Biomedical Engineering Reference
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TBSO
CO
2
Et
TBSO
CO
2
Et
2
6
Ph
2
Se
2
O
3
, SO
3.
Py
Et
3
N, THF, rt to 50°C
TBSO
TBSO
O
O
8
63%
OTBS
OTBS
11
Br
Br
393
394
OTBS
TBSO
OTBS
H
H
CO
2
Et
6
H
EtO
2
C
H
8
H
H
TBSO
2
TBSO
OTBS
H
H
O
O
H
11
H
H
Br
Br
396
395
OH
H
O
O
H
F
H
steps
A
H
HO
D
H
E
B
C
O
H
H
(-)-FR182877
397
SCHEME 9.69
Synthesis of FR182877
397
by Evans and coworkers.
conjugated double bond at C2-C3 within compound
393
using Ph
2
Se
2
O
3
,Py
SO
3
,
and Et
3
N in THF, leading to the intermediate
(Scheme 9.69) [151]. This
macrocycle contains a 1,3-diene and an activated dienophile suitable for an intra-
molecular Diels-Alder reaction with normal electron demand to furnish the inter-
mediate
394
395
. This tricyclic compound
395
in turn undergoes a second intramolecular
cycloaddition using
as a single
diastereomer in an excellent 63% yield. The high stereoselectivity in this domino
process can be explained by a fixed orientation of the reacting diene and dienophile
moieties caused by themacrocyclic core. The synthesis of the natural product
,
-unsaturated ketone to afford pentacycle
396
a
b
397
was
397
eventually completed after four additional steps. The synthesis of FR182877 (
)
using a transannular double cycloaddition strategy has also been accomplished by
Sorensen and coworkers [152] and Nakada and coworkers [153].
The antiangiogenic properties of the novel fungal metabolites epoxyquinols A
402
and B
403
, which bear a unique pentaketide dimeric structure, have been studied
by various groups including the group of Osada [154]. These molecules inhibit the
endothelial migration induced by vascular endothelial growth factor. The two natural
products contain a total of 12 stereogenic centers within the heptacyclic framework,
making them a challenging synthetic target. Hayashi and coworkers used a domino
oxidation/6
-electrocyclization/Diels-Alder reaction approach [155] to build this
ring framework, similar to that first described by Porco for the synthesis of torreyanic
acid [156,157]. In their approach, epoxycyclohexenone
p
containing an allylic
alcohol moiety was initially oxidized using MnO
2
to afford the corresponding
aldehyde
398
399
that then underwent a 6
-electrocyclization to afford two 2
H
-pyran
p
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