Biomedical Engineering Reference
In-Depth Information
O
R
R
R
R
R
1
O
H
N
NO
2
H
R
2
R
1
H
NO
2
H
- H
2
O
+ H
2
O
- R
2
NH
R
2
R
1
62
Enamine
formation
Michael reaction
and hydrolysis
SCHEME 6.12
Formation of enamine and its Michael addition onto nitroalkene.
Hayashi and coworkers developed a one-pot three-step process involving a
Michael reaction between alkoxy aldehyde
64
and nitroalkene
65
catalyzed by
diphenylprolinol
silyl ether
ent
-
54
, a Horner-Wadsworth-Emmons
reaction
with vinylphosphonate
66
and a
p
-toluene thiol addition to afford the substituted
cyclohexane
in high yield and excellent enantio- and diastereoselectivity
(Scheme 6.13). This method eventually allowed the synthesis of oseltamivir
67
63
in
high yield [24].
Frondosin B (
) is amember of amarine sesquiterpene family that was isolated
from the marine sponge
Dysidea frondosa
and found to be a micromolar inhibitor of
interleukin-8 receptors and protein kinase C (Scheme 6.14) [25].
MacMillan and coworkers established a highly efficient three-step total syn-
thesis of frondosin B (
68
) featuring an enantioselective Michael reaction between
the commercially available boronic acid
68
69
and crotonaldehyde (
70
) catalyzed by the
imidazolidinone organocatalyst
71
to afford the adduct
72
(Scheme 6.14). Addition of
the vinyl lithium reagent prepared
in situ
fromhydrazone
73
and
t-
BuLi then provided
allylic alcohol
, which was then engaged in a cyclization and a deprotection of the
allylic alcohol to afford frondosin B (
74
68
) [26].
Ph
Ph
H
ent
-
54
(5 mol%)
1.
OTMS
STol
H
ClCH
2
CO
2
H (20 mol%)
CH
2
Cl
2
, rt, 40 min
O
CO
2
Et
O
NO
2
+
O
t-
BuO
2
C
(EtO)
2
P(O)
CO
2
Et
66
2.
t-
BuO
2
C
Cs
2
CO
3
, 0°C, 3 h, evaporation
then EtOH, rt, 15 min
TolSH, EtOH, -15°C, 36 h
NO
2
64
65
67
(ee = 96%)
3.
70%
Horner-Wadsworth-Emmons
O
CO
2
Et
Michael
AcHN
Michael
NH
2
Oseltamivir
(
63
)
SCHEME 6.13
One-pot three-step process for the oseltamivir framework.
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