Straightforward synthesis of 3'-deoxy-3',4'-didehydronucleoside-5'- aldehydes via 2',3'-O-orthoester group elimination: A simple route to 3',4'-didehydronucleosides

Article abstract of DOI:10.1016/j.tetlet.2010.10.117

Straightforward, high-yielding syntheses of 3'-deoxy-3',4'- didehydronucleoside-5'-aldehydes and 3'-deoxy-3',4'-didehydronucleosides starting from 2',3'-O-orthoester derivatives of ribonucleosides are described.

Full text of DOI:10.1016/j.tetlet.2010.10.117

Tetrahedron Letters 51 (2010) 6874–6876
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Straightforward synthesis of 30-deoxy-30,40-didehydronucleoside-50-aldehydes
via 20,30-O-orthoester group elimination: a simple route to
30,40-didehydronucleosides
⇑
ˇ
´
Magdalena Petrová, Miloš Budešínsky, Ivan Rosenberg
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v. v. i., Flemingovo nám. 2, 166 10 Prague 6, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Straightforward, high-yielding syntheses of 30-deoxy-30,40-didehydronucleoside-50-aldehydes and 30-
deoxy-30,40-didehydronucleosides starting from 20,30-O-orthoester derivatives of ribonucleosides are
described.
Article history:
Received 16 September 2010
Revised 3 October 2010
Accepted 22 October 2010
Available online 30 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Moffat oxidation
b-Elimination
Nucleoside-50-aldehydes
30,40-Didehydronucleosides
20,30-O-Orthoester
Nucleoside analogs containing an unsaturated sugar part are
generally recognized as an important class of biologically active
compounds with significant antiviral (anti-HIV, anti-HVB, anti-HCV,
etc.) and antitumor activities.1–4 Whereas several 20,30-unsaturated
derivatives are in use or in clinical trials,4 the 30,40-unsaturated
nucleosides have been reported only rarely, mostly as intermedi-
ates of multistep synthetic routes (for adenine,5–9 hypoxanthine,6,7
and uracil10 nucleosides). Recently, 30-deoxy-30,40-didehydrocyti-
dine was identified in a mixture with 20-deoxy-10,20-didehydrocyti-
protected with 20,30-O-orthoester or 20,30-O-isopropylidene moie-
ties.19–21
In our study on oxidation of the 50-OH group of ribonucleosides
with various 20,30-O-protecting groups we found that upon Moffat
oxidation (DMSO/DCC/TFA/pyridine) of 20,30-O-methoxymethylid-
ene ribonucleosides 1, two major products were formed: the ex-
pected 20,30-O-methoxymethylidene-50-aldehyde 2 and a more
polar compound, the structure of which was assigned, according
to NMR spectra, as 30-deoxy-30,40-didehydronucleoside-50-alde-
hyde 3 (Scheme 1). The rapid conversion of 2 into 3 was achieved
by addition of triethylamine to the reaction mixture. The resulting
aldehydes 3 are stable upon isolation and characterization. In order
to overcome work-up difficulties involving removal of excess
DMSO and the side product dicyclohexyl urea, and to increase
the isolated yields of aldehydes 3, the Moffat oxidation procedure
was modified using DMF as the solvent, a six-molar excess of
DMSO with respect to the nucleoside, and EDC instead of DCC.
The crude oxidation mixture was then treated briefly with Et3N
to complete the elimination, quenched using oxalic acid to decom-
pose excess EDC, and concentrated at 35 °C in vacuo (13 Pa). No
formation of by-products during this work-up was detected. This
procedure afforded 30,40-didehydro-50-aldehydes 3a–e, both in
the purine and pyrimidine series, in isolated yields of 69–89%
(Scheme 1). A lower yield of cytosine derivative 3c was due to par-
tial loss of the N-benzoyl group during work-up of the oxidation
mixture. Therefore, we performed, in three cases, the reduction
step without isolation of aldehydes 3, providing 30,40-didehydronu-
dine as
a
tumor supressor.11,12 Although formation of the
corresponding 30-deoxy-30,40-didehydronucleoside-50-aldehydes
upon prolonged treatment of the 20,30-O-acetal or ketal derivatives
of ribonucleoside-50-aldehydes with either silica gel or with a base
has been patented,10,13 no synthetic use for this approach has been
reported in the literature. Later, 20-deoxy-30,40-didehydropyrimi-
dine nucleosides were prepared by treatment of a 20-deoxy-50-eth-
oxycarbonyl-30-O-mesylnucleoside derivative with
a base in
DMF.14 In the ribo series, the reported synthetic approaches em-
ployed conventional dehydrohalogenation of 30-deoxy-30-halo
derivatives6,8,15–17 prepared from nucleoside 20,30-O-orthoesters,5
or oxidative elimination of 30-deoxy-30-phenylseleno derivatives
obtained by a multistep procedure.18 The formation of 30-deoxy-
30,40-didehydronucleoside derivatives as minor side products was
observed upon Wittig reaction of nucleoside-50-aldehydes
⇑
Corresponding author.
E-mail address: ivan@uochb.cas.cz (I. Rosenberg).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.117

M. Petrová et al. / Tetrahedron Letters 51 (2010) 6874–6876
6875
B
B
B
HO
O
B
HO
c
b
O
O
O
a
O
O
4a-e
O
O
O
O
OH
OH
d
CH3O
CH3O
2a-e
1a-e
3a-e
4f-h
a) DMF-DMSO-EDC-pyridine-TFA; b) Et3N; c) NaBH4, MeOH, DMF; d) for 4b-d CH3NH2-EtOH
B
U
ABz CBz GiBu
T
A
C
G
a
b
c
d
e
f
g
h
1
3
1
1
4
3
89 78
80 82
69
76
87 87
4
4
4
4
94
-
-
71a 64a 52a 82a
-
-
-
-
82b 87b 72b
-
-
-
93 85 86
a Yield from 1 over two steps with isolation of aldehyde 3.
b Yield from 1 over two steps without isolation of aldehyde 3.
Scheme 1. Synthesis and isolated yields (%) of 30,40-didehydronucleoside derivatives 3 and 4.
U
O
5´
O
U
U
1´
HO
O
RCOOR´
R´OH
+
O
O
4´
a, b
3´
2´
H
3a
OH
U
O
R
O
OR´
O
R
O
OR´
Et3N
1a
5a
5b
R = H; R´ = CH3
R = -CH3; R´ = C2H5
R = -C6H5; R´ = C2H5
O
O
+
6a R1 = HCO
OR1
6b R1 = CH3CO;
6c R1 = C6H5CO
a) DMF-DMSO-EDC-pyridine-TFA; b)Et3N
Scheme 2. Proposed elimination mechanisms.
cleosides 4c–e in excellent yields of 82%, 87%, and 72%, respectively
(Scheme 1).
isolated as the only nucleoside product. Since both 20-O-acetyl
and 20-O-benzoyl groups would be stable under the nearly aprotic
conditions of the oxidation–elimination reaction, the plausibility
of the reaction mechanism originally proposed by Zhang19 was
confirmed unambiguously.
The isolated 30,40-didehydro-50-aldehydes 3a–d were reduced
into the corresponding 30,40-didehydro-nucleosides 4a–d in high
yields (76–94%; Scheme 1) by treatment with NaBH4 in ice-cold
DMF, containing a five-molar excess of methanol with respect to
the aldehyde. Under these conditions, the N-acyl protecting groups
on the nucleobase were stable. Their subsequent removal using an
8 M ethanolic solution of methylamine provided 30,40-didehydro-
nucleosides 4f–h (Scheme 1) in high yields (85–93%).
In conclusion, we have found that 20,30-O-orthoester derivatives
of ribonucleoside-50-aldehydes undergo base-catalyzed elimina-
tion of the orthoester moiety resulting in a quantitative yield of
30-deoxy-30,40-didehydronucleoside-50-aldehydes. The 50-aldehyde
group can be smoothly and rapidly reduced to give 30-deoxy-
30,40-didehydronucleosides using NaBH4 in DMF with a limited
amount of methanol, without the loss of N-acyl protecting groups.
Moreover, the 30-deoxy-30,40-didehydronucleoside-50-aldehydes
themselves represent useful and challenging synthons, offering a
wide range of chemical transformations either on the 50-aldehyde
group (e.g., Wittig reactions and nucleophilic additions22,23) or on
the vinyl ether type double bond (electrophilic reactions providing
a variety of C40-branched nucleoside derivatives9,15,18). Further
study is underway.
Considering the elimination mechanism, Zhang et al.19
explained the observed minor formation of a 30-deoxy-30,40-dide-
hydroadenosine derivative during the Wittig reaction of 20,30-O-
ethoxymethylideneadenosine-50-aldehyde via orthoester moiety
elimination, enabled by the increased acidity of H40 resulting
from the presence of a neighboring 50-aldehyde group. Deproto-
nation of H40 by the action of a base triggers elimination of the
orthoester moiety upon cleavage of the C30–O30 linkage and
formation of the 30,40-double bond to give 30-deoxy-30,40-didehy-
dronucleoside 3 possessing a free 20-hydroxy group (Scheme 2,
red arrows). However, another mechanism involving the forma-
tion of 20-O-acylnucleoside 6 and an alcohol (Scheme 2, blue ar-
rows) can also be considered since, in the case of 20,30-O-
alkoxymethylidenenucleoside 1, the formed labile 20-O-formyl
derivative 6a would be prone to rapid deformylation during iso-
lation. In order to decide which mechanism is likely, we subjected
20,30-O-1-ethoxyethylideneuridine (5a) and 20,30-O-ethoxybenzy-
lideneuridine (5b) to the oxidation–elimination reaction and care-
fully analyzed the products. No formation of 20-O-acetyl 6b and
20-O-benzoyl 6c derivatives, respectively, was observed (Scheme
2) and compound 3a possessing a free 20-hydroxy group was
Acknowledgments
Support by the Grant 203/09/0820 (Czech Science Foundation)
and Research Centers KAN200520801 (Acad. Sci. CR) and
LC06077 (Ministry of Education, CR), under the Institute research
project Z40550506, is gratefully acknowledged. The authors are in-
ˇ
ˇ
debted to Dr. Zdenek Tocík for valuable discussions, Eva Zborní-
ková, MSc. for excellent technical assistance, the staff of the Mass
ˇ
Spectrometry Group of IOCB AS CR, v.v.i. (Dr Josef Cvacka, Head)
for HR-MS spectra, and Dr. Pavel Fiedler for measurement and
interpretation of IR spectra.

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Chemical Society, New York, NY, Sept 1969, CARB 16.
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