Nucleic Acids in Chemistry and Biology

transformation has allowed the syntheses of several pyranopyrimidine nucleosides (Figure 3.27d) that
have been shown to display important anti-viral activity, especially against Varicella Zoster Virus (VZV).^68
The related palladium-catalysed Heck reactionhas also been used to prepare C-5 alkenyl analogues of
pyrimidine nucleosides.^48 Initial chemistry developed by Bergstrom^69 used C-5 chloromercuri-derivatised
pyrimidine nucleosides (Figure 3.28). While these derivatives are still employed, the commercially available
and less-toxic C-5-iodopyrimidine nucleosides have been increasingly used (Figure 3.28). In each case the
(E)-, trans-alkene is the major product.
Halogenation at C-8 of purine nucleosides can be achieved by use of acidified bromine water or N-
bromosuccinimide in water, while the other halogens are normally incorporated by use of N-iodosuccinimide,
chlorine or fluorine, respectively.^60 Nucleophilic displacement of the bromide provides convenient access
to 8-substituted purine nucleosides, whilst palladium-catalysed substitution of bromine furnishes a wide
variety of C-8 alkynyl-, alkenyl- and alkyl-substituted analogues (Figure 3.29).44,60

Nucleosides and Nucleotides 95

HO O

HO

N

NH

O

O

I

HO O

HO

N

NH

O

O

R

HO O

HO

N

N

NH 2

O O

HO

HO

N

N

NH 2

O

ClHg

HO O

HO

N

N

NH 2

O

R = CO 2 R' ; CH 2 NH 2 , Br

R' = alkyl, aryl, NCCH 2 CH 2 −, HOCH 2 CH 2 −,

CF 3 CH 2 −, MeOCH 2 CH 2 −

(iii) or (iii),(iv)

(i) (ii)

Figure 3.28 Palladium-catalysed coupling reactions as routes to C-5 alkenyl-substituted pyrimidine nucleosides.
Reagents:(i) Hg(OAc) 2 then NaCl; (ii) Li 2 PdCl 4 , ClCH 2 CH^ CH 2 in MeOH; (iii) Pd(OAc) 2 , Ph 3 P,
Et 3 N, H 2 C^ CH R (for RCH 2 NH 2 , CF 3 CO-protected derivative used in coupling) DMF or dioxan;
and (iv) NH 4 OH for RNH 2 or HO- then N-bromosuccinimide, heat for RBr

HO O

HO

N

NH

N

N

O

NH 2

Br HN NH

N

HO O

HO

N

NH

N

N

O

NH 2

HO O

HO

N

NH

N

N

O

NH 2

Br

HR

HO O

HO

N

NH

N

N

O

NH 2

R

CO 2 Me

O O O(CH 2 ) 9 −

H (CH 2 ) 4 CONH(CH 2 ) 9 −

O NH

HN

H

S

(i)

(ii)

+ R =

Figure 3.29 Syntheses of some C8-substituted purine nucleosides. Reagents: (i) histamine, Et 3 N, H 2 O, heat;
and (ii) (PPh 3 ) 4 Pd, CuI, Et 3 N, DMF