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O
BocHN
O
(1) DIBAL-H/HMPA, 0
o
C
(1) LiOH
O
(2) DCC/DMAP/
7,10-diTroc-10-DAB
(2)
Ph
O
Ph
NBoc
Ph
Ph
90% (de 86%)
TrocO
HO
BocHN
O
BocHN
O
O
O
OTroc
OH
(1) Me
3
NO/OsO
4
Ph
O
Ph
O
(2) Separation
(3) Zn-Cu/AcOH
OH
OH
HO
H
HO
H
O
O
AcO
AcO
BzO
BzO
7a
2'(R)-OH
7b
2'(S)-OH
Scheme 3-3. Preparation of 2
0
-hydroxymethyl doctaxel.
as well as C-2 meta-substituted benzoyl groups
23
that had been recognized to
enhance the in vitro activity of paclitaxel analogs, some promising taxoids were
prepared. Additional modification on the C-3
0
alkenyl group (isobutenyl), that is,
preparation of taxoids bearing 3
0
-cyclopropane and 3
0
-epoxide moieties, is also
encouraging.
24
The cyclopropantion of isobutenyl-substitued lactams occurred
stereospecifically, and epoxidation occurred in a highly stereoselective manner to
furnish the lactams ready for C-13 side-chain incorporation. Two 3
0
-cyclopropane
8a-b and one 3
0
(R)-epoxide taxanes 9a, all with IC
50
less than 1 nM, are among the
most potent analogs in this series. Although 10 to 30 times less active than 9a, the
cytotoxicity of 3
0
(S)-epoxide 9b is still comparable with that of paclitaxel.
O
O
R
O
Boc
O
O
Boc
NH
O
OH
O
NH
O
OH
O
O
OH
O
OH
HO
H
O
BzO
HO
H
AcO
O
BzO
AcO
8a
R=Et
8b
R=cyclopropane
9a
(R)-epoxide
9b
(S)-epoxide
Recently, Ojima et al.
25-27
described the synthesis of some taxanes with C-13
fluorine-substituted isoserine side chains. In pharmaceutical practices, the fluorine
atom is usually introduced as an isosteric atom of the hydrogen atom, but it showed
higher or sometimes unique activity against its hydrogen-containing counterparts.
Flourine also blocks the metabolism of the parent molecule, which led to the
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