Solid phase synthesis of nucleobase and ribose modified inosine nucleoside analogues

Article abstract of DOI:10.1080/15257770701506608

The synthesis and the use of new N-1-dinitrophenyl-inosine based solid support is reported. The support, which binds the nucleoside by a 5′-O-monomethoxytrityl function, reacting with N-nucleophiles allowed the synthesis of a small library of N-1 alkylated inosine and AICAR derivatives. Moreover, the obtained supports, after the cleavage of the 2′ -3′ ribose bond, furnished a set of new N-1 alkylated-2′ -3′ -secoinosine derivatives in high yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770701506608

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Nucleosides, Nucleotides and Nucleic
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Solid Phase Synthesis of Nucleobase
and Ribose Modified Inosine Nucleoside
Analogues
Giorgia Oliviero a , Jussara Amato a , Stefano D'Errico a , Nicola
Borbone a , Gennaro Piccialli a & Luciano Mayol a
a Dipartimento di Chimica delle Sostanze Naturali , Università di
Napoli Federico II , Napoli, Italy
Published online: 05 Dec 2007.
To cite this article: Giorgia Oliviero , Jussara Amato , Stefano D'Errico , Nicola Borbone , Gennaro
Piccialli & Luciano Mayol (2007) Solid Phase Synthesis of Nucleobase and Ribose Modified Inosine
Nucleoside Analogues, Nucleosides, Nucleotides and Nucleic Acids, 26:10-12, 1649-1652, DOI:
10.1080/15257770701506608
To link to this article: http://dx.doi.org/10.1080/15257770701506608
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Nucleosides, Nucleotides, and Nucleic Acids, 26:1649–1652, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701506608
SOLID PHASE SYNTHESIS OF NUCLEOBASE AND RIBOSE MODIFIED
INOSINE NUCLEOSIDE ANALOGUES
Giorgia Oliviero, Jussara Amato, Stefano D’Errico, Nicola Borbone,
Gennaro Piccialli, and Luciano Mayol
Dipartimento di Chimica delle Sostanze
2
Naturali, Universita` di Napoli Federico II, Napoli, Italy
The synthesis and the use of new N-1-dinitꢁrophenyl-inosine based solid support is reported.
2
The support, which binds the nucleoside by a 5 -O-monomethoxytrityl function, reacting with N-
nucleophiles allowed the synthesis of a small library of N-1 alkylated inosine and AICAR deriva-
tives. Moreover, the obtained supports, after the cleavage of the 2 ꢁ-3 ꢁ ribose bond, furnished a set of
new N-1 alkylated-2 ꢁ-3 ꢁ-secoinosine derivatives in high yields.
Keywords N-1-Dinitrophenyl-inosine based solid support; N-nucleophiles;
2ꢁ-3ꢁ-seconucleosides
Nucleosides are biomolecules possessing a pivotal role in the metabolism.
In fact, they are involved, as tri-phosphate derivatives, in the nucleic acid
replications and in a very wide number of interactions with enzymes, struc-
tural proteins, and nucleic acids. Furthermore, nucleosides are involved
with a broad array of biological targets of therapeutic importance and a
number of their derivatives exhibit antineoplastic,[1] antibiotic,[2] and an-
tiviral properties.[3] A variety of solid phase combinatorial strategies have
been reported for the preparation of nucleoside and small oligonucleotide
analogues libraries.[4] In an effort to enlarge the nucleoside chemical reac-
tivity on the solid phase, and, thus, the number of accessible structurally
diverse analogues, we report here the new acid labile nucleoside func-
tionalized support 2, which binds the N-1-dinitrophenyl-inosine derivative
1 through the 5ꢁ-O-ribose position. These support has been employed in
the solid phase synthesis of N-1 substituted inosine 4a-e, the related 2ꢁ-,3ꢁ-
seconucleoside derivatives 6a–e and the 5-aminoimidazole-4-carboxamide
riboside (AICAR) 8. The solid phase strategy is based on our previous stud-
ies on the C-2 reactivity of N-1-dinitrophenyl-2ꢁ-deoxyinosine towards N-
nucleophiles[5,6] to obtain N-1 substituted inosine and AICAR derivatives.
Address correspondence to Giorgia Oliviero, Dipartimento di Chimica delle Sostanze Naturali,
Universita` di Napoli Federico II, via D. Montesano 49, Napoli I-80131, Italy. E-mail: golivier@unina.it
1649

1650
G. Oliviero et al.
SCHEME 1 i) 2 or 3 (1.5 eq.) in pyridine (1.5 mL/250 mg of resin), DMAP (0.2 eq.), 24 hours r.t;
ii: R1-NH2/DMF (38.0 eq), 8 hours 50◦C; iii) TFA 2% solution in DCM; iv: EDA/DMF (1:1, w/w) 8
hours 50◦C; v: NaIO4 (10 eq.) in DMF/H2O (1:1,v/v), 12 hours, 60◦C; resin washings and treatment
with NaBH4 (20 eq.) in EtOH, 2 hours, r.t.
The reported reaction mechanism indicates that when a strong electron-
withdrawing group (such as the 2,4-dinitrophenyl or the nitro group[7]) is
attached to the N-1 atom of the hypoxanthine ring, the C-2 carbon become
electrophilic enough to react with amino nucleophiles (R1-NH2) leading to
R1-N-1 substituted inosine derivatives by a fast opening and re-closure of the
six terms purine cycle.
Support 2 was obtained by reaction of the commercially avail-
able polystyrenemonomethoxytrityl chloride (MMTCl) with the 1-(2,4-
dinitrophenyl)-inosine[8] 1 (Scheme 1). The structure and the loading of
1
the support 2 (1.2–1.3 meq/g) was confirmed analyzing, by H NMR and
quantitative UV experiments, the released inosine 1 by treatment with 2%
TFA in DCM. The reaction of support 2 (100 mg, 0.13 mmol) with N-
nucleophiles (5.0 mmol, R1-NH2, Table 1 entry a–e) in DMF (8 hours, at
50◦C) gave supports 3a–e. The reaction of 2 with ethylenediamine (Table 1,
entry f) furnished, as expected,[9] the support 7 bearing AICAR in almost
quantitative yields. The structures of the supports 3a–e and 7 were ascer-
tained by HPLC, 1H NMR, and MS analyses of the corresponding detached

1651

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G. Oliviero et al.
1
crude materials 4a–e and 8. The product yields and the H NMR selected
data are reported in Table 1. The second goal of this work was aimed to
combining the set of the N-1 alkylations of the supports 3a–e with the 2ꢁ-
3ꢁ-oxidative cleavage of the ribose to obtain the related 2ꢁ-3ꢁ-seconucleoside
derivatives.[10] In a typical reaction the support 3a–e (100 mg) was left in
contact with a solution of NaIO4 (1.3 mmol) in DMF/H2O (1:1,v/v) and
shaken for 12 hours at 60◦C. The resulting support was treated with NaBH4
(2.6 mmol) in EtOH and shaken for 2.0 hours at room temperature. Af-
ter washings, the resins 5a–e were analyzed by detachment of the nucle-
osidic material by TFA treatment. HPLC analyses indicated that the 2ꢁ-3ꢁ-
secoinosine derivatives 6a–e were obtained in 75–85% yields. The structures
of 6a–e were confirmed by 1H NMR (Table 1) and MS analyses.
In conclusion, we have reported the synthesis of the new N-1-
dinitrophenyl-inosine based solid support 2, which allowed the synthesis of
small libraries of N-1 alkylated inosine derivatives 4a–e and N-1 alkylated 2ꢁ-
3ꢁ-secoinosine derivatives 6a–e in good yields. Further studies are currently
in progress in this direction to obtain new series of modified nucleoside
analogues.
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