Synthesis of nucleoside derivatives via heterocyclocondensation reactions

Article abstract of DOI:10.1016/j.tetlet.2008.03.069

A new synthesis of nucleoside analogues has been developed. The cyclocondensation of a glycosylated diazadiene or thiazadiene, with acyl chlorides or α-halogenoketones, respectively, resulted in good yields and excellent regioselectivities. We report an e

Full text of DOI:10.1016/j.tetlet.2008.03.069

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3273–3275
Synthesis of nucleoside derivatives via
heterocyclocondensation reactions
Vincent Kikelj, Paul Setzer, Karine Julienne, Jean-Claude Meslin, David Deniaud *
`
´
Universite´ de Nantes, CEISAM, Chimie Et Interdisciplinarite´, Synthese, Analyse, Modelisation, UFR des Sciences et des Techniques,
`
2, rue de la Houssiniere, BP 92208, 44322 Nantes Cedex 3, France
`
CNRS, UMR CNRS 6230, UFR des Sciences et des Techniques, 2, rue de la Houssiniere, BP 92208, 44322 Nantes Cedex 3, France
Received 14 February 2008; revised 6 March 2008; accepted 17 March 2008
Available online 19 March 2008
Abstract
A new synthesis of nucleoside analogues has been developed. The cyclocondensation of a glycosylated diazadiene or thiazadiene, with
acyl chlorides or a-halogenoketones, respectively, resulted in good yields and excellent regioselectivities. We report an efficient method
for the production of glucosyl pyrimidinones and glucosylamino thiazoles.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Nucleosides; Cyclocondensations; Diazadienes; Thiazadienes; Glycosyl heterocycles; Glycosylamino heterocycles
There has been recent interest in the synthesis of N-gly-
cosyl heterocycles as nucleoside analogues, which exhibit
biological and pharmaceutical activities.1,2 Several varia-
tions have been made on both the heterocyclic base and
the sugar moiety in the search for effective and selective
derivatives.3,4 Classically, the strategy for the synthesis of
nucleosides has been the condensation of glycosides with
activated nucleobases.5–7 More rarely, the heterocyclic
Surprisingly, only few [4+2] cycloaddition or cyclocon-
densation reactions have been described for the synthesis
of nucleoside analogues by the construction of the hetero-
cyclic moiety.15–18 Recently, we described intermolecular
[4+2] cyclizations between an azadienium iodide and glyco-
syl isothiocyanates affording N-glycosyl pyrimidines.19 We
now report an alternative approach to this class of nucleo-
side analogues, based on [4+2] cyclization reactions, in
which the carbohydrate moiety is at first linked to the
heterodiene rather than to the dienophile. Peracetylated
1-glucosyl-1,3-diazabuta-1,3-diene 1 was used as a model
to prove the feasibility of the methodology. Previously,
we described the reactivity of variously substituted 1,3-
diazabutadienic chains towards dienophiles or electrophiles
for the preparation of thioxopyrimidinones,20,21 thiadi-
azine-1,1-dioxydes,22 thiazolopyrimidines,23 imidazobenzo-
thiazoles24 or pyrimidothiazines.25 Here, we describe
cyclocondensations between glucosyl diazadiene 1 and acyl
chlorides in a basic medium to afford N-glucosyl pyrimidi-
nones 2–5 (Scheme 1).
´
moieties are built by the cycloaddition reactions. The Are-
valo group has been largely involved in asymmetric [3+2]
cycloadditions of 1,3-thiazolium-4-olates using carbohy-
drates as stereodifferentiating elements.8,9 A modified Huis-
gen 1,3-dipolar cycloaddition reaction (click chemistry) of
glycosyl azides with terminal acetylenes is an efficient
method and has been notably developed by Houston10–12
and Rutjes.13 The cycloaddition reactions of 4-nitro and
5-nitro-1-vinylimidazoles have been investigated by Rams-
den.14 The cycloadducts obtained are potential intermedi-
ates for the synthesis of purine nucleoside analogues via
reduction to the corresponding aminoimidazoles.
Glucosyl diazadiene 1 was obtained in six steps from
peracetylated glucoside, via glucosyl isothiocyanate 6
(Scheme 2).26 Glycosyl isothiocyanates have been widely
*
Corresponding author. Tel.: +33 2 51 12 54 06; fax: +33 2 51 12 54 02.
E-mail address: david.deniaud@univ-nantes.fr (D. Deniaud).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.069

3274
V. Kikelj et al. / Tetrahedron Letters 49 (2008) 3273–3275
N
N
R
N
CH2Cl2, rt
RCH2COCl
Et3N
Cl
N
N
+
R
MeS
N O
Sugar
O
MeS
N
Sugar
MeS
MeS
N
Sugar
Et3N, 4 h
(-HCl)
1
2-5
1
N
R
OAc
R
O
(-HNMe2)
Sugar=
N
N
O
H
O
AcO
AcO
MeS
N
N
Sugar
OAc
Sugar
Scheme 1. General strategy for the synthesis of nucleosides.
2 (78%) R=Ph
3 (82%) R=CO2Me
4 (67%) R=OMe
5 (60%) R=H
H
NH3 (g), 30 min
NCS
N
NH2
Sugar
Sugar
6
Scheme 3. Synthesis of glucosyl pyrimidinones.
S
Toluene, 0 °C
7 (98%)
H
possibly involve a [4+2] cycloaddition (with an in situ gen-
erated ketene from acyl chloride and triethylamine), or two
ionic steps (acylation of the anomeric nitrogen atom, follo-
wed by the cyclization with the loss of hydrochloric acid).
To complete this study we investigated the reactivity of
compound 8,30 containing a thiazadiene chain, towards a-
halogenoketones to give glucosylamino thiazoles 10–12.
Very little work related with exocyclic amino nucleosides
has been carried out despite such compounds showing
interesting activities. For example, Clitocine, a natural
ribofuranosylamino pyrimidine, is an inhibitor of adeno-
sine kinase and exhibits insecticidal activity.31,32 Synthetic
exocyclic amino nucleosides like ribofuranosylamino
pyrimido[5,4-d]pyrimidine show antitumour and antiviral
properties.33,34 Other glucosylamino pyrimidines,35,36 tri-
azines37 and triazoles,38 with various activities, have also
been reported. Classically, these exocyclic amino nucleo-
sides are prepared by the condensation reaction of glyco-
sylamine derivatives with chloronucleobases (Kamikawa’s
procedure)39 or by the coupling of silylated aminohetero-
cycles with peracetylated glycosides (Kini’s synthesis).40,41
On the basis of the above literature, it is of interest to
develop new methodologies for the synthesis of compounds
containing a similar structural feature. Amino thiazoles 10–
12 were thus synthesized from b-glucosyl thiazadiene 8. The
cyclocondensation reactions were performed between the
thiazadiene chain and a-bromo- or chloro-ketones. The
spontaneous deamination of the intermediate cycloadduct
afforded b-aminosugars 10–12 in good yields (Scheme 4).
The b anomeric configuration was fully preserved, and we
observed only 1,2-trans glucosidic linkage. No intermediate
could be isolated; however, the alkylation of the sulphur
atom is thought to occur first, with triethylamine neutraliz-
ing the hydracid generated during the ring closure step.
In summary, we have shown that glucosyl heterodienes
(diazadiene or thiazadiene) can be used as the building
blocks for regioselective heterocyclocondensation reactions
with acyl chlorides or a-halogenoketones to prepare nucle-
oside or aminonucleoside analogues (glucosyl or glucosyl-
amino heterocycles). Further studies will aim to couple
other dienophiles to variously glycosylated heterodiene
skeletons.
DMF-DMA, 2 h
CH2Cl2, reflux
MeI, 18 h
THF, rt
N
N N
Sugar
S
8 (96%)
Et3N, 1 h
CH2Cl2, 0 °C
N
N
H
I
N
N
N
Sugar
MeS
N
Sugar
SMe
9 (99%)
1 (96%)
Scheme 2. Synthesis of the key intermediate glucosyl diazadiene.
used as important intermediates in synthetic approaches to
nucleoside analogues.27,28 The reaction of b-glucosyl isothi-
ocyanate 6 with ammonia gas gave thiourea derivative 7 in
98% yield without deacetylation of the sugar moiety. The
subsequent treatment using N,N-dimethylformamide
dimethyl acetal afforded the desired thiazadiene 8 in good
yield. The alkylation of compound 8 with methyliodide
provided the corresponding S-methyl salt 9 containing
the diazadiene chain. This iodide 9 was dehydrohalogenat-
ed using triethylamine giving rise to the key intermediate
glucosyl diazadiene 1. The structure of 1 was assigned by
the full analysis of the 1H, 13C, HMBC and HMQC
NMR spectra.29
The treatment of b-glucosyl diazadiene 1 with acyl chlo-
rides was then investigated. The reactions were performed
at room temperature in dichloromethane with triethyl-
amine. The cyclocondensations occurred, followed by the
loss of dimethylamine, leading to b-glucosyl pyrimidin-4-
ones 2–5 in good yields and excellent regioselectivities
1
(Scheme 3). The H NMR spectra of 2–4 showed a singlet
(or a doublet for 5) in position 6 due to the loss of
dimethylamine, and thus excluded the regioisomeric pyrim-
idin-5-one structure. The retention of the anomeric config-
uration has been easily confirmed by measuring the
anomeric coupling constant J1,2. The J1,2 value (ꢀ9.5 Hz)
indicated glucoses 2–5 to be b.
Neither a first intermediate resulting from the acylation
of the anomeric nitrogen atom, nor the cycloadduct before
deamination, could be isolated. Therefore, it has not been
possible to ascertain the reaction mechanism, which could

V. Kikelj et al. / Tetrahedron Letters 49 (2008) 3273–3275
3275
18. Ogura, H.; Takahashi, H.; Sato, O. Chem. Pharm. Bull. 1981, 29,
1838.
19. Pearson, M. S. M.; Robin, A.; Bourgougnon, N.; Meslin, J. C.;
Deniaud, D. J. Org. Chem. 2003, 68, 8583.
20. Landreau, C.; Deniaud, D.; Reliquet, F.; Reliquet, A.; Meslin, J. C.
Heterocycles 2000, 53, 2667.
N
S
O
N
CH2Cl2 or THF
R
+
HN
X
rt or reflux
Et3N, 22 h
Sugar
X=Br or Cl
8
21. Landreau, C.; Deniaud, D.; Reliquet, F.; Reliquet, A.; Meslin, J. C. J.
Heterocycl. Chem. 2001, 38, 93.
22. Friot, C.; Reliquet, A.; Reliquet, F.; Meslin, J. C. Synthesis 2000, 5,
695.
23. Landreau, C.; Deniaud, D.; Reliquet, A.; Meslin, J. C. Synthesis 2001,
13, 2015.
N
X
H
(-HX)
N
O
HN
S
Sugar
R
24. Landreau, C.; Deniaud, D.; Evain, M.; Reliquet, A.; Meslin, J. C. J.
Chem. Soc., Perkin Trans. 1 2002, 6, 741.
25. Landreau, C.; Deniaud, D.; Meslin, J. C. J. Org. Chem. 2003, 68,
4912.
26. Kuehne, M.; Gyoergydeak, Z.; Lindhorst, T. K. Synthesis 2006, 6,
949.
N
N
S
O
R
O
R
(-HNMe2)
N
S
HN
Sugar
H
HN
Sugar
10 (78%), R=p-ClPh
11 (62%), R=CF3
12 (74%), R=Me
27. Fuentes, J.; Angulo, M.; Pradera, M. A. J. Org. Chem. 2002, 67, 2577.
28. Ro¨ckendorf, N.; Lindhorst, T. K. Top. Curr. Chem. 2001, 217, 201.
29. Spectroscopic data of compound 1: Mp: 109–110 °C. IR (KBr): 2963,
1751, 1730, 1635, 1588 cmÀ1 1H NMR (DMSO) d 1.86, 1.93, 1.98,
.
Scheme 4. Synthesis of glucosylamino thiazoles.
2.01 (4s, 12H, CH3); 2.20 (s, 3H, SCH3); 2.96, 3.06 (2s, 6H, N(CH3)2);
3.91–4.05 (m, 2H, H5 and H6a); 4.14 (dd, 1H, J = 12.2 Hz, J = 5.1 Hz,
H6b); 4.81 (t, 1H, J = 9.4 Hz, H2); 4.91 (t, 1H, J = 9.4 Hz, H4); 5.24 (t,
1H, J = 9.4 Hz, H3); 5.40 (d, 1H, J = 9.4 Hz, H1); 7.86 (s, 1H, H4
diene). 13C NMR (DMSO) d 13.9, 20.3, 20.5, 34.1, 39.9, 62.3, 68.7,
72.0, 72.2, 72.8, 85.2, 154.9, 166.1, 168.8, 169.3, 169.6, 170.1. MS m/z:
476 (100, [M+H]+). HRMS (ESI) m/z calcd for C19H30N3O9S
[M+H]+ 476.1703, found 476.1705.
Acknowledgements
The French Ministry of Education and CNRS are grate-
fully acknowledged for financial support.
References and notes
30. Spectroscopic data of compound 8: Mp: 89–90 °C. IR (KBr): 3354,
2940, 1750, 1629, 1507, 1224 cmÀ1 1H NMR (CDCl3) d 2.03, 2.05,
.
2.08 (3s, 12H, CH3); 3.06, 3.17 (2s, 6H, N(CH3)2); 3.89 (ddd, 1H,
J = 9.7 Hz, J = 4.3 Hz, J = 2.1 Hz, H5); 4.12 (dd, 1H, J = 12.4 Hz,
J = 2.1 Hz, H6a); 4.33 (dd, 1H, J = 12.4 Hz, J = 4.3 Hz, H6b); 5.08 (t,
1H, J = 9.7 Hz, H2); 5.11 (t, 1H, J = 9.7 Hz, H4); 5.38 (t, 1H,
J = 9.7 Hz, H3); 5.96 (t, 1H, J = 9.7 Hz, H1); 7.08 (d, 1H, J = 9.7 Hz,
NH); 8.81 (s, 1H, H4 diene). 13C NMR (CDCl3) d 20.6, 20.7, 35.9,
41.5, 61.7, 68.3, 70.6, 73.0, 73.4, 82.5, 163.0, 169.6, 169.9, 170.7, 170.8,
196.6. MS m/z: 462 (100, [M+H]+). HRMS (ESI) m/z calcd for
C18H28N3O9S [M+H]+ 462.1546, found 462.1548.
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