Biomedical Engineering Reference
In-Depth Information
classes to which the build/couple/pair approach can be applied. The first example
is focused toward the synthesis of three-dimensional fragments for potential use
in fragment-based drug discovery. The work highlighted was carried out by Hung
et al. and is part of a larger synthetic effort aimed at producing a range of chiral
bicyclic corestructures that could be used to enrich existing fragment collections that
are generally biased toward “flat”sp
2
-rich compounds [58]. The authors employed
the build/couple/pair approach to efficiently provide a number of fused bicyclic and
spirocyclic compounds that were compliant with the fragment rule of 3, the number
of physicochemical parameters that can be applied to fragment-based drug discovery
(Scheme 1.6) [59].
The build stage of the synthesis involved the synthesis of
29
from proline employ-
ing Seebach et al.'s concept of self-reproduction of chirality [60] or the purchase of
the commercially available derivative
30
. The couple stage then involved the addi-
tion of other latently reactive appendages, by either functionalization of the proline
nitrogen or by peptide coupling of amine groups to the free carboxylic acid of
30
.
These groups were then paired to generate the bicyclic architectures desired. In the
majority of cases, this was achieved by the ring-closing metathesis of alkene groups
but two other approaches: hydantoin formation and oxy-Michael addition to a vinyl
sulfone. In a slight addition to the standard build/couple/pair protocol, the authors
suggested a post-pairing stage, where the functional group diversity of the compound
collection is increased. Two post-pairing modifications—methyl ester hydrolysis and
reduction of the alkene groups to give the saturated species—were implemented,
which altered the electronic and conformational properties of the fragments but did
not significantly change the molecular weight. Then the authors used computational
methods to compare their compounds to an existing fragment collection and found
that although, as expected, the shapes of the compounds in the various collections
were mutually exclusive, their physical properties remained comparable and thus
within the desired range for fragments [58].
The second example was targeted toward the synthesis of a small library of
macrocyclic compounds. In this work, Isidro-Llobet et al. produced a small library of
macrocyclic peptidomimetics in an efficient manner employing the build/couple/pair
approach (Scheme 1.7) [61]. In the build stage they produced a number of alkyne-acid
and azido-amine building blocks using standard methods. These building blocks were
then coupled to give the required linear azido-alkyne precursor (
31
), and macrocy-
clization was achieved by the pairing of these functional groups in two variations of
the azide-alkyne cycloaddition reaction to produce a triazole. The copper-catalyzed
azide-alkyne cycloaddition (CuAAC) provided the 1,4-isomer of the triazole (
32
),
and the ruthenium-catalyzed variant (RuAAC) gave the 1,5-isomer (
33
). This use of
different catalysts for essentially the same process to produce molecular diversity has
been dubbed “catalyst control” [62].
Further diversity was then introduced into their compound set when the attached
ester and and amine functionalities were paired to give diketopiperazine (DKP)
moieties (
34
and
35
). In total, they were able to produce a small proof-of-concept
library of 14 macrocyclic compounds.
