A short and highly stereoselective synthesis of α-(2-aminothiazolyl)-C-nucleosides

Article abstract of DOI:10.1016/S0040-4039(03)00159-X

A short route to novel α-(2-aminothiazolyl)-C-nucleosides has been developed. The key step was the high diastereoselective reduction of the hemiacetal intermediates using L-Selectride, which afforded the corresponding R-diols in quantitative yields. These diols were converted, after C4-C1 ring closure and protecting groups cleavage, to their corresponding free α-C-nucleosides.

Full text of DOI:10.1016/S0040-4039(03)00159-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2199–2202
A short and highly stereoselective synthesis of
a-(2-aminothiazolyl)-C-nucleosides
Jean-Michel Navarre,a Dominique Guianvarc’h,b Audrey Farese-Di Giorgio,a Roger Condoma and
Rachid Benhidaa,b,
*
aLaboratoire de Chimie Bioorganique UMR 6001CNRS, Universite´ de Nice-Sophia Antipolis, Parc Valrose, 06108 Nice Cedex 2,
France
bInstitut de Chimie des Substances Naturelles, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Received 12 December 2002; accepted 8 January 2003
Abstract—A short route to novel a-(2-aminothiazolyl)-C-nucleosides has been developed. The key step was the high diastereo-
selective reduction of the hemiacetal intermediates using L-Selectride, which afforded the corresponding R-diols in quantitative
yields. These diols were converted, after C4–C1 ring closure and protecting groups cleavage, to their corresponding free
a-C-nucleosides. © 2003 Elsevier Science Ltd. All rights reserved.
Numerous natural or synthetic nucleosides deriving
from a five-membered-ring nucleobase and displaying a
potent antitumoral or antiviral activity, have been
described (Fig. 1).1
interferon-a (a-INF-peg), is the unique drug to date
used for the treatment of hepatitis C virus (HCV)
infection.3 In the case of pyrazomycin, both a and b
anomers were isolated from natural sources and formed
the subject of extensive studies.4
For example, thiazofurin is a C-nucleoside which has
been shown to inhibit the inosine 5%-monophosphate
dehydrogenase (IMPDH), thus inducing a shutdown of
the guanine nucleotide synthesis and causing the apop-
tosis of human erythroleukemia cells.2 Ribavirin, a
synthetic nucleoside, in combination with the pegylated
The chemical and enzymatic stability of the CꢀC glyco-
sidic bond in the C-nucleosides is also an attractive
feature of these analogues. Recently, several synthetic
C-nucleosides have been studied not only as chemother-
apeutic agents,5 but also as building blocks in artificial
DNA and RNA syntheses (antisens and anti-gene
strategies)6 and in a number of other biochemical appli-
cations.7 Therefore,
a large number of synthetic
approaches to C-nucleosides have been recently
reported.8 However, synthetic difficulties in terms of
yield and/or stereoselectivity have been frequently
encountered.9
In a previous report, some of us described a useful
stereocontrolled synthesis of imidazole and indole C-
nucleosides.10 This methodology, based on the neigh-
boring protecting group effect and the assistance of
NH-containing heterocycles to undergo an a-hydroxy
elimination, cannot be applied to the synthesis of thia-
zole C-nucleosides. As an alternative route to this end,
Figure 1. Structure of some potent five-membered ring
nucleosides.
we describe herein
a short, stereocontrolled and
efficient strategy for the synthesis of a-(2-aminothia-
zolyl)-C-nucleosides starting from the ribonolactone 1.
The key step is the highly syn-diastereoselective reduc-
tion of the hydroxyketones (hydroxyketone in equi-
* Corresponding author. Tel.: +00 33 (0)4 92 07 61 53; fax: +00 33
(0)4 92 07 61 51; e-mail: benhida@unice.fr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00159-X

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J.-M. Na6arre et al. / Tetrahedron Letters 44 (2003) 2199–2202
Table 1.
Entry
Substrate
Base (equiv.)
Temperature
Yielda
(°C)
1
2
3
4
5
6
7
R=H
R=H
LDA (2 equiv.)
– (4 equiv.)
BuLi (2 equiv.)
–
t-BuLi (2 equiv.) −78
LDA (1.1 equiv.) −78
−78
−20
−78
−20
2a (28)
– (15)
2a (30)
– (25)
2a (35)
2b (73)
– (68)
R=H
R=Me
–
Scheme 1.
– (2 equiv.)
–
a Yield of pure isolated products.
librium with the hemiacetal form, see Scheme 3) which
afforded a quantitative yield of the corresponding diols.
Then, sequential ring closure-protecting groups cleav-
age allowed access to C-nucleosides with a blocked
a-configuration (Scheme 2).
Thus, the 2-Boc-aminothiazole was first subjected to
the condensation conditions (LDA (2 equiv.)/THF/−
78°C) with lactone 1. Contrary to our previous experi-
ence with imidazole analogues, only low yields were
obtained with 2-Boc-aminothiazole (Table 1). The
hemiacetal 2a was isolated as a mixture of two
diastereoisomers (Scheme 1). Therefore, a careful opti-
mization of base and base stoichiometry, temperature
and time was carried out. Unfortunately, only a poor
yield was obtained when using a large excess of LDA
(entry 2), which results in part from the observed
retro-aldol reaction. Moreover, we did not observe any
improvement with other metalating agents such as BuLi
or t-BuLi or when the reactions were performed at
−20°C (Table 1). This result is probably due to a
weakly reactive di-anion species, arising from a double
deprotonation that occurs on NH-Boc and at C5-posi-
tion, during the lithiation of the heterocycle. Indeed,
the use of the N,N-Boc,Me-aminothiazole (R=Me)11
under the same condensation conditions gave a satisfac-
tory yield of the coupled product 2b (entries 6 and 7).12
Scheme 2. Reagents and conditions: (a) reducing agent, THF
(−30 to 0°C); (b) pTSA, toluene, 50°C; (c) H2SO4, dioxane.
The next steps were then pursued with both hemiacetals
2a and 2b (Scheme 2).13 Thus, the reduction of these
hemiacetals using NaBH4 in THF proceeded in quanti-
tative yield to give an equimolar mixture of
diastereomeric diols of 3a and 3b (R/S=1/1), respec-
tively. Moreover, treatment of compounds 2a and 2b
with standard reducing agents such as LiAlH4 or LiBH4
had no significant impact on the diastereomeric ratio
(data not shown). The absence of diastereofacial
hydride differentiation is most probably due to the
planar ketone-thiazole conformation which allowed
hydride delivery on both faces. Hence, we envisioned
the use of hindered reducing reagents to increase the
facial selectivity of hydride addition. Interestingly, a
high stereocontrol (R/S]95/5)14 was observed when
the reduction of 2a,b was performed with L-Selectride,
a highly reactive and hindered reagent.15 Indeed, only
compounds 3aR and 3bR were isolated from this reac-
tion. This result is, as expected, in accordance with the
Felkin–Anh model (Scheme 3).16
Diols 3a,bR were then cyclized using p-toluenesulfonic
acid. However, the C-nucleosides 4a,ba were obtained
together with their respective derivatives 5a,ba as a
result of isopropylidene cleavage (88% overall yield,
ratio 4/5=3/1). The isopropylidene deprotection could
be avoided by using a Dean–Stark water distillation
during reaction. Otherwise, when the reaction was per-
formed with an excess of pTSA, compounds 5a,ba were
only isolated. It should be mentioned that when the
diols 3a,bR were cyclized using the standard DEAD/
PPh3 treatment, their respective protected C-nucleoside
4a,ba were obtained in rather low yields together with
other non-identified side products as attested by TLC
analysis.

J.-M. Na6arre et al. / Tetrahedron Letters 44 (2003) 2199–2202
2201
5. (a) Walker, J. A., II; Liu, W.; Wise, D. S.; Drach, J. C.;
Townsend, L. B. J. Med. Chem. 1998, 41, 1236–1241; (b)
Franchetti, P.; Marchetti, S.; Cappellaci, L.; Jayaram, H.
N.; Yalowitz, J. A.; Goldstein, B. M.; Barascut, J.-L.;
Dukhan, D.; Imbach, J.-L.; Grifantini, M. J. Med. Chem.
2000, 43, 1264–1270.
6. (a) Von Krosigk, U.; Benner, S. A. J. Am. Chem. Soc.
1995, 117, 5361–5362; (b) Chen, D. L.; McLaughlin, L.
W. J. Org. Chem. 2000, 65, 7468–7474; (c) Berger, M.;
Luzzi, S. D.; Henry, A. A.; Romesberg, F. E. J. Am.
Chem. Soc. 2002, 124, 1222–1226; (d) Guianvarc’h, D.;
Fourrey, J.-L.; Maurisse, R.; Sun, J. S.; Benhida, R. Org.
Lett. 2002, 4, 4209–4212.
7. (a) Tanaka, K.; Shionoya, M. J. Org. Chem. 1999, 64,
5002–5003; (b) Wenska, G.; Skalski, B.; Gdaniec, Z.;
Adamiak, R. W.; Matulic-Adamic, J.; Beigelman, L. J.
Photochem. Photobio. 2000, 133, 169–176; (c) Dzantiev,
L.; Alekseyev, Y. O.; Morales, J. C.; Kool, E. T.;
Romano, L. J. Biochemistry 2001, 40, 3215–3221.
8. (a) Trost, B. M.; Kallander, L. S. J. Org. Chem. 1999, 64,
5427–5435; (b) Franchetti, P.; Cappellaci, L.; Marchetti,
S.; Martini, C.; Costa, B.; Varani, K.; Borea, P. A.;
Grifantini, M. Bioorg. Med. Chem. 2000, 8, 2367–2373;
(c) Ramasamy, K. S.; Bandaru, R.; Averett, D. J. Org.
Chem. 2000, 65, 5849–5851; (d) Franchetti, P.; Marchetti,
S.; Cappellaci, L.; Yalowitz, J. A.; Jayaram, H. N.;
Goldstein, B. M.; Grifantini, M. Bioorg. Med. Chem.
Lett. 2001, 11, 67–69; (e) Araki, L.; Harusawa, S.;
Fukuda, M.; Kurihara, T. Heterocycles 2001, 55, 1907–
1917.
Scheme 3. Felkin–Anh model for the reduction step.
Acidic treatment of both 4aa, 5aa and 4ba, 5ba
afforded the free a-C-nucleosides 6aa and 6ba, respec-
tively (93%). Importantly, epimerization of the C1%-
stereocenter in 4 and/or 5 was not observed after acidic
(p-TSA or H2SO4) treatment.15 In the same way, the
1/1 diastereomeric mixtures of diols 3a,b (R/S) result-
ing from NaBH4 reduction of 2a,b were converted to
their respective free C-nucleosides 6a,b, isolated as an
equimolar mixture of a and b anomers.
In summary, we have described a short, stereoselective
and efficient synthesis of a-(2-aminothiazolyl)-C-
nucleosides. The sequential cyclization–cleavage could
be performed in one-pot and high yield, making the
methodology quite attractive. This process also toler-
ates other sensitive functional groups and allows con-
ventional
post-synthetic
modifications.
Further
investigations aimed at the synthesis of the b anomers
following a chelation-based stereocontrolled process
from the same intermediates, are in progress and will be
reported in due course.
9. (a) Gudmundsson, K. S.; Drach, J. C.; Townsend, L. B.
J. Org. Chem. 1997, 62, 3453–3459; (b) Matulic-Adamic,
J.; Beigelman, L. Tetrahedron Lett. 1997, 38, 203–206; (c)
Sollogoub, M.; Fox, K. R.; Powers, V. E. C.; Brown, T.
Tetrahedron Lett. 2002, 43, 3121–3123.
Acknowledgements
10. (a) Guianvarc’h, D.; Benhida, R.; Fourrey, J.-L. Tetra-
hedron Lett. 2001, 42, 647–650; (b) Guianvarc’h, D.;
Fourrey, J.-L.; Tran Huu Dau, M.-E.; Gue´rineau, V.;
Benhida, R. J. Org. Chem. 2002, 67, 3724–3732.
11. The N,N-Boc,Me-aminothiazole was obtained in quanti-
tative yield from Boc-aminothiazole (NaH, DMF, MeI).
We failed to prepare the di-Boc protected aminothiazole
by using standard conditions (low yields). However, when
the N,N-Benzyl,Boc-aminothiazole was used in the con-
densation step with lactone 1, the hemiacetal adduct was
obtained in low yield, due to the observed side products
resulting from the alkylation at the benzylic position
(-CH2Ph).
We thank Dr. P. Vierling for his interest to this work
and CNRS for financial support, after our recent mov-
ing from Gif-sur-Yvette (ICSN) to Universite´ de Nice-
Sophia Antipolis.
References
1. For reviews on the chemistry, biochemistry, and synthesis
of C-nucleoside analogues, see: (a) Hacksell, U.; Daves,
G. D., Jr. Prog. Med. Chem. 1985, 22, 1–65; (c) Postema,
M. H. D. Tetrahedron 1992, 48, 8545–8599; (d) Watan-
abe, K. A. Chemistry of Nucleosides and Nucleotides;
Townsend, L. B., Ed.; Plenum Press: New York, 1994;
Vol. 3, pp. 421–535; (e) Jaramillo, C.; Knapp, S. Synthe-
sis 1994, 1–20; (f) Togo, H.; He, W.; Waki, Y.;
Yokoyama, M. Synlett 1998, 700–716.
1
12. 2a (major diastereomer): H NMR (200 MHz, CDCl3) l
t
1.06 (s, 9H, Bu), 1.33 (s, 3H, CH3), 1.44 (s, 3H, CH3),
1.61 (s, 9H, Boc), 2.82 (br s, 1H, OH), 3.72–3.95 (m, 3H,
H4%, 2H5%), 4.64 (t, J=5.8 Hz, H3%), 4.96 (d, 1H, J=5.5
Hz, H2%), 7.31–7.52 (m, 6H, H–Ar), 7.60–7.80 (m, 4H,
H–Ar), 8.41 (s, 1H). 13C NMR (50 MHz, CDCl3) l 19.37,
26.10, 26.81, 26.92, 27.09, 28.31, 64.79, 72.80, 77.08,
81.16, 83.28, 111.34, 127.69, 127.83, 127.92, 128.05,
129.86, 130.10, 130.21, 133.08, 133.18, 135.52, 135.67,
146.22, 152.28, 166.20. MS (ESI+) m/z=627 (MH+). Rf=
0.70 (hexane/AcOEt: 50/50).
2. Franchetti, P.; Cappellacci, L.; Grifantini, M. Farmaco
1996, 51, 457–469.
3. Review: Dymock, B. W.; Jones, P. S.; Wilson, F. X.
Antiviral Chem. Chemother. 2000, 11, 79–96.
4. De Bernardo, S.; Weigele, M. J. Org. Chem. 1976, 41,
287–290 and references cited therein. Recent examples:
(a) Popsavin, M.; Torovic, L.; Spaic, S.; Stankov, S.;
Popsavin, V. Tetrahedron Lett. 2000, 41, 5737–5740; (b)
Manferdini, M.; Morelli, C. F.; Veronese, A. C. Tetra-
hedron 2002, 58, 1005–1010.
1
2b (major diastereomer): H NMR (200 MHz, CDCl3) l
t
1.06 (s, 9H, Bu), 1.34 (s, 3H, CH3), 1.44 (s, 3H, CH3),
1.60 (s, 9H, Boc), 2.90 (br s, 1H, OH), 3.60 (s, 3H, CH3),
3.60–3.80 (m, 3H, H4%, 2H5%), 4.58 (t, 1H, J=5.8 Hz,

2202
J.-M. Na6arre et al. / Tetrahedron Letters 44 (2003) 2199–2202
H3%), 4.96 (d, 1H, J=5.7 Hz, H2%), 7.25–7.45 (m, 6H,
77.43, 83.18, 110.26, 128.21, 128.26, 130.31, 133.09,
133.30, 133.67, 135.07, 135.91, 135.97, 162.35. MS (ESI+)
m/z=643 (MH+). Rf=0.22 (hexane/AcOEt=70/30).
(3bS): 1H NMR (200 MHz, CDCl3–CD3OD) l 0.99 (s,
H–Ar), 7.53–7.50 (m, 4H, H–Ar), 8.45 (s, 1H). 13C NMR
(50 MHz, CDCl3) l 19.04, 25.86, 26.59, 26.88, 27.89,
33.99, 64.55, 72.58, 76.20, 81.01, 86.18, 111.07, 127.51,
127.74, 129.53, 130.10, 130.15, 131.58, 132.80, 135.37,
135.86, 145.08, 146.65, 152.60, 166.30. MS (ESI+) m/z=
641 (MH+). Rf=0.15 (hexane/AcOEt: 80/20). Mp=63–
64°C.
t
9H, Bu), 1.19 (s, 3H, CH3), 1.28 (s, 3H, CH3), 1.48 (s,
9H, Boc), 3.42 (s, 3H, CH3), 3.60–3.80 (m, 4H, H3%, H4%,
2H5%), 4.00 (t, 1H, J=7.1 Hz, H2%), 4.78 (d, 1H, J=7.3
Hz, H1%), 7.25–7.45 (m, 7H, H–Ar), 7.50–7.70 (m, 4H,
H–Ar). 13C NMR (50 MHz, CDCl3) l 19.69, 27.29,
28.64, 34.42, 65.71, 70.50, 73.65, 79.65, 83.85, 110.20,
128.21, 128.26, 130.34, 133.27, 133.36, 133.59, 135.78,
135.96, 135.99, 153.42, 162.60. MS (ESI+) m/z=643
(MH+). Rf=0.25 (hexane/AcOEt=70/30).
13. Spectral data of selected compounds:
1
t
(3aR): H NMR (200 MHz, CDCl3) l 1.05 (s, 9H, Bu),
1.33 (s, 3H, CH3), 1.40 (s, 3H, CH3), 1.56 (s, 9H, Boc),
3.65–4.00 (m, 4H, H3%, H4%, 2H5%), 4.29 (dd, 1H, J=2.5
and 7.5 Hz, H2%), 5.10 (d, 1H, J=2 Hz, H1%), 7.33 (s, 1H,
H-thiazole), 7.35–7.45 (m, 6H, H–Ar), 7.61–7.71 (m, 4H,
1
t
(4ba): H NMR (200 MHz, CDCl3) l 1.07 (s, 9H, Bu),
1.26 (s, 3H, CH3), 1.42 (s, 3H, CH3), 1.57 (s, 9H, Boc),
3.51 (s, 3H, CH3), 3.81 (m, 2H, 2H5%), 4.11 (m, 2H, H3%,
H4%), 4.34 (dd, 1H, J=6.7 and 3.3 Hz, H2%), 6.04 (d, 1H,
J=3.3 Hz, H1%), 7.25–7.45 (m, 6H, H–Ar), 7.49 (s, 1H,
H–thiazole), 7.60–7.70 (m, 4H, H–Ar). 13C NMR (50
MHz, CDCl3) l 14.28, 19.37, 26.93, 27.77, 28.30, 34.10,
64.37, 64.82, 72.81, 73.36, 75.81, 81.76, 110.65, 127.91,
129.97, 133.06, 135.63, 137.93, 154.02, 163.20. MS (ESI+)
m/z=625 (MH+). Rf=0.26 (hexane/AcOEt=70/30).
14. The R and S configurations of diols were determined on
the basis of the anomeric stereochemistry of their cyclized
products (Cosy–Noesy experiments). The R/S ratio was
1
H–Ar). (3aS) H NMR (200 MHz, CDCl3) l 1.08 (s, 9H,
tBu), 1.28 (s, 3H, CH3), 1.37 (s, 3H, CH3), 1.56 (s, 9H,
Boc), 3.65–4.00 (m, 4H, H3%, H4%, 2H5%), 4.08 (t, 1H,
J=7.4 Hz, H2%), 4.87 (d, 1H, J=7.6 Hz, H1%), 7.33 (s,
1H, H-thiazole), 7.35–7.45 (m, 6H, H–Ar), 7.61–7.71 (m,
4H, H–Ar). 13C NMR (3a R/S) (50 MHz, CDCl3) l
19.28, 26.85, 27.00, 27.14, 28.33, 65.21, 65.33, 67.15,
70.18, 73.26, 75.93, 79.31, 82.57, 83.47, 109.84, 109.92,
127.84, 129.94, 131.37, 131.67, 132.74, 132.84, 132.93,
134.18, 134.41, 135.57, 152.91, 162.06. MS (3a R/S)
(ESI+) m/z=629 (MH+). Rf (3a R/S)=0.42 (hexane/
AcOEt=50/50).
1
(3bR): 1H NMR (200 MHz, CDCl3–CD3OD) l 1.00 (s,
obtained by both H NMR and HPLC analyses.
t
15. Reduction of arylketone has been extensively studied by
Dondoni et al. see for example: Dondoni, A.; Perrone, D.
Synthesis 1993, 1162–1176.
16. (a) Cherest, M.; Felkin, H. Tetrahedron Lett. 1968, 9,
2199–2204; (b) Anh, N. T. Top. Curr. Chem. 1980, 88,
145.
9H, Bu), 1.26 (s, 3H, CH3), 1.33 (s, 3H, CH3), 1.50 (s,
9H, Boc), 3.44 (s, 3H, CH3), 3.60–3.95 (m, 4H, H3%, H4%,
2H5%), 4.20 (dd, 1H, J=3.0 and 7.5 Hz, H2%), 5.10 (br s,
1H, H1%), 7.35–7.50 (m, 7H, H–Ar), 7.55–7.75 (m, 4H,
H–Ar). 13C NMR (50 MHz, CDCl3) l 19.64, 27.23,
27.44, 27.52, 28.64, 34.37, 65.46, 67.81, 73.55, 76.26,