Biomedical Engineering Reference
In-Depth Information
5.5.
ENYNE METATHESIS
1,3-Diene is a ubiquitous structural motif found in both designed and natural
substances, and it is also a versatile functionality in organic synthesis. As such, the
construction of this structural motif has been the center of a number of synthetic
investigations. The use of metathesis reaction in the construction of 1,3-dienes
provides a conceptually contrasting approach [42], as exemplified in a recent
synthesis of the (
)-cortistatin A core structure reported by Stoltz and coworkers
[43], where a cascade ring-closing enyne metathesis/ring-closing olefin metathesis
was at the center of their synthetic strategy. In this instance, the cascade metathesis
precursor
þ
68
was prepared from allylic acetate
67
throughanintramolecular
hetero-S
N
2
0
reaction,
a process
that
also gives
rise
to the undesired
diastereoisomeric diene-yne
69
as an inseparable mixture. Treatment of a mixture
of diene-yne
with Grubbs second generation metathesis catalyst
smoothly delivered hexacyclic diene
68
and
69
in 37% and
44% yields, respectively. A plausible mechanism of this transformation began
with the initiation at the sterically most accessible alkene terminus in both
substrates
74
and pentacyclic triene
75
, which then underwent intramolecular enyne metathesis to
generate ruthenium carbene intermediates
68
and
69
70
71
, respectively. Subsequent
ring-closing olefin metathesis of the geometrically feasible ruthenium carbenoid
72
and
afforded the cascade product
74
, whereas ruthenium carbenoid
73
underwent
termination to give triene
(Scheme 5.21).
The concept of enyne metathesis could also be realized in an intermolecular
sense, as illustrated in the total synthesis of (
75
)-amphidinolide K reported by Lee and
coworkers [44]. The use of alkynyl boronate
as the alkyne coupling partner serves
as a powerful demonstration of this venerable reaction in complex molecular settings.
The enyne cross-metathesis reaction between alkynyl boronate
76
77
proceeded smoothly under the influence of Grubbs second generation catalyst to
76
and olefin
AcO
O
O
O
MgBr
2.
OEt
2
, 2,6-DTBP
PhH/CH
3
CN, 80°C
O
O
O
O
O
HO
+
H
H
H
(1/1 mixture)
67
68
G-II
, (15 mol%)
CH
2
Cl
2
, 25°C
69
79%
LnRu
LnRu
LnRu
LnRu
O
O
O
O
O
O
O
O
O
O
O
O
+
+
H
H
H
H
72
73
70
71
N
O
O
OH
Me
O
O
O
O
+
HO
D
B
C
H
H
O
A
H
E
74
(37%)
75
(44%)
H
Me
2
N
(
+
)-Cortistatin A
SCHEME 5.21
Enyne ring-closing metathesis in the synthesis of the (
þ
)-cortistatin A core
by Stoltz and coworkers.
Search WWH ::
Custom Search