Base-modified nucleosides from carbohydrate derived oxazolidinethiones: A five-step process

Article abstract of DOI:10.1016/S0040-4039(01)00357-4

Starting from unprotected carbohydrates, base-modified nucleosides could be reached in four steps through the condensation of anthranilic acid with a suitably protected sugar-derived 2-alkylthio-1,3-oxazoline.

Full text of DOI:10.1016/S0040-4039(01)00357-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2977–2980
Base-modified nucleosides from carbohydrate derived
oxazolidinethiones: a five-step process
Jolanta Girniene,a,b David Gueyrard,a Arnaud Tatiboue¨t,a,* Algirdas Sackusb and Patrick Rollina
aICOA, UMR CNRS 6005, Universite´ d’Orle´ans, BP 6759, F-45067 Orle´ans, France
bDepartment of Organic Chemistry, Kaunas University of Technology, LT-3028 Kaunas, Lithuania
Received 9 February 2001; accepted 3 March 2001
Abstract—Starting from unprotected carbohydrates, base-modified nucleosides could be reached in four steps through the
condensation of anthranilic acid with a suitably protected sugar-derived 2-alkylthio-1,3-oxazoline. © 2001 Elsevier Science Ltd.
All rights reserved.
Synthetic base-modified nucleosides and nucleotides
have an important impact in various fields. Their bio-
logical properties have found application in antiviral
tools against VZV and HIV,1 in evaluation and study
of DNA damages,2 as well as in the anti-sense approach
and DNA-probe technology with fluorescence proper-
ties.3 Investigations were also undertaken on the
physico-chemical parts of DNA base-to-base interac-
tions (hydrogen bonding and stacking).4 Two general
methods for nucleoside preparation have been reported
in the literature, one using the glycosylation method5
which may lead to anomeric selectivity problems, the
other based on a multistep process to construct entirely
the base from the sugar.6
cation of the process of anthranilic acid condensation
with per-benzylated OZT led to new homochiral quina-
zolinone derivatives. Application of the cyclocondensa-
tion process to sugar-derived OZT constitutes
a
promising extension of this reaction to new base-
modified nucleosides.
Preparing the sugar derived OZT 1a–f is straightfor-
ward (Scheme 1).10 Standard conditions were applied to
various series of sugars:
-ribose (aldopentose series) as well as
-sorbose (hexoketose series). On native or partially
protected sugars (1-O-benzyl- -fructose and 1-O-ben-
zyl- -sorbose), the OZT were obtained in one step
D
- and
L
-arabinose,
D-xylose,
D
D
-fructose and
L
D
L
using potassium thiocyanate in acidic conditions (80–
100%). This reaction allowed us to produce diverse
OZT 1a–f in which the configuration of the sugar ring
was perfectly defined. A furano-conformation, confirm-
Our convergent approach to artificial nucleoside syn-
thesis involves a sugar derived 1,3-oxazolidine-2-thione
(OZT) and anthranilic acid. Condensation reactions of
anthranilic acid derivatives have already been
explored.7 Within the frame of a research program
centered on the preparation and reactivity of chiral
natural OZT, such reactions were developed.8,9 Appli-
1
ed by H and 13C NMR spectrum11 and an anomeric
configuration controlled by the location of the hydroxyl
group on C-2 were observed. In addition, in
and -sorbo-derivatives, known to usually give mix-
D-fructo-
L
Scheme 1.
* Corresponding author. Fax: 33 (0)2-38-49-72-81; e-mail: arnaud.tatibouet@univ-orleans.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00357-4

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J. Girniene et al. / Tetrahedron Letters 42 (2001) 2977–2980
Some preliminary attempts with other 1,2-aminoaro-
matic acids were undertaken as a possible extension of
Table 1. Application of the procedure to aldoses and
ketoses
the method. We employed the -xylo-derivative 1c as a
D
model using the typical procedure.12 The results (Table
2) showed that the presence of an electron withdrawing
group hampered the reaction. The replacement of ben-
zene by a pyridine ring (2-aminonicotinic acid) expect-
edly did not allow the formation of the desired
compound.
Sugars
R
2a–f (%)
3a–f (%)
D
-Arabinose
H
H
H
H
38
41
48
42
64
38
78
79
75
65
14
16
L
-Arabinose
D
-Xylose
-Ribose
D
1-O-Benzyl-
1-O-Benzyl-
D
-fructose
-sorbose
CH2OBn
CH2OBn
L
In order to validate our approach to base-modified
nucleosides, we have investigated the ring-cleavage of
quinazolinones 3. Inspired by the well documented
2,2%-anhydronucleoside chemistry we have reacted the
D
-arabino derivative 3a in basic conditions.15 This reac-
tures of compounds, the benzyl protection on the first
position determined the formation of only one
stereoisomer of the four that could be expected from
the unprotected sugar.12
tion is effective in good yield (67%) and in our case,
takes place with no inversion of configuration. We
obtained a -arabino compound 4a, which incorporates
a quinazolinedione system as the base. The 2,2%-anhy-
dronucleoside 3a was also submitted to acidic condi-
tions to afford 4a with a better yield of 74%.16 Further
hydrogenolysis of benzyl groups (H2 and Pd/C)
D
Prior to cyclocondensation, the OZT has to be acti-
vated through S-alkylation.13 This sequence furnishes
per-O- and -S-benzylated compounds 2a–f in reason-
able yields for a two-step sequence (Table 1).
afforded the
D
-arabinonucleoside analog 5a with 74%
yield (Scheme 2).17
Condensation of the 2-alkylthio-1,3-oxazoline deriva-
tives 2a–f with anthranilic acid in dry ethanol offers an
efficient access to sugar derived quinazolinones 3a–f
In summary, a concise (five steps) and practical synthe-
sis of base-modified nucleosides has been disclosed
starting from native carbohydrates through OZT
derivatives. This procedure constitutes an original
application of cyclocondensations involving anthranilic
acid and analogs. The reaction has been extended with
success to different sugar series (pentoses and hexoses)
and also to diverse heterocyclic systems. Further explo-
ration of the chemistry is currently performed to obtain
mostly in good yields.14 In the case of
D
-fructo and
L
-sorbo derivatives, however, yields were quite poor.
Those results might be explained by a steric hindrance
of the benzyloxymethyl group attached to the anomeric
carbon. Moreover, a competing nucleophilic attack of
ethanol providing the corresponding 2-ethoxy-1,3-oxa-
zoline analogs was observed. Improvement of the con-
ditions was investigated using different solvents such as
DMF or tert-butanol. In aprotic media (DMF), no
condensation was detected and in tert-butanol only a
very slow reaction occurred. Activation was performed
through addition of two equivalents of camphorsul-
fonic acid. In such conditions, cyclocondensations
D
-ribo and 2-deoxy-D-ribo analogs.
Acknowledgements
occurred in reasonable yield for
D
-fructo and
L
-sorbo
This work was supported by a TEMPUS-PHARE
grant (J.G.) and an MENRT grant (D.G.).
derivatives (57 and 70%, respectively).
Table 2. Extension to diverse amino-aromatic acids
Scheme 2.

J. Girniene et al. / Tetrahedron Letters 42 (2001) 2977–2980
2979
References
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Compound 1a (0.657 g, 3.42 mmol) was dissolved in
DMF and cooled under argon in an ice–water bath. NaH
(0.45 g, 60%, 11.3 mmol) was added. After a few minutes,
benzyl bromide (1.34 mL, 11.3 mmol) was added drop-
wise over a 10 min period. The mixture was left overnight
at room temperature, then diluted with water and
extracted with ethyl acetate. The organic phase was
washed twice with water, brine and was then dried with
MgSO4. After evaporation, the residue was purified on
silica gel to furnish the per-benzylated oxazoline 2a (0.695
g, 1.5 mmol). [h]D20 −71 (c 1.16, CHCl3); 1H NMR (250
MHz, CDCl3) 3.20 (dd, 1H, J5a,5b=10 Hz, J5a,4=7 Hz,
H-5a), 3.40 (dd, 1H, J5b,4=5.5 Hz, H-5b), 4.04 (m, 1H,
H-3), 4.19 (s, 2H, CH2Ph), 4.23 (m, 1H, H-4), 4.36 (d,
1H, J=12.1 Hz, CH2Ph), 4.43 (d, 1H, J=12.1 Hz,
CH2Ph), 4.49 (d, 1H, J=12.1 Hz, CH2Ph), 4.55 (d, 1H,
J=12.1 Hz, CH2Ph), 4.85 (dd, 1H, J1,2=6 Hz, J2,3=1
Hz, H-2), 6.01 (d, 1H, J1,2=6 Hz, H-1), 7.10–7.30 (m,
15H, H-arom); 13C NMR (63 MHz, CDCl3) 36.1 (CH2S-),
69.4 (CH2), 71.6 (CH2), 73.1 (C-5), 81.9 (C-3), 85.4 (C-4),
88.1 (C-2), 100.7 (C-1), 126.4, 126.7, 127.0, 127.5, 127.7,
127.8, 128.2, 128.3, 128.4, 128.9, 136.4, 136.9, 137.5,
137.8, 138.8, 169.2; ISMS m/z 462 (m+H)+.
14. Typical procedure for condensation: Compound 2a (0.2 g;
0.43 mmol) was dissolved in dry ethanol in the presence
,
of 3 A molecular sieves. Anthranilic acid (0.071 g, 0.52
mmol) was added and the solution heated under reflux
for 24 h. The mixture was then evaporated, extracted
with CH2Cl2, washed twice with saturated NaHCO3,
dried over MgSO4 and purified by silica gel flash chro-
matography. The
D-arabino-quinazolinone derivative 3a
(0.155 g, 0.34 mmol) was isolated in 79% yield. [h]2D0 −191
(c 0.59, CHCl3); 1H NMR (250 MHz, CDCl3) 3.34 (m,
2H, H-5), 4.16 (d, 1H, J=12.5 Hz, CH2Ph), 4.22 (d, 1H,
J=12.5 Hz, CH2Ph), 4.42 (m, 1H, H-4), 4.57 (d, 1H,
J=12 Hz, CH2Ph), 4.63 (d, 1H, J=12 Hz, CH2Ph), 5.22
(d, 1H, J1,2=6 Hz, H-3), 6.57 (d, 1H, J1,2=6 Hz, H-1),
7.01–7.04 (m, 2H, H-arom), 7.17–7.20 (m, 3H, H-arom),
7.31–7.37 (m, 6H, H-arom), 7.48 (d, 1H, J=7.2 Hz,
H-quinazolinone), 7.66 (m, 1H, H-quinazolinone), 8.22
(m, 1H, H-quinazolinone); 13C NMR (63 MHz, CDCl3)
69.1, 72.6, 73.5, 83.6, 85.4, 86.0, 87.7, 119.0 (C-1), 125.0,
126.4, 127.3, 127.9, 128.0, 128.2, 128.4, 128.5, 128.8,
135.2, 136.5, 137.2, 149.2 (CꢀN), 154.7 (CO); ISMS m/z
457 (m+H)+.
10. Bromund, W.; Herbst, R. M. J. Org. Chem. 1945, 267–
276.
11. Davidson, R. M.; Byrd, G. D.; White, E.; Margolis, S.
A.; Coxon, B. Magn. Reson. Chem. 1986, 24, 929–937.
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Ewing, D. J. Chem. Soc., Chem. Commun. 1988, 671–672;
(b) Lichtenthaler, F. W.; Klotz, J.; Flath, F.-J. Liebigs
Ann. Chem. 1995, 2069–2080.
15. Schinadzi, R. F.; Chen, M. S.; Prusoff, W. H. J. Med.
Chem. 1979, 22, 1273–1277.
16. The
D-arabino-quinazolinone derivative 3a was dissolved
13. Typical procedure for OZT preparation and benzylation:
in ethanol then NaOH 5% was added and the solution
was stirred at room temperature for 7 days. The solution
was evaporated, extracted with ethyl acetate, washed with
water until neutral and then dried over MgSO4. The
quinazolinedione 4a was isolated in 67% yield. [h]2D0 −85
(c 0.65, CHCl3); 1H NMR (250 MHz, CDCl3) 3.53 (s,
1H, OH), 3.74 (dd, 1H, J5a,5b=10.4 Hz, J4,5a=3.0 Hz,
H-5a), 3.89 (dd, 1H, J4,5b=8.0 Hz, H-5b), 4.12 (ddd, 1H,
D
-Arabinose (1 g, 6.67 mmol) and KSCN (1.3 g, 13.4
mmol) were dissolved in cold water and then 37% HCl
(1.1 mL) was added. The solution was kept at room
temperature for 2 hours then at 55°C overnight. The
solution was evaporated and purified over silica gel with
ethyl acetate as eluent. The
D-arabino-OZT derivative 1a
(1.1 g, 5.75 mmol) was isolated in 86% yield. [h]2D0 −52 (c
1.07, CH3OH); 1H NMR (250 MHz, DMSO) 3.15–3.35
(m, 2H, H-5), 3.84 (t, 1H, J=6.0 Hz, H-3), 4.23 (m, 1H,
H-4), 4.94 (t, 1H, J=5.5 Hz, OH), 5.03 (d, 1H, J1,2=5.5
Hz, H-2), 5.69 (d, 1H, J=4.0 Hz, OH), 5.78 (d, 1H,
J3,4=7.5 Hz, J4,5b=8.0 Hz, J4,5a=3.0 Hz, H-4), 4.29 (dd,
1H, J2,3=5.5 Hz, J3,4=7.5 Hz, H-3), 4.52–4.72 (m, 4H,
H-2, CH2Ph), 4.85 (d, 1H, J=11.5 Hz, CH2Ph), 6.78 (d,
1H, J1,2=8.0 Hz, H-1), 6.93 (d, 1H, Ja,b=8.0 Hz, Ha),
7.12 (t, 1H, Jc,b=Jc,d=8.0 Hz, Hc), 7.24–7.47 (m, 10H,
J
1,2=5.5 Hz, H-1), 10.8 (s, 1H, NH); 13C NMR (63 MHz,

2980
J. Girniene et al. / Tetrahedron Letters 42 (2001) 2977–2980
H-arom.), 7.53 (t, 1H, Jb,a=Jb,c=7.0 Hz, Hb), 7.91 (d,
filtrated over Celite and was washed with pyridine to
afford pure 5a (0.46 mg, 0.016 mmol) with 74% yield.
[h]2D0 −27 (c 1, pyridine); 1H NMR (250 MHz, DMSO–
D2O) 3.55–3.68 (m, 3H, H-5a, H-5b and H-4), 4.18–
4.28 (m, 2H, H-2 and H-3), 6.55 (d, 1H, J1,2=7.5 Hz,
1H, Jd,c=8.0 Hz, Hd), 9.64 (s, 1H, NH); 13C NMR (63
MHz, CDCl3) 70.9 (C-5), 72.2 (CH2Ph), 73.2 (CH2Ph),
78.8 (C-2), 79.1 (C-4), 82.0 (C-1), 85.8 (C-3), 114.4 (C),
115.1 (Ca), 123.4 (Cc), 127.6, 127.8, 127.6, 127.8, 127.9,
128.0, 128.2, 128.3, 128.5, 128.6, 135.4 (Cd), 137.9 (C),
138.3 (C), 151.9, (CO), 163.1 (CO); ISMS m/z 457 (m−
H2O+H)+, 475 (m+H)+, 497 (m+Na)+.
H-1), 7.16 (m, 2H, Ha and Hc), 7.59 (dt, 1H, Jb,a
=
Jb,c=8.0 Hz, Jb,d=1.5 Hz, Hb), 7.85 (d, 1H, Jd,c=8.0
Hz, Hd); 13C NMR (63 MHz, DMSO–D2O) 62.1 (C-5),
76.2 (C-2 or 3), 76.9 (C-2 or 3), 81.4 (C-1), 83.0 (C-4),
114.2 (C), 115.4 (Ca), 122.9 (Cc), 127.8 (Cd), 135.6 (Cb),
139.9 (C), 150.4 (CO), 162.5 (CO); ISMS m/z 295 (m+
H)+, 317 (m+Na)+.
17. The
D-arabinoquinazolinedione 4a (0.1 g, 0.021 mmol)
was dissolved in methanol, then Pd/C (10%, 0.2 g) was
added and the mixture stirred overnight under H2 at
room temperature. After completion, the solution was
.
.