Design and synthesis of carbocyclic versions of furanoid nucleoside phosphonic acid analogues as potential anti-HIV agents

Article abstract of DOI:10.1080/15257770.2011.605781

Novel 5′-norcarbocyclic adenine and guanine phosphonic acid analogues with 6′,6′-difluorine moiety were designed and synthesized from commercially available epichlorohydrin 5. A regioselective Mitsunobu reaction successfully proceeded from an allylic functional group 16b at low reaction temperature in polar cosolvent to give purine phosphonate analogues 17 and 24, respectively. The purine nucleoside phosphonate and phosphonic acid analogues were subjected to antiviral screening against HIV-1. Adenine analogue 21 and its SATE prodrug 29 show significant anti-HIV activity in MT-4 cell lines. Copyright Taylor and Francis Group, LLC.

Full text of DOI:10.1080/15257770.2011.605781

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Design and Synthesis of Carbocyclic
Versions of Furanoid Nucleoside
Phosphonic Acid Analogues as Potential
Anti-Hiv Agents
Eunae Kim a , Guang Huan Shen a & Joon Hee Hong a
a BK-21 Project Team, College of Pharmacy, Chosun University,
Kwangju, Republic of Korea
Available online: 03 Oct 2011
To cite this article: Eunae Kim, Guang Huan Shen & Joon Hee Hong (2011): Design and Synthesis of
Carbocyclic Versions of Furanoid Nucleoside Phosphonic Acid Analogues as Potential Anti-Hiv Agents,
Nucleosides, Nucleotides and Nucleic Acids, 30:10, 798-813
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Nucleosides, Nucleotides and Nucleic Acids, 30:798–813, 2011
Copyright ꢀC Taylor and Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770.2011.605781
DESIGN AND SYNTHESIS OF CARBOCYCLIC VERSIONS
OF FURANOID NUCLEOSIDE PHOSPHONIC ACID ANALOGUES
AS POTENTIAL ANTI-HIV AGENTS
Eunae Kim, Guang Huan Shen, and Joon Hee Hong
BK-21 Project Team, College of Pharmacy, Chosun University, Kwangju, Republic of Korea
Novel 5ꢁ-norcarbocyclic adenine and guanine phosphonic acid analogues with 6ꢁ,6ꢁ-difluorine
2
moiety were designed and synthesized from commercially available epichlorohydrin 5. A regioselective
Mitsunobu reaction successfully proceeded from an allylic functional group 16b at low reaction
temperature in polar cosolvent to give purine phosphonate analogues 17 and 24, respectively. The
purine nucleoside phosphonate and phosphonic acid analogues were subjected to antiviral screening
against HIV-1. Adenine analogue 21 and its SATE prodrug 29 show significant anti-HIV activity
in MT-4 cell lines.
Keywords Anti-HIV agents; 6ꢁ,6ꢁ-difluoro-5ꢁ-norcarbocyclic nucleoside; Mitsunobu
reaction
INTRODUCTION
Since the discovery of human immunodeficiency syndrome (AIDS),
there has been intense effort to find compounds that can selectively block the
replication of HIV. One logical approach to the discovery of new and potent
HIV inhibitors involves the design of phosphate analogues where the phos-
phate moiety is changed to isosteric and isoelectronic phosphonates. These
enzymatically and chemically stable phosphonate analogues, which mimic
the nucleoside monophosphates by passing the initial enzymatic phospho-
rylation,[1] could lead to more effective antiviral agents against HIV.[2]
Several phosphonate and phosphonic acid derivatives of purines and
pyrimidines have emerged as potent antiviral agents.[3] The spatial location
of the oxygen atom, namely the β-position from the phosphorus atom in
the nucleoside analogue, plays a critical role in the antiviral activity. This
Received 15 June 2011; accepted 12 July 2011.
This work was supported by the National Research Foundation of Korea Grant, funded by the
Korean Government (MEST) (20100009002).
Address correspondence to Dr. Joon Hee Hong, BK-21 Project Team, College of Pharmacy, Chosun
University, Kwangju 501-759, Republic of Korea. E-mail: hongjh@chosun.ac.kr
798

6ꢁ,6ꢁ-Difluoro-5ꢁ-Norcarbocyclic Nucleoside Analogues
799
O
NH2
NH
N
N
O
N
HO
O
N
N
P
O
HO
OH
O
2
1
NH2
N
NH2
N
N
N
N
O
O
N
N
HO P
O
N
HO P
O
O
OH
OH
4
3
FIGURE 1 Rationale for target nucleoside analogue.
increased antiviral activity with this oxygen atom may be attributed to the in-
creased binding capacity of the phosphonate analogues to target enzymes.[4]
Successful phosphonate mimicking of the phosphate functionality has
been discovered in the series of (phosphonomethoxy)alkyl adenine deriva-
tive 1 and its analogues as broad spectrum antiviral agents.[5] Recently, pyrim-
idine isonucleoside 2[6] with a methylene moiety in place of carbon atom of
the furanose ring was reported to show antiviral activity, especially anti-HIV
activity (Figure 1). Molecular modeling studies demonstrated the presence
of an electronegative moiety at the 6ꢁ-position that could accommodate these
substitutions and has contributed to the observed enhancement in potency
in anti-HIV activity.[7]
The phosphonate analogue 3 was successfully prepared and evaluated
for its inhibitory effect on the replication of retroviruses, including Raucher-
murine Leukemia virus (R-MuLV) and HIV-1. Furthermore, compound 3
was superior to d4T in inhibiting R-MuLV at three orders magnitude low
concentration, indicating that the murine model might be useful to evaluate
3 for its in vivo efficacy against the retrovirus.[8] Recently, Boojamra et al.
reported a different synthetic scheme[9] of potent 5ꢁ-norcarbocyclic adenine
analogue 4 from the previously reported methods.[10]
Stimulated by these findings that 6ꢁ-electropositive nucleoside analogues
and 5ꢁ-nornucleoside phosphonates have excellent biological activities, we
sought to synthesize a novel class of nucleosides comprising 6ꢁ,6ꢁ-difluoro-
5ꢁ-norcarbocyclic phosphonic acid analogues in order to search for more
effective therapies against HIV and to provide analogues for probing the
conformational preferences of enzymes associated with the nucleoside ki-
nases of nucleosides and nucleotides.
As depicted in Scheme 1, the target compounds were prepared from
ketone derivative 6, which was synthesized from the commercially available

800
E. Kim et al.
F F
i
O
ref.11
BnO
OBn
O
65%
BnO
OBn
6
Cl
7
5
ii
96%
F F
F F
OP
iii
F F
iv
73%
HO
OH
HO
OP
65%
O
8
P = TBDMS
10
9
v
80%
F F
F F
F F
vii
OH
PMBO
OP
vi
73%
PMBO
OP
HO
92%
13
iv
12
11
87%
F F
F F
F F
O
viii
PMBO
v
X
Y
OH
15
PMBO
PMBO
75%
14
16a: X = OH, Y = H (35%)
16b: X = H, Y = OH (36%)
Reagents: i) DAST, CH2Cl2; ii) H2, Pd/C, MeOH; iii) TBDMSCl, imidazole,
DMF; iv) (COCl)2, DMSO, TEA; v) vinylMgBr, THF; vi) PMBCl, NaH, DMF;
vii) TBAF, THF; viii) Grubbs (II), CH2Cl2.
SCHEME 1 Synthesis of difluoro cyclopentene intermediate.
epichlorohydrin 5 via a known procedure.[11] The reaction of 6 with
DAST led to the key gem-difluoro compound 7 with 65% yield. Catalytic
hydrogenolysis and selective monosilylation of corresponding diol 8 gave
alcohol derivative 9. Swern oxidation[12] of 9 provided an aldehyde 10,
which was subjected to the carbonyl addition reaction by vinylmagensium
bromide[13] to furnish the alcohol 11, which was successfully protected
using p-methoxybenzyl chloride (PMBCl)[14] to provide compound 12.
Removal of the silyl protecting group of 12 using t-butylammonium
fluoride (TBAF) gave the primary alcohol 13, which was oxidized to the
aldehyde 14 using same oxidation conditions as described for 10. The
aldehyde 10 was subjected to the second nucleophilic Grignard conditions

6ꢁ,6ꢁ-Difluoro-5ꢁ-Norcarbocyclic Nucleoside Analogues
801
H
F F
F F
OH
H
PMBO
H
PMBO
1.6%
OH
16b
H
2.7%
16a
FIGURE 2 NOE differences between the proximal hydrogens of 16a and 16b.
with vinylmagnesium bromide to give divinyl 15, which was subjected to
ring-closing metathesis (RCM) conditions using second generation Grubbs
catalyst (C46H65Cl2N2PRu)[15] to provide 5ꢁ,5ꢁ-difluorocyclopentenol 16a
(35%) and 16b (36%), which were readily separated by silica gel column
chromatography. The nuclear Overhauser enhancement (NOE) exper-
iments with cyclopentenols 16a and 16b confirmed these assignments.
As expected, NOE enhancements were found between the cis-oriented
hydrogens. Upon irradiation of C1-H, weak NOE patterns were observed
at the proximal hydrogens of compound 16b [C4-CH- (1.6%)] versus
that of compound 16a [C4-CH- (2.7%)] (Figure 2). To synthesize the
desired 5ꢁ-norcarbocyclic adenosine nucleoside analogues, the protected
cyclopentenol 16b was treated with 6-chloropurine under Mitsunobu
conditions[16] (DEAD and PPh3). The appropriate choice of solvent system,
temperature, and procedure is essential for the regioselectivity and for
the yield. In purine synthesis, a mixture of dioxane and DMF instead
of THF was used as the solvent for the coupling of the cyclopentenol
16b with 6-chloropurine. The heterocyclic bases had a better solubility
in the dioxane–DMF mixture, resulting in better yields. Slow addition of
diethyl azodicarboxylate (DEAD) to a mixture of cyclopentenol 16b, tri-
phenylphosphine, and 6-chloropurine in anhydrous cosolvent
(dioxane–DMF) gave a yellow solution, which was stirred for 2 hours
at −30◦C and further stirred overnight at room temperature to give the
protected 6-chloropurine analogue 17 as the only N 9-regioisomer [UV
(MeOH) λmax 263.5 nm].[17] The PMB protection group was removed
with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ)[18] to produce the
5ꢁ-nornucleoside analogue 18, which was treated with diethylphospho-
nomethyl triflate[19] using lithium t-butoxide to yield the nucleoside
phosphonate analogue 19 (Scheme 2). The chlorine group of 19 was then
converted to amine with methanolic ammonia at 65◦C to give the corre-
sponding adenine phosphonate derivative 20. Hydrolysis of 20 by treatment
with bromotrimethylsilane in CH3CN in the presence of 2,6-lutidine gave
an adenine phosphonic acid derivative 21 (Scheme 2).[20]
The cyclopentenol intermediate 16b was also used for the synthesis of
2,6-disubstituted purine analogues such as guanine derivative 27. Regiose-
lective coupling of enol 16b with 2-fluoro-6-chloropurine[21] under similar

802
E. Kim et al.
Cl
N
F F
i
F F
PMBO
N
PMBO
OH
N
51%
N
17
ii
16b
60%
Cl
Cl
N
N
O
EtO P
EtO
F F
F F
iii
58%
N
N
O
N
N
HO
N
N
18
19
iv
61%
NH2
N
NH2
N
N
N
O
EtO P
EtO
O
HO P
HO
F F
F F
v
O
O
N
N
92%
N
N
21
20
Reagents: i) 6-chloropurine, DEAD, PPh3, 1,4-dioxane/DMF (v:v);
ii) DDQ, CH2Cl2/H2O (10:1); iii) (EtO)2POCH2OTf, LiO-t-Bu, THF;
iv) NH3/MeOH, 65 oC, 12 h; v) TMSBr, 2,6-lutidine, CH3CN, 12 h.
SCHEME 2 Synthesis of 6ꢁ,6ꢁ-diffluoro cyclopentenyl adenine phosphonic acid 21.
conditions for 6-chloropurine gives analogue 24. Bubbling ammonia into
compound 24 gave separable 2-fluoro-6-aminopurine[22] analogue 25 (14%)
and 2-amino-6-chloropurine analogue 26 (55%). 2-Amino-6-chloropurine
derivative 26 was treated with TMSBr to give phosphonic acid and sequen-
tially treated with sodium methoxide and 2-mercaptoethanol in methanol
to give desired guanine phosphonic acid 27 (Scheme 3).[23] To synthesize
the thioester prodrug of adenine analogue, derivative 21 was reacted with
thioester 28[24] in the presence of 1-(2-mesitylenesulfonyl)-3-nitro-1H-1,2,4-
triazole (MSNT)[25] to provide the bis(SATE) derivative as a target com-
pound 29 (Scheme 4).
The synthesized nucleoside phosphonate, phosphonic acid, and
thioester 20, 21, 26, 27, and 29 were then evaluated for antiviral activity
against HIV. The procedures for measuring the antiviral activity toward wild-
type HIV and cytotoxicity have been reported previously.[26] As shown in
Table 1, adenine nucleoside phosphonic ester 29 exhibits significant anti-
HIV activity. However, nucleoside analogues 20, 21, 26, and 27 showed weak
anti-HIV activity or cytotoxicity at concentrations up to 100 µM.

6ꢁ,6ꢁ-Difluoro-5ꢁ-Norcarbocyclic Nucleoside Analogues
803
O
F F
F F
PMBO
O
P OEt
OEt
OH
i
PMBO
59%
22
16b
ii
64%
Cl
N
O
N
F F
O
F F
O
P OEt
OEt
iii
46%
HO
N
O
P OEt
OEt
N
F
23
24
iv
O
N
X
N
NH
NH2
N
O
N
O
F F
N
HO P
HO
O
F F
v
N
O
P OEt
OEt
N
Y
66%
27
25: X = NH2, Y = F (14%)
26: X = Cl, Y = NH2(55%)
Reagents: i) (EtO)2POCH2OTf, LiO-t-Bu, THF; ii) DDQ, CH2Cl2/H2O
(10:1); iii) 2-fluoro-6-chloropurine, DEAD, PPh3, 1,4-dioxane/DMF (v:v);
iv) NH3/DME, rt; v) (a) TMSBr, 2,6-lutidine, CH3CN; (b) NaOMe,
HSCH2CH2OH, MeOH.
SCHEME 3 Synthesis of 6ꢁ,6ꢁ-difluoro cyclopentenyl guanine phosphonic acid 27.
NH2
N
NH2
N
N
O
i
N
N
N
O
F F
O
HO P
32%
S
N
O
O P
F F
N
O
O
O
O
OH
HO
S
S
28
29
21
Reagents: i) thioester, 28, 1-(2-mesitylenesulfonyl)-3-nitro-1H-1,2,4-triazole,
pyridine.
SCHEME 4 Synthesis of target bis(SATE) prodrug of adenine analogue 29.

804
E. Kim et al.
TABLE 1 Median effective (EC50) and inhibitory (CC50) concentration of synthesized
nucleoside analogues in MT-4 cells
Anti-HIV-1
Cytotoxicity in PMB
Compound no.
EC50 (µM)b
cells CC50 (µM)c
20
21
87.8
19
98
90
26
27
90
32
>100
90
29
10.8
1.3
90
98
d4Ta
a d4T: 2ꢁ,3ꢁ-dideoxy-2ꢁ,3ꢁ-didehydrothymidine.
bEC50(µM): EC50 values represent the concentration required to inhibit 50% of the
virus-induced cytopathicity.
cCC50(µM): IC50 values indicate concentration required to reduce cell viability by
50%.
In summary, based on the potent anti-HIV activity of 6ꢁ-electropositive
nucleosides and 5ꢁ-norcarbocyclic nucleoside analogues, we have designed
and successfully synthesized novel 6ꢁ,6ꢁ-difluoro-5ꢁ-norcarbocyclic nucleo-
side analogues starting from epichlorohydrin 5. Although the adenine 5ꢁ-
nornucleoside analogue 3 inhibits in vitro anti-HIV activity comparable to
that of d4T, the synthesized carbocyclic version 21 shows weak anti-HIV
activity. Because rigid cyclopentene carbocycles are not perfect mimics for
ribofuranose moiety, the mechanisms of virus inhibition, i.e., either phos-
phorylation or inhibition of RNA synthesis, might be impaired in these
compounds. Difluorination of 6ꢁ-position is another possible reason for the
apparent lack of activity. Figure 3 shows the superposition of the calculated
low energy conformers of 3 and 21, highlighting the two different parts such
as purine bases and phosphonic acid functional moieties.
The synthesized nucleoside prodrug 29 exhibited encouraging improve-
ment in cell-based activity compared with phosphonic acid 21. A significant
FIGURE 3 Superimposed conformations of nucleoside analogue 3, as anti-HIV agent and an adenosine
phosphonic acid derivative 21. The lowest energy conformation for each molecule was calculated with
the modeling package Spartan 02i and energy minimization with semi-empirical force field (PM3).

6ꢁ,6ꢁ-Difluoro-5ꢁ-Norcarbocyclic Nucleoside Analogues
805
step forward in terms of activity could then be made with the introduction
of SATE protecting group as a prodrug scaffold.
EXPERIMENTAL
Melting points were determined on a Mel-temp II laboratory device and
remain uncorrected. NMR spectra were recorded on a JEOL 300 Fourier
transform spectrometer (JEOL, Tokyo, Japan); chemical shifts are reported
in parts per million (δ) and signals are reported as s (singlet), d (dou-
blet), t (triplet), q (quartet), m (multiplet), and dd (doublet of doublets).
UV spectra were obtained on a Beckman DU-7 spectrophotometer (Beck-
man, South Pasadena, CA, USA). MS spectra were collected in electrospray
ionization (ESI) mode. The elemental analyses were performed using a
Perkin-Elmer 2400 analyzer (Perkin-Elmer, Norwalk, CT, USA). TLC was
performed on Uniplates (silica gel) purchased from Analtech Co. (7558,
Newark, DE, USA). All reactions were carried out under an atmosphere
of nitrogen, unless otherwise specified. Dry dichloromethane, benzene,
and pyridine were obtained by distillation from CaH2. Dry THF was ob-
tained by distillation from Na and benzophenone immediately prior to
use.
2,2-Difluoro-1,3-bis-benzyloxy-propane (7): A solution of compound 6
(129 mg, 0.48 mmol) in anhydrous CH2Cl2 (38 mL) was treated with DAST
(0.496 mL, 3.76 mmol) under argon at room temperature. The reaction
mixture was stirred for 6 hours and was then quenched by adding a satu-
rated solution of NaHCO3 in water. The organic phase was separated, and
the aqueous layer was extracted with CH2Cl2 (3 × 80 mL). The organic
layer was dried over anhydrous magnesium sulfate, filtered, and evaporated
to dryness. The residue was purified by silica gel column chromatography
(EtOAc/hexane, 1:10) to give the gem-difluorinated product 7 (91 mg, 65%)
as a colorless syrup: 1H NMR (CDCl3, 300 MHz) δ 7.34–7.28 (m, 10H), 4.65
(s, 4H), 3.71 (t, J = 9.8 Hz, 4H); 13C NMR (CDCl3, 75 MHz) δ 136.1, 128.5,
128.3, 128.0, 113.9 (t, J = 213 Hz), 78.5 (t, J = 20.8 Hz), 74.1; Anal. Calc.
for C17H18F2O2: C, 69.85; H, 6.21; Found: C, 69.82; H, 6.18; MS m/z 293
(M+H)+.
2,2-Difluoro-1,3-bis-hydroxy-propane (8): To a solution of 7 (450 mg,
1.54 mmol) in n-propanol (10 mL), Pd/C (10%, 340 mg, 0.31 mmol) was
added. The mixture was thoroughly deoxygenated, saturated with hydrogen
gas (1.1 bar), and then stirred at 50◦C for 24 hours. The charcoal was then
removed by filtration through a short Celite pad. The filtrate was concen-
trated to dryness to give crude 8 (165.7 mg, 96%), which was subjected to
the next reaction procedure without further purification.
3-(t-Butyldimethylsilanyloxy)-2,2-difluoro-propan-1-ol (9): To a stirred so-
lution of previous compound 8 (165.7 mg, 1.478 mmol) and imidazole (201

806
E. Kim et al.
mg, 2.956 mmol) in anhydrous DMF (8 mL), t-butyldimethylsilyl chloride
(269 mg, 1.625 mmol) was slowly added at 0◦C. The mixture was stirred at the
same temperature for 4 hours, and quenched by adding a NaHCO3 aqueous
solution (3 mL). The mixture was extracted using diethyl ether (80 mL ×
2), dried over MgSO4, filtered, and then evaporated to dryness. The residue
was purified by silica gel column chromatography (EtOAc/hexane, 1:7) to
give 9 (217 mg, 65%) as a colorless syrup: 1H NMR (CDCl3, 300 MHz) δ 4.20
(t, J = 8.1 Hz, 2H), 3.86 (t, J = 8.6 Hz, 2H), 0.83 (s, 9H), 0.02 (s, 6H); 13
C
NMR (CDCl3, 75 MHz) δ 119.5 (t, J = 210.2 Hz), 72.2 (t, J = 20.3 Hz), 68.5
(t, J = 19.8 Hz), 25.6, 18.4, -5.4; Anal. Calc. for C9H20F2O2Si: C, 47.76; H,
8.91; Found: C, 47.79; H, 8.88; MS m/z 227 (M+H)+.
3-(t-Butyldimethylsilanyloxy)-2,2-difluoro-propenal (10): To a mixture of
allylic alcohol 9 (468 mg, 2.07 mmol), manganese (IV) dioxide (539 mg,
6.2 mmol) and CCl4 (10 mL) were added and refluxed overnight. Additional
manganese (IV) dioxide (90 mg, 1.03 mmol) was added and refluxed for an
additional 12 hours. The progress of the reaction was monitored by TLC.
The resulting mixture was filtered through a pad of celite, and then washed
with ethyl acetate. The filtrate and washings were condensed in vacuo and the
residue was purified by silica gel column chromatography (EtOAc/hexane,
1:20) to give α,β-unsaturated aldehyde 10 (339 mg, 73%) as a colorless oil.
1H NMR (CDCl3, 300 MHz) δ 9.73 (s, 1H), 4.48 (t, J = 9.4 Hz, 2H), 0.83 (s,
9H), 0.02 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 119.5 (t, J = 211.2 Hz), 72.2
(t, J = 18.6 Hz), 68.9 (t, J = 19.6 Hz), 25.6, 18.4, −5.4; MS m/z 225 (M+H)+.
( )-5-(t-Butyldimethylsilanyloxy)-4,4-difluoro-pent-1-en-3-ol (11): To a
solution of 10 (1.05 g, 4.68 mmol) in dry THF (12 mL), vinylmagnesium
bromide (5.14 mL, 1.0 M solution in THF) was slowly added at 0◦C and
stirred 6 hours at 0◦C. Saturated NH4Cl solution (5 mL) was added to the
mixture, which was slowly warmed to room temperature. The mixture was
diluted with water (100 mL) and extracted with EtOAc (2 × 100 mL). The
combined organic layer was washed with brine, dried over anhydrous MgSO4,
filtered, and evaporated to dryness. The residue was purified by silica gel col-
umn chromatography (EtOAc/hexane, 1:15) to give 11 (944 mg, 80%) as a
colorless oil: 1H NMR (CDCl3, 300 MHz) δ 5.93 (m, 1H), 5.29–5.24 (m, 2H),
4.47 (m, 1H), 4.13 (m, 2H), 0.81 (s, 9H), 0.01 (s, 6H); 13C NMR (CDCl3, 75
MHz) δ 139.5, 122.2 (t, J = 198.2 Hz), 81.5 (dd, J = 20.8, 18.9 Hz), 70.6 (t,
J = 20.1 Hz), 25.2, 18.7, -5.6; Anal. Calc. for C11H22F2O2Si: C, 52.35; H, 8.79;
Found: C, 52.39; H, 8.81; MS m/z 253 (M+H)+.
( )-t-Butyl-[2,2-difluoro-3-(4-methoxybenzyloxy)-pent-4-enyloxy]-
dimethylsilane (12): NaH (60% in mineral oil, 66.4 mg, 1.66 mmol) was
added portion-wise to a cooled (0◦C) solution of secondary alcohol 11 (349
mg, 1.385 mmol) and p-methoxybenzyl chloride (0.206 mL, 1.52 mmol)
in anhydrous DMF (6 mL). The reaction mixture was stirred overnight
at room temperature. The solvent was removed in vacuo and the residue
was diluted with H2O (60 mL) followed by extraction with diethyl ether

6ꢁ,6ꢁ-Difluoro-5ꢁ-Norcarbocyclic Nucleoside Analogues
807
(2 × 60 mL). The combined organic layer was washed with brine, dried
over anhydrous MgSO4, and concentrated under vacuum. The residue was
purified by silica gel column chromatography (EtOAc/hexane, 1:16) to give
12 (376 mg, 73%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.31–7.25
(m, 2H), 6.94–6.88 (m, 2H), 5.90 (m, 1H), 5.29–5.24 (m, 2H), 4.63 (s,
2H), 4.49 (s, 2H), 4.11–4.08 (m, 2H), 3.74 (s, 3H), 0.82 (s, 9H), 0.01 (s,
6H); 13C NMR (CDCl3, 75 MHz) δ 159.3, 138.6, 130.5, 129.3, 122.0 (dd, J =
201.2, 50.2 Hz), 115.5, 114.2, 84.1 (dd, J = 19.8, 17.4 Hz), 73.6, 70.3 (t, J =
19.4 Hz), 56.3, 25.7, 18.4, −5.5; Anal. Calc. for C19H30F2O3Si: C, 61.26; H,
8.12; Found: C, 61.28; H, 8.10; MS m/z 373 (M+H)+.
( )-2,2-Difluoro-3-(4-methoxybenzyloxy)-pent-4-en-1-ol (13): To a solu-
tion of 12 (1.05 g, 2.82 mmol) in THF (20 mL), TBAF (4.2 mL, 1.0 M
solution in THF) was added at 0◦C. The mixture was stirred overnight at
room temperature and concentrated in vacuo. The residue was purified by
silica gel column chromatography (Hexane/EtOAc, 4:1) to give 13 (670 mg,
92%): 1H NMR (CDCl3, 300 MHz) δ 7.30–7.23 (m, 2H), 6.92–6.85 (m, 2H),
5.89 (m, 1H), 5.32–5.25 (m, 2H), 4.64 (s, 2H), 4.08 (m, 2H), 3.87 (m, 2H),
3.75 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 159.4, 138.2, 130.7, 128.2, 120.5
(dd, J = 208.6, 32.8 Hz), 116.0, 114.1, 83.5 (dd, J = 20.4, 14.7 Hz), 73.6,
67.2 (dd, J = 18.8, 10.6 Hz), 56.3; Anal. Calc. for C13H16F2O3: C, 61.26; H,
8.12; Found: C, 61.28; H, 8.10; MS m/z 259 (M+H)+.
( )-2,2-Difluoro-3-(4-methoxybenzyloxy)-2-methylene-pent-4-enal (14):
Difluorinated aldehyde derivative 14 was synthesized from 13 by a similar
procedure as described for 10: yield 87%; 1H NMR (CDCl3, 300 MHz) δ 9.79
(m, 1H), 7.30–7.23 (m, 2H), 6.91–6.85 (m, 2H), 5.89 (m, 1H), 5.27–5.23
(m, 2H), 4.62 (s, 2H), 4.27–4.23 (m, 1H), 3.71 (s, 3H); 13C NMR (CDCl3,
75 MHz) δ 159.5, 137.8 (dd, J = 220.4, 53.2 Hz), 136.3, 131.1, 129.6, 115.9,
115.2, 80.2 (dd, J = 20.4, 14.6 Hz), 74.0, 56.1.
(rel)-(3R and3S,5S)-4,4-Difluoro-5-(4-methoxy-benzyloxy)-hepta-1,6-dien-
3-ol (15): Divinyl analogue 15 was synthesized as a diastereomeric mix-
ture from aldehyde derivative 14 by a procedure similar to that described
1
for 15 as diastereomeric mixture: yield 75%; H NMR (CDCl3, 300 MHz)
δ 7.32–7.23 (m, 2H), 6.93–6.83 (m, 2H), 5.91–5.87 (m, 2H), 5.25–5.21
(m, 4H), 4.65 (m, 2H), 4.45 (m, 1H), 4.12–4.06 (m, 1H), 3.74 (s, 3H).
(rel)-(1S,4R)-5,5-Difluoro-4-(4-methoxy-benzyloxy)-cyclopent-2-enol (16a)
and (rel)-(1R,4R)-5,5-difluoro-4-(4-methoxy-benzyloxy)-cyclopent-2-enol (16b):
To a solution of 15 (160 mg, 0.562 mmol) in dry methylene chloride (6 mL)
was added second generation Grubbs catalyst (30.0 mg, 0.0352 mmol). The
reaction mixture was refluxed overnight and cooled to room temperature.
The mixture was concentrated in vacuo, and the residue was purified by silica
gel column chromatography (EtOAc/hexane, 1:10) to give cyclopentenol
1
16a (50 mg, 35%) and 16b (52 mg, 36%). Data for 16a: H NMR (CDCl3,
300 MHz) δ 7.33–7.27 (m, 2H), 6.93–6.85 (m, 2H), 5.62–5.47 (m, 2H),
4.62–4.57 (m, 3H), 4.21 (m, 1H), 3.74 (s, 3H); 13C NMR (CDCl3, 75 MHz)

808
E. Kim et al.
δ 159.6, 131.2, 130.7, 129.2, 122.7 (dd, J = 210.2, 60.5 Hz), 115.2, 84.6 (dd,
J = 20.2, 10.4 Hz), 80.3 (ddd, J = 18.8, 10.8, 2.8 Hz), 74.2, 57.1; Anal. Calc.
for C13H14F2O3: C, 60.93; H, 5.51; Found: C, 60.89; H, 5.49; MS m/z 257
1
(M+H)+; Data for 16b: H NMR (CDCl3, 300 MHz) δ 7.30–7.24 (m, 2H),
6.90–6.82 (m, 2H), 5.61–5.45 (m, 2H), 4.61–4.55 (m, 3H), 4.21–4.18 (m,
1H), 3.74 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 159.4, 131.0, 130.1, 128.8,
123.1 (dd, J = 208.2, 48.6 Hz), 114.4, 83.8 (dd, J = 18.8, 12.6 Hz), 79.5 (dd,
J = 19.0, 10.2 Hz), 73.9, 56.5; Anal. Calc. for C13H14F2O3: C, 60.93; H, 5.51;
Found: C, 60.89; H, 5.49; MS m/z 257 (M+H)+.
(rel)-(1S,4R)-9-[5,5-Difluoro-4-(4-methoxybenzyloxy)-cyclopent-2-en-1-
yl] 6-chloropurine (17): To a solution containing compound 16b
(95 mg, 0.372 mmol), triphenylphosphine (264 mg, 1.008 mmol), and
6-chloropurine (115 mg, 0.744 mmol) in anhydrous cosolvent (1,4-dioxane,
4.0 mL and DMF, 3.0 mL), diethyl azodicarboxylate (DEAD) (0.135 mL,
0.744 mmol) was added dropwise at −30◦C for 15 minutes under nitrogen.
The reaction mixture was stirred for 2 hours at the same temperature under
nitrogen and further stirred overnight at room temperature. The solvent
was evaporated to dryness and the residue was purified by silica gel column
chromatography (EtOAc/hexane, 2:1) to give compound 17 (74 mg, 51%):
mp 168–171◦C; UV (MeOH) λmax 263.5 nm: 1H NMR (CDCl3, 300 MHz) δ
8.68 (s, 1H), 8.29 (s, 1H), 7.27–7.20 (m, 2H), 6.90–6.85 (m, 2H), 5.63–5.57
(m, 2H), 5.05 (m, 1H), 4.65 (s, 2H), 4.18 (ddd, J = 16.2, 10.0, 2.8 Hz,
1H), 3.74 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 159.5, 151.6, 151.0, 145.2,
132.4, 130.7, 129.8, 128.9, 119.0 (dd, J = 198.4, 50.6 Hz), 115.8, 85.2 (dd,
J = 18.6, 12.4 Hz), 73.8, 65.2 (dd, J = 20.2, 10.4 Hz), 57.5; Anal. Calc. for
C18H15ClF2N4O2: C, 55.04; H, 3.85; N, 14.26; Found: C, 55.09; H, 3.81; N,
14.23; MS m/z 393 (M+H)+.
(rel)-(1S,4R)-9-(5,5-Difluoro-4-hydroxy-cyclopent-2-en-1-yl)
6-chloropurine (18): To a solution of compound 17 (199 mg, 0.507 mmol)
in CH2Cl2/H2O (10 mL, 10:1 v/v) was added DDQ (170 mg, 0.747 mmol),
and the mixture was stirred overnight at room temperature. Saturated
NaHCO3 (1.2 mL) was added to quench the reaction, which was then stirred
for 3 hours at room temperature. The mixture was diluted with water (150
mL) and extracted with CH2Cl2 (3 × 150 mL). The combined organic layer
was dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to
dryness and the residue was purified by silica gel column chromatography
(EtOAc/hexane/MeOH, 4:1:0.03) to give compound 18 (83 mg, 60%): mp
176–178◦C; UV (MeOH) λmax 265.0 nm; 1H NMR (DMSO-d6, 300 MHz) δ
8.67 (s, 1H), 8.28 (s, 1H), 5.63–5.59 (m, 2H), 5.04–5.00 (dd, J = 16.8, 9.8 Hz,
1H), 4.56–4.52 (m, 1H); 13C NMR (DMSO-d6, 75 MHz) δ 151.7, 151.3,
151.1, 145.2, 132.5, 130.2, 129.3, 121.1 (dd, J = 192.2, 40.2 Hz), 81.5 (dd,
J = 18.4, 12.0 Hz), 64.6 (dd, J = 19.4, 11.0 Hz); Anal. Calc. for
C10H7ClF2N4O: C, 44.05; H, 2.59; N, 20.55; Found: C, 44.01; H, 2.61; N,
20.53; MS m/z 273 (M+H)+.

6ꢁ,6ꢁ-Difluoro-5ꢁ-Norcarbocyclic Nucleoside Analogues
809
(rel)-(1S,4R)-Diethyl [9-(5,5-difluoro-4-hydroxy-cyclopent-2-en-1-yl) 6-
chloropurine] phosphonate (19): Both LiOt-Bu (1.488 mL of 0.5 M solution
in THF, 0.744 mmol) and a solution of diethyl phosphonomethyltriflate
(209 mg, 0.696 mmol) in 6.0 mL of THF were slowly added to a solution of
nucleoside analogue 18 (95 mg, 0.348 mmol) in 6.0 mL of THF at −40◦C
and stirred overnight at room temperature under nitrogen. The mixture
was quenched by adding saturated NH4Cl solution (5 mL) and further di-
luted with additional H2O (100 mL). The aqueous layer was extracted with
EtOAc (3 × 100 mL). The combined organic layer was dried over anhy-
drous MgSO4 and evaporated to dryness. The residue was purified by silica
gel column chromatography (MeOH/Hexane/EtOAc, 0.03:4:1) to give 19
(85 mg, 58%) as a foam: 1H NMR (DMSO-d6, 300 MHz) δ 8.69 (s, 1H), 8.28
(s, 1H), 5.62–5.56 (m, 2H), 5.03–4.97 (ddd, J = 18.6, 10.3, 3.2 Hz, 1H),
4.35–4.31 (m, 4H), 4.13 (m, 1H), 4.01 (d, J = 8.1 Hz, 2H), 1.37 (m 6H); 13C
NMR (DMSO-d6, 75 MHz) δ 151.6, 151.0, 145.3, 132.6, 130.6, 128.7, 118.1
(dd, J = 190.6, 52.4 Hz), 88.5 (dd, J = 19.8, 10.2 Hz), 66.3 (dd, J = 18.8,
9.8 Hz), 64.8, 63.2, 14.7; Anal. Calc. for C15H18ClF2N4O4P: C, 42.62; H, 4.29;
N, 13.25; Found: C, 42.59; H, 4.31; N, 13.22; MS m/z 423 (M+H)+.
(rel)-(1S,4R)-Diethyl [9-(5,5-difluoro-4-hydroxy-cyclopent-2-en-1-yl) ade-
nine] phosphonate (20): A solution of 19 (120 mg, 0.283 mmol) in saturated
methanolic ammonia (10 mL) was stirred for 12 hours at 65◦C in a steel
bomb, and the volatiles were evaporated to dryness. The residue was pu-
rified by silica gel column chromatography (MeOH/CH2Cl2, 1:10) to give
20 (69 mg, 61%) as a white solid: mp 158–161◦C; UV (MeOH) λmax 262.5
nm; 1H NMR (DMSO-d6, 300 MHz) δ 8.29 (s, 1H), 8.18 (s, 1H), 5.63–5.58
(m, 2H), 5.04 (dd, J = 19.2, 10.8 Hz, 1H), 4.34–4.30 (m, 4H), 4.18 (m,
1H), 3.99 (d, J = 8.2 Hz, 2H), 1.36 (m 6H); 13C NMR (DMSO-d6, 75 MHz) δ
155.3, 152.6, 150.4, 130.4, 119.3, 117.2 (dd, J = 196.7, 42.8 Hz), 87.1 (dd, J =
19.2, 11.0 Hz), 65.3 (dd, J = 19.0, 10.4 Hz), 64.2, 63.4, 15.1; Anal. Calc. for
C15H20F2N5O4P (+ MeOH): C, 44.14; H, 5.56; N, 16.08; Found: C, 44.11; H,
5.53; N, 16.10; MS m/z 404 (M+H)+.
(rel)-(1S,4R)-[9-(5,5-Difluoro-4-hydroxy-cyclopent-2-en-1-yl) adenine] 4-
phosphonic acid (21): To a solution of the nucleoside phosphonate 20
(84 mg, 0.21 mmol) in anhydrous CH3CN (8 mL) and 2,6-lutidine (0.489 mL,
4.2 mmol) was added trimethylsilyl bromide (0.277 mL, 2.1 mmol). The mix-
ture was heated for 12 hours at 50◦C under nitrogen gas and then concen-
trated in vacuo. The residue was partitioned between CH2Cl2 (60 mL) and
distilled purified water (50 mL). The aqueous layer was washed with CH2Cl2
(2 × 60 mL) and then freeze-dried to give phosphonic acid 21 (67 mg,
92%) as a yellowish foam: UV (H2O) λmax 265.5 nm; 1H NMR (DMSO-d6,
300 MHz) δ 8.26 (s, 1H), 8.12 (s, 1H), 5.62-5.57 (m, 2H), 5.01 (ddd, J =
19.6, 11.0, 2.8 Hz, 1H), 4.19 (ddd, J = 18.8, 10.8, 3.4 Hz, 1H), 3.98 (d,
J = 8.0 Hz, 2H); 13C NMR (DMSO-d6, 75 MHz) δ 154.7, 152.5, 150.3, 130.7,
129.2, 119.3, 117.7 (dd, J = 198.2, 52.8 Hz), 88.0 (dd, J = 20.4, 9.8 Hz), 64.5

810
E. Kim et al.
(dd, J = 19.2, 10.2 Hz), 63.4, 62.8; Anal. Calc. for C11H12F2N5O4P (+H2O):
C, 36.17; H, 3.86; N, 19.18; Found: C, 36.15; H, 3.85; N, 19.20; MS m/z 348
(M+H)+.
(rel)-(1R,4R)-[5,5-Difluoro-4-(4-methoxybenzyloxy)-cyclopent-2-enyloxy
methyl]-phosphonic acid diethyl ester (22): Diethylphosphonate analogue
22 was synthesized from 16b by a similar procedure used for 19: yield
59%; 1H NMR (CDCl3, 300 MHz) δ 7.28–7.23 (m, 2H), 6.90–6.85 (m, 2H),
5.61–5.58 (m, 2H), 4.46 (s, 2H), 4.34–4.30 (m, 4H), 4.18–4.14 (m, 2H), 4.02
(d, J = 8.2 Hz, 2H), 3.74 (s, 3H), 1.36 (m 6H); 13C NMR (CDCl3, 75 MHz)
δ 159.4, 130.6, 129.4, 119.4 (dd, J = 194.6, 50.4 Hz), 116. 3, 86.5 (dd, J =
19.4, 10.6 Hz), 73.2, 64.7, 63.3 (dd, J = 18.4, 9.2 Hz), 62.6, 55.3, 14.3; Anal.
Calc. for C18H25F2O6P: C, 53.20; H, 6.20; Found: C, 53.24; H, 6.17; MS m/z
407 (M+H)+.
(rel)-(1R,4R)-(5,5-Difluoro-4-hydroxy-cyclopent-2-enyloxymethyl)-
phosphonic acid diethyl ester (23): Deprotection of 22 was performed
under a similar procedure as described for the preparation of 18: yield
64%; 1H NMR (CDCl3, 300 MHz) δ 5.62–5.58 (m, 2H), 4.58 (ddd, J = 18.6,
10.2, 2.8 Hz, 1H), 4.32–4.28 (m, 4H), 4.18 (ddd, J = 19.2, 12.6, 4.0 Hz, 1H),
4.01 (d, J = 8.0 Hz, 2H), 1.37 (m 6H); 13C NMR (CDCl3, 75 MHz) δ 130.6,
129.7, 122.2 (dd, J = 190.6, 44.8 Hz), 86.7 (dd, J = 21.2, 10.6 Hz), 79.4 (dd,
J = 19.7, 10.5 Hz), 64.5, 63.8, 14.5; Anal. Calc. for C10H17F2O5P: C, 41.96;
H, 5.99; Found: C, 41.99; H, 6.01; MS m/z 287 (M+H)+.
(rel)-(1S,4R)-Diethyl [9-(5,5-difluoro-4-hydroxy-cyclopent-2-en-1-yl) 2-
fluoro-6-chloropurine] phosphonate (24): Mitsunobu coupling of 23 with
2-fluoro-6-chloropurine was performed under a similar reaction condition
as described for 17: yield 46%; UV (MeOH) λmax 269.5 nm; 1H NMR (CDCl3,
300 MHz) δ 8.41 (s, 1H), 5.61–5.54 (m, 2H), 5.08 (ddd, J = 19.2, 11.4, 3.4
Hz, 1H), 4.27–4.20 (m, 5H), 4.00 (d, J = 8.1 Hz, 2H), 1.37 (m 6H); 13C NMR
(CDCl3, 75 MHz) δ 155.2, 152.7, 148.2, 144.5, 130.6, 129.2, 128.4, 118.3 (dd,
J = 194.2, 58.6 Hz), 87.3 (dd, J = 20.4, 9.8 Hz), 66.4 (dd, J = 18.9, 8.8 Hz),
64.5, 63.6, 62.4, 16.3; Anal. Calc. for C15H17ClF3N4O4P: C, 40.88; H, 3.89; N,
12.71; Found: C, 40.92; H, 3.92; N, 12.68; MS m/z 441 (M+H)+.
(rel)-(1S,4R)-Diethyl [9-(5,5-difluoro-4-hydroxy-cyclopent-2-en-1-yl) 2-
fluoro-6-aminopurine] phosphonate (25) and (rel)-(1ꢁS,4ꢁR)-diethyl [9-
(5,5-difluoro-4-hydroxy-cyclopent-2-en-1-yl) 2-amino-6-chloropurine] phos-
phonate (26): Dry ammonia gas was bubbled into a stirred solution of 24
(560 mg, 1.27 mmol) in DME (20 mL) at room temperature overnight.
The salts were removed by filtration and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column chromatog-
raphy (MeOH/CH2Cl2, 1:12) to give 25 (75 mg, 14%) and 26 (305 mg, 55%),
respectively: Data for 25; UV (MeOH) λmax 268.0 nm; 1H NMR (DMSO-d6,
300 MHz) δ 8.43 (s, 1H), 5.60–5.57 (m, 2H), 5.03 (dd, J = 19.0, 10.2 Hz,
1H), 4.23–4.17 (m, 5H), 4.03 (d, J = 8.0 Hz, 2H), 1.35–1.38 (m 6H); 13C
NMR (DMSO-d6, 75 MHz) δ 154.6, 152.2, 147.3, 145.6, 130.8, 129.5, 128.6,

6ꢁ,6ꢁ-Difluoro-5ꢁ-Norcarbocyclic Nucleoside Analogues
811
118.6 (dd, J = 196.6, 52.8 Hz), 86.2 (dd, J = 20.2, 9.4 Hz), 65.2 (dd, J =
19.8, 9.4 Hz), 63.8, 62.9, 17.1; Anal. Calc. for C15H19F3N5O4P: C, 42.76; H,
4.55; N, 16.62; Found: C, 42.79; H, 4.57; N, 16.59; MS m/z 422 (M+H)+.
Data for 26; UV (MeOH) λmax 310.0 nm; 1H NMR (DMSO-d6, 300 MHz) δ
8.43 (s, 1H), 5.62–5.58 (m, 2H), 5.04 (dd, J = 19.3, 10.4 Hz, 1H), 4.21–4.16
(m, 5H), 4.01 (d, J = 8.0 Hz, 2H), 1.36 (m 6H); 13C NMR (DMSO-d6, 75
MHz) δ 155.7, 153.1, 148.3, 144.9, 130.5, 129.2, 128.2, 118.6 (dd, J = 198.1,
56.2 Hz), 88.1 (dd, J = 20.7, 9.6 Hz), 64.6 (dd, J = 19.4, 9.9 Hz), 63.4, 62.5,
16.5; Anal. Calc. for C15H19F3N5O4P: C, 42.76; H, 4.55; N, 16.62; Found: C,
42.71; H, 4.54; N, 16.65; MS m/z 438 (M+H)+.
(rel)-(1S,4R)-9-(5,5-difluoro-4-hydroxy-cyclopent-2-en-1-yl) guanine]
phosphonic acid (27): To a solution of 26 (20.8 mg, 0.0495 mmol) dry
DMF (7 mL) was added trimethylsilyl bromide (114 µL, 0.862 mmol) at
room temperature. After this mixture was stirred for 2 days, the solvent was
removed, co-evaporating three times with methanol. The residue was dis-
solved in MeOH (2.0 mL) and 2-mercaptoethanol (13.9 µL, 0.198 mmol)
and NaOMe (10.7 mg, 0.198 mmol) was added to the mixture. The mix-
ture was refluxed for 5 hours under N2, cooled, neutralized with glacial
AcOH, and evaporated to dryness under vacuum. The residue was purified
by chromatography on a column of reversed-phase C18 silica gel eluting
water to give 27 (6.8 mg, 66%) as a solid. UV (MeOH) λmax 254.0 nm; 1H
NMR (DMSO-d6, 300 MHz) δ 7.98 (s, 1H), 5.61–5.56 (m, 2H), 5.02 (ddd, J
= 20.4, 10.6, 3.2 Hz, 1H), 4.16 (ddd, J = 18.8, 9.6, 2.8 Hz, 1H), 4.00 (d, J
= 8.1 Hz, 2H); 13C NMR (DMSO-d6, 75 MHz) δ 157.2, 153.8, 149.1, 141.5,
131.1, 130.2, 119.5, 118.2 (dd, J = 192.5, 46.6 Hz), 86.5 (dd, J = 19.4, 10.2
Hz), 64.5, 54.4 (dd, J = 19.6, 9.8 Hz); Anal. Calc. for C11H12F2N5O5P (+1.0
H2O): C, 34.66; H, 3.70; N, 18.37; Found: C, 34.64; H, 3.68; N, 18.40; MS m/z
364 (M+H)+.
(rel)-(1S,4R)-Bis(SATE) phosphoester of [9-(5,5-difluoro-4-hydroxy-
cyclopent-2-en-1-yl] adenine (29): A solution of adenine phosphonic acid
derivative 21 (117 mg, 0.338 mmol) and tri-n-butylamine (189 mg,
1.02 mmol) in methanol (8 mL) was mixed for 30 minutes and evapo-
rated to dryness under reduced pressure. The residue was thoroughly dried
with anhydrous ethanol and toluene. The resulting foamy solid was dissolved
in anhydrous pyridine (20 mL), to which thioester 28 (1.04 g, 6.4 mmol)
and 1-(2-mesitylenesulfonyl)-3-nitro-1H-1,2,4-triazole (402 mg, 1.356 mmol)
were added. The mixture was stirred overnight at room temperature and
quenched with tetrabutylammonium bicarbonate buffer (20.0 mL, 1 M so-
lution, pH 8.0). The mixture was concentrated under reduced pressure and
the residue was diluted with water (150 mL) and extracted with CHCl3 (150
mL) two times. The combined organic layer was washed with brine, dried
over Na2SO4, filtered, and evaporated to dryness under vacuum. The residue
was purified by silica gel column chromatography (MeOH/Hexane/EtOAc,
0.04:3:1) to give 29 (68 mg, 32%) as a white solid: mp 140–143◦C; UV

812
E. Kim et al.
(MeOH) λmax 260.0 nm; 1H NMR (CDCl3, 300 MHz) δ 8.28 (s, 1H), 8.11 (s,
1H), 5.59–5.54 (m, 2H), 5.02 (dd, J = 18.8, 10.2 Hz, 1H), 4.21–4.15 (m, 3H),
3.94–3.94 (m, 4H), 3.18–3.15 (m, 4H), 1.23–1.19 (m, 18); 13C NMR (CDCl3,
75 MHz) δ 202.9, 154.8, 152.2, 147.5, 144.6, 130.7, 129.0, 119.8, 118.2 (dd, J
= 190.3, 48.8 Hz), 87.7 (dd, J = 19.8, 10.2 Hz), 65.8 (dd, J = 20.0, 9.8 Hz),
64.3, 62.8, 58.5, 49.3, 34.8, 25.7; Anal. Calc. for C25H36F2N5O6PS2 (+ 1.0
MeOH): C, 46.76; H, 6.04; N, 10.49; Found: C, 46.79; H, 6.02; N, 10.51; MS
m/z 636 (M+H)+.
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