Biomedical Engineering Reference
In-Depth Information
groups were reduced by borane in THF to yield appropriate secondary amines
97
. Following cyclization with various imidazoles and cleavage from the resin
afforded the nonplanar bis-heterocycles derived from imidazolidin-2-one
98
(X
=
O), imidazolidine-2-thione
98
(X
=
S), piperazine-2,3-dione
99
, and piperazine
100
,
respectively.
In addition to ethylenediamines,
o
-phenylenediamines were often used for the syn-
thesis of a wide range of diverse heterocycles (Scheme 7.17) [36-39]. The synthetic
route most frequently used included nucleophilic substitution of fluorine in 1-fluoro-
2-nitrobenzenes by polymer-supported amines, either on Rink resin (resin
101
) [37]
or on BAL resin after reductive amination (resin
102
) [36].
o
-Phenylenediamine
was also immobilized to selenium resin via one of the amino groups (resin
102
)
[38]. Alternatively, the synthesis started from
o
-phenylenediamine attached to the
resin-bound imidazole (resin
103
) [39].
Polymer-supported
o
-phenylenediamines
101
to
103
that have two diversity posi-
tions already built were further transformed into nitrogen-containing heterocyclic
compounds, including benzimidazoles
104
[36,37] and
105
[39], benzoimidazolim-
ine
106
[39], benzotriazoles
107
[37], quinoxalinones
108
[36,37], dihydroquinoxali-
nones
109
[36], quinoxalinedione
110
[39], benzodiazepinediones
111
[37], benzimi-
dazopyrimidinones
112
[38], and finally, benzoimidazodiazepinones
113
[38]. Those
chemistries were generally based on reduction of a nitro group, acylation, alkylation,
and intramolecular cyclization.
Parallel solid-phase synthesis of a library containing 384 natural product-like
diaza-bridged heterocycles was based on tandem acidolytic cleavage and in situ
iminium formation, followed by Pictet-Spengler intramolecular cyclization (Scheme
7.18) [40]. The synthesis was carried out on Wang resin that was converted to
bromoacetal resin
114
. The bromine was substituted with amines, yielding precursor
115
, which was acylated with Fmoc-Trp-OH and Fmoc(
O
-diTBS)DOPA to afford
derivatives
116
and
117
. The Fmoc-protecting group was cleaved and the liberated
amines were acylated with carboxylic acids to afford cyclization precursors
118
to
121
. The last step, Pictet-Spengler intramolecular cyclization, was performed in neat
formic acid and led to final compounds
122
to
125
, respectively.
The last example of polymer-supported synthesis-generating nitrogenous multiple-
core scaffolds represents stereoselective synthesis of skeletons having up to six
stereocenters [41]. A library yielding 29,400 discrete compounds, including 10 dis-
tinct polycyclic skeletons, was synthesized using a split-and-pool technique. Many
building blocks were evaluated for their compatibility with the synthetic route pro-
posed. Selected building blocks were then used for the DOS. Specifically, 40 of
the 64 hydroxyaldehydes tested were attached to the macrobeads through silyla-
tion of the hydroxyl group. For simplicity, only polymer-supported vanillin deriva-
tive
127
is portrayed [step (i), Scheme 7.19]. In the next combinatorial step, 41
of the 53 originally disubstituted cyclic dienophiles underwent double addition
to afford derivatives
129
and
131
[step (ii)], while 22 of 44 tri- and tetrasubsti-
tuted cyclic dienophiles underwent monocycloaddition and yielded intermediates
130
[step (iii))].
