Nucleic Acids in Chemistry and Biology

Oligonucleotides containing thioguanine have been used widely for studying RNA and DNA–protein
interactions, as the thiocarbonyl group is a weaker hydrogen bond acceptor than a carbonyl group. In add-
ition, the long wavelength absorption of thioguanine (340–350 nm) allows its use as a spectral probe
of conformation, while photoactivation enables the formation of covalent cross-links for studying 3-D
structures.^2

3.1.4.2 Modified Sugars. Ribonucleosides in which the 2-hydroxyl moiety has been replaced by

a fluorine,2,3,72amino2,3or methoxy group2,3,77have been used extensively in the study of the properties
of RNA and ribozymes and within antisense oligonucleotides by Eckstein and Sproat. Synthetic routes
to the former compounds are derived from O^2 ,2-cyclonucleosides (Figure 3.34). Early work in Todd’s
group identified cyclonucleosides as intermediates in the conversion of 5-O-acetyl-2-O-tosyluridine into
2 -deoxy-2-iodouridine using sodium iodide, which gives retention of configuration at C-2. Such
cyclonucleosides(or anhydronucleosides) can be prepared by use of a variety of condensing agents and
are stable, isolable compounds.^78 Jack Fox showed that their reactions with a variety of nucleophiles^8
under anhydrous acidic conditions leads to cleavage of the O^2 -C-2ether linkage and the formation of sub-
stituted nucleosides with the ribose configuration at C-2(Figure 3.34). Hydrolysis under aqueous acidic
conditions provides a route to arabinonucleosides, (C-2 epimer of ribonucleosides) many of which are
biologically active anti-viral compounds. Cyclonucleosides also support the synthesis of 2-azido and 2-
amino analogues (Figure 3.34),^31 while 2-modified-2-deoxyuridines can also be transformed into the
corresponding cytidine analogues via4-triazolo derivatives (Figure 3.31).
Purine nucleosides bearing 2-azido or 3-azido (and amino) substituents can be prepared from
2 -azido-2-deoxyuridineor 3 -azido-2,3-dideoxyuridineusing chemical transglycosylation,31,32while
2 -fluorinated nucleosides have been obtained by fluorination of 3,5- and base-protected ara-G and ara-A
nucleosides using diethylaminosulfur trifluoride (DAST)79,80(Figure 3.35). Cyclonucleoside formation
has also been used for the preparation of 3-modified-2,3-dideoxynucleosides as exemplified by the syn-
thesis of the anti-viral compound AZT(Figure 3.36).^81
2 -Deoxy-2-methoxynucleosides ( 2 -O-methylnucleosides) of uridine and cytidine can be prepared
through alkylation at the 2-hydroxyl group of suitable precursors (Figure 3.37).2,3,77The corresponding
adenosine analogue may be obtained from 2-O-methyluridine by chemical transglycosylation^82 (Figure
3.38). Alkylation of the natural nucleosides at the 2-position requires protection of the reactive lactam
functions on uracil and guanine and the use of 3,5-bis-silylated precursors avoids problems of separating
2-and 3-alkylated products. However, alkylation of the unprotected riboside of 2-amino-6-chloropurine

98 Chapter 3

O

HO

HO

N

N

O

O

HO O

HO X

N

NH

O

O

HO O

HO

OH

N

NH

O

O O

HO

HO N 3

N

NH

O

O O

HO

HO NH 2

N

NH

O

O

O

HO

HO OH

N

NH

O

O

(ii)

(iii) X = F, Cl, I

(iv)

(v)

(i)

Figure 3.34 O^2 ,2-Cyclonucleosides as precursors to 2-modified pyrimidine nucleosides. Reagents: (i) (PhO) 2 CO,
NaHCO 3 , DMF, heat; (ii) HX in dioxan; (iii) Haq; (iv) TMSN 3 , LiF, TMEDA, DMF, heat; and (v) Ph 3 P,
aq NH 4 OH, dioxan

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