Design, synthesis and antifungal activity of the novel water-soluble prodrug of antifungal triazole CS-758

Article abstract of DOI:10.1248/cpb.58.794

CS-758 was selected as a candidate for clinical trials, but since its water-solubility was insufficient for an injectable formulation, phosphoryl ester prodrugs were designed. In this study, the synthesis and evaluation of these injectable prodrugs are described. Phosphoryl ester 17h was soluble in water, and was stable in both water and in a solid state. 17h was converted to CS-758 in human liver microsome and was also converted to CS-758 in rats after intravenous (i.v.) administration with good conversion speed and efficiency. 17h (i.v.) reduced the viable cell counts in kidneys in a murine hematogenous Candida albicans infection model and in lungs in a murine pulmonary Aspergillus fumigatus infection model, wherein the effects were comparable to or slightly superior to that of CS-758 (per os).

Full text of DOI:10.1248/cpb.58.794

794
Regular Article
Chem. Pharm. Bull. 58(6) 794—804 (2010)
Vol. 58, No. 6
Design, Synthesis and Antifungal Activity of the Novel Water-Soluble
Prodrug of Antifungal Triazole CS-758
Yoshiko KAGOSHIMA,a Makoto MORI,b Eiko SUZUKI,c Nobue KOBAYASHI,c Takahiro SHIBAYAMA,c
Mikie KUBOTA,d Yasuki KAMAI,d and Toshiyuki KONOSU*,a
a Medicinal Chemistry Research Laboratories II, Daiichi Sankyo Co., Ltd.; c Drug Metabolism & Pharmacokinetics
Research Laboratories, Daiichi Sankyo Co., Ltd.; d Biological Research Laboratories IV, Daiichi Sankyo Co., Ltd.;
1–16–13 Kitakasai, Edogawa-ku, Tokyo 134–8630, Japan: and b Medicinal Chemistry Research Laboratories I, Daiichi
Sankyo Co., Ltd.; 1–2–58 Hiromachi, Shinagawa-ku, Tokyo 140–8710, Japan.
Received November 12, 2009; accepted March 15, 2010; published online March 16, 2010
CS-758 was selected as a candidate for clinical trials, but since its water-solubility was insufficient for an
injectable formulation, phosphoryl ester prodrugs were designed. In this study, the synthesis and evaluation of
these injectable prodrugs are described. Phosphoryl ester 17h was soluble in water, and was stable in both water
and in a solid state. 17h was converted to CS-758 in human liver microsome and was also converted to CS-758 in
rats after intravenous (i.v.) administration with good conversion speed and efficiency. 17h (i.v.) reduced the viable
cell counts in kidneys in a murine hematogenous Candida albicans infection model and in lungs in a murine pul-
monary Aspergillus fumigatus infection model, wherein the effects were comparable to or slightly superior to that
of CS-758 (per os).
Key words water-soluble prodrug; phosphate ester; antifungal azole; CS-758
There is a great medical need for an injectable antifungal drugs) illustrated in Chart 1.
agent with a broad spectrum for the treatment of severe deep
In these prodrugs, two auxiliary units, a self-cleavable
mycoses of hospitalized patients.1—4) Currently, injectable linker and a solubilizing part, were lined up to be linked to
antifungal azoles, fluconazole (FLCZ), fosfluconazole5) and the parent prodrug CS-758. First, the solubilizing part of the
voriconazle6) are available for parenteral use, but they have prodrug could be rapidly hydrolyzed by an esterase to gener-
limitations in terms of antifungal spectra and safety, respec- ate an unstable intermediate, and then it would undergo a
tively. Most of the azoles under development have a broader
spectrum but cannot be administered parenterally because of
low water-solubility.7—10) There have been some efforts to
overcome this problem by using a prodrug approach.11—14)
Previously, we identified CS-75815—17) which has a broad
antifungal spectrum covering Aspergillus spp., FLCZ-resist-
ant Candida spp. and has a good safety profile, including low
drug–drug interaction. Since the water solubility of CS-758
was, however, too low for a parenteral formulation, we con-
ducted a study on a prodrug of CS-758 which should have
sufficient water solubility and efficient bioconversion.
CS-758 has two obvious functional groups, namely the
tertiary hydroxy and the triazole groups, with the possibility
of being linked to a pro-moiety. It is known that water-solu-
ble prodrugs can be readily accessed by alkylating a triazole
ring with halomethyl acetate derivatives to give a quaternary
ammonium salt prodrug.12,14,18) Phosphonooxymethy ether of
ravuconazole has also been reported13) (Fig. 1).
However, the prodrugs in these classes liberate an equiva-
lent amount of formaldehyde or quinone methide in vivo
when cleaved. Consequently, we focused our efforts on iden-
tifying a suitable, safe, polar group with which we could
Fig. 1. Structural Formulas of Prodrugs of Triazole Antifungal Agents
functionalize CS-758 on the tertiary hydroxy group and
recently reported the novel prodrug 119) of CS-758 (Fig. 2).
Compound 1 had good water solubility, and its in vivo effi-
cacy was comparable to or slightly superior to efficacy of
CS-758, but there was some room for improvement in both
the conversion speed and the conversion efficiency. We
thought that the slow conversion speed of 1 to CS-758 was
due to steric hindrance of the tertiary hydroxy group and
planned the general concept of prodrugs (cascade type pro- Fig. 2. Structural Formulas of CS-758 and the Prodrug of CS-758 (1)
© 2010 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: cpbc090891@yahoo.co.jp

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795
rapid and spontaneous intra-molecular cyclization to release with acid chlorides because of its steric hindrance, the
CS-758 and a lactone.20)
sodium alkoxide form of CS-758, which was generated from
In this paper, we describe the design and synthesis of CS-758 and NaH in tetrahydrofuran (THF), could be reacted
water-soluble prodrugs of CS-758, and their physicochemical with acid chloride 8 at room temperature to afford the desired
and biological properties.
ester 9 in 63% yield. Removal of two allyl groups of 9 was
First, we designed and synthesized the prodrug 2. We accomplished by the use of tetrakis(triphenylphosphine)pal-
chose a 4-hydroxybutyrate moiety as the self-cleavable linker ladium and pyrrolidine in CH2Cl2 to afford the desired com-
and a phosphoric acid ester moiety as the solubilizing part pound as a pyrrolidinium salt. The salt was purified with a C-
because phosphoric acid ester has good water solubility and 18 reverse phase column, and then the counter ion was
dephosphorylation is a familiar enzyme response. 4-Hydroxy- exchanged using Dowex 50Wꢀ8 (Na form) to give sodium
butyrate ester afforded by dephosphorylation was expected to salt 2.
afford a lactone and the parent drug CS-758. The synthesis
The pharmacokinetic (PK) profile after intravenous (i.v.)
of compound 2 is shown in Chart 2.
bolus administration of 2 to rats at a dose of 2 mg (CS-758
Sodium 4-hydroxybutyrate 4 was reacted with 4-methoxy- equivalent)/kg is shown in Fig. 3. As expected, compound 2
benzyl chloride to afford 4-methoxybenzyl ester 5. As the disappeared from plasma within 1 h and rapid formation of
ester 5 was unstable, 5 was used for the next step without dephosphorylated intermediate alcohol was observed by
further purification. 5 was phosphorylated by using the pro- HPLC identification. Though the intermediate alcohol disap-
cedure developed by Fraser–Reid21) to give the phosphoryl peared from plasma rapidly and formation of CS-758 was
ester 6. The 4-methoxybenzyl (PMB) group of 6 was removed
using trifluoroacetic acid (TFA) and anisole to obtain the car-
boxylic acid 7, which was treated with oxalyl chloride in
CH2Cl2 to afford the corresponding acid chloride 8. Though
the tertiary hydroxy group of CS-758 was almost unreactive
Fig. 3. Plasma Level of CS-758 and Intermediate Alcohol after i.v. Ad-
ministration of 2 to Rats at a Dose of 2 mg (CS-758 Equivalent)/kg (Average
Chart 1. General Concept of Cascade-Type Prodrugs
of Three Rats)
Reagents and conditions: (a) 4-(MeO)BnCl, DMF, 80 °C; (b) i-Pr2NP(OAllyl)2, 1H-tetrazole, CH2Cl2; (c) t-BuOOH, CH2Cl2; (d) TFA, anisole; (e) (COCl)2, cat. DMF,
CH2Cl2; (f) NaH, 8, THF; (g) Pd(PPh3)4, pyrrolidine, CH2Cl2, then Dowex 50Wꢀ8 (Na form).
Chart 2. Synthesis of 2
Reagents and conditions: (a) NaOH aq., MeOH, THF; (b) 4-(MeO)BnCl, DMF, 80 °C; (c) i-Pr2NP(OAllyl)2, 1H-tetrazole, CH2Cl2; (d) t-BuOOH, CH2Cl2; (e) TFA,
anisole; (f) (COCl)2, cat. DMF, CH2Cl2; (g) NaH, 15, THF; (h) Pd(PPh3)4, pyrrolidine, CH2Cl2, then Dowex 50Wꢀ8 (Na form).
Chart 3. Synthesis of 3

796
Vol. 58, No. 6
Fig. 4. Plasma Level of CS-758 after i.v. Administration of 3 to Rats at a
Dose of 2 mg (CS-758 Equivalent)/kg (Average of Three Rats)
observed, the conversion efficiency was 3.4% and there are
some room for improvement.
We assumed that conformational restriction of linker part
might hasten intra-molecular cyclization of the intermediate
alcohol and high conversion efficiency might be achieved.
On the basis of this supposition, we designed compound 3,
which employs a 2-(hydroxymethyl)benzoyl moiety as the
self-cleavable linker and a phosphoric acid ester moiety as
the solubilizing part.
Compound 3 was synthesized in a similar manner to 2.
The phthalide ring in 10 was opened by treatment with 1 eq
of NaOH to afford sodium salt 11. The sodium salt 11 was
treated with 4-methoxybenzyl chloride to give the unstable
hydroxy ester 12. The ester 12 was treated with diallyl diiso-
propylphosphoramidite in the presence of 1H-tetrazole and
oxidized successively with tert-butyl hydroperoxide to give
the corresponding phosphate 13. The 4-methoxybenzyl group
of 13 was removed by TFA and the afforded carboxylic acid
14 was treated with oxalyl chloride to give acid chloride 15.
The oxide anion prepared from CS-758 was esterified with
15 to afford ester 16 and the desired compound 3 was
afforded by deprotection of the phosphoryl group.
Fig. 5. Structural Formulas of Compounds 17a—k
Table 1. Conversion of Compounds 3, and 17a—k to CS-758 in Human
Plasma and Liver Microsome
Human plasmaa)
30 min 120 min
Human liver microsomea)
Compd.
30 min
120 min
3
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢂ
ꢃ
ꢃ
ꢂ
ꢃꢃ
ꢂ
ꢂ
ꢃ
ꢃꢃ
ꢃꢃ
ꢂ
ꢃ
ꢃꢃ
ꢃ
ꢂ
ꢃꢃ
ꢃ
ꢃ
ꢃ
ꢃꢃ
ꢃꢃ
ꢃ
17a
17b
17c
17d
17e
17f
17g
17h
17i
17j
17k
ꢃ
ꢃꢃ
a) ꢁ, no detetction or very low formation of CS-758 (conversion yield: ꢄ20%); ꢂ,
low formation of CS-758 (conversion yield: 20—40%); ꢃ, middle formation of CS-
758 (conversion yield: 40—70%); ꢃꢃ, high formation of CS-758 (conversion yield:
ꢅ70%).
The PK profile after i.v. bolus administration of 3 to rats at
a dose of 2 mg (CS-758 equivalent)/kg is shown in Fig. 4.
Compound 3 was converted to CS-758 rapidly and dephos-
phorylated intermediate alcohol was not observed in plasma.
Thus, the conformational restriction had a distinct effect on
the conversion rate of intermediate alcohols to drug CS-758.
Compounds 17e—g were synthesized as depicted in Chart
5. Diols 25e—g were reacted with 1 eq of tert-butylchlorodi-
Compared with 1,19) the conversion speed of 3 to CS-758 methylsilane (TBSCl) in THF at 0 °C to afford isomers
was improved. In the case of 3, maximum drug concentration 26e—g preferentially. The structure of 26e—g was deter-
time (Tmax) is 0.5 h, whereas Tmax was 1.3 h in the case of 1. mined by measuring the nuclear Overhauser effect (NOE) in
The conversion efficiency (BA)22) of compound 3 to CS-758 the 1H-NMR spectrum. Phosphorylation of 26e—g with dial-
was 28.7%.
lyl diisopropylphosphoramidite and successive oxidation
Aiming to further improve the conversion efficiency, we with tert-butyl hydroperoxide gave phosphate esters 27e—g.
decided to continue modifying compound 3, as shown in Fig. The silyl group of 27e—g was removed with tetrabutylam-
5. We expected that certain steric effects or electric effects in monium fluoride in THF and the following oxidization
the linker part might improve the conversion efficacy and with Jones reagent afforded carboxylic acids 29e—g. Acid
conversion speed. In compounds 17a—i, substituents were chlorides 30e—g were reacted with the sodium alkoxide
introduced to the benzene ring of the linker part and in com- form of CS-758 to give 31e—g. Removal of the two allyl
pounds 17j and k, the linker benzene ring was replaced by a groups in 31e—g was accomplished by use of bis(triph-
naphthalene or furanyl ring. These compounds were synthe- enylphosphine)dichloropalladium and tri(n-butyl)tin hydride
sized as follows.
in dichloromethane. The sodium salt 17e—g was prepared by
Compounds 17a—d, h and i were synthesized in a similar treatment with sodium hydrogen carbonate and purified by
manner starting from corresponding phthalide derivatives C-18 reverse-phase column chromatography. 17j and 17k
(Chart 4).
were synthesized in a manner similar to the synthesis of

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797
Reagents and conditions: (a) NaOH aq., MeOH, THF; (b) 4-(MeO)BnCl, DMF, 80 °C; (c) i-Pr2NP(OAllyl)2, 1H-tetrazole, CH2Cl2; (d) t-BuOOH, CH2Cl2; (e) TFA,
anisole; (f) (COCl)2, cat. DMF, CH2Cl2; (g) NaH, 23a—d, h, i, THF; (h) PdCl2(PPh3)2, n-Bu3SnH, CH2Cl2, then NaHCO3 aq.
Chart 4. Synthesis of 17a—d, h and i
Reagents and conditions: (a) TBSCl, imidazole, THF; (b) i-Pr2NP(OAllyl)2, 1H-tetrazole, CH2Cl2; (c) t-BuOOH, CH2Cl2; (d) TBAF, THF, r.t.; (e) Jones reagent, ace-
tone; (f) (COCl)2, cat. DMF, CH2Cl2; (g) NaH, 30e—g, THF; (h) PdCl2(PPh3)2, n-Bu3SnH, CH2Cl2, then NaHCO3 aq.
Chart 5. Synthesis of 17e—g
17e—g (Charts 6, 7).
administration to rats (2 mg of CS-758 equivalent/kg) is
Compounds 17a—k were incubated with human plasma or shown in Figs. 8 and 9, respectively. When 17h was adminis-
with human liver microsome and the conversion of these tered to rats, CS-758 was quickly formed (Tmax; 0.7 h) and a
compounds to CS-758 was determined. The results are sum- high concentration of CS-758 was observed (Cmax; 0.512 mg/
marized in Table 1.
ml). CS-758 was eliminated slowly (t1/2; 5.7 h) and the BA of
Compounds 17a—k were not converted to CS-758 in CS-758 was almost quantitative (94.4%). Interestingly, when
human plasma, but these compounds were converted to CS- 17i was administered to rats, 17i was eliminated from plasma
758 effectively in human liver microsome. In compounds within 1 h. But the conversion efficiency of 17i was far less
17a—d, which had a F atom on the benzene ring, 17a and than that of 17h. The reason for this large difference between
17d were superior. The steric effect of the F atoms which are 17h and 17i in the conversion to CS-758 was undefined.
situated in a-position or d-position on the benzene ring (po-
The in vivo efficacies of the prodrug 17h (i.v. administra-
sition number shown in Chart 4) might hasten second sponta- tion) and CS-758 (oral administration) were evaluated in a
neous cleavage of the –O–CH2–Ar–C(ꢆO)– linker. Com- hematogenous C. albicans infection model in mice (Fig. 10)
pounds 17e—g, which have a substituent on the d-position of and in a pulmonary A. fumigatus infection model in mice
benzene ring gave favorable results, but the conversion speed (Fig. 11). In the hematogenous C. albicans infection model,
and conversion efficiency of these compounds were inferior i.v.-administered prodrug 17h exhibited high activity which
to 17d. In these compounds, 17h and 17i which had CN was almost equal to or slightly better than that of orally
group at b-position or g-position on the benzene ring af- administered CS-758. In a pulmonary aspergillosis model in
forded best results. The electron-withdrawing group on the mice, the efficacy of iv-administered 17h was superior to that
benzene ring might hasten cyclization of the –O–CH2–Ar– of orally administered CS-758.
C(ꢆO)– group. Also a compound with a furan ring in the
linker part (17k) and a compound with a naphthalene ring in (ꢅ30 mg/ml in water) and sufficient stability in solution at
the linker part (17j) showed good results. around neutral conditions. 17h was also stable in solid state
The disappearance of 17h and 17i, and the formation of as an amorphous salt.
Furthermore compound 17h had good water solubility
CS-758 after incubation with human liver microsome are
In summary, we developed a widely applicable prodrug
shown in Figs. 6 and 7, respectively. These compounds were technique for the solubilization of compounds having a hy-
converted to CS-758 within 1 h with excellent conversion droxy group. We identified the phosphoryl ester prodrug 17h,
efficacy.
which showed potent antifungal activity against both
The in vivo conversion of 17h and 17i to CS-758 upon i.v. hematogenous candidasis and pulmonary aspergillosis in

798
Vol. 58, No. 6
Reagents and conditions: (a) i-Pr2NP(OAllyl)2, 1H-tetrazole, CH2Cl2; (b) t-BuOOH, CH2Cl2; (c) TBAF, THF, r.t.; (d) Jones reagent, acetone; (e) (COCl)2, cat. DMF,
CH2Cl2; (f) NaH, 36, THF; (g) PdCl2(PPh3)2, n-Bu3SnH, CH2Cl2, then NaHCO3 aq.
Chart 6. Synthesis of 17j
Reagents and conditions: (a) TBSCl, imidazole, THF; (b) i-Pr2NP(OAllyl)2, 1H-tetrazole, CH2Cl2; (c) t-BuOOH, CH2Cl2; (d) TBAF, AcOH, THF, r.t.; (e) MnO2,
CH2Cl2; (f) NaClO2, 2-methyl-2-butene, NaH2PO4, (g) (COCl)2, cat. DMF, CH2Cl2; (h) NaH, 44, THF; (i) Pd(PPh3)4, pyrrolidine, CH2Cl2, then Dowex 50Wꢀ8 (Na form).
Chart 7. Synthesis of 17k
Fig. 6. Conversion of 17h (ꢀ) to CS-758 (ꢁ) in Human Liver Microsome
Fig. 7. Conversion of 17i (ꢀ) to CS-758 (ꢁ) in Human Liver Microsome
organic layer was dried over anhydrous magnesium sulfate, and the solvent
was distilled off under reduced pressure to give a crude product of 5 as an
oil. The crude oil of 5 was dissolved in CH2Cl2 (5 ml), and tetrazole (700 mg,
10 mmol) and diallyl diisopropylphosphoramidite (1.5 g, 6.1 mmol) were
added at 0 °C. The mixture was stirred at room temperature for 30 min, and
methanol (0.1 ml) was added to the mixture. The mixture was stirred for
5 min at room temperature and tert-butyl hydroperoxide (ca. 5 M nonane
solution, 1.5 ml, ca. 7.5 mmol) was added to the solution at 0 °C followed by
stirring the mixture at room temperature for 30 min. Saturated NaHCO3
solution and an aqueous solution of sodium thiosulfate were added to the
mixture, and the mixture was stirred for 10 min. The product was extracted
with EtOAc and the organic layer was washed with brine, dried over anhy-
drous magnesium sulfate and the solvent was removed under reduced pres-
sure to give an oily residue. The residue was subjected to chromatography
on silica gel (30 g) column (EtOAc : hexaneꢆ2 : 3—1 : 1) to give 6 (1.55 g,
81% yield) as a colorless oil. 1H-NMR (400 MHz, CDCl3) d: 2.01 (2H,
quint, Jꢆ7 Hz), 2.47 (2H, t, Jꢆ7 Hz), 3.81 (3H, s), 4.10 (2H, q, Jꢆ7 Hz),
4.50—4.55 (4H, m), 5.06 (2H, s), 5.25 (2H, br d, Jꢆ10 Hz), 5.36 (2H, br d,
Jꢆ17 Hz), 5.93 (2H, ddt, Jꢆ17, 10, 5 Hz), 6.84 (2H, d, Jꢆ9 Hz), 7.29 (2H,
d, Jꢆ9 Hz). IR (neat) cmꢁ1: 1731, 1613, 1516, 1464, 1254. MS m/z (FAB):
mice via i.v. administration. Because there are few injectable
antifungal azole agents with a broad spectrum, 17h could be
a promising drug for the treatment of fungal infections.
Experimental
1H-NMR spectra were recorded either on a Varian Mercury 400 (400
MHz) or a Varian Mercury 500 (500 MHz) spectrometer using tetramethylsi-
lane as an internal standard. MS and high-resolution MS (HR-MS) were
recorded either on a JEOL HX-100, a SX-102A or a JMS-AX-505H mass
spectrometer. Melting points were determined using a Yanagimoto micro
melting point apparatus and are uncorrected. IR spectra were recorded on a
JASCO FT-IR 8900 spectrometer. Optical rotations were measured on a
JASCO P-1030 polarimeter.
4-Methoxybenzyl 4-{[Bis(allyloxy)phosphoryl]oxy}butanoate (6) To
a suspension of a sodium 4-hydroxybutyrate (630 mg, 5.00 mmol) in N,N-
dimethylformamide (DMF) (3.5 ml) was added 4-methoxybenzyl chloride
(783 mg, 5.00 mmol), and the mixture was heated at 80 °C for 3 h. Water and
EtOAc were added to the mixture and the organic layer was separated. The

June 2010
799
Fig. 8. Plasma Level of CS-758 after i.v. Administration of 17h to Rats at
Fig. 9. Plasma Level of CS-758 after i.v. Administration of 17i to Rats at a
a Dose of 2 mg (CS-758 Equivalent)/kg (Average of Three Rats)
Dose of 2 mg (CS-758 Equivalent)/kg (Average of Three Rats)
Fig. 10. In Vivo Efficacy of Compound 17h (i.v.) against Murine Intravenous Infection with C. albicans SANK51486 Compared with That of CS-758 (p. o.)
Fig. 11. In Vivo Efficacy of Compound 17h (i.v.) against Murine Intratracheal Infection with A. fumigatus TIMM1776 Compared with That of CS-758 (p. o.)
385 (Mꢃꢃ1).
methanolꢆ1 : 0—10 : 1) to afford 9 (862 mg, 63% yield) as a pale yellow
amorphous solid. H-NMR (400 MHz, CDCl3) d: 1.35 (3H, dd, Jꢆ7, 2 Hz),
1
4-{[Bis(allyloxy)phosphoryl]oxy}butanoic Acid (7) To a mixture of 6
(700 mg, 1.82 mmol) and anisole (0.7 ml) was added TFA (3 ml) at room 1.90—2.10 (2H, m), 2.46 (1H, dt, Jꢆ17, 7 Hz), 2.57 (1H, dt, Jꢆ 17, 7 Hz),
temperature. The mixture was stirred at room temperature for 15 min, then
3.04 (1H, tt, Jꢆ11, 5 Hz), 3.52 (2H, t, Jꢆ11 Hz), 3.90 (1H, q, Jꢆ7 Hz), 4.12
diluted with toluene (5 ml), and the solvent was distilled off under reduced (2H, q, Jꢆ7 Hz) 4.15—4.25 (2H, m), 4.55—4.60 (4H, m), 5.00 (1H, d, Jꢆ
pressure to give crude product of 7 as a pale yellow oil. The crude oil of 7
was used for the next step without further purification. H-NMR (400 MHz,
CDCl3) d: 2.03 (2H, quint, Jꢆ7 Hz), 2.51 (2H, t, Jꢆ7 Hz), 4.16 (2H, q, Jꢆ
7 Hz), 4.55—4.60 (4H, m), 5.29 (2H, br d, Jꢆ10 Hz), 5.39 (2H, br d, Jꢆ
17 Hz), 5.94 (2H, ddt, Jꢆ17, 10, 5 Hz), 11.29 (1H, br s).
4 Hz), 5.27 (2H, d, Jꢆ11 Hz), 5.35 (2H, s), 5.38 (2H, d, Jꢆ17 Hz), 5.85 (1H,
dd, Jꢆ15, 4 Hz), 5.90—6.00 (2H, m), 6.58 (1H, dd, Jꢆ16, 11 Hz), 6.74 (1H,
d, Jꢆ15 Hz), 6.85—6.95 (3H, m), 7.30—7.45 (3H, m), 7.57 (1H, t, Jꢆ8 Hz),
7.90 (1H, s), 7.92 (1H, s). IR (KBr) cmꢁ1: 2233, 1741, 1615, 1600, 1504.
MS m/z (FAB): 789 (Mꢃꢃ1).
1
(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)buta-1,3-
dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-
Disodium 4-{[(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)
buta-1,3-dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-1-
triazol-1-yl)butan-2-yl 4-{[Bis(allyloxy)phosphoryl]oxy}butanoate (9) (1H-1,2,4-triazol-1-yl)butan-2-yl]oxy}-4-oxobutyl Phosphate (2) Pyrro-
DMF (0.05 ml) and oxalyl chloride (350 mg, 2.76 mmol) were added to the lidine (644 mg, 9.06 mmol) was added to the solution of 9 (350 mg, 0.453
solution of 7 in CH2Cl2 (3.5 ml) and the mixture was stirred at room temper-
mmol), tetrakis(triphenylphosphine)palladium (5 mg, 0.0043 mmol), and
ature for 1 h, then toluene was added, and the mixture was concentrated triphenylphosphine (5 mg, 0.019 mmol) in CH2Cl2 (3 ml) at room tempera-
under reduced pressure to afford 8 as a crude material. Sodium hydride
(55% dispersion in mineral oil; 80 mg, 1.83 mmol) was added to the solution
of CS-758 (936 mg, 1.73 mmol) in THF (10 ml) at room temperature. The
mixture was stirred for 3 h. The obtained suspended mixture was cooled to
ture under N2 atomsphere. After the reaction mixture was stirred for 1 h, it
was diluted with toluene and the solvent was distilled off under reduced
pressure. The residue was purified by reverse phase column chromatography
using Cosmosil 75 C18-PREP (water : methanolꢆ1 : 0—4 : 6). The concen-
0 °C, and the crude material of 8 was added to the mixture. The mixture was trated eluates were passed through an ion exchange column of Dowex
stirred at room temperature for 30 min. After cooling, the mixture was parti- 50Wꢀ8 (Na form). The collected fractions were concentrated under reduced
tioned between EtOAc and an aqueous solution of ammonium chloride, and pressure and lyophilized to afford 2 (233 mg, 64% yield) as an amorphous
the organic layer was washed with brine, dried over anhydrous magnesium colorless solid. 1H-NMR (400 MHz, D2O) d: 1.13 (3H, d, Jꢆ7 Hz), 1.68
sulfate and the solvent was distilled off under reduced pressure. The oily (2H, quint, Jꢆ7 Hz), 2.35—2.50 (2H, m), 2.87 (1H, m), 3.43 (1H, t,
residue was purified by chromatography on silica gel (30 g) (EtOAc : Jꢆ12 Hz), 3.46 (1H, t, Jꢆ12 Hz), 3.55—3.65 (3H, m), 3.95—4.05 (2H, m),

800
Vol. 58, No. 6
zoate (21a) In a similar manner to 13, 21a was obtained from 18a in 24%
yield as a colorless oil. 1H-NMR (400 MHz, CDCl3) d: 3.81 (3H, s), 4.49—
4.54 (4H, m), 5.22—5.35 (6H, m), 5.33 (2H, dd, Jꢆ17, 1 Hz), 5.90 (2H, ddt,
Jꢆ17, 11, 5 Hz), 6.91 (2H, d, Jꢆ9 Hz), 7.10 (1H, t, Jꢆ8 Hz), 7.32 (1H, d,
4.97 (1H, d, Jꢆ4 Hz), 5.13 (1H, d, Jꢆ15 Hz), 5.26 (1H, d, Jꢆ15 Hz), 5.65
(1H, dd, Jꢆ15, 5 Hz), 6.42 (1H, dd, Jꢆ15, 10 Hz), 6.64 (1H, d, Jꢆ16 Hz),
6.80—6.90 (3H, m), 7.25—7.35 (3H, m), 7.51 (1H, t, Jꢆ7 Hz), 7.82 (1H, s),
8.13 (1H, s). IR (KBr) cmꢁ1: 3432, 2231, 1740, 1615, 1599, 1503, 1418,
1387, 1276, 1257, 1142. MS m/z (FAB): 753 (Mꢃꢃ1). Anal. Calcd for
C31H30F3N4O8PSNa2·3H2O: C, 46.16; H, 4.50; N, 6.95; Na, 5.70. Found: C,
46.41; H, 4.83; N, 7.04; Na, 5.37.
Jꢆ8 Hz), 7.39 (2H, d, Jꢆ9 Hz), 7.43 (1H, td, Jꢆ8.6 Hz). IR (CHCl3) cmꢁ1
1727, 1614, 1516, 1465, 1268, 1114, 1034. MS m/z (FAB): 451 (Mꢃꢃ1).
:
2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-6-fluorobenzoic Acid (22a)
In a similar manner to 7, 22a was obtained from 21a in quantitative yield as
a colorless oil. The crude product of 22a was used for the next step without
further purification.
4-Methoxybenzyl 2-({[Bis(allyloxy)phosphoryl]oxy}methyl)benzoate
(13) An aqueous solution (4.8 ml) of sodium hydroxide (0.56 g, 10 mmol)
was added to a solution of phthalide (1.34 g, 10 mmol) in THF (30 ml). After
the reaction mixture was stirred at room temperature for 3 h, the solution
was concentrated under reduced pressure, and the residue was dried using a
vacuum pump to give 11 as a crude material. 4-Methoxybenzyl chloride
(2.04 g, 13 mmol) was added to the solution of the crude material of 11 in
DMF (30 ml), and, and then the mixture was stirred at 80 °C for 1 h. After
cooling the mixture, a saturated NH4Cl solution was added to the mixture,
and the product was extracted with EtOAc. The organic layer was washed
with water and then with brine, and the solvent was distilled off under re-
duced pressure to afford crude product of 12 as the residue. The residue was
dissolved in CH2Cl2 (70 ml), and tetrazole (1.4 g, 20 mmol) and diallyl diiso-
propylphosphoramidite (2.45 g, 10 mmol) were added at 0 °C, then the mix-
ture was stirred at room temperature for 30 min, and methanol (0.1 ml) was
added to the mixture. The mixture was stirred for 5 min further, and tert-
butyl hydroperoxide (ca. 5 M nonane solution, 4.6 ml, ca. 23 mmol) was
added at 0 °C followed by stirring the mixture at room temperature for
30 min. Saturated NaHCO3 solution and an aqueous solution of sodium thio-
sulfate were added to the mixture, and the mixture was stirred for 10 min
and then partitioned between EtOAc and water. The organic layer was
washed successively with saturated NaHCO3 solution, saturated NH4Cl solu-
tion, and an aqueous solution of sodium chloride, and then dried over anhy-
drous MgSO4, and the solvent was distilled off under reduced pressure to
give an oily residue. The residue was chromatographed on silica gel
(EtOAc : hexaneꢆ2 : 3—1 : 1) to give 13 (1.76 g, 40% yield) as a colorless
(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)buta-1,3-
dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-
triazol-1-yl)butan-2-yl 2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-6-fluo-
robenzoate (24a) In a similar manner to 9, 24a was obtained from CS-758
and 22a in 51% yield as a pale yellow amorphous solid. 1H-NMR
(400 MHz, CDCl3) d: 1.43 (3H, dd, Jꢆ7, 1 Hz), 3.05 (1H, tt, Jꢆ11, 5 Hz),
3.44 (1H, t, Jꢆ11 Hz), 3.51 (1H, t, Jꢆ11 Hz), 3.98 (1H, q, Jꢆ7 Hz), 4.08
(1H, ddd, Jꢆ11, 5, 2 Hz), 4.18 (1H, ddd, Jꢆ11, 5, 2 Hz), 4.53—4.59 (4H,
m), 4.96 (1H, d, Jꢆ4 Hz), 5.24 (2H, dt, Jꢆ10, 1 Hz), 5.31—5.40 (4H, m),
5.44 (1H, d, Jꢆ15 Hz), 5.56 (1H, dd, Jꢆ15, 3 Hz), 5.83 (1H, dd, Jꢆ15,
4 Hz), 5.93 (2H, ddt, Jꢆ16, 10, 6 Hz), 6.55 (1H, dd, Jꢆ15, 11 Hz), 6.73 (1H,
d, Jꢆ16 Hz), 6.88—6.98 (2H, m), 6.93 (1H, dd, Jꢆ16, 11 Hz), 7.11 (1H, td,
Jꢆ8, 1 Hz), 7.34 (1H, dd, Jꢆ10, 1 Hz), 7.40 (1H, dd, Jꢆ8, 1 Hz), 7.48—
7.59 (4H, m), 7.88 (1H, s), 7.89 (1H, s). IR (CHCl3) cmꢁ1: 2233, 1727,
1614, 1504, 1277, 1140, 1034. MS m/z (FAB): 855 (Mꢃꢃ1).
Disodium 2-({[(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)
buta-1,3-dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-
1-(1H-1,2,4-triazol-1-yl)butan-2-yl]oxy}carbonyl)-3-fluorobenzyl Phos-
phate (17a) To a solution of 24a (650 mg, 0.76 mmol) in CH2Cl2 (20 ml),
dichlorobis(triphenylphosphine)palladium (16.0 mg, 0.023 mmol) was added
at room temperature. To this mixture, tri(n-butyl)tin hydride (786.7 mg,
2.70 mmol) was added over 10 min and stirred for 30 min. Hexane,
methanol, saturated NaHCO3 solution were added to the mixture, and the
aqueous layer was concentrated to afford crude residue. The residue was pu-
rified by reverse phase column chromatography using Cosmosil 75 C18-
PREP (Nacalai Tesque, Inc.; 15 g) (water : methanolꢆ4 : 6—3 : 7). The col-
lected fractions were concentrated under reduced pressure and lyophilized to
afford 17a (440.5 mg, 71% yield) as an amorphous colorless solid. 1H-NMR
(400 MHz, CD3OD) d: 1.39 (3H, dd, Jꢆ7, 1 Hz), 3.06 (1H, tt, Jꢆ11, 5 Hz),
3.25 (1H, t, Jꢆ11 Hz), 3.49 (1H, t, Jꢆ11 Hz), 3.94 (1H, ddd, Jꢆ11, 5, 2 Hz),
4.10 (1H, q, Jꢆ7 Hz), 4.15 (1H, ddd, Jꢆ11, 5, 2 Hz), 4.95 (1H, d, Jꢆ4 Hz),
5.03 (1H, dd, Jꢆ15, 5 Hz), 5.27 (1H, dd, Jꢆ15, 5 Hz), 5.52 (1H, dd, Jꢆ15,
3 Hz), 5.62 (1H, d, Jꢆ15 Hz), 5.83 (1H, dd, Jꢆ15, 4 Hz), 6.54 (1H, dd,
Jꢆ15, 11 Hz), 6.79 (1H, d, Jꢆ16 Hz), 6.99—7.15 (4H, m), 7.50—7.58 (3H,
m), 7.62 (1H, td, Jꢆ8, 6 Hz), 7.79 (1H, t, Jꢆ8 Hz), 7.88 (1H, d, Jꢆ8 Hz),
8.00 (1H, s), 8.33 (1H, s). IR (KBr) cmꢁ1: 2231, 1724, 1614, 1504, 1278,
1257, 1140, 1113, 1055, 975. MS m/z (FAB): 819 (Mꢃꢃ1). [a]D25 ꢃ56.4°
(cꢆ1.02, MeOH).
1
oil. H-NMR (400 MHz, CDCl3) d: 3.82 (3H, s), 4.57 (4H, m), 5.24 (2H, d,
Jꢆ10.3 Hz), 5.28 (2H, s), 5.35 (2H, d, Jꢆ19.0 Hz), 5.55 (2H, d, Jꢆ6.6 Hz),
5.93 (2H, ddd, Jꢆ 18.0, 10.3, 5.2 Hz), 6.92 (2H, d, Jꢆ8.8 Hz), 7.35—7.38
(1H, m), 7.38 (2H, d, Jꢆ8.8 Hz), 7.56 (1H, m), 7.69 (1H, d, Jꢆ7.3 Hz), 8.01
(1H, d, Jꢆ6.6 Hz). MS m/z (FAB): 433 (Mꢃꢃ1).
2-({[Bis(allyloxy)phosphoryl]oxy}methyl)benzoic Acid (14) In a simi-
lar manner to 7, 14 was obtained from 13 in quantitative yield as a colorless
oil. The crude product of 14 was used for the next step without further pu-
1
rification. H-NMR (400 MHz, CDCl3) d: 4.60—4.63 (4H, m), 5.27 (2H, d,
Jꢆ10.2 Hz), 5.28 (2H, d, Jꢆ16.9 Hz), 5.63 (2H, d, Jꢆ7.3 Hz), 5.95 (ddd,
Jꢆ16.9, 10.2, 5.3 Hz), 7.41—7.45 (1H, m), 7.60—7.63 (1H, m), 7.69—7.71
(1H, m), 8.10 (1H, d, Jꢆ8.1 Hz).
(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)buta-1,3-
dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-1-(1H-1,
2,4-triazol-1-yl)butan-2-yl 2-({[Bis(allyloxy)phosphoryl]oxy}methyl)ben-
zoate (16) In a similar manner to 9, 16 was obtained from 14 and CS-758
in 76% yield as a colorless amorphous solid. 1H-NMR (400 MHz, CDCl3) d:
1.45 (3H, dd, Jꢆ7, 2 Hz), 3.05 (1H, tt, Jꢆ11, 5 Hz), 3.50 (1H, t, Jꢆ11 Hz),
3.53 (1H, t, Jꢆ11 Hz), 4.01 (1H, q, Jꢆ7 Hz), 4.10—4.20 (2H, m), 4.50—
4.60 (4H, m), 4.99 (1H, d, Jꢆ4 Hz), 5.24 (2H, br d, Jꢆ10 Hz), 5.34 (2H,
br d, Jꢆ18 Hz), 5.40—5.55 (4H, m), 5.71 (1H, dd, Jꢆ15, 4 Hz), 5.85—6.00
(2H, m), 6.57 (1H, dd, Jꢆ15, 11 Hz), 6.73 (1H, d, Jꢆ15 Hz), 6.85—6.95
(3H, m), 7.34 (1H, dd, Jꢆ10, 1 Hz), 7.35—7.45 (3H, m), 7.57 (1H, t, Jꢆ
8 Hz), 7.62 (1H, td, Jꢆ7, 1 Hz), 7.72 (1H, d, Jꢆ8 Hz), 7.76 (1H, d, Jꢆ9 Hz),
7.90 (1H, s), 7.91 (1H, s). IR (KBr) cmꢁ1: 2231, 1724, 1615, 1504. MS m/z
(FAB): 837 (Mꢃꢃ1).
4-Methoxybenzyl 2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-5-fluoroben
-
zoate (21b) In a similar manner to 13, 21b was obtained from 18b in 27%
yield as a colorless oil. 1H-NMR (400 MHz, CDCl3) d: 3.82 (3H, s), 4.53—
4.58 (4H, m), 5.25 (2H, dq, Jꢆ10, 1 Hz), 5.28 (2H, s), 5.35 (2H, dq, Jꢆ17,
1 Hz), 5.49 (2H, d, Jꢆ7 Hz), 5.93 (2H, ddt, Jꢆ17, 10, 5 Hz), 6.92 (2H, d,
Jꢆ8 Hz), 7.25 (1H, td, Jꢆ8, 3 Hz), 7.38 (2H, d, Jꢆ8 Hz), 7.66 (1H, dd, Jꢆ8,
5 Hz), 7.69 (1H, dd, Jꢆ9, 3 Hz). IR (CHCl3) cmꢁ1: 1719, 1516, 1272, 1031,
989. MS m/z (FAB): 451 (Mꢃꢃ1).
2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-5-fluorobenzoic Acid (22b)
In a similar manner to 7, 22b was obtained from 21b in quantitative yield as
a colorless oil. The crude product of 22b was used for the next step without
further purification.
(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)buta-1,3-
dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-
triazol-1-yl)butan-2-yl 2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-5-fluo-
robenzoate (24b) In a similar manner to 9, 24b was obtained from CS-
758 and 22b in 56% yield as a pale yellow amorphous solid. 1H-NMR (400
MHz, CDCl3) d: 1.45 (3H, dd, Jꢆ7, 2 Hz), 3.03 (1H, tt, Jꢆ11, 4 Hz), 3.53
(1H, t, Jꢆ11 Hz), 3.53 (1H, t, Jꢆ11 Hz), 4.00 (1H, q, Jꢆ7 Hz), 4.15—4.20
(2H, m), 4.54—4.58 (4H, m), 5.00 (1H, d, Jꢆ4 Hz), 5.24 (2H, dd, Jꢆ10,
1 Hz), 5.35 (2H, dd, Jꢆ18, 1 Hz), 5.40—5.49 (4H, m), 5.85 (1H, dd, Jꢆ15,
4 Hz), 5.92 (2H, ddt, Jꢆ18, 10, 5 Hz), 6.58 (1H, dd, Jꢆ15, 11 Hz), 6.73 (1H,
d, Jꢆ16 Hz), 6.90—7.00 (3H, m), 7.29—7.38 (3H, m), 7.40 (1H, dd, Jꢆ8,
1 Hz), 7.53—7.60 (2H, m), 7.69 (1H, dd, Jꢆ9, 6 Hz), 7.90 (1H, s), 7.93 (1H,
s). IR (CHCl3) cmꢁ1: 2233, 1728, 1615, 1504, 1276, 1139, 1025. MS m/z
(FAB): 855 (Mꢃꢃ1).
Disodium 2-({[(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)
buta-1,3-dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-1-
(1H-1,2,4-triazol-1-yl)butan-2-yl]oxy}carbonyl)benzyl Phosphate (3) In
a similar manner to 2, 3 was obtained from 16 in 76% yield as a colorless
1
amorphous solid. H-NMR (400 MHz, D2O) d: 1.27 (3H, d, Jꢆ7 Hz), 2.95
(1H, m), 3.40 (1H, t, Jꢆ11 Hz), 3.45 (1H, t, Jꢆ11 Hz), 3.79 (1H, q,
Jꢆ7 Hz), 3.93 (1H, m), 4.05 (1H, m), 4.90 (1H, dd, Jꢆ16, 7 Hz), 4.95 (1H,
d, Jꢆ5 Hz), 5.03 (1H, dd, Jꢆ16, 7 Hz), 5.35 (1H, d, Jꢆ15 Hz), 5.44 (1H,
br d, Jꢆ15 Hz), 5.67 (1H, m), 6.34 (1H, m), 6.68 (1H, br d, Jꢆ15 Hz),
6.85—7.00 (3H, m), 7.20—7.30 (1H, m), 7.30—7.45 (3H, m), 7.50—7.65
(3H, m), 7.76 (1H, d, Jꢆ8 Hz), 7.84 (1H, s), 8.23 (1H, s). IR (KBr) cmꢁ1
:
3414, 2231, 1722, 1615, 1503, 1418, 1387, 1275, 1257, 1205, 1139. MS m/z
(FAB): 801 (Mꢃꢃ1). Anal. Calcd for C35H30F3N4O8PSNa2·4H2O: C, 48.17;
H, 4.39; N, 6.24; Na, 5.27. Found: C, 47.94; H, 4.31; N, 6.39; Na, 5.07.
4-Methoxybenzyl 2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-6-fluoroben-

June 2010
801
Disodium 2-({[(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)
buta-1,3-dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)
-1-(1H-1,2,4-triazol-1-yl)butan-2-yl]oxy}carbonyl)-4-fluorobenzyl
Phosphate (17b) In a similar manner to 17a, 17b was obtained from 24b
in 13% yield as a colorless solid. 1H-NMR (400 MHz, CD3OD) d: 1.41 (3H,
dd, Jꢆ7, 1 Hz), 3.02 (1H, tt, Jꢆ11, 5 Hz), 3.49 (1H, t, Jꢆ11 Hz), 3.54 (1H,
t, Jꢆ11 Hz), 4.04 (1H, q, Jꢆ7 Hz), 4.08 (1H, ddd, Jꢆ11, 5, 2 Hz), 4.17 (1H,
ddd, Jꢆ11, 5, 2 Hz), 5.02 (1H, d, Jꢆ5 Hz), 5.18 (1H, dd, Jꢆ16, 6 Hz), 5.30
(1H, dd, Jꢆ16, 6 Hz), 5.51 (1H, dd, Jꢆ15, 3 Hz), 5.59 (1H, d, Jꢆ15 Hz),
5.86 (1H, dd, Jꢆ15, 5 Hz), 6.58 (1H, dd, Jꢆ15, 11 Hz), 6.79 (1H, d, Jꢆ15 Hz),
7.03—7.13 (3H, m), 7.33 (1H, td, Jꢆ9, 3 Hz), 7.43 (1H, dd, Jꢆ10, 3 Hz),
7.49—7.58 (3H, m), 7.79 (1H, t, Jꢆ8 Hz), 7.99 (1H, s), 8.10 (1H, dd,
Jꢆ9, 6 Hz), 8.36 (1H, s). IR (KBr) cmꢁ1: 2231, 1727, 1614, 1503, 1275, 1199,
1140, 1052, 975. MS m/z (FAB): 819 (Mꢃꢃ1). [a]D25 ꢃ22.8° (cꢆ0.94,
MeOH).
4-Methoxybenzyl 2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-4-fluoroben-
zoate (21c) In a similar manner to 13, 21c was obtained from 18c in 46%
yield as a colorless oil. 1H-NMR (400 MHz, CDCl3) d: 3.82 (3H, s), 4.58—
4.61 (4H, m), 5.26 (2H, s), 5.26 (2H, dq, Jꢆ11, 1 Hz), 5.38 (2H, dq, Jꢆ17,
1 Hz), 5.54 (2H, d, Jꢆ7 Hz), 5.95 (2H, ddt, Jꢆ17, 11, 5 Hz), 6.91 (2H, d,
Jꢆ9 Hz), 7.02 (1H, td, Jꢆ9.2 Hz), 7.37 (2H, d, Jꢆ9 Hz), 7.43 (1H, dd,
Jꢆ10, 2 Hz), 8.06 (1H, dd, Jꢆ9, 6 Hz). IR (CHCl3) cmꢁ1: 1714, 1613, 1590,
1516, 1261, 1120, 1031. MS m/z (FAB): 451 (Mꢃꢃ1).
ddd, Jꢆ12, 5, 2 Hz), 4.18 (1H, ddd, Jꢆ12, 5, 2 Hz), 4.44—4.56 (4H, m),
4.97 (1H, d, Jꢆ4 Hz), 5.21 (2H, d, Jꢆ10 Hz), 5.31 (2H, d, Jꢆ17 Hz), 5.43—
5.54 (4H, m), 5.83 (1H, dd, Jꢆ15, 4 Hz), 5.89 (2H, ddt, Jꢆ17, 10, 5 Hz),
6.55 (1H, dd, Jꢆ15, 11 Hz), 6.73 (1H, d, Jꢆ15 Hz), 6.87—6.93 (3H, m),
7.29—7.35 (2H, m), 7.39—7.49 (4H, m), 7.57 (1H, t, Jꢆ8 Hz), 7.93 (1H, s),
8.00 (1H, s). IR (CHCl3) cmꢁ1: 2233, 1732, 1504, 1462, 1276, 1141, 1023,
991. MS m/z (FAB): 855 (Mꢃꢃ1).
Disodium 2-({[(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)
buta-1,3-dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-
1-(1H-1,2,4-triazol-1-yl)butan-2-yl]oxy}carbonyl)-6-fluorobenzyl Phos-
phate (17d) In a similar manner to 17a, 17d was obtained from 24d in
1
75% yield as a colorless solid. H-NMR (400 MHz, CD3OD) d: 1.43 (3H,
dd, Jꢆ7, 1 Hz), 2.98 (1H, tt, Jꢆ11, 5 Hz), 3.48 (1H, t, Jꢆ11 Hz), 3.53 (1H,
t, Jꢆ11 Hz), 4.03 (1H, q, Jꢆ7 Hz), 4.05 (1H, ddd, Jꢆ11, 5, 2 Hz), 4.14 (1H,
ddd, Jꢆ11, 5, 2 Hz), 5.00 (1H, d, Jꢆ4 Hz), 5.25 (1H, dd, Jꢆ12, 5 Hz), 5.32
(1H, ddd, Jꢆ12, 5, 2 Hz), 5.52 (1H, dd, Jꢆ15, 3 Hz), 5.69 (1H, d, Jꢆ15 Hz),
5.84 (1H, dd, Jꢆ15, 4 Hz), 6.56 (1H, dd, Jꢆ15, 10 Hz), 6.78 (1H, d,
Jꢆ15 Hz), 7.00—7.13 (2H, m), 7.09 (1H, dd, Jꢆ15, 10 Hz), 7.34 (1H, t,
Jꢆ9 Hz), 7.42 (1H, td, Jꢆ8, 5 Hz), 7.49—7.54 (2H, m), 7.62—7.70 (2H, m),
7.78 (1H, t, Jꢆ8 Hz), 7.96 (1H, s), 8.70 (1H, s). IR (KBr) cmꢁ1: 2230, 1731,
1614, 1504, 1275, 1142, 1048, 975. MS m/z (FAB): 819 (Mꢃꢃ1). [a]D25
ꢃ5.4° (cꢆ0.91, MeOH).
4-Methoxybenzyl 2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-5-cyanoben-
zoate (21h) In a similar manner to 13, 21h was obtained from 18h in 15%
yield as a colorless oil. 1H-NMR (400 MHz, CDCl3) d: 3.83 (3H, s), 4.57—
4.61 (4H, m), 5.27 (2H, dd, Jꢆ11, 1 Hz), 5.29 (2H, s), 5.37 (2H, dd, Jꢆ17,
1 Hz), 5.58 (2H, d, Jꢆ7 Hz), 5.94 (2H, ddt, Jꢆ17, 11, 5 Hz), 6.94 (2H, d,
Jꢆ9 Hz), 7.38 (2H, d, Jꢆ9 Hz), 7.83 (1H, dd, Jꢆ8, 1 Hz), 7.87 (1H, d,
Jꢆ8 Hz), 8.30 (1H, d, Jꢆ1 Hz). IR (CHCl3) cmꢁ1: 2236, 1722, 1516, 1255,
1175, 1031. MS m/z (FAB): 458 (Mꢃꢃ1).
2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-5-cyanobenzoic Acid (22h)
In a similar manner to 7, 22h was obtained from 21h in quantitative yield as
a colorless oil. The crude product of 22h was used for the next step without
further purification.
2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-4-fluorobenzoic Acid (22c)
In a similar manner to 7, 22c was obtained from 21c in quantitative yield as
a colorless oil. The crude product of 22c was used for the next step without
further purification.
(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)buta-1,3-
dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-
triazol-1-yl)butan-2-yl 2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-4-fluo-
robenzoate (24c) In a similar manner to 9, 24c was obtained from CS-758
and 22c in 55% yield as a pale yellow amorphous solid. 1H-NMR (400 MHz,
CDCl3) d: 1.45 (3H, dd, Jꢆ7, 2 Hz), 3.03 (1H, tt, Jꢆ11, 5 Hz), 3.50 (1H, t,
Jꢆ11 Hz), 3.53 (1H, t, Jꢆ11 Hz), 4.01 (1H, q, Jꢆ7 Hz), 4.10—4.20 (2H,
m), 4.57—5.61 (4H, m), 4.99 (1H, d, Jꢆ4 Hz), 5.26 (2H, dt, Jꢆ10, 1 Hz),
5.37 (2H, dt, Jꢆ17, 1 Hz) 5.41—5.52 (4H, m), 5.84 (1H, dd, Jꢆ15, 4 Hz),
5.95 (2H, ddt, Jꢆ17, 10, 5 Hz), 6.57 (1H, dd, Jꢆ15, 11 Hz), 6.74 (1H, d, Jꢆ
15 Hz), 6.89—6.94 (2H, m), 6.94 (1H, dd, Jꢆ15, 11 Hz), 7.06 (1H, td, Jꢆ8,
3 Hz), 7.26—7.41 (3H, m), 7.46 (1H, dd, Jꢆ10, 3 Hz), 7.57 (1H, t, Jꢆ8 Hz),
7.81 (1H, dd, Jꢆ8, 6 Hz), 7.89 (1H, s), 7.89 (1H, s). IR (CHCl3) cmꢁ1: 2232,
1721, 1614, 1590, 1504, 1275, 1140, 1028. MS m/z (FAB): 855 (Mꢃꢃ1).
Disodium 2-({[(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)
buta-1,3-dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-1-
(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)buta-1,3-
dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-1-(1H-1,
2,4-triazol-1-yl)butan-2-yl 2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-5-
cyanobenzoate (24h) In a similar manner to 9, 24h was obtained from
1
CS-758 and 22h in 23% yield as a pale yellow amorphous solid. H-NMR
(400 MHz, CDCl3) d: 1.45 (3H, dd, Jꢆ7, 2 Hz), 3.02 (1H, tt, Jꢆ12, 5 Hz),
3.54 (1H, t, Jꢆ12 Hz), 3.55 (1H, t, Jꢆ12 Hz), 4.00 (1H, q, Jꢆ7 Hz), 4.14—
4.19 (2H, m), 4.58—4.61 (4H, m), 5.01 (1H, d, Jꢆ4 Hz), 5.26 (2H, dd, Jꢆ
10, 1 Hz), 5.36 (2H, d, Jꢆ17 Hz), 5.47 (2H, s), 5.52 (2H, d, Jꢆ7 Hz), 5.87
(1H, dd, Jꢆ15, 4 Hz), 5.94 (2H, ddt, Jꢆ17, 10, 6 Hz), 6.58 (1H, dd, Jꢆ15,
11 Hz), 6.73 (1H, d, Jꢆ16 Hz), 6.90—7.00 (3H, m), 7.31—7.37 (2H, m),
7.40 (1H, dd, Jꢆ8, 1 Hz), 7.57 (1H, t, Jꢆ8 Hz), 7.88—7.92 (4H, m), 8.18
(1H, s). IR (KBr) cmꢁ1: 2232, 1731, 1615, 1504, 1276, 1142, 1027. MS m/z
(FAB): 862 (Mꢃꢃ1).
(1H-1,2,4-triazol-1-yl)butan-2-yl]oxy}carbonyl)-5-fluorobenzyl
Phos-
phate (17c) In a similar manner to 17a, 17c was obtained from 24c in 64%
yield as a colorless solid. 1H-NMR (400 MHz, CD3OD) d: 1.41 (3H, dd,
Jꢆ7, 1 Hz), 3.04 (1H, tt, Jꢆ11, 4 Hz), 3.48 (1H, t, Jꢆ11 Hz), 3.54 (1H, t,
Jꢆ11 Hz), 4.05 (1H, q, Jꢆ7 Hz), 4.08 (1H, ddd, Jꢆ11, 4, 2 Hz), 4.17 (1H,
ddd, Jꢆ11, 4, 2 Hz), 5.03 (1H, d, Jꢆ5 Hz), 5.20 (1H, dd, Jꢆ17, 5 Hz), 5.34
(1H, dd, Jꢆ17, 5 Hz), 5.50 (1H, dd, Jꢆ15, 3 Hz), 5.58 (1H, d, Jꢆ15 Hz),
5.87 (1H, dd, Jꢆ15, 5 Hz), 6.58 (1H, dd, Jꢆ15, 11 Hz), 6.80 (1H, d,
Jꢆ15 Hz), 6.98—7.05 (3H, m), 7.10 (1H, dd, Jꢆ15, 11 Hz), 7.48—7.54
(3H, m), 7.77—7.81 (2H, m), 7.87 (1H, dd, Jꢆ10, 3 Hz), 7.96 (1H, s), 8.31
(1H, s). IR (KBr) cmꢁ1: 2231, 1724, 1613, 1503, 1256, 1140, 1117, 1051,
977. MS m/z (FAB): 819 (Mꢃꢃ1). [a]D25 ꢃ28.3° (cꢆ0.86, MeOH).
4-Methoxybenzyl 2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-3-fluoroben-
zoate (21d) In a similar manner to 13, 21d was obtained from 18d in 31%
yield as a colorless oil. 1H-NMR (400 MHz, CDCl3) d: 3.82 (3H, s), 4.49—
4.53 (4H, m), 5.22 (2H, d, Jꢆ10, 1 Hz), 5.31 (2H, s), 5.33 (2H, d, Jꢆ17,
1 Hz), 5.52 (2H, dd, Jꢆ7, 1 Hz), 5.91 (2H, ddt, Jꢆ17, 10, 5 Hz), 6.91 (2H, d,
Jꢆ8 Hz), 7.25 (1H, dt, Jꢆ1,8 Hz), 7.37—7.42 (1H, m), 7.39 (2H, d, Jꢆ
8 Hz), 7.72 (1H, d, Jꢆ8 Hz). IR (CHCl3) cmꢁ1: 1724, 1516, 1462, 1272,
1171, 1029. MS m/z (FAB): 451 (Mꢃꢃ1).
2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-3-fluorobenzoic acid (22d)
In a similar manner to 7, 22d was obtained from 21d in quantitative yield as
a colorless oil. The crude product of 22d was used for the next step without
further purification.
(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)buta-1,3-
dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-
triazol-1-yl)butan-2-yl 2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-3-fluo-
robenzoate (24d) In a similar manner to 9, 24d was obtained from CS-
758 and 22d in 55% yield as a pale yellow amorphous solid. 1H-NMR (400
MHz, CDCl3) d: 1.44 (3H, dd, Jꢆ7, 2 Hz), 3.03 (1H, tt, Jꢆ12, 5 Hz), 3.46
(1H, t, Jꢆ12 Hz), 3.51 (1H, t, Jꢆ12 Hz), 3.99 (1H, q, Jꢆ7 Hz), 4.09 (1H,
Disodium 4-Cyano-2-({[(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-cyano-2-flu-
orophenyl)buta-1,3-dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluo-
rophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-yl]oxy}carbonyl)benzyl Phos-
phate (17h) In a similar manner to 17a, 17h was obtained from 24h in
1
39% yield as a colorless solid. H-NMR (400 MHz, CD3OD) d: 1.41 (3H,
dd, Jꢆ7, 1 Hz), 3.04 (1H, tt, Jꢆ11, 5 Hz), 3.48 (1H, t, Jꢆ11 Hz), 3.54 (1H,
t, Jꢆ11 Hz), 4.01 (1H, q, Jꢆ7 Hz), 4.05 (1H, ddd, Jꢆ11, 5, 2 Hz), 4.18 (1H,
ddd, Jꢆ11, 5, 2 Hz), 5.01 (1H, d, Jꢆ4 Hz), 5.25 (1H, dd, Jꢆ18, 6 Hz), 5.39
(1H, dd, Jꢆ18, 5 Hz), 5.52 (1H, dd, Jꢆ15, 3 Hz), 5.58 (1H, d, Jꢆ15 Hz),
5.90 (1H, dd, Jꢆ15, 4 Hz), 6.58 (1H, dd, Jꢆ15, 11 Hz), 6.79 (1H, d, Jꢆ
16 Hz), 7.02—7.12 (3H, m), 7.50—7.54 (3H, m), 7.78 (1H, t, Jꢆ8 Hz), 7.93
(1H, dd, Jꢆ8, 2 Hz), 8.01 (2H, s), 8,31 (1H, d, Jꢆ8 Hz), 8.40 (1H, s). IR
(KBr) cmꢁ1: 3423, 2232, 1729, 1615, 1504, 1141, 1054, 976. MS m/z
(FAB): 826 (Mꢃꢃ1). [a]D25 ꢃ31.2° (cꢆ0.73, MeOH).
4-Methoxybenzyl 2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-4-cyanoben-
zoate (21i) In a similar manner to 13, 21i was obtained from 18i in 26%
yield as a colorless oil. 1H-NMR (400 MHz, CDCl3) d: 3.82 (3H, s), 4.58—
4.62 (4H, m), 5.29 (2H, dd, Jꢆ10, 1 Hz), 5.29 (2H, s), 5.39 (2H, dd, Jꢆ17,
1 Hz), 5.53 (2H, d, Jꢆ7 Hz), 5.96 (2H, ddt, Jꢆ17, 10, 5 Hz), 6.92 (2H, d, Jꢆ
9 Hz), 7.37 (2H, d, Jꢆ9 Hz), 7.65 (1H, dd, Jꢆ8, 2 Hz), 8.00 (1H, br s), 8.09
(1H, d, Jꢆ8 Hz). IR (CHCl3) cmꢁ1: 2237, 1721, 1613, 1516, 1266, 1031,
990. MS m/z (FAB): 458 (Mꢃꢃ1).
2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-4-cyanobenzoic Acid (22i)
In a similar manner to 7, 22i was obtained from 21i in quantitative yield as a
colorless oil. The crude product of 22i was used for the next step without
further purification.

802
Vol. 58, No. 6
(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)buta-1,3-
dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-1-(1H-
To a solution of 28e (2.62 g, 7.88 mmol) in acetone (25 ml) was added Jones
reagent (ca. 32 mmol) at 0 °C and the reaction mixture was stirred at room
1,2,4-triazol-1-yl)butan-2-yl 2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-4- temperature for 1 h. Then 2-propanol (1 ml) was added to the reaction mix-
cyanobenzoate (24i) In a similar manner to 9, 24i was obtained from CS- ture. The insoluble material was filtered off, and then the filtrate was concen-
758 and crude 22i in 54% yield as a pale yellow amorphous solid. 1H-NMR trated under reduced pressure to give an oily residue. The residue was puri-
(400 MHz, CDCl3) d: 1.43 (3H, dd, Jꢆ7, 2 Hz), 3.01 (1H, tt, Jꢆ11, 5 Hz),
3.48 (1H, t, Jꢆ11 Hz), 3.52 (1H, t, Jꢆ11 Hz), 4.01 (1H, q, Jꢆ7 Hz), 4.09
fied by flash chromatography on silica gel (EtOAc : CH2Cl2ꢆ1 : 10—1 : 1) to
afford 29e (2.065 g, 76% yield) as a pale brown oil. 1H-NMR (400 MHz,
(1H, ddd, Jꢆ11, 5, 2 Hz), 4.17 (1H, ddd, Jꢆ11, 5, 2 Hz), 4.56—4.62 (4H, CDCl3) d: 4.50—4.62 (4H, m), 5.23 (2H, br d, Jꢆ10 Hz), 5.34 (2H, dq, Jꢆ
m), 4.99 (1H, d, Jꢆ4 Hz), 5.29 (2H, d, Jꢆ11 Hz), 5.38 (2H, dd, Jꢆ17, 1 Hz),
5.45—5.50 (4H, m), 5.83 (1H, dd, Jꢆ15, 4 Hz), 5.95 (2H, ddt, Jꢆ17, 11, 5
17, 1 Hz), 5.64 (2H, dd, Jꢆ7, 2 Hz), 5.91 (2H, ddt, Jꢆ17, 10, 6 Hz), 7.39
(1H, t, Jꢆ8 Hz), 7.57 (1H, d, Jꢆ8 Hz), 7.81 (1H, d, Jꢆ8 Hz). IR (CHCl3)
Hz), 6.56 (1H, dd, Jꢆ15, 10 Hz), 6.75 (1H, d, Jꢆ16 Hz), 6.93—6.96 (2H, cmꢁ1: 2951, 1727, 1267, 1025. MS m/z (FAB): 347 (Mꢃꢃ1).
m), 6.94 (1H, dd, Jꢆ16, 10 Hz), 7.33—7.39 (2H, m), 7.40 (1H, dd, Jꢆ8, 1
Hz), 7.58 (1H, t, Jꢆ8 Hz), 7.69 (1H, dd, Jꢆ8, 1 Hz), 7.82 (1H, d, Jꢆ8 Hz),
7.87 (1H, s), 7.91 (1H, s), 8.03 (1H, s). IR (CHCl3) cmꢁ1: 2235, 1729, 1616,
1504, 1277, 1141, 1028, 991. MS m/z (FAB): 862 (Mꢃꢃ1).
(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)buta-1,3-
dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-1-(1H-1,
2,4-triazol-1-yl)butan-2-yl 2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-3-
chlorobenzoate (31e) In a similar manner to 9, 31e was obtained from
1
Disodium 5-Cyano-2-({[(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-cyano-2-flu- CS-758 and crude 31e in 72% yield as a pale yellow amorphous solid. H-
orophenyl)buta-1,3-dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluo-
rophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-yl]oxy}carbonyl)benzyl Phos- 5 Hz), 3.45 (1H, t, Jꢆ11 Hz), 3.51 (1H, t, Jꢆ11 Hz), 4.00 (1H, q, Jꢆ7 Hz),
NMR (400 MHz, CDCl3) d: 1.44 (3H, dd, Jꢆ7, 2 Hz), 3.02 (1H, tt, Jꢆ11,
phate (17i) In a similar manner to 17a, 17i was obtained from 24i in 79%
4.07 (1H, ddd, Jꢆ11, 5, 2 Hz), 4.18 (1H, ddd, Jꢆ11, 5, 2 Hz), 4.45—4.58
yield as a colorless solid. 1H-NMR (400 MHz, CD3OD) d: 1.40 (3H, dd, Jꢆ (4H, m), 4.96 (1H, d, Jꢆ4 Hz), 5.20 (2H, br d, Jꢆ10 Hz), 5.31 (2H, br d, Jꢆ
7, 1 Hz), 3.02 (1H, tt, Jꢆ11, 5 Hz), 3.45 (1H, t, Jꢆ11 Hz), 3.53 (1H, t, Jꢆ 17 Hz), 5.45 (1H, dd, Jꢆ15, 3 Hz), 5.51 (1H, d, Jꢆ15 Hz), 5.56 (1H, dd, Jꢆ
11 Hz), 4.00 (1H, q, Jꢆ7 Hz), 4.02 (1H, ddd, Jꢆ11, 5, 2 Hz), 4.16 (1H, ddd, 10, 6 Hz), 5.59 (1H, dd, Jꢆ10, 6 Hz), 5.82 (1H, dd, Jꢆ15, 4 Hz), 5.85—5.94
Jꢆ11, 5, 2 Hz), 5.01 (1H, d, Jꢆ4 Hz), 5.21 (1H, dd, Jꢆ17, 5 Hz), 5.36 (1H,
dd, Jꢆ17, 6 Hz), 5.55 (2H, s), 5.86 (1H, dd, Jꢆ15, 4 Hz), 6.57 (1H, dd, Jꢆ Jꢆ16, 11 Hz), 6.87—7.03 (2H, m), 7.32—7.50 (5H, m), 7.57 (1H, t, Jꢆ8
15, 11 Hz), 6.80 (1H, d, Jꢆ15 Hz), 7.02—7.08 (2H, m), 7.10 (1H, dd, Jꢆ15, Hz), 7.63 (1H, dd, Jꢆ8, 1 Hz), 7.94 (1H, s), 8.00 (1H, s). IR (CHCl3) cmꢁ1
(2H, m), 6.55 (1H, dd, Jꢆ15, 11 Hz), 6.73 (1H, d, Jꢆ16 Hz), 6.95 (1H, dd,
:
11 Hz), 7.49—7.58 (3H, m), 7.66 (1H, dd, Jꢆ8, 1 Hz), 7.80 (1H, t, Jꢆ8 Hz),
7.83 (1H, d, Jꢆ8 Hz), 7.96 (1H, s), 8.37 (1H, s), 8.50 (1H, s). IR (KBr)
cmꢁ1: 3422, 2232, 1731, 1615, 1503, 1276, 1257, 1140, 1053, 977. MS m/z
(FAB): 826 (Mꢃꢃ1). [a]D25 ꢃ31.7° (cꢆ0.97, MeOH).
2233, 1732, 1504, 1276, 1140, 1019, 991. MS m/z (FAB): 871 (Mꢃꢃ1).
Disodium 2-Chloro-6-({[(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-
fluorophenyl)buta-1,3-dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluo-
rophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-yl]oxy}carbonyl)benzyl Phos-
[2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-6-chlorophenyl]methanol phate (17e) In a similar manner to 17a, 17e was obtained from 31e in 30%
(26e) Imidazole (1.19 g, 17.5 mmol) and tert-butylchlorodimethylsilane yield as a colorless solid. 1H-NMR (400 MHz, CD3OD) d: 1.42 (3H, dd, Jꢆ
(2.64 g, 17.5 mmol) were added to
a
solution of 3-chloro-1,2-benzene-
7, 2 Hz), 2.98 (1H, tt, Jꢆ11, 5 Hz), 3.46 (1H, t, Jꢆ11 Hz), 3.52 (1H, t,
Jꢆ11 Hz), 4.00—4.06 (2H, m), 4.14 (1H, ddd, Jꢆ11, 5, 2 Hz), 5.00 (1H, d,
dimethanol (25e, 3.02 g, 17.5 mmol) in THF (40 ml) at 0 °C and the mixture
was stirred at room temperature for 1 h. Then the reaction mixture was Jꢆ4 Hz), 5.35 (1H, dd, Jꢆ11, 4 Hz), 5.42 (1H, dd, Jꢆ11, 4 Hz), 5.53 (1H,
poured into ice-water and the aqueous water was extracted with EtOAc. The dd, Jꢆ15, 3 Hz), 5.67 (1H, d, Jꢆ15 Hz), 5.83 (1H, dd, Jꢆ15, 4 Hz), 6.55
combined organic layer was washed with brine, and dried over MgSO4. The
solvent was removed under reduced pressure and the residue was purified by (1H, t, Jꢆ8 Hz), 7.49—.54 (2H, m), 7.62—7.71 (3H, m), 7.78 (1H, t,
flash chromatography on silica gel (EtOAc : hexaneꢆ1 : 5) to afford 26e
Jꢆ8 Hz), 7.98 (1H, s), 8.63 (1H, s). IR (KBr) cmꢁ1: 2231, 1732, 1615, 1503,
(1H, dd, Jꢆ15, 11 Hz), 6.78 (1H, d, Jꢆ15 Hz), 7.00—7.16 (3H, m), 7.38
1
(3.69 g, 73% yield) as a colorless oil. H-NMR (400 MHz, CDCl3) d: 0.13 1275, 1257, 1142, 1105, 1048, 974. MS m/z (FAB): 835 (Mꢃꢃ1). [a]D25
(6H, s), 0.92 (9H, s), 2.93 (1H, t, Jꢆ7 Hz), 4.83 (2H, s), 4.86 (2H, d, Jꢆ7
Hz), 7.19—7.25 (2H, m), 7.37 (1H, dd, Jꢆ8, 2 Hz). IR (CHCl3) cmꢁ1: 2959,
2931, 1732, 1257, 1049, 839. MS m/z (FAB): 287 (Mꢃꢃ1).
ꢃ7.7° (cꢆ1.20, MeOH).
[2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-6-methylphenyl]methanol
(26f) In a similar manner to 26e, 26f was obtained from 25f in 68% yield
as a colorless oil. 1H-NMR (400 MHz, CDCl3) d: 0.13 (6H, s), 0.92 (9H, s),
Diallyl 2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-6-chlorobenzyl Phos-
phate (27e) Tetrazole (2.23 g, 31.9 mmol) and diallyl diisopropylphospho- 2.46 (3H, s), 3.04 (1H, t, Jꢆ6 Hz), 4.72 (2H, d, Jꢆ6 Hz), 4.80 (2H, s), 7.11
ramidite (3.91 g, 16.0 mmol), were added to the solution of 26e (3.66 g,
(1H, dd, Jꢆ6, 2 Hz), 7.15—7.19 (2H, m). IR (CHCl3) cmꢁ1: 3459, 1732,
12.8 mmol) in CH2Cl2 at 0 °C. The mixture was warmed to room tempera- 1599, 1471, 1257, 1061, 1038, 1005, 840. MS m/z (FAB): 267 (Mꢃꢃ1).
ture, then stirred for 30 min, and methanol (0.1 ml) was added. The mixture
Diallyl 2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-6-methylbenzyl Phos-
phate (27f) In a similar manner to 27e, 27f was obtained from 26f in 74%
was stirred for 5 min further, and tert-butyl hydroperoxide (ca. 80% di-tert-
butylperoxide solution, 1.8 g, ca. 16 mmol) was added at 0 °C followed by yield as a colorless oil. 1H-NMR (400 MHz, CDCl3) d: 0.09 (6H, s), 0.93
stirring the mixture at room temperature for 30 min. Saturated NaHCO3
(9H, s), 2.44 (3H, s), 4.45—4.51 (4H, m), 4.86 (2H, s), 5.20—5.25 (4H, m),
solution and saturated Na2S2O3 solution were added to reaction mixture and 5.32 (2H, dq, Jꢆ17, 1 Hz), 5.89 (2H, ddt, Jꢆ17, 10, 6 Hz), 7.13 (1H, d, Jꢆ7
the reaction mixture was stirred for 10 min. Water and EtOAc were added to Hz), 7.25 (1H, t, Jꢆ7 Hz), 7.32 (1H, d, Jꢆ7 Hz). IR (CHCl3) cmꢁ1: 1598,
the reacton mixture. The combined organic layer was washed with water and 1732, 1471, 1464, 1258, 1005. MS m/z (FAB): 427 (Mꢃꢃ1).
brine, and then dried over MgSO4, and the solvent was distilled off under
Diallyl 2-(Hydroxymethyl)-6-methylbenzyl Phosphate (28f) In a sim-
reduced pressure to give an oily residue. The residue was chromatographed ilar manner to 28e, 28f was obtained from 27f in 87% yield as a colorless
on silica gel (EtOAc : hexaneꢆ1 : 5—2 : 3) to give 27e (4.52 g, 79% yield) as
oil. 1H-NMR (400 MHz, CDCl3) d: 2.46 (3H, s), 3.33 (1H, t, Jꢆ6 Hz),
4.36—4.49 (4H, m), 4.75 (2H, d, Jꢆ6 Hz), 5.22 (2H, br d, Jꢆ11 Hz), 5.30
a colorless oil. 1H-NMR (400 MHz, CDCl3) d: 0.11 (6H, s), 0.94 (9H, s),
4.51—4.55 (4H, m), 4.88 (2H, s), 5.23 (2H, br d, Jꢆ10 Hz), 5.30 (2H, d, Jꢆ (2H, dq, Jꢆ17, 1 Hz), 5.32 (2H, d, Jꢆ10 Hz), 5.86 (2H, ddt, Jꢆ17, 11, 5
7 Hz), 5.34 (2H, dq, Jꢆ17, 1 Hz), 5.91 (2H, ddt, Jꢆ17, 10, 5 Hz), 7.28— Hz), 7.18 (1H, t, Jꢆ4 Hz), 7.26—7.28 (2H, m). IR (CHCl3) cmꢁ1: 3607,
7.34 (2H, m), 7.44 (1H, d, Jꢆ7 Hz). IR (CHCl3) cmꢁ1: 2956, 2931, 1259,
1018, 989, 839. MS m/z (FAB): 447 (Mꢃꢃ1).
1732, 1598, 1466, 1266, 1006. MS m/z (FAB): 313 (Mꢃꢃ1).
2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-3-methylbenzoic Acid (29f)
Diallyl 2-Chloro-6-(hydroxymethyl)benzyl Phosphate (28e) Tetra- In a similar manner to 29e, 29f was obtained from 28f in 71% yield as a col-
butylammonium fluoride (1 N THF solution; 10 ml, 10 mmol) was added to a
solution of 27e (4.41 g, 9.87 mmol) in THF (50 ml). The mixture was stirred
orless oil. 1H-NMR (400 MHz, CDCl3) d ppm: 2.49 (3H, s), 4.43—4.55
(4H, m), 5.22 (2H, dd, Jꢆ10, 1 Hz), 5.32 (2H, dq, Jꢆ17, 1 Hz), 5.53 (2H, d,
at room temperature for 40 min. Water and EtOAc were added to the mixture Jꢆ8 Hz), 5.88 (2H, ddt, Jꢆ17, 10, 6 Hz), 7.34 (1H, t, Jꢆ7 Hz), 7.38 (1H, dd,
and the organic layer was separated. The organic layer was washed with Jꢆ8, 1 Hz), 7.72 (1H, d, Jꢆ8 Hz). IR (CHCl3) cmꢁ1: 2960, 1725, 1271,
brine, dried and concentrated in vacuo. The resulting residue was chro- 1012. MS m/z (FAB): 327 (Mꢃꢃ1).
matographed on silica gel (EtOAc : hexaneꢆ1 : 1—3 : 1) to afford 28e
(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)buta-1,3-
dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-
triazol-1-yl)butan-2-yl 2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-3-methyl-
benzoate (31f) In a similar manner to 9, 31f was obtained from CS-758
1
(2.71 g, 83% yield) as a colorless oil. H-NMR (400 MHz, CDCl3) d: 3.49
(1H, t, Jꢆ6 Hz), 4.47—4.51 (4H, m), 4.78 (2H, d, Jꢆ6 Hz), 5.23 (2H, br d,
Jꢆ10 Hz), 5.33 (2H, br d, Jꢆ18 Hz), 5.40 (2H, d, Jꢆ9 Hz), 5.89 (2H, ddt,
Jꢆ18, 10, 6 Hz), 7.32 (1H, t, Jꢆ8 Hz), 7.37—7.40 (2H, m). IR (CHCl3) and 29f in 69% yield as a pale yellow amorphous solid. 1H-NMR (400 MHz,
cmꢁ1: 3608, 1732, 1268, 1028, 987. MS m/z (FAB): 333 (Mꢃꢃ1).
2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-3-chlorobenzoic Acid (29e) 3.45 (1H, t, Jꢆ11 Hz), 3.51 (1H, t, Jꢆ11 Hz), 4.00 (1H, q, Jꢆ7 Hz), 4.09
CDCl3) d: 1.44 (3H, dd, Jꢆ7, 2 Hz), 2.51 (3H, s), 3’.04 (1H, tt, Jꢆ11, 5 Hz),

June 2010
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(1H, ddd, Jꢆ11, 5, 2 Hz), 4.19 (1H, ddd, Jꢆ11, 5, 2 Hz), 4.42—4.55 (4H, t, Jꢆ11 Hz), 3.88 (3H, s), 4.01—4.77 (2H, m), 4.15 (1H, ddd, Jꢆ11, 5, 2
m), 4.96 (1H, d, Jꢆ5 Hz), 5.19 (2H, br d, Jꢆ10 Hz), 5.30 (2H, br d, Jꢆ18 Hz), 5.00 (1H, d, Jꢆ4 Hz), 5.28 (1H, dd, Jꢆ10, 4 Hz), 5.32 (1H, dd, Jꢆ10,
Hz), 5.43—5.56 (4H, m), 5.83 (1H, dd, Jꢆ16, 5 Hz), 5.82—5.92 (2H, m),
6.55 (1H, dd, Jꢆ16, 11 Hz), 6.73 (1H, d, Jꢆ16 Hz), 6.86—6.99 (3H, m),
7.30—7.35 (2H, m), 7.39—7.43 (3H, m), 7.48 (1H, td, Jꢆ9, 6 Hz), 7.57
4 Hz), 5.58 (1H, dd, Jꢆ15, 3 Hz), 5.68 (1H, d, Jꢆ15 Hz), 5.84 (1H, dd, Jꢆ
15, 4 Hz), 6.56 (1H, dd, Jꢆ11, 15 Hz), 6.78 (1H, d, Jꢆ15 Hz), 6.99—7.13
(2H, m), 7.08 (1H, dd, Jꢆ15, 11 Hz), 7.21 (1H, d, Jꢆ7 Hz), 7.30 (1H, d, Jꢆ
(1H, t, Jꢆ8 Hz), 7.94 (1H, s), 8.00 (1H, s). IR (CHCl3) cmꢁ1: 2233, 1727, 7 Hz), 7.36 (1H, t, Jꢆ8 Hz), 7.51 (1H, t, Jꢆ8 Hz), 7.52 (1H, t, Jꢆ8 Hz),
1616, 1504, 1419, 1387, 1276, 1141, 1211. MS m/z (FAB): 851 (Mꢃꢃ1).
Disodium 2-({[(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)
buta-1,3-dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-1-
7.62—7.70 (1H, m), 7.78 (1H, t, Jꢆ8 Hz), 7.97 (1H, s), 8.62 (1H, s). IR
(KBr) cmꢁ1: 2231, 1730, 1615, 1503, 1278, 1142, 1054. MS m/z (FAB): 831
(Mꢃꢃ1). [a]D25 ꢃ15.4° (cꢆ0.84, MeOH).
(1H-1,2,4-triazol-1-yl)butan-2-yl]oxy}carbonyl)-6-methylbenzyl
Phos-
Diallyl [8-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-1-naphthyl]methyl
Phosphate (33) In a similar manner to 27e, 33 was obtained from 32 in
phate (17f) In a similar manner to 17a, 17f was obtained from 31f in 57%
yield as a colorless solid. 1H-NMR (400 MHz, CD3OD) d: 1.41 (3H, dd, Jꢆ
7, 2 Hz), 2.58 (3H, s), 2.99 (1H, tt, Jꢆ11, 5 Hz), 3.45 (1H, t, Jꢆ11 Hz), 3.52
(1H, t, Jꢆ11 Hz), 4.03 (1H, ddd, Jꢆ11, 5, 2 Hz), 4.08 (1H, q, Jꢆ7 Hz), 4.14
1
81% yield as a colorless oil. H-NMR (400 MHz, CDCl3) d: 0.03 (6H, s),
0.87 (9H, s), 4.37—4.45 (4H, m), 5.16 (2H, br d, Jꢆ10 Hz), 5.24 (2H, dq,
Jꢆ18, 1 Hz), 5.25 (2H, s), 5.80 (2H, d, Jꢆ10 Hz), 5.77—5.86 (2H, m),
(1H, ddd, Jꢆ11, 5, 2 Hz), 4.99 (1H, d, Jꢆ5 Hz), 5.15 (1H, dd, Jꢆ11, 4 Hz), 7.44—7.48 (2H, m), 7.61 (1H, dd, Jꢆ7, 1 Hz), 7.69 (1H, dd, Jꢆ7, 1 Hz),
5.30 (1H, dd, Jꢆ11, 4 Hz), 5.51 (1H, dd, Jꢆ15, 4 Hz), 5.69 (1H, d, Jꢆ15 7.84 (1H, dd, Jꢆ8, 1 Hz), 7.89 (1H, dd, Jꢆ7, 1 Hz). IR (CHCl3) cmꢁ1: 1732,
Hz), 5.83 (1H, dd, Jꢆ16, 5 Hz), 6.55 (1H, dd, Jꢆ15, 11 Hz), 6.77 (1H, d, Jꢆ 1471, 1464, 1259, 1027, 999. MS m/z (FAB): 463 (Mꢃꢃ1).
15 Hz), 7.01—7.11 (3H, m), 7.27 (1H, t, Jꢆ8 Hz), 7.41 (1H, d, Jꢆ7 Hz),
Diallyl [8-(Hydroxymethyl)-1-naphthyl]methyl Phosphate (34) In a
7.49—7.54 (3H, m), 7.64 (1H, td, Jꢆ9, 6 Hz), 7.77 (1H, t, Jꢆ8 Hz), 7.98 similar manner to 28e, 34 was obtained from 33 in 59% yield as a colorless
1
(1H, s), 8.60 (1H, s). IR (KBr) cmꢁ1: 2231, 1725, 1615, 1503, 1276, 1141,
1048, 974. MS m/z (FAB): 815 (Mꢃꢃ1). [a]D25 ꢃ16.3° (cꢆ1.01, MeOH)
[2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-6-methoxyphenyl]methanol
(26g) In a similar manner to 26e, 26g was obtained from 25g in 53% yield
oil. H-NMR (400 MHz, CDCl3) d: 4.41—4.46 (4H, m), 5.18 (2H, br d, Jꢆ
10 Hz), 5.19 (2H, s), 5.26 (2H, br d, Jꢆ17 Hz), 5.82 (2H, d, Jꢆ9 Hz), 5.84
(2H, ddt, Jꢆ17, 10, 6 Hz), 7.47 (1H, t, Jꢆ7 Hz), 7.49 (1H, t, Jꢆ7 Hz), 7.61
(1H, dd, Jꢆ7, 1 Hz), 7.71 (1H, dd, Jꢆ7, 1 Hz), 7.88 (1H, d, Jꢆ7 Hz), 7.92
as a colorless oil. H-3 and 1H-NMR (400 MHz, CDCl3) d: 0.11 (6H, s), 0.91 (1H, d, Jꢆ7 Hz). IR (CHCl3) cmꢁ1: 3603, 1732, 1270, 1028, 990. MS m/z
(9H, s), 3.03 (1H, br), 3.86 (3H, s), 4.77 (2H, s), 4.79 (2H, s), 6.88 (1H, d, (FAB): 349 (Mꢃꢃ1).
Jꢆ8 Hz), 6.94 (1H, d, Jꢆ8 Hz), 7.24 (1H, t, Jꢆ8 Hz). IR (CHCl3) cmꢁ1
:
8-({[Bis(allyloxy)phosphoryl]oxy}methyl)-1-naphthoic Acid (35) In a
similar manner to 29e, 35 was obtained from 34 in quantitative yield as a
2957, 2931, 1588, 1472, 1463, 1264. MS m/z (FAB): 283 (Mꢃꢃ1). The
structure of 26g was assigned by means of NOE when positive NOE was colorless oil. This compound was used for the next step without further pu-
found between signals of the methylene protons of the CH2OTBS group and
the proton in position 3 of the benzene ring.
rification.
(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)buta-
Diallyl 2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-6-methoxybenzyl 1,3-dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-1-(1H-
Phosphate (27g) In a similar manner to 27e, 27g was obtained from 26g 1,2,4-triazol-1-yl)butan-2-yl 8-({[Bis(allyloxy)phosphoryl]oxy}methyl)-1-
in 60% yield as a colorless oil. 1H-NMR (400 MHz, CDCl3) d: 0.10 (6H, s),
naphthoate (37) In a similar manner to 9, 37 was obtained from CS-758
0.93 (9H, s), 3.84 (3H, s), 4.49—4.52 (4H, m), 4.86 (2H, s), 5.22 (2H, dd, and 35 in 52% yield as a pale yellow amorphous solid. 1H-NMR (400 MHz,
Jꢆ10, 1 Hz), 5.25 (2H, d, Jꢆ6 Hz), 5.33 (2H, dd, Jꢆ17, 1 Hz), 5.91 (2H,
ddt, Jꢆ17, 10, 5 Hz), 6.83 (1H, d, Jꢆ8 Hz), 7.12 (1H, d, Jꢆ8 Hz), 7.33 (1H,
CDCl3) d: 1.47 (3H, dd, Jꢆ7, 2 Hz), 3.18 (1H, tt, Jꢆ11, 5 Hz), 3.46 (1H, t,
Jꢆ11 Hz), 3.55 (1H, t, Jꢆ11 Hz), 4.20 (1H, ddd, Jꢆ11, 5, 2 Hz), 4.22—4.42
t, Jꢆ8 Hz). IR (CHCl3) cmꢁ1: 2956, 2931, 1591, 1472, 1270, 1015. MS m/z (6H, m), 4.94 (1H, d, Jꢆ4 Hz), 5.13 (2H, br d, Jꢆ11 Hz), 5.20 (2H, br d, Jꢆ
(FAB): 443 (Mꢃꢃ1).
18 Hz), 5.34 (1H, dd, Jꢆ14, 10 Hz), 5.43—5.56 (3H, m), 5.70—5.82 (3H,
Diallyl 2-(Hydroxymethyl)-6-methoxybenzyl Phosphate (28g) In a m), 6.50 (1H, dd, Jꢆ15, 11 Hz), 6.70 (1H, d, Jꢆ15 Hz), 6.90 (1H, dd, Jꢆ15,
similar manner to 28e, 28g was obtained from 27g in 93% yield as a color- 11 Hz), 6.90—6.95 (1H, m), 7.14 (1H, td, Jꢆ8, 3 Hz), 7.33 (1H, dd, Jꢆ10,
1
less oil. H-NMR (400 MHz, CDCl3) d: 3.3 (1H, br), 3.86 (3H, s), 4.42— 1 Hz), 7.38—7.44 (3H, m), 7.56 (1H, t, Jꢆ8 Hz), 7.58 (1H, t, Jꢆ8 Hz), 7.79
4.50 (4H, m), 4.75 (2H, s), 5.22 (2H, d-like, Jꢆ10 Hz), 5.32 (2H, d-like, Jꢆ (1H, s), 7.83—7.89 (3H, m), 8.01 (1H, s), 8.05 (1H, dd, Jꢆ6, 3 Hz). IR
17 Hz), 5.34 (2H, d, Jꢆ10 Hz), 5.89 (2H, ddt, Jꢆ17, 10, 6 Hz), 6.88 (1H, d, (KBr) cmꢁ1: 3431, 2230, 1718, 1615, 1503, 1274, 1143, 1039, 1011. MS
Jꢆ8 Hz), 7.06 (1H, d, Jꢆ8 Hz), 7.35 (1H, t, Jꢆ8 Hz). IR (CHCl3) cmꢁ1
3385, 1473, 1463, 1271, 1021, 989. MS m/z (FAB): 329 (Mꢃꢃ1).
2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-3-methoxybenzoic Acid (29g)
:
m/z (FAB): 887 (Mꢃꢃ1).
Disodium [8-({[(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)
buta-1,3-dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-1-
In a similar manner to 29e, 29g was obtained from 28g in 60% yield as a (1H-1,2,4-triazol-1-yl)butan-2-yl]oxy}carbonyl)-1-naphthyl]methyl
colorless oil. 1H-NMR (400 MHz, CDCl3) d: 3.89 (3H, s), 4.47—4.57 (4H, m),
5.21 (2H, d-like, Jꢆ10 Hz), 5.32 (2H, d-like, Jꢆ17 Hz), 5.53 (2H, d, Jꢆ8 Hz),
5.90 (2H, ddt, Jꢆ17, 10, 6 Hz), 7.07 (1H, dd, Jꢆ8, 1 Hz), 7.41 (1H, t,
Phosphate (17j) In a similar manner to 17a, 17j was obtained from 37 in
1
27% yield as a colorless solid. H-NMR (400 MHz, CD3OD) d: 1.48 (3H,
dd, Jꢆ7, 2 Hz), 3.15 (1H, tt, Jꢆ11, 5 Hz), 3.49 (1H, t, Jꢆ11 Hz), 3.58 (1H,
Jꢆ8 Hz), 7.48 (1H, d, Jꢆ8 Hz). IR (CHCl3) cmꢁ1: 1725, 1587, 1461, 1272, t, Jꢆ11 Hz), 4.17 (1H, ddd, Jꢆ11, 5, 2 Hz), 4.24 (1H, ddd, Jꢆ11, 5, 2 Hz),
1021, 989. MS m/z (FAB): 343 (Mꢃꢃ1).
(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)buta-1,3-
dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-1-(1H-
4.34 (1H, q, Jꢆ7 Hz), 5.00 (1H, d, Jꢆ4 Hz), 5.21 (1H, dd, Jꢆ15, 8 Hz), 5.26
(1H, dd, Jꢆ15, 8 Hz), 5.59 (1H, dd, Jꢆ15, 3 Hz), 5.69 (1H, d, Jꢆ15 Hz),
5.82 (1H, dd, Jꢆ16, 4 Hz), 6.54 (1H, dd, Jꢆ16, 11 Hz), 6.77 (1H, d, Jꢆ16
1,2,4-triazol-1-yl)butan-2-yl 2-({[Bis(allyloxy)phosphoryl]oxy}methyl)-3- Hz), 7.02 (1H, ddd, Jꢆ13, 9, 3 Hz), 7.07 (1H, dd, Jꢆ16, 11 Hz), 7.30 (1H,
methoxybenzoate (31g) In a similar manner to 9, 31g was obtained from td, Jꢆ8, 3 Hz), 7.42 (1H, t, Jꢆ8 Hz), 7.49—7.54 (2H, m), 7.58 (1H, t,
1
CS-758 and 29g in 49% yield as a pale yellow amorphous solid. H-NMR
(400 MHz, CDCl3) d: 1.44 (3H, dd, Jꢆ7, 2 Hz), 3.04 (1H, tt, Jꢆ12, 5 Hz),
3.45 (1H, t, Jꢆ12 Hz), 3.51 (1H, t, Jꢆ12 Hz), 3.89 (3H, s), 3.98 (1H, q, Jꢆ
Jꢆ8 Hz), 7.70 (1H, d, Jꢆ7 Hz), 7.77 (1H, t, Jꢆ7 Hz), 7.84 (1H, d, Jꢆ8 Hz),
7.96 (1H, td, Jꢆ9, 6 Hz), 8.05 (1H, s), 8.09 (1H, dd, Jꢆ8, 1 Hz), 8.19 (1H, d,
Jꢆ7 Hz), 8.39 (1H, s). MS m/z (FAB): 851 (Mꢃꢃ1). [a]D25 ꢃ63.0° (cꢆ0.61,
7 Hz), 4.09 (1H, ddd, Jꢆ12, 5, 2 Hz), 4.18 (1H, ddd, Jꢆ12, 5, 2 Hz), 4.43— MeOH).
4.55 (4H, m), 4.96 (1H, d, Jꢆ4 Hz), 5.19 (2H, dd, Jꢆ10, 1 Hz), 5.31 (2H,
[4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-3-furyl]methanol (39) In
dq, Jꢆ17, 1 Hz), 5.43—5.55 (4H, m), 5.83 (1H, dd, Jꢆ15, 4 Hz), 5.84— a similar manner to 26e, 39 was obtained from 38 in 50% yield as a color-
1
5.94 (2H, m), 6.56 (1H, dd, Jꢆ15, 10 Hz), 6.73 (1H, d, Jꢆ16 Hz), 6.93 (1H,
less oil. H-NMR (400 MHz, CDCl3) d: 0.125 (6H, s), 0.916 (9H, s), 3.177
dd, Jꢆ16, 10 Hz), 6.86—7.00 (2H, m), 7.12 (1H, d, Jꢆ8 Hz), 7.16 (1H, d, (1H, t, Jꢆ6 Hz), 4.522 (2H, d, Jꢆ6 Hz), 4.640 (2H, s), 7.317 (1H, s), 7.371
Jꢆ8 Hz), 7.34 (1H, dd, Jꢆ9, 1 Hz), 7.39 (2H, t, Jꢆ8 Hz), 7.48 (1H, td, Jꢆ9, (1H, s). IR (CHCl3) cmꢁ1: 3449, 2956, 2931, 2859, 1471, 1258, 1040. MS
6 Hz), 7.57 (1H, t, Jꢆ8 Hz), 7.93 (1H, s), 8.00 (1H, s). IR (CHCl3) cmꢁ1
:
m/z (FAB): 243 (Mꢃꢃ1).
2233, 1731, 1504, 1462, 1277, 1141, 1059, 1018, 991. MS m/z (FAB): 867
Diallyl [4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-3-furyl]methyl Phos-
phate (40) In a similar manner to 27e, 40 was obtained from 39 in 93%
yield as a colorless oil. 1H-NMR (400 MHz, CDCl3) d: 0.083 (6H, s), 0.908
(9H, s), 4.55—4.55 (4H, m), 4.627 (2H, s), 5.003 (2H, d, Jꢆ8, 2 Hz), 5.328
(Mꢃꢃ1).
Disodium 2-({[(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)
buta-1,3-dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-1-
(1H-1,2,4-triazol-1-yl)butan-2-yl]oxy}carbonyl)-6-methoxybenzyl Phos- (2H, dd, Jꢆ10.4, 1.2 Hz), 5.340 (1H, dddd, Jꢆ17, 1.5, 1.5, 1.2 Hz), 5.912
phate (17g) In a similar manner to 17a, 17g was obtained from 31g in
(2H, ddt, Jꢆ17, 10, 5 Hz), 7.328 (1H, s), 7.447 (1H, s). IR (CHCl3) cmꢁ1
24% yield as a colorless solid. H-NMR (400 MHz, CD3OD) d: 1.42 (3H, 2956, 2931, 1258, 1010. MS m/z (FAB): 403 (Mꢃꢃ1).
dd, Jꢆ7, 2 Hz), 3.00 (1H, tt, Jꢆ11, 5 Hz), 3.46 (1H, t, Jꢆ11 Hz), 3.52 (1H, Diallyl [4-(Hydroxymethyl)-3-furyl]methyl Phosphate (41) In a simi-
:
1

804
Vol. 58, No. 6
lar manner to 28e, 41 was obtained from 40 in 76% yield as a colorless oil.
1H-NMR (400 MHz, CDCl3) d: 3.168 (1H, t-like, Jꢆca. 6 Hz), 4.523 (4H,
td, Jꢆ7, 1.2 Hz), 4.580 (2H, d, Jꢆ6 Hz), 5.050 (2H, d, Jꢆ9.5 Hz), 5.255
(2H, dd-like, Jꢆ10, ca. 1.2 Hz), 5.350 (2H, dt-like, Jꢆ17, ca. 1.2 Hz), 5.917
References and Notes
1) Maesaki S., Kohno S., Saishin Igaku, 47, 277—285 (1992).
2) Saxena S., Khan J. A., Ghosh P. C., J. Antimicrob. Chemother., 42,
635—642 (1998).
3) Petit C., Cheron M., Joly V., Rodrigues J. M., Bolard J., Gaboriau F., J.
Antimicrob. Chemother., 42, 779—785 (1998).
(2H, ddt, Jꢆ 17, 10, 6 Hz), 7.414 (1H, s), 7.483 (1H, s). IR (CHCl3) cmꢁ1
3401, 1602, 1554, 1462, 1424, 1267, 1022. MS m/z (FAB): 289 (Mꢃꢃ1).
:
Diallyl (4-Formyl-3-furyl)methyl Phosphate (42) To a solution of 41
(113 mg, 0.39 mmol) in CH2Cl2 (2 ml), activated manganese dioxide (0.52 g,
6.0 mmol) was added, then the reaction mixture was stirred at room tempera-
ture for 8 h. Then activated manganese dioxide (40 mg, 0.46 mmol) was fur-
ther added to the solution and the mixture was stirred at room temperature
for 1.5 h. EtOAc was added to the solution and filtered. The filtrate was con-
centrated under reduced pressure, and the obtained residue was purified by
flash chromatography to afford 42 (101 mg, 90% yield) as a colorless oil.
1H-NMR (400 MHz, CDCl3) d: 4.569 (4H, dd-like, Jꢆ7, 6 Hz), 5.245 (2H,
dd-like, Jꢆ6, 1 Hz), 5.259 (2H, dd-like, Jꢆ11, 1 Hz), 5.369 (2H, dd-like, Jꢆ
17, 1 Hz), 5.943 (2H, d, Jꢆ17, 11, 6 Hz), 7.569 (1H, br s), 8.046 (1H, d, Jꢆ
1.6 Hz), 9.971 (1H, s). IR (CHCl3) cmꢁ1: 1689, 1544, 1273, 1147, 1027. MS
m/z (EI): 287 (Mꢃꢃ1).
4-({[Bis(allyloxy)phosphoryl]oxy}methyl)-3-furoic Acid (43) A solu-
tion of sodium chlorite (122 mg, 1.35 mmol) and sodium dihydrogen phos-
phate dihydrate (1.034 g, 6.76 mmol) in water (1.2 ml) was added to a solu-
tion of diallyl (4-formyl-3-furyl)methyl phosphate 42 (97 mg, 0.34 mmol)
and 2-methyl-2-butene (1.18 g, 19.9 mmol) in tert-butyl alcohol (2.70 ml) at
0 °C. The mixture was stirred for 2 h at room temperature, and partitioned
between EtOAc and an aqueous solution of sodium chloride, then the or-
4) Kawakami Y., Nagino K., Shinkai K., Sobue S., Abe M., Ishiko J.,
Nippon Yakurigaku Zasshi, 124, 41—51 (2004).
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11) Ohwada J., Murasaki C., Yamazaki T., Ichihara S., Umeda I., Shimma
N., Bioorg. Med. Chem. Lett., 12, 2775—2780 (2002).
ganic layer was dried over anhydrous magnesium sulfate and the solvent was 12) Ichikawa T., Kitazaki T., Matsushita Y., Yamada M., Hayashi R., Ya-
distilled off under reduced pressure. The residue was subjected to chro-
maguchi M., Kiyota Y., Okonogi K., Itoh K., Chem. Pharm. Bull., 49,
matography on a silica gel (2 g) column (EtOAc) to afford 43 (74 mg, 72%
yield) as a colorless oil. H-NMR (400 MHz, CDCl3) d: 4.572 (4H, dd-like, 13) Ueda Y., Matiskella J. D., Golik J., Connolly T. P., Hudyma T. W.,
1102—1109 (2001).
1
Jꢆ7, 6 Hz), 5.25 (4H, d-like, Jꢆ9 Hz), 5.367 (2H, dd-like,Jꢆ17, 1.4 Hz),
5.940 (2H, ddt, Jꢆ17, 10, 6 Hz), 7.533 (1H, d, Jꢆca. 1.4 Hz), 8.059 (1H, d,
Jꢆca. 1.7 Hz). IR (CHCl3) cmꢁ1: 1736, 1697, 1549, 1269, 1149, 1029. MS
m/z (EI): 303 (Mꢃꢃ1).
Venkatesh S., Dali M., Kang S.-H., Barbour N., Tejwani R., Varia S.,
Knipe J., Zheng M., Mathew M., Mosure K., Clark J., Lamb L., Medin
I., Gao Q, Huang S., Chena C.-P., Bronsona J. J., Bioorg. Med. Chem.
Lett., 13, 3669—3672 (2003).
(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)buta-1,
3-dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-1-(1H-
1,2,4-triazol-1-yl)butan-2-yl 4-({[Bis(allyloxy)phosphoryl]oxy}methyl)-3-
furoate (45) In a similar manner to 9, 45 was obtained from CS-758 and
43 in 70% yield as a colorless amorphous solid. 1H-NMR (400 MHz,
CDCl3) d: 1.43 (3H, dd, Jꢆ7, 2 Hz), 3.05 (1H, tt, Jꢆ11, 5 Hz), 3.53 (2H, t,
Jꢆ11 Hz), 3.96 (1H, q, Jꢆ7 Hz), 4.14—4.22 (2H, m), 4.53 (4H, br t, Jꢆ7
Hz), 5.01 (1H, d, Jꢆ5 Hz), 5.10—5.18 (2H, m), 5.25 (2H, d, Jꢆ10 Hz), 5.35
(2H, dd, Jꢆ17, 1 Hz), 5.40 (1H, dd, Jꢆ15, 3 Hz), 5.47 (1H, d, Jꢆ15 Hz),
5.85 (1H, dd, Jꢆ15, 5 Hz), 5.92 (2H, ddt, Jꢆ17, 10, 5 Hz), 6.58 (1H, dd,
Jꢆ15, 11 Hz), 6.74 (1H, d, Jꢆ16 Hz), 6.88—6.93 (2H, m), 6.93 (1H, dd,
14) Ohwada J., Tsukazaki M., Hayase T., Oikawa N., Isshiki Y., Fukuda
H., Mizuguchi E., Sakaitani M., Shiratori Y., Yamazaki T., Ichihara S.,
Umeda I., Shimma N., Bioorg. Med. Chem. Lett., 13, 191—196
(2003).
15) Oida S., Tajima Y., Konosu T., Nakamura Y., Somada A., Tanaka T.,
Habuki S., Harasaki T., Kamai Y., Fukuoka T., Ohya S., Yasuda. H.,
Chem. Pharm. Bull., 48, 694—707 (2000).
16) Konosu T., Oida S., Nakamura Y., Seki S., Uchida T., Somada A.,
Mori M., Harada Y., Kamai Y., Harasaki T., Fukuoka T., Ohya S., Ya-
suda H., Shibayama T., Inoue S., Nakagawa A., Seta Y., Chem. Pharm.
Bull., 49, 1647—1650 (2001).
Jꢆ16, 11 Hz), 7.32—7.37 (2H, m), 7.40 (1H, dd, Jꢆ 8, 1 Hz), 7.56—7.59 17) Kamai Y., Harasaki T., Fukuoka T., Ohya S., Uchida K., Yamaguchi
(2H, m), 7.89 (1H, s), 7.92 (2H, s). IR (KBr) cmꢁ1: 2230, 1727, 1615, 1504,
1276, 1258, 1143, 1051, 1021, 973. MS m/z (FAB): 827 (Mꢃꢃ1).
H., Kuwahara S., Antimicrob. Agents Chemother., 46, 367—370
(2002).
Disodium [4-({[(2R,3R)-3-({trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)
buta-1,3-dien-1-yl]-1,3-dioxan-5-yl}sulfanyl)-2-(2,4-difluorophenyl)-
1-(1H-1,2,4-triazol-1-yl)butan-2-yl]oxy}carbonyl)-3-furyl]methyl Phos-
phate (17k) In a similar manner to 2, 17k was obtained from 45 in 87%
yield as a colorless solid. 1H-NMR (400 MHz, CD3OD) d: 1.38 (3H, dd,
Jꢆ7, 2 Hz), 3.07 (1H, tt, Jꢆ11, 5 Hz), 3.54 (1H, t, Jꢆ11 Hz), 3.55 (1H, t,
Jꢆ11 Hz), 4.00 (1H, q, Jꢆ7 Hz), 4.16 (2H, dd, Jꢆ11, 5 Hz), 4.98 (1H, ddd,
Jꢆ15, 6, 1 Hz), 5.03 (1H, ddd, Jꢆ15, 6, 1 Hz), 5.05 (1H, d, Jꢆ4 Hz), 5.51
18) Davidsen S. K., Summers J. B., Albert D. H., Holms J. H., Heyman H.
R., Magoc T. J., Conway R. G., Rhein D. A., Carter G. W., J. Med.
Chem., 37, 4423—4429 (1994).
19) Kagoshima Y., Mori M., Suzuki E., Shibayama T., Iida T., Kamai Y.,
Konosu T., Bioorg. Med. Chem. Lett., 19, 3559—3563 (2009).
20) Similar water-soluble prodrug strategy was reported previously: Mat-
sumoto H., Sohma Y., Kimura T., Hayashi Y., Kiso Y., Bioorg. Med.
Chem. Lett., 11, 605—609 (2001).
(2H, s), 5.88 (1H, dd, Jꢆ15, 4 Hz), 6.59 (1H, dd, Jꢆ15, 11 Hz), 6.79 (1H, d, 21) Bannwarth W., Küng E., Tetrahedron Lett., 30, 4219—4222 (1989).
Jꢆ15 Hz), 6.97—7.06 (2H, m), 7.01 (1H, dd, Jꢆ15, 11 Hz), 7.48—7.54 22) Bioavailability (BA) was calculated by the following. BA (%)ꢆ{[area
(3H, m), 7.69 (1H, q, Jꢆ2 Hz), 7.78 (1H, t, Jꢆ8 Hz), 7.92 (1H, s), 7.99 (1H,
d, Jꢆ1 Hz), 8.27 (1H, s). IR (KBr) cmꢁ1: 2231, 1726, 1615, 1503, 1143,
1101, 1052, 975. MS m/z (ESI): 745 [M (non sodium part)ꢃ1]ꢁ.
under the curve (AUC) of CS-758 after iv administration of the pro-
drug]/(AUC of CS-758 after iv administration of CS-758 dissolved in
polyethylene glycol solution)}ꢀ100.
Acknowledgements We would like thank Mr. Nobuyuki Suzuki and
colleagues in Analytical & Quality Evaluation Research Laboratories of our
company for the solubility and stability tests.