Biomedical Engineering Reference
In-Depth Information
Pd(PPh
3
)
4
(5 mol%
)
1.
n
-BuLi , dry ZnBr
2
I
OTHP
OTHP
OTHP
H
R
+
94% for R = MgCl
2. , Pd(PPh
3
)
4
(5 mol%)
I
R= MgCl or ZnBr
9
10
12
11
O
O
82%
O
8
O
O
SCHEME 2.3
Synthesis of freelingyne
8
.
cross-couplings, two of them performed with an organozinc species (Scheme 2.3) [6].
The synthesis consisted of dissymetrizing acetylene. Since this could not be done
efficiently through Sonogashira coupling, ethynyl magnesium or ethynyl zinc
derivatives were reacted with alkenyl iodide
, obtained in one step from propargyl
alcohol, in the presence of a palladium catalyst to afford enyne
9
10
. A second Negishi
coupling was then performed with iodo furan
.
After four steps, including a tandem Sonogashira coupling/lactonization, freelingyne
(
11
as the coupling partner to provide
12
8
) was finally obtained in good yield and an excellent stereoisomeric purity (>98%).
2.2.1.3. Phomallenic Acid C Phomallenic acid C (
) [7] exhibits a large
spectrum of antibacterial activities against important pathogens, such as
Staphylo-
coccus aureus
,
Bacillus subtilis
, and
Haemophilus influenzae
. It belongs to a family of
molecules of prime importance since phomallenic acids can serve as leads for the
development of novel antibacterial agents against resistant strains. From a structural
point of view, phomallenic acid C possesses a unique diyne-allene structure that
confers the chirality to the molecule (Scheme 2.4).
In the synthesis published by Wu and coworkers [8],
13
the chirality was
transferred from the optically active alcohol
through a
copper-mediated bromination. The diyne moiety was then introduced by a Pd-
catalyzed cross-coupling [9]. The major problem of the synthesis was the potential
loss of chiral integrity during the coupling reaction. To investigate this phenomenon, a
model study was performed on bromallene
14
to the bromoallene
15
by applying a Sonogashira or a Negishi
coupling (Scheme 2.5). As shown by Elsevier and Vermeer [10], these reactions
proceeded with inversion of stereochemistry, even though the stereoinversion was not
total. The choice of bromoallene
16
was based on the presence of two elements of
chirality: the first one arising from the axial chirality of the allene moiety and the
second one coming from the chiral tetrahedral carbon. As such, the first element of
chirality would be modified during the coupling reaction while the second one would
remain unchanged. Moreover, an incomplete stereoinversion would lead to the
16
H
H
CO
2
H
CO
2
H
CO
2
MOM
5
5
4
C
C
TMS
H
Br
H
HO
Phomallenic acid C
13
15
14
n
-Pr
SCHEME 2.4
Wu's retrosynthetic analysis of phomallenic acid C
13
.
Search WWH ::
Custom Search