Asymmetric Synthesis, Antifungal Activity and Molecular Modeling of Iodiconazole Isomers
-
1
ride (50 mL) and tert-butyl hydroperoxide (5.5 mol•L
added into this mixture and stirred for 1 h, then sepa-
rated. The organic phase was mixed with water (50 mL)
and its pH value was adjusted to 4 with HCl (1 mol•
L ). The mixture was separated again, and the diethyl
ether was washed with brine (50 mL×3), dried over
anhydrous sodium sulphate, and concentrated to give
in n-heptane) (34.4 mL, 189.2 mmol, 3.2 equiv.) was
added into the solution successively. The resulted mix-
ture was stirred for 8 h at −20 ℃, and quenched with
tartaric acid (10%) (200 mL). It was warmed to room
temperature gradually. Then the reaction mixture was
filtered by celite and methylene chloride layer was
separated, dried over anhydrous sodium sulphate, and
concentrated to give the crude product. It was purified
through column chromatography over silica gel with
-
1
(S)-7 (0.4 g, 70% yield) as pale yellow oil. It was used
directly in the next step without further purification.
2
5
1
[
D
3
α] 4.3 (c=0.8 in THF). H NMR (600 MHz, CDCl )
δ: 8.00 (s, 1H), 7.77 (s, 1H), 6.71-7.12 (m, 3H), 4.75
d, J=14.9 Hz, 1H), 4.44 (d, J=14.9 Hz, 1H), 2.87 (d,
hexane/EtOAc (15∶1) as the eluent to yield 5 (4.7 g,
(
1
13
4
4% yield) as pale yellow oil. H NMR (600 MHz,
J=4.6 Hz, 1H), 2.80 (d, J=4.6 Hz, 1H); C NMR (150
CDCl
3
) δ: 7.39-7.43 (m, 1H), 6.70-6.99 (m, 2H),
.13 (d, J=11.3 Hz, 1H), 3.90 (d, J=12.6 Hz, 1H),
.30 (d, J=5.0 Hz, 1H), 2.85 (d, J=5.2Hz, 1H). The ee
MHz, CDCl ) δ: 163.12 (dd, JC-F=10.6, 251.2 Hz),
3
4
3
1
1
60.59 (dd, JC-F=111.9, 248.6 Hz), 151.78, 144.11,
29.59 (dd, JC-F=5.2, 9.5 Hz), 119.52 (d, JC-F=14.8
value of 5 was determined when it was converted to 6.
Hz), 111.68 (d, JC-F=21.5 Hz), 104.00 (t, JC-F=25.7
i
HPLC (Chiralpak OD, PrOH/hexane=10/90, flow rate
Hz), 56.21, 53.51, 52.14; IR (neat) ν: 3124, 1618, 1599,
1
2
.0 mL/min, λ=254 nm): tminor=18.9 min (R), tmajor
=
−1
1
557, 1506, 1426, 1273, 1141 cm ; HRMS (ESI) calcd
2
5
6.4 min (S), ee=68%; [α] −17.9 (c=0.3 in THF).
+
D
for C H F N O (M+H ) 238.0786, found 238.0791.
1
1
9
2
3
(
R)-2-(2,4-Difluorophenyl)-3-(1H-1,2,4-triazol-1-
(S)-Iodiconazole
1-(4-Iodophenyl)-N-methyl-
yl)propane-1,2-diol (6) Compound 5 (4.7 g, 25.2
mmol, 1.0 equiv.) was dissolved into tetrahydrofuran
methanamine (1.6 g, 6.5 mmol, 3.8 equiv.) was added
into the solution of compound 7 (0.4 g, 1.7 mmol, 1.0
equiv.) and triethylamine (0.6 g, 5.9 mmol, 3.5 equiv.)
in ethanol (50 mL), and the resulting mixture was
heated under reflux for 10 h. Then, ethanol was re-
moved through evaporation, and the residue was dis-
solved into ethyl acetate (150 mL), washed with brine
(
150 mL), and 1,2,4-triazole (3.5 g, 50.7 mmol, 2.0
equiv.) and anhydrous potassium carbonate (7.0 g, 50.6
mmol, 2.0 equiv.) were added. The mixture was heated
under reflux for 48 h, then cooled to room temperature
and concentrated in vacuum. The residue was dissolved
into methylene chloride (200 mL), washed with brine
(
50 mL×3), dried over anhydrous sodium sulphate, and
(
50 mL×3), dried over anhydrous sodium sulphate.
concentrated to give the crude product. It was purified
through column chromatography over silica gel with
MeOH/DCM (1∶150) as the eluent to yield (S)-iodico-
nazole (0.6 g, 73% yield) as white solid. It was recrys-
tallized from ethyl acetate and hexane and enantiomeri-
cally pure product was obtained in 59% recrystallization
After distilling off the solvent under reduced pressure,
the residue was diluted with hexane (30 mL), stirred for
1
5 min, and filtered to afford 2.0 g of crude product,
which was recrystallized from acetonitrile to give opti-
cally pure (R)-6 (1.2 g, 18%) as white solid. m.p. 95-
2
5
2
5
9
6 ℃ (m.p. 92-93 ℃, Ref: 10); [α] −65.0 (c=2.0
D
yield. m.p. 65-66 ℃; [α] 58.0 (c=0.4, ethyl ace-
D
1
1
in MeOH). H NMR (600 MHz, d -DMSO) δ: 8.29 (s,
6
tate); H NMR (600 MHz, CDCl ) δ: 8.08 (s, 1H), 7.74
3
1
1
H), 7.71 (s, 1H), 7.37-7.41 (m, 1H), 7.11-7.15 (m,
H), 6.94 (td, J=2.2, 8.1 Hz, 1H), 5.75 (brs, 1H), 5.07
(
s, 1H), 7.59 (d, J=8.3 Hz, 2H), 754-7.58 (m, 1H),
6
1
3
.86 (d, J=8.3 Hz, 2H), 6.75-6.82 (m, 3H), 5.20 (brs,
H), 4.50 (d, J=14.5 Hz, 1H), 4.43 (d, J=14.5 Hz, 1H),
.41 (d, J=13.2 Hz, 1H), 3.31 (d, J=13.2 Hz, 1H),
(
t, J=5.8 Hz, 1H), 4.59 (d, J=14.3 Hz, 1H), 4.56 (d,
J=14.3 Hz, 1H), 3.70 (dd, J=4.6, 11.2 Hz, 1H), 3.64
13
(
dd, J=4.6, 11.2 Hz, 1H); C NMR (150 MHz, CDCl )
3
3.07 (d, J=13.8 Hz, 1H), 2.80 (d, J=13.8 Hz, 1H),
13
δ: 161.60 (dd, JC-F=12.5, 245.0 Hz), 159.00 (dd, JC-F
=
2.02 (s, 3H); C NMR (150 MHz, CDCl ) δ: 162.17 (dd,
3
1
9
1
2.5, 245.0 Hz), 150.34, 144.80, 130.32 (dd, JC-F=6.8,
.0 Hz), 124.93 (d, JC-F=13.2 Hz), 110.68 (d, JC-F
8.2 Hz), 103.71 (t, JC-F=26.3 Hz), 71.53 (d, JC-F=5.0
JC-F=11.5, 249.2 Hz), 158.27 (dd, JC-F=111.9, 248.6
=
Hz), 151.78, 144.11, 129.59 (dd, JC-F=5.2, 9.5 Hz),
119.52 (d, JC-F=14.8 Hz), 111.68 (d, JC-F=21.5 Hz),
104.00 (t, JC-F=25.7 Hz), 56.21, 53.51, 52.14; HPLC
i
Hz), 65.83, 54.14; HPLC (Chiralpak OD, PrOH/hexane
10/90, flow rate 1.0 mL/min, λ=254 nm): tmajor
8.9 min (R), tminor=26.4 min (S), ee>99%; IR (neat) ν:
i
=
1
3
=
(Chiralpak AD, PrOH/hexane=10/90, flow rate 0.8
mL/min, λ=254 nm): tminor=11.0 min (R), tmajor=12.1
min (S), ee>99%; IR (neat) ν: 3384, 1616, 1598, 1556,
−1
439, 1599, 1556, 1499, 1278, 1140, 1123 cm ; HRMS
+
−1
(
ESI) calcd for C H F N O (M+H ) 256.0892,
1498, 1421, 1272, 1204 cm ; HRMS (ESI) calcd for
11
11
2
3
2
+
found 256.0900.
C H F IN O (M+H ) 485.0644, found 485.0661.
1
9
19
2
4
(S)-1-((2-(2,4-Difluorophenyl)oxiran-2-yl)methyl)-
(R)-Iodiconazole The chiral center was generated
1
H-1,2,4-triazole (7) Methanesulphonyl chloride (0.4
through diethyl-D-(−)-tartrate induced asymmetric
Sharpless epoxidation, and (R)-iodiconazole was pre-
pared with a similar procedure as described above. m.p.
g, 3.6 mmol, 1.5 equiv.) was added into a solution of
compound 6 (0.6 g, 2.4 mmol, 1.0 equiv.) and triethyl-
amine (1.1 g, 11.4 mmol, 4.7 equiv.) in diethyl ether
2
5
55-56 ℃; ee=92%; [α]
−49.0 (c=0.5, ethyl ace-
D
(
100 mL). After stirring for 1 h, water (50 mL) was
tate).
Chin. J. Chem. 2013, 31, 1139—1143
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1141