Biomedical Engineering Reference
In-Depth Information
90
91a
91b
-
-
92a
92b
-
-
93
94
-
SCHEME 2.32
Stille and Negishi cross-coupling conditions used in the synthesis of the
compound
94
.
different conditions tried in order to optimize the synthesis of
93
, only poor
stereoselectivity (
E
/
Z
ΒΌ
4:1) and moderate yield (55%) were obtained although both
protodestannylation and homocoupling by-products were also formed, which may be
due to a slow transmetalation of the vinyl stannane
92a
to the Pd(II) intermediate.
The configurationally pure (
E
,
E
)-diene
was obtained in 81% yield via a modified
Negishi coupling (method B) between the (
E
)-vinyl zinc intermediate
91b
and
the (
E
)-vinyl iodide
93
. The overall rate enhancement of the one-pot sp
2
-sp
2
Pd
(0)-catalyzed cross-coupling under the Negishi conditions was due to (1) the double
transmetalation process (Zr-Zn-Pd), which shows a lowkinetic barrier with respect to
the single transmetalation process (Zr-Pd) endowed by high activation energy [40,41],
(2) the good nucleophilicity of the (
E
)-vinyl zinc intermediate
92b
(allowing
easier transmetalation), and (3) the enhanced accessibility and electrophilicity of
the (
E
)-vinyl iodide
91b
was eventually
completed after deprotection of the silyl group followed by oxidation of the primary
alcohol (Scheme 2.32).
92b
. The synthesis of the
N-
Boc-Valine-Adda
94
2.2.2.4. Thiazolylpeptides GE2270 A, Amythiamicins C and D The
Negishi cross-coupling reaction has also been applied to the total synthesis of three
complex naturally occurring macrocyclic thiopeptides [42,43] endowed with anti-
biotic activity: the thiazolylpeptides GE2270 A
95
[44,45] and amythiamicins
C
96
[46] and D
[46] (Figure 2.2).
The potent antibiotic thiazolylpeptide GE2270 A
97
is a 29-membered macro-
lactam isolated from
Planobispora rosea
ATCC 53773, whose structure was first
reported in 1991 [47,48]. The synthetic strategy relies on the assembly of all the
fragments by consecutive and regioselective cross-coupling reactions carried out on
2,6-dibromo-3-iodopyridine
95
98
[44,45]. GE2270 A
95
was obtained in 20 steps
(longest linear sequence) and 4.8% overall yield [45].
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