Facile synthesis of 1′,2′-cis-β-pyranosyladenine nucleosides

Article abstract of DOI:10.1016/j.carres.2007.08.009

1′,2′-cis-β-Glycosyladenine nucleosides, such as β-altroside, β-mannoside, and β-idoside, were efficiently synthesized from the corresponding 1′,2′-trans-β-6-chloropurine derivatives, β-glucoside, and β-galactoside. Nucleophilic substitution of the O-trif

Full text of DOI:10.1016/j.carres.2007.08.009

Available online at www.sciencedirect.com
Carbohydrate Research 342 (2007) 2641–2648
Note
Facile synthesis of 10,20-cis-b-pyranosyladenine nucleosides
Takayuki Ando,a Hisashi Shinohara,b Xiong Luo,b Mahmoud Kandeelb and
Yukio Kitadea,b,c,
*
aCenter for Emerging Infectious Diseases, Gifu University, Yanagido 1-1, Gifu 501-1193, Japan
bDepartment of Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido 1-1, Gifu 501-1193, Japan
cCenter for Advanced Drug Research, Gifu University,Yanagido 1-1, Gifu 501-1193, Japan
Received 27 April 2007; received in revised form 25 July 2007; accepted 19 August 2007
Available online 23 August 2007
Abstract—10,20-cis-b-Glycosyladenine nucleosides, such as b-altroside, b-mannoside, and b-idoside, were efficiently synthesized from
the corresponding 10,20-trans-b-6-chloropurine derivatives, b-glucoside, and b-galactoside. Nucleophilic substitution of the O-tri-
fluoromethanesulfonyl groups at the C-20 and/or 30 was carried out using tetrabutylammonium acetate or cesium acetate under mild
conditions. Subsequent deprotection and amidation afforded the desired compounds, 10,20-cis-b-pyranosyladenine nucleosides.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Keywords: Pyranosyladenine; 10,20-cis-Glycoside; Pyranosyl nucleoside
Various nucleosides containing pyranosyl rings instead
of furanosyl ones for the sugar portion have been syn-
thesized along with their analogues1 in order to develop
antileukemia,2 antitumor,3 and antimicrobial4 reagents,
and enzyme inhibitors.5 In addition, amidite derivatives
of pyranosyl nucleosides were used as modified oligonu-
cleotides to clarify the importance of the core sugar
structure.6–11
It has been reported that 10,20-trans-pyranosyl nucleo-
sides are more abundant than 10,20-cis-pyranosyl ones.
For example, b-glucosyladenine 1,12b-galactosyladenine
2,13 and b-allosyladenine 314 (Fig. 1) were easily synthe-
sized under various coupling conditions, and they were
subsequently deprotected. Due to C-20 acyl group hav-
ing strong neighboring participation, 10,20-trans-glyco-
sides were selectively synthesized. On the other hand,
it is more difficult to synthesize 10,20-cis-b-glycosides,
such as b-altroside 4, b-mannoside 5,15 and b-idoside
6, because both anomeric effect and neighboring partici-
pation act to construct thermodynamically stable a-gly-
coside formation during the glycosylation reaction
(Scheme 1). Several synthetic methods involving direct
glycosylation using the corresponding glycosyl donor
and an insoluble silver salt,16 and intramolecular agly-
con delivery (IAD)17–19 were developed to facilitate con-
struction of 1,2-cis-glycosides for O-glycosylation.
However, idose and altrose are considered as rare sugars
and are therefore expensive for use in the optimization
of reaction conditions and as starting materials.
We have devised a versatile method for the synthesis
of 10,20-cis-b-pyranosyladenine nucleosides from the
corresponding protected 10,20-trans-b-glycosyl-6-chlo-
ropurine derivatives (Scheme 2). Glucose and galactose
are relatively inexpensive starting materials used in the
synthetic step. The hydroxy group was epimerized by
SN2 substitution of the O-trifluoromethanesulfonyl
(TfO) group with either tetrabutylammonium acetate
(TBAA) or CsOAc under mild conditions. Subsequent
deprotection and amidation at the 6-position yielded
the title compounds.
Under reflux condition, peracetylated glucose (glc) or
galactose (gal) was transformed with trimethylsilyl tri-
fluoromethanesulfonate (TMSOTf) into reactive cat-
ions, that were combined with silylated 6-chloropurine
to yield peracetylated b-glucosyl- and b-galactosyl-6-
chloropurine derivatives (Scheme 3). Deacetylation
was carried out using methanolic ammonia at 0 ꢁC.
*
Corresponding author. Tel./fax: +81 58 2932640; e-mail: ykkitade@
gifu-u.ac.jp
0008-6215/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2007.08.009

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T. Ando et al. / Carbohydrate Research 342 (2007) 2641–2648
Figure 1. Various pyranosyladenine nucleosides.
Scheme 1.
Scheme 2. Synthetic plan for 10,20-cis-b-D-glycosyladenine nucleosides.
Scheme 3. Reagents and conditions: (a) TMSOTf, ClCH2CH2Cl, rt, 5 h; (b) NH3–MeOH, 0 ꢁC, 3 h; (c) BDA, CSA, CH3CN, rt, 18 h; (d) Ac2O,
pyridine, rt, 5 h.
Compounds 7 and 8 were obtained by the introduction
of a benzylidene group at the 40 and 60 positions, respec-
tively. The structures of these compounds were deter-
mined based on the spectra of the corresponding
acetylated derivatives 7a and 8a. Significant signals in
1
the H NMR spectra were those of doublet anomeric

T. Ando et al. / Carbohydrate Research 342 (2007) 2641–2648
2643
0
0
protons (J1 ;2 9.6 Hz, for glc, 9.2 Hz for gal) that indi-
cated the b-glycosidic linkage. Treatment of 7 with tri-
fluoromethanesulfonic anhydride (Tf2O) and pyridine
in CH2Cl2 at 0 ꢁC yielded the 20,30-di-O-trifluoro-
methanesulfonyl intermediate 9 at 95% yield. The inver-
sion of the 20 and 30 positions of 9 by nucleophilic
substitution with the acetoxy anion from TBAA or
CsOAc was carried out in DMF.20 The protected b-
altrosyl-6-chloropurine 10 was obtained as a single iso-
mer in 65% (by TBAA method) and 86% yield (by the
CsOAc method) (Scheme 4).
11 and 14 were treated with Tf2O and pyridine in
CH2Cl2 to afford the corresponding trifluoro-
methanesulfonyl intermediates 12 and 15, respectively.
Inversion of triflated positions of 12 and 15 to yield b-
mannosyl- and b-allosyl-6-chloropurine at 90% (for
13) and 88% (for 16) yield, respectively, was achieved
as described. Finally, O-deacetylation, amidation of
the 6 position, and removal of the benzylidene group
yielded 10,20-cis-b-glycosyladenine derivatives (4 and 5)
and b-allosyladenine 3, respectively.
Similarly, treatment of b-galactosyl-6-chloropurine 8
with Tf2O and pyridine, followed by nucleophilic substi-
tution with TBAA, deprotection, and amidation affor-
ded the desired b-idosyladenine 6 (Scheme 5).
A mixture of trimethylacetyl chloride and pyridine in
CH2Cl2 were used for the selective monoprotection of
the hydroxy group of compound 7. The desired 30-OH
protected compound 11 (32%), 20-OH protected com-
pound 14 (37%), and the unreacted starting material
(28%) were obtained. The 20,30-di-O-trimethylacetylated
compound was not obtained. However, the regioselec-
tivity of protection was not very high; the undesired
20-O-trimethylacetyl-30-O-trifluoromethanesulfonyl com-
pound 15 obtained from 14 was also an important inter-
mediate in the synthesis of b-allopyranosyladenine.
Further, the separation of these regioisomers by silica
gel chromatography was relatively easy. Compounds
0
0
0
0
0
0
The J1 ;2 , J2 ;3 and J3 ;4 values were analyzed (summa-
rized in Table 1) in order to define the stereochemistry of
0
0
hydroxy groups. The J1 ;2 values of 10, 13, and 18 (1.6–
2.0 Hz) demonstrated that the relationships between H-
10 and H-20 supported the 10,20-cis-b assignment. Fur-
0
0
0
0
thermore, the J2 ,3 and J3 ,4 values of 10, 16, and 18
were less (2.0–3.6 Hz) than those of the corresponding
compounds 7a and 8a (9.6 and 9.2 Hz, respectively).
This information indicated that the ring proton at
C-30 of 10, 16, and 18 was located in the equatorial
Scheme 4. Reagents and conditions: (a) Tf2O, pyridine, CH2Cl2, 0 ꢁC, 30 min (for 9) or 10 min (for 12 and 15); (b) TBAA, DMF, 40 ꢁC, 24 h (for 10)
or 0 ꢁC, 30 min (for 13) AcOCs, DMF, 40 ꢁC, 1 h (for 16); (c) NH3–MeOH, 120 ꢁC, 24 h; (d) CSA, MeOH, rt, 18 h; (e) PivCl, pyridine, CH2Cl2, 0 ꢁC,
18 h.
Scheme 5. Reagents and conditions: (a) Tf2O, pyridine, CH2Cl2, 0 ꢁC, 30 min; (b) TBAA, DMF, 40 ꢁC, 24 h; (c) NH3–MeOH, 120 ꢁC, 24 h; (d) CSA,
MeOH, rt, 18 h.

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T. Ando et al. / Carbohydrate Research 342 (2007) 2641–2648
Table 1. Coupling constants
1.2. General procedure
Compound
Coupling constant (Hz)
1.2.1. General procedure A for the silylation of 6-
chloropurine. To a suspended solution of 6-chloropu-
rine (6-CP) in dichloroethane (10 mL for 100 mg of 6-
CP) was added N,O-bis(trimethylsilyl)acetamide (BSA,
1.5 equiv for 6-CP) and the mixture was stirred under re-
flux conditions for 30 min. The reaction solution was di-
rectly used for the coupling reaction with peracetylated
sugar.
0
0
0
0
0
0
J1 ;2
J2 ;3
J3 ;4
7a
10
13
16
8a
18
9.6
2.0
1.6
9.6
9.2
2.0
9.2
3.6
3.6
3.2
10.0
3.2
9.6
3.6
10.8
2.8
3.6
2.0
position, and that the configuration of 30-OH group was
axial.
1.2.2. General procedure B for deacetylation and amida-
tion of the 6-chloro group. The compound was treated
with methanolic ammonia (50 mL, 27–32% w/w) at
120 ꢁC in a sealed tube for 24 h. The reaction mixture
was evaporated under reduced pressure.
In conclusion, we successfully synthesized 10,20-cis-b-
glycosyladenine nucleosides by inverting the configura-
tion of the hydroxy group. Nucleophilic substitution
yielded considerably higher amounts of the glucose
derivative than the galactose derivative. It is assumed
that the 40 axial hydroxy group and 40,60-O-benzylidene
group caused steric hindrance around the 20 position of
the galactose moiety. Changing the protective group of
the galactose portion may solve this problem and in-
crease the inversion yield; this technique is currently un-
der investigation.
1.2.3. General procedure C for removal of the benzylidene
group. Camphorsulfonic acid (CSA, 0.01 equiv for
starting material) was added to a solution of the residue
obtained after general procedure B in MeOH (10 mL)
and the mixture was stirred for 18 h at rt. After neutral-
ization with Et3N, the reaction mixture was
concentrated.
The synthetic method described in this paper may be
applied to other bases, such as guanine, thymine, cyto-
sine, and uracil. Furthermore, trifluoromethanesulfonyl
intermediates may also be useful for modification of the
sugar portion with various nucleophiles in order to
introduce various functional groups and construct dou-
ble bond in the pyranose ring.
1.3. 9-(40,60-O-Benzylidene-b-D-glucopyranosyl)-H-6-
chloropurine (7)
To a solution of silylated 6-CP in dichloroethane, which
was obtained from 6-CP (300 mg, 1.94 mmol) by using
general procedure (A) were added 1,2,3,4,6-penta-O-
acetyl-b-D-glucose (1.14 g, 2.91 mmol) and TMSOTf
(528 lL, 2.91 mmol), and the stirring was continued
for 2 h under reflux condition. The mixture was neutral-
ized with triethylamine and concentrated. Column chro-
matography (CHCl3–MeOH, 150:1 to 70:1) of the
residue on silica gel gave acetylated glucosyl 6-CP deriv-
ative. Deacetylation was performed under the treatment
with methanolic ammonia at 0 ꢁC for 3 h. The reaction
mixture was evaporated under the reduced pressure,
and the residue was purified by silica gel column chro-
matography (CHCl3–MeOH, 3:1) and crystallization
from MeOH. To a suspended solution of deacetylated
compound were added benzaldehydedimethyl acetal
(1.31 mL, 8.73 mmol) and CSA (34 mg, 0.15 mmol)
and the mixture was stirred at rt for 18 h. The mixture
was neutralized with Et3N, concentrated, and extracted
with EtOAc. The extract was washed with water, dried
(Na2SO4), and concentrated. The crystallization from
EtOAc gave 7 (230 mg, 74%). [a]D ꢀ35 (c 0.01 CHCl3);
1H NMR (DMSO-d6): d 8.91 (s, 1H, H-2), 8.82 (s, 1H,
1. Experimental
1.1. General methods
Specific rotations were determined with a Horiba SEPA-
300 high sensitive polarimeter at 25 ꢁC. 1H and 13C
NMR spectra were recorded at 400 MHz on a JEOL
AL-400 (operated at 400 and 100 MHz, respectively)
by using CDCl3 with TMS as the internal standard,
DMSO-d6, and CD3OD. The spin multiplicities are indi-
cated by the following symbols s (singlet), d (doublet),
dd (doublet of doublet), t (triplet), ddd (doublet of dou-
blet of doublet), q (quartet), m (multiplet), and br
(broad). Coupling constants (J) are expressed in Hertz.
Mass spectra (EIMS and HRESIMS) were recorded at
70 eV on Shimadzu GCMS QP 2010A and a JEOL
JMS-700/GI spectrometer. Reactions were monitored
by thin-layer chromatography using E. MERCK Silica
Gel 60F254 glass plate. Silica gel column chromatogra-
phy was carried out on Wako gel C-300. HPLC was per-
formed using the Shimadzu HPLC 10A VP-series
attached with a YMC ODS-AM column (250 mm ·
20 mm) for separation or an YMC ODS-M80 column
(150 mm · 8 mm) for analysis.
0
0
H-8), 7.48–7.36 (m, 5H, PhCH), 5.77 (d, 1H, J1 ;2
9.6 Hz, H-10), 5.64 (s, 1H, PhCH), 4.25–4.18 (m, 2H,
H-20, H-30), 3.80–3.62 (m, 4H, H-40, 50, 60ax, 60eq);
13C NMR (DMSO-d6): d 152.0, 149.4, 146.4, 137.6,
131.1, 128.9, 128.2, 128.0 (2C, Ph), 126.4 (2C, Ph),

T. Ando et al. / Carbohydrate Research 342 (2007) 2641–2648
2645
100.8, 94.2, 84.1, 80.2, 73.0, 71.9, 68.8; EI MS (m/z, rel-
ative intensity): 403 (Mꢀ, 4.8), 250 (25.5), 197 (18), 183
(72), 155 (100), 119 (17), 105 (51.8); HRESIMS m/z
calcd for C18H18ClN4O5 [M+H]+: 405.0966. Found,
405.0987.
trated, and extracted with CH2Cl2. The extract was
washed with 2 M HCl, satd Na2CO3, and water, dried
(Na2SO4), and concentrated. The crystallization from
EtOAc–hexane gave 8a (57 mg, 117 lmol) in 95% yield
1
as white crystal. [a]D ꢀ30 (c 0.01, CHCl3); H NMR
(CDCl3): d 8.78 (s, 1H, H-2), 8.46 (s, 1H, H-8), 7.48–
1.4. 9-(20,30-Di-O-acetyl-40,60-O-benzylidene-b-D-gluco-
pyranosyl)-H-6-chloropurine (7a)
7.41 (m, 5H, PhCH), 5.98 (d, 1H, J1 ;2 9.2 Hz, H-10),
0
0
5.91 (t, 1H, J2 ;3 10.0 Hz, H-20), 5.60 (s, 1H, PhCH),
0
0
5.25 (dd, 1H, J3 ;4 3.6 Hz, H-30), 4.59 (d, 1H, H-40),
4.32 and 4.12 (2d, 2H, H-60a, H-60b), 3.90 (s, 1H, H-
50), 2.12 and 1.77 (2s, 6H, 2CH3CO); 13C NMR
(CDCl3): d 170.4, 169.0, 152.3, 151.5, 143.4, 137.1,
133.7, 131.5, 129.5, 128.4 (2C, Ph), 126.2 (2C, Ph),
101.2, 81.0, 73.0, 71.8, 69.1, 68.5, 67.8, 20.8, 20.2; HRE-
SIMS m/z calcd for C22H22ClN4O5 [M+H]+: 488.1177.
Found, 488.1154.
0
0
To a solution of 7 (50 mg, 124 lmol) in pyridine (1 mL)
was added Ac2O (1 mL), and the mixture was stirred for
5 h at rt. After completion of the reaction, MeOH was
added, and the mixture was stirred for 20 min, concen-
trated, and extracted with CH2Cl2. The extract was
washed with 2 M HCl, satd Na2CO3, and water, dried
(Na2SO4), and concentrated. The crystallization from
EtOAc–hexane gave 7a (54 mg, 111 lmol) in 90% yield
1
as white crystal. [a]D ꢀ32.5 (c 0.01, CHCl3); H NMR
1.7. 9-(40,60-O-Benzylidene-20,30-di-O-trifluoromethane-
sulfonyl-b-D-glucopyranosyl)-H-6-chloropurine (9)
(CDCl3): d 8.81 (s, 1H, H-2), 8.30 (s, 1H, H-8), 7.48–
7.38 (m, 5H, PhCH), 5.99 (d, 1H, J1 ;2 9.6 Hz, H-10),
0
0
5.73 (d, 1H, J2 ;3 9.2 Hz, H-20), 5.60 (s, 1H, PhCH),
To a suspended solution of 7 (30 mg, 74 lmol) in
CH2Cl2 (3 mL) was added Tf2O (37 lL, 222 lmol) and
pyridine (36 lL, 444 lmol) and the mixture was stirred
at 0 ꢁC for 30 min. After completion of the reaction,
MeOH was added, and the mixture was stirred for
10 min at rt, concentrated, and extracted with CHCl3.
The extract was washed with 2 M HCl, satd aq NaH-
CO3, and water, dried (Na2SO4), and concentrated. Col-
umn chromatography (EtOAc–hexane, 1:3) of the
residue on silica gel gave 9 (47 mg, 95%) as white solid.
0
0
5.60 (t, 1H, J3 ;4 9.6 Hz, H-30) 4.40 (br q, 1H, H-40),
3.99–3.82 (m, 2H, H-60ax, 60eq), 2.09 and 1.80 (2s, 6H,
2CH3CO); 13C NMR (CDCl3): d 169.8, 169.2, 152.6,
151.7, 151.6, 143.0, 136.3, 129.4, 128.4 (2C, Ph), 126.1
(2C, Ph), 101.8, 81.7, 77.9, 71.7, 70.8, 69.8, 68.0, 67.3;
HRESIMS m/z calcd for C22H22ClN4O7 [M+H]+:
489.1177. Found, 489.1201.
0
0
1.5. 9-(40,60-O-Benzylidene-b-D-galactopyranosyl)-H-6-
chloropurine (8)
1
[a]D ꢀ19.2 (c 0.013, CHCl3); H NMR (CDCl3): d 8.81
(s, 1H, H-2), 8.20 (s, 1H, H-8), 6.00 (br t, 1H, H-20),
0
0
0
0
Compound 8 (240 mg, 593 lmol) was prepared from
1,2,3,4,6-penta-O-acetyl-b-D-galactose (300 mg, 769
lmol) in 77% yield as described from 7 after crystalliza-
5.32 (1H, t, J2 ;3 9.6 Hz, J3 ;4 10.0 Hz), 4.48 (dd, 1H,
Jgem 16 Hz, J5 ;6 ax 9.6 Hz, H-60ax), 4.22 (t, 1H, J4 ;5
0
0
0
0
9.6 Hz, H-40), 3.88 (m, 2H, H-50, H-60eq), 13C NMR
(CDCl3): d 152.8, 152.2, 151.6, 143.3, 135.3, 132.0,
129.7, 129.0, 128.4 (2C, Ph), 126.0 (2C, Ph), 102.2,
82.3, 82.1 78.5, 77.2, 76.7, 69.0, 67.5; EI MS (m/z, rela-
tive intensity) 667 (Mꢀ, 8), 413 (12.4), 385 (49.4), 263
(100), 241 (8), 229 (13.7), 155 (23), 105 (86); HRESIMS
m/z calcd for C20H16F6N4O5S2 [M+H]+: 668.9951.
Found, 668.9975.
1
tion from EtOAc. [a]D ꢀ30 (c 0.01, CHCl3); H NMR
(DMSO-d6): d 8.89 (s, 1H, H-2), 8.86 (s, 1H, H-8),
8.31–7.36 (m, 5H, Ph), 5.68 (d, 1H, J1 ;2 9.6 Hz, H-10),
0
0
5.39 and 5.29 (2d, 2H, JH ;OH 5.4, 5.6 Hz, OH-20, OH-
0
0
30), 4.49 (dt, J2 ;3 9.6 Hz 1H, H-20), 4.24 (d, 1H, H-40),
4.00 (q, 2H, H-60a, H-60b), 3.91 (s, 1H, H-50), 3.78
(ddd, 1H, H-30); 13C NMR (DMSO-d6): d 152.1,
151.9, 149.3, 146.3, 138.7, 131.1, 128.8, 128.0 (2C, Ph),
126.8 (2C, Ph), 100.3, 84.0, 75.8, 72.2, 68.6, 68.1, 67.8;
EI MS (m/z, relative intensity): 405 (2.6), 298 (2.8),
269 (3.3), 250 (13.6), 183 (75), 155 (100), 107 (46), 91
(10.7), 79 (15.7); HRESIMS m/z calcd for
C18H18ClN4O5 [M+H]+: 405.0966. Found, 405.0933.
0
0
1.8. 9-(20,30-Di-O-acetyl-40,60-O-benzylidene-b-D-altro-
pyranosyl)-H-6-chloropurine (10)
To a solution of 9 (400 mg, 598 lmol) in DMF (4 mL)
was added CsOAc (344 mg, 1.79 mmol) and 18-crown-
6 (473 mg, 1.79 mmol) or TBAA (540 mg, 1.79 mmol),
and the mixture was stirred at 40 ꢁC for 24 h and was
concentrated. Column chromatography (EtOAc–hexane
1:2) of the residue on silica gel gave 10 (190 mg, 65%
from CsOAc method, 250 mg 86% from TBAA methods)
1.6. 9-(20,30-Di-O-acetyl-40,60-O-benzylidene-b-D-galacto-
pyranosyl)-H-6-chloropurine (8a)
To a solution of 8 (50 mg, 124 lmol) in pyridine (1 mL)
was added Ac2O (1 mL), and the mixture was stirred for
5 h at rt. After completion of the reaction, MeOH was
added, and the mixture was stirred for 20 min, concen-
1
as white solid. [a]D ꢀ33.9 (c 0.053, CHCl3); H NMR
(CDCl3): d 8.78 (s, 1H, H-2), 8.30 (s, 1H, H-8), 7.46–
7.38 (m, 5H, Ph), 6.47 (d, 1H, J1 ;2 2.0 Hz, H-10), 5.68
0
0

2646
T. Ando et al. / Carbohydrate Research 342 (2007) 2641–2648
(s, 1H, PhCH), 5.62 (t, 1H, J3 ;4 3.6 Hz, H-30), 5.29 (dd,
and pyridine (0.65 mL, 8.1 mmol), and the mixture
was stirred at 0 ꢁC for 10 min. After completion of the
reaction, MeOH was added, and the mixture was stirred
for 10 min at rt, concentrated, and extracted with
CHCl3. The extract was washed with 2 M HCl, satd
aq NaHCO3, and water, dried (Na2SO4), and concen-
trated. Column chromatography (EtOAc–hexane, 1:1)
of the residue on silica gel gave 12 (230 mg, 91%) as
white solid. [a]D ꢀ44.4 (c 0.02, CHCl3); 1H NMR
(CDCl3): d 8.84 (s, 1H, H-2), 8.25 (s, 1H, H-8), 7.42–
0
0
1H, J2 ;3 3.6 Hz, H-20), 4.44 (dd, 1H, Jgem 10.4 Hz, J5 ;6 eq
0
0
0
0
9.2 Hz, H-60eq), 4.32 (dt, 1H, J4 ;5 5.2 Hz, H-50), 3.95 (t,
0
0
1H, J5 ;6 ax 10.0 Hz, H-60ax), 2.28 and 2.09 (2s, 6H,
2CH3CO); 13C NMR (CDCl3): d 168.8, 168.1, 152.4,
151.4, 150.4, 143.0, 136.6, 131.2, 129.3, 128.4 (2C, Ph),
126.0 (2C, Ph), 102.1, 79.5, 76.7, 74.3, 68.9, 68.4, 67.4,
66.6, 20.9, 20.5; EI MS (m/z, relative intensity): 487
(Mꢀ, 26), 428 (12), 369 (14), 339 (46), 322 (24), 295
(18), 263 (42), 237 (79), 209 (27), 183 (34), 155 (100),
105 (99), 77 (22.7), 55 (11.6); HRESIMS m/z calcd for
C22H22ClN4O5 [M+H]+: 489.1177. Found, 489.1215.
0
0
7.37 (m, 5H, Ph), 6.00 (d, 1H, J1 ;2 9.6 Hz, H-10), 5.90
0
0
(br t, 1H, H-20), 5.76 (t, 1H, J2 ;3 , J3 ;4 9.6 Hz, H-30),
0
0
0
0
0
0
5.61 (s, 1H, PhCH2), 4.40 (ddd, 1H, J4 ;5 9.6 Hz, H-
50), 4.04 (br t, 1H, H-40), 3.92–3.83 (m, 2H, H-60ax, H-
60eq), 1.25 (1s, 9H, 3CH3); 13C NMR (CDCl3): d
176.6, 152.5, 151.6, 151.4, 142.9, 135.7, 131.3, 129.5,
128.3 (2C, Ph), 125.9 (2C, Ph), 101.8, 83.4, 81.6, 77.2,
69.6, 69.4, 67.8, 38.8, 26.6 (3C, 3CH3); HRESIMS m/z
calcd for C24H25ClF3N4O8S [M+H]+: 621.1034. Found,
621.1075.
1.9. 9-(40,60-O-Benzylidene-30-O-trimethylacetyl-b-D-
glucopyranosyl)-H-6-chloropurine (11) and 9-(40,60-O-
benzylidene-20-O-trimethylacetyl-b-D-glucopyranosyl)-
H-6-chloropurine (14)
To a solution of 7 (92 mg, 227 lmol) in CH2Cl2 (10 mL)
was added trimethylacetyl chloride (55 lL, 454 lmol)
and pyridine (368 lL, 4.54 mmol), and the mixture was
stirred at 0 ꢁC for 18 h. After completion of the reaction,
MeOH was added, and the mixture was stirred for
10 min at rt, concentrated, and extracted with CHCl3.
The extract was washed with 2 M HCl, satd aq NaHCO3,
and water, dried (Na2SO4), and concentrated. Column
chromatography (EtOAc–hexane, 1:1) of the residue on
silica gel gave 11 (71 mg, 32%) and 14 (82 mg 37%) as
1.11. 9-(20-O-Acetyl-40,60-O-benzylidene-30-O-trimethyl-
acetyl-b-D-mannopyranosyl)-H-6-chloropurine (13)
To a suspended solution of 12 (65 mg, 105 lmol) in
DMF (5 mL), was added CsOAc (60 mg, 314 lmol)
and 18-crown-6 (83 mg, 314 lmol), and the mixture
was stirred at 0 ꢁC for 30 min. After completion of the
reaction, the mixture was concentrated, and extracted
with CHCl3. The extract was washed with 2 M HCl, satd
aq NaHCO3, and water, dried (Na2SO4), and concen-
trated. Column chromatography (EtOAc–hexane, 1:1)
of the residue on silica gel gave 13 as white powder
(50 mg, 90%). [a]D ꢀ8.4 (c 0.018, CHCl3); 1H NMR
(CDCl3): d 8.70 (s, 1H, H-2), 8.30 (s, 1H, H-8), 7.47–
1
white solid. 11: [a]D ꢀ46.9 (c 0.016, CHCl3); H NMR
(CDCl3): d 8.79 (s, 1H, H-2), 8.34 (s, 1H, H-8), 7.46–
7.36 (m, 5H, Ph), 5.97 (d, 1H, J1 ;2 9.6 Hz, H-10), 5.63
0
0
(s, 1H, PhCH), 5.31 (t, 1H, J2 ;3 9.6 Hz, H-30), 4.50
0
0
(ddd, 1H, J2 ;3 8.8 Hz, H-20), 3.98 (br t, 1H, H-40),
3.88–3.81 (m, 3H, H-50, H-60ax, H-60eq), 1.25 (1s, 9H,
3CH3CO); 13C NMR (CDCl3): d 180.1, 152.3, 151.6,
143.8, 136.5, 131.8, 129.2, 128.3 (2C, Ph), 125.8 (2C,
Ph), 101.2, 85.1, 77.8, 75.2, 72.0, 69.5, 68.1, 39.2, 27.1
(3C, 3CH3); HRESIMS m/z calcd for C23H26ClN4O6
[M+H]+: 489.1541. Found, 489.1484. Compound 14:
0
0
7.37 (m, 5H, Ph), 6.34 (d, 1H, J1 ;2 1.6 Hz, H-10), 5.75
0
0
(dd, 1H, J2 ;3 3.6 Hz, H-20), 5.69 (s, 1H, PhCH), 5.47
0
0
(dd, 1H, J3 ;4 10.8 Hz, H-30), 4.45 (dd, 1H, Jgem
0
0
10.4 Hz, J5 ;6 eq 4.8 Hz, H-60eq), 4.23 (t, 1H, J4 ;5
0
0
0
0
1
0
0
[a]D ꢀ17.4 (c 0.023, CHCl3); H NMR (CDCl3): d 8.78
10.0 Hz, H-40), 4.00 (1H, t, J5 ;6 ax 9.6 Hz, H-60ax), 3.87
(dt, 1H, H-50), 2.10 (s, 3H, CH3CO), 1.17 (s, 9H,
3CH3); 13C NMR (CDCl3): d 176.9, 168.7, 152.4,
151.4, 150.3, 142.8, 136.5, 131.0, 129.2, 128.3 (2C, Ph),
125.8 (2C, Ph), 101.6, 81.0, 75.2, 70.7, 69.5, 69.1, 67.9,
38.9, 26.9 (3C, 3CH3), 20.4; EI MS (m/z, relative inten-
sity): 529.2 (M, 0.5), 263.0 (5.4), 183 (5.0), 157 (4.0),
105.1 (15.5), 85.2 (20.0), 69.0 (5.3), 57.1 (100); HRE-
SIMS m/z calcd for C25H28ClN4O7 [M+H]+: 531.1647.
Found, 531.1623.
(s, 1H, H-2), 8.33 (s, 1H, H-8), 7.52–7.39 (m, 5H, Ph),
5.96 (d, 1H, J1 ;2 9.6 Hz, H-10), 5.63 (s, 1H, PhCH),
0
0
5.59 (t, 1H, J2 ;3 9.2 Hz, H-20), 4.40 (br t, 1H, H-40),
3.87–3.82 (m, 3H, H-50, H-60ax, H-60eq), 1.25 (1s, 9H,
3CH3CO); 13C NMR (CDCl3): d 180.1, 152.3, 151.6,
143.8, 136.5, 131.8, 129.2, 128.3 (2C, Ph), 125.8 (2C,
Ph), 101.4, 85.1, 77.9, 75.0, 72.0, 69.5, 68.1, 39.4, 27.2
(3C, 3CH3); HRESIMS m/z calcd for C23H26ClN4O6
[M+H]+: 489.1541. Found, 489.1501.
0
0
1.10. 9-(40,60-O-Benzylidene-20-O-trifluoromethanesulfon-
yl-30-O-trimethylacetyl-b-D-glucopyranosyl)-H-6-chlo-
ropurine (12)
1.12. 9-(40,60-O-Benzylidene-30-O-trifluoromethanesulfon-
yl-20-O-trimethylacetyl-b-D-glucopyranosyl)-H-6-chlo-
ropurine (15)
To a suspended solution of 11 (200 mg, 410 lmol) in
CH2Cl2 (5 mL) was added Tf2O (136 lL, 810 lmol)
Compound 15 (240 mg, 386 lmol) was prepared from 14
(200 mg, 410 lmol) as described from 12 in 94% yield

T. Ando et al. / Carbohydrate Research 342 (2007) 2641–2648
2647
after silica gel chromatography (EtOAc–hexane, 1:3).
1.15. 9-(20,30-O-Acetyl-40,60-O-benzylidene-b-D-idopyran-
osyl)-H-6-chloropurine (18)
1
[a]D ꢀ13.8 (c 0.014, CHCl3); H NMR (CDCl3): d 8.82
(s, 1H, H-2), 8.30 (s, 1H, H-8), 7.50–7.40 (m, 5H, Ph),
6.00 (d, 1H, J1 ;2 9.2 Hz, H-10), 5.91 (t, 1H, J2 ;3
Compound 18 (40 mg, 60 lmol) was prepared from 17
(201 mg, 300 lmol) as described from 10 in 20% yield
after silica gel chromatography (EtOAc). [a]D +22.2 (c
0
0
0
0
9.2 Hz, H-20), 5.68 (s, 1H, PhCH), 5.32 (t, 1H, J3 ;4
0
0
9.2 Hz, H-30), 4.45 and 3.90 (2q, 2H, H-60ax, H-60eq),
1
4.16 (t, 1H, J4 ;5 9.2 Hz, H-40), 3.90 (m, 1H, H-50),
1.25 (s, 9H, 3CH3); 13C NMR (CDCl3): d 176.5, 152.7,
151.8, 151.5, 142.9, 135.7, 131.3, 129.5, 128.3 (2C, Ph),
125.9 (2C, Ph), 101.8, 83.2, 81.3, 77.3, 69.6, 69.4, 67.8,
38.8, 26.6 (3C, 3CH3); HRESIMS m/z calcd for
0.022, CHCl3); H NMR (CDCl3): d 8.79 (s, 1H, H-2),
0
0
8.47 (s, 1H, H-8), 7.50–7.41 (m, 5H, PhCH), 6.30 (d,
1H, J1 ;2 2.0 Hz, H-10), 5.95 (t, 1H, J2 ;3 3.2 Hz, H-20),
0
0
0
0
5.60 (s, 1H, PhCH), 5.35 (dd, 1H, J3 ;4 2.0 Hz, H-30),
4.59 (d, 1H, H-40), 4.32 and 4.12 (2d, 2H, H-60a, 60b),
3.90 (s, 1H, H-50), 2.14 and 1.83 (2s, 6H, CH3CO); 13C
NMR (CDCl3): d 170.5, 168.9, 152.2, 151.3, 143.1,
137.1, 133.7, 131.5, 129.5, 128.4 (2C, Ph), 126.2 (2C,
Ph), 101.4, 80.9, 73.0, 71.5, 69.5, 68.1, 67.5, 20.9, 20.1;
HRESIMS m/z calcd for C22H22ClN4O5 [M+H]+:
488.1177. Found, 488.1198.
0
0
C24H25ClF3N4O8S
621.1054.
[M+H]+:
621.1034.
Found,
1.13. 9-(30-O-Acetyl-40,60-O-benzylidene-20-O-trimethyl-
acetyl-b-D-allopyranosyl)-H-6-chloropurine (16)
To a solution of 15 (35 mg, 105 lmol) in DMF (5 mL)
was added CsOAc (32 mg, 314 lmol), and the mixture
was stirred at 40 ꢁC for 1 h, and was concentrated. Col-
umn chromatography (EtOAc–hexane 1:2) of the resi-
due on silica gel gave 16 (24 mg, 80%) as white
powder. [a]D +5.6 (c 0.018, MeOH); 1H NMR (CDCl3):
d 8.81 (s, 1H, H-2), 8.27 (s, 1H, H-8), 7.46–7.37 (m, 5H,
1.16. 9-b-D-Altropyranosyladenine (4)
Compound 4 (45 mg, 0.15 mmol) was obtained from 10
(80 mg, 0.164 mmol) using general procedure (B) and
(C) in 92% followed by preparative HPLC (MeOH–
H2O, 7:93) and recrystallization from MeOH. [a]D
1
+52.8 (c 0.018, MeOH); H NMR (DMSO-d6): d 8.24
Ph), 6.21 (d, 1H, J1 ;2 9.6 Hz, H-10), 6.02 (t, 1H,
0
0
0
0
(s, 1H, H-2), 8.12 (s, 1H, H-8), 6.05 (s, 1H, J1 ;2
J2 ;3 3.2 Hz, J3 ;4 2.8 Hz, H-30), 5.68 (dd, 1H, H-20),
5.64 (s, 1H, PhCH), 4.42 (dd, 1H, Jgem 10.4 Hz, H-
0
0
0
0
2.0 Hz, H-10), 5.64, 5.28, and 4.69 (3d, 3H, OH-20,
OH-30, OH-40), 4.49 (t, 1H, OH-60), 3.87–3.46 (m, 6H,
H-20, 30, 40, 50, 60a, and 60b); 13C NMR (DMSO-d6): d
155.9, 152.4, 148.6, 140.1, 117.9, 78.5, 77.2, 71.0, 70.5,
63.6, 61.4: EI MS (m/z, relative intensity) 297 (M, 3.7),
164 (100), 148 (8.8), 135 (88.7), 119 (6), 108 (17.5); HRE-
SIMS m/z calcd for C11H16N5O5 [M+H]+: 297.2673.
Found, 297.2648.
60eq), 4.31 (m, 1H, H-50), 4.04 (dd, 1H, J4 ;5 9.6 Hz,
H-40), 3.84 (t, 1H, H-60ax), 2.23 (s, 3H, CH3CO), 0.82
(s, 9H, 3CH3); 13C NMR (CDCl3): d 176.1, 169.4,
152.5, 151.7, 143.2, 136.4, 131.5, 129.3, 128.3 (2C, Ph),
126.1 (2C, Ph), 101.8, 79.6, 68.5, 68.5, 67.5, 67.2,
38.6, 26.5 (3C, 3CH3), 20.8; HRESIMS m/z calcd
for C25H28ClN4O7 [M+H]+: 531.1647. Found,
531.1665.
0
0
1.17. 9-b-D-Mannopyranosyladenine (5)
1.14. 9-(40,60-O-Benzylidene-20,30-di-O-trifluoromethane-
sulfonyl-b-D-galactopyranosyl)-H-6-chloropurine (17)
Compound 5 (24 mg, 80 lmol) was obtained from 13
(50 mg, 94 lmol) in 85% using general procedure (B)
and (C) followed by preparative HPLC (MeOH–H2O,
5:95) and recrystallization from MeOH. [a]D +14.8 (c
Compound 17 (804 mg, 1.20 mmol) was prepared from
8 (546 mg, 1.35 mmol) as described from 9 in 89% yield
after silica gel chromatography (EtOAc–Hexane, 1:3).
1
0.024, H2O); H NMR (DMSO-d6): d 8.24 (s, 1H, H-
2), 8.12 (s, 1H, H-8), 5.88 (s, 1H, J1 ;2 1.6 Hz, H-10),
5.63, 5.25, and 4.77 (3d, 3H, OH-20, OH-30, OH-40),
4.40 (t, 1H, OH-60), 3.87–3.46 (m, 6H, H-20, 30, 40, 50,
60a, and 60b); 13C NMR (DMSO-d6): d 155.9, 152.4,
148.6, 140.1, 117.9, 78.5, 77.2, 71.0, 70.5, 63.6, 61.4: EI
MS (m/z, relative intensity) 297 (M, 5.7), 164 (100),
148 (9.8), 135 (88.7), 119 (6), 108 (18); HRESIMS m/z
calcd for C11H16N5O5 [M+H]+: 297.2673. Found,
297.2653.
0
0
1
[a]D +16.7 (c 0.033, CHCl3); H NMR (DMSO-d6): d
8.81 (s, 1H, H-2), 8.36 (s, 1H, H-8), 7.58–7.46 (m, 5H,
Ph), 6.11 (d, 1H, J1 ;2 9.2 Hz, H-10), 5.78 (br t, 1H, H-
0
0
20), 5.27 (dd, 1H, J2 ;3 9.6 Hz, J3 ;4 3.6 Hz, H-30), 4.83
(d, 1H, H-50), 4.40 and 4.19 (2dd, 2H, Jgem 13.2 Hz,
H-60ax, H-60eq), 3.96 (s, 1H, H-50); 13C NMR
(DMSO-d6): 152.8, 152.0, 151.7, 142.6, 136.0, 131.5,
129.8, 128.6 (2C, Ph), 126.0 (2C, Ph), 101.4, 81.3, 78.2,
76.9, 76.7, 73.8, 68.7, 67.9; EI MS (m/z, relative inten-
sity): 668 (Mꢀ, 6), 535 (17.7), 413 (31.6), 369 (11.5),
234 (24.3), 229 (14.5), 183 (19.3), 155 (29.1), 105 (100),
69 (31.0); HRESIMS m/z calcd for C20H16ClFN4O9S2
[M+H]+: 668.9951. Found, 668.9934.
0
0
0
0
1.18. 9-b-D-Allopyranosyladenine (3)
Compound 3 (26 mg, 87 lmol) was obtained from 16
(50 mg, 94 lmol) in 93% using general procedure (B)

2648
T. Ando et al. / Carbohydrate Research 342 (2007) 2641–2648
2. Lerner, L. M.; Sheid, B.; Gaetjens, E. J. Med. Chem. 1987,
30, 1521–1525.
3. Sugawa, T.; Kuwada, Y.; Imai, K.; Morinaga, K.;
Kaziwara, K.; Tanaka, K. Takeda kenkyusyo nenpo.
1961, 20, 1–20.
and (C) followed by preparative HPLC (MeOH–H2O,
7:93) and recrystallization from MeOH. [a]D +94.1 (c
1
0.017, H2O); H NMR (DMSO-d6): d 8.58 (s, 1H, H-
2), 8.31 (s, 1H, H-8), 7.22 (br s, 2H, NH2), 5.71 (d,
1H, J1 ;2 9.6 Hz, H-10), 5.15, 5.05, and 4.80 (3d, 3H,
H-20, 30, and 40), 4.50 (br t, 1H, H-60), 4.21–3.33 (m,
6H, H-20, 30, 40, 50, 60a, and 60b): 13C NMR (DMSO-
d6): d 155.9, 152.4, 148.6, 140.1, 117.9, 78.5, 77.2, 71.0,
70.5, 63.6, 61.4: EI MS (m/z, relative intensity) 297
(M, 3.7), 164 (100), 148 (8.8), 135 (88.7), 119 (6), 108
(17.5); HRESIMS m/z calcd for C11H16N5O5 [M+H]+:
297.2673. Found, 297.2645.
0
0
4. Lerner, L. M.; Rossi, R. R. Biochemistry 1972, 11, 272–
277.
5. Tsuboike, K.; Minamoto, K.; Mizuno, G.; Yanagihara, K.
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1364.
8. Ermolinsky, B. S.; Fomitcheva, M. V.; Efimtseva, E. V.;
Mikhailov, S. N.; Esipov, D. S.; Boldyreva, E. F.;
Korobko, V. G.; van Aerscot, A.; Herdewijn, P. Russ. J.
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Eschenmoser, A. Helv. Chim. Acta 2001, 84, 1778–1804.
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1.19. 9-b-D-Idopyranosyladenine (6)
Compound 6 (23 mg, 78 mmol) was obtained from 18
(45 mg, 92 lmol) in 85% using general procedure (B)
and (C) followed by preparative HPLC (MeOH–H2O,
5:95) and recrystallization from MeOH. [a]D +52.8 (c
12. Masson, G. J.; Leonard, S. J. Chem. Soc. 1938, 259–
261.
1
0.026, H2O); H NMR (DMSO-d6): d 8.26 (s, 1H, H-
2), 8.15 (s, 1H, H-8), 5.97 (s, 1H, J1 ;2 2.0 Hz, H-10),
5.40, 5.20, and 4.64 (3d, 3H, OH-20, OH-30, OH-40),
4.49 (t, 1H, OH-60), 3.90–3.46 (m, 6H, H-20, 30, 40, 50,
60a, and 60b); 13C NMR (DMSO-d6): d 155.9, 152.4,
148.6, 140.1, 115.8, 79.5, 77.1, 71.0, 70.5, 63.5, 61.1: EI
MS (m/z, relative intensity) 297 (M, 7.4), 164 (100),
148 (11.0), 135 (78.5), 119 (7), 108 (19.5); HRESIMS
m/z calcd for C11H16N5O5 [M+H]+: 297.2673. Found,
297.2655.
0
0
13. Wolfrom, M. L.; Foster, A. B.; McWain, P.; Beben-
burug, W.; Thompson, A. J. Org. Chem. 1961, 26, 3095–
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References
1. Vorbruggen, H.; Ruh-Pohlenz, C. In Hand book of
¨
Nucleoside Synthesis; Wiley–VCH: Weinheim, 2001, and
references cited therein.