Biomedical Engineering Reference
In-Depth Information
N
OH
OH
N
MeO
1.
MeO
MeO
NMe
3
RuO
4
, CH
2
Cl
2
(100%)
(CF
3
CO)
2
O
MeO
MeO
MeO
2.
NMe
3
BH
4
, MeOH (90%)
OH
HN
99%
O
N
1
3
NH
2
CF
3
2
4
HO
CF
3
CH
2
OH
I(OAc)
2
70%
5
O
OH
O
NEt
3
[(CO
3
)
2-
]
1/2
MeO
MeO
NMe
3
BH
4
MeO
H
H
N
N
Cu(SO
4
)
2
or NiCl
2
MeOH
MeO
MeO
N
MeO
CF
3
80%
98%
(±)-Epimaritidine
8
(±)-Oxomaritidine
7
6
O
SCHEME 11.1
Palladium(O)-catalyzed direct arylation.
norbelladine derivative
was achieved with trifluoroacetic
anhydride and a immobilized dimethylaminopyridine (DMAP) resin to give the
amide
3
. Trifluoroacetylation of
3
4
. Intramolecular phenolic oxidative cyclization of
4
to form the spirodienone
6
was achieved using immobilized hypervalent iodine
5
, a reagent developed specifi-
6
cally for this task [19]. Finally, treatment of
with immobilized carbonate in
methanol
resulted in a rapid deprotection and spontaneous
intramolecular
1,4-addition to give (
in 98% yield. Subsequent borohydride
reduction in the presence of an
in situ
copper or nickel boride species delivered the
second natural product epimaritidine
)-oxomaritidine
7
as its racemate.
The next challenge was to extend the number of sequential reaction steps
that could be achieved by these methods; consequently, the analgesic alkaloid
(
8
was chosen as a suitable proof of principal target. Here, a total
of 10 immobilized reagent and sequestering agents were employed in a successive
fashion (Scheme 11.2) [12]. Furthermore,
)-epibatidine
17
17
was obtained directly from the reaction
sequence in
90% purity without any chromatographic purification.
In this work, aldehyde
H
via borohydride reduction,
followed by oxidation with perruthenate. Using the Henry reaction catalyzed
by polymeric base, compound
10
was prepared from
9
10
was converted to the corresponding nitrostyrene
11
after elimination of the intermediate trifluoroacetate with an immobilized
diethylamine base. Cyclohexanone
13
was obtained via a Diels-Alder reaction of
11
. Following carbonyl reduction and
conversion to the corresponding mesylate, (
with the silyl-protected 2-oxadiene
12
was obtained. Nickel boride
generated on a polymeric support was particularly effective for achieving selective
nitro reduction without affecting the aromatic chloride and this method formed
the desired amine
)-
14
was achieved in the presence
of immobilized
N
-phenyl-
tris
(dimethylamino)iminophosphorane (PS-BEMP)
using an immobilized benzylamine to scavenge the uncyclized minor mesylate
diastereomer. Epimerization of this compound to (
15
in high yield. Cyclization of
15
17
was mediated
using pulsed microwave irradiation in the presence of potassium
tert
-butoxide in
tert-
butanol, furnishing the thermodynamicallymore stable
exo
isomer. The natural
)-epibatidine
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