Nucleic Acids in Chemistry and Biology

The synthetic methodology for the preparation of nucleosides using Lewis acid catalysts, most com-
monly, trimethylsilyl triflate (TMSOTf, Me 3 Si-O-SO 2 CF 3 ), in combination with silylated bases has come
to be known as the Vorbrüggen procedure.21,22It works very well for a large number of nucleoside ana-
logues with modified bases that are difficult to prepare by other methods. The control of stereochemistry
in the ribo-series is due to the formation of an intermediate acyloxonium ion as mentioned earlier (Figure
3.3). Consequently, when the sugar component lacks a 2-acyloxy substituent, glycosylic bond formation
shows reduced stereoselectivity. Regioselectivity depends on the capture of the intermediate oxonium ion
by the most electronegative nitrogen on the base and consequently, a mixture of regioisomers can result.
Under appropriate conditions, the thermodynamically favoured N-9-alkylated purines and N-1-alkylated
pyrimidines can be isolated in good yields.^23 Trimethylsilyl triflate is a weaker Lewis acid than SnCl 4 and
allows generation of the acyloxonium ion of the sugar without the formation of -complexes with the sily-
lated base.^24 These latter species can dramatically increase the amounts of undesired regioisomers such as
N-3-monoalkylated and N-1, N-3 bis-alkylated pyrimidines.
The usual glycosyl component employed in the Vorbrüggen preparation of 2-deoxyribonucleosides,
namely 2-deoxy-3,5-di-O-(4-toluoyl)ribofuranosyl chloride^25 (chlorosugar), can be isolated as the pure,
crystalline -anomer; but it undergoes rapid anomerisation at elevated temperatures, in polar solvents and
in the presence of Lewis acids. However, the reaction of certain silylated pyrimidine bases with the chloro-
sugar in chloroform provides a good compromise between the rate and yield of glycosylation on the one
hand with minimal anomerisationof the sugar component that would otherwise lead to the -nucleoside^26
(Figure 3.8). The addition of CuI can also increase the stereoselectivity by increasing the rate of the nucle-
ophilic substitution.^27 In contrast, pure -nucleoside may be isolated by adding the silylated nucleobase
to a solution of the chlorosugar that has been allowed to anomerise by standing in acetonitrile.^26 While
the silyl base procedure is still widely used for the synthesis of 2-deoxyribonucleosides of pyrimidines,
the reaction of a purinyl anion with the chlorosugar is generally the method of choice for preparing
2 -deoxyribonucleosides of purines (see Section 3.1.1.8).

3.1.1.5 Transglycosylation. It is often relatively easy to convert a natural nucleoside, typically

2 -deoxythymidine, into a nucleoside with a modified sugar residue: for instance the drug 3-azido-2,3-
dideoxythymidine (AZT). However, it can be difficult to achieve the same chemical transformation of
2 -deoxyadenosine into 3-azido-2,3-dideoxyadenosine. In such cases the sugar moiety can be transferred

82 Chapter 3

N

N

OEt

OEt (i) BzO O

BzO OBz

BzO O Cl

BzO OBz

N

N

OEt

OEt O

BzO

BzO OBz

N

N

NH 2

NH 2

(ii)

(iii)

Cl

N

N

OEt

OCH 2 CH 3

Cl

BzO O

BzO OBz

N

N

OEt

O

(iv) (iii)

HO O

HO OH

N

NH

O

O

HO O

HO OH

N

N

NH 2

O

Figure 3.7 The quaternization (Hilbert–Johnson) method of nucleoside synthesis. Reagents: (i) CH 3 CN, 10°C;
(ii) CH 3 CN, reflux; (iii) NH 3 , MeOH; and (iv) NaOH aq

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