Biomedical Engineering Reference
In-Depth Information
SCHEME 7.19
Synthesis of a library containing 29,400 distinct compounds. Reagents
and conditions: (i) 4-hydroxy-3-methoxybenzaldehyde (as one of 40 hydroxy-substituted
aromatic aldehydes), 2,6-lutidine, DCM; (ii)
N
-ethylmaleimide (as one of 41 disubstituted
dienophiles), toluene; (iii) 2,5-diphenyl-[1,4]benzoquinone (as one of 22 tri- and tetrasubsti-
tuted dienophiles), toluene.
Combination of all building blocks selected represented 29,400 different poly-
cyclic compounds. Generic structures of 10 skeletons are portrayed in Figure 7.1.
After finishing the synthesis, the library macrobeads were arrayed into wells, tar-
get compounds cleaved from the resin, and a stock solution of library compounds
prepared and submitted for protein-binding and phenotypic assays.
7.2.1.2.2 Heterocycles with More Heteroatoms
DOS of seven structurally unre-
lated skeletons containing nitrogenous and oxygenous heterocycles having a four-
to seven-membered ring and including both planar and nonplanar scaffolds utilized
-acylamino ketone
142
attached to the polystyrene resin (Scheme 7.20) [42]. The
synthesis started with sulfonylation of polymer-supported primary amines
140
with
4-Ns-Cl followed by
N
-alkylation and cleavage of the 4-Ns-protective group. Sub-
sequent acylation with different acids yielded intermediates
142
, which were further
transformed to final heterocycles.
The first heterocycle, dihydropyrrolone
143
, was obtained by intramolecular Wittig
reaction. The second, pyrazinone
144
, was achieved by using two different pathways.
The first involved substitution of bromine (R
4
=
Br) with NH
2
NH
2
ยท
H
2
Otoafford
hydrazinoderivative, which cyclized spontaneously during TFA-mediated cleavage.
The second route involved cleavage of Fmoc-protective group (R
4
NH-Fmoc) and
spontaneous cyclization to yield pyrazinone
144
. The seven-membered heterocycle,
=
