78.07, 62.84,
20.69; IR (CDCl3) νmax 1336, 1367, 1385, 1476, 1567, 1595,
1746, 1763, 2927 cm-1; LRMS 265(M•+ - 2H, 1), 244(2), 208-
(100), 206(100), 189(4), 171(100), 150(15), 136(81), 126(7), 115-
(100), 101(39), 87(14), 75(40), 63(19), 50(31); Anal. (C13H11ClO4)
C, H.
Pour et al.
C
AA′BB′), 7.49 (1H, d, J ) 1.9 Hz, H4), 5.24 (1H, td, J 1 ) 1.9
Hz, J 2 ) 3.8 Hz, H5), 4.51 (1H, dd, J 1 ) 3.8 Hz, J 2 ) 12.1 Hz,
-CH2O-), 4.40 (1H, dd, J 1 ) 3.8 Hz, J 2 ) 12.1 Hz, -CH2O-),
1.12 (9H, s, tBu); 13C NMR (75 MHz, CDCl3) δ 178.14, 170.69,
143.92, 132.12, 131.97, 128.57, 127.88, 124.08, 78.52, 61.99,
38.87, 26.99; IR (CDCl3) νmax 1281, 1335, 1401, 1462, 1480,
1488, 1590, 1730, 1768, 2937, 2976 cm-1; LRMS 353(M•+, 1),
315(1), 272(1), 252(100), 250(98), 222(2), 194(4), 180(23), 171-
(47), 143(1), 126(3), 115(58), 101(26), 87(6), 75(22), 63(11), 50-
(17); Anal. (C16H17BrO4) C, H.
3-(3-Ch lor op h en yl)-5-p iva loyloxym eth yl-2H,5H-fu r a n -
2-on e (3c). White crystals, mp 59-60 °C; 1H NMR (300 MHz,
CDCl3) δ 7.84-7.81 (1H, m, Ar), 7.75-7.70 (1H, m, Ar), 7.52
(1H, d, J ) 1.9 Hz, H4), 7.40-7.35 (2H, m, Ar), 5.26 (1H, td,
Ack n ow led gm en t. This work was supported by
Charles University (Project Nos. 259/2001/B and 27/
1999/B) and by the Ministry of Education of the Czech
Republic (Project Nos. MSM 111600001 and 111600002).
J 1 ) 1.9 Hz, J 2 ) 3.9 Hz, H5), 4.50 (1H, dd, J 1 ) 3.9 Hz, J 2
)
12.0 Hz, -CH2O-), 4.40 (1H, dd, J 1 ) 3.9 Hz, J 2 ) 12.0 Hz,
-CH2O-), 1.13 (9H, s, tBu); 13C NMR (75 MHz, CDCl3) δ
178.13, 170.52, 144.72, 134.77, 131.99, 130.67, 130.02, 129.74,
127.10, 125.18, 78.49, 62.04, 38.87 26.99; IR (CDCl3) νmax 1281,
1335, 1369, 1399, 1462, 1480, 1568, 1595, 1731, 1767, 2874,
2910, 2937, 2976 cm-1; LRMS 307(M•+ - 2H, 1), 293(1), 279-
(1), 257(1), 208(33), 206(100), 171(75), 150(7), 136(41), 115-
(49), 101(17), 87(5), 75(17), 63(8), 50(14); Anal. (C16H17ClO4)
C, H.
Refer en ces
(1) For two reviews on newer triazole derivatives in the clinic, see
the following. (a) Fung, J . C.; Bonner, D. P. Recent Developments
in Pradimycin-benacomycin and Triazole Antibiotics Expert
Opin. Invest. Drugs 1997, 6, 129-145. (b) Turner, W. W.;
Rodriguez, M. J . Recent Advances in the Medicinal Chemistry
of Antifungal Agents. Curr. Pharm. Des. 1996, 2, 209-224.
(2) (a) Itoh, K.; Okonogi, K.; Tasaka, A.; Hayashi, R.; Tamura, N.;
Tsuchimori, N.; Kitazaki, T.; Matsushita, Y.; Obita, J . TAK-187,
a New Antifungal Triazole: Synthesis and Antifungal Activity.
Presented at the 36nd Interscience Conference on Antimicrobial
Agents and Chemotherapy (ICAAC), September 1966, New
Orleans, LA. (b) Tasaka, A.; Kitazaki, T.; Tamura, N.; Tsuchi-
mori, N.; Matsushita, Y.; Hayashi, R.; Okonogi, K.; Itoh, K.
Optically Active Antifungal Azoles. VII. Synthesis and Antifun-
gal Activity of Stereoisomers of 2-[(1R,2R)-2-(2,4-Difluorophenyl)-
2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[(2,2,3,3-
tetrafluoropropoxy)phenyl]-3-(2H,4H)-1,2,4-triazolone (TAK 187).
Chem. Pharm. Bull. 1997, 45, 321-326.
(3) For a review on ER-30346 (licensed to Bristol-Myers Squibb; the
new laboratory code for this compound is BMS-207,-147), see
the following. Naito, T.; Hata, K.; Tsuruoka, A. Drugs Future
1996, 21, 20-24.
(4) Konosu, T.; Tajima, Y.; Takeda, N.; Miyaoka, T.; Kasahara, M.;
Yasuda, H.; Oida, S. Triazole Antifungals. IV. Synthesis and
Antifungal Activities of 3-Acylamino-2-aryl-2-butanol Deriva-
tives. Chem. Pharm. Bull. 1991, 39, 2581-2589.
(5) Bartroli, J .; Turmo, E.; Alguero´, M.; Boncompte, E.; Vericat, M.
L.; Conte, L.; Ramis, J .; Merlos, M.; Garc´ıa-Rafanell, J .; Forn,
J . New Azole Antifungals. 3. Synthesis and Antifungal Activity
of 3-Substituted-4(3H)-quinazolinones. J . Med. Chem. 1998, 41,
1869-1882.
(6) For a review on voriconazole, see the following. Voriconazole
(UK-109496). Drugs Future 1997, 22, 326-327.
(7) (a)For a review on SCH-56592, see the following. Drugs Future
1997, 22, 203-204. (b) Cacciapuoti, A.; Loebenberg, D.; Corcoran,
E.; Menzel, F., J r.; Moss, E. L., J r.; Norris, C.; Michalski, M.;
Raynor, K.; Halpern, J .; Mendrick, C.; Arnold, B.; Antonacci, B.;
Parmegiani, R.; Yarosh-Tomaine, T.; Miller, G. H.; Hare, R. S.
In vitro and in vivo activities of SCH-5692 (posaconazole), a new
triazole antifungal agent, against Aspergillus and Candida.
Antimicrob. Agents Chemother. 2000, 44, 2017-2022.
(8) Pour, M.; Sˇpula´k, M.; Balsˇa´nek, V.; Kunesˇ, J .; Buchta, V.;
Waisser, K. 3-Phenyl-5-methyl-2H,5H-furan-2-ones: Tuning
Antifungal Activity by Varying Substituents on the Phenyl Ring.
Bioorg. Med. Chem. Lett. 2000, 10, 1893-1895.
3-(4-Br om op h en yl)-5-h yd r oxym et h yl-2H ,5H -fu r a n -2-
on e (4). White crystals, mp 104-105 °C; 1H NMR (300 MHz,
CDCl3) δ 7.76-7.71 (2H, m, AA′BB′), 7.58 (1H, d, J ) 1.9 Hz,
H4), 7.57-7.52 (2H, m, AA′BB′), 5.15 (1H, ddd, J 1 ) 1.9 Hz,
J 2 ) 3.8 Hz, J 3 ) 5.2 Hz, H5), 4.08-3.99 (1H, m, -CH2O-),
3.89-3.80 (1H, m, -CH2O-); 13C NMR (75 MHz, CDCl3) δ
171.29, 144.99, 132.08, 131.89, 128.58, 128.06, 123.93, 81.19,
62.77; IR (CDCl3) νmax 1297, 1328, 1403, 1488, 1590, 1764,
2878, 2934, 3606 cm-1; LRMS 269(M•+, 1), 252(100), 250(100),
222(4), 194(11), 182(59), 180(58), 171(96), 143(3), 126(7), 115-
(100), 101(56), 87(14), 75(51), 63(21), 50(37); Anal. (C11H9BrO3)
C, H.
3-(4-Br om op h e n yl)-5-(4-ch lor ob e n zoyloxym e t h yl)-
2H,5H-fu r a n -2-on e (4a ). White crystals, mp 211-213 °C; 1H
NMR (300 MHz, CDCl3) δ 7.95-7.89 (2H, m, AA′BB′), 7.74-
7.69 (2H, m, AA′BB′), 7.58 (1H, d, J ) 1.9 Hz, H4), 7.57-7.51
(2H, m, AA′BB′), 7.42-7.37 (2H, m, AA′BB′), 5.37 (1H, ddd,
J 1 ) 1.9 Hz, J 2 ) 3.9 Hz, J 3 ) 5.2 Hz, H5), 4.68 (1H, dd, J 1
)
3.9 Hz, J 2 ) 12.0 Hz, -CH2O-), 4.59 (1H, dd, J 1 ) 5.2 Hz, J 2
) 12.0 Hz, -CH2O-); 13C NMR (75 MHz, CDCl3) δ 170.59,
165.23, 143.58, 140.13, 132.49, 131.97, 131.06, 128.92, 128.59,
127.77, 127.37, 124.22, 78.21, 63.47; IR (CDCl3) νmax 1270,
1335, 1403, 1489, 1489, 1529, 1595, 1724, 1769, 2955, 3088
cm-1; LRMS 405(M•+ - 3H, 1), 377(3), 315(2), 252(100), 250-
(92), 194(5), 185(31), 171(47), 115(61), 101(27), 87(7), 75(26),
63(10), 50(18); Anal. (C18H12BrClO4) C, H.
3-(4-Br om op h en yl)-5-a cetyloxym eth yl-2H,5H-fu r a n -2-
1
on e (4b). White crystals, mp 70-71 °C; H NMR (300 MHz
CDCl3) δ 7.76-7.71 (2H, m, AA′BB′), 7.57-7.52 (2H, m
overlapped, AA′BB′), 7.53 (1H, d overlapped, J ) 1.9 Hz, H4),
5.26-5.21 (1H, m, H5), 4.44-4.32 (2H, m, -CH2O-), 2.05 (3H,
s, -CH3); 13C NMR (75 MHz, CDCl3) δ 170.60, 170.56, 143.81,
132.16, 131.91, 128.58, 127.84, 124.10, 78.09, 62.84, 20.57; IR
(CDCl3) νmax 1336, 1367, 1385, 1403, 1488, 1590, 1649, 1747,
1766, 2957, 3089 cm-1; LRMS 315(M•+ + 4H, 1), 272(1), 252-
(100), 250(99), 233(2), 194(4), 180(12), 171(42), 143(1), 126(3),
115(55), 101(22), 87(5), 75(18), 63(8), 50(13); Anal. (C13H11BrO4)
C, H.
(9) Zapf, S.; Anke, T.; Sterner, O. Incrustoporine, a New Antibiotic
from Incrustoporia carneola (Bres.) Ryv. (Basidiomycetes). Acta
Chem. Scand. 1995, 49, 233-234.
(10) National Committee for Clinical Laboratory Standards. Reference
method for broth dilution antifungal susceptibility testing of
yeasts: Approved standard; NCCLS Document M27-A; NC-
CLS: Villanova, PA, 1997.
3-(4-Br om op h en yl)-5-p iva loyloxym eth yl-2H,5H-fu r a n -
2-on e (4c). White crystals, mp 140-141 °C; 1H NMR (300
MHz, CDCl3) δ 7.74-7.69 (2H, m, AA′BB′), 7.58-7.53 (2H, m,
J M010155X