Biomedical Engineering Reference
In-Depth Information
as the major products. The iminium chemistry that enabled synthesis of heterocy-
cles with skeletal diversity also proceeded with full control of their stereochemistry
(Scheme 7.21) [43].
7.4 APPENDAGE DIVERSITY
Appendage diversity is achieved by incorporation of various substructures onto a
common-core unit. To enhance the diversity with an array of compounds, the substruc-
tural elements need to possess an inherent diversity and contribute to the topographic
variability of individual compounds. As an example we included a combinatorial
library of bis-heterocyclic structures. The diversity is achieved by incorporation of
the second heterocycle (the appendage) into three different positions of the parent
molecule.
The synthesis of bis-heterocyclic compounds, where two heterocyclic cores were
connected by a variable spacer, was carried out in polypropylene-reaction vessels
by using split-and-split methodology and was made “by hand” without sophisticated
instrumentation [65]. Traditionally, generic combinatorial libraries contain one het-
erocyclic scaffold, and therefore their diversity is limited. The library compounds
herein presented are composed of two different heterocyclic rings connected by
a spacer that gave access to highly diverse library members
243
,
245
, and
247
(Scheme 7.34).
Benzimidazole and thiazole were used as core units because of their drug-likeness.
The building blocks for assembling the benzimidazole core were selected to enable
the introduction of functionalized spacers in any of three diversity positions of ben-
zimidazole. The spacer in position 1 of the benzimidazole ring was introduced in
the first combinatorial step by reductive amination of the aldehyde linker with a
protected amino alcohol. The terminal hydroxyl group was then converted into an
N
N
N
R
2
R
3
R
3
R
2
R
3
R
2
N
N
N
X
NH
X
R
1
R
1
X
R
1
242
246
244
N
N
N
R
2
R
3
N
R
2
R
3
R
3
R
2
N
N
N
N
H
N
R
1
R
1
Het
2
Het
2
R
1
N
Het
2
247
243
245
SCHEME 7.34
Bis-heterocyclic library members.
