Nucleic Acids in Chemistry and Biology

Aristeromycin was first prepared in racemic form by Shealy and Clayson in 1966 and its laevorotatory
enantiomer was discovered 2 years later as a metabolite of Streptomyces citricolour, now named aris-
teromycin. New concepts of carbocyclic nucleosides emerged in 1981 with the isolation of neplanocin A
from Ampullariella regularis(Figure 3.20).
Many syntheses use the key ‘carbocyclic ribofuranosylamine’ which is made from cyclopentadiene in
five steps and then built into pyrimidine or purine carbocyclic nucleosides by standard methods.^55 The
adaptation of this route for the introduction of a fluorine atom into the 6-position (which may mimic an
oxygen lone pair of electrons in binding to a receptor) presents a good example of the development of such
syntheses to highly modified sugars (Figure 3.20).
The use of Pd(0)-catalysed allylic substitution chemistry developed by Tsuji and Trost^48 using activated
cyclopentenes has been widely employed in the syntheses of carbocyclic nucleosides (Figure 3.21). The
resolution of the two enantiomers of the readily accessible lactone, as shown in Figure 3.22, allows an
efficient route to carbocyclic nucleosides. The reactions proceed through the formation of a cationic
3 -allylpalladium(II) complex that undergoes nucleophilic attack by the nucleobase at the least hindered
site. The formation of regioisomers in these reactions, particularly with purines, is common.
The Mitsunobu reaction has also been used for the synthesis of several carbocyclic nucleosides. An
example of its use in a synthesis of neplanocin A^56 is shown in Figure 3.23.

3.1.2.3 Dioxolane and Oxathiolane Nucleosides. A recent development has been the introduction

of a second heteroatom into the ‘sugar’ ring. For example, 2,3-dioxolane nucleosides have been made and
found to have useful anti-HIV activity. The preparation of 2,3-dideoxy-3-oxacytidine by Chu is a good
example of stereospecific control in such syntheses (Figure 3.24). Liotta^57 has synthesised the racemic 1,3-
oxathiolane analogue of 5-fluorodeoxycytidine and separated the enantiomers by the action of pig liver
esterase on their 5-butyroyl derivatives. Unexpectedly, he found that it is the unnatural L-()-isomer,
which has both higher anti-viral activity and lower toxicity than the D-()-enantiomer (Figure 3.24).

3.1.3 Synthesis of Acyclonucleosides

The success of acyclovirfor the treatment of genital herpes infections has stimulated much work in this
area. In these acyclonucleosides (or seco-nucleosides) the base is usually adenine, guanine or a related

90 Chapter 3

HO

HO OH

N

N

N

N

NH 2

HH

HO

HO

N

NH

O

O

R

OH

HO

HO OH

N

N

N

N

NH 2

HO NH 2

OO

HO

HO

HO

HO

O

HO

HO

N 3

XY HO

HO

XY

N

NH

O

O

R

HO

N

N

N

N

NH 2

aristeromycin neplanocin A

(±)

carbovir

Figure 3.20 Structures of aristeromycin and neplanocin A (upper). Synthesis of carbocyclic analogues of deoxy- and
ribo-uridine (RH) and thymidine (RMe) where X and/or Y are H or F (lower)

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