A general route to D- and L-six-membered nucleoside analogues

Article abstract of DOI:10.1080/15257770701508166

A simple synthetic route for novel L-(as well as D-) six-membered nucleosides is described. Particularly, we have provided a general approach to the synthesis of azasugar-based nucleosides, which preparation has been easily achieved starting from the coup

Full text of DOI:10.1080/15257770701508166

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A General Route to D- and L-Six-
Membered Nucleoside Analogues
a
a
a
Annalisa Guaragna , Daniele D'Alonzo , Mauro De Nisco , Silvana
a
a
Pedatella & Giovanni Palumbo
a
Dipartimento di Chimica Organica e Biochimica , Università di
Napoli Federico II , Napoli, Italy
Published online: 10 Dec 2007.
To cite this article: Annalisa Guaragna , Daniele D'Alonzo , Mauro De Nisco , Silvana Pedatella
&
Giovanni Palumbo (2007) A General Route to D- and L-Six-Membered Nucleoside Analogues,
Nucleosides, Nucleotides and Nucleic Acids, 26:8-9, 959-962, DOI: 10.1080/15257770701508166
To link to this article: http://dx.doi.org/10.1080/15257770701508166
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Nucleosides, Nucleotides, and Nucleic Acids, 26:959–962, 2007
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701508166
A GENERAL ROUTE TO
ANALOGUES
D
- AND -SIX-MEMBERED NUCLEOSIDE
L
Annalisa Guaragna, Daniele D’Alonzo, Mauro De Nisco, Silvana Pedatella,
and Giovanni Palumbo Dipartimento di Chimica Organica e Biochimica,
Universit a` di Napoli Federico II, Napoli, Italy
2
2
A simple synthetic route for novel L- (as well as D-) six-membered nucleosides is described. Partic-
ularly, we have provided a general approach to the synthesis of azasugar-based nucleosides, which
preparation has been easily achieved starting from the coupling of our three carbon homologating
agent 1 with the well known Garner aldehyde 4. Further suitable and stereocontrolled functional-
izations of the intermediate 9 will provide, after the base insertion, a wide class of six membered
modified azanucleosides to be tested as NRTIs.
Keywords azasugar-based nucleosides; six-membered modified azanucleosides.
In the search for effective, selective and nontoxic antiviral agents, a vari-
ety of strategies have been devised to design nucleoside analogues. These
strategies have involved several formal modifications of the naturally oc-
[
1]
curring nucleosides, especially alterations of the carbohydrate moiety.
Modifications[ have concerned, for instance, the inversion of hydroxyl
group configurations, their elimination leading to bioactive dideoxy- or
didehydro-nucleosides (e.g., ddC and d4T, respectively) or the replace-
ment of the endocyclic oxygen of the sugar moiety with an heteroatom
2]
(
3TC). In addition, since the discovery of Lamivudine (3TC, β-
deoxy-3-thiacytidine) as potent inhibitor of reverse transcriptase (NRTI),
-nucleoside enantiomers have been re-evaluated as an emerging class of
L
-(-)-2-
L
antiviral agents[ and a great deal of efforts have been focused towards the
3]
synthesis of new -sugar-based nucleoside analogues as potential NRTIs. As
L
[4]
part of our current interest in polyhydroxylated compounds, we designed
and set up a new general approach to the synthesis of azasugar based nu-
cleoside analogues, as well as hexopyranosyl nucleosides, belonging to both
D
- or -series.
L
Address correspondence to Annalisa Guaragna, Dipartimento di Chimica Organica e Biochimica,
Universit a` di Napoli Federico II, Via Cynthia, 4 I-80126 Napoli, Italy. E-mail: guaragna@unina.it.
9
59

9
60
A. Guaragna et al.
SCHEME 1 Retrosynthetic path for L-six-membered nucleoside analogues.
As depicted in Scheme 1,
starting from our three-carbon homologating agent 1 and chiral elec-
L
-nucleoside analogues easily can be prepared
[5]
trophiles such as 2,3-O-isopropylidene-L-glyceraldehyde, Garner aldehyde,
as well as (R)-benzyl glycidyl ether.
The current strategy comprises the following major steps: (i) prepara-
tion of 2 by three-carbon homologation; (ii) synthesis of the 2,3-unsaturated
six-membered ring 3 by carbon skeleton cyclization; (iii) suitable double
bond functionalization and base insertion.
Obviously, it would be possible to synthesize -analogues simply by re-
D
placing the chiral electrophiles with their enantiomers.
In this preliminary communication, the synthesis of azanucleosides by a
noncarbohydrate based route is reported.
The synthesis began with the coupling of 1, prepared in a few steps from
methyl pyruvate,[ with Garner aldehyde 4 (Scheme 2). Under our con-
5]
[6]
ditions, a solution of 4 and a catalytic amount of Ti(O-i-Pr) in THF was
4
added at low temperature to the in situ prepared C-3 lithiated carbanion
of 1, providing an anti/syn (6:4 dr) diastereomeric mixture of alcohols 5
in 83% yield. After mixture separation by SiO flash chromatography, the
2
more abundant anti-5 diastereoisomer was chosen as a model to test the
whole synthetic path. Acetylation of the secondary hydroxyl function, using
Ac O in Py, afforded 6 in almost quantitative yield.
2
4
-Methoxybenzyl protecting group removal was next attempted
(
Scheme 2) by treating 6 with DDQ (1.2 eq.) in CH Cl /H O (18:1).
2
2
2
[5]
As we have previously described with similar substrates, such removal
SCHEME 2 Homologation reaction and MPM group removal.

D- and L- Six-Membered Nucleoside Analogues
961
conditions led quantitatively to the formation of a formyl function rather
than the expected primary alcohol. Then, treatment of the aldehyde 7 in
the presence of acidic Amberlyst in methanol allowed, in a one-pot simple
procedure, the cleavage of the oxazolidine ring and the cyclization to afford
the unstable bicyclic compound 8 (Scheme 3). After the acetylation of the
crude residue, an α:β diastereomeric mixture of 9 (85:15 dr) was obtained
in 97% overall yield. The key intermediate 9 was then coupled with the hete-
[7]
rocyclic bases, under standard conditions, to afford nucleoside derivatives
1
0 (β:α = 90:10). Diastereomeric ratio of the O-methyl glycoside 9 and of
1
the nucleoside 10 has been determined by HNMR analysis.
As reported in Scheme 3, the versatility of 9 allows the preparation of
unsaturated and saturated azanucleosides 13 and 14. Indeed, compatibly
with each substrate, desulfurization will be performed prior or after the
◦
base insertion by means of Raney-Ni (1:10 w/w) in THF at 0 C, or using a
large excess of Raney-Ni in order to obtain the over-reduction product. Suit-
able functionalizations at C-2/C-3 positions, carried out on the compound
1
3, will fulfil the wide class of six-membered azanucleosides to be tested as
NRTIs.
Works are still in progress concerning the synthesis of
L
-pyranosyl nu-
cleosides, through the employment of different electrophiles (as shown in
the retrosynthetic path), by means of a similar synthetic route to that so far
described.
SCHEME 3 Carbon skeleton cyclization and base insertion.

9
62
A. Guaragna et al.
In summary, a versatile and profitable approach to the synthesis of -
L
azapyranosyl nucleosides has been opened up. The versatility of such a
method lies in producing intermediates bearing a double bond at C-2/
C-3 positions (like 11), which can be properly functionalized (or completely
reduced) to afford a wide class of target molecules.
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