Nucleic Acids in Chemistry and Biology

3.1.2 Building the Base onto a C-1 Substituent of the Sugar

This approach^49 to nucleoside synthesis has three important features. Historically it was used in Todd’s group
for a regiospecific synthesis of adenosine (Figure 3.16). Later, it became the preferred route for the synthesis
of C-nucleosides and some unusual N-nucleosides. Most recently, it has emerged as the most flexible path-
way for the synthesis of nucleosides with highly modified sugars linked to normal or to modified bases.

3.1.2.1 Nucleosides with Modified Bases. A good example of the use of this route is the synthesis of

the fluorescent base Wyosine, which is found in the anticodon loop of some species of tRNA^50 (Sections 7.2.4
and 7.3.2). In this case, the isocyanate function is the foundation for construction of the tricyclic imidazopurine
base. The same isocyanate precursor has been used in a synthesis of 5-azacytidine (Figure 3.17). This nucleo-
side is elaborated by a Streptomycesspecies and has been used in the treatment of certain leukaemias.
Syntheses of these types based on 1-amino-1-deoxy-
-D-ribofuranose have the general advantage that
the place of attachment of the sugar onto the heterocyclic base is unambiguous and is not determined by

Nucleosides and Nucleotides 87

90%

X = MeS, 68% (29% N-2 isomer)

X = Cl, 61% (26% N-2 isomer)

O

p-TolO

p-TolO

N N

Cl

Cl

O

p-TolO

p-TolO

N

N

N

X

O

p-TolO

p-TolO

N

N

NO 2

78%

p-TolO O

p-TolO

N

N

NN

N

OMe

20% (19% N-2 isomer, 13% N-1 isomer,

10% isomers with α-configuration)

NH 2

Figure 3.14 Purine nucleoside analogues prepared by the nucleobase anion route. Reagents: Purine analogue, KOH,
TDA-1, CH 3 CN then 3,5-di-O-p-toluoyl-b-D-ribofuranosyl chloride

HN

NH

O

O

HO

HO OH

N O

N

OBut

ButO

Li

OO

OO

Ph

Ph

O

R

BrMg R

H 3 C

pTolO O

pTolO

Cl

R

O

pTolO

pTolO

R

H 3 C

+

β-pseudouridine

26%α/β=1:2.3

(i), (ii)

(iii)

R=F,25%β

R=CH 3 , 22%β

+

Figure 3.15 Syntheses of C-nucleosides via carbanion condensations at C-1 of pentose derivatives. Reagents:
(i) THF, 78°C; (ii) mild acid hydrolysis; and (iii) THF,40°C