Biomedical Engineering Reference
In-Depth Information
)-gigantecin, to examine the feasibility of the
proposed tandem ring-closing olefin metathesis/cross-metathesis sequence to assem-
ble the entire carbon backbone of the targeted natural product, a stepwise approach
was first attempted that uncovered some unexpected findings. In this instance, the
metathesis studies commenced with triene silaketal
In Hoye's total synthesis of (
þ
, which was subjected to the
action of Hoveyda-Grubbs second generation catalyst. Instead of the anticipated ring-
closing event engaging the C15 and C16 termini (gigantecin numbering), macrocyclic
compound
154
was obtained in 67% yield as the result of carbon-carbon bond
formation between C8 and C16. Subsequent olefin cross-metathesis between mac-
rocyclic alkene
155
,
and a diimide reduction of its two disubstituted olefins followed by global desilylation
afforded 14-deoxy-9-oxygigantecin in 48% overall yield from
155
and alkenyl butenolide
156
then delivered trienyl butenolide
157
. Overall, this two-
step process represented the relocation of the C9 and C14 carbon atoms as the result of
the undesired regioselection in the initial ring-closing metathesis event. Fortuitously,
this complication was of no concern upon returning to their original proposal of a one-
pot cascade reaction. In this instance, treatment of a CH
2
Cl
2
solution containing
silaketal
155
with Grubbs second generation catalyst
through slow syringe pump addition smoothly delivered trienyl butenolide
154
and alkenyl butenolide
156
159
in
63% yield, accompanied with a small amount of
(ca. 10%). Presumably, instead
of the intended initial ring-closing metathesis, in fact the two type I alkenes
157
154
and
156
as a fleeting intermediate.
Ring-closing olefin metathesis engaging the silaketal-tethered vinyl termini (C15 and
C16) in
participate in an olefin cross-metathesis to generate
158
then completes the tandem metathesis event. Finally, diimide reduction
followed by removal of the silyl protecting groups/tether furnished (
þ
)-gigantecin
in 69% yield over two steps (Scheme 5.36) [65].
158
8
O
TIPSO
G-II
(20 mol%)
16
15
8
HG-II
(15 mol%)
TIPSO
15
16
O
TIPSO
O
O
PhMe, 80°C
O
CH
2
Cl
2
, 45°C
C
12
H
25
O
O
O
Si
C
12
H
25
O
O
Si
67%
Ph
Ph
Ph
Ph
154
156
155
1. TsNHNH
2
2. HF/CH
3
CN
TIPSO
O
OH
O
O
HO
9
O
48%
O
O
O
O
C
12
H
25
O
14
Si
OH
14-Deoxy-9-oxygigantecin
OH
O
Ph
C
12
H
25
Ph
157
G-II
(20 mol%)
CH
2
Cl
2
, 45°C, 9 h
TIPSO
16
15
O
TIPSO
TIPSO
O
O
O
O
C
12
H
25
O
O
C
12
H
25
O
O
O
Si
Si
Ph
Ph
Ph
Ph
154
TIPSO
158
O
156
O
63%
1. TsNHNH
2
2. HF/CH
3
CN
69%
OH
TIPSO
16
15
8
14
O
TIPSO
O
HO
O
O
O
O
9
O
O
OH
OH
C
12
H
25
C
12
H
25
O
O
Si
159
(
+
)-Gigantecin
Ph
Ph
SCHEME 5.36
Tandem cross-metathesis/ring-closing metathesis in the total synthesis of
(
þ
)-gigantecin by Hoye et al.
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