An enantioselective synthesis of voriconazole

Article abstract of DOI:10.1021/jo4019528

A new seven-step sequence to access voriconazole, a clinically used antifungal agent, was developed. The initial catalytic asymmetric cyanosilylation is the key to constructing the consecutive tetra- and trisubstituted stereogenic centers. The fluoropyrimidine unit frequently triggered unexpected side reactions, but careful amendment of the reaction sequence allowed for the concise enantioselective synthesis.

Full text of DOI:10.1021/jo4019528

Article
pubs.acs.org/joc
An Enantioselective Synthesis of Voriconazole
Keiji Tamura,† Makoto Furutachi,† Naoya Kumagai,*,† and Masakatsu Shibasaki*,†,‡
†Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
‡JST, ACT-C, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
S
* Supporting Information
ABSTRACT: A new seven-step sequence to access voricona-
zole, a clinically used antifungal agent, was developed. The
initial catalytic asymmetric cyanosilylation is the key to
constructing the consecutive tetra- and trisubstituted stereo-
genic centers. The fluoropyrimidine unit frequently triggered
unexpected side reactions, but careful amendment of the
reaction sequence allowed for the concise enantioselective
synthesis.
voriconazole. Catalytic asymmetric cyanosilylation was the key
as the initial chirality introduction step.
INTRODUCTION
■
Invasive fungal diseases are life-threatening and devastating
opportunistic infectious symptoms in immunocompromised
patients.1 Voriconazole (Vfend) is a clinically used triazole
antifungal agent in both intravenous and oral formulations,2
and a primary drug for invasive aspergillosis in first line
treatment (Figure 1).1b,3 Voriconazole is an advanced triazole
RESULTS AND DISCUSSION
Retrosynthesis of voriconazole is delineated in Scheme 1. 1,2,4-
Triazole was planned to be installed at the last step, and the
■
Scheme 1. Retrosynthetic Analysis
Figure 1. Structure of antifungal agents fluconazole and voriconazole.
fungicide with a very broad antifungal spectrum.4 The structure
of voriconazole is similar to a precedent triazole antifungal,
fluconazole, sharing 2,4-difluorobenzene, 1,2,4-triazole, and
tertiary alcohol substructures. However, the replacement of
one of the two 1,2,4-triazole groups in fluconazole by
fluoropyrimidine breaks the symmetry of the molecule,
significantly increasing the molecular complexity together
with an extra stereogenic center because of an additional
methyl group. The original enantioselective synthetic route for
voriconazole developed by Pfizer relied on optical resolution to
construct the consecutive tetra- and trisubstituted stereogenic
centers, although the overall synthesis is scalable for large-scale
production.2b,5 We envisioned applying our asymmetric catalyst
designed for the enantioselective construction of stereogenic
tertiary alcohols to the synthesis of voriconazole.6 Herein, we
report a seven-step sequence for enantioselective synthesis of
pendant methyl group is to be formed by Wittig methylenation
and diastereoselective hydrogenation. The precursor α-
epoxyketone would be derived from cyanohydrin 2. The
epoxide ring was disconnected to α-chloromethylcarbinol, and
metalated pyrimidine would be appended to the cyano group to
furnish the requisite acylpyrimidine unit. The optically pure
cyanohydrin 2 would be obtained from catalytic asymmetric
cyanosilylation of commercially available functionalized ketone
1.
Received: September 5, 2013
© XXXX American Chemical Society
A
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Scheme 2. Enantioselective Synthesis of Voriconazole
Scheme 2 outlines the seven-step synthetic route delivering
voriconazole. Its associated unproductive transformations are
summarized in Schemes 3 and 4, most of which were ascribed
to the peculiar reactivity caused by the presence of the fluorine-
substituted pyrimidine. The initial catalytic asymmetric
cyanosilylation of ketone 1 was promoted by a Gd-based
asymmetric catalyst.7−9 Gd(HMDS)3 and sugar-derived chiral
ligand 310,11 were mixed in a ratio of 2:3 at −30 °C, producing
a putative polymetallic catalyst composed of Gd:3 = 2:3,
Scheme 4. Unfruitful Pathways for 1,2,4-Triazole Installation
Scheme 3. Unproductive Pathways
B
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suggested by ESI-MS analysis in the presence of TMSCN.7b
With 2 mol % of the catalyst (based on Gd), catalytic
asymmetric cyanosilylation of 1 and TMSCN proceeded
smoothly at −30 °C in propionitrile to afford the desired
TMS-protected cyanohydrin 2 in 92% yield and 80% ee.12
Because 2 was prone to retroreaction under acidic and basic
conditions, 2 was immediately transformed into the corre-
sponding aldehyde 4 by reduction with DIBAL. Installation of
fluorine-substituted pyrimidine was effected with an aryllithium
reagent prepared by selective lithiation of 4-bromo-5-
conditions using sodium 1,2,4-triazolide led to epimerization
and epoxide opening to give (E)-16 triggered by deprotonation
at C3 (Scheme 4c). In contrast to hydrogenation conditions
(Scheme 3c), (Z)-16 readily underwent ipso substitution under
basic conditions, and its cyclized compound 20 was isolated.
The use of Lewis or protic acid favored the formation of 21,
which was presumably produced via SN1-like addition of N4 of
1,2,4-triazole.26 Regioselective epoxide opening at the less
hindered site slowly proceeded with 1,2,4-triazole in refluxing
ethanol to give voriconazole 40% (53% brsm) together with the
production of a marginal amount of 12 and N4-adduct 13 in
(27%).27 Enantioenrichment of the thus obtained voriconazole
(80% ee) from isopropanol afforded optically pure voriconazole
(>99% ee) in 49% yield.
fluoropyrimidine13 with BuLi in ether at −78 °C. Lithiation
n
in THF led to significant decomposition of the reagent and
barely produced the desired product.14 The transient product 5
readily underwent silyl group transfer to give a mixture of
tertiary and secondary TMS ethers 5 and 6.15 Subsequent
treatment of the reaction mixture with TBAF and acetic acid at
room temperature cleaved the TMS group to give diol 7, and
concomitant displacement of the terminal chloro leaving group
by the adjacent tertiary alcohol produced α-epoxyalcohol 8.
Corey−Kim oxidation of the diastereomixture of 8 using
odorless dodecyl methyl sulfide and N-chlorosuccinimide gave
α-epoxyketone 9 in 97% yield.16 Although the direct addition of
lithiated fluoropyrimidine to cyanohydrin TMS ether 2 to
obviate the reduction/oxidation sequence was attempted,
extensive manipulations of reaction conditions resulted in the
formation of complicated mixtures (Scheme 3a). Given the
preferential formation of (2R,3R)-8, nucleophilic methylation
of mesylate 14 via inversion of configuration was extensively
investigated to introduce the requisite 3S-methyl group;
however, all attempts were unproductive. The formation of
unexpected byproducts was triggered by deprotonation of the
benzylic proton, as exemplified by the formation of 15,17 which
appeared impossible to suppress (Scheme 3b). This finding
directed our attention to the introduction of the requisite
methyl group by Wittig methylenation followed by diaster-
eoselective hydrogenation. The exomethylene group of 10 was
CONCLUSION
■
In conclusion, a seven-step enantioselective synthesis of
voriconazole was achieved. Catalytic asymmetric cyanosilylation
of a commercially available functionalized ketone was applied as
the initial step to construct the tetrasubstituted stereogenic
center. Although voriconazole is a relatively small chemical
entity, unexpected undesired reactions frequently took place,
partly because of the presence of the fluoropyrimidine unit.
Further refinement of the synthetic route for large-scale
production is currently under way.
EXPERIMENTAL SECTION
■
General Procedures. The reactions were performed in a round-
bottom flask with a Teflon-coated magnetic stirring bar and a 3-way
glass stopcock under Ar atmosphere unless otherwise noted. Air- and
moisture-sensitive liquids were transferred via a gastight syringe and a
stainless steel needle. All workup and purification procedures were
carried out with reagent-grade solvents under ambient atmosphere.
Flash chromatography was performed using silica gel 60 (230−400
mesh). Chemical shifts for protons are reported as δ in units of parts
per million downfield from tetramethylsilane and are referenced to
residual protons in the NMR solvent (CDCl3 δ 7.24 ppm). For 13C
NMR, chemical shifts are reported in the scale relative to the NMR
solvent (CDCl3 77.0 ppm) as an internal reference. For 19F NMR,
chemical shifts are reported in the scale relative to trifluoroacetic acid
(76.5 ppm) as an external reference. NMR data are reported as
follows: chemical shifts, multiplicity (s: singlet, d: doublet, dd: doublet
of doublets, t: triplet, q: quartet, sep: septet, m: multiplet, br: broad
signal), coupling constant (Hz), and integration. Optical rotation was
measured using a 2 mL cell with a 1.0 dm path length. Compounds 2,
4, and 12 are known compounds (CAS Registry No. 861718-83-4,
861718-85-6, and 86404-63-9, respectively).
t
constructed using Ph3P+MeBr− and BuOK at room temper-
ature, and the resulting Ph3PO was efficiently removed by
the addition of MgCl2 in toluene.18 Despite an extensive
investigation using transition metal catalysts, hydrogenation of
10 barely proceeded to afford the desired product 11. Reactions
using heterogeneous Pd catalysts19 or homogeneous Crabtree’s
catalyst20 gave an E,Z-mixture of allylic alcohol 16, which was
presumably produced by oxidative addition at the benzylic C−
O bond and subsequent hydrogenolysis of the resulting π-allyl
metal complex (Scheme 3c). Whereas 10 remained unchanged
with Wilkinson’s catalyst,21 Pd/C and its modified variant with
ethylenediamine promoted the hydrogenation to afford
predominantly the undesired diastereomer of 11.22,23 To
perturb the diastereoselectivity in the hydrogenation, prior
installation of 1,2,4-triazole was attempted; however, an
undesired SN2′-type conjugate addition occurred to give (E)-
17 and 18, which was produced from (Z)-17 by the following
ipso substitution of fluoride (Scheme 4a). The fluoropyrimidine
unit was inherently reactive toward nucleophilic substitution,
and an attempted epoxide-opening reaction of α-epoxyketone 9
with sodium 1,2,4-triazolide gave 19 (Scheme 4b). Eventually,
we found that diimide reduction using 2,4,6-triisopropylbenze-
nesulfonylhydrazide under basic conditions produced 11 in
80% yield with preferential formation of the desired
diastereomer (69:31).24,25 Facile chromatographic separation
allowed us to isolate the desired diastereomers in 57%, which
was subjected to the final 1,2,4-triazole installation. The basic
(S)-3-Chloro-2-(2,4-difluorophenyl)-2-((trimethylsilyl)oxy)-
propanenitrile (2). To a flame-dried 10 mL test tube equipped with a
magnetic stirring bar and a 3-way glass stopcock was added ligand 3
(39.0 mg, 0.0847 mmol) in the glovebox. THF (1.8 mL) was added at
0 °C. To the resulting solution was added Gd(HMDS)3 (0.175 M
solution in THF, 0.305 mL, 0.0533 mmol) at the same temperature,
and the resulting solution was stirred at 45 °C for 30 min. After
cooling to room temperature, the solvent was removed under reduced
pressure, and the resulting residue was dried in vacuo (2 mmHg) at 45
°C for 3 h. The complex was taken up with EtCN (1.7 mL), and the
mixture was stirred at −30 °C. To the resulting mixture was added
TMSCN (0.51 mL, 3.82 mmol), and the mixture was stirred at the
same temperature for 20 min. To the solution was added ketone 1
(485 mg, 2.54 mmol), and the reaction mixture was stirred at the same
temperature for 3 h. The reaction mixture was quenched with H2O.
The aqueous layer was extracted twice with EtOAc. The combined
organic layers were dried over MgSO4, filtered, and concentrated
under reduced pressure to give crude product 2. Yield and
enantioselectivity were determined to be 92% and 80% ee,
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respectively, by GC analysis (based on absolute calibration method).
The spectroscopic data were consistent with the reported values.7b
(S)-3-Chloro-2-(2,4-difluorophenyl)-2-((trimethylsilyl)oxy)-
propanal (4). The crude 2 (92% yield, 494 mg, 1.70 mmol) was taken
up with toluene (1.7 mL), and the resulting solution was stirred at −78
°C. To the solution was added 1.0 M DIBAL in toluene (3.14 mL,
3.14 mmol), and the reaction mixture was stirred at the same
temperature for 2 h. The reaction mixture was quenched with a
saturated NH4Cl aq and 1 N HCl aq. To the resulting mixture was
added Celite, and the mixture was stirred at room temperature for 30
min. The resulting slurry was filtered through a pad of Celite, and the
aqueous layer was extracted twice with EtOAc. The combined organic
layers were washed with H2O and dried over MgSO4. After removal of
volatiles under reduced pressure, the resulting residue was purified
using silica-gel column chromatography (n-hexane/EtOAc = 95:5) to
give 351 mg of 4 (70% for 2 steps) as a colorless oil. The spectroscopic
data were consistent with the reported values.7b
78.5 (d, J = 5.8 Hz), 70.3, 50.4 (d, J = 7.2 Hz), −0.354; IR (neat,
cm−1) ν 3375, 2056, 2962, 1620; HRMS (ESI) Anal. Calcd. for
C16H19O2N2ClSiF3 m/z 391.0851 [M + H]+, found 391.0853.
(1R,2S)-3-Chloro-2-(2,4-difluorophenyl)-1-(5-fluoropyrimidin-4-
yl)propane-1,2-diol (7). To a solution of 6 (63.9 mg, 0.163 mmol) in
EtOH (326 μL) was added 0.01 N HCl in EtOH (326 μL) at room
temperature, and then the resulting mixture was stirred at the same
temperature for 3 h. The reaction mixture was quenched with a
saturated NaHCO3 aq. The aqueous layer was extracted two times
with EtOAc. The combined organic layers were dried over MgSO4,
filtered, and concentrated under reduced pressure. Purification by
silica-gel column chromatography (n-hexane/EtOAc = 50:50) gave
1
45.8 mg of 7 (88% yield) as a colorless crystal: mp 154−158 °C; H
NMR (400 MHz, CDCl3) δ 8.93 (d, J = 2.5 Hz, 1H), 8.36 (d, J = 1.4
Hz, 1H), 7.26−7.20 (m, 1H), 6.81−6.69 (m, 2H), 5.50 (d, J = 10.6
Hz, 1H), 4.41 (d, J = 11.4 Hz, 1H), 4.26 (d, J = 11.4 Hz, 1H), 4.09 (d,
J = 10.6 Hz, 1H), 4.02 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 163.0
(dd, J = 251, 12 Hz), 159.3 (dd, J = 248, 11 Hz), 154.7 (d, J = 276
Hz), 153.8 (d, J = 4.3 Hz), 153.6 (d, J = 8.7 Hz), 145.4 (d, J = 22 Hz),
130.0 (dd, J = 10, 5.8 Hz), 122.2 (dd, J = 13, 4.3 Hz), 111.4 (dd, J =
22, 2.9 Hz), 104.2 (dd, J = 28, 25 Hz), 78.6 (d, J = 5.8 Hz), 68.4, 50.2
(d, J = 7.2 Hz); IR (neat, cm−1) ν 3473, 3201, 2850, 1617, 1498, 1409;
HRMS (ESI) Anal. Calcd. for C13H10O2N2ClF3Na m/z 341.0275 [M
+ Na]+, found 341.0279.
(1R,2S)-3-Chloro-2-(2,4-difluorophenyl)-1-(5-fluoropyrimidin-4-
yl)-2-((trimethylsilyl)oxy)propan-1-ol (5). A flame-dried 10 mL test
tube equipped with a magnetic stirring bar and a 3-way glass stopcock
n
was charged with Et2O (0.3 mL). Then 2.69 M BuLi solution in n-
hexane (0.19 mL) was added via a gastight syringe with a stainless steel
needle under an Ar atmosphere. To the resulting mixture was added 4-
bromo-5-fluoropyrimidne (91.2 mg, 0.515 mmol) in Et2O (0.7 mL) at
−78 °C, and the mixture was stirred at the same temperature for 10
min. ZnI2 (165 mg, 0.515 mmol) was added and then stirred for 20
min. To the resulting mixture was added aldehyde 4 (137 mg, 0.468
mmol) in Et2O (1.3 mL) at −78 °C, and the solution was stirred at the
same temperature for 30 min. The reaction mixture was quenched
with H2O. The aqueous layer was extracted two times with EtOAc.
The combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification by silica-gel column
chromatography (n-hexane/EtOAc = 70:30) gave 37.9 mg of 5 (21%
(R)-((R)-2-(2,4-Difluorophenyl)oxiran-2-yl)(5-fluoropyrimidin-4-
yl)methanol (8). A flame-dried 10 mL test tube equipped with a
magnetic stirring bar and a 3-way glass stopcock was charged with
n
Et2O (0.3 mL). 2.69 M BuLi solution in n-hexane (0.23 mL, 0.598
mmol) was added via a gastight syringe with a stainless steel needle
under an Ar atmosphere. To the resulting mixture was added 4-bromo-
5-fluoropyrimidine13 (106 mg, 0.598 mmol) in Et2O (0.8 mL) at −78
°C, and the mixture was stirred at the same temperature for 10 min.
Aldehyde 4 (117 mg, 0.399 mmol) in Et2O (0.9 mL) was added to the
resulting mixture at −78 °C, and the mixture was stirred at the same
temperature for 30 min. The reaction mixture was quenched with silica
gel. Then the resulting mixture was warmed to room temperature and
stirred for 30 min. After cooling the reaction mixture to 0 °C, acetic
acid (50.2 μL, 0.877 mmol) and 1.0 M TBAF solution in THF (1.76
mL, 1.76 mmol) were added. After stirring the resulting mixture at
room temperature for 8 h, H2O was added. The aqueous layer was
extracted twice with EtOAc. The combined organic layers were dried
over MgSO4, filtered, and concentrated under reduced pressure. The
resulting residue was purified using silica-gel column chromatography
(n-hexane/EtOAc = 70:30) to give 55.2 mg of diastereomixture of 8
(49% yield, (2R,3R):(2R,3S) = 85:15 by 1H NMR analysis) as a
colorless oil. Diastereomixture of 8 was submitted to the next reaction.
Diastereomers were separable by silica-gel column chromatography (n-
hexane/EtOAc = 70:30). Major isomer: colorless oil; [α]D27 −2.94 (c
1
yield, diastereomeric ratio was determined to be 93/7 by H NMR
1
analysis) as a colorless solid: mp 119−123 °C; H NMR (400 MHz,
CDCl3) δ 8.95 (d, J = 2.8 Hz, 1H), 8.22 (d, J = 0.92 Hz, 1H), 6.96−
6.90 (m, 1H), 6.83−6.78 (m, 1H), 6.71−6.66 (m, 1H), 5.32 (d, J = 9.7
Hz, 1H), 4.56 (d, J = 12.6 Hz, 1H), 4.45 (d, J = 9.7 Hz, 1H), 4.42 (d, J
= 12.6 Hz, 1H), 0.250 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 163.0
(dd, J = 250, 13 Hz), 159.5 (dd, J = 247, 13 Hz), 154.6 (d, J = 266
Hz), 153.8 (d, J = 7.2 Hz), 153.1−152.9 (m), 144.3 (d, J = 22 Hz),
130.2 (dd, J = 10, 5.8 Hz), 122.9 (dd, J = 13, 2.9 Hz), 110.8 (dd, J =
21, 3.6 Hz), 104.0 (dd, J = 28, 25 Hz), 83.7 (d, J = 5.8 Hz), 71.6, 49.7
(d, J = 8.7 Hz), 2.35; IR (neat, cm−1) ν 3500, 3056, 2961, 1616, 1586,
1498, 1404; HRMS (ESI) Anal. Calcd. for C16H18O2N2ClSiF3Na m/z
413.0670 [M + Na]+, found 413.0666.
(1R,2S)-3-Chloro-2-(2,4-difluorophenyl)-1-(5-fluoropyrimidin-4-
yl)-1-((trimethylsilyl)oxy)propan-2-ol (6). A flame-dried 10 mL test
tube equipped with a magnetic stirring bar and a 3-way glass stopcock
1
n
0.85, CHCl3); H NMR (400 MHz, CDCl3) δ 8.96 (d, J = 2.8 Hz,
was charged with Et2O (0.2 mL). Then 2.69 M BuLi solution in n-
1H), 8.45 (s, 1H), 7.17−7.11 (m, 1H), 6.76−6.67 (m, 2H), 5.34 (d, J
= 9.6 Hz, 1H), 4.02 (d, J = 9.6 Hz, 1H), 3.44 (d, J = 5.3 Hz, 1H), 2.81
(d, J = 5.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 163.1 (dd, J =
247, 10 Hz), 160.5 (dd, J = 245, 9.6 Hz), 155.0 (d, J = 267 Hz), 153.9
(d, J = 7.7 Hz), 153.3 (d, J = 14 Hz), 144.6 (d, J = 21 Hz), 130.8 (dd, J
= 9.6, 5.8 Hz), 119.1 (dd, J = 15, 3.8 Hz), 111.4 (dd, J = 22, 3.4 Hz),
103.6 (dd, J = 25, 25 Hz), 68.2, 59.0, 50.5; 19F NMR (376 MHz,
CDCl3) δ −108.3, −112.0, −135.9; IR (neat, cm−1) ν 3414, 3077,
2318, 1619, 1589, 1507, 1403; HRMS (ESI) Anal. Calcd. for
C13H9O2N2F3Na m/z 305.0508 [M + Na]+, found 305.0512. Minor
hexane (0.21 mL) was added via a gastight syringe with a stainless steel
needle under an Ar atmosphere. To the resulting mixture was added 4-
bromo-5-fluoropyrimidne (99.3 mg, 0.515 mmol) in Et2O (0.8 mL) at
−78 °C, and the mixture was stirred at the same temperature for 10
min. To the resulting mixture was added aldehyde 3 (117 mg, 0.399
mmol) in Et2O (1.0 mL) at −78 °C, and the mixture was stirred at the
same temperature for 30 min. The reaction mixture was quenched
with H2O. The aqueous layer was extracted two times with EtOAc.
The combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification by silica-gel column
chromatography (n-hexane/EtOAc = 70:30) gave 77.0 mg of 6 (49%
27
isomer: white solid; mp 79−82 °C; [α]D −16.5 (c 0.56, CHCl3); 1H
1
NMR (400 MHz, CDCl3) δ 8.97 (d, J = 2.8 Hz, 1H), 8.55 (d, J = 1.2
Hz, 1H), 7.27−7.21 (m, 1H), 6.83−6.78 (m, 1H), 6.75−6.69 (m, 1H),
5.31 (d, J = 7.4 Hz, 1H), 3.82 (d, J = 7.4 Hz, 1H), 3.20 (d, J = 4.6 Hz,
1H), 2.93 (d, J = 4.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 163.2
(dd, J = 250, 12 Hz), 161.0 (dd, J = 250, 12 Hz), 155.5 (d, J = 269
Hz), 153.9 (d, J = 7.2 Hz), 153.1 (d, J = 13 Hz), 145.0 (d, J = 20 Hz),
131.3 (dd, J = 10, 5.8 Hz), 119.4−119.3 (m), 111.4 (dd, J = 22, 2.9
Hz), 103.9 (dd, J = 25, 25 Hz), 69.5, 59.3, 51.2; 19F NMR (376 MHz,
CDCl3) δ −108.1, −111.1, −135.2; IR (neat, cm−1) ν 3189, 3057, 280,
yield, diastereomeric ratio was determined to be 72:28 by H NMR
analysis) as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 8.87 (d, J
= 2.5 Hz, 1H), 8.38 (d, J = 1.8 Hz, 1H), 7.35−7.28 (m, 1H), 6.77−
6.71 (m, 1H), 6.69−6.64 (m, 1H), 5.51 (s, 1H), 4.62 (s, 1H), 4.27 (d,
J = 11.2 Hz, 1H), 4.11 (dd, J = 11.2, 1.2 Hz, 1H), 0.046 (s, 9H); 13C
NMR (150 MHz, CDCl3) δ 162.8 (dd, J = 250, 13 Hz), 159.1 (dd, J =
247, 12 Hz), 155.1 (d, J = 267 Hz), 154.5 (d, J = 10 Hz), 153.8 (d, J =
7.2 Hz), 145.4 (d, J = 22 Hz), 130.5 (dd, J = 9.4, 6.5 Hz), 122.3 (dd, J
= 13, 4.3 Hz), 111.3 (dd, J = 21, 3.6 Hz), 103.9 (dd, J = 28, 25 Hz),
D
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2359, 1620, 1589, 1507, 1403; HRMS (ESI) Anal. Calcd. for
C13H9O2N2F3Na m/z 305.0508 [M + Na]+, found 305.0509.
1H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 2.8 Hz, 1H), 8.44 (d, J =
1.8 Hz, 1H), 7.16−7.10 (m, 1H), 6.77−6.69 (m, 2H), 3.90 (q, J = 7.3
Hz, 1H), 3.07 (d, J = 4.8 Hz, 1H), 2.86 (d, J = 4.8 Hz, 1H), 1.34 (d, J
= 7.3 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 162.7 (dd, J = 248, 12
Hz), 160.7 (dd, J = 249, 12 Hz), 157.0 (d, J = 13 Hz), 156.4 (d, J =
266 Hz), 154.2 (d, J = 7.2 Hz), 144.3 (d, J = 22 Hz), 130.8 (dd, J = 8.7,
5.8 Hz), 122.1 (dd, J = 14, 4.3 Hz), 111.1 (dd, J = 21, 3.6 Hz), 103.9
(dd, J = 25, 25 Hz), 59.1, 51.0, 39.0, 13.2; 19F NMR (376 MHz,
CDCl3) δ −109.1, −111.1, −135.7; IR (neat, cm−1) ν 3069, 2975,
2943, 2377, 2353, 2310, 1585, 1507, 1402; HRMS (ESI) Anal. Calcd.
for C14H12ON2F3 m/z 281.0896 [M + H]+, found 281.0890.
(R)-(2-(2,4-Difluorophenyl)oxiran-2-yl)(5-fluoropyrimidin-4-yl)-
methanone (9). To a suspension of N-chlorosuccinimide (2.18 g, 16.3
mmol) in THF (33.0 mL) was added n-dodecylmethylsulfide (4.85
mL, 19.0 mmol) at 0 °C, and the resulting mixture was stirred at the
same temperature for 10 min. After cooling the reaction mixture to
−30 °C, a solution of diastereomixtures of 8 (1.53 g, 5.44 mmol) in
THF (40 mL) was added, and the reaction mixture was stirred at the
same temperature for 1 h. To the resulting mixture was added Et3N
(4.55 mL, 32.6 mmol), and the mixture was stirred at the same
temperature for 2 h. The reaction mixture was quenched with H2O.
The organic layer was washed twice with H2O, dried over MgSO4,
filtered, and concentrated under reduced pressure. The resulting
residue was purified using silica-gel column chromatography (n-
hexane/EtOAc = 70:30) to give 1.48 g of 9 (97% yield) as a colorless
(2R,3S)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-
1,2,4-triazol-1-yl)butan-2-ol (Voriconazole), and (2R,3S)-2-(2,4-
Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(4H-1,2,4-triazol-4-yl)-
butan-2-ol (13). To a solution of 11 (373 mg, 1.33 mmol) in EtOH
(1.5 mL) was added 1,2,4-triazole (2.76 g, 39.9 mmol) at room
temperature, and the resulting mixture was stirred at 80 °C (bath
temp.) for 18 h. The reaction mixture was quenched with H2O. The
aqueous layer was extracted three times with EtOAc. The combined
organic layers were dried over MgSO4, filtered, and concentrated
under reduced pressure. The resulting residue was purified using silica-
gel column chromatography (CHCl3/MeOH = 10:1) to give 186 mg
of voriconazole (40% yield, recovered 10: 24%, 53% based on the
recovered starting material) as a colorless crystal and 13 (125 mg, 27%
yield) as a colorless crystal. 161 mg of voriconazole (enantiomeric
excess: 80%) was taken up with isopropanol (483 μL) at 65 °C, and
the resulting solution was stirred at room temperature for 1 h. After
additional stirring at 0 °C for 1.5 h, the resulting crystal was filtered
and dried in vacuo to give 85.7 mg of voriconazole (enantiomeric
excess: 99.3%). 67.1 mg of voriconazole (enantiomeric excess: 99.3%)
was taken up with isopropanol (168 μL) and n-hexane (168 μL) at 65
°C, and the resulting solution was stirred at room temperature for 1 h.
After additional stirring at 0 °C for 12 h, the resulting crystal was
filtered and dried in vacuo to give 61.5 mg of voriconazole
(enantiomeric excess: >99%) as a colorless crystal: mp 134−136 °C;
27
oil: [α]D 40.6 (c 0.85, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.00
(d, J = 2.8 Hz, 1H), 8.73 (d, J = 1.4 Hz, 1H), 7.48−7.42 (m, 1H),
6.93−6.89 (m, 1H), 6.86−6.80 (m, 1H), 3.73 (d, J = 5.5 Hz, 1H), 3.32
(d, J = 5.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 193.1 (d, J = 3.8
Hz), 163.6 (dd, J = 253, 11 Hz), 161.7 (dd, J = 250, 13 Hz), 154.8 (d, J
= 275 Hz), 153.7 (d, J = 7.7 Hz), 148.1 (d, J = 8.6 Hz), 147 (d, J = 21
Hz), 130.6 (dd, J = 11, 5.8 Hz), 117.6 (dd, J = 16, 3.8 Hz), 111.8 (dd, J
= 23, 4.3 Hz), 104.2 (dd, J = 25, 25 Hz), 59.6, 52.4; 19F NMR (376
MHz, CDCl3) δ −106.9, −110.0, −133.3; IR (neat, cm−1) ν 3080,
2963, 2310, 1722, 1619, 1509, 1402, 1294; HRMS (ESI) Anal. Calcd.
for C13H8O2N2F3 m/z 281.0532 [M + H]+, found 281.0535.
(R)-4-(1-(2-(2,4-Difluorophenyl)oxiran-2-yl)vinyl)-5-fluoropyrimi-
dine (10). To a suspension of methyltriphenylphosphonium bromide
(640 mg, 1.79 mmol) in toluene (2.0 mL) was added tBuOK (201 mg,
1.79 mmol), and the resulting mixture was stirred at 120 °C for 1 h.
After cooling the reaction mixture to 0 °C, a solution of 9 (251 mg,
0.896 mmol) in toluene (7 mL) was added, and the resulting mixture
was stirred at room temperature for 3 h. The reaction mixture was
quenched with H2O. The organic layer was washed with H2O, dried
over MgSO4, filtered, and concentrated under reduced pressure. The
resulting crude mixture was taken up with toluene (4.5 mL), and then
MgCl2 (512 mg, 5.38 mmol) was added. The reaction mixture was
stirred at 65 °C for 1 h. After cooling to room temperature, the
resulting mixture was filtered, and concentrated under reduced
pressure. The resulting residue was purified using silica-gel column
chromatography (n-hexane/EtOAc = 70:30) to give 212 mg of 10
27
25
[α]D −57.3 (c 1.0, MeOH, synthetic sample), [α]D −62 (c 1.0,
MeOH, reported in ref 2b); 1H NMR (400 MHz, CDCl3) δ 8.91 (d, J
= 2.5 Hz, 1H), 8.59 (d, J = 1.4 Hz, 1H), 7.94 (s, 1H), 7.61−7.55 (m,
1H), 7.52 (s, 1H), 6.84−6.77 (m, 2H), 6.46 (s, 1H), 4.69 (d, J = 14.2
Hz, 1H), 4.29 (d, J = 14.2 Hz, 1H), 4.11 (q, J = 7.1 Hz, 1H), 1.08 (d, J
= 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.8 (dd, J = 250, 13
Hz), 159.3 (d, J = 12.5 Hz), 158.4 (dd, J = 248, 11 Hz), 155.7 (d, J =
267 Hz), 153.4 (d, J = 8.6 Hz), 150.9, 145.3 (d, J = 21 Hz), 143.9,
130.6 (dd, J = 9.6, 5.8 Hz), 123.5 (dd, J = 12, 3.8 Hz), 111.6 (dd, J =
20, 2.9 Hz), 104.1 (dd, J = 28, 26 Hz), 77.5 (d, J = 4.8 Hz), 57.3 (d, J =
4.8 Hz), 36.8 (d, J = 4.8 Hz), 16.1; IR (neat, cm−1) ν 3197, 2994,
2979, 1619, 1587, 1496, 1451, 1408; HRMS (ESI) Anal. Calcd. for
C16H14ON5F3Na m/z 372.1043 [M + Na]+, found 372.1037. The
enantiometric excess of voriconazole was determined by chiral HPLC
analysis (DAICEL, CHIRALCEL OD-H, flow rate =1.0 mL/min, n-
hexane:EtOH = 85:25, detection at 254 nm, column temp. 23 °C, tR =
17.7 min (voriconazole), tR = 20.8 min (ent-voriconazole). 13: mp
27
(85% yield) as a colorless crystal: mp 60−62 °C; [α]D 65.8 (c 0.72,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 3.0 Hz, 1H), 8.50
(d, J = 3.2 Hz, 1H), 7.55−7.49 (m, 1H), 6.80−6.76 (m, 1H), 6.73−
6.68 (m, 1H), 6.20 (br s, 1H), 6.16 (s, 1H), 3.33 (d, J = 5.3 Hz, 1H),
3.17 (d, J = 5.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 162.8 (dd, J
= 250, 12 Hz), 161.5 (dd, J = 252, 13 Hz), 155.7 (d, J = 270 Hz),
153.9 (d, J = 8.6 Hz), 150.7 (d, J = 8.6 Hz), 145.5 (d, J = 24 Hz), 140.4
(d, J = 5.8 Hz), 131.6 (dd, J = 9.6, 4.8 Hz), 124.8 (dd, J = 9.6, 1.9 Hz),
121.5 (dd, J = 13, 3.8 Hz), 111.1 (dd, J = 21, 3.8 Hz), 104.1 (dd, J =
25, 25 Hz), 57.9, 54.8; 19F NMR (376 MHz, CDCl3) δ −108.9,
−109.5, −131.7; IR (neat, cm−1) ν 3062, 2997, 2374, 2352, 1894,
1617, 1579, 1507, 1403, 1283; HRMS (ESI) Anal. Calcd. for
C14H10ON2F3 m/z 279.0740 [M + H]+, found 279.0736.
28
1
185−188 °C; [α]D −46.3 (c 1.0, CHCl3); H NMR (400 MHz,
CDCl3) δ 8.97 (s, 1H), 8.62 (s, 1H), 7.84 (s, 2H), 7.51−7.45 (m, 1H),
6.81−6.74 (m, 2H), 6.46 (brs, 1H), 4.51 (d, J = 14.2 Hz, 1H), 4.02 (q,
J = 6.9 Hz, 1H), 3.95 (d, J = 14.2 Hz, 1H), 1.04 (d, J = 6.9 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 163.0 (dd, J = 251, 12 Hz), 159.1 (d, J
4-((S)-1-((R)-2-(2,4-Difluorophenyl)oxiran-2-yl)ethyl)-5-fluoropyri-
midine (11). To a solution of 10 (23.5 mg, 0.0845 mmol) in MeOH
(84.5 μL) was added NaHCO3 (9.2 mg, 0.110 mmol) and 2,4,6-
triisopropylbenzenesulfonylhydrazide (30.2 mg, 0.101 mmol) at room
temperature, and the resulting mixture was stirred at the same
temperature for 18 h. The reaction mixture was quenched with H2O.
The aqueous layer was extracted three times with EtOAc. The
combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. The resulting residue was
purified using silica-gel column chromatography (n-hexane/EtOAc =
50:50) to give 18.9 mg of 11 as a diastereomixture (80% yield,
(2R,3S):(2R,3R) = 69:31 by 1H NMR analysis). Further purification of
the diastereomixture of 11 using silica-gel column chromatography (n-
hexane/diisopropyl ether =20:80) gave 13.4 mg of 11 (57% yield,
= 13.0 Hz), 157.9 (dd, J = 246, 12 Hz), 155.6 (d, J = 266 Hz), 153.8
(d, J = 8.7 Hz), 146.0 (d, J = 22 Hz), 143.1, 131.2 (dd, J = 9.4, 5.1 Hz),
122.3 (dd, J = 12, 4.3 Hz), 112.3 (dd, J = 20, 2.9 Hz), 104.2 (dd, J =
27, 27 Hz), 77.7 (d, J = 4.3 Hz), 53.3 (d, J = 5.8 Hz), 36.4 (d, J = 4.3
Hz), 16.2; 19F NMR (376 MHz, CDCl3) δ −109.0, −110.3, −135.7;
IR (neat, cm−1) ν 3360, 3114, 2982, 2940, 2376, 1620, 1588, 1498,
1406; HRMS (ESI) Anal. Calcd. for C16H15ON5F3 m/z 350.1223 [M
+ H]+, found 350.1228.
(R)-((R)-2-(2,4-Difluorophenyl)oxiran-2-yl)(5-fluoropyrimidin-4-
yl)methyl methanesulfonate (14). To a solution of 8 (20.5 mg,
0.0726 mmol) in CH2Cl2 (363 μL) was added Et3N (22.3 μL, 0.160
mmol) and MsCl (6.20 μL, 0.0799 mmol) at 0 °C, and the resulting
mixture was stirred at the same temperature for 1 h. The reaction
28
single diastereomer) as a colorless oil: [α]D −24.2 (c 0.47, CHCl3);
E
dx.doi.org/10.1021/jo4019528 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mixture was quenched with H2O. The aqueous layer was extracted
three times with CHCl3. The combined organic layers were dried over
MgSO4, filtered, and concentrated under reduced pressure. The
resulting residue was purified using preparative TLC (n-hexane/EtOAc
= 50:50) to give 26.7 mg of 14 (quantitative yield) as a colorless oil:
[α]D28 −12.8 (c 1.24, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.98 (d,
J = 2.5 Hz, 1H), 8.58 (s, 1H), 7.38−7.32 (m, 1H), 6.87−6.83 (m, 1H),
6.74−6.69 (m, 1H), 6.03 (s, 1H), 3.40 (d, J = 4.6 Hz, 1H), 3.07 (s,
3H), 2.97 (d, J = 4.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 163.4
(dd, J = 252, 11 Hz), 160.6 (dd, J = 250, 12 Hz), 155.3 (d, J = 270
Hz), 154.4 (d, J = 7.7 Hz), 149.1 (d, J = 11 Hz), 145.6 (d, J = 21 Hz),
131.5 (dd, J = 9.6, 4.8 Hz), 117.8 (dd, J = 14, 3.8 Hz), 111.8 (dd, J =
22, 3.8 Hz), 103.8 (dd, J = 25, 25 Hz), 76.9, 56.8, 51.0, 38.9; 19F NMR
(376 MHz, CDCl3) δ −106.9, −111.1, −134.2; IR (neat, cm−1) ν
3081, 3028, 2939, 1620, 1585, 1509, 1365; HRMS (ESI) Anal. Calcd.
for C14H12O4N2F3S m/z 361.0465 [M + H]+, found 361.0468.
(E)-2-(2,4-Difluorophenyl)-1-(5-fluoropyrimidin-4-yl)-3-hydroxy-
prop-1-en-1-yl methanesulfonate (15). Attmpts to obtain methylated
product resulted in failure, and 15 was isolated from the complicated
H2O. The aqueous layer was extracted three times with EtOAc. The
combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. The resulting residue was
purified using preparative TLC (CHCl3/MeOH = 10:1) to give 41.1
mg of (E)-17 (66% yield) as a colorless amorphous and 11.3 mg of 18
(19% yield) as a colorless oil. (E)-17: 1H NMR (400 MHz, CDCl3) δ
8.90 (d, J = 2.7 Hz, 1H), 8.19 (d, J = 1.8 Hz, 1H), 8.08 (s, 1H), 7.87
(s, 1H), 7.00−6.94 (m, 1H), 6.70−6.62 (m, 2H), 5.50 (s, 2H), 4.69 (s,
2H); 13C NMR (100 MHz, CDCl3) δ 163.0 (dd, J = 252, 12 Hz),
159.4 (dd, J = 251, 12 Hz), 154.3 (d, J = 269 Hz), 154.3 (d, J = 7.7
Hz), 153.2 (d, J = 12 Hz), 152.1, 145.9 (dd, J = 1.9, 1.9 Hz), 145.4 (d,
J = 23 Hz), 143.8, 131.8 (dd, J = 9.6, 4.8 Hz), 128.0 (d, J = 4.8 Hz),
122.6 (dd, J = 15, 3.4 Hz), 111.4 (dd, J = 22, 3.4 Hz), 104.3 (dd, J =
25, 25 Hz), 62.9 (d, J = 1.9 Hz), 48.9; 19F NMR (376 MHz, CDCl3) δ
−107.9, −109.3, −129.9; IR (neat, cm−1) ν 3369, 2352, 1614, 1580,
1504, 1272, 1141; HRMS (ESI) Anal. Calcd. for C16H12ON5F3Na m/z
370.0886 [M + Na]+, found 370.0884. 18: 1H NMR (600 MHz,
CDCl3) δ 8.72 (s, 1H), 8.34 (s, 1H), 8.24 (s, 1H), 7.85 (s, 1H), 7.81−
7.77 (m, 1H), 7.05−7.02 (m, 1H), 6.95−6.92 (m, 1H), 5.18 (br s,
2H), 5.08 (s, 2H); 13C NMR (150 MHz, CDCl3) δ 163.7 (dd, J = 253,
12 Hz), 160.0 (dd, J = 251, 13 Hz), 151.9, 151.4, 148.0, 146.6, 144.8,
144.0, 138.5, 132.0 (dd, J = 9.4, 5.1 Hz), 126.7, 118.0 (dd, J = 16, 4.3
Hz), 112.4 (d, J = 22 Hz), 104.9 (dd, J = 26, 26 Hz), 68.7 (d, J = 4.3
Hz), 44.5; 19F NMR (376 MHz, CDCl3) δ −106.1, −108.2; IR (neat,
cm−1) ν 3102, 3050, 2924, 2852, 1504, 1413; HRMS (ESI) Anal.
Calcd. for C16H12ON5F2 m/z 328.1005 [M + H]+, found 328.1006.;
HRMS (ESI) Anal. Calcd. for C16H12ON5F2 m/z 328.1005 [M + H]+,
found 328.1006.
1
mixture. Tentative assignment was made with H NMR, NOE, and
HRMS. To a solution of 14 (24.6 mg, 0.0683 mmol) in THF (136 μL)
was added 0.97 M MeMgBr in THF (0.21 mL, 0.205 mmol) at 0 °C,
and the resulting mixture was stirred at room temperature for 6 h. The
reaction mixture was quenched with 1 N HCl aq. The aqueous layer
was extracted twice with EtOAc, and the combined organic layers were
dried over MgSO4. After removal of volatiles under reduced pressure,
the resulting residue was purified using preparative TLC (CHCl3/
MeOH = 10:1) to give 3.3 mg of 15 (ca. 13% yield, with some
unidentified materials) as a yellow oil. 15: 1H NMR (600 MHz,
CDCl3) δ 9.11 (d, J = 2.7 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H), 7.62−7.58
(m, 1H), 7.01−6.98 (m, 1H), 6.94−6.90 (m, 1H), 4.30 (s, 2H), 2.73
(s, 3H); HRMS (ESI) Anal. Calcd. for C14H12O4N2F3S m/z 361.0465
[M + H]+, found 361.0469.
(R)-(5-(1H-1,2,4-Triazol-1-yl)pyrimidin-4-yl)(2-(2,4-
difluorophenyl)oxiran-2-yl)methanone (19). To a solution of 9 (10.8
mg, 0.0385 mmol) in DMF (193 μL) was added 1,2,4-sodium
triazolide (5.26 mg, 0.0578 mmol) at room temperature, and the
resulting mixture was stirred at the same temperature for 1 h. The
reaction mixture was quenched with H2O. The aqueous layer was
extracted three times with EtOAc. The combined organic layers were
dried over MgSO4, filtered, and concentrated under reduced pressure.
The resulting residue was purified using silica-gel column chromatog-
raphy (n-hexane/EtOAc = 50:50) to give 10.9 mg of 19 (86% yield) as
(E)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)but-2-en-1-
ol ((E)-16) and (Z)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-
yl)but-2-en-1-ol ((Z)-16). To a solution of 10 (25.5 mg, 0.0917 mmol)
in EtOH (917 μL) was added 10% Pd/C (20.8 mg) at room
temperature under argon atmosphere. The resulting suspension was
stirred at the same temperature under H2 atmosphere for 1 h. After
evacuation of H2, argon was backfilled, and the resulting suspension
was filtered and concentrated under reduced pressure. The resulting
residue was purified using preparative TLC (n-hexane/EtOAc =
50:50) to give 11.1 mg of 16 (44% yield, E/Z = 2.2/1) as a colorless
28
1
a colorless solid: [α]D 27.4 (c 0.1, CHCl3); H NMR (400 MHz,
CDCl3) δ 9.22 (s, 1H), 9.05 (s, 1H), 8.60 (s, 1H), 8.11 (s, 1H), 7.47−
7.41 (m, 1H), 6.94−6.89 (m, 1H), 6.88−6.83 (m, 1H), 3.70 (d, J = 5.7
Hz, 1H), 3.20 (d, J = 5.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
194.6, 163.5 (dd, J = 252, 13 Hz), 161.6 (dd, J = 252, 12 Hz), 156.8,
154.5, 153.5, 150.0, 142.4, 130.6 (dd, J = 9.6, 4.8 Hz), 129.2, 117.4
(dd, J = 16, 2.9 Hz), 111.5 (dd, J = 22, 3.8 Hz), 104.1 (dd, J = 25, 25
Hz), 59.4, 52.7; 19F NMR (376 MHz, CDCl3) δ −107.2, −109.9; IR
(neat, cm−1) ν 3415, 3132, 3104, 2925, 2354, 1720, 1618, 1509, 1463,
1431; HRMS (ESI) Anal. Calcd. for C15H10O2N5F2 m/z 330.0797 [M
+ H]+, found 330.0802.
1
oil: H NMR for E isomer (600 MHz, CDCl3) δ 8.87 (d, J = 2.7 Hz,
1H), 8.26 (d, J = 2.1 Hz, 1H), 6.84−6.80 (m, 1H), 6.72−6.68 (m,
1H), 6.61−6.57 (m, 1H), 4.60 (s, 2H), 2.26 (s, 3H); 13C NMR for E
isomer (150 MHz, CDCl3) δ 162.5 (dd, J = 250, 12 Hz), 160.0 (dd, J
= 251, 13 Hz), 156.6 (d, J = 12 Hz), 154.2 (d, J = 7.2 Hz), 154.1 (d, J
= 266 Hz), 144.8 (d, J = 23 Hz), 137.8, 132.2 (dd, J = 8.7, 5.8 Hz),
131.5 (d, J = 2.9 Hz), 122.8 (dd, J = 16, 4.3 Hz), 110.9 (dd, J = 21, 3.6
Hz), 104.0 (dd, J = 26, 26 Hz), 62.4, 17.9; 19F NMR for E isomer (376
MHz, CDCl3) δ −109.5, −109.7, −132.0; 1H NMR for Z isomer (600
MHz, CDCl3) δ 9.03 (d, J = 2.7 Hz, 1H), 8.64 (d, J = 2.1 Hz, 1H),
7.39−7.34 (m, 1H), 6.96−6.86 (m, 2H), 4.04 (s, 2H), 1.94 (s, 3H);
13C NMR for Z isomer (150 MHz, CDCl3) δ 162.7 (dd, J = 251, 11
Hz), 159.4 (dd, J = 248, 11 Hz), 155.4 (d, J = 267 Hz), 155.3 (d, J =
13 Hz), 154.0 (d, J = 7.2 Hz), 145.7 (d, J = 25 Hz), 138.4, 132.6 (d, J =
4.3 Hz), 131.2 (dd, J = 9.4, 5.1 Hz), 123.2 (dd, J = 17, 3.6 Hz), 111.7
(dd, J = 21, 3.6 Hz), 104.2 (dd, J = 26, 26 Hz), 64.1, 19.0 (d, J = 4.3
Hz); 19F NMR for Z isomer (376 MHz, CDCl3) δ −109.7, −110.1,
−130.9; IR (E/Z mixture) (neat, cm−1) ν 3378, 3063, 2924, 2876,
1614, 1583, 1503, 1402; HRMS (ESI) Anal. Calcd. for C14H12ON2F3
m/z 281.0896 [M + H]+, found 281.0894.
7-(2,4-Difluorophenyl)-8-methyl-6H-pyrano[3,2-d]pyrimidine
(20). To a solution of 11 (26.5 mg, 0.0946 mmol) in DMF (265 μL)
was added 1,2,4-sodium triazolide (86.1 mg, 0.946 mmol) at room
temperature, and the resulting mixture was stirred at 60 °C for 1 h.
The reaction mixture was quenched with H2O. The aqueous layer was
extracted three times with EtOAc. The combined organic layers were
dried over MgSO4, filtered, and concentrated under reduced pressure.
The resulting residue was purified using preparative TLC (n-hexane/
EtOAc = 50:50) to give 9.1 mg of (E)-16 (34% yield) as a pale purple
oil and 10.7 mg of 20 (44% yield) as a colorless crystal. Spectroscopic
data of (E)-16 is described above. 20: 1H NMR (400 MHz, CDCl3) δ
8.77 (s, 1H), 8.22 (s, 1H), 7.25−7.19 (m, 1H), 6.97−6.88 (m, 2H),
4.97 (s, 2H), 2.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.1 (dd,
J = 251, 13 Hz), 159.9 (dd, J = 252, 13 Hz), 152.0, 149.2, 147.9, 143.2,
132.3, 131.2 (dd, J = 9.6, 4.8 Hz), 130.0, 119.9 (dd, J = 17, 6.2 Hz),
111.9 (dd, J = 21, 3.8 Hz), 104.8 (dd, J = 25, 25 Hz), 68.6 (d, J = 2.9
Hz), 12.6; 19F NMR (376 MHz, CDCl3) δ −108.0, 108.3; IR (neat,
cm−1) ν 3069, 2852, 1614, 1574, 1506, 1465, 1414; HRMS (ESI) Anal.
Calcd. for C14H11ON2F2 m/z 261.0834 [M + H]+, found 261.0828.
(3R)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-2-(4H-
1,2,4-triazol-4-yl)butan-1-ol (21). To a solution of 11 (8.3 mg, 0.0296
(E)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-4-(1H-1,2,4-
triazol-1-yl)but-2-en-1-ol ((E)-17) and 8-((1H-1,2,4-Triazol-1-yl)-
methyl)-7-(2,4-difluorophenyl)-6H-pyrano[3,2-d]pyrimidine (18).
To a solution of 10 (50.0 mg, 0.180 mmol) in DMF (500 μL) was
added 1,2,4-triazole (124 mg, 1.80 mmol) and K2CO3 (248 mg, 1.80
mmol) at room temperature, and the resulting mixture was stirred at
the same temperature for 2 h. The reaction mixture was quenched with
F
dx.doi.org/10.1021/jo4019528 | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
mmol) in EtOH (33.2 μL) was added 1,2,4-triazole (61.4 mg, 0.888
mmol) and LiCl (7.54 mg, 0.178 mmol) at room temperature, and the
resulting mixture was stirred at 80 °C (bath temp.) for 5 h. The
reaction mixture was quenched with H2O. The aqueous layer was
extracted three times with EtOAc. The combined organic layers were
dried over MgSO4, filtered, and concentrated under reduced pressure.
The resulting residue was purified using preparative TLC (CHCl3/
MeOH = 10:1) to give 3.6 mg of 21 (35% yield) as a colorless
(7) (a) Yabu, K.; Masumoto, S.; Yamasaki, S.; Hamashima, Y.; Kanai,
M.; Du, W.; Curran, D. P.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123,
9908. (b) Suzuki, M.; Kato, N.; Kanai, M.; Shibasaki, M. Org. Lett.
2005, 7, 2527.
(8) For recent reviews of catalytic asymmetric cyanation: (a) Brunel,
J.-M.; Holmes, I. P. Angew. Chem., Int. Ed. 2004, 43, 2752. (b) Chen,
F.-X.; Feng, X. Curr. Org. Chem. 2006, 3, 77. (c) North, M.; Usanov,
D. L.; Young, C. Chem. Rev. 2008, 108, 5146. (d) Wang, W.; Liu, X.;
Lin, L.; Feng, X. Eur. J. Org. Chem. 2010, 4751. (e) Ohkuma, T.;
Kurono, N. Synlett 2012, 1865.
1
amorphous: H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.37 (s,
1H), 7.87 (s, 2H), 7.02−6.96 (m, 1H), 6.69−6.64 (m, 1H), 6.51−6.46
(m, 1H), 6.17 (br s, 1H), 4.55 (s, 2H), 4.24 (q, J = 6.9 Hz, 1H), 1.54
(d, J = 6.9 Hz, 3H) (in DMSO-d6, doublet peak of OH proton was
observed (J = 4.6 Hz), supporting that 21 is an isomeric primary
alcohol formed by epoxide opening from the more congested carbon);
13C NMR (150 MHz, CDCl3) δ 162.6 (dd, J = 251, 12 Hz), 158.9 (d, J
= 13 Hz), 157.8 (dd, J = 244, 12 Hz), 154.6 (d, J = 266 Hz), 153.2 (d,
J = 8.7 Hz), 145.4 (d, J = 22 Hz), 143.3, 130.0 (dd, J = 9.4, 5.1 Hz),
124.0 (dd, J = 13, 2.9 Hz), 111.9 (dd, J = 22, 2.9 Hz), 104.2 (dd, J =
27, 27 Hz), 76.8, 51.6 (d, J = 4.3 Hz), 36.7 (d, J = 5.8 Hz), 14.6; 19F
NMR (376 MHz, CDCl3) δ −108.8, −109.5, −137.1; IR (neat, cm−1)
3378, 3123, 2979, 2238, 1616, 1590, 1498, 1404; HRMS (ESI) Anal.
Calcd. for C16H15ON5F3 m/z 350.1223 [M + H]+, found 350.1222.
(9) For selected examples of catalytic asymmetric cyanation of
ketones: (a) Choi, M. C. K.; Chan, S. S.; Matsumoto, K. Tetrahedron
Lett. 1999, 38, 6669. (b) Belokon’, Y. N.; Green, B.; Ikonnikov, N. S.;
North, M.; Tararov, V. I. Tetrahedron Lett. 1999, 40, 8147.
(c) Hamashima, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2000, 122, 7412. (d) Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2001, 123,
6195. (e) Deng, H.; Isler, M. P.; Snapper, M. L.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2002, 41, 1009. (f) Chen, F.; Feng, X.; Qin, B.;
Zhang, G.; Jiang, Y. Org. Lett. 2003, 5, 949. (g) Kim, S. S.; Song, D. H.
Eur. J. Org. Chem. 2005, 1777. (h) Achard, T. R. J.; Clucterbuck, L. A.;
North, M. Synlett 2005, 1828. (i) Ryu, D. H.; Corey, E. J. J. Am. Chem.
Soc. 2005, 127, 5384. (j) Fuerst, D. E.; Jacobsen, E. N. J. Am. Chem.
Soc. 2005, 127, 8964. (k) Liu, X.; Qin, B.; Zhou, X.; He, B.; Feng, X. J.
Am. Chem. Soc. 2005, 127, 12224. (l) Alaaeddine, R. T.; Thomas, C.
M.; Carpentier, J.-F. Adv. Synth. Catal. 2008, 350, 731. (m) Hatano,
M.; Ikeno, T.; Matsumura, T.; Torii, S.; Ishihara, K. Adv. Synth. Catal.
2008, 350, 1776. (n) Khan, N. H.; Agrawal, S.; Kureshy, R. I.; Abdi, S.
H. R.; Prathap, K. J.; Jasra, R. V. Chirality 2009, 21, 262. (o) Yoshinaga,
K.; Nagata, T. Adv. Synth. Catal. 2009, 351, 1495. (p) Rajagopal, G.;
Selvaraj, S.; Dhahagani, K. Tetrahedron: Asymmetry 2010, 21, 2265.
(q) Cao, J.-J.; Zhou, F.; Zhou, J. Angew. Chem., Int. Ed. 2010, 49, 4976.
(r) Uemura, M.; Kurono, N.; Sakai, Y.; Ohkuma, T. Adv. Synth. Catal.
2012, 354, 2023.
(10) For utility of the sugar-based ligand 3 in the enantioselective
synthesis of biologically active compounds: (a) Yabu, K.; Masumoto,
S.; Kanai, M.; Curran, D. P.; Shibasaki, M. Tetrahedron Lett. 2002, 43,
2923. (b) Masumoto, S.; Suzuki, M.; Kanai, M.; Shibasaki, M.
Tetrahedron Lett. 2002, 43, 8647. (c) Yabu, K.; Masumoto, S.; Kanai,
M.; Du, W.; Curran, D. P.; Shibasaki, M. Heterocycles 2003, 59, 369.
(d) Masumoto, S.; Suzuki, M.; Kanai, M.; Shibasaki, M. Tetrahedron
2004, 60, 10497. (e) Maki, K.; Motoki, R.; Fujii, K.; Kanai, M.;
Kobayashi, T.; Tamura, S.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127,
17111. See also ref 7.
ASSOCIATED CONTENT
■
S
* Supporting Information
Additional experimental procedures and H and 13C NMR
1
spectra of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: nkumagai@bikaken.or.jp.
*E-mail: mshibasa@bikaken.or.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JST, ACT-C, and
KAKENHI (No. 25713002). Dr. Ryuichi Sawa and Ms. Yumiko
Kubota are gratefully acknowledged for technical assistance
with the NMR analysis.
(11) Kato, N.; Tomita, D.; Maki, K.; Kanai, M.; Shibasaki, M. J. Org.
Chem. 2004, 69, 6128.
(12) Absolute configuration of 2 was determined by following the
reported procedure in ref 7b.
(13) Reich, M.; Schunk, S.; Jostock, R.; De Vry, J. ; Kneip, C.;
Germann, T.; Engels, M. WO2012038081, 2012.
(14) 4-Lithio-5-fluoropyrimidine was used in THF in ref 6.
(15) See Experimental Section for details.
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■
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H
dx.doi.org/10.1021/jo4019528 | J. Org. Chem. XXXX, XXX, XXX−XXX