Biomedical Engineering Reference
In-Depth Information
Br
Br
Zn /TMSCl
BrCH
2
CH
2
B
r
THF/DMA
(2.5:1)
rt, 30 min
I
N
N
N
S
F
Pd
2
(dba
3
) (6 mol%)
tpf (12 mol%)
THF/DMA (4:1)
45°C, 12 h
(First step)
Br
Br
O
I
ZnI
O
HN
98
99
N
NH
OEt
E
N
S
D
2 steps
56%
O
S
MeHN
O
Br
R
1
Southern fragment (
100
,
R
1
= CH
2
OCH
3
)
Southern fragment (
105
,
R
1
= H)
N
A
Cl
O
Br
N
A
OR
2
N
S
F
Cl
G
S
N
O
O
PdCl
2
(PPh
3
)
2
(30 mol%)
DMA
45°C, 3 h
HN
NH
OEt
N
N
N
A
O
S
D
Br
S
R
1
(R
2
=
t
-Bu)
O
(Second step)
N
S
MeHN
F
101
(R
1
= CH
2
OCH
3
, 87%)
106
(R
1
= H, 79%)
O
O
HN
NH
OEt
N
O
O
Zn
BrCH
2
CH
2
Br
TMSCl/DMA
N
OR
2
OR
2
O
Br
S
D
NH
2
4 steps
S
O
+
R
1
S
N
S
N
O
MeHN
rt, 30 min
H
2
N
S
25 %
CO
2
Et
(R
2
=
t
-Bu)
104
(R
1
= CH
2
OCH
3
, R
2
=
t
-Bu, 48%)
107
(R
1
= H, 49%)
Br
ZnBr
102
(R
2
=
t
-Bu)
108
(R
2
= CH
3
)
103
(R
2
=
t
-Bu)
109
(R
2
= CH
3
)
SCHEME 2.33
Assembly of the southern fragments
100
and
105
.
amount of catalyst (30 mol%) and a large excess of 2-zincated thiazole
103
, to afford
70% conversion of the starting 2,6-dibromopyridine
. Longer reaction times
proved to be detrimental as the coupling was also affecting the C2 position of
101
.
Amythiamicins were isolated in 1994 from the fermentation broth of
Amyco-
latopsis
sp. MI481-42F4, a microorganism found in soil samples collected in
Nerima-ku in Japan [49-51]. The synthesis of amythiamicin C
101
96
[46] follows the
same synthetic pathway as that of thiopeptide GE2270 A
95
[45]: in the first step,
the southern fragment
105
undergoes Negishi cross-coupling with 3-zincated
2,6-dibromopyridine
in good
yield (79%) (Scheme 2.33). To achieve complete conversion of the starting material,
the use of an additional amount of 3-zincated 2,6-dibromopyridine
99
, affording the 2,6-dibromopyridine derivative
106
was necessary.
A regioselective Negishi cross-coupling is also evoked for the second step. Hence,
2,6-dibromopyridine
99
106
reacts with 2-zincated
tert
-butyl thiazole-5-carboxylate
103
, affording 2-bromo derivative
107
in the same moderate yield (49%) as for
104
[45] (Scheme 2.33). Subsequent attachment of the eastern fragment (third
step, Figure 2.4) through an amide bond formation followed by an intramolecular
Stille cross-coupling (fourth step) to form the macrolactam and the elaboration of
the northern fragment to anchor the diketopiperazine moiety eventually led to the
completion of the synthesis.
The 2,6-dibromopyridine
106
was also used in the first step of the
synthesis of amythiamicin D
97
[46], which also featured an amide bond
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