General and modular synthesis of isomeric 5-substituted pyridin-2-yl and 6-substituted pyridin-3-yl C-ribonucleosides bearing diverse alkyl, aryl, hetaryl, amino, carbamoyl, and hydroxy groups

Article abstract of DOI:10.1021/jo200949c

A general modular and practical methodology for preparation of diverse 5-substituted pyridin-2-yl and 6-substituted pyridin-3-yl C-ribonucleosides was developed. Regioselective lithiation of 2,5-dibromopyridine proceeded at position 5 or 2 depending on th

Full text of DOI:10.1021/jo200949c

ARTICLE
pubs.acs.org/joc
General and Modular Synthesis of Isomeric 5-Substituted Pyridin-2-yl
and 6-Substituted Pyridin-3-yl C-Ribonucleosides Bearing Diverse
Alkyl, Aryl, Hetaryl, Amino, Carbamoyl, and Hydroxy Groups
ꢀ
Martin Stefko, Lenka Slavꢀetínskꢁa, Blanka Klepetꢁaꢀrovꢁa, and Michal Hocek*
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead & IOCB Research Center,
Flemingovo nꢁam. 2, CZ-16610 Prague 6, Czech Republic.
S Supporting Information
b
ABSTRACT: A general modular and practical methodology for
preparation of diverse 5-substituted pyridin-2-yl and 6-substi-
tuted pyridin-3-yl C-ribonucleosides was developed. Regiose-
lective lithiation of 2,5-dibromopyridine proceeded at position
5 or 2 depending on the solvent, and the resulting bromopyridyl
lithium species underwent additions to TBS-protected ribono-
lactone and follow-up transformations to corresponding acety-
lated hemiketal intermediates 7 and 10 that were diastereoselectively reduced to give either 5-bromopyridin-2-yl or 6-bromopyridin-
3-yl silyl-protected C-ribonucleosides 8 or 11 in 68% and 77% overall yields as pure β-anomers. These bromopyridyl C-nucleoside
intermediates were then subjected to a series of palladium-catalyzed cross-coupling reactions, aminations, aminocarbonylations, and
hydroxylations to give a series of protected 1β-(5-alkyl-, 5-aryl-, 5-amino-, 5-carbamoyl-, and 5-hydroxypyridin-2-yl)-C-ribonucleo-
sides 13aꢀi and β-(6-alkyl-, 6-aryl-, 6-amino-, 6-carbamoyl-, and 6-hydroxypyridin-3-yl)-C-ribonucleosides 15aꢀi. Deprotection of
silylated nucleosides by Et3N 3HF, TBAF, or TFA gave a series of free C-nucleosides 14aꢀi and 16aꢀi.
3
Chart 1. Selected Known C-Ribonucleosides
’ INTRODUCTION
The syntheses, as well as the importance, biological activities,
and other applications of C-nucleosides as hydrolytically stable
analogues of natural N-nucleosides were thoroughly discussed
and summarized in several recent reviews.1 Our group is
interested in development of general and modular methods
of synthesis of diverse substituted (het)aryl-C-nucleosides. Our
approach is based on synthesis of halo(het)aryl-C-nucleoside
intermediates and their follow-up derivatizations by means of
cross-coupling reactions, HartwigꢀBuchwald aminations,
aminocarbonylations,2 and hydroxylations.3 In this way, we
have prepared 3- and 4-substituted benzene,4 6-substituted
pyridin-2-yl5 and pyridin-3-yl,6 5-substituted thiophen-2-yl,7
5-substituted furan-2-yl,8 and 2,4-disubstituted pyrimidin-5-yl9
C-20-deoxyribonucleosides some of which were used for chemi-
cal biology studies on DNA polymerases and primases.10 In the
ribonucleoside series, we reported only the synthesis of
benzene11,2,3 and 6-substituted pyridin-2-yl12 derivatives so
far (Chart 1).
Some other types of pyridine C-ribonucleosides have been
reported and applied in diverse areas (Chart 1). 2-Aminopyridin-
5-yl C-ribonucleosides were prepared13 as deletion analogues of
cytidine for probing the function of cytosine in ribozymes, and
the corresponding 20-deoxyribonucleosides were used14 for
synthesis of triplex-forming oligonucleotides (ONs). 2-Oxopyri-
din-5-yl C-ribonucleosides served15 as deletion analogues of uridine
for prospective RNA studies. 2-Oxopyridin-3-yl C-ribonucleosides16
selectively pair with 6-substituted-2-aminopurines17 and were used
in extension of the genetic alphabet for transcription to synthetize
modified RNA18 and to construct proteins containing unnatural
amino acids.19 5-Carbamoylpyridin-2-yl C-ribonucleoside was
prepared20 as a nicotinamide ribonucleoside analogue. Isomeric
6-substituted pyridin-3-yl C-ribonucleosides occur21 only very scar-
cely in the literature. In all the above-mentioned cases, each single
Received: May 10, 2011
Published: July 08, 2011
r
2011 American Chemical Society
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Chart 2. Pyridine C-Nucleosides from This Work and Their
Possible H-Bonding Interactions
workup gave the desired hemiketal 5 in very good 73% yield as a
pure R-anomer (17 was formed in less than 2%). Then we turned
our attention to reduction of 5 under standard conditions using
Et3SiH/BF3 Et2O, but all attempts to perform this reduction
3
failed and only unreacted starting material was isolated. There-
fore, in analogy to previous works of others15,23 and us,12 we tried
to convert the hemiketal 5 to its O-acetate 6 which should be
more reactive toward the reduction. Thus, the hemiketal alk-
oxide, generated by addition of monolithiated pyridine 2 to
lactone 4 was directly in situ acylated on treatment with Ac2O to
give the hemiketal-acetate 6 in low yield of 18% accompanied by
hemiketal 5 (51%).
As an alternative, we focused on acetylations of isolated pure
hemiketal 5. Its acylations with Ac2O or AcCl in the presence of
catalytic amount of DMAP in pyridine were tested, but only very
low conversions (∼5%) to 6 were observed. However, the
treatment of 5 with LiHMDS at room temperature followed by
addition of Ac2O led to the formation of unexpected opposite β-
anomer hemiketal-acetate 7 in 30%. It seems that R-alkoxide X,
generated by deprotonation of R-hemiacetal 5, is at room
temperature transformed to thermodynamically more stable
β-anomer Y which upon quenching with Ac2O gives acetal 7
(Scheme 2). In order to increase the yield of 7, an optimized
protocol using 4.5 equiv of the LiHMDS, added to 5 in three
portions, was developed. Addition of each portion was followed
by quenching with Ac2O (1.5 equiv). This methodology was
efficient even on a large-scale synthesis, yielding acylated hemi-
ketal 7 in 84% yield. The reductive deacetylation of R-acetal 6
under standard conditions (3 equiv of Et3SiH and 1.5 equiv of
derivative was prepared by a specific multistep sequence involving
C-glycosidation reaction with a protected functionalized pyridine
organometallic reagent.
To complement the series of isomeric pyridine C-ribonu-
cleosides, we report here on a general synthesis of two
important underexplored types of analogues: 5-substituted
pyridin-2-yl and 6-substituted pyridin-3-yl C-ribonucleosides
(Chart 2). The former type bearing polar substituents (NH2,
O) should retain H-bonding ability to form WatsonꢀCrick
pairs but lacks functionality for minor-groove interactions,
whereas the derivatives bearing nonpolar substituents
(halogen, methyl, etc.) are shape mimetics of the natural
pyrimidines lacking any H-donors. The latter type contains
an H-acceptor in the minor groove but the H-bonding at the
WatsonꢀCrick is altered. Therefore, these compounds have
great potential in studying mechanism of incorporation by
RNA polymerases and as building blocks for construction of
modified RNAs.
BF3 Et2O at 0 °C) gave the desired 5-bromopyridin-2-yl C-ri-
3
bonucleoside 8 in 79% yield as a pure β-anomer. Interestingly,
the reduction of the epimeric β-acetal 7 under the same condi-
tions proceeded with inversion of configurayion at C-10 to furnish
8 in 81% yield as a single diastereomer. The stereochemistry of all
nucleosides 5ꢀ8 was verified by ROESY spectra.
For the synthesis of 6-substituted pyridin-3-yl C-ribonucleo-
sides, we adopted an analogous synthetic strategy using the
lithiation of 2,5-dibromopyridine 1 at position 5 (Scheme 1,
hꢀj). Thus, the lithiation of 1 in diethyl ether at ꢀ78 °C using
nBuLi resulted in selective formation of 2-bromo-5-lithiopyri-
dine 3 which upon coupling with lactone 4 furnished hemiketal 9
in 51% yield (only the R-anomer was formed) and side-product
12 (12% yield) formed by migration of TBS-protecting group
from 20-OH to hemiketal. In order to achieve complete con-
sumption of lactone 4, 5 equiv of pyridine 1 had to be used.
Structure of compound 12 was proved by X-ray structure analysis
(Figure 1). To suppress the formation of undesired 12, quench-
ing of the reaction mixture with MeOH at ꢀ78 °C was found to
be very efficient giving the desired hemiketal 9 in very good 75%
yield with only a trace amount of 12 (>2%).
’ RESULTS AND DISCUSSION
The key intermediates for the two classes of target C-nucleo-
sides were the corresponding suitably protected 5-bromopyridin-
2-yl and 6-bromopyridin-3-yl C-ribonucleosides. The synthesis
of both of them was based on known22 dichotomy in regiose-
lective lithiation of 2,5-dibromopyridine 1. In toluene, a debro-
molithiation proceeds22 at position 2 leading to 5-bromo-2-
lithiopyridine 2, whereas in Et2O at position 5 to furnish
2-bromo-5-lithiopyridine 3 (Scheme 1). Thus, the lithiation of
1 with nBuLi in toluene for 30 min at ꢀ78 °C selectively formed
2 which was immediately reacted with TBS-protected lactone 4
(0.5 equiv) for 10 min to afford the corresponding hemiketal 5 as
a pure R-anomer in poor 24% yield accompanied by a side-
product 17 (12%) formed by a migration of TBS group from 20-
OH to the hemiketal OH. In order to achieve complete conver-
sion of the starting lactone 4 and suppress formation of the
undesired 17, an extensive optimization was required. The
optimized conditions used 6 equiv of 1 (for lithiation to 2),
resulting in complete conversion of lactone 4 within 10 min
Subsequent quenching with MeOH at ꢀ78 °C and aqueous
Reduction of 9 under standard conditions (3 equiv of Et3SiH,
1.5 equiv of BF3 Et2O at 0 °C) failed similarly to the reduction of
3
5. Again, we relied on acetylation of the hemiketal to increase the
reactivity toward the reduction. Thus, the addition of 5-lithio-2-
bromopyridine 3 to lactone 4 at ꢀ78 °C followed by direct in situ
quenching with Ac2O gave a mixture of acylated ketal 10 and
hemiketal 9 in 54% and 11% yield, respectively. Unreacted
hemiketal 9 could be transformed to 10 upon reaction with
LiHMDS at ꢀ78 °C followed by quenching with A2O in 80%
yield. It is noteworthy to mention that in this case, no inversion of
anomeric configuration was observed at ꢀ78 °C (in contrast to
analogous acetylation of 5, vide supra). Subsequent reduction of
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Scheme 1a
a Reagents and conditions: (a) 1, nBuLi, toluene, ꢀ78 °C, 30 min; (b) 4, ꢀ78 °C, 10 min then MeOH gives 5 (73% based on 4); (c) Et3SiH, BF3 Et2O,
3
DCM, 0 °C, 10 min, 0%; (d) 4, ꢀ78 °C, 10 min then Ac2O, ꢀ78 °Cf r.t. gives 6 (18% based on 4); (e) LiHMDS then Ac2O, toluene, r.t. gives 7 (84%
from 4); (f) Et3SiH, BF3 Et2O, DCM, 0 °C, 10 min gives 8 (81% from 7); (g) Et3SiH, BF3 Et2O, DCM, 0 °C, 10 min gives 8 (79% from 6); (h) 1, Et2O,
3
3
nBuLi, ꢀ78 °C, 30 min; (i) 4, ꢀ78°C, 10 min then MeOH gives 9 (75% based on 4); (j) Et3SiH, BF3 Et2O, DCM, 0 °C, 10 min 0%; (k) 4, ꢀ78°C, 10
3
min then Ac2O followed by LiHMDS, then Ac2O gives 10 (77% based on 4); (l) Et3SiH, BF3 Et2O, DCM, ꢀ10 °C, 5 min gives 11 (71% from 10).
3
Scheme 2. Synthesis of Acylated Hemiketal 7: Proposed
Mechanism of Inversion at the Anomeric Carbon
Figure 1. Chemical and X-ray structure of the side-product 12. Thermal
ellipsoids are drawn at the 50% probability level. Hydrogen atoms on
TBS groups were omitted for clarity.
LiHMDS to the crude reaction mixture at ꢀ78 °C followed by
quenching with another portion of Ac2O and workup afforded
crude hemiketal 10. This was directly, without purification, used
in final reduction step, yielding after silica gel column chroma-
tography the desired bromopyridine C-ribonucleoside 11 as a
pure β-anomer in very good 77% overall yield based on lactone 4.
With the key intermediates 8 and 11 in hand, we turned our
attention to palladium-catalyzed cross-couplings, aminations,
aminocarbonylations, and hydroxylations (Scheme 3, Table 1,
Scheme 4, Table 2). Coupling of 8 with trimethylaluminium
under standard conditions using Pd(PPh3)4 in THF at 65 °C
gives 5-methylpyridin-2-yl C-ribonucleoside 13a in 90% yield
(Scheme 2, Table 1, entry 1). 5-Phenylpyridin-2-yl C-ribonucleo-
side 13b was prepared by SuzukiꢀMiyaura cross-coupling of
phenylboronic with 8 in toluene at 100 °C under catalysis of
Pd(PPh3)4 and K2CO3 in 89% yield (entry 2). In order to
introduce hetaryl substituents, the Stille cross-coupling reactions
using PdCl2(PPh3)2 in DMF were used. Reactions of 8 with
10 by Et3SiH (3 equiv) in the presence of BF3 Et2O (1.5 equiv)
3
at ꢀ10 °C furnished the desired TBS-protected 6-bromopyridin-
3-yl C-ribonucleoside 11 in 71% yield as a pure β-anomer.
This stepwise synthetic sequence was quite laborious, requir-
ing isolation of each intermediate, and gave the desired C-ribo-
nucleoside intermediate 11 in 54% overall yield based on lactone
4. In order to increase the overall yield and simplify the isolation
process we have further optimized the whole synthetic sequence.
Thus, the lithiation of pyridine 1 (5 equiv to 4) followed by
coupling with lactone 4 and quenching with Ac2O gave a crude
mixture of compounds 9 and 10. Subsequent addition of
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Scheme 3. Synthesis of a Series of 5-Substituted Pyridin-2-yl C-Ribonucleosides
Table 1. Functional Group Transformations of 8 Followed by Deprotection
entry
reagent
catalyst
ligand/Base
solvent
other conditions
reaction (yield)
deprotection (yield)
1
2
3
4
5
6
7
8
9
Me3Al
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd2dba3
THF
12 h, 65 °C
3 h, 100 °C
2 h, 100 °C
1.5 h, 100 °C
11 h 50 °C
3 h 60 °C
6 h, 80 °C
1.5 h, 80 °C
1.5 h 80 °C
13a (90%)
13b (89%)
13c (84%)
13d (63%)
13e (63%)
13f (70%)
13g (74%)
13h (80%)
13i (73%)
14a (83%)
14b (80%)
14c (83%)
14d (83%)
14e (75%)
14f (76%)
14g (75%)
14h (81%)
14i (74%)
a
PhB(OH)2
K2CO3
toluene
DMF
2-Bu3Sn- thiophene b
2-Bu3Sn- Pyridine c
LiN(SiMe3)2
Me2NH d
NH3f CO(1 atm)
DMF
PtBu3 HBF4
THF
3
Pd2dba3
JohnPhos e/tBuONa
Xantphos g/ K3PO4
Xantphos g/ K3PO4
Lh
toluene
toluene
toluene
dioxane/H2O
Pd(OAc)2
Pd(OAc)2
Pd2dba3
Me2NH HCl CO(1 atm)
3
KOH
a PhB(OH)2 = phenylboronic acid . b 2-Bu3Sn-thiophene = 2-(tributylstannyl)thiophene. c 2-Bu3Sn-pyridine = 2-(tributylstannyl)pyridine. d 2 M
solution in THF. JohnPhos = (2-biphenyl)di-tert-butylphosphane. 0.5 M in 1,4-dioxane. g Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethyl-
e
f
xanthene. h L = di-tert-butylphosphino-3,4,5,6-tetramethyl-20,40,60-triisopropylbiphenyl.
2-thienyl(tributyl)stannane proceeded very smoothly within 2 h
at 100 °C to give the desired 5-(2-thienyl)pyridine 13c in 84%
yield (entry 3). Reaction of 8 with 2-pyridyl(tributyl)stannane
(entry 4) required only 1.5 h to reach complete conversion and
the target 5,20-bipyridine-2-yl C-ribonucleoside 13d was isolated
in 63% yield (entry 4). Palladium-catalyzed amination reactions
(HartwigꢀBuchwald)24 were used for the synthesis of primary
and tertiary amines. Primary aminopyridine derivate 13e was
prepared by reaction of 8 with lithium bis(trimethylsilyl)amide
(LiHMDS) in the presence of Pd2dba3 and Buchwald-type
biaryl-ligand. When (2-biphenyl)dicyclohexylphosphane (cHex
JohnPhos)25,26 was employed as a ligand, no reaction occurred
even after long reaction time of 48 h at 50 °C. Only the use of
tri-tert-butylphosphane (generated in situ from tri-tert-butylpho-
sphonium tetrafluoroborate) gave the target 5-aminopyridine
C-ribonucleoside 13e in acceptable 63% yield after prolonged
reaction time (11 h) at 50 °C (entry 5). The dimethylamino
group was introduced by the reaction of 8 with dimethyl-
amine (2 M solution in THF) in a sealed tube in the presence
of Pd2dba3, 2-(di-tert-butylphosphanyl)biphenyl (JohnPhos),
and tBuONa. A short reaction time of 3 h (60 °C) was sufficient
to give dimethylaminopyridine C-ribonucleoside 13f in very
good 70% yield (entry 6).
isolated in improved 74% yield after somewhat longer (6 h)
reaction time (entry 7). Reaction of 8 with dimethylamine
hydrochloride resulted in formation of N,N-dimethyl carboxa-
mide 13h in 80% yield (entry 8). Recently developed3 palladium-
catalyzed hydroxylation using KOH, Pd2dba3, and di-tert-butyl-
phosphino-3,4,5,6-tetramethyl-20,40,60-triisopropylbiphenyl was
applied for the conversion of 8 to corresponding hydroxypyr-
idine 13i. The reaction was performed in 1,4-dioxaneꢀwater
(3:1) and proceeded smoothly at 80 °C in a short reaction time
(1.5 h) to afford the desired hydroxypyridine C-ribonucleoside
13i in very good 73% yield.
For final deprotection of the silylated nucleosides 13aꢀi,
reaction with Et3N 3HF27 was used. Heating at 40 °C for 2
3
days followed by treatment with NaHCO3 resulted in complete
cleavage of TBS-protecting groups. Chromatographic purifica-
tion on reverse-phase flash chromatography and subsequent
lyophilization/crystallization give free nucleosides 14aꢀd,f,h in
good yields (76ꢀ83%, Table 1, entries 1ꢀ4, 6, 8, last column).
Due to strongly hydrophilic character of compounds 14e,g,i
highly polar impurities could not be removed by reverse-phase
chromatography. Therefore, ion-exchange chromatography
Dowex 50 in H+ cycle was used to remove polar salts while the
pyridine C-nucleosides were eluted after washing with 25%
aqueous ammonia. Subsequent purification on reverse-phase
flash chromatography and lyophilization give free nucleosides
14e,g,i in good yields (74ꢀ75%, Table 1, entries 5, 7, 9, last
column).
Primary and tertiary carboxamides 13g and 13h were prepared
by Pd-catalyzed aminocarbonylation2 reactions in the presence
of Pd(OAc)2, Xantphos, and K3PO4. Reaction of ammonium
chloride (NH4Cl) with 8 in the presence of 5 mol % Pd(OAc)2
and 10 mol % of Xantphos gives amide 13g in 50% after a short
reaction time (1.5 h) at 80 °C. When 0.5 M THF solution of
ammonia was used instead of NH4Cl, primary amide 13g was
Analogously, we prepared a series of 6-substituted pyridin-3-yl
C-ribonucleosides starting from intermediate 11 (Scheme 4,
Table 2). Methyl, phenyl, 2-thienyl, and 2-pyridyl substituents
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Scheme 4. Synthesis of a Series of 6-Substituted Pyridin-3-yl C-Ribonucleosides
Table 2. Functional Group Transformations of 11 Followed by Deprotection
entry
reagent
catalyst
ligand/Base
solvent
other conditions
reaction (yield)
deprotection (yield)
1
2
3
4
5
6
7
8
9
Me3Al
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd2dba3
THF
2 h, 70 °C
1.5 h, 110 °C
1.5 h, 110 °C
4.5 h, 80 °C
5 h 50 °C
4.5 h 65 °C
2 h, 80 °C
3 h, 80 °C
4 h 80 °C
15a (93%)
15b (95%)
15c (81%)
15d (51%)
15e (88%)
15f (89%)
15g (81%)
15h (76%)
15i (79%)
16a (90%)
16b (91%)
16c (89%)
16d (52%)
16e (65%)e
16f (88%)
16g (85%)
16h (88%)
16i (41%) k
a
PhB(OH)2
K2CO3
toluene
DMF
2-Bu3Sn- thiophene b
2-Bu3Sn- pyridine c
LiN(SiMe)2
DMF
cHex JohPhosd
JohnPhos g/tBuONa
Xantphos i/ K3PO4
Xantphos i/ K3PO4
Lj
THF
Me2NH f
Pd2dba3
toluene
toluene
toluene
dioxane/H2O
NH3h CO(1 atm)
Me2NH f CO(1 atm)
KOH
Pd(OAc)2
Pd(OAc)2
Pd2dba3
a PhB(OH)2 = phenylboronic acid. b 2-Bu3Sn-thiophene = 2-(tributylstannyl)thiophene. c 2-Bu3Sn-pyridine = 2-(tributylstannyl)pyridine. d CHex
JohPhos = 2-(dicyclohexylphosphino)biphenyl. e TBAF was used for cleavage of TBS groups. f 2 M solution in THF. g JohnPhos = (2-biphenyl)di-tert-
butylphosphane. h 0.5 M solution in 1,4-dioxane. i Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. j L = di-tert-butylphosphino-3,4,5,6-
tetramethyl-20,40,60-triisopropylbiphenyl. k Trifluoroacetic acid was used for the cleavage of TBS groups.
were introduced using standard cross-couplings to give the
protected alkyl, aryl, and hetaryl C-nucleosides 15aꢀd in 93%,
95%, 81%, and 51%, respectively (entries 1ꢀ4). Reaction of 11
with LiHMDS in the presence of Pd2dba3 and cHex JohnPhos
was very efficient, yielding target aminopyridine 15e in 88% yield
(entry 5). Dimethylaminopyridine 15f was prepared in excellent
89% yield using the same conditions as in the previous series
(entry 6). Palladium-catalyzed aminocarbonylation under atmo-
spheric CO pressure was used for the synthesis of corresponding
carboxamides. Thus, reaction of 11 with NH3 (0.5 M in 1,4-dioxane)
and HNMe2 (2 M in THF) in the presence of Pd(OAc)2, Xantphos,
and K3PO4 at 80 °C produced target primary and tertiary amides 15g
and 15h in 81% and 76% yield, respectively. Palladium-catalyzed
hydroxylation using KOH, Pd2dba3 and di-tert-butylphosphino-
3,4,5,6-tetramethyl-20,40,60-triisopropylbiphenyl in 1,4-dioxaneꢀ
water was used for the conversion of bromopyridine 11 to corre-
sponding pyridone 15i in 79% yield.
For the final cleavage of TBS-protecting groups, treatment
with Et3N 3HF for 2 days at 40 °C followed by basic workup was
3
successfully applied for compounds 15aꢀd,fꢀh. Chromato-
graphic purification by reverse-phase flash chromatography and
subsequent lyophilization/crystallization give free nucleosides
16aꢀd,fꢀh in good yields (52ꢀ91%, Table 2, entries 1ꢀ4, 6, 8,
last column). For compound 15g, ion-exchange chromatography
(Dowex 50 in H+ cycle, eluting with water and then 25% aqueous
NH3) had to be used prior to the reverse-phase flash chroma-
tography purification, giving free 16g in 85% yield. For the
Figure 2. X-ray structures of compounds (a) 14a, (b) 14f, (c) 14h, and
(d) 16c.
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Table 3. Conformational Analysis of the Sugar Part of Se-
lected Nucleosides 14
considerable cytotoxicity, and therefore they are good candidates
for conversion to nucleoside triphosphates as model compounds
for studying specificity and fidelity of RNA polymerases and
primases or could serve as building blocks for modification or
construction of base-modified RNAs (artificial ribozymes, ribos-
witches, aptamers, etc.).
compd
R
solvent
PN ΦN PS ΦS XN:XS rms
14a
Me
Ph
DMSO-d6
CDCl3
10 35 131 35 52:48 0.012
ꢀ29 35 146 35 40:60 0.000
14b
14c
14d
14f
DMSO-d6
CDCl3
4
35 127 35 49:51 0.004
’ EXPERIMENTAL SECTION
ꢀ29 35 146 35 42:58 0.000
10 35 132 35 51:49 0.011
ꢀ29 35 146 35 40:60 0.000
15 35 138 35 53:47 0.027
ꢀ34 35 144 35 40:60 0.000
10 35 133 35 49:51 0.010
ꢀ31 35 142 35 40:60 0.000
11 35 139 35 50:50 0.011
ꢀ35 35 145 35 36:64 0.000
All cross-coupling reactions were carried out in evacuated flame-dried
glassware with magnetic stirring under argon atmosphere. THF, toluene,
and hexanes were dried and distilled from sodium/benzophenone.
Other reagents were purchased from commercial suppliers and used
as received. NMR spectra were recorded on a 400 MHz spectrometer
(1H at 400 MHz, 13C at 100.6 MHz), 500 MHz spectrometer (1H at 500
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 referenced to the residual
solvent signal (1H NMR δ 2.50 ppm, 13C NMR 39.7 ppm). Chemical
shifts are given in ppm (δ scale), coupling constants (J) in hertz.
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 established by two-dimensional
ROESY spectra. Melting points were determined on a Kofler block and
are uncorrected. Optical rotations were measured at 25 °C, [R]D values
2-thienyl DMSO-d6
CDCl3
2-py
DMSO-d6
CDCl3
Me2N
DMSO-d6
CDCl3
14h
CONMe2 DMSO-d6
CDCl3
deprotection of aminopyridine C-nucleoside 15e, TBAF was
found as a reagent of choice. Subsequent ion-exchange chroma-
tography (Dowex 50 in H+ cycle) and reverse-phase chromatog-
raphy furnished free C-nucleoside 16e in 65% yield. Desilylation
of compound 15i was performed by treatment with TFA. Free
nucleoside 16i was purified by ion-exchange chromatography
followed by reverse-phase chromatography, yielding 16i in 41%.
Structures of several free C-ribonucleosides were determined
by single-crystal X-ray diffraction (Figure 2). Surprisingly, the
solid-state conformation of the sugar part in compounds 14a,
14f, and 16c was found to be C20-endo (S-type) typical for 20-
deoxyribonucleosides, whereas only amide 14h adopted ex-
pected C30-endo configuration (N-type). No intramolecular
H-bonds from 50-OH to pyridine nitrogen were observed (in
contrast to previously reported12 6-substituted pyridin-2-yl
C-ribonucleosides). Therefore, we have determined solution
are given in 10ꢀ1 deg cm2
single crystals was carried out on an X-ray diffractometer using CuKR
radiation (λ = 1.54180 Å).
g
ꢀ1. The X-ray diffraction experiment of
3
3
1β-(5-Bromopyridin-2-yl)-2,3,5-tri-O-(tert-butyldimethy-
lsilyl)-D-ribofuranose (5). To a cooled (ꢀ78 °C) solution of 2,5-
dibromopyridine 1 (11.3 g, 47.7 mmol, 6 equiv) in toluene (406 mL)
was added n-BuLi (33 mL, 52.5 mmol, 6.6 equiv, 1.6 M in hexanes)
dropwise over a period of 10 min. The resulting brown-yellow solution
was stirred for a further 30 min at ꢀ78 °C, the solution of lactone 4
(3.9 g, 7.9 mmol) in toluene (42 mL) was added dropwise over 10 min,
and the mixture was stirred for another 10 min. Subsequently absol
MeOH (4.8 mL, 119 mmol, 15 equiv) was added, and the resulting
orange-yellow solution was heated to ambient temperature. The reac-
tion mixture was then poured into 2 M HCl (300 mL) and extracted into
hexanes (2 ꢁ 900 mL). The combined organic layers were washed with
2 M HCl (300 mL), sat. aq NaHCO3 (300 mL), dried over MgSO4, and
concentrated under reduced pressure. The crude product was chroma-
tographed on silica gel in gradient hexanes to 9% Et2O in hexanes to
give 5 (3.7 g, 73%) as a yellowish oil. HRMS (ESI) C28H55NO5Si3Br:
1
conformation of selected nucleosides by H NMR in DMSO-
d6 and CDCl3. The results (Table 3) indicate that in solution, the
equilibrium of both conformers is ca. 1:1 in DMSO whereas in
CDCl3 the N-conformers slightly prevail.
In conclusion, a novel modular diversity-oriented synthesis of
a large series of isomeric 5-substituted pyridin-2-yl and 6-sub-
stituted pyridin-3-yl C-ribonucleosides bearing diverse alkyl, aryl,
hetaryl, amino, carbamoyl, and hydroxy groups was developed
starting from 2,5-dibromopyridine. Its regioselective lithiation at
position 2 (in toluene) or at position 5 (in Et2O) gave the
corresponding isomeric bromopyridyl lithium species that after
addition to TBS-protected ribonolactone 4 and follow-up trans-
formations gave the corresponding acylated hemiketals 7 and 10.
These readily underwent reductive deacetoxylation using Et3-
1
[M + H] calculated 648.2566, found 648.2556. H NMR (500 MHz,
CDCl3): ꢀ0.39, ꢀ0.10, 0.07, 0.09, 0.14, and 0.15 (6 ꢁ s, 6 ꢁ 3H,
CH3Si); 0.78, 0.92, and 0.95 (3 ꢁ s, 3 ꢁ 9H, (CH3)3C); 3.68 (dd, 1H,
0
0
0
0
0
Jgem = 10.8 Hz, J5 a,4 = 7.1 Hz, H-5 a); 3.76 (dd, 1H, Jgem = 10.8 Hz, J5 b,4
= 3.9 Hz, H-50b); 4.20 (ddd, 1H, J4 ,5 a = 7.0 Hz, J4 ,5 b = 3.9 Hz, J4 ,3 = 0.9
0
0
0
0
0
0
Hz, H-40); 4.30 (dd, 1H, J3 ,2 = 4.5 Hz, J3 ,4 = 1.0 Hz, H-3 ); 4.68 (d, 1H,
0
0
0
0
0
J2 ,3 = 4.5 Hz, H-20); 5.14 (s, 1H, OH-10); 7.72 (dd, 1H, J3,4 = 8.5 Hz,
J3,6 = 0.8 Hz, H-3); 7.79 (dd, 1H, J4,3 = 8.5 Hz, J4,6 = 2.4 Hz, H-4); 8.62
(dd, 1H, J6,4 = 2.4 Hz, J6,3 = 0.8 Hz, H-6). 13C NMR (125.7 MHz,
CDCl3): ꢀ5.50, ꢀ5.47, ꢀ5.3, ꢀ4.9, ꢀ4.54, and ꢀ4.52 (CH3Si); 17.9,
18.0, and 18.3 ((CH3)3C); 25.7, 25.8, and 25.9 ((CH3)3C); 63.2 (CH2-
50); 74.7 (CH-30); 75.0 (CH-20); 85.1 (CH-40); 103.3 (C-10); 120.2
(C-5); 123.4 (CH-3); 138.7 (CH-4); 149.7 (CH-6); 157.2 (C-2). IR
0
0
SiH/BF3 Et2O to give a facile access to multigram amounts of
3
key protected 5-bromypyridin-2-yl and 6-bromopyridin-3-yl
C-ribonucleoside intermediates 8 and 11 in good overall yields
(68% and 77%). These intermediates were good substrates for
Pd-catalyzed cross-coupling reactions with alkylaluminum, aryl-
boronic acids, and hetarylstannanes to give alkyl, aryl, or hetaryl
derivatives. Primary and tertiary amines and carboxamines were
easily prepared by HartwigꢀBuchwald aminations and Pd-
catalyzed aminocarbonylations. Recently developed Pd-catalyzed
hydroxylation was used for the preparation of corresponding
hydroxypyridine and pyridone C-nucleosides. Free nucleosides
14aꢀi and 16aꢀi were prepared by desilylation of the intermedi-
spectrum (CCl4): 2957, 2929, 1858, 1471, 1463, 1259, 1116, 1009 cmꢀ1
.
1β-(5-Bromopyridin-2-yl)-1,3,5-tri-O-(tert-butyldimethy-
lsilyl)-D-ribofuranose (17). Isolated as a side-product in the synth-
esis of 5. HRMS (ESI) C28H55NO5Si3Br: [M + H] calculated 648.2566,
1
found 648.2556. H NMR (500 MHz, CDCl3): ꢀ0.25, 0.047, 0.052,
0.06, 0.12, and 0.13 (6 ꢁ s, 6 ꢁ 3H, CH3Si); 0.86, 0.91, and 0.93 (3 ꢁ s,
0
0
3 ꢁ 9H, (CH3)3C); 3.06 (d, JOH,2 = 11.2 Hz, OH-2 ); 3.76 ꢀ 3.82 (m,
0
2H, H-50); 3.87 (dd, 1H, J2 ,OH = 11.2 Hz, J2 ,3 = 6.2 Hz, H-2 ); 4.23 (dd,
0
0
0
ates by Et3N 3HF, TBAF, or TFA. They did not exert any
3
6624
dx.doi.org/10.1021/jo200949c |J. Org. Chem. 2011, 76, 6619–6635

The Journal of Organic Chemistry
ARTICLE
0
0
0
0
0
0
0
1H, J3 ,2 = 6.2 Hz, J3 ,4 = 2.3 Hz, 0H-3 ); 4.26 (bddd, 1H, J4 ,5 a = 4.4 Hz,
(CH-4); 149.0 (CH-6); 156.1 (C-2); 167.5 (CO). IR spectrum (CCl4):
2956, 2930, 2858, 1756, 1578, 1559, 1472, 1464, 1366, 1253, 1213, 1171,
0
0
0
0
J4 ,5 b = 3.5 Hz, J4 ,3 = 2.3 Hz, H-4 ); 7.57 (dd, 1H, J3,4 = 8.4 Hz, J3,6 = 0.8
Hz, H-3); 7.75 (dd, 1H, J4,3 = 8.4 Hz, J4,6 = 2.4 Hz, H-4); 8.64 (dd, 1H,
1121, 1072, 988 cmꢀ1
.
J
6,4 = 2.4 Hz, J6,3 = 0.8 Hz, H-6). 13C NMR (125.7 MHz, CDCl3): ꢀ5.5,
1β-(5-Bromopyridin-2-yl)-1-deoxy-2,3,5-tri-O-(tert-butyl-
dimethylsilyl)-D-ribofuranose (8). Et3SiH (3.5 mL, 21.7 mmol,
3 equiv) was added in one portion to a stirred solution of acylated
hemiketal 7 (5.0 g, 7.23 mmol) in dry dichloromethane (36 mL) on ice
ꢀ5.4, ꢀ4.9, ꢀ4.7, ꢀ3.7, and ꢀ3.1 (CH3Si); 18.1, 18.3, and 18.4
((CH3)3C); 25.8, 25.9, and 26.0 ((CH3)3C); 63.4 (CH2-50); 72.9
(CH-30); 77.6 (CH-20); 86.1 (CH-40); 103.7 (C-10); 119.9 (C-5);
122.2 (CH-3); 138.6 (CH-4); 149.7 (CH-6); 160.0 (C-2).
bath (0 °C) under argon. After 5 min, BF3 Et2O (1.3 mL, 10.8 mmol,
3
1r-(5-Bromopyridin-2-yl)-1-O-acetyl-2,3,5-tri-O-(tert-but-
yldimethylsilyl)-D-ribofuranose (6). To a cooled (ꢀ78 °C) solu-
tion of 2,5-dibromopyridine 1 (267 mg, 1.13 mmol, 6 equiv) in toluene
(14 mL) was added n-BuLi (0.7 mL, 1.13 mmol, 6 equiv, 1.6 M in
hexanes) dropwise over a period of 10 min. The resulting brown-yellow
solution was stirred for a further 30 min at ꢀ78 °C, a solution of lactone
4 (92 mg, 0.19 mmol) in toluene (1 mL) was added dropwise over a
period of 1 min, and the stirring was continued for another 10 min.
Subsequently, Ac2O (130 μL, 1.35 mmol, 7.2 equiv) was added
dropwise. and the resulting orange-yellow solution was allowed to warm
to ambient temperature. The reaction mixture was then poured into sat.
aq NaHCO3 (20 mL), carefully neutralized, extracted to hexanes (2 ꢁ
80 mL), dried over Na2SO4, and concentrated under reduced pressure.
The crude product was chromatographed on silica gel in gradient
hexanes to 5% Et2O in hexanes to give 6 (23 mg, 18%) as a yellowish
oil. HRMS (ESI) C30H56NO6Si3BrNa: [M + Na] calculated 712.2491,
1.5 equiv) was slowly added in one portion, and the resulting mixture
was stirred for an additional 5 min. Subsequently, Et3N (20 mL) was
added, and the reaction mixture was evaporation under reduced
pressure. The crude product was directly chromatographed on silica
gel in gradient hexanes to 2% Et2O in hexanes to give 8 (3.7 g, 81%) as a
colorless oil. HRMS (ESI) C28H55NO4Si3Br: [M + H] calculated
632.2617, found 632.2617. 1H NMR (500 MHz, CDCl3): ꢀ0.17,
ꢀ0.04, 0.06, 0.07, 0.10, and 0.11 (6 ꢁ s, 6 ꢁ 3H, CH3Si); 0.84, 0.91,
0
0
and 0.93 (3 ꢁ s, 3 ꢁ 9H, (CH3)3C); 3.76 (dd, 1H, Jgem = 11.1 Hz, J5 a,4
=
0
2.9 Hz, H-50a); 3.87 (dd, 1H, Jgem = 11.1 Hz, J5 b,4 = 3.8 Hz, H-5 b); 4.07
0
0
(btd, 1H, J4 ,3 = J4 ,5 b = 4.0 Hz, J4 ,5 a = 2.9 Hz, H-40); 4.10 (bt, 1H, J3 ,2
=
0
0
0
0
0
0
0
0
J3 ,4 = 4.1 Hz, H-30); 4.14 (dd,01H, J2 ,1 = 5.4 Hz, J2 ,3 = 4.1 Hz, H-20);
0
0
0
0
0
0
0
0
4.90 (d, 1H, J1 ,2 = 5.4 Hz, H-1 ); 7.54 (bd, 1H, J3,4 = 8.4 Hz, H-3); 7.77
(dd, 1H, J4,3 = 8.4 Hz, J4,6 = 2.4 Hz, H-4); 8.62 (bd, H, J6,4 = 2.4 Hz, H-6).
13C NMR (125.7 MHz, CDCl3): ꢀ5.41, ꢀ5.39, ꢀ4.95, ꢀ4.61, ꢀ4.59,
and ꢀ4.4 (CH3Si); 18.00, 18.04, and 18.4 ((CH3)3C); 25.80, 25.85, and
26.0 ((CH3)3C); 62.8 (CH2-50); 72.5 (CH-30); 78.5 (CH-20); 84.4 (CH-
10); 84.7 (CH-40); 119.4 (C-5); 123.0 (CH-3); 138.8 (CH-4); 149.9
(CH-6); 159.2 (C-2). IR spectrum (CCl4): 2956, 1930, 1858, 1472, 1463,
1
found 712.2493. H NMR (500 MHz, CDCl3): ꢀ0.38, ꢀ0.10, 0.06,
0.080, 0.088, and 0.090 (6 ꢁ s, 6 ꢁ 3H, CH3Si); 0.87, 0.89, and 0.94
(3 ꢁ s, 3 ꢁ 9H, (CH3)3C); 2.09 (s, 3H, CH3CO); 3.78 (dd, 1H, Jgem
=
0
1362, 1256, 1155, 1130, 1119, 1077, 1009 cmꢀ1
.
0
0
0
0
11.3 Hz, J5 a,4 = 2.1 Hz, H-5 a); 3.95 (dd, 1H, Jgem = 11.3 Hz, J5 b,4 = 2.9
0
Hz, H-50b); 4.08 (d, 10H, J2 ,3 = 5.1 Hz, H0-2 ); 4.17 (dd, 1H, J3 ,2 = 5.1
0
0
0
0
1β-(6-Bromopyridin-3-yl)-2,3,5-tri-O-(tert-butyldimethyl-
silyl)-D-ribofuranose (9). To a cooled (ꢀ78 °C) solution of 2,5-
dibromopyridine 1 (519 mg, 2.19 mmol, 5 equiv) in Et2O (26 mL) was
added n-BuLi (1.6 mL, 2.52 mmol, 5.75 equiv, 1.6 M in hexanes)
dropwise over a period of 3 min. The resulting red solution was stirred
for a further 30 min at ꢀ78 °C, a solution of lactone 4 (215 mg,
0.438 mmol) in Et2O (3 mL) was added dropwise in 3 min, and stirring
was continued for another 10 min. Subsequently, absol MeOH
(0.18 mL, 4.38 mmol, 10 equiv) was added at ꢀ78 °C, and the resulting
orange-yellow solution was allowed to warm to ambient temperature.
The reaction mixture was then poured into 2 M HCl (30 mL) and
extracted to Et2O (2 ꢁ 70 mL). Combined organic layers were washed
with 2 M HCl (30 mL) and sat. aq NaHCO3 (30 mL), dried over
MgSO4, and concentrated under reduced pressure. The crude product
was chromatographed on silica gel in gradient hexanes to 2% Et2O in
hexanes to give 9 (213 mg, 75%) as a yellowish oil. HRMS (ESI)
0
0
Hz, J3 ,4 = 2.6 Hz, H-3 ); 4.27 (m, 1H, H-4 ); 7.59 (dd, 1H, J3,4 = 8.5 Hz,
J
3,6 = 0.7 Hz, H-3); 7.74 (dd, 1H, J4,3 = 8.5 Hz, J4,6 = 2.4 Hz, H-4); 8.55
(dd, 1H, J6,4 = 2.4 Hz, J6,3 = 0.7 Hz, H-6). 13C NMR (125.7 MHz,
CDCl3): ꢀ5.62, ꢀ5.61, ꢀ5.5, ꢀ4.6, ꢀ4.40, and ꢀ4.37 (CH3Si); 17.9,
18.1, and 18.3 ((CH3)3C); 21.9 (CH3CO); 25.74, 25.79, and 25.9
((CH3)3C); 62.6 (CH2-50); 72.1 (CH-30); 79.6 (CH-20); 87.3 (CH-40);
105.6 (C-10); 119.9 (C-5); 122.3 (CH-3); 138.8 (CH-4); 149.3 (CH-6);
157.3 (C-2); 169.8 (CO). IR spectrum (KBr): 2956, 2930, 1858, 1754,
1472, 1463, 1263, 1255, 1094, 1009, 839 cmꢀ1
.
1β-(5-Bromopyridin-2-yl)-1-O-acetyl-2,3,5-tri-O-(tert-but-
yldimethylsilyl)-D-ribofuranose (7). To a solution of 5 (5.0 g,
7.7 mmol) in toluene (46 mL) was added LiHMDS (11.6 mL, 11.6
mmol, 1 M in THF, 1.5 equiv) at room temperature. The reaction
mixture was stirred for 5 min, Ac2O (1.1 mL, 11.6 mmol, 1.5 equiv) was
added dropwise, and the stirring was continued for another 5 min
(addition of 1.5 equiv of LiHMDS followed by Ac2O (1.5 equiv) was
repeated two more times). Then sat. aq NaHCO3 (300 mL) was added,
and the mixture was stirred for 10 min at room temperature, transferred
to separatory funnel, and extracted with EtOAc (2 ꢁ 600 mL). The
organic layers were dried over Na2SO4, concentrated under reduced
pressure, and chromatographed on silica gel column eluting in gradient
hexanes to 10% EtOAc in hexanes to give 7 (4.36 g, 84%) as a yellowish
oil. HRMS (ESI) C30H56NO6Si3BrNa: [M + Na] calculated 712.2491,
found 712.2492. 1H NMR (500 MHz, DMSO-d6): ꢀ0.64, ꢀ0.01, 0.03,
0.04, 0.11, and 0.15 (6 ꢁ s, 6 ꢁ 3H, CH3Si); 0.62, 0.88, and 0.90 (3 ꢁ s, 3
ꢁ 9H, (CH3)3C); 1.92 (s, 3H, CH3CO); 3.69 (dd, 1H, Jgem = 12.2 Hz,
1
C28H55NO5Si3Br: [M + H] calculated 648.2566, found 648.2568. H
NMR (500 MHz, CDCl3): ꢀ0.50, ꢀ0.10, 0.12, 0.127, and 0.134 (6 ꢁ s,
6 ꢁ 3H, CH3Si); 0.84, 0.92, and 0.95 (3 ꢁ s, 3 ꢁ 9H, (CH3)3C); 3.80
0
0
0
(dd, 1H, Jgem = 11.1 Hz,0J5 a,4 = 2.4 Hz, H-5 a); 3.84 (dd, 1H, Jgem = 11.1
0
0
0
0
0
Hz, J5 b,4 = 3.3 Hz, H-5 b); 4.01 (d, 1H, J2 ,3 = 4.6 Hz, H-2 ); 4.18 (dd,
0
0
0
0
0
0
1H, J3 ,2 = 4.6 Hz, J3 ,4 = 0.7 Hz, H-3 ); 4.23 (m, 1H, H-4 ); 5.13 (s, 1H,
OH-10); 7.42 (dd, 1H, J5,4 = 8.3 Hz, J5,2 = 0.7 Hz, H-5); 7.80 (dd, 1H,
J4,5 = 8.3 Hz, J4,2 = 2.5 Hz, H-4); 8.59 (dd, 1H, J2,4 = 2.5 Hz, J2,5 = 0.7 Hz,
H-2). 13C NMR (125.7 MHz, CDCl3): ꢀ5.63, ꢀ5.62, ꢀ5.4, ꢀ4.8,
ꢀ4.58, and ꢀ4.46 (CH3Si); 17.81, 17.85, and 18.3 ((CH3)3C); 25.70,
25.74, and 25.9 ((CH3)3C); 63.5 (CH2-50); 74.9 (CH-30); 77.7 (CH-
20); 85.5 (CH-40); 102.8 (C-10); 126.9 (CH-5); 136.1 (C-3); 137.4
(CH-4); 141.9 (C-6); 149.3 (CH-2). IR spectrum (CCl4): 3499, 2956,
J5 a,4 = 3.2 Hz, H-50a); 3.94 (dd, 1H, Jgem = 12.2 Hz, J5 b,4 = 2.3 Hz,
0
0
0
0
H-50b); 4.18 (bdt, 1H, J4 ,3 = 8.0 Hz, J4 ,5 a = J4 ,5 b = 2.7 Hz, H-40); 4.24
0
0
0
0
0
0
2931, 1585, 1472, 1462, 1363, 1257, 1103 cmꢀ1
.
0
0
0
0
0
0
0
(d, 1H, J2 ,3 = 3.5 Hz, H-2 ); 4.55 (dd, 1H, J3 ,4 = 8.1 Hz, J3 ,2 = 3.5 Hz,
H-30); 7.50 (dd, 1H, J3,4 = 8.5 Hz, J3,6 = 0.8 Hz, H-3); 8.02 (dd, 1H, J4,3
=
1β-(6-Bromopyridin-3-yl)-1,3,5-tri-O-(tert-butyldimethy-
lsilyl)-D-ribofuranose (12). Isolated as a side-product in the synth-
esis of 9. HRMS (ESI) C28H55NO5Si3Br: [M + H] calculated 648.2566,
found 648.2566. 1H NMR (500 MHz, CDCl3): ꢀ0.32, 0.06, 0.07, 0.11,
0.12, and 0.13 (6 ꢁ s, 6 ꢁ 3H, CH3Si); 0.84, 0.90, and 0.93 (3 ꢁ s, 3 ꢁ
8.5 Hz, J4,6 = 2.4 Hz, H-4); 8.60 (dd, 1H, J6,4 = 2.4 Hz, J6,3 = 0.8 Hz, H-6).
13C NMR (125.7 MHz, DMSO-d6): ꢀ5.4, ꢀ5.28, ꢀ5.27, ꢀ4.7, ꢀ4.4,
and ꢀ3.8 (CH3Si); 17.8, 18.1, and 18.4 ((CH3)3C); 21.9 (CH3CO);
25.7, 26.1, and 26.2 ((CH3)3C); 61.1 (CH2-50); 70.9 (CH-30); 78.6
(CH-20); 83.9 (CH-40); 107.9 (C-10); 119.4 (C-5); 125.3 (CH-3); 138.5
9H, (CH3)3C); 2.99 (d, 1H, JOH,2 = 12.4 Hz, OH-20); 3.70 (dd, 1H,
0
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dx.doi.org/10.1021/jo200949c |J. Org. Chem. 2011, 76, 6619–6635

The Journal of Organic Chemistry
ARTICLE
0
0
J2 ,OH = 12.4 Hz, J2 ,3 = 6.4 Hz, H-20); 3.77 (dd, 1H, Jgem = 11.0 Hz,
J3 ,4 = 1.5 Hz, J3 ,1 = 0.5 Hz, H-3 ); 4.75 (bd, 1H, J1 ,2 = 8.2 Hz, H-1 );
7.42 (bd, 1H, J5,4 = 8.3 Hz, H-5); 7.67 (ddd, 1H, J4,5 = 8.2 Hz, J4,2 = 2.4
0
0
0
0
0
0
0
0
0
0
J5 a,4 = 2.6 Hz, H-50a); 3.83 (dd, 1H, Jgem = 11.0 Hz, 0J5 b,4 = 3.2 Hz,
0
0
0
0
H-50b); 4.20 (dd, 1H, J3 ,2 = 6.4 Hz, J3 ,4 = 1.7 Hz, H-3 ); 4.24 (td, 1H,
Hz, J4,1 = 0.6 Hz, H-4); 8.36 (dt, 1H, J2,4 = 2.4 Hz, J2,5 = J2,1 = 0.6 Hz,
H-2).13C NMR (150.9 MHz, CDCl3): ꢀ5.6, ꢀ5.4, ꢀ5.3, ꢀ4.50,
ꢀ4.48, and ꢀ4.39 (CH3Si); 17.8, 18.0, and 18.3 ((CH3)3C); 25.76,
25.83, and 25.9 ((CH3)3C); 63.6 (CH2-50); 74.0 (CH-30); 79.5 (CH-
20); 79.8 (CH-10); 86.7 (CH-40); 127.5 (CH-5); 135.9 (C-3); 136.9
(CH-4); 141.2 (C-6); 148.9 (C-2). IR spectrum (CCl4): 2956, 2930,
0
0
0
0
0
0
0
0
0
0
0
0
0
J
4 ,5 a = J4 ,5 b = 2.9 Hz, J4 ,3 = 1.7 Hz, H-4 ); 7.40 (dd, 1H, J5,4 = 8.3 Hz,
J5,2 = 0.8 Hz, H-5); 7.77 (dd, 1H, J4,5 = 8.3 Hz, J4,2 = 2.5 Hz, H-4); 8.55
(dd, 1H, J2,4 = 2.5 Hz, J2,5 = 0.8 Hz, H-2). 13C NMR (125.7 MHz,
CDCl3): ꢀ5.7, ꢀ5.4, ꢀ4.9, ꢀ4.7, ꢀ3.6, and ꢀ2.9 (CH3Si); 17.9, 18.2,
and 18.4 ((CH3)3C); 25.8, 25.9, and 26.0 ((CH3)3C); 63.6 (CH2-50);
72.9 (CH-30); 79.0 (CH-20); 86.8 (CH-40); 102.9 (C-10); 127.0 (CH-
5); 136.3 (CH-4); 138.9 (C-3); 141.4 (C-6); 147.9 (CH-2).
2859, 1585, 1564, 1472, 1463, 1257, 1153, 1113, 1089 cmꢀ1
.
1β-(6-Bromopyridin-3-yl)-1-deoxy-2,3,5-tri-O-(tert-buty-
ldimethylsilyl)-D-ribofuranose (11): Optimized Procedure
Starting from 1. To a cooled (ꢀ78 °C) solution of 2,5-dibromopyr-
idine 1 (1.54 g, 6.47 mmol, 5 equiv) in Et2O (78 mL) was added n-BuLi
(4.7 mL, 7.45 mmol, 5.75 equiv, 1.6 M in hexanes) dropwise over a
period of 3 min. The resulting red solution was stirred for a further 30
min at ꢀ78 °C, a solution of lactone 4 (636 mg, 1.29 mmol) in Et2O
(9.0 mL) was added dropwise over a period of 3 min, and the stirring was
continued for another 10 min. Subsequently, Ac2O (920 μL, 9.72 mmol,
7.5 equiv) was added dropwise, and resulting yellow solution was
allowed to warm to ambient temperature. The mixture was then cooled
to ꢀ78 °C, and LiHMDS (6.5 mL, 6.5 mmol, 5 equiv 1.0 M in THF) was
added. The resulting yellow solution was stirred for a further 3 min,
Ac2O (613 μL, 6.47 mmol, 5 equiv) was added, and the reaction mixture
was allowed to warm to ambient temperature and quenched with sat. aq
NaHCO3 (200 mL). After additional stirring for a further 20 min, the
reaction mixture was extracted with Et2O (2 ꢁ 300 mL), dried over
Na2SO4, and concentrated under reduced pressure. The resulting
brown-orange solid was suspended in hexanes (500 mL), and the
organic layer was filtered off and concentrated under reduced pressure
to afford crude 10 as a yellowish oil (1.26 g). Crude 10 was dissolved in
dry CH2Cl2 (9 mL) and cooled to ꢀ10 °C, Et3SiH (871 μL, 5.47 mmol,
3 equiv) was added, and the resulting solution was stirred for a further
1β-(6-Bromopyridin-3-yl)-1-O-acetyl-2,3,5-tri-O-(tert-but-
yldimethylsilyl)-D-ribofuranose (10). To a cooled (ꢀ78 °C)
solution of 2,5-dibromopyridine 1 (1.18 g, 5.0 mmol, 5 equiv) in Et2O
(60 mL) was added n-BuLi (3.6 mL, 5.73 mmol, 5.75 equiv, 1.6 M in
hexanes) dropwise over a period of 3 min. The resulting red solution was
stirred for a further 30 min at ꢀ78 °C, a solution of lactone 4 (489 mg,
1.00 mmol) in Et2O (7.0 mL) was added dropwise over a period of
3 min, and the stirring was continued for another 10 min. Subsequently,
Ac2O (760 μL, 7.47 mmol, 7.5 equiv) was added dropwise, and the
resulting yellow solution was allowed to warm to ambient temperature.
Then the mixture was cooled to ꢀ78 °C, and LiHMDS (5.0 mL,
5.00 mmol, 5 equiv 1.0 M in THF) was added. The resulting yellow
solution was stirred for a further 5 min, Ac2O (470 μL, 5.0 mmol, 5
equiv) was added, and the reaction was allowed to warm to ambient
temperature and quenched with sat. aq NaHCO3 (200 mL). After
additional stirring for a further 15 min, the mixture was extracted with
Et2O (2 ꢁ 300 mL), dried over Na2SO4, and concentrated under
reduced pressure. The resulting brown-orange solid was suspended in
hexanes (500 mL), and the organic layer was filtered off and concen-
trated under reduced pressure to afford a yellowish oil. The crude
product was chromatographed on silica gel in gradient hexanes to 6%
EtOAc in hexanes to give 10 (528 mg, 77%) as a light yellow oil. HRMS
(ESI) C30H57NO6Si3Br: [M + H] calculated 690.2672, found 690.2673.
1H NMR (500 MHz, DMSO-d6): ꢀ0.51, ꢀ0.09, 0.07, 0.09, 0.098, and
0.104 (6 ꢁ s, 6 ꢁ 3H, CH3Si); 0.85, 0.86, and 0.92 (3 ꢁ s, 3 ꢁ 9H,
5 min. Subsequently, BF3 Et2O (544 μL, 4.56 mmol, 2.5 equiv) was
3
added dropwise. After 15 min, Et3N (15 mL) was added, and the
reaction mixture was warmed up to room temperature and concentrated
under reduced pressure. The crude product was chromatographed on
silica gel in gradient hexanes to 2.7% Et2O in hexanes to give 11 (629 g,
77%, based on lactone 4) as a colorless oil.
(CH3)3C); 2.01 (s, 3H, CH3CO); 3.79 (d, 1H, J2 ,3 = 5.3 Hz, H-20);
0
0
0
0
0
3.80 (dd, 1H, Jgem = 11.5 Hz,0J5 a,4 = 2.4 Hz, H-5 a); 3.88 (dd, 1H, Jgem
=
0
0
0
0
0
0
11.5 Hz, J5 b,4 = 3.1 Hz, H-5 b); 4.10 (dd, 1H, J3 ,2 = 5.4 Hz, J3 ,4 = 1.2
Hz, H-30); 4.21 (btd, 1H, J4 ,5 a = J4 ,5 b = 2.7 Hz, J4 ,3 = 1.1 Hz, H-40);
0
0
0
0
0
0
1β-(5-Methylpyridin-2-yl)-2,3,5-tri-O-(tert-butyldimethy-
lsilyl)-D-ribofuranose (13a). Me3Al (0.93 mL, 1.86 mmol, 2 equiv, 2
M in toluene) was added to a vigorously stirred solution of 8 (587 mg,
0.927 mmol) and Pd(PPh3)4 (54 mg, 0.043 mmol, 5 mol %) in THF
(13 mL) under argon. The mixture was stirred at 65 °C for 12 h,
quenched by pouring into saturated NaH2PO4 (50 mL), and extracted
to EtOAc (3 ꢁ 50 mL). The crude product was chromatographed on
silica gel in gradient hexanes to 3.5% EtOAc in hexanes to give 13a (472
mg, 90%) as colorless oil. HRMS (ESI) C29H58NO4Si3: [M + H]
calculated 568.3668, found 568.3671. 1H NMR (500 MHz, DMSO-d6):
ꢀ0.25, ꢀ0.11, 0.05, 0.07, 0.08, and 0.09 (6 ꢁ s, 6 ꢁ 3H, CH3Si); 0.77,
0.89, and 0.90 (3 ꢁ s, 3 ꢁ 9H, (CH3)3C); 2.28 (s, 3H, CH3-5); 3.70
7.61 (dd, 1H, J4,3 = 8.3 Hz, J4,6 = 2.5 Hz, H-4); 7.67 (dd, 1H, J3,4 = 8.3 Hz,
J3,6 = 0.8 Hz, H-3); 8.31 (bdd, 1H, J6,4 = 2.4 Hz, J6,3 = 0.8 Hz, H-6). 13
C
NMR (125.7 MHz, DMSO-d6): ꢀ5.8, ꢀ5.6, ꢀ5.4, ꢀ4.7, ꢀ4.5, and
ꢀ4.2 (CH3Si); 17.68, 17.72, and 18.0 ((CH3)3C); 21.8 (CH3CO);
25.70, 25.73, and 25.9 ((CH3)3C); 63.0 (CH2-50); 72.0 (CH-30); 80.2
(CH-20); 88.0 (CH-40); 104.5 (C-10); 127.5 (CH-3); 135.8 (C-5); 136.4
(CH-4); 140.9 (C-2); 147.4 (CH-6); 168.4 (CO). IR spectrum
(CCl4):2955, 2931, 2859, 1758, 1242, 1365, 1119, 840 cmꢀ1
.
1β-(6-Bromopyridin-3-yl)-1-deoxy-2,3,5-tri-O-(tert-buty-
ldimethylsilyl)-D-ribofuranose (11). Et3SiH (630 μL, 3.9 mmol, 3
equiv) was added in one portion to a stirred solution of acylated
hemiketal 10 (905 mg, 1.3 mmol) in dry dichloromethane (7 mL)
(dd, 1H, Jgem = 11.2 Hz, J5 a,4 = 3.4 Hz, H-50a); 3.80 (dd, 1H, Jgem
=
0
0
0
0
0
0
0
0
0
0
0
11.2 Hz, J5 b,4 = 4.2 Hz, H-5 b); 3.92 (bq, 1H, J4 ,3 = J4 ,5 a = J4 ,5 b = 3.7
cooled to ꢀ10 °C. After 5 min, BF3 Et2O (234 μL, 2.0 mmol,
3
Hz, H-40); 4.10 (m, 1H, H-30); 4.16 (dd, 01H, J2 ,1 = 5.9 Hz, J2 ,3 = 4.4
0
0
0
0
1.5 equiv) was slowly added, and the resulting mixture was stirred
for an additional 5 min. Subsequently, Et3N (20 mL) was added, and
the reaction mixture was evaporation under reduced pressure. The
crude product was directly chromatographed on silica gel in gradient
hexanes to 2% Et2O in hexanes to give 11 (588 mg, 71%) as a colorless
oil. HRMS (ESI) C28H55NO4Si3Br: [M + H] calculated 632.2617,
Hz, H-20); 4.70 (d, 1H, J1 ,2 = 5.9 Hz, H-1 ); 7.45 (bd, 1H, J3,4 = 7.9 Hz,
H-3); 7.57 (ddd, 1H, J4,3 = 7.9 Hz, J4,6 = 2.3 Hz, JLR = 0.8 Hz, H-4); 8.35
(dt, 1H, J6,4 = 2.3 Hz, J6,3 = JLR = 0.8 Hz, H-6). 13C NMR (125.7 MHz,
DMSO-d6): ꢀ5.3, ꢀ5.1, and ꢀ4.6 (CH3Si); 17.8 (CH3-5); 17.88,
17.98, and 18.2 ((CH3)3C); 25.8, 25.9, and 26.0 ((CH3)3C); 62.9
(CH2-50); 72.8 (CH-30); 78.1 (CH-20); 84.3 and 84.4 (CH-10,40); 121.1
(CH-3); 132.3 (C-5); 136.9 (CH-4); 149.1 (CH-6); 157.1 (C-2). IR
spectrum (CCl4): 2956, 2929, 2858, 1602, 1574, 1472, 1463, 1389,
0
0
1
found 632.2614. H NMR (600 MHz, CDCl3): ꢀ0.44, ꢀ0.10, 0.08,
0.09, 0.10, and 0.11 (6 ꢁ s, 6 ꢁ 3H, CH3Si); 0.81, 0.92, and 0.93 (3 ꢁ s,
0
0 0
3 ꢁ 9H, (CH3)3C); 3.75 (dd, 1H, Jgem = 11.1 Hz, J5 a,4 = 2.7 Hz,
1362, 1254, 1155, 997, 838 cmꢀ1
.
H-50a); 3.78 (dd, 1H, Jgem = 11.1 Hz, J5 b,4 = 3.5 Hz, H-5 b); 3.83 (dd,
0
0
J2 ,1 = 8.2 Hz, J2 ,3 = 4.4 Hz, H-20); 4.04 (ddd, 1H, J4 ,5 b = 3.5 Hz,
1β-(5-Phenylpyridin-2-yl)-2,3,5-tri-O-(tert-butyldimethyl-
silyl)-D-ribofuranose (13b). Compound 8 (504 mg, 0.796 mmol),
0
0
0
0
0
0
J4 ,5 a = 2.7 Hz, J4 ,3 = 1.4 Hz, H-40); 4.11 (ddd, 1H, J3 ,2 = 4.4 Hz,
0
0
0
0
0
0
6626
dx.doi.org/10.1021/jo200949c |J. Org. Chem. 2011, 76, 6619–6635

The Journal of Organic Chemistry
ARTICLE
K2CO3 (243 mg, 1.75 mmol, 2.2 equiv), Pd(PPh3)4 (46 mg, 0.040
mmol, 5 mol %), and PhB(OH)2 (194 mg, 1.59 mmol, 2 equiv) were
dissolved in toluene (16 mL) under argon, and the mixture was stirred at
100 °C for 3 h. The reaction mixture was concentrated under reduced
pressure, and crude product was chromatographed on silica gel in
toluene to give 13b (446 mg, 89%) as a colorless oil. HRMS (ESI)
C34H60NO4Si3: [M + H] calculated 630.3825, found 630.3828. 1H
NMR (500 MHz, CDCl3): ꢀ0.12, ꢀ0.01, 0.109, 0.112, 0.13, and 0.14
MgSO4. After evaporation of solvents under reduced pressure, the
crude product was chromatographed on silica gel in gradient hexanes
to 10% EtOAc in hexanes to obtain 13d (119 mg, 63%) as a colorless
oil. HRMS (ESI) C33H59N2O4Si3 [M + H] calculated 631.3777,
found 631.3780. 1H NMR (500 MHz, CDCl3): ꢀ0.16, ꢀ0.04, 0.07,
0.08, 0.12, and 0.14 (6 ꢁ s, 6 ꢁ 3H, CH3Si); 0.84, 0.92, and 0.95 (3 ꢁ
0
0 0
s, 3 ꢁ 9H, (CH3)3C); 3.80 (dd, 1H, Jgem = 11.1 Hz, J5 a,4 = 3.2 Hz,
H-50a); 3.91 (dd, 1H, Jgem = 11.1 Hz, J5 b,4 = 4.1 Hz, H-5 b); 4.11 (td,
0
0
0
0
0
0
0
0
0
0
0
0
(6 ꢁ s, 6 ꢁ 3H, CH3Si); 0.86, 0.95, and 0.96 (3 ꢁ s, 3 ꢁ 9H, (CH3)3C);
J4 ,3 = J4 ,5 b = 4.1 Hz, J4 ,5 a = 3.2 Hz, H-40); 4.15 (t, 1H, J3 ,4 = J3 ,2
=
3.83 (dd, 1H, Jgem = 11.1 Hz,0J5 a,4 = 3.5 Hz, H-5 a); 3.91 (dd, 1H, Jgem
=
=
4.2 Hz, H-30); 4.22 (dd, 1H, J2 ,1 = 5.6 Hz, J2 ,3 = 4.2 Hz, H-2 ); 5.01
(d, 1H, J1 ,2 = 5.6 Hz, H-1 ); 7.29 (ddd, 1H, J5,4 = 7.2 Hz, J5,6 = 4.8
Hz, J5,3 = 1.4 Hz, H-5-py); 7.72 (bd, 1H, J3,4 = 8.1 Hz, H-3); 7.76 (dt,
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
11.1 Hz, J5 b,4 = 4.5 Hz, H-5 b); 4.12 (td, J4 ,3 = J4 ,5 b = 4.2 Hz, J4 ,5 a
3.5 Hz, H-40); 4.20 (bt, 1H, J3 ,4 = J3 ,2 = 4.1 Hz, H-30); 4.30 (dd, 1H,
0
0
0
0
J2 ,1 = 5.7 Hz, J2 ,3 = 4.3 Hz, H-20); 5.02 (d, 1H, J1 ,2 = 5.7 Hz, H-10);
7.40 (m, 1H, H-p-Ph); 7.47 (m, 2H, H-m-Ph); 7.58 (m, 2H, H-o-Ph);
7.65 (bd, 1H, J3,4 = 8.1 Hz, H-3); 7.86 (dd, 1H, J4,3 = 8.1 Hz, J4,6 = 2.4 Hz,
H-4); 8.83 (dd, 1H, J6,4 = 2.4 Hz, J6,3 = 0.8 Hz, H-6). 13C NMR (125.7
MHz, CDCl3): ꢀ5.34, ꢀ5.31, ꢀ4.8, ꢀ4.48, ꢀ4.47, and ꢀ4.3 (CH3Si);
18.10, 18.13, and 18.5 ((CH3)3C); 25.93, 25.97, and 26.1 ((CH3)3C);
63.4 (CH2-50); 73.1 (CH-30); 78.6 (CH-20); 84.5 (CH-10); 85.1 (CH-
40); 121.9 (CH-3); 127.2 (CH-o-Ph); 128.1 (CH-p-Ph); 129.1 (CH-m-
Ph); 135.0 (CH-4); 135.8 (C-5); 137.9 (C-i-Ph); 147.0 (C-6); 159.0
(C-2). IR spectrum (CCl4): 2957, 2930, 2858, 1597, 1473, 1362, 1258,
1H, J3,4 = 7.9 Hz, J3,5 = J3,6 = 1.3 Hz, H-3-py); 7.79 (ddd, 1H, J4,3
=
0
0
0
0
0
0
8.0 Hz, J4,5 = 7.1 Hz, J4,6 = 1.8 Hz, H-4-py); 8.31 (dd, 1H, J4,3 = 8.2
Hz, J4,6 = 2.3 Hz, H-4); 8.72 (ddd, 1H, J6,5 = 4.8 Hz, J6,4 = 1.8 Hz,
J6,3 = 1.0 Hz, H-6-py); 9.13 (dd, 1H, J6,4 = 2.3 Hz, J6,3 = 0.8 Hz, H-6).
13C NMR (125.7 MHz, CDCl3): ꢀ5.39, ꢀ5.33, ꢀ4.9, ꢀ4.6, and
ꢀ4.4 (CH3Si); 18.0, 18.1, and 18.5 ((CH3)3C); 25.85, 25.88, and
26.1 ((CH3)3C); 63.1 (CH2-50); 72.7 (CH-30); 78.6 (CH-20); 84.7
(CH-10); 84.8 (CH-40); 120.6 (CH-3-py); 121.6 (CH-3); 122.7
(CH-5-py); 133.7 (C-5); 134.8 (CH-4); 137.0 (CH-4-py); 147.2
(C-6); 150.0 (CH-6-py); 154.8 (C-2-py); 160.9 (C-2). IR spectrum
(CCl4): 2956, 2930, 2858, 1588, 1472, 1464, 1254, 1154, 1120, 1077,
1155, 1120, 1006 cmꢀ1
.
968, 838 cmꢀ1
.
1β-[5-(2-Thienyl)pyridin-2-yl]-1-deoxy-2,3,5-tri-O-(tert-
butyldimethylsilyl)-D-ribofuranose (13c). DMF (15 mL) was
added to a flame-dried and argon-purged flask containing 8 (600 mg,
0.948 mmol) and PdCl2(PPh3)2 (33 mg, 0.047 mmol, 5 mol %). After
5 min stirring at room temperature, tributyl(thiophen-2-yl)stannane
(0.4 mL, 1.33 mmol, 1.4 equiv) was added, and reaction vessel was
immersed to oil bath (100 °C) and stirred for 2 h. After cooling to
room temperature, the crude reaction mixture was diluted with Et2O
(100 mL), washed with 2 M HCl (2 ꢁ 100 mL) and saturated
NaHCO3 (100 mL), and dried over MgSO4. After evaporation of
solvents under reduced pressure, crude product was chromato-
graphed on silica gel in gradient hexanes to 2% EtOAc in hexanes
to obtain 13c (509 mg, 84%) as a colorless oil. HRMS (ESI)
C32H58NSO4Si3: [M + H] calculated 636.3389, found 636.3395.
1H NMR (500 MHz, CDCl3): ꢀ0.10, 0.00, 0.101, 0.104, 0.13, and
1β-(5-Aminopyridin-2-yl)-1-deoxy-2,3,5-tri-O-(tert-buty-
ldimethylsilyl)-D-ribofuranose (13e). LiN(SiMe3)2 (0.58 mL,
0.575 mmol, 2 equiv 1 M solution in THF) was added to a flame-dried
and argon-purged flask containing 8 (182 mg, 0.288 mmol), Pd2(dba)3,
(13 mg, 0.014 mmol, 5 mol %), and tri-tert-butylphosphonium tetra-
fluoroborate (17 mg, 0.058 mmol, 20 mol %), and the mixture was
stirred at 50 °C for 11 h. After cooling to room temperature, the reaction
mixture was diluted with Et2O (30 mL), washed with 2 M HCl (10 mL)
and 1 M NaOH (15 mL), and dried over MgSO4. The crude product was
chromatographed on silica gel in gradient hexanes to 17% EtOAc in
hexanes to give 13e (103 mg, 63%) as a yellowish oil. HRMS (ESI)
1
C28H57N2O4Si3: [M + H] calculated 569.3621, found 569.3622. H
NMR (500 MHz, DMSO-d6): ꢀ0.27, ꢀ0.13, 0.05, 0.068, 0.071, and
0.08 (6 ꢁ s, 6 ꢁ 3H, CH3Si); 0.76, 0.89, and 0.90 (3 ꢁ s, 3 ꢁ 9H,
(CH3)3C); 3.67 (dd, 1H, Jgem = 11.1 Hz, J5 a,4 = 3.6 Hz, H-50a); 3.72
0
0
0.14 (6 ꢁ s, 6 ꢁ 3H, CH3Si); 0.87, 0.95, and 0.96 (3 ꢁ s, 3 ꢁ 9H,
0
0
0
0
0
0
0
0
(CH3)3C); 3.81 (dd, 1H, Jgem = 11.1 Hz, J5 a,4 = 3.5 Hz, H-5 a); 3.90
(dd, 1H, Jgem = 11.1 Hz, J5 b,4 = 4.6 Hz, H0-5 b); 3.84 (m, 1H, H-4 ); 4.09
0
0
0
0
0
0
0
0
0
0
(dd, 1H, Jgem = 11.1 Hz, J5 b,4 = 4.3 Hz, H-5 b); 4.11 (btd, 1H, J4 ,5 b
=
(dd, 1H, J3 ,2 = 4.4 Hz, J3 ,4 = 3.1 Hz H-3 ); 4.12 (dd, 1H, J2 ,1 = 6.4 Hz,
J4 ,3 = 4.2 Hz, J4 ,5 a = 3.6 Hz, H-40); 4.17 (t, 1H, J3 ,2 = J3 ,4 = 4.3 Hz,
J2 ,3 = 4.4 Hz, H-20); 4.57 (d, 1H, J1 ,2 = 6.4 Hz, H-10); 5.25 (s, 2H,
NH2); 6.86 (dd, 1H, J4,3 = 8.4 Hz, J4,6 = 2.7 Hz, H-4); 7.17 (d, 1H, J3,4
0
0
0
0
0
0
0
0
0
0
0
0
0
H-30); 4.29 (bdd, 1H, J2 ,1 = 5.4 Hz, J2 ,3 = 4.4 Hz, H-2 ); 4.98 (d, 1H,
=
0
0
0
0
J1 ,2 = 5.5 Hz, H-10); 7.11 (dd, 1H, J4,5 = 5.1 Hz, J4,3 = 3.6 Hz, H-4-
thienyl); 7.34 (bdd, 1H, J5,4 = 5.0 Hz, J5,3 = 1.2 Hz, H-5-thienyl); 7.35
8.4 Hz, H-3); 7.85 (d, 1H, J6,4 = 2.7 Hz, H-6). 13C NMR (125.7 MHz,
DMSO-d6): ꢀ5.34, ꢀ5.31, ꢀ4.84, ꢀ4.56, ꢀ4.48, and ꢀ4.41 (CH3Si);
17.9, 18.0, and 18.2 ((CH3)3C); 25.87, 25.93, and 26.0 ((CH3)3C); 63.2
(CH2-50); 73.1 (CH-30); 77.6 (CH-20); 84.0 and 84.3 (CH-10,40); 120.1
(CH-4); 122.1 (CH-3); 135.3 (CH-6); 144.4 (C-5); 146.4 (C-2). IR
spectrum (CCl4): 3481, 3397, 2956, 2930, 2886, 2858, 1616, 1472,
1463, 1389, 1354, 1254, 1135, 1078, 838 cmꢀ1
0
0
(bdd, 1H, J3,4 = 3.5 Hz, J3,5 = 1.2 Hz, H-3-thienyl); 7.59 (bd, 1H, J3,4
=
8.2 Hz, H-3); 7.83 (dd, 1H, J4,3 = 8.1 Hz, J4,6 = 2.3 Hz, H-4); 8.85 (bd,
1H, J6,4 = 2.3 Hz, H-6). 13C NMR (125.7 MHz, CDCl3): ꢀ5.34,
ꢀ5.30, ꢀ4.76, ꢀ4.50, 4.47, and ꢀ4.29 (CH3Si); 18.09, 18.12, and
18.5 ((CH3)3C); 25.93, 25.97, and 26.1 ((CH3)3C); 63.3 (CH2-50);
73.0 (CH-30); 78.5 (CH-20); 84.7 (CH-10); 84.9 (CH-40); 121.9
(CH-3); 124.2 (CH-3-thienyl); 125.8 (CH-5-thienyl); 128.2 (CH-4-
thienyl); 129.5 (C-5); 133.5 (CH-4); 140.6 (C-2-thienyl); 146.0
(C-6); 159.1 (C-2). IR spectrum (CCl4): 2956, 2930, 2858, 1600,
1β-[5-(Dimethylamino)pyridin-2-yl]-1-deoxy-2,3,5-tri-O-
(tert-butyldimethylsilyl)-D-ribofuranose (13f). Toluene (0.5 mL)
and Me2NH (1.1 mL, 2.18 mmol, 6 equiv; 2 M solution in THF) were
added to a flame-dried and argon-purged flask containing 8 (230 mg,
0.363 mmol), Pd2(dba)3 (17 mg, 0.018 mmol, 5 mol %), (2-biphenyl)-di-
tert-butylphosphine (22 mg, 0.073 mmol, 20 mol %), and sodium tert-
butoxide (35 mg, 0.363 mmol, 1 equiv). The resulting mixture was stirred
at 60 °C for 3 h, diluted with Et2O (50 mL), filtered through a plug of
Celite, and concentrated under reduced pressure. The crude product was
chromatographed onsilica in gradient hexanes to9% EtOAc inhexanes, to
give 13f (152 mg, 70%) as a colorless oil. HRMS (ESI) C30H61N2O4Si3:
1578, 1472, 1463, 1282, 1256, 1145, 1080 cmꢀ1
.
1β-[5-(2-Pyridyl)pyridin-2-yl]-1-deoxy-2,3,5-tri-O-(tert-
butyldimethylsilyl)-D-ribofuranose (13d). DMF (5 mL) was
added to a flame-dried and argon-purged flask containing 8 (189 mg,
0.30 mmol), and PdCl2(PPh3)2 (11 mg, 0.015 mmol, 5 mol %). After
5 min stirring at room temperature, tributyl(pyridin-2-yl)stannane
(0.15 mL, 0.45 mmol, 1.5 equiv) was added, and reaction vessel was
immersed to oil bath preheated to 100 °C. After 1.5 h, the crude
reaction mixture was diluted with Et2O (300 mL), washed with 2 M
HCl (2 ꢁ 100 mL) and saturated NaHCO3 (100 mL), and dried over
1
[M + H] calculated 597.3934, found 597.3935. H NMR (500 MHz,
CDCl3): ꢀ0.22, ꢀ0.08, 0.067, 0.075, 0.09, and 0.10 (6 ꢁ s, 6 ꢁ 3H,
CH3Si); 0.80, 0.91, and 0.93 (3 ꢁ s, 3 ꢁ 9H, (CH3)3C); 2.95 (s, 6H,
6627
dx.doi.org/10.1021/jo200949c |J. Org. Chem. 2011, 76, 6619–6635

The Journal of Organic Chemistry
ARTICLE
0
0
J1 ,2 = 5.2 Hz, H-1 ); 7.70 (d, 1H, J3,4 = 8.0 Hz, H-3); 7.74 (dd, 1H, J4,3 =
0
0
0
0
(CH3)2N); 3.76 (dd, 1H, Jgem = 10.9 Hz, J5 a,4 = 3.7 Hz, H-5 a); 3.80 (dd,
1H, Jgem = 10.9 Hz, J5 b,4 = 5.0 Hz, H-5 b); 4.02 (dt, 1H, J4 ,5 b = 4.9 Hz,
8.0 Hz, J4,6 = 2.0 Hz, H-4); 8.63 (bd, H, J6,4 = 2.1 Hz, H-6). 13C NMR
(125.7 MHz, CDCl3): ꢀ5.41, ꢀ5.39, ꢀ4.9, ꢀ4.62, ꢀ4.59, and ꢀ4.4
(CH3Si); 18.00, 18.02, and 18.4 ((CH3)3C); 25.81, 25.84, and 26.0
((CH3)3C); 35.47 and 39.54 ((CH3)2N); 62.8 (CH2-50); 72.4 (CH-30);
78.6 (CH-20); 84.7 (CH-10,40); 121.2 (CH-3); 130.9 (C-5); 135.7 (CH-
4); 147.0 (CH-6); 161.8 (C-2); 169.1 (CO). IR spectrum (CCl4): 2956,
2930, 22858, 1646, 4597, 1472, 1463, 1393, 1255, 1155, 1120, 1083,
0
0
0
0
0
J4 ,3 = J4 ,5 a = 3.6 Hz, H-40); 4.13 (dd, 1H, J3 ,2 = 4.4 Hz, J3 ,4 = 3.4 Hz,
0
0
0
0
0
0
0
0
H-30); 4.18 (dd, 1H, J2 ,1 = 6.1 Hz, J2 ,3 = 4.3 Hz, H-20); 4.84 (d, 1H,
0
0
0
0
0
0
0
J1 ,2 = 6.1 Hz, H-1 ); 6.93 (dd, 1H, J4,3 = 8.7 Hz, J4,6 = 3.1 Hz, H-4); 7.33
(d, 1H, J3,4 = 8.7 Hz, H-3); 8.10 (bd, H, J6,4 = 3.1 Hz, H-6). 13C NMR
(125.7 MHz, CDCl3): ꢀ5.41, ꢀ5.37, ꢀ4.95, ꢀ4.60, ꢀ4.55, and ꢀ4.46
(CH3Si); 18.02, 18.06, and 18.4 ((CH3)3C); 25.84, 25.89, and 26.0
((CH3)3C); 40.3 ((CH3)2N); 63.4 (CH2-50); 73.1 (CH-30); 77.8
(CH-20); 84.3 (CH-10); 84.7 (CH-40); 119.1 (CH-4); 122.1 (CH-3);
134.5 (CH-6); 145.6 (C-5); 147.4 (C-2). IR spectrum (CCl4): 2956,
878 cmꢀ1
.
1β-(5-Hydroxypyridin-2-yl)-1-deoxy-2,3,5-tri-O-(tert-but-
yldimethylsilyl)-D-ribofuranose (13i). A septum-sealed flask con-
taining 8 (342 mg, 0.540 mmol), Pd2bda3 (12 mg, 0.014 mmol, 2.5 mol
%), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-20,40,60-triisopropylbi-
phenyl (26 mg, 0.054 mmol, 10 mol %) and KOH (91 mg, 1.62 mmol, 3
equiv) was evacuated and backfilled with argon. Then 1,4-dioxane
(0.8 mL) and water (0.3 mL) were added. The resulting dark-brown
reaction mixture was immersed into preheated oil bath (80 °C) and
stirred for 1.5 h. After the completion of the reaction (monitored by
TLC, hexanes/EtOAc 10:1), the mixture was cooled to room tempera-
ture, diluted with THF (10 mL), filtered through a plug of Celite
(eluting with THF), and concentrated under reduced pressure. The
crude product was purified by flash chromatography on silica gel in
gradient chloroform to 13% ethyl acetate in chloroform, furnishing 13i
(227 mg, 73%) as a white foam. HRMS (ESI) C28H56NO5Si3: [M + H]
calculated 570.3461, found 570.3463. 1H NMR (500 MHz, DMSO-d6):
ꢀ0.29, ꢀ0.13, 0.05, 0.07, and 0.08 (6 ꢁ s, 6 ꢁ 3H, CH3Si); 0.76, 0.891,
and 0.895 (3 ꢁ s, 3 ꢁ 9H, (CH3)3C); 3.68 (dd, 1H, Jgem = 11.2 Hz,
2929, 2857, 1595, 1592, 1500, 1463, 1361, 1253, 1155, 1140, 1079 cmꢀ1
.
1β-[5-(Carbamoyl)pyridin-2-yl]-1-deoxy-2,3,5-tri-O-(tert-
butyldimethylsilyl)-D-ribofuranose (13g). A flame-dried sep-
tum-sealed flask (30 mL) containing 8 (478 mg, 0.755 mmol),
Pd(OAc)2 (17 mg, 0.076 mmol, 5 mol %), Xantphos (87 mg, 0.151
mmol, 10 mol %), and K3PO4 (481 mg, 2.27 mmol, 3 equiv) was
evacuated and backfilled with CO(g). Then, toluene (3 mL) and NH3
(6 mL, 3.02 mmol, 4 equiv; 0.5 M solution in dioxane) were added via
syringe. The reaction mixture was stirred at room temperature for
5 min and then immersed into a preheated oil bath (80 °C) and
vigorously stirred for 6 h. After cooling to the room temperature,
Et2O (15 mL) was added, and the reaction mixture was filtered
through a plug of Celite (eluting with Et2O) and concentrated under
reduced pressure. The crude product was purified by flash chroma-
tography on silica gel in gradient hexanes to 25% EtOAc in hexanes to
give 13g (335 mg, 74%) as a white solid. HRMS (ESI) C29H57N2O5-
1
J5 a,4 = 3.6 Hz, H-50a); 3.74 (dd, 1H, Jgem = 11.2 Hz, J5 b,4 = 4.6 Hz,
0
0
0
0
Si3: [M + H] calculated 597.3570, found 597.3575. H NMR (500
H-50b); 3.88 (dt, 1H, J4 ,5 b = 4.6 Hz, J4 ,5 a = J4 ,3 = 3.3 Hz, H-4 ); 4.09
(dd, 1H, J3 ,2 = 4.4 Hz, J3 ,4 = 3.1 Hz H-3 ); 4.14 (dd, 1H, J2 ,1 = 6.5 Hz,
0
0
0
0
0
0
0
MHz, CDCl3): ꢀ0.19, ꢀ0.05, 0.062, 0.063, 0.11, and 0.12 (6 ꢁ s, 6 ꢁ
0
0
0
0
0
0
0
3H, CH3Si); 0.83, 0.91, and 0.93 (3 ꢁ s, 3 ꢁ 9H, (CH3)3C); 3.78 (dd,
0
0
0
0
0
0
0
0
0
1H, Jgem = 11.2 Hz, J5 a,4 = 2.7 Hz, H-5 a); 3.90 (dd, 1H, Jgem = 11.2
J2 ,3 = 4.4 Hz, H-2 ); 4.64 (d, 1H, J1 ,2 = 6.5 Hz, H-1 ); 7.10 (dd, 1H, J4,3
= 8.5 Hz, J4,6 = 2.8 Hz, H-4); 7.35 (bd, 1H, J3,4 = 8.5 Hz, H-3); 8.04 (dd,
1H, J6,4 = 2.8 Hz, J6,3 = 0.6 Hz, H-6); 9.85 (s, 1H, OH-5). 13C NMR
(125.7 MHz, DMSO-d6): ꢀ5.32, ꢀ5.29, ꢀ4.95, ꢀ4.55, ꢀ4.47, and
ꢀ4.40 (CH3Si); 17.90, 17.99, and 18.2 ((CH3)3C); 25.85, 25.94, and
26.02 ((CH3)3C); 63.2 (CH2-50); 73.1 (CH-30); 77.9 (CH-20); 83.8
(CH-10); 84.6 (CH-40); 122.5 (CH-3,4); 136.9 (CH-6); 150.0 (C-2);
153.3 (C-5). IR spectrum (CCl4): 2956, 2930, 2858, 1472, 1463, 1255,
Hz, J5 b,4 = 3.5 Hz, H-50b); 4.09 ꢀ 4.12 (m, 2H, H-30,40); 4.16 (dd,
0
0
1H, J2 ,1 = 5.6 Hz, J2 ,3 = 3.9 Hz, H-20); 5.00 (d, 1H, J1 ,2 = 5.6 Hz,
H-10); 5.91 and 6.41 (2 ꢁ bs, 2 ꢁ 1H, NH2); 7.76 (d, 1H, J3,4 = 8.2 Hz,
H-3); 8.16 (dd, 1H, J4,3 = 8.2 Hz, J4,6 = 2.3 Hz, H-4); 9.03 (bd, 1H,
J6,4 = 2.3 Hz, H-6). 13C NMR (125.7 MHz, CDCl3): ꢀ5.42, ꢀ5.38,
ꢀ5.0, ꢀ4.6, and ꢀ4.4 (CH3Si); 17.97, 18.03, and 18.4 ((CH3)3C);
25.79, 25.84, and 26.0 ((CH3)3C); 62.8 (CH2-50); 72.7 (CH-30); 78.7
(CH-20); 84.3 (CH-10); 85.1 (CH-40); 121.5 (CH-3); 128.0 (C-5);
136.5 (CH-4); 147.0 (CH-6); 164.1 (C-2); 167.1 (CO). IR spectrum
(CCl4):2956, 2930, 2858, 1687, 1598, 1472, 1463, 1390, 1362, 1254,
0
0
0
0
0
0
1155, 1120, 1077, 838 cmꢀ1
.
1β-(6-Methylpyridin-3-yl)-2,3,5-tri-O-(tert-butyldimethyl-
silyl)-D-ribofuranose (15a). Me3Al (0.76 mL, 1.51 mmol, 2 equiv, 2
M in toluene) was added to a vigorously stirred solution of 11 (479 mg,
0.757 mmol) and Pd(PPh3)4 (44 mg, 0.038 mmol, 5 mol %) in THF
(11 mL) under argon. The mixture was stirred at 70 °C for 2 h, quenched
by pouring into saturated NaH2PO4 (50 mL), and extracted to EtOAc (3
ꢁ 50 mL). The crude product was chromatographed on silica gel in
gradient hexanes to 7.5% EtOAc in hexanes to give 15a (400 mg, 93%) as
colorless oil. HRMS (ESI) C29H58NO4Si3: [M + H] calculated
568.3668, found 568.3666. 1H NMR (500 MHz, CDCl3): ꢀ0.44,
ꢀ0.11, 0.09, 0.10, 0.11, and 0.12 (6 ꢁ s, 6 ꢁ 3H, CH3Si); 0.81, 0.93,
and 0.94 (3 ꢁ s, 3 ꢁ 9H, (CH3)3C); 2.56 (s, 3H, CH3); 3.76 (dd, 1H,
1155, 1119 cmꢀ1
.
1β-[5-(Dimethylcarbamoyl)pyridin-2-yl]-1-deoxy-2,3,5-
tri-O-(tert-butyldimethylsilyl)-D-ribofuranose (13h). A flame-
dried septum-sealed flask containing 8 (551 mg, 0.871 mmol), Pd-
(OAc)2 (9.8 mg, 0.044 mmol, 5 mol %), Xantphos (50 mg, 0.087 mmol,
10 mol %), K3PO4 (1109 mg, 5.22 mmol, 6 equiv), and Me2NH HCl
(213 mg, 2.61 mmol, 3 equiv) was evacuated and backfilled with CO(g)
3
.
Then, toluene (3.5 mL) was added, and the reaction mixture was stirred
at room temperature for 5 min, immersed into a preheated oil bath
(80 °C), and vigorously stirred for 1.5 h under CO atmosphere
(baloon). After the completion of the reaction (monitored by TLC,
Hexanes/EtOAc 8:2), the mixture was cooled to room temperature,
diluted with Et2O (20 mL), filtered through a plug of Celite (eluting with
Et2O), and concentrated under reduced pressure. The crude product
was purified by flash chromatography on silica gel in gradient hexanes to
17% ethyl acetate in hexanes, furnishing 13h (435 mg, 80%) as a
colorless oil. HRMS (ESI) C31H61N2O5Si3: [M + H] calculated
625.3883, found 625.3880. 1H NMR (500 MHz, CDCl3): ꢀ0.15,
ꢀ0.04, 0.059, 0.063, 0.11, and 0.12 (6 ꢁ s, 6 ꢁ 3H, CH3Si); 0.83,
0.91, and 0.93 (3 ꢁ s, 3 ꢁ 9H, (CH3)3C); 3.00 and 3.12 (2 ꢁ s, 2 ꢁ 3H,
Jgem = 11.0 Hz, J5 a,4 = 3.2 Hz, H-50a); 3.79 (dd, 1H, Jgem = 11.0 Hz,
0
0
0
0
0
0
0
0
0
0
J5 b,4 = 3.6 Hz, H-5 b); 3.86 (dd, 1H, J2 ,1 = 8.0 Hz, J2 ,3 = 4.4 Hz, H-2 );
4.04 (td, 1H, J4 ,5 a = J4 ,5 b = 3.4 Hz, J4 ,3 = 1.7 Hz, H-40); 4.13 (dd, 1H,
0
0
0
0
0
0
0
0
0
0
0
0
0
0
J3 ,2 = 4.5 Hz, J3 ,4 = 1.7 Hz, H-3 ); 4.77 (d, 1H, J1 ,2 = 8.0 Hz, H-1 ); 7.12
(d,1H, J3,4 = 8.0 Hz, H-3); 7.71 (bd, 1H, J3,4 = 8.0 Hz, H-4); 8.47 (d, 1H,
J6,4 = 2.2 Hz, H-6). 13C NMR (125.7 MHz, CDCl3): ꢀ5.5, ꢀ5.4, ꢀ5.3,
ꢀ4.49, ꢀ4.47, and ꢀ4.40 (CH3Si); 17.9, 18.1, and 18.4 ((CH3)3C); 23.8
(CH3); 25.8, 25.9, and 26.0 ((CH3)3C); 63.7 (CH2-50); 73.9 (CH-30);
79.4 (CH-20); 80.5 (CH-10); 86.4 (CH-40); 122.9 (CH-3); 133.2 (C-5);
135.1 (CH-4); 147.5 (CH-6); 157.6 (C-2). IR spectrum (CCl4): 2956,
2858, 1605, 1472, 1463, 1257, 1153, 1113, 838 cmꢀ1
.
(CH3)2N); 3.78 (dd, 1H, Jgem = 11.2 Hz, J5 a,4 = 2.9 Hz, H-50a); 3.90
0
0
(dd, 1H, Jgem = 11.2 Hz, J5 b,4 = 3.7 Hz, H-50b); 4.06 ꢀ 4.12 (m, 2H,
1β-(6-Phenylpyridin-3-yl)-2,3,5-tri-O-(tert-butyldimethy-
lsilyl)-D-ribofuranose (15b). Compound 11 (458 mg, 0.724 mmol),
0
0
H-30,40); 4.16 (dd, 1H, J2 ,1 = 5.3 Hz, J2 ,3 = 3.8 Hz, H-2 ); 4.97 (d, 1H,
0
0
0
0
0
6628
dx.doi.org/10.1021/jo200949c |J. Org. Chem. 2011, 76, 6619–6635

The Journal of Organic Chemistry
ARTICLE
K2CO3 (221 mg, 1.59 mmol, 2.2 equiv), Pd(PPh3)4 (42 mg, 0.036
mmol, 5 mol %), and PhB(OH)2 (177 mg, 1.45 mmol, 2 equiv) were
dissolved in toluene (15 mL) under argon, and the mixture was stirred at
110 °C for 1.5 h. The reaction mixture was filtered through a plug of
Celite and concentrated under reduced pressure. The crude product was
chromatographed on silica gel in gradient hexanes to 6% Et2O in hexanes
to give 15b (437 mg, 95%) as a colorless oil. HRMS (ESI) C34H60NO4-
Si3: [M + H] calculated 630.3825, found 630.3823. 1H NMR (500 MHz,
CDCl3): ꢀ0.40, ꢀ0.09, 0.110, 0.113, 0.13, and 0.15 (6 ꢁ s, 6 ꢁ 3H,
51%) as a colorless oil. HRMS (ESI) C33H59N2O4Si3 [M + H]
calculated 631.3777, found 631.3775. 1H NMR (500 MHz, DMSO-
d6): ꢀ0.49, ꢀ0.13, 0.10, 0.116, 0.122, and 0.14 (6 ꢁ s, 6 ꢁ 3H,
CH3Si); 0.77, 0.92, and 0.93 (3 ꢁ s, 3 ꢁ 9H, (CH3)3C); 3.78 (dd,
0
0
0
1H, Jgem = 11.2 Hz, J5 a,4 = 3.1 Hz, H-5 a); 3.83 (dd, 1H, Jgem = 11.2
Hz, J5 b,4 = 4.2 Hz, H-50b); 3.99 (bddd, J4 ,5 b = 4.2 Hz, J4 ,5 a = 3.0
0
0
0
0
0
0
0
0
0
0
0
0
0
Hz, J4 ,3 = 1.4 Hz, H-4 ); 4.00 (dd, 1H, J2 ,1 = 8.2 Hz, J2 ,3 = 4.4 Hz,
H-20); 4.14 (dd, 1H, J3 ,2 = 4.4 Hz, J3 ,4 = 1.4 Hz, H-3 ); 4.74 (d, 1H,
0
0
0
0
0
0
0
0
J1 ,2 = 8.2 Hz, H-1 ); 7.45 (ddd, 1H, J5,4 = 7.5 Hz, J5,6 = 4.8 Hz, J5,3
=
CH3Si); 0.82 and 0.95 (3 ꢁ s, 3 ꢁ 9H, (CH3)3C); 3.80 (dd, 1H, Jgem
=
1.2 Hz, H-5-py); 7.94 (btd, 1H, J4,3 = J4,5 = 7.7 Hz, J4,6 = 1.9 Hz, H-4-
py); 7.95 (bdd, 1H, J4,3 = 8.2 Hz, J4,6 = 2.2 Hz, H-4); 8.35 (dd, 1H,
0
0
0
0
0
11.0 Hz, J5 a,4 = 3.2 Hz, H-5 a); 3.82 (dd, 1H, Jgem = 11.0 Hz, J5 b,4 = 3.8
Hz, H-50b); 3.92 (dd, 1H, J2 ,1 = 7.8 Hz, J2 ,30 = 4.4 Hz, H-2 ); 4.08 (td,
J3,4 = 8.2 Hz, J3,6 = 0.8 Hz, H-3); 8.38 (dt, 1H, J3,4 = 8.0 Hz, J3,5
=
0
0
0
0
0
0
0
0
0
0
0
0
0
1H, J4 ,5 a = J4 ,5 b = 3.50Hz, J4 ,3 = 1.8 Hz, H-4 ); 4.17 (dd, 1H, J3 ,2 = 4.4
J3,6 = 1.1 Hz, H-3-py); 8.65 (bd, 1H, J6,4 = 2.3 Hz, H-6); 8.68 (ddd,
Hz, J3 ,4 = 1.8 Hz, H-3 ); 4.86 (d, 1H, J1 ,2 = 7.8 Hz, H-1 ); 7.41 (m, 1H,
H-p-Ph); 7.48 (m, 2H, H-m-Ph); 7.70 (d, 1H, J3,4 = 8.2 Hz, H-3); 7.88
(m, 1H, H-4); 8.00 (m, 2H, H-o-Ph); 8.68 (d, 1H, J6,4 = 2.2 Hz, H-6).
13C NMR (125.7 MHz, CDCl3): ꢀ5.5, ꢀ5.4, ꢀ5.2, ꢀ4.47, ꢀ4.45,
and ꢀ4.40 (CH3Si); 17.9, 18.1, and 18.4 ((CH3)3C); 25.8, 25.9, and 26.0
((CH3)3C); 63.7 (CH2-50); 73.9 (CH-30); 79.5 (CH-20); 80.6 (CH-10);
86.3 (CH-40); 120.1 (CH-3); 127.0 (CH-o-Ph); 128.7 (CH-m,p-Ph);
134.7 (C-5); 135.3 (CH-4); 139.4 (C-i-Ph); 148.5 (CH-6); 156.9 (C-2).
1H, J6,5 = 4.7 Hz, J6,4 = 1.8 Hz, J6,3 = 0.9 Hz, H-6-py). 13C NMR
(125.7 MHz, DMSO-d6): ꢀ5.42, ꢀ5.34, ꢀ5.32, ꢀ4.50, ꢀ4.45, and
ꢀ4.36 (CH3Si); 17.7, 18.0, and 18.2 ((CH3)3C); 25.8, 25.9, and 26.0
((CH3)3C); 63.5 (CH2-50); 74.1 (CH-30); 79.1 (CH-20); 80.1 (CH-
10); 86.2 (CH-40); 120.0 (CH-3); 120.6 (CH-3-py); 124.4 (CH-5-
py); 135.6 (CH-4); 136.4 (C-5); 137.5 (CH-4-py); 148.3 (CH-6);
149.5 (CH-6-py); 155.2 and 155.3 (C-2, C-2-py). IR spectrum
(CCl4): 2956, 2930, 2858, 1591, 1577, 1560, 1472, 1462, 1255,
0
0
0
0
0
IR spectrum (CCl4): 2956, 2930, 1599, 1565, 1473, 1257, 1153 cmꢀ1
.
1153, 1113 cmꢀ1
.
1β-[6-(2-Thienyl)pyridin-3-yl]-1-deoxy-2,3,5-tri-O-(tert-
butyldimethylsilyl)-D-ribofuranose (15c). DMF (12 mL) was
added to a flame-dried and argon-purged flask containing 11
(453 mg, 0.716 mmol) and PdCl2(PPh3)2 (25 mg, 0.036 mmol,
5 mol %). After 5 min stirring at room temperature, tributyl(thiophen-
2-yl)stannane (320 μL, 1.00 mmol, 1.4 equiv) was added, and
reaction vessel was immersed to oil bath (110 °C) and stirred for
1.5 h. After cooling to room temperature, the crude reaction mixture
was diluted with Et2O (100 mL), washed with 2 M HCl (2 ꢁ 100 mL)
and saturated NaHCO3 (100 mL), and dried over MgSO4. After
evaporation of solvents under reduced pressure, the crude product
was chromatographed on silica gel in gradient hexanes to 6% Et2O in
hexanes to obtain 15c (370 mg, 81%) as a colorless oil. HRMS (ESI)
C32H58NSO4Si3: [M + H] calculated 636.3389, found 636.3387. 1H
NMR (500 MHz, CDCl3): ꢀ0.38, ꢀ0.09, 0.103, 0.104, 0.12, and 0.14
(6 ꢁ s, 6 ꢁ 3H, CH3Si); 0.83, 0.94, and 0.95 (3 ꢁ s, 3 ꢁ 9H,
1β-(6-Aminopyridin-3-yl)-1-deoxy-2,3,5-tri-O-(tert-butyl-
dimethylsilyl)-D-ribofuranose (15e). LiN(SiMe3)2 (1.1 mL, 1.1
mmol, 1.5 equiv 1 M solution in THF) was added to a flame-dried and
argon-purged flask containing 11 (464 mg, 0.733 mmol), Pd2(dba)3,
(17 mg, 0.018 mmol, 2.5 mol %), and tri-tert-butylphosphonium tetra-
fluoroborate (26 mg, 0.073 mmol, 10 mol %), and the mixture was
stirred at 50 °C for 5 h. After cooling to room temperature, the reaction
mixture was diluted with Et2O (60 mL), washed with 2 M HCl (2 ꢁ
30 mL) and 1 M NaOH (30 mL), and dried over MgSO4. The crude
product was chromatographed on silica gel in gradient chloroform to
1.2% MeOH in chloroform to give 15e (367 mg, 88%) as a yellowish oil.
HRMS (ESI) C28H57N2O4Si3: [M + H] calculated 569.3621, found
1
569.3620. H NMR (500 MHz, CDCl3): ꢀ0.36, ꢀ0.09, 0.087, 0.093,
0.10, and 0.11 (6 ꢁ s, 6 ꢁ 3H, CH3Si); 0.81, 0.930, and 0.933 (3 ꢁ s, 3 ꢁ
9H, (CH3)3C); 3.71 ꢀ 3.79 (m, 2H, H-50); 3.84 (dd, 1H, J2 ,1 = 8.1 Hz,
0
0
0
0
0
0
0
0
0
0
0
J2 ,3 = 4.5 Hz, H-2 ); 4.00 (td, 1H, J4 ,5 a = J4 ,5 b = 3.4 Hz, J4 ,3 = 1.6 Hz,
(CH3)3C); 3.79 (m, 2H, H-50); 3.90 (dd, 1H, J2 ,1 = 7.7 Hz, J2 ,3 = 4.4
H-40); 4.11 (dd, 1H, J3 ,2 = 4.5 Hz, J3 ,4 = 1.6 Hz, H-30); 4.66 (d, 1H,
0
0
0
0
0
0
0
0
0
Hz, H-20); 4.06 (td, 1H, J4 ,5 a = J4 ,5 b = 3.5 Hz, J4 ,3 = 2.0 Hz, H-4 );
J1 ,2 = 8.1 Hz, H-10); 4.89 (bs, 2H, NH2); 6.55 (dd, 1H, J3,4 = 8.6 Hz,
J3,6 = 0.6 Hz, H-3); 7.61 (dd, 1H, J4,3 = 8.6 Hz, J4,6 = 2.3 Hz, H-4); 7.99
(bd, 1H, J6,4 = 2.2 Hz, H-6). 13C NMR (125.7 MHz, CDCl3): ꢀ5.5,
ꢀ5.4, ꢀ5.1, ꢀ4.48, ꢀ4.44, and ꢀ4.41 (CH3Si); 17.9, 18.1, and 18.4
((CH3)3C); 25.8, 25.9, and 26.0 ((CH3)3C); 63.8 (CH2-50); 74.0 (CH-
30); 79.0 (CH-20); 80.4 (CH-10); 86.2 (CH-40); 109.1 (CH-3); 126.1
(C-5); 137.7 (CH-4); 144.6 (CH-6); 157.5 (C-2). IR spectrum (CCl4):
34813509, 3408, 2956, 2930, 2858, 1616, 1500, 1257, 1154 cmꢀ1
1β-[6-(Dimethylamino)pyridin-3-yl]-1-deoxy-2,3,5-tri-O-
(tert-butyldimethylsilyl)-D-ribofuranose (15f). Me2NH
(1.6 mL, 3.13 mmol, 7 equiv; 2 M solution in THF) was added to
a flame-dried and argon-purged flask containing 11 (283 mg,
0.447 mmol), Pd2(dba)3 (10 mg, 0.011 mmol, 2.5 mol %),
(2-biphenyl)-di-tert-butylphosphine (14 mg, 0.045 mmol,
10 mol %), and sodium tert-butoxide (43 mg, 0.447 mmol, 1
equiv). The resulting mixture was stirred at 65 °C for 4.5 h,
diluted with Et2O (75 mL), filtered through a plug of Celite, and
concentrated under reduced pressure. The crude product was
chromatographed on silica in gradient hexanes to 6% EtOAc in
hexanes to give 15f (237 mg, 89%) as colorless oil. HRMS (ESI)
C30H61N2O4Si3: [M + H] calculated 597.3934, found 597.
3933.1H NMR (500 MHz, DMSO-d6): ꢀ0.41, ꢀ0.14, 0.08,
0.09, and 0.10 (6 ꢁ s, 6 ꢁ 3H, CH3Si); 0.76, 0.906, and 0.909
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
4.15 (dd, 1H, J3 ,2 = 4.4 Hz, J3 ,4 = 1.9 Hz, H-3 ); 4.81 (d, 1H, J1 ,2
=
7.7 Hz, H-10); 7.11 (dd, 1H, J4,5 = 5.1 Hz J4,3 = 3.7 Hz, H-4-thienyl);
7.38 (dd, 1H, J5,4 = 5.1 Hz, J5,3 = 1.2 Hz, H-5-thienyl); 7.59 (m, 1H,
H-3-thienyl); 7.61 (bd, 1H, J3,4 = 8.2 Hz, H-3); 7.87 (bd, 1H, J3,4 = 8.2
Hz, H-4); 8.54 (d, 1H, J6,4 = 2.2 Hz, H-6). 13C NMR (125.7 MHz,
CDCl3): ꢀ5.5, ꢀ5.4, ꢀ5.1, ꢀ4.47, ꢀ4.45, and ꢀ4.42 (CH3Si); 17.9,
18.1, and 18.4 ((CH3)3C); 25.8, 25.9, and 26.0 ((CH3)3C); 63.7
(CH2-50); 73.8 (CH-30); 79.4 (CH-20); 80.7 (CH-10); 86.2 (CH-40);
118.3 (CH-3); 124.4 (CH-3-thienyl); 127.3 (CH-5-thienyl); 128.0
(CH-4-thienyl); 134.6 (C-5); 135.1 (CH-4); 144.9 (C-2-thienyl);
148.3 (CH-6); 152.1 (C-2). IR spectrum (CCl4): 2956, 2930, 2585,
1730, 1598, 1473, 1257, 1115 cmꢀ1
.
1β-[6-(2-Pyridyl)pyridin-3-yl]-1-deoxy-2,3,5-tri-O-(tert-
butyldimethylsilyl)-D-ribofuranose (15d). DMF (6 mL) was
added to a flame-dried and argon-purged flask containing 11
(366 mg, 0.578 mmol) and PdCl2(PPh3)2 (20 mg, 0.029 mmol,
5 mol %). After 5 min stirring at room temperature, tributyl(pyridin-
2-yl)stannane (280 μL, 0.867 mmol, 1.5 equiv) was added, and the
reaction vessel was immersed to oil bath preheated to 80 °C. After
4.5 h, crude reaction mixture was diluted with Et2O (300 mL),
washed with 2 M HCl (2 ꢁ 100 mL) and sat. NaHCO3 (100 mL),
and dried over MgSO4. After evaporation of solvents under reduced
pressure, crude product was chromatographed on silica gel in
gradient hexanes to 6% EtOAc in hexanes to obtain 15d (186 mg,
(3 ꢁ s, 3 ꢁ 9H, (CH3)3C); 2.99 (s, 6H, (CH3)2N); 3.70 (dd, 1H,
0
0
0
Jgem = 11.0 Hz, J5 a,4 = 3.5 Hz, H-5 a); 3.73 (dd, 1H, Jgem = 11.1
6629
dx.doi.org/10.1021/jo200949c |J. Org. Chem. 2011, 76, 6619–6635

The Journal of Organic Chemistry
ARTICLE
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Hz, J5 b,4 = 4.2 Hz,0H-5 b); 3.86 (btd, 1H, J4 ,5 a = J4 ,5 b = 3.8 Hz,
J5 b,4 = 3.7 Hz, H-5 b); 3.88 (dd, 1H, J2 ,1 = 8.0 Hz, J2 ,3 = 4.4 Hz, H-2 );
0
0
0
0
0
0
0
0
0
0
0
0
0
J4 ,3 = 1.6 Hz, H-4 ); 3.91 (dd, 1H, J2 ,1 = 8.1 Hz, J2 ,3 = 4.5 Hz,
4.07 (ddd, 1H, J4 ,5 b = 3.7 Hz, J4 ,5 a = 2.8 Hz, J4 ,3 = 1.6 Hz, H-4 ); 4.14
H-20); 4.09 (dd, 1H, J3 ,2 = 4.5 Hz, J3 ,4 = 1.6 Hz, H-3 ); 4.49 (d,
(dd, 1H, J3 ,2 = 4.4 Hz, J3 ,4 = 1.6 Hz, H-3 ); 4.85 (d, 1H, J1 ,2 = 8.0 Hz,
0
0
0
0
0
0
0
0
0
0
0
0
1H, J1 ,2 = 8.1 Hz, H-10); 6.59 (d, 1H, J3,4 = 8.8 Hz, H-3); 7.49
(dd, 1H, J4,3 = 8.8 Hz, J4,6 = 2.4 Hz, H-4); 7.99 (d, 1H, J6,4
H-10); 7.64 (dd, 1H, J3,4 = 8.0 Hz, J3,6 = 0.9 Hz, H-3); 7.95 (dd, 1H, J4,3
=
0
0
=
8.1 Hz, J4,6 = 2.2 Hz, H-4); 8.60 (bd, 1H, J6,4 = 2.3 Hz, H-6). 13C NMR
(125.7 MHz, CDCl3): ꢀ5.54, ꢀ5.43, ꢀ5.26, ꢀ4.47, ꢀ4.45, and ꢀ4.36
(CH3Si); 17.89, 18.04, and 18.33 ((CH3)3C); 25.78, 25.85, and 25.97
((CH3)3C); 35.8 and 39.0 (CH3)2N); 63.6 (CH2-50); 74.0 (CH-30);
79.6 (CH-20); 80.3 (CH-10); 86.7 (CH-40); 123.4 (CH-3); 135.9 (CH-
4); 137.8 (C-5); 146.2 (CH-6); 153.2 (C-2); 168.3 (CO). IR spectrum
(CCl4): 2955, 2930, 2858, 1642, 1505, 1472, 1463, 1407, 1257,
2.4 Hz, H-6). 13C NMR (125.7 MHz, DMSO-d6): ꢀ5.4,
ꢀ5.3, ꢀ5.0, ꢀ4.46, ꢀ4.44, and ꢀ4.40 (CH3Si); 17.8, 18.0, and
18.2 ((CH3)3C); 25.82, 25.95, and 25.99 ((CH3)3C); 37.9
((CH3)2N) 63.6 (CH2-50); 73.9 (CH-30); 78.3 (CH-20); 80.5
(CH-10); 85.4 (CH-40); 105.4 (CH-3); 122.5 (C-5); 136.1 (CH-
4); 146.9 (CH-6); 159.3 (C-2). IR spectrum (CCl4): 2955, 2930,
1922, 1611, 1563, 1514, 1472, 1463, 1256, 1151 cmꢀ1
.
1153 cmꢀ1
.
1β-[6-(Carbamoyl)pyridin-3-yl]-1-deoxy-2,3,5-tri-O-(tert-
butyldimethylsilyl)-D-ribofuranose (15g). A flame-dried sep-
tum-sealed flask (30 mL) containing 11 (304 mg, 0.480 mmol),
Pd(OAc)2 (5.4 mg, 0.024 mmol, 5 mol %), Xantphos (28 mg, 0.048
mmol, 10 mol %), and K3PO4 (306 mg, 1.44 mmol, 3 equiv) was
evacuated and backfilled with CO(g). Then, toluene (0.5 mL) and NH3
(3.8 mL, 1.92 mmol, 4 equiv; 0.5 M solution in 1,4-dioxane) were
added via syringe. The reaction mixture was stirred at room tempera-
ture for 5 min, immersed into a preheated oil bath (80 °C), and
vigorously stirred for 2 h. After cooling to the room temperature, Et2O
(20 mL) was added, and the reaction mixture was filtered through a
plug of Celite (eluting with Et2O) and concentrated under reduced
pressure. The crude product was purified by flash chromatography on
silica gel in gradient chloroform to 7.4% EtOAc in chloroform to give
15g (233 mg, 81%) as a white foam. HRMS (ESI) C29H57N2O5Si3:
1β-(6-Oxo-1H-pyridin-3-yl)-1-deoxy-2,3,5-tri-O-(tert-but-
yldimethylsilyl)-D-ribofuranose (15i). Septum-sealed flask con-
taining 11 (430 mg, 0.679 mmol), Pd2dba3 (16 mg, 0.017 mmol, 2.5 mol
%), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-20,40,60-triisopropylbi-
phenyl (33 mg, 0.068 mmol, 10 mol %), and KOH (114 mg, 2.03 mmol,
3 equiv) was evacuated and backfilled with argon. Then 1,4-dioxane
(1 mL) and water (0.3 mL) were added. The resulting dark-brown
reaction mixture was immersed into preheated oil bath (80 °C) and
stirred for 4 h. After the completion of the reaction (monitored by TLC,
hexanes/EtOAc 10:1), the mixture was cooled to room temperature,
diluted with THF (20 mL), filtered through a plug of Celite (eluting with
THF), and concentrated under reduced pressure. The crude product
was purified by flash chromatography on silica gel in gradient chloroform
to 36% ethyl acetate in chloroform furnishing 15i (306 mg, 79%) as a
white foam. HRMS (ESI) C28H56NO5Si3: [M + H] calculated 570.3461,
1
1
[M + H] calculated 597.3570, found 597.3573. H NMR (500 MHz,
found 570.3460. H NMR (500 MHz, CDCl3): ꢀ0.27, ꢀ0.07, 0.075,
CDCl3): ꢀ0.49, ꢀ0.10, 0.10, 0.11, 0.12, and 0.13 (6 ꢁ s, 6 ꢁ 3H,
0.080, 0.095, and 0.104 (6 ꢁ s, 6 ꢁ 3H, CH3Si); 0.81, 0.91, and 0.92
0
00
CH3Si); 0.81, 0.93, and 0.94 (3 ꢁ s, 3 ꢁ 9H, (CH3)3C); 3.78 (dd, 1H,
(3 ꢁ s, 3 ꢁ 9H, (CH3)3C); 3.69 (dd, 1H, Jgem = 11.0 Hz, J5 a,4 = 4.0 Hz,
J
gem = 11.1 Hz, J5 a,4 = 2.7 Hz, H-50a); 3.82 (dd, 1H, Jgem = 11.1 Hz,
H-50a); 3.72 (dd, 1H, Jgem = 11.0 Hz, J5 b,4 = 3.0 Hz, H-5 b); 3.82 (dd,
1H, J2 ,1 = 8.1 Hz, J2 ,3 = 4.4 Hz, H-2 ); 3.97 (bddd, 1H, J4 ,5 a = 4.0 Hz,
4 ,5 b = 3.0 Hz, J4 ,3 = 1.4 Hz, H-4 ); 4.09 (dd, 1H, J3 ,2 = 4.5 Hz, J3 ,4
0
0
0
0
J5 b,4 = 3.6 Hz, H-50b); 3.88 (dd, 1H, J2 ,1 = 8.2 Hz, J2 ,3 = 4.4 Hz,
0
0
0
0
0
0
0
0
0
0
0
0
0
H-20); 4.08 (ddd, 1H, J4 ,5 b = 3.6 Hz, J4 ,5 a = 2.7 Hz,0J4 ,3 = 1.4 Hz,
J
=
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
H-40); 4.14 (dd, 1H, J3 ,2 = 4.4 Hz, J3 ,4 = 1.5 Hz, H-3 ); 4.87 (d, 1H,
1.4 Hz, H-30); 4.53 (d, 1H, J1 ,2 = 8.1 Hz, H-1 ); 6.55 (d, 1H, J3,4 = 9.4
Hz, H-3); 7.35 (bd, 1H, J6,4 = 2.5 Hz, H-6), 7.61 (dd, 1H, J4,3 = 9.4 Hz,
J4,6 = 2.5 Hz, H-4). 13C NMR (125.7 MHz, CDCl3): ꢀ5.55, ꢀ5.47,
ꢀ4.97, ꢀ4.53, ꢀ4.41, and ꢀ4.39 (CH3Si); 17.9, 18.0, and 18.3
((CH3)3C); 25.78, 25.83, and 25.9 ((CH3)3C); 63.8 (CH2-50); 74.0
(CH-30); 78.2 (CH-20); 79.8 (CH-10); 86.2 (CH-40); 119.4 (C-5);
120.0 (CH-3); 132.7 (CH-6); 140.8 (CH-4); 165.4 (C-2). IR spectrum
0
0
0
0
0
0
0
0
0
0
J1 ,2 = 8.2 Hz, H-1 ); 5.62 and 7.97 (2 ꢁ m, 2 ꢁ 1H, NH2); 8.00 (bdd,
1H, J4,3 = 8.0 Hz, J4,6 = 2.2 Hz, H-4); 8.19 (dd, 1H, J3,4 = 8.0 Hz, J3,6
=
0.8 Hz, H-3); 8.59 (bd, 1H, J6,4 = 2.3 Hz, H-6). 13C NMR (125.7 MHz,
CDCl3): ꢀ5.54, ꢀ5.43, ꢀ5.35, ꢀ4.47, ꢀ4.46, and ꢀ4.35 (CH3Si);
17.86, 18.05, and 18.34 ((CH3)3C); 25.77, 25.85, and 25.97
((CH3)3C); 63.6 (CH2ꢀ50); 74.1 (CH-30); 79.7 (CH-20); 80.3
(CH-10); 86.9 (CH-40); 122.3 (CH-3); 135.8 (CH-4); 140.2 (C-5);
146.7 (CH-6); 148.6 (C-2); 166.4 (CO). IR spectrum (CCl4): 3528,
3458, 3401, 3277, 3199, 3148, 1700, 1597, 1575, 1556, 1409, 1257,
(CCl4): 2956, 2930, 1665, 1631, 1554, 1472, 1257, 838 cmꢀ1
.
General Procedure for the Deprotection of TBS Group.
Method A. Et3N 3HF (98 μL, 1.00 mmol, 6 equiv) was added to the
3
1153, 1113 cmꢀ1
.
solution of silylated compound 13aꢀh, 15aꢀd,f,h (0.10 mmol) in THF
(1.00 mL), and the resulting mixture was stirred at 40 °C for 2 days. After
the reaction was complete (monitored by TLC eluted in CHCl3/MeOH
8:2), solvent was removed under reduced pressure, the crude product
was dissolved in water, and solid NaHCO3 was added until pH 8.
Solvents were removed under reduced pressure, and the crude product
purified by reversed-phase chromatography (H2O/MeOH as an eluent)
to obtain free C-ribonucleosides 14aꢀh, 16aꢀd,f,h.
1β-[5-(Dimethylcarbamoyl)pyridin-2-yl]-1-deoxy-2,3,5-
tri-O-(tert-butyldimethylsilyl)-D-ribofuranose (15h). A flame-
dried septum-sealed flask containing 11 (350 mg, 0.553 mmol), Pd-
(OAc)2 (6.2 mg, 0.028 mmol, 5 mol %), Xantphos (32 mg, 0.055 mmol,
10 mol %), K3PO4 (352 mg, 1.66 mmol, 3 equiv), and Me2NH HCl
3
(1.1 mL, 2.21 mmol, 4 equiv) was evacuated and backfilled with CO(g)
.
Then, toluene (4.4 mL) was added, and the reaction mixture was stirred
at room temperature for 5 min, immersed into a preheated oil bath
(80 °C), and vigorously stirred for 3 h under CO atmosphere (balloon).
After the completion of the reaction (monitored by TLC, hexanes/
EtOAc 8:2), the mixture was cooled to room temperature, diluted with
Et2O (20 mL), filtered through a plug of Celite (eluting with Et2O), and
concentrated under reduced pressure. The crude product was purified
by flash chromatography on silica gel in gradient chloroform to 14%
ethyl acetate in chloroform furnishing 15h (728 mg, 76%) as colorless
oil. HRMS (ESI) C31H61N2O5Si3: [M + H] calculated 625.3883, found
General Procedure for the Deprotection of TBS Group.
Method B. Et3N 3HF (98 μL, 1.00 mmol, 6 equiv) was added to the
3
solution of silylated compound 13i, 16g (0.10 mmol) in THF
(1.00 mL), and the resulting mixture was stirred at 40 °C for 2 days.
After the reaction was complete (monitored by TLC eluted in CHCl3/
MeOH 8:2), solvent was removed under reduced pressure, the crude
product was dissolved in water, and solid NaHCO3 was added until pH
8. The solution was then passed through a column packed with Dowex
50 in H+ cycle, and the column was washed with 250 mL of water
followed by 100 mL of 25% aqueous ammonia. The resulting ammonia
fraction was concentrated under reduced pressure, and crude product
was purified by reversed-phase chromatography (H2O/MeOH) to
obtain free C-ribonucleosides 14i.
1
625.3883. H NMR (500 MHz, CDCl3): ꢀ0.43, ꢀ0.09, 0.097, 0.102,
0.11, and 0.12 (6 ꢁ s, 6 ꢁ 3H, CH3Si); 0.81, 0.92, and 0.94 (3 ꢁ s, 3 ꢁ
9H, (CH3)3C); 3.06 and 3.13 (2 ꢁ s, 2 ꢁ 3H, (CH3)2N); 3.77 (dd, 1H,
Jgem = 11.0 Hz, J5 a,4 = 2.8 Hz, H-50a); 3.81 (dd, 1H, Jgem = 11.0 Hz,
0
0
6630
dx.doi.org/10.1021/jo200949c |J. Org. Chem. 2011, 76, 6619–6635

The Journal of Organic Chemistry
ARTICLE
1β-(5-Methylpyridin-2-yl)-1-deoxy-D-ribofuranose (14a).
Compound 14a was prepared from 13a (420 mg, 0.739 mmol) accord-
ing to general procedure (Method A), in 83% yield as a white solid.
Crystallization from EtOAc/MeOH furnished colorless crystals: mp
141ꢀ142 °C. HRMS (ESI) C11H16NO4: [M + H] calculated 226.1074,
C14H15NO4S 1/4H2O: C, 56.46; H, 5.25; N, 4.70. Found: C, 56.67; H,
5.01; N, 4.68.
3
1β-[5-(2-Pyridyl)pyridin-2-yl]-1-deoxy-D-ribofuranose (14d).
Compound 14d was prepared from 13d (227 mg, 0.360 mmol) according
to general procedure (Method A), in 83% yield, as a white solid, which after
lyophilization furnished a white hygroscopic powder. HRMS (ESI)
found 226.1074. 1H NMR (500 MHz, DMSO-d6): 2.28 (s, 3H, CH3-5);
1
0
0
0
0
0
3.51 (ddd, 1H, Jgem = 11.8 Hz, J5 a,OH = 6.3 Hz, J5 a,4 = 4.3 Hz, H-5 a);
C15H17N2O4: [M + H] calculated 289.1183, found 289.1183. H NMR
0
0
0
0
3.64 (ddd, 1H, Jgem = 11.8 Hz, J5 b,OH = 5.0 Hz, J5 b,4 = 3.6 Hz, H-5 b);
(500 MHz, DMSO-d6): 3.55 (ddd, 1H, Jgem = 11.8 Hz, J5 a,OH = 5.8 Hz,
3.84 (bddd, 1H, J4 ,3 = 5.6 Hz, J4 ,5 a = 4.2 Hz, J4 ,5 b = 3.6 Hz, H-40); 3.88
J5 a,4 = 4.3 Hz, H-5 a); 3.68 (ddd, 1H, Jgem = 11.8 Hz, J5 a,OH = 4.9 Hz, J5 b,4
0
0
0
0
0
0
0
0
0
0
0
0
(q, 1H, J3 ,2 = J3 ,4 = J3 ,OH = 5.3 Hz H-30); 3.97 (dt, 1H, J2 ,OH = 5.7 Hz,
= 3.5 Hz, H-50b); 3.89 (ddd, J4 ,3 = 5.6 Hz, J4 ,5 a = 4.3 Hz, J4 ,5 b = 3.5 Hz,
0
0
0
0
0
0
0
0
0
0
0 0
J2 ,1 = J2 ,3 = 4.9 Hz, H-20); 4.68 (d, 1H, J1 ,2 = 4.7 Hz, H-1 ); 4.83 (d,
H-40); 3.92 (bq, 1H, J3 ,4 = J3 ,2 = J3 ,OH = 4.2 Hz, H-30); 4.04 (dd, 1H, J2 ,
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0 0
1H, JOH,3 = 5.6 Hz, OH-3 ); 4.96 (dd, 1H, JOH,5 a = 6.3 Hz, JOH,5 b = 5.0
OH = 5.8 Hz, J2 ,1 = J2 ,3 = 4.8 Hz, H-2 ); 4.79 (d, 1H, J1 ,2 = 4.8 Hz, H-1 );
0
0
Hz, OH-50); 5.01 (d, 1H, JOH,2 = 5.7 Hz, OH-2 ); 7.42 (d, 1H, J3,4 = 7.9
4.89 (d, 1H, JOH,3 = 5.5 Hz, OH-3 ); 4.95 (t, 1H, JOH,5 a = JOH,5 b = 5.5 Hz,
0
0
0
0
OH-50); 5.12 (d, 1H, JOH,2 = 5.8 Hz, OH-2 ); 7.41 (ddd, 1H, J5,4 = 7.5 Hz,
0
0
Hz, H-3); 7.58 (bdd, 1H, J4,3 = 7.9 Hz, J4,6 = 2.3 Hz, H-4); 8.34 (bd, 1H,
6,4 = 2.3 Hz, H-6). 13C NMR (125.7 MHz, DMSO-d6): 17.7 (CH3-5);
J
5,6 = 4.8 Hz, J5,3 = 1.1 Hz, H-5-py); 7.69 (bd, 1H, J3,4 = 8.2 Hz, H-3); 7.93
(bddd, 1H, J4,3 = 7.8 Hz, J4,5 = 7.6 Hz, J4,6 = 1.8 Hz, H-4-py); 8.05 (dt, 1H,
J3,4 = 8.0 Hz, J3,5 = J3,6 = 1.1 Hz, H-3-py); 8.42 (dd, 1H, J4,3 = 8.2 Hz, J4,6
J
62.0 (CH2-50); 71.2 (CH-30); 76.7 (CH-20); 84.4 (CH-40); 85.3 (CH-
10); 121.0 (CH-3); 132.0 (C-5); 137.2 (CH-4); 149.0 (CH-6); 157.8
(C-2). IR spectrum (KBr): 2927, 2874, 1607, 1577, 1493, 1384, 1115,
=
2.3 Hz, H-4); 8.70 (ddd, 1H, J6,5 = 4.8 Hz, J6,4 = 1.9 Hz, J6,3 = 1.0 Hz, H-6-
py); 9.19 (dd, 1H, J6,4 = 2.3 Hz, J6,3 = 0.9 Hz, H-6). 13C NMR (125.7 MHz,
DMSO-d6): 61.9 (CH2-50); 71.2 (CH-30); 76.9 (CH-20); 84.5 (CH-40);
85.4 (CH-10); 120.8 (CH-3-py); 121.3 (CH-3); 123.3 (CH-5-py); 133.2
(C-5); 134.7 (CH-4); 137.6 (CH-4-py); 147.1 (C-6); 150.0 (CH-6-py);
153.9 (C-2-py); 161.3 (C-2). [R]20D = ꢀ35.4 (c 1.78, MeOH). Anal. Calcd
1052, 830 cmꢀ1. [R]20 = ꢀ31.4 (c 2.26, MeOH). Anal. Calcd for
D
C11H15NO4: C, 58.66; H, 6.71; N, 6.22. Found: C, 58.52; H, 6.67;
N, 6.09.
1β-(5-Phenylpyridin-2-yl)-1-deoxy-D-ribofuranose (14b).
Compound 14b was prepared from 13b (416 mg, 0.660 mmol)
according to general procedure (Method A), in 80% yield as a white
solid which crystallized from EtOAc/MeOH as a white cotton-like solid:
mp 132ꢀ134 °C. HRMS (ESI) C16H18NO4: [M + H] calculated
288.1230, found 288.1230. 1H NMR (500 MHz, DMSO-d6): 3.55
for C15H16N2O4 1/4H2O: C, 61.53; H, 5.68; N, 9.57. Found: C, 61.28; H,
3
5.44; N, 9.48.
1β-(5-Aminopyridin-2-yl)-1-deoxy-D-ribofuranose (14e).
Compound 14e was prepared from 13e (500 mg, 0.880 mmol)
according to general procedure (Method A), in 75% yield, as a yellowish
oil, which after lyophilization furnished a yellow hygroscopic solid.
(bdt, 1H, Jgem = 11.8 Hz, J5 a,4 = J5 a,OH = 4.5 Hz, H-50a); 3.67 (bdt,
0
0
0
1H, Jgem = 11.8 Hz, J5 b,4 = J5 b,OH = 3.5 Hz, H-50b); 3.88 (bddd, J4 ,3
=
=
0
0
0
0
0
5.5 Hz, J4 ,5 a = 4.2 Hz, J4 ,5 b = 3.7 Hz, H-40); 3.93 (bt, 1H, J3 ,4 = J3 ,2
HRMS (ESI) C10H15N2O4: [M + H] calculated 227.1026, found
0
0
0
0
0
0
0
0
1
0
5.2 Hz, H-30); 4.05 (m, 1H, H-20); 4.77 (d, 1H, J1 ,2 = 4.9 Hz, H-1 ); 4.88
(m, 1H, OH-30); 4.95 (m, 1H, OH-50); 5.09 (m, 1H, OH-20); 7.42 (m,
1H, H-p-Ph); 7.50 (m, 2H, H-m-Ph); 7.65 (bd, 1H, J3,4 = 8.2 Hz, H-3);
7.73 (m, 2H, H-o-Ph); 8.06 (dd, 1H, J4,3 = 8.2 Hz, J4,6 = 2.4 Hz, H-4);
8.83 (dd, 1H, J6,4 = 2.4 Hz, J6,3 = 0.9 Hz, H-6). 13C NMR (125.7 MHz,
DMSO-d6): 61.9 (CH2-50); 71.2 (CH-30); 76.8 (CH-20); 84.6 (CH-40);
85.3 (CH-10); 121.5 (CH-3); 127.0 (CH-o-Ph); 128.2 (CH-p-Ph);
129.3 (CH-m-Ph); 134.7 (C-5); 134.9 (CH-4); 137.2 (C-i-Ph); 146.9
(C-6); 159.8 (C-2). IR spectrum (KBr): 3369, 2926, 2872, 1603, 1482,
1454, 1372, 1355, 1312, 1207, 1109, 1056 cmꢀ1. [R]20D = ꢀ38.7 (c 2.40,
MeOH). Anal. Calcd for C16H17NO4: C, 66.89; H, 5.96; N, 4.88. Found:
C, 66.79; H, 5.84; N, 4.78.
227.1026. H NMR (500 MHz, DMSO-d6): 3.47 (bdm, 1H, Jgem
=
0
0
11.7 Hz, H-50a); 3.59 (dd, 1H, Jgem = 11.7 Hz, J5 b,4 = 3.7 Hz, H-50b);
0
0
3.78 (bddd, 1H, J4 ,3 = 5.3 Hz, J4 ,5 a = 4.2 Hz, J4 ,5 b = 3.7 Hz, H-40); 3.89
0
0
0
0
0
0
(t, 1H, J3 ,2 = J3 ,4 = 5.2 Hz H-30); 3.96 (t, 1H, J2 ,1 = J2 ,3 = 5.1 Hz,
0
0
0
0
0
0
0
0
H-20); 4.53 (d, 1H, J1 ,2 = 5.0 Hz, H-10); 4.78 ꢀ 5.10 (m, 3H, OH-
0
0
20,30,50); 5.26 (s, 2H, NH2-5); 6.88 (dd, 1H, J4,3 = 8.3 Hz, J4,6 = 2.7 Hz,
H-4); 7.11 (bd, 1H, J3,4 = 8.4 Hz, H-3); 7.86 (dd, 1H, J6,4 = 2.7 Hz, J6,3
=
0.7 Hz, H-6). 13C NMR (125.7 MHz, DMSO-d6): 62.3 (CH2-50); 71.4
(CH-30); 76.3 (CH-20); 84.4 (CH-40); 85.3 (CH-10); 120.4 (CH-4);
122.1 (CH-3); 135.3 (CH-6); 144.35 (C-5); 147.3 (C-2). IR spectrum
(KBr): 3421, 1630, 1498, 1307, 1114, 1052, 1024 cmꢀ1. [R]20D = ꢀ35.4
(c 2.85, MeOH).
1β-[5-(2-Thienyl)pyridin-2-yl]-1-deoxy-D-ribofuranose (14c).
Compound 14c was prepared from 13c (450 mg, 0.707 mmol) according to
general procedure (Method A), in 83% yield, as a white solid, which after
lyophilization furnished a white hygroscopic powder. Crystallization from
EtOAc/MeOH yielded a white cotton-like solid: mp 155ꢀ156 °C. HRMS
1β-[5-(Dimethylamino)pyridin-2-yl]-1-deoxy-D-ribofura-
nose (14f). Compound 14f was prepared from 13f (450 mg, 0.754
mmol) according to general procedure (Method A), in 76% yield, as a
yellowish solid. Crystallization from EtOAc/MeOH yielded yellowish
crystals: mp 158ꢀ161 °C. HRMS (ESI) C12H19N2O4: [M + H]
1
1
calculated 255.1339, found 255.1340. H NMR (500 MHz, DMSO-
(ESI) C14H16NO4S: [M + H] calculated 294.0795, found 294.0795. H
0
0
0
d6): 2.91 (s, 6H, (CH3)2N); 3.48 (dd, 1H, Jgem = 11.7 Hz, J5 a,4 = 4.4 Hz,
NMR (500 MHz, DMSO-d6): 3.54 (ddd, 1H, Jgem = 11.8 Hz, J5 a,OH = 6.1
H-50a); 3.61 (dd, 1H, Jgem = 11.7 Hz, J5 b,4 = 3.7 Hz, H-50b); 3.81 (dt,
0
0
0
0
0
0
Hz, J5 a,4 = 4.3 Hz,0H-5 a); 3.66 (ddd, 1H, Jgem = 11.8 Hz, J5 b,OH = 5.2 Hz,
1H, J4 ,3 = 5.2 Hz, J4 ,5 a = J4 ,5 b = 4.0 Hz, H-40); 3.90 (q, 1H, J3 ,2 = J3 ,4
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0 0
J5 b,4 =3.5Hz, H-5 b); 3.87 (bddd, 1H, J4 ,3 =5.5 Hz, J4 ,5 a =4.2Hz, J4 ,5 b
=
= J3 ,OH = 5.2 Hz H-30); 3.99 (q, 1H, J2 ,OH = J2 ,1 = J2 ,3 = 5.2 Hz, H-20);
0
3.6 Hz, H-4 ); 3.91 (bq, 1H, J3 ,2 = J3 ,4 = J3 ,OH = 5.3 Hz, H-30); 4.02 (bdt,
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0 0
4.61 (d, 1H, J1 ,2 = 5.0 Hz, H-1 ); 4.78 (d, 1H, JOH,3 = 5.5 Hz, OH-3 );
1H, J2 ,3 = J2 ,OH = 5.5 Hz, J2 ,1 = 4.9 Hz, H-2 ); 4.74 (d, 1H, J1 ,2 = 4.8 Hz,
4.90 (d, 1H, JOH,2 = 5.7 Hz, OH-20); 5.03 (bs, 1H, OH-50); 7.08 (dd,
H-10); 4.88 (d, 1H, JOH,3 = 5.5 Hz, OH-3 ); 4.92 (t, 1H, JOH,5 a = JOH,5 b
=
0
0
0
0
0
5.6 Hz, OH-50);5.09(d, 1H, JOH,2 = 5.7 Hz, OH-2 );7.19(dd, 1H, J4,5 =5.0
0
0
1H, J4,3 = 8.7 Hz, J4,6 = 3.1 Hz, H-4); 7.27 (d, 1H, J3,4 = 8.6 Hz, H-3);
8.03 (bd, 1H, J6,4 = 3.0 Hz, H-6). 13C NMR (125.7 MHz, DMSO-d6):
40.0 ((CH3)2N); 62.3 (CH2-50); 71.4 (CH-30); 76.4 (CH-20); 84.4
(CH-40); 85.1 (CH-10); 119.3 (CH-4); 121.8 (CH-3); 133.8 (CH-6);
145.7 (C-5); 147.6 (C-2). IR spectrum (KBr): 2812, 1362, 1226, 1170,
Hz, J4,3 = 3.7 Hz, H-4-thienyl); 7.61 (bd, 1H, J3,4 = 8.2 Hz, H-3); 7.63 (dd,
1H, J3,4 =3.7Hz, J3,5 =1.1Hz, H-3-thienyl);7.64(dd, 1H, J5,4 =5.0Hz, J5,3
=
1.1 Hz, H-5-thienyl); 8.03 (dd, 1H, J4,3 = 8.2 Hz, J4,6 = 2.4 Hz, H-4); 8.83
(dd, 1H, J6,4 = 2.4 Hz, J6,3 = 0.9 Hz, H-6). 13C NMR (125.7 MHz, DMSO-
d6): 61.9 (CH2-50); 71.2 (CH-30); 76.8 (CH-20); 84.5 (CH-40); 85.3 (CH-
10); 121.7 (CH-3); 125.1 (CH-3-thienyl); 126.9 (CH-5-thienyl); 128.9
(CH-4-thienyl); 133.5 (CH-4); 139.7 (C-5); 140.7 (C-2-thienyl); 145.5
(C-6); 159.8 (C-2). IR spectrum (KBr): 3341, 2914, 1633, 1482, 1389,
1121, 1088, 1061 cmꢀ1. [R]20D = ꢀ34.3 (c 3.21, MeOH). Anal. Calcd for
1128 cmꢀ1. [R]20 = ꢀ40.0 (c 3.87, MeOH). Anal. Calcd for
D
C12H18N2O4 1/4H2O: C, 55.69; H, 7.21; N, 10.82. Found: C, 55.72;
3
H, 7.07; N, 10.63.
1β-[5-(Carbamoyl)pyridin-2-yl]-1-deoxy-D-ribofuranose
(14g). Compound 14g was prepared from 13g (300 mg, 0.503 mmol)
6631
dx.doi.org/10.1021/jo200949c |J. Org. Chem. 2011, 76, 6619–6635

The Journal of Organic Chemistry
ARTICLE
3.49 ꢀ 3.59 (m, 2H, H-50); 3.70 (m, 1H, H-20); 3.82 (td, 1H, J4 ,5 a
=
0
0
according to general procedure (Method A), in 75% yield, as a colorless
oil, which after lyophilization furnished a white hygroscopic cotton-like
solid. HRMS (ESI) C11H15N2O5: [M + H] calculated 255.0976, found
255.0976. 1H NMR (500 MHz, DMSO-d6): 3.53 (dm, 1H, Jgem = 11.8
Hz, H-50a); 3.65 (dm, 1H, Jgem = 11.8 Hz, H-50b); 3.85 ꢀ 3.90 (m, 2H,
J4 ,5 b = 4.4 Hz, J4 ,3 = 3.2 Hz, H-40); 3.91 (m, 1H, H-30); 4.56 (d, 1H,
0
0
0
0
0
J1 ,2 = 7.4 Hz, H-1 ); 4.83 (t, 1H, JOH,5 a = JOH,5 b = 5.6 Hz, OH-50); 4.94
0
0
0
0
(d, 1H, JOH,3 = 4.6 Hz, OH-30); 5.01 (d, 1H, JOH,2 = 7.0 Hz, OH-20);
7.21 (bd, 1H, J3,4 = 8.0 Hz, H-3); 7.67 (bdd, 1H, J4,3 = 8.1 Hz, J4,6 = 2.3
Hz, H-4); 8.42 (bd, 1H, J6,4 = 2.2 Hz, H-6).13C NMR (125.7 MHz,
DMSO-d6): 23.9 (CH3); 62.2 (CH2-50); 71.7 (CH-30); 77.8 (CH-20);
80.9 (CH-10); 85.6 (CH-40); 122.8 (CH-3); 133.8 (C-5); 134.4 (CH-4);
147.3 (CH-6); 157.1 (C-2). IR spectrum (KBr): 3421, 2922, 1610, 1497,
0
0
H-30,40); 3.98 (bq,01H, J2 ,1 = J2 ,3 = J2 ,OH = 4.8 Hz, H-200); 4.77 (d, 1H,
0
0
0
0
0
0
0
0
J1 ,2 = 4.7 Hz, H-1 ); 4.89 (d, 1H, JOH,3 = 5.1 Hz, OH-3 ); 4.92 (t, 1H,
JOH,5 a = JOH,5 b = 5.5 Hz, OH-50); 5.13 (d, 1H, JOH,2 = 5.7 Hz, OH-2 );
0
0
0
0
7.56 (bs, 1H, NHa); 7.66 (bd, 1H, J3,4 = 8.1 Hz, H-3); 8.13 (bs, 1H,
NHb); 8.18 (dd, 1H, J4,3 = 8.2 Hz, J4,6 = 2.3 Hz, H-4); 8.96 (dd, 1H, J6,4
=
1118, 1032 cmꢀ1. [R]20 = ꢀ26.4 (c 1.94, MeOH). Anal. Calcd for
D
2.3 Hz, J6,3 = 0.8 Hz, H-6). 13C NMR (125.7 MHz, DMSO-d6): 61.7
(CH2-50); 71.0 (CH-30); 76.9 (CH-20); 84.5 (CH-40); 85.4 (CH-10);
120.7 (CH-3); 128.7 (C-5); 135.9 (CH-4); 148.1 (CH-6); 163.6 (C-2);
166.5 (CO). IR spectrum (KBr): 1670, 1615, 1407, 1112, 1051,
C11H15NO4 0.6 H2O: C, 55.97; H, 6.92; N, 5.93. Found: C, 56.28; H,
3
6.67; N, 5.52.
1β-(6-Phenylpyridin-3-yl)-1-deoxy-D-ribofuranose (16b).
Compound 16b was prepared from 15b (395 mg, 0.627 mmol)
according to general procedure (Method A), in 91% yield as a white
solid, which after lyophilization furnished a white hygroscopic powder.
HRMS (ESI) C16H18NO4: [M + H] calculated 288.1230, found
288.1230. H NMR (500 MHz, DMSO-d6): 3.57 (ddd, 1H, Jgem
860 cmꢀ1. [R]20 = ꢀ32.2 (c 2.02, MeOH). Anal. Calcd for
D
C11H14N2O5 H2O: C, 48.53; H, 5.92; N, 10.29. Found: C, 48.41; H,
3
5.55; N, 10.00.
1
1β-[5-(Dimethylcarbamoyl)pyridin-2-yl]-1-deoxy-D-ribo-
furanose (14h). Compound 14h was prepared from 13h (440 mg,
0.704 mmol) according to general procedure (Method A), in 81% yield,
as a colorless oil, which after lyophilization furnished a white hygro-
scopic powder. Crystallization from EtOAc/MeOH yielded white
crystals: mp 142ꢀ143 °C. HRMS (ESI) C13H19N2O5: [M + H]
=
=
0
0
0
0
11.7 Hz, J5 a,OH = 5.4 Hz, J5 a,4 = 4.4 Hz, H-5 a); 3.60 (ddd, 1H, Jgem
0
0
0
0
0
0
0
11.7 Hz, J5 b,OH = 5.5 Hz, J5 b,4 = 4.4 Hz, H-5 b); 3.78 (td, 1H, J2 ,1 = J2 ,
0
0
0
0
0
0
0
OH = 7.2 Hz, J2 ,3 = 5.2 Hz, H-2 ); 3.87 (td, 1H, J4 ,5 a = J4 ,5 b = 4.4 Hz,
0
0
0
0
0
0
0
0
J4 ,3 = 3.1 Hz, H-4 ); 3.96 (btd, 1H, J3 ,2 = J3 ,OH = 4.7 Hz, J3 ,4 = 3.2 Hz,
0
H-30); 4.67 (d, 1H, J1 ,2 = 7.5 Hz, H-1 ); 4.88 (t, 10H, JOH,5 a = JOH,5 b
=
0
0
0
0
0
1
5.5 Hz, OH-50); 4.99 (d, 1H, JOH,3 = 4.6 Hz, OH-3 ); 5.10 (d, 1H, JOH,2
calculated 283.1289, found 283.1288. H NMR (500 MHz, DMSO-
0
= 7.1 Hz, OH-20); 7.43 (m, 1H, H-p-Ph); 7.49 (m, 2H, H-m-Ph); 7.89
d6): 2.93 and 3.00 (2 ꢁ s, 2 ꢁ 3H, (CH3)2N); 3.53 (ddd, 1H, Jgem = 11.9
0
0
0
0
Hz, J5 a,OH = 6.0 Hz, J5 a,4 = 4.2 Hz, H-5 a); 3.65 (ddd, 1H, Jgem = 11.9
0
(ddd, 1H, J4,3 = 8.2 Hz, J4,6 = 2.2 Hz, J4,1 = 0.6 Hz, H-4); 7.94 (dd, 1H,
Hz, J5 b,OH = 5.2 Hz, J5 b,4 = 3.5 Hz, H-50b); 3.87 (m, 1H, H-40); 3.89
0
0
0
J
3,4 = 8.2 Hz, J3,6 = 0.9 Hz, H-3); 8.08 (m, 2H, H-o-Ph); 8.67 (dt, 1H, J6,4
= 2.2 Hz, J6,3 = J6,1 = 0.7 Hz, H-6). 13C NMR (125.7 MHz, DMSO-d6):
62.2 (CH2-50); 71.8 (CH-30); 77.9 (CH-20); 80.8 (CH-10); 85.8 (CH-
40); 119.9 (CH-3); 126.6 (CH-o-Ph); 128.9 (CH-m-Ph); 129.1 (CH-p-
Ph); 135.2 (CH-4); 135.7 (C-5); 138.8 (C-i-Ph); 148.0 (CH-6); 155.5
(bq, 1H, J3 ,2 = J3 ,4 = J3 ,OH = 5.1 Hz, H-30); 4.00 (q, 1H, J2 ,1 = J2 ,3
=
0
0
0
0
0
0
0
0
0
0
J
2 ,OH = 5.0 Hz, H-20); 4.74 (d, 1H, J1 ,2 = 4.9 Hz, H-10); 4.90 (d, 1H,
0
0
0
JOH,3 = 5.1 Hz, OH-3 ); 4.91 (t, 1H, JOH,5 a = JOH,5 b = 5.6 Hz, OH-50);
0
0
0
0
0
0
5.12 (d, 1H, JOH,2 = 5.6 Hz, OH-2 ); 7.63 (bd, 1H, J3,4 = 8.0 Hz, H-3);
(C-2). IR spectrum (KBr): 3410, 2925, 1601, 1565, 1479, 1120 cmꢀ1
.
7.83 (dd, 1H, J4,3 = 8.0 Hz, J4,6 = 2.2 Hz, H-4); 8.55 (dd, 1H, J6,4 = 2.2 Hz,
J6,3 = 0.9 Hz, H-6). 13C NMR (125.7 MHz, DMSO-d6): 35.0
((CH3)2N); 61.9 (CH2-50); 71.2 (CH-30); 76.8 (CH-20); 84.6 (CH-
40); 85.3 (CH-10); 120.9 (CH-3); 131.3 (C-5); 135.6 (CH-4); 147.1
(CH-6); 161.7 (C-2); 168.1 (CO). IR spectrum (KBr): 3371, 2929,
[R]20D = ꢀ37.3 (c 2.2, MeOH). Anal. Calcd for C16H17NO4 H2O: C,
3
64.65; H, 6.12; N, 4.73. Found: C, 64.81; H, 6.13; N, 4.65.
1β-[6-(2-Thienyl)pyridin-3-yl]-1-deoxy-D-ribofuranose (16c).
Compound 16c was prepared from 15c (348 mg, 0.547 mmol) according
to general procedure (Method A), in 89% yield, as a white solid, which after
lyophilization furnished white hygroscopic powder. HRMS (ESI)
C14H16NO4S: [M + H] calculated 294.0795, found 294.0795. 1H NMR
2971, 1625, 1511, 1481, 1454, 1403, 1267, 1202, 1094, 1052 cmꢀ1
.
[R]20 = ꢀ37.1 (c 2.25, MeOH). Anal. Calcd for C13H18N2O5: C,
D
55.31; H, 6.43; N, 9.92. Found: C, 55.24; H, 6.56; N, 9.90.
0
1β-[5-Hydroxypyridin-2-yl]-1-deoxy-D-ribofuranose (14i).
Compound 14i was prepared from 13i (652 mg, 1.14 mmol) according
to general procedure (Method B), in 74% yield, as a colorless oil, which
after lyophilization furnished a white hygroscopic powder. HRMS (ESI)
C10H14NO5: [M + H] calculated 228.0867, found 228.0866. 1H NMR
(500 MHz, DMSO-d6): 3.48 (bd, 1H, Jgem = 11.9 Hz, H-50a); 3.60 (bd,
(500 MHz, DMSO-d6): 3.54 (ddd, 1H, Jgem = 11.7 Hz, J5 a,OH = 5.4 Hz,
J5 a,4 = 4.4 Hz, H-50a); 3.58 (ddd, 1H, Jgem = 11.8 Hz, J5 b,OH = 5.5 Hz,
0
0
0
J5 b,4 = 4.3 Hz, H-50b); 3.76 (m, 1H, H-20); 3.85 (td, 1H, J4 ,5 a = J4 ,5 b
=
0
0
0
0
0 0
0
0
0
0
0 0
4.3 Hz, J4 ,3 = 3.1 Hz, H-4 ); 3.94 (m, 1H, H-3 ); 4.63 (d, 1H, J1 ,2 = 7.4 Hz,
H-10); 4.86 (t, 1H, JOH,5 a = JOH,5 b = 5.5 Hz, OH-50); 4.98 (d, 1H, JOH,3
=
=
0
0
0
4.0 Hz, OH-30); 5.10 (d, 1H, JOH,2 = 5.8 Hz, OH-20); 7.16 (dd,1H, J4,5
0
1H, Jgem = 11.9 Hz, H-50b); 3.80 (bddd, 1H, J4 ,3 = 5.3 Hz, J4 ,5 a = 4.5
5.0 Hz, J4,3 = 3.7 Hz, H-4-thienyl); 7.61 (dd, 1H, J5,4 = 5.0 Hz, J5,3 = 1.2 Hz,
H-5-thienyl); 7.78 (dd, 1H, J3,4 = 3.7 Hz, J3,5 = 1.2 Hz, H-3-thienyl); 7.83
(bdd, 1H, J4,3 = 8.3 Hz, J4,6 = 2.2 Hz, H-4); 7.88 (dd, 1H, J3,4 = 8.2 Hz, J3,6 =
0
0
0
0
Hz, J4 ,5 b = 3.8 Hz, H-40); 3.88 (q, 1H, J3 ,2 = J3 ,4 = J3 ,OH = 5.3 Hz
0
0
0
0
0
0
0
H-30); 3.96 (bdt, 1H, J2 ,OH = 5.7 Hz, J2 ,1 = J2 ,3 = 5.2 Hz, H-2 ); 4.61 (d,
0
0
0
0
0
0
0
0
0
0
0
1H, J1 ,2 = 5.1 Hz, H-1 ); 4.80 (d, 1H, JOH,3 = 5.6 Hz, OH-3 ); 4.93 (bs,
0.9 Hz, H-3); 8.52 (bd, 1H, J6,4 = 2.2 Hz, H-6). 13C NMR (125.7 MHz,
DMSO-d6): 62.1 (CH2-50); 71.7 (CH-30); 77.8 (CH-20); 80.8 (CH-10);
85.7 (CH-40); 118.3 (CH-3); 125.2 (CH-3-thienyl); 128.3 (CH-5-thienyl);
128.6 (CH-4-thienyl); 135.1 (CH-4); 135.5 (C-5); 144.7 (C-2-thienyl);
147.7 (CH-6); 151.3 (C-2). IR spectrum (KBr): 3420, 2914, 1600, 1480,
1396, 1313, 1122, 2055, 1027, 818 cmꢀ1. [R]20D = ꢀ50.6 (c 1.9, DMSO).
Anal. Calcd for C14H15NO4S: C, 57.32; H, 5.17; N, 4.78. Found: C, 57.08;
H, 5.00; N, 4.66.
1H, OH-50); 4.93 (d, 1H, JOH,2 = 5.8 Hz, OH-20); 7.13 (dd, 1H, J4,3
=
0
8.4 Hz, J4,6 = 2.9 Hz, H-4); 7.32 (bd, 1H, J3,4 = 8.4 Hz, H-3); 8.05 (dd,
1H, J6,4 = 2.8 Hz, J6,3 = 0.7 Hz, H-6); 9.84 (s, 1H, OH-5). 13C NMR
(125.7 MHz, DMSO-d6): 62.1 (CH2-50); 71.3 (CH-30); 76.4 (CH-20);
84.5 (CH-40); 85.0 (CH-10); 122.4 (CH-3); 122.7 (CH-4); 136.9 (CH-
6); 150.9 (C-2); 153.1 (C-5). IR spectrum (KBr): 3430, 1583, 1495,
1275, 1249, 1106, 1051 cmꢀ1. [R]20D = ꢀ30.4 (c 2.04, MeOH). Anal.
Calcd for C10H13NO5 3/2H2O: C 47.24; H, 6.34; N, 5.51., Found: C
1β-[6-(2-Pyridyl)pyridin-3-yl]-1-deoxy-D-ribofuranose (16d).
Compound 16d was prepared from 15d (148 mg, 0.234 mmol) according
to general procedure (Method A), in 52% yield, as a white solid, which after
lyophilization furnished a white hygroscopic powder. HRMS (ESI)
3
47.34; H, 6.19; N, 5.48.
β-(6-Methylpyridin-3-yl)-1-deoxy-D-ribofuranose (16a).
Compound 16a was prepared from 15a (374 mg, 0.658 mmol)
according to general procedure (Method A), in 90% yield as a white
solid, which after lyophilization furnished a white hygroscopic powder.
HRMS (ESI) C11H16NO4: [M + H] calculated 226.1074, found
226.1074. 1H NMR (500 MHz, DMSO-d6): 2.44 (s, 3H, CH3);
1
C15H17N2O4: [M + H] calculated 289.1183, found 289.1183. H NMR
0
0
0
(500 MHz, DMSO-d6): 3.56 (bdt, 1H, Jgem = 11.7 Hz, J5 a,OH = J5 a,4 = 4.8
Hz, H-50a); 3.60 (bddd, 1H, Jgem = 11.7 Hz, J5 a,OH = 5.2 Hz, J5 b,4 = 4.5 Hz,
0
0
0
H-50b); 3.78 (m, 1H, H-20); 3.88 (td, 1H, J4 ,5 a = J4 ,5 b = 4.4 Hz,
0
0
0 0
6632
dx.doi.org/10.1021/jo200949c |J. Org. Chem. 2011, 76, 6619–6635

The Journal of Organic Chemistry
ARTICLE
0
0
0
0
0
0
0
0
0
0
0
0
J4 ,3 = 3.1 Hz, H-4 ); 3.96 (m, 1H, H-3 ); 4.69 (d, 1H, J1 ,2 = 7.5 Hz, H-1 );
1H, J1 ,2 = 7.5 Hz, H-1 ); 4.87 (t, 1H, JOH,5 a = JOH,5 b = 5.5 Hz, OH-50);
4.88 (t, 1H, JOH,5 a = JOH,5 b = 5.6 Hz, OH-50); 5.01 (bm, 1H, OH-30); 5.12
(bm, 1H, OH-20); 7.44 (ddd, 1H, J5,4 = 7.5 Hz, J5,6 = 4.8 Hz, J5,3 = 1.2 Hz,
H-5-py); 7.94 (btd, 1H, J4,3 =J4,5 =7.7Hz, J4,6 = 1.8 Hz, H-4-py); 7.95 (bdd,
1H, J4,3 = 8.2 Hz, J4,6 = 2.1 Hz, H-4); 8.36 (dd, 1H, J3,4 = 8.1 Hz, J3,6 = 0.9 Hz,
H-3); 8.38 (dt, 1H, J3,4 =7.9Hz, J3,5 =J3,6 = 1.1 Hz, H-3-py); 8.68 (ddd, 1H,
J6,5 = 4.8 Hz, J6,4 = 1.9 Hz, J6,3 = 1.0 Hz, H-6-py); 8.69 (dm, 1H, J6,4 = 2.1
Hz, H-6).13C NMR (125.7 MHz, DMSO-d6): 62.2 (CH2-50); 71.8 (CH-
30); 77.9 (CH-20); 80.8 (CH-10); 85.9 (CH-40); 120.1 (CH-3); 120.6
(CH-3-py); 124.3 (CH-5-py); 135.1 (CH-4); 137.5 (C-5); 137.5 (CH-4-
py); 147.7 (CH-6); 149.5 (CH-6-py); 154.7 (C-2); 155.4 (C-2-py).
5.01 (d, 1H, JOH,3 = 4.5 Hz, OH-3 ); 5.14 (d, 1H, JOH,2 = 7.1 Hz, OH-
0
0
0
0
0
20); 7.61 (m, 1H, NH2-a); 7.97 (ddd, 1H, J4,3 = 8.0 Hz, J4,6 = 2.1 Hz,
0
J4,1 = 0.6 Hz, H-4); 8.01 (dd, 1H, J3,4 = 8.0 Hz, J3,6 = 0.9 Hz, H-3); 8.08
0
(m, 1H, NH2-b); 8.63 (bdt, 1H, J6,4 = 2.0 Hz, J6,3 = J6,1 = 0.7 Hz, H-6).
13C NMR (125.7 MHz, DMSO-d6): 62.1 (CH2-50); 71.7 (CH-30); 78.0
(CH-20); 80.6 (CH-10); 85.9 (CH-40); 121.7 (CH-3); 135.1 (CH-4);
140.0 (C-5); 146.7 (CH-6); 149.8 (C-2); 166.2 (CO). IR spectrum
(KBr): 3411, 1683, 1574, 1418, 1059 cmꢀ1. [R]20 = ꢀ30.9 (c 2.08,
D
MeOH).
1β-[6-(Dimethylcarbamoyl)pyridin-3-yl]-1-deoxy-D-ribo-
furanose (16h). Compound 16h was prepared from 15h (250 mg, 0.4
mmol) according to general procedure (Method A), in 88% yield, as a
colorless oil, which after lyophilization furnished a white hygroscopic
powder. HRMS (ESI) C13H18N2O5Na: [M + Na] calculated 305.1108,
found 305.1107. 1H NMR (500 MHz, DMSO-d6): 2.94 and 3.00 (2 ꢁ s,
IR spectrum (KBr): 3458, 3429, 3306, 1462, 1124, 1056, 1026 cmꢀ1
.
[R]20D = ꢀ60.0 (c 1.85, DMSO). Anal. Calcd for C15H16N2O4 1/4H2O:
3
C, 61.53; H, 5.68; N, 9.57. Found: C, 61.83; H, 5.70; N, 9.20.
1β-(6-Aminopyridin-3-yl)-1-deoxy-D-ribofuranose (16e).
TBAF 3H2O (886 mg, 2.81 mmol, 4 equiv) was added to a solution of
3
0
16e (400 mg, 0.702 mmol) in THF (7 mL), and the resulting mixture
was stirred for 3 h at room temperature. After evaporation of the solvent
under reduced pressure, the resulting yellow oil was dissolved in water
(30 mL) and filtered off. The filtrate was passed through column packed
with Dowex 50 in H+ cycle, and the column was washed with water
(500 mL) and then eluted with 75 mL of 10% aqueous ammonia. The
ammonia fraction was concentrated under reduced pressure and purified
by reversed-phase chromatography (H2O/MeOH as an eluent). Sub-
sequent lyophilization furnished compound 16e (103 mg, 65%) as a
white hygroscopic powder. HRMS (ESI) C10H14N2O4: [M + H]
2 ꢁ 3H, (CH3)2N); 3.54 (ddd, 1H, Jgem = 11.7 Hz, J5 a,OH = 5.4 Hz,
0
0
0
0
J5 a,4 = 4.4 Hz, H-5 a); 3.58 (ddd, 1H, Jgem = 11.8 Hz, J5 b,OH = 5.5 Hz,
J5 b,4 = 4.3 Hz, H-50b); 3.75 (td, 1H, J2 ,1 = J2 ,OH = 7.3 Hz, J2 ,3
=
0
0
0
0
0
0
0
5.2 Hz, H-20); 3.87 (td, 1H, J4 ,5 a = J4 ,5 b = 4.3 Hz, J4 ,3 = 3.0 Hz, H-4 );
0
0
0
0
0
0
0
3.94 (m, 1H, H-30); 4.66 (d, 1H, J1 ,2 = 7.6 Hz, H-10); 4.86 (t, 1H,
0
0
0
0
0
0
J
OH,5 a = JOH,5 b = 5.5 Hz, OH-50); 5.01 (d, 1H, JOH,3 = 4.5 Hz, OH-3 );
0
0
5.11 (d, 1H, JOH,2 = 7.1 Hz, OH-2 ); 7.53 (dd, 1H, J3,4 = 8.0 Hz, J3,6 = 0.9
0
Hz, H-3); 7.91 (ddd, 1H, J4,3 = 8.0 Hz, J4,6 = 2.1 Hz, J4,1 = 0.5 Hz, H-4);
8.58 (dm, 1H, J6,4 = 2.1 Hz, H-6).13C NMR (125.7 MHz, DMSO-d6):
35.0 and 38.5 ((CH3)2N); 62.1 (CH2-50); 71.7 (CH-30); 77.9 (CH-20);
80.6 (CH-10); 85.9 (CH-40); 122.7 (CH-3); 135.0 (CH-4); 137.7 (C-5);
146.5 (CH-6); 153.8 (C-2); 168.2 (CO). IR spectrum (KBr): 3426,
2930, 1627, 1407, 1099 cmꢀ1. [R]20D = ꢀ34.0 (c 2.04, MeOH). Anal.
1
calculated 227.1026, found 227.1026. H NMR (500 MHz, DMSO-
0
0
0
d6): 3.47 (dd, 1H, Jgem = 11.6 Hz, J5 a,4 = 4.8 Hz, H-5 a); 3.51 (dd, 1H,,
0
0
0
0
0
J
gem = 11.6 Hz, J5 b,4 = 4.4 Hz, H-50b); 3.68 (bdd, 1H, J2 ,1 = 7.4 Hz,
0
0
0
0
0
0
0
0
J2 ,3 = 5.5 Hz, H-2 ); 3.73 (td, 1H, J4 ,5 a = J4 ,5 b = 4.6 Hz, J4 ,3 = 3.4 Hz,
Calcd for C13H18N2O5 H2O: C, 51.99; H, 6.71; N, 9.33. Found: C,
3
H-40); 3.87 (dd, 1H, J3 ,2 = 5.2 Hz, J3 ,4 = 3.4 Hz, H-30); 4.37 (d, 1H,
0
0
0
0
52.22; H, 6.48; N, 8.97.
J1 ,2 = 7.4 Hz, H-10); 4.62 - 5.02 (m, 3H, OH-20, 30, 50); 5.86 (s, 2H,
0
0
1β-(6-Oxo-1H-pyridin-3-yl)-1-deoxy-D-ribofuranose (16i).
15i (207 mg, 0.363 mmol) was dissolved in TFA/H2O (9:1, 1.1 mL) and
stirred at room temperature for 2 h. The reaction mixture was then
coevaporated with MeOH (3 ꢁ 100 mL), dissolved in water, and filtered
off, and the filtrate was passed through column packed with DOWEX 50
in H+ cycle. The column was washed with 250 mL of water followed by
75 mL of 25% NH4OH. Ammonia solutions were concentrated under
reduced pressure and purified by reversed-phase chromatography
(H2O/MeOH as an eluent). Subsequent lyophilization furnished com-
pound 16i (34 mg mg, 41%) as a white hygroscopic powder. HRMS
(ESI) C10H12NO5: [M ꢀ H] calculated 226.0721, found 226.0721. 1H
0
NH2); 6.42 (d, 1H, J3,4 = 8.5 Hz, H-3); 7.38 (dd, 1H, J4,3 = 8.5 Hz, J4,6
=
2.3 Hz, H-4); 7.85 (d, 1H, J6,4 = 2.3 Hz, H-6). 13C NMR (125.7 MHz,
DMSO-d6): 62.3 (CH2-50); 71.64 (CH-30); 77.0 (CH-20); 81.4
(CH-10); 85.2 (CH-40); 107.8 (CH-3); 124.0 (C-5); 135.9 (CH-4);
146.5 (CH-6); 159.6 (C-2). IR spectrum (KBr): 3480, 3379, 1636, 1569,
1511, 1130, 1018 cmꢀ1. [R]20D = ꢀ37.0 (c 1.6, MeOH).
1β-[6-(Dimethylamino)pyridin-3-yl]-1-deoxy-D-ribofura-
nose (16f). Compound 16f was prepared from 15f (434 mg, 0.727
mmol) according to general procedure (Method A), in 88% yield, as a
yellowish solid. HRMS (ESI) C12H19N2O4: [M + H] calculated
1
NMR (500 MHz, DMSO-d6): 3.46 (ddd, 1H, Jgem = 11.7 Hz, J5 a,OH
=
=
0
255.1339, found 255.1339. H NMR (500 MHz, DMSO-d6): 3.00 (s,
0
6H, (CH3)2N); 3.46 ꢀ 3.56 (m, 2H, H-50); 3.70 (td, 1H, J2 ,OH = J2 ,1
=
=
5.5 Hz, J5 a,4 = 4.4 Hz, H-5 a); 3.51 (ddd, 1H, Jgem = 11.7 Hz, J5 b,OH
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
5.6 Hz, J5 b,4 = 4.3 Hz, H-5 b); 3.68 (btd, 1H, J2 ,1 = J2 ,OH = 7.2 Hz, J2 ,3
7.0 Hz, J2 ,3 = 5.5 Hz, H-2 ); 3.76 (td, 1H, J4 ,5 a = J4 ,5 b = 4.5 Hz, J4 ,3
= 5.3 Hz, H-20); 3.74 (td, 1H, J4 ,5 a = J4 ,5 b = 4.3 Hz, J4 ,3 = 3.1 Hz,
3.4 Hz, H-40); 3.89 (m, 1H, H-30); 4.43 (d, 1H, J1 ,2 = 7.4 Hz, H-1 ); 4.77
0
0
0
0
0
0
0
0
0
(t, 1H, JOH,5 a = JOH,5 b = 5.5 Hz, OH-50);04.84 (d, 1H, JOH,3 = 4.7 Hz,
H-40); 3.87 (bddd, 1H, J3 ,2 = 5.2 Hz, J3 ,OH = 4.5 Hz, J3 ,4 = 3.1 Hz,
0
0
0
0
0
0
0
0
0
OH-30); 4.86 (d, 1H, JOH,2 = 6.9 Hz, OH-2 ); 6.61 (dd, 1H, J3,4 = 8.8 Hz,
H-30); 4.31 (d, 1H, J1 ,2 = 7.5 Hz, H-1 ); 4.80 (t, 1H, JOH,5 a = JOH,5 b
=
0
0
0
0
0
5.6 Hz, OH-50); 4.860 (d, 1H, JOH,3 = 4.5 Hz, OH-30); 4.90 (d, 1H,
0
J3,6 = 0.6 Hz, H-3); 7.50 (bdd, 1H, J4,3 = 8.8 Hz, J4,6 = 2.4 Hz, H-4); 8.04
(dm, 1H, J6,4 = 2.4 Hz, H-6). 13C NMR (125.7 MHz, DMSO-d6): 38.0
((CH3)2N); 62.3 (CH2-50); 71.7 (CH-30); 77.1 (CH-20); 81.3 (CH-10);
85.2 (CH-40); 105.6 (CH-3); 123.7 (C-5); 135.9 (CH-4); 146.4 (CH-
6); 159.1 (C-2). IR spectrum (KBr): 3410, 2918, 1617, 1524, 1404,
0
JOH,2 = 6.9 Hz, OH-2 ); 6.32 (d, 1H, J3,4 = 9.5 Hz, H-3); 7.29 (bd, 1H,
J6,4 = 2.6 Hz, H-6); 7.47 (dd, 1H, J4,3 =8.5Hz,J4,6 = 2.6 Hz, H-4); 11.47 (bs,
1H, NH).13C NMR (125.7 MHz, DMSO-d6): 62.1 (CH2-50); 71.6 (CH-
30); 76.3 (CH-20); 80.2 (CH-10); 85.3 (CH-40); 117.6 (C-5); 120.0 (CH-
3); 133.2 (CH-6); 140.1 (CH-4); 162.5 (C-2). IR spectrum (KBr): 3404,
1115, 1054 cmꢀ1. [R]20 = ꢀ40.8 (c 2.0, MeOH). Anal. Calcd for
D
C12H18N2O4 2/3 H2O: C, 54.13; H, 7.32; N, 10.52. Found: C, 54.22;
3354, 1660, 1662, 1549, 1466, 1427, 1116, 1059, 1014 cmꢀ1. [R]20
=
D
3
ꢀ45.2 (c 1.91, MeOH). Anal. Calcd for C10H13NO5 1/3 H2O C, 51.50;
H, 7.16; N, 10.14.
3
H, 5.91; N, 6.01. Found: C, 51.66; H, 5.91; N, 6.02.
1β-[6-(Carbamoyl)pyridin-3-yl]-1-deoxy-D-ribofuranose
(16g). Compound 16g was prepared from 15g (216 mg, 0.361 mmol)
according to general procedure (Method B), in 85% yield, as a colorless
oil, which after lyophilization furnished a white hygroscopic solid.
HRMS (ESI) C11H14N2O5Na: [M + Na] calculated 277.0795, found
Conformational Analysis. A conformational analysis of the
ribose ring was performed using program PSEUROT 6.328 used for
description of five-membered ring conformation. Known parametriza-
tion for ribose, directly extracted vicinal protonꢀproton coupling
constants, and procedure MANY were used as an input for nonlinear
NewtonꢀRaphson minimization implemented in PSEUROT. The
results were postprocessed using program MULDER,29 gaining values
277.0795. 1H NMR (500 MHz, DMSO-d6): 3.51 ꢀ 3.62 (m, 2H, H-50);
0
0
0
0
0
0
3.74 (btd, 1H, J2 ,OH = J2 ,1 = 7.2 Hz, J2 ,30 = 5.3 Hz, H-2 ); 3.88 (td, 1H,
0
0
0
0
0
0
0
J4 ,5 a = J4 ,5 b = 4.3 Hz, J4 ,3 = 3.0 Hz, H-4 ); 3.94 (m, 1H, H-3 ); 4.71 (d,
6633
dx.doi.org/10.1021/jo200949c |J. Org. Chem. 2011, 76, 6619–6635

The Journal of Organic Chemistry
ARTICLE
for north and south conformers (phase angle P, puckering amplitude Φ,
equilibrium ratio X).
’ REFERENCES
ꢀ
(1) (a) Stambaskꢁy, J.; Hocek, M.; Koꢀcovskꢁy, P. Chem. Rev. 2009,
Single Crystal X-ray Structure Analysis. The diffraction data of
single crystals were collected on an X-ray diffractometer with CuKR
(λ=1.54180 Å) at 150 K (12, 14a, 14f, 14h) or at 170 K (16c). Both
structures were solved by direct methods with SIR9230 and refined by
full-matrix least-squares on F with CRYSTALS.31 All hydrogen atoms
were located in a difference map, but those attached to carbon atoms
were repositioned geometrically and then refined with riding con-
straints, while all other atoms were refined anisotropically in both cases.
Crystal data for 12 (colorless, 0.08 ꢁ 0.32 ꢁ 0.75 mm). C28H54-
Br1N1O5Si3, orthorhombic, space group P212121, a = 8.32986(10) Å, b =
11.95103(15) Å, c = 35.3621(5) Å, V = 3520.31(8) Å3, Z = 4, M = 648.90,
17910 reflections measured, 7383 independent reflections. Final R = 0.038,
wR = 0.046, GoF = 0.928 for 6927 reflections with I > 2σ(I) and 344
parameters. Flack parameter x = 0.048(14). CCDC 821676.
Crystal data for 14a (colorless, 0.04 ꢁ 0.44 ꢁ 0.69 mm). C11H15-
N1O4, monoclinic, space group P21, a = 5.03627(13) Å, b = 10.7538(3) Å,
c = 10.1690(3) Å, β = 97.824(2)°, V = 545.62(2) Å3, Z = 2, M = 225.24,
4227 reflections measured, 2208 independent reflections. Final R = 0.040,
wR = 0.047, GoF = 1.025 for 2110 reflections with I > 2σ(I) and 146
parameters, Flack parameter x = 0.07(18). CCDC 821675.
Crystal data for 14f (colorless, 0.16 ꢁ 0.60 ꢁ 0.68 mm). C12H18-
N2O4, monoclinic, space group P21, a = 4.99794(7) Å, b = 10.75451(16)
Å, c = 11.36720(17) Å, β = 91.1917(13)°, V = 610.859(15) Å3, Z = 2, M
= 254.29, 4271 reflections measured, 2438 independent reflections.
Final R = 0.030, wR = 0.033, GoF = 1.058 for 2421 reflections with
I > 2σ(I) and 165 parameters. Flack parameter x = 0.29(13). CCDC
821677.
Crystal data for 14h (colorless, 0.26 ꢁ 0.65 ꢁ 0.69 mm). C13H18-
N2O5, monoclinic, space group P21, a = 6.8778(3) Å, b = 10.4003(5) Å,
c = 9.7635(4) Å, β = 105.007(5)°, V = 674.58(5) Å3, Z = 2, M = 282.30,
6885 reflections measured, 2616 independent reflections. Final R = 0.029,
wR = 0.037, GoF = 0.933 for 2604 reflections with I > 2σ(I) and 183
parameters. Flack parameter x = 0.09(11). CCDC 821678.
109, 6729–6764. (b) Adamo, M. F. A.; Pergoli, R. Curr. Org. Chem. 2008,
12, 1544–1569. (c) Wu, Q. P.; Simons, C. Synthesis 2004, 1533–1553.
ꢀ
(2) Stefko, M.; Pohl, R.; Hocek, M. Tetrahedron 2009, 65, 4471–4483.
ꢀ
(3) Stefko, M.; Hocek, M. Synthesis 2010, 4199–4206.
(4) (a) Hocek, M.; Pohl, R.; Klepetꢁaꢀrovꢁa, B. Eur. J. Org. Chem.
2005, 4525–4528. (b) Joubert, N.; Urban, M.; Pohl, R.; Hocek, M.
Synthesis 2008, 1918–1932.
(5) Urban, M.; Pohl, R.; Klepetꢁaꢀrovꢁa, B.; Hocek, M. J. Org. Chem.
2006, 71, 7322–7328.
(6) Joubert, N.; Pohl, R.; Klepetꢁaꢀrovꢁa, B.; Hocek, M. J. Org. Chem.
2007, 72, 6797–6805.
(7) Bꢁarta, J.; Pohl, R.; Klepetꢁaꢀrovꢁa, B.; Ernsting, N. P.; Hocek, M.
J. Org. Chem. 2008, 73, 3798–3806.
(8) Bꢁarta, J.; Slavꢀetínskꢁa, L.; Klepetꢁaꢀrovꢁa, B.; Hocek, M. Eur. J. Org.
Chem. 2010, 5432–5443.
(9) Kubelka, T.; Slavꢀetínskꢁa, L.; Klepetꢁaꢀrovꢁa, B.; Hocek, M. Eur. J.
Org. Chem. 2010, 2666–2669.
(10) (a) Hari, Y.; Hwang, G. T.; Leconte, A. M.; Joubert, N.; Hocek,
M.; Romesberg, F. E. ChemBioChem 2008, 9, 2796–2799. (b) Urban,
M.; Joubert, N.; Hocek, M.; Alexander, R. E.; Kuchta, R. D. Biochemistry
2009, 48, 10866–10881. (c) Urban, M.; Joubert, N.; Purse, B. W.;
Hocek, M.; Kuchta, R. D. Biochemistry 2010, 49, 727–735.
ꢀ
(11) Stefko, M.; Pohl, R.; Klepetꢁaꢀrovꢁa, B.; Hocek, M. Eur. J. Org.
Chem. 2008, 1689–1704.
ꢀ
(12) Stefko, M.; Slavꢀetínskꢁa, L.; Klepetꢁaꢀrovꢁa, B.; Hocek, M. J. Org.
Chem. 2010, 75, 442–449.
(13) (a) Lu, J.; Li, N.-S.; Koo, S. C.; Piccirilli, J. A. J. Org. Chem. 2009,
74, 8021–8030. (b) Sollogoub, M.; Fox, K. R.; Powers, V. E. C.; Brown,
T. Tetrahedron Lett. 2002, 43, 3121–3123.
(14) (a) Hildbrand, S.; Blaser, A.; Parel, S.; Leumann, C. J. Am.
Chem. Soc. 1997, 119, 5499–5511. (b) Reese, C. B.; Wu, Q. Org. Biomol.
Chem. 2003, 1, 3160–3172.
(15) Matulic-Adamic, J.; Biegelman, L. Tetrahedron Lett. 1997, 38,
1669–1672.
(16) Matulic-Adamic, J.; Beigelman, L. Tetrahedron Lett. 1997, 38,
203–206.
(17) Hirao, I.; Fujiwara, T.; Kimoto, M.; Yokoyama, S. Bioorg. Med.
Chem. Lett. 2004, 14, 4887–4890.
(18) Kimoto, M.; Endo, M.; Mitsui, T.; Okuni, T.; Hirao, I.;
Yokoyama, S. Chem. Biol. 2004, 11, 47–55.
(19) Hirao, I.; Ohtsuki, T.; Fujiwara, T.; Mitsui, T.; Yokogawa, T.;
Okuni, T.; Nakayama, H.; Takio, K.; Yabuki, T.; Kigawa, T.; Kodama, K.;
Yokogawa, T.; Nishikawa, K.; Yokoyama, S. Nat. Biotechnol. 2002, 20,
177–182.
Crystal data for 16c (colorless, 0.07 ꢁ 0.17 ꢁ 0.51 mm).
C14H15N1O4S1, monoclinic, space group P21, a = 4.9831(3) Å, b =
11.6287(8) Å, c = 11.8750(8) Å, β = 100.351(7)°, V = 676.92(8) Å3, Z =
2, M = 293.34, 5444 reflections measured, 2758 independent reflections.
Final R = 0.055, wR = 0.068, GoF = 1.071 for 2417 reflections with I >
2σ(I) and 218 parameters. Flack parameter x = 0.05(4). The thienyl ring
has been found to be disordered over two sites (57: 43). The disordered
non-hydrogen atoms were refined anisotropically, but several restraints
were used to regularize the geometry of the thienyl ring. CCDC 822843.
’ ASSOCIATED CONTENT
(20) Alderweireldt, F. C.; Vrijens, I.; Esmans, E. L.; Wotring, L. L.;
Townsend, L. B.; Balzarini, J.; De Clercq, E. Nucleosides Nucleotides
1989, 8, 891–894.
S
Supporting Information. CIF files for crystal structures
b
and copies of the H and 13C NMR spectra of all new com-
1
(21) (a) Belmans, M.; Vrijens, I.; Esmans, E.; Domisse, R.; Lepoivre,
J.; Alderweireldt, F.; Townsend, L. B.; Wotring, L.; De Clercq, E.
Nucleosides Nucleotides 1986, 5, 441–455. (b) De Vos, E.; Esmans, E.;
Lepoivre, J.; Alderweireldt, F.; Domisse, R.; Francois, P.; Touillaux, R.;
Balzarini, J.; De Clercq, E. Nucleosides Nucleotides 1991, 10, 1573–1598.
(c) Ijima, T.; Furukawa, H. J. Heterocycl. Chem. 1988, 25, 503–507.
(d) Stuiver, L.; Pankiewicz, K.; Patterson, S.; Otto, M. J.; Watanabe, K. A.
WO 2002048165 A2 (2001).
(22) Wang, X.; Rabat, P.; O’Shea, P.; Tillyer, R.; Grabowski, E. J. J.;
Reider, P. J. Tetrahedron Lett. 2000, 41, 4335–4338.
(23) (a) Dondoni, A.; Scherrmann, M.-C. J. Org. Chem. 1994, 59,
6404–6412. (b) Gudmundsson, K. S.; Drach, J. D.; Townsend, L. B.
Tetrahedron Lett. 1996, 37, 2365–2368.
pounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Phone: +420 220183324. Fax: +420 220183559. E-mail: hocek@
uochb.cas.cz
’ ACKNOWLEDGMENT
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.
(24) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576,
125–146.
(25) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L.
J. Org. Chem. 2000, 65, 1158–1174.
6634
dx.doi.org/10.1021/jo200949c |J. Org. Chem. 2011, 76, 6619–6635

The Journal of Organic Chemistry
ARTICLE
(26) Lee, D.-Y.; Hartwig, J. F. Org. Lett. 2005, 7, 1169–1172.
ꢀ
(27) Capek, P.; Pohl, R.; Hocek, M. J. Org. Chem. 2005, 70,
8001–8008.
(28) van Wijk, J., Haasnoot, C. A. G., de Leeuw, F. A. A. M.,
Huckriede, B. D., Westra Hoekzema, A., Altona, C. PSEUROT 6.2
1993, PSEUROT 6.3 1999; Leiden Institute of Chemistry, Leiden
University.
(29) Padrta, P.; Sklenꢁaꢀr, V. J. Biomol. NMR 2002, 24, 339–349.
(30) Altomare, A.; Cascarano, G.; Giacovazzo, G.; Guagliardi, A.;
Burla, M. C.; Polidori, G.; Camalli, M. J. Appl. Crystallogr. 1994, 27,
435–435.
(31) Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.;
Watkin, D. J. J. Appl. Crystallogr. 2003, 36, 1487–1487.
6635
dx.doi.org/10.1021/jo200949c |J. Org. Chem. 2011, 76, 6619–6635