An efficient approach for the synthesis of 1′-O-α-methyl pyrrolo[2,3-d]pyrimidine isonucleosides

Article abstract of DOI:10.1055/s-0030-1259961

A series of novel 1′-O-methyl isonucleosides were efficiently and stereoselectively synthesized with 1,2,3,5-tetra-O-acetyl-D-ribofuranose as the starting material. The key steps include regioselective and stereoselective deprotection of the 2,4-dichlorobenzyl group at C2, triflation, and substitution with appropriate nucleobases using cesium carbonate as the base. Removal of the residual 2,4-dichlorobenzyl groups and subsequent transformation afforded the title compounds in 30-37% overall yield. The products represent a new type of isonucleosides with 1-O-substitution. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1259961

PAPER
1213
An Efficient Approach for the Synthesis of 1¢-O-a-Methyl Pyrrolo[2,3-d]pyr-
imidine Isonucleosides
S
a
ynthesis of
1
¢
-
O
-
a
a
-Methyl
P
n
yrrolo[2,3-
d
]
g
pyrimidine Isonucl
S
eosides ong,a Ruchun Yang,b Haixin Ding,b Qi Sun,b Qiang Xiao,*b Yong Ju*a
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Ministry of Education, Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. of China
Fax +86(10)62781695; E-mail: juyong@tsinghua.edu.cn
Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science and Technology Normal University, Nanchang 330013, P. R. of China
Fax +86(791)6422903; E-mail: xiaoqiang@tsinghua.org.cn
b
Received 26 December 2010; revised 7 February 2011
cules, isonucleosides, which attach nucleobases at C2 po-
sition instead of C1 of D-ribose,8 exhibit significant
antiviral and anticancer activity with improved chemical
and enzymatic stability.9 Therefore, pyrrolo[2,3-d]pyrim-
Abstract: A series of novel 1¢-O-a-methyl isonucleosides were ef-
ficiently and stereoselectively synthesized with 1,2,3,5-tetra-O-
acetyl-D-ribofuranose as the starting material. The key steps include
regioselective and stereoselective deprotection of the 2,4-dichlo-
robenzyl group at C2, triflation, and substitution with appropriate idine isonucleosides, which combine the strength of the
nucleobases using cesium carbonate as the base. Removal of the re-
above two approaches, appear to be an interesting type of
sidual 2,4-dichlorobenzyl groups and subsequent transformation af-
nucleoside analogue. In our effort to investigate the bio-
forded the title compounds in 30–37% overall yield. The products
logical significance of pyrrolo[2,3-d]pyrimidine isonucle-
represent a new type of isonucleosides with 1¢-O-substitution.
osides, especially 1¢-O-a-methyl isonucleosides, an
Key words: pyrrolo[2,3-d]pyrimidine, isonucleoside, regioselec-
tive deprotection, triflate, cesium carbonate
efficient approach was highly required. Up to now, how-
ever, the synthesis of pyrrolo[2,3-d]pyrimidine
isonucleosides10 and 1¢-O-substituted isonucleosides has
been rarely reported. Their preparation has always suf-
Modified nucleosides represent an important class of an-
fered from long synthetic routes, expensive reagents,
complex reactions, and poor overall yields.11 Herein, we
report a short and practical route for the synthesis of a se-
ries of novel 1¢-O-a-methyl pyrrolo[2,3-d]pyrimidine iso-
nucleosides.
tiviral, antibiotic, and anticancer agents, and are widely
used in research in medicine and molecular biology.
Among the numerous nucleoside analogues that have
been obtained from either natural or synthetic sources,
pyrrolo[2,3-d]pyrimidine nucleosides, also called 7-de-
azapurine nucleosides, have received much attention due to
their excellent biological activity. As shown in Figure 1,
tubercidin (I) from Streptomyces tubercidicus,1 as well as
its 5-substituted derivatives toyocamycin (II) and sangi-
vamycin (III) from Streptomyces toyocaensis2 and
Streptomyces3 are known antibiotics. Other synthetic pyr-
rolo[2,3-d]pyrimidine derivatives also exhibit attractive
biological activity, such as antitumor, antiviral, antibacte-
rial, antifungal,4 antitrypanosomal,5 immunosuppressive,6
antiasthma, antioxidant, and neuroprotective7 activities.
AcO
HO
O
O
OAc
OAc
OMe
OH
a
b
AcO
HO
1
Cl2BnO
Cl2BnO
O
O
OMe
c
(α only)
OMe
OH
Cl2BnO
Cl2BnO
OBnCl2
2
3
Scheme 1 Reagents and conditions: (a) (i) NaOMe, MeOH, r.t.; (ii)
Dowex-50w H+ (87%), b/a 3:1; (b) 2,4-dichlorobenzyl chloride, NaH,
DMF, 0 °C to r.t. (91%), b/a 3:1; (c) SnCl4, CH2Cl2, 0 °C, 28 h (85%).
NH2
X
N
I X = H (tubercidin)
N
N
II X = CN (toyocamycin)
The key intermediate 3 for our route was prepared by the
method reported by Brown et al. with slight modifica-
tion.12 Treatment of 1,2,3,5-tetra-O-acetyl-D-ribofuranose
with sodium methoxide in methanol, followed by direct
addition of Dowex-50 H+ resin gave 1 in excellent yield.
2,4-Dichlorobenzyl chloride (Cl2Bn–Cl) was used as pro-
tecting reagent due to the fact that it is less irritant than
benzyl bromide and the resulting product could be easily
purified for large-scale production.13 Reaction of com-
pound 1 with sodium hydride and 2,4-dichlorobenzyl
chloride afforded 2, which could be precipitated with wa-
ter and recrystallized from acetonitrile, as a pale yellow
powder in 91% yield. Selective deprotection of 2 with
tin(IV) chloride in dichloromethane resulted in the forma-
HO
III X = CONH2 (sangivamycin)
O
HO
OH
Figure 1
Other than variations on nucleobases, another approach to
the development of nucleoside analogues focuses on the
modification of the D-ribose. Among this type of mole-
SYNTHESIS 2011, No. 8, pp 1213–1218
Advanced online publication: 16.03.2011
DOI: 10.1055/s-0030-1259961; Art ID: F56910SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
1

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Y. Song et al.
PAPER
Cl2BnO
OMe
O
O
Cl2BnO
OBnCl2
Cl2BnO
O
OMe
OBnCl2
SnCl4
Cl2BnO
Cl2BnO
O
Cl2BnO
Cl2BnO
2
Me
Cl
O
O
SnCl4
Me
Cl2BnO
Cl2Bn
OMe
OBnCl2
O
O
Sn Cl
Cl2BnO
Cl2BnO
O
SnCl4
Cl
Cl
Cl2Bn
A
Cl2BnO
Cl2BnO
O
O
Me
O
H2O
– Cl2BnCl
OMe
OH
Cl2BnO
O
Cl
Cl
Cl2BnO
Sn
Cl
3
(α only)
B
Scheme 2 Proposed mechanism for tin(IV) chloride mediated regioselective deprotection of 2
tion of methyl 3,5-bis-O-(2,4-dichlorobenzyl)-a-D-ribo- with nucleobases under normal conditions [e.g., K2CO3/
furanose (3) in high yield (Scheme 1).
18-crown-6/DMF,9b–d,11c,e KOH/TDA-1/MeCN,16 DBU/
DMF(MeCN),11d,17 NaH/DMF(MeCN),18 and Cs2CO3/
DMF19]. Microwave irradiation, which has been reported
to facilitate coupling reactions, showed no effect in this
reaction. Meanwhile, even the elimination product could
not be detected, which indicated a more reactive leaving
group was needed. To solve this problem, trifluo-
romethanesulfonate (triflate) was used as a more efficient
leaving group.20 Compound 3 was converted into 4 with
trifluoromethanesulfonic anhydride in 74% yield. Cou-
pling of 4 with pyrrolo[2,3-d]pyrimidine nucleobases was
tested with a series of bases as above. It was found that the
reaction using cesium carbonate as the base proceeded
most smoothly to afford 5a, which was possibly due to the
cesium effect.21 The same conditions were also efficient
for the synthesis of adenine isonucleosides 5c. The trans-
formation of 5a to 6a and 6b was conducted using report-
ed methods22 in 77% and 91% yields, respectively
(Scheme 3).
Regioselective deprotection of benzyl groups on furano-
sides with Lewis acids, such as tin(IV) chloride and titani-
um(IV) chloride, has been reported in particular cases.14
Combining Sinäy and Meguro’s10,14c,15 speculation, we
presumed that an intermediate A could form between
tin(IV) chloride and the two alkoxy oxygen atoms from
C1 and C2 of the a-anomer, but not the b anomer. After
the benzyl group was attacked by intramolecular chloride,
the metal alkoxide B is hydrolyzed by water to give the re-
gioselective deprotected riboside 3 with the a-configura-
tion only (Scheme 2). The anomeric hydrogen atom
shows a characteristic double peak with coupling constant
J = 4.4 Hz. The structure of 3 was further determined by
1H and 13C NMR, HSQC, and NOESY.
Activation of the hydroxy group at C2 with methane-
sulfonate and benzenesulfonate failed to result in coupling
Cl2BnO
Cl2BnO
Deprotection of 6a, 6b, and 5c in the presence of triethyl-
amine and 10% palladium hydroxide on carbon under a
hydrogen atmosphere gave the corresponding products
7a–c in excellent yields. As the 1¢-O-a-methyl group is
unstable under acidic condition, adding triethylamine is
necessary to obviate the anomerization. Compound 7b
was refluxed in 2 M aqueous sodium hydroxide for 1.5
hours to afford 7d in 84% yield (Scheme 4).22
O
O
a
b
OMe
OTf
OMe
OH
Cl2BnO
Cl2BnO
4
3
Cl
NH2
B
Cl2BnO
N
N
O
N
N
B =
OMe
N
N
N
Cl2BnO
5c
5a
In conclusion, we report a short and efficient approach for
the synthesis of four new isonucleosides characterized by
the 1¢-O-a-methyl group in 30–37% overall yield. It has
the merits of being cost effective, using mild reaction pro-
tocols, and giving easy access to diverse derivatives. The
preliminary biological tests showed their potential as
CGRP (Calcitonin Gene-Related Peptide) receptor antag-
onists. Further efforts to incorporate these isonucleosides
to DNA are in progress and will be reported in due course.
Cl
N
OMe
NH2
N
N
N
d
c
N
N
N
N
O
N
Cl2BnO
Cl2BnO
Cl2BnO
O
O
OMe
OMe
OMe
OBnCl2
OBnCl2
OBnCl2
6b
5a
6a
Scheme 3 Reagents and conditions: (a) Tf2O, py, –40 °C to 0 °C
(74%); (b) Cs2CO3, DMF, 5a (87%), 5c (79%); (c)NH3/MeOH, 120
°C, 12 h (77%); (d) NaOMe, r.t. 12 h (91%).
Synthesis 2011, No. 8, 1213–1218 © Thieme Stuttgart · New York

PAPER
Synthesis of 1¢-O-a-Methyl Pyrrolo[2,3-d]pyrimidine Isonucleosides
1215
A small amount of the mixture was purified over a column (silica
gel, PE–EtOAc, 5:1) to afford the b- and a-anomers, respectively,
for analysis.
B
B
Cl2BnO
HO
O
O
a
OMe
OMe
OBnCl2
OH
b-Anomer
1H NMR (400 MHz, CDCl3): d = 3.37 (s, 3 H), 3.66 (dd, J = 10.8,
5.2 Hz, 1 H), 3.75 (dd, J = 10.4, 3.6 Hz, 1 H), 3.98 (d, J = 4.4 Hz, 1
H), 4.18 (t, 1 H), 4.37 (m, 1 H), 4.61–4.75 (m, 6 H, 2 OCH2Ar), 5.00
(s, 1 H), 7.16–7.46 (m, 9 H, HAr).
13C NMR (100 MHz, CDCl3): d = 135.0, 134.6, 134.4, 134.4, 134.3,
134.0, 133.7, 133.6, 133.5, 130.4, 129.9, 129.4, 129.4, 129.3, 127.5,
127.4, 127.4, 106.5, 81.1, 80.6, 79.5, 72.1, 70.2, 69.4, 69.3, 55.6.
6a, 6b, 5c
NH2
NH2
OMe
N
N
N
N
N
B =
N
N
N
N
N
7a
7c
7b
OMe
HRMS (ESI): m/z [M + Na]+ calcd for C27H24Cl6NaO5: 660.9647;
O
found: 660.9645.
N
HN
b
N
N
N
O
N
HO
a-Anomer
HO
O
1H NMR (400 MHz, CDCl3): d = 3.51 (s, 3 H), 3.64 (m, 2 H), 3.94
(t, 1 H), 4.00 (dd, J = 6.0, 3.6 Hz, 1 H), 4.34 (d, J = 3.2 Hz, 1 H),
4.53 (d, J = 12.8 Hz, 1 H), 4.58 (d, J = 12.8 Hz, 1 H), 4.67 (dd,
J = 13.2, 4.0 Hz, 2 H), 4.76 (dd, J = 13.6, 1.2 Hz, 1 H), 5.05 (d,
J = 4.0 Hz, 2 H), 7.16–7.50 (m, 9 H).
13C NMR (100 MHz, CDCl3): d = 134.7, 134.1, 134.0, 133.7, 133.6,
133.3, 133.2, 130.2, 130.2, 129.9, 129.2, 129.0, 128.9, 127.2, 127.1,
102.2, 81.6, 78.9, 76.8, 70.7, 70.1, 69.1, 69.1, 55.6.
OMe
OMe
OH
7d
OH
7b
Scheme 4 Reagents and conditions: (a) 20% Pd(OH)2, H2, Et3N,
EtOAc, MeOH, 7a (92%), 7b (94%), 7c (88%); (b) aq NaOH, reflux,
1.5 h (84%).
HRMS (ESI): m/z [M + Na]+ calcd for C27H24Cl6NaO5: 660.9647;
found: 660.9644.
Pd(OH)2/C, SnCl4, and Cs2CO3 were purchased from Sigma Ald-
rich. MeOH, Pyridine and CH2Cl2 were dried and distilled prior to
use. TLC was performed using silica gel GF-254 plates (Qing-Dao
Chemical Company, China) with detection by UV, or charting with
10% H2SO4 in EtOH. Column chromatography was performed on
silica gel (200–300 mesh, purchased from Qing-Dao Chemical
Company, China). NMR spectra were recorded on Bruker AV400
spectrometer. 1H and 13C NMR spectra were calibrated with TMS
as internal standard. The ESI-HRMS were obtained on a Bruker
Dalton microTOFQ II spectrometer in positive ion mode.
Methyl 3,5-Bis-O-(2,4-dichlorobenzyl)-a-D-ribofuranoside (3)
To a stirred soln of 2 (34.74 g, 53.7 mmol) in anhyd CH2Cl2 (347
mL) was added 1 M SnCl4 in CH2Cl2 soln (54 mL, 54.0 mmol) drop-
wise at 0 °C under argon. The mixture was stirred for 28 h until the
starting material had disappeared (TLC). H2O (50 mL) and CH2Cl2
(200 mL) were added to quench the reaction. The organic layer was
separated, washed with H2O (3 × 300 mL), 0.2 M HCl (1 × 150 mL),
sat. NaHCO3 (1 × 150 mL), and brine (2 × 150 mL), dried (anhyd
Na2SO4), and evaporated under reduced pressure. The residual was
purified by column chromatography (silica gel, PE–EtOAc, 3:1) to
afford 3 as a pale-yellow oil; yield: 22.3 g (85%); Rf = 0.42 (PE–
EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): d = 2.93 (d, J = 11.2 Hz, 1 H, 2-OH),
3.48 (s, 3 H, 1-OCH3), 3.59 (d, J = 4.0 Hz, 2 H, H5), 3.85 (m, 1 H,
H3), 4.17 (m, 1 H, H2), 4.23 (d, J = 3.2 Hz, 1 H, H4), 4.55 (dd,
J = 18.0, 12.8 Hz, 2 H, 5-OCH2Ar), 4.66 (d, J = 13.6 Hz, 1 H, 3-
OCH2Ar), 4.75 (d, J = 13.2 Hz, 1 H, 3-OCH2Ar), 4.91 (d, J = 4.4
Hz, 1 H), 7.20–7.42 (m, 6 H, HAr).
Methyl D-Ribofuranoside (1)
To a stirred soln of 1,2,3,5-tetra-O-acetyl-D-ribofuranose (720.0 g,
2.26 mol) in anhyd MeOH was added Na (1.0 g, 43.5 mmol) and the
mixture was stirred at r.t. overnight until no reactant was detected
(TLC). Dowex-50 H+ resin was added and the mixture was adjusted
to pH 3. After stirring at r.t. for 15 h and filtration, the solvent was
removed and the residual was purified by column chromatography
(silica gel, CH2Cl2–MeOH, 10:1) to afford 1 as a mixture of b- and
a-anomers as a brown oil; yield: 323.0 g (87%, b/a 3:1); Rf = 0.49
(b-anomer), 0.37 (a-anomer) (CH2Cl2–MeOH, 10:1).
13C NMR (100 MHz, CDCl3): d = 134.7, 134.6, 134.4, 133.9, 133.9,
130.3, 130.1, 129.5, 129.4, 127.4, 127.4, 103.1, 81.9, 77.8, 72.3,
71.2, 70.4, 69.8, 55.9.
13C NMR (100 MHz, CDCl3): d = 109.1, 103.2, 85.1, 84.6, 75.8,
72.1, 71.7, 71.0, 63.6, 63.0, 56.0, 56.0.
HRMS (ESI): m/z [M + Na]+ calcd for C20H20Cl4NaO5: 502.9957;
MS (ESI): m/z = 165 [M + H+]
found: 502.9959.
Methyl 2,3,5-Tris-O-(2,4-dichlorobenzyl)-D-ribofuranoside (2)
To a stirred soln of 1 (13.84 g, 84 mmol) and 2,4-dichlorobenzyl
chloride (70.1 mL, 504 mmol) in anhyd DMF (138 mL) at 0 °C was
added NaH (60% dispersion in mineral oil, 20.16 g, 504 mmol) in 4
portions. The mixture was allowed to warm up to r.t. over 1 h and
stirred at r.t. for 12 h. H2O (300 mL) was added to quench the reac-
tion. The precipitate was filtered, washed with H2O (2 × 100 mL),
and recrystallized (MeCN, 50 mL). The solid was collected by fil-
tration and washed with MeCN (2 × 100 mL) to afford 2 as a mix-
ture of b- and a-anomers as a pale-yellow powder that was used
directly without further separation; yield: 49.68 g (91%, b/a 3:1);
Rf = 0.49 (b-anomer), 0.15 (a-anomer) (PE–EtOAc, 5:1).
Methyl 3,5-Bis-O-(2,4-dichlorobenzyl)-2-O-(trifluoromethyl-
sulfonyl)-a-D-ribofuranoside (4)
To a stirred soln of 3 (3.73 g, 7.67 mmol) in anhyd pyridine (40 mL)
was added Tf2O (2.60 g, 11.5 mmol) dropwise at –40 °C under ar-
gon. The mixture was allowed to warm up to 0 °C over 1 h. Then,
ice was added to quench the reaction. After concentration under re-
duced pressure, the residual was purified by column chromatogra-
phy (silica gel, PE–EtOAc, 5:1) to afford 4 as a colorless oil; yield:
3.51 g (74%); Rf = 0.64 (PE–EtOAc, 3:1).
1H NMR (400 MHz, CDCl3): d = 3.52 (s, 3 H, OCH3), 3.60 (dd,
J = 10.8, 2.8 Hz, 1 H, H5a), 3.71 (dd, J = 10.8, 2.0 Hz, 1 H, H5b),
4.16 (t, J = 5.6 Hz, 1 H, H3), 4.28 (d, J = 2.0 Hz, 1 H, H4), 4.50–
Synthesis 2011, No. 8, 1213–1218 © Thieme Stuttgart · New York

1216
Y. Song et al.
PAPER
4.75 (m, 4 H, 2 OCH2Ar), 5.07 (m, 1 H, H2), 5.13 (d, J = 4.0 Hz, 1
H, H1), 7.22–7.43 (m, 6 H, HAr).
13C NMR (100 MHz, CDCl3): d = 134.7, 134.6, 134.2, 134.1, 133.9,
133.8, 130.7, 130.3, 129.6, 129.4, 127.7, 127.5, 120.5, 117.3, 101.4,
81.6, 80.8, 76.1, 70.5, 70.1, 69.6, 56.6.
HRMS (ESI): m/z [M + Na]+ calcd for C21H19Cl4F3NaO7S:
634.9450; found: 634.9455.
OCH2Ar), 5.11 (s, 1 H, H1¢), 5.35 (d, J = 2.8 Hz, 1 H, H2¢), 6.33 (br
s, 2 H, 4-NH2), 6.34 (d, J = 3.6 Hz, 1 H, H5), 7.17–7.40 (m, 7 H,
HAr, H6), 8.22 (s, 1 H, H2).
13C NMR (100 MHz, CDCl3): d = 156.9, 150.5, 150.1, 134.6, 134.5,
134.3, 134.0, 133.9, 130.8, 130.3, 129.5, 129.5, 127.4, 127.3, 123.2,
117.9, 107.9, 103.3, 99.4, 84.9, 81.5, 70.4, 69.7, 69.6, 65.6, 55.4.
HRMS (ESI): m/z [M + H]+ calcd for C26H25Cl4N4O4: 597.0624;
found: 597.0628.
4-Chloro-7-[methyl 3,5-bis-O-(2,4-dichlorobenzyl)-a-D-ara-
binofuranosid-2-yl]-7H-pyrrolo[2,3-d]pyrimidine (5a)
To a soln of 4 (1.01 g, 1.64 mmol) and 4-chloro-7H-pyrrolo[2,3-
d]pyrimidine (224 mg, 1.67 mmol) in anhyd DMF (33 mL) was
added Cs2CO3 (540 mg, 1.67 mmol) and the mixture was stirred at
r.t. for 5 h under argon. The solvent was removed under vacuum and
the residual was purified by column chromatography (silica gel,
PE–EtOAc, 5:1) to afford 5a as a colorless oil; yield: 877 mg (87%);
Rf = 0.39 (PE–EtOAc, 4:1).
1H NMR (400 MHz, CDCl3): d = 3.44 (s, 3 H, 1¢-OCH3), 3.81 (dd,
J = 10.8, 3.2 Hz, 1 H, H5¢a), 3.97 (dd, J = 10.8, 2.0 Hz, 1 H, H5¢b),
4.31 (m, 1 H, H3¢), 4.39 (m, 1 H, H4¢), 4.49 (d, J = 12.4 Hz, 1 H,
OCH2Ar), 4.60 (d, J = 12.4 Hz, 1 H, OCH2Ar), 2.72 (dd, J = 12.8,
3.2 Hz, 2 H, OCH2Ar), 5.13 (s, 1 H, H1¢), 5.42 (d, J = 2.4 Hz, 1 H,
H2¢), 6.53 (d, J = 3.6 Hz, 1 H, H5), 7.17–7.40 (m, 7 H, HAr, H6),
8.67 (s, 1 H, H2).
7-[Methyl 3,5-Bis-O-(2,4-dichlorobenzyl)-a-D-arabinofura-
nosid-2-yl]-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (6b)
A soln of 5a (570 mg, 0.92 mmol) in 0.5 M NaOMe (20 mL) was
stirred at r.t. for 12 h until no reactant was detected (TLC). The mix-
ture was concentrated to dryness and the residual was purified by
column chromatography (silica gel, PE–EtOAc, 5:1) to afford 6b as
a colorless oil; yield: 515 mg (91%); Rf = 0.40 (PE–EtOAc, 4:1).
1H NMR (400 MHz, CDCl3): d = 3.42 (s, 3 H, 1¢-OCH3), 3.80 (dd,
J = 11.2, 3.6 Hz, 1 H, H5¢a), 3.94 (dd, J = 11.2, 2.4 Hz, 1 H, H5¢b),
4.14 (s, 3 H, 6-OCH3), 4.31 (dd, J = 6.4, 3.2 Hz, 1 H, H3¢), 4.37 (m,
1 H, H4¢), 4.43–4.72 (m, 4 H, 2 OCH2Ar), 5.14 (s, 1 H, H1¢), 5.38
(d, J = 2.4 Hz, 1 H, H2¢), 6.49 (d, J = 3.2 Hz, 1 H, H5), 7.02–7.37
(m, 7 H, HAr, H6), 8.48 (s, 1 H, H2).
13C NMR (100 MHz, CDCl3): d = 163.4, 151.8, 151.3, 134.6, 134.4,
134.2, 133.9, 133.7, 130.7, 130.2, 129.4, 127.4, 127.1, 123.9, 107.8,
105.8, 99.8, 84.6, 81.4, 70.4, 69.7, 69.5, 65.9, 55.4, 54.0.
HRMS (ESI): m/z [M + Na]+ calcd for C27H25Cl4N3NaO5: 634.0441;
found: 634.0443.
13C NMR (100 MHz, CDCl3): d = 152.7, 151.2, 151.0, 134.7, 134.5,
134.4, 134.3, 134.1, 133.8, 130.7, 130.4, 129.6, 129.5, 127.5, 127.4,
127.3, 117.9, 107.6, 100.8, 84.8, 81.7, 70.5, 69.7, 69.4, 65.9, 55.4.
HRMS (ESI): m/z [M + Na]+ calcd for C26H22Cl5N3NaO4: 637.9945;
found: 637.9946.
4-Amino-7-[methyl a-D-arabinofuranosid-2-yl]-7H-pyrro-
lo[2,3-d]pyrimidine (7a); Typical Procedure for the Prepara-
tion of 7a–c
9-[Methyl 3,5-bis-O-(2,4-dichlorobenzyl)-a--D-arabinofura-
nosid-2-yl]adenine (5c)
To a soln of 6a (250 mg, 0.42 mmol) in EtOAc (5 mL) and MeOH
(5 mL) was added 20% Pd(OH)2/C (100 mg, 0.14 mmol) and Et3N
(176 mg, 1.74 mmol). After stirring at r.t. for 1 h under a H2 atmo-
sphere, another 20% Pd(OH)2/C (100 mg, 0.14 mmol) was intro-
duced. The mixture was allowed to stir overnight until only a single
spot was detected (TLC), and filtered and concentrated to dryness.
The residual was purified by column chromatography (silica gel,
CH2Cl2–MeOH, 10:1) to afford 7a as a colorless oil; yield: 107 mg
(92%); Rf = 0.42 (CH2Cl2–MeOH, 8:1).
1H NMR (400 MHz, DMSO-d6): d = 3.26 (s, 3 H, 1¢-OCH3), 3.59
(dd, J = 12.0, 4.4 Hz, 1 H, H5¢a), 3.75 (dd, J = 12.0. 1.2 Hz, 1 H,
H5¢b), 3.90 (m, 1 H, H4¢), 4.30 (t, J = 6.8 Hz, 1 H, H3¢), 4.94–4.98
(m, 2 H, H2¢, 1¢), 5.68 (br s, 1 H, 3¢-OH), 6.80 (d, J = 3.2 Hz, 1 H,
H5), 7.35 (d, J = 3.2 Hz, 1 H, H6), 7.80 (br s, 2 H, 4-NH2), 8.19 (s,
1 H, H2).
To a soln of 4 (306 mg, 0.49 mmol) and adenine (100 mg, 0.74
mmol) in anhyd DMF (15 ml) was added Cs2CO3 (242 mg, 0.74
mmol) and the mixture was stirred at 60 °C for 5 h under argon fol-
lowed by concentration in vacuo. The residual was purified by col-
umn chromatography (silica gel, CH2Cl2–MeOH, 40:1) to afford 5c
as a colorless oil; yield: 236 mg (79%); Rf = 0.18 (CH2Cl2–MeOH,
50:1).
1H NMR (400 MHz, CDCl3): d = 3.42 (s, 3 H, 1¢-OCH3), 3.76 (dd,
J = 11.2, 3.2 Hz, 1 H, H5¢a), 3.93 (dd, J = 11.2, 2.4 Hz, 1 H, H5¢b),
4.36 (m, 1 H, H4¢), 4.41 (dd, J = 6.4, 3.2 Hz, 1 H, H3¢), 4.52–4.71
(m, 4 H, 2 OCH2Ar), 5.11 (t, J = 1.6 Hz, 1 H, H2¢), 5.20 (s, 1 H,
H1¢), 6.18 (br s, 2 H, 6-NH2), 7.03–7.34 (m, 6 H, HAr), 7.91 (s, 1 H,
H8), 8.35 (s, 1 H, H2).
13C NMR (100 MHz, CDCl3): d = 160.0 (C6), 153.5 (C2), 149.9
(C4), 139.3 (C8), 134.7, 134.4, 134.4, 134.3, 134.0, 133.7, 130.8,
130.4, 129.6, 127.5, 127.3, 119.8 (C5), 107.0 (C1¢), 84.0 (C3¢), 81.7
(C4¢), 70.5 (5¢-OCH2Ar), 69.8 (3¢-OCH2Ar), 69.3 (C5¢), 66.5 (C2¢),
55.6 (1¢-OCH3).
13C NMR (100 MHz, DMSO-d6): d = 156.0 (C4), 149.8 (C7a),
149.1 (C2), 124.0 (C6), 106.9 (C1¢), 103.0 (C4a), 101.8 (C5), 84.2
(C4¢), 75.7 (C3¢), 68.2 (C2¢), 61.3 (C5¢), 55.4 (1¢-OCH3).
HRMS (ESI): m/z [M + H]+ calcd for C12H17O4N4: 281.1244; found:
281.1246.
HRMS (ESI): m/z [M + Na]+ calcd for C25H23Cl4N5NaO4: 620.0396;
found: 620.0392.
4-Methoxy-7-[methyl a-D-arabinofuranosid-2-yl]-7H-pyrro-
lo[2,3-d]pyrimidine (7b)
Compound 7b was prepared as described for 7a using 6b (571 mg,
0.92 mmol) as a colorless oil; yield: 257 mg (94%); Rf = 0.18
(CH2Cl2–MeOH, 30:1).
1H NMR (400 MHz, DMSO-d6): d = 3.27 (s, 3 H, 1¢-OCH3), 3.61
(m, 1 H, H5¢a), 3.77 (m, 1 H, H5¢b), 3.93 (m, 1 H, H4¢), 4.04 (s, 3
H, 6-OMe), 4.36 (q, J = 13.2, 6.4 Hz, 1 H, H3¢), 4.96 (t, J = 4.2 Hz,
1 H, 5¢-OH), 5.02 (d, J = 3.2 Hz, 1 H, H1¢), 5.05 (m, 1 H, H2¢), 5.66
(d, J = 6.0 Hz, 1 H, 3¢-OH), 6.60 (d, J = 3.6 Hz, 1 H, H5), 7.53 (d,
J = 3.6 Hz, 1 H, H6), 8.43 (s, 1 H, H2).
4-Amino-7-[methyl 3,5-bis-O-(2,4-dichlorobenzyl)-a-D-ara-
binofuranosid-2-yl]-7H-pyrrolo[2,3-d]pyrimidine (6a)
A soln of 5a (428 mg, 0.69 mmol) in methanolic NH3 (saturated
with NH3 at 0 °C, 20 mL) was introduced into an autoclave and
stirred at 120 °C for 12 h. After cooling, the mixture was concen-
trated to dryness and the residual was purified by column chroma-
tography (silica gel, PE–EtOAc, 1:1) to afford 6a as a colorless oil;
yield: 319 mg (77%); Rf = 0.29 (PE–EtOAc, 1:1).
1H NMR (400 MHz, CDCl3): d = 3.41 (s, 3 H, 1¢-OCH3), 3.78 (dd,
J = 10.8, 3.6 Hz, 1 H, H5¢a), 3.92 (dd, J = 10.8, 2.0 Hz, 1 H, H5¢b),
4.25 (m, 1 H, H3¢), 4.36 (m, 1 H, H4¢), 4.44–4.72 (m, 4 H, 2
Synthesis 2011, No. 8, 1213–1218 © Thieme Stuttgart · New York

PAPER
Synthesis of 1¢-O-a-Methyl Pyrrolo[2,3-d]pyrimidine Isonucleosides
1217
13C NMR (100 MHz, DMSO-d6): d = 163.3 (C4), 152.6 (C7a),
151.4 (C2), 126.0 (C6), 106.9 (C1¢), 105.6 (C4a), 99.5 (C5), 84.2
(C4¢), 75.7 (C3¢), 68.5 (C2¢), 61.3 (C5¢), 55.4 (1¢-OCH3), 54.4 (4-
OCH3).
(5) Kim, Y. A.; Sharon, A.; Chu, C. K. J. Med. Chem. 2008, 51,
3934.
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Bernacki, R. J. J. Med. Chem. 1989, 32, 799. (b) Huryn, D.
M.; Sluboski, B. C.; Tam, S. Y.; Weigele, M.; Sim, I.;
Anderson, B. D.; Mitsuya, H.; Brodert, S. J. Med. Chem.
1992, 35, 2347. (c) Tino, J. A.; Clark, J. M.; Field, A. K.;
Jacobs, G. A.; Lis, K. A.; Michalik, T. L.; McGeever-Rubin,
B.; Slusarchyk, W. A.; Spergel, S. H.; Sundeen, J. E.;
Tuomari, A. V.; Weaver, E. R.; Young, M. G.; Zahler, R.
J. Med. Chem. 1993, 36, 1221. (d) Franchetti, P.;
Cappellacci, L.; Grifantini, M.; Memini, L.; Sheikha, G. A.;
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La Colla, P. J. Med. Chem. 1994, 37, 3534. (e) Alexander,
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Zhang, L. H. Bioorg. Med. Chem. 1996, 4, 609. (g) Jin, D.
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12, 1101. (h) Guenther, S.; Balzarini, J.; De Clercq, E.; Nair,
V. J. Med. Chem. 2002, 45, 5426.
HRMS (ESI): m/z [M + Na]+ calcd for C13H17N3NaO5: 318.1060;
found: 318.1056.
3-[Methyl a-D-arabinofuranosid-2-yl]adenine (7c)
Compound 7c was prepared as described for 7a using 5c (290 mg,
0.48 mmol) as a colorless oil; yield: 119 mg (88%); Rf = 0.18
(CH2Cl2–MeOH, 15:1).
1H NMR (400 MHz, DMSO-d6): d = 3.28 (s, 3 H, 1¢-OCH3), 3.59
(d, J = 10.8 Hz, 1 H, H5¢a), 3.75 (d, J = 12.0 Hz, 1 H, H5¢b), 3.92
(m, 1 H, H4¢), 4.45 (q, J = 13.2, 6.8 Hz, 1 H, H3¢), 4.74 (m, 1 H,
H2¢), 4.96 (br s, 1 H, 5¢-OH), 5.18 (d, J = 3.2 Hz, 1 H, H1¢), 5.73 (d,
J = 5.2 Hz, 1 H, 3¢-OH), 7.28 (br s, 2 H, 6-NH2), 8.16 (s, 1 H, H2),
8.24 (s, 1 H, H8).
13C NMR (100 MHz, DMSO-d6): d = 156.9 (C6), 153.3 (C2), 150.3
(C4), 140.7 (C8), 119.8 (C5), 106.0 (C1¢), 84.0 (C4¢), 74.8 (C3¢),
68.2 (C2¢), 61.3 (C5¢), 55.5 (1¢-OCH3).
HRMS (ESI): m/z [M + H]+ calcd for C11H16O4N5: 282.1197; found:
282.1189.
7-[Methyl a-D-arabinofuranosid-2-yl]-3,7-dihydro-4H-pyrro-
lo[2,3-d]pyrimidin-4-one (7d)
Compound 7b (202 mg, 0.68 mmol) was dissolved in 2 M NaOH
(20 mL) and the soln was refluxed for 1.5 h. After cooling, the mix-
ture was neutralized with 1 M HCl and concentrated to dryness. The
residual was purified by column chromatography (silica gel,
CH2Cl2–MeOH, 10:1) to afford 7d as a colorless oil; yield: 162 mg
(84%); Rf = 0.32 (CH2Cl2–MeOH, 10:1).
1H NMR (400 MHz, DMSO-d6): d = 3.26 (s, 3 H, 1¢-OCH3), 3.59
(dd, J = 12.4, 4.8 Hz, 1 H, H5¢a), 3.75 (d, J = 12.0 Hz, 1 H, H5¢b),
3.90 (m, 1 H, H4¢), 4.28 (t, J = 6.8 Hz, 1 H, H3¢), 4.38 (br s, 1 H, 5¢-
OH), 4.93 (d, J = 6.4 Hz, 1 H, H2¢), 4.96 (s, 1 H, H1¢), 5.66 (br s, 1
H, 3¢-OH), 6.55 (d, J = 3.6 Hz, 1 H, H5), 7.22 (d, J = 3.6 Hz, 1 H,
H6), 7.92 (s, 1 H, H2), 11.94 (br s, 1 H, 3-NH).
13C NMR (100 MHz, DMSO-d6): d = 159.2 (C4), 148.5 (C7a),
144.5 (C2), 122.0 (C6), 108.8 (C4a), 107.2 (C1¢), 103.5 (C5), 84.1
(C4¢), 76.0 (C3¢), 68.5 (C2¢), 61.2 (C5¢), 55.4 (1¢-OCH3).
HRMS (ESI): m/z [M + Na]+ calcd for C12H15N3NaO5: 304.0904;
found: 304.0912.
(10) Talekar, R. R.; Wightman, R. H. Tetrahedron 1997, 53,
3831.
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J. Org. Chem. 1998, 63, 347. (d) Lei, Z.; Min, J. M.; Zhang,
L. H. Tetrahedron: Asymmetry 2000, 11, 2899. (e) Bera, S.;
Mickle, T.; Nair, V. Nucleosides Nucleotides 1999, 18,
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Irigaray, N.; Atkinson, E. M.; Holden-Dye, L. M.; Fox, K.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
(15) (a) Lecourt, T.; Hérault, A.; Pearce, A. J.; Sollogoub, M.;
Sinäy, P. Chem. Eur. J. 2004, 12, 2960. (b) Jia, C.; Zhang,
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Acknowledgment
(16) (a) Seela, F.; Kretschmer, U. J. Heterocycl. Chem. 1990, 27,
479. (b) Seela, F.; Westermann, B.; Bindig, U. J. Chem.
Soc., Perkin Trans. 1 1988, 697. (c) Ugarkar, B. G.;
Castellino, A. J.; DaRe, J. M.; Kopcho, J. J.; Wiesner, J. B.;
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(d) Ugarkar, B. G.; Castellino, A. J.; DaRe, J. S.; Ramirez-
Weinhouse, M.; Kopcho, J. J.; Rosengren, S.; Erion, M. D.
J. Med. Chem. 2003, 46, 4750.
This work was supported by the Chinese Ministry of Education, the
NSF of China (No.20972086, 20502009) and SRFDP (No.
20090002110060).
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