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AcO
NHBz
AcO
O
OH
NHBz
O
O
O
OR
Ph
O
R
OR
Ph
O
OH
OH
HO
O
HO
BzO
O
AcO
BzO
AcO
80a
R=Ac
80b
R=H
80c
R=Cl
80d
R=Br
81a
R=H
81b
R=SO
81c
R=SO
2
AcO
NHBz
O
O
OH
Ph
O
R
OH
HO
O
BzO
AcO
82a
R=N
3
82b
R=NH
2
3.2.4.2 C-6 Substitutions
6a-OH paclitaxel 80a, the major metabolite of paclitaxel in human that has been known
to be less cytotoxic than paclitaxel (both 6-hydroxylation and 3
0
-p-phenyl-hydroxylation
were detected in mice, whereas 6a-hydroxylation predominated in humans), can
be prepared via epimerization of 6a-OH-7-epi-paclitaxel 81a.
123,124
Taxoid 81a,
which was prepared via dihydroxylation of
6,7
taxane, was slightly less active
than paclitaxel. 6a-F, Cl, and Br paclitaxels 80b-d were designed and prepared as
the metabolic site blocked analogs, but they could not alter their in vitro and in
vivo efficacies significantly.
125
6a-Hydroxy-7-epi-paclitaxel 6,7-O,O
0
-cyclosulfite
81b and 6,7-O,O
0
-cyclosulfate 81c were obtained from 81a,and6b-azido- (82a) and
6b-amino-7-epi-paclitaxel (82b) were also prepared from the same intermediate.
Taxoid 82a was two to three times more cytotoxic than paclitaxel, but 82b and
81b were less active, and 81c was essentially inactive.
126
Synthesis of 7-deoxy-6a-hydroxypaclitaxel was realized through the regiospeci-
fic reduction of 6,7-a-thiocarbonate 83 as the key step. 2
0
-TES-7-deoxy-6a-hydro-
AcO
AcO
NHBz
O
Bz
O
S
O
O
NH
O
Ph
O
O
Ph
O
R
OH
OTES
HO
HO
H
O
O
BzO
BzO
AcO
AcO
83
84a
R=
α−
OH
84b
R=
β−
OH
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