Biomedical Engineering Reference
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synthesis in monitoring intermediate transformations. Fluorous thiol linker allowed
in-process analysis in a solution-phase environment and enabled F-SPE for the
purification of reaction mixtures. A range of post-Pummerer reaction modifications
and linker cleavage methods were thus developed to generate different heterocyclic
frameworks. The post-Pummerer reactions include cycloadditions to cleave the linker
and form spiro- and fused-heterocyclic compounds such as
63
and
64
. Other
modifications such as oxidative reactions to form
65
and 1,2-diketones
66
and
fluorination reactions to form
67
were also achieved.
10.5.
FLUOROUS MIXTURE SYNTHESIS
In fluorous mixture synthesis (FMS), different fluorous linkers attached to starting
materials are mixed together for multistep synthesis. The fluorous linkers hold the
reaction intermediates together as a family and alloweasy separations fromnonfluorous
compounds by F-SPE. At the end of the synthesis, the mixture of fluorous linker
attached products are separated by fluorous HPLC (F-HPLC) based on the fluorine
content of the fluorous tag, and individual pure products are obtained after fluorous
linker cleavage. Curran and coworkers introduced FMS in 2001 [45], and the concept
was further applied to the solution-phase synthesis of enantiomers, diasteromers, and
analogues of natural products and libraries of complex molecules [46,47].
Isolated from
Mappia foetida
,(
S
)-mappicine is active against the herpes
viruses (HSV) [48]. Its ketone analogue nothapodytine B is active against human
cytomegalovirus (HCMV) [49]. Quasiracemic FMS of mappicines was developed by
Curran and coworkers to prepare both (
)-mappicine (Scheme 10.16) [50].
Enantiomeric (
R
)- and (
S
)-alcohols were individually attached to silanes containing
C
6
F
13
and C
8
F
17
tags to form quasi-enantiomers (
R
)-
68a
and (
S
)-
69b
. An equimolar
mixture of these two compounds was then subjected to TMS group exchange with
þ
)- and (
OMe
N
Et
Me
3
Si
OSi(
i
-Pr)CH
2
CH
2
C
6
F
13
O
)-
68a
(
R
1. ICl, BBr
3
2. CHCCH
2
Br, NaH
PhNC, (Me
3
Sn)
2
h
N
OMe
Et
I
OSi(
i
-Pr)CH
2
CH
2
Rf
N
Et
M-
69
(Rf = C
6
F
13
or C
8
F
17
)
Me
3
Si
OSi(
i
-Pr)CH
2
CH
2
C
8
F
17
Set of 2 compounds
)-
68b
Set of 2 compounds
(
S
O
O
O
1. F-HPLC
2. TBAF
N
N
N
+
N
N
N
Et
Et
Et
RfCH
2
CH
2
(
i
-Pr)
2
SiO
HO
HO
M-
70
(+)-Mappicine
71a
(
-
)-Mappicine
71b
Set of 2 compounds
SCHEME 10.16
Quasiracemic FMS of (
þ
)- and (
)-mappicines.
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