Biomedical Engineering Reference
In-Depth Information
CO
2
H
N
H
TBSO
OTBS
2
(10 mol%)
O
O
Pyridine
O
NH
O
+
+
H
H
NMP, -4°C
O
Me
H
NH
2
Me
33
42
23
43
1.
p
-MeO-C
6
H
4
MgBr
CuI, Et
2
O, -40°C
2. SO
3
·py, Et
3
N, DMSO
CH
2
Cl
2
, 0°C
3. LiAlH(O
t-
Bu)
3
, THF
-78°C
69%
(4 steps)
TBSO
anti
:
syn
= 32:1
H
NBz
OBz
H
NBz
OBz
NH
OH
1. RuO
2
NaIO
4
O
O
MeO
2. CH
2
N
2
O
Me
Me
Me
OMe
OMe
OMe
47%
syn
:
anti
= 14:1
44
(ee = 96%)
41
45
SCHEME 6.9
Synthesis of the
N
-terminal amino acid unit of nikkomycins.
as
46
-
48
, Michael donors such as
49
and
50
, Michael acceptors such as
51
and
52
, and
multiple related compounds (Figure 6.3) [19].
Hayashi and coworkers found that diphenylprolinol silyl ether
catalyzed the
enantioselective Michael addition of nitromethane on the
a
,
b
-unsaturated aldehyde
53
54
(Scheme 6.10) [19d]. Oxidation of the latter
followed by reduction of the nitro group provided baclofen
to afford the corresponding adduct
55
57
[20], a therapeutically
useful GABA
B
receptor agonist.
Pregabalin
[21], an important anticonvulsant drug, was also synthesized
through a similar two-step sequence starting from
60
59
and using catalyst
ent
-
54
(Scheme 6.11) [19d].
Ar
Me
O
Ar
N
Me
Ar
N
O
Catalysts:
H
H
Me
OTMS
Ar
Me
X
Ar
46
47
48
R
O
Michael donors:
X
R
N
R
49
50
R
Michael acceptors:
NO
2
R
O
R
51
52
FIGURE 6.3
Catalysts, donors and acceptors of Michael reaction.
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