D. Zanini et R. Roy, NOVEL DENDRITIC ALPHA-SIALOSIDES - SYNTHESIS OF GLYCODENDRIMERS BASEDON A 3,3'-IMINOBIS(PROPYLAMINE) CORE, Journal of organic chemistry, 61(21), 1996, pp. 7348-7354
The cluster or multivalent effect has been recognized as an effective
means by which to increase binding interactions between carbohydrates
and proteins. In fact, it has been demonstrated that sialylated multib
ranched L-lysine dendrimers were potent inhibitors of hemagglutination
of human erythrocytes by Influenza viruses. In a continuation of thes
e studies, the synthesis of novel glycodendrimers with even valencies
from 2 to 16 and ending with equidistant thiosialoside residues is des
cribed. These symmetrical dendrimers were more readily characterized b
y standard NMR spectral techniques than previously reported nonsymmetr
ical dendrimers of this general type. The synthesis of the dendritic c
ore was based on the regioselective protection of the primary amines o
f 3,3'-iminobis(propylamine) (4) using benzyl cyanoformate. The result
ing secondary amine 5 was alkylated with tert-butyl bromoacetate to pr
ovide divalent core structure 6 with Cbz protected amines and acid pro
tected tert-butyl ester. Sequential deprotection by trifluoroacetolysi
s or hydrogenation afforded acid 7 or diamine 8 as key precursors, res
pectively. The two fragments were coupled using HOBt/DIC strategy to p
rovide Cbz-protected dendrimers with valencies of 2, 4, 8, and 16 in t
he first, second, third, and fourth generations, respectively, in reas
onable to good yields (42-82%). Cbz-protected precursors were efficien
tly transformed into N-chloroacetylated dendrimers by hydrogenolysis a
nd treatment of the resulting amines with chloroacetic anhydride (82-9
1%). N-Chloroacetylated dendrimers were then treated with an excess of
2-thiosialic acid derivative 3 to give fully protected sialodendrimer
s in 76-96% yields. Deprotection of sialodendrimers under Zemplen cond
itions followed by methyl ester saponification and purification by gel
permeation chromatography afforded symmetrical dendritic alpha-thiosi
alosides 21, 23, 25, and 27 in fair yields (47-58%). These novel sialo
dendrimers, in keeping with their design, are currently being evaluate
d as inhibitors of human erythrocyte hemagglutination by Influenza vir
uses.