Organic Chemistry of Drug Synthesis. Volume 7

The preparation of this agent starts with the fully protected arabinose
derivative ( 121 ). Treatment of 121 with hydrogen bromide leads to
migration of the benzoyl group to the anomeric position adjacent to the
ring oxygen with displacement of the acetate ( 122 ). The free ring hydroxyl
function is then converted to a good leaving group by reaction with sulfuryl
chloride followed by pyrrole to yield 123. Reaction of product 123 with
tetrabutylammonium fluoride leads to displacement of the sulfonamide
fragment by fluorine with inversion of configuration. The anomeric
acetate ( 124 ) is next replaced by bromine by means of hydrogen
bromide. Compound 125 is then allowed to react with silylated thymine
( 126 ); this leads to the glycosylated base 127 with loss of the silyl
groups. Treatment of intermediate 127 with mild base leads to hydrolysis
of the last benzoyl protecting groups. Thus, the antiviral agentclevudine
( 128 ) is obtained.^18
A cytosine derivative with a highly modified sugar showed significant
antitumor activity in a variety of model systems. This activity did not,
however, hold up in the clinic resulting in discontinuation of further clini-
cal trials.^19 Reaction of cytidine ( 129 ) with the bis(chlorotetraisopropyl-
siloxane) ( 130 ) results in reaction with the hydroxyl groups at positions
3 and 5 of the sugar, forming a bridged structure in which the oxygen atoms
at those positions are protected. The difunctional reagent is apparently too
long to form the more common 2,3 cyclic protected derivative. Oxidation
by means of oxalyl chloride in DMF then gives ketone 132. That
function is then condensed with the ylide from the complex phosphonate
133 to afford. The substituted exomethylene derivative ( 134 ). Reaction
of 134 with tributyl tin hydride results in replacement of the phenyl sulfone

HO

HO O N

N

O

NH 2

OH

129

+

SiCl

O

SiCl

O N

N

O

NH 2

OH

O

Si

OSi O

131

O N

N

O

NH 2

O

O

Si

OSi O

132

Swern

CHCH 3 OpCH

3 O F

SO 2 C 6 H 5

O

1. LiN(SiMe 3 ) 2

O N

N

O

NH 2

O

Si

OSi O

134

F

SO 2 C 6 H 5

2.

O Bu 3 SnH

N

N

O

NH 2

O

Si

OSi O

135

F

SnBu 3

KF

O N

N

O

NH 2

HO

HO

F

H

136

130

133

130 SIX-MEMBERED HETEROCYCLES