Biomedical Engineering Reference
In-Depth Information
H
H
i-
Pr-O
O
i-
Pr-O
O
ZnCl
1. Cp
2
ZrHCl
2. ZnCl
2
65
Br
Pd(PPh
3
)
4
(5 mol%)
DIBAH
81%
Br
Br
CH
3
OTIPS
H
H
3
C
66
i-
Pr-O
O
OTIPS
67
SCHEME 2.24
Negishi coupling in the preparation of
67
.
Me
2
Zn
Pd(PPh
3
)
4
(10 mol%)
THF
Br
CH
3
Me
H
H
i-
Pr-O
O
i-
Pr-O
O
OTIPS
68%
OTIPS
H
3
C
67
cis
-64a
(
cis/trans
> 97:3)
SCHEME 2.25
Key step for the preparation of anguinomycin C
62
.
Et
2
Zn
cat. Pd
Br
CH
3
Et
Et
CH
3
H
H
H
i-
Pr-O
O
i-
Pr-O
O
i-
Pr-O
O
+
THF
OTIPS
OTIPS
OTIPS
H
3
C
67
cis
-64b
trans
-64b
SCHEME 2.26
Key step for the preparation of anguinomycin D
63
.
When the same Pd(PPh
3
)
4
-catalyzed reaction was performed on
67
using Et
2
Zn
to eventually obtain anguinomycin D
63
, the reaction was not complete and yielded a
mixture of isomers
cis
-
(Scheme 2.26).
Various palladium catalysts were also studied and, depending on the ligand,
complete conversion could be obtained along with complete selectivity. To prepare
the required
cis
-
64b
and
trans
-
64b
, PdCl
2
(DPEphos) appeared to be the best catalyst, providing
the desired compound in 84% yield as a single isomer. Multistep transformation of
cis
-
64b
64a
and
cis
-
64b
eventually led to anguinomycins C
62
and D
63
, respectively.
2.2.1.10. Synthesis of Scyphostatin Scyphostatin
was isolated from a
culture broth of
Dasyscyphus mollissimus
in 1997 [26]. It is a potent inhibitor of
sphingomyelinase (N-Smase), which is an enzyme that regulates the level of ceramide
in a wide variety of mammalian cells by cleaving the phosphoester linkage of
sphingomyelin. Consequently, scyphostatin and analogues are expected to be
promising candidates for the treatment of pathogenic states, such AIDS, inflam-
mation, and immunological disorders. Scyphostatin was first synthesized by Katoh
and coworkers [27,28].
The retrosynthesis of scyphostatin
68
68
shown in Scheme 2.27 features a Negishi
coupling between vinyl iodide
.
This coupling reaction seemed straightforward but difficulties arose when
trying to generate the organozinc species from iodide
70
and alkyl iodide
71
(Scheme 2.28). Different
conditions were used [
t-
BuLi (2 equiv), ZnCl
2
(1 equiv) in THF or Et
2
O; activated
zinc; Rieke zinc; zinc couple] but resulted in complete failure. Eventually, the use of
71
Search WWH ::
Custom Search