by tributyl tin ( 135 ). Treatment of 135 with potassium fluoride results in
cleavage of the silicon–oxygen bonds, as well as replacement of tin by
hydrogen. This reaction leads to the antimetabolitetezacitabine( 136 ).^20
Zidovudine, better known as AZT, was the first drug that showed any
activity against HIV. This compound comprises thymidine in which an
azide group replaces hydroxyl on the sugar moiety. The finding that this
agent was effective against HIV set off the search for additional reverse
transcriptase inhibitors in the hope that they would be active against
strains of the virus that had developed resistance to AZT. Replacement
of one of the carbon atoms in the saccharide by another element has
proven a particularly fruitful stratagem. Plentiful ascorbic acid ( 137 ) com-
prises the starting material for an early synthesis fortroxacitabine( 146 ).
Reaction of 137 with the acetal ( 138 ) forms the cyclic acetal ( 139 )from
the two terminal hydroxyls as a mixture of enantiomers. Oxidation with
peroxide cleaves the furenone ring with loss of a carbon atom to afford
the hydroxy acid ( 140 ). Ruthenium trichloride next cleaves off the terminal
carboxyl group to give 141. The two isomers are then separated by flash
chromatography. Oxidation with lead tetraacetate disposes of the final car-
boxyl group with concomitant transfer of an acetate ( 142 ). Catalytic hydro-
genation results in loss of the benzyl protecting group. The thus-revealed
hydroxyl group is acylated to afford the diacetate ( 143 ). Glycosylation
with cytidine involves the by now familiar theme. Thus, reaction of acetate
OO
OH
OH
HOHO137O OCHO
CH 3 OC 6 H 5138OO
OH
O OH
OC 6 H (^5) O
C 6 H 5
139
H 2 O 2 CO^2 H
CO 2 H
HO
O
C 6 H 5 O O
140
RuCl 3
O
C 6 H 5 O O
141
- Separate
2. PbOAc
OCOCH 3
O
O O
142OCOCH 3
O
AcO O
143- H 2
- Ac 2 O
+NNNHSi(CH 3 )OSi(CH 3 ) 3
144N
O
AcO OONH 2- Separate
2. NaOH N
O
HO O
ONH 2145 146- COMPOUNDS WITH TWO HETEROATOMS 131