Biomedical Engineering Reference
In-Depth Information
Suga-Ibata reaction of oxazole
264
proceeded with aromatic aldehydes to afford
intermediates
265
. Subsequent alkylation with benzylhalides yielded compounds
bearing azide moiety
266
, which were ready for the pair phase [step (iii)], Staudinger-
type reduction, which resulted in spontaneous cyclization to appropriate spirocyclic
and fused lactams
267
to
270
. Lactams were alkylated to the target products
271
to
274
[step (iv)]. In addition, methyl esters
266
were converted into the corresponding
amides
275
to complement the complexity of the library. The pair phase of the B/C/P
pathway is very often connected narrowly with the folding pathway. For example,
the pair phase in the synthesis discussed above (Scheme 7.38) [68] resulted in either
spirocyclic or fused lactams
267
to
270
, depending on the type of azide moiety (R
1
and R
2
) attached to the intermediates
266
.
The following syntheses included the folding process in the pair phase [2,53,69-
71]. Various
-amino acids were coupled by traditional solid-phase peptide synthesis
to afford masked peptide aldehydes
280
(Scheme 7.39). In the pair phase the aldehyde
was liberated and reacted immediately with the amide backbone to yield
N
-acyl
iminium intermediates, which were stabilized by internal nucleophiles to provide a
wide range of diverse heterocyclic scaffolds
281
to
289
.
7.6 SCAFFOLD HOPPING
Last but not least, access to chemical diversity represents the
scaffold hopping
approach
, a term introduced in 1999 [72]. For medicinal chemists this method rep-
resents an important drug-design strategy. The aim of scaffold hopping is to discover
structurally novel compounds starting from known active compounds by modifying
the central core structure of the molecule [73]. Scaffold hopping can be used not only
for improving the selectivity/specificity of a lead compound, but also for replacing
a component of a molecule that is undesirable (e.g., for its toxicity or insolubil-
ity) or to avoid intellectual property infringements [74]. For example, replacement
of the 1
H
-pyrazolo[4,3-
d
]pyrimidin-7(6
H
)-one core in Sildenafil to imidazo[5,1-
f
][1,2,4]triazin-4(3
H
)-one led to Vardenafil [75].
Scaffold hopping was classified into four categories: heterocycle replacement,
ring opening and closure, peptidomimetics, and topology-based scaffold hopping
[76]. Only a few examples of scaffold hopping were reported on solid phase.
An example of the ring opening and closure category is a conversion of
polymer-supported
N
-alkyl-2-nitro-
N
-(2-oxo-2-arylethyl)benzenesulfonamides
290
into 2
H
-indazole 1-oxides and quinazolines, respectively (Scheme 7.40) [77].
The presence of an “activated” methylene derived from glycine was critical
for the transformation to quinazolines. Exposure of
N
-alkyl-2-nitro-
N
-(2-oxo-2-
arylethyl)benzenesulfonamides
290
to a base led to formation of polymer-supported
2
H
-indazole 1-oxides
291
. While following cleavage from the support, derivatives
not bearing the methylene afforded indazoles
292
[78], the presence of methylene
activated by the neighboring carbonyl group had a crucial influence on further trans-
formations of indazoles
291
to quinazolines
293
. An exposure to DBU in DMF led
