The Journal of Organic Chemistry
ARTICLE
(m, 4H). 13C NMR (CD3OD, 75.5 MHz): δ 53.5, 70.7, 121.8, 128.8 (2C),
(c 1, CH2Cl2). Analytical separation (HPLC). Chiralcel OJ-H n-
hexane/2-propanol (85:15), 0.8 mL/min, 40 °C, tR(R) = 20.5 min,
tR(S) = 34.3 min.
35Cl37
130.2, 130.4, 133.7, 135.4, 139.3, 139.6. MS (ESIþ, m/z): 259 ((
ClM
35Cl35
þ H)þ, 64%), 257 ((
ClM þ H)þ, 100%). HRMS (ESIþ, m/z):
calcd for (C11H11Cl2N2O)þ (M þ H)þ 257.0243, found 257.0242. (R)-
4 [R]D20 = -77.5° (c 1, CHCl3). (S)-4 [R]D20 = þ78.4° (c 1, MeOH).
Analytical separation (HPLC): Chiralcel IA n-hexane/2-propanol
(85:15), 0.8 mL/min, 20 °C, tR(R) = 9.4 min, tR(S) = 11.9 min.
Synthesis of (R)-1-(2-(2,4-Dichlorobenzyloxy)-2-(2,4-
dichlorophenyl)ethyl)-1-H-imidazole (Miconazole, 1a).23
To a solution of (R)-4 (100 mg, 0.39 mmol) in dry THF (5.5 mL) at
-78 °C under a nitrogen atmosphere was added a 30% dispersion of KH
in mineral oil (71 mg, 0.53 mmol). The resulting suspension was stirred
for 2 h at -78 °C. After this time, 18-crown-6 (103 mg, 0.39 mmol) and
1-(bromomethyl)-2,4-dichlorobenzene (11a; 187 mg, 0.78 mmol) were
successively added. Then, the mixture was stirred for 4 h at room
temperature, and after this time the reaction was quenched with H2O
(10 mL), the aqueous solution was extracted with CH2Cl2 (3 ꢀ 15 mL),
the organic phases were combined, dried over Na2SO4, and filtered, and
the solvent was removed by distillation under reduced pressure, giving a
crude reaction mixture that was purified by flash chromatography
(eluent gradient 100% CH2Cl2 to 5% MeOH/95% CH2Cl2), affording
127 mg of (R)-1a as a viscous oil (79%). Rf (5% MeOH/CH2Cl2): 0.31.
IR (NaCl): ν 3194, 3113, 2932, 2883, 1590, 1563, 1506, 1471, 1383,
1232, 1094, 1043, 866, 820 cm-1. 1H NMR (CDCl3, 300.13 MHz): δ
4.08 (dd, 1H, 2JHH = 14.5 Hz, 3JHH = 7.4 Hz), 4.24 (dd, 1H, 2JHH = 14.5
Biological Evaluation. The antimicrobial activities of the corre-
sponding racemic mixtures and single enantiomers were performed
using the microdilution method, as recommended in documents M27-A
for yeast29 and M38-P for filamentous fungi,30 using 96-well microtiter
plates. The sensitivities to the antimicrobial compounds were checked
by visual inspection of the microbial growth on each well, after 24 h of
incubation for C. krusei or 48 h for C. neoformans, P. chrysogenum, and A.
niger. The given values were the average from six independent experi-
ments, with 20% standard deviation between them (see Table 2).
’ ASSOCIATED CONTENT
S
Supporting Information. Text and figures giving details
b
of the HPLC and GC methods and full characterization data for
all novel organic compounds. This material is available free of
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: vgs@uniovi.es (V.G.); vicgotfer@uniovi.es (V.G.-F.).
Tel: þ34 98 5103448. Fax: þ34 98 5103448.
Hz, 3JHH = 2.7 Hz), 4.35 (d, 1H, 2JHH = 12.6 Hz), 4.50 (d, 1H, 2JHH
=
12.6 Hz), 5.03 (dd, 1H, 3JHH = 7.4 Hz, 3JHH = 2.7 Hz), 6.91 (s, 1H), 7.03
(s, 1H), 7.15-7.46 (m, 7H). 13C NMR (CDCl3, 75.5 MHz): δ 51.1,
68.1, 77.4, 119.6, 127.2, 127.8, 128.2, 129.1 (2C), 129.5, 129.8, 133.1,
133.2, 133.6 (2C), 134.2, 134.9, 137.7. MS (EIþ, m/z): 418
’ ACKNOWLEDGMENT
We thank Novo Nordisk Co. for the generous gift of CAL-B
(Novozyme 435). Financial support of this work by the Spanish
Ministerio de Ciencia e Innovaciꢀon (MICINN) through projects
CTQ 2007-61126 and BIO 2008-03683 is gratefully acknowl-
edged. V.G.-F. thanks the MICINN for a postdoctoral grant
(Ramꢀon y Cajal Program). J.M.-S. thanks the MICINN for a
predoctoral fellowship (FPU Program).
37Cl37Cl35Cl35
35Cl35Cl35Cl35
37Cl35Cl35Cl35
(
(
ClMþ, 14%), 416
(
ClMþ, 28%), 414
37Cl35Cl35Cl35
ClMþ, 23%), 335 (
ClM - CH2C3H2N2þ, 37%),
161 (C7H537Cl35Clþ, 65%), 159 (C7H535Cl2þ, 100%). HRMS (ESIþ,
m/z): calcd for (C18H15Cl4N2O)þ (M þ H)þ 414.9933, found
20
20
414.9949. (R)-1a [R]D = -65.0° (c 1, CH2Cl2). (S)-1a [R]D
=
þ68.7° (c 1, CH2Cl2). Analytical separation (HPLC). Chiralcel OJ-H n-
hexane/2-propanol (85:15), 0.8 mL/min, 40 °C, tR(R) = 21.6 min,
tR(S) = 28.8 min.
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dichlorophenyl)ethyl]-1H-imidazole (Econazole, 1b). To a
solution of (R)-4 (49 mg, 0.19 mmol) in dry THF (2.2 mL) at
-78 °C under a nitrogen atmosphere was added a 30% dispersion of
KH in mineral oil (33 mg, 0.26 mmol). The resulting suspension was
stirred for 2 h at -78 °C. After this time 18-crown-6 (51 mg, 0.19 mmol)
and 1-(bromomethyl)-4-chlorobenzene (11b; 117 mg, 0.57 mmol) were
successively added. Then the mixture was stirred overnight at room
temperature. The reaction was quenched with H2O (5 mL), the aqueous
phase was extracted with CH2Cl2 (3 ꢀ 10 mL), the organic phases were
combined, dried over Na2SO4, and filtered, and the solvent was removed
by distillation under reduced pressure, giving a crude reaction mixture
that was purified by flash chromatography (eluent gradient 100%
CH2Cl2 to 5% MeOH/95% CH2Cl2), affording 62 mg of (R)-1b as a
viscous oil (86%). Rf (2% MeOH/CH2Cl2): 0.29. IR (NaCl): ν 3111,
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1
3066, 2935, 2869, 1590, 1561, 1492, 1470, 1090, 1044, 821 cm-1. H
NMR (CDCl3, 300.13 MHz): δ 4.01 (dd, 1H, 2JHH = 14.5 Hz, 3JHH = 7.7
Hz), 4.17 (m, 2H), 4.41 (d, 1H, 2JHH = 11.8 Hz), 4.94 (dd, 1H, 3JHH
=
7.6 Hz, 3JHH = 2.7 Hz), 6.87 (s, 1H), 6.98-7.07 (m, 3H), 7.23-7.35 (m,
4H), 7.40-7.47 (m, 2H). 13C NMR (75.5 MHz): δ 51.3, 70.7, 76.8,
119.7, 127.9, 128.4, 128.6 (2C), 128.9 (2C), 129.2, 129.6, 133.3, 133.8,
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37Cl37Cl35
133.9, 134.9, 135.3, 137.8. MS (EIþ, m/z): 384 (
(
ClMþ, 10%), 382
37Cl35Cl35
35Cl35Cl35
ClMþ, 32%), 380 (
ClMþ, 33%), 257 (C11H937Cl
35ClN2Oþ, 65%), 255 (C11H935Cl2N2Oþ, 100%). HRMS (ESIþ, m/z):
calcd for (C18H16Cl3N2O)þ (M þ H)þ 381.0323, found 381.0333. (R)-
20
20
1b [R]D = -88.5° (c 1, CH2Cl2). (S)-1b [R]D = þ87.1°
2121
dx.doi.org/10.1021/jo102459w |J. Org. Chem. 2011, 76, 2115–2122