Nucleic Acids in Chemistry and Biology

face to give the natural
-anomer (Baker’s 1,2-trans-rule). While the formation of the acyloxonium inter-
mediate ensures good stereocontrol in the syntheses of ribonucleosides, since the halides of 2-deoxyribo-
sugars cannot form an acyloxonium ion, mixtures of - and
-nucleosides result.
This method gives good
-stereochemical control for ribo- and xylo-nucleosides by using peracylated
ribose and xylose derivatives; while arabinose and lyxose sugars with a 2-acyloxy substituent will give
-anomers. In cases where a hydroxyl group at C-2 is protected as a benzyl ether or by an isopropylidene
or carbonate group cyclized onto the adjacent 3-hydroxyl group, the neighbouring group participation is
not possible and mixtures of anomers are formed. Similarly for nucleosides with modified sugars such as
2-deoxy-2-fluoro- or 2-deoxy-2-azido-D-ribofuranose there is no anomeric control. The ability to control
the anomeric stereochemistry in the syntheses of ribonucleosides bearing modified bases has led to the
development of a number of methods for the preparation of 2-deoxyribonucleosides by 2 -deoxygenation,
subsequent to the glycosylation step. The most widely used method involves Barton reduction of a 2-thio-
carbonate40,41as shown in Figure 3.11. This scheme also illustrates the use of the bifunctional silylating
agent 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane, the Markiewicz reagent, which can be used for simul-
taneous protection of both the 3- and 5-hydroxyl groups of ribonucleosides. The direct synthesis of
2 -deoxyribonucleosides with good stereocontrol generally involves reaction of a purine anion or silylated
pyrimidine base with an -chlorosugar under carefully chosen conditions (see Sections 3.1.1.4 and 3.1.1.8).

3.1.1.8 Nucleobase Anions. The reaction of the anion of a purine with 2-deoxy-3,5-di-O-(4-toluoyl)-

D-ribofuranosyl chloride (‘chlorosugar’) proceeds rapidly in acetonitrile viaan SN2 process. Useful
reviews of this subject have been published.42–44In procedures developed by Seela, the potassium salt of the
nucleobase is used in acetonitrile.^45 The methodology is applicable to the glycosylation of purines and related
deazapurine and azapurine derivatives. In a complementary procedure developed by Robins, sodium hydride
is used to generate the nucleophilic purinyl anion that reacts with the chlorosugar in acetonitrile to afford

Nucleosides and Nucleotides 85

HO O

HO

N

NH

O

O

H 3 C

HO O

N 3

N

N

N

N

NMe 2

81%

HO O

HO

OPO^23

(i) (i)

HO O

HO

N

NH

O

O

HO O

HO

N

N

N

NH 2

79%

HO O

HO

OPO 32

(ii) (ii)

OH OH OH

Figure 3.10 Enzymatic transglycosylation synthesis of nucleosides. Reagents: (i) Thymidine phosphorylase, purine
nucleoside phosphorylase, N^6 -dimethylamino purine; and (ii) uridine phosphorylase, purine nucleo-
side phosphorylase, 4-amino-1H-imidazo[4,5-c]pyridine

O O

O OH

B

Si

Sii-Pr

i-Pr

O

i-Pr

i-Pr

O O

O O

B

Si

Sii-Pr

i-Pr

O

i-Pr

i-Pr

C

S

OPh

HO O

HO OH

B

(i) (ii) (iii), (iv) HO O

HO

B

B = Ura, Cyt, Gua or Ade

Figure 3.11 Conversion of ribonucleosides into 2-deoxyribonucleosides. Reagents: (i) (i-Pr 2 SiCl) 2 O, DMF,
imidazole; (ii) PhOC(S)Cl, DMAP, Et 3 N; (iii) Bu 3 SnH, AIBN; and (iv) TBAF in THF