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Br
Pd
Br
Pd
•
Pd(OAc)
2
LiBr
•
•
G-I
High dilution
47%
O
O
O
O
6
7
8
9
N
OH
Br
Br
H
Me
H
Br
H
HO
D
B
C
O
O
A
E
H
O
O
37%
H
H
H
Me
2
N
11
10
9
(
+
)-Cortistatin A
SCHEME 5.5
Ring-closing allene metathesis in the synthesis of the (
)-cortistatin A core by
Gung and Craft.
unprecedented transannular [4+3]-cycloaddition reaction. Synthesis of the [4+3]-
cycloaddition precursor featured an unusual yet effective form of ring-closing
metathesis, engaging bis-allenyl substrate
. In this instance, under the influence of
the Grubbs first generation catalyst, the ring closure of bis-allene
6
6
took place under
high dilution conditions to give furanyl allene
in 47% yield. After some initial
explorations to identify reaction conditions to selectively activate the allene moiety of
7
7
in the presence of the electron-rich furan, it was found that by treating furanyl allene
7
with a catalytic amount of Pd(OAc)
2
in the presence of LiBr, presumably through
the intermediacy of (
p
-allyl)palladium intermediate
9
, tetracyclic bromide
11
was
obtained in 37% yield (Scheme 5.5) [12].
Isolated from the Mediterranean sponge
Reniera sarai
, (-)-sarain A is a
structurally daunting marine natural product that contains a highly functionalized
diazatricycloundecane core and two macrocycles, 13 membered and 14 membered.
In addition, the sensitivity of (-)-sarain A toward pH and solvent conditions with its
proximal tertiary amine and aldehyde moieties further complicated its purification
and characterization. In 2006, Overman and coworkers successfully executed the
total synthesis of (-)-sarain A with an ingenious approach that featured a ring-
closing metathesis reaction to construct the saturated 13-membered macrocycle. In
viewof the complexity of themetathesis precursor
, particularlywith the presence
of the basic tertiary amine, ring-closing metathesis was anticipated to be challeng-
ing [13]. In the presence of the Grubbs second generation catalyst, substrate
12
12
afforded the desired product
in the modest 17% yield and was accompanied by
side products predominated by the undesired dimer
13
15
(61% yield). After extensive
optimization, macrocycle
with
the Grubbs first generation catalyst at high dilution conditions with rigorous
exclusion of oxygen. The construction of the saturated 13-membered ring was
completed through hydrogenation of olefin
13
couldbeisolatedin75
85% yield by treating
12
13
in the presence of Pd/C to give
tricyclic intermediate
(95% yield), which underwent further transformations to
furnish (-)-sarain A (Scheme 5.6) [14].
In the first total synthesis of (
14
)-okilactomycin by Smith et al., the venerable
ring-closing olefin metathesis reaction once again proved its efficiency in the
construction of macrocyclic motifs. The structural complexity of this antitumor
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