First synthesis of 1-deazacytidine, the C-nucleoside analogue of cytidine

Article abstract of DOI:10.1016/S0040-4039(02)00481-1

The synthesis of 1-deazacytidine, the C-nucleoside analogue of cytidine, is described. It involves coupling of a protected 2-amino-5-bromopyridine with perbenzylated ribonolactone and transformation of the pyridine ring into the desired substituted pyrido

Full text of DOI:10.1016/S0040-4039(02)00481-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3121–3123
First synthesis of 1-deazacytidine, the C-nucleoside analogue of
cytidine
Matthieu Sollogoub,a,† Keith R. Fox,b Vicki E. C. Powersa and Tom Browna,*
aDepartment of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
bDivision of Biochemistry and Molecular Biology, School of Biological Sciences, University of Southampton,
Bassett Crescent East, Southampton SO16 7PX, UK
Received 18 January 2002; revised 28 February 2002; accepted 8 March 2002
Abstract—The synthesis of 1-deazacytidine, the C-nucleoside analogue of cytidine, is described. It involves coupling of a protected
2-amino-5-bromopyridine with perbenzylated ribonolactone and transformation of the pyridine ring into the desired substituted
pyridone. This synthesis completes the family of C-nucleosidic analogues of natural nucleosides. © 2002 Elsevier Science Ltd. All
rights reserved.
Nucleoside analogues that are only minimally altered
with respect to the corresponding natural nucleosides
are valuable tools in structure activity studies.1,2 A very
simple alteration is the replacement of the nitrogen
linking the base to the sugar by a carbon, forming
C-nucleosidic analogues of the natural nucleosides. In
the case of the pyrimidines, but not the purines, this
changes the hydrogen bond recognition properties of
the base (Fig. 1). An attractive feature of these ana-
logues is the stability of the bond between base and
sugar towards both chemical and enzymatic hydrolysis.
Furthermore, C-nucleosides, such as showdomycin,3
show a broad spectrum of biological activity and so
have stimulated considerable interest as potential anti-
tumour, anti-bacterial and anti-cancer agents.4
C-Nucleosidic analogues of adenosine (9-deazaadeno-
sine)5 and guanosine (9-deazaguanosine)6 have been
synthesised and studied. 1-Deazauridine7 was synthe-
sised some time ago but the authors encountered prob-
lems with its stability. To the best of our knowledge
1-deazacytidine has never been synthesised.
NH2
N
O
N
H
N
H
N
NH
NH2
HO
HO
N
O
O
As synthetic targets, C-glycosides have received much
attention8 and amongst them C-nucleosides have been
widely studied.9 The synthesis of C-nucleosides bearing
functionalised pyridine rings has mainly been
approached by two methods: Heck-type coupling to a
glycal10,11 or nucleophilic attack on a lactone followed
by dehydroxylation.1,12,13 We decided to use the latter
because it allowed more flexibility and was potentially
higher yielding.
HO OH
HO OH
9-deazaadenosine
9-deazaguanosine
NH2
NH
O
NH
HO
HO
O
OH
O
O
1-Deazacytidine is a 2-oxygenated pyridine, a family of
compounds which is difficult to prepare.14 In an initial
study (Scheme 1) we followed a known route15 to the
pyridone 5. Acetylation of 2-amino-5-bromo-pyridine 1
in the presence of acetic anhydride gave 2 in 97% yield,
which was oxidised to the N-oxide 3 with mCPBA in
85% yield. Compound 3 underwent a rearrangement16
upon heating in acetic anhydride, and deacetylation of
the resulting acetate 4 gave the pyridone 5. This
HO OH
1-deazacytidine
HO OH
1-deazauridine
Figure 1.
* Corresponding author. Fax: +44 23 80 592 991; e-mail: tb2@
soton.ac.uk
† Present address: De´partement de Chimie, Ecole Normale
Supe´rieure, 24, rue Lhomond, 75231 Paris, Cedex 05, France.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00481-1

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M. Sollogoub et al. / Tetrahedron Letters 43 (2002) 3121–3123
Scheme 1. (i) Ac2O, 80°C, 24 h, 97%; (ii) mCPBA (1.5 equiv.), CH2Cl2, rt, 12 h, 85%; (iii) Ac2O, reflux, 1 h; (iv) NaOH, MeOH,
rt, 2 h, 58% (two steps); (v) BnBr (2.5 equiv.), Ag2CO3 (0.6 equiv.), tol., 60°C, 24 h, 41%; (vi) KOH, MeOH, pyr., H2O, 110°C,
24 h, 94%; (vii) BnBr (3 equiv.), NaH (3 equiv.), DMF, rt, 12 h, 87%; (viii) (a) nBuLi (1 equiv.), −78°C, 3 h, (b) 9 (1 equiv.),
−78°C, 2 h, 0°C, 3 h, (c) BF3–OEt2 (3 equiv.), Et3SiH (3 equiv.), CH2Cl2, −78°C“rt, 12 h, 34%.
product was transformed into the fully benzyl-protected
pyridine 817 by selective O-benzylation of the pyridone18
in the presence of silver carbonate (41%), followed by
deacylation with potassium hydroxide (94%) and final
benzylation of the amino group (87%). Bromide–lithium
exchange in 8 with nBuLi at −78°C and in situ reaction
with lactone 9 furnished a mixture of hemiacetals that
were subsequently reduced with excess of Et3SiH/
BF3·OEt2 to give 10 as a mixture of isomers in 34% yield.
Difficulties in deprotection of this compound and low
yields encountered throughout the synthesis led us to
strive for a more efficient route. In an alternative
approach (Scheme 2) we decided to couple 2-amino-5-
bromo-pyridine to the ribose moiety before transforming
it to the pyridone. A previous synthesis of the 2-amino-
pyridine C-nucleoside of ribose13 utilised the stabase
protecting group, but in our hands PMB protected
2-amino-5-bromo-pyridine 11 was more efficient.
Scheme 2. (i) PMBCl (2.5 equiv.), NaH (2.5 equiv.), DMF, rt, 6 h, 64%; (ii) (a) nBuLi (1 equiv.), −78°C, 3 h, (b) 9 (1 equiv.),
−78°C, 2 h, 0°C, 3 h; (c) BF3–OEt2 (3 equiv.), Et3SiH (3 equiv.), CH2Cl2, −78°C“rt, 12 h, 64%; (iii) TFA, rt, 24 h, 88%; (iv) Ac2O,
pyr., rt, 2 h, 91%; (v) (a) BBr3 (5 equiv.), CH2Cl2, −78°C, 4 h, (b) Ac2O, pyr, rt, 1 h, 91%; (vi) mCPBA (1.5 equiv.), CH2Cl2, rt,
12 h, 89%; (vii) Ac2O, 140°C, 30 min, 84%; (viii) conc. aq. NH3, 60°C, 24 h (79%).

M. Sollogoub et al. / Tetrahedron Letters 43 (2002) 3121–3123
3123
2-Amino-5-bromo-pyridine
1
was protected using
7. (a) Mertes, M. P.; Zielinski, J.; Pillar, C. J. Med. Chem.
1967, 10, 320; (b) Knackmuss, H.-J.; Briaire, J. Liebigs
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Postema, M. H. D. Tetrahedron 1992, 48, 8545.
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Chem. 1997, 68, 223; (b) Nasr, A. Z. Adv. Heterocyclic
Chem. 1998, 70, 163.
10. Chen, J. J.; Walker, J. A., II; Liu, W.; Wise, D. S.;
Townsend, L. B. Tetrahedron Lett. 1995, 36, 8363.
11. Hsieh, H.-P.; McLaughlin, L. W. J. Org. Chem. 1995, 60,
5356.
12. Piccirilli, J. A.; Krauch, T.; MacPherson, L. J.; Benner, S.
A. Helv. Chim. Acta 1991, 74, 397.
PMBCl and NaH yielding 11 (64%). Bromide–lithium
exchange in PMB-protected 11 with nBuLi at −78°C
and in situ reaction with lactone 9 furnished the hemi-
acetal that was subsequently reduced with excess of
Et3SiH/BF3·OEt2 to provide 12 as a single isomer in
64% yield. PMB groups were removed with TFA to
afford the known amine 1313 confirming the stereoselec-
tivity of the formation of 12. The 1H NMR spectrum of
13 was consistent with that reported in the literature.19
The primary amino group of 13 was acetylated and the
benzyl groups were cleaved using BBr3 and replaced
with acetates (91%) to give 14. It is also possible to
debenzylate 13 and convert the fully deprotected
nucleoside to 14 with acetic anhydride in pyridine, but
this is lower yielding. The pyridine 14 was oxidised to
the N-oxide with mCPBA and rearranged using Ac2O
at reflux to give the peracetylated pyridine derivative 15
in 75% yield over two steps. The final product 1620 was
obtained (79%) as a foam by heating 15 in concentrated
aqueous ammonia and removing the solvent under
reduced pressure.
13. Hildbrand, S.; Blaser, A.; Parel, S. P.; Leumann, C. J. J.
Am. Chem. Soc. 1997, 119, 5499.
14. Rozen, S.; Hebel, D.; Zamir, D. J. Am. Chem. Soc. 1987,
109, 3789.
15. Kelly, T. R.; Jagoe, C. T.; Gu, Z. Tetrahedron Lett. 1991,
32, 4263.
16. Katada, M. J. Pharm. Soc. Jpn. 1947, 67, 51.
17. Timpe, W.; Dax, K.; Weidmann, H. Carbohydr. Res.
1975, 39, 53.
18. (a) Hopkins, G. C.; Jonak, J. P.; Minnemeyer, H. J.;
Tieckelmann, H. J. Org. Chem. 1967, 32, 4040; (b) Shiao,
M.-J.; Tarng, K.-Y. Heterocycles 1990, 31, 819.
19. NMR data for 13: 1H NMR (300 MHz, CDCl3) 3.58 (dd,
J=10.5, 3.9 Hz, 1H), 3.63 (dd, J=10.5, 4.2 Hz, 1H), 3.79
(dd, J=7.4, 5.2 Hz, 1H), 4.01 (dd, J=5.2, 3.3 Hz, 1H),
4.31 (app.q, J=4.1 Hz, 1H), 4.41–4.62 (m, 6H), 4.90 (d,
J=7.4 Hz, 1H), 6.42 (d, J=8.5 Hz, 1H), 7.20–7.38 (m,
15H), 7.45 (dd, J=8.5, 2.2 Hz, 1H), 8.07 (d, J=2.2 Hz,
1H). 13C NMR (75.42 MHz, CDCl3) 70.7, 72.1, 72.5,
73.6, 77.6, 80.6, 81.8, 83.4, 108.6, 125.6, 127.8–128.6
(15C), 136.4, 137.8, 138.0, 138.2, 146.8, 158.5.
20. All compounds were fully characterised. Spectroscopic
data for 16: 1H NMR (300 MHz, D2O): l 3.63 (t, J=10.9
Hz, 1H), 3.71 (dd, J=5.5 Hz, J=10.5 Hz, 1H), 3.88
(ddd, J=3 Hz, J=5.5 Hz, J=10.5 Hz, 1H), 3.94 (dd,
J=3 Hz, J=10.4 Hz, 1H), 4.24 (t, J=3 Hz, 1H), 4.56 (d,
J=10.4 Hz, 1H), 5.76 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.4
Hz, 1H); 13C NMR (100 MHz, D2O): l 65.2, 67.1, 69.1,
71.2, 71.3, 91.9, 109.6, 144.4, 144.8, 162.7; MS/ES+: 243
(M+H)+. HRMS/ES+ m/z calcd for C10H14N2O5 (MH+)
243.0982 found 243.0976.
Acknowledgements
This work was funded by the Cancer Research
Campaign.
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