Biomedical Engineering Reference
In-Depth Information
R
2
N
Me
Me
R
1
Me
Me
1. Hg(OTf)
2
, R
1
C
N
R
1
Ref. [
48
]
N
2. NaBH(OAc)
3
CH
2
Cl
2
, rt
O
Me
Me
Me
Me
OH
O
N
(+)/(-)-
84
20 members
(+)/(-)-
82
(+)/(-)-
83
H
Ref. [48]
R
1
R
2
R
3
O
N
HO
(+)/(-)-
92
480 members
HO
2
C
NH
O
1. Methyl glycinate
PhH/DMF/MeOH, 90°C
2. AgOAc-(
R
)/(
S
)-quinap
DIPEA,
t
-butyl acrylate
THF, -45°C
t
-BuO
2
C
H
R
4
O
Ref. [
48
]
R
3
O
N
R
3
H
RO
R
3
CO
2
Me
H
NH
O
RO
RO
R
4
Ph
85
(+)/(-)-
86
(+)/(-)-
87
24 members
O
Ph
i
-Pr
i
-Pr
Ref. [48]
Ph
O
N
Si
R =
Ph
H
R
5
O
RO
R
6
O
O
R
6
O
R
5
N
Mg(ClO
4
)
2
, HC(OMe)
3
Py, PhMe, rt
O
Ph
O
O
I
O
NH
H
O
H
I
R
3
O
O
R
5
N
H
HN
R
6
HO
H
Ph
N
H
NH
RO
O
I
R
4
88
(+)/(-)-
89
90
(+)/(-)-
91
16 members
(+)/(-)-
93
384 members
SCHEME 15.8
small molecule hybrids in a few synthetic steps, readily available for biological
screening (Scheme 15.8, for clarity, only one diastereoisomer is represented for each
library) [48]. Small libraries of 10-24 analogues of three structurally distinct
fragments, similar to those found in Nature, were synthesized in solution and solid
phases. The substrates were then coupled in a convergent manner, leading to a
collection of structurally diverse small molecule dimers. Bridged piperidines
83
were
obtained in enantiopure forms from both enantiomers of
b
-pinene
via a mercury-
catalyzed Ritter reaction [49]. Further chemical modifications provided analogues
82
,
bearing additional structural diversity, and an alkoxy side functionality suitable for a
late-stage coupling with other sublibrary members. Fused pyrrolidine scaffolds were
obtained from a novel asymmetric silver-catalyzed azomethine ylide cycloaddition.
Aromatic aldehydes
84
were first loaded onto a solid support, condensed with methyl
glycinate, and then reacted with
tert
-butyl acrylate in the presence of Ag(I) acetate-
(
R
)/(
S
)-quinap (1-(2-diphenylphosphino-1-naphtyl)isoquinoline). Subsequent cou-
pling of
85
86
with a series of amino acids gave rise to a library of supported pyrrolidines
87
in enantiopure forms. A third sublibrary was obtained in a single step from
supported aldehydes
88
,(
þ
)- and (
)-5,6-diphenyl-morpholin-2-one
89
, and
a
,
b
-unsaturated ketones
via a Lewis acid-catalyzed Williams three-component
reaction to provide enantiomerically pure spirooxindoles
90
[50]. Finally, sublibraries
were deprotected and coupled to afford a 480-member library-containing dimer
91
92
and a 384-member library-containing dimer
, both libraries containing all enantio-
and diastereoisomeric combinations. Representative samples were analyzed by NMR
spectroscopy to ensure sufficient purity (
93
80%) of small molecule hybrids for the
purpose of biological evaluation. This synthetic method has demonstrated its utility in
generating structurally complex and diverse small molecule hybrids, readily available
for biological evaluation, and could potentially be adapted to other molecular
scaffolds. Additional chemical investigation to modulate the selectivity of the
three-component condensation would be needed for expanding the size of the library.
H
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