Facile Approaches to 2-Deoxy- d -glucose and 2-Deoxy-α- d -glucopyranonucleosides from d -Glucal

Article abstract of DOI:10.1055/s-0036-1589501

Convenient and stereoselective methods for the preparation of 2-deoxy- d -glucose and purine 2-deoxy-α- d -glucopyranonucleosides were developed. Halogen-mediated O-glycosidation of d -glucal by bromine in MeOH followed by reductive removal of the halo group and hydrolysis of methoxy group by zinc in saturated aqueous sodium dihydrogen phosphate gave 2-deoxy- d -glucose. Treatment of 3,4,6-tri- O -acetyl- d -glucal with IBr and 2,6-dichloropurine based on haloetherification and subsequent reductive removal of iodine and deprotection allowed the isolation of purin-9-yl 2-deoxy-α- d -glucopyranonucleoside. Preparation of several purin-9-yl 2-deoxy-α- d -glucopyranoside derivatives is also reported. Their configuration was confirmed by single crystal X-ray analysis of the key intermediate 2,6-dichloro-9-(2-iodo-2-deoxy-α- d -glucopyranosyl)purine.

Full text of DOI:10.1055/s-0036-1589501

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–F
paper
A
en
W. Xu et al.
Paper
Synthesis
Facile Approaches to 2-Deoxy-D-glucose and 2-Deoxy-α-D-gluco-
pyranonucleosides from D-Glucal
Wenke Xua
Hui Yanga
Yingju Liua
Yingchun Huaa
Bin Hea
OAc
OAc
O
OAc
O
OAc
O
AcO
AcO
AcO
AcO
NB
Br
I
OAc
OAc
Zn/NaH2PO4
Xin Ninga
OH
OH
O
Zhiyan Qina
Hong-Min Liua,b
Feng-Wu Liu*a,b
OH
O
OH
NB
HO
HO
O
OMe
HO
HO
OH
Br
OH
NB: nucleobase
a School of Pharmaceutical Sciences, Zhengzhou Universit,
P. R. of China
fwliu@zzu.edu.cn
b Collaborative Innovation Center of Henan New Drug Research
and Safety Evaluation, P. R. of China
Received: 20.04.2017
Accepted after revision: 24.04.2017
Published online: 07.06.2017
has remained unattractive, as the protected glucals often
give rearranged by-products under acidic conditions.7,8 To
avoid the rearrangement reaction, various methods have
been developed such as catalytic addition of alcohol by
TMSI-PPh3,9 CeCl3·7H2O-NaI,1b and halogen-mediated O-
glycosidation by NIS10 or I2-Cu(OAc)2.11 There are several
limitations to these methods including high cost of cata-
lysts and tedious procedures hampering their wider use.
Hence, the development of simple, convenient, and cheap
method to produce the 2-deoxy-D-glucose and 2-deoxyglu-
cosides is desirable. As a continuation of our work on carbo-
hydrate chemistry, we have now developed a concise and
efficient method for the preparation of the 2-deoxy-D-glu-
cose from D-glucal based on the halogen-mediated O-glyco-
sidation. It is noteworthy that in this method, reductive re-
moval of a halo group and hydrolysis of an alkoxy group to
give 2-deoxy-D-glucose were conducted at the same step in
one-pot. Inspired by the previous introduction of diethoxy-
phosphorylmethoxy group to furanoid glycal by IBr via ha-
loetherification,12 we attempted to introduce nucleobases
to 3,4,6-tri-O-acetyl-D-glucal to synthesize 2-deoxynucleo-
side analogues. As a result, a stereoselective approach to
purin-9-yl 2-deoxy-α-D-glycosides from 3,4,6-tri-O-acetyl-
D-glucal (4) via halo-mediated nucleophilic addition of pu-
rine was developed.
DOI: 10.1055/s-0036-1589501; Art ID: ss-2017-h1887-op
Abstract Convenient and stereoselective methods for the preparation
of 2-deoxy-D-glucose and purine 2-deoxy-α-D-glucopyranonucleosides
were developed. Halogen-mediated O-glycosidation of D-glucal by bro-
mine in MeOH followed by reductive removal of the halo group and hy-
drolysis of methoxy group by zinc in saturated aqueous sodium dihy-
drogen phosphate gave 2-deoxy-D-glucose. Treatment of 3,4,6-tri-O-
acetyl-D-glucal with IBr and 2,6-dichloropurine based on haloetherifica-
tion and subsequent reductive removal of iodine and deprotection al-
lowed the isolation of purin-9-yl 2-deoxy-α-D-glucopyranonucleoside.
Preparation of several purin-9-yl 2-deoxy-α-D-glucopyranoside deriva-
tives is also reported. Their configuration was confirmed by single crys-
tal X-ray analysis of the key intermediate 2,6-dichloro-9-(2-iodo-2-de-
oxy-α-D-glucopyranosyl)purine.
Key words glucal, 2-deoxy-D-glucose, 2-deoxy-α-D-glucopyranonu-
cleoside, halogen-mediated O-glycosidation, stereoselective synthesis
The 2-deoxy-D-glucose scaffold is widely found in many
biologically active compounds, such as aureolic acids, anth-
racyclines, cardiac glycosides, avermectins, erythromycins,
and many others.1 In particular, it was shown that 2-deoxy-
D-glucose inhibits the growth of many tumor cells.2 The
compound has a long history of use as a building block in
carbohydrate chemistry for its effectiveness as glycosyl do-
nor.3–5 As a result, numerous researchers have initiated pro-
grams aimed at the development of methods for the prepa-
ration of 2-deoxyglucose and 2-deoxyglucosides.6 In many
documented methods, 3,4,6-tri-O-acetyl-D-glucal (4) is the
most widely used intermediate.
Our investigations for the envisaged protocol com-
menced with the preparation of the essential intermediate,
3,4,6-tri-O-acetyl-D-glucal (4). On survey of the literature,
3,4,6-tri-O-acetyl-D-glucal (4) was most often prepared by
the classical Fisher–Zach reductive elimination of 2,3,4,6-
tetra-O-acetyl-D-glucopyranosyl bromide using zinc dust in
acetic acid.13 Over the years, numerous reductive reagents
have been used for the preparation of glycals from per-
acetylated glycopyranosyl bromide, such as vitamin B-
The acid-catalyzed addition of water or alcohol to the
glucal 4 appears to be the most direct method for the syn-
thesis of 2-deoxyhexopyranoses or pyranosides. However,
the generality of these methods to prepare 2-deoxy sugars
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

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W. Xu et al.
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Synthesis
12/Zn/NH4Cl,14 Cr(II) complexes,15 Zn/NaH2PO4/EtOAc,6a and
titanium(III) reagents.16
in a one-pot procedure (Scheme 2). This is the first report of
this efficient method.
Based on the literature,6a,b,17 3,4,6-tri-O-acetyl-D-glucal
(4) was prepared from commercially available D-glucose by
following the procedures as shown in Scheme 1.
Furthermore, based on the experience of introducing
the diethoxyphosphorylmethoxy group to furanoid glycal
via haloetherification in our previous work,12 and synthesis
of 2-deoxy-N-glycosides from glucal in the presence of NIS
by the De Castro group,18 we speculated that the nucleo-
base could also be introduced to the glucal under suitable
conditions. Thus, 2,6-dichloropurine was selected as the
nucleobase to be used in the introduction reaction for its
good solubility. To a solution of fully protected glucal 4 in
dichloromethane was added a suspension of 2,6-dichloro-
purine sodium salt in THF, followed by iodine monobro-
mide under stirring at –40 °C. The mixture was stirred for
an hour under nitrogen and then worked up to furnish
product 8 as a white foam. Compound 8 was elucidated as
2,6-dichloropurin-9-yl 3,4,6-tri-O-acetyl-2-iodo-2-deoxy-
hexopyranoside by NMR and HRMS spectral analysis. Sub-
sequently, we tried to further confirm the absolute configu-
ration of C-1′ by analysis of the 1H NMR spectral data. In the
1H NMR spectrum, the coupling constant between H-1′ and
H-2′ is 10.4 Hz, a large constant, which indicated two axial-
H’s in trans position. Further analysis of the coupling be-
tween H-2′ and H-3′, revealed that the J2,3 value is 3.1 Hz, a
small constant, which showed that both H-2′ and H-3′ at-
oms should be in cis direction. Based on the mechanism of
haloetherification, the stereochemistry of glycosylation
is governed by trans-diaxial addition.4 Therefore, we can
deduce that the 2-iodo-2-deoxypynanonucleoside is an
α-anomer.
Subsequently, transformation of fully acetylated glucal
4 into 2-deoxy-D-glucose (7) was investigated. Initially, di-
rect synthesis of methyl 2-deoxy-D-glucopyranoside and
then hydrolysis to remove the methyl of 1-methoxy group
were investigated. In view of previous studies, CeCl3·7H2O-
9
NaI1b and TMSI-PPh3 systems are effective catalysts in dif-
ferent substrates to synthesize 2-deoxyglucopyranosides.
Both systems were utilized in the conversion of 3,4,6-tri-O-
acetyl-D-glucal (4) to methyl 3,4,6-tri-O-acetyl-2-deoxy-D-
glucopyranoside. In spite of tremendous efforts to optimize
reaction conditions, the yield of target product using Ce-
Cl3·7H2O-NaI was lower than 40%, which was too low to
9
continue the synthesis. Synthesis with TMSI-PPh3 was
even worse as no product was obtained. From here, we in-
vestigated utilizing a 2-halo-2-deoxyglycoside intermediate
by halogen-mediated O-glycosidation of glucal. In order to
avoid the prevalent Ferrier rearrangement reaction of
acetylated glucal under acidic conditions, we decided to use
free glucal 5 as the key intermediate. Compound 4 was first
deprotected with sodium hydroxide in methanol. Then bro-
mine was added to the resulting reaction mixture. The mix-
ture was stirred under detection by TLC until free glucal
disappeared. After workup, methyl 2-bromo-2-deoxyhexo-
pyranoside (6) was obtained in 91% yield from 4. Finally, re-
ductive elimination of the bromide on C-2 of compound 6
was investigated. When a variety of reducing agents were
screened for the reaction, we unexpectedly found that the
same conditions for the preparation of fully protected glu-
cal 4 from 2,3,4,6-tetra-O-acetyl-D-glucopyranosyl bromide
(3) gave a more polar product than methyl 2-deoxyhexopy-
ranoside as observed by TLC. The resulting product was pu-
rified by silica gel chromatography and structurally con-
The absolute configuration of the nucleoside was also
confirmed as α-anomer by X-ray crystallographic analysis
of a suitable crystal of 8 after recrystallization from ethanol
1
(Figure 1). The pyranose ring adopts a chair C4 conforma-
tion. The large 1-purinyl and 2-iodo groups located at op-
posite sides of pyranose ring were in equatorial position
due to their large steric hindrance, which forced the gener-
1
4
firmed as 2-deoxy-D-glucose 7 (62% yield) by H and 13C
ally stable C1 pyranose ring to change into the unfavored
NMR spectral analysis. That is, removal of the 2-bromo
group and hydrolysis of the 1-methoxy had been achieved
by using the Zn/NaH2PO4/acetone system at the same step
1C4 conformation and the smaller 3,4-di-O-acetyl and 5-ac-
etoxymethyl to be in axial positions. Furthermore, the two-
dimensional NOESY spectrum of compound 8 in deuterated
chloroform was recorded (Figure 2). The NOE correlations
from H-1′ to H-6′ and H-2′ to H-8, respectively, indicated
OAc
O
OH
O
OAc
O
OH
O
i
AcO
AcO
HO
HO
ii
OH
i
AcO
AcO
HO
HO
AcO
OH
OAc
2
1
5
4
OAc
OH
O
OAc
O
OH
O
O
iii
ii
AcO
AcO
HO
HO
iii
AcO
AcO
HO
HO
OMe
OH
AcO
Br
Br
3
4
6
7
Scheme 1 Synthesis of 3,4,6-tri-O-acetyl-D-glucal (4). Reagents and
conditions: i. Ac2O, HClO4, 3 h; ii. PBr3, H2O, 94% from 1; iii. Zn, sat. aq
NaH2PO4, acetone, 86%.
Scheme 2 Conversion of glucal 4 to 2-deoxy-D-glucose (7). Reagents
and conditions: i. NaOH, MeOH, 0 °C, 2 h; ii. Br2, MeOH, 10 min, 91%
from 4; iii. Zn, sat. aq NaH2PO4, acetone, 5 h, 62%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

C
W. Xu et al.
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Synthesis
that the H-1′ and AcOCH2 group are located on one side,
H-2′ and purinyl group are on another side of the pyranose
ring. This result is consistent with the α-configuration of
C-1′ by X-ray crystallographic analysis.
Then, removal of the 2-iodo group of intermediate 8
with hypophosphorous acid (H3PO2) and 2,2-azobisisobu-
tyronitrile (AIBN) gave compound 9, and deprotection of
the acetyl group in methanol and ethanol gave 2-deoxy-α-
D-glucopyranoside 10 and 11, respectively. Finally, other
2,6-disubstituted purin-9-yl 2-deoxy-D-glucopyranosides
12–14 were obtained by treatment of 10 with various nuc-
leophiles (Scheme 3).
In summary, we have developed a facile and efficient
method for the synthesis of 2-deoxy-D-glucose via halogen-
mediated O-glycosidation of the intermediate glucal, in
which reductive removal of a bromine at C-2 and hydrolysis
of a methoxy group at C-1 were accomplished in one step.
Furthermore, 2-deoxy-α-D-glucopyranosides were stereo-
selectively synthesized by haloetherification of fully acetyl-
1
ated glucal. Unusual C4 conformation of pyranose ring of
intermediate 9 was found in the study by X-ray single crys-
tallographic analysis. This work provides pharmaceutical
researchers and chemists alternative methods for the syn-
thesis of 2-deoxy-D-glucose and 2-deoxynucleosides.
Reagents and solvents were purchased from commercial sources. 1,4-
Dioxane, CH2Cl2, MeCN, and THF were distilled over CaH2. Melting
points were determined on a XT5B melting-point apparatus and are
uncorrected. 1H and 13C NMR spectra were acquired on a Bruker
Avance III-400 spectrometer at 300 K with chemical shifts (δ) given in
parts per million relative to TMS as the internal standard (δ = 0.00).
High-resolution mass spectra (HRMS) were taken with a Q-Tof Micro-
mass spectrometer. TLC was performed on silica gel GF254 plates and
detected by placing under the UV lamp (254 nm), or visualized by
spraying the plates with 5% ethanolic ammonium phosphomolybdate
and charring them with a heating gun. Column chromatography was
conducted using a column of silica gel (200–300 mesh).
Figure 1 ORTEP of compound 8
(6')H
H(6')
H(8)
H(1')
AcO
N
OAc
O
N
Cl
I
OAc H(2')
N
N
X-ray diffraction analysis was carried out on an Agilent Xcalibur Gem-
ini, Eos CCD diffractometer with graphite-monochromated Cu-Kα (λ =
1.54178 Å) radiation. An orthorhombic crystal was selected and
mounted on a glass fiber. All data were collected at a temperature of
Cl
Figure 2 NOE effects of compound 8 in CDCl3
AcO
AcO
N
N
OAc
O
OAc
O
OAc
N
N
Cl
Cl
ii
i
O
I
AcO
AcO
OAc
OAc
N
N
N
N
Cl
Cl
4
8
9
HO
HO
N
OH
O
N
OH
O
R1
N
iii, or iv, or v
N
R
vi, or vii
or viii
10
OH
N
N
OH
N
N
R2
Cl
12: R1 = NHMe, R2 = NHMe
13: R1 = NH2, R2 = Cl
14: R1 = OMe, R2 = OMe
10: R = OMe
11: R = OEt
Scheme 3 Synthesis of 2-deoxyglucopynanoside derivatives. Reagents and conditions: i. 2,6-dichloropurine, NaH, IBr, 55%; ii. H3PO2, Et3N, AIBN, 86%;
iii. NaOH in MeOH, for 10, 91%; iv. K2CO3 in EtOH, for 11, 75%; v. 40% aq MeNH2, 100 °C, 2 h, for 12, 93%; vi. Aq 28% NH4OH, 100 °C, 1 h, for 13, 90%;
vii. NaOMe in MeOH, 95 °C, 2 h, for 14, 95%.
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291 K. X-ray diffraction intensities were collected, integrated, and
scaled with the CrysAlisPro suite of programs. The structure was
solved via direct methods and expanded using the Fourier technique.
The non-hydrogen atoms were refined with anisotropic thermal pa-
rameters. Hydroxyl hydrogen atoms were refined with isotropic ther-
mal parameters. Other hydrogen atoms were included but not re-
fined. All calculations were performed using the SHELX-97 crystallo-
graphic software package.
13C NMR for (101 MHz, D2O): δ (β-anomer) = 93.4, 76.0, 70.8, 70.4,
60.9, 39.5.
1H NMR and 13C NMR values for α-anomer were omitted.
HRMS (ESI): m/z [M + H]+ calcd for C6H12O5 + H: 165.0757; found:
165.0759.
2,6-Dichloro-9-(3,4,6-tri-O-acetyl-2-iodo-2-deoxy-α-D-glucopyra-
nosyl)-9H-purine (8)
To a solution of 2,6-dichloropurine (700 mg, 3.7 mmol) in anhyd THF
(10 mL) was added NaH (60% in oil, 163 mg, 4.07 mmol), and the mix-
ture was stirred for 30 min at r.t. Then, the mixture was added to a
solution of 4 (500 mg) in anhyd CH2Cl2 (8 mL) at –40 °C under N2, fol-
lowed by the addition of IBr (180 μL). After stirring at –40 °C for 1 h,
the solution was concentrated under vacuum to dryness. Sat. aq
NaHCO3 (10 mL) and CH2Cl2 (30 mL) were added to the residue. The
organic layer was separated and washed with sat. aq Na2S2O3 (3 × 10
mL), and dried (anhyd Na2SO4) overnight. The solvent was removed
under vacuum and the residue was purified by silica gel column chro-
matography (2.5% EtOAc in CH2Cl2) to give the product as a white
foam (594 mg, 55%); mp 143–145 °C; Rf = 0.3 (2.5% EtOAc in CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 8.25 (s, 1 H, H-8), 6.30 (d, J = 10.4 Hz, 1
H, H-1′), 5.85 (dd, J = 10.4, 3.1 Hz, 1 H, H-2′), 5.48 (t, J = 3.0 Hz, 1 H, H-
3′), 5.17 (dd, J = 12.3, 10.1 Hz, 1 H, H-6′a), 4.85 (dd, J = 3.4, 1.7 Hz, 1 H,
H-4′), 4.45 (d, J = 9.5 Hz, 1 H, H-5′), 3.93 (dd, J = 12.4, 3.4 Hz, 1 H, H-
6′b), 2.30 (s, 3 H, CH3), 2.26 (s, 3 H, CH3), 2.06 (s, 3 H, CH3).
3,4,6-Tri-O-acetyl-D-glucal (4)
Treatment of D-glucose (1) with Ac2O in the presence of HClO4 afford-
ed 1,2,3,4,6-penta-O-acetyl-α-D-glucose (2). Bromination of 2 by PBr3
in H2O gave 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (3).
The fully protected glucosyl bromide 3 was treated with Zn in sat. aq
NaH2PO4 containing acetone (22% volume) at r.t. to furnish 3,4,6-tri-
O-acetyl-D-glucal (4) in 86% yield.
For full experimental details, see the Supporting Information.
D-Glucal 5
NaOH (8.6 g, 0.22 mol) was added to a solution of the glucal 4 (60 g,
0.22 mol) in anhyd MeOH (170 mL) with stirring at 0 °C. The solution
was stirred at r.t. for 2 h to give 5. The solution was directly used in
the next step without any further purification.
1H NMR (400 MHz, DMSO-d6): δ = 6.29 (dd, J = 6.0, 1.2 Hz, 1 H, H-1),
5.11 (d, J = 5.5 Hz, 1 H, H-2), 4.89 (d, J = 5.5 Hz, 1 H, H-3), 4.65–4.53
(m, 2 H, H-4, H-5), 3.99–3.90 (m, 1 H, H-6a), 3.77–3.65 (m, 1 H, H-6b),
3.64–3.54 (m, 2 H, OH), 3.37 (dd, J = 8.8, 6.4 Hz, 1 H, OH).
13C NMR (101 MHz, CDCl3): δ = 171.2, 169.3, 168.4, 153.3, 152.6,
152.2, 145.9, 131.5, 80.2, 76.7, 70.9, 66.8, 59.2, 22.5, 20.9, 20.8.
HRMS (ESI): m/z [M + Na]+ calcd for C17H17Cl2IN4O7Na: 608.9411;
found: 608.9421.
13C NMR (101 MHz, DMSO-d6): δ = 143.3, 104.8, 79.8, 69. 6, 68.9, 60.8.
HRMS (ESI): m/z [M + H]+ calcd for C6H10O4 + H: 147.0652; found:
147.0652.
2,6-Dichloro-9-(3,4,6-tri-O-acetyl-2-deoxy-α-D-glucopyranosyl)-
9H-purine (9)
Methyl 2-Bromo-2-deoxy-D-glucoside (6)
To solution of 8 (300 mg, 0.51 mmol) in anhyd 1,4-dioxane (8 mL)
were added H3PO2 (117 μL, 2.55 mmol) and Et3N (390 μL, 2.80 mmol).
The mixture was stirred and heated to reflux. A solution of 2,2′-azo-
bis(2-methylpropionitrile) (102 mg, 0.68 mmol) in anhyd 1,4-dioxane
(5 mL) was added in portions over 30 min and the mixture was
stirred for 5 h. After concentration under vacuum, EtOAc (20 mL) and
H2O (10 mL) were added to the residue. The organic layer was dried
(anhyd Na2SO4) overnight and concentrated under vacuum to dry-
ness. The residue was purified by silica gel column chromatography
(Rf = 0.3, 33% EtOAc in hexane) to give the product 9 as a white foam
(230 mg, 86%); mp 117–118 °C.
Bromine (14 mL, 0.27 mol) was added to a solution of 5 obtained as
above from glucal 4 (60 g, 0.22 mol) and the reaction mixture was
stirred at 0 °C for 10 min. The reaction mixture became colorless. The
resulting mixture was filtered, and the filter cake was washed with
MeOH (50 mL). The combined MeOH solution was concentrated un-
der vacuum. The residue was dissolved in anhyd EtOH and filtered
again. The filtrate was concentrated under vacuum to afford the crude
6 (72 g, 91%) as a syrup. The crude product was used in the next step
without any further purification.
2-Deoxy-D-glucose (7)
1H NMR (400 MHz, CDCl3): δ = 8.38 (s, 1 H, H-8), 6.28 (dd, J = 5.9, 4.7
Hz, 1 H, H-1′), 5.49–5.24 (m, 1 H, H-3′), 5.04 (t, J = 6.4 Hz, 1 H, H-6′a),
4.59 (dd, J = 12.3, 7.2 Hz, 1 H, H-4′), 4.21–3.94 (m, 2 H, H-5′, H-6′b),
3.24 (ddd, J = 14.5, 6.1, 4.3 Hz, 1 H, H-2′a), 2.53–2.32 (m, 1 H, H-2′b),
2.18 (s, 3 H, CH3), 2.13 (s, 3 H, CH3), 2.10 (s, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 170.6, 169.6, 169.5, 153.4, 152.7,
152.2, 144.6, 131.3, 78.3, 73.2, 68.2, 67.1, 61.0, 30.8, 20.9, 20.74,
20.69.
Sat. aq NaH2PO4 (500 mL) was added to the solution of the above-ob-
tained crude product 6 (72 g, 0.28 mol) in acetone (150 mL) followed
by Zn powder (170 g, 2.6 mol). After stirring the reaction mixture for
5 h at r.t., the mixture was filtered. The filtrate was adjusted to pH 7
with 20% aq NaOH, and the solid was filtered off. The filtrate was
mixed with anhyd EtOH (5.2 L) and cooled to –20 °C for 5 h. Solids
were filtered off again. The filtrate was concentrated under vacuum
and purified by silica gel column chromatography to give the title
product 7 as a white solid [62%, a mixture of β- and α-anomer, β/α is
about 1:0.22 (mol/mol) based on the 1H NMR analysis]; mp 145–
146 °C; Rf = 0.3 (12% MeOH in EtOAc).
HRMS (ESI): m/z [M + Na]+ calcd for C17H18Cl2N4O7Na: 483.0445;
found: 483.0455.
1H NMR for (400 MHz, D2O): δ (β-anomer) = 4.83 (dd, J = 9.8, 2.0 Hz, 1
H, H-1), 3.80 (dd, J = 12.2, 2.3 Hz, 1 H, H-3), 3.67–3.54 (m, 2 H, H-4, H-
5), 3.28 (ddd, J = 9.7, 6.0, 2.3 Hz, 1 H, H-6a), 3.22–3.02 (m, 1 H, H-6b),
2.16 (ddd, J = 12.4, 5.0, 2.0 Hz, 1 H, H-2a), 1.41 (td, J = 12.1, 9.8 Hz, 1 H,
H-2b).
2-Chloro-6-methoxy-9-(2-deoxy-α-D-glucopyranosyl)-9H-purine
(10)
NaOH (40 mg, 1 mmol) was added to a solution of 9 (460 mg, 1 mmol)
in anhyd MeOH (8 mL), and the reaction mixture was stirred at r.t. for
0.5 h. The resultant mixture was concentrated under vacuum and the
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residue purified by silica gel column chromatography (Rf = 0.3, 10%
MeOH in EtOAc) to give the product 10 as a white foam (300 mg,
91%); mp 104–105 °C.
vacuum to dryness and the residue was purified by silica gel column
chromatography (Rf = 0.3, 20% MeOH in EtOAc) to give the product 13
as a white solid (86 mg, 90%); mp 169–171 °C.
1H NMR (400 MHz, (400 MHz, DMSO-d6): δ = 8.53 (s, 1 H, H-8), 6.20
(t, J = 4.2 Hz, 1 H, H-1′), 5.15 (d, J = 4.5 Hz, 1 H, OH), 5.05 (d, J = 4.7 Hz,
1 H, OH), 4.62 (t, J = 5.8 Hz, 1 H, OH), 4.12 (s, 3 H, OCH3), 3.81 (d, J = 3.3
Hz, 1 H, H-5′), 3.64 (dd, J = 10.4, 5.9 Hz, 1 H, H-6′a), 3.61–3.52 (m, 1 H,
H-6′b), 3.30 (m, 2 H, H-3′, H-4′), 2.91 (m,, 1 H, H-2′a), 2.06–1.93 (m, 1
H, H-2′b).
1H NMR (400 MHz, DMSO-d6): δ = 8.28 (s, 1 H, H-8), 7.81 (s, 2 H, NH2),
6.10 (t, J = 4.3 Hz, 1 H, H-1′), 5.13 (d, J = 4.5 Hz, 1 H, OH), 5.04 (d, J = 5.4
Hz, 1 H, OH), 4.62 (t, J = 5.8 Hz, 1 H, OH), 3.90–3.74 (m, 1 H, H-5′), 3.65
(ddd, J = 11.5, 5.6, 2.4 Hz, 1 H, H-6′a), 3.58 (dt, J = 11.5, 5.7 Hz, 1 H, H-
6′b), 3.37–3.31 (m, 1 H, H-3′), 3.30–3.22 (m, 1 H, H-4′), 2.86 (dt, J =
13.9, 4.2 Hz, 1 H, H-2′a), 1.96 (ddd, J = 14.3, 9.5, 5.2 Hz, 1 H, H-2′b).
13C NMR (101 MHz, DMSO-d6): δ = 161.3, 153.3, 151.9, 143.6, 120.7,
13C NMR (101 MHz, DMSO-d6): δ = 157.3, 153.5, 150.7, 140.5, 118.5,
79.5, 77.6, 70.5, 68.7, 60.8, 55.4, 34.3.
78.8, 77.5, 70.6, 68.8, 60.9, 34.5.
HRMS (ESI): m/z [M + Na]+ calcd for C11H12Cl2N4O4Na: 357.0128;
HRMS (ESI): m/z [M + Na]+ calcd for C11H14ClN5O4Na: 338.0627;
found: 357.0130.
found: 338.0633.
2-Chloro-6-ethoxy-9-(2-deoxy-α-D-glucopyranosyl)-9H-purine
2,6-Dimethoxy-9-(2-deoxy-α-D-glucopyranosyl)-9H-purine (14)
(11)
Na (100 mg, 1.2 mmol) was added to a solution of 10 (100 mg, 0.3
mmol) in anhyd MeOH (6 mL) and the mixture stirred at 95 °C in tef-
lon-sealed bomb for 2 h. The solvent was removed under vacuum, and
the residue was purified by silica gel column chromatography (Rf =
0.3, 10% MeOH in CH2Cl2) to give the product 14 as a white solid (94
mg, 95%); mp 82–83 °C.
1H NMR (400 MHz, DMSO-d6): δ = 8.25 (s, 1 H, H-8), 6.14 (t, J = 4.2 Hz,
1 H, H-1′), 5.11 (d, J = 4.6 Hz, 1 H, OH), 4.99 (d, J = 5.4 Hz, 1 H, OH),
4.59 (t, J = 5.9 Hz, 1 H, OH), 4.05 (s, 3 H, CH3), 3.94 (s, 3 H, CH3), 3.84
(m, 1 H, H-6′a), 3.67 (ddd, J = 11.7, 6.1, 2.3 Hz, 1 H, H-5′), 3.56 (m, 1 H,
H-6′b), 3.32–3.21 (m, 2 H, H-3′, H-4′), 3.05 (m, J = 13.9, 4.0 Hz, 1 H, H-
2′a), 2.04–1.81 (m, 1 H, H-2′b).
K2CO3 (230 mg, 1.67 mmol) was added to a solution of 9 (460 mg, 1
mmol) in anhyd EtOH (8 mL) and anhyd CH2Cl2 (8 mL), and the mix-
ture was stirred at r.t. for 0.5 h. The solvent was removed under vacu-
um, and the residue was purified by silica gel column chromatogra-
phy (Rf = 0.3, 10% MeOH in CH2Cl2) to give the product 11 as a white
foam (258 mg, 75%); mp 90–92 °C.
1H NMR (400 MHz, DMSO-d6): δ = 8.52 (s, 1 H, H-8), 6.20 (dd, J = 10.2,
5.9 Hz, 1 H, H-1′), 5.16 (t, J = 5.8 Hz, 1 H, OH), 5.06 (t, J = 6.1 Hz, 1 H,
OH), 4.64 (m, 1 H, OH), 4.60 (q, J = 8.0 Hz, 2 H, CH2), 3.81 (d, J = 4.7 Hz,
1 H, H-5′), 3.71–3.47 (m, 2 H, H-6′), 3.28 (m, 2 H, H-3′, H-4′), 2.90 (dt,
J = 14.1, 4.2 Hz, 1 H, H-2′a), 2.05–1.93 (m, 1 H, H-2′b), 1.45–1.36 (t, J =
8.0 Hz, 3 H, CH3).
13C NMR (101 MHz, DMSO-d6): δ = 161.9, 161.4, 153.4, 141.6, 117.3,
79.5, 77.4, 70.8, 68.9, 61.1, 55.2, 54.4, 34.4.
13C NMR (101 MHz, DMSO-d6): δ = 161.0, 153.4, 151.9, 143.5, 120.6,
79.4, 77.6, 70.5, 68.7, 64.3, 60.9, 34.3, 14.7.
HRMS (ESI): m/z [M + Na]+ calcd for C12H15ClN4O5Na: 353.0623;
HRMS (ESI): m/z [M + Na]+ calcd for C13H18N4O6Na: 349.1119; found:
349.1121.
found: 353.0625.
2,6-Dimethylamino-9-(2-deoxy-α-D-glucopyranosyl)-9H-purine
(12)
Funding Information
Financial support from National Natural Science Foundation of China
A 40% solution of MeNH2 in H2O (2 mL) was added to a solution of 10
(100 mg, 0.3 mmol) in 1,4-dioxane (10 mL) and the mixture was
stirred at 100 °C in a teflon-sealed bomb for 2 h. The reaction mixture
was concentrated under vacuum to dryness and the residue was puri-
fied by silica gel column chromatography (Rf = 0.3, 10% MeOH in
EtOAc) to give the product 12 as a white foam (91 mg, 93%); mp 130–
131 °C.
1H NMR (400 MHz, DMSO-d6): δ = 7.81 (s, 1 H, H-8), 7.20 (s, 1 H, NH),
6.30 (s, 1 H, NH), 6.00 (t, J = 4.1 Hz, 1 H, H-1′), 5.04 (d, J = 14.8 Hz, 1 H,
OH), 4.99 (s, 1 H), 4.59 (s, 1 H, OH), 3.95–3.79 (m, 1 H, H-5′), 3.66–3.58
(m, 2 H, H-6′), 3.24 (m, 2 H, H-3′, H-4′), 2.91 (m, 4 H, H-2′a, CH3), 2.79
(d, J = 4.7 Hz, 3 H, CH3), 1.96–1.84 (m, 1 H, H-2′b).
(21372207) is gratefully acknowledged.
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Supporting Information
Supporting information for this article is available online at
https://doi.org /10.1055/s-0036-1589501.
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References
(1) (a) Sabesan, S.; Neira, S. J. Org. Chem. 1991, 56, 5468. (b) Yadav, J.
S.; Reddy, B. V. S.; Bhaskar Reddy, K.; Satyanarayana, M. Tetrahe-
dron Lett. 2002, 43, 7009.
(2) (a) Aft, R. L.; Zhang, F. W.; Gius, D. Brit. J. Cancer 2002, 87, 805.
(b) Kang, H. T.; Hwang, E. S. Life Sci. 2006, 78, 1392.
(3) Christopher, L. F.; Richard, W. F. J. Org. Chem. 1999, 64, 1424.
(4) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl.
1996, 35, 1380.
13C NMR (101 MHz, DMSO-d6): δ = 160.5, 155.7, 138.5, 135.9, 114.0,
78.0, 77.1, 70.9, 69.0, 61.1, 34.7, 28.7, 21.2.
HRMS (ESI): m/z [M + Na]+ calcd for C13H20N6O4Na: 347.1438; found:
347.1446.
6-Amino-2-chloro-9-(2-deoxy-α-D-glucopyranosyl)-9H-purine
(13)
(5) Marzabadi, C. H.; Dios, A.; Geer, A.; Franck, R. W. J. Org. Chem.
1998, 63, 6673.
(6) For example: (a) Miller, J. N.; Pongdee, R. Tetrahedron Lett. 2013,
54, 3185. (b) Zhao, J.; Wei, S.; Ma, X.; Shao, H. Carbohydr. Res.
2010, 345, 168. (c) Nord, L. D.; Dalley, N. K.; McKernan, P. A.;
Aq 28% NH4OH (1.5 mL) was added to a solution of 10 (100 mg, 0.3
mmol) in 1,4-dioxane (10 mL), and the mixture was stirred at 100 °C
in a teflon-sealed bomb for 1 h. The mixture was concentrated under
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

F
W. Xu et al.
Paper
Synthesis
Robins, R. K. J. Med. Chem. 1987, 30, 1044. (d) Gervay, J.;
Danishefsky, S. J. Org. Chem. 1991, 56, 5448. (e) Marzabadi, C.
H.; Franck, R. W. Tetrahedron 2000, 56, 8385.
(12) Liu, F.; Liu, Y.; Xu, R.-G.; Dai, G.; Zhao, L.-X.; Wang, Y.; Liu, H.-M.;
Liu, F.-W.; Pannecouque, C.; Herdewijn, P. Chemistry & Biodiver-
sity 2015, 12, 813.
(7) Ciment, D. M.; Ferrier, R. J. J. Chem. Soc. C 1966, 441.
(8) Bolitt, V.; Mioskowski, C.; Lee, S.-G.; Falck, J. R. J. Org. Chem.
1990, 55, 5812.
(9) Cui, X.-K.; Zhong, M.; Meng, X.-B.; Li, Z.-J. Carbohydr. Res. 2012,
358, 19.
(13) Fischer, E.; Zach, K. Sitzungsber. Kl. Preuss. Akad. Wiss. 1913, 27,
311.
(14) Forbes, C. L.; Frank, R. W. J. Org. Chem. 1999, 64, 1424.
(15) Kovacs, G.; Toth, K.; Dinya, Z.; Somsak, L.; Micskei, K. Tetrahe-
dron 1999, 55, 5253.
(10) Durham, T. B.; Roush, W. R. Org. Lett. 2003, 5, 1875.
(11) Sirion, U.; Purintawarrakun, S.; Sahakitpichan, P.; Saeeng, R.
Carbohydr. Res. 2010, 345, 2401.
(16) Spencer, R. P.; Schwartz, J. Tetrahedron 2000, 56, 2103.
(17) Binch, H.; Stangier, K.; Thiem, J. Carbohydr. Res. 1998, 306, 409.
(18) Meyerhoefer, T. J.; Kershaw, S.; Caliendo, N.; Eltayeb, S.;
Hanawa-Romero, E.; Bykovskaya, P.; Huang, V.; Marzabadi, C.
H.; De Castro, M. Eur. J. Org. Chem. 2015, 2457.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F