Biomedical Engineering Reference
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CHO
H
CO
2
Me
CO
2
Me
o
-Dichlorobenzene
180°C, 1 h
CHO
+
HO
OH
HO
-
CO
2
Me
CHO
76%
302
303
(4:1)
301
HO
2
C
CHO
HO
Sordaricin
304
SCHEME 9.52
Synthesis of sordaricin (
304
) by Mander and Thomson.
The sordarins have been highlighted as a class of potent antifungal agents with
in vivo
activity against several pathogenic fungi, including
Pneumocystis carinii.
After
the first approach that explored a biomimetic intramolecular [4
þ
2]-cycloaddition,
a second approach was investigated involving a cycloreversion/intramolecular
[4
resulted in the loss of cyclo-
pentadiene to give a 1,3-butadiene as intermediate that subsequently was trapped by a
tethered dienophile in an intramolecular Diels-Alder reaction to afford the desired
302
þ
2]-cycloaddition (Scheme 9.52). Thus, heating
301
together with a small amount of the isomer
303
(4:1). Compound
302
was then
hydrolyzed to give the natural product sordaricin (
304
).
) is a natural product isolated from the brightly
colored poison-arrow frog
Dendrobates histrionicus
. The biological activity of com-
pounds found in this frog species has been widely studied and in the case of HTX
identified as a noncompetitive inhibition of the acetylcholine receptor. The group of
Holmes devised a total synthesis based on an initial heating of isoxazolidine
(
)-Histrionicotoxin (HTX,
308
305
containing a (
Z
)-configured
as
intermediate with loss of styrene (Scheme 9.53) [119]. A subsequent intramolecular
1,3-dipolar cycloaddition then afforded the desired cycloadduct
,
-unsaturated nitrile to presumably give nitrone
306
a
b
in high yield (78-
82%). This process almost exclusively generates a single regioisomer with three new
stereogenic centers. This domino sequence is part of the enantioselective total
synthesis of (
307
)-histrionicotoxin (
308
) that proceeds with 16% overall yield starting
from 5-TBDPSO-1-pentyne.
The combination of two pericyclic reactions as a [4
2]-cyclo-
addition is a very elegant method in the synthesis of natural products [120]. One of the
most beautiful examples is Denmark's total synthesis of (
þ
2]- and [3
þ
), a
pyrrolizidine alkaloid from
Castanospermum australe
with glycosidase inhibition
properties [121]. In this synthesis, first a hetero-Diels-Alder reaction of the
a
þ
)-1-
epi
-australine (
313
,
-unsaturated nitro compound
309
with enol ether
310
takes place to afford nitrone
b
311
. Further
manipulation of the latter then leads to (
þ
)-1-
epi
-australine (
313
) in a few
steps (Scheme 9.54).
that undergoes a 1,3-dipolar cycloaddition to form compound
312
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