Aryloxyacetic esters structurally related to α-Asarone as potential antifungal agents

Article abstract of DOI:10.1007/s00044-009-9170-3

A series of aryloxyacetic ester analogues 8-13 was synthesized based on the potential pharmacophores of the antifungal agents α-Asarone (1) and 2-5. Their antifungal activity was tested in vitro for their growth inhibitory activities against pathogenic fungi. The in vitro antifungal evaluation of these alkyl and aryl esters shows that derivatives 10 displayed the highest antifungal and fungicidal activities against Cryptococcus neoformans and C. gattii. These results support the idea that the phenoxyacetic frame is a potent pharmacophore for the design of potential antifungal drugs. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00044-009-9170-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2010) 19:33–57
DOI 10.1007/s00044-009-9170-3
ORIGINAL RESEARCH
Aryloxyacetic esters structurally related to a-Asarone
as potential antifungal agents
´
´
Fabiola Jimenez Æ Marıa del Carmen Cruz Æ
´ ˜
´
´
Clara Zuniga Æ Marıa A. Martınez Æ
´
´
German Chamorro Æ Francisco Dıaz Æ
´
Joaquın Tamariz
Received: 22 August 2008 / Accepted: 6 February 2009 / Published online: 20 March 2009
¨
Ó Birkhauser Boston 2009
Abstract A series of aryloxyacetic ester analogues 8–13 was synthesized based on the
potential pharmacophores of the antifungal agents a-Asarone (1) and 2–5. Their anti-
fungal activity was tested in vitro for their growth inhibitory activities against pathogenic
fungi. The in vitro antifungal evaluation of these alkyl and aryl esters shows that
derivatives 10 displayed the highest antifungal and fungicidal activities against Cryp-
tococcus neoformans and C. gattii. These results support the idea that the phenoxyacetic
frame is a potent pharmacophore for the design of potential antifungal drugs.
Keywords a-Asarone ꢀ Antifungal activity ꢀ Cryptococcus neoformans var.
neoformans ꢀ Cryptococcus gattii ꢀ Phenoxyacetic frame
´
´
´
F. Jimenez ꢀ M. Cruz ꢀ C. Zun˜iga ꢀ F. Dıaz ꢀ J. Tamariz (&)
´
´
Departamento de Quımica Organica, Escuela Nacional de Ciencias Biologicas,
Instituto Politecnico Nacional, Prol. Carpio y Plan de Ayala, 11340 Mexico, DF, Mexico
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´
´
e-mail: jtamariz@woodward.encb.ipn.mx
M. Cruz
Centro de Investigacion en Biotecnologıa Aplicada, Instituto Politecnico Nacional,
´
Km 15 Carretera Sta. Ines Tecuexcomac, Tepetitla 90700, Tlaxcala, Mexico
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´
´
´
C. Zun˜iga ꢀ G. Chamorro
´
Laboratorio de Toxicologıa Preclınica, Escuela Nacional de Ciencias Biologicas,
Instituto Politecnico Nacional, Prol. Carpio y Plan de Ayala, 11340 Mexico, DF, Mexico
´
´
´
´
´
M. A. Martınez
Departamento de Microbiologıa, Escuela Nacional de Ciencias Biologicas,
´
´
´ ´
Instituto Politecnico Nacional, Prol. Carpio y Plan de Ayala, 11340 Mexico, DF, Mexico

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Med Chem Res (2010) 19:33–57
Introduction
Since in the last two decades the incidence of invasive fungal infections has risen
sharply, it has become imperative to enlarge the number of antifungal drugs with
more potent activity and less toxicity (Maertens and Boogaerts, 2005; Datry and
Bart-Delabesse, 2006). Until recently, such treatment was composed of amphoter-
icin B and azoles (Vazquez and Sobel, 2006). However, fungal pathogens acquire
resistance, which hampers effective treatment strategies (Prasad et al., 2002). These
mainly opportunistic fungi acquire resistance during prophylaxis, intermittent or
monotherapy, for instance, in the case of the resistance of Candida species,
Cryptococcus neoformans and the recently accepted species (Kwon-Chung et al.,
2002) C. gattii to flucytosine, amphotericin B, and azoles (Kwon-Chung et al.,
2002; White et al., 1998; Sterling and Merz, 1998; Vanden Bossche et al., 1998;
Pfaller et al., 2004).
a-Asarone (1) has been isolated from multiple natural sources, such as Acorus
´
family and Guatteria gaumeri (Martınez, 1992), and it displays a broad spectrum of
biological activity. It has powerful hypolipidemic activity (Chamorro et al., 1993;
Gardun˜o et al., 1997), showing high binding affinity to hepatic 3-hydroxy-3-
´
´
methylglutaryl-CoA reductase (HMGR) (Rodrıguez-Paez et al., 2003). It has also
been isolated from the seed extracts of Daucus carota, and was active in antilarvaric
assays of the yellow-fever- and dengue-transmitting mosquito Aedes aegyptii, as
well as in nematicidal (Caenorhabditis elegans and Panagrellus redivivus) and
antifeedant (Helicovarpa zea, Heliothis virescens, and Manduca sexta) activity
evaluations (Momin and Nair, 2002). In particular, a-Asarone (1) has exhibited
activity against the yeasts Candida albicans, Candida parapsilasis, and Candida
krusei (Momin and Nair, 2002).
b-Asarone and the trimethoxyphenyl compound 2, whose structure is closely
related to 1, have shown marked activity against larvae of Aedes aegyptii, as well as
antifungal activity (Lee et al., 2004; Ioset et al., 2000). Some other analogues such
as anethole (3) and methyleugenol (4) enhance the fungicidal action of the bicyclic
sesquiterpene called polygodial upon combined administration (Kubo et al., 2001),
and alkyl gallates 5 exhibit antifungal activity against S. cerevisiae at any growth
stage (Kubo et al., 2002).
We have reported that phenoxyacetic acids and esters 6, which take advantage of
some structural pharmacophoric features of both a-Asarone (1) (Chamorro et al.,
´
1998; Dıaz et al., 1993) and fibrates, displayed a significant hypocholesterolemic
´
activity (Labarrios et al., 1999; Cruz et al., 2003; Zun˜iga et al., 2005). Recently, a
number of fibrate mimetic amides, which were prepared and evaluated biologically,
showed a decrease of serum cholesterol and a lowering of low-density lipoprotein
´
(LDL) cholesterol (Hernandez et al., 2004). Phenoxyacetic acids 7 have been
reported to exhibit antimicrobial, herbicidal, and low and moderate fungicidal
activities (Nair and Burke, 1988; Zawadowska, 1962, 1963; Suyama and Kato,
1989; Purohit and Shah, 1999; Arcamone et al., 1957). The latter reports together
with our results suggest that the phenoxyacetic moiety has a high pharmacophore
value, independently of other groups present in the benzene ring.

Med Chem Res (2010) 19:33–57
35
Structure 1-5
Owing to the significant antifungal activity of 1–5, in this report we address the
evaluation of the series of analogues 8–13 as potential antifungal agents that contain
a combination of pharmacophores of the former compounds and those related to the
phenoxyacetic acid compounds 7.
Structure 6-7
Results
Synthesis
Esters 8a–e were prepared by a two-step reaction synthesis, starting from the
reaction of phenol 14 with sodium chloroacetate under basic conditions to furnish
phenoxyacetic acid 17, in good yield (75%). The latter was treated with a series of
alcohols (i-PrOH, n-PrOH, n-amylOH, n-dodecylOH, or ClC6H4OH) to give the
series 8a–e, respectively, e.g., 8a with R = i-Pr, R1 = R2 = H (Scheme 1). Unlike
derivatives 8a–c, which were obtained in high yields (81–86%) after treating the
phenoxyacetic acid 17 with the desired alcohol in the presence of pTsOH at r.t.,
derivatives 8d and 8e were more efficiently prepared (71–80%) with in situ
formation of the respective acid chloride, by treating the same phenoxyacetic acid

36
Med Chem Res (2010) 19:33–57
with thionyl chloride, then adding the corresponding alcohol (i-PrOH, n-PrOH, n-
amylOH, n-dodecylOH, or ClC6H4OH). Series of esters 9a–e, which has a methyl
group at the para position with respect to the acetic ester moiety, was prepared from
phenol 15 through an analogous synthetic route to that for the series 8, and
conserving the same series of alcohols, e.g., 9c with R = n-amyl, R1 = H,
R2 = Me (Scheme 1). The overall yields of esters 9a–e were satisfactory (68–85%).
Concerning the series of derivatives 10a–e, the reactions proceeded efficiently from
phenol 16 via the aryloxyacetic acid 19 to give the desired products, e.g., 10e with
R = C6H4–4–Cl, R1 = OMe, R2 = Me (Scheme 1), in good yields (64–86%).
Preparation of the isomeric phenoxyacetic esters 11–13 followed a similar
synthetic route to that of the previous series (Scheme 2). Thus, the 2-, 3-, and 4-
methoxyphenols 20–22 were treated with sodium chloroacetate to give the
phenoxyacetic acids 23–25 (80–85%), respectively. Through an analogous
esterification to that of the series shown in Scheme 1, we obtained the three
series of esters 11a–g, 12a–g, and 13a–g, respectively, e.g., 11a with R = Me,
R1 = OMe, R2 = R3 = Me; 12e with R = n-amyl, R1 = R3 = H, R2 = OMe;
and 13g with R = C6H4–4–Cl, R1 = R2 = H, R3 = Me (Scheme 2). In general,
the yields were rather high (79–95%), except for derivative 12g, which was
isolated in 60% yield. In these series, the methyl and ethyl esters were also
included (i.e., 11a,b, 12a,b, and 13a,b), considering that similar esters were
biologically active in compounds 7.
Scheme 1 Preparation of the series 8–10

Med Chem Res (2010) 19:33–57
37
Scheme 2 Preparation of the series 11–13
Table 1 In vitro antifungal
Compound
C. neoformans var. neoformansb
C. gattiib
activities (MIC50, lg/ml) of
aryloxyacetic esters 8–12a
Ketoconazole
0.12
0.03
4
0.06
0.03
4
Itraconazole
Fluconazole
Amphotericin B
Caspofungine
8c
0.12
8
0.12
16
16
2
9a
8
128
a
10a
10b
10c
10e
11a
11e
12d
64
0.25
All the prepared series, 8–13,
were tested, but only the
derivatives exhibiting MIC50
\32 lg/ml in any of the
Cryptococcus species are
included
2
0.25
0.5
32
0.25
0.5
16
0.5
128
b
MIC50 was evaluated by the
modified CLSI M27-A2 broth
microdilution method
64
64
0.5
Antifungal activity
All the prepared series, 8–13, were evaluated in the in vitro antifungal activity tests.
Table 1 summarizes the minimal inhibitory concentration 50% (MIC50) required for
the 50% inhibition of fungal growth only for those analogues that showed antifungal
activity\32 lg/ml, in which ketoconazole, itraconazole, fluconazole, amphotericin

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Med Chem Res (2010) 19:33–57
Table 2 In vitro fungicide activities (MFC, lg/ml) of aryloxyacetic esters 8–12a
Compound
C. neoformans var. neoformansb
C. gattiib
8c
64
2
c
9a
[64
c
10a
10b
10c
10e
11a
11e
12d
a
0.25
d
d
c
0.5
0.25
[64
[64
[64
0.5
c
c
c
Only the derivatives exhibiting IC50% \32 lg/ml against any of the Cryptococcus strains are included
b
MFC (lg/ml) estimations were determined by directly plating dilutions of culture medium from wells
with no growth onto potato dextrose agar and incubating the plates at 35°C for 48 h
c
Not tested
d
Decreased growth rate in the Petri dish
B, and caspofungine are listed as the reference compounds. Except for caspofun-
gine, the remainder of the latter compounds were susceptible to both strains.
Fungicidal activity
The minimal fungicidal concentrations (MFCs) were examined only for those
compounds showing a significant MIC50 activity (\32 lg/ml), and the results are
summarized in Table 2.
Discussion
To establish the minimal pharmacophore features associated with the antifungal
activity of these compounds, we prepared a series of homologous esters 8a–e with
no substituents at the benzene ring (Scheme 1). The fact that the lipophilic effect
might play a role in facilitating the transport of the drugs through the lipophilic
membranes of the yeasts (White et al., 1998) prompted us to choose a series of long
and lineal hydrocarbon chains for the partnership alcohols, as well as an aromatic
ring substituted by a chlorine atom. In the series of esters 9a–e, a methyl group was
introduced at the para position with respect to the acetic ester moiety, conserving
the same series of alcohols (Scheme 1). An additional methoxy group, which was
introduced in the series 9a–e to be evaluated as the series of derivatives 10a–e, was
attached to the C-2 carbon atom of the benzene ring with the aim of mimicking the
structure of compounds 6. The structural simplicity of these analogues was also a
characteristic in the series of ortho, meta, and para isomeric phenoxyacetic esters
11–13 (Scheme 2).
For series 8 and 9, only compounds 8c and 9a exhibited antifungal activity,
though the latter was not active against Cryptococcus gattii. In contrast, series 10

Med Chem Res (2010) 19:33–57
39
was largely the most active among all those tested. Thus, derivatives 10a and 10c
exhibited high antifungal activity against C. gattii, but 10b and 10e were even more
active against both Cryptococcus species. It is worth noting that this series, which
bears the methoxy group at the C-2 carbon atom of the benzene ring, displayed more
potency than its demethoxylated analogues 9a–e.
Considering these results, we prepared (Scheme 2) and tested the isomeric series
11–13, in order to evaluate the role of the methoxy group in a benzene ring without
the methyl group. However, only derivatives 11a, 11e, and 12d showed antifungal
activity. Actually, their activity was limited against the two Cryptococcus species,
in which compounds 11a and 12d were highly active. Acid precursors 23–25 were
also tested but no activity was shown at all.
As these results suggest that the ester function is necessary for exhibiting
antifungal activity, the lipophilic effect provided by the hydrocarbon ester chain
would contribute to such activity. However, there was not a lineal correlation
between the length of the ester chain and the antifungal activity, since the ester
analogues with the longest chain (n-dodecyl) did not show any significant activity.
Conformational and steric factors might counterbalance the potential lipophilic
effect, thus inhibiting the approach to the receptor.
Although not all compounds demonstrated fungicidal activity, some of the most
active antifungal ones did. In particular, compound 10e was the most active agent
against both Cryptococcus species. In contrast, its analogue 10b was only fungistatic,
and analogues 10a and 10c maintained fungicidal activity only against the C. gattii
strain. It is interesting to note that the fungicidal activity of these aryloxyacetic esters
was reached at a similar potency to that of the antifungal activity.
In summary, the above results agree with our hypothesis, suggesting that the
aryloxyacetic moiety has a pharmacophore value for the antifungal activity.
Derivatives bearing both the methyl and the methoxy groups (10), related to a-
Asarone (1) and aryloxyacetic compounds 7, proved to be the most potent
antifungal agents. Moreover, some of them also exhibited a high fungicidal activity.
It is likely that the hydrophobicity introduced by the ester group can explain the
differences in activity of the tested esters with respect to the corresponding inactive
aryloxyacetic acids. Therefore, the most active analogues described in this report,
which were designed considering some of the possible combinations of the
pharmacophores present in the structures of compounds 1–7, proved to be highly
promising fungicidal agents. In addition, the series 8–13 exhibits high economy in
terms of the number of pharmacophores present and, as a consequence, in the
synthetic methodology leading to its preparation.
Experimental
Chemistry
Melting points were determined with an Electrothermal capillary melting point
apparatus and are reported uncorrected. Infrared (IR) spectra were recorded on a
Perkin-Elmer 1600 spectrophotometer (Perkin-Elmer Corp., Norwalk, CT, USA).

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Med Chem Res (2010) 19:33–57
1H and 13C nuclear magnetic resonance (NMR) spectra were recorded on a Varian
Mercury-300 (300 MHz and 75.4 MHz) (Varian, Palo Alto, CA, USA) instrument,
with CDCl3 as solvent and trimethylsilane (TMS) (Aldrich Chemical Co.,
Milwaukee, WI, USA) as internal standard. Mass spectra (MS) spectrometry were
taken, in electron impact (70 eV) mode, on a Hewlett-Packard 5971A (Hewlett-
Packard Co., Palo Alto, CA, USA) spectrometer. Microanalyses were performed by
M-H-W Laboratories (Phoenix, AZ, USA). Starting materials and reagents were
purchased from Aldrich Chemical Co. (Milwaukee, WI, USA), and were used
without any further purification. Analytical thin-layer chromatography (TLC) was
performed on precoated TLC sheets of silica gel 60 F254 (Merck, Darmstadt,
Germany), visualizing by long- and short-wavelength ultraviolet (UV) lamps. Flash
column chromatography was performed on silica gel (230–400 mesh, Natland Int.,
USA). All air moisture sensitive reactions were carried out under nitrogen using
oven-dried glassware.
General procedure for the preparation of phenoxyacetic acids
Solutions of NaOH (4.4 g, 0.11 mol) in 20 ml H2O and of sodium chloroacetate
(12.8 g, 0.11 mol) in 20 ml H2O were successively added dropwise at room
temperature to the corresponding phenol 14–17 or 20, 21 (0.1 mol). The mixture
was stirred and heated to 60°C for 12 h. HCl (36%) was added until pH 2, and a
precipitate was formed, which was filtered and purified by recrystallization (hexane/
EtOAc, 2:8).
Phenoxyacetic acid (17)
Following the general procedure with 9.4 g of 14, gave 11.4 g (75%) of 17 as a
white solid: Rf 0.44 (hexane/EtOAc/AcOH, 1:1:0.1); mp 98–100°C [lit. (Guha,
1950) 96–97°C]; IR (KBr) 3350–2393, 1732, 1703, 1598, 1584, 1498, 1437, 1310,
1
1288, 1231, 1094, 754 cm-1; H NMR (300 MHz, CDCl3) d 4.69 (s, 2H, OCH2),
6.88–6.95 (m, 2H, H-2), 6.98–7.50 (m, 1H, H-4), 7.26–7.35 (m, 2H, H-3), 10.75 (br
s, 1H, CO2H); 13C NMR (75.4 MHz, CDCl3) d 64.6 (OCH2), 114.5 (C-2), 122.0 (C-
4), 129.6 (C-3), 157.3 (C-1), 175.0 (CO).
4-Methylphenoxyacetic acid (18)
Following the general procedure with 10.8 g (0.1 mol) of 15, gave 13.3 g (80%)
of 18 as a white solid: Rf 0.43 (hexane/EtOAc/AcOH, 2:3:0.1); mp 138–139°C
[lit. (Guha, 1950) 134–135°C]; IR (KBr) 3260–2360, 1735, 1705, 1511, 1436,
1
1289, 1236, 1089, 814 cm-1; H NMR (300 MHz, CDCl3) d 2.29 (s, 3H, CH3),
4.65 (s, 2H, OCH2), 6.79–6.86 (m, 2H, H-2, H-6), 7.06–7.13 (m, 2H, H-3, H-5),
7.75–8.30 (br s, 1H, CO2H); 13C NMR (75.4 MHz, CDCl3) d 21.0 (CH3), 64.9
(OCH2), 114.4 (C-2, C-6), 130.1 (C-3, C-5), 131.5 (C-4), 155.2 (C-1), 174.4 (CO).

Med Chem Res (2010) 19:33–57
41
2-Methoxy-4-methylphenoxyacetic acid (19)
Following the general procedure with 13.8 g (0.1 mol) of 16, gave 15.7 g (80%) of
19 as a white solid: Rf 0.35 (hexane/EtOAc/AcOH, 1:1:0.1); mp 121–122°C [lit.
(Guha, 1950) 121–122°C]; IR (KBr) 3550–2490, 1771, 1740, 1511, 1466, 1269,
1
1146, 1037, 816 cm-1; H NMR (300 MHz, CDCl3) d 2.28 (s, 3H, CH3), 3.84 (s,
3H, OCH3), 4.64 (s, 2H, OCH2), 6.67 (br d, J = 8.1 Hz, 1H, H-5), 6.71 (br s, 1H, H-
3), 6.77 (d, J = 8.1 Hz, 1H, H-6), 10.58 (br s, 1H, CO2H); 13C NMR (75.4 MHz,
CDCl3) d 21.0 (CH3), 55.7 (OCH3), 67.3 (OCH2), 113.0 (C-6), 115.8 (C-3), 121.0
(C-5), 133.2 (C-4), 144.7 (C-1), 149.3 (C-2), 173.8 (CO); MS (70 eV) m/z 196 (M?,
100), 137 (82), 109 (35), 91 (23), 77 (13).
2-Methoxyphenoxyacetic acid (23)
Following the general procedure with 12.4 g (0.1 mol) of 20, gave 15.5 g (85%) of
23 as a white solid: Rf 0.65 (EtOAc/AcOH, 10:0.1); mp 120–122°C [lit. (Csiba
et al., 1968) 128°C]; IR (KBr) 3280–2340, 1741, 1710, 1589, 1509, 1457, 1425,
1
1332, 1254, 1233, 1130, 1025, 753 cm-1; H NMR (300 MHz, acetone-d6) d 3.81
(s, 3H, OCH3), 4.69 (s, 2H, OCH2), 6.83–7.00 (m, 4H, ArH), 7.83 (br, 1H, CO2H);
13C NMR (75.4 MHz, acetone-d6) d 55.2 (OCH3), 65.6 (OCH2), 112.5 (ArH), 114.5
(ArH), 120.6 (ArH), 122.1 (ArH), 147.7 (Ar), 149.8 (Ar), 169.8 (CO); MS (70 eV)
m/z 182 (M?, 3), 138 (7), 123 (20), 109 (7), 95 (42), 77 (100), 65 (27), 63 (17).
3-Methoxyphenoxyacetic acid (24)
Following the general procedure with 12.4 g (0.1 mol) of 21, gave 14.56 g (80%) of
24 as a white solid: Rf 0.51 (hexane/EtOAc/AcOH, 1:1:0.1); mp 117–119°C [lit.
(Csiba et al., 1968) 114–115°C]; IR (KBr) 3292–2380, 1744, 1712, 1598, 1494,
1
1466, 1430, 1270, 1247, 1208, 1183, 1158, 1047, 923, 842, 765 cm-1; H NMR
(300 MHz, CDCl3) d 3.79 (s, 3H, OCH3), 4.67 (s, 2H, OCH2), 6.48–6.61 (m, 3H, H-
2, H-4, H-6), 7.17–7.24 (m, 1H, H-5), 8.92 (br s, 1H, CO2H); 13C NMR (75.4 MHz,
CDCl3) d 55.3 (OCH3), 64.7 (OCH2), 101.3 (C-2), 106.3 (ArH), 107.8 (ArH), 130.1
(ArH), 158.5 (Ar), 160.9 (Ar), 174.0 (CO); MS (70 eV) m/z 182 (M?, 7), 137 (14),
125 (26), 109 (36), 107 (22), 94 (20), 77 (100), 65 (30), 63 (42).
4-Methoxyphenoxyacetic acid (25)
Following the general procedure with 12.4 g (0.1 mol) of 22, gave 15.47 g (85%) of
25 as a white solid: Rf 0.51 (hexane/EtOAc/AcOH, 1:1:0.2); mp 110-112°C [lit.
(Csiba et al., 1968) 110–112°C]; IR (KBr) 3270–2430, 1735, 1508, 1461, 1426,
1291, 1271, 1226, 1089, 1037, 905, 825, 754 cm-1; 1H NMR (300 MHz, CDCl3) d
3.76 (s, 3H, OCH3), 4.62 (s, 2H, OCH2), 6.80–6.90 (m, 4H, ArH), 9.70 (br s, 1H,
CO2H); 13C NMR (75.4 MHz, CDCl3) d 55.7 (OCH3), 65.7 (OCH2), 114.8 (ArH),
115.9 (ArH), 151.6 (Ar), 154.7 (Ar), 174.7 (CO); MS (70 eV) m/z 182 (M?, 4), 123
(100), 109 (15), 95 (79), 81 (19), 77 (35), 65 (54), 63 (34).

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General procedure for the preparation of esters
Method A
A mixture of the corresponding phenoxyacetic acid 17–19 and 23–25 (1 mol
equiv.), p-TsOH (0.1 mol equiv.), and the corresponding alcohol (20 mol equiv.)
was stirred at room temperature for 2–12 h. The remained alcohol was removed
under vacuum, the oily residue was dissolved in EtOAc (20 ml), and was washed
with aqueous saturated solution of NaHCO3 until neutral. The organic layer was
dried (Na2SO4) and the solvent was removed under vacuum. The residue was
purified by column chromatography over silica gel (hexane/EtOAc, 9:1).
Method B
A mixture of the corresponding phenoxyacetic acid, 17–19 and 23–25 (1.0 mol
equiv.) and N,N-dimethylaminopyridine (DMAP) (0.1 mol equiv.) in dry CH2Cl2
(10 ml) was heated to reflux, then SOCl2 (1.5 mol equiv.) was added dropwise, and
maintained for 2 h. After evaporating under vacuum, the residue was added at 5°C
to a stirring mixture of dry K2CO3 (1.1 mol equiv) and the corresponding alcohol in
dry toluene (30 ml). The mixture was stirred at room temperature for 24 h, then icy
H2O (10 ml) was added, and extracted with toluene (3 9 20 ml). The organic layer
was washed with brine (3 9 10 ml), dried (Na2SO4), and the solvent was removed
under vacuum. The residue was purified by column chromatography over silica gel
(hexane/EtOAc, 9:1).
Isopropyl phenoxyacetate (8a) (Rivalle and Bisagni, 1972)
Following method A, with a mixture of 1.0 g (6.6 mmol) of 17, 0.11 g (0.66 mmol)
of p-TsOH, and 7.92 g (132 mmol) of i-PrOH, gave 1.1 g (86%) of 8a as a colorless
oil: Rf 0.40 (hexane/EtOAc, 9:1); IR (film) 2981, 1780, 1753, 1599, 1494, 1377,
1
1287, 1200, 1100, 1086, 754, 691 cm-1. H NMR (300 MHz, CDCl3) d 1.26 (d,
J = 6.3 Hz, 3H, (CH3)2CHOCO), 4.58 (s, 2H, OCH2), 5.14 (sep, J = 6.3 Hz, 1H,
(CH3)2CHO), 6.87–6.93 (m, 2H, H-2, H-6), 6.95–7.02 (m, 1H, H-4), 7.24–7.32 (m,
2H, H-3, H-5); 13C NMR (75.4 MHz, CDCl3) d 21.6 (OCH(CH3)2), 65.4 (OCH2),
69.0 (OCH(CH3)2), 114.5 (C-2, C-6), 121.5 (C-4), 129.4 (C-3, C-5), 157.7 (C-1)
168.4 (CO2); MS (70 eV) m/z 194 (M?, 64), 152 (3), 107 (100), 94 (19), 77 (65), 65
(5), 51 (17), 43 (44). Anal. Calcd. for C11H14O3: C, 68.02; H, 7.26. Found: C, 68.30;
H, 7.14.
n-Propyl phenoxyacetate (8b) (Tolstikov et al., 1983)
Following method A, with a mixture of 1.0 g (6.6 mmol) of 17, 0.11 g (0.66 mmol)
of p-TsOH, and 7.92 g (132 mmol) of n-PrOH, gave 1.07 g (84%) of 8b as a
colorless oil: Rf 0.50 (hexane/EtOAc, 9:1); IR (film) 2967, 1758, 1734, 1599, 1495,
1288, 1193, 1087, 754, 691 cm-1
.
1H NMR (300 MHz, CDCl3) d 0.89
(t, J = 7.3 Hz, 3H, CH3CH2CH2O), 1.58–1.71 (m, 2H, CH3CH2CH2O), 4.13

Med Chem Res (2010) 19:33–57
43
(t, J = 6.6 Hz, 2H, CH3CH2CH2O), 4.59 (s, 2H, OCH2), 6.86–6.91 (m, 2H, ArH),
6.93–6.99 (m, 1H, ArH), 7.22–7.30 (m, 2H, ArH); 13C NMR (75.4 MHz, CDCl3) d
10.0 (CH3CH2CH2O), 21.7 (CH3CH2CH2O), 65.0 (CH3CH2CH2O), 65.5 (OCH2),
114.4 (ArH), 121.4 (ArH), 129.3 (ArH), 157.6 (Ar), 168.8 (CO2); MS (70 eV) m/z
194 (M?, 76), 152 (13), 107 (100), 94 (22), 79 (26), 77 (74), 65 (10), 51 (19), 43
(32). Anal. Calcd. for C11H14O3: C, 68.02; H, 7.26. Found: C, 67.96; H, 7.13.
n-Amyl phenoxyacetate (8c)
Following method A, with a mixture of 1.0 g (6.6 mmol) of 17, 0.11 g (0.66 mmol)
of p-TsOH, and 11.6 g (130 mmol) of n-amylOH, gave 1.19 g (81%) of 8c as a
colorless oil: Rf 0.44 (hexane/EtOAc, 9:1); IR (film) 2956, 2932, 1759, 1735, 1596,
1
1495, 1286, 1192, 1086, 754, 690 cm-1. H NMR (300 MHz, CDCl3) d 0.88 (t,
J = 6.9 Hz, 3H, CH3(CH2)3CH2O), 1.22–1.36 (m, 4H, 2CH2), 1.58–1.70 (m, 2H,
CH2), 4.19 (t, J = 6.7 Hz, 2H, CH3(CH2)3CH2O), 4.61 (s, 2H, OCH2), 6.86–6.93
(m, 2H, ArH), 6.94–7.10 (m, 1H, ArH), 7.23–7.32 (m, 2H, ArH); 13C NMR
(75.4 MHz, CDCl3) d 13.8 (CH3(CH2)3CH2O), 22.1 (CH3CH2(CH2)2CH2O), 27.8
(EtCH2CH2CH2O), 28.1 (PrCH2CH2O), 65.2 (OCH2 or BuCH2O), 65.3 (BuCH2O
or OCH2), 114.5 (ArH), 121.6 (ArH), 129.4 (ArH), 157.7 (Ar), 169.0 (CO2); MS
(70 eV) m/z 222 (M?, 64), 152 (76), 107 (100), 94 (29), 79 (26), 77 (85), 65 (11),
51 (19), 43 (81). Anal. Calcd. for C13H18O3: C, 70.24; H, 8.16. Found: C, 70.10;
H, 7.97.
n-Dodecyl phenoxyacetate (8d)
Following method B, with 1.0 g (6.6 mmol) of 17, 0.079 g (0.65 mmol) of DMAP
in CH2Cl2 (20 ml), 1.18 g (9.9 mmol) of SOCl2, 0.99 g (7.2 mmol) of K2CO3, and
1.34 g (7.2 mmol) of n-dodecyl alcohol in toluene (30 ml), gave 1.68 g (80%) of 8d
as a colorless oil: Rf 0.51 (hexane/EtOAc, 9:1); IR (film) 2924, 2854, 1762, 1735,
1597, 1496, 1286, 1192, 1087, 753, 690 cm-1. 1H NMR (300 MHz, CDCl3) d 0.88
(t, J = 6.7 Hz, 3H, CH3(CH2)10CH2O), 1.25 (br s, 18H, 9CH2), 1.58–1.67 (m, 2H,
CH2), 4.18 (t, J = 6.7 Hz, 2H, CH3(CH2)10CH2O), 4.62 (s, 2H, OCH2), 6.85–6.93
(m, 2H, ArH), 6.95–7.01 (m, 1H, ArH), 7.24–7.32 (m, 2H, ArH); 13C NMR
(75.4 MHz, CDCl3) d 14.1 (CH3), 22.7 (CH2), 25.7 (CH2), 28.5 (CH2), 29.1 (CH2),
29.3 (CH2), 29.4 (CH2), 29.5 (CH2), 29.59 (CH2), 29.61 (CH2), 31.9 (CH2), 65.3
(ArOCH2 or CH3(CH2)10CH2O), 65.4 (CH3(CH2)10CH2O or ArOCH2), 114.6
(ArH), 121.6 (ArH), 129.5 (ArH), 157.8 (Ar), 169.1 (CO2); MS (70 eV) m/z 320
(M?, 90), 213 (4), 152 (100), 107 (65), 77 (41), 57 (19), 43 (26). Anal. Calcd. for
C20H32O3: C, 74.95; H, 10.06. Found: C, 74.69; H, 9.99.
4-Chlorophenyl phenoxyacetate (8e)
Following method B, with 1.0 g (6.6 mmol) of 17, 0.079 g (0.65 mmol) of DMAP
in CH2Cl2 (20 ml), 1.18 g (9.9 mmol) of SOCl2, 0.99 g (7.2 mmol) of K2CO3, and
0.92 g (7.2 mmol) of 4-chlorophenol in toluene (30 ml), gave 1.22 g (71%) of 8e as
a white solid: Rf 0.37 (hexane/EtOAc, 9:1); mp 100–101°C [lit. (Khan and Bahel,

44
Med Chem Res (2010) 19:33–57
1976) 82°C]; IR (KBr) 3093, 3059, 1775, 1591, 1493, 1436, 1229, 1174, 1088, 849,
1
751, 692 cm-1; H NMR (300 MHz, CDCl3) d 4.86 (s, 2H, OCH2), 6.94–7.01 (m,
2H, ArH), 7.02–7.09 (m, 3H, ArH), 7.28–7.38 (m, 4H, ArH); 13C NMR (75.4 MHz,
CDCl3) d 65.3 (OCH2), 114.7 (PhH), 122.1 (PhH), 122.6 (ArH), 129.6 (PhH or
ArH), 129.7 (ArH or PhH), 131.6 (Ar), 148.5 (Ar), 157.6 (Ph), 169.3 (CO2); MS
(70 eV) m/z 264 (M? ? 2, 8), 262 (M?, 19), 236 (5), 234 (13), 141 (8), 128 (9), 107
(100), 99 (17), 79 (19), 77 (55), 63 (9), 51 (15). Anal. Calcd. for C14H11ClO3: C,
64.01; H, 4.22. Found: C, 63.85; H, 4.10.
Isopropyl 4-methylphenoxyacetate (9a) (Rivalle and Bisagni, 1972)
Following method A, with a mixture of 1.0 g (6.0 mmol) of 18, 0.1 g (0.6 mmol) of
p-TsOH, and 7.2 g (120 mmol) of i-PrOH, gave 1.01 g (81%) of 9a as a colorless
oil: Rf 0.43 (hexane/EtOAc, 9:1); IR (film) 2981, 2925, 1756, 1730, 1511, 1288,
.
1200, 1178, 1107, 1081, 817 cm-1 1H NMR (300 MHz, CDCl3) d 1.25 (d,
J = 6.3 Hz, 6H, OCH(CH3)2), 2.26 (s, 3H, CH3), 4.53 (s, 2H, OCH2), 5.12 (m,
J = 6.3 Hz, 1H, OCH(CH3)2), 6.74–6.82 (m, 2H, ArH), 7.03–7.09 (m, 2H, ArH);
13C NMR (75.4 MHz, CDCl3) d 20.2 (CH3Ar), 21.5 ((OCH(CH3)2)), 65.5 (OCH2),
68.7 (OCH(CH3)2), 114.3 (ArH), 129.7 (ArH), 130.6 (Ar), 155.6 (Ar), 168.4 (CO2);
MS (70 eV) m/z 208 (M?, 85), 166 (40), 121 (100), 108 (22), 91 (64), 77 (14), 65
(24), 43 (42).
n-Propyl 4-methylphenoxyacetate (9b) (Voronkov et al., 1990)
Following method A, with a mixture of 1.0 g (6.0 mmol) of 18, 0.1 g (0.6 mmol) of
p-TsOH, and 7.2 g (120 mmol) of n-PrOH, gave 1.0 g (80%) of 9b as a colorless
oil: Rf 0.45 (hexane/EtOAc, 9:1); IR (film) 2967, 2927, 1759, 1734, 1511, 1289,
1
1193, 1084, 817 cm-1. H NMR (300 MHz, CDCl3) d 0.91 (t, J = 7.3 Hz, 3H,
OCH2CH2CH3), 1.61–1.73 (m, 2H, OCH2CH2CH3), 2.27 (s, 3H, CH3Ar), 4.14 (t,
J = 6.7 Hz, 2H, OCH2CH2CH3), 4.57 (s, 2H, OCH2), 6.77–6.83 (m, 2H, ArH),
7.02–7.08 (m, 2H, ArH); 13C NMR (75.4 MHz, CDCl3) d 10.0 (CH3CH2CH2OCO),
20.2 (CH3Ar), 21.7 (CH3CH2CH2OCO), 65.3 (OCH2), 66.5 (CH3CH2CH2OCO),
114.3 (ArH), 129.7 (ArH), 130.6 (Ar), 155.6 (Ar), 169.0 (CO2); MS (70 eV) m/z
208 (M?, 100), 166 (9), 121 (81), 108 (17), 107 (16), 91 (59), 77 (15), 65 (17).
n-Amyl 4-methylphenoxyacetate (9c)
Following method A, with a mixture of 1.0 g (6.0 mmol) of 18, 0.1 g (0.6 mmol) of
p-TsOH, and 10.6 g (120 mmol) of n-amyl alcohol, gave 1.2 g (85%) of 9c as a
colorless oil: Rf 0.55 (hexane/EtOAc, 9:1); IR (film) 2957, 2928, 1760, 1734, 1511,
1
1288, 1192, 1084, 817 cm-1; H NMR (300 MHz, CDCl3) d 0.87 (t, J = 6.9 Hz,
3H, OCH2(CH2)3CH3), 1.22–1.36 (m, 4H, 2CH2), 1.54–1.67 (m, 2H, CH2), 2.25
(s, 3H, CH3Ar), 4.15 (t, J = 6.9 Hz, 2H, OCH2(CH2)3CH3), 4.55 (s, 2H, OCH2),
6.73–6.82 (m, 2H, ArH), 6.98–7.08 (m, 2H, ArH); 13C NMR (75.4 MHz, CDCl3)
d 13.8 (CH3(CH2)3CH2O), 20.3 (CH3Ar), 22.1 (CH3CH2(CH2)2CH2O), 27.7
(EtCH2CH2CH2O), 28.1 (PrCH2CH2O), 65.2 (OCH2 or BuCH2O), 65.3 (BuCH2O

Med Chem Res (2010) 19:33–57
45
or OCH2), 114.3 (ArH), 129.8 (ArH), 130.7 (Ar), 155.6 (Ar), 169.1 (CO2); MS
(70 eV) m/z 236 (M?, 100), 166 (58), 121 (89), 108 (28), 91 (66), 77 (14), 65 (14).
Anal. Calcd. for C14H20O3: C, 71.15; H, 8.53. Found: C, 71.21; H, 8.36.
n-Dodecyl 4-methylphenoxyacetate (9d)
Following method B, with 1.0 g (6.0 mmol) of 18, 0.073 g (0.6 mmol) of DMAP in
CH2Cl2 (20 ml), 1.07 g (9.0 mmol) of SOCl2, 0.91 g (6.6 mmol) of K2CO3, and
1.22 g (6.6 mmol) of n-dodecyl alcohol in toluene (30 ml), gave 1.67 g (83%) of 9d as
a colorless oil: Rf 0.62 (hexane/EtOAc, 9:1); IR (film) 2922, 2853, 1761, 1737, 1512,
1461, 1288, 1187, 1083, 817 cm-1; 1H NMR (300 MHz, CDCl3) d0.89 (t, J = 6.7 Hz,
3H, OCH2CH2(CH2)9CH3), 1.27 (sa, 18H, 9CH2), 1.58–1.68 (m, 2H, OCH2CH2
(CH2)9CH3), 2.27 (s, 3H, CH3Ar), 4.18 (t, J = 6.7 Hz, 2H, OCH2(CH2)10 CH3), 4.57
(s, 2H, OCH2), 6.76–6.83 (m, 2H, ArH), 7.03–7.10 (m, 2H, ArH); 13C NMR
(75.4 MHz, CDCl3) d 14.0 (CH3), 20.3 (CH3Ar), 22.6 (CH2), 25.7 (CH2), 28.4 (CH2),
29.1 (CH2), 29.2 (CH2), 29.4 (CH2), 29.45 (CH2), 29.53 (CH2), 29.54 (CH2), 31.8
(CH2), 65.2 (CH3(CH2)10CH2O or OCH2), 65.4 (OCH2 or CH3(CH2)10CH2O), 114.4
(ArH), 129.8 (ArH), 130.7 (Ar), 155.7 (Ar), 169.0 (CO2); MS (70 eV) m/z 334 (M?,
52), 166 (90), 121 (100), 108 (33), 91 (73), 69 (20), 57 (40), 55 (35), 43 (53). Anal.
Calcd. for C21H34O3: C, 74.04; H, 10.25. Found: C, 75.61; H, 10.12.
4-Chlorophenyl 4-methylphenoxyacetate (9e)
Following method B, with 1.0 g (6.0 mmol) of 18, 0.073 g (0.6 mmol) of DMAP in
CH2Cl2 (20 ml), 1.07 g (9.0 mmol) of SOCl2, 0.91 g (6.6 mmol) of K2CO3, and
0.85 g (6.6 mmol) of 4-chlorophenol in toluene (30 ml), gave 1.13 g (68%) of 8e as
a white solid: Rf 0.55 (hexane/ EtOAc, 9:1); mp 105–106°C [lit. (Khan and Bahel,
1
1976) 83°C]; IR (KBr) 1767, 1513, 1488, 1252, 1206, 1084, 848, 811 cm-1; H
NMR (300 MHz, CDCl3) d 2.29 (s, 3H, CH3Ar), 4.82 (s, 2H, OCH2), 6.83–6.90 (m,
2H, ArH), 7.02–7.08 (m, 2H, Ar0H), 7.08–7.14 (m, 2H, ArH), 7.30–7.36 (m, 2H,
Ar0H); 13C NMR (75.4 MHz, CDCl3) d 20.5 (CH3Ar), 65.6 (OCH2), 114.3 (ArH),
122.6 (Ar0H), 129.6 (ArH or Ar0H), 130.1 (Ar0H or ArH), 131.4 (Ar), 131.6 (Ar0),
148.5 (Ar0), 155.7 (Ar), 167.5 (CO2); MS (70 eV) m/z 278 (M??2, 11), 276 (M?,
26), 248 (6), 141 (6), 121 (100), 99 (20), 91 (62), 65 (23).
Isopropyl 2-(2-methoxy-4-methylphenoxy)acetate (10a)
Following method A, with a mixture of 1.0 g (5.1 mmol) of 19, 0.088 g
(0.51 mmol) of p-TsOH, and 6.12 g (102 mmol) of i-PrOH, gave 1.03 g (85%)
of 10a as a pale yellow oil: Rf 0.43 (hexane/EtOAc, 8:2); IR (film) 2980, 2936,
1754, 1729, 1512, 1465, 1267, 1200, 1146, 1107, 1069, 1036, 800 cm-1; 1H NMR
(300 MHz, CDCl3) d 1.25 (d, J = 6.3 Hz, 6H, OCH(CH3)2), 2.29 (s, 3H, CH3Ar),
3.86 (s, 3H, OCH3), 4.61 (s, 2H, OCH2), 5.12 (m, 2H, OCH(CH3)2), 6.63–6.75 (m,
3H, ArH); 13C NMR (75.4 MHz, CDCl3) d 20.9 (CH3Ar), 21.6 (OCH(CH3)2), 55.6
(OCH3), 66.8 (OCH2), 68.7 (OCH(CH3)2), 112.9 (C-6), 114.4 (C-3), 120.6 (C-5),
132.0 (C-4), 145.0 (C-1), 149.2 (C-2), 168.6 (CO2); MS (70 eV) m/z 238 (M?, 68),

46
Med Chem Res (2010) 19:33–57
196 (32), 151 (39), 137 (100), 123 (14), 109 (17), 91 (29), 77 (10). Anal. Calcd. for
C13H18O4: C, 65.52; H, 7.61. Found: C, 65.32; H, 7.50.
n-Propyl 2-(2-methoxy-4-methylphenoxy)acetate (10b)
Following method A, with a mixture of 1.0 g (5.1 mmol) of 19, 0.088 g
(0.51 mmol) of p-TsOH, and 6.12 g (102 mmol) of n-PrOH, gave 1.04 g (86%)
of 10b as a colorless oil: Rf 0.40 (hexane/EtOAc, 8:2); IR (film) 2966, 2937, 1758,
1
1732, 1511, 1464, 1266, 1192, 1145, 1073, 1036, 799 cm-1; H NMR (300 MHz,
CDCl3) d 0.88 (t, J = 7.2 Hz, 3H, OCH2CH2CH3), 1.57–1.70 (m, 2H, OCH2CH2
CH3), 2.27 (s, 3H, CH3Ar), 3.83 (s, 3H, OCH3), 4.11 (t, J = 6.7 Hz, 2H,
OCH2CH2CH3), 4.63 (s, 2H, OCH2), 6.61–6.73 (m, 3H, ArH); 13C NMR
(75.4 MHz, CDCl3) d 10.1 (OCH2CH2CH3), 20.9 (CH3Ar), 21.8 (OCH2CH2CH3),
55.6 (OCH3), 66.58 (OCH2 or OCH2CH2CH3), 66.60 (OCH2CH2CH3 or OCH2),
112.9 (C-6), 114.4 (C-3), 120.6 (C-5), 132.1 (C-4), 145.0 (C-1), 149.2 (C-2), 169.2
(CO2); MS (70 eV) m/z 238 (M?, 100), 196 (2), 151 (18), 137 (83), 123 (12), 109
(31), 91 (30), 77 (14). Anal. Calcd. for C13H18O4: C, 65.52; H, 7.61. Found: C,
65.38; H, 7.72.
n-Amyl 2-(2-methoxy-4-methylphenoxy)acetate (10c)
Following method A, with a mixture of 1.0 g (5.1 mmol) of 19, 0.088 g
(0.51 mmol) of p-TsOH, and 8.98 g (102 mmol) of n-amylOH, gave 1.15 g
(85%) of 10c as a colorless oil: Rf 0.48 (hexane/EtOAc, 8:2); IR (film) 2957, 2932,
;
1759, 1734, 1512, 1464, 1267, 1192, 1147, 1073, 1037, 799 cm-1 1H NMR
(300 MHz, CDCl3) d 0.86 (t, J = 6.7 Hz, 3H, OCH2(CH2)3CH3), 1.20–1.32 (m, 4H,
OCH2(CH2)3CH3), 1.55–1.66 (m, 2H, OCH2(CH2)3CH3), 2.27 (s, 3H, CH3Ar), 3.83
(s, 3H, OCH3), 4.15 (t, J = 6.7 Hz, 2H, OCH2(CH2)3CH3), 4.63 (s, 2H, OCH2),
6.61–6.73 (m, 3H, ArH); 13C NMR (75.4 MHz, CDCl3) d 13.8 (OCH2(CH2)3CH3),
20.9 (CH3Ar), 22.1 (OCH2(CH2)2CH2CH3), 27.8 (O(CH2)2CH2CH2CH3), 28.1
(OCH2CH2(CH2)2CH3), 55.6 (OCH3), 65.1 (OCH2(CH2)3CH3), 66.7 (OCH2), 113.0
(C-6), 114.5 (C-3), 120.7 (C-5), 132.1 (C-4), 145.0 (C-1), 149.3 (C-2), 169.2 (CO2);
MS (70 eV) m/z 266 (M?, 49), 196 (4), 151 (13), 137 (100), 123 (11), 109 (24), 91
(33), 77 (14). Anal. Calcd. for C15H22O4: C, 67.64; H, 8.32. Found: C, 67.74; H,
8.16.
n-Dodecyl 2-(2-methoxy-4-methylphenoxy)acetate (10d)
Following method B, with 1.0 g (5.1 mmol) of 19, 0.062 g (0.51 mmol) of DMAP
in CH2Cl2 (20 ml), 0.91 g (7.6 mmol) of SOCl2, 0.77 g (5.6 mmol) of K2CO3, and
1.04 g (5.6 mmol) of n-dodecyl alcohol in toluene (30 ml), gave 1.41 g (76%) of
10d as a colorless oil: Rf 0.54 (hexane/EtOAc, 8:2); IR (film) 2923, 2853, 1760,
1
1737, 1512, 1462, 1268, 1192, 1152, 1073, 1037, 799 cm-1; H NMR (300 MHz,
CDCl3) d 0.85 (t, J = 6.9 Hz, 3H, OCH2CH2(CH2)9CH3), 1.23 (br s, 18H, 9CH2),
1.56–1.63 (m, 2H, OCH2CH2(CH2)9CH3), 2.27 (s, 3H, CH3Ar), 3.83 (s, 3H, OCH3),
4.15 (t, J = 6.9 Hz, 2H, OCH2(CH2)10CH3), 4.63 (s, 2H, OCH2), 6.61–6.73 (m, 3H,

Med Chem Res (2010) 19:33–57
47
ArH); 13C NMR (75.4 MHz, CDCl3) d 14.0 (CH3), 20.9 (CH3Ar), 22.6 (CH2), 25.7
(CH2), 28.4 (CH2), 29.1 (CH2), 29.2 (CH2), 29.41 (CH2), 29.46 (CH2), 29.53 (CH2),
29.55 (CH2), 31.8 (CH2), 55.7 (OCH3), 65.2 (CH3(CH2)10CH2O), 66.6 (OCH2),
113.0 (C-6), 114.4 (C-3), 120.7 (C-5), 132.1 (C-4), 145.0 (C-1), 149.3 (C-2), 169.2
(CO2); MS (70 eV) m/z 364 (M?, 100), 320 (45), 196 (7), 152 (59), 137 (42), 107
(34), 77 (26), 43 (30). Anal. Calcd. for C22H36O4: C, 72.42; H, 9.95. Found: C,
72.21; H, 9.82.
4-Chlorophenyl 2-(2-methoxy-4-methylphenoxy)acetate (10e)
Following method B, with 1.0 g (5.1 mmol) of 19, 0.062 g (0.51 mmol) of DMAP
in CH2Cl2 (20 ml), 0.91 g (7.6 mmol) of SOCl2, 0.77 g (5.6 mmol) of K2CO3, and
0.72 g (5.6 mmol) of 4-chlorophenol in toluene (30 ml), gave 1.0 g (64%) of 10e as
a white solid: Rf 0.4 (hexane/EtOAc, 8:2); mp 90–91°C (hexane/EtOAc, 8:2); IR
(KBr) 1780, 1512, 1487, 1264, 1200, 1141, 1085, 1038, 841 cm-1 1H NMR
;
(300 MHz, CDCl3) d 2.31 (s, 3H, CH3Ar), 3.86 (s, 3H, OCH3), 4.88 (s, 2H, OCH2),
6.69 (dm, J = 8.1 Hz, 1H, H-5), 6.74 (d, J = 1.8 Hz, 1H, H-3), 6.85 (d,
J = 8.1 Hz, 1H, H-6), 7.02–7.07 (m, 2H, Ar0H), 7.29–7.34 (m, 2H, Ar0H); 13C
NMR (75.4 MHz, CDCl3) d 21.0 (CH3Ar), 55.7 (OCH3), 67.0 (OCH2), 113.2 (C-6),
115.5 (C-3), 120.8 (C-5), 122.6 (C-20, C-60), 129.4 (C-30, C-5’), 131.4 (C-40), 132.9
(C-4), 144.8 (C-1), 148.5 (C-10), 149.6 (C-2), 167.6 (CO2); MS (70 eV) m/z 308
(M??2, 14), 306 (M?, 41), 151 (100), 136 (97), 123 (8), 91 (30), 77 (13). Anal.
Calcd. for C16H15ClO4: C, 62.65; H, 4.93. Found: C, 62.63; H, 5.05.
Methyl 2-(2-methoxyphenoxy)acetate (11a)
Following method A, with a mixture of 1.0 g (5.5 mmol) of 23, 0.095 g
(0.55 mmol) of p-TsOH, and 3.5 g (110 mmol) of MeOH, gave 0.97 g (90%) of
11a as a white solid: Rf 0.43 (29 hexane/EtOAc, 8:2); mp 48–50°C (hexane/EtOAc,
8:2) [lit. (Ahvonen et al., 1983) 47°C]; IR (film) 2953, 1759, 1504, 1444, 1252,
1
1206, 1178, 1128, 1027, 747 cm-1; H NMR (300 MHz, CDCl3) d 3.77 (s, 3H,
CH3OCO), 3.86 (s, 3H, OCH3), 4.68 (s, 2H, OCH2), 6.79–7.00 (m, 4H, ArH); 13C
NMR (75.4 MHz, CDCl3) d 52.2 (CH3OCO), 55.8 (OCH3), 66.3 (OCH2), 111.9
(ArH), 114.1 (ArH), 120.6 (ArH), 122.5 (ArH), 147.1 (Ar), 149.5 (Ar), 169.5 (CO2);
MS (70 eV) m/z 196 (M?, 100), 137 (25), 123 (40), 122 (40), 95 (31), 77 (46), 65
(10).
Ethyl 2-(2-methoxyphenoxy)acetate (11b) (Myska et al., 1961)
Following method A, with a mixture of 1.0 g (5.5 mmol) of 23, 0.095 g
(0.55 mmol) of p-TsOH, and 5.1 g (110 mmol) of EtOH, gave 1.06 g (92%) of
11b as a colorless oil: Rf 0.52 (29 hexane/EtOAc, 8:2); IR (film) 2980, 1756, 1734,
;
1593, 1502, 1458, 1252, 1196, 1178, 1128, 1073, 1027, 746 cm-1 1H NMR
(300 MHz, CDCl3) d 1.24 (t, J = 7.2 Hz, 3H, OCH2CH3), 3.84 (s, 3H, OCH3), 4.21
(q, J = 7.2 Hz, 2H, OCH2CH3), 4.65 (s, 2H, OCH2), 6.78–6.97 (m, 4H, ArH); 13C
NMR (75.4 MHz, CDCl3) d 14.0 (OCH2CH3), 55.7 (OCH3), 61.1 (OCH2CH3), 66.3

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(OCH2), 111.9 (ArH), 114.1 (ArH), 120.5 (ArH), 122.3 (ArH), 147.1 (Ar), 149.4
(Ar), 168.9 (CO2); MS (70 eV) m/z 210 (M?, 100), 137 (35), 123 (37), 122 (55),
109 (14), 95 (25), 77 (41).
Isopropyl 2-(2-methoxyphenoxy)acetate (11c) (Myska et al., 1961)
Following method A, with a mixture of 1.0 g (5.5 mmol) of 23, 0.095 g
(0.55 mmol) of p-TsOH, and 6.6 g (110 mmol) of n-PrOH, which was heated to
60°C for 12 h to give 1.08 g (88%) of 11c as a colorless oil: Rf 0.41 (hexane/EtOAc,
8:2); IR (film) 2980, 2937, 1753, 1729, 1593, 1502, 1457, 1376, 1285, 1199, 1177,
1128, 1106, 1070, 1027, 743 cm-1 1H NMR (300 MHz, CDCl3) d 1.22 (d,
;
J = 6.3 Hz, 6H, OCH(CH3)2), 3.85 (s, 3H, OCH3), 4.62 (s, 2H, OCH2), 5.10 (sep,
J = 6.3 Hz, 1H, OCH(CH3)2), 6.77–6.98 (m, 4H, ArH); 13C NMR (75.4 MHz,
CDCl3) d 21.7 (OCH(CH3)2), 55.8 (OCH3), 66.5 (OCH2), 68.9 (OCH(CH3)2), 112.0
(ArH), 114.2 (ArH), 120.6 (ArH), 122.3 (ArH), 147.3 (Ar), 149.5 (Ar), 168.5 (CO2);
MS (70 eV) m/z 224 (M?, 100), 182 (34), 137 (68), 123 (50), 122 (85), 109 (22), 95
(20), 92 (24), 77 (61), 65 (11), 51 (11), 43 (56).
n-Propyl 2-(2-Methoxyphenoxy)acetate (11d) (Myska et al., 1961)
Following method A, with a mixture of 1.0 g (5.5 mmol) of 23, 0.095 g
(0.55 mmol) of p-TsOH, and 6.6 g (110 mmol) of n-PrOH, gave 1.06 g (86%) of
11d as a colorless oil: Rf 0.59 (29 hexane/EtOAc, 8:2); IR (film) 2965, 2837, 1756,
1
1733, 1593, 1501, 1458, 1250, 1192, 1176, 1126, 1072, 1027, 970, 744 cm-1; H
NMR (300 MHz, CDCl3) d 0.88 (t, J = 7.3 Hz, 3H, OCH2CH2CH3), 1.57–1.70 (m,
2H, OCH2CH2CH3), 3.85 (s, 3H, OCH3), 4.12 (t, J = 6.7 Hz, 2H, OCH2CH2CH3),
4.67 (s, 2H, OCH2), 6.77–6.99 (m, 4H, ArH); 13C NMR (75.4 MHz, CDCl3) d 10.1
(OCH2CH2CH3), 21.8 (OCH2CH2CH3), 55.7 (OCH3), 66.3 (OCH2), 66.6
(OCH2CH2CH3), 111.9 (ArH), 114.0 (ArH), 120.5 (ArH), 122.3 (ArH), 147.1
(Ar), 149.4 (Ar), 169.0 (CO2); MS (70 eV) m/z 224 (M?, 99), 182 (4), 137 (65), 123
(84), 122 (100), 109 (33), 95 (42), 93 (30), 77 (84), 65 (18), 52 (19), 52 (19), 43
(24).
n-Amyl 2-(2-methoxyphenoxy)acetate (11e)
Following method A, with a mixture of 1.0 g (5.5 mmol) of 23, 0.095 g
(0.55 mmol) of p-TsOH, and 9.7 g (110 mmol) of n-amylOH, gave 1.24 g (90%)
of 11e as a colorless oil: Rf 0.45 (hexane/EtOAc, 8:2); IR (film) 2965, 2932, 2870,
1758, 1733, 1593, 1502, 1459, 1250, 1192, 1176, 1127, 1073, 1027, 975, 743 cm-1
;
1H NMR (300 MHz, CDCl3) d 0.82 (t, J = 6.9 Hz, 3H, OCH2(CH2)3CH3), 1.18–
1.28 (m, 4H, OCH2(CH2)3CH3), 1.53–1.62 (m, 2H, OCH2(CH2)3CH3), 3.80 (s, 3H,
OCH3), 4.12 (t, J = 6.7 Hz, 2H, OCH2(CH2)3CH3), 4.63 (s, 2H, OCH2), 6.75–6.94
(m, 4H, ArH); 13C NMR (75.4 MHz, CDCl3) d 13.7 (OCH2(CH2)3CH3), 22.0
(OCH2(CH2)2CH2CH3), 27.6 (O(CH2)2CH2CH2CH3), 28.0 (OCH2CH2(CH2)2CH3),
55.6 (OCH3), 65.0 (OCH2(CH2)3CH3), 66.2 (OCH2), 111.9 (ArH), 114.1 (ArH),
120.4 (ArH), 122.2 (ArH), 147.1 (Ar), 149.4 (Ar), 168.9 (CO2); MS (70 eV) m/z

Med Chem Res (2010) 19:33–57
49
252 (M?, 89), 182 (14), 137 (62), 123 (88), 122 (100), 109 (29), 95 (34), 93 (27), 77
(80), 65 (15), 43 (34). Anal. Calcd. for C14H20O4: C, 66.64; H, 7.94. Found: C,
66.83; H, 7.95.
n-Dodecyl 2-(2-Methoxyphenoxy)acetate (11f)
Following method B, with a mixture of 1.0 g (5.5 mmol) of 23, 0.067 g (0.55 mmol)
of DMAP in CH2Cl2 (20 ml), 0.98 g (8.25 mmol) of SOCl2, 0.835 g (6.05 mmol) of
K2CO3, and 1.12 g (6.05 mmol) of n-dodecyl alcohol in toluene (30 ml), gave 1.63 g
(85%) of 11f as a colorless oil: Rf 0.55 (hexane/EtOAc, 8:2); IR (film) 2928, 2853,
1760, 1593, 1503, 1460, 1252, 1177, 1128, 1073, 1029, 742 cm-1 1H NMR
;
(300 MHz, CDCl3) d 0.85 (t, J = 6.7 Hz, 3H, OCH2CH2(CH2)9CH3), 1.27 (br s,
18H, 9CH2), 1.54–1.64 (m, 2H, OCH2CH2(CH2)9CH3), 3.86 (s, 3H, OCH3), 4.16
(t, J = 6.7 Hz, 2H, OCH2(CH2)10CH3), 4.67 (s, 2H, OCH2), 6.78–6.99 (m, 4H, ArH);
13C NMR (75.4 MHz, CDCl3) d 14.1 (CH3), 22.6 (CH2), 25.7 (CH2), 28.5 (CH2), 29.1
(CH2), 29.3 (CH2), 29.4 (CH2), 29.50 (CH2), 29.57 (CH2), 29.59 (CH2), 31.9 (CH2),
55.8 (OCH3), 65.3 (CH3(CH2)10CH2O), 66.4 (OCH2), 112.0 (ArH), 114.2 (ArH),
120.7 (ArH), 122.4 (ArH), 147.3 (Ar), 149.6 (Ar), 169.1 (CO2); MS (70 eV) m/z 350
(M?, 100), 182 (29), 137 (72), 123 (51), 122 (77), 109 (16), 95 (24), 77 (53), 55 (45),
43 (64).
4-Chlorophenyl 2-(2-methoxyphenoxy)acetate (11g)
Following method B, with a mixture of 1.0 g (5.5 mmol) of 23, 0.067 g
(0.55 mmol) of DMAP in CH2Cl2 (20 ml), 0.98 g (8.25 mmol) of SOCl2, 0.835 g
(6.05 mmol) of K2CO3, and 0.72 g (5.6 mmol) of 4-chlorophenol in toluene
(30 ml), gave 1.28 g (80%) of 11g as a white solid: Rf 0.52 (29 hexane/EtOAc,
8:2); mp 93–94°C (hexane/EtOAc, 8:2); IR (KBr) 2924, 1780, 1592, 1502, 1486,
1457, 1252, 1198, 1165, 1127, 1086, 1014, 742 cm-1; 1H NMR (300 MHz, CDCl3)
d 3.88 (s, 3H, OCH3), 4.91 (s, 2H, OCH2), 6.87–7.06 (m, 6H, H-5), 7.29–7.35 (m,
2H, ArH); 13C NMR (75.4 MHz, CDCl3) d 55.8 (OCH3), 66.6 (OCH2), 112.2
(ArH), 115.1 (ArH), 120.7 (ArH), 122.6 (ArH), 123.0 (ArH), 129.5 (ArH), 131.4
(Ar), 147.0 (Ar), 148.5 (Ar), 149.8 (Ar), 167.5 (CO2); MS (70 eV) m/z 294 (M??2,
3), 292 (M?, 14), 137 (100), 122 (78), 92 (22), 77 (44). Anal. Calcd. for
C15H13ClO4: C, 61.54; H, 4.47. Found: C, 61.70; H, 4.63.
Methyl 2-(3-methoxyphenoxy)acetate (12a) (Myska et al., 1961)
Following method A, with a mixture of 1.0 g (5.5 mmol) of 24, 0.095 g
(0.55 mmol) of p-TsOH, and 3.5 g (110 mmol) of MeOH, gave 0.99 g (92%) of
12a as a colorless oil: Rf 0.30 (hexane/EtOAc, 8:2); IR (film) 1759, 1592, 1492,
;
1456, 1436, 1265, 1195, 1152, 1086, 1036, 835, 760, 685 cm-1 1H NMR
(300 MHz, CDCl3) d 3.72 (s, 3H, CH3OCO), 3.75 (s, 3H, OCH3), 4.57 (s, 2H,
OCH2), 6.41–6.54 (m, 3H, ArH), 7.14 (t, J = 8.1 Hz, 1H, ArH); 13C NMR
(75.4 MHz, CDCl3) d 52.0 (CH3OCO), 55.0 (OCH3), 64.9 (OCH2), 101.0 (ArH),
106.0 (ArH), 107.2 (ArH), 129.8 (ArH), 158.7 (Ar), 160.6 (Ar), 169.1 (CO2); MS

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Med Chem Res (2010) 19:33–57
(70 eV) m/z 196 (M?, 100), 137 (53), 109 (20), 107 (50), 92 (23), 77 (31), 64 (15),
63 (13).
Ethyl 2-(3-methoxyphenoxy)acetate (12b) (Myska et al., 1961)
Following method A, with a mixture of 1.0 g (5.5 mmol) of 24, 0.095 g
(0.55 mmol) of p-TsOH, and 5.1 g (110 mmol) of EtOH, gave 1.0 g (88%) of
12b as a colorless oil: Rf 0.40 (hexane/EtOAc, 8:2); IR (film) 1756, 1730, 1594,
;
1492, 1457, 1266, 1193, 1152, 1086, 1032, 835, 761, 685 cm-1 1H NMR
(300 MHz, CDCl3) d 1.27 (t, J = 7.2 Hz, 3H, OCH2CH3), 3.75 (s, 3H, OCH3), 4.24
(q, J = 7.2 Hz, 2H, OCH2CH3), 4.57 (s, 2H, OCH2), 6.44–6.56 (m, 3H, ArH), 7.16
(t, J = 8.1 Hz, 1H, ArH); 13C NMR (75.4 MHz, CDCl3) d 14.0 (OCH2CH3), 55.0
(OCH3), 61.1 (OCH2CH3), 65.1 (OCH2), 101.1 (ArH), 106.2 (ArH), 107.3 (ArH),
129.8 (ArH), 158.8 (Ar), 160.7 (Ar), 168.7 (CO2); MS (70 eV) m/z 210 (M?, 100),
182 (5), 137 (60), 124 (11), 109 (23), 107 (58), 92 (27), 77 (34).
Isopropyl 2-(3-methoxyphenoxy)acetate (12c) (Myska et al., 1961)
Following method A, with a mixture of 1.0 g (5.5 mmol) of 24, 0.095 g
(0.55 mmol) of p-TsOH, and 6.6 g (110 mmol) of n-PrOH, which was heated to
60°C for 12 h to give 1.05 g (85%) of 12c as a colorless oil: Rf 0.45 (hexane/EtOAc,
8:2); IR (film) 1753, 1730, 1593, 1492, 1456, 1284, 1266, 1194, 1154, 1105, 1087,
1039, 834, 762, 686 cm-1; 1H NMR (300 MHz, CDCl3) d 1.23 (d, J = 6.3 Hz, 6H,
OCH(CH3)2), 3.73 (s, 3H, OCH3), 4.52 (s, 2H, OCH2), 5.10 (m, 1H, OCH(CH3)2),
6.41–6.54 (m, 3H, ArH), 7.13 (t, J = 8.1 Hz, 1H, ArH); 13C NMR (75.4 MHz,
CDCl3) d 21.5 (OCH(CH3)2), 55.0 (OCH3), 65.3 (OCH2), 68.9 (OCH(CH3)2), 101.1
(ArH), 106.1 (ArH), 107.2 (ArH), 129.7 (ArH), 158.9 (Ar), 160.6 (Ar), 168.2 (CO2);
MS (70 eV) m/z 224 (M?, 100), 182 (43), 165 (8), 137 (89), 124 (17), 109 (20), 107
(54), 92 (28), 77 (30), 64 (13), 43 (42).
n-Propyl 2-(3-Methoxyphenoxy)acetate (12d) (Myska et al., 1961)
Following method A, with a mixture of 1.0 g (5.5 mmol) of 24, 0.095 g
(0.55 mmol) of p-TsOH, and 6.6 g (110 mmol) of n-PrOH, which was heated to
60°C for 12 h to give 1.06 g (86%) of 12d as a colorless oil: Rf 0.48 (hexane/
EtOAc, 8:2); IR (film) 1757, 1597, 1491, 1460, 1269, 1194, 1153, 1085, 1044, 836,
736, 686 cm-1
;
1H NMR (300 MHz, CDCl3) d 0.90 (t, J = 7.5 Hz, 3H,
OCH2CH2CH3), 1.58–1.71 (m, 2H, OCH2CH2CH3), 3.74 (s, 3H, OCH3), 4.13 (t,
J = 6.6 Hz, 2H, OCH2CH2CH3), 4.57 (s, 2H, OCH2), 6.43–6.54 (m, 3H, ArH), 7.14
(t, J = 8.1 Hz, 1H, ArH); 13C NMR (75.4 MHz, CDCl3) d 10.1 (OCH2CH2CH3),
21.7 (OCH2CH2CH3), 55.0 (OCH3), 65.1 (OCH2), 66.6 (OCH2CH2CH3), 101.1
(ArH), 106.2 (ArH), 107.2 (ArH), 129.8 (ArH), 158.9 (Ar), 160.7 (Ar), 168.8 (CO2);
MS (70 eV) m/z 224 (M?, 100), 182 (37), 165 (8), 137 (78), 124 (19), 109 (38), 107
(65), 92 (44), 77 (42), 64 (20), 63 (17).

Med Chem Res (2010) 19:33–57
51
n-Amyl 2-(3-methoxyphenoxy)acetate (12e)
Following method A, with a mixture of 1.0 g (5.5 mmol) of 24, 0.095 g
(0.55 mmol) of p-TsOH, and 9.7 g (110 mmol) of n-amylOH, gave 1.1 g (80%)
of 12e as a colorless oil: Rf 0.53 (hexane/EtOAc, 8:2); IR (film) 2958, 1759, 1736,
;
1596, 1492, 1460, 1267, 1193, 1154, 1087, 1042, 762, 686 cm-1 1H NMR
(300 MHz, CDCl3) d 0.88 (t, J = 6.9 Hz, 3H, OCH2(CH2)3CH3), 1.22–1.38 (m, 4H,
OCH2(CH2)3CH3), 1.58–1.68 (m, 2H, OCH2(CH2)3CH3), 3.75 (s, 3H, OCH3), 4.18
(t, J = 6.6 Hz, 2H, OCH2(CH2)3CH3), 4.59 (s, 2H, OCH2), 6.44–6.55 (m, 3H,
ArH), 7.16 (t, J = 8.0 Hz, 1H, ArH); 13C NMR (75.4 MHz, CDCl3) d 13.8
(OCH2(CH2)3CH3), 22.1 (OCH2(CH2)2CH2CH3), 27.8 (O(CH2)2CH2CH2CH3),
28.1 (OCH2CH2(CH2)2CH3), 55.1 (OCH3), 65.2 (OCH2(CH2)3CH3 or OCH2),
65.3 (OCH2 or OCH2(CH2)3CH3), 101.2 (ArH), 106.2 (ArH), 107.3 (ArH), 129.8
(ArH), 158.9 (Ar), 160.7 (Ar), 168.8 (CO2); MS (70 eV) m/z 252 (M?, 87), 182
(13), 137 (17), 123 (100), 109 (15), 107 (13), 92 (14), 77 (17). Anal. Calcd. for
C14H20O4: C, 66.64; H, 7.94. Found: C, 66.51; H, 7.96.
n-Dodecyl 2-(3-methoxyphenoxy)acetate (12f)
Following method B, with a mixture of 1.0 g (5.5 mmol) of 24, 0.067 g (0.55 mmol)
of DMAP in CH2Cl2 (20 ml), 0.98 g (8.25 mmol) of SOCl2, 0.835 g (6.05 mmol) of
K2CO3, and 1.12 g (6.05 mmol) of n-dodecyl alcohol in toluene (30 ml), gave 1.57 g
(82%) of 12f as a colorless oil: Rf 0.63 (hexane/EtOAc, 8:2); IR (film) 2922, 2853,
1760, 1597, 1491, 1461, 1269, 1193, 1154, 1086, 1043, 835, 761, 685 cm-1; 1H NMR
(300 MHz, CDCl3) d 0.87 (t, J = 6.6 Hz, 3H, OCH2CH2(CH2)9CH3), 1.24 (br s,
18H, 9CH2), 1.56–1.69 (m, 2H, OCH2CH2(CH2)9CH3), 3.75 (s, 3H, OCH3), 4.18 (t,
J = 6.6 Hz, 2H, OCH2(CH2)10CH3), 4.58 (s, 2H, OCH2), 6.43–6.55 (m, 3H, ArH),
7.12–7.19 (m, 1H, ArH); 13C NMR (75.4 MHz, CDCl3) d 14.0 (CH3), 22.6 (CH2),
25.7 (CH2), 28.5 (CH2), 29.1 (CH2), 29.3 (CH2), 29.4 (CH2), 29.50 (CH2), 29.55
(CH2), 29.57 (CH2), 31.8 (CH2), 55.1 (OCH3), 65.3 (CH3(CH2)10CH2O or OCH2),
65.4 (OCH2 or CH3(CH2)10CH2O), 101.2 (ArH), 106.3 (ArH), 107.3 (ArH), 129.9
(ArH), 159.0 (Ar), 160.8 (Ar), 168.9 (CO2); MS (70 eV) m/z 350 (M?, 100), 184 (52),
182 (91), 138 (15), 137 (20), 125 (9), 109 (8), 77 (6). Anal. Calcd. for C21H34O4: C,
71.96; H, 9.78. Found: C, 72.04; H, 9.76.
4-Chlorophenyl 2-(3-methoxyphenoxy)acetate (12g)
Following method B, with a mixture of 1.0 g (5.5 mmol) of 24, 0.067 g
(0.55 mmol) of DMAP in CH2Cl2 (20 ml), 0.98 g (8.25 mmol) of SOCl2, 0.835 g
(6.05 mmol) of K2CO3, and 0.78 g (6.05 mmol) of 4-chlorophenol in toluene
(30 ml), gave 0.96 g (60%) of 12g as a white solid: Rf 0.46 (hexane/EtOAc, 8:2);
mp 67–68°C (hexane/EtOAc, 8:2); IR (KBr) 1780, 1598, 1488, 1266, 1198, 1146,
1086, 836, 742, 685 cm-1; 1H NMR (300 MHz, CDCl3) d 3.77 (s, 3H, OCH3), 4.82
(s, 2H, OCH2), 6.51–6.60 (m, 3H, ArH), 7.02–7.08 (m, 2H, ArH), 7.17–7.24 (m, 1H,
ArH), 7.29–7.36 (m, 2H, ArH); 13C NMR (75.4 MHz, CDCl3) d 55.2 (OCH3), 65.2
(OCH2), 101.4 (ArH), 106.3 (ArH), 107.7 (ArH), 122.6 (ArH), 129.5 (ArH), 130.0

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(ArH), 131.5 (Ar), 148.4 (Ar), 158.7 (Ar), 160.9 (Ar), 167.1 (CO2); MS (70 eV) m/z
294 (M??2, 9), 292 (M?, 29), 165 (10), 137 (100), 109 (12),107 (45), 92 (21), 77
(25). Anal. Calcd. for C15H13ClO4: C, 61.54; H, 4.47. Found: C, 61.51; H, 4.41.
Methyl 2-(4-Methoxyphenoxy)acetate (13a)
Following method A, with a mixture of 1.0 g (5.5 mmol) of 25, 0.095 g
(0.55 mmol) of p-TsOH, and 3.5 g (110 mmol) of MeOH, gave 1.01 g (94%) of
13a as a white solid: Rf 0.49 (hexane/EtOAc, 8:2); mp 49–50°C [lit. (Hayashi et al.,
1983) 44–46°C] (hexane/EtOAc, 8:2); IR (film) 1759, 1507, 1438, 1201, 1178,
1083, 1031, 825 cm-1; 1H NMR (300 MHz, CDCl3) d 3.66 (s, 3H, CH3OCO), 3.69
(s, 3H, OCH3), 4.94 (s, 2H, OCH2), 6.73–6.81 (m, 4H, ArH); 13C NMR (75.4 MHz,
CDCl3) d 51.7 (CH3OCO), 55.2 (OCH3), 65.7 (OCH2), 114.3 (ArH), 115.4 (ArH),
151.6 (Ar), 154.2 (Ar), 169.3 (CO2); MS (70 eV) m/z 196 (M?, 52), 137 (10), 123
(100), 107 (8), 95 (16), 77 (10).
Ethyl 2-(4-methoxyphenoxy)acetate (13b) (Benjamin et al., 1998)
Following method A, with a mixture of 1.0 g (5.5 mmol) of 25, 0.095 g (0.55 mmol)
of p-TsOH, and 5.1 g (110 mmol) of EtOH, gave 1.09 g (95%) of 13b as a colorless
oil: Rf 0.46 (hexane/EtOAc, 8:2); IR (film) 1756, 1730, 1506, 1441, 1193, 1081,
1
1031, 825 cm-1; H NMR (300 MHz, CDCl3) d 1.23 (t, J = 7.2 Hz, 3H, OCH2
CH3), 3.69 (s, 3H, OCH3), 4.19 (q, J = 7.2 Hz, 2H, OCH2CH3), 4.50 (s, 2H, OCH2),
6.73–6.83 (m, 4H, ArH); 13C NMR (75.4 MHz, CDCl3) d 13.9 (OCH2CH3), 55.3
(OCH3), 61.0 (OCH2CH3), 66.0 (OCH2), 114.3 (ArH), 115.5 (ArH), 151.7 (Ar),
154.2 (Ar), 168.9 (CO2); MS (70 eV) m/z 210 (M?, 57), 137 (16), 123 (100), 107
(12), 95 (10), 77 (12).
Isopropyl 2-(4-methoxyphenoxy)acetate (13c) (Myska et al., 1961)
Following method A, with a mixture of 1.0 g (5.5 mmol) of 25, 0.095 g
(0.55 mmol) of p-TsOH, and 6.6 g (110 mmol) of n-PrOH, which was heated to
60°C for 12 h to give 1.13 g (92%) of 13c as a colorless oil: Rf 0.40 (hexane/EtOAc,
8:2); IR (film) 2981, 2936, 1752, 1729, 1506, 1456, 1442, 1376, 1287, 1197, 1106,
1
1080, 1034, 825 cm-1; H NMR (300 MHz, CDCl3) d 1.22 (d, J = 6.3 Hz, 6H,
OCH(CH3)2), 3.71 (s, 3H, OCH3), 4.49 (s, 2H, OCH2), 5.09 (sep, J = 6.3 Hz, 1H,
OCH(CH3)2), 6.76–6.84 (m, 4H, ArH); 13C NMR (75.4 MHz, CDCl3) d 21.5
(OCH(CH3)2), 55.4 (OCH3), 66.2 (OCH(CH3)2), 68.8 (OCH2), 114.4 (ArH), 115.6
(ArH), 151.8 (Ar), 154.2 (Ar), 168.6 (CO2); MS (70 eV) m/z 224 (M?, 74), 182
(57), 137 (39), 123 (100), 109 (21), 107 (17), 92 (18), 77 (18).
n-Propyl 2-(4-methoxyphenoxy)acetate (13d) (Myska et al., 1961)
Following method A, with a mixture of 1.0 g (5.5 mmol) of 25, 0.095 g
(0.55 mmol) of p-TsOH, and 6.6 g (110 mmol) of n-PrOH, gave 1.16 g (95%) of
13d as a colorless oil: Rf 0.49 (hexane/EtOAc, 8:2); IR (film) 2965, 1757, 1733,

Med Chem Res (2010) 19:33–57
53
1
1507, 1463, 1441, 1270, 1238, 1191, 1083, 1034, 825 cm-1; H NMR (300 MHz,
CDCl3) d 0.87 (t, J = 7.5 Hz, 3H, OCH2CH2CH3), 1.56–1.72 (m, 2H, OCH2CH2
CH3), 3.69 (s, 3H, OCH3), 4.10 (t, J = 6.7 Hz, 2H, OCH2CH2CH3), 4.52 (s, 2H,
OCH2), 6.73–6.86 (m, 4H, ArH); 13C NMR (75.4 MHz, CDCl3) d 10.0
(OCH2CH2CH3), 21.6 (OCH2CH2CH3), 55.3 (OCH3), 65.9 (OCH2CH2CH3), 66.4
(OCH2), 114.3 (ArH), 115.5 (ArH), 151.7 (Ar), 155.2 (Ar), 169.0 (CO2); MS
(70 eV) m/z 224 (M?, 66), 182 (4), 137 (18), 123 (100), 109 (12), 92 (10), 77 (11).
n-Amyl 2-(4-Methoxyphenoxy)acetate (13e)
Following method A, with a mixture of 1.0 g (5.5 mmol) of 25, 0.095 g
(0.55 mmol) of p-TsOH, and 9.7 g (110 mmol) of n-amylOH, gave 1.27 g (92%)
of 13e as a colorless oil: Rf 0.56 (hexane/EtOAc, 8:2); IR (film) 2954, 1757, 1507,
1462, 1283, 1183, 1083, 1036, 826, 721 cm-1; 1H NMR (300 MHz, CDCl3) d 0.83
(t, J = 6.9 Hz, 3H, OCH2(CH2)3CH3), 1.16–1.33 (m, 4H, OCH2(CH2)3CH3), 1.52–
1.64 (m, 2H, OCH2(CH2)3CH3), 3.67 (s, 3H, OCH3), 4.11 (t, J = 6.6 Hz, 2H,
OCH2(CH2)3CH3), 4.50 (s, 2H, OCH2), 6.73–6.82 (m, 4H, ArH); 13C NMR
(75.4 MHz, CDCl3) d 13.6 (OCH2(CH2)3CH3), 22.0 (OCH2(CH2)2CH2CH3), 27.6
(O(CH2)2CH2CH2CH3), 27.9 (OCH2CH2(CH2)2CH3), 55.2 (OCH3), 64.9 (OCH2
(CH2)3CH3 or OCH2), 65.9 (OCH2 or OCH2(CH2)3CH3), 114.3 (ArH), 115.5 (ArH),
151.8 (Ar), 154.2 (Ar), 168.9 (CO2); MS (70 eV) m/z 252 (M?, 70), 182 (24), 137
(21), 123 (100), 109 (12), 107 (11), 92 (9), 77 (21). Anal. Calcd. for C14H20O4: C,
66.64; H, 7.94. Found: C, 66.54; H, 7.92.
n-Dodecyl 2-(4-methoxyphenoxy)acetate (13f)
Following method B, with a mixture of 1.0 g (5.5 mmol) of 25, 0.067 g
(0.55 mmol) of DMAP in CH2Cl2 (20 ml), 0.98 g (8.25 mmol) of SOCl2, 0.835 g
(6.05 mmol) of K2CO3, and 1.12 g (6.05 mmol) of n-dodecyl alcohol in toluene
(30 ml), gave 1.59 g (83%) of 13f as a colorless oil: Rf 0.61 (hexane/EtOAc, 8:2);
IR (film) 2924, 2853, 1760, 1508, 1462, 1284, 1191, 1084, 1038, 826, 721 cm-1; 1H
NMR (300 MHz, CDCl3) d 0.87 (t, J = 6.7 Hz, 3H, OCH2CH2(CH2)9CH3), 1.24
(br s, 18H, 9CH2), 1.56–1.70 (m, 2H, OCH2CH2(CH2)9CH3), 3.74 (s, 3H, OCH3),
4.17 (t, J = 6.7 Hz, 2H, OCH2(CH2)10CH3), 4.56 (s, 2H, OCH2), 6.78–6.87 (m, 4H,
ArH); 13C NMR (75.4 MHz, CDCl3) d 14.0 (CH3), 22.6 (CH2), 25.7 (CH2), 28.5
(CH2), 29.1 (CH2), 29.3 (CH2), 29.4 (CH2), 29.50 (CH2), 29.57 (CH2), 29.59 (CH2),
31.8 (CH2), 55.5 (OCH3), 65.3 (CH3(CH2)10CH2O or OCH2), 66.2 (OCH2 or
CH3(CH2)10CH2O), 114.6 (ArH), 115.7 (ArH), 152.0 (Ar), 154.4 (Ar), 169.3 (CO2);
MS (70 eV) m/z 350 (M?, 100), 182 (9), 137 (11), 123 (38), 107 (6), 77 (5). Anal.
Calcd. for C21H34O4: C, 71.96; H, 9.78. Found: C, 72.02; H, 9.78.
4-Chlorophenyl 2-(4-methoxyphenoxy)acetate (13g)
Following method B, with a mixture of 1.0 g (5.5 mmol) of 25, 0.067 g
(0.55 mmol) of DMAP in CH2Cl2 (20 ml), 0.98 g (8.25 mmol) of SOCl2, 0.835 g
(6.05 mmol) of K2CO3, and 0.78 g (6.05 mmol) of 4-chlorophenol in toluene

54
Med Chem Res (2010) 19:33–57
(30 ml), gave 1.27 g (79%) of 13g as a white solid: Rf 0.31 (hexane/EtOAc, 8:2);
mp 103–104°C (hexane/EtOAc, 8:2); IR (KBr) 1773, 1512, 1437, 1237, 1182, 1086,
1
1026, 830 cm-1; H NMR (300 MHz, CDCl3) d 3.77 (s, 3H, OCH3), 4.80 (s, 2H,
OCH2), 6.83–6.96 (m, 4H, ArH), 7.02–7.08 (m, 2H, ArH), 7.30–7.38 (m, 2H, ArH);
13C NMR (75.4 MHz, CDCl3) d 55.5 (OCH3), 66.3 (OCH2), 114.7 (ArH), 116.0
(ArH), 122.6 (ArH), 129.6 (ArH), 131.6 (ArH), 131.6 (Ar), 148.5 (Ar), 151.8 (Ar),
154.8 (Ar), 167.6 (CO2); MS (70 eV) m/z 294 (M??2, 15), 292 (M?, 43), 164 (5),
137 (100), 109 (29),107 (28), 92 (24), 77 (28). Anal. Calcd. for C15H13ClO4: C,
61.54; H, 4.47. Found: C, 61.71; H, 4.57.
Pharmacology
All synthesized compounds were assessed in vitro for fungal activity. This activity
was performed by minimal inhibitory concentration 50% (MIC50) against two
strains of Candida from American Type Culture Collection (ATCC): C. parapsi-
losis ATCC 22019, susceptible to fluconazole (Quemical Iberica; Madrid, Spain),
and C. krusei ATCC 6258, resistant to fluconazole, as well as against two clinical
isolated of Cryptococcus, C. neoformans and C. gattii, both of which have been
isolated from Mexican patients and identified at the Medical Mycology Laboratory,
´
Escuela Nacional de Ciencias Biologicas, Instituto Politecnico Nacional, in Mexico
City. The isolates were identified presumptively as C. neoformans by capsule
production and positive urea test. To distinguish the species of Cryptococcus,
isolates were streaked on Niger agar for the presence of laccases, and canavanine–
glycine–bromothymol blue (CGB) agar plates for resistance to L-canavanine
culture. To ensure viability and purity, the strains were grown onto potato dextrose
agar (DIBICO; Mexico City, Mexico). Stock solutions for ketoconazole (Sigma),
itraconazole (European Pharmacopoeiae; Strasbourg, France), fluconazole (Chem-
ical Iberica; Madrid, Spain), amphotericin B (Sigma; St. Louis MO, USA), and
caspofungine (Merck, Mexico) were serially diluted in dimethyl sulfoxide at 1009,
and dilutions of antifungal drugs were prepared (amphotericin B, ketoconazole, and
itraconazole, range 16–0.03 lg/mL; fluconazole and phenoxyacetic derivates, range
128–0.25 lg/mL).
In vitro susceptibility testing was performed by Clinical and Laboratory
Standards Institute (CLSI) M27-A2 standardized method for yeast (National
Committee for Clinical Laboratory Standards, 2002). Yeasts cells were suspended
in sterile normal saline and adjusted to 0.5 McFarland standard. Roswell Park
Memorial Institute (RPMI) 1640 culture medium containing l-glutamine and 0.165
M 3-(N-morpholine)propansulfonic acid (MOPS, Sigma) at pH 7.0 was used. CLSI
M27-A was modified for the Cryptococcus strains, in which during incubation
agitation was included (125 rpm/min) (Orbital Shaker, New Bronswick Scientific
Co., USA). Assays were performed four times with each strain, obtaining
reproducible results. The MIC50 value was defined as the minimal concentration
of a drug at which B50% growth inhibition occurred in comparison with nondrug
control. Growth evaluation was determined at 24 h for Candida strains and at 48 h
for Cryptococcus species by optical density (Labsystems Multiskan Plus, serial RS

Med Chem Res (2010) 19:33–57
55
232C; Helsinki, Finland) at 405 nm. Clinical and Laboratory Standard Index (CLSI)
M27-A2 micromethod-established cutoff points for strain sensitivity and resistance
to the drugs employed were as follows: amphotericin B (B2 lg/mL, sensi-
tive; [3 lg/mL, resistant); ketoconazole and itraconazole (B0.125 lg/mL,
sensitive; C1.0 lg/mL, resistant), and fluconazole (B8 lg/mL, sensitive; C64 lg/
mL, resistant). None of the synthesized compounds (a-Asarone analogues) inhibited
the growth of both strains of Candida when tested at a concentration range of
0.25–128 lg/mL after 48 h of incubation. However, several derivatives showed
evidence of modest to strong activity against both Cryptococcus yeasts.
MFC was defined as the minimal concentration at which no visible growth was
observed, and represents killing of C99% of the original inoculum [B3 colony
forming units (CFU)/Petri dish]. MFC determination was performed similarly
to that for MIC50; the MFC were determined in microplates with inoculum size of
1.0–2.5 9 104 yeast cells/mL, on RPMI 1640 medium (MOPS, Sigma) and
incubated with agitation at 35°C for 48 h. MFC estimations were determined by
directly plating dilutions of culture medium from wells with no growth onto potato
dextrose agar (DIBICO; Mexico City, Mexico) and incubating the plates at 35°C for
48 h.
´
Acknowledgments We are grateful to Dr. Cesar H. Hernandez for helpful comments, and Alan Larsen
for reviewing the English in the manuscript. F.J., M.C.C., and C.Z. thank CONACYT for awarded
scholarships. G.C. is indebted to CONACYT (Grant 38431 N) and to SIP-IPN (970423, 990175,
20060583, and 20070339) for financial support. M.C.Cruz, M.A.M., G.C., F.D., and J.T. are fellows of
the EDI/IPN and COFAA/IPN programs.
References
Ahvonen T, Brunow G, Kristersson P, Lundquist K (1983) Stereoselective syntheses of lignin model
compounds of the b-O-4 and b-1 types. Acta Chem Scand B 37:845–849. doi:10.3891/acta.chem.
scand.37b-0845
Arcamone F, Berti G, Carboni S, De Fazi R, Di Marco A, Ghione M (1957) Benzoic acid and
phenoxyacetic acid derivatives and their antituberculotic and fungicidal effects. Farmaco Ed Sci 12:
15–27
Benjamin I, Hong H, Avny Y, Davidov D, Neumann R (1998) Poly(phenylenevinylene) analogs with ring
substituted polar side chains and their use in the formation of hydrogen bonding based self-
assembled multilayers. J Mater Chem 8:919–924. doi:10.1039/a707365h
Chamorro G, Salazar M, Salazar S, Mendoza T (1993) Pharmacology and toxicology of Guatteria
gaumeri and alpha-asarone. Rev Invest Clin 45:597–604
´
´
´
Chamorro G, Gardun˜o L, Sanchez A, Labarrios F, Salazar M, Martınez E, Dıaz F, Tamariz J (1998)
Hypolipidaemic activity of dimethoxy unconjugated propenyl side-chain analogs of a-asarone in mice.
Drug DevRes 43:105–108. doi:10.1002/(SICI)1098-2299(199802)43:2\105::AID-DDR3[3.0.CO;2-O
´
´
Cruz MC, Salazar M, Garciafigueroa Y, Hernandez D, Dıaz F, Chamorro G, Tamariz J (2003) Hypolipidemic
activity of new phenoxyacetic derivatives related to a-asarone with minimal pharmacophore features.
Drug Dev Res 60:186–195. doi:10.1002/ddr.10281
Csiba I, Krasnec L, Stuchlik M (1968) Study of solubility of some water-soluble derivatives of arylalkyl
ethers. I. Preparation and solubility of aryloxyacetic acids. Cesko-Slovenska Farm 17:28–33
Datry A, Bart-Delabesse E (2006) Caspofungin: mode of action and therapeutic applications. Rev Med
Interne 27:32–39. doi:10.1016/j.revmed.2005.05.012
´
Dıaz F, Mun˜oz H, Labarrios F, Chamorro G, Salazar M, Morelos ME, Tamariz J (1993) Synthesis and
hypolipidemic activity of some a-asarone analogs. Med Chem Res 3:101–109

56
Med Chem Res (2010) 19:33–57
Gardun˜o L, Salazar M, Salazar S, Morelos ME, Labarrios F, Tamariz J, Chamorro GA (1997)
Hypolipidaemic activity ofalpha-asarone inmice. J Ethnopharmacol 55:161–163. doi:10.1016/S0378-
8741(96)01492-4
Guha S (1950) On the preparation of bactericidals from organomercurials. Part 1. J Indian Chem Soc
27:357–360
Hayashi M, Wada K, Munakata K (1983) Synthesis and nematicidal activity of phenoxypropionic acid
derivative. Agric Biol Chem 47:2653–2655
´
´
Hernandez D, Bernal P, Cruz A, Garciafigueroa Y, Gardun˜o L, Salazar M, Dıaz F, Chamorro G, Tamariz J
(2004) Potent hypolipidemic activity of mimetic amides of fibrates based on the 2-methoxy-4-(2-
propenyl)phenoxyacetic scaffold. Drug Dev Res 61:19–36. doi:10.1002/ddr.10333
Ioset JR, Marston A, Gupta MP, Hostettmann K (2000) Antifungal and larvicidal compounds from the
root bark of Cordia alliodora. J Nat Prod 63:424–426. doi:10.1021/np990393j
Khan RH, Bahel SC (1976) Studies on haloaromatics and haloheterocyclics. Part I. Synthesis of some
new haloaromatics from aryloxy acetic acids as possible fungicides. Agric Biol Chem 40:2481–2483
Kubo I, Fujita K, Lee SH (2001) Antifungal mechanism of polygodial. J Agric Food Chem 49:1607–
1611. doi:10.1021/jf000136g
Kubo I, Xiao P, Ki Nihei, Ki Fujita, Yamagiwa Y, Kamikawa T (2002) Molecular design of antifungal
agents. J Agric Food Chem 50:3992–3998. doi:10.1021/jf020088v
Kwon-Chung KJ, Boekhout T, Fell JW, Diaz M (2002) Proposal to conserve the name Cryptococcus
gattii against C. hondurianus and C. bacillisporus (Basidiomycota, Hymenomycetes, Tremellomy-
cetidae). Taxon 51:804–806. doi:10.2307/1555045
´
´
Labarrios F, Gardun˜o L, Vidal MR, Garcıa R, Salazar M, Martinez E, Dıaz F, Chamorro G, Tamariz J
(1999) Synthesis and hypolipidaemic evaluation of a series of alpha-asarone analogues related to
clofibrate in mice. J Pharm Pharmacol 51:1–7. doi:10.1211/0022357991772015
Lee JY, Lee JY, Yun BS, Hwang BK (2004) Antifungal activity of b-asarone from rhizomes of Acorus
gramineus. J Agric Food Chem 52:776–780. doi:10.1021/jf035204o
Maertens J, Boogaerts M (2005) The place for itraconazole in treatment. J Antimicrob Chemother 56:i33–i38.
doi:10.1093/jac/dki222
´
´
Martınez M (1992) Las Plantas Medicinales de Mexico. Botas, Mexico City, pp 125–127
Momin RA, Nair MG (2002) Pest-managing efficacy of trans-asarone isolated from Daucus carota
L. seeds. J Agric Food Chem 50:4475–4478. doi:10.1021/jf020209r
Myska J, Ettel V, Bomar M (1961) Methoxyphenoxyacetic acids and their esters. Coll Czech Commun
26:902–905
Nair MG, Burke BA (1988) A new fatty acid methyl ester and other biologically active compounds from
Aspergillus niger. Phytochemistry 27:3169–3173. doi:10.1016/0031-9422(88)80021-9
National Committee for Clinical Laboratory Standards (2002) Reference method for broth dilution
antifungal susceptibility testing of yeasts. Approved standard-second edition. Document M27-A.
National Committee for Clinical Laboratory Standards, Wayne, Pa
Pfaller MA, Messer SA, Boyken L, Rice C, Tendolkar S, Hollis RJ, Diekema DJ (2004) Cross-resistance
between fluconazole and ravuconazole and the use of fluconazole as a surrogate marker to predict
susceptibility and resistance to ravuconazole among 12, 796 clinical isolates of Candida spp. J Clin
Microbiol 42:3137–3141. doi:10.1128/JCM.42.7.3137-3141.2004
Prasad R, Panwar SL, Smriti (2002) Drug resistance in yeasts: an emerging scenario. Adv Microb Physiol
46:155–201. doi:10.1016/S0065-2911(02)46004-3
Purohit DM, Shah VH (1999) Synthesis and antimicrobial activity of 1,1,1-trichloro-2-(40-carboxymeth-
oxyphenyl)-2-(carboxyaryl/carboxymethoxyaryl)ethanes. J Inst Chem 71:58–59
´
Rivalle C, Bisagni E (1972) Transformations thermales d’a-aryloxy-cetones. III. a-aryloxypinacolones
´
diversement substituees. Bull Soc Chim Fr 7:2749–2755
´
´
´
´
´
Rodrıguez-Paez L, Juarez-Sanchez M, Antunez-Solıs J, Baeza I, Wong C (2003) Alpha-asarone inhibits
HMG-CoA reductase, lowers serum LDL-cholesterol levels and reduces biliary CSI in hypercho-
lesterolemic rats. Phytomedicine 10:397–404. doi:10.1078/0944-7113-00274
Sterling TR, Merz WG (1998) Resistance to amphotericin B: emerging clinical and microbiological
patterns. Drug Resist Updat 1:161–165. doi:10.1016/S1368-7646(98)80034-4
Suyama T, Kato S (1989) Phenoxyacetic acid derivative. Jpn Kokai Tokio Koho. JP 63139148. Chem
Abstr 110:75063w
Tolstikov GA, Miftakhov MS, Danilova NA, Galin FZ (1983) The x-chain for 16-aryloxy[17.18.19.20]tet-
ranorprostaglandins. Zh Org. Khim 19:1857–1866

Med Chem Res (2010) 19:33–57
57
Vanden Bossche H, Dromer F, Improvisi I, Lozano-Chiu M, Rex JH, Sanglard D (1998) Antifungal drug
resistance in pathogenic fungi. Med Mycol 36:119–128
Vazquez JA, Sobel JD (2006) Anidulafungin: a novel echinocandin. Clin Infect Dis 43:215–222. doi:
10.1086/505204
Voronkov MG, Dubinskaya EI, Dolmaa G, Klyba LV (1990) Allyl esters of (aryloxy)acetic acids and
their reactions with triethylsilane. Zh Obsh Khim 60:1083–1086
White TC, Marr KA, Bowden RA (1998) Clinical, cellular, and molecular factors that contribute to
antifungal drug resistance. Clin Microbiol Ver 11:382–402
Zawadowska I (1962) Synthesis of some derivatives of nitrophenoxyacetic acids and their activity against
human pathogenic fungi. Acta Pol Pharm 19:263–267
Zawadowska I (1963) Synthesis of phenoxyacetic and phenoxypropionic acids with aldehyde, acetyl, and
carboxy groups in the nucleus, and their activity against human pathogenic fungi. Acta Pol Pharm 20:
25–30
´ ˜
˜
´
´
Zuniga C, Garduno L, Cruz MC, Salazar M, Perez-Pasten R, Chamorro G, Labarrios F, Tamariz J (2005)
Design of new potent hypolipidemic agents with the synergistic structural properties of a-asarone
and fibrates. Drug Dev Res 64:28–40. doi:10.1002/ddr.10418