New modular and efficient approach to 6-substituted pyridin-2-yl C-nucleosides

Article abstract of DOI:10.1021/jo061080d

A novel modular, efficient, and practical methodology of preparation of 6-substituted pyridin-2-yl C-nucleosides was developed. An addition of 2-lithio-6-bromopyridine 2b to TBDMS-protected 2-deoxyribonolactone 5 gave aduct 7 as an equilibrium mixture of anomeric hemiketals 1-(6-bromopyridin-2-yl)-1- hydroxynucleosides 7a,b and its open form 7c. Reduction of the adduct 7 with Et₃SiH and BF₃-Et₂O afforded the desired 6-bromonucleoside 8a as pure β-anomer in a total yield of 32% over two steps from 5. Intermediate 8a was then subjected to a series of palladium catalyzed cross-coupling reactions and aminations to give a series of protected 1β-(6-alkyl-, 6-aryl-, and 6-aminopyridin-2-yl)-2-deoxyribonucleosides 9. Catalytic hydrogenation of 8a gave an unsubstituted pyridine C-nucleoside, and diazotative oxodeamination of 6-aminopyridine nucleoside 9f by isopentyl nitrite in acetic acid gave 6-oxopyridine nucleoside 10i. Deprotection of silylated nucleosides 9 by Et₃N-SHF gave a series of free C-nucleosides 10.

Full text of DOI:10.1021/jo061080d

New Modular and Efficient Approach to 6-Substituted
Pyridin-2-yl C-Nucleosides
Milan Urban, Radek Pohl, Blanka Klepeta´ˇrova´, and Michal Hocek*
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, CZ-16610,
Prague 6, Czech Republic
hocek@uochb.cas.cz
ReceiVed May 26, 2006
A novel modular, efficient, and practical methodology of preparation of 6-substituted pyridin-2-yl
C-nucleosides was developed. An addition of 2-lithio-6-bromopyridine 2b to TBDMS-protected
2-deoxyribonolactone 5 gave aduct 7 as an equilibrium mixture of anomeric hemiketals 1-(6-bromopyridin-
2-yl)-1-hydroxynucleosides 7a,b and its open form 7c. Reduction of the adduct 7 with Et3SiH and
BF3‚Et2O afforded the desired 6-bromonucleoside 8a as pure â-anomer in a total yield of 32% over
two steps from 5. Intermediate 8a was then subjected to a series of palladium catalyzed cross-coupling
reactions and aminations to give a series of protected 1â-(6-alkyl-, 6-aryl-, and 6-aminopyridin-2-yl)-
2-deoxyribonucleosides 9. Catalytic hydrogenation of 8a gave an unsubstituted pyridine C-nucleoside,
and diazotative oxodeamination of 6-aminopyridine nucleoside 9f by isopentyl nitrite in acetic acid gave
6-oxopyridine nucleoside 10i. Deprotection of silylated nucleosides 9 by Et3N‚3HF gave a series of free
C-nucleosides 10.
Introduction
because of favorable packing and desolvation energy as
compared to canonical hydrophilic nucleobases.3 Triphosphates
of some of the C-nucleosides are efficiently incorporated to
DNA by DNA polymerase.4 Pyridine C-nucleosides are a very
interesting subclass because of their equivocal nature between
hydrophilic and hydrophobic species, but there were just a few
C-Nucleosides are an important class of compounds charac-
terized by replacement of a labile nucleosidic C-N bond by a
stable hardly degradable C-C bond. Many of them possess
antiviral or antineoplastic activities.1 Quite recently, C-nucleo-
sides bearing hydrophobic aryl groups as nucleobase surrogates
attracted great attention because of their use in the extension of
the genetic alphabet.2 In oligonucleotide duplexes, they selec-
tively pair with the same or other hydrophobic nucleobase
(3) (a) Ogawa, A. K.; Abou-Zied, O. K.; Tsui, V.; Jimenez, R.; Case, D. A.;
Romesberg, F. E. J. Am. Chem. Soc. 2000, 122, 9917-9920. Wu, Y. Q.;
Ogawa, A. K.; Berger, M.; Mcminn, D. L.; Schultz, P. G.; Romesberg, F.
E. J. Am. Chem. Soc. 2000, 122, 7621-7632. (c) Guckian, K. M.; Krugh,
T. R.; Kool, E. T. J. Am. Chem. Soc. 2000, 122, 6841-6847. (d) Parsch,
J.; Engels, J. W. J. Am. Chem. Soc. 2002, 124, 5664-5672. (e) Lai, J. S.;
Qu, J.; Kool, E. T. Angew. Chem., Int. Ed. 2003, 42, 5973-5977. (f) Lai,
J. S.; Kool, E. T. J. Am. Chem. Soc. 2004, 126, 3040-3041. (g) Rˇ eha, D.;
Hocek, M.; Hobza, P. Chem.sEur. J. 2006, 12, 3587-3595.
(4) Henry, A. A.; Olsen, A. G.; Matsuda, S.; Yu, C.; Geierstanger, B.
H.; Romesberg, F. E. J. Am. Chem. Soc. 2004, 126, 6923-6931. (b) Henry,
A. A.; Yu, C. Z.; Romesberg, F. E. J. Am. Chem. Soc. 2003, 125, 9638-
9646. (c) Hwang, G. T.; Romesberg, F. E. Nucleic Acids Res. 2006, 34,
2037-2045. (d) Matsuda, S.; Henry, A. A.; Romesberg, F. E. J. Am. Chem.
Soc. 2006, 128, 6369-6375.
* To whom correspondence should be addressed. Phone: +420 220183324.
Fax: +420 220183559.
(1) Examples: (a) Franchetti, P.; Cappellacci, L.; Griffantini, M.; Barzi,
A.; Nocentini, G.; Yang, H. Y.; O’Connor, A.; Jayaram, H. N.; Carrell, C.;
Goldstein, B. M. J. Med. Chem. 1995, 38, 3829-3837. (b) Walker, J. A.;
Liu, W.; Wise, D. S.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 1998,
41, 1236-1241.
(2) 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.
10.1021/jo061080d CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/22/2006
7322
J. Org. Chem. 2006, 71, 7322-7328

6-Substituted Pyridin-2-yl C-Nucleosides
rather scattered examples of syntheses of 3-pyridyl ribo-5 and
2-deoxyribonucleosides6 as analogues of canonical pyrimidines.
There are several synthetic approaches7 to C-nucleosides: (i)
additions of organometallics to ribono- or 2-deoxyribonolac-
tones,4,8 (ii) coupling of a halogenose with organometallics
(usually highly toxic diarylcadmium species),9 (iii) electrophilic
substitutions of electron rich aromatics with sugars under Lewis
acid catalysis,10 or (iv) Heck-type coupling of aryl iodides with
glycals.6,11 All these approaches suffer from poor yields,
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. Therefore, development of general and possibly
also modular approaches to the synthesis of these extremely
important compounds is of great interest.
SCHEME 1. Reactions of Halogenose 3 and Lactone 5 with
Organometallicsa
We are currently involved in development of modular
methodologies based on larger scale syntheses of versatile
C-nucleoside intermediates and their further use for a generation
of series of diverse derivatives. Recently, we have developed a
modular approach consisting of the preparation of bromophenyl
C-nucleosides12 followed by the displacement of the bromine
for alkyl or aryl substituents by cross-coupling reactions.
Another modular methodology was based on construction of
an aromatic ring on deoxyribose by cyclotrimerizations of
1-ethynyl-2-deoxyribose with R,ω-diynes.13 Here we wish to
report on an efficient and modular synthesis of diverse
6-substituted 2-pyridyl C-nucleosides. One of the most interest-
ing aspects of these novel nucleobases is their positioning of a
nitrogen as hydrogen-bond acceptor in the minor groove of
DNA.
a Reagents and conditions: (a) (i) Mg, THF, rt, 1 h; (b) in the absence
or in the presence of the following additives: (i) ZnCl2; (ii) CdCl2; (iii)
CuI; (iv) Zn(CN)2; (v) CuCN; THF, rt, 2 h-1 day; (c) THF, rt, 2 h; (d)
Et3N‚3HF, THF, rt, 14 h, 57% from 2a.
SCHEME 2. Synthesis of Bromoderivatives 8a and 8ba
Results and Discussion
Our approach of choice for the synthesis of the title
6-substituted 2-pyridyl C-nucleosides was based on the synthesis
of a suitably protected 6-bromopyrinin-2-yl C-nucleoside in-
termediate and on its further synthetic transformations (cross-
coupling, amination, etc.). Therefore, our first efforts were
(5) (a) Matulic-Adamic, J.; Beigelman, L. Tetrahedron Lett. 1997, 38,
203-206. (b) Matulic-Adamic, J.; Beigelman, L. Tetrahedron Lett. 1997,
38, 1669-1672. (c) Sollogoub, M.; Fox, K. R.; Powers, V. E. C.; Brown,
T. Tetrahedron Lett. 2002, 43, 3121-3123.
(6) Sun, Z.; Ahmed, S.; McLaughlin, L. W. J. Org. Chem. 2006, 71,
2922-2926.
(7) Wu, Q. P.; Simons, C. Synthesis 2004, 1533-1553.
(8) (a) Matsuda, S.; Romesberg, F. E. J. Am. Chem. Soc. 2004, 126,
14419-14427. (b) Mathis, G.; Hunziker, J. Angew. Chem., Int. Ed. 2002,
41, 3203-3205. (c) Brotschi, C.; Ha¨berli, A.; Leumann, C. J. Angew. Chem.,
Int. Ed. 2001, 40, 3012-3014. (d) Brotschi, C.; Mathis, G.; Leumann, C.
J. Chem.sEur. J. 2005, 11, 1911-1923. (e) Zahn, A.; Brotschi, C.;
Leumann, C. J. Chem.sEur. J. 2005, 11, 2125-2129. (f) Reese, C. B.;
Wu, Q. Org. Biomol. Chem. 2003, 1, 3160-3172.
(9) (a) Chaudhuri, N. C.; Kool, E. T. Tetrahedron Lett. 1995, 36, 1795-
1798. (b) Ren, R. X.-F.; Chaudhuri, N. C.; Paris, P. L.; Rumney, S., IV;
Kool, E. T. J. Am. Chem. Soc. 1996, 118, 7671-7678. (c) Griesang, N.;
Richert, C. Tetrahedron Lett. 2002, 43, 8755-8758. (d) Aketani, S.; Tanaka,
K.; Yamamoto, K.; Ishihama, A.; Cao, H.; Tengeiji, A.; Hiraoka, S.; Shiro,
M.; Shinoya, M. J. Med. Chem. 2002, 45, 5594-5603.
a Reagents and conditions: (a) n-BuLi, THF, -78 °C, 10 min; (b) 5,
THF, -78 °C, 30 min, 61%; (c) Et3SiH, BF3‚Et2O, CH2Cl2, 0 °C, ca. 45
min, 53%; (d) Et3N‚3HF, THF, rt, 12 h, 92%; (e) Ac2O, py, 14 h, rt, 76%.
devoted to the synthesis of the corresponding bromopyridine
nucleoside intermediate. Several reactions have been studied
for this purpose on the basis of literature analogy (Scheme 1).
2,6-Dibromopyridine (1a) was used as a starting compound for
monometalation. Its reaction with magnesium gave bromo-
pyridine Grignard reagent 2a that was used itself or transmeta-
lated with ZnCl2, CdCl2, Zn(CN)2, or CuCN. Toluoyl protected
1R-chloro-1,2-dideoxyribose 3 was our first starting sugar of
choice that was subjected to a series of reactions with 2a in the
(10) (a) Yokoyama, M.; Nomura, M.; Togo, H.; Seki, H. J. Chem. Soc.,
Perkin Trans. 1 1996, 2145-2149. (b) He, W.; Togo, H.; Yokoyama, M.
Tetrahedron Lett. 1997, 38, 5541-5544. (c) Hainke, S.; Arndt, S.; Seitz,
O. Org. Biomol. Chem. 2005, 3, 4233-4238.
(11) (a) Wang, Z. X.; Wiebe, L. I.; De Clercq, E.; Balzarini, J.; Knaus,
E. E. Can. J. Chem. 2000, 78, 1081-1088. (b) Ha¨berli, A.; Leumann, C.
J. Org. Lett. 2001, 3, 489-492.
(12) Hocek, M.; Pohl, R.; Klepeta´rˇova´, B. Eur. J. Org. Chem. 2005,
4525-4528.
(13) Nova´k, P.; Pohl, R.; Kotora, M.; Hocek, M. Org. Lett. 2006, 8,
2051-2054.
J. Org. Chem, Vol. 71, No. 19, 2006 7323

Urban et al.
SCHEME 3. Cross-Coupling and Amination Reactions of 8a
ently, the hemiketal formation is reversible and the â-hemiketal
7a is reduced preferentially to give good yield of 8a and other
desilylated â-anomers. We found that Et3SiH (5 equiv) should
be added to the solution of 7 in three portions, and each portion
must be followed by a dropwise addition of diluted BF3‚Et2O
in order to minimize desilylation followed by elimination to
furan. Despite the problems with purification and characteriza-
tion of the intermediate adduct 7, we were able to isolate the
desired â-C-nucleoside 8a in acceptable total yield of 32% over
two steps based on starting lactone 5.
Having a practical multigram scale procedure for a prepara-
tion of 6-bromopyridine nucleoside 8a in hand, we decided to
study its reactivity, that is, cross-coupling reactions with diverse
organometallics and other transformations that lead to a variety
of new nucleosides. To have more freedom in the use of diverse
reagents, we sought to prepare also the acyl-protected bromopyri-
dine nucleoside. The silyl group in nucleoside 8a was cleaved
under standard conditions15 using Et3N‚3HF in THF to give free
nucleoside 8b, which was then acetylated with acetic anhydride
in pyridine to give acetylated nucleoside 8c in 76% yield.
The first target derivative was an unsubstituted pyridine
nucleoside 9a. Interestingly, attempts to apply an analogous
procedure as in synthesis of 8a, the addition of 2-lithiopyridine
generated from 2-bromopyridine to lactone 5, have failed. The
addition proceeded with only a very low yield (ca. 25%) and
the following reduction with Et3SiH gave a furan as the only
product. Even an extensive optimization of this procedure has
not brought any improvement. Therefore, we have used cata-
lytical hydrogenolysis of bromine in nucleoside 8a using H2
over Pd/C. The first experiment was performed in a mixture of
EtOH, THF, and H2O to give the desired nucleoside 9a in only
low yield (about 10%) accompanied by some unreacted starting
compound and polar byproducts. Apparently, HBr resulting in
the reaction cleaved the protecting groups and caused side
reactions. Therefore, we have added Et3N to neutralize the HBr,
and under these modified conditions the reaction was completed
within 30 min to give cleanly the desired nucleoside 9a in 81%
yield.
absence or in the presence of additive metal salts under various
conditions. Unfortunately, no desired nucleoside was ever
isolated. In all cases, the reaction mixtures contained mainly
furan 4, degraded halogenose, and 2-bromopyridine side prod-
ucts (Scheme 1).
Having no encouraging results with halogenose 3, further
efforts focused on TBDMS-protected 2-deoxyribonolactone 5,
which is very easily available in two steps from 2-deoxyribose.14
Despite the higher stability of lactone 5, the first reaction with
(6-bromopyridin-2-yl)magnesium bromide 2a also led to furan
byproduct 6a. More successful was an application of the
organolithium species. 2-Lithio-6-bromopyridine 2b generated
by the reaction of 2,6-dibromopyridine 1a with n-butyllithium
at -78 °C in 10 min reacted with lactone 5 to afford adduct 7
in 61% yield (Scheme 2). Adduct 7 was isolated as a chromat-
ographically homogeneous equilibrium mixture of â- and
R-anomeric hemiketals 7a,b and an open form 7c in the ratio
7:5:9 (determined by COSY, HMBC, and ROESY spectra, see
Supporting Information). Hemiketal formation from γ-hydroxy-
ketones analogous to 7 is known8f to be reversible forming an
equilibrium of the three forms.
A reduction of the adduct 7 was then performed with Et3SiH
(in analogy to literature8) in different solvents (toluene, CH2-
Cl2, MeCN) in the presence of different Lewis acids (BF3‚Et2O,
SnCl4, ZnCl2). The optimum procedure made use of BF3‚Et2O
in CH2Cl2 at 0 °C to give an acceptable 53% yield of nucleoside
8a. Its structure was determined by NMR spectroscopy (NOE,
see Supporting Information) to be pure desired â-anomer. Side-
products of this reaction were partially and fully desilylated
derivatives of the â-anomeric configuration (ca. 15%). Appar-
Pd-catalyzed cross-coupling reactions were used for introduc-
tion of alkyl or aryl substituents. The reactions of 8a with
trimethylaluminum, triethylaluminum, phenylboronic acid, and
benzylzinc chloride were performed under standard conditions
for each type of reaction using standard catalysis of Pd(PPh3)4
and with no optimization (Scheme 3, Table 1). In all of these
reactions, the desired nucleosides 9b-e were obtained in good
isolated yields (>70%).
Hartwig-Buchwald aminations16,17 were used for introduction
of N-substituents. Lithium bis(trimethylsilyl)amide (LiN-
TABLE 1. Reagents, Conditions, and Yields of Reactions Presented in Scheme 3
other
conditions
yield
(%)
deprotection
product
yield
(%)
entry
reagent
catalyst
ligand/base
Et3N
solvent
product
1
2
3
4
5
6
7
H2
Pd/C
THF, EtOH, H2O
THF
rt, 101 kPa
12 h, 70 °C
20 h, 70 °C
12 h, 100 °C
18 h, 70 °C
2 h, rt
9a
9b
9c
9d
9e
9f
81
78
90
72
77
83
50
10a
10b
10c
10d
10e
10f
84
80
74
56
66
68
78
Me3Al
Et3Al
PhB(OH)2
BnZnCl
LiN(SiMe3)2
MeNH2‚HCl
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3
Pd2(dba)3
THF
K2CO3
toluene
THF
P(t-Bu)3‚HBF4
THF
bdtbp,a t-BuONa
toluene
24 h at rt,
9g
10g
8 h at 80 °C
24 h at rt,
8 h at 80 °C
8
Me2NH‚HCl
Pd2(dba)3
bdtbp,a t-BuONa
toluene
9h
48
10h
57
a bdtbp ) (2-biphenyl)di-tert-butylphosphine.
7324 J. Org. Chem., Vol. 71, No. 19, 2006

6-Substituted Pyridin-2-yl C-Nucleosides
SCHEME 4. Synthesis and Rearrangement of N-oxide 12a
(SiMe3)2) was used as an ammonia equivalent for the introduc-
tion of an amino group. Its reaction with 8a was performed in
the presence of Pd2(dba)3 and P(t-Bu)3 (generated in situ from
P(t-Bu)3‚HBF4 using excess of the amide) to give the desired
aminopyridine nucleoside 9f in good yield of 80%. When using
a less reactive zinc bis[bis(trimethylsilyl)]amide,16 low yield
(27%) of 9f was obtained. Buchwald17 reactions were used for
the introduction of substituted amino groups. The reactions of
8a with methylamine and dimethylamine hydrochlorides were
performed under standard conditions in the presence of Pd2-
(dba)3, 2-(di-tert-butylphosphino)biphenyl, and an excess of
t-BuONa as base to give the target substituted amines 9g,h in
ca. 50% yields. TLC analysis showed some unreacted starting
material and some polar byproducts: Apparently, the stability
of the silyl groups on longer time heating under basic conditions
is rather limited, and the desilylated products undergo side
reactions, for example, eliminations. Nevertheless, the 50%
yields obtained from the optimized procedure were satisfactory
for our purposes since the desired compounds were easily
isolated and unreacted starting compound 8a was recovered
(13%) and reused.
a Reagents and conditions: (a) H2, P/C, THF, EtOH, H2O, rt, 101 kPa,
30 min, 85%; (b)MCPBA/CH2Cl2, 14 h, rt, 62%; (c) MeONa, MeOH, rt, 6
h, 70%; (d) Ac2O, reflux, 6 h, 72%.
SCHEME 5. Preparation of 6-Oxopyridin-2-yl Nucleoside
14a
All silylated nucleosides 9a-h were deprotected using Et3N‚
3HF in THF15 to give a series of title free 6-substituted pyridine
C-nucleosides 10a-h in good yields.
a Reagents and conditions: (a) isopentyl nitrite, 80% AcOH in H2O, 70
°C, 3 h, 48%.
Having an access to pyridine C-nucleosides bearing C- and
N-substituents in the position 6, we turned our attention to the
attachment of O-substituents, in particular to the synthesis of
pyridone 10i which may be considered as an analogue of uracil.
Bromopyridines are known to react5,18,19 with BnONa to give
(benzyloxy)pyridine that could be hydrogenolytically depro-
tected to pyridones. However our attepmts on substitution of
the bromine in nucleosides 8a,b with BnONa, generated from
BnOH and NaH under different conditions yielded either
products of degradation or furan 6a, although an analogous
reaction of 2-bromo-6-methylpyridine gave 1-benzyloxy-6-
methylpyridine in high yield of 80%. Other attempts to prepare
pyridone 10i were also unsuccessful (for details, see Supporting
Information). Another method for synthesis of pyridones makes
use5,20 of a rearrangement of pyridine-N-oxides by heating with
Ac2O. Therefore, we prepared the N-oxide nucleoside 12a.
Catalytic hydrogenolysis of acetylated bromopyridine nucleoside
8c was performed with H2 over Pd/C using AcONa as a weak
base because of the low stability of acetates in basic conditions
to give pyridine nucleoside 11 in 85%. Pyridine 11 was then
oxidized with MCPBA to the N-oxide 12a in 62% yield.
Attempted rearrangement of 12a to pyridone upon heating in
acetic anhydride was not successful, giving furan 13 as the only
product (Apparently, the oxidation took place at the position 1′
followed by eliminations) (Scheme 4). Acylated N-oxide
nucleoside was deprotected to free nucleoside 12b using
treatment with NaOMe in methanol.
Diazotation of 2-aminopyridines in diluted aqueous solutions
is another approach21 to pyridones, and its variant using isoamyl
nitrite in aqueous acetic acid is often used22 in nucleoside
chemistry to convert adenine to hypoxanthine derivatives.
Therefore we treated aminopyridine C-nucleoside 9f with
isopentyl nitrite in 80% aqueous AcOH at 70 °C for 3 h to
afford the desired 6-oxopyridin-2-yl C-nucleoside 10i in 48%
yield (Scheme 5). The moderate yield of this reaction was due
to partial degradation of the C-nucleoside skeleton and due to
some loss during isolation of the polar free nucleoside on column
chromatography. Despite the lower yield, the reaction is
reasonably clean and practical for the preparation of the pyridone
nucleoside 10i.
All compounds were fully characterized, and the crystal
structures of 10e,h were also determined by X-ray diffraction.
NMR conformation analyses (see Supporting Information)
indicate that in DMSO solution, the free nucleosides 10a-h
occur in the ratio C2′-endo/C4′-exo conformers of ca. 4:1 in
all of the compounds with no significant substituent effect.
According to the X-ray diffraction, the C-nucleosides 10e,h
occur in solid state in solely C2′-endo form and in syn-
conformation of the nucleobase because of strong hydrogen-
bonds between the 5′-OH group and the nitrogen atom in
pyridine (Figure 1).
In conclusion, a modular and reasonably practical methodol-
ogy of the synthesis of 6-substituted pyridin-2-yl C-nucleosides
was developed. It is based on cross-coupling reactions and
Hartwig-Buchwald aminations of 6-bromopyridin-2-yl C-nucleo-
side 8a available in multigram quantities by an addition of
6-bromo-2-lithiopyridine to silylated 2-deoxyribonolactone fol-
(14) (a) Deriaz, R. E.; Overend, W. G.; Stacey, M.; Teece, E. G.;
Wiggins, L. F. J. Chem. Soc. 1949, 1879-1883. (b) Walker, J. A., II; Chen,
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Lee, D.-Y.; Hartwig, J. F. Org. Lett. 2005, 7, 1169-1172.
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(20) (a) Adamczyk, M.; Akireddy, S. R.; Reddy, R. E. Tetrahedron 2002,
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76, 1286-1291.
(21) Adams, R. A.; Schrecker, A. W. J. Am. Chem. Soc. 1949, 71, 1186-
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4621-4625.
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J. Org. Chem, Vol. 71, No. 19, 2006 7325

Urban et al.
Jgem ) 10.8, J5′b,4′ ) 5.5, H-5′b), 3.74 (dd, 1H, Jgem ) 10.8, J5′a,4′
) 3.8, H-5′a), 4.00 (ddd, 1H, J4′,5′ ) 5.5, 3.8, J4′,3′ ) 2.4, H-4′),
4.39 (dt, 1H, J3′,2′ ) 5.5, 2.4, J3′,4′ ) 2.4, H-3′), 5.23 (dd, 1H, J1′,2′
) 9.5, 6.2, H-1′), 7.34 (dd, 1H, J5,4 ) 7.5, J5,3 ) 1.7, H-5), 7.50 (t,
1H, J4,3 ) 7.7, J4,5 ) 7.5, H-4), 7.53 (dd, 1H, J3,4 ) 7.7, J3,5 ) 1.7,
H-3). 13C NMR (125.8 MHz, CDCl3): -5.5, -5.4, -4.8, and -4.6
(CH3-Si), 18.0 and 18.3 (C(CH3)3), 25.8 and 25.9 ((CH3)3C), 42.5
(CH2-2′), 63.5 (CH2-5′), 73.7 (CH-3′), 80.2 (CH-1′), 88.3 (CH-4′),
118.9 (CH-3), 126.4 (CH-5), 138.8 (CH-4), 141.0 (C-6), 164.4 (C-
2). IR spectrum: 2956, 2930, 2898, 2858, 2804, 1584, 1557, 1472,
1463, 1440, 1409, 1390, 1362, 1258, 1154, 1108, 1095. [R]20
)
D
+44.0 (c 5.98, CHCl3). Anal. Calcd for C22H40BrNO3Si2 (502.6):
C, 52.57; H, 8.02; Br, 15.90; N 2.79. Found: C, 52.46; H, 8.13;
Br, 15.76; N, 2.67.
1â-(Pyridin-2-yl)-1,2-dideoxy-3,5-di-O-(t-butyldimethylsilyl)-
D-ribofuranose (9a). 10% Pd/C (400 mg, 24 mol %) was added to
a solution of 8a (800 mg, 1.6 mmol) in a mixture of THF (40 mL),
EtOH (40 mL), H2O (4 mL), and Et3N (2.4 mL). The reaction flask
was then sealed with septum, evacuated, and filled with H2 (101
kPa). After the reaction was completed (30 min), the Pd catalyst
was filtered off, the filtrate was poured into water, and crude product
was extracted with EtOAc. Chromatography on HPFC in gradient
from 5% EtOAc in hexane to 50% EtOAc in hexane gave 9a (546
mg, 81%) as colorless oil (for characterization data, see Supporting
Information).
1â-(6-Methylpyridin-2-yl)-1,2-dideoxy-3,5-di-O-(t-butyldi-
methylsilyl)-D-ribofuranose (9b). Me3Al (1 mmol) was added
dropwise to a vigorously stirred solution of 8a (250 mg, 0.5 mmol)
and Pd(PPh3)4 (30 mg, 0.025 mmol) in THF (10 mL) under argon.
The mixture was stirred at 70 °C for 12 h and then worked up by
pouring onto a mixture of ice and NH4Cl and extracted to ethyl
acetate. Crude product 9b was chromatographed on silica gel
(20 g) in gradient hexane to 10% EtOAc in hexane to give 9b
(170 mg, 78%) as oil (for characterization data, see Supporting
Information).
FIGURE 1. ORTEP drawing of 10e (a) and 10h (b) with atom
numbering scheme. Thermal ellipsoids are drawn at the 50% prob-
ability level.
lowed by reduction with Et3SiH in the presence of BF3‚Et2O.
It enables the synthesis of a large series of pyridine C-nucleo-
sides bearing diverse C- (alkyl or aryl) or N- (unsubstituted,
mono-, and dialkylamino) groups from one common intermedi-
ate. These C-nucleosides will be now used for chemical and
enzymatical incorporations to oligonucleotides and DNA du-
plexes and studied as candidates for the extension of genetic
alphabet.
1â-(6-Ethylpyridin-2-yl)-1,2-dideoxy-3,5-di-O-(t-butyldimeth-
ylsilyl)-D-ribofuranose (9c). Et3Al (4 mmol) was dropwise added
to a vigorously stirred solution of 8a (1 g, 2 mmol) and Pd(PPh3)4
(120 mg, 0.1 mmol) in THF (40 mL). The mixture was stirred at
70 °C for 20 h and then worked up. Crude product 9c was
chromatographed on silica gel (20 g) in gradient hexane to 10%
EtOAc in hexane to give 9c (810 mg, 90%) as a colorless oil (for
characterization data, see Supporting Information).
1â-(6-Phenylpyridin-2-yl)-1,2-dideoxy-3,5-di-O-(t-butyldi-
methylsilyl)-D-ribofuranose (9d). Compound 8a (250 mg, 0.5
mmol), K2CO3 (100 mg, 0.72 mmol), Pd(PPh3)4 (30 mg, 0.025
mmol), and PhB(OH)2 (120 mg, 1 mmol) were dissolved in toluene
(15 mL) and the mixture was stirred at 100 °C for 12 h. The reaction
mixture was worked up and crude product 9d was chromatographed
on silica gel (20 g) in gradient hexane to 10% EtOAc in hexane to
give 9d (180 mg, 72%) as a colorless oil (for characterization data,
see Supporting Information).
1â-(6-Benzylpyridin-2-yl)-1,2-dideoxy-3,5-di-O-(t-butyldi-
methylsilyl)-D-ribofuranose (9e). THF (30 mL) was added to a
flame-dried and argon-purged flask containing 8a (0.8 g, 1.6 mmol)
and Pd(PPh3)4 (100 mg, 5 mol %), and the mixture was stirred
until clear solution formed. Then commercial solution of benzylzinc
chloride (3.2 mmol) in THF was added dropwise, and the mixture
was stirred at 70 °C for 18 h. After the work up, the product was
chromatographed on silica gel (150 g) in gradient hexane to 10%
EtOAc in hexane to give 9e (630 mg, 77%) as a colorless oil (for
characterization data, see Supporting Information).
1â-(6-Aminopyridin-2-yl)-1,2-dideoxy-3,5-di-O-(t-butyldi-
methylsilyl)-D-ribofuranose (9f). LiN(SiMe3)2 (2.5 mL, 1 M
solution in THF, 2.5 mmol) was added to a flame-dried argon-
purged flask containing 8a (0.7 g, 1.4 mmol), P(t-Bu)3‚HBF4 (50
mg, 12 mol %), and Pd2(dba)3 (84 mg, 6.6 mol %), and the mixture
was stirred at room temperature for 2 h. The reaction was quenched
by the addition of Et2O and one drop of 2 M aqueous solution of
Experimental Section
Synthesis of Adduct 7. n-Butyllithium (3.6 mL, 1.6 M solution
in hexane) was added dropwise to a solution of 2,6-dibromopyridine
1a (1.3 g, 5.5 mmol) in dry THF (20 mL) at -78 °C under argon.
The mixture was stirred for 10 min and then added dropwise to a
stirred solution of lactone 5 (1.08 g, 3.0 mmol) in THF (42 mL)
cooled at -78 °C. The reaction mixture was worked up after 30
min by pouring onto a mixture of ice and NH4Cl and extraction to
ethyl acetate. Crude product was chromatographed on silica gel in
gradient (hexane-10% EtOAc in hexane) which gave adduct 7 as
an inseparable mixture/equilibrium of hemiketals and open hydroxy-
ketone 7a,b,c in ratio 7:5:9 (0.88 g, 57%) as a colorless oil (for
characterization data, see Supporting Information).
1â-(6-Bromopyridin-2-yl)-1,2-dideoxy-3,5-di-O-(t-butyldi-
methylsilyl)-D-ribofuranose (8a). Et3SiH (150 µL, 0.9 mmol)
was added dropwise to a solution of 7 (200 mg, 0.39 mmol) in
CH2Cl2 (1 mL) in ice-brine bath under argon. After 10 min, a
solution of BF3‚Et2O (65 µL, 0.6 mmol) in CH2Cl2 (0.25 mL) was
added dropwise, and after 10 min another portion of Et3SiH (100
µL, 0.6 mmol) was added. After another 10 min, a further portion
of BF3‚Et2O (30 µL, 0.24 mmol) in CH2Cl2 (0.1 mL) was added.
Finally, after 10 min, the last portion of Et3SiH (100 µL, 0.6 mmol)
followed by BF3‚Et2O (15 µL, 0.12 mmol) was added. The mixture
was worked up after 15 min and crude product was chromato-
graphed on silica gel in gradient hexane-10% EtOAc in hexane
to give 8a (103 mg, 53%). The product was isolated as a colorless
oil, which spontaneously crystallized within 2 months: mp 37-38
°C. MS (FAB): 502 (M + 1), 446, 424. HRMS (FAB) for C22H40-
1
BrNO3Si2: [M + H] calculated, 502.1808; found, 502.1821. H
NMR (500 MHz, CDCl3): 0.069, 0.074, 0.083, and 0.087 (4 × s,
4 × 3H, CH3-Si), 0.89 and 0.91 (2 × s, 2 × 9H, (CH3)3C), 1.97
(ddd, 1H, Jgem ) 12.8, J2′b,1′ ) 9.5, J2′b,3′ ) 5.5, H-2′b), 2.34 (ddd,
1H, Jgem ) 12.8, J2′a,1′ ) 6.2, J2′a,3′ ) 2.4, H-2′a), 3.64 (dd, 1H,
7326 J. Org. Chem., Vol. 71, No. 19, 2006

6-Substituted Pyridin-2-yl C-Nucleosides
HCl and worked up. Chromatography on silica gel (50 g) with
gradient CHCl3 to 5% MeOH in CHCl3 gave 9f (363 mg, 83%) as
a light brown oil (for characterization data, see Supporting
Information).
1H, J3,4 ) 7.7, H-3), 7.65 (t, 1H, J4,3 ) 7.7, J4,5 ) 7.5, H-4). 13C
NMR (100.6 MHz, DMSO-d6): 24.1 (CH3), 42.4 (CH2-2′), 62.7
(CH2-5′), 72.5 (CH-3′), 80.4 (CH-1′), 88.2 (CH-4′), 117.5 (CH-3),
122.4 (CH-5), 137.3 (CH-4), 157.1 (C-6), 161.8 (C-2). IR
(CHCl3): 3612, 3192, 2922, 1601, 1598, 1465, 1380, 1081, 1047,
990. [R]20D ) -12.2 (c 2.72, CHCl3). Anal. Calcd for C11H15NO3
(209.2): C, 63.14; H, 7.23; N, 6.69. Found: C, 62.86; H, 7.35; N,
6.22.
1â-(6-Methylaminopyridin-2-yl)-1,2-dideoxy-3-O-(t-butyldi-
methylsilyl)-D-ribofuranose (9g). A solution of 8a (600 mg, 1.2
mmol) in toluene (4 mL) was added to an argon-purged dry flask
containing Pd2(dba)3 (5.5 mg, 1 mol %), (2-biphenyl)-di-tert-
butylphosphine (7.2 mg, 2 mol %), sodium tert-butoxide (660 mg,
11 mmol), and MeNH2‚HCl (240 mg, 3.6 mmol). The mixture was
stirred at room temperature for 2 days and then heated at 80 °C for
1 day. The mixture was then worked up, and crude product 9g was
chromatographed on silica gel from CHCl3 to 5% MeOH in CHCl3
to give 9g (200 mg, 50%) as a light brown oil (for characterization
data, see Supporting Information) and unreacted 8a (75 mg, 13%),
which was recycled.
1â-(6-Dimethylaminopyridin-2-yl)-1,2-dideoxy-3,5-di-O-(t-bu-
tyldimethylsilyl)-D-ribofuranose (9h). A solution of 8a (1 g, 2
mmol) in toluene (4 mL) was added to an argon-purged dry flask
containing Pd2(dba)3 (9.2 mg, 1 mol %), (2-biphenyl)-di-tert-
butylphosphine (12 mg, 2 mol %), sodium tert-butoxide (1.1 g, 11
mmol), and Me2NH‚HCl (500 mg, 6.1 mmol). The mixture was
stirred at room temperature for 2 days and then heated at 80 °C for
1 day. Then the mixture was worked up, and crude product 9h
was chromatographed on silica gel in gradient hexane to 10%
EtOAc in hexane to give 9h (450 mg, 48%) as an yellow oil (for
characterization data, see Supporting Information).
1â-(6-Ethylpyridin-2-yl)-1,2-dideoxy-D-ribofuranose (10c). Com-
pound 10c was prepared from 9c (600 mg, 1.3 mmol) by the general
procedure. Crystallization from EtOAc/heptane at -78 °C yielded
10c (220 mg, 74%) as colorless crystals, mp 55-59 °C. MS
(FAB): 224 (M + 1), 199, 181. HRMS (FAB) for C12H17NO3:
1
[M + H] calculated, 224.1287; found, 224.1277. H NMR (400
MHz, DMSO-d6): 1.20 (t, 3H, Jvic ) 7.6; CH3CH2), 1.94 (ddd,
1H, Jgem ) 12.7, J2′b,1′ ) 9.6, J2′b,3′ ) 5.6, H-2′b), 2.14 (ddd, 1H,
Jgem ) 12.7, J2′a,1′ ) 6.2, J2′a,3′ ) 2.2, H-2′a), 2.70 (q, 2H, Jvic )
7.6; CH2CH3), 3.46 (dt, 1H, Jgem ) 11.6, J5′,OH ) 5.8, J5′b,4′ ) 5.3,
H-5′b), 3.50 (ddd, 1H, Jgem ) 11.6, J5′,OH ) 5.8, J5′a,4′ ) 4.5, H-5′a),
3.85 (td, 1H, J4′,5′ ) 5.3, 4.5, J4′,3′ ) 2.2, H-4′), 4.20 (m, 1H, J3′,2′
) 5.6, 2.2, J3′,OH ) 3.9, J3′,4′ ) 2.2, H-3′), 4.99 (t, 1H, JOH,5′ ) 5.8,
OH-5′), 5.03 (dd, 1H, J1′,2′ ) 9.6, 6.2, H-1′), 5.04 (d, 1H, JOH,3′
)
3.9, OH-3′), 7.14 (dd, 1H, J5,4 ) 7.7, J5,3 ) 1.0, H-5), 7.29 (dd,
1H, J3,4 ) 7.8, J3,5 ) 1.0, H-3), 7.67 (t, 1H, J4,3 ) 7.8, J4,5 ) 7.7,
H-4). 13C NMR (100.6 MHz, DMSO-d6): 13.9 (CH3CH2), 30.7
(CH2CH3), 42.3 (CH2-2′), 62.8 (CH2-5′), 72.5 (CH-3′), 80.4 (CH-
1′), 88.2 (CH-4′), 117.9 (CH-3), 120.9 (CH-5), 137.3 (CH-4), 161.6
(C-2), 162.1 (C-6). IR (CHCl3): 3612, 3195, 3069, 2976, 2875,
General Procedure for the Deprotection of TBDMS-Group.15
Et3N‚3HF (320 µL, 1.95 mmol) was added to a solution of
compounds 9a-h (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 10:1), solvents were removed
under reduced pressure, and crude product was chromatographed
on silica gel (20 g) eluted with gradient CHCl3-15% MeOH in
CHCl3 to give products 10a-h.
1599, 1578, 1467, 1458, 1438, 1333, 1065, 1178, 1090. [R]20
)
D
-5.8 (c 2.08, CHCl3). Anal. Calcd for C12H17NO3 (223.3): C,
64.55; H, 7.67; N, 6.27. Found: C, 64.26; H, 7.91; N, 5.82.
1â-(6-Phenylpyridin-2-yl)-1,2-dideoxy-D-ribofuranose (10d).
Compound 10d was prepared from 9d (500 mg, 1.0 mmol) by the
general procedure. Crystallization from EtOAc/heptane yielded 10d
(170 mg, 56%) as colorless crystals, mp 93-95 °C. MS (FAB):
272 (M + 1), 182. HRMS (FAB) for C16H17NO3: [M + H]
calculated, 272.1286; found, 272.1291. 1H NMR (400 MHz,
DMSO-d6): 2.03 (ddd, 1H, Jgem ) 12.8, J2′b,1′ ) 9.7, J2′b,3′ ) 5.5,
H-2′b), 2.21 (ddd, 1H, Jgem ) 12.8, J2′a,1′ ) 6.1, J2′a,3′ ) 2.2, H-2′a),
3.47 (dt, 1H, Jgem ) 11.4, J5′,OH ) 5.6, J5′b,4′ ) 5.6, H-5′b), 3.51
(ddd, 1H, Jgem ) 11.4, J5′,OH ) 5.6, J5′a,4′ ) 4.9, H-5′a), 3.88 (td,
1H, J4′,5′ ) 5.6, 4.9, J4′,3′ ) 2.3, H-4′), 4.24 (m, 1H, J3′,2′ ) 5.5,
2.2, J3′,OH ) 3.9, J3′,4′ ) 2.3, H-3′), 4.85 (t, 1H, JOH,5′ ) 5.6, OH-
5′), 5.11 (d, 1H, JOH,3′ ) 3.9, OH-3′), 5.15 (dd, 1H, J1′,2′ ) 9.7,
6.1, H-1′), 7.40-7.52 (m, 4H, H-3 and H-m,p-PhH), 7.83 (dd, 1H,
J5,4 ) 7.9, J5,3 ) 1.5, H-5), 7.87 (t, 1H, J4,5 ) J4,3 ) 7.9, H-4),
8.06 (m, 2H, H-o-Ph). 13C NMR (100.6 MHz, DMSO-d6): 42.1
(CH2-2′), 62.7 (CH2-5′), 72.5 (CH-3′), 80.6 (CH-1′), 88.3 (CH-4′),
119.2 (CH-5), 119.4 (CH-3), 126.8 (CH-o-Ph), 128.9 (CH-m-Ph),
129.2 (CH-p-Ph), 138.1 (CH-4), 138.8 (C-i-Ph), 155.3 (C-6), 162.2
(C-2). IR (CHCl3): 3612, 3270, 3091, 3066, 3034, 1605, 1595,
1582, 1571, 1457, 1078, 1046, 991. [R]20D ) +37.5 (c 3.68, CHCl3).
Anal. Calcd. for C16H17NO3 (271.3): C, 70.83; H, 6.32; N, 5.16.
Found: C, 70.34; H, 6.22; N, 4.76.
1â-(Pyridin-2-yl)-1,2-dideoxy-D-ribofuranose (10a). Compound
10a was prepared from 9a (494 mg, 1.2 mmol) by the general
procedure to yield 10a (192 mg, 84%) as a colorless oil. MS
(FAB): 196 (M + 1), 185. HRMS (FAB) for C10H13NO3: [M +
1
H] calculated, 196.0973; found, 196.0978. H NMR (400 MHz,
DMSO-d6): 1.92 (ddd, 1H, Jgem ) 12.8, J2′b,1′ ) 9.8, J2′b,3′ ) 5.6,
H-2′b), 2.14 (ddd, 1H, Jgem ) 12.8, J2′a,1′ ) 6.0, J2′a,3′ ) 2.1, H-2′a),
3.46 (dt, 1H, Jgem ) 11.4, J5′b,OH ) 5.8, J5′b,4′ ) 5.8, H-5′b), 3.48
(ddd, 1H, Jgem ) 11.4, J5′a,OH ) 5.8, J5′a,4′ ) 4.8, H-5′a), 3.85 (td,
1H, J4′,5′ ) 5.8, 4.8, J4′,3′ ) 2.3, H-4′), 4.19 (m, 1H, J3′,2′ ) 5.6,
2.1, J3′,OH ) 4.0, J3′,4′ ) 2.3, H-3′), 4.89 (t, 1H, JOH,5′ ) 5.8, OH-
5′), 5.06 (dd, 1H, J1′,2′ ) 9.8, 6.0, H-1′), 5.08 (d, 1H, JOH,3′ ) 4.0,
OH-3′), 7.26 (ddd, 1H, J5,4 ) 7.5, J5,6 ) 4.9, J5,3 ) 1.2, H-5), 7.51
(dt, 1H, J3,4 ) 7.9, J3,5 ) 1.2, J3,6 ) 1.0, H-3), 7.77 (td, 1H, J4,3
7.9, J4,5 ) 7.5, J4,6 ) 1.9, H-4), 8.48 (ddd, 1H, J6,5 ) 4.9, J6,4
)
)
1.9, J6,3 ) 1.0, H-6). 13C NMR (100.6 MHz, DMSO-d6): 42.3 (CH2-
2′), 62.7 (CH2-5′), 72.4 (CH-3′), 80.4 (CH-1′), 88.2 (CH-4′), 120.5
(CH-3), 122.7 (CH-5), 137.0 (CH-4), 148.8 (CH-6), 162.3 (C-2).
IR (CHCl3): 3612, 3208, 2926, 2868, 1599, 1575, 1477, 1446,
1438, 1150, 1101, 1081, 991. [R]20 ) +16.3 (c 3.61, CHCl3).
1â-(6-Benzylpyridin-2-yl)-1,2-dideoxy-D-ribofuranose (10e).
Compound 10e was prepared from 9e (530 mg, 1.0 mmol) by the
general procedure. Crystallization from EtOAc/heptane gave 10e
(194 mg, 66%) as colorless crystals, mp 110-112 °C. MS (FAB):
286 (M + 1), 196. HRMS (FAB) for C17H19NO3: [M + H]
calculated, 286.1443; found, 286.1452. 1H NMR (400 MHz,
DMSO-d6): 1.94 (ddd, 1H, Jgem ) 12.8, J2′b,1′ ) 9.6, J2′b,3′ ) 5.5,
H-2′b), 2.15 (ddd, 1H, Jgem ) 12.8, J2′a,1′ ) 6.2, J2′a,3′ ) 2.2, H-2′a),
D
1â-(6-Methylpyridin-2-yl)-1,2-dideoxy-D-ribofuranose (10b).
Compound 10b was prepared from 9b (500 mg, 1.1 mmol) by the
general procedure. Crystallization from EtOAc/heptane yielded 10b
(190 mg, 80%) as colorless crystals, mp 95-97 °C. MS (FAB):
210 (M + 1), 201, 185. HRMS (FAB) for C11H15NO3: [M + H]
calculated, 210.1130; found, 210.1122. 1H NMR (400 MHz,
DMSO-d6): 1.91 (ddd, 1H, Jgem ) 12.8, J2′b,1′ ) 9.6, J2′b,3′ ) 5.6,
H-2′b), 2.13 (ddd, 1H, Jgem ) 12.8, J2′a,1′ ) 6.2, J2′a,3′ ) 2.2, H-2′a),
3.48 (dd, 2H, J5′,OH ) 5.8, J5′,4′ ) 4.4, H-5′), 3.85 (td, 1H, J4′,5′
4.4, J4′,3′ ) 2.3, H-4′), 4.04 (s, 2H, CH2Ph) 4.21 (m, 1H, J3′,2′
)
)
2.43 (s, 3H, CH3), 3.46 (dt, 1H, Jgem ) 11.1, J5′,OH ) 4.9, J5′b,4′
)
4.9, H-5′b), 3.49 (ddd, 1H, Jgem ) 11.1, J5′,OH ) 5.4, J5′a,4′ ) 4.2,
H-5′a), 3.84 (td, 1H, J4′,5′ ) 4.9, 4.2, J4′,3′ ) 2.3, H-4′), 4.19 (m,
1H, J3′,2′ ) 5.6, 2.2, J3′,OH ) 3.9, J3′,4′ ) 2.3, H-3′), 5.01 (t, 1H,
JOH,5′ ) 5.4, 4.9, OH-5′), 5.02 (dd, 1H, J1′,2′ ) 9.6, 6.2, H-1′), 5.06
(d, 1H, JOH,3′ ) 3.9, OH-3′), 7.12 (d, 1H, J5,4 ) 7.5, H-5), 7.28 (d,
5.5, 2.2, J3′,OH ) 4.0, J3′,4′ ) 2.3, H-3′), 4.99 (t, 1H, JOH,5′ ) 5.8,
OH-5′), 5.05 (dd, 1H, J1′,2′ ) 9.6, 6.2, H-1′), 5.05 (d, 1H, JOH,3′
)
4.0, OH-3′), 7.13 (d, 1H, J5,4 ) 7.7, J5,3 ) 1.0, H-5), 7.19 (m, 1H,
H-p-Ph), 7.25-7.31 (m, 4H, H-o,m-Ph), 7.33 (dd, 1H, J3,4 ) 7.8,
J3,5 ) 1.1, H-3), 7.67 (t, 1H, J4,3 ) 7.8, J4,5 ) 7.7, H-4). 13C NMR
J. Org. Chem, Vol. 71, No. 19, 2006 7327

Urban et al.
(100.6 MHz, DMSO-d6): 42.3 (CH2-2′), 43.8 (CH2Ph), 62.7 (CH2-
5′), 72.5 (CH-3′), 80.4 (CH-1′), 88.2 (CH-4′), 118.1 (CH-3), 121.8
(CH-5), 126.3 (CH-p-Ph), 128.6 (CH-m-Ph), 129.0 (CH-o-Ph),
137.6 (CH-4), 139.9 (C-i-Ph), 159.8 (C-6), 161.9 (C-2). IR
(CHCl3): 3612, 3370, 3205, 3088, 3066, 3030, 1612, 1597, 1576,
Anal. Calcd. for C12H18N2O3‚H2O (255.3): C, 58.28; H, 7.74; N,
11.33. Found: C, 58.30; H, 7.97; N, 11.27.
1â-(6-Oxopyridin-2-yl)-1,2-dideoxy-D-ribofuranose (10i). Iso-
pentyl nitrite (100 µL, 0.75 mmol) was added to a solution of amine
9f (100 mg, 0.23 mmol) in 80% aqueous AcOH (5 mL), and the
mixture was heated at 70 °C for 3 h. The solvents were evaporated,
and crude pyridone 10i was purified by chromatography on silica
gel (50 g) in 10% MeOH in CHCl3. Crystallization from MeOH
yielded needles of 10i (23 mg, 48%), mp 173-175 °C. MS
(FAB): 212 (M + 1), 160. HRMS (FAB) for C10H13NO4: [M +
1445, 1427, 1337, 1047, 995. [R]20 ) +17.0 (c ) 4.35, CHCl3).
D
Anal. Calcd. for C17H19NO3 (285.3): C, 71.56; H, 6.71; N, 4.91.
Found: C, 71.39; H, 6.69; N, 4.68.
1â-(6-Aminopyridin-2-yl)-1,2-dideoxy-D-ribofuranose (10f).
Compound 10f was prepared from 9f (600 mg, 1.4 mmol) using
the general procedure for desilylation. Lyophylization from t-BuOH
yielded 10f (195 mg, 68%) as a light brown solid, mp 121-124
°C. MS (FAB): 211 (M + 1). HRMS (FAB) for C10H15N2O3: [M
+ H] calculated, 211.1083; found, 211.1079. 1H NMR (400 MHz,
DMSO-d6): 1.88 (ddd, 1H, Jgem ) 12.8, J2′b,1′ ) 9.7, J2′b,3′ ) 5.7,
H-2′b), 2.06 (ddd, 1H, Jgem ) 12.8, J2′a,1′ ) 6.2, J2′a,3′ ) 2.2, H-2′a),
3.41 (dd, 1H, Jgem ) 11.4, J5′b,4′ ) 5.5, H-5′b), 3.46 (dd, 1H, Jgem
1
H] calculated, 212.0922; found, 212.0917. H NMR (500 MHz,
DMSO-d6): 1.91 (ddd, 1H, Jgem ) 12.8, J2′b,1′ ) 9.7, J2′b,3′ ) 5.6,
H-2′b), 2.12 (ddd, 1H, Jgem ) 12.8, J2′a,1′ ) 6.2, J2′a,3′ ) 2.0, H-2′a),
3.51 (t, 2H, J5′,OH ) J5′,4′ ) 4.1, H-5′), 3.82 (td, 1H, J4′,5′ ) 4.1,
J4′,3′ ) 2.2, H-4′), 4.21 (ddt, 1H, J3′,2′ ) 5.6, 2.0, J3′,OH ) 3.8, J3′,4′
) 2.2, H-3′), 4.85 (dd, 1H, J1′,2′ ) 9.6, 6.2, H-1′), 5.16 (d, 1H,
JOH,3′ ) 3.8, OH-3′), 5.22 (bt, 1H, JOH,5′ ) 4.1, OH-5′), 6.21 (d,
1H, J5,4 ) 9.1, H-5), 6.22 (bd, 1H, J3,4 ) 6.8, H-3), 7.37 (dd, 1H,
J4,5 ) 9.1, J4,3 ) 6.8, H-4), 11.35 (bs, 1H, NH). 13C NMR (100.6
MHz, DMSO-d6): 42.1 (CH2-2′), 62.2 (CH2-5′), 72.5 (CH-3′), 76.5
(CH-1′), 88.2 (CH-4′), 102.2 (CH-3), 118.2 (CH-5), 141.1 (CH-
4), 150.2 (C-2), 163.0 (C-6). IR (KBr): 3302, 3150, 1645, 1601,
) 11.4, J5′a,4′ ) 4.8, H-5′a), 3.79 (td, 1H, J4′,5′ ) 5.5, 4.8, J4′,3′
)
2.3, H-4′), 4.20 (m, 1H, J3′,2′ ) 5.7, 2.2, J3′,OH ) 4.0, J3′,4′ ) 2.3,
H-3′), 4.82 (dd, 1H, J1′,2′ ) 9.7, 6.2, H-1′), 5.00 (d, 1H, JOH,3′
4.0, OH-3′), 5.91 (bs, 2H, NH2), 6.32 (dd, 1H, J5,4 ) 8.3, J5,3
)
)
1.0, H-5), 7.29 (dt, 1H, J3,4 ) 7.2, J3,5 ) 1.0, J3,NH ) 0.5, H-3),
7.34 (dd, 1H, J4,5 ) 8.3, J4,3 ) 7.2, H-4). 13C NMR (100.6 MHz,
DMSO-d6): 42.0 (CH2-2′), 62.8 (CH2-5′), 72.5 (CH-3′), 80.1 (CH-
1′), 88.0 (CH-4′), 107.1 (CH-5), 108.0 (CH-3), 138.0 (CH-4), 159.0
(C-6), 160.1 (C-2). IR (CHCl3): 3612, 3514, 3413, 3195, 1619,
1546, 1441, 1318, 1174, 1169, 1019, 1032. [R]20 ) +136.6 (c
D
2.50, MeOH). Anal. Calcd for C10H13NO4‚2H2O (247.2): C, 48.58;
H, 6.93; N, 5.67. Found: C, 48.95; H, 6.65; N, 5.63.
Single-Crystal X-ray Structure Analysis. X-ray diffraction
experiment of single crystals was carried out on Xcalibur X-ray
diffractometer using Cu KR radiation (λ ) 1.54180 Å), and
diffraction data were collected at 150 K. Both structures were solved
by direct methods with SIR9223 and refined by full-matrix least-
squares on F with CRYSTALS.24 The hydrogen atoms were all
located in a difference map, but those attached to carbon atoms
were repositioned geometrically. All hydrogen atoms were initially
refined with soft restraints on the bond lengths and angles to
regularize their geometry after which the positions were refined
anisotropically with riding constraints.
10e. C17H19N1O3, monoclinic, space group P21, a ) 5.7642(4)
Å, b ) 8.9642(5) Å, c ) 14.5185(9) Å, â ) 99.674(5)°, V )
739.52(8) Å3, Z ) 2, M ) 285.33, 11291 reflections measured,
2790 independent reflections. Final R ) 0.0303, wR ) 0.0335,
GOF ) 1.1287 for 2574 reflections with I > 1.96σ(I) and 192
parameters. CCDC 608613.
1601, 1580, 1438, 1333, 1065, 1178, 1166, 1100, 1090, 995. [R]20
) +56.2 (c 3.30, CHCl3).
D
1â-(6-Methylaminopyridin-2-yl)-1,2-dideoxy-D-ribofura-
nose (10g). Compound 10g was prepared from 9g (200 mg, 0.6
mmol) by the general procedure to give 10g (103 mg, 78%) as
light brown oil. MS (FAB): 225 (M + 1), 135. HRMS (FAB) for
C11H16N2O3: [M + H] calculated, 225.1239; found, 225.1247. 1H
NMR (400 MHz, DMSO-d6): 1.97 (ddd, 1H, Jgem ) 12.8, J2′b,1′
)
9.5, J2′b,3′ ) 5.4, H-2′b), 2.06 (ddd, 1H, Jgem ) 12.8, J2′a,1′ ) 6.2,
J2′a,3′ ) 2.1, H-2′a), 2.72 (d, 3H, JCH3,NH ) 4.9, CH3N), 3.43 (dd,
1H, Jgem ) 11.4, J5′b,4′ ) 5.4, H-5′b), 3.46 (dd, 1H, Jgem ) 11.4,
J5′a,4′ ) 4.8, H-5′a), 3.81 (td, 1H, J4′,5′ ) 5.4, 4.8, J4′,3′ ) 2.1, H-4′),
4.18 (m, 1H, J3′,2′ ) 5.4, 2.1, J3′,OH ) 3.9, J3′,4′ ) 2.1, H-3′), 4.75
(b, 1H, OH-5′), 4.87 (dd, 1H, J1′,2′ ) 9.5, 6.2, H-1′), 5.00 (d, 1H,
JOH,3′ ) 3.9, OH-3′), 6.31 (dd, 1H, J5,4 ) 8.2, H-5), 6.41 (b, 1H,
NH), 6.55 (d, 1H, J3,4 ) 7.0, H-3), 7.33 (dd, 1H, J4,5 ) 8.2, J4,3
)
7.0, H-4). 13C NMR (100.6 MHz, DMSO-d6): 28.1 (CH3N), 41.9
(CH2-2′), 63.0 (CH2-5′), 72.8 (CH-3′), 80.5 (CH-1′), 88.0 (CH-4′),
106.7 (CH-5), 108.0 (CH-3), 137.3 (CH-4), 159.1 (C-6), 160.0 (C-
2). IR (CHCl3): 3611, 3444, 1607, 1579, 1515, 1476, 1430, 1159,
10h. C12H20N2O4, monoclinic, space group P21, a ) 9.319(3)
Å, b ) 7.204(2) Å, c ) 9.825(3) Å, â ) 102.12(3)°, V ) 644.9(3)
Å3, Z ) 2, M ) 256.30, 8962 reflections measured, 2423
independent reflections. Final R ) 0.0281, wR ) 0.0341, GOF )
1.0626 for 2393 reflections with I > 1.96σ(I) and 165 parameters.
CCDC 608614.
1100, 798. [R]20 ) +60.0 (c 3.28, MeOH).
D
1â-(6-Dimethylaminopyridin-2-yl)-1,2-dideoxy-D-ribofura-
nose (10h). Compound 10h was prepared from 9h (600 mg, 1.3
mmol) by the general procedure. Crystallization from EtOAc/
heptane gave 10h (175 mg, 57%) as pink crystals, mp 56-59
°C. MS (FAB): 239 (M + 1), 221, 209. HRMS (FAB) for
C12H18N2O3: [M + H] calculated, 239.1395; found, 239.1407. 1H
Acknowledgment. This work is a part of the research project
Z4 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).
NMR (400 MHz, DMSO-d6): 1.96 (ddd, 1H, Jgem ) 12.7, J2′b,1′
9.6, J2′b,3′ ) 5.5, H-2′b), 2.07 (ddd, 1H, Jgem ) 12.7, J2′a,1′ ) 6.1,
J2′a,3′ ) 2.2, H-2′a), 2.98 (s, 6H, (CH3)2N), 3.40 (dt, 1H, Jgem
)
Supporting Information Available: Detailed description and
discussion of unsuccessful experiments, conformation analysis of
nucleosides 10, general experimental methods, synthesis and
characterization data of compounds 5, 6b, 8b,c, 11, 12a,b, and 13,
analytical and spectral data of compounds 7 and 9a-h, and copies
of important NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
)
11.2, J5′b,OH ) 5.9, J5′b,4′ ) 5.9, H-5′b), 3.45 (ddd, 1H, Jgem ) 11.2,
J5′a,OH ) 5.9, J5′a,4′ ) 4.9, H-5′a), 3.80 (ddd, 1H, J4′,5′ ) 5.9, 4.9,
J4′,3′ ) 2.2, H-4′), 4.17 (m, 1H, J3′,2′ ) 5.5, 2.2, J3′,OH ) 3.9, J3′,4′
) 2.2, H-3′), 4.74 (t, 1H, JOH,5′ ) 5.9, OH-5′), 4.89 (dd, 1H, J1′,2′
) 9.6, 6.1, H-1′), 5.00 (d, 1H, JOH,3′ ) 3.9, OH-3′), 6.49 (dd, 1H,
J5,4 ) 8.5, J5,3 ) 0.8, H-5), 6.65 (d, 1H, J3,4 ) 7.3, H-3), 7.45 (dd,
1H, J4,5 ) 8.5, J4,3 ) 7.3, H-4). 13C NMR (100.6 MHz, DMSO-
d6): 37.8 ((CH3)2N), 41.6 (CH2-2′), 62.9 (CH2-5′), 72.6 (CH-3′),
80.6 (CH-1′), 87.9 (CH-4′), 104.8 (CH-5), 108.0 (CH-3), 137.8 (CH-
4), 158.6 (C-6), 159.9 (C-2).). IR (CHCl3): 3611, 3369, 2824, 2806,
1605, 1568, 1510, 1433, 1172, 1099. [R]20D ) -4.7 (c 3.84, CHCl3).
JO061080D
(23) Altomare, A.; Cascarano, G.; Giacovazzo G.; Guagliardi A.;
Burla M. C.; Polidori, G.; Camalli, M. J. Appl. Crystallogr. 1994, 27,
435-435.
(24) Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.; Watkin,
D. J. J. Appl. Crystallogr. 2003, 36, 1487-1487.
7328 J. Org. Chem., Vol. 71, No. 19, 2006