Biomedical Engineering Reference
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R 3
R 3
R 3
O
O
O
NH 2
NH
NH
Cl
NH
R 2
R 2
R 1
R 1
N
NH
N
N
N
R 4
HN
254
248
251
R 3
R 4
O
R 3
O
O
N
N
Cl
NH
R 5
NH
S
NH
S
R 2
R
R 5
N
N
R 2
R 1
N
N
N
N
N
N
R 4
R 5
252
249
S
255
Cl
N
R 4
S
R 2
R 3
R 5
N
N
N
N
N
N
N
N
R 4
R 5
R 1
N
N
S
N
N
R 5
R 1
R 3
R 2
S
250
253
256
SCHEME 7.35
Benzimidazole connected to thiazole core at three positions by different
spacers.
amino group via mesylation to afford structure 248 (after introduction of an o -
aminobenzene moiety) (Scheme 7.35). Alternatively, acylation of polymer-supported
o -phenylenediamines with Fmoc-amino acid introduced the spacer in position 2
(structure 251 ). To introduce the spacer at position 6 of benzimidazole ring, a 1,2-
dichloro-4-fluoro-5-nitrobenzene was used. First, the fluorine was substituted with
polymer-supported amines and the chlorine in the para position with respect to the
nitro group was subsequently displaced by a secondary diamine (piperazine) to afford
structure 254 (after acylation of aniline nitrogen). As an example, we included the
reaction sequence for the synthesis of one sublibrary (Scheme 7.36). The reaction
sequence involved reduction, acylation, alkylation, and cyclization reactions; over
100 derivatives were prepared.
7.5 BUILD/COUPLE/PAIR STRATEGY
In 2008, Nielsen and Schreiber introduced a new term for a general approach to
synthesis of stereochemically and skeletally diverse small molecules, referred to
as the build/couple/pair (B/C/P) strategy (Scheme 7.37) [2]. The B/C/P approach
describes the synthesis of small molecules having diverse skeletons, stereochemistry,
and appendages [66]. The B/C/P pathway starts with the build phase, in which
building blocks with preexisting stereogenic centers are synthesized [67]. Building
blocks also bear functionalities suitable for further coupling reactions. The following
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