142 with the silylated derivative 144 in the presence of Lewis acid leads to
the coupling product 145 with loss of the silyl groups. Separation of the
diastereomers followed by treatment with dilute base affords the reverse
transcriptase inhibitor ( 146 ).^21
Replacement of one of the sugar carbon atoms by sulfur leads to the HIV
reverse transcriptase inhibitoremtricitabine( 151 ). As an additional depar-
ture from the natural nucleoside, this agent features a fluorine atom on the
pyrimidine ring. This compound ( 151 ) can be prepared by a scheme ana-
logous to that used to prepare the des-fluoro predecessor lamivudine. Thus,
reaction of the benzoyl ester of glycolaldehyde ( 147 ) with the dimethyl
actetal thioglycolaldehyde ( 148 ), affords the surrogate sugar ( 149 )ina
single step. This condensation may be viewed as starting with addition
of sulfur to the free carbonyl in aldehyde 148. Displacement of one of
the methoxy acetals by the newly formed hydroxyl closes the ring. That
product is next reacted with the trimethylsylilated cytidine derivative 150
in the presence of a Lewis acid to afford the glycosilated fluorocytosine
151. Separation of diastereomers followed by removal of the benzoate pro-
tecting group affords 151.^22
O
CH=OC 6 H 5 CO
HSOCH 3
OCH 3+
SC 6 H 5 CO O O
OCH 3
149FNHSi(CH 3 ) 3(CH 3 ) 3 SiO
150NNH 2HOFSHO O N151147 148NNMigraine headaches are quite resistant to conventional peripheral or
central analgesics. The discovery of the indole-based triptamine HT1D
antagonists, such as sumatriptan for the first time provided a means for
relieving attacks of this sometimes disabling condition. The discovery of
a structurally unrelated antagonist broadened the SAR for the design of
triptamine HT1Dantagonist. Reaction of the benzopyran acid ( 152 ) with
thionyl chloride leads to the corresponding acid chloride. Hydrogenation
of a solution of that intermediate in thiophene stops at the aldehyde
stage ( 153 ). Reductive amination with benzylamine gives the secondary
amine ( 154 ). Treatment with acrylonitrile leads to conjugate addition and
formation of 155. Exhaustive hydrogenation of that product leads to
reduction of the nitrile to a primary amine and at the same time removes
the benzyl protecting group. Thus, the diamine ( 156 ) is obtained. In one
scheme for adding the terminal heterocycle, the diamine is alkylated
132 SIX-MEMBERED HETEROCYCLES