Modular and practical synthesis of 6-substituted pyridin-3-yl C-nucleosides

Article abstract of DOI:10.1021/jo0709504

(Chemical Equation Presented) A novel modular and practical methodology for preparation of 6-substituted pyridin-3-yl C-nucleosides was developed. The Heck reaction of 2-chloro-5-iodopyridine with a 3′-TBDMS-protected glycal gave a 6-chloropyridin-3-yl nu

Full text of DOI:10.1021/jo0709504

Modular and Practical Synthesis of 6-Substituted Pyridin-3-yl
C-Nucleosides
Nicolas Joubert, Radek Pohl, Blanka Klepeta´ˇrova´, and Michal Hocek*
Gilead Sciences & IOCB Research Center, Institute of Organic Chemistry and Biochemistry, V.V.i.,
Academy of Sciences of the Czech Republic, CZ-16610, Prague 6, Czech Republic
hocek@uochb.cas.cz
ReceiVed May 7, 2007
A novel modular and practical methodology for preparation of 6-substituted pyridin-3-yl C-nucleosides
was developed. The Heck reaction of 2-chloro-5-iodopyridine with a 3′-TBDMS-protected glycal gave
a 6-chloropyridin-3-yl nucleoside analogue, which was then desilylated, selectively reduced, and reprotected
to give the TBDMS-protected 6-chloropyridin-3-yl C-2′-deoxyribonucleoside as a pure â-anomer in a
total yield of 39% over four steps. This key intermediate was then subjected to a series of palladium-
catalyzed cross-coupling reactions, aminations, and alkoxylations to give a series of protected 1â-(6-
alkyl-, 6-aryl-, 6-hetaryl, 6-amino-, and 6-tert-butoxypyridin-3-yl)-2′-deoxyribonucleosides. 6-Unsubstituted
pyridin-3-yl C-nucleoside was prepared by catalytic hydrogenation of the chloro derivative and
6-oxopyridine C-nucleoside by treatment of the 6-tert-butoxy derivative with TFA. Deprotection of all
the silylated nucleosides by Et3N‚3HF gave a series of free C-nucleosides (10 examples).
Introduction
the C-nucleosides are efficiently incorporated to DNA by DNA
polymerases;3 however, further extension of the duplex is much
more problematic. Recent studies show crucial importance of
minor-groove interactions4,5 of the artificial nucleobase with the
enzyme. Therefore, the most promising candidates for efficient
incorporation and extension are the triphosphates of hetaryl-C-
nucleosides,4,6 such as pyridine nucleosides, possessing equivo-
cal nature between hydrophilic and hydrophobic species.
C-Nucleosides are an important class of compounds charac-
terized by replacement of a labile glycosidic C-N bond by a
stable hardly degradable C-C bond. C-Nucleosides bearing
hydrophobic aryl groups as nucleobase surrogates attract great
attention due to their use in the extension of the genetic
alphabet.1 In oligonucleotide duplexes, they selectively pair with
the same or other hydrophobic nucleobase due to increased
packing and favorable desolvation energy as compared to
canonical hydrophilic nucleobases.2 Triphosphates of some of
(1) Reviews: (a) Wang, L.; Schultz, P. G. Chem. Commun. 2002, 1-11.
(b) Henry, A. A.; Romesberg, F. E. Curr. Opin. Chem. Biol. 2003, 7, 727-
733. (c) Kool, E. T.; Morales, J. C.; Guckian, K. M. Angew. Chem., Int.
Ed. 2000, 39, 990-1009. (d) Kool, E. T. Acc. Chem. Res. 2002, 35, 936-
943.
* To whom correspondence should be addressed. Phone: +420 220183324.
Fax: +420 220183559.
10.1021/jo0709504 CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/01/2007
J. Org. Chem. 2007, 72, 6797-6805
6797

Joubert et al.
There are several synthetic approaches7 to C-nucleosides: (i)
additions of organometallics to ribono- or 2-deoxyribonolac-
tones;3,8,9 (ii) coupling of a halogenose with organometallics
(usually highly toxic diarylcadmium species10 or arylcuprates11);
(iii) electrophilic substitutions of electron-rich aromatics with
sugars under Lewis acid catalysis;12 (iv) Heck-type coupling
of aryl iodides with glycals9,13-15 or opening of glycal epoxides
with arylaluminum reagents.16 Most of these approaches suffer
from rather poor yields and/or insufficient anomeric selectivity
and necessity to optimize reaction and separation conditions for
each particular C-nucleoside, which makes it very difficult to
prepare larger series of derivatives. Often the target 2′-deoxy-
ribo-C-nucleosides17 must be prepared indirectly via additions
to ribonolactones, followed by reduction and Barton deoxygen-
ation at the 2′-position. Therefore, development of a general
and also possibly modular approaches to the synthesis of these
extremely important compounds is still of great interest.
We are currently involved in the development of modular
methodologies based on larger scale syntheses of versatile
C-nucleoside intermediates and their further use for a generation
of a series of diverse derivatives. Recently, we have developed
a modular approach consisting of the preparation of 3- and
4-bromophenyl C-nucleosides18 or 6-bromopyridin-2-yl C-
nucleoside,19 followed by displacement of the bromine for alkyl,
aryl, or amino substituents by cross-coupling reactions and
Hartwig-Buchwald aminations. Other groups have recently also
applied this approach3a,20 for analogous C-nucleosides. Another
modular methodology was based on construction of an aromatic
ring on deoxyribose by cyclotrimerizations of 1-ethynyl-2-
deoxyribose with R,ω-diynes.21 As the pyridine C-nucleosides
are important analogues of pyrimidine nucleosides and there
are just a few rather scattered examples of syntheses of 3-pyridyl
ribo-22 and 2-deoxyribonucleosides,9,13 we wish to report here
on a modular and practical synthesis of diverse 6-substituted
pyridin-3-yl C-nucleosides.
Results and Discussion
Our selected approach of choice for the synthesis of a series
of 6-substituted 3-pyridyl C-nucleosides was based on the
synthesis of a suitably protected 6-halo 3-pyridyl C-nucleoside
intermediate and on its further synthetic transformations (cross-
coupling, amination, etc.). Therefore, our first efforts were
devoted to the synthesis of the corresponding halopyridine
nucleoside intermediate. Several reactions have been studied
for this purpose, in analogy with the literature (Scheme 1). 2,5-
Dibromopyridine 1a was reported to be selectively lithiated in
position 523 to give 5-lithio-2-bromopyridine 2a, which should
react with TBDMS-protected 2′-deoxyribonolactone 3.24 Un-
fortunately, in our hands, the lithiation did not proceed
selectively and, even after attempted optimizing of the condi-
tions, complex mixtures of products were obtained. In order to
perform reactions selectively in the position 5 of the pyridine
moiety, we tried lithiation of 2-chloro-5-iodopyridine 1b or bis-
PMB-protected 2-amino-5-bromopyridine 1c,25 followed by
addition to lactone 3. In all cases, complex mixtures of
unseparable products were formed and/or dehalogenation of
pyridine was observed. Similar reactivity was observed when
we replaced lactone 3 with lactol 4 (easily obtained from lactone
3 in 92% yield, by reduction in presence of DIBALH in Et2O
at -70 °C in 40 min).26 For more details on the unsuccessful
approaches, see Supporting Information.
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6798 J. Org. Chem., Vol. 72, No. 18, 2007

Synthesis of 6-Substituted Pyridin-3-yl C-Nucleosides
TABLE 1. Optimization of the Heck Reaction
entry
glycal
Pd catalyst
ligand
solvent
base
(nBu)3N
(iPr)2NEt
(iPr)2NEt
(iPr)2NEt
K2CO3
Et3N
(nBu)3N
(nBu)3N
(nBu)3N
(nBu)3N + AgNO3
Ag2CO3
Ag2CO3
(nBu)3N + AgNO3
Ag2CO3
T (°C)
time
product (yield)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
7a
7a
7b
7b
7b
7b
7b
7b
7b
7b
7b
7b
7a
7a
Pd(OAc)2
Pd2dba3
Pd2dba3
AsPh3
(PhF5)3P
bdtbpa
(PhF5)3P
AsPh3
bdtbpa
dppfb
AsPh3
AsPh3
AsPh3
AsPh3
AsPh3
AsPh3
AsPh3
DMF
70
50
60
60
80
80
80
80
60
60
60
60
60
60
1 day
2 days
4 days
2 days
2 days
5 days
2 days
2 days
5 days
16 h
16 h
16 h
16 h
16 h
degradation
no reaction
no reaction
degradation
degradation
degradation
degradation
degradation
8b (14%)
8b (40%)
8b (65%)
8b (0%)
8a (traces)
8a (16%)
CH3CN
CH3CN
CH3CN
DMF
DMF
CH3CN
DMF
CHCl3
CHCl3
CHCl3
C2H4Cl2
CHCl3
CHCl3
Pd2dba3
Pd(OAc)2
Pd(OAc)2
Pd2dba3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
a bdtbp ) (2-biphenyl)di-tert-butylphosphine. b dppf ) diphenylphosphinoferrocene.
SCHEME 1. Reactions of Lactone 3 and Lactol 4 with
Organometallicsa
SCHEME 2. Optimization of the Heck Reaction
observed when using the AsPh3 ligand in DMF at 70 °C, while
the use of P(C6F5)3 in acetonitrile did not give any reaction
(Scheme 2 and Table 1, entries 1 and 2). Therefore, we have
further performed Heck reactions with mono-3′-TBDMS-
protected glycal 7b which was known26,30 to have superior
reactivity. Nevertheless, the first experiments under analogous
conditions did not bring any improvement (entries 3-8). Only
the use of Pd(OAc)2/AsPh3 in chloroform in the presence of
(n-Bu)3N afforded the desired compound 8b in a low but
encouraging yield (14% yield, entry 9). In order to improve
the reactivity of the glycal in the Heck reaction, we decided to
use some silver salts as additives.31 When silver nitrate was
added in addition to tributylamine, the yield reached 40% (entry
10). When silver carbonate was used as a base and additive
(without tributylamine), the desired compound 8b was obtained
in good yield of 65% as a pure â-anomer (entry 11). This
reaction is very sensitive to solventseven the replacement of
chloroform by dichloroethane led to degradation with no traces
of the product (entry 12). Finally, application of the optimized
conditions on bis-protected glycal 7a gave the desired nucleoside
8a in very low yields confirming that the 5′-TBDMS protecting
group decreases the reactivity of the glycal (entries 14 and 15).
Therefore, the preparative procedure involved the reaction of
2-chloro-5-iodopyridine (1b) with mono-TBDMS-protected
glycal 7b in the presence of Pd(OAc)2/AsPh3 and Ag2CO3 in
chloroform to give the desired C-nucleoside precursor 8b in
acceptable 65% yield even on 10 mmol scale.
a Reagents and conditions: (a) BuLi, toluene, -100 to -70 °C, 10 min;
with or without the following additive: (i) ZnCl2; (ii) CuI (b) 3, toluene,
-100 to -70 °C, 10 min; (c) 4, toluene, -100 to -70 °C, 10 min.
Having no encouraging results with the addition of lithiated
pyridines to lactone 3 or lactol 4, we focused our attention on
the palladium-catalyzed Heck reaction27 of iodopyridine 1b with
bis-TBDMS-protected glycal 7a or mono-3′-TBDMS-protected
glycal 7b.15 The starting bis-TBDMS-protected glycal 7a was
obtained by a one-pot mesylation-elimination sequence from
lactol 4, by treatment with MsCl and Et3N in CH2Cl2. Mono-
TBDMS-3′-protected glycal 7b was prepared via selective 5′-
desilylation of 7a in the presence of TBAF in THF at 0 °C in
60% yield.28 First we have tried the Heck reaction of 2-chloro-
5-iodopyridine with bis-TBDMS-protected glycal 7a under
conditions analogous to the literature.29 Only degradation was
(29) (a) Chen, J. J.; Walker, J. A., II; Liu, W.; Wise, D. S.; Townsend,
L. B. Tetrahedron Lett. 1995, 36, 8363-8366. (b) Matsuda, S.; Romesberg,
F. E. J. Am. Chem. Soc. 2004, 126, 14419-14427.
(30) (a) Mortensen, M. A.; Coleman, R. S. Tetrahedron Lett. 2003, 44,
1215-1219. (b) Hikishima, S.; Minakawa, N.; Kuramoto, K.; Fujisawa,
Y.; Ogawa, M.; Matsuda, A. Angew. Chem., Int. Ed. 2005, 44, 596-598.
(c) Okamoto, A.; Tainaka, K.; Fujiwara, Y. J. Org. Chem. 2006, 71, 3592-
3598.
(27) Review on the Heck reaction in synthesis of C-nucleosides:
Wellington, W. E.; Benner, S. A. Nucleosides, Nucleotides, Nucleic Acids
2006, 25, 1309-1333.
(28) Coleman, R. S.; Madaras, M. N. J. Org. Chem. 1998, 63, 5700-
5703.
(31) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009-
3066.
J. Org. Chem, Vol. 72, No. 18, 2007 6799

Joubert et al.
SCHEME 3. Synthesis, Cross-Coupling, and Amination Reactions of Chloroderivative 11a
a Reagents and conditions: (a) Et3N‚3HF, THF, rt, 5 min; (b) NaBH(OAc)3, CH3CN, AcOH, 0 °C, 5 min, 70%, two steps; (c) TBDMSCl, imidazole,
DMF, rt, 16h, 87%; (d) see Table 2 ; (e) Et3N‚3HF, THF, rt, 16 h.
TABLE 2. Reactions of Intermediate 11 and Deprotections
other
conditions
yield
(%)
deprotection
product
yield
(%)
entry
reagent
catalyst
Pd/C
ligand/base
Et3N
solvent
product
1
2
3
4
5
6
7
8
9
H2
Me3Al
Et3Al
THF, EtOH, H2O
THF
rt, 101 kPa
72 h, 70 °C
18 h, 70 °C
20 h, 60 °C
72 h, 60 °C
18 h, 95 °C
18 h, 95 °C
21 h, 60 °C
60 h, 70 °C
24 h, 90 °C
12a
12b
12c
12d
12e
12f
12g
12h
12i
82
90
81
76
60
65
49f
90
60
51
13a
13b
13c
13d
13e
13f
13g
13h
13i
86
90
89
85
80
90
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3
PdCl2dppf
PdCl2dppf
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
THF
THF
THF
BnZnBr
PhB(OH)2
KF, P(t-Bu)3‚HBF4
2-Bu3Sn-Pyd
6-Bu3Sn-[2,2′]-biPye
LiN(SiMe3)2
Me2NH.HCl
tBuONa
DMF
DMF
85 (42)g
90
84
bdCypa
THF
CyPF-tBu,b tBuONa
bdtbpc
DME
toluene
10
12j
a bdCyp ) (2-biphenyl)dicyclohexylphosphine. b CyPF-tBu ) Josiphos ligand. c bdtbp ) (2-biphenyl)di-tert-butylphosphine. d Py ) pyridine. e 6-Bu3Sn-
[2,2′]-biPy ) 6-tributylstannyl-[2,2′]-bipyridine. f Estimated yield based on NMR purity (70%) of crude product. g isolated yield over two steps in parenthesis.
The subsequent step was the desilylation of 8b (Scheme 3).
The common use of TBAF in THF32 for desilylation led in our
case to an unseparable mixture of compounds, whereas the
complex Et3N‚3HF in THF at 0 °C in 5 min gave us the desired
ketone 9, which was directly reduced in the following step using
triacetoxyborohydride33 in a mixture of acetonitrile and acetic
acid. The reduction proceeded very well to give the final
C-nucleoside 10 in a good yield of 70% for the two steps. In
accord with the literature precedent,15 the pathway via Heck
reaction afforded 10 as a single diastereoisomer of desired
â-erythro-configuration (confirmed by 1H NMR ROESY spec-
troscopy). In order to facilitate further functional group trans-
formations on the heterocycle ring, the nucleoside 10 was
protected using TBDMSCl with imidazole in DMF to afford
the fully protected key intermediate â-C-nucleoside 11 in 87%
yield (39% overall yield in 10 mmol scale over four steps from
glycal 7b, Scheme 3).
C-nucleosides (Scheme 3, Table 2). The first target derivative
was the 6-unsubstituted pyridine nucleoside 12a. We performed
a catalytical hydrogenolysis of chlorine in nucleoside 11, using
H2 over Pd/C for 3 h, in a mixture of EtOH, THF, and H2O, in
presence of Et3N (to neutralize HCl to avoid formation of
byproducts and deprotection of silyl groups), to give the desired
nucleoside 12a in 86% yield (entry 1).
Pd-catalyzed cross-coupling reactions were used for introduc-
tion of alkyl or aryl substituents. The reactions of 11 with
trimethylaluminum, triethylaluminum, and benzylzinc bromide
were performed under standard conditions in THF using
standard catalysis of Pd(PPh3)4 and with no optimization.
Though the lower reactivity of chlorine (in comparison of
bromine)17 made the reaction last 3 days to reach completion
(TLC monitoring), in all of these reactions, the desired nucleo-
sides, 12b, 12c, and 12d respectively (entries 2-4), were
obtained in good isolated yields (>75%). In the case of the
Suzuki cross-coupling, specific conditions were used to over-
come the low reactivity of chlorine.34 Reaction of 11 with
phenylboronic acid was performed in presence of Pd2(dba)3,
KF, and P(tBu)3‚HBF4 in THF (in analogy to literature34
conditions), but the reaction was still very slow to give the
desired nucleoside 12e with a satisfactory yield of 60% only
after 72 h at 60 °C (entry 5). The Stille cross-coupling reactions35
of 11 with 2-Bu3Sn-pyridine and 6-Bu3Sn-2,2′-bipyridine in the
Having a practical, reproducible, and scalable procedure for
the preparation of the protected 6-chloropyridine C-nucleoside
11 in hand, we decided to submit it to various cross-coupling
reactions and other transformations to prepare a series of new
(32) Fraley, A. W.; Chen, D.; Johnson, K.; McLauglin, L. W. J Am.
Chem. Soc. 2003, 125, 616-617.
(33) Hsieh, H.-P.; McLaughlin, L. W. J. Org. Chem. 1995, 60, 5356-
5359.
6800 J. Org. Chem., Vol. 72, No. 18, 2007

Synthesis of 6-Substituted Pyridin-3-yl C-Nucleosides
SCHEME 4. Preparation of 6-Oxopyridin-3-yl Nucleoside
14a
presence of PdCl2dppf in DMF were used for the synthesis of
2,2′-bipyridin-5-yl and [2,2′;6′,2′′]terpyridin-5-yl C-nucleosides
12f and 12g (entries 6 and 7), interesting metal-chelating
C-nucleoside ligands. While, in the former case, the desired
bipyridine product 12f was isolated in acceptable yield of 65%,
the terpyridine product 12g was not fully purified even after
repeated chromatography (entry 7) and was used in the
subsequent deprotection step in crude form (ca. 70% NMR
purity).
Hartwig-Buchwald aminations36,37 were performed for in-
troduction of N-substituents. Lithium bis(trimethylsilyl)amide
(LiN(SiMe3)2) was used as an ammonia equivalent for introduc-
tion of amino group. In our first attempt, the reaction of LiN-
(SiMe3)2 with 11 was performed in the presence of Pd2(dba)3
and P(tBu)3 (generated in situ from P(tBu)3‚HBF4 using excess
of the amide) in THF in analogy to our previous work19 on
bromopyridine nucleosides. This reaction gave only traces of
the desired product, due to low reactivity of chlorine. Therefore,
(2-biphenyl)dicyclohexylphosphine, known to be a superior
ligand for amination of 2-chloropyridine,38 was used under
analogous conditions to give the desired aminopyridine nucleo-
side 12h in good yield of 78% (entry 8). Hartwig-Buchwald39
reactions were also used for introduction of a substituted amino
group. We used conditions for aminations of chloropyridine
recently developed by Hartwig.40 The reaction of 11 with
dimethylamine hydrochloride was performed in the presence
of Pd2(dba)3, Josiphos ligand CyPF-tBu, and excess of tBuONa
as base to give the target substituted amine 12i in 60% yield
(entry 9). Analogous reaction of 11 with sodium tert-butoxide
in the absence of an amine using Pd2(dba)3/(2-biphenyl)di-tert-
butylphosphine catalytic system in toluene gave preparatively
the 6-(tert-butoxy)pyridine C-nucleoside 12j in 51% yield (entry
10).
a Reagents and conditions: (a) isopentyl nitrite, 80% AcOH in H2O, 70
°C, 1 h 40, impure compound; (b) TFA, rt, 20 min, 84%.
All the silylated nucleosides 12a-i were deprotected using
Et3N‚3HF in THF41 to give the free 6-substituted pyridine
C-nucleosides 13a-i in good yields (>80%). Even in case of
the crude protected terpyridine nucleoside 12g (containing
unseparable impurities), the corresponding free terpyridine
C-nucleoside 13g was isolated in pure form after deprotection
(preparative yield of 42% over two steps). This novel C-
nucleoside is of particular interest due to metal chelating
properties of the terpyridine unit.42
We were also interested in the synthesis of pyridin-2-one
C-nucleoside, which is a “deletion-modified” analogue of
uridine.43 Diazotation of 2-aminopyridines using isoamyl nitrite
in aqueous acetic acid is a classical approach44 to pyridones
successfully used recently for the 6-linked 2-pyridone C-nucleo-
side.19 Unfortunately, in this case, treatment of aminopyridine
C-nucleoside 12h with isopentyl nitrite in 80% aqueous AcOH
at 70 °C for 100 min afforded the desired 6-oxopyridin-3-yl
FIGURE 1. ORTEP drawing of 10 (a) and 13i (b) with atom
numbering scheme. Thermal ellipsoids are drawn at the 50% probability
level.
C-nucleoside 14 accompanied by some unseparable impurities.
Therefore, we have prepared the target pyridone by complete
deprotection of the 6-(tert-butoxy)pyridine derivative 12j on
treatment with TFA for 20 min to give the desired free pyridone
C-nucleoside 14 in 84% yield (Scheme 4).
All compounds were fully characterized, and the crystal
structures of 10 and 13h were also determined by X-ray
diffraction (Figure 1). NMR conformation analysis (see Sup-
porting Information) indicates that, in DMSO or methanol
(34) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020-
4028.
(35) Champouret, Y. D. M.; Chaggar, R. K.; Dadhiwala, I.; Fawcett, J.;
Solan, G. A. Tetrahedron 2006, 62, 79-89.
(36) (a) Lee, S.; Jorgensen, M.; Hartwig, J. F. Org. Lett. 2001, 3, 2729-
2732. (b) Lee, D.-Y.; Hartwig, J. F. Org. Lett. 2005, 7, 1169-1172.
(37) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J.
Org. Chem. 2000, 65, 1158-1174.
(42) Related examples of metallo base pairs: (a) Weizman, H.; Tor, Y.
J. Am. Chem. Soc. 2001, 123, 3375-3376. (b) Meggers, E.; Holland, P.
L.; Tolman, W. B.; Romesberg, F. E.; Schultz, P. G. J. Am. Chem. Soc.
2000, 122, 10714-10715. (c) Tanaka, T.; Tengeiji, A.; Kato, T.; Toyama,
N.; Shiro, M.; Shionoya, M. J. Am. Chem. Soc. 2002, 124, 12495-12498.
(d) Clever, G. H.; Carell, T. Angew. Chem., Int. Ed. 2007, 46, 250-253.
(43) Matulic-Adamic, J.; Beigelman, L. Tetrahedron Lett. 1997, 38,
1669-1672.
(38) Huang, X.; Buchwald, S. L. Org. Lett. 2001, 3, 3417-3419.
(39) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J.
Org. Chem. 2000, 65, 1158-1174.
(40) Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig, J. F. Angew. Chem.,
Int. Ed. 2005, 44, 1371-1375.
(41) Cˇ apek, P.; Pohl, R.; Hocek, M. J. Org. Chem. 2005, 70, 8001-
8008.
(44) Adams, R. A.; Schrecker, A. W. J. Am. Chem. Soc. 1949, 71, 1186-
1195.
J. Org. Chem, Vol. 72, No. 18, 2007 6801

Joubert et al.
analysis, a sample was chromatographed on silica gel in gradient
hexane to hexane/EtOAc 3/7 to give the desired nucleoside 9 as a
colorless oil (for characterization data, see Supporting Information).
NaBH(OAc)3 (322.0 mg, 1.52 mmol) was added to a dried flask
containing a solution of the crude nucleoside 9 in a mixture of
AcOH/CH3CN 2/1 (15 mL) at 0 °C under argon. After 5 min
(disappearance of 9 observed by TLC), a solution of EtOH/H2O
1/1 (10 mL) was added to neutralize the solution. Then the solvents
were evaporated in vacuum, and the crude product was chromato-
graphed on silica gel in gradient EtOAc to EtOAc/MeOH 9/1.
Crystallization from EtOAc/heptane gave the desired nucleoside
10 (161 mg, 70% for two steps) as colorless crystals (for
characterization data, see Supporting Information).
solution, the free nucleosides 10, 13a-i, and 14 occur prefer-
entially in the C2′-endo conformer, in a C2′-endo versus
C3′-endo conformer ratio dependent on the substituent effect.
According to the X-ray diffraction, the C-nucleoside 13h occurs
in the solid state in the expected C2′-endo conformation;
however, the chloropyridine nucleoside 10 occurs in the
C3′-endo form in the solid state (in contrast to C2′-endo
conformation prefered in solution). Both of these crystal
structures reveal anti-conformation of the nucleobase due to
intermolecular hydrogen bonds between the 5′-OH group and
nitrogen atom in the pyridine of a neighbor molecule (see Figure
S1 in Supporting Information).
1â-(6-Chloropyridin-3-yl)-1,2-dideoxy-3,5-di-O-(tert-butyl-
dimethylsilyl)-D-ribofuranose (11). To a dried flask containing a
solution of the nucleoside 10 (486 mg, 2.12 mmol) in dry DMF
(9.8 mL) at 0 °C under argon were added imidazole (576 mg, 8.46
mmol) and then TBDMSCl (797 mg, 5.29 mmol), and the solution
was allowed to warm to rt and was stirred for 16 h. The reaction
mixture was then poured into a saturated solution of NaCl (100
mL) and extracted with EtOAc (3 × 30 mL). Collected organic
fractions were washed with a saturated NaCl solution, dried over
MgSO4, and the solvents were evaporated under vacuum. The crude
product was chromatographed on silica gel in gradient hexane to
hexane/EtOAc 9/1 to give the desired nucleoside 11 (169 mg,
73%) as a colorless oil: MS (FAB) m/z 458 (M + 1); HRMS (FAB)
for C22H41NO3Si2Cl [M + H] calcd 458.2314, found 458.2334;
1H NMR (500 MHz, CDCl3) δ 0.07, 0.08 and 0.10 (3 × s, 12H,
CH3-Si), 0.90 and 0.92 (2 × s, 2 × 9H, (CH3)3C), 1.87 (ddd, 1H,
Jgem ) 12.6 Hz, J2′b,1′ ) 10.5 Hz, J2′b,3′ ) 5.3 Hz, H-2′b), 2.15
(ddd, 1H, Jgem ) 12.6 Hz, J2′a,1′ ) 5.4 Hz, J2′a,3′ ) 1.6 Hz, H-2′a),
3.64 (dd, 1H, Jgem ) 10.8 Hz, J5′b,4′ ) 5.2 Hz, H-5′b), 3.75 (dd,
In conclusion, a modular and reasonably practical methodol-
ogy of the synthesis of 6-substituted pyridin-3-yl C-nucleosides
was developed based on cross-coupling reactions and Hartwig-
Buchwald aminations of 6-chloropyridin-3-yl C-nucleoside 11,
available in four steps (36%) from monosilylated glycal 7b via
a Heck reaction. The methodology enables the synthesis of a
large series of pyridine C-nucleosides bearing diverse C (alkyl,
aryl, or hetaryl), N (unsubstituted and dialkylamino), or O
(alkoxy or oxo) groups from one common intermediate. These
C-nucleosides are interesting building blocks for construction
of modified nucleic acids (including metal chelating oligonucleo-
tides and metallo base pairs) and potential candidates for
extension of the genetic alphabet.
Experimental Section
1â-(6-Chloropyridin-3-yl)-1,2-dideoxy-2,3-didehydro-3-O-
(tert-butyldimethylsilyl)-D-ribofuranose (8b). CHCl3 (62 mL) was
added to an argon-purged, dried flask containing Pd(OAc)2 (302
mg, 1.4 mmol) and AsPh3 (863 mg, 2.80 mmol), and the mixture
was stirred at rt for 30 min. Then 2-chloro-5-iodopyridine (2.42 g,
9.90 mmol), a solution of glycal 7b (1.52 g, 6.60 mmol) in CHCl3
(62 mL), and Ag2CO3 (2.78 g, 9.90 mmol) were added, and the
reaction mixture was stirred until the disappearance of glycal 7b
(typically 16 h, checked by TLC). The reaction mixture was then
cooled, the solvents were removed in vacuum, and the crude product
was chromatographed on silica gel in gradient hexane to hexane/
EtOAc 8/2 to give the desired nucleoside 8b (1.47 g, 65%) as a
yellow oil: MS (FAB) m/z 342 (M + 1); HRMS (FAB) for
C16H25O3SiCl [M + H] calcd 342.1292, found 342.1276; 1H NMR
(400 MHz, CDCl3) δ 0.24 (s, 6H, CH3Si), 0.96 (s, 9H, (CH3)3C),
3.74 (dd, 1H, Jgem ) 12.0 Hz, J5′b,4′ ) 3.7 Hz, H-5′b), 3.79 (ddd,
1H, Jgem ) 12.0 Hz, J5′a,4′ ) 3.0 Hz, J5′a,2′ ) 0.7 Hz, H-5′a), 4.63
(dq, 1H, J4′,1′ ) 3.9 Hz, J4′,5′ ) 3.7, 3.0 Hz, J4′,2′ ) 1.9 Hz, H-4′),
4.81 (br t, 1H, J2′,4′ ) 1.9 Hz, J2′,1′ ) 1.6 Hz, H-2′), 5.75 (dd, 1H,
J1′,4′ ) 3.9 Hz, J1′,2′ ) 1.6 Hz, H-1′), 7.32 (dd, 1H, J3,4 ) 8.2 Hz,
J3,6 ) 0.7 Hz, H-3), 7.77 (dd, 1H, J4,3 ) 8.2 Hz, J4,6 ) 2.5 Hz,
H-4), 8.38 (br d, 1H, J6,4 ) 2.5 Hz, H-6); 13C NMR (100.6 MHz,
CDCl3) δ -5.0 and -4.9 (CH3Si), 18.0 (C(CH3)3), 25.5 ((CH3)3C),
62.9 (CH2-5′), 81.8 (CH-1′), 83.5 (CH-4′), 100.3 (CH-2′), 124.3
(CH-3), 137.0 (C-5), 137.9 (CH-4), 148.7 (CH-6), 151.2 (C-2),
152.3 (C-3′); IR spectrum (CHCl3) 3605, 1766, 1709, 1662, 1604,
1589, 1570, 1485, 1463, 1441, 1395, 1367, 1287, 1259, 1137, 1110,
1089, 1048, 939, 838 cm-1. Due to nonremovable traces of
heterocycle, no more analyses were performed, and the product
was used for the next step without any problem.
1H, Jgem ) 10.8 Hz, J5′a,4′ ) 3.5 Hz, H-5′a), 3.98 (ddd, 1H, J4′,5′
)
5.2, 3.5 Hz, J4′,3′ ) 1.9 Hz, H-4′), 4.39 (m, 1H, J3′,2′ ) 5.3, 1.6 Hz,
J3′,4′ ) 1.9 Hz, J3′,1′ ) 0.6 Hz, H-3′), 5.15 (m, 1H, J1′,2′ ) 10.5, 5.4
Hz, J1′,3′ ) J1′,3 ) J1′,4 ) J1′,6 ) 0.6 Hz, H-1′), 7.28 (dt, 1H, J3,4
8.2 Hz, J3,6 ) 0.9 Hz, J3,1′ ) 0.6 Hz, H-3), 7.71 (ddd, 1H, J4,3
)
)
8.3 Hz, J4,6 ) 2.5 Hz, J4,1′ ) 0.6 Hz, H-4), 8.36 (dt, 1H, J6,4 ) 2.5
Hz, J6,3 ) 0.9 Hz, J6,1′ ) 0.6 Hz, H-6); 13C NMR (125.7 MHz,
CDCl3) δ -5.2, -5.4, -4.72 and -4.67 (CH3-Si), 18.0 and 18.3
(C(CH3)3), 25.8 and 25.9 ((CH3)3C), 44.4 (CH2-2′), 63.7 (CH2-5′),
74.3 (CH-3′), 77.2 (CH-1′), 88.7 (CH-4′), 123.9 (CH-3), 136.7
(CH-4), 137.0 (C-5), 147.7 (CH-6), 150.4 (C-2); IR spectrum
(CHCl3): 3054, 2898, 1591, 1567, 1472, 1463, 1406, 1390, 1362,
1258, 1092, 940, 838, 681 cm-1; [R]20 +16.0 (c 6.88, CHCl3).
D
Anal. Calcd for C22H40ClNO3Si2 (458.2): C, 57.67; H, 8.80; Cl,
7.74; N, 3.06. Found: C, 57.82; H, 9.01; Cl, 7.71; N, 3.00.
1â-(Pyridin-3-yl)-1,2-dideoxy-3,5-di-O-(tert-butyldimethylsi-
lyl)-D-ribofuranose (12a). To a solution of the nucleoside 11 (289
mg, 0.63 mmol) in a mixture of THF/EtOH/H2O 10/10/1 (23 mL)
at rt were added 10% Pd/C (170 mg, 0.23 mmol) and Et3N (0.66
mL). The flask was evacuated and then filled with H2 (100 kPa)
and stirred at rt. After the reaction was completed (50 min, checked
by TLC), the Pd was filtered off, and the filtrate was poured into
water and extracted with EtOAc. Collected organic fractions were
dried on MgSO4, and solvents were evaporated under vacuum. The
crude product was chromatographed on silica gel in gradient hexane
to hexane/EtOAc 9/1 to give the desired nucleoside 12a (220 mg,
82%) as a colorless oil (for characterization data, see Supporting
Information).
1â-(6-Methylpyridin-3-yl)-1,2-dideoxy-3,5-di-O-(tert-butyldi-
methylsilyl)-D-ribofuranose (12b). A solution of Me3Al (1.3 mmol)
in THF was dropwise added to a vigorously stirred solution of 11
(300 mg, 0.65 mmol) and Pd(PPh3)4 (39 mg, 0.033 mmol) in THF
(13 mL). The mixture was stirred at 60 °C for 72 h and then worked
up. Crude product 12b was chromatographed on silica gel in
gradient hexane to hexane/EtOAc 9/1 to give 12b (259 mg, 90%)
as a colorless oil (for characterization data, see Supporting
Information).
1â-(6-Chloropyridin-3-yl)-1,2-dideoxy-D-ribofuranose (10). To
a dried flask containing a solution of the nucleoside 8b (346 mg,
1.01 mmol) in dry THF (2.6 mL) at 0 °C under argon was added
Et3N‚HF (420 µL, 2.58 mmol). After disappearance of the nucleo-
side 8b (typically 2 min, checked by TLC), the reaction mixture
was filtered on a small pad of silica gel (1.5 cm) and eluted with
EtOAc. The solvents were removed under vacuum, and the crude
product was used without further purification in the next step. For
6802 J. Org. Chem., Vol. 72, No. 18, 2007

Synthesis of 6-Substituted Pyridin-3-yl C-Nucleosides
1â-(6-Ethylpyridin-3-yl)-1,2-dideoxy-3,5-di-O-(tert-butyldi-
methylsilyl)-D-ribofuranose (12c). A solution of Et3Al (1.4 mmol)
in THF was dropwise added to a vigorously stirred solution of 11
(325 mg, 0.7 mmol) and Pd(PPh3)4 (43 mg, 0.035 mmol) in THF
(14 mL). The mixture was stirred at 70 °C for 48 h and then worked
up. Crude product 12c was chromatographed on silica gel in
gradient hexane to hexane/EtOAc 9/1 to give 12c (260 mg, 81%)
as a colorless oil (for characterization data, see Supporting
Information).
1â-(6-Benzylpyridin-3-yl)-1,2-dideoxy-3,5-di-O-(tert-butyldi-
methylsilyl)-D-ribofuranose (12d). THF (9 mL) was added to a
flame-dried and argon-purged flask containing 11 (214 mg, 0.47
mmol) and Pd(PPh3)4 (29 mg, 5 mol %), and the mixture was stirred
until clear solution formed. Then commercial solution of benzylzinc
bromide (0.94 mmol) in THF was added dropwise, and the mixture
was stirred at 60 °C for 20 h. After the workup, the product was
chromatographed on silica gel in gradient hexane to 10% EtOAc
in hexane to give 12d (182 mg, 76%) as a yellow oil (for
characterization data, see Supporting Information).
1â-(6-Phenylpyridin-3-yl)-1,2-dideoxy-3,5-di-O-(tert-butyldi-
methylsilyl)-D-ribofuranose (12e). Compound 11 (91 mg, 0.20
mmol), KF (38 mg, 0.66 mmol), Pd2dba3 (10 mg, 0.01 mmol),
P(t-Bu)3‚HBF4 (6 mg, 0.02 mmol), and PhB(OH)2 (27 mg, 0.22
mmol) were dissolved in THF (0.4 mL), and the mixture was stirred
at 60 °C for 72 h. The reaction mixture was worked up, and crude
product 12e was chromatographed on silica gel in gradient hexane
to hexane/EtOAc 9/1 to give 12e (60 mg, 60%) as a colorless oil
(for characterization data, see Supporting Information).
1â-(2,2′-Bipyridin-5-yl)-1,2-dideoxy-3,5-di-O-(tert-butyldi-
methylsilyl)-D-ribofuranose (12f). 2-Tributylstannylpyridine (1.20
mL, 4.37 mmol) was added dropwise under argon to a stirred
solution of 11 (200 mg, 0.44 mmol) and PdCl2dppf (16 mg, 0.02
mmol) in DMF (2.0 mL). The mixture was stirred at 95 °C for 18
h and then worked up. Crude product 12f was chromatographed
two times on silica gel in gradient hexane to hexane/EtOAc 1/1 to
give 12f (142 mg, 65%) as a colorless oil (for characterization data,
see Supporting Information).
1â-([2,2′;6′,2′′]-Terpyridin-5-yl)-1,2-dideoxy-3,5-di-O-(tert-bu-
tyldimethylsilyl)-D-ribofuranose (12g). n-BuLi (1.44 mL, solution
1.6 M in hexane) was added to a solution of 6-bromo[2,2′]bipyridine
(440 mg, 1.90 mmol) in THF (14.4 mL) under argon at -72 °C,
and the mixture was stirred for 2 min followed by addition of
Bu3SnCl (660 µL, 2.43 mmol). After being stirred for 20 min at
-72 °C, the reaction was allowed to warm to rt, and the solvent
was evaporated under vaccum. The crude 6-stannyl[2,2′]bipyridine
was dissolved in DMF (2.3 mL) and added through septum to a
flask containing 11 (320 mg, 0.7 mmol) and PdCl2dppf (26 mg,
0.04 mmol) sealed under argon. The reaction mixture was stirred
at 95 °C for 18 h and then worked up. Crude product 12g was
chromatographed two times on silica gel in gradient hexane to
hexane/EtOAc 1/1 to give 12g (284 mg) as a pale yellow oil (for
characterization data, see Supporting Information), which contained
some unseparable impurities (purity ca. 70% estimated from NMR;
yield calculated on content of pure 12g is ca. 49%). This compound
was directly used in the next step of deprotection.
1â-(6-Aminopyridin-3-yl)-1,2-dideoxy-3,5-di-O-(tert-butyldi-
methylsilyl)-D-ribofuranose (12h). LiN(SiMe3)2 (2.16 mL, 1 M
solution in THF, 2.16 mmol) was added to a flame-dried argon-
purged flask containing 11 (500 mg, 1.08 mmol), 2-(dicyclohexyl-
phosphino)biphenyl (77 mg, 0.22 mol), and Pd2(dba)3 (100 mg,
0.11 mol), and the mixture was stirred at 60 °C for 21 h. The
reaction was quenched by the addition of Et2O and 4 drops of 2 M
aqueous solution of HCl and worked up. Chromatography on silica
gel with gradient CHCl3 to 10% MeOH in CHCl3 gave 12h (459
mg, 90%) as a yellow oil (for characterization data, see Supporting
Information).
2 mol %) in DME (1.5 mL) was added to an argon-purged dry
flask containing 11 (275 mg, 0.6 mmol), sodium tert-butoxide (159
mg, 1.5 mmol), and Me2NH‚HCl (150 mg, 1.5 mmol). The mixture
was stirred at 70 °C for 60 h. Then the mixture was worked up,
and crude product 12i was chromatographed on silica gel in gradient
hexane to 10% EtOAc in hexane to give 12i (167 mg, 60%) as a
yellow oil (for characterization data, see Supporting Information).
1â-[6-(tert-Butyloxy)pyridin-3-yl]-1,2-dideoxy-3,5-di-O-(tert-
butyldimethylsilyl)-D-ribofuranose (12j). A solution of 11 (300
mg, 0.65 mmol) in toluene (1.5 mL) was added to an argon-purged
dry flask containing Pd2dba3 (30 mg, 5 mol %), (2-biphenyl)-di-
tert-butylphosphine (10 mg, 5 mol %), and sodium tert-butoxide
(193 mg, 2 mmol). The mixture was stirred at 90 °C for 17 h. Then
the mixture was worked up, and crude product 12j was chromato-
graphed on silica gel in gradient hexane to 5% EtOAc in hexane
to give 12j (164 mg, 51%) as a colorless oil (for characterization
data, see Supporting Information).
General Procedure for the Deprotection of TBDMS Group.
Et3N‚3HF (320 µL, 1.95 mmol) was added to a solution of
compounds 12a-i (0.4 mmol) in THF (2 mL), and the mixture
was stirred at room temperature for 14 h. After the reaction was
completed (TLC in hexane/EtOAc 9/1), solvents were removed
under reduced pressure. Then the crude product was dissolved in
MeOH (2 mL), and a 1 M aqueous solution of sodium hydroxide
(8 mL) was added to neutralize the mixture. Then the solvents were
removed under reduced pressure, and the crude product was
chromatographed on silica gel eluted with gradient CHCl3-20%
MeOH in CHCl3 to give products 13a-i.
1â-(Pyridin-3-yl)-1,2-dideoxy-D-ribofuranose45 (13a). Com-
pound 13a was prepared from 12a (178 mg, 0.42 mmol) by the
general procedure. Crystallization from EtOAc/heptane gave 13a
(70 mg, 86%) as colorless crystals: mp 52-54 °C; MS (FAB) m/z
196 (M + 1); HRMS (FAB) for C10H14NO3 [M + H] calcd
1
196.0974, found 196.0978; H NMR (500 MHz, CD3OD) δ 1.96
(ddd, 1H, Jgem ) 13.1 Hz, J2′b,1′ ) 10.5 Hz, J2′b,3′ ) 5.9 Hz, H-2′b),
2.27 (ddd, 1H, Jgem ) 13.1 Hz, J2′a,1′ ) 5.5 Hz, J2′a,3′ ) 1.7 Hz,
H-2′a), 3.69 (d, 2H, J5′,4′ ) 4.8 Hz, H-5′), 3.97 (td, 1H, J4′,5′ ) 4.8
Hz, J4′,3′ ) 2.4 Hz, H-4′), 4.35 (dddd, 1H, J3′,2′ ) 5.9, 1.7 Hz, J3′,4′
) 2.4 Hz, J3′,1′ ) 0.6 Hz, H-3′), 5.18 (dd, 1H, J1′,2′ ) 10.5, 5.5 Hz,
H-1′), 7.42 (ddd, 1H, J5,4 ) 7.9 Hz, J5,6 ) 5.0 Hz, J5,2 ) 0.6 Hz,
H-5), 7.91 (dddd, 1H, J4,5 ) 7.9 Hz, J4,2 ) 2.2 Hz, J4,6 ) 1.6 Hz,
J4,1′ ) 0.6 Hz, H-4), 8.44 (dd, 1H, J6,5 ) 5.0 Hz, J6,4 ) 1.6 Hz,
H-6), 8.58 (dt, 1H, J2,4 ) 2.2 Hz, J2,5 ) J2,1′ ) 0.6 Hz, H-2); 13C
NMR (125.7 MHz, CD3OD) δ 44.9 (CH2-2′), 63.9 (CH2-5′), 74.4
(CH-3′), 79.1 (CH-1′), 89.5 (CH-4′), 125.1 (CH-5), 136.1 (CH-4),
140.0 (C-3), 148.2 (CH-2), 149.2 (CH-6); IR spectrum (KBr) 3401,
1723, 1690, 1635, 1594, 1582, 1481, 1426, 1196, 1029, 1001, 808,
713, 632 cm-1; [R]20 +25.5 (c 2.65, MeOH).
D
1â-(6-Methylpyridin-3-yl)-1,2-dideoxy-D-ribofuranose (13b).
Compound 13b was prepared from 12b (223 mg, 0.51 mmol) by
the general procedure. Crystallization from EtOAc/heptane gave
13b (96 mg, 90%) as colorless crystals: mp 118-120 °C; MS
(FAB) m/z 210 (M + 1); HRMS (FAB) for C11H16NO3 [M + H]
calcd 210.1130, found 210.1136; 1H NMR (600 MHz, DMSO-d6)
δ 1.79 (ddd, 1H, Jgem ) 12.7 Hz, J2′b,1′ ) 10.5 Hz, J2′b,3′ ) 5.6 Hz,
H-2′b), 2.07 (ddd, 1H, Jgem ) 12.7 Hz, J2′a,1′ ) 5.4 Hz, J2′a,3′ ) 1.6
Hz, H-2′a), 2.44 (s, 3H, CH3), 3.42 (br dt, 1H, Jgem ) 11.4 Hz,
J5′b,4′ ) 5.5 Hz, J5′b,OH ) 5.0 Hz, H-5′b), 3.49 (br dt, 1H, Jgem
)
11.4 Hz, J5′a,OH ) 5.0 Hz, J5′a,4′ ) 4.9 Hz, H-5′a), 3.78 (ddd, 1H,
J4′,5′ ) 5.5, 4.9 Hz, J4′,3′ ) 2.1 Hz, H-4′), 4.20 (m, 1H, J3′,2′ ) 5.6,
1.6 Hz, J3′,OH ) 3.8 Hz, J3′,4′ ) 2.1 Hz, H-3′), 4.79 (br t, 1H, JOH,5′
) 5.0 Hz, OH-5′), 5.01 (dd, 1H, J1′,2′ ) 10.5, 5.4 Hz, H-1′), 5.09
(d, 1H, JOH,3′ ) 3.8 Hz, OH-3′), 7.20 (d, 1H, J3,4 ) 8.0 Hz, H-3),
7.66 (dd, 1H, J4,3 ) 8.0 Hz, J4,6 ) 2.3 Hz, H-4), 8.41 (d, 1H, J6,4
) 2.3 Hz, H-6); 13C NMR (151 MHz, DMSO-d6) δ 23.9 (CH3),
43.6 (CH2-2′), 62.6 (CH2-5′), 72.7 (CH-3′), 77.3 (CH-1′), 88.1
1â-(6-Dimethylaminopyridin-3-yl)-1,2-dideoxy-3,5-di-O-(tert-
butyldimethylsilyl)-D-ribofuranose (12i). A solution of Pd(OAc)2
(9.2 mg, 1 mol %) and (2-biphenyl)-di-tert-butylphosphine (12 mg,
(45) Eaton, M. A. W.; Millican, T. A.; Mann, J. J. Chem. Soc., Perkin
Trans. 1 1988, 545-548.
J. Org. Chem, Vol. 72, No. 18, 2007 6803

Joubert et al.
(CH-4′), 122.9 (CH-3), 134.4 (CH-4), 135.1 (C-5), 147.1 (CH-6),
157.0 (C-2); IR spectrum (KBr) 3300, 3116, 2970, 1607, 1573,
1496, 1429, 1395, 1381, 1299, 1258, 1088, 1054, 1036, 1009, 734,
J6,4 ) 2.3 Hz, J6,3 ) 0.8 Hz, J6,1′ ) 0.5 Hz, H-6); 13C NMR (151
MHz, DMSO-d6) δ 43.6 (CH2-2′), 62.6 (CH2-5′), 72.7 (CH-3′), 77.3
(CH-1′), 88.2 (CH-4′), 120.0 (CH-3), 126.7 (CH-o-Ph), 129.0
(CH-m-Ph), 129.1 (CH-p-Ph), 135.2 (CH-4), 137.0 (C-5), 138.8
(C-i-Ph), 147.9 (CH-6), 155.4 (C-2); IR spectrum (KBr) 3421, 3275,
3088, 3062, 3029, 1598, 1586, 1560, 1500, 1476, 1447, 1399, 1317,
1291, 1157, 1096, 1090, 1075, 1064, 1053, 1019, 980, 781, 738,
723 cm-1; [R]20 +74.2 (c 2.53, MeOH). Anal. Calcd for
D
C11H15NO3 (209.3): C, 63.14; H, 7.23; N, 6.69. Found: C, 63.34;
H, 7.18; N, 6.53.
1â-(6-Ethylpyridin-3-yl)-1,2-dideoxy-D-ribofuranose (13c). Com-
pound 13c was prepared from 12c (221 mg, 0.49 mmol) by the
general procedure. Crystallization from EtOAc/heptane gave 13c
(98 mg, 89%) as colorless crystals: mp 82-84 °C; MS (FAB) m/z
224 (M + 1); HRMS (FAB) for C12H18NO3 [M + H] calcd
224.1287, found 224.1289; 1H NMR (500 MHz, DMSO-d6) δ 1.20
(t, 3H, Jvic ) 7.6 Hz, CH3CH2), 1.81 (ddd, 1H, Jgem ) 12.7 Hz,
691, 616, 544 cm-1; [R]20 +69.1 (c 2.58, MeOH). Anal. Calcd
D
for C16H17NO3 (271.3): C, 70.83; H, 6.32; N, 5.16. Found: C,
70.85; H, 6.34; N 5.10.
1â-(2,2′-Bipyridin-5-yl)-1,2-dideoxy-D-ribofuranose8c,d (13f).
Compound 13f was prepared from 12f (280 mg, 0.56 mmol) by
the general procedure. Lyophilization from H2O gave 13f (137 mg,
90%) as a pink gum: MS (FAB) m/z 273 (M + 1); HRMS (FAB)
for C15H17N2O3 [M + H] calcd 273.1239, found 273.1236; 1H NMR
J2′b,1′ ) 10.5 Hz, J2′b,3′ ) 5.6 Hz, H-2′b), 2.08 (ddd, 1H, Jgem
)
12.7 Hz, J2′a,1′ ) 5.3 Hz, J2′a,3′ ) 1.4 Hz, H-2′a), 2.71 (q, 2H, Jvic
) 7.6 Hz, CH2CH3), 3.43 and 3.48 (2 × dt, 2H, Jgem ) 11.4 Hz,
J5′,OH ) 5.6 Hz, J5′,4′ ) 5.3 Hz, H-5′), 3.80 (td, 1H, J4′,5′ ) 5.3 Hz,
J4′,3′ ) 2.0 Hz, H-4′), 4.21 (m, 1H, J3′,2′ ) 5.6, 1.4 Hz, J3′,OH ) 3.8
Hz, J3′,4′ ) 2.0 Hz, H-3′), 4.79 (t, 1H, JOH,5′ ) 5.6 Hz, OH-5′),
5.02 (dd, 1H, J1′,2′ ) 10.5, 5.3 Hz, H-1′), 5.10 (d, 1H, JOH,3′ ) 3.8
(500 MHz, CD3OD) δ 2.01 (ddd, 1H, Jgem ) 13.1 Hz, J2′b,1′
)
10.5 Hz, J2′b,3′ ) 5.9 Hz, H-2′b), 2.30 (ddd, 1H, Jgem ) 13.1 Hz,
J2′a,1′ ) 5.5 Hz, J2′a,3′ ) 1.7 Hz, H-2′a), 3.71 (d, 2H, J5′,4′ ) 4.9 Hz,
H-5′), 4.00 (td, 1H, J4′,5′ ) 4.9 Hz, J4′,3′ ) 2.4 Hz, H-4′), 4.38 (dddd,
1H, J3′,2′ ) 5.9, 1.7 Hz, J3′,4′ ) 2.4 Hz, J3′,1′ ) 0.5 Hz, H-3′), 5.24
(dd, 1H, J1′,2′ ) 10.5, 5.5 Hz, H-1′), 7.42 (ddd, 1H, J5′′,4′′ ) 7.5
Hz, OH-3′), 7.20 (d, 1H, J3,4 ) 8.0 Hz, H-3), 7.67 (dd, 1H, J4,3
)
8.0 Hz, J4,6 ) 2.2 Hz, H-4), 8.45 (d, 1H, J6,4 ) 2.2 Hz, H-6); 13C
NMR (125.7 MHz, DMSO-d6) δ 14.1 (CH3CH2), 30.5 (CH2CH3),
43.5 (CH2-2′), 62.6 (CH2-5′), 72.7 (CH-3′), 77.3 (CH-1′), 88.1
(CH-4′), 121.7 (CH-3), 134.5 (CH-4), 135.3 (C-5), 147.3 (CH-6),
162.1 (C-2); IR spectrum (KBr) 3401, 1607, 1571, 1494, 1458,
Hz, J5′′,6′′ ) 4.9 Hz, J5′′,3′′ ) 1.2 Hz, H-5′′), 7.92 (ddd, 1H, J4′′,3′′ )
8.0 Hz, J4′′,5′′ ) 7.5 Hz, J4′′,6′′ ) 1.8 Hz, H-4′′), 7.98 (ddd, 1H, J4,3
) 8.2 Hz, J4,6 ) 2.2 Hz, J4,1′ ) 0.7 Hz, H-4), 8.27 (dd, 1H, J3,4
8.2 Hz, J3,6 ) 0.9 Hz, H-3), 8.29 (dt, 1H, J3′′,4′′ ) 8.0 Hz, J3′′,5′′
)
)
1.2 Hz, J3′′,6′′ ) 1.0 Hz, H-3′′), 8.683 (ddd, 1H, J6′′,5′′ ) 4.9 Hz,
J6′′,4′′ ) 1.8 Hz, J6′′,3′′ ) 1.0 Hz, H-6′′), 8.67 (dt, 1H, J6,4 ) 2.2
Hz, J6,3 ) 0.9 Hz, J6,1′ ) 0.6 Hz, H-6); 13C NMR (125.7
MHz, CD3OD) δ 44.8 (CH2-2′), 63.9 (CH2-5′), 74.4 (CH-3′),
79.1 (CH-1′), 89.5 (CH-4′), 122.3 (CH-3), 122.6 (CH-3′′),
125.2 (CH-5′′), 136.4 (CH-4), 138.7 (CH-4′′), 139.7 (C-5), 148.4
(CH-6), 150.2 (CH-6′′), 156.4 (C-2), 157.0 (C-2′′); IR spectrum
(KBr) 3409, 3056, 1628, 1590, 1575, 1558, 1490, 1462, 1436, 1255,
1434, 1408, 1374, 1310, 1259, 1136, 1036, 999, 842 cm-1; [R]20
+56.8 (c 2.68, MeOH).
D
1â-(6-Benzylpyridin-3-yl)-1,2-dideoxy-D-ribofuranose (13d).
Compound 13d was prepared from 12d (104 mg, 0.20 mmol) by
the general procedure to yield 13d (49 mg, 85%) as a white gum:
MS (FAB) m/z 286 (M + 1); HRMS (FAB) for C17H19NO3 [M +
1] calcd 286.1443, found 286.1452; 1H NMR (600 MHz, DMSO-
d6) δ 1.80 (ddd, 1H, Jgem ) 12.7 Hz, J2′b,1′ ) 10.5 Hz, J2′b,3′ ) 5.5
Hz, H-2′b), 2.07 (ddd, 1H, Jgem ) 12.7 Hz, J2′a,1′ ) 5.4 Hz, J2′a,3′
1148, 1092, 1065, 1051, 1026, 994, 797, 751, 640, 620, 400 cm-1
;
[R]20 +49.3 (c 4.50, MeOH).
D
) 1.5 Hz, H-2′a), 3.41 (dt, 1H, Jgem ) 11.4 Hz, J5′b,OH ) J5′b,4′
5.5 Hz, H-5′b), 3.47 (ddd, 1H, Jgem ) 11.4 Hz, J5′a,OH ) 5.5 Hz,
J5′a,4′ ) 4.8 Hz, H-5′a), 3.78 (ddd, 1H, J4′,5′ ) 5.5, 4.8 Hz, J4′,3′
)
1â-([2,2′;6′,2′′]-Terpyridin-5-yl)-1,2-dideoxy-D-ribofuranose
(13g). Compound 13g was prepared from crude 12g (284 mg) by
the general procedure. Lyophilization from H2O gave 13g (102 mg,
85%; 42% isolated yield over two steps) as a white gum: MS (FAB)
m/z 350 (M + 1); HRMS (FAB) for C20H20N3O3 [M + H] calcd
)
2.0 Hz, H-4′), 4.05 (s, 2H, CH2Ph), 4.20 (m, 1H, J3′,2′ ) 5.5, 1.5
Hz, J3′,OH ) 3.8 Hz, J3′,4′ ) 2.0 Hz, J3′,1′ ) 0.5 Hz, H-3′), 4.77 (br
t, 1H, JOH,5′ ) 5.5 Hz, OH-5′), 5.01 (dd, 1H, J1′,2′ ) 10.5, 5.4 Hz,
H-1′), 5.09 (d, 1H, JOH,3′ ) 3.8 Hz, OH-3′), 7.18 (m, 1H, H-p-Ph),
7.23 (dd, 1H, J3,4 ) 8.0 Hz, J3,6 ) 0.6 Hz, H-3), 7.25-7.29 (m,
1
350.1505, found 350.1509; H NMR (500 MHz, CD3OD) δ 2.03
(ddd, 1H, Jgem ) 13.1 Hz, J2′b,1′ ) 10.5 Hz, J2′b,3′ ) 5.9 Hz, H-2′b),
2.31 (ddd, 1H, Jgem ) 13.1 Hz, J2′a,1′ ) 5.5 Hz, J2′a,3′ ) 1.7 Hz,
H-2′a), 3.73 (d, 2H, J5′,4′ ) 4.9 Hz, H-5′), 4.01 (td, 1H, J4′,5′ ) 4.9
4H, H-o,m-Ph), 7.68 (ddd, 1H, J4,3 ) 8.0 Hz, J4,6 ) 2.3 Hz, J4,1′
)
0.4 Hz, H-4), 8.46 (dt, 1H, J6,4 ) 2.3 Hz, J6,3 ) J6,1′ ) 0.6 Hz,
H-6); 13C NMR (151 MHz, DMSO-d6) δ 43.4 (CH2-2′), 43.7
(CH2Ph), 62.6 (CH2-5′), 72.7 (CH-3′), 77.3 (CH-1′), 88.1 (CH-4′),
122.7 (CH-3), 126.3 (CH-p-Ph), 128.6 (CH-m-Ph), 129.1 (CH-m-
Ph), 134.7 (CH-4), 135.6 (C-5), 140.2 (C-i-Ph), 147.5 (CH-6), 159.9
(C-2); IR spectrum (KBr) 3428, 3028, 1629, 1608, 1571, 1494,
1453, 1091, 1075, 1052, 742, 700, 580 cm-1; [R]20D +57.2 (c 2.55,
MeOH).
Hz, J4′,3′ ) 2.5 Hz, H-4′), 4.38 (dt, 1H, J3′,2′ ) 5.9, 1.7 Hz, J3′,4′ )
2.5 Hz, H-3′), 5.25 (dd, 1H, J1′,2′ ) 10.5, 5.5 Hz, H-1′), 7.43 (ddd,
1H, J5′′′4′′′ ) 7.5 Hz, J5′′′,6′′′ ) 4.8 Hz, J5′′′,3′′′ ) 1.2 Hz, H-5′′′), 7.95
(ddd, 1H, J4′′′,3′′′ ) 8.0 Hz, J4′′′,5′′′ ) 7.5 Hz, J4′′′,6′′′ ) 1.8 Hz, H-4′′′),
7.99 (ddd, 1H, J4,3 ) 8.2 Hz, J4,6 ) 2.2 Hz, J4,1′ ) 0.6 Hz, H-4),
8.00 (t, 1H, J4′′,3′′ ) J4′′,5′′ ) 7.8 Hz, H-4′′), 8.326 and 8.328 (2 ×
dd, 2 × 1H, J3′′,4′′ ) J5′′,4′′ ) 7.8 Hz, J3′′,5′′ ) 2.3 Hz, H-3′′,5′′),
8.54 (dd, 1H, J3,4 ) 8.2 Hz, J3,6 ) 0.8 Hz, H-3), 8.56 (dt, 1H,
J3′′′,4′′′ ) 8.0 Hz, J3′′′,5′′′ ) 1.2 Hz, J3′′′,6′′′ ) 0.9 Hz, H-3′′′), 8.64
(ddd, 1H, J6′′′,5′′′ ) 4.8 Hz, J6′′′,4′′′ ) 1.8 Hz, J6′′′,3′′′ ) 0.9 Hz, H-6′′′),
1â-(6-Phenylpyridin-3-yl)-1,2-dideoxy-D-ribofuranose (13e).
Compound 13e was prepared from 12e (101 mg, 0.20 mmol) by
the general procedure. Crystallization from iPrOH/heptane gave 13e
(44 mg, 80%) as colorless crystals: mp 78-80 °C; MS (FAB) m/z
272 (M + 1); HRMS (FAB) for C16H18NO3 [M + H] calcd
272.1287, found 272.1278; 1H NMR (600 MHz, DMSO-d6) δ 1.87
(ddd, 1H, Jgem ) 12.8 Hz, J2′b,1′ ) 10.5 Hz, J2′b,3′ ) 5.5 Hz, H-2′b),
2.15 (ddd, 1H, Jgem ) 12.8 Hz, J2′a,1′ ) 5.5 Hz, J2′a,3′ ) 1.6 Hz,
H-2′a), 3.47 (dt, 1H, Jgem ) 11.4 Hz, J5′b,OH ) 5.7 Hz, J5′b,4′ ) 5.4
Hz, H-5′b), 3.52 (ddd, 1H, Jgem ) 11.4 Hz, J5′a,OH ) 5.7 Hz, J5′a,4′
) 4.9 Hz, H-5′a), 3.84 (td, 1H, J4′,5′ ) 5.4, 4.9 Hz, J4′,3′ ) 2.0 Hz,
H-4′), 4.25 (m, 1H, J3′,2′ ) 5.5, 1.6 Hz, J3′,OH ) 3.8 Hz, J3′,4′ ) 2.0
Hz, H-3′), 4.83 (br t, 1H, JOH,5′ ) 5.7 Hz, OH-5′), 5.12 (dd, 1H,
J1′,2′ ) 10.5, 5.5 Hz, H-1′), 5.14 (d, 1H, JOH,3′ ) 3.8 Hz, OH-3′),
7.42 (m, 1H, H-p-Ph), 7.48 (m, 2H, H-m-Ph), 7.87 (ddd, 1H, J4,3
8.67 (dt, 1H, J6,4 ) 2.2 Hz, J6,3 ) 0.8 Hz, J6,1′ ) 0.6 Hz, H-6); 13
C
NMR (125.7 MHz, CD3OD) δ 44.8 (CH2-2′), 64.0 (CH2-5′), 74.4
(CH-3′), 79.2 (CH-1′), 89.5 (CH-4′), 122.05 and 122.07 (CH-3′′
and CH-5′′), 122.4 (CH-3), 122.8 (CH-3′′′), 125.3 (CH-5′′′), 136.4
(CH-4), 138.7 (CH-4′′′), 139.2 (CH-4′′), 139.7 (C-5), 148.2
(CH-6), 150.1 (CH-6′′′), 156.4, 156.5 and 156.6 (C-2, C-2′′ and
C-6′′), 157.2 (C-2′′′); IR spectrum (KBr) 3421, 3062, 1630, 1598,
1584, 1561, 1492, 1475, 1454, 1431, 1414, 1263, 1148, 1102, 1093,
1080, 1051, 1027, 999, 991, 826, 787, 762, 640, 631, 619, 400
cm-1; [R]20 +52.8 (c 2.03, MeOH).
D
1â-(6-Aminopyridin-3-yl)-1,2-dideoxy-D-ribofuranose (13h).
Compound 13h was prepared from 12h (159 mg, 0.36 mmol) by
the general procedure. Lyophilization from H2O gave 13h (69 mg,
90%) as a yellow oil: MS (FAB) m/z 211 (M + 1); HRMS (FAB)
for C10H15N2O3 [M + 1] calcd 211.1083, found 211.1080; 1H NMR
) 8.2 Hz, J4,6 ) 2.3 Hz, J4,1′ ) 0.5 Hz, H-4), 7.92 (dd, 1H, J3,4
)
8.2 Hz, J3,6 ) 0.8 Hz, H-3), 8.07 (m, 2H, H-o-Ph), 8.67 (dt, 1H,
6804 J. Org. Chem., Vol. 72, No. 18, 2007

Synthesis of 6-Substituted Pyridin-3-yl C-Nucleosides
(500 MHz, DMSO-d6) δ 1.80 (ddd, 1H, Jgem ) 12.8 Hz, J2′b,1′
)
2.4 Hz, J3′,1′ ) 0.6 Hz, H-3′), 4.94 (dd, 1H, J1′,2′ ) 10.5, 5.4 Hz,
H-1′), 6.56 (ddd, 1H, J3,4 ) 9.4 Hz, J3,6 ) 0.7 Hz, J3,1′ ) 0.4 Hz,
H-3), 7.47 (dt, 1H, J6,4 ) 2.6 Hz, J6,3 ) J6,1′ ) 0.7 Hz, H-6), 7.71
(ddd, 1H, J4,3 ) 9.4 Hz, J4,6 ) 2.6 Hz, J4,1′ ) 0.3 Hz, H-4); 13C
NMR (151 MHz, CD3OD) δ 43.66 (CH2-2′), 63.84 (CH2-5′), 74.28
(CH-3′), 78.33 (CH-1′), 89.16 (CH-4′), 120.76 (CH-3), 122.69
(C-5), 133.44 (CH-4), 142.70 (CH-6), 165.53 (C-2); IR spectrum
(KBr) 3428, 1687, 1659, 1618, 1551, 1207, 1183, 1091, 1050, 1004,
10.5 Hz, J2′b,3′ ) 5.7 Hz, H-2′b), 1.92 (ddd, 1H, Jgem ) 12.8 Hz,
J2′a,1′ ) 5.4 Hz, J2′a,3′ ) 1.6 Hz, H-2′a), 3.39 (br dd, 1H, Jgem
11.4 Hz, J5′b,4′ ) 5.5 Hz, H-5′b), 3.44 (br dd, 1H, Jgem ) 11.4 Hz,
J5′a,4′ ) 4.8 Hz, H-5′a), 3.70 (ddd, 1H, J4′,5′ ) 5.5, 4.8 Hz, J4′,3′
)
)
2.1 Hz, H-4′), 4.16 (br dt, 1H, J3′,2′ ) 5.7, 1.6 Hz, J3′,4′ ) 2.1 Hz,
H-3′), 4.72 (br s, 1H, OH-5′), 4.82 (dd, 1H, J1′,2′ ) 10.5, 5.4 Hz,
H-1′), 5.00 (br s, 1H, OH-3′), 5.83 (br s, 2H, NH2), 6.41 (d, 1H,
J3,4 ) 8.8 Hz, H-3), 7.36 (dd, 1H, J4,3 ) 8.8 Hz, J4,6 ) 2.3 Hz,
H-4), 7.84 (d, 1H, J6,4 ) 2.3 Hz, H-6); 13C NMR (125.7 MHz,
DMSO-d6) δ 42.99 (CH2-2′), 62.72 (CH2-5′), 72.72 (CH-3′), 77.56
(CH-1′), 87.69 (CH-4′), 107.89 (CH-3), 125.11 (C-5), 135.84
(CH-4), 146.33 (CH-6), 159.64 (C-2); IR spectrum (KBr) 3420,
2804, 2756, 2739, 2678, 2601, 2492, 1672, 1632, 1559, 1507, 1476,
799, 722, 550 cm-1; [R]20 +44.1 (c 1.71, MeOH).
D
Single-Crystal X-ray Structure Analysis. X-ray crystallo-
graphic analysis of single crystals of 10 (colorless, 0.14 × 0.47 ×
0.53 mm) and 13i (colorless, 0.07 × 0.16 × 0.46 mm) was
performed with Xcalibur X-ray diffractometr with Cu KR (λ )
1.54180 Å), data collected at 150 K. Both structures were solved
by direct methods with SIR9246 and refined by full-matrix least-
squares on F with CRYSTALS.47 The hydrogen atoms were all
located in a difference map, but those attached to carbon atoms
were repositioned geometrically and then refined with riding
constraints, while all other atoms were refined anisotropically in
both cases.
Crystal data for 10: CCDC642287; C10H12Cl1N1O3, monoclinic,
space group P21, a ) 7.1887(1) Å, b ) 7.5136(1) Å, c ) 9.5782-
(1) Å, â ) 96.1275(9)°, V ) 514.389(8) Å3, Z ) 2, M ) 229.66,
9510 reflections measured, 2070 independent reflections. Final R
) 0.0288, wR ) 0.0328, GoF ) 0.9217 for 2053 reflections with
I > 1.96σ(I) and 138 parameters.
1434, 1398, 1092, 1050 cm-1; [R]20 +25.9 (c 2.32, MeOH).
D
1â-(6-Dimethylaminopyridin-3-yl)-1,2-dideoxy-D-ribofura-
nose (13i). Compound 13i was prepared from 12i (176 mg, 0.38
mmol) by the general procedure. Crystallization from EtOAc/
heptane gave 13i (75 mg, 84%) as colorless crystals: mp 104-
106 °C; MS (FAB) m/z 238 (M + 1); HRMS (FAB) for C12H18N2O3
1
[M + H] calcd 238.1317, found 238.1324; H NMR (600 MHz,
DMSO-d6) δ 1.82 (ddd, 1H, Jgem ) 12.8 Hz, J2′b,1′ ) 10.6 Hz, J2′b,3′
) 5.6 Hz, H-2′b), 1.95 (ddd, 1H, Jgem ) 12.8 Hz, J2′a,1′ ) 5.3 Hz,
J2′a,3′ ) 1.6 Hz, H-2′a), 3.00 (s, 6H, (CH3)2N), 3.40 (br dt, 1H, Jgem
) 11.3 Hz, J5′b,4′ ) 5.7 Hz, J5′b,OH ) 5.4 Hz, H-5′b), 3.45 (br dt,
1H, Jgem ) 11.3 Hz, J5′a,OH ) 5.4 Hz, J5′a,4′ ) 4.9 Hz, H-5′a), 3.72
(ddd, 1H, J4′,5′ ) 5.7, 4.9 Hz, J4′,3′ ) 2.1 Hz, H-4′), 4.18 (m, 1H,
J3′,2′ ) 5.6, 1.6 Hz, J3′,OH ) 3.8 Hz, J3′,4′ ) 2.1 Hz, H-3′), 4.75 (br
t, 1H, JOH,5′ ) 5.4 Hz, OH-5′), 4.89 (dd, 1H, J1′,2′ ) 10.6, 5.3 Hz,
Crystal data for 13i: CCDC642288; C12H18N2O3, orthorhombic,
space group P212121, a ) 5.6723(1) Å, b ) 10.6767(1) Å, c )
19.4350(1) Å, V ) 1177.01(2) Å3, Z ) 4, M ) 238.28, 17723
reflections measured, 2401 independent reflections. Final R )
0.0340, wR ) 0.0439, GoF ) 1.0980 for 1947 reflections with I >
1.96σ(I) and 156 parameters.
H-1′), 5.03 (d, 1H, JOH,3′ ) 3.8 Hz, OH-3′), 6.63 (d, 1H, J3,4
)
8.8 Hz, H-3), 7.52 (dd, 1H, J4,3 ) 8.8 Hz, J4,6 ) 2.4 Hz, H-4),
8.03 (dt, 1H, J6,4 ) 2.4 Hz, J6,3 ) J6,1′ ) 0.6 Hz, H-6); 13C NMR
(151 MHz, DMSO-d6) δ 38.03 ((CH3)2N), 43.09 (CH2-2′), 62.71
(CH2-5′), 72.73 (CH-3′), 77.35 (CH-1′), 87.75 (CH-4′), 106.01
(CH-3), 124.82 (C-5), 136.19 (CH-4), 145.60 (CH-6), 158.73
(C-2); IR spectrum (KBr) 3401, 3308, 2815, 1609, 1559, 1414,
Acknowledgment. This work is a part of the research project
Z04 055 905. It was supported by the Centre of Biomolecules
and Complex Molecular Systems (LC 512) and by NIH, Fogarty
International Center (Grant 1R03TW007372-01).
1437, 1320, 1074, 1051, 1032, 1012, 995 cm-1; [R]20 +40.3 (c
D
2.65, MeOH). Anal. Calcd for C12H18N2O3 (238.3): C, 60.49; H,
7.61; N, 11.76. Found: C, 60.76; H, 7.75; Cl, 7.71; N, 11.72.
1â-(6-Oxopyridin-3-yl)-1,2-dideoxy-D-ribofuranose (14). Com-
pound 12j (84 mg, 0.17 mmol) was dissolved in TFA (2 mL), and
the solution was stirred until the reaction was completed (ca. 20
min, TLC). Then, TFA was evaporated and crude pyridone 14 was
purified by chromatography on silica gel in gradient CHCl3 to 50%
MeOH in CHCl3. Lyophilization from H2O gave 14 (30 mg, 84%)
as colorless crystals: mp 157-159 °C; MS (FAB) m/z 212 (M +
Supporting Information Available: Detailed description of
unsuccessful experiments, conformation analysis of nucleosides,
general methods, synthesis, and characterization data of compounds
4, 7a,b, 12a-i, cif files for 10 and 13i, and copies of all NMR
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org. CCDC642287 and CCDC642288 contain the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
1); HRMS (FAB) for C10H14NO4 [M + H] calcd 212.0923, found
1
212.0920; H NMR (600 MHz, CD3OD) δ 1.95 (ddd, 1H, Jgem
)
JO0709504
13.1 Hz, J2′b,1′ ) 10.5 Hz, J2′b,3′ ) 5.9 Hz, H-2′b), 2.11 (ddd, 1H,
Jgem ) 13.1 Hz, J2′a,1′ ) 5.4 Hz, J2′a,3′ ) 1.7 Hz, H-2′a), 3.64 (dd,
(46) Altomare, A.; Cascarano, G.; Giacovazzo, G.; Guagliardi, A.; Burla,
M. C.; Polidori, G.; Camalli, M. J. Appl. Crystallogr. 1994, 27, 435-435.
(47) Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.; Watkin,
D. J. J. Appl. Crystallogr. 2003, 36, 1487-1487.
1H, Jgem ) 11.7 Hz, J5′b,4′ ) 4.9 Hz, H-5′b), 3.66 (dd, 1H, Jgem
)
11.7 Hz, J5′a,4′ ) 4.6 Hz, H-5′a), 3.90 (td, 1H, J4′,5′ ) 4.9, 4.6 Hz,
J4′,3′ ) 2.4 Hz, H-4′), 4.32 (dddd, 1H, J3′,2′ ) 5.9, 1.7 Hz, J3′,4′
)
J. Org. Chem, Vol. 72, No. 18, 2007 6805