Biomedical Engineering Reference
In-Depth Information
OTIPS
F2,3
OTIPS
F2,3
OH
OTIPS
F0,1
OTIPS
F0,1
1. [Ph
3
PCuH]
6
(71%)
2. LiAl(O
t
-Bu)H
-5 to 20°C
(88%)
O
M-
80
Ba(OH)
2
+
TrO
TrO
80%
M-
83
TMS
TMS
M-
84
M-
85
FmocO
O
P
FmocO
OTIPS
F0
TIPS
F2
O
O
steps
76a
86a
O
e
FmocO
O
P
TIPS
F3
O
OTIPS
F1
FmocO
O
steps
76b
FmocO
O
86b
P
O
OMe
FmocO
TIPS
F2,3
O
OTIPS
F0,1
O
F-HPLC
demix
steps
FmocO
O
P
TIPS
F3
O
OTIPS
F0
FmocO
O
steps
76c
O
OMe
M-
86
86c
O
e
FmocO
O
P
TIPS
F3
O
OTIPS
F1
FmocO
O
steps
76d
86d
O
OMe
SCHEME 10.20
Synthesis of four stereoisomers of cytostatin
76a-76d
.
pairs of quasi-racemic mixtures of M-
86
each has a different fluorine tag, they were
demixed by the tag-based fluorous HPLC to afford 4 separated fluorous compounds
86a
,
86b
,
86c
, and
86d
. Each of these four separated compounds underwent further
transformations followed by fluorous linker cleavage to give four stereoisomers
76a
,
76b
,
76c
, and
76d
. After TLC analysis and
1
H
NMR comparison of the four
compounds with the natural sample, it was concluded that compound
76a
had the
same configuration of cytostatin and thus confirmed the original structure character-
ization. This work demonstrated the power of FMS for making natural stereoisomers
for structure determination. Since the preparation of four stereoisomers was carried out
in a one-pot fashion, significant efforts were saved in the multistep synthesis.
Natural resorcylic acid lactones (RAL) such as radicicol A, L-783277, and
LL-Z1640-2 are known to be potent and irreversible kinase inhibitors (Figure 10.3)
[56]. For QSAR studies, Winssinger and coworkers developed an FMS method based
on the previously reported fluorous total synthesis of radicicol A [57] and synthesized
a compound library containing 51 analogues [58]. In the FMS, each of three propargyl
O
O
O
OH
OH
OH
O
O
O
OH
OH
OH
MeO
O
MeO
O
MeO
O
OMe
OH
OMe
OH
OH
LL-Z1640-2
FIGURE 10.3
Structures of radicicol A, L-783277 and LL-Z1640-2.
Radicicol A
L-783277
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