Biomedical Engineering Reference
In-Depth Information
R
1
R
1
O
CO
2
(CH
2
)
3
Rf
O
O
H
O
H
CO
2
(CH
2
)
3
Rf
NCO
R
1
H
O
R
4
K
2
CO
3
μ
w 100°C, 5 min
F-SPE, HPLC
79-85%
R
3
R
3
N
N
N
R
3
NH
N
N
R
4
HN
DMAP
F-SPE
86-92%
N
R
4
H
H
O
O
O
H
O
R
2
R
2
53
57
54
R
2
SCHEME 10.12
Synthesis of hydantion-fused tricyclic compounds.
stereocenters on the central pyrrolidine ring and up to four points of diversity (from
R
1
to R
4
). In addition, the ring skeleton of these compounds resembled the structures
of some known biologically active compounds. Hence, the structure of compound
54
is similar to tricyclic thrombin inhibitors [40], the structure of compound
55
is similar
to diketopiperazine-based inhibitors of human hormone-sensitive lipase [41], while
the structure of compound
56
contains a privileged benzodiazepine moiety that exists
in numerous pharmaceutically interesting compounds. The common intermediates
53
were made by a one-pot [3
þ
2] cycloaddition between an azomethine ylide generated
from
52
and an aldehyde and a maleimide. The cycloadditions were stereoselective
and afforded
53
as single diastereomers.
The synthesis of hydantoin-fused tricyclic compounds
54
was accomplished via
the two-step sequence shown in Scheme 10.12 [39,42]. Hence, the reaction of
53
with
an excess of phenyl isocyanate and a catalytic amount of
N,N
-4-dimethylaminopyridine
(DMAP) in toluene gave ureas
57
that after F-SPE purification were heated at 100
C
under microwave irradiation for 5min in the presence of K
2
CO
3
to cleave the fluorous
linker and form the hydantoin-fused products
54
.
The synthesis of piperazinedione-fused tricyclic compounds
55
was accom-
plished by Werner and coworkers (Scheme 10.13) [43]. Hence, the [3
2] cyclo-
addition products
53
were treated with chloroacetyl chloride to afford
N
-acylated
products
58
. The chloro group of
58
was then displaced with an amine to afford
59
.
Finally, the microwave-promoted cyclization cleaved the fluorous linker and
generated the piperazinediones
55
,whichwerepurifiedbyLCtoensure
þ
95%
H
purities.
In the synthesis of benzodiazepine-fused tetracyclic compounds
56
, the [3
2]
cycloaddition compounds
53
were used for
N
-acylation to afford
60
, followed by the
sonication-promoted nitro group reduction with zinc dust in acetic acid to give
61
þ
R
1
R
1
ClCH
2
COCl, DMAP
Molecular sieves
Cl
2
, 60°C, 2 h
O
O
H
H
CO
2
(CH
2
)
3
C
8
F
17
CO
2
(CH
2
)
3
C
8
F
17
R
4
NH
2
F
2
CH-CF
2
CH
2
OH
R
3
NH
R
3
N
N
N
Cl
O
μ
w 150°C, 15 min
F-SPE
70-85%
H
H
O
O
53
58
R
2
R
2
R
1
O
O
O
R
4
H
CO
2
(CH
2
)
3
C
8
F
17
AcOH
μ
w 225°C, 1 h
H
R
1
R
3
N
R
4
N
R
3
N
N
N
H
N
Prep-LC
11-69% from
58
O
O
H
H
O
O
R
2
R
2
59
SCHEME 10.13
Synthesis of piperazinedione-fused tricyclic compounds.
55
(90 analogs)
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