The concept of inhibiting cell growth by providing false substrates
in fact well predates its application to antiviral agents. The first HIV
reverse transcriptase drug, zidovudine (AZT) was actually first prepared
as a potential anticancer agent. An enzymatic reaction provides a
one-step entry to the antileukemia compound nelarabine ( 94 ). Thus
reaction of 6-methoxyguanine ( 91 ), with uracyl arabinoside ( 92 ) in the
presence of the enzymes uridine phosphorylase and purine nucleotide
phosphorylase in effect transfer the sugar from the pyrimidine to the
purine, yielding 93.^14
N
N NHNOCH 3H 2 N91+HN
NOO
OHO OHHO92Enzymes N
N NNOCH 3H 2 N+HN
NHOO
OHO OHHO9394The antitumor chemotherapy agentclofarabine( 104 ) sports halogen
on the purine as well as on the sugar. The major portion of the synthesis
involves preparation of the requisite fluorine-substituted furanose ( 101 ).
The sequence begins with the conversion of the only free hydroxyl in
allofuranose bis(acetonide) ( 95 ) to its tosylate ( 96 ). This group is then
displaced by fluorine in its reaction with potassium fluoride to afford
( 97 ). Acid hydrolysis then removes the two acetonide protecting groups.
Reaction with benzoyl chloride proceeds to form the benzoate ester
( 98 ) from the most sterically accessible hydroxyl group. Treatment of
98 with periodate cleaves the 2,3 vicinal diol to form a transient inter-
mediate, such as 99. What had been formerly one of the side-chain
hydroxyl groups then forms an acetal with one of the newly revealed alde-
hydes to afford the new furanose ( 100 ) (the product from attack on the
other carbonyl would be a dioxolane, which would reopen under reaction
conditions). Reaction with acetic anhydride converts the anomeric
hydroxyl to its acetate. That group is then replaced by the better
leaving group bromine by means of hydrogen bromide ( 101 ).
Glycosylation of the trimethylsilylated purine ( 102 ) leads to the coupling
product ( 103 ). Ammonia then replaces chlorine at 4 by an amine and at
the same time removes the benzoyl protecting group. Thus, clofarabine
( 104 ) is obtained.^15
200 BICYCLIC FUSED HETEROCYCLES