A new general synthesis of isomeric nucleosides

Article abstract of DOI:10.1016/S0040-4039(01)01118-2

An efficient new method for the synthesis of isonucleosides is described. The key step in the synthesis was the direct coupling of purine and pyrimidine bases with the cyclic sulfate of a carbohydrate intermediate. This reaction proceeded with high regiospecificity and stereospecificity.

Full text of DOI:10.1016/S0040-4039(01)01118-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5813–5815
A new general synthesis of isomeric nucleosides
Sanjib Bera and Vasu Nair*
Department of Chemistry, The University of Iowa, Iowa City, IA 52242, USA
Received 12 June 2001; revised 21 June 2001; accepted 22 June 2001
Abstract—An efficient new method for the synthesis of isonucleosides is described. The key step in the synthesis was the direct
coupling of purine and pyrimidine bases with the cyclic sulfate of a carbohydrate intermediate. This reaction proceeded with high
regiospecificity and stereospecificity. © 2001 Elsevier Science Ltd. All rights reserved.
Isomeric nucleosides (or isonucleosides) as potential
antiviral agents have been the subject of intense interest
in our laboratory for a number of years.1–4 Included
within this family are those compounds where the base
is transposed from the natural 1%-position to the iso-
meric 2%-position (Fig. 1). For example, 4(S)-(6-amino-
pyrimidine isonucleosides in which the pyrimidine base
can be condensed directly and in good yields to give the
N-1 alkylated products; (3) our previous attempt11 to
couple nucleobases directly with the cyclic sulfite 3 had
limitations because of low yields and generality; for the
pyrimidine bases, the coupling reactions did not occur
at all.
9H-purin-9-yl)-tetrahydro-1(S)-furanmethanol
[1a,
B=adenine] is an isomeric dideoxynucleoside synthe-
sized in our laboratory.1 It has potent anti-HIV activity
against HIV-1 and HIV-2.4 In addition, it has been
reported that isodeoxynucleoside (1b), having guanine
as a nucleobase, had significant activities against HSV-1
and HSV-2.5
To overcome these and related difficulties, we devel-
oped a new approach to isonucleosides that utilized a
cyclic sulfate derivative 4 of a carbohydrate as a key
intermediate (Scheme 1). When treated with purine and
pyrimidine bases, this cyclic sulfate underwent direct
coupling with regiospecificity, stereospecificity and
good overall yields.
While some approaches have been reported for the
synthesis of isodideoxynucleosides (1a, B=purine and
pyrimidine bases), there is no general method available
for the synthesis of both purine and pyrimidine
isodeoxynucleosides (1b) from a readily available car-
bohydrate precursor by direct coupling.
Cyclic sulfate 4 was synthesized from cyclic sulfite 311
by oxidation12 with RuCl3/NaIO4 under conditions of
phase transfer catalysis. Compound 4, the key precur-
sor, was condensed with purine and pyrimidine bases to
produce isonucleosides. For the synthesis of purine
nucleosides, the adenine base was deprotonated with
DBU in CH3CN to give the adenylate anion, which
reacted with the intermediate 4 at C-2 position exclu-
sively and with the inversion of configuration to give
the adenine derivative 5a. Treatment of 5a with 2%
aqueous HCl in MeOH13 at 65°C gives the unprotected
In addition, the methods reported earlier1,6–10 for the
synthesis of isonucleosides suffered from the following
drawbacks: (1) the relatively large number of synthetic
steps involved that make the syntheses cumbersome
and that reduce the overall yield of the desired product;
(2) the lack of a general method for the synthesis of
OH
B
B
HO
OH
HO
OH
B
B
O
O
O
O
OH
1b
1a
Figure 1.
* Corresponding author. Fax: +1 319 353 2621; e-mail: vasu-nair@uiowa.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01118-2

5814
S. Bera, V. Nair / Tetrahedron Letters 42 (2001) 5813–5815
RO
RO
RO
O
O
O
RuCl3/NaIO4
BH/DBU
CH3CN
SOCl2/Py
CH3CN-CCl4-H2O
O
O
HO
O
OH
O
S
S
O
3
O
O
BH = Nucleobases
R = TBDPS
4
R1
N
R1
N
N
N
N
N
R2
N
R2
N
RO
HO
2% aq. HCl/MeOH
O
O
O
HO
6
O
O
Et3NH
S
O
5
a: R1 = NH2, R2 = H
b: R1 = OH, R2 = NH2
a: R1 = NH2, R2 = H
b: R1 = Cl, R2 =NH2
Scheme 1.
O
O
R3
R3
NH
NH
RO
O
BH/DBU
N
O
N
O
2% aq. HCl/MeOH
HO
HO
O
CH3CN
O
S
O
O
S
O
O
HO
O
O
O
Et3NH
4
O
a: R3 = H
b: R3 = F
c: R3 = CH3
8
a: R3 = H
7
b: R3 = F
c: R3 = CH3
Scheme 2.
isonucleoside 6a (60% yield from 4).14 Similarly, treat-
ment of 4 with 2-amino-6-chloropurine followed by the
treatment of the resulting nucleoside sulfate 5b with 2%
aqueous HCl in MeOH gave the guanine derivative 6b
(57% yield from 4).
Acknowledgements
We thank the NIH (NIAID) for support of these
studies.
For the synthesis of pyrimidine isonucleosides, cyclic
sulfate 4 was treated with uracil, 5-fluorouracil and
thymine in a similar manner to give the nucleoside
sulfates 7a–c (Scheme 2). These sulfates were treated
with 2% HCl in MeOH to produce the unprotected
isonucleosides 8a–c (46–59% from 4).15
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(v/v) of a 37% aqueous HCl solution was heated at 65°C
for 20 h. The solvent was evaporated to dryness, coevap-
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15. General procedure for the synthesis of 8: To a suspension
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pension was heated under reflux for 1 h. To the resulting
clear solution was added a solution of sulfate 4 in
CH3CN (10 mL/mmol). The reaction mixture was then
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in 59, 46 and 55% yields, respectively, from 4. Data of
compound 8b: white solid (hygroscopic); umax (MeOH)
274 nm (m 8100); 1H NMR (MeOH-d4): 7.96 (d, J=6.9
Hz, 1H), 4.88 (m, 1H), 4.24 (m, 1H), 4.13 (dd, J=6.7,
10.7 Hz, 1H), 4.02 (dd, J=3.1, 10.7 Hz, 1H), 3.84 (d,
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14. General method for the synthesis of 6: To a suspension of
purine base in anhydrous CH3CN (10–15 mL/mmol
base), DBU (1.05 equiv.) was added and the suspension
was stirred at room temperature for 0.5 h. To the result-
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CH3CN (10 mL/mmol). The reaction mixture was then
heated at 75°C for 2 h. The solvent was evaporated under
reduced pressure and the residue was purified over silica
.