Biomedical Engineering Reference
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(5th step)
Northern fragment
Fragment
coupling
(5th step)
H
2
N
Northern fragment
Fragment
coupling
O
O
O
O
N
OR
N
(4th step)
(2nd step)
Negishi
coupling
Negishi
coupling
G
G
N
N
S
S
(4th step)
(3rd step)
Macrocyclization by Stille coupling
Macrocyclization by Stille coupling
N
N
A
A
N
N
S
(1st step)
S
B
B
C
(1st step)
C
Negishi
coupling
S
S
Negishi
coupling
N
Eastern fragment
N
Eastern fragment
N
N
S
S
F
F
OH
HN
O
HN
O
O
O
O
O
HN
HN
N
N
(2nd step)
NH
NH
(3rd step)
NH
NH
E
E
Fragment
coupling
N
N
Fragment
coupling
S
S
D
D
O
O
S
S
H
O
H
O
O
H
Southern fragment
Southern fragment
O
Amythiamicin C
96
GE2270 A
95
R =
N
Structure variation
with respect to
GE2270 A
95
=
O
Amythiamicin D
97
R = Me
FIGURE 2.4
Retrosynthetic analysis of thiopeptides GE2270 A
95
and amythiamicins C
96
and D
97
.
According to the retrosynthetic sequence (Figure 2.4 and Scheme 2.33), the first
Negishi cross-coupling allows to link the southern fragment
100
, on the side of
2-iodothiazole (ring F), to 3-zincated 2,6-dibromopyridine
99
.
This Negishi cross-coupling was carried out in the presence of tri(2-furyl)
phosphane (tfp) as the ligand to afford 2,6-dibromopyridine
in good yield (87%)
and as a single diastereoisomer (Scheme 2.33). The second Negishi coupling
allowed to link the northern fragment to the pyridine core. Hence,
tert
-butyl
2-bromothiazole-4-carboxylate
101
102
was reductively zincated to derivative
103
and
coupled to afford the 2-bromopyridine derivative
in moderate yield (48%)
(Scheme 2.33). Unfortunately, the second Negishi coupling proved to be difficult
and the optimization of the reaction was not trivial. When a large excess of zinc
reagent (20 equiv) was used, an inseparable mixture of unreacted starting material
(50%), along with the desired coupling product 2-bromopyridine derivative
104
, was
obtained. The reaction proved to be sensitive to the order of addition of the reagents.
Hence, when the 2-zincated thiazole
104
103
was added to the solution containing the
catalyst and the 2,6-dibromopyridine
, the reaction was not always completely
reproducible. This problem was solved by mixing the 2-zincated thiazole
101
103
and
the catalyst, followed by the slow addition of the 2,6-dibromopyridine
in the
appropriate solvent. A catalyst screening was also undertaken that revealed that
among all the palladium catalysts explored, only PdCl
2
(PPh
3
)
2
and PdCl
2
(dppf)
3
[dppf
101
ΒΌ
(diphenylphosphino)ferrocene] were suitable. In all the other cases, the
coupling failed with complete recovery of the starting materials, or a rapid and
unselective substitution was observed on both C2 and C6 positions of the pyridine
core
101
. A regioselective Negishi coupling was only possible when using a large
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