Efficient synthesis of α- and β-2′-deoxy-heteroaryl-C- nucleosides

Article abstract of DOI:10.1055/s-2008-1072589

A short and efficient method for the synthesis of a series of 2′-deoxy-heteroaryl-C-nucleosides has been developed by the application of aryl-aldol condensation followed by p-toluene-sulfonic acid (PTSA)-mediated isopropylidene cleavage and subsequent cycloetherification. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072589

LETTER
1225
Efficient Synthesis of a- and b-2¢-Deoxy-heteroaryl-C-nucleosides
Synthesis of
a-
and
b
-2
a
¢
-Deoxy-he
r
teroaryl
i
-
C
-nuc
e
leoside
s
Spadafora, Alain Burger,* Rachid Benhida*
Laboratoire de Chimie des Molécules Bioactives et des Arômes, UMR 6001 CNRS, Institut de Chimie de Nice, Université de Nice-Sophia
Antipolis, 28 Avenue de Valrose, 06108 Nice Cedex 2, France
Fax +33(4)92076151; E-mail: benhida@unice.fr
Received 22 January 2008
Abstract: A short and efficient method for the synthesis of a series
Fluo
fluorophore
type A
of 2¢-deoxy-heteroaryl-C-nucleosides has been developed by the
application of aryl–aldol condensation followed by p-toluene-
sulfonic acid (PTSA)-mediated isopropylidene cleavage and subse-
quent cycloetherification.
O
Ar
HO
HO
Key words: C-nucleosides, aryl–aldol condensation, cycloetherifi-
cation
C-nucleosides 4a–f
Ar = phenyl, thiophene, benzothiophene, furan,
benzofuran
C-Nucleosides are well-known nucleoside analogues that
contain a carbon–carbon linkage between the furanose
ring and the heterocyclic base, instead of the carbon–ni-
trogen bond in the classical N-nucleosides. The presence
of such a C–C bond confers to these analogues higher sta-
bility towards chemical and enzymatic hydrolysis than the
N-nucleoside derivatives. Another attractive feature of C-
nucleosides arises from their high-potential value as ther-
apeutic agents and biochemical probes.1 They have been
found in a number of natural and synthetic products such
as tiazofurin, pyrazofurin, formycin, showdomycin, and
pseudouridine reported as potent antitumor or antibiotic
compounds.2 Therefore a large number of synthetic ap-
proaches to C-ribofuranosyl nucleosides have recently
been explored.1,3 However, less attention has been fo-
cused on their 2¢-deoxy analogues which are promising
targets in medicinal chemistry and especially in the grow-
ing nucleic acid chemistry by their incorporation into arti-
ficial DNA and RNA oligonucleotides.4
Figure 1 Structure of targeted C-nucleosides
tion of 2¢-deoxy-C-nucleosides 4a–f as advanced
precursors. A sensitive and functionalized fluorophore
would be introduced at a late stage making the methodol-
ogy more attractive for post-functionalization.
Therefore, we set out to develop an efficient synthetic
methodology which would allow the access of 2¢-deoxy-
heterocyclic C-nucleosides 4a–f precursors of both a- and
b-anomeric configuration.
We report herein a short synthesis (two, three steps) of 2¢-
deoxy-C-nucleosides 4a–f starting from the masked deox-
yribose aldehyde 1.10 The two key steps consist into (i)
aryl–aldol-like condensation and (ii) tandem 3¢,4¢-isopro-
pylidene
(Scheme 1).
cleavage–C¢4–C1¢
cycloetherification
First, the aryl condensation on aldehyde 1 was studied by
varying the nature of the aryl and the base, the reaction
temperature and the stoichiometry. Then, the alcohols 2a–
f were obtained by slow addition of electrophile 1 to the
freshly lithiated aryl species. The results of this study are
summarized in Table 1. For exemple, the regiocontrolled
ortho lithiation of benzofuran using LDA in THF at –
78 °C or 0 °C followed by addition of the protected alde-
hyde 1 afforded the alcohol product 2a in low yield
(Table 1, entries 1 and 2). Interestingly and as expected,
the use of a strong n-BuLi base at 0 °C increase the yield
to 83% by increassing the lithiation efficiency. The alco-
hol 2a was obtained as a mixture of R and S diastereomers
in a 2:3 ratio (Table 1, entry 3).11
One of the most well-known strategies is the conversion
of ribo-C-nucleosides into their 2¢-deoxy analogues using
the radical Barton–McCombie 2¢-deoxygenation method-
ology which requires additional steps and, thus, decreases
the overall yield.5 The standard SN2 process of an activat-
ed sugar or base construction have also been largely used
but were in some cases low yielding.6 The Heck reaction
between halogenated aryls and protected glycals is also a
known strategy to construct C-nucleosides. However, this
approach requires protection–deprotection steps to avoid
functional group interconversion and yields are generally
very low particularly with electron-rich aromatics.7
In connection with our ongoing project aimed at using a-
and b-2¢-deoxy-heteroaryl-C-nucleosides of type A
(Figure 1) as probe-like C-nucleosides by their incorpora-
tion into oligonucleotides,8,9 we envisioned the prepara-
1
The R/S ratio was determined based on H NMR of the
crude product, and the stereochemistry of each diol was
assigned based on the anomeric stereochemistry of their
respective cyclized products 3a–f (vide infra). All the oth-
er heterocycles were subjected to the same reaction condi-
tions. Furan and benzothiophene also react cleanly with
aldehyde 1 giving the desired products 2b (65%) and 2c
SYNLETT 2008, No. 8, pp 1225–1229
x
x.
x
x.
2
0
0
8
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1072589; Art ID: G04008ST
© Georg Thieme Verlag Stuttgart · New York

1226
M. Spadafora et al.
LETTER
Ar
Li
O
OH
O
O
TBDPSO
H
TBDPSO
Ar
2a–f
condensation
O
O
1
cleavage–cycloetherification
(one or two steps)
O
Ar
HO
HO
4a–f
Scheme 1 Synthetic strategy (i) aryl–aldol condensation and (ii) isopropylidene cleavage–cycloetherification
Table 1 Addition of Electrophile 1 to Lithiated Aryl Species
Ar
Li
HO
O
TBDPSO
1
Ar
2a–f
conditions
O
Entrya
Aryl
Base
Temp (°C)
Time (h)
Yield of 2a–f (%)b
R/S Ratioc
1
2
3
LDA
LDA
n-BuLi
–78
0
0
4
1.5
1.5
2a 30
2a 35
2a 83
40:60
40:60
35:65
O
O
4
5
LDA
n-BuLi
0
0
1
1
2b 10
2b 65
50:50
50:50
6
LDA
–78
1
2c 81
45:55
S
S
7
8
LDA
n-BuLi
–78
–78 to 0
1
1
2d 89
2e 82
40:60
40:60
Br
9
10
n-BuLi
n-BuLi
0
–78
0.5
4
2f 40
2f 75
50:50
40:60
Br
a Aryl (2 equiv), base (2.1 equiv), THF.
b Yield of pure isolated products.
c S/R Ratio based on 1H NMR.
(81%), respectively. However, the LDA was found to be and subsequent C4¢–C1¢ cyclization. The conditions used
more effective with benzothiophene than furan and ben- in this study are depicted in Table 2.
zofuran (Table 1, entries 1, 2, 4, and 6) due in part to the
sulfur stabilization of the lithiated intermediate in the case
of the benzothiophene derivative. In the case of 2-bro-
For the survey of the cycloetherification reaction condi-
tions, we started with benzofuran alcohol 2a for which the
diastereomeric diols were easily separated (Table 2). We
mothiophene, halogen–metal exchange followed by addi-
first try the in situ mesylation followed by isopropylidene
tion of 1 afforded the 2-thiophenyl alcohol 2e in 82%
cleavage using SnCl2 to perform the direct cyclization
starting from 2a (R/S = 40:60). Unfortunately, under these
conditions only a poor yield of the cyclized product 3a
was obtained (Table 2, entry 1). Treatment of 2a (R/S =
yield (Table 1, entry 8) while the use of LDA under the
same reaction conditions gave the 2-bromothiophenyl-
substituted product at the 5-position in 89% yield (meta-
lation at position 5, Table 1, entry 7).12 Interestingly, the
40:60) with TFA (Table 2, entry 2) afforded the free nu-
bromine atom remained intact and should allow post-syn-
thetic transformation. In the same way, treatment of bro-
mobenzene with n-BuLi at –78 °C, using the same
protocol, led to the desired compound 2f in 75% yield
cleoside 4a (25% yield) as a mixture of a/b anomers in a
30:70 ratio, with a partial anomerization in favor of the b
anomer. Related a-to-b epimerization has been reported
recently using TFA and benzenesulfonic acid.13 Interest-
(Table 1, entry 10).
ingly, conversion of 2a into 3a was best achieved using
With alcohols 2a–f in hand, the synthesis of C-nucleo- PTSA in refluxing toluene and gave a good yield of 3a
sides was next studied, following isopropylidene cleavage (70%, entry 3) with an unchanged a/b ratio (a/b = 40:60).
Synlett 2008, No. 8, 1225–1229 © Thieme Stuttgart · New York

LETTER
Synthesis of a- and b-2¢-Deoxy-heteroaryl-C-nucleosides
1227
Table 2 Synthesis of C-Nucleosides, Isopropylidene Cleavage, and C4¢–C1¢ Cyclization
HO
O
Ar
O
Ar
O
Bu4NF, THF
cleavage
TBDPSO
Ar
TBDPSO
HO
cycloetherification
O
HO
HO
2a–f
3a–f
4a–f
Entry
R/S Ratio of alcohols 2a–f
Conditions
a/b Ratioa of products 3a–f,
Nucleosides 4a–f (yield, %)b
(yield, %)b
1
2
3
4
5
2a (40:60)
2a (40:60)
2a (40:60)
2a (100:0)
2a (0:100)
MsCl then SnCl2
TFA, dioxane, H2O
PTSA, toluene
PTSA, toluene
PTSA, toluene
3a (<10)
–
a,b-3a 40:60 (70)
a-3a >95:5 (72)
b-3a >5:95 (75)
a,b-4a (25)c
a,b-4a (83)
a-4a (85)
b-4a (95)
6
7
8
9
2b (40:60)
2d (40:60)
2e (40:60)
2f (40:60)
PTSA, toluene
PTSA, toluene
PTSA, toluene
PTSA, toluene
a,b-3b 40:60 (72)
a,b-3d 40:60 (86)
a,b-3e 40:60 (95)
a,b-3f 40:60 (70)
a,b-4b (89)
a,b-4d (86)
a,b-4e (90)
a,b-4f (85)
a The S/R and a/b ratios based on 1H NMR of the crude products.
b Yield of pure isolated products.
c With TFA only 4a was obtained in 30:70 a/b ratio.
In view of this observation, it appears that alcohols 2a cy- In conclusion, we have developed a short and straightfor-
clize, under PTSA treatment, according to an SN2 process. ward synthesis of 2¢-deoxy-C-nucleosides featuring aryl
This result was attested by treatment of separated pure and heteroaryl nucleobases. The methodology involves
(R)-2a and (S)-2a under the same reaction conditions sequential aryl–aldol condensation and tandem isopropyl-
(Table 2, entries 4 and 5), which afforded the cyclized idene cleavage–cycloetherification. The process is also
products a-3a and b-3a, respectively without any epimer- compatible with sensitive groups and allows access to ha-
ization. This novel procedure was then applied to the other logenated heterocyclic nucleosides. Moreover, the pres-
alcohols 2b–f. In all cases, these mild conditions gave sat- ence of bromine would provide useful post-synthetic
isfactory yields of the cyclized products 3b–f (Table 2, transformations for the preparation of 2¢-deoxythiophen-
entries 6–9).14
yl-C-nucleosides functionalized with fluorophores for
their incorporation into oligonucleotides. This work is un-
der way.
The a/b-anomeric configuration of each C-nucleoside 3a–
f was established by 2D COSY–NOESY experiments.
The most significant NOE correlations are represented in
Figure 2 for the benzofuryl nucleosides a-3a and b-3a. In-
deed, the b configuration was clearly evidenced by the ob-
served NOE correlation between H1¢ and H4¢. In the same
way, we observed for the other anomer clear NOE corre-
lations between H1¢–H3¢ and H1¢–H5¢ in accordance with
an a configuration.
Acknowledgment
The authors thank ANR (Agence Nationale de la Recherche),
CNRS and Ministère de l’Education Nationale et de la Recherche
for financial support and for a doctoral fellowship (MENRT) to M.
Spadafora.
References and Notes
H
H
H
H
(1) For recent reviews on the chemistry of C-glycoside
analogues, see: (a) Wu, Q.; Simons, C. Synthesis 2004,
1533. (b) Bililign, T.; Griffith, B. R.; Thorson, J. S. Nat.
Prod. Rep. 2005, 22, 742. (c) Lee, D. Y. W.; He, M. S. Curr.
Top. Med. Chem. 2005, 5, 1333.
O
H
O
H
TBDPSO
O
TBDPSO
O
HO
HO
β-3a
α-3a
(2) For a brief overview of the biological and clinical impact of
tiazofurin, see: (a) For pyrazofurin and formycin, see:
Grifantini, M. Curr. Opin. Investig. Drugs 2000, 1, 257.
(b) Shaban, M. A. E.; Nasr, A. Z. In Advances in
Heterocyclic Chemistry, Vol. 68; Katritzky, A. R., Ed.;
Academic Press: San Diego, 1997, 259. (c) For
Figure 2 a/b-Configuration assignment (NOESY correlations)
The last step is the cleavage of the TBDPS protecting
group. Thus, treatment of protected precursors 3a–f with
Bu4NF in THF afforded good yields (83–95%) of the cor-
responding free nucleosides 3a–f, respectively
(Table 2).15
showdomycin, see: Shaban, M. A. E.; Nasr, A. Z. In
Synlett 2008, No. 8, 1225–1229 © Thieme Stuttgart · New York

1228
M. Spadafora et al.
LETTER
Advances in Heterocyclic Chemistry, Vol. 70; Katritzky, A.
R., Ed.; Academic Press: San Diego, 1998, 230.
(d) Nishimura, H.; Mayama, M.; Komatsu, Y.; Kato, H.;
Shimsoka, N.; Tanaka, Y. J. Antibiot., Ser. A 1964, 17, 148.
(e) Rabinovitz, M.; Uehara, Y.; Vistica, D. T. Science 1979,
206, 1085. (f) Barett, A. G. M.; Broughton, H. B. J. Org.
Chem. 1986, 51, 495.
furan), 7.26 (m, 2 H, 2 × H-Ar), 7.36 (m, 7 H, 6 × H-Ph and
1 × H-Ar), 7.55 (m, 1 H, H-Ar), 7.64 (m, 4 H, 4 × H-Ph) ppm.
13C NMR (50 MHz, CDCl3): d = 19.10 (Me3C), 25.44
(Me2C), 26.75 (Me3C), 27.91 (Me2C), 35.36 (C-2¢), 62.19
(C-5¢), 68.14 (C-1¢), 76.85 (C-3¢), 77.51 (C-4¢), 102.49 (C-
3), 108.78 (Me2C), 111.15 (C-7), 120.96 (C-4), 122.63 (C-
5), 123.92 (C-6), 127.70 (C-Ph), 127.72 (C-Ar), 129.77,
132.90, and 135.51 (C-Ph), 154.75 (C-Ar), 158.64 (C-2)
ppm. MS (ESI+): m/z = 568.5 [MK+], 552.6 [MNa+].
Compound (R)-2a: TLC (cyclohexane–EtOAc, 7:3).
Rf = 0.40. 1H NMR (200 MHz, CDCl3): d = 1.00 (s, 9 H, t-
Bu), 1.26 (s, 3 H, CH3), 1.38 (s, 3 H, CH3), 2.22–2.45 (m, 2
H, 2 × H-2¢), 3.69–3.74 (m, 2 H, 2 × H-5¢), 4.20–4.29 (m, 1
H, H-4¢), 4.42–4.52 (m, 1 H, H-3¢), 5.08–5.16 (m, 1 H, H-1¢),
6.65 (s, 1 H, H-furan), 7.26 (m, 2 H, 2 × H-Ar), 7.36 (m, 7
H, 6 × H-Ph and 1 × H-Ar), 7.55 (m, 1 H, H-Ar), 7.64 (m, 4
H, 4 × H-Ph) ppm. 13C NMR (50 MHz, CDCl3): d = 19.19
(Me3C), 25.54 (Me2C), 26.86 (Me3C), 28.08 (Me2C), 34.12
(C-2¢), 62.36 (C-5¢), 66.52 (C-1¢), 74.52 (C-3¢), 77.48 (C-4¢),
102.69 (C-3), 108.35 (Me2C), 111.21 (C-7), 120.99 (C-4),
122.75 (C-5), 123.97 (C-6), 127.79 (C-Ph), 128.30 (C-Ar),
129.87, 133.04, and 135.62 (C-Ph), 154.90 (C-Ar), 159.56
(C-2) ppm. MS (ESI+): m/z = 552.6 [MNa+], 450.7.
(12) All products gave satisfactory spectral data. Data for
selected products are given here.
(3) (a) Adamo, M. F. A.; Adlington, R. M.; Baldwin, J. E.; Day,
A. L. Tetrahedron 2004, 60, 841. (b) Hashmi, I. A.; Ali, F.
I.; Feist, H.; Michalik, M.; Reinke, H.; Peseke, K. Synthesis
2007, 2819. (c) Oda, H.; Hanami, T.; Iwashita, T.; Kojima,
M.; Itoh, M.; Hayashizaki, Y. Tetrahedron 2007, 63, 11021.
(d) Hainke, S.; Singh, I.; Hemmings, J.; Seitz, O. J. Org.
Chem. 2007, 72, 8811.
(4) (a) Kool, E. T. Acc. Chem. Res. 2002, 35, 936. (b) Sismour,
A. M.; Benner, S. A. Nucleic Acids Res. 2005, 33, 5640.
(c) Leconte, A. M.; Matsuda, S.; Hwang, G. T.; Romesberg,
F. E. Angew. Chem. Int. Ed. 2006, 45, 4326.
(5) See, for example: (a) Tanaka, K.; Shinoya, M. J. Org. Chem.
1999, 64, 5002. (b) Seela, F.; Debelak, H. J. Org. Chem.
2001, 66, 3303.
(6) See, for example: (a) Chen, D.-W.; Beuscher, A. E.;
Stevens, R. C.; Wirsching, P.; Lerner, R. A.; Janada, K. D. J.
Org. Chem. 2001, 66, 1725. (b) Griesang, N.; Richert, C.
Tetrahedron Lett. 2002, 43, 8755. (c) Aketani, S.; Tanaka,
K.; Yamamoto, K.; Ishihama, A.; Cao, H.; Tengeiji, A.;
Hiraoka, S.; Shiro, M.; Shionoya, M. J. Med. Chem. 2002,
45, 5594.
Compound (R,S)-2b: TLC (cyclohexane–EtOAc, 7:3):
Rf = 0.70–0.75. 1H NMR (200 MHz, CDCl3): d = 1.04 (s, 9
H, t-Bu), 1.34 (s, 3 H, CH3), 1.41 (s, 3 H, CH3), 1.50–2.2 (m,
2 H, H-2¢), 3.68–3.71 (m, 2 H, 2 × H-5¢), 4.21–4.42 (m, 2 H,
H-4¢, H-3¢), 4.88–4.95 (m, 1 H, H-1¢), 6.25–6.26 (m, 2 H,
2 × H-Ar), 7.38–7.41 (m, 7 H, 6 × H-Ph, 1 × H-Ar), 7.62–
7.66 (m, 4 H, 4 × H-Ph) ppm. 13C NMR (50 MHz, CDCl3):
d = 19.29 (Me3C), 25.66 (Me2C), 26.93 (Me3C), 28.14
(Me2C), 35.40 (C-2¢), 62.43 (C-5¢), 67.64–65.66 (C-1¢),
76.54–74.36 (C-3¢), 77.18 (C-4¢), 106.01–108.69 (C-Ar),
108.83 (Me2C), 110.26–111.95 (C-Ar), 127.91, 129.96,
133.17, 135.70, 142.03 (C-Ph and C-Ar) ppm. MS (ESI+):
m/z = 503.2 [MNa+].
Compound (R,S)-2e: TLC (cyclohexane–EtOAc, 7:3).
Rf = 0.50–0.53. 1H NMR (200 MHz, CDCl3): d = 0.96 (s, 9
H, t-Bu), 1.27 (s, 3 H, CH3), 1.31 (s, 3 H, CH3), 1.50–2.11
(m, 2 H, H-2¢), 3.59–3.65 (m, 2 H, 2 × H-5¢), 4.12–4.22 (m,
1 H, H-4¢), 4.30–4.37 (m, 1 H, H-3¢), 5.00–5.10 (m, 0.4 H,
H-1¢), 5.11–5.20 (m, 0.6 H, H-1¢), 6.80–6.89 (m, 2 H, 2 × H-
Ar), 7.20–7.26 (m, 1 H, H-Ar), 7.30–7.40 (m, 6 H, 6 × H-
Ph), 7.52–7.58 (m, 4 H, 4 × H-Ph) ppm. 13C NMR (50 MHz,
CDCl3): d = 19.29 (Me3C), 25.63 (Me2C), 26.98 (Me3C),
28.17 (Me2C), 37.91 (C-2¢), 62.54 (C-5¢), 68.01 (C-1¢), 77.37
(C-3¢), 77.62 (C-4¢), 108.42 (Me2C), 123.27, 124.43, 126.85,
127.88, 129.96, 133.10, 135.69, 149.07 (C-Ph and C-Ar)
ppm. MS (ESI+): m/z = 534.6 [MK+], 518.7 [MNa+], 497.6
[MH+].
(7) (a) For the synthesis of aryl C-glycosides via the Heck
reaction, see: Wellington, K. W.; Benner, S. A. Nucleosides,
Nucleotides Nucleic Acids 2005, 1309; (review). (b) Oda,
H.; Hanami, T.; Iwashita, T.; Kojima, M.; Itoh, M.;
Hayashizaki, Y. Tetrahedron 2007, 63, 12747.
(8) (a) Guianvarc’h, D.; Benhida, R.; Fourrey, J.-L.; Maurisse,
R.; Sun, J.-S. Chem. Commun. 2001, 1814.
(b) Guianvarc’h, D.; Fourrey, J.-L.; Sun, J.-S.; Maurisse, R.;
Benhida, R. Bioorg. Med. Chem. 2003, 11, 2751.
(c) Guianvarc’h, D.; Fourrey, J.-L.; Tran Huu Dau, M.-E.;
Guérineau, V.; Benhida, R. J. Org. Chem. 2002, 67, 3724.
(d) Guianvarc’h, D.; Fourrey, J.-L.; Maurisse, R.; Sun, J.-S.;
Benhida, R. Org. Lett. 2002, 4, 4209.
(9) Ratiometric fluorescent probes will be used (unpublished
results). For classical fluorescent nucleosides, see: Wilson,
J. N.; Kool, E. T. Org. Biomol. Chem. 2006, 4, 4265.
(10) (a) Joos, P. E.; Esmans, E. L.; Domise, R. A.; De Bruyn, A.;
Balzarini, J. M.; De Clercq, E. D. Helv. Chim. Acta 1992, 75,
613. (b) Aldehyde 1 was obatined from 2¢-deoxyribose in
four steps and 62% overall yield.
(11) Typical Procedure
To a solution of benzofuran (2 mmol) in anhyd THF (6 mL)
was added dropwise n-BuLi (1.6 M in hexane, 2 mmol) at
0 °C. The mixture was stirred for 30 min and aldehyde 1
(412 mg, 1 equiv) in anhyd THF (2 mL) was slowly added.
The reaction was stirred during 90 min and warmed slowly
to r.t., then quenched with a cold solution of NH4Cl and
extracted with CH2Cl2 (3 × 40 mL). The combined organic
layers were dried (MgSO4) and evaporated under reduced
pressure to give a crude oil. Silica gel column chroma-
tography purification using gradient elution [cyclohexane
(100%) to EtOAc–cyclohexane (8:92)] afforded (S)-2a and
(R)-2a as yellow oils (440 mg, 83%, R/S = 35:65).
Compound (S)-2a: TLC (cyclohexane–EtOAc, 7:3).
Rf = 0.49. 1H NMR (200 MHz, CDCl3): d = 0.95 (s, 9 H, t-
Bu), 1.28 (s, 3 H, CH3), 1.37 (s, 3 H, CH3), 2.06–2.27 (m, 1
H, H-2¢), 2.37–2.47 (m, 1 H, H-2¢), 3.72 (d, 2 H, J = 6.3 Hz,
2 × H-5¢), 4.30 (q, 1 H, J = 6.2 Hz, H-4¢), 4.42–4.52 (m, 1 H,
H-3¢), 5.12 (dd, 1 H, J = 3.8, 8.7 Hz, H-1¢), 6.67 (s, 1 H, H-
(13) Jiang, Y. L.; Stivers, J. T. Tetrahedron Lett. 2003, 44, 4051.
(14) General Procedure
To a solution of 2a (R or S, 1 mmol) in toluene (25 mL) was
added PTSA (0.2 mmol, 0.2 equiv). The mixture was stirred
at 50 °C for 4 h then quenched with a sat. soln of NaHCO3
and extracted with CH2Cl2 (3 × 30 mL). The combined
organic layers were dried over MgSO4 and evaporated under
reduced pressure to give a crude oil. Silica gel column
chromatography purification using gradient elution
[cyclohexane (100%) to EtOAc–cyclohexane (20:80)]
afforded 3a as a yellow oil.
Compound a-3a: TLC (cyclohexane–EtOAc, 7:3).
Rf = 0.43. 1H NMR (200 MHz, CDCl3): d = 1.08 (s, 9 H, t-
Bu), 2.27–2.39 (m, 1 H, H-2¢), 2.66–2.80 (m, 1 H, H-2¢),
3.69–3.88 (m, 2 H, 2 × H-5¢), 4.16–4.20 (m, 1 H, H-4¢), 4.52–
Synlett 2008, No. 8, 1225–1229 © Thieme Stuttgart · New York

LETTER
Synthesis of a- and b-2¢-Deoxy-heteroaryl-C-nucleosides
1229
4.59 (m, 1 H, H-3¢), 5.24–5.31 (dd, 1 H, J = 8.0, 5.3 Hz, H-
4.04 (q, 1 H, J = 4.7 Hz, H-4¢), 4.43–4.45 (q, 1 H, J = 5.7 Hz,
H-3¢), 5.21 (t, 1 H, J = 6.9 Hz, H-1¢), 6.67 (s, 1 H, H-furan),
7.16–7.20 (t, 1 H, J = 7.2 Hz, H-Ar), 7.22–7.25 (m, 1 H, H-
Ar), 7.42 (d, 1 H, J = 8.2 Hz, H-Ar), 7.50 (d, 1 H, J = 7.6 Hz,
H-Ar) ppm. 13C NMR (CDCl3, 125 MHz): d = 39.23 (C-2¢),
58.74 (C-5¢), 62.74 (C-3¢), 73.23 (C-1¢), 85.69 (C-4¢), 103.95
(C-3), 111.35 (C-7), 121.85 (C-4), 122.87 (C-5), 124. (C-6),
128.15 (C-Ar), 154.75 (C-Ar), 157.30 (C-2) ppm. MS
(ESI+): m/z = 256.7 [MNa+], 241.9 [MLi+], 214.7 [M+ –
H2O].
1¢), 6.69 (s, 1 H, H-furan), 7.39–7.66 (m, 10 H, 6 × H-Ph and
4 × H-Ar), 7.67–7.71 (m, 4 H, 4 × H-Ph) ppm. 13C NMR (50
MHz, CDCl3): d = 19.40 (Me3C), 27.05 (Me3C), 39.40 (C-
2¢), 64.98 (C-5¢), 74.04 and 74.78 (C3¢, C-1¢), 86.53 (C-4¢),
103.95, 111.48, 121.31, 123.03, 124.54, 127.97, 129.99,
135.75, 156.72 (C-Ph and C-Ar) ppm. MS (ESI+):
m/z = 510.8 [MK+], 495.1 [MNa+].
Compound b-3a: TLC (cyclohexane–EtOAc, 7:3):
Rf = 0.26. 1H NMR (200 MHz, CDCl3): d = 1.07 (s, 9 H, t-
Bu), 2.20–2.42 (m, 1 H, H-2¢), 2.47–2.56 (m, 1 H, H-2¢),
3.68–4.01 (m, 2 H, 2 × H-5¢), 4.02–4.07 (m, 1 H, H-4¢), 4.62–
4.67 (m, 1 H, H-3¢), 5.30 (dd, 1 H, J = 9.3, 6.2 Hz, H-1¢),
6.63 (s, 1 H, H-furan), 7.31–7.60 (m, 10 H, 6 × H-Ph and 4
× H-Ar), 7.62–7.79 (m, 4 H, 4 × H-Ph) ppm. 13C NMR (50
MHz, CDCl3): d = 19.40 (Me3C), 27.05 (Me3C), 39.56 (C-
2¢), 64.77 (C-5¢), 73.82 (C-1¢), 74.40 (C-3¢), 87.22 (C-4¢),
104.08, 111.43, 121.16, 122.81, 124.34, 127.90, 129.96,
135.74, 156.72 (C-Ph and C-Ar) ppm. MS (ESI+):
Compound b-4a: TLC (CH2Cl2–MeOH, 98:2). Rf = 0.28. 1H
NMR (500 MHz, CDCl3): d = 2.17–2.30 (m, 1 H, H-2¢),
2.45–2.51 (m, 1 H, H-2¢), 3.75 (d, 2 H, J = 4.4 Hz, 2 × H-5¢),
4.05 (m, 1 H, H-4¢), 4.56 (m, 1 H, H-3¢), 5.30 (dd, 1 H,
J = 6.6, 8.8 Hz, H-1¢), 6.67 (s, 1 H, H-furan), 7.18–7.21 (m,
1 H, H-Ar), 7.22–7.25 (m, 1 H, H-Ar), 7.45 (d, 1 H, J = 8.3
Hz, H-Ar), 7.52 (d, 1 H, J = 7.8 Hz, H-Ar) ppm. 13C NMR
(125 MHz, CDCl3): d = 39.91 (C-2¢), 58.82 (C-5¢), 63.54 (C-
3¢), 73.78 (C-1¢), 87.73 (C-4¢), 104.23 (C-3), 111.45 (C-7),
121.12 (C-4), 122.89 (C-5), 124.46 (C-6), 128.15 (C-Ar),
155.18 (C-Ar), 156.81 (C-2) ppm. MS (ESI+): m/z = 256.7
[MNa+], 241.9 [MLi+], 214.7 [M+ – H2O].
m/z = 510.8 [MK+], 495.1 [MNa+].
(15) Compound a-4a: TLC (CH2Cl2–MeOH, 98:2). Rf = 0.3. 1H
NMR (500 MHz, CDCl3): d = 2.33–2.37 (m, 1 H, H-2¢),
2.61–2.64 (m, 1 H, H-2¢), 3.73–3.76 (m, 2 H, 2 × H-5¢), 4.01–
Synlett 2008, No. 8, 1225–1229 © Thieme Stuttgart · New York

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