Biomedical Engineering Reference
In-Depth Information
1. H-G 2nd
generation cat.
CH
2
Cl
2
, reflux
2. P(CH
2
OH)
3
, Et
3
N
3. F-SPE
41%
O
PPh
3
, DEAD
THF, 25°
C
F-SPE
98%
O
O
O
N
N
TsN
TsN
OH
+
MeO
MeO
NHNs
41
C
8
F
17
C
8
F
17
40
42
Ph
N
O
O
O
PhN
O
PhN
O
H
H
H
1. PhSH, DBU
MeCN
2. BnNCO
F-SPE
79%
N
N
O
O
O
N
O
N
N
CH
2
Cl
2
N
H
H
O
O
OMe
Rf-O
TsN
Rf-O
Ns
F-SPE
86%
C
8
F
17
N
Ns
43
44
45
Ph
N
H
O
O
PhN
H
TFA (3 mol%)
CH
2
Cl
2
F-SPE
67%
O
N
N
O
N
N
H
O
H
HO
Cl
Rf =
Ru
H-G 2nd
generation
catalyst
Cl
NTs
OMe
N
O
C
8
F
17
46
N
H
O
Ph
SCHEME 10.9
Dihydropyran linker-facilitated synthesis.
microwave heating afforded cycloaddition products
37
. Under these conditions, the
dihydrofuran ringwas subsequently oxidized to the corresponding furan. The fluorous
linker was finally cleaved by Pd-catalyzed Suzuki or Buchwald reactions to form
38
and
39
, respectively.
In addition to fluorous benzaldehydes, other convertible linkers have been
developed for the synthesis of heterocyclic compounds. Nelson and coworkers, for
example, introduced fluorous dihydropyran linker
40
for the protection of amino and
hydroxyl groups. Scheme 10.9 highlights the utility of the linker in the synthesis of
highly condensed heterocyclic compound
46
[37]. The fluorous linker was attached to
sulfonamide
41
through the Fukuyama-Mitsunobu reaction to form compound
42
.
Cascade metathesis using the Hoveyda-Grubbs second generation catalyst (H-G 2
nd
)
cleaved the central dihydropyran ring and produced compound
43
. The latter was then
used in a Diels-Alder reaction with 4-phenyl-1,2,4-triazole-3,5-dione to afford
44
as
a single diastereoisomer. The removal of the
o
-nitrophenylsulfonyl (Ns) group from
44
followed by the reaction with an isocyanate gave urea
45
. Finally, the fluorous
group was removed by treatment with TFA to afford product
46
. In this multistep
synthesis, all the intermediates and the final product were isolated from the reaction
mixture by F-SPE.
Fluorous amino ester is another important convertible linker that can be cleaved
through cyclization while concomitantly forming new cyclic skeletons. Sun and
coworkers employed this type of linker in the synthesis of hydantoin-fused tetra-
hydro-
b
-carboline analogues (Scheme 10.10) [38]. Both hydantoin and tetrahydro-
b
-carboline are known pharmacophores. The combined tetracyclic scaffold
could thus potentially generate appealing molecules for drug discovery screening.
Methods for solution-phase and soluble polymer-supported synthesis of hydantoin-
fused tetrahydro-
-carboline have been adapted for the fluorous synthesis of
51
.
The fluorous alcohol was attached to Boc-
L
-tryptophan
47
using DCC and DMAP as
the coupling agents. After Boc deprotection with TFA, fluorous amino ester
48
was
b
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