Biomedical Engineering Reference
In-Depth Information
O
O
O
S
S
S
N
H
H
H
N
N
N
N
O
N
O
N
O
O
O
O
HN
HN
Ph
HN
NH
NH
NH
N
N
N
S
S
S
O
Bistratamide H
O
Tenuecyclamide A
O
Didmolamide A
S
O
H2N
H
2
N
N
N
S
CO
2
H
21
S
CO
2
Et
CO2Me
23
1. PyBOP
i
-Pr
2
NEt, THF
2. 1M LiOH
THF-H
2
O
79%
F-TeocHN
N
N
F-TeocHN
N
1. PyBOP
i
-Pr
2
NEt, THF
2. 1M LiOH
THF-H
2
O
88%
N
S
CO
2
H
O
20
22
O
S
O
N
H
O
S
N
H
1. TBAF, THF
2. PyBOP, DMAP
DMF-CH
2
Cl
2
35%
O
N
F-TeocHN
N
H
N
N
O
N
HN
CO
2
H
S
NH
N
O
S
O
Bistratamide H
24
O
O
O
N
Si(CH
2
CH
2
C
8
F
17
)
3
O
O
F-Teoc-OSu
SCHEME 10.5
Fluorous Teoc-facilitated synthesis of bistratamide H.
Isolated from ascidians
Lissoclinum bistratum
, bistratamides and related
compounds such as didmolamides and tenuecyclamides have shown moderate
cytotoxic activity, antidrug resistance, and antimicrobial properties, as well as the
ability to inhibit the division of sea urchin embryos [25]. Bistratamides have a unique
macrolactam structure that contains three amide moieties, two thiazoles and an
oxazole. Takeuchi and coworkers developed the 2-[tri(perfluorodecyl)silyl]ethoxy-
carbonyl (F-Teoc) linker and employed it in the fluorous synthesis of bistratamide H
(Scheme 10.5) [26].
The F-Teoc linker attached thiazole amino acid
20
was coupled with thiazole
amino ester
21
in the presence of benzotriazol-1-yl-oxy-tris-pyrrolidinophosphonium
hexafluorophosphate (PyBOP) and
i
-Pr
2
NEt. The resulting thiazole dipeptide ester
was hydrolyzed with LiOH followed by extraction with FC-72 (perfuorohexanes) to
afford thiazole dipeptide acid
22
. This compound was coupled with oxazole amino
acid methyl ester
23
followed by hydrolysis and FC-72 extraction to give tripeptide
methyl acid
24
. Cleavage of the F-Teoc linker with TBAF followed by the intra-
molecular amidation and preparative TLC purification finally gave bistratamide H in
35% yield. It is noteworthy that the F-Teoc used in this work has three C
8
F
17
CH
2
CH
2
chains with a total of 51 fluorine atoms. It is considered a “heavy fluorous” tag
that allows attached molecules to be separated by fluorous liquid-liquid extraction
(F-LLE) using FC-72 as the fluorous solvent.
Search WWH ::
Custom Search