Nucleic Acids in Chemistry and Biology

through nucleophilic addition of the 5-hydroxyl group to C-6. The lower reactivity of iodine and the require-
ment for acidic conditions that might result in some cleavage of the glycosylic bond has led to the use of
alternative iodinating agents such as ICl or N-iodosuccinimide/dibutylsulfide in DMSO. When performed
under anhydrous conditions, halogenation is presumed to proceed by normal electrophilic aromatic substitu-
tion. In a variation of this chemistry, the use of ICl and sodium azide in acetonitrile provides excellent
yields of 5-iodouridine and 5-iodo-2-deoxyuridine. Fluorination of uridine or its analogues can be achieved
in high yield by reaction with trichlorofluoromethane in methanol followed by elimination in the presence
of triethylamine. The mechanism is analogous to that shown in Figure 3.26.
A number of 5-halopyrimidine nucleosides are known to display biological activity (Sections 3.7.1 and
3.7.2). 5-Iodo-2-deoxyuridine shows anti-viral activity, while the most notable of these analogues is
5-fluorouraciland its corresponding 2-deoxyribonucleoside. The active species in vivo, 5-fluoro-2-
deoxyuridine 5-monophosphate, is a potent inhibitor of thymidylate synthase and displays anti-tumour
activity.^19 F- and^18 F-containing species have been used for NMR studies61,62involving nucleic acids and
for radioimaging of tumours,^63 respectively.
The application of palladium-catalysed chemistry to pyrimidine nucleosides^48 has made 5-iodo-2-
deoxyuridine an important precursor for the preparation of C-5 modified 2-deoxyuridine analogues. Sub-
stitution at C-5 produces analogues that can still form Watson–Crick base pairs, while many C-5-substituted
dUTPs are good substrates for DNA polymerase enzymes. The Sonogashira reactionallows coupling of

Nucleosides and Nucleotides 93

HO O

HO X

N

NH

O

O

Br Br

HO O

HO X

N

NH

O

O

HBr

HO

HO O

HO X

N

NH

O

O

HBr

H

HO

HO O

HO X

N

NH

O

O

Br

X = H, OH

(i) (ii)

Figure 3.26 Mechanism of halogenation at C-5 of pyrimidine nucleosides. Reagents: (i) Br 2 , H 2 O; and
(ii) EtOH, heat

N

N NH

N

Cl

Cl

N

N N

N

Cl

AcO O Cl

NH

N N

N

O

HO O NH 2

N

N NH

O

HO O

HO

N NH 2

HO O

HO OH

base

HO O

HO OH

base

HO O

HO OH

base

HO O

HO OH

base

HO

HO

N

N N

N

NH 2

HO O

HO

N

N N

N

NH 2

gancyclovir (DHPG) DHPA penciclovir

(i), (ii) (iii), (iv)

acyclovir

Figure 3.25 Relationship of various acyclonucleosides to natural prototypes, with exciseable parts in red (top),
synthesis of acyclovir and structures of several acyclonucleosides (bottom). Reagents: (i) HMDS,
(NH 4 ) 2 SO 4 ; (ii) 2-(bromomethoxy)ethyl acetate, Hg(CN) 2 , TMSCl; (iii) NaOH; and (iv) NH 3 /MeOH