Nucleic Acids in Chemistry and Biology

purine, which can be converted into adenine or guanine as a result of metabolic deamination or hydroxy-
lation (i.e.prodrugs, Section 3.7). The mode of action of acyclovir in Herpes Simplex Virus (HSV)-
infected cells involves its specific phosphorylation by the thymidine kinase expressed by the virus. This is
followed by further phosphorylation by cellular kinases to afford the triphosphate, which is a selective and
potent inhibitor of the HSV DNA polymerase. In principle, four sections of the sugar ring can be ‘cut
away’ and promising biological results have been found in three of these areas. Formally, one can excise
(1) C-2, (2) C-3, (3) C-2C-3, or (4) O-4C-4C-5as shown in Figure 3.25. The syntheses of all
of these types of acyclonucleoside are invariably based on N-9 alkylation of a chloropurine precursor, with
subsequent amination and manipulation of the necessary protecting groups. Alkylation of the silylated
chloropurine in the presence of mercury(II) cyanide normally gives excellent yields of the desired N-9
regioisomer^58 (Figure 3.25). Seco-carbocyclic nucleosides have also been found to have useful antiviral
activity. One example is penciclovir, N-9-(4-hydroxy-3-hydroxymethylbutyl)guanine.

3.1.4 Syntheses of Base and Sugar-Modified Nucleosides

A vast number of nucleosides bearing modified bases or sugars have been made. Many display significant
biological activity, while others have been used for applications in molecular biology, such as nucleic acid
sequencing and labelling and investigations of nucleic-acid structure and protein–nucleic acid inter-
actions. However, the majority of these involve modification to the heterocyclic base or modification to the
C-2and/or C-3positions of the sugar. The following is a selective overview of the chemical syntheses of
pentofuranosyl nucleosides either modified at C-2or C-3or on the heterocyclic base. By contrast, modi-
fications at the 5-position of the nucleoside do not involve stereochemical control. Many transformations
typical for chemical modification of primary hydroxyl groups have been used on nucleosides, e.g., dis-
placement of a tosylate, halogenation in the presence of triphenylphosphine or the Mitsunobu reaction.

3.1.4.1 Modified Bases. The halogenationof pyrimidine nucleosides at C-5^59 and purine nucleo-

sides at C-8^60 is known for all four halogens, although the 5-iodopyrimidine and 8-bromopurine analogues
have been most widely used for subsequent functionalization at these positions of the nucleobases. The
nucleoside bases 5-iodocytosine and 5-iodouracil can be readily transformed into other 5-substituted
analogues by use of palladium chemistry; while nucleophilic displacement of bromine or the palladium-
catalysed modification at the 8-position of purine nucleosides gives a variety of 8-substituted analogues.^48
Uridine and cytidine and their analogues can be halogenated using bromine water or iodine in aqueous
acid/chloroform. These reactions appear to involve a 5-halogeno-6-hydroxy-5,6-dihydropyrimidine
adduct (Figure 3.26), which is subsequently dehydrated to give the 5-substituted nucleoside. For 2,3-
isopropylidine-protected ribonucleosides, there is some evidence that an analogous intermediate is formed

92 Chapter 3

O

O

OH

OH

OBz

O

O

TBDPSO

OH

OH

O

O

HO N

N

NH 2

O

N

N

NH 2

O

F

O

S

HO

O

O

TBDPSO

COOH

O

O

TBDPSO

OAc

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

(iv)

(v)

L-2',3'-dideoxy-3'-

D- 2',3'-dideoxy-3'-oxacytidine thia-5-fluorocytidine

Figure 3.24 Synthesis of D-2,3-dideoxy-3-oxacytidine from 4-O-benzoyl-1,6-anhydro-D-mannose (upper) and structure
of L-2,3-dideoxy-3-thia-5-fluorocytidine (lower right). Reagents: (i) NaIO 4 ; (ii) NaBH 4 ; (iii) TBDPSCl,
pyridine; (iv) Pb(OAc) 4 ; and (v) silylated N^4 -acetylcytosine, TMS triflate, 1,2-dichloroethane

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