Synthesis of 2,3,4-trideoxy-4,4-difluoro-D-ribo-hexopyranose adenosines

Article abstract of DOI:10.1055/s-0028-1083331

A novel synthetic route to 2,3,4-trideoxy-4,4-difluoro-β- D- ribo- hexopyranose adenosine and 2,3,4-trideoxy-2,3-didehydro-4,4-difluoro-β-D- ribo-hexopyranose adenosine has been developed. The approach highlights the highly regio- and stereoselective pall

Full text of DOI:10.1055/s-0028-1083331

602
PAPER
Synthesis of 2,3,4-Trideoxy-4,4-difluoro-D-ribo-hexopyranose Adenosines
S
ynthesis
u
of
A
denosine
n
D
erivative
s
Xu,a Xingang Zhang,a Xiao-Long Qiu,a Feng-Ling Qing*a,b
a
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, P. R. of China
College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620,
b
P. R. of China
Fax +(86)2164166128; E-mail: flq@mail.sioc.ac.cn
Received 3 September 2008; revised 14 October 2008
nucleosides have never been reported. As part of our con-
tinuous study to develop new antiviral and anticancer
agents, we designed gem-difluorinated hexopyranosyl nu-
cleosides 1 and 3, in which the hydroxy groups at C4 in 5
Abstract: A novel synthetic route to 2,3,4-trideoxy-4,4-difluoro-b-
D-ribo-hexopyranose adenosine and 2,3,4-trideoxy-2,3-didehydro-
4,4-difluoro-b-D-ribo-hexopyranose adenosine has been developed.
The approach highlights the highly regio- and stereoselective palla-
dium-catalyzed glycosylation of Boc-protected pyranose, which and 6 were replaced with a CF2 group based on the idea
was prepared from the oxidation–cyclization of a difluorinated diol.
The diol was provided through ozonization and Lindlar reduction of
optically pure enynic alcohol.
that the gem-difluoromethylene group (CF2) is the chemi-
cal isostere for hydroxy group.12 Herein, we describe an
efficient synthesis of target molecules 1 and 3 from a flu-
orinated building block.
Key words: nucleosides, fluorinated compounds, palladium-cata-
lyzed glycosylation
NH2
N
NH2
N
N
N
OH
OH
N
The discovery of a large and varied class of natural bioac-
tive hexopyranosyl nucleoside-containing products, such
as blasticidin,1 gougerotin,2 hikizimycin,3 and mildiomy-
cin,4 has inspired many efforts on the synthesis of hexopy-
ranosyl nucleosides as potential anticancer and antiviral
agents.5 Among these hexopyranosyl nucleosides, 2,3-
dideoxypyranosyl nucleosides and 2,3-unsaturated hex-
opyranosyl nucleosides constitute a distinct class of bio-
active compounds. They have been demonstrated to show
anticancer and antiviral activities. For example, 2,3-
dideoxy-b-D-ribo-hexopyranose adenosine (5) and 2,3-di-
dehydro-b-D-ribo-hexopyranose adenosine (6) were syn-
thesized as a selective inhibitor of protein synthesis and
several transplantable animal tumors6,7 (Figure 1). Inter-
estingly, the presence of a double bond at C2–C3 of pyra-
nose ring in 6 can make it adopt a twisted half-chair
conformation that is similar to the furanose rings of the
naturally occurring nucleosides.6a,8 Based on this fact,
many furanose ring mimic nucleosides bearing a 2,3-dide-
hydropyranose ring have been used in various biological
systems.9 Thus, there has been a great demand for effi-
cient synthetic methods to access these valuable com-
pounds. On the other hand, special attention has also been
paid to the gem-difluoromethylene group (CF2) because
the introduction of this group into organic compounds can
bring about remarkable changes in physical, chemical,
and biological properties.10 The well-known example is
Gemcitabine,11 a gem-difluoromethylenated nucleoside,
which has been used for treatment of lung, ovarian, renal,
pancreatic, head, and neck cancers. However, to the best
of our knowledge, the gem-difluorinated hexopyranosyl
O
N
O
N
N
F
HO
F
1 and 3
5 and 6
Figure 1 Hexopyranosyl nucleosides 5, 6 and design of 2,3,4-tride-
oxy-4,4-difluoro-b-D-ribo-hexopyranose adenosines
Very recently, our group has reported the preparation of
gem-difluorinated 1,2-disubstituted carbocyclic nucleo-
sides via palladium-catalyzed glycosylation. We found
that the nitrogen nucleophilic bases can specifically attack
the more electrophilic carbon of intermediate 9 resulting
only in g-substituted product 8 (Scheme 1).13 Interesting-
ly, O’Doherty’s group reported that palladium-catalyzed
glycosylation of hexopyranosyl substrates with various
alcohol nucleophiles proceeded smoothly with excellent
stereocontrol and the more electrophilic Pd-p-allyl inter-
mediate I (Scheme 1) is essential to the reaction.14 Em-
ploying this strategy, they successfully synthesized
hexopyranosyl nucleosides.7c Thus, taking all these re-
sults together, we planned to install the base moiety of tar-
get molecule 1 by palladium-catalyzed N-glycosylation
(Scheme 2). We envisaged that the presence of an elec-
tron-withdrawing CF2 group in intermediate 11 would di-
rect bases regioselectively and stereoselectively to attack
the carbon far away from the CF2 group. Therefore, the
palladium-catalyzed glycosylation of the difluorinated
pyranose 12 with base would give nucleoside 10, a precur-
sor of 1. Compound 12 could be prepared from diol 13 by
oxidation of the primary hydroxyl to aldehyde followed
by the simultaneous cyclization. Diol 13 could be easily
obtained via ozonization and Lindlar reduction of our re-
ported optically pure alcohol (R)-14 (Scheme 2).15
SYNTHESIS 2009, No. 4, pp 0602–0608
x
x
.
x
x
.2
0
0
9
Advanced online publication: 27.01.2009
DOI: 10.1055/s-0028-1083331; Art ID: F19008SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Adenosine Derivatives
603
of the primary hydroxy group of diol 16 and subsequent
removal of TBS group with TBAF provided the gem-
difluorinated alcohol 13 in 70% yield (Scheme 3).
BnO
F
F
BnO
H
BnO
BnO
F
F
Pd(0)/PPh3
N
OCO2Me
The preparation of lactol 17 was initially carried out by
the Giacomelli’s procedure for the selective oxidation of
primary alcohol to aldehyde in the presence of trichloro-
isocyanuric acid (TCCA) and catalytic TEMPO
(Table 1).16 However, when diol 13 was treated with 1.0
equivalent of TCCA and catalytic TEMPO at room tem-
perature, only a trace amount of the desired lactol 17 was
produced and lactone 18 was formed as the major product
(42%) (Table 1, entry 1). The oxidation of diol 13 with
bis(acetoxyiodo)benzene (BAIB) afforded the desired
lactol 17 in 21% yield (anti/syn = 4:1), but lactone 18 was
still produced in 32% yield (entry 3). To prepare lactol 17
efficiently, the complete conversion of diol 13 to lactone
18 and then reduction of 18 to lactol 17 were investigated.
The peroxidation of diol 13 with 3.0 equivalents of TCCA
provided lactone 18 in 47% yield (entry 2). We were
pleased to find that lactone 18 was isolated in 76% yield
when BAIB was used instead of TCCA (entry 4).
H
via 9
O
N
O
Bz
7
8
strong electron-withdrawing group
BnO
F
F
O
L2Pd
BnO
H
X
O
X
PdL2
OTBS
9
I
more electrophilic
Scheme 1
OBz
O
Table 1 Oxidation of Diol 13
F
X
PdL2
OBz
F
TCCA or BAIB
TEMPO (cat.)
CH2Cl2, r.t.
O
OBz
OH
O
B
11
O
OBoc
OH
F
O
O
1
BzO
OH
+
F
BzO
F
BzO
Pd-catalyzed
N-glycosylation
F
F
F
F
F
10
F
F
12
B = 6-chloropurine
13
17
18
oxidation
cyclization
Entry Oxidant Equiv Yield (%) of 17
Yield (%) of 18
OH
OH
OTBS
1
2
3
4
TCCA
TCCA
BAIB
BAIB
1.0
3.0
1.0
3.0
trace
–
42
47
32
76
BzO
OH
Ph
F
F
F
F
13
(R)-14
21a
–
Scheme 2
a Ratio of anti/syn = 4:1, determined by 19F NMR spectroscopy.
Thus, the synthesis of the target molecules was started
from (R)-14. Treatment of (R)-14 with O3 followed by
NaBH4-mediated reduction gave diol 15 in 75% yield.
Hydrogenation of diol 15 in the presence of Lindlar cata-
lyst gave (Z)-diol 16 in 83% yield. Selective benzoylation
Reduction of lactone 18 with DIBAL-H afforded diol 19
in 70% yield with anti-isomer as the major product (anti/
O3, –78 °C;
then NaBH4
r.t., 1 h
OH
OH
F
OTBS
OTBS
HO
Ph
75%
F
F
F
15
(R)-14
Lindlar catalyst
H2, hexane, r.t.
83%
1) BzCl, Py
CH2Cl2, –78 °C
2) TBAF, THF
r.t., overnight
OH
F
OH
F
BzO
OH
HO
OTBS
70% for two steps
F
F
13
16
Scheme 3
Synthesis 2009, No. 4, 602–608 © Thieme Stuttgart · New York

604
J. Xu et al.
PAPER
19
syn = 4:1, determined by F NMR spectroscopy). Selec-
tive benzoylation of the primary hydroxy group of diol 19
provided lactol 17 in 87% yield (Scheme 4).
Pd(PPh3)4
(5 mol%)
PPh3 (10 mol%)
OH
OBoc
(Boc)2O, DMAP
6-chloropurine
THF, 60 °C, 4 h
CH2Cl2, 0 °C to r.t.
O
O
OH
OH
BzO
BzO
OBz
O
90%
BzCl, Py
CH2Cl2
–78 °C
DIBAL-H
CH2Cl2
–78 °C
anti/syn = 4:1
F
F
F
O
F
O
O
20
17
HO
BzO
BzO
87%
70%
F
F
F
F
F
F
Cl
N
Cl
N
N
N
OBz
19
anti/syn = 4:1
17
18
N
N
O
O
+
N
N
F
F
Scheme 4
F
F
21 (39%)
10 (10%)
With the key lactol 17 in hand, we then paid our attention
to the palladium-catalyzed gylcosylation for the installa-
tion of base (Scheme 5). Treatment of 17 with (Boc)2O
gave compound 20. As we expected, treatment of 20 with
6-chloropurine in the presence of catalytic Pd(PPh3)4 at
60 °C in THF gave exclusively g-substituted diastereoiso-
mers 10 and 21. More gratifyingly, these two diastereo-
isomers could be readily separated by flash
chromatography and their absolute configurations were
elucidated from NOESY experiments based on the known
configuration at C5 as derived from (R)-14. It was note-
worthy that the ratio of 10:21 was the same to that of syn/
anti-20. This result showed that this palladium-catalyzed
gylcosylation was completely stereocontrolled. That is to
say, syn-20 provided only the b-anomer 10 and anti-20
gave only the a-anomer 21, which is consistent with a p-
allylpalladium intermediate.
Scheme 5
Figure 2 ORTEP drawing of the X-ray crystallographic structure of
compound 4
In conclusion, we have accomplished the synthesis of
2,3,4-trideoxy-4,4-difluoro-b-D-ribo-hexopyranose ade-
nosines 1, 3 and their a-anomers 2, 4 using palladium-cat-
alyzed glycosylation as a key step. The high regio- and
stereoselectivities of such palladium-catalyzed glycosyla-
tion could be used as an efficient and practical strategy for
the synthesis of other gem-difluorinated hexopyranosyl
substrates. Antiviral and cytotoxicity evaluations of 1–4
are currently in progress and will be reported soon.
Exposure of 10 and 21 to saturated methanolic ammonia
at 80 °C gave gem-difluorinated 2,3-unsaturated hexopy-
ranose adenosines 3 and 4 in 73 and 80% yield, respec-
tively. The structure of compound 4 was further
confirmed by X-ray diffraction (Figure 2).17 Finally, hy-
drogenation of 3 and 4 in the presence of catalytic Pd/C
gave the target molecules 2,3,4-trideoxy-4,4-difluoro-D-
ribo-hexopyranose adenosines 1 and 2 in 87 and 90%
yield, respectively (Scheme 6).
NH2
N
NH2
N
OH
Pd/C, H2
r.t., 26 h
OH
NH3–MeOH
80 °C, 24 h
N
N
O
N
N
O
10
N
N
87%
73%
F
F
F
F
1
3
NH2
N
NH2
N
N
N
OH
OH
Pd/C, H2
r.t., 26 h
NH3–MeOH
80 °C, 24 h
N
O
N
O
21
N
N
90%
F
80%
F
F
F
2
4
Scheme 6
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Synthesis of Adenosine Derivatives
605
(10 mL) was added and the mixture was stirred for 30 min. The mix-
ture was washed sequentially with aq 1 N HCl (50 mL), sat. aq
NaHCO3 (30 mL), and brine (30 mL). The organic layer was dried
(Na2SO4), filtered, and the solvent was removed in vacuo. The res-
idue was purified by flash silica gel column chromatography (PE–
EtOAc, 10:1 to 6:1) to give 2.5 g of the product benzoate. The prod-
uct was dissolved in THF (30 mL) and TBAF (7 mL, 1 M in THF)
was added. The mixture was stirred overnight at r.t. After removal
of the solvent in vacuo, the residue was purified by flash silica gel
column chromatography (PE–EtOAc, 1:1) to give 13 (1.55 g, 70%
for two steps); [a]D26 +4.8 (c 0.65, CHCl3).
THF and benzene were distilled from sodium metal. CH2Cl2 was
distilled from CaH2. Melting points are uncorrected. Petroleum
ether (PE) used refers to the fraction boiling in the range 60–90 °C.
1H and 13C NMR spectra were recorded on a Bruker AM300 spec-
trometer. 19F NMR spectra were recorded on a Bruker AM300 spec-
trometer (CFCl3 as external standard and low field is positive).
Chemical shifts (d) are reported in ppm, and coupling constants (J)
are in Hz.
(R)-6-(tert-Butyldimethylsilyloxy)-3,3-difluorohex-4-yne-1,2-
diol (15)
IR (film): 1755, 1726, 1453, 1230, 1070, 711 cm–1.
Ozone was bubbled through a solution of (R)-14 (4.45 g, 12.6
mmol) in MeOH–CH2Cl2 (70 mL:70 mL) for 45 min at –78 °C till
a blue color persisted. Then, N2 was bubbled through the solution
until the blue color disappeared and NaBH4 (2.35 g, 63.5 mmol) was
added. After warming to r.t. and stirring for 1 h, the reaction was
quenched with sat. aq NH4Cl (50 mL). The layers were separated
and the aqueous phase was extracted with CH2Cl2 (3 × 30 mL). The
combined organic layers were washed with brine (50 mL), dried
(Na2SO4) and concentrated under vacuo to give the crude product.
Purification by flash silica gel column chromatography (PE–
EtOAc, 1:1) yielded 15 (2.66 g, 75%) as a clear oil; [a]D26 +8.9 (c
1.03, CHCl3).
1H NMR (300 MHz, CDCl3): d = 8.03 (d, J = 1.5 Hz, 2 H), 7.61 (t,
J = 1.2 Hz, 1 H), 7.45 (t, J = 7.5 Hz, 2 H), 6.15–6.06 (m, 1 H),
5.72–5.56 (m, 1 H), 4.62–4.46 (m, 2 H), 4.43–4.38 (m, 2 H), 4.27–
4.17 (m, 1 H).
13C NMR (75.5 MHz, CDCl3): d = 167.0, 139.0 (t, J = 3.9 Hz),
133.5, 129.7, 129.3, 128.5, 122.0 (t, J = 19.6 Hz), 120.2 (t,
J = 183.8 Hz), 72.0 (t, J = 22.5 Hz), 63.8, 58.7.
19F NMR (282 MHz, CDCl3): d = –100.83 (dm, J = 234.1 Hz, 1 F),
–105.00 (ddd, J = 228.1, 14.9 Hz, 3.7 Hz, 1 F).
MS (MALDI): m/z = 273.1 [M + H]+.
IR (film): 3400, 2933, 2861, 1213, 1110, 1074, 838, 781 cm–1.
HRMS (MALDI): m/z [M + Na]+ calcd for C13H14F2O4 + Na:
295.0752; found: 295.0758.
1H NMR (300 MHz, CDCl3): d = 4.40 (t, J = 5.1 Hz, 2 H), 4.02–
3.77 (m, 3 H), 2.86 (br, 2 H), 0.90 (s, 9 H), 0.13 (s, 6 H).
(R)-(3,3-Difluoro-6-oxo-3,6-dihydro-2H-pyran-2-yl)methyl
Benzoate (18)
13C NMR (75.5 MHz, CDCl3): d = 112.9 (t, J = 236.8 Hz), 88.4 (t,
J = 7.0 Hz), 75.5 (t, J = 38.7 Hz), 74.1 (t, J = 27.9 Hz), 61.2 (t,
J = 2.9 Hz), 51.3, 25.7, 18.3, –5.3.
19F NMR (282 MHz, CDCl3): d = –94.98 to –95.04 (m, 2 F).
MS (MALDI): m/z = 303.1 [M + Na]+.
To a solution of benzoate 13 (106 mg, 0.39 mmol) in anhyd CH2Cl2
(3 mL) were added BAIB (376 mg, 1.20 mmol) and TEMPO (12
mg, 20 mmol%) at 0 °C. After stirring the mixture for 3 h at r.t., the
reaction was quenched with aq Na2S2O3 (2 mL). The aqueous phase
was extracted with CH2Cl2 (3 × 2 mL) and the combined organic
layers were washed sequentially with sat. aq NaHCO3 (3 mL),
NH4Cl (3 mL), and brine (3 mL). The combined organic layers were
dried (Na2SO4), filtered, and the solvent was removed in vacuo. The
residue was purified by flash silica gel column chromatography
(PE–EtOAc, 4:1) to give 18 (79 mg, 76%) as a clear oil; [a]D26 –2.3
(c 1.25, CHCl3).
HRMS (MALDI): m/z [M + Na]+ calcd for C12H22F2O3Si + Na:
303.1199; found: 303.1202.
(R,Z)-6-(tert-Butyldimethylsilyloxy)-3,3-difluorohex-4-ene-1,2-
diol (16)
A suspension of Lindlar catalyst (0.44 g) and diol 15 (2.88 g, 10.3
mmol) in hexane (150 mL) was stirred under H2 for 48 h at r.t. Fil-
tration and removal of the solvent gave the crude product, which
was purified by flash silica gel column chromatography (PE–
IR (film): 1755, 1726, 1453, 1230, 1070, 711 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.03 (d, J = 1.5 Hz, 2 H), 7.61 (t,
J = 1.2 Hz, 1 H), 7.45 (t, J = 7.5 Hz, 2 H), 6.89–6.82 (m, 1 H), 6.37
(d, J = 10.2 Hz, 1 H), 5.04–4.92 (m, 1 H), 4.82 (dd, J = 12.6, 3.6 Hz,
1 H), 4.68 (q, J = 6.9 Hz, 1 H).
13C NMR (75.5 MHz, CDCl3): d = 165.8, 159.4, 137.1 (dd,
J = 26.3, 19.6 Hz), 133.5, 129.7, 129.0, 128.5, 126.7 (t, J = 6.7 Hz),
111.9 (t, J = 182.0 Hz), 60.4 (t, J = 3.9 Hz).
19F NMR (282 MHz, CDCl3): d = –106.82 (dt, J = 291.0, 8.2 Hz, 1
F), –108.75 (dd, J = 271.3, 19.5 Hz, 1 F).
MS (MALDI): m/z = 286.0 [M + NH4]+.
26
EtOAc, 1:1) to give 16 (2.40 g, 83%) as a clear oil; [a]D +4.9 (c
0.48, CHCl3).
IR (film): 3400, 2933, 2861, 2257, 1213, 1110, 1074, 838, 781 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.00 (m, 1 H), 5.54 (q, J = 13.8
Hz, 1 H), 4.43 (s, 1 H), 3.95–3.80 (m, 3 H), 0.90 (s, 9 H), 0.08 (s, 6
H).
13C NMR (75.5 MHz, CDCl3): d = 140.1 (t, J = 5.6 Hz), 120.7 (dd,
J = 31.9, 25.7 Hz), 117.4 (t, J = 140.4 Hz), 73.7 (t, J = 29.0 Hz),
61.0 (t, J = 4.2 Hz), 59.8 (t, J = 4.8 Hz), 25.9, 18.3, –5.3.
HRMS (MALDI): m/z [M + Na]+ calcd for C13H10F2O4 + Na:
291.0439; found: 291.0443.
19F NMR (282 MHz, CDCl3): d = –101.76 (dt, J = 260.3, 11.8 Hz,
1 F), –105.23 (dt, J = 258.6, 13.3 Hz, 1 F).
MS (MALDI): m/z = 305.1 [M + Na]+.
HRMS (MALDI): m/z [M + Na]+ calcd for C12H24F2O3Si + Na:
(6R)-5,5-Difluoro-6-(hydroxymethyl)-5,6-dihydro-2H-pyran-2-
ol (19)
305.1355; found: 305.1367.
To a solution of lactone 18 (122 mg, 0.46 mmol) in anhyd CH2Cl2
(5 mL) was added DIBAL-H (2 mL, 1.0 M in toluene) at –78 °C.
The mixture was stirred for 1 h at the same temperature, and then
MeOH (7 mL) was added. The mixture was warmed to r.t. and fil-
tered. The filtrate was dried (Na2SO4), filtered, and the solvent was
removed in vacuo. The residue was purified by flash silica gel col-
umn chromatography (PE–EtOAc, 1:2) to give 19 (53 mg, 70%) as
a white solid.
(R,Z)-3,3-Difluoro-2,6-dihydroxyhex-4-enyl Benzoate (13)
To a solution of Z-diol 16 (2.40 g, 8.5 mmol) in anhyd CH2Cl2 (100
mL) was slowly added pyridine (14 mL) followed by BzCl (0.85
mL, 0.88 equiv) at –78 °C. The mixture was stirred for 1 h at the
same temperature, and then another portion of BzCl (0.23 mL, 0.24
equiv) was added. After stirring the mixture for another 1 h, MeOH
Synthesis 2009, No. 4, 602–608 © Thieme Stuttgart · New York

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J. Xu et al.
PAPER
IR (film): 3204, 1387, 1158, 1103, 1073, 1053, 1025, 937, 868, 789,
754 cm–1.
1H NMR (300 MHz, CD3OD): d = 6.17 (dd, J = 9.9, 2.7 Hz, 1 H),
5.89 (t, J = 9.0 Hz, 1 H), 5.34–5.28 (m, 1 H), 4.21(dq, J = 7.2, 3.9
Hz, 1 H), 3.83 (dd, J = 12.0, 3.3 Hz, 1 H), 3.70–3.59 (m, 1 H).
13C NMR (75.5 MHz, CD3OD): d (major product) = 135.2 (t,
J = 6.7 Hz), 123.0 (dd, J = 23.0, 19.6 Hz), 113.5 (dd, J = 182.6,
175.3 Hz), 87.5, 70.5 (dd, J = 23.0, 18.6 Hz), 58.4 (d, J = 5.1 Hz);
d (minor product) = 138.1 (t, J = 7.3 Hz), 123.6 (t, J = 21.4 Hz),
113.5 (dd, J = 182.6, 175.3 Hz), 91.5, 76.3 (t, J = 19.6 Hz), 58.5 (d,
J = 3.9 Hz).
13C NMR (75.5 MHz, CDCl3): d (major product) = 151.6, 133.1,
131.2 (t, J = 7.0 Hz), 128.4, 128.3, 125.8 (dd, J = 23.2, 19.0 Hz),
89.0, 83.5, 70.0 (dd, J = 23.2, 18.3 Hz), 60.6 (d, J = 5.2 Hz);
d (minor product) = 166.0, 133.1, 132.8 (t, J = 7.0 Hz), 129.8,
129.7, 129.6, 125.1 (t, J = 21.4 Hz), 90.0, 83.6, 73.4 (dd, J = 23.2,
19.3 Hz), 61.7 (d, J = 5.2 Hz).
19F NMR (282 MHz, CDCl3): d (major product) = –109.99 (ddd,
J = 260.9, 21.6, 2.3 Hz, 1 F), –114.27 (dd, J = 273.0, 8.5 Hz, 1 F);
d (minor product) = –98.24 (dm, J = 265.9 Hz, 1 F), –109.45 (dm,
J = 273.8 Hz, 1 F).
MS (MALDI): m/z = 388.2 [M + NH4]+.
19F NMR (282 MHz, CD3OD): d (major product) = –109.18 (dd,
J = 278.6, 21.7 Hz, 1 F), –114.02 (ddd, J = 279.5, 9.0, 3.1 Hz, 1 F);
d (minor product) = –102.34 (dd, J = 274.9, 6.5 Hz, 1 F), –107.60
(ddd, J = 274.1, 11.3, 6.8 Hz, 1 F).
HRMS (MALDI): m/z [M+] calcd For C18H20F2O6: 370.1228;
found: 370.1245.
[(2R,6R)-6-(6-Chloro-7H-purin-7-yl)-3,3-difluoro-3,6-dihydro-
2H-pyran-2-yl]methyl Benzoate (10) and [(2R,6S)-6-(6-Chloro-
7H-purin-7-yl)-3,3-difluoro-3,6-dihydro-2H-pyran-2-yl]meth-
yl Benzoate (21)
To a solution of compound 20 (130 mg, 0.35 mmol) and 6-chloro-
purine (105 mg, 0.68 mmol) in THF (10 mL) was added Pd(PPh3)4
(20 mg, 5 mmol%) and PPh3 (9 mg, 10 mmol%). The mixture was
stirred at 60 °C for 5 h and then cooled to r.t. After concentration,
the crude product was purified by flash silica gel column chroma-
tography (PE–EtOAc, 1:1) to give 21 (55 mg, 39%) and 10 (14 mg,
10%) as foams.
MS (MALDI): m/z = 225.1 [M + CH3COO]–.
[(2R)-3,3-Difluoro-6-hydroxy-3,6-dihydro-2H-pyran-
2-yl]methyl Benzoate (17)
To a solution of diol 19 (70 mg, 0.42 mmol) in anhyd CH2Cl2 (6
mL) was slowly added pyridine (1 mL) followed by BzCl (55 mL)
at –78 °C. After stirring the mixture for 1 h at the same temperature,
MeOH (2 mL) was added and the mixture was stirred for another 30
min. The mixture was washed sequentially with aq 1 N HCl (5 mL),
sat. aq NaHCO3 (3 mL), and brine (3 mL). The resultant organic
layer was dried (Na2SO4), filtered, and the solvent was removed in
vacuo. The residue was purified by flash silica gel column chroma-
tography (PE–EtOAc, 4:1) to give 17 (99 mg, 87%) as a clear oil.
10
[a]D26 +53.7 (c 0.65, CHCl3).
IR (film): 3116, 1724, 1590, 1564, 1397, 1337, 1272, 1158, 1093,
1052, 948, 831, 711, 636, 566 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.76 (s, 1 H), 8.24 (s, 1 H), 8.02
(d, J = 8.1 Hz, 2 H), 7.57 (t, J = 8.1 Hz, 1 H), 7.43 (t, J = 7.2 Hz, 2
H), 6.76 (t, J = 4.8 Hz, 1 H), 6.45–6.37 (m, 2 H), 4.82–4.79 (m, 1
H), 4.59–4.47 (m, 2 H).
13C NMR (75.5 MHz, CDCl3): d = 171.3, 157.7, 156.6 (d, J = 39.9
Hz), 148.0, 138.6, 137.5 (t, J = 6.7 Hz), 136.7, 134.9, 134.5, 133.6,
132.8 (dd, J = 23.6, 20.2 Hz), 117.2 (dd, J = 184.3, 179.2 Hz), 81.9,
80.6 (dd, J = 23.6, 19.6 Hz), 65.8 (d, J = 4.5 Hz).
19F NMR (282 MHz, CDCl3): d = –106.14 (ddd, J = 282.8, 18.0, 7.9
Hz, 1 F), –107.90 (dt, J = 283.1, 4.5 Hz, 1 F).
IR (film): 3500, 1725, 1453, 1281, 1103, 1027, 712 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.06 (d, J = 6.0 Hz, 2 H), 7.60 (t,
J = 7.2 Hz, 1 H), 7.45 (t, J = 7.8 Hz, 2 H), 6.26–6.19 (m, 1 H), 6.05
(t, J = 9.9 Hz, 1 H), 5.56 (t, J = 3.3 Hz, 0.8 H), 5.49 (t, J = 5.7 Hz,
0.2 H), 4.77–4.55 (m, 3 H).
13C NMR (75.5 MHz, CDCl3): d (major product) = 166.6, 134.2 (t,
J = 7.0 Hz), 133.3, 129.4, 128.6, 128.5, 128.4, 124.0 (dd, J = 22.9,
19.2 Hz), 88.1, 68.3 (dd, J = 23.1, 18.3 Hz), 61.2 (d, J = 4.9 Hz);
d (minor product) = 166.6, 136.9 (t, J = 7.0 Hz), 133.4, 130.0,
129.9, 129.7, 129.5, 124.4 (t, J = 22.0 Hz), 91.8, 73.6 (t, J = 42.1
Hz), 61.4 (d, J = 3.6 Hz).
19F NMR (282 MHz, CDCl3): d (major product) = –109.99 (dd,
J = 258.9, 20.6 Hz, 1 F), –114.27 (dd, J = 269.5, 9.6 Hz, 1 F);
d (minor product) = –105.15 (dm, J = 271.8 Hz, 1 F), –106.38 (dm,
J = 279.2 Hz, 1 F).
MS (MALDI): m/z = 407.0 [M + H]+.
HRMS (MALDI): m/z [M + H]+ calcd for C18H14ClF2N4O3:
407.0717; found: 407.0727.
MS (MALDI): m/z = 288.2 [M + NH4]+.
21
HRMS (MALDI): m/z [M+] calcd for C13H12F2O4: 270.0704; found:
[a]D26 –47.7 (c 0.17, MeOH).
270.0709.
IR (film): 2926, 1724, 1591, 1565, 1338, 1276, 1197, 1160, 1096,
1053, 947, 832, 711, 636, 565 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.72 (s, 1 H), 8.21 (s, 1 H), 8.06
(d, J = 6.0 Hz, 2 H), 7.60 (t, J = 7.2 Hz, 1 H), 7.45 (t, J = 7.8 Hz, 2
H), 6.71–6.51 (m, 3 H), 4.70–4.56 (m, 2 H), 4.40–4.30 (m, 1 H).
13C NMR (75.5 MHz, CDCl3): d = 165.7, 152.6, 151.5 (d, J = 11.0
Hz), 143.2, 133.3, 131.9, 129.6 (t, J = 6.9 Hz), 129.3, 129.0, 128.3,
128.0 (d, J = 3.2 Hz), 127.8, 112.0 (dd, J = 184.8, 178.1 Hz), 76.0,
70.9 (dd, J = 23.5, 18.9 Hz), 60.1 (d, J = 4.6 Hz).
19F NMR (282 MHz, CDCl3): d = –109.42 (dd, J = 268.7, 16.1 Hz,
1 F), –111.89 (ddd, J = 272.7, 7.3, 3.4 Hz, 1 F).
[(2R)-6-(tert-Butoxycarbonyloxy)-3,3-difluoro-3,6-dihydro-2H-
pyran-2-yl]methyl Benzoate (20)
Lactol 17 (100 mg, 0.37 mmol) was dissolved in CH2Cl2 (8 mL) and
the solution was cooled to 0 °C. A solution of (Boc)2O (92 mg, 0.42
mmol) and DMAP (20 mg) in CH2Cl2 (2 mL) was added to the mix-
ture. The mixture was stirred at r.t. for 4 h. After concentration, the
crude product was purified by flash silica gel column chromatogra-
phy (PE–EtOAc, 10:1) to give 20 (123 mg, 90%) as a clear oil.
IR (film): 2983, 1756, 1729, 1454, 1396, 1372, 1329, 1278, 1257,
1158, 1110, 1068, 953, 849, 712 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.06 (d, J = 6.0 Hz, 2 H), 7.60 (t,
J = 7.2 Hz, 1 H), 7.45 (t, J = 7.8 Hz, 2 H), 6.26–6.13 (m, 3 H), 4.80–
4.48 (m, 3 H), 1.46 (s, 9 H).
MS (MALDI): m/z = 407.0 [M + H]+.
HRMS (MALDI): m/z [M + H]+ calcd for C18H14ClF2N4O3:
407.0717; found: 407.0717.
Synthesis 2009, No. 4, 602–608 © Thieme Stuttgart · New York

PAPER
Synthesis of Adenosine Derivatives
607
[(2R,6S)-6-(6-Amino-7H-purin-7-yl)-3,3-difluoro-3,6-dihydro-
2H-pyran-2-yl]methanol (4)
13C NMR (75.5 MHz, CD3OD): d = 167.2, 155.4, 152.0, 148.6,
139.1, 118.4 (t, J = 178.7 Hz), 77.9, 75.0 (t, J = 22.5 Hz), 57.8, 27.9
(t, J = 18.6 Hz), 24.7.
19F NMR (282 MHz, CD3OD): d = –102.42 (dm, J = 210.7 Hz, 1 F),
–114.12 (ddd, J = 206.1, 27.3, 13.3 Hz, 1 F).
MS (MALDI): m/z = 286.0 [M + H]+.
HRMS (MALDI): m/z [M + H]+ calcd for C11H14F2N5O2: 286.1110;
Methanolic ammonia (20 mL) was added to compound 21 (49 mg,
0.12 mmol) and the mixture was stirred overnight at 80 °C. After
evaporation of the solvent, the crude product was purified by flash
silica gel column chromatography (MeOH–EtOAc, 1:10) to give 4
(27 mg, 80%) as a white solid; mp 172–174 °C; [a]D24 –88.3 (c 0.25,
MeOH).
IR (film): 1650, 1601, 1475, 1172, 1151, 1094, 1036, 836 cm–1.
found: 286.1105.
1H NMR (300 MHz, CD3OD): d = 8.23 (s, 1 H), 8.20 (s, 1 H), 6.65–
[(2R,6R)-6-(6-Amino-7H-purin-7-yl)-3,3-difluorotetrahydro-
2H-pyran-2-yl]methanol (1)
Using the same conditions as described for compound 2, compound
1 (10 mg, 87%) was prepared as a white solid from compound 3 (11
mg, 0.04 mmol); mp 256–258 °C; [a]D26 –4.4 (c 0.05, MeOH).
6.38 (m, 3 H), 4.19–4.07 (m, 1 H), 3.97–3.68 (m, 2 H).
13C NMR (75.5 MHz, DMSO-d6): d = 156.6, 153.5, 149.9, 140.4,
132.8 (t, J = 11.6 Hz), 126.0 (t, J = 29.4 Hz), 119.4, 114.4, 75.3,
73.7 (t, J = 28.4 Hz), 58.1.
19F NMR (282 MHz, CD3OD): d = –110.77 (ddd, J = 256.6, 19.5,
4.8 Hz, 1 F), –113.95 (ddd, J = 268.7, 9.6, 4.5 Hz, 1 F).
MS (MALDI): m/z = 306.2 [M + Na]+.
HRMS (MALDI): m/z [M + Na]+ calcd for C11H11F2N5O2 + Na:
306.0773; found: 306.0774.
IR (film): 2920, 1652, 1475, 1170, 1144, 1033, 840 cm–1.
1H NMR (300 MHz, CD3OD): d = 8.27 (s, 1 H), 8.14 (s, 1 H), 5.94
(d, J = 10.8 Hz, 1 H), 4.10–3.94 (m, 1 H), 3.83 (d, J = 12.6 Hz, 1 H),
3.64 (dd, J = 12.6, 7.8, 1 H), 2.55 (dd, J = 11.7, 5.7 Hz, 1 H), 2.37–
2.18 (m, 3 H).
19F NMR (282 MHz, CD3OD): d = –110.60 (d, J = 246.5 Hz, 1 F),
–120.10 (dm, J = 174.3 Hz, 1 F).
Crystal Data17
C11H11F2N5O2, M = 283.25, orthorhombic, space group P212121,
a = 6.3537(8) Å, b = 12.6258(15) Å, c = 15.2441(17) Å,
V = 1222.9 (3) Å3, Z = 4, Dx = 1.538 mg·m–3, Absorption coeffi-
cient 0.131 mm–1, F(000) = 584, Crystal size 0.468 × 0.395 × 0.201
mm3, 6951 reflections collected [R(int)] = 0.1288, 1477 unique,
wR2 = 0.1291, R = 0.0561 on I values of 1419 diffraction with I >
2s(I); R = 0.0577, wR2 = 0.1309 for all data and 191 parameters.
Unit cell determination and intensity data collection
(qmax = 26.49°) were performed on a Bruker SMART APEX2 at
293 (2) K. The structure was solved by direct method and refined by
the full-matrix least-squares on F2.
MS (MALDI): m/z = 330.0 [M + HCOO]–.
HRMS (MALDI): m/z [M + H]+ calcd for C11H14F2N5O2: 286.1110;
found: 286.1098.
Acknowledgment
National Natural Science Foundation of China, and Shanghai Mu-
nicipal Scientific Committee are greatly acknowledged for funding
this work.
[(2R,6R)-6-(6-Amino-7H-purin-7-yl)-3,3-difluoro-3,6-dihydro-
2H-pyran-2-yl]methanol (3)
Using the same conditions as described for compound 4, compound
3 (7 mg, 73%) was prepared as a white solid from compound 10 (14
mg, 0.03 mmol); mp 109–110 °C; [a]D24 +14.0 (c 0.05, MeOH).
References
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IR (film): 1657, 1602, 1575, 1171, 1146, 1087, 1036, 841 cm–1.
1H NMR (300 MHz, CD3OD): d = 8.24 (s, 1 H), 8.14 (s, 1 H), 6.66
(t, J = 6.0 Hz, 1 H), 6.60 (d, J = 22.3 Hz, 1 H), 6.39 (t, J = 8.7 Hz,
1 H), 4.28–4.19 (m, 1 H), 3.95 (dd, J = 12.0, 2.7 Hz, 1 H), 3.70 (dd,
J = 12.3, 4.2 Hz, 1 H).
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8.2 Hz, 1F), –109.1 (dm, J = 262.3 Hz, 1 F).
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306.0773; found: 306.0778.
[(2R,6S)-6-(6-Amino-7H-purin-7-yl)-3,3-difluorotetrahydro-
2H-pyran-2-yl]methanol (2)
A suspension of Pd/C (12 mg) and compound 4 (20 mg, 0.07 mmol)
in MeOH–EtOAc (5 mL:5 mL) was stirred under H2 for 26 h at r.t.
Filtration and removal of the solvent gave the crude product, which
was purified by flash silica gel column chromatography (MeOH–
EtOAc = 1:10) to give 2 (18 mg, 90%) as a white solid; mp 234–
236 °C; [a]D24 +30.3 (c 0.22, MeOH).
IR (film): 2928, 1655, 1474, 1172, 1147, 1036, 840 cm–1.
1H NMR (300 MHz, CD3OD): d = 8.24 (s, 1 H), 8.12 (s, 1 H), 6.21
(s, 1 H), 3.94–3.75 (m, 3 H), 2.85–2.76 (m, 1 H), 2.35–2.28 (m, 1
H).
Synthesis 2009, No. 4, 602–608 © Thieme Stuttgart · New York

608
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Synthesis 2009, No. 4, 602–608 © Thieme Stuttgart · New York