Synthesis of acyclic nucleotide analogues possessing a difluoromethylene phosphonyl group at the side chain

Article abstract of DOI:10.1016/j.tet.2003.10.064

A synthetic approach to a new type of acyclic nucleotide analogues 8 and 9 was examined. The design was based on acyclic modification of MRS 2179, a P2Y₁-antagonist, and replacement of one of two phosphate groups characterized by MRS 2179 with an isosteric difluoromethylenephosphonyl group. The nucleotide analogues 8 and 9 were enantio-divergently prepared as their ester-protecting derivatives from a highly differentiated 1,5-pentanediol derivative possessing a difluoromethylenephosphonyl group at the 3-position.

Full text of DOI:10.1016/j.tet.2003.10.064

Tetrahedron 59 (2003) 10223–10230
Synthesis of acyclic nucleotide analogues possessing a
difluoromethylene phosphonyl group at the side chain
*
Tetsuo Murano, Yoko Yuasa, Hirokuni Kobayakawa, Tsutomu Yokomatsu
and Shiroshi Shibuya
*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 4 October 2003; revised 22 October 2003; accepted 22 October 2003
Abstract—A synthetic approach to a new type of acyclic nucleotide analogues 8 and 9 was examined. The design was based on acyclic
modification of MRS 2179, a P2Y1-antagonist, and replacement of one of two phosphate groups characterized by MRS 2179 with an isosteric
difluoromethylenephosphonyl group. The nucleotide analogues 8 and 9 were enantio-divergently prepared as their ester-protecting
derivatives from a highly differentiated 1,5-pentanediol derivative possessing a difluoromethylenephosphonyl group at the 3-position.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
modified in the base and ribose moieties have been designed
and synthesized.7 For instance, the introduction of chlorine
atom at the 2-position and the N 6-methyl modification
resulted in the enhancement of antagonistic activity.
N 6-Methyl-20-deoxyadenosine 30,50-bisphosphate 3 greatly
enhanced competitive antagonistic activity more than the
parent A3P5P (Fig. 1).
Numerous kinds of nucleoside and nucleotide analogues have
been synthesized based on the modification of naturally
occurring nucleosides and nucleotides by an application of
bioisosteres to develop biologically active compounds which
are more resistant to enzymatic hydrolysis and degradation.
The incorporation of a biomimetic functional group to the
parent compounds confers on them a promising usefulness in
the search for new therapeutic agents.1 We are interested in a
synthesis of P2Y receptor agonists and antagonists by
modification of adenosine bisphophates, which have been
known to show affinity to P2Y receptors.
A variety of modified cyclic and acyclic nucleotide
Agonist binding at P2Y1 receptors is known to result in
activation of phospholipase C (PLC), which generates
inositol phosphates and diacylglycerol from phosphatidyl-
inositol 4,5-bisphosphate.2 The P2Y1 receptor is present in
heart, skeletal and various smooth muscles, prostate, ovary,
and brain.3 A P2Y1 receptor in platelets is involved in
ADP-promoted aggregation.4 Thus, a selective P2Y1
receptor antagonist may have potential as an antithrombotic
agent, while a selective receptor agonist may have potential
as an antihypertensive or antidiabetic agent.5 The bis-
phosphate derivatives of naturally occurring nucleosides
including adenosine 30,50-bisphosphate 1 (A3P5P) and
adenosine 20,50-bisphosphate 2 (A2P5P) were reported to
act as competitive antagonists or partial agonists of P2Y1
receptors.6 A new series of deoxyadenosine bisphosphates
Keywords: acyclic nucleotide analogues; difluoromethylenephosphonates;
adenosine bisphosphates; MRS 2179; P2Y receptors.
*
Corresponding authors. Tel.: þ81426763251; fax: þ81426763239
(T.Y.); tel./fax: þ81426766576 (Y.Y.);
e-mails: yokomatu@ps.toyaku.ac.jp; yuasay@ps.toyaku.ac.jp
Figure 1.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.10.064

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T. Murano et al. / Tetrahedron 59 (2003) 10223–10230
of two phosphate groups characterized by adenosine
bisphosphates and their acyclic analogues. Herein, we
wish to report an enantio-divergent synthesis of a new class
of nucleotide analogues 24 and 28, protecting derivatives of
8 and 9 (Fig. 3).
2. Results and discussion
2.1. Synthesis of protected 1,5-pentanediol derivatives
possessing a difluoromethylenephosphonate moiety
The concept of the synthetic approach to the nucleotide
analogues 8 and 9 is based on the following two points. One
is the modification of 20-deoxyadenosine bisphosphate
derivative 10 (MRS 2179) to an acyclic structure by
removal of the oxygen atom from the 2-deoxyfuranose
ring. Since bisphosphate 10 was reported to show
potentially antagonistic activity to P2Y1, investigation on
the synthesis of the acyclic analogues is of considerable
interest from the study aimed at synthesis of a biological
probe for this receptor and its ligand (Fig. 4).
Figure 2.
analogues were synthesized to discuss the structure–
activity relationships to P2Y1 receptor antagonists and
agonists.7 The synthetic study of pharmacological probes
for the selective P2Y1 agonists and antagonists with high
affinity is an interesting subject not only for the discovery of
new therapeutic drugs but also for the investigation of the
role of this receptor in vivo from the points of view of
medicinal chemistry. Acyclic nucleotide analogues 4–7,
designed by modification of adenosine bisphosphates, were
reported to show antithrombotic activity (Fig. 2).7
Figure 4.
The other is the replacement of one of two phosphate
functional groups (R-OPO3H2) in 10 by a,a-difluoromethyl-
enephosphonic acid (R-CF2PO3H2, a,a-DFMPA) func-
tionality. a,a-DFMPA is considered to act as an
essentially non-hydrolyzable and metabolically stable
bioisostere of monophosphates due to their closely similar
physical properties. Recently, various kinds of a,a-DFMPA
derivatives have been prepared for the development of
potential enzyme inhibitors and useful probes to elucidate
biochemical processes.8 Nucleotide analogues containing
an a,a-DFMPA moiety have also received much attention
The properties of these acyclic analogues have stimulated us
to develop a synthetic method directed toward novel acyclic
nucleotide analogues 8 and 9 in which a difluoromethyl-
enephosphonyl is incorporated as an isosteric group for one
Figure 3.
Figure 5.

T. Murano et al. / Tetrahedron 59 (2003) 10223–10230
10225
Scheme 1.
Scheme 2.
in chemical and biological areas owing to the enhancement
of chemical and enzymatic stability relative to that of the
parent nucleotide.9 Thus, acyclic nucleotide analogues 8
and 9 would be expected to show antithrombotic activity.
The protected 1,5-pentanediol derivative 11 was considered
as the common key intermediate for enantio-divergent
synthesis of both enantiomers 8 and 9 via the mono-
protected derivatives 12 and 13 through the selective
removal of the protective groups of two primary hydroxyl
groups (Fig. 5).
diimidazole in THF. In this reaction, careful control of the
reaction temperature (658C) was necessary to minimize
formation of the cyclization product 19. Deoxygenation of
18 with n-Bu3SnH afforded 20 in 91% yield. Oxidation of
20 with m-CPBA in CH2Cl2, followed by aqueous
quenching gave the requisite phosphonate derivative 11 in
75% yield (Scheme 2).
2.2. Synthesis of acyclic nucleotide analogues
Selective deprotection of either the TIPS- or benzyl group of
11 could yield the requisite 12 and 13. Compound 12 was
obtained in quantitative yield by of 11 exposure to p-TsOH
in MeOH. Conversion of 12 to the phosphate 21 was easily
achieved by treatment with (EtO)2POCl in 72% yield.
Successively, hydrogenolysis of 24 over 10% Pd–C in
MeOH yielded the required alcohol 22 in 94% yield.
Condensation of 22 with 6-chloropurine under the
Mitsunobu conditions (PPh3, DIAD, THF) gave 23 in 88%
yield. The methylamination of 23 with 2 M MeNH2
provided 24 in 89% yield (Scheme 3).
The chiral synthesis of 11 was examined from trans-lactone
1410 through reductive ring opening-deoxygenation
sequence (vide infra). The enantiomerically pure trans-
lactone 14 was prepared from 1,2-O-isopropylidene-(R)-
glyceraldehyde through the previously described method10
as outlined in Scheme 1.
Reductive ring-opening reaction of 1410 with LiBH4/
B(OMe)3 resulted in decomposition and no desired
reduction product was obtained. Then reduction of phos-
phonothioate analogue 15,10 a base-resistant congener of 14,
was examined. Reduction of 15 with LiBH4/B(OMe)3 under
the same condition afforded the corresponding diol 16 in
95% yield. Selective protection of the primary hydroxyl
group with TIPS was successfully achieved by treatment
with triisopropylsilyl triflate (TIPSOTf) in the presence of
2,6-lutidine to provide TIPS ether 17 in 81% yield. To
remove the hydroxyl group, 17 was converted to thio-
carbonylimidazolide 18 by treatment with thiocarbonyl-
On the other hand, the benzyl group of 11 was removed by
hydrogenolysis in the presence of 10% Pd–C to give 13 in
quantitative yield. Treatment of 13 with (EtO)2POCl,
followed by deprotection of the TIPS group with p-TsOH
provided 26, the enantioisomer of 22, in 77% yield. The
condensation of 26 with 6-chloropurine by the Mitsunobu
reaction (PPh3, DIAD, THF) afforded 27 in 85% yield. The
methylamination of 27 with 2 M MeNH2 gave 28 in 86%

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T. Murano et al. / Tetrahedron 59 (2003) 10223–10230
Scheme 3.
Scheme 4.
yield. The biological evaluation of novel nucleotide
analogues 8 and 9 will be examined after hydrolysis of 24
and 28 (Scheme 4).
(0.14 mL, 1.3 mmol) at 08C. The reaction mixture was
allowed to warm to room temperature and stirred for 8 h.
Then the reaction mixture was poured into saturated
aqueous NH4Cl solution and the whole mixture was
extracted with ether three times. The combined organic
layer was dried over MgSO4, and concentrated in vacuo.
The remaining residue was chromatographed on silica gel.
Elution with hexane/AcOEt (5:1) afforded 16 (5.02 g, 95%)
as an oil: [a]2D5¼þ1.1 (c 1.5, CHCl3); 1H NMR (400 MHz,
CDCl3) d 7.41–7.24 (5H, m), 4.59 (1H, d, J¼11.9 Hz), 4.55
(1H, d, J¼11.9 Hz), 4.51–4.44 (1H, m), 4.33–4.18 (4H, m),
3.84–3.72 (1H, m), 3.71–3.50 (3H, m), 2.99 (1H, b), 2.73–
2.56 (1H, m), 2.38 (1H, b), 2.08–1.95 (2H, m), 1.35 (3H, t,
J¼7.0 Hz), 1.35 (3H, t, J¼7.1 Hz); 13C NMR (100 MHz,
3. Experimental
3.1. General
All reactions were carried out under a nitrogen atmosphere
unless otherwise specified. Optical rotations were recorded
on a JASCO DIP-360 digital polarimeter under standard
conditions. NMR data were obtained on a Bruker DPX 400
or a Varian Mercury-300 BB using CDCl3 or CD3OD as a
solvent. 13C NMR (100 MHz) and 31P NMR (162 MHz)
CDCl3) d 137.6, 128.4, 127.8, 127.7, 123.0 (dt, JCP
¼
1
171.9 Hz, JCF¼270.0 Hz), 73.3, 72.5, 66.9 (d, JCP¼3.5 Hz),
were taken with broad-band H decoupling. The chemical
shift data for each signal on 1H NMR (400 MHz) are
expressed as relative ppm from CHCl3 (d 7.26) or CH3OH
(d 3.30). The chemical shifts of 13C are reported relative to
CDCl3 (d 77.0) or CD3OD (d 49.0). The chemical shifts of
31P are recorded relative to external 85% H3PO4. 19F NMR
spectra (376 MHz) were measured using benzotrifluoride
(BTF) as an internal reference. IR spectra were recorded on
a JASCO FTIR-620 spectrometer. Mass spectra were
measured on a Micromass LCT using electrospray ioni-
zation (ESI) techniques.
64.6 (d, JCP¼6.5 Hz), 64.5 (d, JCP¼6.5 Hz), 43.0 (dt, JCP
16.7 Hz, JCF¼17.7 Hz), 26.0 (d, JCP¼1.6 Hz), 16.0 (d, JCP
¼
¼
6.3 Hz); 19F NMR (376 MHz, CDCl3) d 245.9 (1F, ddd,
JHF¼18.7 Hz, JFF¼292.5 Hz, JPF¼111.4 Hz), 246.8 (1F,
ddd, JHF¼18.7 Hz, JFF¼292.5 Hz, JPF¼111.4 Hz); 31P
NMR (162 MHz, CDCl3) d 75.6 (t, JPF¼111.4 Hz); IR
(neat) 3398, 2981, 2904, 1455, 1390, 1020 cm21; ESIMS
m/z 435 (MþþNa), 413 (MþþH), 395 (Mþ2OH). Anal.
calcd for C17H27O5F2PS: C, 49.51; H, 6.60. Found: C,
49.60; H, 6.56.
3.1.2. 5-O-Benzyl-2,3-dideoxy-3-[(diethoxyphosphoro-
thioyl)(difluoro)methyl]-1-O-(triisopropylsilyl)-D-erythro-
pentitol (17). To a stirred solution of 16 (5.02 g, 12.2 mmol)
in CH2Cl2 (70 mL) was added 2,6-lutidine (2.1 mL,
3.1.1. 5-O-Benzyl-2,3-dideoxy-3-[(diethoxyphosphoro-
thioyl)(difluoro)methyl]-D-erythro-pentitol (16). To a
stirred solution of lactone 1510b (5.22 g, 12.8 mmol) in
THF was added LiBH4 (840 mg, 38.4 mmol) and B(OMe)3

T. Murano et al. / Tetrahedron 59 (2003) 10223–10230
10227
18.3 mmol) and TIPSOTf (3.6 mL, 13.4 mmol) at 2788C.
After being stirred for 1 h at the same temperature, the
reaction was quenched with methanol (3 mL) at 2788C. The
reaction mixture was diluted with CHCl3 (100 mL) and
washed with saturated aqueous Na2CO3 solution and brine.
The organic layer was dried over anhydrous MgSO4, and
concentrated in vacuo. The remaining residue was chro-
matographed on silica gel. Elution with hexane/AcOEt
(20:1) yielded 17 (5.6 g, 81%) as an oil: [a]2D5¼23.5 (c 1.1,
MeOH); 1H NMR (400 MHz, CDCl3) d 7.36–7.24 (5H, m),
4.59 (1H, d, J¼12.0 Hz), 4.53 (1H, d, J¼12.0 Hz), 4.52–
4.44 (1H, m), 4.31–4.19 (4H, m), 3.83 (1H, dt, J¼9.9,
6.0 Hz), 3.71 (1H, dt, J¼9.9, 6.5 Hz), 3.56 (1H, dd, J¼7.6,
9.7 Hz), 3.49 (1H, dd, J¼5.2, 9.7 Hz), 2.97 (1H, d, J¼
5.0 Hz), 2.74–2.57 (1H, m), 2.06–1.90 (2H, m), 1.35 (3H, t,
J¼7.1 Hz), 1.34 (3H, t, J¼7.1 Hz), 1.13–0.97 (21H, m); 13C
NMR (100 MHz, CDCl3) d 138.0, 128.3, 127.6 (2C), 123.2
(dt, JCP¼171.8 Hz, JCF¼269.8 Hz), 73.1, 72.6, 67.1 (d,
JCP¼1.9 Hz), 64.6 (d, JCP¼7.0 Hz), 64.4 (d, JCP¼ 7.1 Hz),
62.0, 42.2 (dt, JCP¼15.6 Hz, JCF¼18.4 Hz), 25.9 (d,
JCP¼2.4 Hz), 17.9, 16.0 (d, JCP¼6.3 Hz), 11.8; 19F NMR
(376 MHz, CDCl3) d 244.9 (1F, ddd, JHF¼16.9 Hz, JFF¼
292.9 Hz, JPF¼112.5 Hz), 247.7 (1F, ddd, JHF¼20.1 Hz,
JFF¼292.9 Hz, JPF¼112.5 Hz); 31P NMR (162 MHz,
CDCl3) d 76.0 (t, JPF¼112.5 Hz); IR (neat) 3063, 1463,
1390, 1098, 1022 cm21; ESIMS m/z 591 (MþþNa). Anal.
calcd for C26H47O5F2PSSi: C, 54.91; H, 8.33. Found: C,
55.24; H, 8.45.
(d, JCP¼6.8 Hz), 64.6 (d, JCP¼6.8 Hz), 61.6, 39.8 (dt,
6.2 Hz), 11.9; 19F NMR (376 MHz, CDCl3) d 247.4 (1F,
JCP¼16.5 Hz, JCF¼19.4 Hz), 27.6, 18.0, 16.1 (d, JCP
¼
ddd, JHF¼16.6 Hz, JFF¼294.4 Hz, JPF¼111.8 Hz), 250.0
(1F, ddd, JHF¼19.2 Hz, JFF¼294.4 Hz, JPF¼111.8 Hz); 31
P
NMR (162 MHz, CDCl3) d 75.5 (t, JPF¼111.8 Hz); IR
(neat) 3047, 3016, 2829, 1464, 1390, 1326, 1285, 1230,
1104 cm21; ESIMS m/z 551 (Mþ2OC(S)C3H3N2). Anal.
calcd for C30H49N2O5F2PS2Si: C, 53.08; H, 7.28; N, 4.13.
Found: C, 53.31; H, 7.35; N, 4.45.
3.1.4. O,O-Diethyl (2R)-4-(benzyloxy)-1,1-difluoro-2-{2-
[(triisopropylsilyl)oxy]ethyl}butylphosphonothioate (20).
To a stirred solution of 19 (1.66 g, 2.45 mmol) in toluene
(18 mL) was added n-Bu3SnH (0.99 mL, 3.68 mmol) and
AIBN (0.1 g) in small portions over 1 h at 1008C. After the
reaction mixture had been stirred for 4 h at the same
temperature, the reaction mixture was evaporated. The
resulting residue was chromatographed on silica gel. Elution
with hexane/AcOEt (20:1) afforded 20 (1.23 g, 91%) as an
oil: [a]2D5¼þ3.6 (c 1.1, MeOH); 1H NMR (400 MHz,
CDCl3) d 7.37–7.23 (5H, m), 4.50 (2H, s), 4.28–4.16 (4H,
m), 3.76 (2H, t, J¼6.7 Hz), 3.57 (2H, t, J¼7.1 Hz), 2.67–
2.47 (1H, m), 2.23–2.04 (2H, m), 1.79–1.68 (1H, m), 1.66–
1.56 (1H, m), 1.33 (6H, t, J¼7.1 Hz), 1.11–0.98 (21H, m);
13C NMR (100 MHz, CDCl3) d 138.5, 128.3, 127.5, 127.4,
123.4 (dt, JCP¼173.2 Hz, JCF¼268.7 Hz), 72.8, 68.2, 64.2
(d, JCP¼6.8 Hz), 61.1, 36.6 (dt, JCP¼16.3 Hz, JCF
¼
19.4 Hz), 31.1 (d, JCP¼2.9 Hz), 28.0 (d, JCP¼2.5 Hz),
18.0, 16.1 (d, JCP¼6.3 Hz), 11.9; 19F NMR (376 MHz,
CDCl3) d 247.8 (1F, ddd, JHF¼17.7 Hz, JFF¼289.1 Hz,
JPF¼114.5 Hz), 249.0 (1F, ddd, JHF¼18.5 Hz, JFF¼
289.1 Hz, JPF¼114.5 Hz); 31P NMR (162 MHz, CDCl3) d
76.8 (t, JPF¼114.5 Hz); IR (neat) 2942, 2866, 1098,
1024 cm21; ESIMS m/z 575 (MþþNa), 553 (MþþH), 379
(Mþ2OTIPS). Anal. calcd for C26H47O4F2PSSi: C, 56.49;
H, 8.57. Found: C, 56.20; H, 8.49.
3.1.3. 5-O-Benzyl-2,3-dideoxy-3-[(diethoxyphosphoro-
thioyl)(difluoro)methyl]-4-O-(1H-imidazol-1-ylcarbo-
nothioyl)-1-O-(triisopropylsilyl)-D-erythro-pentitol (18)
and (4S,5S)-5-[(benzyloxy)methyl]-2-ethoxy-3,3-di-
fluoro-4-{2-[(triisopropylsilyl)oxy]ethyl}-1,2-oxaphos-
pholane 2-sulfide (19). A mixture of 17 (15.91 g,
28.0 mmol) and 1,10-thiocarbonyldiimidazole (14.97 g,
84.0 mmol) in THF (170 mL) was heated at 658C for 15 h.
The reaction mixture was evaporated and the remaining
residue was chromatographed on silica gel. Elution with
hexane/AcOEt (15:1) gave cyclization product 19 (5.85 g,
3.1.5. Diethyl (2R)-4-(benzyloxy)-1,1-difluoro-2-{2-[(tri-
isopropylsilyl)oxy]ethyl}butylphosphonate (11). To a
stirred solution of 20 (4.25 g, 7.69 mmol) in CH2Cl2
(230 mL) was added m-CPBA (6.64 g, 38.45 mmol) at
08C. After being stirred for 15 min at room temperature, the
reaction mixture was washed with saturated aqueous
Na2CO3 solution and brine. The organic layer was dried
over MgSO4, and concentrated in vacuo. The resulting
residue was chromatographed on silica gel. Elution with
hexane/AcOEt (15:1) afforded 11 (3.11 g, 75%) as an oil.
[a]2D5¼þ0.20 (c 1.0, MeOH); 1H NMR (400 MHz, CDCl3) d
7.35–7.22 (5H, m), 4.50 (2H, s), 4.31–4.18 (4H, m), 3.77
(2H, t, J¼6.6 Hz), 3.58 (2H, t, J¼6.9 Hz), 2.52–2.32 (1H,
m), 2.24–2.03 (2H, m), 1.78–1.67 (1H, m), 1.66–1.54 (1H,
m), 1.37 (3H, t, J¼7.0 Hz), 1.35 (3H, t, J¼7.0 Hz), 1.13–
0.97 (21H, m); 13C NMR (100 MHz, CDCl3) d 138.5, 128.3,
127.5, 127.4, 122.8 (dt, JCP¼211.4 Hz, JCF¼263.0 Hz),
1
40%) as an oil: H NMR (400 MHz, CDCl3) d 7.37–7.24
(5H, m), 4.83–4.70 (1H, m), 4.63–4.52 (2H, m), 4.35–4.22
(2H, m), 3.87–3.63 (4H, m), 3.25–3.01 (1H, m), 1.99–1.87
(1H, m), 1.83–1.71 (1H, m), 1.38–1.31 (3H, m), 1.15–0.99
(21H, m); 19F NMR (376 MHz, CDCl3) d 249.5 (0.7F, ddd,
JHF¼13.3 Hz, JFF¼269.2 Hz, JPF¼115.9 Hz), 253.7 (0.3F,
ddd, JHF¼26.8 Hz, JFF¼269.1 Hz, JPF¼120.2 Hz), 254.0
(0.7F, ddd, JHF¼23.6 Hz, JFF¼262.9 Hz, JPF¼82.9 Hz),
258.7 (0.3F, ddd, JHF¼11.1 Hz, JFF¼269.1 Hz, JPF¼
91.9 Hz); 31P NMR(162 MHz, CDCl3) d 82.2 (0.7P, dd,
JPF¼82.9, 115.9 Hz), 79.6 (0.3P, dd, JPF¼91.9, 120.2 Hz);
ESIMS m/z 523 (MþþH). Successive elution with hexane/
AcOEt (5:1) afforded 18 (6.71 g, 35%) as an oil: [a]2D5¼
1
þ19.8 (c 1.0, MeOH); H NMR (400 MHz, CDCl3) d 8.29
(1H, s), 7.60 (1H, s), 7.34–7.22 (5H, m), 7.02 (1H, s), 6.27
(dt, J¼1.7, 6.0 Hz), 4.60 (1H, d, J¼12.2 Hz), 4.56 (1H, d,
J¼12.2 Hz), 4.28–4.13 (4H, m), 3.94 (1H, dd, J¼6.2,
10.8 Hz), 3.90–3.81 (2H, m), 3.77 (1H, dd, J¼5.8,
10.8 Hz), 3.24–3.08 (1H, m), 2.28–2.17 (1H, m), 1.97–
1.85 (1H, m), 1.30 (6H, t, J¼7.1 Hz), 1.13–0.98 (21H, m);
13C NMR (100 MHz, CDCl3) d 183.1, 137.5, 136.8, 130.7,
72.8, 68.2, 64.3 (d, JCP¼6.9 Hz), 61.1, 37.0 (dt, JCP
¼
15.1 Hz, JCF¼19.3 Hz), 31.0 (d, JCP¼2.7 Hz), 28.0 (d,
JCP¼2.0 Hz), 18.0, 16.3 (d, JCP¼5.4 Hz), 11.9; 19F NMR
(376 MHz, CDCl3) d 247.8 (1F, ddd, JHF¼17.2 Hz, JFF¼
301.2 Hz, JPF¼111.0 Hz), 249.1 (1F, ddd, JHF¼18.8 Hz,
JFF¼301.2 Hz, JPF¼111.0 Hz); 31P NMR (162 MHz,
CDCl3) d 7.55 (t, JPF¼111.0 Hz); IR (neat) 2942, 2866,
1099, 1027 cm21; ESIMS m/z 537 (MþþH). Anal. calcd for
128.3, 127.7, 127.5, 122.0 (dt, JCP¼174.5 Hz, JCF
¼
270.5 Hz), 118.0, 79.2 (d, JCP¼2.8 Hz), 73.1, 67.7, 64.7

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T. Murano et al. / Tetrahedron 59 (2003) 10223–10230
C26H47O5F2PSi: C, 58.19; H, 8.83. Found: C, 57.93; H,
8.55.
difluoro-2-(2-hydroxyethyl)butylphosphonate (22). A
mixture of 21 (850 mg, 1.65 mmol), 10% Pd–C (170 mg)
and MeOH (12 mL) was stirred under a hydrogen
atmosphere at room temperature for 15 h. After removal
of Pd–C by filtration, the filtrate was concentrated under
reduced pressure to give an oily residue, which was
chromatogaraphed on silica gel. Elution with CHCl3/
MeOH (30:1) afforded 22 (660 mg, 94%) as an oil:
3.1.6. Diethyl (2R)-4-(benzyloxy)-1,1-difluoro-2-(2-
hydroxyethyl)butylphosphonate (12). To a stirred solution
of 11 (100 mg, 0.19 mmol) in MeOH (6 mL) was added
p-TsOH·H2O (10 mg) and stirred for 15 h at room
temperature. The reaction mixture was neutralized with
saturated aqueous NaHCO3 solution. The organic layer was
removed in vacuo. The oily residue was suspended with
H2O and then extracted with EtOAc. The combined organic
layer was washed with brine, dried over MgSO4 and
evaporated. The remaining residue was chromatographed
on silica gel. Elution with AcOEt afford 12 (72 mg, 100%)
as an oil: [a]2D5¼þ0.35 (c 1.2, MeOH); 1H NMR (400 MHz,
CDCl3) d 7.40–7.23 (5H, m), 4.52 (2H, s), 4.33–4.20 (4H,
m), 3.72 (2H, t, J¼6.0 Hz), 3.68–3.53 (2H, m), 2.57–2.38
(1H, m), 2.25–2.05 (2H, m), 1.79–1.67 (1H, m), 1.66–1.50
(1H, m), 1.37 (3H, t, J¼7.0 Hz), 1.36 (3H, t, J¼7.1 Hz); 13C
NMR (100 MHz, CDCl3) d 137.9, 128.4, 127.7, 122.6 (dt,
1
[a]2D5¼28.6 (c 1.3, CHCl3); H NMR (400 MHz, CDCl3)
d 4.34–4.23 (4H, m), 4.22–4.05 (6H, m), 3.80–3.66 (2H,
m), 2.63–2.44 (1H, m), 2.31–2.20 (1H, m), 2.19–2.08 (1H,
m), 1.85–1.74 (1H, m), 1.68–1.56 (1H, m), 1.38 (6H, t,
J¼7.1 Hz), 1.34 (6H, t, J¼7.1 Hz); 13C NMR (100 MHz,
CDCl3) d 122.3 (dt, JCP¼211.5 Hz, JCF¼263.5 Hz), 65.5,
64.4 (d, JCP¼5.9 Hz), 63.7, 59.5 (d, JCP¼7.2 Hz), 36.6 (dt,
JCP¼15.6 Hz, JCF¼19.1 Hz), 30.5, 28.5, 16.2 (d,
JCP¼4.7 Hz), 15.9 (d, JCP¼5.9 Hz); 19F NMR (376 MHz,
CDCl3) d 247.7 (1F, ddd, JHF¼15.6 Hz, JFF¼301.8 Hz,
JPF¼109.3 Hz), 249.9 (1F, ddd, JHF¼19.2 Hz, JFF¼
301.8 Hz, JPF¼109.3 Hz); 31P NMR (162 MHz, CDCl3) d
7.21 (1P, t, JPF¼109.3 Hz), 20.39 (1P, s); IR (neat) 3431,
2986, 1265, 1029 cm21; ESIMS m/z 449 (MþþNa). Anal.
calcd for C14H30O8F2P2: C, 39.44; H, 7.09. Found: C, 39.32;
H, 6.89.
JCP¼211.4 Hz, JCF¼263.2 Hz), 73.0, 68.5, 64.5 (d, JCP
¼
7.0 Hz), 60.0, 37.4 (dt, JCP¼15.3 Hz, JCF¼19.2 Hz), 30.7
(d, JCP¼1.7 Hz), 27.4 (d, JCP¼3.3 Hz), 16.3 (d, JCP
¼
5.4 Hz); 19F NMR (376 MHz, CDCl3) d 248.7 (1F, ddd,
JHF¼17.0 Hz, JFF¼300.1 Hz, JPF¼110.3 Hz), 250.4 (1F,
ddd, JHF¼19.2 Hz, JFF¼300.1 Hz, JPF¼110.3 Hz); 31P
NMR (162 MHz, CDCl3) d 7.40 (t, JPF¼110.3 Hz); IR
(neat) 3444, 2938, 2871, 1261, 1026 cm21; ESIMS m/z 403
(MþþNa), 381 (MþþH), 363 (Mþ2OH). Anal. calcd for
C17H27O5F2P: C, 53.68; H, 7.16. Found: C, 53.53; H, 7.09.
3.1.9. Diethyl (2R)-4-(6-chloro-9H-purin-9-yl)-2-{2-
[(diethoxyphophoryl)oxy]ethyl}-1,1-difluorobutylphos-
phonate (23). To a stirred solution of 22 (660 mg,
1.55 mmol) in THF (3 mL) was added a solution of
triphenylphosphine (490 mg, 1.86 mmol) and 6-chloro-
purine (290 mg, 1.86 mmol) in THF (5 mL) at 08C. To
this solution was added dropwise a solution of diisopropyl-
azodicarboxylate (0.37 mL, 1.86 mmol) in THF over a
period of 5 min. The reaction mixture was warmed to room
temperature and stirred for 18 h. The solution was
concentrated under reduced pressure, and the residue was
chromatographed on silica gel. Elution with CHCl3/MeOH
(30:1) to afford 23 (770 mg, 88%) as an oil: [a]2D5¼þ5.9 (c
3.1.7. Diethyl (2R)-4-(benzyloxy)-2-{2-[(diethoxypho-
phoryl)oxy]ethyl}-1,1-difluorobutylphosphonate
(21).
To a stirred solution of 12 (100 mg, 0.26 mmol) in
CH2Cl2 (1 mL) was added pyridine (8.4 mL, 1.04 mmol)
and (EtO)2POCl (42 mL, 0.29 mmol) at 08C and then further
stirred for 18 h at the same temperature. A saturated
aqueous KHSO4 solution was then added and extracted
with EtOAc. The reaction mixture was washed with
saturated aqueous Na2CO3 and brine. The organic layer
was dried over MgSO4 and concentrated in vacuo. The
remaining residue was chromatographed on silica gel.
Elution with EtOAc gave 21 (96 mg, 72%) as an oil:
[a]2D5¼22.9 (c 1.1, CHCl3); 1H NMR (400 MHz, CDCl3) d
7.37–7.21 (5H, m), 4.52 (1H, d, J¼12.1 Hz), 4.48 (1H, d,
J¼12.1 Hz), 4.33–4.18 (4H, m), 4.17–4.02 (6H, m), 3.58
(2H, t, J¼6.5 Hz), 2.56–2.35 (1H, m), 2.29–2.16 (2H, m),
1.92–1.79 (1H, m), 1.75–1.63 (1H, m), 1.37 (3H, t, J¼
6.9 Hz), 1.35 (3H, t, J¼7.0 Hz), 1.31 (3H, dt, J¼0.6,
7.1 Hz), 1.30 (3H, dt, J¼0.6, 7.1 Hz); 13C NMR (100 MHz,
CDCl3) d 138.1, 128.0, 127.2, 122.1 (dt, JCP¼211.4 Hz,
JCF¼263.2 Hz), 72.5, 67.3, 65.1 (d, JCP¼4.9 Hz), 64.2 (d,
JCP¼6.9 Hz), 63.4 (d, JCP¼5.7 Hz), 36.9 (dt, JCP¼15.8 Hz,
JCF¼19.3 Hz), 28.3, 27.6, 16.0 (d, JCP¼4.9 Hz), 15.8 (d,
JCP¼6.4 Hz); 19F NMR (376 MHz, CDCl3) d 247.6 (1F,
ddd, JHF¼16.6 Hz, JFF¼302.5 Hz, JPF¼109.3 Hz), 249.4
1
1.4, CHCl3); H NMR (400 MHz, CDCl3) d 8.74 (1H, s),
8.26 (1H, s), 4.45 (2H, t, J¼7.6 Hz), 4.34–4.06 (10H, m),
2.54–2.28 (3H, m), 2.21–2.08 (1H, m), 1.93–1.80 (1H, m),
1.38 (3H, t, J¼7.1 Hz), 1.37 (3H, t, J¼7.0 Hz), 1.33 (6H, t,
J¼7.0 Hz); 13C NMR (100 MHz, CDCl3) d 151.6, 145.5,
131.5, 121.7 (dt, JCP¼211.3 Hz, JCF¼263.8 Hz), 64.7 (2C),
64.6, 63.8 (d, JCP¼5.6 Hz), 42.0, 37.6 (dt, JCP¼15.6 Hz,
JCF¼19.7 Hz), 28.1, 27.9, 16.2 (d, JCP¼ 4.6 Hz), 15.9 (d,
JCP¼6.3 Hz); 19F NMR (376 MHz, CDCl3) d 247.4 (1F,
ddd, JHF¼15.4 Hz, JFF¼303.9 Hz, JPF¼ 107.0 Hz), 249.3
(1F, ddd, JHF¼17.9 Hz, JFF¼303.9 Hz, JPF¼107.0 Hz); 31
P
NMR (162 MHz, CDCl3) d 6.42 (1P, t, JPF¼107.0 Hz),
20.34 (1P, s); IR (neat) 2985, 1561, 1263, 1029 cm21
;
ESIMS m/z 585 (MþþNa), 563 (MþþH). Anal. calcd for
C19H31N4O7ClF2P2: C, 40.54; H, 5.55; N, 9.95. Found: C,
40.50; H, 5.64; N, 9.98.
3.1.10. Diethyl (2R)-4-[(diethoxyphophoryl)oxy]-1,1-di-
fluoro-2-{2-[6-(methylamino)-9H-purin-9-yl]ethyl}butyl-
phosphonate (24). A mixture of 23 (670 mg, 1.19 mmol) in
an aqueous MeNH2 solution (2.0 M, 10 mL) was stirred for
4 h at room temperature. The solution was concentrated
under reduced pressure, and the residue was purified by
silica gel column chromatography (CHCl3:MeOH 50:1) to
afford 24 (590 mg, 89%) as an oil: [a]2D5¼þ6.6 (c 1.2,
(1F, ddd, JHF¼18.6 Hz, JFF¼302.5 Hz, JPF¼109.3 Hz); 31
P
NMR (162 MHz, CDCl3) d 7.03 (1P, t, JPF¼109.3 Hz),
20.76 (1P, s); IR (neat) 2985, 1271, 1029 cm21; ESIMS m/z
539 (MþþNa). Anal. calcd for C21H36O8F2P2: C, 48.84; H,
7.03. Found: C, 48.78; H, 6.92.
3.1.8. Diethyl (2R)-4-[(diethoxyphophoryl)oxy]-1,1-

T. Murano et al. / Tetrahedron 59 (2003) 10223–10230
10229
1
CHCl3); H NMR (400 MHz, CDCl3) d 8.39 (1H, s), 7.82
4.0 Hz), 17.9, 16.2 (d, JCP¼5.4 Hz), 16.0 (d, JCP¼6.6 Hz),
11.8; 19F NMR (376 MHz, CDCl3) d 247.8 (1F, ddd, JHF
(1H, s), 5.71 (1H, b), 4.32 (1H, t, J¼7.5 Hz), 4.29–4.20
(4H, m), 4.19–4.03 (6H, m), 3.21 (3H, b), 2.48–2.24 (3H,
m), 2.18–2.03 (1H, m), 1.93–1.81 (1H, m), 1.37 (3H, t,
J¼7.1 Hz), 1.36 (3H, t, J¼7.1 Hz), 1.33 (3H, t, J¼7.1 Hz),
1.32 (3H, t, J¼7.1 Hz); 13C NMR (100 MHz, CDCl3) d
¼
17.6 Hz, JFF¼302.2 Hz, JPF¼109.8 Hz), 248.8 (1F, ddd,
JHF¼18.0 Hz, JFF¼302.2 Hz, JPF¼109.8 Hz); 31P NMR
(162 MHz, CDCl3) d 7.05 (1P, t, JPF¼109.8 Hz), 20.84
(1P, s); IR (neat) 2943, 2868, 1272, 1030 cm21; ESIMS m/z
605 (MþþNa), 583 (MþþH); HRMS (ESI) calcd for
C23H51O8F2P2Si(MþþH): 583.2797. Found: 583.2794.
155.3, 152.8, 148.6, 139.5, 121.7 (dt, JCP¼210.4 Hz, JCF
¼
263.3 Hz), 119.6, 64.7 (d, JCP¼4.0 Hz), 64.5, 63.6 (d,
JCP¼4.6 Hz), 41.2, 37.4 (dt, JCP¼17.5 Hz, JCF¼18.6 Hz),
28.0, 27.3, 16.1, 15.8 (d, JCP¼5.3 Hz); 19F NMR (376 MHz,
CDCl3) d 247.2 (1F, ddd, JHF¼16.2 Hz, JFF¼304.0 Hz,
JPF¼107.8 Hz), 249.0 (1F, ddd, JHF¼17.7 Hz, JFF¼
304.0 Hz, JPF¼107.8 Hz); 31P NMR (162 MHz, CDCl3) d
6.59 (1P, t, JPF¼107.8 Hz), 20.53 (1P, s); IR (neat) 3417,
2984, 1625, 1263, 1028 cm21; ESIMS m/z 558 (MþþH).
Anal. calcd for C20H35N5O7F2P2: C, 43.09; H, 6.33; N,
12.56. Found: C, 42.67; H, 6.29; N, 12.37.
3.1.13. Diethyl (2S)-4-[(diethoxyphophoryl)oxy]-1,1-
difluoro-2-(2-hydroxyethyl)butylphosphonate (26).
A
mixture of 25 (390 mg, 0.67 mmol), MeOH (20 mL) and
p-TsOHzH2O (60 mg) was stirred for 15 h at room
temperature. The reaction mixture was neutralized with
saturated aqueous NaHCO3 solution. The organic layer was
removed in vacuo. The oily residue was diluted with H2O
and then extracted with EtOAc. The combined organic layer
was washed with brine and dried over anhydrous MgSO4.
The crude materials were purified by silica gel column
chromatography (EtOAc) to afford 26 (220 mg, 77%) as an
oil. The spectroscopic data of 26 were identical to those of
22 except for the specific rotation: [a]2D5¼þ6.7 (c 1.3,
CHCl3).
3.1.11. Diethyl (2R)-1,1-difluoro-4-hydroxy-2-{2-[(triiso-
propylsilyl)oxy]ethyl}butylphosphonate (13). A mixture
of 11 (500 mg, 0.93 mmol), 10% Pd–C (100 mg) and
MeOH (7 mL) was stirred under hydrogen atmosphere for
15 h at room temperature. The mixture was filtered and the
filtrate was concentrated under reduced pressure. The
remaining residue was chromatographed on silica gel.
Elution with hexane/EtOAc (1:1) gave 13 (420 mg, 100%)
as an oil: [a]2D5¼21.2 (c 1.0, MeOH); 1H NMR (400 MHz,
CDCl3) d 4.33–4.21 (4H, m), 3.87–3.72 (4H, m), 2.59–
2.42 (1H, m), 2.19–2.07 (2H, m), 1.76–1.58 (2H, m), 1.38
(3H, t, J¼7.0 Hz), 1.38 (3H, t, J¼7.1 Hz), 1.16–1.00 (21H,
3.1.14. Diethyl (2S)-4-(6-chloro-9H-purin-9-yl)-2-{2-
[(diethoxyphophoryl)oxy]ethyl}-1,1-difluorobutylphos-
phonate (27). This compound (200 mg, 85%) was obtained
from 26 (180 mg, 0.42 mmol), 6-chloropurine (78 mg,
0.5 mmol), triphenylphosphine (132 mg, 0.5 mmol) and
diisopropyl azodicarboxylate (0.1 mL, 0.5 mmol) according
to the same conditions as described in Section 3.1.9 for the
synthesis of 23. The spectral data of 27 were identical with
those of 23 except for the specific rotation: [a]2D5¼23.6
(c 1.6, CHCl3).
m); 13C NMR (100 MHz, CDCl3) d 122.7 (dt, JCP
¼
211.7 Hz, JCF¼263.0 Hz), 64.4 (d, JCP¼7.0 Hz), 64.4 (d,
JCP¼6.9 Hz), 61.5, 60.5, 37.0 (dt, JCP¼15.4 Hz, JCF
¼
19.0 Hz), 30.8 (d, JCP¼0.9 Hz), 30.4 (d, JCP¼3.7 Hz), 17.9,
16.3 (d, JCP¼5.4 Hz), 11.9; 19F NMR (376 MHz, CDCl3) d
248.0 (1F, ddd, JHF¼15.7 Hz, JFF¼300.3 Hz, JPF¼
110.8 Hz), 250.8 (1F, ddd, JHF¼20.9 Hz, JFF¼300.3 Hz,
JPF¼110.8 Hz); 31P NMR (162 MHz, CDCl3) d 7.48
(t, JPF¼110.8 Hz); IR (neat) 3421, 2944, 2868, 1258,
1028 cm21; ESIMS m/z 469 (MþþNa), 273 (Mþ2OTIPS);
HRMS (ESI) calcd for C19H41O5F2NaPSi (MþþNa):
469.2327. Found: 469.2345.
3.1.15. Diethyl (2S)-4-[(diethoxyphophoryl)oxy]-1,1-di-
fluoro-2-{2-[6-(methylamino)-9H-purin-9-yl]ethyl}butyl-
phosphonate (28). This compound (130 mg, 86%) was
obtained from 27 (160 mg, 0.28 mmol) according to the
same conditions as described in Section 3.1.10 for the
synthesis of 24. The spectral data of 28 were identical with
those of 24 except for the specific rotation: [a]2D5¼29.4 (c
1.1, CHCl3).
3.1.12. Diethyl (2S)-4-[(diethoxyphosphoryl)oxy]-1,1-
difluoro-2-{2-[(triisopropylsilyl)oxy]ethyl}butylphos-
phonate (25). To a stirred solution of 13 (420 mg,
0.94 mmol) in pyridine (0.3 mL) was added (EtO)2POCl
(0.15 mL, 1.03 mmol) at 08C. The mixture was stirred for
18 h at the same temperature. Saturated aqueous KHSO4
solution was added and extracted with EtOAc. The extracts
were washed with saturated aqueous Na2CO3 and brine. The
organic layer was dried over anhydrous MgSO4, and
concentrated in vacuo. The remaining residue was purified
by silica gel column chromatography (EtOAc) to afford 25
Acknowledgements
This work was supported in part by Grants-in-Aid for
Scientific Research (C) (to S. S. and T. Y.) and for
Encouragement of Young Scientists (to T. M.) from the
Ministry of Education, Culture, Sports, Science and
Technology of Japan.
1
(410 mg, 75%) as an oil: [a]2D5¼þ0.66 (c 1.2, MeOH); H
NMR (400 MHz, CDCl3) d 4.34–4.22 (4H, m), 4.18–4.06
(6H, m), 3.78 (2H, t, J¼6.4 Hz), 2.53–2.35 (1H, m), 2.29–
2.07 (2H, m), 1.93–1.81 (1H, m), 1.68–1.55 (1H, m), 1.38
(6H, t, J¼7.1 Hz), 1.33 (6H, t, J¼7.1 Hz), 1.14–1.00 (21H,
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