An enantioselective synthesis of the key intermediate for triazole antifungal agents; Application to the catalytic asymmetric synthesis of efinaconazole (jublia)

Article abstract of DOI:10.1021/jo500369y

A new synthetic route, the shortest reported to date, to access a key intermediate for the synthesis of various triazole antifungal agents was developed. The elusive tetrasubstituted stereogenic center that is essential in advanced triazole antifungal agents was constructed via the catalytic asymmetric cyanosilylation of a ketone. The subsequent transformations were performed in two one-pot operations, enhancing the overall synthetic efficiency toward the intermediate. This streamlined synthetic approach was successfully applied to efficient enantioselective syntheses of efinaconazole (Jublia) and ravuconazole.

Full text of DOI:10.1021/jo500369y

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An Enantioselective Synthesis of the Key Intermediate for Triazole
Antifungal Agents; Application to the Catalytic Asymmetric
Synthesis of Efinaconazole (Jublia)
Keiji Tamura,† Naoya Kumagai,*,† and Masakatsu Shibasaki*,†,‡
†Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
‡ACT-C, Japan Science and Technology Agency (JST), 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
S
* Supporting Information
ABSTRACT: A new synthetic route, the shortest reported to date, to access a key intermediate for the synthesis of various
triazole antifungal agents was developed. The elusive tetrasubstituted stereogenic center that is essential in advanced triazole
antifungal agents was constructed via the catalytic asymmetric cyanosilylation of a ketone. The subsequent transformations were
performed in two one-pot operations, enhancing the overall synthetic efficiency toward the intermediate. This streamlined
synthetic approach was successfully applied to efficient enantioselective syntheses of efinaconazole (Jublia) and ravuconazole.
riazole antifungal agents have been in widespread clinical
use for the treatment of various fungal infections, not only
fluconazole with heteroaromatics (e.g., 5-fluoropyrimidine for
voriconazole) and the installation of a methyl group next to the
tetrasubstituted stereogenic center have been proved to be
beneficial structural modifications,6a leading to the identifica-
tion of advanced triazole antifungal agents. As these
modifications break the molecular symmetry of achiral
fluconazole, the development of an efficient enantioselective
synthetic route is in high demand.
Considering the common substructures that are shared in
these antifungal agents, the enantiomerically pure epoxide 1
bearing 2,4-difluorobenzene, 1,2,4-triazole, and a methyl group
is a rational intermediate for their divergent syntheses (Scheme
1). The enantioselective construction of the consecutive tetra-
and trisubstituted stereogenic centers represents a formidable
task in the synthesis of epoxide 1. Because of the pivotal role of
1 in the efficient synthesis of these antifungal agents, various
synthetic approaches toward epoxide 1 have been inves-
tigated.10−12 Almost all of the synthetic routes rely on the use
of D- or L-lactic acid as a chiral pool.11a−c,12 In particular,
Bristol-Myers Squibb has developed an excellent approach
toward epoxide 1 in six steps in 25% overall yield, leading to the
T
high-risk diseases such as acute invasive aspergillosis1 but also
low-risk pathological conditions such as nail infections.2
Although fungal infections are generally regarded as nonfatal
clinical conditions, immunocompromised patients with human
immunodeficiency virus (HIV) infection or undergoing cancer
chemotherapy are susceptible to life-threatening fungal
diseases.3 The representative triazole antifungal agent flucona-
zole (Figure 1), which was developed by Pfizer, is effective
orally against a range of fungal infections.4 However, it is poorly
active against Aspergillus spp., which cause life-threatening
infections in immunocompromised patients, and fluconazole
resistance has been reported in patients receiving long-term
treatment.5 To address these issues, an advanced triazole
antifungal agent, voriconazole (Vfend), was developed.6 This
agent is active against all Candida spp., including fluconazole-
resistant Candida albicans, Candida glabrata, and Candida
krusei, as well as several Aspergillus spp., including the
amphotericin B-resistant Aspergillus terreus.7 Therefore, vor-
iconazole is a primary drug in the first-line treatment of invasive
aspergillosis, as either an intravenous or oral formulation.1a,7f,8
The high potency of voriconazole has inspired extensive efforts
devoted to the development of a variety of synthetic
derivatives.9 The replacement of one of the triazole rings in
Received: February 15, 2014
© XXXX American Chemical Society
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Figure 1. Structures of fluconazole and advanced triazole antifungal agents.
Scheme 1. Enantioselective Synthesis of Epoxide 1, a Key Intermediate for Various Antifungal Agents
scalable synthesis of ravuconazole.10 Although other approaches
utilizing Sharpless asymmetric epoxidation11e or enzymatic
resolution11f have been accomplished, there remains room for
improvement in terms of the number of synthetic steps. The
exploitation of a catalytic asymmetric C−C bond-forming
reaction is a viable option for the integration of the
construction of a molecular skeleton with a stereogenic center.
We recently demonstrated that the catalytic asymmetric
cyanosilylation of a ketone is particularly useful for the
construction of the elusive tetrasubstituted stereogenic center,
culminating in the enantioselective synthesis of voriconazole.13
Herein we report a new route, the shortest reported to date,
to access epoxide 1 in four steps from commercially available
ketone 2 in 29% yield. The key step features the catalytic
asymmetric cyanosilylation to construct the tetrasubstituted
stereogenic center of 3. The utility of this synthetic approach
has been demonstrated by the efficient syntheses of the
significant antifungal agents ravuconazole9b,10 and efinacona-
zole (Jublia).9d,14 Ravuconazole, which bears a functionalized
thiazole, features a broad antifungal spectrum as well as the
longest half-life and has completed P2 clinical trials.
Efinaconazol (Jublia), which possesses a 4-methylenepiperidine
moiety and has recently received approval in Canada,15 is the
first external-use antifungal agent for the treatment of
onychomycosis.16
Our synthesis commenced with the catalytic asymmetric
cyanosilylation of ketone 2, a key reaction promoted by a Gd-
based asymmetric catalyst to construct the tetrasubstituted
stereogenic center (Scheme 2).17−19 A putative Gd-based
polymetallic catalyst composed of Gd and the sugar-derived
chiral ligand 420,21 in a 2:3 ratio, as suggested by ESI-MS
analysis in the presence of TMSCN,17b was generated by
mixing Gd(HMDS)3 and 4 in a 2:3 ratio at −30 °C. The
polymetallic catalyst (2 mol% based on Gd) promoted the
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Scheme 2. Short Synthesis of the Key Intermediate Epoxide 1
catalytic asymmetric cyanosilylation of 2 with TMSCN at −30
°C in propionitrile to afford the desired cyanohydrin 3 with
TMS protection in 92% yield with 80% ee. Because of its
instability under acidic and basic conditions and silica gel
column chromatography, 3 was immediately submitted to
DIBAL reduction to give corresponding aldehyde 5. Our next
focus was the diastereoselective installation of a methyl group
and 1,2,4-triazole. Initially, we faced several undesired trans-
formations. After the formation of secondary alcohol 6 using
organometallic reagents, quenching with acidic or basic aqueous
solutions led to partial migration of the TMS group to provide
a complicated mixture of 6 and 7 and their diastereomers. The
secondary TMS group of 722 was prone to deprotection under
either acidic or basic conditions as well as silica gel column
chromatography. Even when 7 was isolated via laborious
purification and subjected to 1,2,4-triazole introduction under
basic conditions at room temperature, deprotection of the TMS
group occurred and the subsequent formation of epoxide 9
proceeded partially. The suppression of these unwanted
transformations was intractable, and the complicated reaction
mixtures made the purification in each step fruitless. Given that
all of the byproducts could be converted into diol 10, we
anticipated that the sequential manifestation of these undesired
transformations in one-pot would allow direct access to 10.
After extensive manipulations of the reaction conditions, we
found that the installation of the methyl group, the
deprotection of the TMS group, the formation of epoxide 9,
and the installation of 1,2,4-triazole could be carried out in a
one-pot operation. The initial Grignard addition to 5 gave
secondary alcohol 6. Other organometallic reagents resulted in
low yield or low diastereoselectivity.23 Treatment of the
reaction mixture with a 3 N aqueous NaOH solution in the
same flask converted 6 into tertiary alcohol 7 via intramolecular
migration of the TMS group. Successive addition of 1,2,4-
triazole and TBAB as a phase-transfer catalyst initially induced
the removal of TMS to give diol 8, which eventually cyclized to
afford epoxide 9 under basic conditions. Ring opening of
epoxide 9 proceeded slowly to furnish diol 10 in favor of the
desired diastereomer in an 86:14 ratio. The diastereomers were
easily separable using silica gel column chromatography to
provide the requisite diol 10 as a single diastereomer in 65%
yield from aldehyde 5.
Diol 10 is a crystalline solid, and enantioenrichment was
attempted at this stage. When a concentrated acetonitrile
solution oversaturated at 60 °C was submitted to rapid
nucleation with stirring at −20 °C, a nearly racemic solid
(6.3% ee) appeared, and the filtrate was enriched to 97% ee.24
The second cycle of an identical procedure (but with stirring at
0 °C) afforded the enantiopure diol 10 (>99% ee) in 74%
recovery yield after two cycles.25 With the optically pure diol 10
in hand, we examined its transformation to epoxide 1.
Regioselective mesylation of diol 10 proceeded smoothly at 0
°C to provide the transient intermediate 11, which was
subsequently treated with a 3 N aqueous NaOH solution and
TBAB to afford the key intermediate epoxide 1 in 86% yield in
one pot.
Next, we turned our attention to the synthesis of
efinaconazole (Scheme 3). According to the literature
Scheme 3. Synthesis of Efinaconazole (Jublia)
procedure,9d epoxide 1 was subjected to a ring-opening
reaction with 4-methylenepiperidine26 at 80 °C. However,
51% of epoxide 1 remained unchanged after 24 h, and
efinaconazole was isolated in 44% yield. Microwave irradiation
at 120 °C solved this problem, affording efinaconazole in 90%
yield.27 The spectroscopic data of the synthesized sample were
identical to those of the reported one.9d Moreover, we also
demonstrated the synthesis of ravuconazole according to the
literature procedure (Scheme 4).9b,10 Ring opening of epoxide
1 using Et2AlCN provided cyanide 12 in 76% yield. The nitrile
functionality of 12 was transformed into a primary thioamide
with diethyl dithiophosphate to give 13 in excellent yield.
Treatment of 13 with 2-bromo-4′-cyanoacetophenone fur-
nished ravuconazole in 78% yield.
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Scheme 4. Synthesis of Ravuconazole
(d, J = 12.1 Hz, 1H), 3.97 (q, J = 6.3 Hz, 1H), 3.88 (dd, J = 12.1, 1.4
Hz, 1H), 1.10 (d, J = 6.3 Hz, 3H), 0.24 (s, 9H); 13C NMR for (2S,3S)-
6 (100 MHz, CDCl3) δ 162.5 (dd, J = 249, 13 Hz), 159.1 (dd, J = 248,
12 Hz), 131.3 (dd, J = 9.6, 5.8 Hz), 124.0 (dd, J = 13, 4.8 Hz), 110.8
(dd, J = 22, 4.3 Hz), 104.3 (dd, J = 29, 25 Hz), 83.2 (d, J = 4.8 Hz),
72.8 (d, J = 1.9 Hz), 48.6 (d, J = 7.7 Hz), 17.6, 2.33; 19F NMR for
(2S,3S)-6 (376 MHz, CDCl3) δ −107.1, −111.2; IR for (2R,3S)-6
(CHCl3, cm−1) ν 3588, 3467, 2956, 1615, 1498, 1419, 1253; HRMS
for (2R,3S)-6 (ESI-TOF) calcd for C13H19O2ClF2SiNa [M + Na]+ m/
z 331.0703, found 331.0702.
In conclusion, we have developed a new route, the shortest
reported to date, to access the key intermediate epoxide 1 in
29% overall yield in four steps from the commercially available
ketone 2. The key step features a catalytic asymmetric
cyanosilylation using Gd(HMDS)3 and a sugar-derived chiral
ligand to construct the tetrasubstituted stereogenic center that
is essential in advanced triazole antifungal agents. This
streamlined synthetic approach led us to demonstrate
enantioselective efficient syntheses of two significant antifungal
agents.
(2S,3R)-1-Chloro-2-(2,4-difluorophenyl)-3-((trimethylsilyl)-
oxy)butan-2-ol (7). To a solution of (2R,3S)-6 (21.4 mg, 0.0693
mmol) in THF (115 μL) was added 3 N NaOH (46.0 μL, 0.139
mmol) at room temperature, and the reaction mixture was stirred at
the same temperature for 10 min. The reaction mixture was quenched
with saturated aqueous NH4Cl, and 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 preparative TLC (n-hexane/EtOAc
EXPERIMENTAL SECTION
■
General Procedures. The reactions were performed in a round-
bottom flask with a Teflon-coated magnetic stirring bar and a three-
way glass stopcock under an 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 using reagent-grade solvents under
ambient atmosphere. Flash chromatography was performed using silica
gel 60 (230−400 mesh). Chemical shifts (δ) for protons are reported
in units of parts per million downfield from tetramethylsilane and are
referenced to residual protons in the NMR solvent (CDCl3, 7.24
ppm). For 13C NMR, chemical shifts are reported on the scale relative
to the NMR solvent (CDCl3, 77.0 ppm) as an internal reference. For
19F NMR, chemical shifts are reported on the scale relative to
1
= 7:1) to give 12.4 mg of 7 (58% yield) as a colorless oil. H NMR
(400 MHz, CDCl3) δ 7.72−7.65 (m, 1H), 6.92−6.87 (m, 1H), 6.78−
6.72 (m, 1H), 4.31 (q, J = 6.2 Hz, 1H), 4.04 (d, J = 11.4 Hz, 1H), 3.84
(d, J = 11.4 Hz, 1H), 3.12 (s, 1H), 0.90 (d, J = 6.2 Hz, 3H), 0.15 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 162.5 (dd, J = 249, 13 Hz),
158.6 (dd, J = 247, 13 Hz), 130.7 (dd, J = 9.6, 6.7 Hz), 123.4 (dd, J =
13, 3.8 Hz), 111.3 (dd, J = 21, 3.4 Hz), 103.8 (dd, J = 27, 25 Hz), 77.9
(d, J = 5.8 Hz), 70.7 (d, J = 4.8 Hz), 51.5 (d, J = 5.8 Hz), 18.5, 0.21;
19F NMR (376 MHz, CDCl3) δ −109.7, −111.2; IR (CHCl3, cm−1) ν
3545, 2959, 1619, 1503, 1422, 1254; HRMS (ESI-TOF) calcd for
C13H19O2ClF2SiNa [M + Na]+ m/z 331.0703, found 331.0703.
(2S,3R)-1-Chloro-2-(2,4-difluorophenyl)butane-2,3-diol (8).
To a solution of (2R,3S)-6 (31.7 mg, 0.103 mmol) in THF (343
μL) was added 1.0 M TBAF solution in THF (113 μL, 0.113 mmol) at
0 °C, and the reaction mixture was stirred at the same temperature for
15 min. The reaction mixture was quenched with saturated aqueous
NH4Cl, and 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 preparative TLC (CHCl3/MeOH = 10:1) to give 18.3
trifluoroacetic acid (76.5 ppm) as an external reference. NMR data are
reported as follows: chemical shifts (multiplicity, coupling constant in
Hz, integration). Multiplicities are denoted as follows: s, singlet; d,
doublet; dd, doublet of doublets; t, triplet; q, quartet; sep, septet; m,
multiplet; br, broad signal. Optical rotation was measured using a 2 mL
cell with a 1.0 dm path length. Compounds 1, 3, 5, 8, 9, 10, 11, 12,
and 13 are known compounds (CAS registry numbers 127000-90-2,
861718-83-4, 861718-85-6, 832151-94-7, 126918-35-2, 133775-25-4,
133775-26-5, 170862-36-9, and 170863-34-0, respectively).
(2R,3S)-4-Chloro-3-(2,4-difluorophenyl)-3-((trimethylsilyl)-
oxy)butan-2-ol [(2R,3S)-6] and (2S,3S)-4-Chloro-3-(2,4-difluor-
ophenyl)-3-((trimethylsilyl)oxy)butan-2-ol [(2S,3S)-6]. To a
solution of 5 (1.24 g, 4.23 mmol) in THF (6.70 mL) was added
0.92 M MeMgBr solution in THF (6.44 mL, 5.92 mmol) at −78 °C,
and the reaction mixture was stirred at the same temperature for 35
min. The reaction mixture was quenched with saturated aqueous
NH4Cl, and the resulting mixture was warmed to room temperature
and stirred for 20 min. The aqueous layer was extracted twice with
EtOAc. The combined organic layers were washed with H2O, dried
over MgSO4, filtered, and concentrated under reduced pressure. The
resulting residue was purified using silica gel column chromatography
(n-hexane/EtOAc = 85:15) to give 740 mg of (2R,3S)-6 (57% yield)
as a colorless oil and 117 mg of (2S,3S)-6 (9% yield) as a colorless oil.
1H NMR for (2R,3S)-6 (400 MHz, CDCl3) δ 7.53−7.47 (m, 1H),
1
mg of 8 (75% yield) as a colorless crystal. Mp 86−87 °C; H NMR
(400 MHz, CDCl3) δ 7.63−7.57 (m, 1H), 6.93−6.88 (m, 1H), 6.81−
6.75 (m, 1H), 4.27−4.14 (m, 3H), 3.09 (brs, 1H), 2.17 (brs, 1H), 0.96
(d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.7 (dd, J =
250, 12 Hz), 158.6 (dd, J = 247, 12 Hz), 130.1 (dd, J = 9.6, 6.7 Hz),
123.8 (dd, J = 13, 3.8 Hz), 111.4 (dd, J = 21, 3.8 Hz), 104.2 (dd, J =
28, 25 Hz), 77.8 (d, J = 4.8 Hz), 70.0 (d, J = 4.8 Hz), 51.7 (d, J = 5.8
Hz), 18.6; 19F NMR (376 MHz, CDCl3) δ −109.2, −110.7; IR
(CHCl3, cm−1) ν 3433, 3266, 2979, 1617, 1500, 1272; HRMS (ESI-
TOF) calcd for C10H11O2ClF2Na [M + Na]+ m/z 259.0308, found
259.0310.
(R)-1-((R)-2-(2,4-Difluorophenyl)oxiran-2-yl)ethanol (9). To a
solution of (2R,3S)-6 (33.6 mg, 0.109 mmol) in THF (363 μL) was
added 1.0 M TBAF solution in THF (272 μL, 0.272 mmol) at room
temperature, and the reaction mixture was stirred at the same
temperature for 23 h. The reaction mixture was quenched with
saturated aqueous NH4Cl, and 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 preparative TLC (CHCl3/MeOH = 15:1)
6.90−6.85 (m, 1H), 6.77−6.71 (m, 1H), 4.21 (d, J = 12.1 Hz, 1H),
4.20−4.15 (m, 1H), 4.12 (dd, J = 12.1, 1.1 Hz, 1H), 0.90 (d, J = 6.0
Hz, 3H), 0.29 (s, 9H); 13C NMR for (2R,3S)-6 (100 MHz, CDCl3) δ
162.4 (dd, J = 249, 13 Hz), 158.2 (dd, J = 246, 12 Hz), 131.0 (dd, J =
9.1, 6.2 Hz), 124.8 (dd, J = 13, 3.8 Hz), 111.0 (dd, J = 21, 3.4 Hz),
103.9 (dd, J = 29, 26 Hz), 83.2 (d, J = 6.7 Hz), 71.4 (d, J = 3.8 Hz),
50.1 (d, J = 6.7 Hz), 18.6, 2.41; 19F NMR for (2R,3S)-6 (376 MHz,
CDCl3) δ −108.7, −111.6; 1H NMR for (2S,3S)-6 (400 MHz, CDCl3)
δ 7.47−7.41 (m, 1H), 6.90−6.85 (m, 1H), 6.81−6.75 (m, 1H), 4.27
D
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Note
to give 7.4 mg of 9 (34% yield) as a colorless oil. 1H NMR (400 MHz,
CDCl3) δ 7.42−7.36 (m, 1H), 6.89−6.84 (m, 1H), 6.81−6.76 (m,
1H), 4.07 (qd, J = 6.6, 1.6 Hz, 1H), 3.28 (d, J = 5.3 Hz, 1H), 2.78 (dd,
J = 5.3, 0.5 Hz, 1H), 1.14 (dd, J = 6.6, 1.1 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 162.8 (dd, J = 249, 13 Hz), 160.4 (dd, J = 249, 12
Hz), 130.6 (dd, J = 10, 6.2 Hz), 120.6 (dd, J = 15, 3.8 Hz), 111.4 (dd, J
= 21, 3.8 Hz), 103.7 (dd, J = 25, 25 Hz), 68.4 (d, J = 1.9 Hz), 60.6,
51.9, 19.1; 19F NMR (376 MHz, CDCl3) δ −109.6, −111.4; IR
(CHCl3, cm−1) ν 3421, 2980, 2360, 1618, 1507, 1425, 1272; HRMS
(ESI-TOF) calcd for C10H10O2F2Na [M + Na]+ m/z 223.0541, found
223.0543.
column chromatography (CHCl3/MeOH = 10:1) to give 1.59 g of 1
(86% yield) as a pale-yellow solid. Mp 91−92 °C; [α]2D4 −7.75 (c 1.06,
1
MeOH); H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.78 (s, 1H),
7.00−6.95 (m, 1H), 6.77−6.66 (m, 2H), 4.85 (d, J = 14.7 Hz, 1H),
4.40 (d, J = 14.7 Hz, 1H), 3.16 (q, J = 5.6 Hz, 1H), 1.61 (d, J = 5.6 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 162.9 (dd, J = 251, 12 Hz),
160.1 (dd, J = 249, 13 Hz), 151.9, 143.6, 129.3 (dd, J = 9.6, 5.8 Hz),
120.8 (dd, J = 14, 3.8 Hz), 111.6 (dd, J = 22, 3.4 Hz), 103.8 (dd, J =
25, 25 Hz), 60.5, 59.7, 51.6 (d, J = 1.9 Hz), 14.0; 19F NMR (376 MHz,
CDCl3) δ −108.5, −112.6; IR (CHCl3, cm−1) ν 3113, 3096, 3084,
3003, 2969, 1618, 1508, 1424, 1269, 1137; HRMS (ESI-TOF) calcd
for C12H12ON3F2 [M + H]+ m/z 252.0943, found 252.0945. The
enantiomeric excess of 1 was determined by chiral HPLC analysis
[DAICEL, CHIRALCEL OD-H, flow rate = 1.0 mL/min, n-hexane/
EtOH = 85:15, detection at 254 nm, column temperature 23 °C, tR =
10.8 min (1), tR = 12.6 min (ent-1)].
(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-
butane-2,3-diol (10). To a solution of 5 (4.37 g, 14.9 mmol) in THF
(24.9 mL) was added 0.92 M MeMgBr solution in THF (22.7 mL,
20.9 mmol) at −78 °C, and the reaction mixture was stirred at the
same temperature for 40 min and then quenched with 3 N aqueous
NaOH (50 mL, 150 mmol). The resulting mixture was warmed to
room temperature and stirred for 20 min. Triazole (14.2 g, 206 mmol)
and tetrabutylammonium bromide (2.40 g, 7.44 mmol) were added.
After the reaction mixture was stirred at 55 °C for 28 h, H2O was
added. The aqueous layer was extracted twice with EtOAc. The
combined organic layers were washed with H2O, 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 3.09 g of 10 [77% yield, (2R,3R):(2R,3S) =
86:14 by 1H NMR analysis] as a pale-yellow solid. The
diastereomixture was purified again using silica gel column
chromatography (CHCl3/MeOH = 10:1) to give 2.60 g of 10 (65%
yield, single isomer) as a colorless solid. A 467 mg sample of 10
(enantiomeric excess 80%) was taken up with MeCN (3.04 mL) at 60
°C, and the resulting solution was stirred at room temperature for 20
min. After additional stirring at −20 °C for 14 h, the resulting crystal
was filtered and dried in vacuo to give 78.8 mg of 10 (enantiomeric
excess 6.3%). The filtrate was concentrated under reduced pressure
and dried in vacuo to give 376 mg of 10 (enantiomeric excess 97.1%).
Next, 375 mg of 10 (enantiomeric excess: 97.1%) was taken up with
MeCN (563 μL) at 60 °C, and the resulting solution was stirred at
room temperature for 30 min. After additional stirring at 0 °C for 1.5
h, the resulting crystal was filtered. The filtrate was concentrated under
reduced pressure and dried in vacuo to give 343 mg of 10 (74%
recovery yield after two cycles, enantiomeric excess >99%) as a
colorless crystal. Mp for enantiopure diol 10 (enantiomeric excess
>99%), 114−117 °C; mp for racemic diol 10 (enantiomeric excess
(2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylenepiperidin-1-
yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Efinaconazole). To a
solution of 1 (54.2 mg, 0.216 mmol) in EtOH (217 μL) was added
4-methylenepiperidine (147 mg, 1.51 mmol), and the reaction mixture
was stirred at 120 °C for 6 h under microwave irradiation. The
reaction mixture was quenched with H2O, and the aqueous layer was
extracted twice with EtOAc. The combined organic layers were
washed three times with H2O, 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 67.6 mg of efinaconazole (90% yield) as a colorless
1
amorphous solid. [α]2D0 −87.8 (c 1.12, CHCl3); H NMR (400 MHz,
CDCl3) δ 8.00 (s, 1H), 7.76 (s, 1H), 7.51−7.45 (m, 1H), 6.78−6.68
(m, 2H), 5.50 (brs, 1H), 4.85 (d, J = 14.4 Hz, 1H), 4.78 (d, J = 14.4
Hz, 1H), 4.61 (s, 2H), 2.88 (q, J = 6.9 Hz, 1H), 2.66 (br s, 2H), 2.32
(br s, 2H), 2.21−2.17 (m, 4H), 0.93 (dd, J = 6.9, 2.1 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ 162.5 (dd, J = 250, 13 Hz), 158.5 (dd, J =
246, 12 Hz), 151.3, 145.9, 144.4, 130.6 (dd, J = 8.7, 5.8 Hz), 124.7 (dd,
J = 14, 3.6 Hz), 111.4 (dd, J = 20, 2.9 Hz), 108.1, 104.1 (dd, J = 28, 25
Hz), 77.7 (d, J = 5.8 Hz), 64.4, 55.9 (d, J = 8.7 Hz), 52.4, 35.2, 7.63 (d,
J = 2.9 Hz); 19F NMR (376 MHz, CDCl3) δ −105.8, −110.7; IR
(CHCl3, cm−1) ν 3423, 3073, 2979, 2939, 2899, 2810, 1615, 1498,
1418, 1273, 1138; HRMS (ESI-TOF) calcd for C18H23ON4F2 [M +
H]+ m/z 349.1834, found 349.1828.
(2S,3R)-3-(2,4-Difluorophenyl)-3-hydroxy-2-methyl-4-(1H-
1,2,4-triazol-1-yl)butanenitrile (12). To a solution of 1 (415 mg,
1.65 mmol) in toluene (3.30 mL) was added a 1.0 M solution of
Et2AlCN in toluene (6.60 mL, 6.60 mmol) at room temperature, and
the reaction mixture was stirred at 50 °C for 22 h. After the resulting
mixture was cooled to 0 °C, H2O and 1 N HCl were 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 (CHCl3/MeOH = 10:1) to give 349 mg of
12 (76% yield) as a colorless crystal. Mp 182−183 °C; [α]2D5 −28.1 (c
1.6%), 159−160 °C; [α]2D4 −71.0 (c 1.06, MeOH); H NMR (400
1
MHz, CDCl3) δ 7.87 (s, 1H), 7.81 (s, 1H), 7.42−7.36 (m, 1H), 6.77−
6.70 (m, 2H), 4.84−4.76 (m, 2H), 4.30 (qd, J = 6.4, 2.8 Hz, 1H), 0.95
(d, J = 6.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 162.7 (dd, J =
250, 12 Hz), 158.3 (dd, J = 246, 12 Hz), 152.0, 144.2, 130.0 (dd, J =
9.4, 6.5 Hz), 123.2 (dd, J = 14, 3.6 Hz), 111.8 (dd, J = 20, 2.9 Hz),
104.0 (dd, J = 27, 27 Hz), 78.3 (d, J = 5.8 Hz), 70.1 (d, J = 4.3 Hz),
55.4 (d, J = 5.8 Hz), 18.1; 19F NMR (376 MHz, CDCl3) δ −109.4,
−110.0; IR (CHCl3, cm−1) ν 3434, 3139, 2974, 2360, 1619, 1503,
1421, 1273, 1134; HRMS (ESI-TOF) calcd for C12H14O2N3F2 [M +
H]+ m/z 270.1049, found 270.1046. The enantiomeric excess of 10
was determined by chiral HPLC analysis [DAICEL, CHIRALPAK
AD-H, flow rate = 1.0 mL/min, n-hexane/EtOH = 85:15, detection at
254 nm, column temperature 23 °C, tR = 11.4 min (ent-10), tR = 18.4
min (10)].
1
1.14, MeOH); H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.80 (s,
1H), 7.43−7.36 (m, 1H), 6.79−6.72 (m, 2H), 5.48 (s, 1H), 4.94 (d, J
= 14.0 Hz, 1H), 4.79 (d, J = 14.0 Hz, 1H), 3.27 (q, J = 7.2 Hz, 1H),
1.14 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 163.1 (dd, J
= 253, 12 Hz), 157.8 (dd, J = 246, 11 Hz), 152.3, 143.9, 130.9 (dd, J =
9.6, 4.8 Hz), 121.2 (dd, J = 13, 3.4 Hz), 120.0, 112.1 (dd, J = 21, 3.4
Hz), 104.3 (dd, J = 28, 26 Hz), 75.8 (d, J = 4.8 Hz), 55.7 (d, J = 5.8
Hz), 33.4 (d, J = 4.8 Hz), 12.8; 19F NMR (376 MHz, CDCl3) δ
−108.1, −109.6; IR (CHCl3, cm−1) ν 3140, 3003, 2951, 2864, 2246,
1618, 1502, 1422, 1269, 1136; HRMS (ESI-TOF) calcd for
C13H13ON4F2 m/z [M + H]+ 279.1052, found 279.1051.
(2R,3R)-3-(2,4-Difluorophenyl)-3-hydroxy-2-methyl-4-(1H-
1,2,4-triazol-1-yl)butanethioamide (13). To a solution of 12 (151
mg, 0.543 mmol) in H2O (242 μL) and isopropyl alcohol (302 μL)
was added diethyl dithiophosphate (360 μL, 2.28 mmol) at room
temperature, and the reaction mixture was stirred at 80 °C for 9 h.
After the resulting mixture was cooled to room temperature, H2O and
3 N NaOH were added. After the mixture was stirred at the same
temperature for 30 min, EtOAc was added. The aqueous layer was
1-(((2R,3S)-2-(2,4-Difluorophenyl)-3-methyloxiran-2-yl)-
methyl)-1H-1,2,4-triazole (1). To a solution of 10 (1.97 g, 7.32
mmol) in THF (37 mL) were added Et3N (4.50 mL, 32.2 mmol) and
MsCl (1.25 mL, 16.2 mmol) at 0 °C, and the reaction mixture was
stirred at the same temperature for 20 min. Next, 3 N NaOH aqueous
(10 mL, 30.0 mmol) and tetrabutylammonium bromide (1.18 g, 3.66
mmol) were added. The resulting mixture was warmed to room
temperature and stirred at this temperature for 14 h. Saturated
aqueous NH4Cl was added, and the aqueous layer was extracted twice
with EtOAc. The combined organic layers were washed three times
with H2O, dried over MgSO4, filtered, and concentrated under
reduced pressure. The resulting residue was purified using silica gel
E
dx.doi.org/10.1021/jo500369y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
extracted twice with EtOAc. The combined organic layers were
washed three times with H2O, 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 164 mg of 13 (97% yield) as a colorless amorphous solid.
(2) Westerberg, D. P.; Voyack, M. J. Am. Fam. Physician 2013, 88,
762.
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M. M.; Nash, S. L.; Hajjeh, R. A.; Phelan, M. A.; Conn, L. A.; Plikaytis,
B. D.; Warnock, D. W. Clin. Infect. Dis. 2001, 33, 641. (c) Hahn-Ast,
[α]2D3 −137.9 (c 1.08, MeOH); H NMR (400 MHz, CDCl3) δ 8.35
1
C.; Glasmacher, A.; Muckter, S.; Schmitz, A.; Kraemer, A.; Marlein, G.;
̈
(br s, 1H), 7.83 (s, 1H), 7.77 (s, 1H), 7.64 (br s, 1H), 7.45−7.39 (m,
1H), 6.78−6.69 (m, 2H), 5.75 (s, 1H), 5.06 (d, J = 14.2 Hz, 1H), 4.52
(d, J = 14.2 Hz, 1H), 3.70 (q, J = 7.0 Hz, 1H), 1.08 (d, J = 7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 210.2, 162.8 (dd, J = 251, 13
Hz), 157.9 (dd, J = 247, 13 Hz), 151.9, 144.0, 130.5 (dd, J = 9.1, 5.3
Hz), 122.9 (dd, J = 13, 3.8 Hz), 111.6 (dd, J = 21, 3.4 Hz), 104.3 (dd, J
= 27, 25 Hz), 76.9, 55.5 (d, J = 6.7 Hz), 54.4 (d, J = 3.8 Hz), 15.6; 19F
NMR (376 MHz, CDCl3) δ −109.2, −109.3; IR (CHCl3, cm−1) ν
3282, 3185, 1618, 1499, 1423, 1270, 1137; HRMS (ESI-TOF) calcd
for C13H15ON4F2S [M + H]+ m/z 313.0929, found 313.0932.
Brossart, P.; von Lilienfeld-Toal, M. J. Antimicrob. Chemother. 2010,
65, 761.
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Antimicrob. Agents Chemother. 1995, 39, 1. (c) Johnson, E. M.;
Warnock, D. W.; Lunker, J.; Porter, S. R.; Scully, C. J. Antimicrob.
Chemother. 1995, 35, 103.
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Narayanaswami, S.; Ray, S. J.; Richardson, K.; Troke, P. F. Bioorg.
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Patent 5,278,175, 1994. (c) Butters, M.; Ebbs, J.; Green, S. P.; MacRae,
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4-(2-((2R,3R)-3-(2,4-Difluorophenyl)-3-hydroxy-4-(1H-1,2,4-
triazol-1-yl)butan-2-yl)thiazol-4-yl)benzonitrile (Ravucona-
zole). To a solution of 13 (45.8 mg, 0.147 mmol) in EtOH (458
μL) was added 2-bromo-4′-cyanoacetophenone (49.3 mg, 0.220
mmol) at room temperature, and the reaction mixture was stirred at
70 °C for 2 h. After the resulting mixture was cooled to room
temperature, 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 preparative TLC (n-hexane/EtOAc =
50:50) to give 50.0 mg of ravuconazole (78% yield) as a colorless
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amorphous solid. [α]2D5 −26.6 (c 0.91, MeOH); H NMR (600 MHz,
1
Clin. Microbiol. 1998, 36, 198. (d) Chav
́
ez, M.; Bernal, S.; Valverde, A.;
Gutierrez, M. J.; Quindos, G.; Mazuelos, E. M. J. Antimicrob.
́
CDCl3) δ 8.00 (ddd, J = 8.2, 1.8, 1.7 Hz, 2H), 7.82 (s, 1H), 7.72 (ddd,
J = 8.2, 1.8, 1.7 Hz, 2H), 7.66 (s, 1H), 7.62 (s, 1H), 7.50−7.46 (m,
1H), 6.81−6.76 (m, 2H), 5.71 (s, 1H), 4.89 (d, J = 14.4 Hz, 1H), 4.24
(d, J = 14.4 Hz, 1H), 4.06 (q, J = 7.2 Hz, 1H), 1.21 (d, J = 7.2 Hz,
3H); 13C NMR (150 MHz, CDCl3) δ 172.7, 162.8 (dd, J = 251, 12
Hz), 158.3 (dd, J = 246, 12 Hz), 152.6, 151.5, 143.8, 137.9, 132.7,
130.6 (dd, J = 10, 5.8 Hz), 126.7, 123.4 (dd, J = 13, 4.3 Hz), 118.7,
116.0, 111.7 (dd, J = 20, 2.9 Hz), 111.6, 104.1 (dd, J = 27, 27 Hz), 77.3
(d, J = 5.8 Hz), 56.6 (d, J = 4.3 Hz), 44.1 (d, J = 2.9 Hz), 17.4; 19F
NMR (376 MHz, CDCl3) δ −109.1, −109.7; IR (CHCl3, cm−1) ν
3400, 3109, 2981, 2226, 1608, 1499, 1273, 1139; HRMS (ESI-TOF)
calcd for C22H18ON5F2S [M + H]+ m/z 438.1195, found 438.1192.
Chemother. 1999, 44, 697. (e) Espinel-Ingroff, A. J. Clin. Microbiol.
2001, 39, 954. (f) Johnson, L. B.; Kauffman, C. A. Clin. Infect. Dis.
2003, 36, 630.
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Girmenia, C.; Micozzi, A.; Sanguinetti, M.; Viscoli, C. J. Chemother.
2012, 24, 311.
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R.; Okonogi, K.; Itoh, K. Chem. Pharm. Bull. 1996, 44, 314.
(b) Tsuruoka, A.; Kaku, Y.; Kakinuma, H.; Tsukada, I.; Yanagisawa,
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́
J.; Turmo, E.; Alguero, M.; Boncompte, E.; Vericat, M. L.; Conte, L.;
Ramis, J.; Merlos, M.; García-Rafanell, J.; Forn, J. J. Med. Chem. 1998,
41, 1869. (d) Ogura, H.; Kobayashi, H.; Nagai, K.; Nishida, T.; Naito,
T.; Tatsumi, Y.; Yokoo, M.; Arika, T. Chem. Pharm. Bull. 1999, 47,
1417. (e) Konosu, T.; Oida, S.; Nakamura, Y.; Seki, S.; Uchida, T.;
Somada, A.; Mori, M.; Harada, Y.; Kamai, Y.; Harasaki, T.; Fukuoka,
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of synthesized compounds, HPLC
charts for 10 and 1, and characterization of intermediates en
route to 10. This material is available free of charge via the
Internet at http://pubs.acs.org.
Picot, C.; Hed
́
ou, D.; Tonnerre, A.; Chosson, E.; Duflos, M.; Besson,
AUTHOR INFORMATION
T.; Loge, C.; Le Pape, P. ACS Med. Chem. Lett. 2013, 4, 288.
́
■
(10) Pesti, J.; Chen, C.-K.; Spangler, L.; DelMonte, A. J.; Benoit, S.;
Berglund, D.; Bien, J.; Brodfuehrer, P.; Chan, Y.; Corbett, E.; Costello,
C.; DeMena, P.; Discordia, R. P.; Doubleday, W.; Gao, Z.; Gingras, S.;
Grosso, J.; Haas, O.; Kacsur, D.; Lai, C.; Leung, S.; Miller, M.;
Muslehiddinoglu, J.; Nguyen, N.; Qiu, J.; Olzog, M.; Reiff, E.;
Thoraval, D.; Totleben, M.; Vanyo, D.; Vemishetti, P.; Wasylak, J.;
Wei, C. Org. Process Res. Dev. 2009, 13, 716.
Corresponding Authors
*E-mail: nkumagai@bikaken.or.jp.
*E-mail: mshibasa@bikaken.or.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(11) (a) Konosu, T.; Miyaoka, T.; Tajima, Y.; Oida, S. Chem. Pharm.
Bull. 1991, 39, 2241. (b) Konosu, T.; Miyaoka, T.; Tajima, Y.; Oida, S.
Chem. Pharm. Bull. 1992, 40, 562. (c) Tasaka, A.; Tamura, N.;
Matsushima, Y.; Teranishi, K.; Hayashi, R.; Okonogi, K.; Itoh, K.
Chem. Pharm. Bull. 1993, 41, 1035. (d) Saji, I.; Tamoto, K.; Tanaka, Y.;
Miyaguchi, H.; Fujimoto, K.; Ohashi, N. Bull. Chem. Soc. Jpn. 1994, 67,
1427. (e) Bennett, F.; Ganguly, A. K.; Girijavallabhan, V. M.; Pinto, P.
A. Synlett 1995, 1110. (f) Acetti, D.; Brenna, E.; Fuganti, C.; Gatti, F.
G.; Serra, S. Tetrahedron: Asymmetry 2009, 20, 2413.
(12) For selected patents, see: (a) Wang, W.; Ikemoto, T.
WO2002051879, 2002. (b) Kim, B. T.; Min, Y. K.; Lee, Y. S.; Park,
N. K.; Kim, W. J. WO2005014583, 2005. (c) Ishibashi, T.; Muraoka,
H.; Mizuno, T. WO2006059759, 2006.
■
This work was financially supported by JST, ACT-C, and
KAKENHI (25713002). Dr. Ryuichi Sawa and Ms. Yumiko
Kubota are gratefully acknowledged for technical assistance
with the NMR analysis.
REFERENCES
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G
dx.doi.org/10.1021/jo500369y | J. Org. Chem. XXXX, XXX, XXX−XXX