A general regioselective approach to 2,4-disubstituted pyrimidin-5-yl C-2-deoxyribonucleosides

Article abstract of DOI:10.1055/s-0031-1289694

A new modular synthesis of diverse 2,4-disubstituted pyrimidin-5-yl C-2-deoxyribonucleosides by sequential regioselective reactions of 2,6-dichloropyrimidin-5-yl C-nucleoside was developed. The intermediate was prepared by the Heck coupling of 2,6-dichlor

Full text of DOI:10.1055/s-0031-1289694

PAPER
953
A General Regioselective Approach to 2,4-Disubstituted Pyrimidin-5-yl
C-2-Deoxyribonucleosides
Pyrimidine
C
-
N
o
ucleosides máš Kubelka,a Lenka Slavětínská,a Michal Hocek*a,b
a
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6,
Czech Republic
b
Department of Organic and Nuclear Chemistry, Faculty of Science, Charles University in Prague, Hlavova 8, 12843 Prague 2,
Czech Republic
Fax +420(2)20183559; E-mail: hocek@uochb.cas.cz
Received 9 December 2011; revised 5 January 2012
approach to the synthesis of hetaryl C-nucleosides bearing
two different substituents (two-dimensional libraries) by
sequential double substitutions of dihalohetaryl interme-
diates. Recently we have reported a preliminary commu-
Abstract: A new modular synthesis of diverse 2,4-disubstituted py-
rimidin-5-yl C-2¢-deoxyribonucleosides by sequential regioselec-
tive reactions of 2,6-dichloropyrimidin-5-yl C-nucleoside was
developed. The intermediate was prepared by the Heck coupling of
2,6-dichloro-5-iodopyrimidine with glycal followed by desilylation nication on the first example of this approach for the
and reduction. Its mild nucleophilic substitutions or cross-coupling
synthesis of 2,4-disubstituted pyrimidin-5-yl C-nucleo-
sides.9 Here, we present a full paper on a largely extended
reactions proceeded regioselectively at position 4, while at elevated
temperatures or with excess reagent, a double substitution occurred.
series of derivatives and a general approach to this type of
The 2-chloro-4-substituted intermediates underwent another substi-
C-nucleoside.
tution or coupling to afford a two-dimensional library of diverse
2,4-disubstituted pyrimidin-5-yl C-2-deoxyribonucleotides.
The key intermediate was synthesized by employing the
Heck reaction10 between 3¢-(tert-butyldimethylsilyl)-pro-
Key words: nucleosides, cross-coupling, Heck reaction, nucleo-
philic aromatic substitution, regioselectivity
tected glycal 1 and 2,4-dichloro-5-iodopyrimidine (2) in
the presence of palladium(II) acetate, tris(pentafluorophe-
nyl)phosphine, and silver carbonate. Since partial desily-
lation was observed during the reaction and workup, the
intermediate 3 was directly deprotected by treatment with
triethylamine trihydrofluoride in tetrahydrofuran to yield
ketone 4 in an acceptable 42% yield (for two steps) as the
pure b-anomer (Scheme 1). This Heck reaction was suc-
cessfully performed on up to a five-gram scale. The reduc-
tion of the ketone 4 by triacetoxyborohydride gave the key
C-Nucleosides are an important class of molecules rele-
vant to medicinal chemistry and chemical biology.1 Vari-
ous hetaryl-C-2¢-deoxyribonucleosides have been studied
as candidates for novel base pairs in the quest for exten-
sion of the genetic alphabet.2 Some artificial base pairs
were efficiently and selectively replicated by DNA poly-
merases.3 One of the most promising type of artificial
base-pairs is based on 4-substituted 2-methoxyphenyl C-
nucleosides in combination with thioisocarbostyril. These
pairs have been not only replicated and extended,4 but also
used in the first successful polymerase chain reaction
(PCR) with a six-letter genetic alphabet.5 Particularly im-
portant is the presence of a methoxy group as an H-bond
acceptor in the minor groove, which stabilizes the active
site of the polymerase and facilitates extension of the
growing DNA chain. Another rich field of applications of
hetaryl C-deoxyribonucleosides are the mechanistic stud-
ies of specificity of DNA polymerases and primases.6
Cl
Cl
N
N
N
Cl
N
I
2
HO
HO
O
O
Cl
a
OTBS
OTBS
1
3
b
Cl
Cl
N
In recent years, we have been working on a general and
modular approach7 based on the synthesis of halo(het)aryl
C-nucleoside intermediates and their follow-up function-
alizations by cross-couplings, aminations, and other reac-
tions to afford a series (one-dimensional libraries) of
derivatives. Since some dihaloheterocycles can undergo
regioselective or chemoselective nucleophilic displace-
ments and/or cross-couplings,8 we decided to extend our
N
N
N
c
RO
HO
O
O
Cl
Cl
OR
5aa, R = H (82%)
6aa, R = TBS (75%)
O
4
42% over two steps
d
Scheme 1 Synthesis of 2,4-dichloropyrimidin-5-yl C-nucleoside
key intermediates. Reagents and conditions: (a) Pd(OAc)2, (F5C6)3P,
Ag2CO3, CHCl3, 70 °C, 10 h; (b) Et3N·3HF, THF, 0°C, 5 min; (c)
NaBH(OAc)3, MeCN, AcOH, 0 °C, 5 min; (d) TBSCl, imidazole,
DMF, r.t., 14 h.
SYNTHESIS 2012, 44, 953–965
Advanced online publication: 06.02.2012
DOI: 10.1055/s-0031-1289694; Art ID: Z114011SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
2

954
T. Kubelka et al.
PAPER
Table 1 Regioselective Nucleophilic Substitutions
Cl
Y
N
X
Cl
N
X
step 2
TBDMSCl
N
N
N
N
Cl
imidazole
HO
step 1
HO
DMF, r.t., 16 h
TBSO
O
O
O
OH
5aa
OH
OTBS
6ab, 6ac
5ab, 5bb, 5ac, 5cc
Entry
Conditions for step 1
X
Y
Step 1
Step 2
Product
Yield (%)
Product
Yield (%)
1
2
3
4
NH3/MeOH, r.t., 7 d
NH2
NH2
OMe
OMe
Cl
5ab
5bb
5ac
5cc
74
83
78
87
6ab
–
69
–
NH3/MeOH, 120 °C, 12 h
NaOMe, MeOH, r.t., 24 h
NH2
Cl
6ac
–
91
–
NaOMe, MeOH, 120 °C, 12 h
OMe
intermediate 5aa in a good 82% yield. The silylation of functional group transformations, compounds 5ab and
the nucleoside 5aa afforded tert-butyldimethylsilyl- 5ac were protected using tert-butyldimethylsilyl chloride
protected C-nucleoside 6aa in 75% yield.
and imidazole to afford silylated 4-amino-2-chloro deriv-
ative 6ab in 89% yield and 2-chloro-4-methoxy derivative
6ac in 91% yield (Table 1).
The dichloropyrimidine intermediate 5aa and its silylated
analogue 6aa were then used to study the regioselectivity
of nucleophilic substitutions (Table 1) and cross-coupling The application of harsh conditions in the nucleophilic
reactions (Table 2). The chlorine at position 4 was found substitutions afforded disubstituted compounds (Table 1).
to be significantly more reactive than that at position 2. The reaction of 5aa with methanolic ammonia at 120 °C
Therefore, we were able to selectively introduce some gave 2,4-diamino derivative 5bb in 83% yield. Similarly,
functional groups to position 4.
the reaction of 5aa with excess sodium methoxide at 120
°C gave 2,4-dimethoxy derivative 5cc in 87% yield.
Starting from unprotected nucleoside 5aa, the reaction
with methanolic ammonia at room temperature gave regi- Silylated 2,4-dichloropyrimidine C-nucleoside 6aa was
oselectively 2-chloro-4-amino derivative 5ab in a good treated with 1.5 equivalents of methylmagnesium chloride
74% yield. Similarly, treatment of 5aa with sodium meth- in presence of iron(III) acetylacetonate11 to form mono-
oxide in methanol at room temperature proceeded regio- substituted 2-chloro-4-methyl derivative 6ad with reason-
selectively to give 2-chloro-4-methoxy derivative 5ac in able regioselectivity in 46% yield (Table 2) along with
78% yield. The regioselectivity of nucleophilic substitu- unreacted starting compound (50%). The silylated 2-chlo-
tion was verified by 2D NMR experiments and X-ray dif- ro-4-methylpyrimidine C-nucleoside 6ad was deprotect-
fraction of compound 5ac.9 For some follow-up ed by treatment with triethylamine trihydrofluoride in
Table 2 Regioselective Cross-Couplings
Cl
Y
N
X
Y
N
X
N
N
N
step 2
Et3N•3HF
THF, r.t.
N
step 1
TBSO
TBSO
HO
O
O
O
Cl
OTBS
6aa
OTBS
OH
5ad, 5dd, 5ae, 5ea, 5ee, 5ff
6ad, 6dd, 6ae, 6ea, 6ee, 6ff
Entry Conditions for step 1
X
Y
Step 1
Step 2
Product Yield (%) Product Yield (%)
1
2
3
MeMgCl (1.5 equiv), Fe(acac)3, THF, r.t., 8 h
MeMgCl (4 equiv), Fe(acac)3, THF, r.t., 8 h
Me
Me
Cl
6ad
6dd
46
68
5ad
5dd
94
77
Me
Me2NH·HCl, Pd(OAc)2, JohnPhos, t-BuONa, DME, r.t., 48 h
NMe2
Cl
Cl
NMe2
6ae
6ea
71
16
5ae
5ea
94
80
4
5
Me2NH·HCl, Pd(OAc)2, JohnPhos, t-BuONa, DME, 80 °C, 48 h NMe2
PhB(OH)2, Pd(PPh3)4, K2CO3, toluene, 90 °C, 12 h Ph
NMe2
Ph
6ee
6ff
84
61
5ee
5ff
79
72
Synthesis 2012, 44, 953–965
© Thieme Stuttgart · New York

PAPER
Pyrimidine C-Nucleosides
955
tetrahydrofuran to afford free nucleoside 5ad in an excel-
lent 94% yield. The Buchwald–Hartwig reaction was used
to introduce the dimethylamino substituent (Table 2). The
reaction of 6aa with dimethylamine hydrochloride in the
presence of palladium(II) acetate, JohnPhos [(biphenyl-2-
yl)di-tert-butylphosphine], and excess sodium tert-butox-
ide as a base at room temperature gave monosubstituted 2-
chloro-4-(dimethylamino)pyrimidine derivative 6ae in
71% yield. In this case the regioselectivity of amination
was not complete and the second regioisomer 4-chloro-2-
(dimethylamino)pyrimidine derivative 6ea was also iso-
lated as a minor product in 16% yield. Both monosubsti-
tuted dimethylamines 6ae and 6ea were deprotected using
triethylamine trihydrofluoride in tetrahydrofuran to give
free 2-chloro-4-(dimethylamino)- 5ae (94%) and 4-chlo-
ro-2-(dimethylamino)pyrimidine nucleosides 5ea (80%).
Cl
N
X
NH2
N
N
N
NH3, MeOH
HO
HO
O
120 °C, 12 h
O
X
OH
OH
5ac, X = OMe
5ad, X = Me
5ae, X = NMe2
5bc, X = OMe (25%)
5bd, X = Me (68%)
5be, X = NMe2 (71%)
Scheme 2 Nucleophilic amination of 2-chloro-4-substitued pyrimi-
dine C-nucleosides
Methoxylation of free 2-chloropyrimidine C-nucleosides
with sodium methoxide in methanol at 120 °C proceeded
uneventfully and selectively (Scheme 3). In this way, a se-
ries of 4-substituted 2-methoxypyrimidine C-nucleosides
5cb (71%), 5cd (65%), and 5ce (64%) were obtained.
Using harsh conditions and an excess of reagent for the
cross-coupling reactions gave disubstituted products
(Table 2). Cross-coupling of nucleoside 6aa with four
equivalents of methylmagnesium chloride in presence of
iron(III) acetylacetonate gave 2,4-dimethyl derivative
6dd in 68% yield. The Buchwald–Hartwig reaction of 6aa
with four equivalents of dimethylamine hydrochloride in
the presence of palladium(II) acetate, JohnPhos, and sodi-
um tert-butoxide at 80 °C gave 2,4-bis(dimethylami-
no)pyrimidine derivative 6ee in 84% yield. The silylated
disubstituted derivatives 6dd and 6ee were readily depro-
tected by treatment with triethylamine trihydrofluoride to
give the free nucleosides 5dd (77%) and 5ee (79%).
Cl
N
X
OMe
N
N
N
NaOMe
MeOH
HO
HO
O
O
120 °C, 12 h
X
OH
5ab, X = NH2
5ad, X = Me
OH
5cb, X = NH2 (71%)
5cd, X = Me (65%)
5ce, X = NMe2 (64%)
5ae, X = NMe2
Scheme 3 Methoxylation of 2-chloro-4-substitued pyrimidine C-
nucleosides
Several attempts were required for regioselective Suzuki
reaction of C-nucleoside 6aa with phenylboronic acid;
this reaction gave only inseparable mixture of mono- and
disubstituted compounds. The use of harsh conditions and
excess boronic acid afforded 2,4-diphenylpyrimidine de-
rivative 6ff in 61% yield, which was deprotected to give
free nucleoside 5ff in 72% yield.
Silyl-protected 4-substituted 2-chloropyrimidine C-nucleo-
sides were methylated through a cross-coupling reaction
with trimethylaluminum in presence of tetrakis(triphe-
nylphosphine)palladium(0) to prepare 2-methyl-4-substi-
tuted pyrimidine C-nucleosides (Scheme 4). Methoxy-
and (dimethylamino)-substituted derivatives 6ac and 6ae
afforded the corresponding methylated derivatives 6dc
All the 4-monosubstituted 2-chloropyrimidine C-nucleo- (94%) and 6de (89%) in excellent yields. Unfortunately,
sides 5ab, 5ac, 5ad, and 5ae and their silylated derivatives all attempts to introduce a methyl group at position 2 of 4-
6ab, 6ac, 6ad, and 6ae were used for the synthesis of six
Cl
types of disubstituted pyrimidine C-nucleosides bearing
different substituents at positions 2 and 4 (Schemes 2– 7).
N
N
N
X
N
X
The amination of 4-substituted 2-chloropyrimidine nucleo-
sides 5ac–ae with methanolic ammonia at 120 °C gave a
series of 2-amino-4-substituted compounds (Scheme 2).
The only unselective reaction in this series was the amina-
tion of 2-methoxy-4-methoxypyrimidine 5ac. The desired
2-amino-4-methoxypyrimidine derivative 5bc was isolat-
ed in 25% yield, accompanied by 4-amino-2-chloro deriv-
ative 5ab (52%) and 4-amino-2-methoxypyrimidine 5cb
(15%). Under the harsh reaction conditions, the 4-OMe
substituent acts as a leaving group, which can be replaced
by an amino group (leading to 5ab), and methanol may
serve as a nucleophile to methoxylate the C-2 position by
replacing the chlorine atom (leading to 5cb). The amina-
tion of compounds 5ad and 5ae proceeded well to obtain
the desired 2-amino derivatives 5bd (68%) and 5be
(71%).
TBSO
TBSO
O
O
a
OTBS
OTBS
6ab, X = NH2
6ac, X = OMe
6ae, X = NMe2
6db, X = NH2 (0%)
6dc, X = OMe (94%)
6de, X = NMe2 (89%)
b
N
N
X
HO
O
OH
5dc, X = OMe (72%)
5de, X = NMe2 (82%)
Scheme 4 Methylation of 2-chloro-4-substituted pyrimidin-5-yl C-
nucleosides. Reagents and conditions: (a) Me3Al, Pd(PPh3)4, THF, 70
°C, 12 h; (b) Et3N·3 HF, THF, r.t., 14 h.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 953–965

956
T. Kubelka et al.
PAPER
Cl
N
X
Ph
N
amino-2-chloropyrimidine 6ab (palladium-catalyzed
cross-coupling with trimethylaluminum or with methyl-
boronic acid or iron-catalyzed coupling with methylmag-
nesium chloride) were unsuccessful due to the
incompatibility of the free amino group with these cross-
couplings. Silylated C-nucleosides 6dc and 6de were
readily deprotected to obtain free C-nucleosides 5dc
(72%) and 5de (82%).
N
N
TBSO
TBSO
O
O
a
X
OTBS
OTBS
6ab, X = NH2
6ac, X = OMe
6ad, X = Me
6ae, X = NMe2
6fb, X = NH2 (56%)
6fc, X = OMe (62%)
6fd, X = Me (59%)
6fe, X = NMe2 (65%)
Palladium-catalyzed Hartwig–Buchwald reaction was
used for synthesis of 2-(dimethylamino)-4-substituted py-
rimidine C-nucleosides (Scheme 5). The coupling was
performed in the presence of palladium(II) acetate and
JohnPhos to give the desired compounds 6eb (74%), 6ec
(91%), and 6ed (69%). Deprotection of silylated deriva-
tives afforded free nucleosides 5eb (92%), 5ec (85%), and
5ed (85%).
Ph
N
b
N
HO
O
X
OH
5fb, X = NH2 (82%)
5fc, X = OMe (67%)
5fd, X = Me (73%)
5fe, X = NMe2 (76%)
Cl
N
X
NMe2
N
N
Scheme 6 Suzuki reaction of 2-chloro-4-substituted pyrimidin-5-yl
C-nucleosides. Reagents and conditions: (a) PhB(OH)2, Pd(PPh3)4,
K2CO3, toluene, 90 °C, 12 h; (b) Et3N·3 HF, THF, r.t., 14 h.
N
X
TBSO
TBSO
O
O
a
Cl
N
X
H
N
X
OTBS
OTBS
N
N
6ab, X = NH2
6ac, X = OMe
6ad, X = Me
6eb, X = NH2 (74%)
6ec, X = OMe (91%)
6ed, X = Me (69%)
TBSO
TBSO
O
O
a
NMe2
b
N
OTBS
OTBS
N
X
6ab, X = NH2
6ac, X = OMe
6ad, X = Me
6ae, X = NMe2
6gb, X = NH2 (73%)
6gc, X = OMe (75%)
6gd, X = Me (94%)
6ge, X = NMe2 (83%)
HO
O
H
N
X
OH
b
5eb, X = NH2 (92%)
5ec, X = OMe (85%)
5ed, X = Me (85%)
N
HO
O
Scheme 5 Buchwald amination of 2-chloro-4-substituted pyrimi-
din-5-yl C-nucleosides. Reagents and conditions: (a) Me2NH·HCl,
Pd(OAc)2, JohnPhos, t-BuONa, DME, 70 °C, 48 h; (b) Et3N·3HF,
THF, r.t., 14 h.
OH
5gb, X = NH2 (83%)
5gc, X = OMe (73%)
5gd, X = Me (84%)
5ge, X = NMe2 (90%)
For the introduction of the phenyl group, the Suzuki–
Miyaura cross-coupling of phenylboronic acid with com-
pounds 6ab–ae was performed in toluene at 90 °C in pres-
ence of tetrakis(triphenylphosphine)palladium(0) and
potassium carbonate (Scheme 6). A series of four 2-phe-
nyl-4-substituted pyrimidine C-nucleosides 6fb, 6fc, 6fd,
and 6fe were prepared in yields around 60%. The lower
yields are caused mainly by loss during workup and chro-
matography. The treatment of these protected compounds
with triethylamine trihydrofluoride afforded free C-nucleo-
sides 5fb (82%), 5fc (67%), 5fd (73%), and 5fe (76%).
Scheme 7 Hydrogenation of 2-chloro-4-substituted pyrimidin-5-yl
C-nucleosides. Reagents and conditions: (a) H2, Pd/C, EtOH, THF,
H2O, Et3N, r.t., 12 h; (b) Et3N·3 HF, THF, r.t., 14 h.
Hydrogenation of free C-nucleoside 5ab was also at-
tempted, but it surprisingly gave the product of over-
reduction at the benzylic carbon; compound 7 (78%) was
isolated as the sole product (Scheme 8).
Cl
H
N
N
Catalytical hydrogenation of 2-chloro-4-substituted C-nu-
cleosides using atmospheric pressure of hydrogen and
palladium on carbon in a mixture of ethanol, tetrahydrofu-
ran, and water and in the presence of triethylamine gave
4-substituted compounds 6gb, 6gc, 6gd, and 6ge
(Scheme 7). Also these compounds were deprotected to
give free C-nucleosides 5gb (83%), 5gc (73%), 5gd
(84%), and 5ge (90%).
N
N
HO
HO
a
O
OH
NH2
NH2
OH
5ab
OH
7 (78%)
Scheme
8
Hydrogenation of unprotected C-nucleoside 5ab.
Reagents and conditions: (a) H2, Pd/C, EtOH, THF, H2O, Et3N, r.t.,
12 h.
Synthesis 2012, 44, 953–965
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PAPER
Pyrimidine C-Nucleosides
957
1b-(4-Amino-2-chloropyrimidin-5-yl)-3,5-di-O-(tert-butyldi-
methylsilyl)-1,2-dideoxy-D-ribofuranose (6ab); Typical Proce-
dure
In conclusion, we have developed an efficient and fairly
general approach to a 2D library of diverse 2,4-disubsti-
tuted pyrimidine C-2¢-deoxyribonucleosides via regiose-
lective displacement of the corresponding unprotected or
protected 2,4-dichloropyrimidine nucleosides. The chlo-
rine at position 4 is significantly more reactive in nucleo-
philic substitutions and cross-couplings than the chlorine
at position 2. Thus, the nucleophilic substitution of unpro-
tected 2,4-dichloropyrimidine C-nucleoside 5aa with am-
monia or sodium methoxide under mild conditions gave
selectively 2-chloro-4-amino- or 2-chloro-4-methoxypy-
rimidine C-nucleosides, whereas at elevated temperatures
the corresponding disubstituted derivatives were ob-
tained. Similarly, the iron-catalyzed methylation or the
Buchwald–Hartwig dimethylamination (but not the Suzuki
coupling) of silylated 2,4-dichloropyrimidine C-nucleo-
side with one equivalent of the reagent gave selectively 4-
substituted 2-chloropyrimidine intermediate whereas,
with excess reagent, the disubstituted products were
formed. The 4-monosubstituted 2-chloropyrimidine C-
nucleosides served as intermediates for the second nu-
Imidazole (500 mg, 7.34 mmol) and TBSCl (600 mg, 3.98 mmol)
were added to a flame-dried flask containing a soln of the nucleo-
side 5ab (255 mg, 1.04 mmol) in anhyd DMF (10.0 mL) at 0 °C un-
der argon and the soln was allowed to warm to r.t. and was stirred
for 16 h. The mixture was then poured into sat. NaCl (100 mL) and
extracted with EtOAc (3 × 30 mL). The combined organic layers
were dried (MgSO4), and the solvents were evaporated under vacu-
um. The crude product was chromatographed (silica gel, gradient
hexanes to hexanes–EtOAc, 10:1) to give the desired nucleoside
6ab (440 mg, 89%) as a colorless oil.
IR (CCl4): 3483, 3345, 2956, 2899, 1620, 1587, 1554, 1471, 1463,
1410, 1396, 1361, 1260, 1189, 1099, 1006, 967, 939, 837 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 0.06, 0.067, 0.072, and 0.08
(4 × s, 4 × 3 H, CH3Si), 0.87 and 0.88 [2 × s, 2 × 9 H, (CH3)3C],
1.99 (ddd, Jgem = 12.7 Hz, J2¢a,1¢ = 9.7 Hz, J2¢a,3¢ = 6.2 Hz, 1 H, H2¢a),
2.07 (ddd, Jgem = 12.7 Hz, J2¢b,1¢ = 6.1 Hz, J2¢b,3¢ = 2.5 Hz, 1 H, H2¢b),
3.66–3.75 (m, 2 H, H5¢), 3.80 (br q, J4¢,5¢a = J4¢,5¢b = J4¢,3¢ = 3.3 Hz, 1
H, H4¢), 4.35 (br dt, J3¢,2¢a = 6.2 Hz, J3¢,2¢b = J3¢,4¢ = 2.8 Hz, 1 H, H3¢),
4.99 (br dd, J1¢,2¢a = 9.6 Hz, J1¢,2¢b = 6.1 Hz, 1 H, H1¢), 7.26 (v br s, 2
H, NH2-4), 8.03 (d, J6,1¢ = 0.6 Hz, 1 H, H6).
cleophilic substitution or cross-coupling at position 2. Fi- 13C NMR (125.7 MHz, DMSO-d6): d = –5.39, –5.34, –4.69, and
–4.52 (CH3Si), 18.00 and 18.25 [(CH3)3C], 25.93 and 25.99
[(CH3)3C], 39.7 (CH2-2¢), 62.90 (CH2-5¢), 73.31 (CH-3¢), 74.81
nal desilylation of protected nucleosides was readily
performed by treatment with triethylamine trihydrofluo-
(CH-1¢), 87.45 (CH-4¢), 115.44 (C-5), 154.53 (CH-6), 158.76 (C-2),
ride. In total, 29 novel 2,4-disubstituted pyrimidine C-2¢-
162.65 (C-4).
deoxyribonucleosides were prepared by this approach.
Some of them will be transformed to triphosphates and
tested as substrates of DNA polymerases. These studies
HRMS (ESI): m/z [M + H] calcd for C21H41ClN3O3Si2: 474.2369;
found: 474.2369.
are now under way in our laboratory.
3,5-Di-O-(tert-butyldimethylsilyl)-1b-(2-chloro-4-methoxypyri-
midin-5-yl)-1,2-dideoxy-D-ribofuranose (6ac)
Following the typical procedure for 6ab using imidazole (700 mg,
10.28 mmol), TBSCl (1 g, 6.63 mmol), and 5ac (1 g, 0.52 mmol) in
anhyd DMF (15.0 mL). The crude product was chromatographed
All cross-coupling reactions were carried out in evacuated flame-
dried glassware with magnetic stirring under argon atmosphere.
THF and toluene were dried and distilled from Na/benzophenone.
(silica gel, gradient hexanes to hexanes–EtOAc, 50:1) to give the
All reagents were purchased from commercial suppliers and used as
desired nucleoside 6ac (856 mg, 91%) as a colorless oil.
received. NMR spectra were recorded on a 400 MHz spectrometer
(1H at 400 MHz, 13C at 100.6 MHz), 500 MHz spectrometer (1H at
IR (CCl4): 2957, 2898, 1584, 1563, 1473, 1455, 1448, 1392, 1362,
500 MHz and 125.8 MHz at 13C) and/or 600 MHz spectrometer (1H
at 600 MHz, 13C at 151 MHz). The samples were measured in
CDCl3 using TMS as an internal standard or in DMSO-d6 refer-
enced to the residual solvent signal (1H NMR: d = 2.50 ppm, 13C
NMR: d = 39.7 ppm). Complete assignment of all NMR signals was
performed using a combination of 2D-NMR (H,H-COSY, H,C-
HSQC, and H,C-HMBC) experiments and configurations were es-
tablished by 2D ROESY spectra. Mass spectra were measured with
ESI ionization. Melting points were determined on a Kofler block
and are uncorrected. Elemental analyses were measured on PE 2400
Series II CHNS/O (Perkin Elmer, USA, 1999).
941, 838, 682 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.05, 0.06, 0.08, and 0.09 (4 × s,
4 × 3 H, CH3Si), 0.87 and 0.90 [2 × s, 2 × 9 H, (CH3)3C], 1.75 (ddd,
Jgem = 12.6 Hz, J2¢a,1¢ = 9.9 Hz, J2¢a,3¢ = 5.5 Hz, 1 H, H2¢a), 2.25 (ddd,
Jgem = 12.6 Hz, J2¢b,1¢ = 5.8 Hz, J2¢b,3¢ = 2.1 Hz, 1 H, H2¢b), 3.60 (dd,
Jgem = 10.8 Hz, J5¢a,4¢ = 5.3 Hz, 1 H, H5¢a), 3.72 (dd, Jgem = 10.8 Hz,
J
J
5¢b,4¢ = 3.8 Hz, 1 H, H5¢b), 3.94 (ddd, J4¢,5¢a = 5.3 Hz, J4¢,5¢b = 3.8 Hz,
4¢,3¢ = 2.3 Hz, 1 H, H4¢), 4.02 (s, 3 H, CH3O-4), 4.38 (br dt,
J3¢,2¢a = 5.5 Hz, J3¢,4¢ = J3¢,2¢a = 2.2 Hz, 1 H, H3¢), 5.20 (ddm,
J1¢,2¢a = 9.9 Hz, J1¢,2¢b = 5.8 Hz, 1 H, H1¢), 8.45 (d, J6,1¢ = 1.1 Hz, 1 H,
H6).
JohnPhos = (biphenyl-2-yl)di-tert-butylphosphine. The synthesis of
compounds 3, 4, 5aa, 6aa, 5ab, 5bb, 5cb, 5ac, 5cc, 5bc, 6ad, 5ad,
6dd, 5dd, 5bd, 5cd, 6fd, and 5fd and their experimental data can be
found in the previously published preliminary communication.9
13C NMR (125.7 MHz, CDCl3): d = –5.50, –5.41, –4.72, and –4.68
(CH3Si), 18.00 and 18.28 [(CH3)3C], 25.77 and 25.87 [(CH3)3C],
41.80 (CH2-2¢), 54.68 (CH3O-4), 63.40 (CH2-5¢), 72.99 (CH-1¢),
73.82 (CH-3¢), 87.80 (CH-4¢), 121.73 (C-5), 155.52 (CH-6), 158.46
(C-2), 167.28 (C-4).
Deprotection of the TBS Group; General Procedure
HRMS (ESI): m/z [M + H] calcd for C22H42ClN2O4Si2: 488.2293;
found: 488.2294.
Et3N·3 HF (320 mL, 1.95 mmol) was added to a soln of silylated C-
nucleoside (0.4 mmol) in THF (2 mL), and the mixture was stirred
at r.t. for 14 h. When the reaction was complete (TLC: hexane–
EtOAc, 10:1), the solvent was removed under reduced pressure and
the crude product was chromatographed (silica gel, 20 g, gradient
CHCl3 to 15% MeOH–CHCl3) to give free C-nucleosides.
3,5-Di-O-(tert-butyldimethylsilyl)-1b-[2-chloro-4-(dimethyl-
amino)pyrimidin-5-yl]-1,2-dideoxy-D-ribofuranose (6ae)
A soln of Pd(OAc)2 (40 mg, 0.18 mmol) and JohnPhos (110 mg,
0.37 mmol) in DME (10 mL) was added to an argon-purged dry
flask containing 6aa (910 mg, 1.84 mmol), t-BuONa (265 mg, 2.76
mmol), and Me2NH·HCl (180 mg, 2.21 mmol). The mixture was
© Thieme Stuttgart · New York
Synthesis 2012, 44, 953–965

958
T. Kubelka et al.
PAPER
stirred at r.t. for 48 h. After the disappearance of the starting mate-
rial, formation of two products was observed. The mixture was
worked up, and the mixture was chromatographed (silica gel, gradi-
ent hexane to 6% EtOAc–hexane) to give 6ae (660 mg, 71%) as a
colorless oil and byproduct 6ea (148 mg, 16%) as a colorless oil.
13C NMR (125.7 MHz, CD3OD): d = 40.95 [(CH3)2N], 43.22 (CH2-
2¢), 63.59 (CH2-5¢), 73.84 (CH-3¢), 75.40 (CH-1¢), 88.91 (CH-4¢),
118.57 (C-5), 157.57 (CH-6), 158.98 (C-2), 165.07 (C-4).
HRMS (ESI): m/z [M + H] calcd for C11H17ClN3O3: 274.0953;
found: 274.0956.
Compound 6ae
1b-[4-Chloro-2-(dimethylamino)pyrimidin-5-yl]-1,2-dideoxy-D-
ribofuranose (5ea)
Following the general procedure for deprotection using 6ea (93 mg,
0.19 mmol) gave 5ea (40 mg, 80%) as a white solid.
IR (CCl4): 2956, 2898, 2800, 1599, 1548, 1514, 1472, 1463, 1412,
1391, 1361, 1257, 1080, 1006, 939, 838 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.058, 0.062, 0.08, and 0.09 (4 × s,
4 × 3 H, CH3Si), 0.89 and 0.90 [2 × s, 2 × 9 H, (CH3)3C], 1.98 (ddd,
Jgem = 12.6 Hz, J2¢a,1¢ = 10.5 Hz, J2¢a,3¢ = 5.2 Hz, 1 H, H2¢a), 2.07
(ddd, Jgem = 12.6 Hz, J2¢b,1¢ = 4.9 Hz, J2¢b,3¢ = 1.7 Hz, 1 H, H2¢b), 3.15
[s, 2 × 3 H, (CH3)2N], 3.58 (dd, Jgem = 10.8 Hz, J5¢a,4¢ = 5.4 Hz, 1 H,
H5¢a), 3.71 (dd, Jgem = 10.8 Hz, J5¢b,4¢ = 3.7 Hz, 1 H, H5¢b), 3.88
(ddd, J4¢,5¢a = 5.4 Hz, J4¢,5¢b = 3.7 Hz, J4¢,3¢ = 1.9 Hz, 1 H, H4¢), 4.42
(br dt, J3¢,2¢a = 5.1 Hz, J3¢,4¢ = J3¢,2¢a = 1.8 Hz, 1 H, H3¢), 5.25 (dd,
J1¢,2¢a = 10.5 Hz, J1¢,2¢b = 4.9 Hz, 1 H, H1¢), 8.28 (d, J6,1¢ = 0.7 Hz, 1
H, H6).
13C NMR (125.7 MHz, CDCl3): d = –5.52, –5.35, –4.71, and –4.69
(CH3Si), 17.93 and 18.31 [(CH3)3C], 25.74 and 25.90 [(CH3)3C],
40.69 [(CH3)2N], 42.48 (CH2-2¢), 63.53 (CH2-5¢), 73.88 and 74.06
(CH-1¢, CH-3¢), 87.81 (CH-4¢), 117.01 (C-5), 157.27 (CH-6),
158.47 (C-2), 164.09 (C-4).
IR (KBr): 3374, 2798, 1603, 1559, 1513, 1413, 1395, 1175, 1074,
1051, 986, 938, 784 cm–1.
1H NMR (500 MHz, CD3OD): d = 1.88 (ddd, Jgem = 13.1 Hz,
J
2¢a,1¢ = 10.2 Hz, J2¢a,3¢ = 6.0 Hz, 1 H, H2¢a), 2.30 (ddd, Jgem = 13.1
Hz, J2¢b,1¢ = 5.5 Hz, J2¢b,3¢ = 1.9 Hz, 1 H, H2¢b), 3.15 [s, 2 × 3 H,
(CH3)2N], 3.67 (m, 2 H, H5¢), 3.91 (td, J4¢,5¢a = J4¢,5¢b = 4.8 Hz,
J
4¢,3¢ = 2.7 Hz, 1 H, H4¢), 4.32 (br dt, J3¢,2¢a = 6.0 Hz,
J3¢,4¢ = J3¢,2¢b = 2.2 Hz, 1 H, H3¢), 5.26 (br dd, J1¢,2¢a = 10.2 Hz,
J1¢,2¢b = 5.5 Hz, 1 H, H1¢), 8.45 (d, J6,1¢ = 0.7 Hz, 1 H, H6).
13C NMR (125.7 MHz, CD3OD): d = 37.37 [(CH3)2N], 43.16 (CH2-
2¢), 63.76 (CH2-5¢), 74.19 (CH-3¢), 76.39 (CH-1¢), 88.91 (CH-4¢),
120.62 (C-5), 158.48 (CH-6), 160.02 (C-4), 162.59 (C-2).
HRMS (ESI): m/z [M + H] calcd for C11H17ClN3O3: 274.0953;
found: 274.0954.
HRMS (ESI): m/z [M + H] calcd for C23H45ClN3O3Si2: 502.2682;
found: 502.2682.
1b-[2,4-Bis(dimethylamino)pyrimidin-5-yl]-3,5-di-O-(tert-bu-
tyldimethylsilyl)-1,2-dideoxy-D-ribofuranose (6ee); Typical
Procedure
3,5-Di-O-(tert-butyldimethylsilyl)-1b-[4-chloro-2-(dimethyl-
amino)pyrimidin-5-yl]-1,2-dideoxy-D-ribofuranose (6ea)
IR (CCl4): 2955, 2897, 2804, 1578, 1543, 1497, 1471, 1463, 1443,
1399, 1364, 1257, 1091, 1006, 939, 838 cm–1.
A soln of Pd(OAc)2 (5 mg, 0.02 mmol) and JohnPhos (14 mg, 0.05
mmol) in DME (3 mL) was added to an argon-purged dry flask con-
taining 6aa (116 mg, 0.23 mmol), t-BuONa (66 mg, 0.69 mmol),
and Me2NH·HCl (75 mg, 0.92 mmol). The mixture was stirred at 80
°C for 48 h. Then the mixture was diluted with Et2O, poured into
H2O, extracted with Et2O, and dried with MgSO4, and crude 6ee
was chromatographed (silica gel, gradient hexane to 15% EtOAc–
hexane) to give 6ee (103 mg, 84%) as a colorless oil.
1H NMR (500 MHz, CDCl3): d = 0.08, 0.088, and 0.092 (3 × s, 4 × 3
H, CH3Si), 0.90 and 0.91 [2 × s, 2 × 9 H, (CH3)3C], 1.75 (ddd,
Jgem = 12.7 Hz, J2¢a,1¢ = 10.0 Hz, J2¢a,3¢ = 5.4 Hz, 1 H, H2¢a), 2.25
(ddd, Jgem = 12.7 Hz, J2¢b,1¢ = 5.5 Hz, J2¢b,3¢ = 2.0 Hz, 1 H, H2¢b), 3.18
[s, 2 × 3 H, (CH3)2N], 3.58 (dd, Jgem = 10.7 Hz, J5¢a,4¢ = 6.0 Hz, 1 H,
H5¢a), 3.75 (dd, Jgem = 10.7 Hz, J5¢b,4¢ = 4.0 Hz, 1 H, H5¢b), 3.93
(ddd, J4¢,5¢a = 6.0 Hz, J4¢,5¢b = 4.0 Hz, J4¢,3¢ = 2.2 Hz, 1 H, H4¢), 4.39
(br dt, J3¢,2¢a = 5.3 Hz, J3¢,4¢ = J3¢,2¢a = 2.1 Hz, 1 H, H3¢), 5.27 (dd,
J1¢,2¢a = 10.0 Hz, J1¢,2¢b = 5.5 Hz, 1 H, H1¢), 8.40 (d, J6,1¢ = 0.7 Hz, 1
H, H6).
13C NMR (125.7 MHz, CDCl3): d = –5.46, –5.38, –4.71, and –4.66
(CH3Si), 18.00 and 18.33 [(CH3)3C], 25.78 and 25.93 [(CH3)3C],
37.22 [(CH3)2N], 42.24 (CH2-2¢), 63.63 (CH2-5¢), 74.01 (CH-3¢),
75.07 (CH-1¢), 87.65 (CH-4¢), 119.91 (C-5), 156.66 (CH-6), 158.81
(C-4), 160.96 (C-2).
IR (CCl4): 2957, 2896, 2801, 1594, 1499, 1454, 1417, 1406, 1389,
1362, 1257, 1097, 939, 838, 785 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.05, 0.08, and 0.09 (3 × s, 4 × 3
H, CH3Si), 0.90 (s, 2 × 9 H, (CH3)3C], 1.95 (ddd, Jgem = 12.7 Hz,
J
J
2¢a,1¢ = 5.0 Hz, J2¢a,3¢ = 1.6 Hz, 1 H, H2¢a), 2.02 (ddd, Jgem = 12.7 Hz,
2¢b,1¢ = 10.6 Hz, J2¢b,3¢ = 5.1 Hz, 1 H, H2¢b), 3.05 [s, 2 × 3 H,
(CH3)2N-4], 3.12 [s, 2 × 3 H, (CH3)2N-2], 3.49 (dd, Jgem = 10.6 Hz,
J5¢a,4¢ = 7.1 Hz, 1 H, H5¢a), 3.71 (dd, Jgem = 10.6 Hz, J5¢b,4¢ = 4.3 Hz,
1 H, H5¢b), 3.83 (ddd, J4¢,5¢a = 7.1 Hz, J4¢,5¢b = 4.3 Hz, J4¢,3¢ = 1.9 Hz,
1 H, H4¢), 4.39 (br dt, J3¢,2¢b = 5.1 Hz, J3¢,4¢ = J3¢,2¢a = 1.8 Hz, 1 H,
H3¢), 5.20 (dd, J1¢,2¢b = 10.7 Hz, J1¢,2¢a = 5.0 Hz, 1 H, H1¢), 8.10 (br s,
1 H, H6).
HRMS (ESI): m/z [M + H] calcd for C23H45ClN3O3Si2: 502.2582;
found: 502.2582.
13C NMR (125.7 MHz, CDCl3): d = –5.43, –5.35, –4.69, and –4.66
(CH3Si), 17.95 and 18.36 [(CH3)3C], 25.78 and 25.95 [(CH3)3C],
36.87 [(CH3)2N-2], 40.69 [(CH3)2N-4], 41.35 (CH2-2¢), 63.96 (CH2-
5¢), 74.08 (CH-3¢), 74.52 (CH-1¢), 87.20 (CH-4¢), 106.69 (C-5),
156.79 (CH-6), 160.86 (C-2), 164.59 (C-4).
1b-[2-Chloro-4-(dimethylamino)pyrimidin-5-yl]-1,2-dideoxy-D-
ribofuranose (5ae)
Following the general procedure for deprotection using 6ae (254
mg, 0.51 mmol) gave 5ae (130 mg, 94%) as a white solid.
IR (KBr): 3418, 1586, 1544, 1501, 1417, 1398, 1177, 1079, 1046,
988, 941, 776 cm–1.
HRMS (ESI): m/z [M + H] calcd for C25H51N4O3Si2: 511.3494;
found: 511.3493.
1H NMR (500 MHz, CD3OD): d = 2.08 (ddd, Jgem = 13.0 Hz,
J2¢a,1¢ = 10.3 Hz, J2¢a,3¢ = 6.0 Hz, 1 H, H2¢a), 2.22 (ddd, Jgem = 13.0
1b-[2,4-Bis(dimethylamino)pyrimidin-5-yl]-1,2-dideoxy-D-
ribofuranose (5ee)
Following the general procedure for deprotection using 6ee (102
Hz, J2¢b,1¢ = 5.2 Hz, J2¢b,3¢ = 1.9 Hz, 1 H, H2¢b), 3.19 [s, 2 × 3 H,
(CH3)2N], 3.64 (dd, Jgem = 11.8 Hz, J5¢a,4¢ = 4.8 Hz, 1 H, H5¢a), 3.67
(dd, Jgem = 11.8 Hz, J5¢b,4¢ = 4.3 Hz, 1 H, H5¢b), 3.88 (td,
J4¢,5¢a = J4¢,5¢b = 4.6 Hz, J4¢,3¢ = 2.7 Hz, 1 H, H4¢), 4.33 (br dt,
J3¢,2¢a = 6.1 Hz, J3¢,4¢ = J3¢,2¢b = 2.3 Hz, 1 H, H3¢), 5.31 (dd,
J1¢,2¢a = 10.3 Hz, J1¢,2¢b = 5.2 Hz, 1 H, H1¢), 8.30 (d, J6,1¢ = 0.8 Hz, 1
H, H6).
mg, 0.21 mmol) gave 5ee (44 mg, 79%) as a white solid.
IR (KBr): 3408, 3250, 2801, 1594, 1558, 1499, 1454, 1416, 1406,
1390, 1070, 1059, 1035, 785 cm–1.
Synthesis 2012, 44, 953–965
© Thieme Stuttgart · New York

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Pyrimidine C-Nucleosides
959
1H NMR (500 MHz, CD3OD): d = 2.06 (ddd, Jgem = 13.0 Hz,
(C-5), 131.27 (p-CHPh-2), 138.10 and 138.45 (i-CPh-2,4), 157.99
(CH-6), 163.78 (C-2), 165.74 (C-4).
J
2¢a,1¢ = 5.3 Hz, J2¢a,3¢ = 1.8 Hz, 1 H, H2¢a), 2.13 (ddd, Jgem = 13.0 Hz,
2¢b,1¢ = 10.5 Hz, J2¢b,3¢ = 5.9 Hz, 1 H, H2¢b), 3.08 [s, 2 × 3 H,
J
HRMS (ESI): m/z [M + H] calcd for C21H21N2O3: 349.1547; found:
349.1546.
(CH3)2N-4], 3.10 [s, 2 × 3 H, (CH3)2N-2], 3.64 (m, 2 H, H5¢), 3.82
(td, J4¢,5¢a = J4¢,5¢b = 4.8 Hz, J4¢,3¢ = 2.5 Hz, 1 H, H4¢), 4.32 (dddd,
J3¢,2¢b = 5.9 Hz, J3¢,4¢ = 2.5 Hz, J3¢,2¢a = 1.8 Hz, J3¢,1¢ = 0.6 Hz, 1 H,
H3¢), 5.21 (ddt, J1¢,2¢b = 10.5 Hz, J1¢,2¢a = 5.3 Hz, J1¢,3¢ = J1¢,6 = 0.6 Hz,
1 H, H1¢), 8.07 (d, J6,1¢ = 0.6 Hz, 1 H, H6).
1b-[2-Amino-4-(dimethylamino)pyrimidin-5-yl]-1,2-dideoxy-D-
ribofuranose (5be)
Methanolic NH3 (33%, 10 mL) was added to the nucleoside 5ae (60
mg, 0.22 mmol) and the mixture was stirred in a sealed tube for 48
h at 120 °C. The mixture was then cooled, the solvents were re-
moved in vacuo, and the crude product was chromatographed (silica
gel, gradient CHCl3 to CHCl3–MeOH, 6:1). Lyophilization from
H2O gave 5be (40 mg, 71%) as a white gum.
13C NMR (125.7 MHz, CD3OD): d = 37.36 [(CH3)2N-2], 41.00
[(CH3)2N-4], 42.66 (CH2-2¢), 63.86 (CH2-5¢), 75.11 (CH-3¢), 75.92
(CH-1¢), 88.57 (CH-4¢), 108.27 (C-5), 157.12 (CH-6), 161.7 (C-2),
165.86 (C-4).
HRMS (ESI): m/z [M + H] calcd for C13H23N4O3: 283.1765; found:
283.1765.
IR (KBr): 3349, 1659, 1631, 1618, 1597, 1544, 1507, 1464, 1416,
1400, 1385, 1088, 1049 cm–1.
3,5-Di-O-(tert-butyldimethylsilyl)-1,2-dideoxy-1b-(2,4-diphe-
nylpyrimidin-5-yl)-D-ribofuranose (6ff); Typical Procedure
Toluene (5 mL) was added to a flame-dried and argon-purged flask
containing 6aa (190 mg, 0.38 mmol), Pd(PPh3)4 (44 mg, 0.04
mmol), K2CO3 (115 mg, 0.84 mmol), and PhB(OH)2 (280 mg, 2.3
mmol), and the mixture was stirred at 90 °C for 12 h. When the re-
action was complete (TLC; hexanes–EtOAc, 10:1), the mixture was
filtered through Celite, evaporated under reduced pressure, and
chromatographed (silica gel, gradient hexanes to 10% EtOAc–
hexane) to give 6ff (135 mg, 61%) as a colorless oil.
1H NMR (500 MHz, DMSO-d6): d = 1.91 (ddd, Jgem = 12.8 Hz,
J
2¢a,1¢ = 5.2 Hz, J2¢a,3¢ = 1.8 Hz, 1 H, H2¢a), 1.99 (ddd, Jgem = 12.8 Hz,
2¢b,1¢ = 10.5 Hz, J2¢b,3¢ = 5.8 Hz, 1 H, H2¢b), 2.94 [s, 6 H, (CH3)2N],
J
3.42 (m, 2 H, H5¢), 3.64 (td, J4¢,5¢a = J4¢,5¢b = 5.1 Hz, J4¢,3¢ = 2.5 Hz, 1
H, H4¢), 4.15 (m, 1 H, H3¢), 4.72 (br t, JOH,5¢a = JOH,5¢b = 5.6 Hz, 1 H,
OH-5¢), 5.01 (m, 1 H, OH-3¢), 5.02 (dd, J1¢,2¢b = 10.6 Hz, J1¢,2¢a = 5.2
Hz, 1 H, H1¢), 6.09 (s, 2 H, NH2), 7.97 (s, 1 H, H6).
13C NMR (125.7 MHz, DMSO-d6): d = 40.74 [(CH3)2N], 41.49
(CH2-2¢), 62.47 (CH2-5¢), 72.29 (CH-3¢), 73.98 (CH-1¢), 87.33 (CH-
4¢), 108.65 (C-5), 157.00 (CH-6), 161.58 (C-2), 164.88 (C-4).
IR (CCl4): 3087, 3063, 3035, 2956, 2898, 1603, 1587, 1566, 1494,
1471, 1463, 1445, 1389, 1362, 1257, 1180, 1163, 1201, 1029, 939,
838 cm–1.
HRMS (ESI): m/z [M + H] calcd for C11H19N4O3: 255.1452; found:
255.1452.
1H NMR (500 MHz, CDCl3): d = 0.04, 0.06, 0.11, and 0.12 (4 × s,
4 × 3 H, CH3Si), 0.86 and 0.93 [2 × s, 2 × 9 H, (CH3)3C], 1.95 (ddd,
Jgem = 12.7 Hz, J2¢a,1¢ = 10.3 Hz, J2¢a,3¢ = 5.3 Hz, 1 H, H2¢a), 2.05
(ddd, Jgem = 12.7 Hz, J2¢b,1¢ = 5.3 Hz, J2¢b,3¢ = 1.9 Hz, 1 H, H2¢b), 3.65
(dd, Jgem = 10.8 Hz, J5¢a,4¢ = 5.7 Hz, 1 H, H5¢a), 3.79 (dd, Jgem = 10.8
Hz, J5¢b,4¢ = 3.8 Hz, 1 H, H5¢b), 3.92 (ddd, J4¢,5¢a = 5.7 Hz, J4¢,5¢b = 3.7
Hz, J4¢,3¢ = 2.0 Hz, 1 H, H4¢), 4.43 (br dt, J3¢,2¢a = 5.2 Hz,
J3¢,2¢b = J3¢,4¢ = 1.9 Hz, 1 H, H3¢), 5.39 (br dd, J1¢,2¢a = 10.3 Hz,
J1¢,2¢b = 5.3 Hz, 1 H, H1¢), 7.42–7.54 (m, 6 H, m,p-HPh-2,4), 7.63 (m,
2 H, o-HPh-4), 8.52 (m, 2 H, o-HPh-2), 9.09 (d, J6,1¢ = 0.5 Hz, 1 H, H6).
13C NMR (125.7 MHz, CDCl3): d = –5.47, –5.35, –4.77, and –4.76
(CH3Si), 17.88 and 18.34 [(CH3)3C], 25.69 and 25.93 [(CH3)3C],
43.91 (CH2-2¢), 63.62 (CH2-5¢), 74.21 (CH-3¢), 74.87 (CH-1¢),
87.96 (CH-4¢), 128.26 (o-CHPh-2), 128.34 and 128.46 (m-CHPh-2,4),
129.04 (o-CHPh-4), 129.39 (p-CHPh-4), 130.15 (C-5), 130.53 (p-
CHPh-2), 137.53 and 137.76 (i-CPh-2,4), 156.97 (CH-6), 163.00 (C-2),
164.31 (C-4).
1,2-Dideoxy-1b-[4-(dimethylamino)-2-methoxypyrimidin-5-yl]-
D-ribofuranose (5ce)
NaOMe (55 mg, 1.00 mmol) was added to a soln of the nucleoside
5ae (50 mg, 0.18 mmol) in MeOH (10 mL) and then the mixture
was stirred in a sealed tube for 12 h at 120 °C. The mixture was then
cooled, the solvents were removed in vacuo, and the crude product
was chromatographed (silica gel, gradient CHCl3 to CHCl3–MeOH,
12:1). Lyophilization from H2O gave 5ce (32 mg, 64%) as a white
solid.
IR (KBr): 3399, 2820, 1610, 1549, 1518, 1476, 1442, 1416, 1399,
1250, 1090, 1077, 1065, 1055, 1032 cm–1.
1H NMR (500 MHz, CD3OD): d = 2.13 (m, 2 H, H2¢), 3.19 [s, 2 × 3
H, (CH3)2N], 3.63 (dd, Jgem = 11.7 Hz, J5¢a,4¢ = 4.9 Hz, 1 H, H5¢a),
3.66 (dd, Jgem = 11.7 Hz, J5¢b,4¢ = 4.5 Hz, 1 H, H5¢b), 3.85 (td,
J4¢,5¢a = J4¢,5¢b = 4.7 Hz, J4¢,3¢ = 2.7 Hz, 1 H, H4¢), 3.91 (s, 3 H, CH3O-
2), 4.33 (m, 1 H, H3¢), 5.28 (m, 1 H, H1¢), 8.21 (br d, J6,1¢ = 0.6 Hz,
1 H, H6).
13C NMR (125.7 MHz, CD3OD): d = 40.95 [(CH3)2N], 42.93 (CH2-
2¢), 54.72 (CH3O-2), 63.73 (CH2-5¢), 73.98 (CH-3¢), 75.58 (CH-1¢),
88.75 (CH-4¢), 112.87 (C-5), 158.19 (CH-6), 164.85 (C-2), 166.20
(C-4).
HRMS (ESI): m/z [M + H] calcd for C33H49N2O3Si2: 577.3277;
found: 577.3276.
1b-(2,4-Diphenylpyrimidin-5-yl)-1,2-dideoxy-D-ribofuranose
(5ff)
Following the general procedure for deprotection using 6ff (110
mg, 0.19 mmol) gave 5ff (48 mg, 72%) as a white solid.
HRMS (ESI): m/z [M + H] calcd for C12H19N3O4: 270.1448; found:
270.1449.
IR (KBr): 3412, 3086, 3059, 3033, 1603, 1587, 1566, 1536, 1493,
1435, 1424, 1172, 1080, 1047, 1024, 753 cm–1.
3,5-Di-O-(tert-butyldimethylsilyl)-1,2-dideoxy-1b-(4-methoxy-
2-methylpyrimidin-5-yl)-D-ribofuranose (6dc); Typical Proce-
dure
1H NMR (500 MHz, CD3OD): d = 2.11 (m, 2 H, H2¢), 3.73 (m, 2 H,
H5¢), 3.90 (br td, J4¢,5¢a = J4¢,5¢b = 4.5 Hz, J4¢,3¢ = 2.7 Hz, 1 H, H4¢),
4.35 (m, 1 H, H3¢), 5.33 (br ddm, J1¢,2¢a = 9.4 Hz, J1¢,2¢b = 6.6 Hz, 1
H, H1¢), 7.46–7.50 and 7.53–7.57 (2 × m, 2 × 3 H, m,p-HPh-2,4), 7.66
(m, 2 H, o-HPh-4), 8.43 (m, 2 H, o-HPh-2), 9.16 (br d, J6,1¢ = 0.5 Hz, 1
H, H6).
13C NMR (125.7 MHz, CD3OD): d = 43.91 (CH2-2¢), 63.19 (CH2-
5¢), 73.81 (CH-3¢), 75.70 (CH-1¢), 88.69 (CH-4¢), 128.73 (o-CHPh-2),
129.02 (m-CHPh-2,4), 129.61 (o-CHPh-4), 130.10 (p-CHPh-4), 131.06
A 2 M soln of Me3Al in toluene (0.45 mL, 0.8 mmol) was added in
one portion to a vigorously stirred soln of 6ac (200 mg, 0.40 mmol)
and Pd(PPh3)4 (25 mg, 0.020 mmol) in THF (8 mL) under an atmo-
sphere of argon. The mixture was stirred at 70 °C for 12 h, then
worked up by pouring into sat. NaH2PO4 and extracted with EtOAc.
The crude product was chromatographed (silica gel, gradient hex-
ane to hexane–EtOAc, 10:1) to give 6dc (180 mg, 94%) as a color-
less oil.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 953–965

960
T. Kubelka et al.
PAPER
IR (CCl4): 2955, 2897, 1593, 1567, 1466, 1443, 1428, 1410, 1387,
1371, 1362, 1257, 1095, 1031, 942, 838, 673 cm–1.
(CH-3¢), 74.36 (CH-1¢), 87.66 (CH-4¢), 115.66 (C-5), 155.02 (CH-
6), 163.49 (C-4), 165.09 (C-2).
1H NMR (500 MHz, CDCl3): d = 0.058, 0.064, 0.08, and 0.09 (4 × s,
4 × 3 H, CH3Si), 0.88 and 0.91 [2 × s, 2 × 9 H, (CH3)3C], 1.79 (ddd,
Jgem = 12.7 Hz, J2¢a,1¢ = 10.1 Hz, J2¢a,3¢ = 5.5 Hz, 1 H, H2¢a), 2.22
(ddd, Jgem = 12.7 Hz, J2¢b,1¢ = 5.7 Hz, J2¢b,3¢ = 2.0 Hz, 1 H, H2¢b), 2.59
(s, 3 H, CH3-2), 3.58 (dd, Jgem = 10.8 Hz, J5¢a,4¢ = 5.9 Hz, 1 H, H5¢a),
3.73 (dd, Jgem = 10.8 Hz, J5¢b,4¢ = 4.1 Hz, 1 H, H5¢b), 3.93 (ddd,
J4¢,5¢a = 5.9 Hz, J4¢,5¢b = 4.1 Hz, J4¢,3¢ = 2.3 Hz, 1 H, H4¢), 3.96 (s, 3 H,
CH3O-4), 4.39 (br dt, J3¢,2¢a = 5.5 Hz, J3¢,4¢ = J3¢,2¢a = 2.1 Hz, 1 H,
H3¢), 5.22 (dd, J1¢,2¢a = 10.1 Hz, J1¢,2¢b = 5.7 Hz, 1 H, H1¢), 8.43 (d,
HRMS (ESI): m/z [M + H] calcd for C24H48N3O3Si2: 482.3229;
found: 482.3227.
1,2-Dideoxy-1b-[4-(dimethylamino)-2-methylpyrimidin-5-yl)]-
D-ribofuranose (5de)
Following the general procedure for deprotection using 6de (200
mg, 0.42 mmol) gave 5de (86 mg, 82%) as a white solid.
IR (KBr): 3361, 1588, 1544, 1506, 1418, 1399, 1087, 1049, 1029,
982 cm–1.
J6,1¢ = 1.0 Hz, 1 H, H6).
1H NMR (500 MHz, CD3OD): d = 2.08 (ddd, Jgem = 13.1 Hz,
13C NMR (125.7 MHz, CDCl3): d = –5.46, –5.38, –4.70, and –4.67
(CH3Si), 18.02 and 18.32 [(CH3)3C], 25.60 (CH3-2), 25.80 and
25.90 [(CH3)3C], 41.61 (CH2-2¢), 53.48 (CH3O-4), 63.60 (CH2-5¢),
73.40 (CH-1¢), 73.99 (CH-3¢), 87.66 (CH-4¢), 119.21 (C-5), 153.45
(CH-6), 166.06 (C-4), 166.46 (C-2).
J2¢a,1¢ = 10.4 Hz, J2¢a,3¢ = 6.1 Hz, 1 H, H2¢a), 2.20 (ddd, Jgem = 13.1
Hz, J2¢b,1¢ = 5.2 Hz, J2¢b,3¢ = 1.9 Hz, 1 H, H2¢b), 2.44 (s, 3 H, CH3-2),
3.14 [s, 6 H, (CH3)2N], 3.64 (dd, Jgem = 11.7 Hz, J5¢a,4¢ = 4.9 Hz, 1 H,
H5¢a), 3.67 (dd, Jgem = 11.7 Hz, J5¢b,4¢ = 4.5 Hz, 1 H, H5¢b), 3.87 (td,
J4¢,5¢a = J4¢,5¢b = 4.7 Hz, J4¢,3¢ = 2.7 Hz, 1 H, H4¢), 4.33 (br dt,
J3¢,2¢a = 6.1 Hz, J3¢,4¢ = J3¢,2¢b = 2.3 Hz, 1 H, H3¢), 5.30 (br dd,
J1¢,2¢a = 10.4 Hz, J1¢,2¢b = 5.2 Hz, 1 H, H1¢), 8.33 (s, 1 H, H6).
HRMS (ESI): m/z [M + H] calcd for C23H44N2O4Si2: 469.2912;
found: 469.2912.
13C NMR (125.7 MHz, CD3OD): d = 24.99 (CH3-2), 40.95
[(CH3)2N], 43.18 (CH2-2¢), 63.70 (CH2-5¢), 73.99 (CH-3¢), 75.71
(CH-1¢), 88.85 (CH-4¢), 117.26 (C-5), 155.37 (CH-6), 164.65 (CH-
4), 165.82 (C-2).
1,2-Dideoxy-1b-(4-methoxy-2-methylpyrimidin-5-yl)ribofura-
nose (5dc)
Following the general procedure for deprotection using 6dc (135
mg, 0.29 mmol) gave 5dc (50 mg, 72%) as a white gum.
HRMS (ESI): m/z [M + H] calcd for C12H20N3O3: 254.1499; found:
254.1498.
IR (KBr): 3404, 3258, 3145, 2969, 2835, 1594, 1571, 1474, 1460,
1447, 1432, 1393, 1092, 1058, 1030, 787 cm–1.
1H NMR (500 MHz, CD3OD): d = 1.83 (ddd, Jgem = 13.1 Hz,
1b-[4-Amino-2-(dimethylamino)pyrimidin-5-yl]-3,5-di-O-(tert-
butyldimethylsilyl)-1,2-dideoxy-d-ribofuranose (6eb)
Following the typical procedure for 6ee using Pd(OAc)2 (3 mg, 5
mol%) and JohnPhos (8 mg, 10 mol%) in DME (1.5 mL) and 6ab
(122 mg, 0.26 mmol), t-BuONa (63 mg, 0.65 mmol), and
Me2NH·HCl (53 mg, 0.65 mmol) at 70 °C for 48 h. Chromatogra-
phy (silica gel, gradient hexane to 50% EtOAc–hexane) gave 6eb
(92 mg, 74%) as a yellow oil.
J
2¢a,1¢ = 10.2 Hz, J2¢a,3¢ = 6.0 Hz, 1 H, H2¢a), 2.33 (ddd, Jgem = 13.1
Hz, J2¢b,1¢ = 5.7 Hz, J2¢b,3¢ = 2.0 Hz, 1 H, H2¢b), 2.56 (s, 3 H, CH3-2),
3.66 (m, 2 H, H5¢), 3.93 (td, J4¢,5¢a = J4¢,5¢b = 4.9 Hz, J4¢,3¢ = 2.7 Hz, 1
H, H4¢), 4.01 (s, 3 H, CH3O-4), 4.30 (br dtd, J3¢,2¢a = 5.9 Hz,
J
3¢,4¢ = J3¢,2¢a = 2.3 Hz, J3¢,1¢ = 0.5 Hz, 1 H, H3¢), 5.22 (br ddd,
J1¢,2¢a = 10.2 Hz, J1¢,2¢b = 5.7 Hz, J1¢,3¢ = 0.5 Hz, 1 H, H1¢), 8.48 (d,
6,1¢ = 1.0 Hz, 1 H, H6).
J
13C NMR (125.7 MHz, CD3OD): d = 25.09 (CH3-2), 42.67 (CH2-
2¢), 54.35 (CH3O-4), 63.81 (CH2-5¢), 74.11 (CH-3¢), 74.61 (CH-1¢),
88.92 (CH-4¢), 121.11 (C-5), 153.82 (CH-6), 167.70 (C-4), 167.76
(C-2).
IR (CCl4): 3455, 3337, 2956, 2890, 1610, 1546, 1528, 1466, 1415,
1403, 1389, 1257, 1007, 939, 838, 790 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 0.06, 0.070, and 0.072 (3 × s,
4 × 3 H, CH3Si), 0.878 and 0.881 [2 × s, 2 × 9 H, (CH3)3C], 1.81
(ddd, Jgem = 12.8 Hz, J2¢a,1¢ = 5.5 Hz, J2¢a,3¢ = 1.7 Hz, 1 H, H2¢a), 2.09
(ddd, Jgem = 12.8 Hz, J2¢b,1¢ = 10.7 Hz, J2¢b,3¢ = 6.2 Hz, 1 H, H2¢b),
3.01 [s, 2 × 3 H, (CH3)2N], 3.66–3.73 (m, 2 H, H5¢), 3.75 (m, 1 H,
H4¢), 4.34 (ddd, J3¢,2¢b = 6.2 Hz, J3¢,4¢ = 2.6 Hz, J3¢,2¢a = 1.7 Hz, 1 H,
H3¢), 4.84 (dd, J1¢,2¢b = 10.6 Hz, J1¢,2¢b = 5.5 Hz, 1 H, H1¢), 6.21 (br s,
2 H, NH2-4), 7.73 (s, 1 H, H6).
13C NMR (125.7 MHz, DMSO-d6): d = –5.14, –5.04, –4.37, and –
4.23 (CH3Si), 18.25 and 18.55 [(CH3)3C], 26.19 and 26.30
[(CH3)3C], 36.94 [(CH3)2N], 40.3 (CH2-2¢), 63.40 (CH2-5¢), 73.92
(CH-3¢), 77.08 (CH-1¢), 87.55 (CH-4¢), 104.25 (C-5), 154.8 (CH-6),
161.82 (C-2, C-4).
HRMS (ESI): m/z [M + H] calcd for C11H17N2O4: 241.1183; found:
241.1182.
3,5-Di-O-(tert-butyldimethylsilyl)-1,2-dideoxy-1b-[4-(dimethyl-
amino)-2-methylpyrimidin-5-yl)-D-ribofuranose (6de)
Following the typical procedure for 6dc using 2.0 M Me3Al in tol-
uene (0.5 mL, 1.02 mmol) and 6ae (258 mg, 0.51 mmol) and
Pd(PPh3)4 (30 mg, 0.026 mmol) in THF (10 mL). Chromatography
(silica gel, gradient hexane to hexane–EtOAc, 6:1) gave 6de (220
mg, 89%) as a colorless oil.
IR (CCl4): 1956, 1899, 1583, 1547, 1471, 1463, 1400, 1362, 1258,
1092, 939, 838, 681 cm–1.
HRMS (ESI): m/z [M + H] calcd for C23H46N4O3Si2: 483.3181;
found: 483.3179.
1H NMR (500 MHz, CDCl3): d = 0.056, 0.058, 0.08, and 0.09 (4 × s,
4 × 3 H, CH3Si), 0.89 and 0.90 [2 × s, 2 × 9 H, (CH3)3C], 1.98 (ddd,
Jgem = 12.7 Hz, J2¢a,1¢ = 10.6 Hz, J2¢a,3¢ = 5.2 Hz, 1 H, H2¢a), 2.06
(ddd, Jgem = 12.7 Hz, J2¢b,1¢ = 5.0 Hz, J2¢b,3¢ = 1.7 Hz, 1 H, H2¢b), 2.51
(s, 3 H, CH3), 3.09 [s, 2 × 3 H, (CH3)2N], 3.56 (dd, Jgem = 10.7 Hz,
1b-[4-Amino-2-(dimethylamino)pyrimidin-5-yl]-1,2-dideoxy-D-
ribofuranose (5eb)
Following the general procedure for deprotection using 6eb (110
mg, 0.43 mmol) gave 5eb (53 mg, 92%) as a white solid.
J5¢a,4¢ = 5.9 Hz, 1 H, H5¢a), 3.72 (dd, Jgem = 10.7 Hz, J5¢b,4¢ = 3.9 Hz,
1 H, H5¢b), 3.87 (ddd, J4¢,5¢a = 5.9 Hz, J4¢,5¢b = 3.9 Hz, J4¢,3¢ = 1.9 Hz,
1 H, H4¢), 4.42 (dt, J3¢,2¢a = 5.2 Hz, J3¢,4¢ = J3¢,2¢b = 1.8 Hz, 1 H, H3¢),
5.25 (br dd, J1¢,2¢a = 10.6 Hz, J1¢,2¢b = 5.0 Hz, 1 H, H1¢), 8.32 (br s, 1
H, H6).
13C NMR (125.7 MHz, CDCl3): d = –5.50, –5.34, –4.71, and –4.69
(CH3Si), 17.94 and 18.33 [(CH3)3C], 25.56 (CH3), 25.75 and 25.92
[(CH3)3C], 40.69 [(CH3)2N], 42.24 (CH2-2¢), 63.66 (CH2-5¢), 74.01
IR (KBr): 3450, 3339, 3214, 1630, 1609, 1542, 1528, 1465, 1415,
1403, 1087, 1051, 792 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 1.72 (ddd, Jgem = 12.7 Hz,
J
J
2¢a,1¢ = 5.4 Hz, J2¢a,3¢ = 1.3 Hz, 1 H, H2¢a), 2.10 (ddd, Jgem = 12.7 Hz,
2¢b,1¢ = 11.0 Hz, J2¢b,3¢ = 6.1 Hz, 1 H, H2¢b), 3.00 [s, 2 × 3 H,
(CH3)2N], 3.50 (ddd, Jgem = 11.5 Hz, J5¢a,OH = 5.2 Hz, J5¢a,4¢ = 3.3 Hz,
1 H, H5¢a), 3.56 (ddd, Jgem = 11.5 Hz, J5¢b,OH = 4.6 Hz, J5¢b,4¢ = 2.7
Synthesis 2012, 44, 953–965
© Thieme Stuttgart · New York

PAPER
Pyrimidine C-Nucleosides
961
Hz, 1 H, H5¢b), 3.72 (br q, J4¢,3¢ = J4¢,5¢a = J4¢,5¢b = 2.7 Hz, 1 H, H4¢),
4.22 (m, 1 H, H3¢), 4.82 (dd, J1¢,2¢b = 11.0 Hz, J1¢,2¢a = 5.3 Hz, 1 H,
3,5-Di-O-(tert-butyldimethylsilyl)-1,2-dideoxy-1b-[2-(dimethyl-
amino)-4-methylpyrimidin-5-yl)-D-ribofuranose (6ed)
Following the typical procedure for 6ee using Pd(OAc)2 (8 mg, 0.04
mmol) and JohnPhos (21 mg, 0.07 mmol) in DME (3 mL) and 6ad
(330 mg, 0.70 mmol), t-BuONa (170 mg, 1.75 mmol), and
Me2NH·HCl (143 mg, 1.75 mmol) at 70 °C for 48 h. Chromatogra-
phy (silica gel, gradient hexane to 4% EtOAc–hexane) gave 6ed
(234 mg, 69%) as a colorless oil.
H1¢), 5.00 (d,
JOH,3¢ = 3.9 Hz, 1 H, OH-3¢), 5.07 (br t,
JOH,5¢a = JOH,5¢b = 4.8 Hz, 1 H, OH-5¢), 6.40 (br s, 2 H, NH2-4), 7.69
(s, 1 H, H6).
13C NMR (125.7 MHz, DMSO-d6): d = 36.95 [(CH3)2N], 39.7 (CH2-
2¢), 61.94 (CH2-5¢), 72.77 (CH-3¢), 77.88 (CH-1¢), 87.95 (CH-4¢),
104.45 (C-5), 154.79 (CH-6), 161.82 (C-4), 162.12 (C-2).
IR (CCl4): 2955, 2897, 2794, 1594, 1546, 1531, 1472, 1463, 1409,
1390, 1375, 1361, 1257, 1092, 1006, 939, 838 cm–1.
HRMS (ESI): m/z [M – H] calcd for C11H17N4O3: 253.1306; found:
253.1308.
1H NMR (500 MHz, CDCl3): d = 0.055, 0.060, 0.087, and 0.089
(4 × s, 4 × 3 H, CH3Si), 0.89 and 0.91 [2 × s, 2 × 9 H, (CH3)3C],
1.83 (ddd, Jgem = 12.7 Hz, J2¢a,1¢ = 10.5 Hz, J2¢a,3¢ = 5.5 Hz, 1 H,
H2¢a), 2.04 (ddd, Jgem = 12.7 Hz, J2¢b,1¢ = 5.2 Hz, J2¢b,3¢ = 1.7 Hz, 1 H,
H2¢b), 2.36 (s, 3 H, CH3), 3.16 [s, 2 × 3 H, (CH3)2N], 3.54 (dd,
Jgem = 10.6 Hz, J5¢a,4¢ = 6.4 Hz, 1 H, H5¢a), 3.73 (dd, Jgem = 10.6 Hz,
3,5-Di-O-(tert-butyldimethylsilyl)-1,2-dideoxy-1b-[2-(dimethyl-
amino)-4-methoxypyrimidin-5-yl]-D-ribofuranose (6ec)
Following the typical procedure for 6ee using Pd(OAc)2 (8 mg, 0.03
mmol) and JohnPhos (18 mg, 0.06 mmol) in DME (4 mL) and 6ac
(280 mg, 0.60 mmol), t-BuONa (144 mg, 1.5 mmol), and
Me2NH·HCl (123 mg, 1.5 mmol) at 90 °C for 48 h. Chromatogra-
phy (silica gel, gradient hexane to 6% EtOAc–hexane) gave 6ec
(260 mg, 91%) as a colorless oil.
J
5¢b,4¢ = 4.1 Hz, 1 H, H5¢b), 3.90 (ddd, J4¢,5¢a = 6.3 Hz, J4¢,5¢b = 4.1 Hz,
4¢,3¢ = 2.1 Hz, 1 H, H4¢), 4.41 (dt, J3¢,2¢a = 5.4 Hz, J3¢,4¢ = J3¢,2¢b = 1.9
J
Hz, 1 H, H3¢), 5.16 (dd, J1¢,2¢a = 10.5 Hz, J1¢,2¢b = 5.2 Hz, 1 H, H1¢),
8.28 (s, 1 H, H6).
IR (CCl4): 2954, 2930, 2897, 2886, 2858, 2795, 1610, 1557, 1536,
1471, 1463, 1409, 1362, 1292, 1256, 1239, 1185, 1103, 1093, 1031,
1005, 940, 838 cm–1.
13C NMR (125.7 MHz, CDCl3): d = –5.47, –5.39, and –4.67
(CH3Si), 17.99 and 18.34 [(CH3)3C], 21.99 (CH3), 25.79 and 25.92
[(CH3)3C], 36.97 [(CH3)2N], 41.94 (CH2-2¢), 63.74 (CH2-5¢), 74.11
(CH-3¢), 75.24 (CH-1¢), 87.51 (CH-4¢), 119.61 (C-5), 155.05 (CH-
6), 161.50 (C-2), 164.75 (C-4).
1H NMR (500 MHz, CDCl3): d = 0.050, 0.053, and 0.08 (4 × s, 4 × 3
H, CH3Si), 0.89 and 0.90 [2 × s, 2 × 9 H, (CH3)3C], 1.92 (ddd,
Jgem = 12.7 Hz, J2¢a,1¢ = 10.3 Hz, J2¢a,3¢ = 5.4 Hz, 1 H, H2¢a), 2.04
(ddd, Jgem = 12.7 Hz, J2¢b,1¢ = 5.5 Hz, J2¢b,3¢ = 1.9 Hz, 1 H, H2¢b), 3.15
(s, 6 H, [(CH3)2N-2], 3.49 (dd, Jgem = 10.6 Hz, J5¢a,4¢ = 7.1 Hz, 1 H,
H5¢a), 3.70 (dd, Jgem = 10.6 Hz, J5¢b,4¢ = 4.4 Hz, 1 H, H5¢b), 3.89
(ddd, J4¢,5¢a = 7.0 Hz, J4¢,5¢b = 4.4 Hz, J4¢,3¢ = 2.0 Hz, 1 H, H4¢), 3.90
(s, 3 H, CH3O-4), 4.38 (br dtd, J3¢,2¢a = 5.4 Hz, J3¢,4¢ = J3¢,2¢b = 2.0 Hz,
HRMS (ESI): m/z [M + H] calcd for C24H48N3O3Si2: 482.3229;
found: 482.3227.
1,2-Dideoxy-1b-[2-(dimethylamino)-4-methylpyrimidin-5-yl)-
D-ribofuranose (5ed)
J
3¢,1¢ = 0.5 Hz, 1 H, H3¢), 5.15 (br dd, J1¢,2¢a = 10.2 Hz, J1¢,2¢b = 5.5 Hz,
Following the general procedure for deprotection using 6ed (230
mg, 0.48 mmol) gave 6ed (103 mg, 85%) as a white solid.
1 H, H1¢), 8.12 (d, J6,1¢ = 0.8 Hz, 1 H, H6).
13C NMR (125.7 MHz, CDCl3): d = –5.42, –5.39, –4.68, and –4.67
(CH3Si), 18.04 and 18.36 [(CH3)3C], 25.83 and 25.94 [(CH3)3C],
36.98 [(CH3)2N-2], 40.69 (CH2-2¢), 52.85 (CH3O-4), 63.90 (CH2-
5¢), 73.77 (CH-1¢), 74.23 (CH-3¢), 87.32 (CH-4¢), 108.44 (C-5),
155.29 (CH-6), 161.67 (C-2), 166.91 (C-4).
IR (KBr): 3227, 1596, 1533, 1407, 1354, 1187, 1097, 1053, 1023,
894, 791 cm–1.
1H NMR (500 MHz, CD3OD): d = 1.94 (ddd, Jgem = 13.1 Hz,
J2¢a,1¢ = 10.6 Hz, J2¢a,3¢ = 6.1 Hz, 1 H, H2¢a), 2.17 (ddd, Jgem = 13.1
Hz, J2¢b,1¢ = 5.3 Hz, J2¢b,3¢ = 1.7 Hz, 1 H, H2¢b), 2.38 (s, 3 H, CH3),
3.14 [s, 2 × 3 H, (CH3)2N], 3.66 (m, 2 H, H5¢), 3.89 (td,
J4¢,5¢a = J4¢,5¢b = 4.9 Hz, J4¢,3¢ = 2.7 Hz, 1 H, H4¢), 4.33 (br dt,
J3¢,2¢a = 6.2 Hz, J3¢,4¢ = J3¢,2¢b = 2.2 Hz, 1 H, H3¢), 5.20 (br dd,
J1¢,2¢a = 10.6 Hz, J1¢,2¢b = 5.3 Hz, 1 H, H1¢), 8.30 (br d, J6,1¢ = 0.6 Hz,
1 H, H6).
HRMS (ESI): m/z [M + H] calcd for C24H48N3O4Si2: 498.3178;
found: 498.3176.
1,2-Dideoxy-1b-[2-(dimethylamino)-4-methoxypyrimidin-5-yl)-
D-ribofuranose (5ec)
Following the general procedure for deprotection using 6ec (260
mg, 0.52 mmol) gave 5ec (119 mg, 85%) as a white solid.
13C NMR (125.7 MHz, CD3OD): d = 22.01 (CH3), 37.42 [(CH3)2N],
42.75 (CH2-2¢), 63.83 (CH2-5¢), 74.28 (CH-3¢), 76.45 (CH-1¢),
88.83 (CH-4¢), 121.04 (C-5), 156.00 (CH-6), 162.56 (C-2), 166.80
(C-4).
IR (KBr): 3345, 1609, 1553, 1467, 1403, 1357, 1238, 1183, 1087,
1047, 1025, 997, 790 cm–1.
1H NMR (500 MHz, CD3OD): d = 1.96 (ddd, Jgem = 13.1 Hz,
HRMS (ESI): m/z [M + H] calcd for C12H20N3O3: 254.1499; found:
254.1499.
J
2¢a,1¢ = 10.3 Hz, J2¢a,3¢ = 6.0 Hz, 1 H, H2¢a), 2.15 (ddd, Jgem = 13.1
Hz, J2¢b,1¢ = 5.6 Hz, J2¢b,3¢ = 1.9 Hz, 1 H, H2¢b), 3.15 [s, 6 H,
(CH3)2N-2], 3.63 (m, 2 H, H5¢), 3.87 (td, J4¢,5¢a = J4¢,5¢b = 5.1 Hz,
1b-(4-Amino-2-phenylpyrimidin-5-yl)-3,5-di-O-(tert-butyldi-
methylsilyl)-1,2-dideoxy-D-ribofuranose (6fb)
J4¢,3¢ = 2.6 Hz, 1 H, H4¢), 3.94 (s, 3 H, CH3O-4), 3.87 (dtd,
J3¢,2¢b = 6.0 Hz, J3¢,2¢a = J3¢,4¢ = 2.3 Hz, J3¢,1¢ = 0.5 Hz, 1 H, H3¢), 5.14
(ddt, J1¢,2¢a = 10.3 Hz, J1¢,2¢b = 5.6 Hz, J1¢,6¢ = J1¢,3¢ = 0.5 Hz, 1 H, H1¢),
8.11 (d, J6,1¢ = 0.8 Hz, 1 H, H6).
13C NMR (125.7 MHz, CD3OD): d = 37.40 [(CH3)2N-2], 42.28
(CH2-2¢), 53.58 (CH3O-4), 63.98 (CH2-5¢), 74.33 (CH-3¢), 75.20
(CH-1¢), 88.60 (CH-4¢), 109.88 (C-5), 155.99 (CH-6), 162.89 (C-2),
168.31 (C-4).
Following the typical procedure for 6ff using toluene (4 mL), 6ab
(160 mg, 0.34 mmol), Pd(PPh3)4 (78 mg, 0.07 mmol), K2CO3 (70
mg, 0.50 mmol), and PhB(OH)2 (83 mg, 0.68 mmol) at 90 °C for 12
h (monitored by TLC; hexanes–EtOAc, 2:1).Chromatography (sili-
ca gel, gradient hexanes to 8% EtOAc–hexane) gave 6fb (98 mg,
56%) as a colorless oil.
IR (CCl4): 3490, 3358, 3067, 2956, 2899, 1615, 1593, 1582, 1552,
1463, 1416, 1494, 1471, 1463, 1443, 1389, 1363, 1258, 1099, 1072,
1029, 939, 837, 710, 693 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 0.087, 0.089, and 0.093 (4 × s,
4 × 3 H, CH3Si), 0.89 and 0.90 [2 × s, 2 × 9 H, (CH3)3C], 2.05 (br
ddd, Jgem = 12.7 Hz, J2¢a,1¢ = 6.1 Hz, J2¢a,3¢ = 2.3 Hz, 1 H, H2¢a), 2.11
HRMS (ESI): m/z [M + H] calcd for C12H20N3O4: 270.1448; found:
270.1448.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 953–965

962
T. Kubelka et al.
PAPER
(br ddd, Jgem = 12.7 Hz, J2¢b,1¢ = 9.9 Hz, J2¢b,3¢ = 6.0 Hz, 1 H, H2¢b),
3.75 (m, 2 H, H5¢), 3.83 (br q, J4¢,5¢a = J4¢,5¢b = J4¢,3¢ = 3.2 Hz, 1 H,
H4¢), 4.39 (m, 1 H, H3¢), 5.04 (br dd, J1¢,2¢b = 9.9 Hz, J1¢,2¢a = 6.1 Hz,
1 H, H1¢), 6.77 (br s, 2 H, NH2-4), 7.43–7.47 (m, 3 H, m,p-HPh), 8.24
(br d, J6,1¢ = 0.4 Hz, 1 H, H6), 8.29 (m, 2 H, o-HPh).
HRMS (ESI): m/z [M + H] calcd for C28H47N2O4Si2: 531.3069;
found: 531.3067.
1,2-Dideoxy-1b-(4-methoxy-2-phenylpyrimidin-5-yl)-D-ribo-
furanose (5fc)
Following the general procedure for deprotection using 6fc (148
mg, 0.28 mmol) gave 5fc (60 mg, 67%) as a white solid.
13C NMR (125.7 MHz, DMSO-d6): d = –5.35, –5.27, –4.63, and
–4.47 (CH3Si), 18.04 and 18.31 [(CH3)3C], 25.97 and 26.05
[(CH3)3C], 39.8 (CH2-2¢), 63.03 (CH2-5¢), 73.53 (CH-3¢), 75.91
(CH-1¢), 87.54 (CH-4¢), 114.10 (C-5), 127.63 (o-CHPh), 128.43 (m-
CHPh), 130.19 (p-CHPh), 138.10 (i-CPh), 153.45 (CH-6), 161.24 and
162.25 (C-2, C-4).
IR (KBr): 3364, 188, 1556, 1470, 1449, 1415, 1383, 1361, 1096,
1051, 1013, 947, 768 cm–1.
1H NMR (500 MHz, CD3OD): d = 1.91 (ddd, Jgem = 13.1 Hz,
J2¢a,1¢ = 10.2 Hz, J2¢a,3¢ = 6.0 Hz, 1 H, H2¢a), 2.38 (ddd, Jgem = 13.1
HRMS (ESI): m/z [M + H] calcd for C27H46N3O3Si2: 516.3072;
found: 516.3071.
Hz, J2¢b,1¢ = 5.8 Hz, J2¢b,3¢ = 2.0 Hz, 1 H, H2¢b), 3.69 (m, 2 H, H5¢),
3.97 (td, J4¢,5¢a = J4¢,5¢b = 5.0 Hz, J4¢,3¢ = 2.7 Hz, 1 H, H4¢), 4.14 (s, 3
H, CH3O-4), 4.34 (dtd, J3¢,2¢a = 6.0 Hz, J3¢,2¢b = J3¢,4¢ = 2.3 Hz,
1b-(4-Amino-2-phenylpyrimidin-5-yl)-1,2-dideoxy-D-ribofura-
nose (5fb)
Following the general procedure for deprotection using 6fb (92 mg,
J3¢,1¢ = 0.6 Hz, 1 H, H3¢), 5.30 (ddt, J1¢,2¢a = 10.1 Hz, J1¢,2¢b = 5.8 Hz,
J1¢,6 = J1¢,3¢ = 0.8 Hz, 1 H, H1¢), 7.45–7.51 (m, 3 H, m,p-HPh), 8.38
(m, 2 H, o-HPh), 8.67 (d, J6,1¢ = 1.0 Hz, 1 H, H6).
0.19 mmol) gave 5fb (40 mg, 82%) as a white foam.
13C NMR (125.7 MHz, CD3OD): d = 42.70 (CH2-2¢), 54.30 (CH3O-
4), 63.88 (CH2-5¢), 74.19 (CH-3¢), 74.82 (CH-1¢), 88.98 (CH-4¢),
121.90 (C-5), 129.11 (o-CHPh), 129.51 (m-CHPh), 131.82 (p-CHPh),
138.53 (i-CPh), 154.82 (CH-6), 164.51 (C-2), 167.78 (C-4).
IR (KBr): 3464, 3388, 3328, 3068, 1622, 1594, 1582, 1566, 1550,
1497, 1468, 1445, 1411, 1390, 1088, 1048, 1024, 773, 715 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 1.92 (ddd, Jgem = 12.7 Hz,
J
J
2¢a,1¢ = 5.6 Hz, J2¢a,3¢ = 1.5 Hz, 1 H, H2¢a), 2.12 (ddd, Jgem = 12.7 Hz,
2¢b,1¢ = 10.9 Hz, J2¢b,3¢ = 6.1 Hz, 1 H, H2¢b), 3.56 (ddd, Jgem = 11.6
HRMS (ESI): m/z [M + H] calcd for C16H1pN2O4: 303.1339; found:
303.1338.
Hz, J5¢a,OH = 5.3 Hz, J5¢a,4¢ = 3.3 Hz, 1 H, H5¢a), 3.62 (ddd,
Jgem = 11.6 Hz, J5¢b,OH = 4.7 Hz, J5¢b,4¢ = 2.8 Hz, 1 H, H5¢b), 3.82 (br
q, J4¢,5¢a = J4¢,5¢b = J4¢,3¢ = 2.8 Hz, 1 H, H4¢), 4.28 (ddt, J3¢,2¢b = 6.0 Hz,
J3¢,OH = 3.9 Hz, J3¢,2¢a = J3¢,4¢ = 1.8 Hz, 1 H, H3¢), 5.02 (br dd,
J1¢,2¢b = 10.8 Hz, J1¢,2¢a = 5.5 Hz, 1 H, H1¢), 5.10 (d, JOH,3¢ = 3.8 Hz, 1
H, OH-3¢), 5.18 (t, JOH,5¢a = JOH,5¢b = 4.9 Hz, 1 H, OH-5¢), 6.95 (br s,
2 H, NH2-4), 7.42–7.47 (m, 3 H, m,p-HPh), 8.20 (br s, 1 H, H6), 8.28
(m, 2 H, o-HPh).
13C NMR (125.7 MHz, DMSO-d6): d = 39.77 (CH2-2¢), 61.62 (CH2-
5¢), 72.49 (CH-3¢), 76.97 (CH-1¢), 88.10 (CH-4¢), 113.88 (C-5),
127.60 (o-CHPh), 128.38 (m-CHPh), 130.12 (p-CHPh), 138.16 (i-
CPh), 153.80 (CH-6), 161.28 (C-4), 162.26 (C-2).
3,5-Di-O-(tert-butyldimethylsilyl)-1,2-dideoxy-1b-[4-(dimethyl-
amino)-2-phenylpyrimidin-5-yl]-D-ribofuranose (6fe)
Following the typical procedure for 6ff using toluene (5 mL), 6ae
(200 mg, 0.40 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), PhB(OH)2
(98 mg, 0.80 mmol), and K2CO3 (83 mg, 0.60 mmol) at 90 °C for
12 h. Then the mixture was poured onto a mixture of ice (100 mL)
and NH4Cl (1 g), and extracted with CHCl3 (3 × 100 mL). Evapora-
tion of the organic phase followed by chromatography (silica gel,
gradient hexanes to hexanes–EtOAc, 17:1) gave 6fe (141 mg, 65%)
as a colorless oil.
IR (CCl4): 3064, 2956, 2898, 1590, 1573, 1541, 1495, 1471, 1446,
1463, 1415, 1399, 1362, 1258, 1092, 1071, 1027, 1007, 939, 838,
708, 692 cm–1.
HRMS (ESI): m/z [M + H] calcd for C15H18N3O3: 288.1343; found:
288.1344.
1H NMR (500 MHz, CDCl3): d = 0.08, 0.10, and 0.11 (4 × s, 4 × 3
H, CH3Si), 0.91 and 0.92 [2 × s, 2 × 9 H, (CH3)3C], 2.04 (ddd,
Jgem = 12.7 Hz, J2¢a,1¢ = 10.5 Hz, J2¢a,3¢ = 5.2 Hz, 1 H, H2¢a), 2.13
(ddd, Jgem = 12.7 Hz, J2¢b,1¢ = 5.0 Hz, J2¢b,3¢ = 1.7 Hz, 1 H, H2¢b), 3.20
[s, 6 H, (CH3)2N-4], 3.57 (dd, Jgem = 10.7 Hz, J5¢a,4¢ = 6.4 Hz, 1 H,
H5¢a), 3.76 (dd, Jgem = 10.7 Hz, J5¢b,4¢ = 4.1 Hz, 1 H, H5¢b), 3.92
(ddd, J4¢,5¢a = 6.4 Hz, J4¢,5¢b = 4.1 Hz, J4¢,3¢ = 1.9 Hz, 1 H, H4¢), 4.45
(br dt, J3¢,2¢a = 5.1 Hz, J3¢,2¢b = J3¢,4¢ = 1.8 Hz, 1 H, H3¢), 5.35 (br dd,
J1¢,2¢a = 10.5 Hz, J1¢,2¢b = 5.0 Hz, 1 H, H1¢), 7.40–7.47 (m, 3 H, m,p-
HPh), 8.41 (m, 2 H, o-HPh), 8.55 (d, J6,1¢ = 0.7 Hz, 1 H, H6).
13C NMR (125.7 MHz, CDCl3): d = –5.47, –5.36, –4.70, and –4.68
(CH3Si), 17.94 and 18.34 [(CH3)3C], 25.76 and 25.93 [(CH3)3C],
40.71 [(CH3)2N-4], 42.14 (CH2-2¢), 63.74 (CH2-5¢), 74.02 (CH-3¢),
74.49 (CH-1¢), 87.65 (CH-4¢), 116.82 (C-5), 127.97 (o-CHPh),
128.22 (m-CHPh), 130.04 (p-CHPh), 138.15 (i-CPh), 155.69 (CH-6),
161.68 (C-2), 163.46 (C-4).
3,5-Di-O-(tert-butyldimethylsilyl)-1,2-dideoxy-1b-(4-methoxy-
2-phenylpyrimidin-5-yl)-D-ribofuranose (6fc)
Following the typical procedure for 6ff using toluene (8 mL), 6ac
(233 mg, 0.49 mmol), Pd(PPh3)4 (113 mg, 0.10 mmol), K2CO3 (101
mg, 0.73 mmol), and PhB(OH)2 (120 mg, 0.98 mmol) at 90 °C for
12 h (monitored by TLC; hexanes–EtOAc, 2:1). Chromatography
(silica gel, gradient hexanes to 3% EtOAc–hexane) gave 6fc (158
mg, 62%) as a colorless oil.
IR (KBr): 2955, 2930, 2898, 2858, 1589, 1556, 1469, 1416, 1383,
1257, 1106, 1196, 1029, 1020, 838, 705 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.08, 0.09, 0.107, and 0.113 (4 × s,
4 × 3 H, CH3Si), 0.90 and 0.93 [2 × s, 2 × 9 H, (CH3)3C], 1.85 (ddd,
Jgem = 12.7 Hz, J2¢a,1¢ = 10.0 Hz, J2¢a,3¢ = 5.4 Hz, 1 H, H2¢a), 2.29
(ddd, Jgem = 12.7 Hz, J2¢b,1¢ = 5.7 Hz, J2¢b,3¢ = 2.0 Hz, 1 H, H2¢b), 3.59
(dd, Jgem = 10.7 Hz, J5¢a,4¢ = 6.3 Hz, 1 H, H5¢a), 3.77 (dd, Jgem = 10.7
Hz, J5¢b,4¢ = 4.1 Hz, 1 H, H5¢b), 3.98 (ddd, J4¢,5¢a = 6.3 Hz, J4¢,5¢b = 4.1
Hz, J4¢,3¢ = 2.2 Hz, 1 H, H4¢), 4.12 (s, 3 H, CH3O-4), 4.42 (br dt,
J3¢,2¢a = 5.4 Hz, J3¢,2¢b = J3¢,4¢ = 2.1 Hz, 1 H, H3¢), 5.31 (br dd,
J1¢,2¢a = 10.0 Hz, J1¢,2¢b = 5.7 Hz, 1 H, H1¢), 7.45–7.50 (m, 3 H, m,p-
HPh), 8.45 (m, 2 H, o-HPh), 8.66 (d, J6,1¢ = 0.9 Hz, 1 H, H6).
HRMS (ESI): m/z [M + H] calcd for C29H50N3O3Si2: 544.3358;
found: 544.3358.
1,2-Dideoxy-1b-[4-(dimethylamino)-2-phenylpyrimidin-5-yl]-
D-ribofuranose (5fe)
Following the general procedure for deprotection using 6fe (102
mg, 0.21 mmol) gave 5fe (43 mg, 76%) as a white solid.
13C NMR (125.7 MHz, CDCl3): d = –5.43, –5.36, –4.68, and –4.65
(CH3Si), 18.04 and 18.34 [(CH3)3C], 25.82 and 25.92 [(CH3)3C],
41.56 (CH2-2¢), 53.63 (CH3O-4), 63.67 (CH2-5¢), 73.51 (CH-1¢),
74.03 (CH-3¢), 87.73 (CH-4¢), 120.47 (C-5), 128.07 (o-CHPh),
128.43 (m-CHPh), 130.73 (p-CHPh), 137.2 (i-CPh), 153.89 (CH-6),
162.79 (C-2), 166.34 (C-4).
IR (KBr): 3399, 3064, 1592, 1573, 1542, 1497, 1447, 1416, 1399,
1090, 1073, 1049, 1027, 1000, 767, 707 cm–1.
Synthesis 2012, 44, 953–965
© Thieme Stuttgart · New York

PAPER
Pyrimidine C-Nucleosides
963
1H NMR (500 MHz, CD3OD): d = 2.15 (ddd, Jgem = 13.1 Hz,
3,5-Di-O-(tert-butyldimethylsilyl)-1,2-dideoxy-1b-(4-methoxy-
pyrimidin-5-yl)-D-ribofuranose (6gc)
Following the typical procedure for 6gb using 10% Pd/C (112 mg),
6ac (188 mg, 0.38 mmol) in THF (5 mL), EtOH (5 mL), H2O (0.5
mL), and Et3N (0.5 mL). Chromatography (silica gel, gradient hex-
anes to 5% EtOAc–hexane) gave 6gc (131 mg, 75%) as a colorless
oil.
J2¢a,1¢ = 10.4 Hz, J2¢a,3¢ = 6.1 Hz, 1 H, H2¢a), 2.27 (ddd, Jgem = 13.1
Hz, J2¢b,1¢ = 5.3 Hz, J2¢b,3¢ = 1.9 Hz, 1 H, H2¢b), 3.25 [s, 6 H,
(CH3)2N-4], 3.69 (m, 2 H, H5¢), 3.91 (td, J4¢,5¢a = J4¢,5¢b = 4.7 Hz,
J4¢,3¢ = 2.7 Hz, 1 H, H4¢), 4.37 (br dt, J3¢,2¢a = 6.1 Hz,
J3¢,2¢b = J3¢,4¢ = 2.3 Hz, 1 H, H3¢), 5.39 (br dd, J1¢,2¢a = 10.4 Hz,
J1¢,2¢b = 5.3 Hz, 1 H, H1¢), 7.43–7.49 (m, 3 H, m,p-HPh), 8.29 (m, 2
H, o-HPh), 8.54 (d, J6,1¢ = 0.7 Hz, 1 H, H6).
IR (CCl4): 2956, 2901, 1590, 1575, 1477, 1445, 1392, 1362, 1258,
1097, 1037, 939, 838, 788 cm–1.
13C NMR (125.7 MHz, CD3OD): d = 41.03 [(CH3)2N-4], 43.26
(CH2-2¢), 63.76 (CH2-5¢), 74.07 (CH-3¢), 75.86 (CH-1¢), 88.91 (CH-
4¢), 118.31 (C-5), 129.05 (o-CHPh), 129.37 (m-CHPh), 131.43 (p-
CHPh), 139.10 (i-CPh), 156.40 (CH-6), 162.98 (C-2), 164.65 (C-4).
1H NMR (500 MHz, CDCl3): d = 0.06, 0.07, 0.08, and 0.09 (4 × s,
4 × 3 H, CH3Si), 0.88 and 0.91 [2 × s, 2 × 9 H, (CH3)3C], 1.79 (ddd,
Jgem = 12.7 Hz, J2¢a,1¢ = 9.9 Hz, J2¢a,3¢ = 5.5 Hz, 1 H, H2¢a), 2.26 (ddd,
Jgem = 12.7 Hz, J2¢b,1¢ = 5.8 Hz, J2¢b,3¢ = 2.1 Hz, 1 H, H2¢b), 3.60 (dd,
Jgem = 10.8 Hz, J5¢a,4¢ = 5.7 Hz, 1 H, H5¢a), 3.74 (dd, Jgem = 10.8 Hz,
HRMS (ESI): m/z [M + H] calcd for C17H22N3O3: 316.1656; found:
316.1655.
J
J
5¢b,4¢ = 3.9 Hz, 1 H, H5¢b), 3.95 (ddd, J4¢,5¢a = 5.7 Hz, J4¢,5¢b = 3.9 Hz,
4¢,3¢ = 2.3 Hz, 1 H, H4¢), 3.99 (s, 3 H, CH3O-4), 4.39 (br dt,
1b-(4-Aminopyrimidin-5-yl)-3,5-di-O-(tert-butyldimethylsilyl)-
1,2-dideoxy-D-ribofuranose (6gb); Typical Procedure
J3¢,2¢a = 5.5 Hz, J3¢,4¢ = J3¢,2¢a = 2.2 Hz, 1 H, H3¢), 5.25 (dd, J1¢,2¢a = 9.9
Hz, J1¢,2¢b = 5.8 Hz, 1 H, H1¢), 8.59 (br s, 1 H, H6), 8.68 (s, 1 H, H2).
10% Pd/C (70 mg) was added to a soln of 6ab (200 mg, 0.42 mmol)
in a mixture of THF (2 mL), EtOH (2 mL), H2O (0.2 mL), and Et3N
(0.2 mL). The reaction flask was then sealed with a septum, evacu-
ated, and filled with H2 (101 kPa). After the reaction was completed
(12 h), the Pd catalyst was filtered off, the filtrate was poured into
H2O, and crude product was extracted with EtOAc. The chromatog-
raphy (silica gel, gradient hexanes to 50% EtOAc–hexane) gave
6gb (136 mg, 73%) as a colorless oil.
13C NMR (125.7 MHz, CDCl3): d = –5.49, –5.42, –4.71, and –4.67
(CH3Si), 18.01 and 18.30 [(CH3)3C], 25.78 and 25.88 [(CH3)3C],
41.66 (CH2-2¢), 53.75 (CH3O-4), 63.50 (CH2-5¢), 73.23 (CH-1¢),
73.88 (CH-3¢), 87.69 (CH-4¢), 122.92 (C-5), 153.35 (CH-6), 156.85
(CH-2), 166.00 (C-4).
HRMS (ESI): m/z [M + H] calcd for C22H43N2O4Si2: 455.2756;
found: 455.2755.
IR (CCl4): 3495, 3431, 3392, 3365, 3312, 3184, 3046, 2956, 2897,
1611, 1637, 1588, 1561, 1488, 1470, 1465, 1436, 1410, 1390, 1362,
1257, 1097, 1006, 938, 837 cm–1.
1,2-Dideoxy-1b-(4-methoxypyrimidin-5-yl)-D-ribofuranose
(5gc)
Following the general procedure for deprotection using 6gc (111
1H NMR (500 MHz, CDCl3): d = 0.076, 0.078, 0.083, and 0.09
(4 × s, 4 × 3 H, CH3Si), 0.90 (s, 2 × 9 H, (CH3)3C], 1.88 (ddd,
Jgem = 12.9 Hz, J2¢a,1¢ = 5.4 Hz, J2¢a,3¢ = 1.3 Hz, 1 H, H2¢a), 2.29 (ddd,
Jgem = 12.9 Hz, J2¢b,1¢ = 11.2 Hz, J2¢b,3¢ = 6.2 Hz, 1 H, H2¢b), 3.78 (dd,
Jgem = 11.2 Hz, J5¢a,4¢ = 2.0 Hz, 1 H, H5¢a), 3.86 (dd, Jgem = 11.2 Hz,
mg, 0.24 mmol) gave 5gc (40 mg, 73%) as a white solid.
IR (KBr): 3402, 1639, 1590, 1575, 1477, 1445, 1397, 1088, 1051,
788 cm–1.
1H NMR (500 MHz, CD3OD): d = 1.84 (ddd, Jgem = 13.1 Hz,
J5¢b,4¢ = 2.6 Hz, 1 H, H5¢b), 3.95 (q, J4¢,5¢a = J4¢,5¢b = J4¢,3¢ = 2.3 Hz, 1
J2¢a,1¢ = 10.1 Hz, J2¢a,3¢ = 6.0 Hz, 1 H, H2¢a), 2.37 (ddd, Jgem = 13.1
H, H4¢), 4.43 (br ddd, J3¢,2¢b = 6.2 Hz, J3¢,4¢ = 2.4 Hz, J3¢,2¢a = 1.3 Hz,
1 H, H3¢), 5.03 (dd, J1¢,2¢b = 11.2 Hz, J1¢,2¢a = 5.4 Hz, 1 H, H1¢), 5.93
(br s, 2 H, NH2), 8.06 (s, 1 H, H6), 8.45 (s, 1 H, H2).
Hz, J2¢b,1¢ = 5.7 Hz, J2¢b,3¢ = 2.0 Hz, 1 H, H2¢b), 3.67 (m, 2 H, H5¢),
3.95 (td, J4¢,5¢a = J4¢,5¢b = 4.9 Hz, J4¢,3¢ = 2.7 Hz, 1 H, H4¢), 4.04 (s, 3
H, CH3O-4), 4.31 (br dtd, J3¢,2¢a = 6.0 Hz, J3¢,4¢ = J3¢,2¢b = 2.3 Hz,
13C NMR (125.7 MHz, CDCl3): d = –5.53, –5.52, –4.74, and –4.59
(CH3Si), 18.00 and 18.48 [(CH3)3C], 25.77 and 25.86 [(CH3)3C],
40.26 (CH2-2¢), 63.13 (CH2-5¢), 73.80 (CH-3¢), 78.46 (CH-1¢),
88.66 (CH-4¢), 114.81 (C-5), 153.42 (CH-6), 157.88 (CH-2),
161.08 (C-4).
J
3¢,1¢ = 0.6 Hz, 1 H, H3¢), 5.25 (ddq, J1¢,2¢a = 10.2 Hz, J1¢,2¢b = 5.7 Hz,
J1¢,3¢ = J1¢,6 = Jl.r. = 0.8 Hz, 1 H, H1¢), 8.63 (br t, J6,1¢ = J6,2 = 0.8 Hz,
1 H, H6), 8.65 (br s, 1 H, H2).
13C NMR (125.7 MHz, CD3OD): d = 41.18 (CH2-2¢), 53.17 (CH3O-
4), 62.35 (CH2-5¢), 72.65 (CH-3¢), 73.10 (CH-1¢), 87.56 (CH-4¢),
123.17 (C-5), 152.31 (CH-6), 156.38 (CH-2), 166.30 (C-4).
HRMS (ESI): m/z [M + H] calcd for C21H42N3O3Si2: 440.2759;
found: 440.2757.
HRMS (ESI): m/z [M + H] calcd for C10H15N2O4: 227.1026; found:
227.1026.
1b-(4-Aminopyrimidin-5-yl)-1,2-dideoxy-D-ribofuranose (5gb)
Following the general procedure for deprotection using 6gb (120
mg, 0.27 mmol) gave 5gb (48 mg, 83%) as a white solid.
3,5-Di-O-(tert-butyldimethylsilyl)-1,2-dideoxy-1b-(4-methylpy-
rimidin-5-yl)-D-ribofuranose (6gd)
Following the typical procedure for 6gb using 10% Pd/C (120 mg),
6ad (201 mg, 0.42 mmol), THF (4 mL), EtOH (4 mL), H2O (0.5
mL), and Et3N (0.5 mL). Chromatography (silica gel, gradient hex-
ane to 6% EtOAc–hexane) gave 6gd (174 mg, 94%) as a colorless
oil.
IR (KBr): 3323, 1627, 1599, 1558, 1480, 1417, 1340, 1261, 1079,
1045, 957 cm–1.
1H NMR (500 MHz, CD3OD): d = 2.01 (ddd, Jgem = 13.1 Hz,
J2¢a,1¢ = 5.4 Hz, J2¢a,3¢ = 1.3 Hz, 1 H, H2¢a), 2.29 (ddd, Jgem = 13.1 Hz,
J2¢b,1¢ = 11.1 Hz, J2¢b,3¢ = 6.2 Hz, 1 H, H2¢b), 3.73 (dd, Jgem = 11.6 Hz,
J5¢a,4¢ = 3.0 Hz, 1 H, H5¢a), 3.76 (dd, Jgem = 11.6 Hz, J5¢b,4¢ = 2.9 Hz,
IR (CCl4): 3048, 2956, 2897, 1578, 1559, 1472, 1463, 1399, 1392,
1373, 1362, 1257, 1094, 1006, 939, 838 cm–1.
1 H, H5¢b), 3.96 (br q, J4¢,5¢a = J4¢,5¢b = J4¢,3¢ = 2.7 Hz, 1 H, H4¢), 4.42
(dddd, J3¢,2¢b = 6.2 Hz, J3¢,4¢ = 2.4 Hz, J3¢,2¢a = 1.3 Hz, J3¢,1¢ = 0.5 Hz, 1
H, H3¢), 5.06 (br dd, J1¢,2¢b = 11.1 Hz, J1¢,2¢a = 5.4 Hz, 1 H, H1¢), 8.06
(s, 1 H, H6), 8.28 (s, 1 H, H2).
13C NMR (125.7 MHz, CD3OD): d = 40.56 (CH2-2¢), 62.95 (CH2-
5¢), 74.36 (CH-3¢), 78.85 (CH-1¢), 89.63 (CH-4¢), 117.09 (C-5),
153.23 (CH-6), 158.16 (CH-2), 162.74 (C-4).
1H NMR (500 MHz, CDCl3): d = 0.06 and 0.08 (4 × s, 4 × 3 H,
CH3Si), 0.87 and 0.90 [2 × s, 2 × 9 H, (CH3)3C], 1.81 (ddd,
Jgem = 12.6 Hz, J2¢a,1¢ = 10.3 Hz, J2¢a,3¢ = 5.5 Hz, 1 H, H2¢a), 2.19
(ddd, Jgem = 12.6 Hz, J2¢b,1¢ = 5.4 Hz, J2¢b,3¢ = 1.8 Hz, 1 H, H2¢b), 2.49
(s, 3 H, CH3), 3.65 (dd, Jgem = 10.8 Hz, J5¢a,4¢ = 5.1 Hz, 1 H, H5¢a),
3.76 (dd, Jgem = 10.8 Hz, J5¢b,4¢ = 3.6 Hz, 1 H, H5¢b), 3.96 (ddd,
J4¢,5¢a = 5.1 Hz, J4¢,5¢b = 3.6 Hz, J4¢,3¢ = 2.1 Hz, 1 H, H4¢), 4.43 (br dt,
J3¢,2¢a = 5.4 Hz, J3¢,4¢ = J3¢,2¢b = 2.0 Hz, 1 H, H3¢), 5.28 (dd,
HRMS (ESI): m/z [M + H] calcd for C9H14N3O3: 212.1030; found:
212.1029.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 953–965

964
T. Kubelka et al.
PAPER
J1¢,2¢a = 10.3 Hz, J1¢,2¢b = 5.4 Hz, 1 H, H1¢), 8.77 (br s, 1 H, H6), 8.96
(s, 1 H, H2).
1H NMR (500 MHz, CD3OD): d = 2.09 (ddd, Jgem = 13.1 Hz,
J2¢a,1¢ = 10.4 Hz, J2¢a,3¢ = 6.0 Hz, 1 H, H2¢a), 2.24 (ddd, Jgem = 13.1
Hz, J2¢b,1¢ = 5.2 Hz, J2¢b,3¢ = 1.9 Hz, 1 H, H2¢b), 3.16 [s, 6 H,
(CH3)2N], 3.65 (dd, Jgem = 11.8 Hz, J5¢a,4¢ = 4.9 Hz, 1 H, H5¢a), 3.68
(dd, Jgem = 11.8 Hz, J5¢b,4¢ = 4.4 Hz, 1 H, H5¢b), 3.89 (td,
J4¢,5¢a = J4¢,5¢b = 4.6 Hz, J4¢,3¢ = 2.8 Hz, 1 H, H4¢), 4.34 (br dt,
J3¢,2¢a = 6.1 Hz, J3¢,4¢ = J3¢,2¢b = 2.3 Hz, 1 H, H3¢), 5.32 (dd,
J1¢,2¢a = 10.4 Hz, J1¢,2¢b = 5.2 Hz, 1 H, H1¢), 8.40 (s, 1 H, H2), 8.45 (s,
1 H, H6).
13C NMR (125.7 MHz, CD3OD): d = 41.04 [(CH3)2N], 43.27 (CH2-
2¢), 63.67 (CH2-5¢), 73.97 (CH-3¢), 75.72 (CH-1¢), 88.93 (CH-4¢),
120.57 (C-5), 155.19 (CH-6), 156.47 (CH-2), 164.40 (C-4).
13C NMR (125.7 MHz, CDCl3): d = –5.56, –5.45, –4.73, and –4.71
(CH3Si), 17.95 and 18.26 [(CH3)3C], 21.64 (CH3), 25.73 and 25.84
[(CH3)3C], 42.47 (CH2-2¢), 63.39 (CH2-5¢), 74.00 (CH-3¢), 74.88
(CH-1¢), 87.97 (CH-4¢), 133.58 (C-5), 153.93 (CH-6), 157.07 (CH-
2), 163.41 (C-4).
HRMS (ESI): m/z [M + H] calcd for C22H43N2O3Si2: 439.2807;
found: 439.2805.
1,2-Dideoxy-1b-(4-methylpyrimidin-5-yl)-D-ribofuranose (5gd)
Following the general procedure for deprotection using 6gd (170
mg, 0.39 mmol) gave 5gd (68 mg, 84%) as a white solid.
HRMS (ESI): m/z [M + H] calcd for C11H18N3O3: 240.1343; found:
240.1342.
IR (KBr): 3309, 1579, 1444, 1397, 1351, 1313, 1253, 1091, 1052,
1019, 881, 750 cm–1.
(2R,3R)-5-(4-Aminopyrimidin-5-yl)pentane-1,2,3-triol (7)
Following the typical procedure for 6gb using 10% Pd/C (70 mg),
5ab (103 mg, 0.42 mmol), THF (4 mL), EtOH (4 mL), H2O (0.5
mL), and Et3N (0.5 mL). Chromatography (silica gel, gradient
CHCl3 to 50% MeOH–CHCl3) gave 7 (69 mg, 78%) as a white sol-
id.
1H NMR (500 MHz, CD3OD): d = 1.90 (ddd, Jgem = 13.0 Hz,
J2¢a,1¢ = 10.4 Hz, J2¢a,3¢ = 6.0 Hz, 1 H, H2¢a), 2.36 (ddd, Jgem = 13.0
Hz, J2¢b,1¢ = 5.6 Hz, J2¢b,3¢ = 1.9 Hz, 1 H, H2¢b), 2.55 (s, 3 H, CH3),
3.70 (dd, Jgem = 11.8 Hz, J5¢a,4¢ = 4.9 Hz, 1 H, H5¢a), 3.73 (dd,
Jgem = 11.8 Hz,
J5¢b,4¢ = 4.4 Hz, 1 H, H5¢b), 3.98 (br td,
J4¢,5¢a = J4¢,5¢b = 4.6 Hz, J4¢,3¢ = 2.7 Hz, 1 H, H4¢), 4.37 (br dt,
J3¢,2¢a = 6.1 Hz, J3¢,4¢ = J3¢,2¢b = 2.3 Hz, 1 H, H3¢), 5.35 (br dd,
J1¢,2¢a = 10.4 Hz, J1¢,2¢b = 5.6 Hz, 1 H, H1¢), 8.88 (br d, J6,1¢ = 0.7 Hz,
1 H, H6), 8.90 (s, 1 H, H2).
IR (KBr): 3419, 3220, 1633, 1602, 1560, 1488, 1420, 1075, 1050,
794 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 1.48 (dtd, Jgem = 13.8 Hz,
J2¢a,1¢a = J2¢a,3¢ = 9.3 Hz, J2¢a,1¢b = 4.8 Hz, 1 H, H2¢a), 1.78 (dddd,
Jgem = 13.8 Hz, J2¢b,1¢b = 9.8 Hz, J2¢b,1¢a = 7.1 Hz, J2¢b,3¢ = 2.8 Hz, 1 H,
H2¢b), 2.39 (ddd, Jgem = 14.4 Hz, J1¢a,2¢a = 9.5 Hz, J1¢a,2¢b = 7.1 Hz, 1
H, H1¢a), 2.48–2.56 (m, 1 H, H1¢b), 3.24–3.40 (m, 3 H, H5¢a, H3¢,
H4¢), 3.52 (ddd, Jgem = 11.0 Hz, J5¢b,OH = 5.9 Hz, J5¢b,4¢ = 3.9 Hz, 1 H,
H5¢b), 4.43 (t, JOH,5¢a = JOH,5¢b = 5.7 Hz, 1 H, OH-5¢), 4.59 (d,
13C NMR (125.7 MHz, CD3OD): d = 21.62 (CH3), 42.92 (CH2-2¢),
63.63 (CH2-5¢), 74.15 (CH-3¢), 76.06 (CH-1¢), 89.25 (CH-4¢),
135.74 (C-5), 154.93 (CH-6), 157.41 (CH-2), 165.75 (C-4).
HRMS (ESI): m/z [M + H] calcd for C10H15N2O3: 211.1077; found:
211.1077.
J
OH,4¢ = 5.2 Hz, 1 H, OH-4¢), 4.65 (d, JOH,3¢ = 6.1 Hz, 1 H, OH-3¢),
3,5-Di-O-(tert-butyldimethylsilyl)-1,2-dideoxy-1b-[4-(dimethyl-
amino)pyrimidin-5-yl]-D-ribofuranose (6ge)
Following the typical procedure for 6gb using 10% Pd/C (155 mg),
6ae (238 mg, 0.47 mmol), THF (4 mL), EtOH (4 mL), H2O (0.5
mL), and Et3N (0.5 mL). Chromatography (silica gel, gradient hex-
ane to 10% EtOAc–hexane) gave 6ge (185 mg, 83%) as a colorless
oil.
6.66 (br s, 2 H, NH2-4), 7.89 (s, 1 H, H6), 8.21 (s, 1 H, H2).
13C NMR (125.7 MHz, DMSO-d6): d = 23.67 (CH2-1¢), 31.24 (CH2-
2¢), 63.66 (CH2-5¢), 70.61 (CH-3¢), 75.09 (CH-4¢), 117.48 (C-5),
153.28 (CH-6), 156.19 (C-2), 162.11 (C-4).
HRMS (ESI): m/z [M + H] calcd for C9H16N3O3: 214.1186; found:
214.1185.
IR (CCl4): 3039, 2955, 2897, 2802, 1583, 1544, 1501, 1471, 1463,
1443, 1398, 1362, 1257, 1089, 1006, 940, 838 cm–1.
Acknowledgment
1H NMR (500 MHz, CDCl3): d = 0.07, 0.085, and 0.092 (4 × s, 4 × 3
H, CH3Si), 0.897 and 0.900 [2 × s, 2 × 9 H, (CH3)3C], 2.01 (ddd,
Jgem = 12.7 Hz, J2¢a,1¢ = 10.5 Hz, J2¢a,3¢ = 5.2 Hz, 1 H, H2¢a), 2.10
(ddd, Jgem = 12.7 Hz, J2¢b,1¢ = 5.0 Hz, J2¢b,3¢ = 1.8 Hz, 1 H, H2¢b), 3.11
[s, 2 × 3 H, (CH3)2N], 3.58 (dd, Jgem = 10.8 Hz, J5¢a,4¢ = 5.7 Hz, 1 H,
H5¢a), 3.73 (dd, Jgem = 10.8 Hz, J5¢b,4¢ = 3.8 Hz, 1 H, H5¢b), 3.89
(ddd, J4¢,5¢a = 5.7 Hz, J4¢,5¢b = 3.8 Hz, J4¢,3¢ = 1.9 Hz, 1 H, H4¢), 4.43
(br dt, J3¢,2¢a = 5.2 Hz, J3¢,4¢ = J3¢,2¢a = 1.8 Hz, 1 H, H3¢), 5.28 (dd,
J1¢,2¢a = 10.5 Hz, J1¢,2¢b = 5.0 Hz, 1 H, H1¢), 8.45 (s, 1 H, H6), 8.55 (s,
1 H, H2).
13C NMR (125.7 MHz, CDCl3): d = –5.51, –5.38, –4.71, and –4.69
(CH3Si), 17.93 and 18.32 [(CH3)3C], 25.74 and 25.90 ([(CH3)3C],
40.78 [(CH3)2N], 42.48 (CH2-2¢), 63.61 (CH2-5¢), 73.99 (CH-3¢),
74.37 (CH-1¢), 87.73 (CH-4¢), 119.07 (C-5), 154.79 (CH-6), 155.96
(CH-2), 163.19 (C-4).
This work was supported by the Academy of Sciences of the Czech
Republic (Z4 055 905), by the Ministry of Education (LC 512), by
the Grant Agency of the ASCR (IAA400550902) and by Gilead
Sciences, Inc.
References
(1) Reviews: (a) Štambaský, J.; Hocek, M.; Kočovský, P. Chem.
Rev. 2009, 109, 6729. (b) Adamo, M. F. A.; Pergoli, R.
Curr. Org. Chem. 2008, 12, 1544. (c) Wu, Q. P.; Simons, C.
Synthesis 2004, 1533.
(2) Reviews: (a) Wang, L.; Schultz, P. G. Chem. Commun.
2002, 1. (b) Henry, A. A.; Romesberg, F. E. Curr. Opin.
Chem. Biol. 2003, 7, 727. (c) Kool, E. T.; Morales, J. C.;
Guckian, K. M. Angew. Chem. Int. Ed. 2000, 39, 990.
(d) Kool, E. T. Acc. Chem. Res. 2002, 35, 936. Recent
papers: (e) Ogawa, A. K.; Abou-Zied, O. K.; Tsui, V.;
Jimenez, R.; Case, D. A.; Romesberg, F. E. J. Am. Chem.
Soc. 2000, 122, 9917. (f) Wu, Y. Q.; Ogawa, A. K.; Berger,
M.; Mcminn, D. L.; Schultz, P. G.; Romesberg, F. E. J. Am.
Chem. Soc. 2000, 122, 7621. (g) Guckian, K. M.; Krugh, T.
R.; Kool, E. T. J. Am. Chem. Soc. 2000, 122, 6841.
(h) Parsch, J.; Engels, J. W. J. Am. Chem. Soc. 2002, 124,
5664. (i) Lai, J. S.; Qu, J.; Kool, E. T. Angew. Chem. Int. Ed.
HRMS (ESI): m/z [M + H] calcd for C23H46N3O3Si2: 468.3072;
found: 468.3070.
1,2-Dideoxy-1b-[4-(dimethylamino)pyrimidin-5-yl]-D-ribofura-
nose (5ge)
Following the general procedure for deprotection using 6ge (174
mg, 0.37 mmol) gave 5ge (80 mg, 90%) as a white solid.
IR (KBr): 3255, 1589, 1540, 1508, 1396, 1046, 972, 936, 789 cm–1.
Synthesis 2012, 44, 953–965
© Thieme Stuttgart · New York

PAPER
2003, 42, 5973. (j) Lai, J. S.; Kool, E. T. J. Am. Chem. Soc.
Pyrimidine C-Nucleosides
965
(7) (a) Hocek, M.; Pohl, R.; Klepetářová, B. Eur. J. Org. Chem.
2005, 4525. (b) Urban, M.; Pohl, R.; Klepetářová, B.;
Hocek, M. J. Org. Chem. 2006, 71, 7322. (c) Joubert, N.;
Pohl, R.; Klepetářová, B.; Hocek, M. J. Org. Chem. 2007,
72, 6797. (d) Štefko, M.; Pohl, R.; Klepetářová, B.; Hocek,
M. Eur. J. Org. Chem. 2008, 1689. (e) Joubert, N.; Urban,
M.; Pohl, R.; Hocek, M. Synthesis 2008, 1918. (f) Bárta, J.;
Pohl, R.; Klepetářová, B.; Ernsting, N. P.; Hocek, M. J. Org.
Chem. 2008, 73, 3798. (g) Štefko, M.; Pohl, R.; Hocek, M.
Tetrahedron 2009, 65, 4471. (h) Štefko, M.; Slavřtínská, L.;
Klepetářová, B.; Hocek, M. J. Org. Chem. 2010, 75, 442.
(i) Bárta, J.; Slavětínská, L.; Klepetářová, B.; Hocek, M.
Eur. J. Org. Chem. 2010, 5432. (j) Štefko, M.; Slavětínská,
L.; Klepetářová, B.; Hocek, M. J. Org. Chem. 2011, 76,
6619.
2004, 126, 3040.
(3) (a) Henry, A. A.; Olsen, A. G.; Matsuda, S.; Yu, C.;
Geierstanger, B. H.; Romesberg, F. E. J. Am. Chem. Soc.
2004, 126, 6923. (b) Henry, A. A.; Yu, C. Z.; Romesberg, F.
E. J. Am. Chem. Soc. 2003, 125, 9638. (c) Hwang, G. T.;
Romesberg, F. E. Nucleic Acids Res. 2006, 34, 2037.
(d) Matsuda, S.; Henry, A. A.; Romesberg, F. E. J. Am.
Chem. Soc. 2006, 128, 6369. (e) Kim, Y.; Leconte, A. M.;
Hari, Y.; Romesberg, F. E. Angew. Chem. Int. Ed. 2006, 45,
7809. (f) Matsuda, S.; Fillo, J. D.; Henry, A. A.; Rai, P.;
Wilkens, S. J.; Dwyer, T. J.; Geierstanger, B. H.; Wemmer,
D. E.; Schultz, P. G.; Spraggon, G.; Romesberg, F. E. J. Am.
Chem. Soc. 2007, 129, 10466. (g) Matsuda, S.; Leconte, A.
M.; Romesberg, F. E. J. Am. Chem. Soc. 2007, 129, 5551.
(h) Hari, Y.; Hwang, G. T.; Leconte, A. M.; Joubert, N.;
Hocek, M.; Romesberg, F. E. ChemBioChem 2008, 9, 2796.
(4) (a) Leconte, A. M.; Hwang, G. T.; Matsuda, S.; Capek, P.;
Hari, Y.; Romesberg, F. E. J. Am. Chem. Soc. 2008, 130,
2336. (b) Seo, Y. J.; Romesberg, F. E. ChemBioChem 2009,
10, 2394. (c) Malyshev, D. A.; Pfaff, D. A.; Ippoliti, S. I.;
Hwang, G. T.; Dwyer, T. J.; Romesberg, F. E. Chem. Eur. J.
2010, 16, 12650. (d) Seo, Y. J.; Malyshev, D. A.; Lavergne,
T.; Ordoukhanian, P.; Romesberg, F. E. J. Am. Chem. Soc.
2011, 133, 19878.
(8) Review: Schöter, S.; Stock, C.; Bach, T. Tetrahedron 2005,
61, 2245.
(9) Kubelka, T.; Slavětínská, L.; Klepetáňová, B.; Hocek, M.
Eur. J. Org. Chem. 2010, 2666.
(10) Review: (a) Wellington, K. W.; Benner, S. A. Nucleosides
Nucleotides Nucleic Acids 2006, 25, 1309. Original paper:
(b) Zhang, H.-C.; Doyle, D. G. J. Org. Chem. 1992, 57,
4690. (c) Chen, D. C.; McLaughlin, L. W. J. Org. Chem.
2000, 65, 7468. (d) Fraley, A. W.; Chen, D.; Johnson, K.;
McLaughlin, L. W. J. Am. Chem. Soc. 2003, 125, 616.
(11) (a) Fürstner, A.; Leitner, A.; Mendez, M.; Krause, H. J. Am.
Chem. Soc. 2002, 124, 13856. (b) Fürstner, A.; Martin, R.
Chem. Lett. 2005, 34, 624. (c) Fürstner, A.; Martin, R.;
Krause, H.; Seidel, G.; Goddard, R.; Lehmann, C. W. J. Am.
Chem. Soc. 2008, 130, 8773. (d) Czaplik, W. M.; Mayer,
M.; Cvengros, J.; von Wangelin, A. J. ChemSusChem 2009,
2, 396.
(5) Malyshev, D.; Seo, Y. J.; Ordoukhanian, P.; Romesberg, F.
E. J. Am. Chem. Soc. 2009, 131, 14620.
(6) (a) Urban, M.; Joubert, N.; Hocek, M.; Alexander, R. E.;
Kuchta, R. D. Biochemistry 2009, 48, 10866. (b) Urban,
M.; Joubert, N.; Purse, B.; Hocek, M.; Kuchta, R.
Biochemistry 2010, 49, 727. (c) Lund, T.; Cavanaugh, N.;
Joubert, N.; Urban, M.; Patro, J.; Hocek, M.; Kuchta, R. D.
Biochemistry 2011, 50, 7243.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 953–965