Biomedical Engineering Reference
In-Depth Information
Deprotective cleavage
R
2
R
2
OMe
O
O
N
R
1
N
R
1
N
TBAF
R
1
N
Me
3
Si
N
OSi(
i
-Pr)
2
CH
2
CH
2
C
8
F
17
R
1
R
1
HO
Rf-TIPS-O
Convertible cleavage
N
O
N
O
R
3
R
3
R
1
Suzuki
R
1
O
O
N
N
R
2
CHO
O
O
R
4
R
4
HN
HN
C
8
F
17
O
2
SO
R
2
R
2
R
1
C
8
F
17
O
2
SO
Cleavage after activation
Nu
S
S
C
8
F
17
C
8
F
17
[O]
NN
N
NN
N
NN
Cl
NuH
N
N
F
3
C
F
3
C
SCHEME 10.1
Three different kinds of linkers and their cleavage.
family. Sclerotigenin and many other members such as circumdatins A-G and
benzomalvins A-C have anti-insect and other attractive biological activities [19].
Zhang and coworkers employed a fluorous trimethoxybenzyl (TMB)-type linker
for the synthesis of 1,4-benzodiazepine-2,5-diones and converted them to scleroti-
genin analogues (Scheme 10.2) [20]. The fluorous TMB-type linker
1
was attached
to four different amino esters under solution-phase reductive amination conditions.
The attached amines
2
then underwent amide coupling with four anthranilic acids
3
in the presence of 1-ethyl-3-(3
0
-dimethylaminopropyl)carbodiimide (EDCI) to
form 16 amides
4
. The formation of 1,4-benzodiazepine-2,5-diones
5
was accom-
plished by base-promoted cyclization of
4
. Reactions of
5
with nine different
azidobenzoyl chlorides
6
afforded 144
N
-acylated products
7
that were treated with
triphenylphosphine (TPP) at room temperature to afford the core of sclerotigenin,
compounds
8
, which were purified by automatic F-SPE. The last step involving
the fluorous linker cleavage was accomplished by treatment of compounds
8
with a
TFA/DMS/H
2
O (90:5:5) solution at room temperature for 3 days and afforded
144 final products of type
9
. The concentrated reaction mixtures were purified by
automatic F-SPE followed by prep-HPLC. Among the 144 sclerotigenin analogues,
103 were obtained exceeding 5mg and with greater than 90% purity.
Bis-indole natural alkaloids possess two indole units linked through a central
five- or six-membered heterocyclic ring. Rebeccamycin and asteriquinone B1 are the
representative compounds that exhibit antitumor activity and are insulin receptor
activators [21]. Some nonnatural bis-indole derivatives with a bis-indolylpyridine
skeleton also have potent cytotoxicity. Hence, to make more synthetic bis-indole
analogues for biological tests, Kasahara and Kondo developed a concise fluorous
route that
involved consecutive cross-coupling reactions of fluorous-tagged
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