Biomedical Engineering Reference
In-Depth Information
Me
O
O
O
N
O
N
I
O
HN
OEt
OTBS
I
Cl
O
BUILD
67
68
69
70
71
R
2
O
O
N
R
1
CH
2
NH
2
t
-BuNC
HN
OH
CHO
72
73
74
75
OTBS
COUPLE
PAIR
OMe
Me
Me
1.
68
,
n
-BuLi, THF, -78 to 40°C
(86%)
N
2
N
O
O
O
N
OMe
O
H
2. LiOH,
i
-PrOH/H
2
O
(93%)
3. 1,1'-Carbonyldiimidazole, CH
2
Cl
2
, rt
then hydrogen methyl malonate,
i
-PrMgBr
(47% over two steps)
4.
69
, 4 Å MS, CH
2
Cl
2
(65%)
5. MsN
3
, Et
3
N, CH
3
CN
(98%)
Rh
2
(O
2
CC
7
H
15
)
4
PhH, 50°C
74%
N
O
67
2
O
O
N
O
76
79
OTBS
OTBS
1.
70
,
n
-BuLi, THF, -78 to 40°C
(40%)
2. LiOH, then ethanolamine, EDC, HOBt
then TIPSCl, imidazole
(97% over three steps)
3.
71
, PhMe, reflux
(41%)
4. MsN
3
, Et
3
N, CH
3
CN
(84%)
O
O
O
O
Me
O
H
OTIPS
Me
N
H
Rh
2
(O
2
CC
7
H
15
)
4
PhH, 50°C
73%
N
2
67
N
2
O
H
N
N
O
N
OR
77
80
O
R
2
R
2
O
1. MeOH reflux
(61%)
N
O
N
NH
t
-Bu
R
1
2.
71
, PhMe
(93%)
Rh
2
(O
2
CC
7
H
15
)
4
PhH, 50°C
57%
72
73
O
O
O
Me
N
O
N
2
NH
t
-Bu
74
75
3. MsN
3
, Et
3
N, CH
3
CN
(98%)
N
N
O
N
O
2
O
R
1
O
Me
78
81
OTBS
OTBS
SCHEME 15.7
imposing the diastereofacial selectivity of the cycloaddition. A modular synthetic
scheme allowed the strategic positioning of indoles and
a
-diazo ketocarbonyl
functionalities that preencoded for the chemical transformation at the origin of the
skeletal diversity. The development of a catalyst to modulate the selectivity of the
cycloaddition is likely to be extremely challenging but would give access to other
molecular architectures.
15.5. RECENT EXAMPLES OF CHEMOSELECTIVE
REACTIONS USED IN DOS
15.5.1. Convergent Synthesis of Small Molecule Hybrids
Complex small molecules can be found in Nature as homo- and heterodimeric forms.
It has been suggested that the dimeric form of these compounds enhances their
binding capabilities, or alternatively combines a dual mode of interaction with
biological targets, each of them originating from each monomer. To explore this
hypothesis, Chen et al. developed a convergent synthetic pathway leading to complex
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