Total synthesis of (2R,4S,2′S,3′R)-hydroxyitraconazole: Implementations of a recycle protocol and a mild and safe phase-transfer reagent for preparation of the key chiral units

Article abstract of DOI:10.1016/j.tetasy.2003.01.001

A convergent total synthesis of enantiomerically-pure (2R,4S,2′S, 3′R)-hydroxyitraconazole 1b is described. The left dioxolane portion of the molecule was prepared in good yield by the conversion of (S)-10 to the corresponding enantiomerically and diastereomerically-pure acetonide (2R,4R)-3 by a recycle protocol involving diastereoselective crystallization of the tosylate salt, followed by re-equilibration of the mother liquor and crystallization. The right-hand triazolone moeity (2S,3R)-4 was generated by alkyaltion of triazolone 6 with enantiomerically pure cyclic sulfate (4R,5R)-7 under mild and essentially non-hazardous reaction conditions (TDA-1, K ₂CO₃, acetonitrile).

Full text of DOI:10.1016/j.tetasy.2003.01.001

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3487–3493
Total synthesis of (2R,4S,2%S,3%R)-hydroxyitraconazole:
implementations of a recycle protocol and a mild and safe
phase-transfer reagent for preparation of the key chiral units
Gerald J. Tanoury,†* Robert Hett, H. Scott Wilkinson, Stephen A. Wald and
Chris H. Senanayake‡*
Department of Process Research and Development, Sepracor Inc., 33 Locke Drive, Marlborough, MA 01752, USA
Received 11 November 2002; accepted 3 January 2003
Abstract—A convergent total synthesis of enantiomerically-pure (2R,4S,2%S,3%R)-hydroxyitraconazole 1b is described. The left
dioxolane portion of the molecule was prepared in good yield by the conversion of (S)-10 to the corresponding enantiomerically
and diastereomerically-pure acetonide (2R,4R)-3 by a recycle protocol involving diastereoselective crystallization of the tosylate
salt, followed by re-equilibration of the mother liquor and crystallization. The right-hand triazolone moeity (2S,3R)-4 was
generated by alkyaltion of triazolone 6 with enantiomerically pure cyclic sulfate (4R,5R)-7 under mild and essentially non-haz-
ardous reaction conditions (TDA-1, K2CO3, acetonitrile).
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
critically important process solutions to our require-
ments for the synthesis of (2R,4S,2%S,3%R)-hydroxyitra-
conazole 1b.
Itraconazole 1a (Sporanox) and its active metabolite,
hydroxyitraconazole 1b, are members of a large class of
azole antifungal compounds.1 In addition to having a
high molecular weight in comparison to other pharma-
ceutical agents, 1a and 1b contain a high degree of
chemical complexity. Efficient syntheses of enantiomeri-
cally-pure cis,syn-hydroxyitraconazole isomers have
been previously reported.2 The key steps in these syn-
theses were an alkylative ring-opening of an enan-
2. Results and discussion
A synthetic analysis of 1b is outlined in Scheme 1.
Paramount to the success of this strategy are the prepa-
rations of dioxolane (2R,4R)-3 and triazolone (2S,3R)-
4 in high diastereomeric and enantiomeric purities. The
use of (2R,4R)-3 for the preparation of left chiral
portion of 1b has been described,2 but a practical and
high yielding synthesis of this fragment has not been
reported. Preparation of (2S,3R)-4 by alkylation of 6
with (4R,5R)-7 has been previously performed using
KH/18-crown-6 in DMF.2 A safe and cost-effective
procedure which obviates the uses of KH and 18-
crown-6 was needed.
tiomerically-pure cyclic sulfate, and
a Buchwald–
Hartwig3 type Pd-catalyzed aromatic amination of two
highly functionalized subunits to give 1b. While these
approaches provided solutions to our synthetic needs,
several synthetic improvements were required: (1) a
practical synthesis of the cis-dioxolane moiety in enan-
tiomerically pure form; and (2) an economic and safe
process for the triazolone alkylation step. In this paper,
we summarize our previous synthetic work and provide
Development of a synthetic route for the preparation of
(2R,4R)-3 in high diastereomeric and enantiomeric
purities is outlined in Scheme 2. The key transforma-
tion involved a diastereoselective ketalization of 9 with
R-12, consisting of four steps: (1) formation of ketotri-
azole 9; (2) tosylation of (S)-isopropylideneglycerol 10;
(3) deprotection of the isopropylidene ketal R-11; and
(4) ketal formation to generate (2R,4R)-3. In accord
* Corresponding author. E-mail: jerry tanoury@vpharm.com
–
† Current address: Department of Process Chemistry, Vertex Pharma-
ceuticals Incorporated, 130 Waverley St., Cambridge, MA 02139-
4242, USA.
‡ Current address: Department of Chemical Development, Boehringer
Ingelheim, 900 Ridgebury Rd., Ridgefield, CT 06877, USA.
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.01.001

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G. J. Tanoury et al. / Tetrahedron: Asymmetry 14 (2003) 3487–3493
with literature precedence,4 reaction of a-chloroketone 8
with 4-amino-1,2,4-triazole followed by treatment with
nitrous acid (NaNO2, HCl) gave 9. Tosylation of (S)-iso-
propylideneglycerol S-10 by a standard protocol (tosyl
chloride in pyridine at 0°C), and hydrolysis with 1 M HCl
in acetone gave (R)-glyceryl tosylate R-12.5 Condensa-
tion of (R)-glyceryl tosylate with 9 was challenging.
Initial efforts on the ketalization resulted in long reaction
times (days) and low yields. In the presence of 30
equivalents of MsOH in refluxing toluene for 7 days
(2R,4R)-3 was isolated in 18% yield.6 After extensive
experimentation and optimization, the use of 3 equiva-
lents of TfOH in toluene at room temperature for 24–36
h provided a 3:1 mixture of (2R,4R)-3 and (2S,4R)-3.
After neutralization and work-up, the crude product was
dissolved in iso-butyl methyl ketone and treated with
tosic acid. A solid crystallized from the solution as a 95:5
mixture of (2R,4R)-3:(2S,4R)-3 as the tosylate salts. The
crude solid product was purified to a single stereoisomer
of (2R,4R)-3 by recrystallization from acetonitrile, and
was isolated in 51% yield from 9.
The observation that a diastereomerically-pure product
could be obtained from the crude 3:1 mixture of isomers
by isolation as the tosylate salt, followed by recrystalliza-
tion from acetonitrile, led to the development of a recycle
protocol to obtain (2R,4R)-3 in high yield and high
diastereomeric purity. Initially, to ensure thermodynamic
equilibrium was attained at a 3:1 mixture of isomers, a
solution of diastereomerically-pure (2R,4R)-3 was con-
verted to the free-base and treated with triflic acid (3
equiv.) in toluene. A 3:1 mixture of diastereomers was
obtained (Eq. (1)). Analogously, when diastereomeri-
cally-pure (2S,4R)-3 was subjected to the identical pro-
cedure a 3:1 mixture of diastereomers was obtained.
Having confirmed that equilibrium was reached during
formation and isolation of (2R,4R)-3, a recycle protocol
was developed.
Scheme 1.
(1)
Scheme 3 shows the recycle process for generation of
(2R,4R)-3 from the reaction of 9 and R-12. As described
above, addition of TsOH to the 3:1 mixture of
diastereomers followed by two recrystallizations of the
crude solid from acetonitrile gave diastereomerically and
enantiomerically-pure (2R,4R)-3. Collection and assay
of the mother liquor from the crude reaction showed a
1:9 mixture of (2R,4R)-3:(2S,4R)-3 tosylate salts. The
solution was neutralized with aqueous K2CO3, dried, and
concentrated. Addition of MIBK and 3 equivalents of
triflic acid effected equilibration to a 3:1 mixture of
isomers. Addition of tosic acid, and isolation and purifi-
cation of the crude solid provided diastereomerically and
enantiomerically-pure (2R,4R)-3. Using the recycle pro-
cedure, (2R,4R)-3 was obtained in 73% total yield after
two recycles.
Scheme 2. Reagents and conditions: (a) 4-amino-4H-1,2,4-tria-
zole, CH2Cl2; Aq. HCl, NaNO2 (Ref. 3); (b) TsCl, pyridine,
0°C; acetone, HCl, reflux (Ref. 4); (c) 3 equiv. TfOH, toluene,
rt, 24-36 h; (d) TsOH, MIBK; CH3CN, recrystallize, 51% yield
from R-12.

G. J. Tanoury et al. / Tetrahedron: Asymmetry 14 (2003) 3487–3493
3489
Scheme 3.
Table 1. Effect of TDA-1 and 18-C-6 on the reaction of
meso-7 with 6 in the presence of basea
Turning our attention to the triazolone moeity, prelim-
inary investigations were performed using the less
costly meso-7 (prepared from meso-2,3-butanediol).
The initial approach entailed the reaction of 6 with
KH/18-crown-6 in DMF, followed by addition of the
cyclic sulfate (Eq. (2)) to give the sulfate intermediate
anti-13.7 Anti-13 was converted to the alcohol by reac-
tion with 48% HBr at 45–50°C for 30–45 min. These
reaction conditions were suitable for the initial syn-
thetic studies of hydroxyitraconazole isomers, but
other approaches were sought to preclude the use of
18-crown-6 due to its toxicity and cost, and the use of
KH due to its high reactivity and flammability.
Entry
Base
Additive
Reaction time Reaction
(h)
completionb(%)
1
2
3
4
5
6
7
Li2CO3
Na2CO3 TDA-1
K2CO3
Li2CO3
Na2CO3 18-C-6
TDA-1
16
16
16
16
16
8
11
31
98
11
50
99
34
TDA-1
18-C-6
K2CO3
K2CO3
18-C-6
None
16
a Reaction conditions: 0.15 M solution of 6, 2.0 equiv. carbonate
base, 1.0 equiv. additive, acetonitrile, 40°C.
b Determined by HPLC analysis.
(2)
Scheme 4. Reagents and conditions: (a) n-BuOH, 0°C, 1 h;
KOH, reflux, 3 h; HCl, 49% yield from 14; (b) Eq. (3);
TBSCl, imidazole, DMF, rt, 48 h, 75% yield.
The replacement of 18-crown-6 was examined by con-
sidering alternative chelating additives. Since cost, low
toxicity, and availability were paramount, tris-[2-
(methoxyethoxy)ethyl]amine
[tris(3,6-dioxaheptyl)-
amine, TDA-1] was selected for study.8 To address the
issues associated with KH, easily-handled carbonate
salts were chosen as replacements. Table 1 shows the
results from a series of experiments comparing TDA-1
and 18-C-6 as additives for the alkylation of 6 with
meso-7 using lithium, sodium, and potassium carbon-
ates as base in acetonitrile at 40°C. From the data,
TDA-1 and 18-C-6 behaved comparably as phase
transfer reagents. With lithium and sodium salts, the
rates of reaction were identical or similar (entries 1
and 2 versus 4 and 5). With potassium carbonate,
however, the alkylation was 2–4 times faster with 18-
C-6 than TDA-1 (entries 3 and 6). When compared to
the result with no additive present (potassium carbon-
ate as base), TDA-1 provided a substantial accelerat-
ing effect (entries 3 versus 7). The data indicated that
TDA-1 would be an excellent phase transfer reagent
for the reaction in Eq. (2), using K2CO3 as base in
acetonitrile. The reaction was performed on (4R,5R)-7
to provide (2R,3R)-4 in 79% yield for two steps (Eq.
(3)).

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G. J. Tanoury et al. / Tetrahedron: Asymmetry 14 (2003) 3487–3493
(3)
two recycles and >99% de and ee. The safety issues
associated with the use of toxic 18-crown-6 and the high
reactivity of the combination of KH with DMF in the
alkylation of 6 were solved by replacement of 18-crown-6
with non-carcinogenic TDA-1 and the use of K2CO3/ace-
tonitrile in the place of KH/DMF. The combined
improvements offered a cost-effective and safe solution
for the total synthesis of cis,syn-hydroxyitraconazole.
4. Experimental
4.1. General
Flash chromatography was performed on EM Science
silica gel 60. Thin layer chromatography was performed
using silica gel 60 F254 plates. All reactions were carried
out in oven-dried glassware under an argon atmosphere.
NMR spectra were recorded on a Varian Inova 300
Scheme 5. Reagents and conditions: (a) NaH, DMF, rt, 4 h;
KOH, IPA, reflux, 16 h, 85%; (b) (2R,4S)-17, Pd2dba3, NaOtBu,
BINAP, toluene, 100°C, 4 h; Bu4NF, THF, 74% for 2 steps.
1
operating at 300 MHz and 75 MHz for H and 13C,
respectively, and referenced to internal standards. Mass
spectra were performed by M-Scan Mass Spectral Anal-
ysis. Elemental analyses were conducted by Galbriath
Laboratories, Inc., 2323 Sycamore Drive, PO Box 1610,
Knoxville, TN 37950-1610. (S)-2,2-Dimethyl-1,3-diox-
olane-4-methanol, p-toluenesulfonylchloride, p-toluene-
sulfonic acid, 4-amino-4H-1,2,4-triazolone, sodium
nitrite, triflic acid, (2R,3R)-(+)-2,3-butanediol, meso-2,3-
butanediol, thionyl chloride, RuCl3–H2O, NaIO4, potas-
sium hydride, 18-crown-6, formic hydrazine, 4-bromo-
phenylisocyanate, TDA-1, imidazole, tert-butyl-
dimethylchlorosilane, hydrobromic acid, N-acetyl-N%-(4-
hydroxyphenyl)piperazine, tris(dibenzylideneacetone)-
dipalladium, (R)-BINAP, sodium tert-butoxide, and
tetra-n-butylammonium fluoride were purchased from
the Aldrich Chemical Company and used without further
purifications. Potassium carbonate and potassium
hydroxide were purchased from Fisher Scientific and
used without further purification. All solvents were
purchased as anhydrous from Aldrich Chemical Com-
pany and used without further purification. 1-(2,4-
Incorporation of the improvements in the synthetic
methodology provided a practical and efficient approach
tothetotalsynthesisof(2R,4S,2%S,3%R)-hydroxyitracona-
zole, as outlined in Schemes 4 and 5. Isocyanate 14 was
converted to triazolone 6 in two steps by condensation
with 15 followed by ring closure and dehydration using
KOH in n-butanol at reflux. Compound 6 was converted
to (2S,3R)-4 according to Eq. (3), followed by silylation
of the hydroxyl group by standard methods to give
(2S,3R)-17. Tosylate (2R,4R)-3 was condensed with
4-(4-hydroxyphenyl)-1-acetylpiperazine to give interme-
diate (2R,4S)-2. Palladium-catalyzed coupling of amine
(2R,4S)-2 with bromide (2S,3R)-17 gave the silylated
penultimate product (2R,4S,2%S,3%R)-18. Subsequent
desilylation provided enantio- and diastereopure
(2R,4S,2%S,3%R)-hydroxyitraconazole in 13% yield via a
13-step convergent synthesis from 9, (R)-12, 4-bromo-
phenyl isocyanate and (2R,3R)-2,3-butanediol.
Dichlorophenyl)-2-(1H6 -1,2,4-triazol-1-yl)ethanone (9)
was prepared according to the method of Astelford et al.3
(R)-3-Tosyloxy-1,2-propanediol (R)-12 was prepared
according to the method of Pirrung et al.4
3. Conclusion
A practical and safe route for the total synthesis of
enantiopure and diastereopure (2R,4S,2%S,3%R)-hydroxy-
itraconazole has been described. The route has provided
an improvement to previous syntheses. The difficulty in
preparing the cis-dioxolane intermediate in high de and
ee was addresssed by taking advantage of the practicality
of an equilibration/recycle method to generate the ther-
modynamically more stable cis stereochemistry. Recrys-
tallization provided the intermediate in 73% yield after
4.2. Preparation of (2R,4R)-2-(2,4-dichlorophenyl)-2-
(1H6 -1,2,4-triazol-1-ylmethyl)-4-tosyloxymethyl-1,3-diox-
olane tosylate (2R,4R)-3, tosylate salt
A suspension of (R)-tosyloxy-1,2-propanediol (R)-12
(10.0 g, 40 mmol) and 1-(2,4-dichlorophenyl)-2-(1H
6 -
1,2,4-triazol-1-yl)ethanone 9 (10.0 g, 39 mmol) in toluene

G. J. Tanoury et al. / Tetrahedron: Asymmetry 14 (2003) 3487–3493
3491
4.4. Preparation of 2,4-dihydro-4-bromophenyl-3H
1,2,4-triazol-3-one 6
6 -
(50 mL) was cooled to 5°C. Triflic acid (15 mL, 160
mmol) was slowly added so that the temperature stayed
below 15°C. After complete addition, the reaction mix-
ture (2 phases) was stirred at 25°C for 60 h. The mixture
was diluted with EtOAc (200 mL) and slowly dropped
into a solution of K2CO3 (50 g, 36.2 mmol) in water (400
mL) at 5°C. The organic layer was separated and the
aqueous layer was extracted with EtOAc (150 mL). The
combined organic extracts were dried over Na2SO4 (10
g) and filtered. A solution of TsOH monohydrate (7.6 g,
40 mmol) in EtOAc (50 mL) was slowly added at 25°C.
The white solid product was filtered after 30 min, washed
and dried to give (2R,4R)-3, tosylate salt containing 5%
of the (2R,4S)-isomer. Two crystallizations from CH3CN
(400 mL) gave 13.5 g of pure (2R,4R)-3, tosylate salt
To formic hydrazine (8.34 g, 0.139 mol) in 1-butanol (600
ml) at 0–5°C was added 4-bromophenylisocyanate (25.00
g, 0.126 mol) portion-wise to maintain the reaction
temperature below 15°C. The reaction mixture was
cooled to 0–5°C, stirred for 15 min, warmed to room
temperature and stirred for another 15 min. Potassium
hydroxide (7.79 g, 0.139 mol) was added, a Dean Stark
trap was added and the reaction mixture was warmed to
reflux for 3 h. After cooling to room temperature, the
solvent was removed to give a white solid. Water (500
ml) was added to the solid and the mixture was stirred
for 1 h to give a slightly beige solution with a white
precipitate. After filtration, the pH of the filtrate was
lowered to 7, and the white solid product was isolated
by filtration and dried in vacuo to give 12.28 g of the title
compound. The above white precipitate was suspended
in water (200 ml) by rapid stirring for 48 h. Filtration of
this mixture and neutralization of the filtrate to pH 7 gave
more solid white product which was dried in vacuo to
give 2.63 g of the title compound. The combined yield
was 14.91 g (49% yield). 1H NMR (300 MHz, d6-DMSO):
l 12.05 (s, 1H), 8.40 (s, 1H), 7.65 (s, 4H). 13C NMR (75
MHz, d6-DMSO): l 152.76, 135.96, 133.43, 132.16,
123.20, 119.22. MS (CI, C8H6BrN3O) m/z 242.21 (M+),
240.21 (M+), 161.46.
1
(50% yield). H NMR (300 MHz, d6-DMSO): l 8.98 (s,
1H), 8.29 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.66 (br s, 1H),
7.50 (d, J=8.1 Hz, 4H), 7.40 (br s, 2H), 7.12 (d, J=8.1
Hz, 2H), 4.82 (br s, 2H), 4.23 (m, 1H), 3.97 (dd, J=11
Hz, 3.4 Hz, 1H), 3.80 (m, 2H), 3.62 (dd, J=8.7 Hz, 5.5
Hz, 1H), 2.42 (s, 3H), 2.28 (s, 3H). 13C NMR (75 MHz,
d6-DMSO): l 148.0, 145.3, 145.1, 144.6, 138.1, 134.8,
134.1, 132.5, 132.0, 130.7, 130.3, 130.1, 128.2, 127.8,
127.4, 125.5, 107.1, 73.7, 69.5, 65.7, 53.5, 21.2, 20.9. MS
(CI) m/z (M+1, C20H19Cl2N3O5S) 484.05. HPLC
purity=99.8 A% (m-bondapack C18 column, 220 nm,
CH3CN: 0.05 M NaH2PO4 (pH=3, 0.1% NEt3) 50: 50,
1 ml/min; trans 13 min, cis 14 min) [h]2D5=+16.6 (c=1,
MeOH)
ee=99.6%
(HPLC
Chiracel
OD-H,
EtOH:HNEt2 100:0.1, 0.25 mL/min, 254 nm, 23 min).
4.5. Preparation of 2,4-dihydro-4-bromophenyl-2-
4.3. Preparation of (4R,5R)-4,5-dimethyl-1,2,3-dioxathi-
olane 2,2-dioxide (4R,5R)-7
[(2S,3R)-(3-hydroxy-2-butyl)]-3H6 -1,2,4-triazol-3-one
(2S,3R)-4
According to the procedure of Sharpless and Gao and
a known prep,7 a three-necked 500 ml RBF fitted with
a reflux condenser and a calcium chloride drying tube
was charged with (2R,3R)-(+)-2,3-butanediol (10.0 g,
10.1 ml, 0.11 mol) and carbon tetrachloride (120 ml).
Thionyl chloride (16.0 g, 9.8 ml, 0.13 mol) was added
dropwise at room temperature. Rapid gas evolution
(HCl) began. The reaction mixture was stirred at room
temperature for 10 min, then warmed to reflux for 30 min
to insure complete removal of HCl gas. The reaction
mixture was cooled to 0°C in an ice-water bath and
acetonitrile (120 ml), RuCl3–H2O (14 mg, 0.07 mmol),
NaIO4 (35.6 g, 0.17 mol) and water (180 ml) were added,
respectively. The reaction mixture was allowed to warm
to room temperature and stirred for 1.5 h. The mixture
was poured into methyl t-butyl ether (900 ml), and water
was added to dissolve the remaining NaIO4 (ca. 600 ml).
The phases were separated and the aqueous phase was
extracted with methyl t-butyl ether (2×100 ml). The
combined organic phases were washed with water (1×50
ml), saturated aqueous sodium bicarbonate (2×50 ml)
and saturated aqueous sodium chloride (1×50 ml). The
organic solution was dried over anhydrous magnesium
sulfate and filtered through a bed of silica gel to give a
clear and colorless solution. The solvent was removed in
vacuo to give 16.01 g (95% yield) of the title compound.
1H NMR (300 MHz, CDCl3): l 4.70 (m, 1H), 1.55 (m,
3H). 13C NMR (75 MHz, CDCl3): l 85.5, 16.5.
To a round-bottomed flask was added potassium carbon-
ate (5.80 g, 42 mmol) and 2,4-dihydro-4-bromophenyl-
3H6 -1,2,4-triazol-3-one (6) (5.00 g, 21 mmol). Acetonitrile
was added (65 mL), followed by TDA-1 (6.79 g, 6.7 mL,
21 mmol). (4R,5R)-4,5-Dimethyl-1,2,3-dioxathiolane-
2,2-dioxide ((4R,5R)-7) (4.12 g, 27.11 mmol) was added,
and the mixture was warmed to 40°C for 16 h. The
mixture was cooled to rt and filtered. The solid was rinsed
with methanol, and the combined filtrates were concen-
trated in vacuo. To the crude intermediate was added
48% HBr (40 mL) and the reaction mixture was warmed
to 50°C for 45 min. The solution was poured into water
(100 mL) and neutralized with saturated aqueous potas-
sium carbonate to pH 7. The aqueous solution was
extracted with MTBE (3×25 mL), and the combined
organic phases dried over anhydrous magnesium sulfate,
filtered, and the solvent was removed in vacuo to give the
crude. The crude material was purified by flash chro-
matography (chloroform/1% methanol) to give 5.15 g
1
(79% yield) of the desired product (2S,3R)-4. H NMR
(300 MHz, CDCl3): l 7.67 (s, 1H), 7.60 (d, J=8.9 Hz,
2H), 7.47 (d, J=8.9 Hz, 2H), 4.28 (dq, J=3.3, 6.8 Hz,
1H), 4.17 (dq, J=3.2, 6.4 Hz, 1H), 1.42 (d, J=7.0 Hz,
3H), 1.23 (d, J=6.5 Hz, 3H). 13C NMR (75 MHz,
CDCl3): l 151.43, 133.25, 132.75, 123.40, 121.28, 69.82,
57.14, 19.32, 12.56. MS (CI, C12H14BrN3O2) m/z 296.15
(M+-H2O), 294.15 (M+-H2O), 242.21, 240.21.

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G. J. Tanoury et al. / Tetrahedron: Asymmetry 14 (2003) 3487–3493
4.6. Preparation of 2,4-dihydro-4-bromophenyl-2-
[(2S,3R)-[3-(1,1-dimethylethyl)dimethylsiloxy-butyl]]-3H
1,2,4-triazol-3-one (2S,3R)-17
temperature, water (300 ml) was added and the mixture
was extracted with dichloromethane (3×200 ml). The
solvents were removed in vacuo and the crude material
was dissolved in ethyl acetate (600 ml) and extracted
with water (4×50 ml). The organic phase was dried over
anhydrous magnesium sulfate, filtered and the solvents
were removed in vacuo to give a brown foam. To this
crude product was added potassium hydroxide (16.18 g,
289 mmol), iso-propyl alcohol (40 ml), and water (10
ml). The reaction mixture was warmed to reflux for 14
h, cooled to room temperature and concentrated in
vacuo. The crude material was purified by flash chro-
matography eluting with a gradient from 3% methanol
in chloroform to 5% triethylamine:3% methanol:
chloroform by increasing the triethylamine concentra-
tion in 1% portions to give 9.45 g (85% yield) of
6
-
To 2,4-dihydro-4-bromophenyl-2-[(1S,2R)-(2-hydroxy-
1-methylpropyl)]-3H-1,2,4-triazol-3-one (2S,3R)-4b
6
(320 mg, 1.0 mmol), imidazole (163 mg, 2.4 mmol), and
tert-butyldimethylchlorosilane (166 mg, 1.1 mmol) at
room temperature was added DMF (1.0 ml). The reac-
tion mixture was stirred at room temperature for 48 h.
Ethyl acetate (3 ml) and water (3 ml) were added, and
the phases were separated. The organic phase was
washed with water, 1.2 N HCl, water, saturated
6
aqueous sodium bicarbonate, saturated aqueous
sodium chloride and dried over anhydrous magnesium
sulfate. After filtration and removal of the solvent in
vacuo, the crude material was purified by flash chro-
matography (10:1 hexane:ethyl acetate) to give 436 mg
(>99% yield) of the desired product (2S,3R)-26. 1H
NMR (300 MHz, CDCl3): l 7.67 (s, 1H), 7.60 (d,
J=8.9 Hz, 2H), 7.47 (d, J=8.9 Hz, 2H), 4.19 (p, J=6.9
Hz, 1H), 4.06 (q, J=6.1 Hz, 1H), 1.44 (d, J=6.7 Hz,
3H), 1.12 (d, J=6.0 Hz, 3H), 0.90 (s, 9H), 0.06 (s, 3H),
0.04 (s, 3H). 13C NMR (75 MHz, CDCl3): l 151.41,
132.99, 132.65 (2C), 123.20 (2C), 120.86, 70.12, 57.00,
25.74 (3C), 20.62, 17.91, 15.03, −4.43, −5.00. MS (CI,
C18H28BrN3O2Si) m/z 428.06 (M+), 426.09 (M+),
412.06, 410.06, 296.16, 294.16, 242.21, 240.21. HPLC:
Chiralpak AD, 10 mm, 4.6 mm×25 cm, Hexane/IPA
(97:3), 1.0 ml/min, 220 nm. (2S,3R)-26: 7.1 min,
(2R,3S)-26: 8.2 min, meso-26: 7.0 min.
1
(2R,4S)-2. H NMR (300 MHz, CDCl3): l 8.20 (s, 1H),
7.89 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.47 (d, J=2.0
Hz, 1H), 7.25 (dd, J=8.9, 2.0 Hz, 1H), 6.88 (d, J=9.0
Hz, 2H), 6.78 (d, J=9.0 Hz, 2H), 4.80 (dAB, J=14.7
Hz, 1H), 4.36 (m, 1H), 3.92 (t, J=6.7 Hz, 1H), 3.79 (m,
2H), 3.48 (dd, J=9.8, 6.5 Hz, 1H), 3.06 (s, 8H). 13C
NMR (75 MHz, CDCl3): l 152.2, 151.2,146.4, 144.8,
135.9, 133.9, 133.0, 131.2, 129.5, 127.1, 118.1 (2C),
115.1 (2C), 107.4, 74.6, 67.5, 67.3, 53.4, 51.1(2C), 45.8
(2C).
4.8. Preparation of (2R,4S)-4-[4-[4-[4-[[2-(2,4-dichloro-
phenyl)-2-(1H6 -1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-
4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-
2-[(2S,3R)-(3-[(1,1-dimethylethyl)dimethylsiloxy-2-
butyl]]-3H6 -1,2,4-triazol-3-one (2R,4S,2%S,3%R)-18
Desired
enantiomer
Isomer % area (ret time)
(2R,4S)-4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H6 -1,2,4-triazol-
1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-piper-
azine (2R,4S)-2 (110 mg, 0.28 mmol), 2,4-dihydro-
4 - bromophenyl - 2 - [(2S,3R) - [3 - (1,1 - dimethylethyl)-
(2S,3R)-17
(2R,3S)-17
meso-17
dimethylsiloxy-2-butyl]]-3H6 -1,2,4-triazol-3-one (2S,3R)-
(2S,3R)-17 99.89
0.11
–
17 (110 mg, 0.25 mmol), tris(dibenzylideneace-
tone)dipalladium (2.3 mg, 0.0025 mmol), R-BINAP
(4.7 mg, 0.0075 mmol) and sodium tert-butoxide (34
mg, 0.35 mmol) were combined in a dry flask. The
contents were vacuum purged with argon (3×). To this
was added degassed toluene (1.25 ml), and the entire
solution was purged by bubbling argon through it. The
reaction mixture was warmed to 85°C for 3 h, cooled to
room temperature, and ethyl acetate and water were
added. The phases were separated and the aqueous
phase was extracted with ethyl acetate (3×). After dry-
ing the combined organic phases over anhydrous mag-
nesium sulfate, filtering and removing the solvent in
vacuo, the crude material was purified by flash chro-
matography (98:2 chloroform:methanol) followed by
purification on a Chromatotron (the plate wetted with
chloroform and eluted with 98:2 chloroform:methanol)
to give 171 mg (81% yield) of the desired product
(2R,4S,2%S,3%R)-18. 1H NMR (300 MHz, CDCl3): l
8.20 (s, 1H), 7.89 (s, 1H), 7.64 (s, 1H), 7.58 (d, J=8.4
Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.40 (d, J=8.9 Hz,
2H), 7.25 (dd, J=8.9, 2.0 Hz, 1H), 7.03 (d, J=9.0 Hz,
2H), 6.94 (d, J=9.0 Hz, 2H), 6.80 (d, J=9.0 Hz, 2H),
4.85 (dAB, J=14.7 Hz, 1H), 4.75 (dAB, J=14.7 Hz, 1H),
4.36 (m, 1H), 4.27 (m, 1H), 4.21 (m, 1H), 3.92 (t, J=6.7
4.7. Preparation of (2R,4S)-4-[4-[[2-(2,4-dichloro-
phenyl)-2-(1H6 -1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-
4-yl]methoxy]phenyl]-piperazine (2R,4S)-2
To a separatory funnel containing 10% aqueous potas-
sium carbonate (150 ml) was added (2R,4R)-3b-TsOH
(15.00 g, 22.8 mmol). Dichloromethane (150 ml) was
added and the mixture was shaken vigorously with
venting. The organic phase was decanted and the proce-
dure was continued until the organic and aqueous
phases were clear. The combined organic phases were
dried over anhydrous magnesium sulfate, filtered and
the solvent was removed in vacuo to give 11.35 g of
(2R,4R)-3b as a clear sticky material. To (2R,4R)-3b
was added N-acetyl-N%-(4-hydroxyphenyl)piperazine 5
(5.06 g, 23.0 mmol) and DMF (100 ml). To the clear
solution was added sodium hydride (1.50g of a 60%
dispersion in oil, 37.5 mmol) in portions. Gas evolution
occurred and a precipitate began to form immediately.
After the addition was complete, the reaction mixture
was warmed to 50°C for 15 h. After cooling to room

G. J. Tanoury et al. / Tetrahedron: Asymmetry 14 (2003) 3487–3493
3493
Hz, 1H), 3.79 (m, 2H), 3.67 (d, J=2.5 Hz, 1H), 3.48 (dd,
References
J=9.8, 6.5 Hz, 1H), 3.36 (m, 4H), 3.24 (m, 4H), 1.43 (d,
J=7.0 Hz, 3H), 1.25 (d, J=6.8 Hz, 3H), 0.90 (s, 9H), 0.08
(s, 3H), 0.06 (s, 3H). 13C NMR (75 MHz, CDCl3): l
152.6, 152.0, 151.3, 150.7, 145.9, 144.9, 136.0, 134.3,
134.0, 133.1, 131.4, 129.6, 127.2, 125.3, 123.7 (2C), 118.4
(2C), 116.6 (2C), 115.2 (2C), 107.6, 74.7, 69.8, 67.6, 67.4,
57.3, 53.5, 50.5 (2C), 49.1 (2C), 19.4, 12.4.
1. (a) Vanden Bossche, H.; Marichal, P.; LeJeune, L.; Coene,
M.-C.; Gorrens, J.; Cools, W. Antimicrob. Agents
Chemotherapy 1993, 37, 2101; (b) Vanden Bossche, H.;
Heeres, J.; Backx, L.; Marichal, P.; Willemsens, G. In
Cutaneous Antifungal Agents; Rippons, J. W.; Fromtling,
R. A., Eds.; Marcel Dekker, Inc: New York, 1993; pp.
171–197; (c) Vanden Bossche, H.; Marichal, P.; Gorrens,
J.; Bellens, D.; Coene, M.-C.; Lauwers, W.; Le Jeune, L.;
Moereels, H.; Janssen, P. A. J. In Mycoses in AIDS
Patients; Vanden Bossche, H.; Mackenzie, D. W. R.;
Causenbergh, G.; Van Cutsem, J.; Drouhet, E.; Dupont,
B., Eds.; Plenum Press: New York, 1990; pp. 223–243; (d)
Banden Bossche, H.; Marichal, P.; Gorrens, J.; Coene,
M.-C.; Willemsens, G.; Bellens, D.; Roels, I.; Moereels,
H.; Janssen, P. A. J. Mycoses 1989, 32 (Suppl. 1), 35; (e)
Vanden Bossche, H.; Marichal, P.; Gorrens, J.; Geerts, H.;
Janssen, P. A. J. Ann. N.Y. Acad. Sci. 1988, 544, 191.
2. (a) Tanoury, G. J.; Senanayake, C. H.; Hett, R.; Hong, Y.;
Wald, S. A. Tetrahedron Letters 1997, 38, 7839; (b)
Tanoury, G. J.; Senanayake, C. H.; Hett, R.; Kuhn, A.
M.; Kessler, D. W.; Wald, S. A. Tetrahedron Letters 1998,
39, 6845.
4.9. Preparation of (2R,4S)-4-[4-[4-[4-[[2-(2,4-
dichlorophenyl)-2-(1H6 -1,2,4-triazol-1-ylmethyl)-1,3-
dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-
dihydro-2-[(2S,3R)-(3-hydroxy-2-butyl)]-3H-1,2,4-
triazol-3-one (2R,4S,2%S,3%R)-hydroxyitraconazole
6
To (2R,4S)-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H6 -1,
2,4 - triazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl]methoxy]-
phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[(2S,3R)-
(3-(1,1-dimethylethyl)dimethylsiloxy-2-butyl)]-3H6 -1,2,4-
triazol-3-one (2R,4S,2%S,3%R)-18 (171 mg, 0.20 mmol) in
THF (0.6 ml) at room temperature was added tetra-n-
butylammonium fluoride (0.3 ml of a 1.0 M solution in
THF, 0.3 mmol). The reaction mixture was stirred at
room temperature for 17 h. Water and chloroform were
added, and the phases were separated. The aqueous
phase was extracted with chloroform (2X), dried over
anhydrous magnesium sulfate, filtered, and the solvent
was removed in vacuo. The crude material was purified
by flash chromatography (95:5 chloroform:methanol) to
give 131 mg (91% yield) of the desired product
(2R,4S,2%S,3%R)-hydroxyitraconazole. 1H NMR (300
MHz, CDCl3): l 8.20 (s, 1H), 7.89 (s, 1H), 7.64 (s, 1H),
7.58 (d, J=8.4 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.40 (d,
J=8.9 Hz, 2H), 7.25 (dd, J=8.9, 2.0 Hz, 1H), 7.03 (d,
J=9.0 Hz, 2H), 6.94 (d, J=9.0 Hz, 2H), 6.80 (d, J=9.0
Hz, 2H), 4.85 (dAB, J=14.7 Hz, 1H), 4.75 (dAB, J=14.7
Hz, 1H), 4.36 (m, 1H), 4.27 (m, 1H), 4.21 (m, 1H), 3.92
(t, J=6.7 Hz, 1H), 3.79 (m, 2H), 3.67 (d, J=2.5 Hz, 1H),
3.48 (dd, J=9.8, 6.5 Hz, 1H), 3.36 (m, 4H), 3.24 (m, 4H),
1.43 (d, J=7.0 Hz, 3H), 1.25 (d, J=6.8 Hz, 3H). 13C
NMR (75 MHz, CDCl3): l 152.6, 152.0, 151.3, 150.7,
145.9, 144.9, 136.0, 134.3, 134.0, 133.1, 131.4, 129.6,
127.2, 125.3, 123.7 (2C), 118.4 (2C), 116.6 (2C), 115.2
(2C), 107.6, 74.7, 69.8, 67.6, 67.4, 57.3, 53.5, 50.5 (2C),
49.1 (2C), 19.4, 12.4. Anal. Calcd for C35H38Cl2N8O5: C,
58.25; H, 5.32; Cl, 9.83; N, 15.53. Found: C, 57.80; H,
5.39; Cl, 9.56; N, 15.55. [h]2D5=12.7 (c=0.1, MeOH).
HPLC purity: 99.0 A% (HPLC m Bondapak C18, 300×3.9
mm; 0.1 M NaClO4-0.01 M NaH2PO4 (pH 3.0)/acetoni-
trile (50:50), 1.0 mL/min, 254 nm, 12.3 min).
3. (a) Wolfe, J. P.; Wagaw, S.; Buchwald, L. S. J. Am. Chem.
Soc. 1996, 118, 7215; (b) Driver, M. S.; Hartwig, J. F. J.
Am. Chem. Soc. 1996, 118, 7217.
4. Astleford, B. A.; Goe, G. L.; Keay, J. G.; Scriven, E. F. V.
J. Org. Chem. 1989, 54, 731.
5. Pirrung, M. C.; Dunlap, S. E.; Trinks, U. P. Helv. Chim.
Acta 1989, 72, 1301.
6. Using MsOH as the acid resulted in a 22:18 mixture of
cis:trans isomers after 7 days at reflux in toluene.
7. For the preparation of 7, see: Gao, Y.; Sharpless, K. B. J.
Am. Chem. Soc. 1988, 110, 7538. Meso-7 was used for
preliminary investigational studies due to its ready
availability compared to (2R,3R)-7.
8. (a) Soula, G. J. Org. Chem. 1985, 50, 3717; (b) Reinholz,
E.; Becker, A.; Hagenbruch, B.; Shafer, S.; Schmitt, A.
Synthesis 1990, 1069; (c) Berens, U.; Scharf, H. D. J. Org.
Chem 1995, 60, 5127; (d) Bartsch, R. A.; Phillips, J. B.
Syn. Comm. 1986, 16, 1777; (e) Eugene, F; Langlois, G;
Laurent, E. J. Fluorine Chem. 1994, 66, 301; (f) Meegan,
M. J.; Fleming, B. G.; Walsh, O. M. J. Chem. Research (S)
1991, 156; (g) Lissel, M. Liebigs Ann. Chem. 1987, 77; (h)
Lucht, B. L.; Bernstien, M. P.; Remenar, J. F.; Collum, D.
B. J. Am. Chem. Soc. 1996, 118, 10707; (i) Schroeder, G.;
Leska, B.; Bartl, F.; Rozalski, B.; Brzezinski, B. J. Mol.
Struct. 1999, 478, 255.